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Approach to the adult with dyspepsia Authors: George F Longstreth, MD, Brian E Lacy, MD, PhD Section Editor: Nicholas J Talley, MD, PhD Deputy Editor: Shilpa Grover, MD, MPH, AGAF All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Dec 17, 2021.

INTRODUCTION Dyspepsia is a common symptom with an extensive differential diagnosis and a heterogeneous pathophysiology. It occurs in up to 20 percent of the population, although prevalence rates are lower using different iterations of the Rome criteria [1,2]. Most affected people do not seek medical evaluation for their symptoms [1,2]. Although dyspepsia does not affect survival, it is responsible for substantial health care costs and significantly affects quality of life [3-6]. This topic will review the definition, etiology, and general approach to the evaluation and management of the patient with dyspepsia. The evaluation and recommendations are largely consistent with the American College of Gastroenterology and American Gastroenterological Association guidelines for the evaluation of dyspepsia [7,8].

ETIOLOGY Approximately 20 to 25 percent of patients with dyspepsia have an underlying organic cause ( table 1). However, up to 75 to 80 percent of patients have functional (idiopathic or nonulcer) dyspepsia with no underlying cause on diagnostic evaluation [9]. (See 'Diagnostic strategies and initial management' below.) Dyspepsia secondary to organic disease — Although there are several organic causes for dyspepsia, the main causes are peptic ulcer disease, Helicobacter pylori, gastroesophageal reflux, medications (nonsteroidal antiinflammatory agents being the most common offender),

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and gastric malignancy (

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table 1). Although gastric cancer as a cause of dyspepsia is a

concern for both health care providers and patients, it is uncommon in North America [8]. ●

Peptic ulcer disease – Upper abdominal pain or discomfort is the most prominent symptom in patients with peptic ulcers. Although discomfort from ulcers is usually centered in the epigastrium, it may occasionally localize to the right or left upper quadrants [10]. While classic symptoms of duodenal ulcer occur when acid is secreted in the absence of a food buffer (ie, two to five hours after meals or on an empty stomach), peptic ulcers can be associated with food-provoked symptoms, and thus, the utility of using symptoms related to food ingestion to predict the presence of an ulcer is unreliable. Peptic ulcers can also be associated with postprandial belching, epigastric fullness, early satiation, fatty food intolerance, nausea, and occasional vomiting. (See "Peptic ulcer disease: Clinical manifestations and diagnosis".)

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Gastroesophageal malignancy – Gastroesophageal malignancy is an uncommon cause of chronic dyspepsia in the Western hemisphere, but the incidence is higher in Asian Americans, Hispanic Americans, and Afro-Caribbean Americans. The incidence of gastroesophageal malignancy increases with age. When present, abdominal pain tends to be epigastric, vague, and mild early in the disease but more severe and constant as the disease progresses. In addition, other symptoms and signs typically evolve with disease progression (eg, anemia, fatigue, weight loss). (See "Epidemiology and pathobiology of esophageal cancer", section on 'Epidemiology' and "Epidemiology of gastric cancer" and "Clinical features, diagnosis, and staging of gastric cancer", section on 'Clinical features'.)

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Biliary pain – Classic biliary pain is characterized by episodic intense dull pain located in the right upper quadrant, epigastrium, or (less often) substernal area that may radiate to the back (particularly the right shoulder blade). The pain is often associated with diaphoresis, nausea, and vomiting. The pain is constant and not colicky [11]. It is not exacerbated or reproduced by movement and is not relieved by squatting, belching, bowel movements, or passage of flatus. The pain typically lasts at least 30 minutes, plateauing within an hour. The pain then starts to subside, with an entire attack usually lasting less than six hours. (See "Approach to the management of gallstones" and "Overview of gallstone disease in adults".)

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Drug-induced dyspepsia – NSAIDs and COX-2 selective inhibitors can cause dyspepsia even in the absence of peptic ulcer disease. Other drugs that have been implicated in drug-induced dyspepsia include calcium channel blockers, methylxanthines, alendronate, orlistat, potassium supplements, acarbose, dabigatran, iron, vitamin D, selective serotonin reuptake inhibitors, sildenafil, sulfonylureas, and certain antibiotics, including

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erythromycin [12,13]. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Gastrointestinal effects'.) ●

Other causes – Celiac disease and chronic pancreatitis may rarely present with dyspeptic symptoms alone. Other rare causes for dyspepsia include infiltrative diseases of the stomach (eg, eosinophilic gastroenteritis [14], Crohn disease, sarcoidosis [15], lymphoma [16], and amyloidosis [17,18]), diabetic radiculopathy [19], metabolic disturbances (eg, hypercalcemia, heavy metal toxicity), hepatoma, steatohepatitis, celiac artery compression syndrome, superior mesenteric artery syndrome, abdominal wall pain [20], and intestinal angina (

table 1). (See "Granulomatous gastritis", section on 'Crohn disease' and

"Extrapulmonary manifestations of sarcoidosis", section on 'Gastrointestinal' and "Celiac artery compression syndrome" and "Superior mesenteric artery syndrome" and "Chronic mesenteric ischemia", section on 'Clinical features' and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Gastrointestinal manifestations'.) Functional dyspepsia — The diagnosis of functional (idiopathic or nonulcer) dyspepsia requires exclusion of other organic causes of dyspepsia [21]. It is defined by the presence of one or more of the following: postprandial fullness, early satiation, epigastric pain, or burning, and no evidence of structural disease to explain the symptoms [22]. The pathophysiology, diagnosis, and management of functional dyspepsia are discussed in detail, separately. (See 'Diagnostic strategies and initial management' below and "Functional dyspepsia in adults".)

INITIAL EVALUATION A history, physical examination, and laboratory evaluation are the first steps in the evaluation of a patient with new onset of dyspeptic symptoms. (See 'History' below and 'Physical examination' below and 'Laboratory tests' below.) The goal of the initial evaluation is to identify alarm features for gastroesophageal malignancy ( table 2), which will direct the diagnostic approach. (See 'Diagnostic strategies and initial management' below.) History — A detailed history is necessary to determine the underlying cause and to identify patients with alarm features (

table 2).

As examples:

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A dominant history of heartburn or regurgitation, is suggestive of gastroesophageal reflux disease (GERD), recognizing that some patients have overlapping GERD and functional dyspepsia [23,24]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Clinical manifestations'.)

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Aspirin and other NSAID use raises the possibility of NSAID dyspepsia and peptic ulcer disease. Radiation of pain to the back or personal or family history of pancreatitis may be indicative of underlying chronic pancreatitis. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Gastrointestinal effects'.)

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Significant weight loss, anorexia, anemia, vomiting, dysphagia, odynophagia, and a family history of gastrointestinal cancers suggest the presence of an underlying gastroesophageal malignancy. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Clinical features'.)

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The presence of severe episodic epigastric or right upper quadrant abdominal pain, usually in association with nausea or vomiting, lasting at least 30 minutes is suggestive of symptomatic cholelithiasis [25]. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Clinical manifestations'.)

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Nausea and vomiting, with or without weight loss, occurring with recurrent or persistent upper abdominal pain raises the possibility of gastroparesis, especially in patients with risk factors. However, both the pathophysiology and symptom expression of functional dyspepsia and gastroparesis are quite similar [26]. An analysis of patients in a multicenter gastroparesis registry recognized the significant overlap in functional dyspepsia and gastroparesis symptoms [27].

Physical examination — The physical examination in patients with dyspepsia is usually normal, except for epigastric tenderness. The presence of epigastric tenderness cannot accurately distinguish organic dyspepsia from functional dyspepsia. Abdominal tenderness on palpation should be evaluated for the presence of Carnett's sign to determine if it is due to pain arising from the abdominal wall rather than due to inflammation of the underlying viscera. The presence of increased local tenderness during muscle tensing (positive Carnett's sign) suggests the presence of abdominal wall pain. However, if the pain is decreased (negative Carnett's sign), the origin of pain is not from the abdominal wall and likely from an intra-abdominal organ, as the tensed abdominal wall muscles protect the viscera. (See "Anterior cutaneous nerve entrapment syndrome", section on 'Diagnostic approach'.) Other informative findings on physical examination include a palpable abdominal mass (eg, hepatoma) or lymphadenopathy (eg, left supraclavicular or periumbilical in gastric cancer), https://www.uptodate.com/contents/20/print

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jaundice (eg, secondary to liver metastasis), a bruit (celiac artery compression syndrome), a succussion splash (gastric outlet obstruction), or pallor secondary to anemia. Ascites may indicate the presence of peritoneal carcinomatosis. Patients with an underlying malignancy may have evidence of muscle wasting, loss of subcutaneous fat, and peripheral edema due to weight loss. Laboratory tests — Routine blood counts and blood chemistry including liver function tests, serum lipase, and amylase, should be performed to identify patients with alarm features (eg, iron deficiency anemia) and underlying metabolic diseases that can cause dyspepsia (eg, diabetes, hypercalcemia) (

table 2). (See "Clinical manifestations of hypercalcemia", section on

'Gastrointestinal abnormalities' and "Diabetic autonomic neuropathy of the gastrointestinal tract".)

DIAGNOSTIC STRATEGIES AND INITIAL MANAGEMENT The approach to, and extent of, diagnostic evaluation of a patient with dyspepsia is based on the clinical presentation, the patient's age, and the presence of alarm features (

table 2). An

approach to the evaluation of a patient with dyspepsia is outlined in the algorithm ( algorithm 1) [28]. Our approach is largely consistent with the American College of Gastroenterology and Canadian Association of Gastroenterology guidelines [8]. The optimal age cut-off for endoscopic evaluation in patients with dyspepsia is controversial and is supported by limited evidence that suggests that the risk of malignancy in most United States populations below the age of 60 years is low. Guidelines also suggest that the age cutoff may vary between countries, depending upon the prevalence of gastric cancer. The American Gastroenterological Association guidelines suggest that it may be reasonable in some resourcerich countries to consider the age of 60 or 65 years as the threshold age at which endoscopy should be offered to all new dyspeptic patients, while an age cutoff of 45 or 50 years may be more appropriate for Asian Americans, Hispanic Americans, and Afro-Caribbean Americans due to an increased risk for gastric cancer, or in populations with a high incidence of gastric cancer in young individuals [11]. A European consensus statement recommends endoscopy in adults older than 45 years old who present with persistent dyspepsia [29]. These recommendations highlight the fact that diagnostic evaluation of the patient with dyspepsia need to be individualized based on symptoms, age, ethnic background, family history, nationality, and regional incidence of gastric cancer. (See "Clinical features, diagnosis, and staging of gastric cancer".) Patient age ≥60 years https://www.uptodate.com/contents/20/print

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Upper endoscopy — We perform an upper endoscopy to evaluate dyspepsia in patients age ≥60 years [8]. Biopsies of the stomach should be obtained to rule out H. pylori. Patients with H. pylori should receive eradication therapy in addition to treatment based on the underlying diagnosis (eg, peptic ulcer disease). After H. pylori treatment, eradication should be assessed. (See "Medical management of gastroesophageal reflux disease in adults" and "Peptic ulcer disease: Treatment and secondary prevention", section on 'Initial management' and "Treatment regimens for Helicobacter pylori in adults".) Multiple studies have evaluated the yield of upper endoscopy in patients with dyspepsia [30-33]. A meta-analysis of nine studies with 5389 patients found that the most prevalent findings in patients with dyspepsia were erosive esophagitis and peptic ulcer disease (pooled prevalence 6 and 8 percent, respectively) [34]. The diagnostic yield of upper endoscopy increases with age [30,32]. In the absence of warning signs, upper endoscopy in younger patients is unlikely to find a worrisome cause. Additional evaluation and management — Most patients with a normal upper endoscopy and routine laboratory tests have functional dyspepsia. However, additional evaluation may be required based on symptoms. (See 'Laboratory tests' above and 'Evaluation of persistent symptoms' below and "Functional dyspepsia in adults".) Patient age 1 percent, vancomycin – 15 to 20 mg/kg IV every 8 to 12 hours (not to exceed 2 g per dose or a total daily dose of 60 mg/kg; adjust dose to achieve vancomycin serum trough concentrations of 15 to 20 mcg/mL). Countries with resistance rates >1 percent include the United States, Canada, China, Croatia, Greece, Italy, Mexico, Pakistan, Poland, Spain, and Turkey [26]. plus

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In adults >50 years of age, ampicillin – 2 g IV every four hours.

A third-generation cephalosporin (eg, ceftriaxone, cefotaxime) should be continued even if in vitro tests demonstrate S. pneumoniae with reduced susceptibility to third-generation cephalosporins (minimum inhibitory concentration ≥1 mcg/mL) [25], since they may provide synergy with vancomycin in this setting [21]. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Streptococcus pneumoniae'.) Immunocompromised patients — For immunocompromised hosts, empiric antibiotic coverage must be directed against L. monocytogenes in addition to standard coverage for S. pneumoniae, regardless of age [19]. Such patients include those who are immunocompromised due to underlying conditions (eg, AIDS, lymphoma), as well as those receiving immunosuppressive agents such as cytotoxic chemotherapy, systemic glucocorticoids, and/or biologic immunomodulators (eg, tumor necrosis factor inhibitors). A more detailed discussion of risk factors for Listeria is found elsewhere. (See "Epidemiology and pathogenesis of Listeria monocytogenes infection", section on 'Predisposing conditions'.) In addition to Listeria coverage, immunocompromised patients warrant expanded gramnegative coverage to include P. aeruginosa. Although it is unclear if all immunocompromised hosts need such coverage, we typically use the fourth-generation cephalosporin cefepime or an antipseudomonal carbapenem in our initial regimen, instead of a third-generation cephalosporin that does not have activity against Pseudomonas. Antipseudomonal coverage is particularly important for those with neutropenia or impaired mucosal barriers (eg, from chemotherapy or severe burns), as well as for those at increased risk of nosocomial exposure. (See "Epidemiology, microbiology, and pathogenesis of Pseudomonas aeruginosa infection", section on 'Epidemiology'.) An appropriate regimen for immunocompromised patients with normal renal function is ( table 3A-B):

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Vancomycin – 15 to 20 mg/kg IV every 8 to 12 hours (not to exceed 2 g per dose or a total daily dose of 60 mg/kg; adjust dose to achieve vancomycin serum trough concentrations of 15 to 20 mcg/mL). plus

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Ampicillin – 2 g IV every 4 hours. plus either

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Cefepime – 2 g IV every 8 hours. or

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Meropenem – 2 g IV every 8 hours. If meropenem is used, initial treatment with ampicillin is not required, as meropenem has activity against Listeria. However, if Listeria is identified as the causative agent, the regimen should be modified to include ampicillin or penicillin (usually in combination with gentamicin). (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Alternatives to ampicillin or penicillin'.) Beta-lactam allergy — The approach to therapy in patients with beta-lactam allergies is

challenging given the importance of early initiation of therapy and the crucial role of betalactam antibiotics in the treatment of bacterial meningitis. The choice of regimen must balance efficacy with the risk and severity of an allergic reaction. (See "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Delayed hypersensitivity reactions" and "Cephalosporin hypersensitivity: Clinical manifestations and diagnosis".) Initial regimen ●

Patients without severe beta-lactam allergy – In general, most patients who are labeled as allergic to penicillin are able to receive a cephalosporin such as ceftriaxone (or cefepime if immunocompromised) (

table 3B and

table 4). More detailed information on

penicillin allergy is found elsewhere. (See "Penicillin allergy: Immediate reactions" and "Penicillin allergy: Immediate reactions", section on 'Immediate versus delayed reactions'.) Meropenem should be used instead of ceftriaxone in patients with isolated mild hives to a cephalosporin without other signs of anaphylaxis (especially if the reaction occurred in childhood and/or >10 years ago) or mild delayed-type reactions to cephalosporins ( table 3B and

table 4).

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Patients with severe beta-lactam allergy – When there is concern for a severe allergy to a penicillin or a cephalosporin (eg, anaphylaxis, Stevens-Johnson syndrome/toxic epidermal necrolysis [SJS/TEN], drug reaction with eosinophilia and systemic symptoms [DRESS], acute generalized exanthematous pustulosis [AGEP]), an appropriate initial regimen for patients with normal renal function includes (

table 3B and

table 4):

• Vancomycin – 15 to 20 mg/kg IV every 8 to 12 hours (not to exceed 2 g per dose or a total daily dose of 60 mg/kg; adjust dose to achieve vancomycin serum trough concentrations of 15 to 20 mcg/mL). plus

• Moxifloxacin – 400 mg IV once daily. In immunocompromised patients, aztreonam should be added to treat Pseudomonas as long as the patient does not have a serious allergy (eg, anaphylaxis, SJS/TEN, DRESS, AGEP) to aztreonam itself or an immediate or IgE-mediated allergy (eg, anaphylaxis, angioedema, hives/urticaria) to ceftazidime. Ceftazidime and aztreonam share an R1 side chain group, and cross-reactivity between the two drugs is possible. (See "Immediate cephalosporin hypersensitivity: Allergy evaluation, skin testing, and cross-reactivity with other beta-lactam antibiotics", section on 'Carbapenems and monobactams'.) ●

Patients who require Listeria coverage – If Listeria coverage is required (patients >50 years of age and/or immunocompromised hosts), trimethoprim-sulfamethoxazole can be initiated (5 mg/kg [based on the trimethoprim component] IV every eight hours in patients with normal renal function) instead of ampicillin (

table 3B and

table 4). However,

there are limited data on the preferred dosing interval, and in case reports, the dose of trimethoprim-sulfamethoxazole has been administered anywhere from every 6 to every 12 hours [8]. If meropenem is used instead of a cephalosporin, additional treatment for Listeria is not required as meropenem has activity against Listeria. (See "Treatment and prevention of Listeria monocytogenes infection", section on 'Alternatives to ampicillin or penicillin'.) Continuing antibiotics — After the initial dose of an antibiotic is administered, the regimen may be able to be modified. As examples: ●

Patients with a severe immediate allergy (eg, anaphylaxis) to a penicillin or cephalosporin may be able to tolerate meropenem, because rates of cross-reactivity between either penicillins or cephalosporins and carbapenems (eg, meropenem) are 6 weeks after completion of treatment. (See "Rapid drug desensitization for immediate hypersensitivity reactions".) Recommended treatment regimens for specific pathogens are discussed in detail separately. (See "Treatment of bacterial meningitis caused by specific pathogens in adults", section on 'Regimens in patients with drug allergies' and "Gram-negative bacillary meningitis: Treatment".)

Health care-associated meningitis — The distribution of causative organisms is appreciably different in patients with health care-associated meningitis (ie, following head trauma or neurosurgery and in patients with internal or external ventricular drains) compared with community-acquired meningitis (

table 3A) [27].

This was illustrated in a review of 326 episodes of health care-associated meningitis in adults and children (most of which were related to recent neurosurgery or the presence of neurosurgical devices) seen between 2003 and 2017 in which 54 percent had a positive CSF https://www.uptodate.com/contents/1290/print

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culture; gram-positive organisms (eg, S. aureus, coagulase-negative staphylococcus, enterococcus) accounted for 52 percent of episodes and gram-negative organisms (eg, Pseudomonas, Escherichia coli, Klebsiella spp, Enterobacter spp) accounted for 48 percent [18]. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Neurosurgery'.) Based upon such observations, empiric therapy must cover both gram-positive and gramnegative pathogens (such as Klebsiella pneumoniae and P. aeruginosa) (

table 3A-B).

Appropriate regimens in patients with normal renal function, pending culture results and susceptibility testing, are [27]: ●

Vancomycin – (

table 5)

plus ●

One of the following antipseudomonal beta-lactams; the decision of which beta-lactam to use should be based upon local in vitro susceptibility patterns:

• Ceftazidime – 2 g IV every eight hours or

• Cefepime – 2 g IV every eight hours or

• Meropenem – 2 g IV every eight hours The dosing of vancomycin used in this setting is based upon recommendations for severe S. aureus infections. (See "Vancomycin: Parenteral dosing, monitoring, and adverse effects in adults", section on 'Severe S. aureus infection'.) For patients with severe beta-lactam allergies (eg, anaphylaxis, SJS/TEN, DRESS, AGEP) and for whom meropenem is contraindicated, aztreonam (2 g IV every 6 to 8 hours) or ciprofloxacin (400 mg IV every 8 to 12 hours) should replace the cephalosporin or carbapenem. A more detailed discussion of agent selection in patients with beta-lactam allergies is discussed above. (See 'Beta-lactam allergy' above.) Once a causative pathogen is identified, the regimen should be narrowed to target the pathogen. (See "Treatment of bacterial meningitis caused by specific pathogens in adults" and "Gram-negative bacillary meningitis: Treatment".)

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Empiric treatment during epidemics — Epidemics of meningitis due to N. meningitidis are reported almost every year from sub-Saharan Africa. The empiric therapy recommended by the World Health Organization for meningococcal meningitis during epidemics is one or two intramuscular injections of long-acting chloramphenicol (oily suspension), although intramuscular ceftriaxone is an acceptable alternative. This is discussed in detail separately.

TAILORING THERAPY Directed therapy against a specific organism is recommended when the clinical presentation and results of the cerebrospinal fluid (CSF) Gram stain are unequivocal ( culture results are available (

table 3C) or once the

table 3D) [31]. For patients with negative CSF culture, therapy is

individualized depending on the remainder of the evaluation and clinical status. Regimens based upon Gram stain — Rather than empiric therapy, intravenous antimicrobial therapy should be directed at the presumed pathogen if the Gram stain is diagnostic ( table 3B-C) [5]. If the CSF findings are consistent with the diagnosis of acute bacterial meningitis but the Gram stain is negative, empiric antimicrobial therapy should be continued. If indicated, antimicrobial therapy should then be modified once the CSF culture and in vitro susceptibility studies are available (

table 3B, 3D). In addition, resistance patterns at a given

hospital should be taken into account when choosing an empiric regimen. ●

If gram-positive cocci are seen on the Gram stain of a patient with community-acquired meningitis, S. pneumoniae should be the suspected pathogen. Vancomycin plus a thirdgeneration cephalosporin (either cefotaxime or ceftriaxone) should be administered. However, in the setting of neurosurgery or head trauma within the past month, a neurosurgical device, or a CSF leak, S. aureus and coagulase-negative staphylococci are more common, and therapy with vancomycin is warranted [27].

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If gram-negative cocci are seen, N. meningitidis is the probable pathogen.

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Gram-positive bacilli suggest L. monocytogenes.

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Gram-negative bacilli usually represent Enterobacteriaceae (eg, Klebsiella spp, E. coli) in cases of community-acquired meningitis. However, if there is a history of neurosurgery or head trauma within the past month or if a neurosurgical device is present, ceftriaxone or cefotaxime should be replaced with ceftazidime, cefepime, or meropenem since such patients are at greater risk for P. aeruginosa and Acinetobacter spp infection [27]; given issues of cephalosporin resistance with Acinetobacter spp, meropenem would be a more appropriate empiric choice when infection caused by this organism is suspected [27]. If

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the Acinetobacter isolate is later found to be resistant to carbapenems, intravenous colistin (usually formulated as colistimethate sodium) or polymyxin B should be substituted for meropenem and should also be administered by the intraventricular or intrathecal route. (See "Acinetobacter infection: Treatment and prevention", section on 'Meningitis'.) Additional information on regimens for patients with beta-lactam allergies is discussed above. (See 'Beta-lactam allergy' above.) Positive cerebrospinal fluid culture — Directed therapy against a specific organism is recommended when the cultures are already positive [31]. If, on the other hand, empiric therapy is begun, the regimen should be adjusted, if necessary, once the culture results are available (

table 3D). Recommended dosages for use in patients with normal renal and

hepatic function are shown in the table (

table 3B). The recommended treatment regimens

for specific pathogens are discussed in detail separately. (See "Treatment of bacterial meningitis caused by specific pathogens in adults" and "Gram-negative bacillary meningitis: Treatment".) Negative cerebrospinal fluid culture — Cessation of antimicrobial therapy is not recommended in patients who have received prior or are receiving concurrent antimicrobial therapy with a negative CSF culture and who are suspected of having bacterial meningitis based on clinical and laboratory findings (eg, CSF pleocytosis). The choice of antimicrobial regimen and duration of administration should be individualized based on risk factors and likely infecting pathogens. ●

Community-acquired meningitis – In patients in whom the diagnosis of bacterial meningitis is uncertain (eg, possible viral meningitis), additional assessment is warranted. This includes reviewing CSF parameters (eg, glucose, protein, white blood cell [WBC] count), reviewing or requesting CSF polymerase chain reaction (PCR) analysis for viruses that may cause meningitis (

table 2), and assessing for alternative diagnoses. If the CSF

PCR is positive for a viral etiology, then antibiotics can be discontinued. Some clinicians calculate a risk score that has been used to identify patients at zero risk for having bacterial meningitis [32]. The following high-risk findings are considered:

• Host factors (eg, age >60 years, or intravenous drug use, or immunosuppressed) • Exam (Glasgow Coma Scale12,000/mm3)

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If none of these are present, it would be appropriate to discontinue antibiotics with careful monitoring. ●

Health care-associated meningitis – Decisions regarding continuation of antibiotic therapy can be particularly challenging in health care-associated meningitis where up to 66 percent of patients have received antibiotic therapy prior to obtaining CSF studies [18] and up to 50 percent of patients have negative CSF cultures [33]. In this setting, the CSF may be infected but partially treated. The decision to discontinue antibiotics should be individualized.

In one cohort study of patients with postoperative meningitis (with no intracranial devices), stopping antibiotics after 72 hours if CSF cultures were negative was safe [34]. All episodes of meningitis were cured, and complications were rare. Various models and parameters to improve diagnostic certainty (eg, CSF lactate, CSF procalcitonin, cell index) have been studied, but they have not been adequately validated in the clinical setting [27,35,36]. Some clinicians, including the author of this topic, calculate the cell index, a ratio of the WBC to red blood cells (RBC) in the CSF divided by the ratio of WBC to RBC in the peripheral blood [35]. In a case-control study in 111 patients with intracranial hemorrhage, the cell index had good discrimination capacity in identifying patients with culture confirmed cases [35]. The mean cell index for those with culture-positive meningitis was 4.299 versus 0.007 in the controls without infection. Despite these findings, any decisions to discontinue antibiotics should be made with appropriate consultation. Infections of CSF shunts and other devices are discussed separately. (See "Infections of cerebrospinal fluid shunts and other devices".)

SUPPORTIVE CARE Fluid management — Careful management of fluid and electrolyte balance is important, since both over- and under-hydration are associated with adverse outcomes. A meta-analysis evaluated three randomized controlled trials of treatment of differing volumes of fluid (maintenance versus restricted fluid) given in the initial management of bacterial meningitis [37]. The largest trial was conducted in a setting with a high mortality rate. There was no significant difference between the two groups in number of deaths or acute severe or mild to moderate neurologic sequelae. However, when neurologic sequelae were defined further, there was a statistically significant difference in favor of the maintenance fluid group in regard to spasticity (relative risk [RR] 0.50, 95% CI 0.27-0.93), seizures at both 72 hours (RR 0.59, https://www.uptodate.com/contents/1290/print

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95% CI 0.42-0.83) and 14 days (RR 0.19, 95% CI 0.04-0.88), and chronic severe neurologic sequelae at three months follow-up (RR 0.42, 95% CI 0.20-0.89). Thus, there is evidence that the use of intravenous maintenance fluids is preferred to restricted fluid intake in the first 48 hours in settings with high mortality rates and when patients present late. There is insufficient evidence to guide practice in other settings. Reduction of intracranial pressure — Patients with bacterial meningitis who have elevations of intracranial pressure (ICP) and who are stuporous or comatose may benefit from insertion of an ICP monitoring device [38,39]. Pressures exceeding 20 mmHg are abnormal and should be treated; there is also rationale for treating smaller pressure elevations (ie, above 15 mmHg) to avoid larger elevations that can lead to cerebral herniation and irreversible brainstem injury. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'ICP monitoring'.) Methods to reduce ICP include elevating the head of the bed to 30° and hyperventilation to maintain PaCO2 between 27 and 30 mmHg. Another method that has been evaluated for reducing ICP is oral administration of the hyperosmolar agent, glycerol. However, a randomized trial in adults with bacterial meningitis in Malawi (a resource-poor country with high HIV prevalence) was stopped early because planned interim analysis demonstrated increased mortality by day 40 in the glycerol group (63 versus 49 percent) [40]. The reason for this finding is unclear but might relate to an increased incidence of seizures in the patients who received glycerol. Another possible reason could be a rebound increase in ICP as the drug is eliminated, although ICP was not monitored in this trial. In contrast with this trial involving adults, some studies using glycerol have shown promising results in children with bacterial meningitis, although further data are needed before it can be recommended. (See "Bacterial meningitis in children: Dexamethasone and other measures to prevent neurologic complications", section on 'Glycerol'.) In a study of 15 patients with bacterial meningitis in whom ICP was monitored, pressure was significantly lowered by a broad range of measures that utilized unconventional volumetargeted intracranial pressure management [41]. These included sedation, glucocorticoids, normal fluid and electrolyte homeostasis, blood transfusion, albumin infusion, decrease of mean arterial pressure, treatment with a prostacyclin analog, and eventually, thiopental, ventriculostomy, and dihydroergotamine. In those not surviving their episode of bacterial meningitis, mean ICP was significantly higher. However, given that this was not a comparative trial, the results must be interpreted with caution. In a prospective intervention-control comparison study of adult patients with acute bacterial meningitis, 53 patients were treated with conventional intensive care and 52 patients were https://www.uptodate.com/contents/1290/print

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given ICP-targeted treatment in the neuro-intensive care unit [42]. ICP-targeted treatment included cerebrospinal fluid (CSF) drainage using external ventricular catheters (48 patients), osmotherapy (21 patients), hyperventilation (13 patients), external cooling (9 patients), high doses of methylprednisolone (3 patients), and deep barbiturate sedation (2 patients), aiming to keep the ICP 50 mmHg. Mortality was significantly lower in the intervention group (10 versus 30 percent). However, this was not a randomized controlled trial and controls were identified retrospectively. Additional data are therefore needed. Induced hypothermia — There has been interest in evaluating induced hypothermia in patients with severe meningitis since there is evidence that it is beneficial in patients with global cerebral hypoxia following cardiac arrest (see "Initial assessment and management of the adult post-cardiac arrest patient", section on 'Temperature management'). However, more data are needed before therapeutic hypothermia can be recommended in patients with severe bacterial meningitis. In an open-label multicenter randomized trial in 49 intensive care units in France, 98 comatose patients were randomly assigned to undergo induced hypothermia with a loading dose of 4°C cold saline and cooling to 32 to 34°C for 48 hours or standard care [43]. The trial was stopped early because of concerns about excess mortality in the induced hypothermia group compared with the control group (51 versus 31 percent; RR 1.99, 95% CI 1.05-3.77). At three months, 86 percent of patients in the hypothermia group had an unfavorable outcome (defined as a Glasgow Coma Scale score of 1 to 4) compared with 74 percent of those in the control group (RR 2.17, 95% CI 0.78-6.01). After adjustment for age, Glasgow Coma Scale score at inclusion, and the presence of septic shock at inclusion, mortality remained higher in the inducedhypothermia group, although the difference was not statistically significant (hazard ratio 1.76, 95% CI 0.89-3.45). The authors concluded that moderate hypothermia did not improve outcomes in patients with severe bacterial meningitis and that it may be harmful. In a study of therapeutic hypothermia in adults with community-acquired bacterial meningitis, the incidence of hospital mortality (20 versus 49 percent) and adverse neurologic outcome (ie, a Glasgow outcome score 1 to 3; 44 versus 66 percent) were significantly lower in patients treated with therapeutic hypothermia [44]. However, the number of enrolled patients was small, and outcomes in this study of the 41 enrolled patients were compared with historical controls.

REPEAT CEREBROSPINAL FLUID ANALYSIS

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Although we do not routinely recommend repeat cerebrospinal (CSF) analysis, there are settings in which repeat lumbar puncture (LP) should be performed in patients with bacterial meningitis [8]: ●

When there is no evidence of improvement by 48 hours after the initiation of appropriate therapy.

●

Two to three days after the initiation of therapy of meningitis due to microorganisms resistant to standard antimicrobial agents (eg, penicillin-resistant pneumococcal infection), especially for those who have also received adjunctive dexamethasone therapy and are not responding as expected, or for infection caused by a gram-negative bacillus, which is much more common with health care-associated infection [6,45].

●

Persistent fever for more than eight days without another explanation.

There is limited utility to routine repeat LP to assess the response to therapy in adults with bacterial meningitis. This was illustrated in a review of 165 adults with meningitis who underwent an end-of-treatment LP [46]. Wide ranges of glucose and protein concentrations and cell counts were found at the end of treatment in patients who were ultimately shown to be cured without further therapy. In addition, repeat CSF examination failed to detect relapse in the two patients who relapsed following treatment, and the CSF test results led to unnecessary testing in 13 patients with abnormal CSF findings at the end of therapy. These results suggest that clinical signs of improvement were a better indicator of response to therapy than the results of CSF analysis after treatment had been completed. While repeat LP is not typically performed, it can be useful in selected cases to confirm diagnosis, exclude relapsing or persistent infection, or therapeutically in those patients with communicating hydrocephalus. In an observational study assessing the utility of repeat LP in patients with clinical deterioration, hydrocephalus, or persistent fever, 9 (7 percent) had CSF cultures positive [47]. The median CSF white blood cell decreased by 19, 84, 93, and 98 percent if the repeat LP was done within 2 days, 3 to 7 days, 8 to 14 days, and by 15 to 21 days, respectively. CSF protein decreased by 75 percent within 3 to 7 days of treatment and CSF glucose levels increased. Repeat CSF cultures should be sterile. For patients in whom repeat cultures are positive despite appropriate therapy with parenteral antibiotic therapy, administration of intrathecal (or intraventricular) antibiotics may be considered [48].

PROGNOSIS https://www.uptodate.com/contents/1290/print

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There is an appreciable mortality rate associated with bacterial meningitis even with the administration of appropriate antibiotics. Mortality — The mortality rate of bacterial meningitis increases linearly with increasing age. In a United States population-based surveillance study between 2003 and 2007, the case-fatality rate in adults was 16.4 percent; among patients between 18 and 34 years of age, the casefatality rate was 8.9 percent compared with 22.7 percent in patients ≥65 years of age [49]. The overall case-fatality rate did not change significantly between 1998 to 1999 and 2006 to 2007. Outcomes also vary depending upon the organism. The following observations from different time periods illustrate the range of findings: ●

In a review of 493 episodes of bacterial meningitis in 445 adults seen at a single center in the United States from 1962 to 1988, the overall mortality rate was 25 percent and did not vary over the course of the study [6]. The mortality rate was higher with health careassociated compared with community-acquired infection (35 versus 25 percent) and was higher with infection due to S. pneumoniae and L. monocytogenes compared with N. meningitidis (28 and 32 versus 10 percent).

●

In a series of 248 patients seen in 1995 in acute care hospitals in 22 counties in four states in the United States, the mortality rate was highest with S. pneumoniae and L. monocytogenes (21 and 15 percent, respectively) and lowest with N. meningitidis (3 percent) [50].

●

A report from the Netherlands evaluated 696 cases of community-acquired acute bacterial meningitis seen between 1998 and 2002 [51]. The overall mortality rate was significantly higher with pneumococcal compared with meningococcal meningitis (30 versus 7 percent). In addition, an unfavorable outcome was six times more common with pneumococcal meningitis, even after adjustment for other clinical predictors.

Risk factors for mortality include older age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white blood cell count of less than 1000 cells/mL, a positive blood culture, and a high serum Creactive protein concentration [11]. Mortality rates of bacterial meningitis may also be elevated in settings with a high prevalence of HIV infection. In a cohort study of patients undergoing lumbar puncture in Botswana, among whom 72 percent had documented HIV infection, the 10-week and 1-year mortality rates among the 238 patients with culture-confirmed pneumococcal meningitis were 47 percent and

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49 percent, respectively [52]. The median CD4 count was 136 cells/microL and 45 percent of the cohort was on antiretroviral therapy. The use of adjunctive dexamethasone is associated with a reduction in mortality in selected patients with bacterial meningitis. This is discussed in detail separately. (See "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults".) Neurologic complications — Neurologic complications are not uncommon in adults with bacterial meningitis. In a review of 493 episodes of bacterial meningitis in adults, for example, 28 percent of community-acquired episodes resulted in one or more neurologic complications [6]. The neurologic complications of bacterial meningitis include: ●

Impaired mental status

●

Increased intracranial pressure and cerebral edema

●

Seizures

●

Focal neurologic deficits (eg, cranial nerve palsy, hemiparesis)

●

Cerebrovascular abnormalities

●

Sensorineural hearing loss

●

Intellectual impairment

These are discussed in detail separately. (See "Neurologic complications of bacterial meningitis in adults".) Prediction of risk — Baseline features can be used to estimate the individual patient's risk for an adverse outcome. A prognostic model was derived from a cohort of 176 adults and then validated in another cohort of 93 patients [5]. In-hospital mortality was 27 percent, and 9 percent had a neurologic deficit at discharge. Three baseline clinical features (hypotension, altered mental status, and seizures) were independently associated with an adverse outcome (defined as in-hospital death or neurologic deficit at discharge) and stratified the patients into three risk groups: ●

Low risk (no clinical risk factors) – 9 percent adverse outcome

●

Intermediate risk (one clinical risk factor) – 33 percent adverse outcome

●

High risk (two or three risk factors) – 56 percent adverse outcome

An additional risk factor for an adverse outcome in this report was advancement from low or intermediate risk to high risk in the emergency department prior to the administration of antibiotics. Although this finding supports the recommendation to avoid delays in antimicrobial therapy in patients with suspected bacterial meningitis, it is also consistent with the hypothesis

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that severely ill patients at the start may have an adverse outcome regardless of the timing of initial therapy [53]. In a retrospective study of 65 patients admitted to the intensive care unit for acute bacterial meningitis, adverse clinical outcomes were noted in 46 patients; these patients were older, had a higher Acute Physiology and Chronic Health Evaluation II score, and a lower Glasgow Coma Scale score [54].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial meningitis in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Bacterial meningitis (The Basics)")

●

Beyond the Basics topics (see "Patient education: Vaccines for adults (Beyond the Basics)" and "Patient education: Vaccines for children age 7 to 18 years (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

Bacterial meningitis is a medical emergency, and immediate steps must be taken to establish the specific cause and initiate effective therapy. The mortality rate of untreated

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disease approaches 100 percent and, even with optimal therapy, there is a high failure rate. (See 'Introduction' above.) ●

If possible, crucial historical information (eg, serious drug allergies, recent exposure to an individual with meningitis) should be obtained before antibiotic treatment of presumed bacterial meningitis is instituted. (See 'History' above.)

●

Initial blood tests should include two sets of blood cultures. The initial approach to management in a patient with suspected bacterial meningitis includes performance of a lumbar puncture (LP) to determine whether the cerebrospinal fluid (CSF) findings are consistent with the diagnosis (

●

algorithm 1). (See 'Pretreatment testing' above.)

We recommend that antimicrobial therapy be initiated immediately after the performance of the LP or, if a computed tomography (CT) scan is going to be performed before LP, immediately after blood cultures are obtained (Grade 1B). The empiric approach to antimicrobial selection in patients with suspected bacterial meningitis is directed at the most likely bacteria based on the patient's age and other host factors (

table 3A-B and

table 4). (See 'Avoidance of delay' above and 'Empiric regimens' above.) ●

As part of empiric therapy for adults in the developed world with suspected bacterial meningitis in whom the organism is not yet known, we recommend administration of dexamethasone (Grade 1B). Adjunctive dexamethasone should be given shortly before or at the same time as the first dose of antibiotics, when indicated. Dexamethasone should be only continued if the CSF Gram stain and/or the CSF or blood cultures reveal Streptococcus pneumoniae. The indications for dexamethasone for patients with suspected or confirmed bacterial meningitis in the developing world depend on the patient population and are discussed in detail elsewhere. (See 'When to administer dexamethasone' above and "Dexamethasone to prevent neurologic complications of bacterial meningitis in adults".)

●

Once the CSF Gram stain results are available, the antimicrobial regimen should be tailored to cover the most likely pathogen. If the CSF findings are consistent with the diagnosis of acute bacterial meningitis but the Gram stain is negative, empiric antibiotic therapy should be continued. (See 'Regimens based upon Gram stain' above.)

●

The antibiotic regimen should be modified further, when indicated, based on the CSF culture and susceptibility results. (See "Treatment of bacterial meningitis caused by specific pathogens in adults".)

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Cessation of antimicrobial therapy is not recommended in patients who have received prior or are receiving concurrent antimicrobial therapy with a negative CSF culture and who are suspected of having bacterial meningitis based on clinical and laboratory findings (eg, CSF pleocytosis). The choice of antimicrobial regimen and duration of administration should be individualized based on risk factors and likely infecting pathogens. Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Swartz MN. Bacterial meningitis--a view of the past 90 years. N Engl J Med 2004; 351:1826. 2. van de Beek D, Brouwer M, Hasbun R, et al. Community-acquired bacterial meningitis. Nat Rev Dis Primers 2016; 2:16074. 3. Oordt-Speets AM, Bolijn R, van Hoorn RC, et al. Global etiology of bacterial meningitis: A systematic review and meta-analysis. PLoS One 2018; 13:e0198772. 4. de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549. 5. Aronin SI, Peduzzi P, Quagliarello VJ. Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med 1998; 129:862. 6. Durand ML, Calderwood SB, Weber DJ, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993; 328:21. 7. Attia J, Hatala R, Cook DJ, Wong JG. The rational clinical examination. Does this adult patient have acute meningitis? JAMA 1999; 282:175. 8. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267. 9. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the head before lumbar puncture in adults with suspected meningitis. N Engl J Med 2001; 345:1727. 10. Salazar L, Hasbun R. Cranial Imaging Before Lumbar Puncture in Adults With CommunityAcquired Meningitis: Clinical Utility and Adherence to the Infectious Diseases Society of America Guidelines. Clin Infect Dis 2017; 64:1657. 11. Bijlsma MW, Brouwer MC, Kasanmoentalib ES, et al. Community-acquired bacterial meningitis in adults in the Netherlands, 2006-14: a prospective cohort study. Lancet Infect Dis 2016; 16:339. https://www.uptodate.com/contents/1290/print

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12. Auburtin M, Wolff M, Charpentier J, et al. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Crit Care Med 2006; 34:2758. 13. Lepur D, Barsić B. Community-acquired bacterial meningitis in adults: antibiotic timing in disease course and outcome. Infection 2007; 35:225. 14. Proulx N, Fréchette D, Toye B, et al. Delays in the administration of antibiotics are associated with mortality from adult acute bacterial meningitis. QJM 2005; 98:291. 15. Køster-Rasmussen R, Korshin A, Meyer CN. Antibiotic treatment delay and outcome in acute bacterial meningitis. J Infect 2008; 57:449. 16. Bodilsen J, Dalager-Pedersen M, Schønheyder HC, Nielsen H. Time to antibiotic therapy and outcome in bacterial meningitis: a Danish population-based cohort study. BMC Infect Dis 2016; 16:392. 17. Nigrovic LE, Malley R, Macias CG, et al. Effect of antibiotic pretreatment on cerebrospinal fluid profiles of children with bacterial meningitis. Pediatrics 2008; 122:726. 18. Rogers T, Sok K, Erickson T, et al. Impact of Antibiotic Therapy in the Microbiological Yield of Healthcare-Associated Ventriculitis and Meningitis. Open Forum Infect Dis 2019; 6:ofz050. 19. Quagliarello VJ, Scheld WM. Treatment of bacterial meningitis. N Engl J Med 1997; 336:708. 20. Hieber JP, Nelson JD. A pharmacologic evaluation of penicillin in children with purulent meningitis. N Engl J Med 1977; 297:410. 21. Sinner SW, Tunkel AR. Antimicrobial agents in the treatment of bacterial meningitis. Infect Dis Clin North Am 2004; 18:581. 22. Brouwer MC, Tunkel AR, van de Beek D. Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clin Microbiol Rev 2010; 23:467. 23. Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study. Lancet Infect Dis 2014; 14:813. 24. Brouwer MC, van de Beek D. Epidemiology of community-acquired bacterial meningitis. Curr Opin Infect Dis 2018; 31:78. 25. van de Beek D, Cabellos C, Dzupova O, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect 2016; 22 Suppl 3:S37. 26. McGill F, Heyderman RS, Michael BD, et al. The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults. J Infect 2016; 72:405. https://www.uptodate.com/contents/1290/print

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27. Tunkel AR, Hasbun R, Bhimraj A, et al. 2017 Infectious Diseases Society of America's Clinical Practice Guidelines for Healthcare-Associated Ventriculitis and Meningitis. Clin Infect Dis 2017. 28. Brouwer MC, Thwaites GE, Tunkel AR, van de Beek D. Dilemmas in the diagnosis of acute community-acquired bacterial meningitis. Lancet 2012; 380:1684. 29. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380:1693. 30. Charlier C, Perrodeau É, Leclercq A, et al. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis 2017; 17:510. 31. Hasbun R. Update and advances in community acquired bacterial meningitis. Curr Opin Infect Dis 2019; 32:233. 32. Hasbun R, Bijlsma M, Brouwer MC, et al. Risk score for identifying adults with CSF pleocytosis and negative CSF Gram stain at low risk for an urgent treatable cause. J Infect 2013; 67:102. 33. Srihawan C, Castelblanco RL, Salazar L, et al. Clinical Characteristics and Predictors of Adverse Outcome in Adult and Pediatric Patients With Healthcare-Associated Ventriculitis and Meningitis. Open Forum Infect Dis 2016; 3:ofw077. 34. Zarrouk V, Vassor I, Bert F, et al. Evaluation of the management of postoperative aseptic meningitis. Clin Infect Dis 2007; 44:1555. 35. Montes K, Jenkinson H, Habib OB, et al. Corrected white blood cell count, cell index, and validation of a clinical model for the diagnosis of health care-associated ventriculitis and meningitis in adults with intracranial hemorrhage. Clin Neurol Neurosurg 2019; 178:36. 36. Hernández Ortiz OH, García García HI, Muñoz Ramírez F, et al. Development of a prediction rule for diagnosing postoperative meningitis: a cross-sectional study. J Neurosurg 2018; 128:262. 37. Oates-Whitehead RM, Maconochie I, Baumer H, Stewart ME. Fluid therapy for acute bacterial meningitis. Cochrane Database Syst Rev 2005; :CD004786. 38. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF. Community-acquired bacterial meningitis in adults. N Engl J Med 2006; 354:44. 39. Kramer AH, Bleck TP. Neurocritical care of patients with central nervous system infections. Curr Infect Dis Rep 2007; 9:308. 40. Ajdukiewicz KM, Cartwright KE, Scarborough M, et al. Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial. Lancet Infect Dis 2011; 11:293. https://www.uptodate.com/contents/1290/print

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41. Lindvall P, Ahlm C, Ericsson M, et al. Reducing intracranial pressure may increase survival among patients with bacterial meningitis. Clin Infect Dis 2004; 38:384. 42. Glimåker M, Johansson B, Halldorsdottir H, et al. Neuro-intensive treatment targeting intracranial hypertension improves outcome in severe bacterial meningitis: an intervention-control study. PLoS One 2014; 9:e91976. 43. Mourvillier B, Tubach F, van de Beek D, et al. Induced hypothermia in severe bacterial meningitis: a randomized clinical trial. JAMA 2013; 310:2174. 44. Kutleša M, Lepur D, Baršić B. Therapeutic hypothermia for adult community-acquired bacterial meningitis-historical control study. Clin Neurol Neurosurg 2014; 123:181. 45. van de Beek D, Drake JM, Tunkel AR. Nosocomial bacterial meningitis. N Engl J Med 2010; 362:146. 46. Durack DT, Spanos A. End-of-treatment spinal tap in bacterial meningitis. Is it worthwhile? JAMA 1982; 248:75. 47. Costerus JM, Brouwer MC, van der Ende A, van de Beek D. Repeat lumbar puncture in adults with bacterial meningitis. Clin Microbiol Infect 2016; 22:428. 48. Ziai WC, Lewin JJ 3rd. Improving the role of intraventricular antimicrobial agents in the management of meningitis. Curr Opin Neurol 2009; 22:277. 49. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364:2016. 50. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. Active Surveillance Team. N Engl J Med 1997; 337:970. 51. van de Beek D, de Gans J, Spanjaard L, et al. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med 2004; 351:1849. 52. Tenforde MW, Mokomane M, Leeme TB, et al. Mortality in adult patients with culturepositive and culture-negative meningitis in the Botswana national meningitis survey: a prevalent cohort study. Lancet Infect Dis 2019; 19:740. 53. Kilpi T, Anttila M, Kallio MJ, Peltola H. Length of prediagnostic history related to the course and sequelae of childhood bacterial meningitis. Pediatr Infect Dis J 1993; 12:184. 54. Fernandes D, Gonçalves-Pereira J, Janeiro S, et al. Acute bacterial meningitis in the intensive care unit and risk factors for adverse clinical outcomes: retrospective study. J Crit Care 2014; 29:347. Topic 1290 Version 49.0

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GRAPHICS

Management algorithm for adults with suspected bacterial meningitis

"STAT" indicates that the intervention should be done emergently. CNS: central nervous system; CSF: cerebrospinal fluid; CT: computed tomography. * Refer to UpToDate topic review on dexamethasone to prevent neurologic complications of bacterial meningitis in adults for specific recommendations. ¶ Refer to UpToDate table on recommendations for empiric antimicrobial therapy for purulent meningitis based on patient age and specific predisposing condition. Δ Administer dexamethasone and antibiotic therapy immediately after CSF is obtained. ◊ Refer to UpToDate table on recommendations for antimicrobial therapy in adults with presumptive pathogen identification by positive Gram stain. § If the diagnosis of bacterial meningitis is likely. Modified with permission from: Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267. Copyright © 2004 University of Chicago Press.

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Graphic 50114 Version 5.0

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Typical cerebrospinal fluid findings in central nervous system infections* Glucose (mg/dL)

Protein (mg/dL)

  1000 Bacterial meningitis

Encephalitis 

100 to 1000 Bacterial or viral meningitis

Ea ba m

TB meningitis

Vi m N

Neurosyphilis

TB

TB meningitis¥ Less common

TB meningitis Fungal meningitis

Neurosyphilis Some viral infections (such as mumps and LCMV)

 

Early bacterial meningitis

Some cases of mumps and LCMV

Encephalitis

En

TB: tuberculosis; LCMV: lymphocytic choriomeningitis virus. * It is important to note that the spectrum of cerebrospinal fluid values in bacterial meningitis is so wide that the absence of one or more of these findings is of little value. Refer to the UpToDate topic reviews on bacterial meningitis for additional details. ¶ 500 mg/dL are an indication of blood-brain barrier disruption or increased intracerebral production of immunoglobulins, and extremely high concentrations, in the range of 2 to 6 g/dL, may be found in association with subarachnoid block. Graphic 76324 Version 11.0

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Differential diagnosis of selected causes of aseptic meningitis Viral Adenovirus

Influenza A and B

Arboviruses

Lymphocytic choriomeningitis virus

Coxsackieviruses types A and B

Measles

Cytomegalovirus

Mumps

Echoviruses

Parainfluenza

Encephalomyocarditis virus

Poliovirus

Epstein-Barr virus

Rotavirus

Herpes simplex type I

Rubella

Herpes simplex type 2

Vaccinia

Human immunodeficiency virus

Varicella-zoster virus

Bacterial Actinomyces spp

Mycoplasma pneumoniae

Bacterial endocarditis

Nocardia spp

Borrelia burgdorferi (Lyme disease) Borrelia recurrentis (relapsing fever)

Parameningeal bacterial infection (epidural, subdural abscess)

Brucella spp

Partially treated bacterial meningitis

Chlamydia spp

Rickettsia spp

Leptospira spp

Spirillum minor (rat bite fever)

Mycobacterium tuberculosis

Treponema pallidum (syphilis)

Mycoplasma hominis ​

Fungal Aspergillus spp Blastomyces dermatitidis Candida spp Coccidioides immitis Cryptococcus neoformans Histoplasma capsulatum Sporothrix schenckii

Parasitic Angiostrongylus cantonensis Taenia solium (cysticercosis) Toxoplasma gondii Trichenella spiralis https://www.uptodate.com/contents/1290/print

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Drug Anti-CD3 monoclonal antibody Azathioprine lbuprofen Other NSAIDs Pyridium (phenazopyridine) Trimethoprim-sulfamethoxazole

Malignancy Leukemia Lymphoma Metatstatic carcinomas and adenocarcinomas

Autoimmune Behçet's disease Sarcoid Systemic lupus erythematosus Vogt-Koyanagi-Harada syndrome

Other Epidermoid cyst Postvaccination NSAIDs: nonsteroidal anti-inflammatory drugs. Modified from Connolly KJ, Hammer SM. The acute aseptic meningitis syndrome. Infect Dis Clin North Am 1990; 4:599.

Graphic 79745 Version 4.0

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Recommendations for empiric antimicrobial therapy for purulent meningitis based on patient age and specific predisposing condition* Predisposing factor

Common bacterial pathogens

Antimicrobial therapy

Age 50 years

S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gramnegative bacilli

Vancomycin plus ampicillin plus a third-generation cephalosporin¶Δ

Basilar skull fracture

S. pneumoniae, H. influenzae, group A beta-hemolytic streptococci

Vancomycin plus a third-generation cephalosporin¶Δ

Penetrating trauma

Staphylococcus aureus, coagulasenegative staphylococci (especially

Vancomycin plus cefepime; OR vancomycin plus ceftazidime; OR

Staphylococcus epidermidis), aerobic gram-negative bacilli (including

vancomycin plus meropenem

Head trauma

Pseudomonas aeruginosa) Postneurosurgery

Immunocompromised state

Aerobic gram-negative bacilli (including P. aeruginosa), S. aureus,

Vancomycin plus cefepime; OR vancomycin plus ceftazidime; OR

coagulase-negative staphylococci (especially S. epidermidis)

vancomycin plus meropenem

S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-

Vancomycin plus ampicillin plus cefepime; OR vancomycin plus

negative bacilli (including P. aeruginosa)

meropenem§

* For recommended doses, refer to the UpToDate content on treatment of bacterial meningitis in children and adults. ¶ Ceftriaxone or cefotaxime. Δ Some experts would add rifampin if dexamethasone is also given. ◊ Add ampicillin if meningitis caused by Listeria monocytogenes is suspected.

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§ Meropenem provides sufficient coverage for Listeria when used as part of an initial regimen. However, if Listeria is identified, the patient should generally be switched to a regimen that includes ampicillin. Refer to the UpToDate topic that discusses treatment of Listeria for a discussion of regimen selection. Modified with permission from: Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004; 39:1267. Copyright © 2004 University of Chicago Press.

Graphic 71968 Version 12.0

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Recommended intravenous dosages of antimicrobial therapy for adults with bacterial meningitis who have normal renal and hepatic function Antimicrobial agent

Dose (adult)

Amikacin

5 mg/kg every 8 hours*

Ampicillin

2 g every 4 hours

Aztreonam

2 g every 6 to 8 hours

Cefepime

2 g every 8 hours

Cefotaxime

2 g every 4 to 6 hours

Ceftazidime

2 g every 8 hours

Ceftriaxone

2 g every 12 hours

Chloramphenicol

1 to 1.5 g every 6 hours¶

Ciprofloxacin

400 mg every 8 to 12 hours

Gentamicin

1.7 mg/kg every 8 hours*

Meropenem

2 g every 8 hours

Moxifloxacin

400 mg every 24 hoursΔ

Nafcillin

2 g IV every 4 hours

Oxacillin

2 g IV every 4 hours

Penicillin G potassium

4 million units every 4 hours

Rifampin

600 mg every 24 hours◊

Tobramycin

1.7 mg/kg every 8 hours*

Trimethoprim-sulfamethoxazole (cotrimoxazole)

5 mg/kg every 8 hours§¥

Vancomycin

15 to 20 mg/kg every 8 to 12 hours‡†

IV: intravenously; MRSA: methicillin-resistant Staphylococcus aureus; IDSA: Infectious Diseases Society of America. * Dose based on ideal body weight or dosing weight except in underweight patients. A calculator for ideal body weight and dosing weight is available in UpToDate. Dosage and interval must be individualized to produce a peak serum concentration of 7 to 9 mg/L and trough 10 years ago.

cefepime or meropenem instead of ceftriaxone or cefotaxime).* If meropenem is used, it provides sufficient coverage for Listeria when used as part of an initial empiric regimen.

Isolated mild hives to a cephalosporin without other signs of anaphylaxis (especially if the reaction occurred in childhood and/or

Meropenem plus Vancomycin

Meropenem provides sufficient coverage for Listeria and Pseudomonas aeruginosa when used as part of an initial empiric regimen.*

>10 years ago) Or Mild delayed type reactions to cephalosporins. Severe immediate allergy (eg, anaphylaxis) to a penicillin and/or cephalosporin Or SJS/TEN, DRESS, or AGEP with any beta-lactam other than aztreonam.

Moxifloxacin¶ plus Vancomycin

If Listeria coverage is required (eg, patients >50 years of age and/or immunocompromised hosts), trimethoprimsulfamethoxazole should be initiated. Immunocompromised patients generally require expanded gram-negative coverage.* If expanded gram-negative coverage is required,

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aztreonam should be added as long as there is no history of serious allergy (eg, anaphylaxis, SJS/TEN, DRESS, AGEP) to aztreonam itself or an immediate or IgE-mediated allergy to ceftazidime.

Other uncommon forms of hypersensitivity Interstitial nephritisΔ , or drug-induced liver diseaseΔ◊ , or

Initial regimen Ceftriaxone or cefotaxime plus Vancomycin

Comments If Listeria coverage is required (eg, patients >50 years of age and/or immunocompromised

drug-induced cytopeniaΔ , or

hosts), trimethoprimsulfamethoxazole should be

serum sicknessΔ

initiated.

 

Immunocompromised patients

 

generally require expanded gram-negative coverage (eg,

 

cefepime or meropenem instead of ceftriaxone or cefotaxime).* If meropenem is used, it provides sufficient coverage for Listeria when used as part of an initial empiric regimen.

This table discusses empiric antibiotic selection for the initial regimen in patients with a beta-lactam allergy. Once the organism is identified, therapy should then be tailored to the best available agent. If the most appropriate treatment was not initiated due to a beta-lactam allergy, the patient should be managed in conjunction with a drug allergy specialist to see if the type of past allergy is amenable to rechallenge or desensitization. IV: intravenous; SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis; DRESS: drug reaction with eosinophilia and systemic symptoms; AGEP: acute generalized exanthematous pustulosis. * Refer to the topic that discusses initial selection of antibiotics for treatment of bacterial meningitis for a more detailed discussion of which patients require expanded gram-negative coverage and regimen selection in this setting. ¶ Patients with a severe immediate allergy (eg, anaphylaxis) to a penicillin or cephalosporin can usually tolerate meropenem, because cross-reactivity rates between penicillins or cephalosporins and carbapenems for patients with proven immediate allergy are -2.5 with a fragility fracture, single vertebral fracture), we suggest denosumab rather than an anabolic agent (Grade 2B). Because of emerging concerns about an increased risk of vertebral fracture after discontinuation of denosumab, the need for indefinite administration of denosumab should be discussed with patients prior to its initiation. (See "Denosumab for osteoporosis", section on 'Duration of therapy'.)

- High risk of breast cancer – For patients with no history of fragility fractures, raloxifene is a reasonable alternative, particularly in women at high risk for breast cancer. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Choice of drug'.) https://www.uptodate.com/contents/2064/print

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Monitoring – For patients starting on therapy, we obtain a follow-up dual-energy x-ray absorptiometry (DXA) of the hip and spine after two years, and if BMD is stable or improved, less frequent monitoring thereafter. (See 'Our approach' above.) The finding of a clinically significant BMD decrease or a new fracture in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. (See 'Bone mineral density decreased or fracture during therapy' above.)

• Decrease in BMD 1 mcg/mL and approximately 10 percent will have levels >3.5 mcg/mL [18,36]. In a randomized trial comparing posaconazole versus voriconazole for the treatment of invasive aspergillosis in 575 patients, all-cause mortality at day 42 was lower in the posaconazole group (15 versus 21 percent, p25 percent have been reported in some centers. This resistance is associated with mutations in the antifungal target gene and appears associated with environmental exposure of Aspergillus to agricultural fungicides [75]. These isolates have been associated with high rates of antifungal failure and increased mortality [68,72,75-77]. Our approach to antifungal therapy when azole resistance is a concern is as follows and is generally consistent with recommendations of an international expert panel on the management of azole-resistant A. fumigatus infections [78]: ●

When the local prevalence of azole resistance is ≥10 percent, options for empiric treatment while awaiting susceptibility results include either a lipid formulation of amphotericin B or combination therapy with voriconazole plus an echinocandin. The rationale for the latter regimen is that if the isolate is susceptible to voriconazole, it has been shown to be associated with improved outcomes including a mortality benefit compared with amphotericin B; the echinocandin has some in vitro activity against Aspergillus spp and, although it is not an appropriate choice for monotherapy, it might help to control the infection even if the isolate is subsequently found to be azole resistant. One study showed that mortality was higher if voriconazole monotherapy was initiated for infection caused by isolates that were eventually found to be resistant to voriconazole than for infections caused by voriconazole-susceptible isolates [77].

●

When the local prevalence of azole resistance is between 5 and 10 percent, appropriate options include monotherapy with either voriconazole or a lipid formulation of amphotericin B or combination therapy with voriconazole plus an echinocandin.

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If the isolate is found to be resistant to azoles, the patient should be treated with an antifungal agent to which the isolate is susceptible.

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If the isolate is found to be susceptible to azoles, the usual approach to therapy should be taken. (See 'Choice of regimen' above.)

●

If the susceptibility results are unknown (eg, if cultures are negative), we favor initial therapy with a lipid formulation of amphotericin B. If the patient has improved after two weeks, the regimen can be deescalated to voriconazole (if there is no concern for Mucorales) or isavuconazole with close clinical follow-up.

Surveillance in the Netherlands revealed the emergence of a set of mutations in A. fumigatus isolates that confers reduced susceptibility to azoles [64]. An amino acid substitution of leucine for histidine at codon 98, in conjunction with a tandem repeat in the gene promoter (TR34/L98H), causes pan-triazole resistance including itraconazole (which is used as an in vitro screen) and increased MICs to voriconazole, isavuconazole, and posaconazole. Among isolates in the surveillance study in the Netherlands (which included several isolates from other countries in Europe), the annual prevalence between 2000 and 2007 ranged from 1.7 to 6 percent [65,66], which increased to 7 percent for 2012 to 2016 [73]. In some centers in the Netherlands, rates of resistance for A. fumigatus have ranged between 10 and 30 percent or more [73,77]. In another surveillance study in the Netherlands, another mutation, TR46/Y121F/T289A, a novel cyp51A-mediated was observed in A. fumigatus clinical and environmental isolates and has also spread as a global clone [75]. Isolates with this mutation are less common than the TR34 mutation and may exhibit a phenotype of cross-resistance to voriconazole and isavuconazole but with MICs to posaconazole that are increased but less highly resistant [75]. It is likely that such resistance has occurred as a result of the widespread use of triazole fungicides in crops in the Netherlands and elsewhere [79]. Another study has found that plant bulbs imported to Ireland from the Netherlands harbored triazole-resistant A. fumigatus [80]. Epidemiology of A. fumigatus drug resistance in other countries is not as well evaluated, but surveillance studies and case series have reported azole-resistant A. fumigatus in additional countries in Europe, the Middle East, Africa, Australia, and North and South America including the United States [72,81,82]. Resistance should be considered in A. fumigatus infection not responding to azole monotherapy. Since the introduction of mold-active triazoles such as voriconazole, the MICs for triazoles have increased among A. fumigatus isolates from high-risk patients with hematologic malignancies or HCT recipients at a cancer center in the United States [83]. Increased MICs were associated with azole exposure during the previous three months; the clinical implications remain unknown. Of note, none of those isolates harbored the TR34/L98H or TR46/Y121F/T289A mutations that confer high-level triazole resistance, which is associated with poor outcomes. Nevertheless, https://www.uptodate.com/contents/2459/print

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these strains with TR34/L98H or TR46/Y121F/T289A mutations have been isolated from patients and from environmental sources in the United States [82,84], suggesting that continued vigilance for the emergence of these strains in the United States is warranted.

IMMUNOMODULATION Reduction of immunosuppression — Whenever possible, the degree of immunosuppression should be decreased as an adjunct to antifungal therapy for the treatment of invasive aspergillosis [1]. The worst outcomes occur in patients with persistent, severe immune dysfunction and in those with organ impairment that limits administration of antifungals. Although the relative contribution of these prognostic indicators is unclear, it is generally accepted that decreasing immune suppression will result in improved outcomes. Invasive aspergillosis occurs most commonly in the setting of immunosuppression, particularly chemotherapy-induced neutropenia or glucocorticoid administration for graft-versus-host disease (GVHD). In neutropenic patients, recovery of bone marrow function is critical to the control of aspergillosis [85]; in the hematopoietic cell transplant (HCT) recipient with aspergillosis, for example, failure to engraft will result in death due to this infection. The high mortality observed in invasive aspergillosis reflects the influence of the underlying disease on outcome and the frequent inability to improve immunosuppression [86]. In a detailed review of 405 patients who had aspergillosis in the setting of HCT or treatment of hematologic malignancy, the most important prognostic factors included clinical variables that dictated overall immune impairment (GVHD severity and human leukocyte antigen mismatch), relative paucity of multiple cell types (neutropenia, monocytopenia, and lymphocytopenia), and kidney and liver impairment [24]. Colony-stimulating factors — At present, we do not recommend routine use of colonystimulating factors in neutropenic patients with invasive aspergillosis [1,87]. Consideration of the risks and benefits should be made on a case-by-case basis. Colony-stimulating growth factors enhance neutrophil chemotaxis and phagocytosis and attract neutrophils to the site of inflammation. In clinical studies, granulocyte colony-stimulating factor (G-CSF) shortens the period of neutropenia following myelosuppressive chemotherapy, leading to shorter hospitalizations, fewer documented infections, and fewer days of antimicrobial therapy. Despite these positive effects, there is currently no definitive proof that hematopoietic growth factors decrease mortality from infection, improve the response rate to antibiotics, or improve overall survival. Furthermore, there is no evidence to support the role of colonystimulating factors to increase innate neutrophil fungicidal capacity. https://www.uptodate.com/contents/2459/print

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Granulocyte transfusions — There are few data to support the use of donor granulocyte transfusions for the management of patients with neutropenia and invasive aspergillosis. Experience has been limited to situations in which severe disease warranted drastic measures. A randomized trial that assessed granulocyte transfusion from G-CSF-dexamethasone-treated donors enrolled few patients with invasive mold infections and did not show any evidence of benefit [88]. The use of granulocyte transfusions is discussed in detail separately. (See "Granulocyte transfusions".)

ROLE OF SURGERY In addition to antifungal therapy, surgical management to debride necrotic tissue may be appropriate as adjunctive therapy in some complex cases with chronic necrotizing disease [89]. The decision of whether to perform surgery depends on many factors, including the extent and location of the lesion(s), the degree of resection required, comorbidities, performance status, the ability of the patient to tolerate surgery, and the underlying disease [1]. Patients with hematologic malignancies and hematopoietic cell transplant (HCT) recipients are rarely appropriate candidates for surgery; surgical complications in this setting are frequent and include bleeding (due to thrombocytopenia), secondary infections including empyema, and nonhealing wounds. Surgery is recommended for localized infections that are easily accessible for debridement (eg, invasive rhinosinusitis, localized cutaneous disease) [1]. Our approach to surgical management for specific clinical manifestations includes the following: ●

Rhinosinusitis – Emergent debridement of Aspergillus rhinosinusitis can limit extension to the orbit and brain and can be lifesaving [1]. Debridement appears to be a useful adjunct to antifungal therapy for Aspergillus rhinosinusitis, according to at least one case series [90]. Radical surgical debridement is required in some cases to achieve cure and sometimes requires multiple surgeries. The need for surgery may depend on the degree of fungal bone invasion at diagnosis and anticipated risks in the setting of severe thrombocytopenia; we have treated some patients successfully with medical therapy alone. (See "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)

●

Primary cutaneous infection – Debridement is recommended for primary cutaneous infection associated with burns or massive soft tissue wounds [1].

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Pulmonary infection – Surgical excision of a pulmonary cavity has been performed in patients with a single pulmonary lesion and recurrent hemoptysis or bacterial

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superinfection [91]. Surgery may be useful in patients with lesions contiguous to the great vessels or pericardium with a high risk for invasion and bleeding, for uncontrolled bleeding, or with invasion of the chest wall or pleural space [1]. It can be considered in patients with a single pulmonary lesion prior to intensive chemotherapy or HCT and in patients with localized pulmonary disease refractory to antifungal therapy; however, risks are substantial and utility is not clear as availability of current antifungals alone may be effective [1]. Risks include persistent pneumothorax as well as spillage of viable fungus into the pleural cavity. We recommend initial medical therapy of pulmonary aspergillosis with sequential follow-up to determine whether surgery is necessary, except in cases of impending major bleeding. Most patients with invasive pulmonary aspergillosis do not require surgery. One retrospective series evaluated 41 patients with hematologic disease complicated by neutropenia and invasive pulmonary aspergillosis [92]. Patients underwent lobectomy (23 patients), wedge resection (16 patients), or enucleation of a mass lesion (2 patients); complication rate and 30-day mortality were both estimated to be 10 percent. Outcomes were generally good (response rate 80 percent) and were associated with successful treatment of the underlying hematologic malignancy. In this study, it was not possible to identify which patients benefited most from a surgical approach. The surgical management of chronic pulmonary aspergillosis is discussed in detail separately. (See "Treatment of chronic pulmonary aspergillosis", section on 'Surgery'.) ●

Endocarditis – Early valve replacement should be performed in patients with Aspergillus endocarditis in an attempt to prevent embolic complications and valvular decompensation [1]. (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)

●

Central nervous system disease – While a mortality benefit to surgery for the management of cerebral lesions in combination with antifungal therapy with voriconazole has been suggested in small studies [11], many patients resolve residual central nervous system disease with current antifungal management and do not require surgical management.

●

Osteomyelitis and septic arthritis – Surgical intervention should be performed in patients with Aspergillus osteomyelitis and/or septic arthritis, when feasible [1].

●

Other – Surgery may also be indicated for settings in which a large degree of necrosis limits antifungal activity (especially in those who have not responded to initial antifungal therapy) and/or there is an imminent threat to the great vessels or uncontrolled bleeding, pericardial involvement, pulmonary lesions contiguous with the heart, or invasion of the pleural space and/or chest wall [1].

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PREVENTION AND EARLY TREATMENT Studies performed in the 1990s and early 2000s reported very poor outcomes for invasive aspergillosis. Mortality rates ranged from 60 to 90 percent and were largely dependent upon the underlying disease [93]. Overall survival has improved but varies depending upon factors such as duration of neutropenia, dosage of glucocorticoids, liver and kidney function, and site and extent of infection [24,94]. A great deal of effort has been put into preventing infections by utilizing prophylactic strategies and into treating invasive aspergillosis as early as possible by either empiric treatment of febrile patients with neutropenia or pre-emptive treatment based upon results of screening assays (eg, galactomannan, beta-D-glucan, and polymerase chain reaction [PCR]) for infection [95,96]. These issues are briefly reviewed here; more extensive discussions are provided separately. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent' and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis' and "Fungal infections following lung transplantation".) Primary prophylaxis — Providing prophylaxis with mold-active drugs can prevent invasive aspergillosis. Which specific patients will benefit from prophylactic strategies remains ill-defined and is partly dependent upon patient characteristics and the epidemiology of invasive fungal infections at individual institutions. Results of several randomized trials are summarized as follows: ●

Posaconazole was more effective than fluconazole or itraconazole for preventing aspergillosis in patients receiving therapy for acute myeloid leukemia (absolute reduction in the posaconazole group -6 percent, 95% CI -9.7 to -2.5 percent) and was associated with improved survival [97]. It was also more effective than fluconazole in allogeneic hematopoietic cell transplant (HCT) recipients with severe graft-versus-host disease (odds ratio [OR] 0.31, 95% CI 0.13-0.75) [98].

●

Voriconazole was associated with fewer cases of documented infections caused by Aspergillus species compared with fluconazole (both with galactomannan antigen monitoring), although these results failed to reach statistical superiority in a study endpoint that included measurement of survival [99].

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Itraconazole may be more effective than fluconazole in preventing aspergillosis in patients with leukemia and in HCT recipients but is generally not recommended due to lack of bioavailability, drug interactions, and toxicity [100-102].

●

Inhaled administration of amphotericin B formulations reduced the incidence of aspergillosis in patients with hematologic malignancies who had prolonged neutropenia (OR 0.26, 95% CI 0.09-0.72) [103].

●

Based upon observational data, inhaled amphotericin B is often used in lung transplant recipients during the early posttransplant period. (See "Fungal infections following lung transplantation".)

Positive results from each of these studies are balanced with the potential drawbacks of prophylaxis, including possible toxicities and drug interactions, costs of the drugs, and the potential generation of microbial resistance. Oral drugs often are poorly absorbed in the setting of gastrointestinal tract mucositis and/or graft-versus-host disease [104]. The use of anti-mold prophylaxis is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".) Empiric therapy — Empiric therapy involves antifungal treatment of febrile patients during periods of neutropenia. This strategy was first introduced as a means to prevent invasive fungal infections in the 1980s after it was noted that many patients with fevers had underlying, otherwise undiagnosed, fungal infections, particularly invasive candidiasis [105]. Such infections were especially common in patients with a long duration of neutropenia who were not receiving azole prophylaxis. Empiric antifungal treatment after a defined duration of persistent fever has become standard practice, and multiple drugs have been studied and approved for this indication. It is important to note that placebo-controlled trials have not been performed to prove the benefit in the era of widespread azole prophylaxis, and the drugs have potential negative effects (eg, toxicity, cost). In high-risk patients with prolonged neutropenia and/or severe immunosuppression (eg, graftversus-host disease, receipt of biologic agents, high-dose glucocorticoids, etc) who have pulmonary nodules, invasive mold infection should be highly suspected and treated while a diagnosis is aggressively pursued. This subject is reviewed in more depth elsewhere. (See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent'.) https://www.uptodate.com/contents/2459/print

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Pre-emptive therapy — Pre-emptive therapy is an early treatment strategy that has been proposed as an alternative to empiric therapy [1]. Pre-emptive therapy involves initiating antifungal therapy based upon the results of serial screening for aspergillosis with galactomannan, beta-D-glucan assays, or PCR if available. Results of studies that have compared pre-emptive therapy to empiric therapy in allogeneic HCT recipients and/or patients with hematologic malignancies have shown: ●

A significant reduction in the use of empiric antifungal therapy (32 versus 15 percent) who were assigned to serial galactomannan and PCR testing compared with those who were assigned to standard diagnosis. There was an increase in the diagnosis of proven or probable invasive aspergillosis, but no difference in mortality among patients was seen [106].

●

No overall clinical or survival benefit to a pre-emptive strategy that involved serial PCR testing [107].

●

No survival benefit of a pre-emptive strategy that used the serum galactomannan assay in combination with other clinical indicators [108]. Probable or proven invasive fungal infections were significantly more common among those who received pre-emptive therapy (9 versus 4 percent), but some of these infections were due to Candida spp rather than molds. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.)

Although the results of these studies suggest benefit of a pre-emptive strategy particularly in limiting antifungal use, none of the trials provides definitive conclusions due to study design issues. Secondary prophylaxis for prevention of relapse — Patients who complete antifungal therapy are at risk for reactivation of aspergillosis if neutropenia recurs. Individuals who are at high risk of relapse, such as those who receive chemotherapy or HCT, require secondary prophylaxis. Secondary prophylaxis involves the continuation or reinitiation of antifungal therapy during periods of increased risk of relapse, such as following chemotherapy or HCT. Voriconazole has been evaluated as secondary prophylaxis to prevent relapsed aspergillosis [109]. In patients at increased risk of relapse following the completion of primary treatment, we recommend reinitiation of antifungal therapy with voriconazole or another mold-active antifungal that the patient responded to and tolerated. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Secondary prophylaxis' and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section on 'Secondary prophylaxis'.) https://www.uptodate.com/contents/2459/print

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The pathogenesis of relapsed invasive aspergillosis is thought to be due to reactivation of a latent subclinical infection that had not been fully eradicated. This may be secondary to the angioinvasive nature of the organism or due to lack of sterilization secondary to poor drug penetration (eg, foreign bodies, vegetations, or lung or bone sequestra) [85]. Factors that predispose patients to relapsing invasive aspergillosis include site of infection (eg, sinuses), use of systemic glucocorticoids, lack of remission of underlying hematologic malignancy, duration of neutropenia, and receipt of an unrelated HCT [85]. The recognition that certain variations in innate immunity increase the risk of invasive aspergillosis suggest that at least some of these infections may represent reinfection due to ongoing high risk of disease; examples include polymorphisms in the genes encoding toll-like receptor-4, dectin-1, and mannose-binding lectin. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Risk factors'.)

PROGNOSTIC FACTORS Invasive aspergillosis is a major cause of death in immunosuppressed patients, particularly following hematopoietic cell transplantation (HCT) [110]. Historically, the one-year mortality rate after onset of invasive aspergillosis in this population was as high as 80 percent [110]. However, results of more recent studies demonstrate improved outcomes, both with regard to estimated attributable and overall mortality [24,94]. In a United States–based multicenter surveillance study that enrolled patients from 2001 to 2005, the 12-week all-cause mortality among HCT recipients with invasive aspergillosis was 58 percent [111]. Lower mortality rates have been observed in trials that included patients other than HCT recipients. As an example, in one trial in which only 29 percent of patients were HCT recipients, the 12-week mortality in patients who received voriconazole was 29 versus 42 percent in those who received amphotericin B deoxycholate [10]. (See 'Voriconazole' above.) Studies evaluating more homogeneous patient populations, such as those done only in HCT recipients, have shown a measurable increase in survival after the diagnosis of invasive aspergillosis in recent years [24,112]. However, variables that influence outcome include a complex combination of host factors, including the underlying disease, as well as the therapies used. Factors predictive of death include disseminated disease, cerebral involvement, persistent and severe neutropenia, administration of glucocorticoids, receipt of human leukocyte antigenmismatched stem cells, and uncontrolled graft-versus-host disease [24,94,113,114]. Multiple host factors, such as pulmonary function prior to transplant, and underlying organ (kidney and liver) function also impact outcomes. There is some indication that recipients of https://www.uptodate.com/contents/2459/print

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nonmyeloablative (or reduced intensity) conditioning regimens have relatively better outcomes after infection compared with patients who received myeloablative therapies [24]. As noted above, glucocorticoid use has been associated with higher mortality rates among HCT recipients in several studies [24,110-114], but, in one study of solid organ transplant recipients, glucocorticoid use resulted in a decreased risk of death [111]. Among patients with COVID-19 coinfection, it is unclear whether mortality rates are higher than in patients who only have COVID-19 infection. A European multicenter case-control study of 823 intensive care unit (ICU) patients found an overall mortality rate for coinfected patients of 52 percent, but coinfection did not increase mortality when compared to patients with only COVID19 in multivariate analysis [115]. In contrast, a prospective study of 108 COVID-19 ICU patients found increased mortality among coinfected patients (odds ratio [OR] for death 4.3; 95% CI 1.512.1) [116]. In a study of allogeneic HCT recipients, those with poorly controlled invasive aspergillosis had lower reactive oxygen species production (which is important for neutrophil-mediated fungal killing) and NK cell counts than patients with well-controlled disease [117]. A delay in diagnosis and in the initiation of appropriate therapy may lead to worse outcomes. In a retrospective study, mortality in patients who received appropriate initial therapy with voriconazole was 24 percent compared with 47 percent in those who received inappropriate initial therapy with voriconazole (ie, in the setting of voriconazole resistance), despite switching to appropriate antifungal therapy after a median of 10 days [77]. The association between antifungal resistance and poor outcomes is discussed in greater detail above. (See 'Antifungal resistance' above.) Serial monitoring with galactomannan or other assays — The serum galactomannan assay has diagnostic value, and serial monitoring may have prognostic value [118-123], as illustrated by the following studies: ●

In a review of 27 studies of patients with hematologic malignancies and proven or probable aspergillosis, patients with persistently positive galactomannan results were significantly more likely to die and to have autopsy-proven aspergillosis than those with a test that normalized in value [118].

●

Another study demonstrated that both the serum galactomannan value at the time of diagnosis of invasive aspergillosis and the one-week galactomannan decay were predictive of all-cause mortality [119]. Each enzyme immunoassay (EIA) unit increase in galactomannan at the time of diagnosis increased the hazard of time to all-cause mortality

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at six weeks by 25 percent, whereas each galactomannan EIA unit decline during the week following the initial test decreased the risk of time to all-cause mortality at six weeks by 22 percent. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen detection'.) In contrast, in bronchoalveolar lavage fluid samples, neither the detection of galactomannan nor the magnitude of the results correlated with mortality in allogeneic cell transplant recipients with invasive pulmonary aspergillosis [122]. (See "Diagnosis of invasive aspergillosis", section on 'Bronchoalveolar lavage fluid'.) There are limited data regarding the use of other assays such as beta-D-glucan or PCR for monitoring response to therapy [124,125].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Aspergillosis".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Invasive aspergillosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

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High prevalence in immunocompromised hosts − Aspergillus species are ubiquitous, but invasive aspergillosis occurs primarily in immunocompromised hosts. Neutropenia and glucocorticoid use are the most common predisposing factors. Invasive aspergillosis is a major cause of death in immunosuppressed patients, particularly following hematopoietic cell transplantation (HCT). (See 'Introduction' above and 'Prognostic factors' above.)

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Importance of early diagnosis and treatment − Optimal management involves early diagnosis and early initiation of antifungal therapy. Surgery and reduction of immunosuppression are important adjunctive components of management in selected patients. (See 'Approach to management' above and 'Role of surgery' above and 'Reduction of immunosuppression' above.)

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Initial therapy − For initial therapy of patients with invasive aspergillosis (ie, diagnosed by culture, galactomannan antigen, or histopathology), we suggest voriconazole rather than other antifungal agents (Grade 2C). For patients with severe or progressive disease, we suggest adding two weeks of echinocandin therapy to voriconazole before transitioning to voriconazole monotherapy (Grade 2C). However, some experts prefer monotherapy with voriconazole for these patients. (See 'Choice of regimen' above and 'Voriconazole' above and 'Voriconazole and an echinocandin' above and 'Dosing and drug effects' above.)

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Alternatives to voriconazole − For patients who cannot tolerate voriconazole or when it is advisable to avoid its side effects, posaconazole or isavuconazole are preferred alternatives. Both have been shown to be as effective as voriconazole and to be better tolerated in randomized trials but clinical experience with each is limited. Liposomal formulations of amphotericin B are additional alternatives, but these agents carry the risk of nephrotoxicity and must be administered intravenously. The decision of which agent to choose depends on organ dysfunction, toxicities, tolerability, severity of illness, and need for intravenous therapy. (See 'Initial therapy' above.)

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Salvage therapy − For salvage therapy in patients who do not respond to initial therapy, we favor an individualized approach. An aggressive and prompt attempt should be undertaken to establish a specific mycologic diagnosis if it was not done previously. Azole drug levels should be measured and if an isolate is available, susceptibility testing performed. For most patients, an empiric change of antifungal therapy to another drug class (usually liposomal amphotericin B) pending a definitive diagnosis is appropriate. For those with confirmed aspergillosis who initially received azole monotherapy or liposomal amphotericin B, we typically give combination therapy with either voriconazole or another azole (isavuconazole or posaconazole) plus an echinocandin. When use of a triazole for salvage therapy is being considered, prior therapeutic regimens, pharmacokinetic factors,

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and possible antifungal resistance should be taken into account. (See 'Salvage therapy' above and 'Echinocandins' above and 'Voriconazole and an echinocandin' above.) ●

Therapeutic drug monitoring − All patients receiving voriconazole for the treatment of invasive aspergillosis, particularly those receiving oral therapy, should undergo monitoring of serum voriconazole trough concentrations. We suggest checking a trough concentration four to seven days into therapy. For most patients, we aim for a target trough serum concentration between 1 and 5.5 mcg/mL, but for those with severe infection (eg, multifocal or disseminated disease, central nervous system infections) or infection with an isolate with an elevated MIC (≥2 mcg/mL), we favor a trough serum concentration between 2 and 6 mcg/mL. (See 'Voriconazole' above.) Posaconazole concentrations can also be measured; we generally monitor concentrations in most patients to document absorption and to assess for potential supratherapeutic levels. Target posaconazole concentrations are >1.5 mg/L to 0.7 mg/L to 40ºC (44 versus 4 percent); serum aminotransferases also tended to be lower (peak serum ALT 296 versus 3234 international units/L). A potential diagnostic challenge in patients presenting with abnormal liver function tests is that the two infections may be present at once. Although nonspecific, serum C-reactive protein (CRP) is often elevated in patients with enteric fever [58]. Cerebrospinal fluid studies are usually normal or reveal a mild pleocytosis (20 x103/mm3 were younger than five years old. In a systematic review, higher case fatality rates were reported among children under five years of age compared with older children and adolescents [60]. Even among infants, there is variability in the severity of the disease. In a series from Chile, febrile infants with enteric fever had relatively mild illnesses not requiring hospitalization [61], while a study from Bangladesh noted a fatality rate of 11 percent [45]. HIV-infected patients — The severity of enteric fever does not appear to be markedly increased in the setting of HIV infection, in contrast to nontyphoidal salmonellosis, in which higher complication rates are seen with HIV coinfection. However, there is some evidence that immunocompromised patients fare poorly with typhoidal infections. One study of four individuals with acquired immunodeficiency syndrome (AIDS) in Peru described atypically severe diarrhea or colitis [40]. In a Tanzanian series of 104 cases of intestinal perforations due to enteric fever treated surgically at a university hospital, mortality was associated with HIVpositivity and low CD4 count at admission, among other factors [62]. Other case reports have documented unusual manifestations of S. Typhi infection such as arteritis [63] or chorioamnionitis [64] in HIV-infected patients. Chronic carriers — In general, chronic carriers do not develop recurrent symptomatic disease. They appear to reach an immunologic equilibrium in which they are chronically colonized, usually in the biliary tract, and may excrete large numbers of organisms, but have a high level of immunity and do not develop clinical disease [25,65-67]. Chronic carriers frequently have high serum antibody titers against the Vi antigen, although the evidence for the utility of this test for identifying carriers is mixed [26,68,69]. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever", section on 'Chronic carriage'.)

DIAGNOSIS Approach — The possibility of enteric fever should be considered in a febrile patient living in, traveling from, or visiting from an endemic area. Duration of fever for more than three days or accompanying gastrointestinal symptoms (abdominal pain, diarrhea, or constipation) should heighten the suspicion. When enteric fever is suspected, blood and stool culture should be performed. A high volume of blood sampled (eg, two to three 20 mL blood cultures in adults [70]) optimizes the yield of blood cultures. Other specimens can be cultured, including bone marrow, which yields the most https://www.uptodate.com/contents/2708/print

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sensitive culture but is invasive and usually not warranted. Evaluation of suspected enteric fever also includes consideration of other potential causes of fever, in particular malaria, amebiasis, rickettsial infections, leptospirosis, dengue fever, and other causes of bacteremia (including typhoidal tularemia) or bacterial gastroenteritis. The differential diagnosis is broad; less common causes include leishmaniasis, Q fever, and melioidosis. (See "Evaluation of fever in the returning traveler".) The diagnosis of enteric fever is made by isolating S. Typhi or Paratyphi from a culture specimen in the setting of a compatible clinical illness. However, culture of most specimens is not highly sensitive, and other diagnostic tests (such as culture-independent methods and serology) are of limited clinical utility. Furthermore, even positive cultures usually require several days to incubate. Thus, when cultures are negative or not available, as in some resource-limited settings, the diagnosis of enteric fever is often made presumptively on the basis of a protracted febrile illness without other explanation. Empiric therapy is often appropriate in the absence of an alternative diagnosis because of the risk for severe sequelae with untreated enteric fever; nevertheless, it is important to recognize that the clinical syndrome of enteric fever is nonspecific, and the positive predictive value of a clinical diagnosis even in high-burden settings is typically less than 50 percent. Culture — Blood cultures are positive in 50 to 70 percent of patients with typhoid, depending upon the series and culture techniques used [71]. Blood cultures may require several days of incubation. The diagnosis can also be made by culture of stool, urine, rose spots, or duodenal contents (via string capsule) [72]. Stool culture is positive in up to 30 to 40 percent of cases, but is often negative by the time that systemic symptoms bring patients to medical attention [61]. Bone marrow culture is the most sensitive diagnostic modality but is rarely indicated in routine clinical practice [73]. It may be reserved for complicated cases, including suspected treatment nonresponse due to antimicrobial resistance. Bone marrow cultures are positive in >90 percent of patients and may remain positive in as many as 50 percent of patients after as many as five days of antibiotics [41]. In a systematic review of 10 studies in which 635 individuals were tested by both blood and bone marrow cultures, the sensitivity of blood culture was 66 percent when bone marrow culture results were used as the reference [71]. S. Typhi isolates should be screened for sensitivity to clinically used fluoroquinolones [74,75], third-generation cephalosporins, ampicillin, trimethoprim-sulfamethoxazole, and azithromycin; the majority of isolates from areas of South Asia are fluoroquinolone nonsusceptible. An outbreak of extensively drug-resistant (XDR) S. Typhi, resistant to chloramphenicol, ampicillin, https://www.uptodate.com/contents/2708/print

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trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins, was recognized in November 2016 in Pakistan and is ongoing [76]. (See "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Fluoroquinolone nonsusceptibility'.) Limitations of serology — Serologic tests such as the Widal test are of limited clinical utility in endemic areas because positive results may represent previous infection. The Widal test detects anti-S. Typhi antibodies, and the minimal titers defined as positive for the O (surface polysaccharide) antigens and H (flagellar) antigens must be determined for individual geographic areas; they are higher in developing regions than in the United States [77]. When paired acute and convalescent samples are studied, a fourfold or greater increase is considered positive. Positive results have been reported in 46 to 94 percent of cases [78]. In a study of healthy blood donors performed in central India, seropositivity for typhoid fever using the S. Typhi O antigen or S. Typhi H antigen was observed in 8 and 14 percent, respectively [78]. In many other settings, specificity of Widal testing has been poorer [79,80]. Culture-independent diagnostic tests — Newer rapid antibody-based diagnostic tests have only moderate diagnostic accuracy in field testing [81-83]. A Cochrane review concluded that rapid diagnostic tests available through 2017 are not sufficiently accurate to replace blood culture [83]. An enzyme-linked immunosorbent assay for antibodies to the capsular polysaccharide Vi antigen may be useful for detection of carriers in high-risk populations [26] but has had limited success in identifying carriers in community-based screens due to highbackground prevalence of Vi-antibody levels in endemic populations [69,84]. Anti-Vi antibodies are not useful for the diagnosis of acute illness [26,68]. Polymerase chain reaction-based diagnostics have had limited sensitivity in most studies given the low concentration of bacteria during bacteremia [85]. Newer approaches are in development; antibody tests to detect serum immunoglobulin A against hemolysin E are promising [86,87].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Acute diarrhea in children".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade https://www.uptodate.com/contents/2708/print

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reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Enteric (typhoid and paratyphoid) fever (The Basics)")

SUMMARY ●

Enteric fever is an invasive bacterial infection acquired through consumption of contaminated food or water. The organisms classically responsible for the enteric fever syndrome are Salmonella enterica serotypes Typhi (formerly S. typhi) and Paratyphi A, B, and C. (See 'Introduction' above.)

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In endemic settings, enteric fever is more common in children and young adults than in older patients. Humans are the only reservoir for S. enterica serotype Typhi. In resourcerich settings, most cases of enteric fever occur in patients who have traveled to endemic regions, particularly south-central Asia. A history of travel to settings in which sanitation is poor or history of contact with a known typhoid case or carrier is useful for identifying patients at risk of infection, although a specific contact is identified in a minority of cases. (See 'Epidemiology' above.)

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Chronic Salmonella carriage is defined as excretion of the organism in stool or urine >12 months after acute infection. Rates of chronic carriage after S. Typhi infection range from 1 to 6 percent. Chronic carriage occurs more frequently in women and in patients with cholelithiasis or other biliary tract abnormalities. Chronic carriers represent an infectious risk to others, particularly in the setting of food preparation. (See 'Chronic carriage' above.)

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Enteric fever usually presents with abdominal pain, fever, and chills approximately 5 to 21 days after ingestion of the causative microorganism. Classic manifestations include relative bradycardia, pulse-temperature dissociation, and "rose spots" (faint salmoncolored macules on the trunk and abdomen). Hepatosplenomegaly, intestinal bleeding,

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and perforation may occur, leading to secondary bacteremia and peritonitis. Laboratory findings may include anemia, leukopenia, leukocytosis, and abnormal liver function tests. (See 'Clinical features' above.) ●

Enteric fever should be suspected in a febrile patient living in, traveling from, or visiting from an endemic area, particularly if the duration of fever is more than three days or if the patient also has gastrointestinal symptoms. The diagnosis of enteric fever is made by culture of the causative microorganism in the setting of a compatible clinical illness. The organism can be cultured from blood, stool, urine, rose spots, duodenal contents, or bone marrow, but most cultures are not highly sensitive. In many cases the diagnosis of enteric fever is made presumptively in patients with protracted fever without alternative explanation. (See 'Diagnosis' above.)

ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Elizabeth L Hohmann, MD, and Edward T Ryan, MD, DTMH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES

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74. Crump JA, Mintz ED. Global trends in typhoid and paratyphoid Fever. Clin Infect Dis 2010; 50:241. 75. Parry CM, Thuy CT, Dongol S, et al. Suitable disk antimicrobial susceptibility breakpoints defining Salmonella enterica serovar Typhi isolates with reduced susceptibility to fluoroquinolones. Antimicrob Agents Chemother 2010; 54:5201. 76. Klemm EJ, Shakoor S, Page AJ, et al. Emergence of an Extensively Drug-Resistant Salmonella enterica Serovar Typhi Clone Harboring a Promiscuous Plasmid Encoding Resistance to Fluoroquinolones and Third-Generation Cephalosporins. mBio 2018; 9. 77. Watson KC. Laboratory and clinical investigation of recovery of Salmonella typhi from blood. J Clin Microbiol 1978; 7:122. 78. Shukla S, Patel B, Chitnis DS. 100 years of Widal test & its reappraisal in an endemic area. Indian J Med Res 1997; 105:53. 79. Levine MM, Grados O, Gilman RH, et al. Diagnostic value of the Widal test in areas endemic for typhoid fever. Am J Trop Med Hyg 1978; 27:795. 80. House D, Wain J, Ho VA, et al. Serology of typhoid fever in an area of endemicity and its relevance to diagnosis. J Clin Microbiol 2001; 39:1002. 81. Maude RR, de Jong HK, Wijedoru L, et al. The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh. Trop Med Int Health 2015; 20:1376. 82. Thriemer K, Ley B, Menten J, et al. A systematic review and meta-analysis of the performance of two point of care typhoid fever tests, Tubex TF and Typhidot, in endemic countries. PLoS One 2013; 8:e81263. 83. Wijedoru L, Mallett S, Parry CM. Rapid diagnostic tests for typhoid and paratyphoid (enteric) fever. Cochrane Database Syst Rev 2017; 5:CD008892. 84. Khanam F, Darton TC, Meiring JE, et al. Salmonella Typhi Stool Shedding by Patients With Enteric Fever and Asymptomatic Chronic Carriers in an Endemic Urban Setting. J Infect Dis 2021; 224:S759. 85. Parry CM, Wijedoru L, Arjyal A, Baker S. The utility of diagnostic tests for enteric fever in endemic locations. Expert Rev Anti Infect Ther 2011; 9:711. 86. Andrews JR, Khanam F, Rahman N, et al. Plasma Immunoglobulin A Responses Against 2 Salmonella Typhi Antigens Identify Patients With Typhoid Fever. Clin Infect Dis 2019; 68:949. 87. Kumar S, Nodoushani A, Khanam F, et al. Evaluation of a Rapid Point-of-Care Multiplex Immunochromatographic Assay for the Diagnosis of Enteric Fever. mSphere 2020; 5. https://www.uptodate.com/contents/2708/print

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Topic 2708 Version 31.0

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GRAPHICS

Infections in returning travelers by region of exposure, 1996 to 2011

This map indicates the number of cases of selected acute and potentially life-threatening diseases region reported among 82,825 travelers from resource-rich countries to various tropical regions between 1996 to 2011. Data are from the GeoSentinel surveillance network. Reproduced with permission of American Society of Tropical Medicine and Hygiene, Jensenius M, Han PV, Schlagenhauf P, et al. Acute and potentially life-threatening tropical diseases in western travelers--a GeoSentinel multicenter study, 1996-2011. Am J Trop Med Hyg 2013; 88:397. Copyright © 2013; permission conveyed through Copyright Clearance Center, Inc.

Graphic 90927 Version 3.0

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Rose spots of typhoid fever

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Rose spots are small (1 to 5 mm), erythematous, blanchable, nontender papules, which begin early during the acute febrile period of typhoid fever. Crops of lesions (10 to 20) appear at irregular intervals for approximately 10 to 14 days, typically distributed on the abdomen, chest, and back. Rarely, vesicular or hemorrhagic lesions appear. The lesions persist for two to three days. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Graphic 111261 Version 2.0

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Contributor Disclosures Jason Andrews, MD Grant/Research/Clinical Trial Support: NIH; Bill and Melinda Gates Foundation. All of the relevant financial relationships listed have been mitigated. Jacob John, MD No relevant financial relationship(s) with ineligible companies to disclose. Richelle C Charles, MD No relevant financial relationship(s) with ineligible companies to disclose. Stephen B Calderwood, MD Consultant/Advisory Boards: Day Zero Diagnostics [Whole genome sequencing for microbial identification and determination of antimicrobial susceptibility]. All of the relevant financial relationships listed have been mitigated. Elinor L Baron, MD, DTMH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Enteric (typhoid and paratyphoid) fever: Treatment and prevention Authors: Jason Andrews, MD, Jacob John, MD, Richelle C Charles, MD Section Editor: Stephen B Calderwood, MD Deputy Editor: Elinor L Baron, MD, DTMH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Apr 26, 2022.

INTRODUCTION Enteric fever is characterized by severe systemic illness with fever and abdominal pain [1]. The organism classically responsible for the enteric fever syndrome is Salmonella enterica serotype Typhi (formerly S. typhi). Other Salmonella serotypes, particularly S. enterica serotypes Paratyphi A, B, or C, can cause a similar syndrome; however, it is usually not clinically useful or possible to reliably predict the causative organism based on clinical findings [2]. The term "enteric fever" is a collective term that refers to both typhoid and paratyphoid fever, and "typhoid" and "enteric fever" are often used interchangeably. The treatment and prevention of enteric fever will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of enteric fever are discussed separately. (See "Pathogenesis of enteric (typhoid and paratyphoid) fever" and "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis".)

ANTIMICROBIAL RESISTANCE Treatment of enteric fever has been complicated by the development and rapid global spread of typhoidal organisms resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. Additionally, development of increasing resistance to fluoroquinolones is a growing challenge.

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Multidrug resistance — Multidrug-resistant (MDR) strains (ie, those resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) are prevalent worldwide, though they have been in decline as other antibiotics have been more widely used for treatment of enteric fever. MDR strains of S. Typhi and S. Paratyphi have caused numerous outbreaks in endemic regions, including South and Southeast Asia, China, and Africa [3-5]. Because of this, ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol fell out of favor as first-line agents for treatment of enteric fever. Prevalence of MDR strains varies, throughout Africa, the Middle East, and Central Asia, from 10 to 80 percent, depending on the country [6-9]. Genome sequencing and analysis of international isolates has identified a predominant MDR S. Typhi strain, H58, that has disseminated throughout Asia and Africa, displacing more susceptible strains and driving ongoing MDR epidemics [10]. As of 2018, approximately 75 percent of strains from Africa remain MDR, without significant change over the past 15 years [11]. However, some locations have reported a decrease in the prevalence of MDR strains. As an example, in a surveillance study from Kolkata, India conducted from 2009 to 2013, 18 percent of S. Typhi and no S. Paratyphi isolates were MDR [12]. A surveillance study of isolates collected across India between 2017 and 2020 demonstrated continued declining numbers, with 2 percent of S. Typhi and no S. Paratyphi A isolates that were MDR [13]. These patterns of resistance are reflected in travelers returning to nonendemic regions. In an analysis of over 1000 isolates submitted to the United States Centers for Disease Control and Prevention (CDC) between 2008 and 2012, most of which were from infections acquired in South Asia, 13 percent of S. Typhi and no S. Paratyphi isolates were MDR strains [14]. In a subsequent Surveillance of Enteric Fever in Asia Project study, a minority of strains from India, Nepal, and Bangladesh were MDR, while the majority of strains from Pakistan continued to show multidrug resistance [15]. Fluoroquinolone nonsusceptibility — Historically, resistance to the early generation quinolone nalidixic acid served as an important marker for decreased susceptibility to fluoroquinolones. However, because of the emergence of newer mechanisms of fluoroquinolone resistance, some isolates may appear to be sensitive to nalidixic acid but still have decreased sensitivity to clinically important fluoroquinolones, calling into question the reliability of using nalidixic acid resistance as a marker of fluoroquinolone resistance. As a result, both the Clinical and Laboratory Standards Institute (CLSI) in the United States and European Committee on Antimicrobial Susceptibility Testing (EUCAST) have specific fluoroquinolone breakpoints for Salmonella isolates [16-18]. https://www.uptodate.com/contents/2712/print

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In many parts of South Asia, over 80 percent of S. Typhi isolated among clinical cases are nonsusceptible to fluoroquinolones [15]. A randomized trial in Nepal comparing ceftriaxone with gatifloxacin, a fluoroquinolone that had proven highly successful in the country just several years prior, had to be terminated early due to high rates of treatment failure in the gatifloxacin arm, which was associated with fluoroquinolone nonsusceptibility. In contrast, fluoroquinolonenonsusceptibility appears less common in other parts of the world. In one multi-country study in Africa, fluoroquinolone nonsusceptibility was only documented in one (Kenya) [19] of six countries performing surveillance. More recently, fluoroquinolone resistant isolates have been reported in Nigeria [20]. Throughout Africa, rates of fluoroquinolone nonsusceptibility in typhoidal Salmonella remain low but are rising [11]. Increasing rates of full resistance to fluoroquinolones have also been reported; in some cases, these resistant isolates have been classified as a subclass of the MDR H58 typhoid strain that had widely disseminated throughout Asia and some African countries [21]. A compilation of studies showed rates of fully quinolone-resistant organisms ranged from 0 to 13 percent, with cases reported from India, Korea, and Nepal [22]. In a systematic review of studies from Nepal, the pooled rates of ciprofloxacin resistance increased in both S. Typhi and S. Paratyphi A, from 1.6 and 3.9 percent in 1998 to 2002 to 10.6 and 14.3 percent in 2008 to 2011 [23]. Cases of highlevel resistance to ciprofloxacin, often conferred by strains containing multiple mutations in the quinolone resistance-determining region (QRDR) have also been reported throughout South Asia in both S. Paratyphi and S. Typhi (MICs of 8 mcg/mL to 16 mcg/mL) [24-26]. Given the rapid global spread of prior drug-resistant Salmonella strains from South Asia, there is concern that these highly resistant strains will soon appear in other parts of the world. Resistance to other agents — Most S. Typhi and S. Paratyphi isolates remain susceptible to azithromycin and ceftriaxone, although resistant isolates have been reported. In particular, resistance to ceftriaxone is increasing, with reports of patients with extendedspectrum beta-lactamase-producing S. Typhi and S. Paratyphi infections [27-29]. (See 'Extensively drug-resistant typhoid' below.) Clearly defined MIC breakpoints for azithromycin susceptibility have not been established, but data suggest that S. Typhi isolates with an MIC ≤16 mcg/mL generally respond well to azithromycin (which is concentrated intracellularly at levels 50 to 100 times greater than serum levels) and can be considered susceptible [30]. A 15 mcg disk susceptibility zone size of ≥13 mm appears consistent with an azithromycin MIC ≤16 mcg/mL (99.7 percent sensitive). The first report of azithromycin resistance (MIC by E-test 64 mcg/mL) in S. Paratyphi A resulting in treatment failure was reported in a traveler returning from Pakistan to Great Britain [31]. The patient was successfully treated with a two-week course of intravenous ceftriaxone, 2 g daily. A https://www.uptodate.com/contents/2712/print

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growing number of azithromycin-resistant S. Typhi and S. Paratyphi A isolates have also been reported from South Asia, although this phenotype has not been seen in ceftriaxone-resistant organisms [32-34]. It appears to be mediated by R717Q/L mutations in the acrB gene [35]. Extensively drug-resistant typhoid — A large outbreak of typhoid fever caused by a strain resistant to chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, fluoroquinolones, and third-generation cephalosporins started in Pakistan in 2016 [36,37]. By the end of 2018, over 5000 cases of this extensively drug-resistant (XDR) S. Typhi strain were reported, with imported cases in the United Kingdom and the United States [38-40]. An unrelated cluster of ceftriaxoneresistant S. Typhi infections has also been linked to travel to Iraq [41]. In 2020, several XDR typhoid cases in individuals without international travel were reported in the United States, suggesting local transmission [42]. The strain remains susceptible to azithromycin and carbapenems, which are the main treatment options for this strain. (See 'Empiric therapy' below.)

ANTIMICROBIAL THERAPY Enteric fever is usually treated with a single antibacterial drug. Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources. The optimal choice of drug and duration of therapy are uncertain [43-45]. The main options are fluoroquinolones, third-generation cephalosporins, and azithromycin. Carbapenems are reserved for suspected infection with extensively drug-resistant (XDR) strains. In some circumstances, older agents such as chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole may be appropriate, but these drugs are generally not used widely because of the prevalence of resistance. Oral chloramphenicol is no longer available in the United States but is still used in other parts of the world. Empiric therapy — When treating presumptively for enteric fever or before results of susceptibility testing are available, appropriate options for empiric therapy depend, in part, on the severity of disease and the risk of infection with an antibiotic-resistant isolate. Severe or complicated disease — For patients who have severe disease (eg, systemic toxicity, depressed consciousness, prolonged fever, organ system dysfunction, or other feature that prompts hospitalization), initial therapy with a parenteral agent is appropriate. The geographic region where infection was likely acquired helps inform the choice of parenteral agent because of the risk of resistance in certain locations:

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Infection acquired outside Pakistan or Iraq – For most patients with severe or complicated enteric fever without recent travel to Pakistan or Iraq, we suggest empiric therapy with ceftriaxone. If ceftriaxone is not available, cefotaxime is a reasonable alternative. Although some studies have demonstrated slower time to defervescence with cephalosporins (compared with fluoroquinolones), resistance to the third-generation cephalosporins is uncommon in most locations, and so ceftriaxone is likely to be an effective empiric agent in individuals without a history of travel to Pakistan or Iraq [3]. However, if there is suspicion for ceftriaxone resistance, a carbapenem can be used while awaiting susceptibility testing [42] (see 'Extensively drug-resistant typhoid' above). Aztreonam has been effective in small trials and can be used for individuals who cannot take cephalosporins because of allergy [46,47]. In situations where the risk of decreased susceptibility to fluoroquinolones is low (eg, disease not acquired from South Asia or Iraq), a parenteral fluoroquinolone is also an appropriate alternative.

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Infection acquired in Pakistan or Iraq – For patients with severe or complicated enteric fever acquired in Pakistan or Iraq (eg, following recent travel to those countries), we suggest empiric therapy with a carbapenem (eg, meropenem). This is because of the presence of XDR S. Typhi in these regions. (See 'Extensively drug-resistant typhoid' above.)

Antibiotic doses and durations are listed in the table (

table 1). Once symptoms improve, the

patient can be transitioned to an oral agent, selected based on results of susceptibility testing, if available. Oral options and data evaluating the efficacy of antibiotic options for enteric fever are discussed elsewhere. (See 'Directed therapy' below.) Adjunctive corticosteroid is an additional consideration for patients with severe enteric fever. (See 'Adjunctive corticosteroids for severe infection' below.) Uncomplicated disease — Patients with uncomplicated disease have no evidence of systemic toxicity and can tolerate oral therapy. Appropriate options for empiric therapy in such patients depend on the risk of infection with an antibiotic-resistant isolate, which differs based on the geographical area where infection was acquired. (See 'Fluoroquinolone nonsusceptibility' above.) ●

Fluoroquinolones (ciprofloxacin or ofloxacin) are the drugs of choice for empiric therapy when infection is expected to be fluoroquinolone susceptible. This includes infection acquired in most areas of sub-Saharan Africa (except for Kenya and Nigeria). However, since fluoroquinolone resistance has emerged quickly in some areas, susceptibility testing and continued surveillance of local resistance rates is recommended to guide empiric treatment. Although fluoroquinolones are not recommended for routine use in children in

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the United States because of arthropathy and cartilage toxicity in exposed immature animals [48,49], clinical studies have not demonstrated sustained injury to developing bones or joints in children treated with available fluoroquinolones [50,51]. Thus, fluoroquinolone use in children is acceptable for severe infection, such as enteric fever, when alternatives are not available or appropriate. ●

In contrast, for empiric oral therapy of patients with infections acquired in South Asia or other areas with a high risk of reduced susceptibility to fluoroquinolones (eg, nalidixic acid resistance), we suggest azithromycin, which achieves excellent intracellular concentrations and has established efficacy. Azithromycin is also expected to have activity against XDR isolates acquired in Pakistan. Increasing numbers of azithromycin-resistant S. Typhi have been reported from South Asia, particularly Bangladesh, so susceptibility testing should be performed. (See 'Fluoroquinolone nonsusceptibility' above and 'Extensively drugresistant typhoid' above.)

Infection with an isolate with reduced susceptibility to fluoroquinolones is associated with longer time to defervescence and higher rates of treatment failure with ciprofloxacin, ofloxacin, and gatifloxacin [43,52-55]. Over a period of 10 years, fluoroquinolone effectiveness markedly declined in this setting as resistance emerged; at the same time, azithromycin remained effective and minimum inhibitory concentrations (MICs) were low and declining [56]. Resistance to azithromycin remains rare. However, azithromycin may be costly or unavailable in certain parts of the world, and parenteral therapy may not be necessary for many uncomplicated infections. In such cases, cefixime is another alternative, but it has some drawbacks (see 'Fluoroquinolonenonsusceptible infection' below). If multidrug resistance is not prevalent, trimethoprimsulfamethoxazole, amoxicillin, and chloramphenicol (if available) are potential options (see 'Multidrug resistance' above). In resource-limited settings, options may be further constrained by cost and availability. Antibiotic doses and durations are listed in the table (

table 1). If susceptibility testing

demonstrates that an empirically chosen agent is active and the patient has improved, that agent can be continued as directed therapy. Data evaluating the efficacy of antibiotic options for enteric fever are discussed elsewhere. (See 'Directed therapy' below.) Directed therapy — Ideally, definitive antimicrobial therapy for enteric fever should be based on results of susceptibility testing. S. Typhi and S. Paratyphi isolates should be directly tested for ciprofloxacin or ofloxacin sensitivity utilizing the breakpoints as described above [16,57,58]. However, such testing may be technically challenging, especially in resource-limited settings. https://www.uptodate.com/contents/2712/print

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Moreover, the diagnosis of enteric fever is often presumptive, without isolation of an organism. In cases in which susceptibility testing cannot be performed, options depend on the likelihood of antimicrobial resistance (see 'Empiric therapy' above). Infectious disease consultation is warranted for such cases if clinicians are not familiar with enteric fever and its treatment. There are no trials demonstrating that combination antimicrobial therapy is superior to monotherapy for enteric fever. In a study of 37 individuals with nalidixic acid-resistant S. Paratyphi A bacteremia who were identified as part of an outbreak among Israeli travelers returning from Nepal, all patients improved without complications, but time to defervescence was shorter among those who were treated with ceftriaxone and azithromycin compared with ceftriaxone alone [59]. Given the small size and observational nature of the study and the finding that all patients were infected by a single strain, additional study is needed to determine if there is any benefit of using two drugs over one. Further study evaluating combination treatment with azithromycin and cefixime versus azithromycin alone is ongoing [60].   Fluoroquinolone-susceptible infection — Fluoroquinolones are considered by many experts to be the drug of choice for susceptible isolates. Of the fluoroquinolones, ciprofloxacin and ofloxacin are widely available and effective. Norfloxacin is very poorly absorbed and should not be used. If a fluoroquinolone cannot be used, alternatives include azithromycin and thirdgeneration cephalosporins. (See 'Fluoroquinolone-nonsusceptible infection' below.) Fluoroquinolones are bactericidal, are concentrated intracellularly and in the bile, and result in rapid elimination of intracellular bacteria. They are more effective than beta-lactams against susceptible organisms. As an example, in an open-label randomized trial among patients older than 15 years, ofloxacin (200 mg orally twice daily for five days) resulted in higher cure rates compared with ceftriaxone (3 g intravenously once daily for three days) [61]. In a separate open-label randomized trial of 82 children, resolution of fever occurred more rapidly (4.4 versus 8.5 days) with ofloxacin (10 mg/kg per day divided twice daily for five days) compared with cefixime (20 mg/kg per day divided twice daily for seven days) [62]. There was one treatment failure in the ofloxacin group compared with 10 treatment failures and one relapse in the cefixime group. Although fluoroquinolones are not recommended for routine use in children in the United States because of arthropathy and cartilage toxicity in exposed immature animals [48,49], clinical studies have not demonstrated sustained injury to developing bones or joints in children treated with available fluoroquinolones [50,51]. Thus, fluoroquinolone use in children is acceptable for a severe infection, such as enteric fever, when alternatives are not available or appropriate. https://www.uptodate.com/contents/2712/print

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Fluoroquinolone-nonsusceptible infection — Fluoroquinolone nonsusceptible infections include those with reduced susceptibility to the fluoroquinolones (ie, nalidixic acid-resistant) and those with frank resistance. In infections with reduced fluoroquinolone susceptibility, treatment with ciprofloxacin or ofloxacin is associated with longer time to defervescence and higher rates of clinical treatment failure [43,63], and so should be avoided. When fluoroquinolones cannot be used, we typically use azithromycin. If azithromycin cannot be used because of cost, availability, or other reasons, other options include third-generation cephalosporins and, if susceptibility is demonstrated, trimethoprim-sulfamethoxazole, amoxicillin, or chloramphenicol. ●

Azithromycin – Azithromycin has good efficacy for enteric fever. In a systematic review that included seven randomized trials of adults and children with enteric fever, azithromycin was at least as effective as comparators (fluoroquinolones, chloramphenicol, ceftriaxone) with regards to clinical failure, time to defervescence, and relapse [64]. For fluoroquinolone-nonsusceptible infection, azithromycin appears superior to ofloxacin. As an example, in an open-label, randomized study among Vietnamese adults and children with uncomplicated typhoid fever due to nalidixic acid-resistant or multidrug-resistant isolates, azithromycin (1 g daily for five days) resulted in a trend towards greater clinical cure rates (82 versus 64 percent), faster time to defervescence (mean 5.8 versus 8.2 days) and lower rates of post-treatment fecal carriage (1.6 versus 19 percent) [65]. Early convalescent fecal shedding may spread the organism in a community even if few of these individuals become chronic carriers.

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Cephalosporins – Third-generation cephalosporins also have demonstrated efficacy but require a longer duration of therapy. Although the optimal duration has not been established, at least 10 to 14 days are warranted because of the risk of relapse with shorter durations [46,66-68]. In two randomized trials, seven days of ceftriaxone (50 to 75 mg/kg per day) resulted in relapse within four weeks in 14 percent of children [66,67]. In one of these studies, children were assigned to seven days of therapy with either azithromycin (10 mg/kg per day; maximum 500 mg) or ceftriaxone (75 mg/kg per day; maximum 2.5 g per day) [66]. There were four relapses with ceftriaxone compared with none with azithromycin (14 versus 0 percent). Among the third-generation cephalosporins, ceftriaxone may be superior to cefotaxime [69]. Oral cefixime has not been extensively compared directly with ceftriaxone, but appears to be of generally comparable efficacy [46,68]. Cefixime for 14 days was comparable to azithromycin given for 7 days (93 versus 87 percent cure) in a study of children with uncomplicated enteric fever in Bangladesh [70]. However, other studies have

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reported a slower time to defervescence and a relatively high rate of on-treatment failure with cefixime compared with other agents [62,71]. Although gatifloxacin had previously been proposed as an option for isolates with reduced susceptibility to fluoroquinolones (ie, nalidixic acid-resistant isolates) because it appeared to retain relatively good activity against them [72-74], the emergence of frankly fluoroquinoloneresistant isolates has limited its utility. Moreover, it is not widely available, having been withdrawn from most countries because of associated dysglycemia. The rise and fall of gatifloxacin as an effective therapy for typhoid has been demonstrated in several trials from Nepal. In an analysis of four trials conducted between 2005 and 2014, gatifloxacin had equivalent or better fever clearance times in the first three trials when compared with cefixime, chloramphenicol, and ofloxacin [56]. However, during the course of the trials, MICs to fluoroquinolones steadily rose, and these higher MICs were associated with slower time to defervescence with gatifloxacin. In the fourth randomized trial, which was conducted from 2011 to 2014 and included children and adults with documented or suspected enteric fever, treatment failure was similar with gatifloxacin versus ceftriaxone, each given for seven days (15 and 16 percent, respectively) [55]. However, among those with culture-confirmed S. Typhi infection, 25 percent had fluoroquinolone-resistant isolates, and failure was greater with gatifloxacin (26 versus 7 percent). The trial was stopped early because of the high rates of fluoroquinolone resistance identified. Fluoroquinolones are therefore no longer considered appropriate empiric therapy for enteric fever in this region.

OTHER TREATMENT CONSIDERATIONS Adjunctive corticosteroids for severe infection — For patients with suspected or known enteric fever and severe systemic illness (delirium, obtundation, stupor, coma, or shock), we suggest adjunctive dexamethasone (3 mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours). In a randomized, prospective, double-blind study performed in Indonesia in the early 1980s among 38 adults and children with severe enteric fever (shock or obtundation), the addition of high-dose dexamethasone to chloramphenicol treatment reduced mortality compared with chloramphenicol alone (10 versus 55 percent) [75]. Adjunctive corticosteroids did not increase the rate of other complications, carriage, or relapse. Subsequent observational studies have also supported the benefit [76,77], but whether the adjunctive dexamethasone is beneficial with other antibiotics or in different clinical settings remains uncertain.

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Ileal perforation — For patients with ileal perforation, prompt surgical intervention is usually indicated, as is broader antimicrobial coverage to cover peritonitis and potential secondary bacteremia with enteric organisms (see "Antimicrobial approach to intra-abdominal infections in adults"). The extent of surgical intervention remains controversial; the best surgical procedure appears to be segmental resection of the involved intestine, when possible [78,79]. In a retrospective review from West Africa including 112 patients undergoing laparotomy for typhoid perforation, most of the perforations were single (77 percent) and in the terminal ileum [80]. Primary repair was successful in 84 percent of cases, although reoperative management was required in some patients who did not respond immediately. Even with surgery, mortality rates of 14, 16, and 34 percent have been reported in series from Nigeria, Togo, and the Ivory Coast, respectively [80-82].

FOLLOW-UP Successful treatment in uncomplicated cases usually results in clinical improvement within three to five days. In most clinical trials, the mean time to defervescence is four to six days, so persistent fevers of this duration following treatment initiation does not imply therapeutic failure. Patients should be subsequently monitored for or instructed to report recurrent symptoms, which could reflect relapse. Relapse — Relapse of enteric fever after clinical cure can occur in immunocompetent individuals; in such cases, it typically occurs two to three weeks after resolution of fever. The risk of relapse depends on the antibiotic used to treat the initial infection. Relapse rates with chloramphenicol, a bacteriostatic agent, were 10 to 25 percent, but subsequent studies that have included multidrug-resistant S. Typhi infections and newer antibiotics have noted lower relapse rates of 1 to 6 percent [46,62,73]. Relapsed infection should be treated with an additional course of antibiotics, guided by susceptibility testing. Usually, the isolate has the same susceptibility pattern as the initial infection. A longer treatment course with a third-generation cephalosporin is also reasonable. Chronic carriage — Chronic carriage of Salmonellae is defined as excretion of the organism in stool for more than 12 months after the acute infection. Post-illness screening for S. Typhi carriage is not routinely performed. Chronic carriage is typically identified through public health mandated screening of food handlers or health care personnel following enteric fever or during an investigation of an outbreak or case in nonendemic areas.

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Chronic carriage rates after S. Typhi infection range from 1 to 6 percent [83]; rates are higher in patients with cholelithiasis or other biliary tract abnormalities [84]. Chronic Salmonella carriage occurs much more frequently with typhoidal strains than nontyphoidal strains. (See "Nontyphoidal Salmonella: Gastrointestinal infection and carriage".) Although chronic carriers are asymptomatic, they represent an infectious risk to others, particularly if involved in food preparation. For this reason, eradication of carriage is usually attempted once such individuals are identified. Chronic carriage may also be an independent risk factor for carcinoma of the gallbladder as well as other cancers [85], but the effect of eradication on this association is unknown. The optimal approach to eradication is uncertain. Fluoroquinolone therapy (eg, ciprofloxacin 500 to 750 mg orally twice daily or ofloxacin 400 mg orally twice daily) for four weeks is a reasonable approach. If eradication is not achieved but thought necessary from a public health perspective, an additional prolonged antibiotic course and cholecystectomy may be warranted. The fluoroquinolones are relatively effective for eradication of chronic carriage. In one study of 23 carriers, the cure rate with norfloxacin (400 mg orally twice daily for 28 days) was 86 percent in those with normal gallbladders and 75 percent in those with gallstones [86]. Several smaller studies, evaluating 10 to 12 patients each, have found that ciprofloxacin (500 or 750 mg orally twice daily) for 14 to 28 days eliminated carriage in 90 to 93 percent of cases [87]. The optimal approach to eradication of fluoroquinolone-nonsusceptible typhoidal Salmonella is not known. There has been some experience with high-dose amoxicillin (eg, 75 to 100 mg/kg per day for four to six weeks) and trimethoprim-sulfamethoxazole with or without rifampin, but the evidence base for these regimens is limited [88-92].

PROGNOSIS Effective antibiotic therapy has dramatically impacted the outcomes of enteric fever. In the preantibiotic era, mortality rates were 15 percent or greater [93,94] and survivors experienced a prolonged illness lasting weeks, with months of subsequent debilitation. Approximately 10 percent of untreated patients relapsed and up to 4 percent become chronic carriers of the organism. Among those receiving medical care in the post-antibiotic era, the average mortality rate from enteric fever is estimated to be less than 1 percent [1]. Although a 2018 systematic review reported a higher case-fatality rate, it was likely an overestimate of contemporary mortality rates, as high rates were seen primarily in older or smaller studies [95]. Mortality rates from https://www.uptodate.com/contents/2712/print

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more recent studies are low. As an example, in a study of nearly 3000 individuals receiving care for culture-confirmed enteric fever in Pakistan from 2012 to 2014, there were no deaths reported [96]. In the United States, a Centers for Disease Control and Prevention compilation of 10 hospital-based typhoid fever series reported a mean case-fatality rate of 2 percent (range 0 to 14.8 percent), but noted that these series capture only the most severe and hospitalized cases in those with access to care [97].

PREVENTION Food and water safety — Enteric fever results from the ingestion of contaminated food or water. The inoculum in food is likely higher than that in contaminated water. Access to fresh water, prioritization of sanitation and hygiene, and education about food and water safety are essential preventive strategies. For travelers, the main mechanism of transmission is ingestion of the local cuisine or water in areas where sanitation and personal hygiene may be poor. Travelers should be advised on behavioral precautions. (See "Travel advice", section on 'Food and water'.) Vaccination In endemic areas — The World Health Organization (WHO) recommends implementation of national typhoid vaccination programs as part of broader control efforts in settings where typhoid is endemic. Of available vaccines, it prefers typhoid conjugate vaccines for their efficacy and established safety in infants and young children, as well as their greater and more durable immunogenicity compared with other vaccines [98]. It recommends administration of typhoid conjugate vaccine for infants and children six months of age or older, with catch-up vaccination campaigns, if possible, for children up to 15 years old. (See 'Licensed vaccines' below.) In nonendemic areas — Typhoid vaccination is indicated in travelers to endemic areas and other individuals with risk for exposure, but available vaccines are not entirely protective. Specific indications and vaccine options vary by country. In the United States, typhoid vaccination is recommended for travelers (even short-term travelers) to areas where there is risk of exposure to S. Typhi, for individuals with intimate exposure to a documented S. Typhi chronic carrier (eg, household contacts), and for individuals whose work exposes them to cultures or specimens containing S. Typhi (eg, laboratory workers) [99]. Typhoid conjugate vaccine is not yet available in the United States. Either the polysaccharide or oral vaccine formulation is appropriate, although the oral vaccine should be avoided in immunocompromised and pregnant individuals since it is a live vaccine. If repeated https://www.uptodate.com/contents/2712/print

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exposure to S. Typhi is expected, repeat typhoid vaccination is advised to maintain immunity. (See "Immunizations for travel", section on 'Typhoid vaccine'.) Vaccination is appropriate even in those who have a history of enteric fever, particularly in those not living in endemic areas, if re-exposure is expected. Natural infection does not provide complete protection against recurrent illness (which is not the same as relapsed infection). One study suggests early treatment of natural infection may blunt humoral responses to capsular antigens [100]. The optimal timing for vaccination following clinical illness is not known. Licensed vaccines — Several typhoid vaccines have been licensed, although they are not all universally available. None are completely effective against S. Typhi and none have been demonstrated to provide protection against paratyphoid fever caused by S. Paratyphi A. ●

Vi typhoid conjugate vaccines (TCV) – These vaccines consist of the Vi polysaccharide antigen linked to various carrier proteins. Typbar-TCV, a Vi-TT (tetanus toxoid) conjugate, is the representative vaccine of this type; it is administered as a single intramuscular dose. The need for revaccination for continued protection is uncertain. It is licensed in India, Nepal, and several other countries, but it is not yet available in Europe or the United States. A second typhoid conjugate vaccine (Typhibev), containing Vi conjugated to CRM197, a nontoxic mutant of diphtheria toxin, was prequalified in December 2020. This vaccine demonstrated safety and noninferior immunogenicity in clinical trials [101] but has not yet been evaluated for clinical efficacy. A Vi-DT (diphtheria toxin) vaccine was found to have noninferior immunogenicity in a Phase 3 trial in Nepal [102]. Two other ViTT conjugate typhoid vaccines (PedaTyph and ZyVac-TCV) are available in India [103]. Emerging evidence suggests good efficacy of TCVs. In several randomized trials from Nepal, Bangladesh, and Malawi, which together included over 100,000 children, vaccine efficacy of Typbar-TCV against culture-confirmed typhoid fever ranged from 81 to 85 percent compared with control vaccines [104-106]. As an example, in the trial from Nepal, among over 20,000 children aged 9 months to 16 years, the incidence of typhoid fever over the year following Typbar-TCV vaccination was 79 cases compared with 428 cases per 100,000 person-years after meningococcal conjugate vaccination (vaccine efficacy 82 percent, 95% CI 59-92) [104]. Typbar-TCV was 97 percent (95% CI 95-98) effective against extensively drug-resistant (XDR) S. Typhi [107]. No major vaccine-associated adverse events were identified in any of the trials. Conjugate vaccines appear to be more immunogenic and better at inducing long-term memory responses compared with other typhoid vaccines [108-110]. In a randomized trial of individuals aged 2 to 45 years in India, the conjugate vaccine (Typbar-TCV) resulted in

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higher seroconversion rates and higher antibody titers after three to five years than the polysaccharide vaccine, especially in young children [109]. It was also safe and immunogenic in a parallel open-label trial of children aged 6 to 23 months, with anti-Vi IgG antibodies persisting up to five years in approximately 85 percent. ●

Vi polysaccharide vaccine – This consists of the Vi polysaccharide antigen. It is administered as a single intramuscular dose. It can also be given subcutaneously. If continued protection is needed, revaccination is recommended every two to three years. In a systematic review and meta-analysis of randomized controlled trials, efficacy at one, two, and three years was 69, 59, and 55 percent [111].

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Ty21a vaccine – This is a live oral vaccine that consists of an attenuated S. Typhi strain Ty21a. It is administered in three to four doses taken on alternate days. If continued protection is needed, revaccination is recommended every three to five years. In a systematic review and meta-analysis of randomized controlled trials, efficacy at one, two, and three years was 45, 59, and 56 percent [111]. There is some evidence that the Ty21a vaccine may confer partial protection against S. Paratyphi B [112]. Adverse effects associated with these vaccines are generally mild (eg, fever or injection site pain or swelling) [104,109,112].

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in adults" and "Society guideline links: Acute diarrhea in children" and "Society guideline links: Travel medicine".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading https://www.uptodate.com/contents/2712/print

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level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Enteric (typhoid and paratyphoid) fever (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Treatment of enteric fever has been complicated by the development of antimicrobial resistance. In particular, resistance to clinically important fluoroquinolones has become a major problem worldwide, particularly in Asia. Most Salmonella Typhi and Salmonella Paratyphi isolates remain susceptible to azithromycin and third-generation cephalosporins. However, an extensively drug-resistant (XDR) isolate has emerged in Pakistan that is resistant to many agents, including third-generation cephalosporins and fluoroquinolones. (See 'Antimicrobial resistance' above.)

●

Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources (

table 1). (See

'Antimicrobial therapy' above.)

• Patients with severe disease (systemic toxicity, depressed consciousness, prolonged fever, organ system dysfunction, or other feature that prompts hospitalization) should be treated initially with a parenteral antibiotic. For such patients, who have acquired infection outside of Pakistan or Iraq, we suggest ceftriaxone (Grade 2B). Cefotaxime or, if the risk of decreased susceptibility to fluoroquinolones is low (eg, disease not acquired from South Asia or Iraq), a parenteral fluoroquinolone is an alternative. If there is suspicion for ceftriaxone resistance, a carbapenem can be used while awaiting susceptibility testing. For patients with severe typhoid fever acquired in Pakistan or Iraq, we suggest empiric therapy with a carbapenem (eg, meropenem) because of the risk of ceftriaxone-resistant and XDR typhoid (Grade 2C).

• For patients with uncomplicated enteric fever, antibiotic selection depends on the likelihood of reduced susceptibility to fluoroquinolones, which is highest in infections acquired in South Asia. In the absence of known or suspected reduced fluoroquinolone susceptibility, we suggest antibiotic therapy with ciprofloxacin (Grade 2B). For patients with uncomplicated enteric fever due to an isolate known or suspected to have https://www.uptodate.com/contents/2712/print

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reduced fluoroquinolone susceptibility (including patients with infection acquired in Pakistan), we suggest azithromycin (Grade 2B). Ceftriaxone is an alternative (except for patients with infection acquired in Pakistan or Iraq). With increasing reports of azithromycin-resistant S. Typhi from South Asia, susceptibility testing should be performed.

• Empiric antibiotic regimens can be adjusted if and when formal sensitivities are available. ●

For patients with suspected or known enteric fever and severe systemic illness (delirium, obtundation, stupor, coma, or shock), we suggest adjunctive dexamethasone (3 mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours) (Grade 2B). (See 'Adjunctive corticosteroids for severe infection' above.)

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Treatment of ileal perforation warrants surgical therapy in addition to antibiotic therapy to cover both enteric fever and enteric organisms. (See 'Ileal perforation' above.)

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Successful treatment in uncomplicated cases usually results in clinical improvement within three to five days, with fever clearance at four to six days. Relapse of enteric fever after clinical cure can occur two to three weeks after resolution of illness and should be treated with an additional course of antibiotics, guided by susceptibility testing. (See 'Relapse' above.)

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Chronic Salmonella carriage is defined as excretion of the organism in stool >12 months after acute infection. Chronic carriers represent an infectious risk to others, particularly in the setting of food preparation. We suggest treatment of chronic carriers with four weeks of fluoroquinolone therapy for eradication of carriage if isolates are fluoroquinolone susceptible (Grade 2C). (See 'Chronic carriage' above.)

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Enteric fever results from the ingestion of contaminated food or water; attention to food safety is important for travelers to regions where sanitation and personal hygiene may be poor. Three vaccines are available globally for protection against S. Typhi: parenteral Vi polysaccharide vaccine, live oral S. Typhi vaccine strain Ty21a, and parenteral Vi conjugate vaccine. None of these vaccines offer complete protection, and periodic revaccination is needed if exposure risk continues. In endemic areas, the World Health Organization (WHO) recommends implementation of national typhoid vaccination programs, preferably with a conjugate typhoid vaccine, as part of broader control efforts. The conjugate vaccine is not available in the United States

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or Europe. (See 'Prevention' above and "Immunizations for travel", section on 'Typhoid vaccine'.)

ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Elizabeth L. Hohmann, MD, and Edward T Ryan, MD, DTMH, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES

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92. Freerksen E, Rosenfeld M, Freerksen R, Krüger-Thiemer M. Treatment of chronic salmonella carriers. Study with 40 cases of S. typhi, 19 cases of S. paratyphi b and 28 cases of S. enteritidis strains. Chemotherapy 1977; 23:192. 93. STUART BM, PULLEN RL. Typhoid; clinical analysis of 360 cases. Arch Intern Med (Chic) 1946; 78:629. 94. WOODWARD TE, SMADEL JE. Preliminary report on the beneficial effect of chloromycetin in the treatment of typhoid fever. Ann Intern Med 1948; 29:131. 95. Pieters Z, Saad NJ, Antillón M, et al. Case Fatality Rate of Enteric Fever in Endemic Countries: A Systematic Review and Meta-analysis. Clin Infect Dis 2018; 67:628. 96. Qamar FN, Yousafzai MT, Sultana S, et al. A Retrospective Study of Laboratory-Based Enteric Fever Surveillance, Pakistan, 2012-2014. J Infect Dis 2018; 218:S201. 97. Crump JA, Ram PK, Gupta SK, et al. Part I. Analysis of data gaps pertaining to Salmonella enterica serotype Typhi infections in low and medium human development index countries, 1984-2005. Epidemiol Infect 2008; 136:436. 98. World Health Organization. Typhoid vaccines: WHO position paper. March 2018. http://app s.who.int/iris/bitstream/handle/10665/272272/WER9313.pdf (Accessed on April 04, 2018). 99. Jackson BR, Iqbal S, Mahon B, Centers for Disease Control and Prevention (CDC). Updated recommendations for the use of typhoid vaccine--Advisory Committee on Immunization Practices, United States, 2015. MMWR Morb Mortal Wkly Rep 2015; 64:305. 100. House D, Ho VA, Diep TS, et al. Antibodies to the Vi capsule of Salmonella Typhi in the serum of typhoid patients and healthy control subjects from a typhoid endemic region. J Infect Dev Ctries 2008; 2:308. 101. Thuluva S, Paradkar V, Matur R, et al. A multicenter, single-blind, randomized, phase-2/3 study to evaluate immunogenicity and safety of a single intramuscular dose of biological E's Vi-capsular polysaccharide-CRM197 conjugate typhoid vaccine (TyphiBEVTM) in healthy infants, children, and adults in comparison with a licensed comparator. Hum Vaccin Immunother 2022; :1. 102. Kumar Rai G, Saluja T, Chaudhary S, et al. Safety and immunogenicity of the Vi-DT typhoid conjugate vaccine in healthy volunteers in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial. Lancet Infect Dis 2022; 22:529. 103. Syed KA, Saluja T, Cho H, et al. Review on the Recent Advances on Typhoid Vaccine Development and Challenges Ahead. Clin Infect Dis 2020; 71:S141. 104. Shakya M, Colin-Jones R, Theiss-Nyland K, et al. Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal. N Engl J Med 2019; 381:2209. https://www.uptodate.com/contents/2712/print

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105. Patel PD, Patel P, Liang Y, et al. Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children. N Engl J Med 2021; 385:1104. 106. Qadri F, Khanam F, Liu X, et al. Protection by vaccination of children against typhoid fever with a Vi-tetanus toxoid conjugate vaccine in urban Bangladesh: a cluster-randomised trial. Lancet 2021; 398:675. 107. Yousafzai MT, Karim S, Qureshi S, et al. Effectiveness of typhoid conjugate vaccine against culture-confirmed Salmonella enterica serotype Typhi in an extensively drug-resistant outbreak setting of Hyderabad, Pakistan: a cohort study. Lancet Glob Health 2021; 9:e1154. 108. Jin C, Gibani MM, Moore M, et al. Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial. Lancet 2017; 390:2472. 109. Mohan VK, Varanasi V, Singh A, et al. Safety and immunogenicity of a Vi polysaccharidetetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: a multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis 2015; 61:393. 110. Voysey M, Pollard AJ. Seroefficacy of Vi Polysaccharide-Tetanus Toxoid Typhoid Conjugate Vaccine (Typbar TCV). Clin Infect Dis 2018; 67:18. 111. Milligan R, Paul M, Richardson M, Neuberger A. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev 2018; 5:CD001261. 112. Levine MM, Ferreccio C, Black RE, et al. Ty21a live oral typhoid vaccine and prevention of paratyphoid fever caused by Salmonella enterica Serovar Paratyphi B. Clin Infect Dis 2007; 45 Suppl 1:S24. Topic 2712 Version 45.0

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GRAPHICS

Antibiotic options and doses for treatment of typhoid fever   Ciprofloxacin

Adults Oral: 500 mg twice daily

Children Oral: 30 mg/kg per day in two divided doses (maximum 1000 mg

Duration 7 to 10 days

per day)* IV: 400 mg twice daily

IV: 20 mg/kg per day in two divided doses (maximum 800 mg per day)*

Ofloxacin¶

400 mg orally or IV twice daily

15 to 30 mg/kg per day orally in two divided

7 to 10 days

doses (maximum 800 mg per day)*¶ based upon limited experience; optimal pediatric dose is not known Ceftriaxone

2 g IV once or twice

50 to 100 mg/kg IV in

daily

one or two divided doses (maximum 4 g

10 to 14 days

per day) Cefotaxime

1 to 2 g IV every six or eight hours

150 to 200 mg/kg IV per day in three to four divided doses

10 to 14 days

(maximum 8 g per day) Cefixime

200 mg orally twice daily

20 mg/kg orally in two divided doses (maximum 400 mg per

10 to 14 days

day) Azithromycin

1 g orally once then 500 mg orally daily OR 1 g orally once daily

10 to 20 mg/kg orally once per day (maximum 1000 mg

5 to 7 days 

per day)  MeropenemΔ

1 to 2 g IV every eight hours

20 to 40 mg/kg every eight hours (maximum

10 to 14 days

6000 mg per day)

Agents of limited usefulness due to the high prevalence of multidrug resistance https://www.uptodate.com/contents/2712/print

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Chloramphenicol◊

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Oral: 500 to 750 mg four times per day

50 to 100 mg/kg per day orally or IV in four

IV: 50 to 100 mg/kg per

divided doses (maximum 3 g per day)

day in four divided doses (maximum 3 g per day) Amoxicillin

1 g orally three times

100 mg/kg per day

daily

orally in three divided doses (maximum 3 g

14 to 21 days

10 to 14 days

per day) TMP-SMX

1 double-strength

8 mg/kg TMP and 40

tablet (160/800 mg) orally twice daily

mg/kg SMX orally in two or four divided

10 to 14 days

doses (maximum 320 mg TMP/1600 mg SMX per day) Antibiotic selection depends upon the severity of illness, local resistance patterns, whether oral medications are feasible, the clinical setting, and available resources. Refer to the topic on treatment of typhoid fever for detailed discussion. The doses listed above are intended for patients with normal renal function; the doses of some of these agents must be adjusted in patients with renal insufficiency. IV: intravenous; TMP-SMX: trimethoprim-sulfamethoxazole (co-trimoxazole). * Although fluoroquinolones are not routinely used as first-line therapy for children 101°F (38.3°C), duration >3 weeks, undiagnosed >1 week; 3: temp >101.3°F (38.5°C), duration >2 weeks, undiagnosed. ¶ Immunocompromised excluded. Δ Systemic review of 18 case series that were written in English and appeared between 2005 to 2015. ◊ Numbers represent percentages. § Includes collagen vascular disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, and vasculitis), and granulomatous diseases (eg, sarcoidosis). Data from: 1. Alt H, Barker H. Fever of unknown origin. JAMA 1930; 94:1457. 2. Petersdorf RG, Beeson RG. Fever of Unexplained Origin: Report on 100 Cases. Medicine (Baltimore) 1961; 40:1. 3. Vanderschueren S, Knockaert D, Adriaenssens T, et al. From Prolonged Febrile Illness to Fever of Unknown Origin: The Challenge Continues. Arch Intern Med 2003; 163:1033. 4. Miller RF, Hingorami AD, Foley NM. Pyrexia of Undetermined Origin in Patients With Human Immunodeficiency Virus Infection and AIDS. Int J STD AIDS 1996; 7:170. 5. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of Unknown Origin in Elderly Patients. J Am Geriatrics Soc 1993; 41:1187. https://www.uptodate.com/contents/2736/print

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6. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A Prospective Multicenter Study on Fever of Unknown Origin: The Yield of a Structured Diagnostic Protocol. Medicine (Baltimore) 2007; 86:26. 7. Fusco MF, Pisapia R, Nardiello S, et al. Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review. BMC Inf Dis 2019; 19:653.

Graphic 54701 Version 7.0

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Case studies of fever of unknown origin: prevalent diagnoses Case study Alt

Diagnosis

1913 to

Petersdorf

de Kleijn

1952 to 1959

1992 to 1994

n = 93

n = 117

1930 n = 23

Vanderschueren 1990 to 1999 n = 192

Miller

Knockaert

1989 to 1993

1980 to 1989

n = 72

n = 41

Location

Boston, United States

Seattle, United States

Netherlands

Belgium

London, United Kingdom

Belgium

Rheumatic fever

2

6

0

0

0

0

Abdominal abscess

1

4

4

5

0

5

Endocarditis

0

5

4

11

0

2

Syphilis

1

1

1

0

0

0

Mycobacterial

6

12

3

8

57

15

Lymphoma

2

8

11

14

7

5

Solid tumor

3

10

7

7

1

7

Sarcoid

0

2

2

10

0

2

Lupus

0

5

2

8

0

0

Rheumatoid arthritis

0

0

2

2

0

5

Giant cell arteritis

0

2

4

11

0

19

Drug fever

0

1

3

4

0

7

Factitious fever

0

3

2

1

3

0

Numbers represent number of cases. Alt H, et al. JAMA 1930; 94:1457. Petersdorf RG. Arch Intern Med 1992; 152:21. de Kleijn EM, et al. Medicine (Baltimore) 1997; 76:392. Vanderschueren S, et al. Arch Intern Med 2003; 163:1033. Miller RF, et al. Int J STD AIDS 1996; 7:170. Knockaert DC, et al. Clin Infect Dis 1994; 18:601.

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Graphic 66395 Version 5.0

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Less common diagnoses of fever of unknown origin Infections

Malignancies

Abscesses (especially intra-abdominal)

Aleukemic leukemia

African tick bite fever*

Atrial myxoma

Amebic liver abscess*

Colon cancer

Anaplasmosis/ehrichiosis*

Hepatocellular carcinoma or other tumors metastatic to the liver

Babesiosis* Brucellosis* Castleman's disease Chikungunya* Chronic active hepatitis Culture-negative endocarditis¶

Behçet's disease Cryoglobulinemia

Granulomatosis with polyangiitis (formerly Wegener's disease)

Lung cancer

Mesothelioma

Diskitis

Multiple myeloma

Filariasis*

Antiphospholipid syndrome

Leukemia

Dengue*

Fascioloiasis*

Allergic granulomatous angiitis

Giant cell arteritis

Dental abscesses

Epididymitis

inflammatory diseases

Kaposi's sarcoma

Lymphoma, especially nonHodgkin's

Cytomegalovirus

Systemic

Myelodysplastic syndromes

Gonococcal arthritis

Renal cell carcinoma

Herpes simplex encephalitis

Sarcoma

Granulomatous hepatitis Hypersensitivity vasculitis

Factitious fever Familial Mediterranean fever Inflammatory bowel disease Neuroleptic malignant syndrome Periodic fever

Retroperitoneal hematomas

Polyarteritis nodosa

Reactive arthritis (formerly Reiter's syndrome)

Lyme disease*

Environmental (metal and polymer fume fevers)

Panaortitis

Kala azar (visceral leishmaniasis)*

Leptospirosis*

Drug feverΔ

Pulmonary emboli

Polymyalgia rheumatica

Lassa fever*

Disorders of temperature regulation (neurologic and dermatologic)

Inflammatory bowel disease

Infectious mononeucleosis

Kikuchi's disease

Miscellaneous

Chronic fatigue syndrome Thyroiditis

Sarcoidosis Still's disease Systemic lupus erythematosis

Osteomyelitis https://www.uptodate.com/contents/2736/print

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Prostatitis Pyelonephritis

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Takayasu's arteritis

Pyometria Q fever* Relapsing fever (Borrelia recurrentis)* Rheumatic fever Sinusitis Toxoplasmosis Typhoid fever* Tuberculosis Whipple's disease Zika virus* More common causes are in bold type. * Travel and environmental exposure histories are especially relevant. ¶ Causes include Actinobacillus spp, Bartonella spp, Brucella spp, Cardiobacterium spp, Chlamydia spp, Coxiella burnetii, Eikenella spp, Haemophilus spp, Histoplasma capsulatum, Kingella spp, Legionella spp, Mycoplasma spp, Tropheryma whipplei, and marantic endocarditis. Δ Antimicrobials (especially sulfonamides and penicillins), antiepileptic, antithyroid, and nonsteroidal anti-inflammatory drugs. Graphic 62509 Version 7.0

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The percentage of patients with fever of unknown origin by cause during four decades

Adapted from: Mourad O, Palda V, Detsky AS. Arch Intern Med 2003; 163:545.

Graphic 73878 Version 3.0

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Contributor Disclosures David H Bor, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter F Weller, MD, MACP Consultant/Advisory Boards: Genzyme [Eosinophilia];GlaxoSmithKline [Eosinophilic diseases];Knopp Biosciences [Hypereosinophilic syndrome treatment]. Other Financial Interest: AstraZeneca [Hypereosinophilic syndrome]. All of the relevant financial relationships listed have been mitigated. Keri K Hall, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Etiologies of fever of unknown origin in adults Author: David H Bor, MD Section Editor: Peter F Weller, MD, MACP Deputy Editor: Keri K Hall, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Apr 13, 2022.

INTRODUCTION Clinicians commonly refer to a febrile illness without an initially obvious etiology or without localizing signs as fever of unknown origin (FUO). This usage is not accurate. Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. FUO refers to a prolonged febrile illness without an established etiology despite intensive evaluation and diagnostic testing. Large case series of FUO applying this definition have been collected over a number of decades; these facilitate an approach to patients with FUO and an understanding of the changing patterns of FUO with time and newer diagnostic techniques. The common and uncommon entities causing FUO in adults will be reviewed here. The definitions of this condition, an approach to the adult with FUO, and the etiology of FUO in children are discussed separately. (See "Approach to the adult with fever of unknown origin" and "Fever of unknown origin in children: Etiology".) Three general categories of illness account for the majority of "classic" FUO cases and have been consistent through the decades: ●

Infections

●

Connective tissue diseases (eg, vasculitis, systemic lupus erythematosus, polymyalgia rheumatica)

●

Malignancies

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COMMON CAUSES The most prevalent causes of FUO are infection, noninfectious inflammatory diseases, and malignancy [1-9]. Infections and malignancies as causes of FUOs have decreased over time, while inflammatory diseases and undiagnosed fevers have increased (

table 1A-B and

figure 1) [10]. Infections and noninfectious inflammatory diseases each account for 15 to 25 percent of FUOs, while malignancies cause less than 20 percent of these fevers. The rate of no diagnosis in studies published since 1990 has varied widely from 9 to 51 percent [3-8,11]. The prevalence of various febrile conditions also reflects geography, subpopulations under study, host and microbial factors, and hospital and health services. In one of the latest published series, 73 patients from the Netherlands seen between December 2003 and July 2005 were evaluated for FUO [8]. The following distribution of causes was noted: ●

Connective tissue diseases – 22 percent

●

Infection – 16 percent

●

Malignancy – 7 percent

●

Miscellaneous – 4 percent

●

No diagnosis – 51 percent

Most adults who remain undiagnosed after an extensive evaluation have a good prognosis [11]. (See "Approach to the adult with fever of unknown origin", section on 'Outcome'.) Infections — Among infections, tuberculosis and abscesses are the most common etiologies. Tuberculosis — Tuberculosis (TB) is the single most common infection in most FUO series. Presentations of TB, which escape early detection, are either extrapulmonary, miliary, or occur in the lungs of patients with significant preexisting pulmonary disease or immunodeficiency. As an example, pulmonary tuberculosis in patients with AIDS is often subtle, and the chest radiograph is normal in 15 to 30 percent of cases [12,13]. (See "Diagnosis of pulmonary tuberculosis in adults".) Disseminated (miliary) TB is readily treatable, while death can occur in patients who remain untreated. Thus, a vigorous search for this disorder should be pursued. The purified protein derivative skin test is positive in fewer than 50 percent of patients with TB who present with an FUO, usually due to cutaneous anergy [14]. The interferon-gamma release assay also has low sensitivity for the diagnosis of active TB [15]. Sputum samples are positive in https://www.uptodate.com/contents/2737/print

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only one-quarter of cases. Because of these difficulties, establishing the diagnosis often requires biopsy of affected nodes, bone marrow, or liver. Techniques for isolation of Mycobacterium tuberculosis from blood include isolator cultures and polymerase chain reaction (PCR) on BACTEC blood culture bottles with evidence of early growth [16,17]. Both of these methods have yielded positive results in approximately 16 days, although PCR may be more sensitive and specific [17]. Abscess — Occult abscesses are usually located in the abdomen or pelvis. Underlying conditions, which predispose to abscess formation, include cirrhosis, steroid or immunosuppressive medications, recent surgery, and diabetes. Abscesses arise when there has been disruption of a barrier such as the bowel wall in appendicitis, diverticulitis, or inflammatory bowel disease. The rupture often seals off spontaneously and local peritonitis is converted to an abscess by host defense mechanisms. Intraabdominal abscesses can develop in subphrenic, omental, pouch of Douglas, pelvic, and retroperitoneal locations in addition to visceral sites. The source of infection in these abscesses can vary with the site of abscess formation: ●

Pyogenic liver abscesses usually follow biliary tract disease or abdominal suppuration such as appendicitis or diverticulitis. Amebic liver abscesses cannot be distinguished on clinical grounds from pyogenic abscesses; amebic serology is positive in more than 95 percent of cases of extraintestinal disease.

●

Hematogenous seeding rather than contiguous spread accounts for the majority of splenic abscesses, which are often missed prior to autopsy; endocarditis is the most common infection currently associated with splenic abscess.

●

Perinephric or renal abscesses usually arise from existing infection in the urinary tract, although urine cultures may be negative or only intermittently positive. (See "Renal and perinephric abscess".)

Osteomyelitis — Osteomyelitis should be considered as a cause of FUO since localized symptoms in some sites may not be prominent. Examples include vertebral osteomyelitis and osteomyelitis of the mandible. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".) Bacterial endocarditis — Cultures are negative in 2 to 5 percent of patients with infective endocarditis even when the utmost care is taken in obtaining the proper number and volume of blood cultures. The frequency of negative cultures is higher in patients who have already been https://www.uptodate.com/contents/2737/print

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treated with antimicrobials, such as intravenous drug users who frequently self-administer antibiotics [18]. Culture negativity is particularly likely with the following organisms, which are more difficult to isolate in culture: ●

Coxiella burnetii (Q fever) and Tropheryma whipplei occasionally cause endocarditis but will not grow using cell free media. (See "Q fever endocarditis" and "Whipple's disease".)

●

Brucella, Mycoplasma, Chlamydia, Histoplasma, Legionella, and Bartonella will not grow unless special media or microbiologic methods are employed.

●

Haemophilus spp, Actinobacillus, Cardiobacterium, Eikenella, and Kingella (the so-called HACEK group) will not be detected unless blood cultures are incubated for 7 to 21 days.

The microbiology laboratory should be notified when endocarditis or other infections with such organisms are suspected, since most laboratories routinely discard blood cultures when there has been no growth after seven days of incubation. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Nonculture-based diagnostic modalities can be used to increase the diagnostic yield when culture-negative endocarditis is suspected (eg, serologic assays or polymerase chain reaction). (See "Culture-negative endocarditis: Epidemiology, microbiology, and diagnosis", section on 'Diagnosis'.) Peripheral manifestations are rarely detected in subacute endocarditis presenting as FUO. Endocarditis in intravenous drug users is often right sided and lacks murmurs, and selfadministration of antimicrobials may obscure the detection of bacteremia. Transesophageal echocardiography is positive in over 90 percent of cases of infective endocarditis presenting as FUO [14]. False-positive results may be due to anatomic abnormalities or noninfective vegetations; false-negative results occur with small vegetations or those that have already embolized. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis", section on 'Echocardiography'.) Rarely, other endovascular infections (eg, mycotic aneurysms, septic thrombophlebitis) can be occult causes of fever. (See "Overview of infected (mycotic) arterial aneurysm" and "Catheterrelated septic thrombophlebitis".) Connective tissue diseases — Adult-onset Still’s disease in young and middle-aged adults and giant cell arteritis (GCA) in older individuals are the most common rheumatologic disorders https://www.uptodate.com/contents/2737/print

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presenting as FUO. GCA accounts for approximately 15 percent of cases of FUO in older adults [14]. Adult-onset Still’s disease — Adult-onset Still’s disease is an inflammatory disorder characterized by quotidian (daily) fevers, arthritis, and an evanescent rash. Patients with adultonset Still’s disease have features similar to children with systemic juvenile idiopathic arthritis. (See "Clinical manifestations and diagnosis of adult-onset Still's disease" and "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".) Giant cell arteritis — The diagnosis of GCA should be considered in a patient over the age of 50 who complains of headache, abrupt loss of vision, symptoms of polymyalgia rheumatica (which can occur without signs of vasculitis), unexplained fever or anemia, and a high erythrocyte sedimentation rate. The manifestations of GCA, however, can vary and may be transient. Jaw claudication, if present, is helpful in suspecting the diagnosis of GCA. Temporal artery biopsy is suggested in all cases of suspected GCA. (See "Clinical manifestations of giant cell arteritis".) Other — Other rheumatic disorders also may present as an FUO, including polyarteritis nodosa [19], Takayasu's arteritis (which is common in Japan), granulomatosis with polyangiitis, and mixed cryoglobulinemia. (See appropriate topic reviews.) Malignancy — The most common malignancies to present with FUO are: ●

Lymphoma, especially non-Hodgkin's

●

Leukemia

●

Renal cell carcinoma

●

Hepatocellular carcinoma or other tumors metastatic to the liver

The most frequent occult malignancies to cause fever are of reticuloendothelial origin (eg, lymphoma and leukemia). Fever is most often evident in advanced lymphomas or in those with aggressive histologic patterns. Computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis and bone marrow biopsy usually identifies the sites of involvement. Myelodysplastic syndromes occasionally present with fever and subtle evidence on blood smear of maturation arrest or dysplastic changes in one or several of the blood cell lines. Aleukemic leukemias are usually of the myeloid line. The diagnosis is made by bone marrow biopsy. Multiple myeloma has also been reported as a cause of FUO [20]. Renal cell carcinoma presents with fever in approximately 20 percent of cases. Microscopic hematuria and erythrocytosis may occur, but frequently there are no urine sediment https://www.uptodate.com/contents/2737/print

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abnormalities and the hematocrit is normal. Other adenocarcinomas also can cause fever, often but not invariably in the presence of hepatic metastases. Atrial myxomas are uncommon but present with fever in approximately one-third of cases. Other findings include arthralgias, emboli, and hypergammaglobulinemia. The diagnosis is usually established by echocardiography. (See "Cardiac tumors".) Drugs — One-third of hospitalized patients suffer from adverse drug reactions, including "drug fever." Drugs cause fever by stimulating an allergic or idiosyncratic reaction or by affecting thermoregulation. Eosinophilia and rash accompany drug fever in only 25 percent of cases; thus, the absence of these findings should not preclude a search for a possible offending drug [21]. The most common drugs that cause fever include: ●

Antimicrobials (sulfonamides, penicillins, nitrofurantoin, vancomycin, antimalarials)

●

H1- and H2-blocking antihistamines

●

Antiseizure medications (barbiturates and phenytoin)

●

Iodides

●

Nonsteroidal antiinflammatory drugs (including salicylates)

●

Antihypertensive drugs (hydralazine, methyldopa)

●

Antiarrhythmic drugs (quinidine, procainamide)

●

Antithyroid drugs

●

Contaminants such as quinine that accompany injected cocaine or heroin

A number of drugs rarely cause fever, such as digoxin and aminoglycosides. Drug reactions occur in as many as 24 percent of patients with AIDS, but rash and nausea are more common at presentation than fever. In two series of patients with AIDS, isolated fever occurred in 1.7 and 0 percent of cases [5,22]. Drug fever may occur shortly after initiating a medication. However, it is not uncommon for several weeks or, in some cases, months to years to elapse prior to the start of fever. The diagnosis of drug fever is made by a therapeutic trial of stopping the suspected drug (with occasional rechallenge). Most patients will defervesce within 72 hours after substituting drugs, although some may not recover for weeks. Clearance of offending drug derivatives may be https://www.uptodate.com/contents/2737/print

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delayed if the derivatives become bound or haptenated on long-lived host proteins. Drugs of the same class should not be reintroduced in a therapeutic trial.

LESS COMMON CAUSES Many of the uncommon causes of FUO are listed in the table (

table 2).

Factitious fever — Factitious fever is usually a manifestation of an underlying psychiatric condition that predominantly affects women and healthcare professionals. Patients with factitious fever feign illness for some secondary gain. They may also display evidence of selfmutilation and may have had multiple hospitalizations, invasive diagnostic tests (eg, cardiac catheterization), and surgery. The response to psychiatric intervention has been discouraging. (See "Factitious disorder imposed on self (Munchausen syndrome)".) Fever elevations may be fabricated through manipulation of thermometers. Manipulated temperature elevations can be extreme, sometimes exceeding 41ºC, and the fever cycles may not be accompanied by the expected patient behavior and physical signs such as chills, covering with blankets, cool extremities, sweats, warm extremities, and tachycardia. Current widespread use of electronic thermometers diminishes the opportunity to manipulate or exchange thermometers. Fever also can be induced by taking medications to which patients are allergic (eg, phenolphthalein) or by injecting foreign matter parenterally (eg, milk, urine, culture material, feces). The resulting illness may be associated with polymicrobial bacteremia, episodes of bacteremia caused by different pathogens, or recurrent soft tissue infections. Disordered heat homeostasis — Disordered heat homeostasis occasionally follows hypothalamic dysfunction (eg, following a massive stroke or anoxic brain injury) or abnormal heat dissipation (from skin conditions such as ichthyosis). Excess heat production may also occur from illnesses such as hyperthyroidism. Dental abscess — Apical dental abscesses are a rare cause of persistent fever that can be overlooked by the patient and physician. Among the 20 case reports in the literature, most individuals defervesced following removal of the decayed teeth, with or without antimicrobial therapy [23]. Other conditions linked to oral disease include brain abscesses, meningitis, mediastinal abscesses, and endocarditis; these are more common than dental FUO. Concurrent infections — The common occurrence of multiple concurrent opportunistic infections in FUO patients with AIDS confounds diagnosticians, particularly when CD4 counts https://www.uptodate.com/contents/2737/print

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are very low. These may include cytomegalovirus, Mycobacterium avium complex, Pneumocystis jirovecii, endemic fungi (eg, Histoplasma capsulatum), and gastrointestinal protozoa (eg, Cryptosporidium, Microsporidium). Other types of immunocompromised hosts may also present with FUO caused by more than one infection. (See "Overview of infections following hematopoietic cell transplantation" and "Infection in the solid organ transplant recipient".) Tickborne illnesses are becoming more prevalent and more widely distributed in the United States. Organisms that cause babesiosis, Lyme disease, and anaplasmosis/ehrlichiosis, which have varying incubation periods and different susceptibilities to antimicrobial agents, may infect an individual concurrently or serially and present as FUOs or relapsing fever syndromes. Furthermore, emerging pathogens such as Borrelia miyamotoi may further confound diagnostic efforts. Other infections — A number of more obscure infections that are associated with FUO and usually have a pulmonary component include Q fever, leptospirosis, psittacosis, tularemia, and melioidosis. Other less common infections that cause FUO but do not have pulmonary manifestations include secondary syphilis, disseminated gonococcemia, chronic meningococcemia, visceral leishmaniasis, Whipple's disease, and yersiniosis. (See appropriate topic reviews.) Alcoholic hepatitis — The characteristic signs and symptoms of alcoholic hepatitis are fever, hepatomegaly, jaundice, and anorexia. Fever is typically modest (101°F (38.3°C), duration >3 weeks, undiagnosed >1 week; 3: temp >101.3°F (38.5°C), duration >2 weeks, undiagnosed. ¶ Immunocompromised excluded. Δ Systemic review of 18 case series that were written in English and appeared between 2005 to 2015. ◊ Numbers represent percentages. § Includes collagen vascular disorders (eg, systemic lupus erythematosus, rheumatoid arthritis, and vasculitis), and granulomatous diseases (eg, sarcoidosis). Data from: 1. Alt H, Barker H. Fever of unknown origin. JAMA 1930; 94:1457. 2. Petersdorf RG, Beeson RG. Fever of Unexplained Origin: Report on 100 Cases. Medicine (Baltimore) 1961; 40:1. 3. Vanderschueren S, Knockaert D, Adriaenssens T, et al. From Prolonged Febrile Illness to Fever of Unknown Origin: The Challenge Continues. Arch Intern Med 2003; 163:1033. 4. Miller RF, Hingorami AD, Foley NM. Pyrexia of Undetermined Origin in Patients With Human Immunodeficiency Virus Infection and AIDS. Int J STD AIDS 1996; 7:170. 5. Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of Unknown Origin in Elderly Patients. J Am Geriatrics Soc 1993; 41:1187. https://www.uptodate.com/contents/2737/print

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6. Bleeker-Rovers CP, Vos FJ, de Kleijn EMHA, et al. A Prospective Multicenter Study on Fever of Unknown Origin: The Yield of a Structured Diagnostic Protocol. Medicine (Baltimore) 2007; 86:26. 7. Fusco MF, Pisapia R, Nardiello S, et al. Fever of unknown origin (FUO): which are the factors influencing the final diagnosis? A 2005–2015 systematic review. BMC Inf Dis 2019; 19:653.

Graphic 54701 Version 7.0

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Case studies of fever of unknown origin: prevalent diagnoses Case study Alt

Diagnosis

1913 to

Petersdorf

de Kleijn

1952 to 1959

1992 to 1994

n = 93

n = 117

1930 n = 23

Vanderschueren 1990 to 1999 n = 192

Miller

Knockaert

1989 to 1993

1980 to 1989

n = 72

n = 41

Location

Boston, United States

Seattle, United States

Netherlands

Belgium

London, United Kingdom

Belgium

Rheumatic fever

2

6

0

0

0

0

Abdominal abscess

1

4

4

5

0

5

Endocarditis

0

5

4

11

0

2

Syphilis

1

1

1

0

0

0

Mycobacterial

6

12

3

8

57

15

Lymphoma

2

8

11

14

7

5

Solid tumor

3

10

7

7

1

7

Sarcoid

0

2

2

10

0

2

Lupus

0

5

2

8

0

0

Rheumatoid arthritis

0

0

2

2

0

5

Giant cell arteritis

0

2

4

11

0

19

Drug fever

0

1

3

4

0

7

Factitious fever

0

3

2

1

3

0

Numbers represent number of cases. Alt H, et al. JAMA 1930; 94:1457. Petersdorf RG. Arch Intern Med 1992; 152:21. de Kleijn EM, et al. Medicine (Baltimore) 1997; 76:392. Vanderschueren S, et al. Arch Intern Med 2003; 163:1033. Miller RF, et al. Int J STD AIDS 1996; 7:170. Knockaert DC, et al. Clin Infect Dis 1994; 18:601.

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Graphic 66395 Version 5.0

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The percentage of patients with fever of unknown origin by cause during four decades

Adapted from: Mourad O, Palda V, Detsky AS. Arch Intern Med 2003; 163:545.

Graphic 73878 Version 3.0

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Less common diagnoses of fever of unknown origin Infections

Malignancies

Abscesses (especially intra-abdominal)

Aleukemic leukemia

African tick bite fever*

Atrial myxoma

Amebic liver abscess*

Colon cancer

Anaplasmosis/ehrichiosis*

Hepatocellular carcinoma or other tumors metastatic to the liver

Babesiosis* Brucellosis* Castleman's disease Chikungunya* Chronic active hepatitis Culture-negative endocarditis¶

Lung cancer

Diskitis

Multiple myeloma

Gonococcal arthritis Herpes simplex encephalitis

Antiphospholipid syndrome Behçet's disease Cryoglobulinemia

Granulomatosis with polyangiitis (formerly Wegener's disease)

Mesothelioma

Filariasis*

Allergic granulomatous angiitis

Leukemia

Dengue*

Fascioloiasis*

diseases

Giant cell arteritis

Dental abscesses

Epididymitis

inflammatory

Kaposi's sarcoma

Lymphoma, especially nonHodgkin's

Cytomegalovirus

Systemic

Myelodysplastic syndromes Renal cell carcinoma Sarcoma

Granulomatous hepatitis Hypersensitivity vasculitis Inflammatory

Miscellaneous Disorders of temperature regulation (neurologic and dermatologic) Drug feverΔ Environmental (metal and polymer fume fevers) Factitious fever Familial Mediterranean fever Inflammatory bowel disease Neuroleptic malignant syndrome Periodic fever Pulmonary

bowel disease

emboli

Panaortitis

Retroperitoneal hematomas

Polyarteritis nodosa

Chronic fatigue

mononeucleosis

Polymyalgia rheumatica

Thyroiditis

Kala azar (visceral leishmaniasis)*

Reactive arthritis (formerly Reiter's

Infectious

Kikuchi's disease Lassa fever* Leptospirosis* Lyme disease*

syndrome

syndrome) Sarcoidosis Still's disease Systemic lupus erythematosis

Osteomyelitis https://www.uptodate.com/contents/2737/print

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Prostatitis Pyelonephritis

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Takayasu's arteritis

Pyometria Q fever* Relapsing fever (Borrelia recurrentis)* Rheumatic fever Sinusitis Toxoplasmosis Typhoid fever* Tuberculosis Whipple's disease Zika virus* More common causes are in bold type. * Travel and environmental exposure histories are especially relevant. ¶ Causes include Actinobacillus spp, Bartonella spp, Brucella spp, Cardiobacterium spp, Chlamydia spp, Coxiella burnetii, Eikenella spp, Haemophilus spp, Histoplasma capsulatum, Kingella spp, Legionella spp, Mycoplasma spp, Tropheryma whipplei, and marantic endocarditis. Δ Antimicrobials (especially sulfonamides and penicillins), antiepileptic, antithyroid, and nonsteroidal anti-inflammatory drugs. Graphic 62509 Version 7.0

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Contributor Disclosures David H Bor, MD No relevant financial relationship(s) with ineligible companies to disclose. Peter F Weller, MD, MACP Consultant/Advisory Boards: Genzyme [Eosinophilia];GlaxoSmithKline [Eosinophilic diseases];Knopp Biosciences [Hypereosinophilic syndrome treatment]. Other Financial Interest: AstraZeneca [Hypereosinophilic syndrome]. All of the relevant financial relationships listed have been mitigated. Keri K Hall, MD, MS No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Approach to the patient with unintentional weight loss Authors: Renuka Gupta, MD, FHM, FACP, Arthur T Evans, MD, MPH Section Editor: Joann G Elmore, MD, MPH Deputy Editor: Lisa Kunins, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Jun 10, 2021.

INTRODUCTION Weight loss is a common problem seen by generalists. Patients who are overweight or obese may intentionally lose weight to improve their health. However, progressive unintentional (involuntary) weight loss often indicates a serious medical or psychiatric illness. This topic will discuss the approach to unintentional weight loss in the adult patient. Weight loss and nutritional issues in older adults and weight loss or inadequate weight gain in children and adolescents is discussed separately. (See "Geriatric nutrition: Nutritional issues in older adults" and "Poor weight gain in children younger than two years in resource-abundant countries: Etiology and evaluation" and "Poor weight gain in children older than two years in resourceabundant countries".) Weight loss in the management of obesity is also discussed separately. (See "Obesity in adults: Overview of management" and "Obesity in adults: Dietary therapy".)

DEFINITIONS ●

Unintentional weight loss – Unintentional weight loss is also referred to as involuntary or unintended weight loss [1]. This term excludes weight loss as an expected consequence of treatment (eg, weight loss from diuretic therapy in patients with heart failure) or as a result of a known illness. Clinically important weight loss is generally defined as loss of more than 5 percent of usual body weight over 6 to 12 months [1,2].

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Clinically significant weight loss and nutritional issues in older adult patients is discussed elsewhere. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Weight loss'.) ●

Cachexia – Cachexia has varying definitions. It is generally defined as weight loss from loss of muscle mass (with or without fat loss). (See "Assessment and management of anorexia and cachexia in palliative care" and "Geriatric nutrition: Nutritional issues in older adults", section on 'Cachexia'.)

●

Sarcopenia – Sarcopenia is a geriatric syndrome characterized by loss of muscle mass, strength, and performance [1]. (See "Geriatric nutrition: Nutritional issues in older adults", section on 'Sarcopenia'.)

EPIDEMIOLOGY The majority of people will eventually meet the criteria for significant unintentional weight loss if they live long enough. It is estimated that 15 to 20 percent of adults ≥65 years have unintentional weight loss if followed over 5 to 10 years [3,4]. Up to 8 percent of outpatients will have unintentional weight loss. Many studies, especially of nursing home residents, report a prevalence of weight loss exceeding 50 percent, which is most commonly multifactorial and associated with functional decline [5,6]. There are fewer estimates of the incidence or prevalence of weight loss in the general population. The best evidence comes from survey studies. One survey including a representative sample of over 9000 adults in the United States found that 5 percent of participants reported unintentional weight loss of at least 5 percent of their usual body weight during the preceding year [7]. There were no important sex differences in weight loss incidence. The strongest independent predictors of unintentional weight loss were age, smoking, and poor self-reported health. In another United States survey including over 5000 participants age ≥50 years, 7 percent of the sample reported unintentional weight loss of 5 percent or more over six months [8]. Prevalence increased with age and was also higher among those with obesity.

MORTALITY AND OTHER HEALTH OUTCOMES Unintentional weight loss is associated with increased mortality [9]. As examples: ●

In a study of over 10,000 adult Israeli men, a 5 kg weight loss over five years without dieting was associated with an 18 percent increase in total mortality over the next 18 years

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[10]. The excess mortality was almost entirely explained by increased cardiovascular deaths, after adjusting for age, baseline cardiovascular risk factors, baseline body mass index (BMI), and other comorbidities. There was no increase in cancer mortality. ●

In the United States National Health and Nutrition Examination Survey (NHANES) II Mortality Study, 5000 participants aged ≥50 years were followed for at least 12 years [8]. Unintentional weight loss was associated with a 24 percent relative increase in mortality during the follow-up period, even among those with obesity.

Mortality rates may be also increased for other specific populations with weight loss. As an example, weight loss among nursing home residents predicts increased mortality, regardless of underlying diagnosis [11-16]. Among patients with advanced lung disease and heart failure, those with weight loss also have increased mortality [17]. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Weight loss and body mass index' and "Malnutrition in advanced lung disease", section on 'Effect on mortality and lung function'.) In addition to higher mortality rates, unintentional weight loss is associated with an increased fracture risk and poor health related outcomes [18,19].

ETIOLOGIES There are many causes of unintentional weight loss (

table 1 and

table 2). In the absence

of fever or other cause for increased energy expenditure (eg, hyperthyroidism), weight loss is predominantly due to decreased food intake. Progressive unintentional weight loss often indicates serious medical or psychiatric illness. Any chronic illness affecting any organ system can cause anorexia and weight loss. In studies that examined the etiologies for unintentional weight loss, malignancy is eventually identified as the primary cause in 15 to 37 percent of patients [15,20-23]. Nonmalignant gastrointestinal causes account for 10 to 20 percent [20,21,24,25]. Psychiatric causes occur in 10 to 23 percent of community-dwelling participants [20,21,23]. Up to 25 percent of cases have unknown causes [4,15,20]. Malignancy — Malignancies (particularly gastrointestinal, pancreatic, lung, lymphoma, renal, and prostate cancers) often cause weight loss [26]. There are multiple mechanisms accounting for weight loss in patients with cancer. Anorexia and weight loss are present in 15 to 40 percent of all cancer patients at diagnosis [27], but the prevalence appears to be highest in those diagnosed with lung cancer (60 percent) or upper gastrointestinal cancer (80 percent) [27-29]. https://www.uptodate.com/contents/2770/print

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Cancer cachexia involves complex metabolic abnormalities that decrease muscle mass. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".) Among patients with unintentional weight loss, only a minority are subsequently diagnosed with malignancy. In a prospective cohort study from Spain, 2677 adults were systematically evaluated for unintentional weight loss and 902 (34 percent) were diagnosed with malignancy over the next five and a half years, although the vast majority of those (883) were diagnosed within the first six months of evaluation [15]. Among patients with unintentional weight loss, malignancy was associated with older age, male sex, active smoking, and greater weight loss. The most common malignancies in these patients were related to the gastrointestinal system (esophagus, stomach, bowel, liver, pancreas, biliary), lung, lymphoma, and urinary tract (kidney, ureter, bladder); cancers of the prostate, breast, and ovary were diagnosed much less frequently. Patients with malignancy as a cause of unintentional weight loss often have one or more abnormalities (signs, symptoms, or laboratory abnormalities) noted during the initial diagnostic evaluation. For example, patients may have pain, abdominal distention, nausea, vomiting, dysphagia, early satiety due to hepatosplenic enlargement or malignant obstruction, hypercalcemia, or symptoms of malabsorption. (See 'Evaluation' below.) In a prospective cohort study of 101 patients, all 22 patients with malignancy had an abnormal laboratory test, with C-reactive protein (CRP), hemoglobin, lactate dehydrogenase, and albumin having the highest sensitivities [30]. Abnormal abdominal ultrasound and chest radiograph had lower sensitivities of 45 and 18 percent, respectively. However, all of these diagnostic tests were also abnormal, but to a lesser extent, among patients with nonmalignant organic disease. Thus, there is no general diagnostic test or group of tests that appears to be specific for malignancy. Nonmalignant gastrointestinal diseases — Numerous nonmalignant gastrointestinal etiologies can cause weight loss. Examples include peptic ulcer disease, diseases that cause malabsorption (eg, celiac disease), and inflammatory bowel disease (IBD). Patients with weight loss from gastrointestinal causes will often have associated gastrointestinal symptoms including: anorexia, abdominal pain, early satiety, dysphagia, odynophagia, diarrhea, steatorrhea, chronic constipation, or evidence of chronic bleeding. They may also have signs and symptoms associated with chronic inflammation, chronic ischemia, obstruction, or fistulas. Patients with IBD may have extraintestinal manifestations (

table 3).

Patients with malabsorption may have weight loss with increased or normal appetite (

table 4

). (See "Approach to the adult patient with suspected malabsorption".)

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Psychiatric disorders — Psychiatric disorders commonly cause weight loss. A prospective cohort study of 2677 patients with unintended weight loss found that 14 percent were the result of psychiatric disorders [15]. Among nursing home patients, psychiatric disorders, particularly depression, account for 31 to 58 percent of cases of unintentional weight loss [11,15,31,32]. ●

Depression – The independent role of depression in weight loss is difficult to determine due to the frequency of overlapping causes, such as social isolation, physical disabilities, dementia, dysphagia, medication/drug use, and multiple chronic diseases. (See "Unipolar depression in adults: Epidemiology".)

●

Eating disorders – In patients who are of normal weight or underweight, obsession with being overweight leads to weight loss as a result of decreased food intake, excessive exercise, self-induced vomiting, drug/herbal medication use, and/or behaviors suggestive of bulimia/anorexia nervosa. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis".)

●

Other – Loss of appetite and unintentional weight loss can also occur in patients with other psychiatric disorders. During the manic phases of bipolar disorder, hyperactivity and preoccupations may interfere with normal eating patterns. In rare circumstances, patients with delusions or paranoia may develop peculiar ideations about food that lead to decreased food intake and subsequent weight loss. (See "Bipolar disorder in adults: Clinical features", section on 'Major depression' and "Psychosis in adults: Epidemiology, clinical manifestations, and diagnostic evaluation".)

Endocrinopathies — Weight loss is a common feature of endocrinopathies. ●

Hyperthyroidism – Weight loss is a classic symptom of hyperthyroidism. Most patients have hyperphagia. Some younger patients with mild hyperthyroidism eat enough to actually gain weight. In older patients, however, hyperthyroidism often causes anorexia with accelerated weight loss. (See "Overview of the clinical manifestations of hyperthyroidism in adults".)

●

Diabetes mellitus – Uncontrolled diabetes mellitus can cause weight loss with increased appetite, particularly with new-onset type 1 diabetes mellitus. Although patients with poorly controlled or undiagnosed type 2 diabetes can occasionally present with weight loss, weight gain is much more common. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents", section on 'Clinical presentation' and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Clinical presentation'.)

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However, some patients with type 2 diabetes can occasionally present with diabetic neuropathic cachexia, an unusual and poorly understood syndrome characterized by profound weight loss (as much as 60 percent of body weight) and often severe neuropathic pain of the anterior thighs [33,34]. ●

Adrenal insufficiency – Chronic primary adrenal insufficiency often presents with significant weight loss, although other associated signs and symptoms are more prominent: dehydration, anorexia, lassitude, fatigue, and weakness. Adrenal insufficiency that is acute or due to hypothalamic or pituitary dysfunction is usually not associated with weight loss. (See "Clinical manifestations of adrenal insufficiency in adults".)

●

Pheochromocytoma – The hyperadrenergic state among patients with pheochromocytoma would theoretically cause weight loss with increased appetite, but only 5 percent of patients with pheochromocytomas report weight loss [35]. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Less common symptoms and signs'.)

Infectious diseases — Many chronic infections lead to unintentional weight loss. As examples: ●

HIV – Patients with HIV infection have total daily energy expenditure similar to normal subjects [36-38]. Weight loss in patients with HIV infection is usually episodic, occurring with secondary infections or gastrointestinal diseases, and leads to a reduction in energy intake. The lethargy and fatigue that accompany infection may help maintain energy balance and weight [38].

●

Tuberculosis – Many patients with active tuberculosis experience weight loss. For reactivation tuberculosis, significant weight loss is one of the cardinal signs and symptoms. (See "Clinical manifestations and complications of pulmonary tuberculosis".)

●

Hepatitis C – Chronic infection with hepatitis C virus can also cause weight loss, in addition to nausea, anorexia, and weakness. (See "Clinical manifestations and natural history of chronic hepatitis C virus infection", section on 'Generalized symptoms'.)

●

Helminthic infections – A number of helminthic infections can cause nutritional deficiencies and weight loss. Specific helminth infections are discussed in the appropriate topics.

Advanced chronic disease — Advanced chronic cardiac, lung, or renal disease are all associated with weight loss.

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Congestive heart failure – Nearly one-half of heart failure patients with New York Heart Association Class III or IV disease lose lean body mass and meet criteria for malnutrition. Weight loss in this population can be associated with anorexia, early satiety, depression, intestinal and liver congestion, and increased levels of cytokines and angiotensin II [39]. The fluid retention associated with chronic heart failure often masks the extensive loss of lean body mass. Weight loss in patients with chronic heart failure is associated with an increased mortality rate. (See "Predictors of survival in heart failure with reduced ejection fraction", section on 'Weight loss and body mass index'.)

●

Chronic lung disease (pulmonary cachexia syndrome) – Chronic weight loss with malnutrition can occur with severe chronic lung disease and has been called the pulmonary cachexia syndrome. Estimates of cachexia in severe chronic obstructive pulmonary disease range from 30 to 70 percent [40]. Progressive weight loss can occur even with adequate caloric intake due to increased respiratory muscle work and possibly systemic inflammation. Often the weight loss is episodic, associated with exacerbations of lung disease, but without any regain in weight after recovery. Glucocorticoid treatment, systemic inflammation, and immobility contribute to the loss of muscle mass in severe lung disease. (See "Malnutrition in advanced lung disease", section on 'Metabolism and caloric intake'.)

●

Advanced kidney disease – In advanced kidney disease, anorexia and other uremic symptoms usually occur when the glomerular filtration rate (GFR) drops below 15 mL/min. As with heart failure, fluid retention in advanced kidney disease often masks the true loss in lean body mass. (See "Overview of the management of chronic kidney disease in adults", section on 'Malnutrition'.)

Neurologic diseases — Several neurologic illnesses, including stroke, dementia, Parkinson disease, and amyotrophic lateral sclerosis, can lead to weight loss. Weight loss may be due to one or more deficits, such as altered cognition, motor dysfunction, and dysphagia, associated with these disorders. (See "Complications of stroke: An overview" and "Clinical manifestations of Parkinson disease" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".) In a prospective cohort study of 1900 people, a decline from midlife weight was associated with an increased risk of mild cognitive impairment [41]. (See "Risk factors for cognitive decline and dementia", section on 'Obesity and body mass index'.) Medications/substances — Over-the-counter, prescription, and illicit drugs can lead to weight loss (

table 1 and

table 5). Weight loss is a known adverse effect of several common

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prescription drugs, including anticonvulsants (

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table 6), diabetes medications (

table 7), and

thyroid medication. Importantly, cholinesterase inhibitors used to treat dementia (eg, donepezil, rivastigmine, galantamine) may contribute to weight loss. A meta-analysis of 25 studies with over 10,000 patients demonstrated that participants taking cholinesterase inhibitors had an increased likelihood of weight loss [42]. Marked weight loss can occur after reduction or withdrawal of some antipsychotic drugs (eg, chlorpromazine, haloperidol, thioridazine, mesoridazine) [43]. Patients who experience weight loss have usually been treated for many years with high doses. Weight loss with withdrawal of newer antipsychotic agents occurs infrequently. Weight loss also occurs with several drugs of abuse: ●

Alcohol – Many alcohol-dependent patients consume most of their calories from alcohol and thus have several nutritional deficiencies in addition to weight loss. However, weight loss in patients with alcoholic cirrhosis may be masked by secondary ascites and fluid retention. (See "Nutritional status in patients with sustained heavy alcohol use".)

●

Cocaine – As many as 40 percent of chronic cocaine users experience weight loss, anorexia, and sleep disturbances. (See "Cocaine use disorder in adults".)

●

Amphetamines – Amphetamines promote release of catecholamines from presynaptic nerve terminals, which can decrease appetite and increase basal metabolism. (See "Methamphetamine use disorder: Epidemiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

●

Marijuana – Withdrawal from chronic marijuana use can cause a syndrome that includes anorexia, weight loss, irritability, and strange dreams [44].

●

Tobacco – Heavy tobacco use leads to weight loss, whereas weight gain occurs with smoking cessation. (See "Benefits and consequences of smoking cessation", section on 'Weight gain'.)

Rheumatologic — Patients with rheumatologic conditions (eg, rheumatoid arthritis, giant cell [temporal] arteritis) often have weight loss as part of systemic symptoms. There are also reports of older patients with unintentional weight loss who are eventually diagnosed with giant cell arteritis but never manifest classic signs or symptoms of the disease [45]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Initial clinical presentation' and "Clinical manifestations of giant cell arteritis", section on 'Constitutional symptoms'.) Other https://www.uptodate.com/contents/2770/print

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Social factors leading to inadequate dietary intake – Patients may have weight loss from inadequate dietary intake due to social factors (eg, inability to obtain food), particularly in older adult patients. (See 'Psychiatric disorders' above and "Geriatric nutrition: Nutritional issues in older adults", section on 'Social factors'.)

●

Athletes – Some persons have vocations that require them to be very lean (eg, longdistance runners, models, ballet dancers, gymnasts). Some persons who engage in intense training must increase their intake of calories considerably to maintain their weight and muscle mass. Increased food intake is not always sufficient to maintain body weight, resulting in transient or persistent weight loss. (See "Exercise physiology".)

EVALUATION The electronic health record may be used to automatically identify patients with 5 percent or greater weight loss to trigger the clinician to investigate the cause. Given the broad differential diagnosis of unintentional weight loss (

table 1), there is no single

diagnostic approach for all patients. The evaluation should begin with verification of the weight loss (patients may complain of weight loss without an objective weight loss), followed by a careful history and physical examination (

algorithm 1). The workup should be individualized,

based on findings from the history and examination. Patients with A, resulting in an exon 14 deletion [del]

●

DPYD*13 SNP, has a nucleotide change 1679T>G, with resultant amino acid substitution I560S

●

DPYD*9B SNP, has a nucleotide change c.2846A>T, with resultant amino acid substitution D949V

HapB3 is composed of three intronic variants (c.483+18G>A, c.680+139G>A, and c.959-51T>C), one synonymous variant (c.1236G>A) and a variant in linkage disequilibrium with HapB3 (an intronic polymorphism c.1129-5923C>G) have been suggested to contribute to fluoropyrimidine toxicity. In Europeans, HapB3 with the intronic variant c.1129-5923C>G is the most common DPYD variant, with carrier frequencies of approximately 5 percent [68]. However, the effects of this variant are modest [69], which probably explains the disparate reports on its influence on FU toxicity [64-67,70]. Although complete DPD deficiency is rare (and usually associated with homozygosity for one of the alleles associated with reduced enzyme activity), partial deficiencies due to the inheritance of one high-risk allele are more common, particularly in Black women. These demographic differences can be illustrated by an analysis of enzyme levels from 258 normal volunteers [71]. No person had complete DPD deficiency, while partial DPD deficiency was present in 12.3, 4.0, 3.5, and 1.9 percent of Black women and men, and White women and men, respectively. Only four (1.6 percent) volunteers (three Black women and one Black man) had profound DPD deficiency. Despite the association of one of these high-risk alleles with severe CRD, we do not routinely test DPYD genotype for all patients initiating fluoropyrimidine therapy. In the United States, one https://www.uptodate.com/contents/2824/print

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of the three high-risk alleles, DPYD*2A, *13, and *9B, is present in fewer than 10 percent of patients in most populations, and inheritance of a high-risk allele is not always associated with life-threatening toxicity (ie, the positive predictive value of having one of these alleles on the risk of severe toxicity is variable). Inheritance of one of these high-risk alleles does not account for the majority of FU-associated severe toxicity, which is estimated to occur in 15 to 30 percent of treated patients (ie, sensitivity is limited). Finally, even if preemptive pharmacogenomics testing is done and these high-risk alleles are not detected, patients can still have lifethreatening toxicity (ie, the specificity is limited). These issues can be illustrated by the following data: ●

In one series, one of the three high-risk DPYD variants was found in only 30 percent of FUtreated patients (13 of 44) who developed grade 3 or 4 toxicity [51]. Similarly, a systematic review by the Clinical Pharmacogenetics Implementation Consortium (CPIC) concluded that between 23 and 38 percent of severe fluoropyrimidine toxicity could be attributed to DPYD variants (clinical sensitivity approximately 31 percent) [72].

●

In a prospective study of 683 patients receiving FU monotherapy, grade 3 or 4 toxicity occurred in 16 percent, and genotyping revealed the DPYD*2A allele in only 5 percent of those with treatment-related toxicity [56]. Furthermore, fewer than half of those who had the DPYD*2A allele developed grade 3 or 4 toxicity (positive predictive value 46 percent). Of interest, there was a gene-sex interaction, resulting in an odds ratio (OR) of 41.8 for male patients but only 1.33 for female patients.

●

In another series of 430 patients initiating therapy with FU or capecitabine for any tumor type, 24 of the 104 patients experiencing grade 3 or 4 toxicity in the first four cycles of therapy (23 percent) were found to have one of four high-risk variant alleles (DPYD*2A, *13, *9B, and one other high-risk allele, 1601G>A) [61]. Only 6 percent of the entire cohort had one of these four variants. In contrast to the prior series, the positive predictive value of having inherited any of these four high-risk alleles for severe (grade 3 or 4) diarrhea, mucositis, or myelosuppression during the first four cycles of therapy in this study was >99 percent.

Some of the inconsistency in study results may be attributable to variations in the treatment regimens across studies. The DPYD*2A allele has been associated with toxicity more frequently when FU was administered in combination with other chemotherapeutic agents rather than as monotherapy [72]. Furthermore, there appears to be significant interethnic differences in frequency and genetic constitution of DPD deficiency [73].

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A major issue is that inheritance of one of these high-risk alleles does not account for all cases of DPD deficiency. Impaired DPD activity has been detected in some patients with normal wildtype DPYD alleles, presumably due to epigenetic mechanisms, including microRNAs, that regulate enzyme activity [74,75]. Despite these difficulties, the potential benefits of identifying patients who have inherited one of these three high-risk alleles in terms of reducing treatment-related toxicity and improving the cost-effectiveness of care can be illustrated by the following reports: ●

In a report of data from a large cohort of patients with stage III colon cancer who were enrolled on the adjuvant NCCTG N0147 trial, the frequency of finding one of the three high-risk DPYD alleles was low overall; of the 2886 patients who were genotyped, 27 (0.9 percent), 4 (0.1 percent), and 32 (1.1 percent) carried the DPYD*2A, *13, and *9B variants, respectively [76]. However, of the 2594 patients with complete adverse event data, grade 3 or 4 adverse events developed in 22 of the 25 patients with the *2A variant (88 percent positive predictive value), in two of four *13 carriers (50 percent), and in 22 of 27 *9B carriers (82 percent). The *2A variant was significantly associated with nausea and vomiting and neutropenia but not diarrhea, while the *9B variant was significantly associated with dehydration, diarrhea, neutropenia, and thrombocytopenia.

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In a more recent series, 1181 patients initiating fluoropyrimidine therapy were prospectively screened for the four most common DPYD variants found in the Netherlands (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A) prior to initiating therapy; 85 patients (8 percent of total) were heterozygous DPYD variant allele carriers and were treated with a reduced dose of fluoropyrimidine [77]. The risk of grade 3 or worse adverse events was 39 percent in patients with DPYD variant alleles compared with 23 percent in DPYD wild-type patients. In pharmacokinetic analyses, mean drug and therapeutic metabolite exposure was similar between DPYD variant allele carriers treated with a reduced dose and wild-type patients. Interestingly, there was no correlation between DPD enzyme activity and the occurrence of severe fluoropyrimidine-related toxicity in DPYD variant allele-carrying patients.

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In a cost-effectiveness analysis of screening patients intended to receive fluoropyrimidinebased chemotherapy for the four most common DPYD variants found in the Netherlands (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A), the expected total costs for the screening strategy were 2599 euros per patient compared with 2650 euros per patient for the non-screening strategy [78]. The study also found that the total costs of hospitalization for five DPYD variant allele carriers that experienced severe toxicity were much higher than prospectively screening the whole study population (232,061 versus 23,718 euros).

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As noted above, the DPYD*2A, DPYD*13, DPYD*9B, and HapB3 variants are the most commonly reported high-risk DPYD variants. Other alleles with equivocal effects on the likelihood of fluoropyrimidine-related toxicity include polymorphisms in the DPYD*4 allele and the DPYD*5 allele [54,62,65,77]. If a high-risk DPYD variant is identified prior to treatment, guidelines for fluoropyrimidine dosing are available from the CPIC (

table 3) [79,80]. However, they do not provide

recommendations on whether and when to perform pharmacogenomics testing. Given the low frequency of finding a predictive allele and the low sensitivity (ie, patients who lack one of these high-risk DPYD variants may still suffer grade 3 or 4 fluoropyrimidine-related toxicity), preemptive genetic testing of all patients due to receive a fluoropyrimidine in order to identify those with DPD deficiency is controversial and not widely practiced [81]. The US Food and Drug Administration (FDA) does not currently require pharmacogenetic testing before fluoropyrimidine administration. In the United States, testing is usually reserved for patients who develop unusually early, severe, treatment-related toxicity (diarrhea, mucositis, myelosuppression, neurotoxicity, cardiotoxicity) in the first cycle of fluoropyrimidine therapy. On the other hand, in March 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recommended all patients planned to receive any fluoropyrimidine therapy undergo pharmacogenomics testing prior to starting therapy [82], and this approach has been adopted in updated guidelines for management of localized colon cancer from the European Society for Medical Oncology (ESMO) [83]. This subject is discussed in detail below. (See 'Testing for DPYD and TYMS variants' below.) TYMS gene variations — In addition to DPYD, high-risk polymorphisms in the thymidylate synthetase gene (TYMS) may be associated with a 1.4- to 2.4-fold increase in the risk of severe toxicity from FU-based chemotherapy; however, the data are less certain than with the high-risk DPYD genotypes. Thymidylate synthetase (TS), a critical enzyme for thymidine production, is potently inhibited by FU. The important polymorphisms that might influence fluoropyrimidine toxicity are outlined in the table ( ●

table 2) and are described in detail in the following sections:

Expression of TYMS is regulated by transcription factors that bind to the promoter region. The 5' untranslated region (UTR) contains a variable number of 28 bp tandem repeats (VNTRs), which can stimulate transcriptional activity. The vast majority of individuals carry TYMS alleles that contain two or three repeats in this promoter region, designated 2R and 3R [84,85]. Patients who are homozygous for the triple repeat (3R/3R) have a greater number of binding sites for transcription factor and higher TS levels compared with those

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who are 2R/2R or 3R/2R; conversely, 2R/2R homozygotes have low TS levels in normal tissues and may be at a greater risk of FU cytotoxicity. Notably, patients who overexpress TS have relative resistance to fluoropyrimidines. ●

An SNP has been described in the 12th nucleotide of the second repeat of the 3R allele, which abolishes a promoter binding site in the 3R allele (designated the 3RC allele) and leads to markedly reduced TS activity [84,86-89]. Others describe greater toxicity with a similar substitution of cytosine for guanine at the 12th nucleotide in two 28 bp repeats in the 5' UTR (designated 2RC) [88,90].

The available data linking these polymorphisms to increased fluoropyrimidine toxicity are conflicting, as evidenced by the following reports: ●

The 2R/2R genotype has been associated with greater toxicity in many [85,91-93], but not all [61,93,94], studies. Even in positive studies, the sensitivity and positive predictive value appear to be limited. As an example, in three studies totaling 200 unselected patients who received FU, 44 (22 percent) developed grade 3 or 4 toxicity [85,91,92]. Only 13 of the 44 had the high-risk 2R/2R genotype (sensitivity 30 percent), while of the 25 patients who inherited the 2R/2R high-risk genotype, only 13 developed grade 3 or 4 toxicity (positive predictive value 52 percent).

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Inheritance of a high-risk 2RC allele has been associated with an increase in toxicity [88,90]. In a series of 1613 patients, 28 had the 2RC variant allele (1.7 percent), and 20 had a high-risk genotype (2RG/2RC, 3RC/2RC, and 2RC/2RC) [90]. Both early severe toxicity and toxicity-related hospitalization were more frequent in risk-associated genotype carriers (OR 3.0 [95% CI 1.04-8.93] and 3.8 [95% CI 1.19-11.9], respectively). Other predictive markers — The contribution of other genetic and nongenetic factors

has not been well studied [95,96]. At least some data suggest marked regional differences in tolerability of fluoropyrimidines, with the highest toxicity rates in the United States and the lowest in East Asia [97]. This may be due, in part, to differences in dietary folic acid intake [97,98]. Reduced folates (such as LV) stabilize the binding of the FU metabolite fluorodeoxyuridine monophosphate to thymidylate synthetase, enhancing the response to fluoropyrimidine therapy [99] but also increasing toxicity. Higher pretreatment serum folate levels have also been linked to greater toxicity from capecitabine, an orally active prodrug of FU [100]. (See 'Capecitabine' below.) Testing for DPYD and TYMS variants — We do not routinely implement testing for DPYD and/or TYMS genotype for all patients initiating fluoropyrimidine therapy, but test for the panel of DPD alleles (rather than just DPYD*2A) in patients who have had severe and unexpected https://www.uptodate.com/contents/2824/print

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toxicity from fluoropyrimidines. TYMS genotyping could be included along with DPYD testing, where available, for patients who have had severe reactions to fluoropyrimidine therapy ( table 2). Pharmacogenetic profiling has the potential to identify patients who may experience severe adverse effects with fluoropyrimidines, but the utility of preemptive testing remains controversial. Some authors suggest genotype testing prior to initiating fluoropyrimidine therapy in all patients, and some institutions have adopted this approach [101-105]. Preemptive testing for DPYD variants is now recommended by the EMA [82] but not the FDA. Furthermore, it has been endorsed (at least prior to administration of adjuvant fluoropyrimidine-containing chemotherapy for localized colon cancer) by ESMO [83], but not by the National Comprehensive Cancer Network (NCCN). Not surprisingly, clinical adoption of pretreatment DPYD testing has been extremely limited in the United States [106]. Although fatal toxicity from fluoropyrimidine therapy is quite rare, preemptive testing for the presence of these four DPD alleles (DPYD*2A, c.2846A>T, c.1679T>G, and c.1236G>A) may prevent severe toxicity and appears to be at least cost-neutral in a European population [78]. An important point is that there are no prospective randomized trials that demonstrate improved toxicity without compromise of efficacy in patients who are preemptively screened versus not screened using any assay for DPD activity, including pharmacogenetic testing for high-risk DPYD and TYMS variants. Preemptive genotyping may not be covered by insurance in the United States, and the turnaround time for various laboratories is listed as up to 10 days. At many institutions, including those of several of the authors and editors associated with this review, genotyping is reserved for those patients who have unexpected toxicity (myelosuppression, mucositis, diarrhea, neurotoxicity, cardiotoxicity) during the first few cycles of fluoropyrimidine therapy. These patients should be suspected of having an at-risk DPYD or TYMS mutation, for which testing for at-risk mutations in DPYD and TYMS is reasonable, as dosing recommendations for DPYD mutation carriers are available from CPIC, and because identification of at-risk mutations may be of use if family members are to be treated in the future with fluoropyrimidines. Any patient who experiences severe toxicity following treatment with a fluoropyrimidine, regardless of whether they have an identified at-risk variant in DPYD or TYMS will require a significant dose reduction if continued treatment is planned. ●

Phenotypic testing as an alternative to genotyping – As an alternative to genotyping, phenotypic testing may be used to assess DPD functionality; DPD deficiency is reflected by a reduced ratio of dihydrouracil: uracil in plasma, or higher levels of uracil [107-109]:

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• One prospective study of 59 patients with GI malignancies assessed DPD function in all patients prior to their initial FU dose by measuring the ratio of dihydrouracil to uracil in blood as a surrogate test. Patients with reduced DPD activity (a dihydrouracil:uracil ratio 16 ng/mL was associated with a 20-fold higher risk to develop grade 4 toxicity, and had a higher sensitivity than assessment for three common DPYD variants, but the combined use of genotyping plus phenotyping did not improve toxicity prediction [108]. Although potentially more rapid than genotyping, these assays are not widely available, at least in the United States. Management of DPD-deficient patients — If a DPYD variant is identified prior to treatment, guidelines for management are available from CPIC (

table 3) [65]. The authors

note that not all patients who harbor reduced- or no-function variants of DPYD manifest toxicity, and, therefore, they recommend increasing the fluoropyrimidine dose in the absence of toxicity or in patients who have subtherapeutic plasma levels. This dose increase is of particular importance for patients being treated with curative intent. Alternative agents are needed for patients who are homozygous (ie, carrying two nonfunctional alleles). The quinazoline folate analog raltitrexed, which is a thymidylate synthetase inhibitor, may be a useful substitute for FU in patients with DPD deficiency [110], but it is not available in the United States. UFT is not a safe substitute for FU in this situation [111] as it is a combination of ftorafur (tegafur), an FU prodrug, plus uracil, which competes with FU for DPD. Where available, another option is close monitoring of FU levels and pharmacokinetically guided dosing. (See "Dosing of anticancer agents in adults", section on 'Therapeutic drug monitoring'.) Guidelines are not available from the CPIC or any other group for management of patients who are identified as having high-risk TYMS variants. Most cases of DPD deficiency are diagnosed only after a severe reaction to FU. Management of these patients should include aggressive hemodynamic support, parenteral nutrition, antibiotics, hematopoietic colony stimulating factors, and, where available, uridine triacetate (see 'Uridine triacetate' below). Dialysis is of no benefit if renal function is normal, since even https://www.uptodate.com/contents/2824/print

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with complete DPD deficiency, FU is rapidly cleared through the urine [42]. Patients diagnosed with DPD deficiency should be advised to inform family members in case they will be treated with fluoropyrimidine chemotherapy in future. Uridine triacetate — Uridine triacetate (originally called vistonuridine) is an orally administered prodrug of uridine, a specific pharmacologic antidote to fluoropyrimidines, including FU and capecitabine. It is a safe and potentially life-saving treatment for overdoses of these agents. Uridine triacetate was studied in 173 adult and pediatric patients who were treated in two separate trials and had either received an overdose of FU or capecitabine (n = 147) or had early-onset, unusually severe, or rapid-onset life-threatening toxicities within 96 hours after receiving FU (n = 26, the fraction who had DPD deficiency as the cause for severe early toxicity could not be determined) [112]. Overall, 137 of 142 assessable overdose patients treated with uridine triacetate (96 percent) survived to 30 days, had rapid reversal of acute neurotoxicity or cardiotoxicity (affecting 12 patients), and either prevention of or recovery from severe mucositis or leucopenia. Among the 26 patients treated for early-onset toxicity following fluoropyrimidine therapy (some of whom presumably had DPD deficiency), 21 survived to 30 days (81 percent); all five deaths were in patients who initiated uridine triacetate beyond 96 hours after the last dose of the fluoropyrimidine. Adverse events attributable to uridine triacetate were mild and infrequent, and included diarrhea, nausea, and vomiting. There are few data on the specific use of uridine triacetate in patients who develop severe fluoropyrimidine toxicity because of DPD deficiency [113]. However, the drug has been shown to prevent fatalities in mice who are treated with FU after receiving an inhibitor of DPD [114]. Thus, DPD-deficient patients who develop early severe toxicity after receiving the first dose of a fluoropyrimidine could also benefit from treatment with uridine triacetate, if the deficiency is identified soon enough after the fluoropyrimidine is administered and the drug can be obtained within 96 hours of the last dose. Uridine triacetate should not be administered for nonemergent toxicities as it may interfere with the efficacy of fluoropyrimidine treatment. Uridine triacetate was approved by the FDA in December 2015 for emergency use following an FU or capecitabine overdose, regardless of the presence of symptoms, for patients who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early-onset, unusually severe adverse reactions (eg, GI toxicity and/or neutropenia) within 96 hours following the end of FU or capecitabine administration [115]. The recommended dose and schedule for adults is 10 g orally every six hours for 20 doses. The recommended dose and schedule for pediatric patients is 6.2 g/m2 of body surface area orally every six hours for 20 doses. Despite its approval, uridine triacetate is not available

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commercially in any country. Ordering information for emergency use of uridine triacetate is available from vistogard.com. Capecitabine — Capecitabine is a rationally designed oral fluoropyrimidine prodrug that is converted to FU in three sequential enzymatic reactions. The dose-limiting toxicities are diarrhea, palmar-plantar erythrodysesthesia, and neutropenia. Capecitabine is associated with higher rates of diarrhea compared with infusional FU regimens [116-118]. Like FU, capecitabine is catabolized by DPD, and there is a risk for early and severe toxicity in those who are DPD deficient. However, the specific genetic markers of capecitabine-related toxicity are less well studied than with other fluoropyrimidines, such as FU. As with FU, routine testing for high-risk DPYD or TYMS alleles is not widely practiced prior to initiation of capecitabine because of the low frequency of finding a high-risk allele and the fact that patients who lack a high-risk variant may still suffer grade 3 or 4 FU-related toxicity. Nevertheless, testing is appropriate for patients who develop early severe toxicity (neutropenia, mucositis, diarrhea, neurotoxicity, and/or cardiotoxicity). (See 'DPD deficiency' above.) To avoid the risk of severe and potentially fatal reactions, the United States prescribing information for capecitabine recommends to withhold or permanently discontinue the drug in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate a near-complete or total absence of DPD activity. Furthermore, it states that no capecitabine dose has been proven safe for patients with complete absence of DPD activity and that there are insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test. However, it stops short of recommending preemptive testing for all patients prior to initiating therapy. Uridine triacetate is approved for emergency use in cases of capecitabine overdose or earlyonset, severe, or life-threatening toxicity, such as might occur in a DPD-deficient patient. (See 'Uridine triacetate' above.) Dosing — There appear to be large regional differences in the tolerance to capecitabine and other fluoropyrimidines [97]. These differences might, in part, be based on populationspecific pharmacogenomic variability (eg, Asian patients seem to tolerate fluoropyrimidines better than non-Asian patients, and although not studied according to ethnicity, genetic factors that are associated with capecitabine sensitivity, such as SNPs, have been identified [119]). However, differences in lifestyle and diet (eg, dietary folate intake) could also contribute. Because of these issues, the optimal dose of capecitabine, particularly for American patients, remains undefined. The initially approved dose for treatment of metastatic breast and https://www.uptodate.com/contents/2824/print

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colorectal cancer was 2500 mg/m2 per day for 14 of every 21 days, but later studies suggest that this dose is too high, particularly in American patients. Lower doses (beginning at 2000 mg per day for 14 of every 21 days) may improve the therapeutic index without compromising efficacy. An alternative capecitabine dosing schedule as has been used in women with breast cancer (2000 mg total dose in two divided doses for seven days on, seven days off) may be associated with less diarrhea [120,121]. (See "Chemotherapy in patients with hormone receptorpositive, HER2-negative advanced breast cancer", section on 'Capecitabine' and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Oral fluoropyrimidines'.) Ftorafur — Two oral formulations of ftorafur (tegafur), a FU prodrug, have been developed and are in use in Japan; neither drug is available in the United States. ●

UFT is a combination of ftorafur with uracil, which has been in widespread use in Japan for over 20 years. UFT is currently not available in the United States. Uracil competitively inhibits the enzyme DPD, leading to higher intratumoral concentrations of FU. Grade 3 or 4 diarrhea is seen in up to 12 percent of patients treated with single-agent UFT and in 8 to 20 percent of those in whom UFT was given with LV [122,123]. Prompt discontinuation of UFT at the onset of diarrhea usually prevents severe GI toxicity.

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S-1 is an oral fluoropyrimidine that includes three different agents: ftorafur, gimeracil (5chloro-2,4 dihydropyridine, a potent inhibitor of DPD), and oteracil (potassium oxonate, which inhibits phosphorylation of intestinal FU, thought responsible for treatment-related diarrhea). In animal models, potassium oxonate is protective against FU-induced diarrhea [124,125]. In a randomized phase III trial of surgery followed by one year of S-1 versus surgery alone in gastric cancer, the incidence of grade 3 or 4 diarrhea was only 3.1 percent with S-1 [126]. However, in a randomized trial of S-1 versus capecitabine as adjuvant therapy for colon cancer, grade 3 or 4 diarrhea occurred more commonly with S-1 than capecitabine (8 versus 2 percent) [127]. Randomized controlled trials of S-1 with oxaliplatin compared with FOLFOX or CAPOX have found a higher incidence of severe diarrhea in the S-1 arm compared with standard therapy [128,129].

Irinotecan — There are two types of diarrhea associated with irinotecan: ●

Early-onset diarrhea with irinotecan occurs during or within several hours of drug infusion in 45 to 50 percent of patients and is cholinergically mediated (ie, related to increased motility) [15]. It is often accompanied by other symptoms of cholinergic excess, including

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abdominal cramping, rhinitis, lacrimation, and salivation. The mean duration of symptoms is 30 minutes; it is usually well controlled by subcutaneous or IV atropine. (See 'Pathogenesis/mechanisms' above.) ●

By contrast, late irinotecan-associated diarrhea is not cholinergically mediated. The pathophysiology of late diarrhea appears to be multifactorial, with contributions from dysmotility and secretory factors, as well as a direct toxic effect on the intestinal mucosa [130,131]. Late diarrhea from irinotecan is unpredictable, noncumulative, and occurs at all dose levels. In early clinical trials of irinotecan, late diarrhea and neutropenia were the main dose-limiting toxicities [132,133]. Diarrhea of any grade was seen in 50 to 88 percent of patients, and it was severe in 9 to 31 percent. Diarrhea has been less common in later studies because of the stricter adherence to management guidelines (including routine early institution of high-dose loperamide) and the use of infusional rather than bolus FU in combination with irinotecan. (See "Management of acute chemotherapy-related diarrhea", section on 'Loperamide and diphenoxylate-atropine'.)

The median time to onset is approximately six days with the 350 mg/m2 every-three-week schedule and 11 days with the weekly schedule (125 mg/m2) [131,134]. Late diarrhea is less common with the every-three-week schedule. In a randomized trial comparing the two administration schedules of single-agent irinotecan, the incidence of severe diarrhea was significantly less with the every-three-week schedule (19 versus 36 percent for weekly therapy) [135]. However, the incidence of cholinergic symptoms was significantly lower with weekly therapy (31 versus 61 percent). In some studies, older age, low performance status, and prior pelvic radiation were found to be predisposing factors [131]. For unclear reasons, diarrhea is more common in White patients than in Black patients receiving irinotecan-based therapy [136]. Irinotecan produces mucosal changes associated with apoptosis, such as epithelial vacuolization, and goblet cell hyperplasia, suggestive of mucin hypersecretion [3]. These changes appear related to the accumulation of the active metabolite of irinotecan, SN-38, in the intestinal mucosa [6]. SN-38 is glucuronidated in the liver and is then excreted in the bile. The conjugated metabolite SN-38G does not appear to cause diarrhea. However, SN-38G can be deconjugated in the intestine by beta-glucuronidase present in intestinal bacteria. A direct correlation has been noted between mucosal damage and either low glucuronidation rates or increased intestinal beta-glucuronidase activity [137-139]. Severe toxicity has been described with irinotecan in patients with Gilbert syndrome who have defective hepatic glucuronidation [138]. (See "Gilbert https://www.uptodate.com/contents/2824/print

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syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Treatment-related toxicity'.) Common genetic polymorphisms of the UDP-glucuronyltransferase (UGT) gene can affect the metabolism of irinotecan. The possible impact of genetic variability on the toxicity of irinotecan is discussed below. (See 'Irinotecan plus FU' below.) UGT1A1 polymorphisms — Preemptive testing for the uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) genotypes that are associated with a poor metabolizer phenotype prior to initiating irinotecan is a controversial and evolving area, and experts differ. Although many institutions do not routinely screen patients, at our institution preemptive testing is recommended for all individuals initiating irinotecan, and we reduce initial starting doses by approximately 30 percent if a high-risk genotype is identified. SN-38 is further metabolized by the polymorphic enzyme UGT1A1. Individuals who inherit certain polymorphisms in the UGT1A1 gene or its promoter have reduced enzymatic activity and they are referred to as having a "poor metabolizer" phenotype because of decreased clearance of SN-38, which increases the risk for severe irinotecan-related neutropenia and, to a lesser degree, diarrhea. Most of the reported data describing the excess toxicity experienced by these individuals are in those carrying one or more *28 alleles, which is the most frequent alteration in European and African ancestries [140]. The *6 polymorphism is also associated with irinotecan toxicity and is more common in East Asian ancestry than in European or African ancestry. The *93 polymorphism is associated with increased SN-38 exposure and irinotecan toxicity and is common in African and European ancestries but less common in East Asian ancestry (

table 4) [140,141]. In general, patients carrying two alleles (eg, homozygotes with

*28/*28, *6/*6, or *6/*28) conferring decreased expression of function are at a higher risk for severe toxicity, compared with those carrying one allele (eg, *1/*28). Some poor metabolizers may be identified because they have Gilbert's syndrome, an inherited deficiency in UGT1A1 enzyme activity caused by polymorphisms in the UGT1A1 gene (typically the *28 allele), and characterized by increased unconjugated bilirubin in the blood, which is usually asymptomatic. Otherwise, the identification of individuals who have a poor metabolizer phenotype requires genetic testing for high-risk alleles. In one study of 1500 patients undergoing routine genotyping at a single institution, 17 percent were found to have a UGT1A1 genotype that would result in a poor metabolizer phenotype (*6/*6, *28/*28, *6/*28) [105]. In January 2022, the FDA modified the irinotecan United States Prescribing Information to specify that individuals who are homozygous for the UGT1A1 *28 or *6 allele and compound https://www.uptodate.com/contents/2824/print

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heterozygotes (*6/*28) are at risk for severe irinotecan toxicity (mainly neutropenia) and both preemptive testing for these UGT1A1 high-risk genotypes and a reduced initial dose of irinotecan in poor metabolizers should be "considered." However, whether preemptive testing for UGT1A1 genotype should be carried out in all individuals prior to receiving irinotecan is a controversial, evolving area, and experts differ. Some, including our institution, screen all patients. However, others do not. Preemptive testing is not widely recommended in various oncology guidelines. This subject is addressed in detail elsewhere. (See "Dosing of anticancer agents in adults", section on 'UGT1A1 polymorphisms and irinotecan'.) Irinotecan plus FU — A standard regimen for treatment of metastatic colorectal cancer is the combination of irinotecan, FU, and LV [142,143]. Both irinotecan and FU have overlapping toxicity profiles; a major concern with early studies of this triplet regimen was the potential for enhanced GI toxicity. The spectrum of GI toxicity with combined irinotecan plus FU and LV is schedule dependent: IFL — In two early trials of bolus irinotecan plus weekly FU and LV (the IFL regimen), unacceptably high rates of early treatment-related mortality were noted [144-146]. In both trials, patients receiving irinotecan plus bolus FU and LV (either daily or weekly) had a threefold higher rate of treatment-related death than those enrolled on other arms [144]. Most of the early deaths appeared to be due to a cluster of mainly GI symptoms that included diarrhea, nausea, vomiting, and abdominal cramping, which was typically accompanied by dehydration, neutropenia, fever, and electrolyte abnormalities [145]. Use of this regimen is no longer recommended, largely because of the risk of diarrhea and neutropenia. FOLFIRI — GI toxicity is less severe with other irinotecan-containing regimens that utilize irinotecan plus LV and short-term infusional FU (eg, FOLFIRI). In at least four trials, rates of grade 3 or 4 diarrhea with FOLFIRI (every-other-week irinotecan plus short-term infusional FU and LV) were between 10 and 14 percent [116,143,147,148]. The better tolerability of regimens in which irinotecan is combined with infusional rather than bolus FU [116] has led to the widespread use of FOLFIRI rather than IFL. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Irinotecan regimens'.) Liposomal irinotecan plus fluorouracil and leucovorin — Liposomal irinotecan is a nanoliposomal encapsulated preparation that allows irinotecan to remain in circulation for a https://www.uptodate.com/contents/2824/print

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longer duration compared with standard irinotecan; this increases drug uptake within tumor cells and conversion of irinotecan to its active form, SN-38 [149]. Liposomal irinotecan is approved in combination with FU/LV for second-line treatment of gemcitabine-refractory metastatic pancreatic cancer based on results from the international phase III NAPOLI-1 trial [150]. Severe diarrhea, which can be of early-onset or late-onset type, occurred in 13 percent of those receiving combination therapy in this trial. As with nonencapsulated irinotecan, the manufacturer of liposomal irinotecan recommends that the starting dose be lowered (from 70 to 50 mg/m2 every two weeks) in patients homozygous for UGT1A1*28. However, it does not specifically recommend testing for the UGT1A1*28 variant prior to starting therapy. (See "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'Liposomal irinotecan'.) Irinotecan plus capecitabine — Several studies of irinotecan plus capecitabine compared with FOLFIRI as treatment of metastatic colorectal cancer have demonstrated high rates GI toxicity [116,151]. The irinotecan doses were 240-250 mg/m2 every 21 days. A more favorable toxicity profile was noted in a phase III randomized trial of XELIRI versus FOLFIRI used a lower irinotecan dose of 200 mg/m2 every 21 days and lower capecitabine dose of 800 mg/m2 twice daily on days 1 through 14, every 21 days [152]. Oxaliplatin combinations — Combinations of oxaliplatin plus FU and LV have become the most widely chosen first-line chemotherapy regimens for metastatic colorectal cancer, at least in North America. In addition, oxaliplatin-containing regimens have also been shown to provide a survival benefit over non-oxaliplatin-containing regimens for adjuvant therapy of stage III colon cancer. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'FOLFOX versus FOLFIRI' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Oxaliplatin-based therapy'.) Enterotoxicity with combined oxaliplatin and FU-containing chemotherapy is dependent on the schedule of FU administration. With oxaliplatin combined with short-term infusional FU (a regimen referred to as FOLFOX), rates of grade 3 or 4 diarrhea are less than 20 percent [153156]. On the other hand, enterotoxicity is much more frequent and severe with regimens that combine oxaliplatin with weekly bolus FU and LV (eg, FLOX) [39], especially those that include daily bolus FU and LV [146]. This was shown in the NSABP C-07 trial, a comparison of the Roswell park regimen without or with (ie, FLOX) oxaliplatin as adjuvant therapy for stage II or III colon cancer [39]. During therapy, 79 of 1857 patients (4.3 percent) developed a syndrome of bowel wall injury characterized by hospitalization for management of severe diarrhea or dehydration and https://www.uptodate.com/contents/2824/print

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radiographic or endoscopic evidence of bowel wall thickening or ulceration, and the incidence was significantly higher in patients assigned to FLOX as compared with FU/LV (5.5 versus 3 percent). The incidence of bowel wall injury during chemotherapy was particularly high with FLOX as compared with FU and LV in patients aged 60 or older (6.7 versus 2.9 percent) and in females (9.1 versus 3.9 percent). Enteric sepsis, characterized by grade 3 or worse diarrhea and grade 4 neutropenia (with or without bacteremia), occurred in 22 patients on FLOX and 8 patients on FU/LV. There were five deaths due to enteropathy, all in patients with enteric sepsis, with or without bowel wall injury. These results underscore the need to closely monitor patients treated with adjuvant FU/LV chemotherapy for diarrhea and provide aggressive management of this symptom complex, particularly if oxaliplatin has been added. Capecitabine plus oxaliplatin — The combination of oxaliplatin and capecitabine (XELOX, also called CAPOX) has also been intensely investigated given its convenience. A phase III comparison of XELOX (capecitabine at 1000 mg/m2 twice a day for 14 days plus oxaliplatin 130 mg/m2 on day 1 every three weeks) versus FOLFOX (continuous infusion of FU at 2250 mg/m2 over 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every six weeks) in patients with metastatic colorectal cancer reported a significantly lower rate of grade 3 or 4 diarrhea with XELOX (14 versus 24 percent) but a significantly higher rate of grade 1 or 2 hyperbilirubinemia (37 versus 21 percent) [157]. The largest amount of safety data for XELOX comes from the IDEA collaboration, an international study that compared three versus six months of adjuvant chemotherapy [158]. The six trials included in the IDEA collaboration included 5071 patients who received XELOX, 2554 for three months and 2517 for six months. As expected, rates of grade 3 or worse diarrhea were higher in patients receiving six months of XELOX versus three months (21.5 versus 17.2 percent), but rates of diarrhea were similar for patients receiving XELOX versus oxaliplatin plus short-term infusional FU (FOLFOX). (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Duration of therapy'.) Fluoropyrimidine, irinotecan and oxaliplatin combinations — Combinations of leucovorinmodulated FU, plus irinotecan, and oxaliplatin (FOLFIRINOX, FOLFOXIRI) have increased rates of diarrhea compared with two-drug chemotherapy regimens such as FOLFOX or FOLFIRI, but they have become the standard of care for many patients with pancreatic cancer and select patients with colorectal cancer due to their superior efficacy and survival data. ●

The ACCORD 11 trial, a randomized comparison of the FOLFIRINOX regimen (

table 5)

against gemcitabine in metastatic pancreatic cancer, showed that 21 of 165 patients (12.7 https://www.uptodate.com/contents/2824/print

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percent) experienced grade 3 or worse diarrhea compared with 3 of 169 patients (1.8 percent) receiving gemcitabine alone [159]. (See "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer", section on 'FOLFOX and FOLFIRINOX'.) ●

Similarly, in a study of modified FOLFIRINOX (

table 6) as adjuvant therapy for pancreatic

cancer, 47 of 238 patients (20 percent) experienced grade 3 or higher diarrhea, and 200 of 238 patients (84.4 percent) experienced diarrhea of any grade [160]. ●

A related regimen, FOLFOXIRI in combination with bevacizumab (

table 7) has been

compared with both FOLFOX/bevacizumab and FOLFIRI/bevacizumab in metastatic colorectal cancer (see "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Three- versus two-drug combinations'):

• The TRIBE study showed that 47 of 250 patients (18.8 percent) who received FOLFOXIRI/bevacizumab experienced grade 3 or higher diarrhea, which was significantly higher than 27 of 254 patients (10.6 percent) who received FOLFIRI/bevacizumab [161].

• The TRIBE 2 study comparing FOLFOXIRI/bevacizumab with FOLFOX/bevacizumab also showed higher rates of grade 1 or 2 diarrhea (50.3 versus 35.1 percent) and grade 3 or higher diarrhea (17.0 versus 5.4 percent) with the four-drug regimen [162]. Pemetrexed — Pemetrexed is an antifolate with activity in NSCLC and mesothelioma. In phase II and III trials of pemetrexed monotherapy, diarrhea (typically grade 1 or 2) has been reported in approximately 10 to 15 percent of patients [163-165]. Pemetrexed in combination with platinum chemotherapy is widely used as treatment for NSCLC. Severe diarrhea is rare with pemetrexed/platinum regimens [166-168]. (See "Systemic chemotherapy for advanced nonsmall cell lung cancer" and "Systemic treatment for unresectable malignant pleural mesothelioma".) Cabazitaxel — Cabazitaxel is a semisynthetic taxane that is approved for the treatment of advanced prostate cancer. Diarrhea is a frequent problem, developing in 15 to 50 percent of treated patients, but it is severe (grade 3 or 4) in only 1 to 6 percent [169-172]. Nevertheless, in a pivotal phase III trial conducted in men with advanced prostate cancer, some deaths occurred in men treated with cabazitaxel that were attributed to diarrhea and electrolyte imbalance [171]. A later study that established the noninferiority of a 20 mg/m2 dose compared with the standard 25 mg/m2 dose showed that diarrhea rates and severity may be dose dependent. While the greatest improvement was in rates of neutropenia (41.8 versus 73.3 percent) and febrile neutropenia (2.1 versus 9.2 percent, the rates of diarrhea of any grade (30.7 versus 39.8 https://www.uptodate.com/contents/2824/print

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percent) and of grade 3 or higher diarrhea (1.4 versus 4.0 percent) were also modestly improved [173]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel'.) Other taxanes — Diarrhea is commonly reported in studies of the other taxanes such as docetaxel, paclitaxel and nanoparticle albumin-bound (nab)-paclitaxel. In studies of docetaxel used for castration-resistant prostate cancer, diarrhea occurred in approximately 35 percent of patients but was grade 3 or higher in less than 3 percent [174,175]. Rates and severity of diarrhea are similar with paclitaxel and nabpaclitaxel compared with docetaxel [176,177]. For example, in the Impassion130 trial comparing nabpaclitaxel plus atezolizumab versus nabpaclitaxel alone, approximately 33 percent of patients experienced diarrhea of any grade, and less than 3 percent experienced grade 3 or higher diarrhea in both study arms [176]. Predictably, combining taxanes with other chemotherapeutic agents can increase both the frequency and severity of diarrhea. For example, in a study of perioperative chemotherapy for gastric cancer, the regimen of FU/LV, oxaliplatin and docetaxel (FLOT) caused significantly more diarrhea than the epirubicin-containing regimens (52 versus 29 percent for grade 1 or 2 and 10 percent versus 4 percent for grade 3 or 4, p = 0.0016) [178]. Bortezomib and other proteasome inhibitors — Diarrhea is commonly seen with bortezomib, a proteasome inhibitor used in the treatment of multiple myeloma [179]. In the pivotal studies with this agent, diarrhea occurred in 51 percent of patients, with 8 percent of the events being grade 3 or 4. (See "Multiple myeloma: Administration considerations for common therapies", section on 'Proteasome inhibitors' and "Multiple myeloma: Treatment of first or second relapse", section on 'Daratumumab, bortezomib, dexamethasone (DVd)'.) Diarrhea is less common and less severe with carfilzomib [180] and the orally active agent ixazomib [181]. Vorinostat and belinostat — Vorinostat, a histone deacetylase inhibitor, was approved by the FDA in 2006 for the management of cutaneous T-cell lymphoma. In the pivotal studies of this agent, diarrhea was observed in 52 percent of the patients, with the great majority of these episodes being grade 1 or 2 events controllable by oral agents [182]. Belinostat is another histone deacetylase inhibitor that is approved for treatment of peripheral T-cell lymphoma. In an initial study, diarrhea was reported in 23 percent of treated patients but was severe in only 2 percent [183]. Lenalidomide and other immunomodulatory imide (IMiD) drugs — Lenalidomide can cause constipation or diarrhea. Pomalidomide can also cause both constipation or diarrhea in https://www.uptodate.com/contents/2824/print

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up to one-third of patients. Among patients with diarrhea, bile salt malabsorption may be one potential etiology that responds to treatment including reduced fat intake and bile acid sequestrants [184]. Risk with molecularly targeted agents — Diarrhea is a common side effect of several molecularly targeted agents. Small molecule EGFR inhibitors — Diarrhea is common in patients receiving small molecule epidermal growth factor receptor (EGFR) TKIs, such as erlotinib, gefitinib, afatinib, dacomitinib, osimertinib, and mobocertinib [167,185-188]. For patients treated with gefitinib and erlotinib, diarrhea is most likely to occur within the first four weeks of treatment initiation; with afatinib, diarrhea is most likely to occur within the first seven days. Although diarrhea is reported in up to 90 percent of patients treated with any of these agents (especially those treated with afatinib [189] and mobocertinib [190]), it is severe in fewer than 20 percent and typically can be easily managed by the use of loperamide. Uncommonly, diarrhea necessitates dose reduction or treatment interruptions. Although diarrhea can have a profound effect on patients, the available evidence suggests that diarrhea may be a surrogate indicator of antitumor efficacy [191,192]. Synergistic toxicity may be a problem when these agents are combined with chemotherapy. Diarrhea has been a significant dose-limiting toxicity in a number of studies combining EGFR inhibitors with concurrent radiation and chemotherapy [193,194]. Anti-EGFR monoclonal antibodies — Cetuximab is a chimeric immunoglobulin G subclass 1 (IgG1) monoclonal antibody that binds to the extracellular domain of the epidermal growth factor receptor (EGFR), competitively inhibiting ligand binding. In contrast with small-molecule EGFR inhibitors, cetuximab-related diarrhea is generally not severe: ●

A phase II study of cetuximab as monotherapy for 346 patients with metastatic colorectal cancer reported diarrhea of any grade in 12.7 percent [195].

●

When toxicities were reported, regardless of attribution to treatment, in a phase II study of patients with lung cancer treated with cetuximab alone, 22.7 percent had diarrhea of any grade [196].

●

Rates of grade 3 or 4 diarrhea in studies of single-agent cetuximab are only 1.5 to 2 percent [195-199].

Panitumumab is a fully human IgG2 monoclonal antibody directed against the EGFR. A phase III comparison of best supportive care (BSC) with or without panitumumab reported diarrhea of https://www.uptodate.com/contents/2824/print

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any grade in 21 percent of patients receiving panitumumab (grade 3, 1 percent), compared with 11 percent with BSC alone (none grade 3) [200]. Similar results are reported by others with panitumumab monotherapy [201]. PI3K inhibitors — There are four approved phosphoinositide 3-kinase (PI3K) inhibitors: idelalisib, duvelisib, alpelisib, and copanlisib; all are associated with diarrhea, which can be severe. ●

Idelalisib – Idelalisib is an oral inhibitor of PI3K delta; it is approved for treatment of relapsed chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Idelalisib'.) Across clinical trials, approximately 14 percent of treated patients have developed severe diarrhea or colitis (grade 3 or worse) [202-204]. Diarrhea can occur at any time during treatment, and it responds poorly to antimotility agents. Following interruption of therapy and, in some cases, the use of glucocorticoids or budesonide [203], the median time to resolution is between one and four weeks. Some patients with moderate to severe diarrhea have developed serious and fatal intestinal perforation. (See 'Idelalisib' below.)

●

Duvelisib – Duvelisib is an oral dual inhibitor of PI3K delta and gamma that is approved for treatment of chronic lymphocytic leukemia. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia".) Serious, including fatal, diarrhea or colitis has been reported in 11 to 18 percent of patients treated with duvelisib [205-207]. The United States Prescribing Information for duvelisib recommends that patients who present with abdominal pain, stool with mucus or blood, peritoneal signs, or grade 3 diarrhea have the drug withheld, and that supportive therapy be initiated with enteric-acting glucocorticoids (eg, budesonide) or systemic steroids.

Both idelalisib and duvelisib carry boxed warnings from the FDA for diarrhea and colitis. ●

Alpelisib – Alpelisib is another inhibitor of PI3K alpha that is approved, in combination with fulvestrant, for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers that have a mutation in the catalytic alpha subunit of PI3K. Diarrhea is common and occurs in approximately 60 percent of treated patients; it is severe (grade 3) in approximately 7 percent [208]. Specific recommendations for treatment

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interruption/dose reduction in the event of diarrhea are outlined in the table ( ●

table 8).

Copanlisib – Copanlisib is a unique inhibitor of PI3K alpha and delta in that it is administered by intravenous infusion and has a lower rate of GI toxicities. In a study of 142 patients with indolent lymphomas treated with copanlisib, 34 percent experienced diarrhea of any grade and only 5 percent experienced grade 3 or higher diarrhea. Only one patient with a known history of diverticulosis experienced grade 4 colitis; there were no perforations or deaths in the study. Copanlisib is approved for use in relapsed follicular lymphoma; the United States Prescribing Information for copanlisib does not carry a boxed warning for colitis or bowel perforation [209].

Small molecule inhibitors of VEGFR — Sorafenib, sunitinib, axitinib, regorafenib, pazopanib, cabozantinib, lenvatinib, and vandetanib are orally active inhibitors of multiple tyrosine kinases including the vascular endothelial growth factor receptor (VEGFR). Diarrhea is a prominent side effect of all VEGFR inhibitors. In clinical trials, diarrhea of any grade has been reported in 30 to 79 percent of patients (highest rates with vandetanib), with severe diarrhea (grade 3 or 4) in 3 to 17 percent [210-216]. (See "Toxicity of molecularly targeted antiangiogenic agents: Noncardiovascular effects", section on 'Gastrointestinal toxicities'.) BCR-ABL1 and KIT tyrosine kinase inhibitors — Imatinib, an inhibitor of BCR-ABL1 and other tyrosine kinases, such as KIT, causes diarrhea in approximately 30 percent of patients, but severe diarrhea is rare [217]. Similarly, dasatinib, which targets BCR-ABL1, KIT, and the Src family of tyrosine kinases (among others), causes diarrhea in approximately 30 percent, which is severe in A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5fluorouracil-associated toxicity. Pharmacogenetics 2002; 12:555. 60. Deenen MJ, Tol J, Burylo AM, et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17:3455. 61. Loganayagam A, Arenas Hernandez M, Corrigan A, et al. Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. Br J Cancer 2013; 108:2505. 62. Deenen MJ, Meulendijks D, Cats A, et al. Upfront Genotyping of DPYD*2A to Individualize Fluoropyrimidine Therapy: A Safety and Cost Analysis. J Clin Oncol 2016; 34:227. 63. Terrazzino S, Cargnin S, Del Re M, et al. DPYD IVS14+1G>A and 2846A>T genotyping for the prediction of severe fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics 2013; 14:1255. 64. Meulendijks D, Henricks LM, Sonke GS, et al. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol 2015; 16:1639. 65. Amstutz U, Farese S, Aebi S, Largiadèr CR. Dihydropyrimidine dehydrogenase gene variation and severe 5-fluorouracil toxicity: a haplotype assessment. Pharmacogenomics 2009; 10:931. 66. Meulendijks D, Henricks LM, van Kuilenburg AB, et al. Patients homozygous for DPYD c.1129-5923C>G/haplotype B3 have partial DPD deficiency and require a dose reduction when treated with fluoropyrimidines. Cancer Chemother Pharmacol 2016; 78:875. 67. van Kuilenburg AB, Meijer J, Mul AN, et al. Intragenic deletions and a deep intronic mutation affecting pre-mRNA splicing in the dihydropyrimidine dehydrogenase gene as novel mechanisms causing 5-fluorouracil toxicity. Hum Genet 2010; 128:529. 68. https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/ (Accessed on Jan uary 11, 2018). 69. Nie Q, Shrestha S, Tapper EE, et al. Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity. Clin Pharmacol Ther 2017; 102:662. 70. Lee AM, Shi Q, Alberts SR, et al. Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients: https://www.uptodate.com/contents/2824/print

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250. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012; 366:1382. 251. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet 2017; 390:1949. 252. González-Martín A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2019; 381:2391. 253. Bhalme M, Hayes S, Norton A, et al. Rituximab-associated colitis. Inflamm Bowel Dis 2013; 19:E41. 254. Larkin PJ, Cherny NI, La Carpia D, et al. Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines. Ann Oncol 2018; 29:iv111. 255. Talley NJ, Phillips SF, Haddad A, et al. GR 38032F (ondansetron), a selective 5HT3 receptor antagonist, slows colonic transit in healthy man. Dig Dis Sci 1990; 35:477. 256. Davies A, Leach C, Caponero R, et al. MASCC recommendations on the management of constipation in patients with advanced cancer. Support Care Cancer 2020; 28:23. 257. Sharma RK. Vincristine and gastrointestinal transit. Gastroenterology 1988; 95:1435. 258. Legha SS. Vincristine neurotoxicity. Pathophysiology and management. Med Toxicol 1986; 1:421. 259. Holland JF, Scharlau C, Gailani S, et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 1973; 33:1258. 260. Anderson H, Scarffe JH, Lambert M, et al. VAD chemotherapy--toxicity and efficacy--in patients with multiple myeloma and other lymphoid malignancies. Hematol Oncol 1987; 5:213. 261. Hohneker JA. A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Semin Oncol 1994; 21:42. 262. Haim N, Epelbaum R, Ben-Shahar M, et al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer 1994; 73:2515. 263. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341:1565. 264. Fine HA, Figg WD, Jaeckle K, et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 2000; 18:708. 265. Dimopoulos MA, Eleutherakis-Papaiakovou V. Adverse effects of thalidomide administration in patients with neoplastic diseases. Am J Med 2004; 117:508. https://www.uptodate.com/contents/2824/print

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266. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357:2133. 267. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med 2007; 357:2123. 268. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5fa97bf5-28a2-48f1-8955-f5601 2d296be. 269. United States Prescribing Information for pomalidomide available at http://www.accessdat a.fda.gov/drugsatfda_docs/label/2013/204026lbl.pdf?et_cid=31038989&et_rid=463638624& linkid=www.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2013%2f204026lbl.pdf (Acc essed on February 12, 2013). 270. Natale RB, Thongprasert S, Greco FA, et al. Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2011; 29:1059. 271. Robinson BG, Paz-Ares L, Krebs A, et al. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab 2010; 95:2664. 272. Wells, SA, Robinson, BG, Gagel, RRF, et al. Vandetanib (VAN) in locally advanced or metastat ic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA) (Abstra ct 5503). J Clin Oncol 2010; 28:421s. Abstract available online at http://www.asco.org/ASCOv 2/Meetings/Abstracts?&vmview=abst_detail_view&confID=74&abstractID=50718 (Accessed on April 25, 2011). 273. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double-blind, placebo-controlled trial of oral docusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013; 45:2. 274. Arnold D, Fuchs CS, Tabernero J, et al. Meta-analysis of individual patient safety data from six randomized, placebo-controlled trials with the antiangiogenic VEGFR2-binding monoclonal antibody ramucirumab. Ann Oncol 2017; 28:2932. 275. Gotlieb WH, Amant F, Advani S, et al. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 2012; 13:154. 276. Chekerov R, Hilpert F, Mahner S, et al. Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19:1247.

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277. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014; 370:699. 278. Kabbinavar FF, Flynn PJ, Kozloff M, et al. Gastrointestinal perforation associated with bevacizumab use in metastatic colorectal cancer: results from a large treatment observational cohort study. Eur J Cancer 2012; 48:1126. 279. McClay H, Cervi P. Thalidomide and bowel perforation: four cases in one hospital. Br J Haematol 2008; 140:360. 280. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=827d60e8-7e07-41b7-c28b-49e f1c4a5a41. 281. United States Prescribing Information for trametinib available at http://www.accessdata.fd a.gov/drugsatfda_docs/label/2017/204114s006lbl.pdf (Accessed on March 16, 2017). Topic 2824 Version 94.0

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GRAPHICS

NCI CTCAE v5.0 diarrhea Adverse event Diarrhea

Grade 1

Grade 2

Grade 3

Grade 4

Increase of G (rs55886062)

–

c.1905+1G>A (rs3918290)

–

Decreased DPD activity Increased toxicity risk Abolished DPD activity (homozygotes) Greatly increased toxicity risk

DPYD*9B

HapB3 collection of SNPs

c.2846A>T (rs67376798) 

–

c.483+18GG>A, c.680+139G>A, and c.95951T>C c.1236G>A occurring in complete linkage with c.11295923C>G

–

–

Deletion

Decreased DPD activity Increased toxicity risk Modest decrease in DPD  Increased toxicity risk

TYMS variants 3'-UTR 6 bp deletion (TTAAAG) (rs34489327; historically rs16430) 5'-TSER

Increased FU responsiveness Increased risk of toxicity

–

2R

28 bp VNTR (2R; 3R) (rs45445694) G>C SNP in 2nd repeat of 3R allele (3RC) (rs34743033)

Decreased TYMS expression

2R/2R or 2R/3RC: Decreased TYMS expression Increased FU responsiveness Increased risk of toxicity

–

3RC

3RC/3RC or 2R/3RC: Decreased TYMS expression Increased FU responsiveness Increased risk of toxicity

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DPYD: gene for dihydropyrimidine dehydrogenase; TYMS: gene for thymidylate synthetase; FU: fluorouracil; DPD: dihydropyrimidine dehydrogenase; SNP: single-nucleotide polymorphism; UTR: untranslated region; bp: base pair; TSER: promoter enhancer region of TYMS; VNTR: variable number of 28 base bp tandem repeats. * Clinicians should be aware that many laboratories restrict DPYD testing to the DPYD*2A variant. Graphic 109665 Version 4.0

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Likely DPD phenotype based upon genotype and recommended dosing of fluoropyrimidines by DPD phenotype[1] Recommended dosing of fluoropyrimidines¶ by DPD phenotype, from CPIC Implications Phenotype

Classification of

for phenotypic measures

Dosing recommendations

DPYD normal metabolizer

Normal DPD activity and "normal" risk for fluoropyrimidine toxicity

Based upon genotype, there is no indication to change dose or therapy. Use label-recommended dosing and administration.

Strong

DPYD intermediate metabolizer

Decreased DPD activity (leukocyte DPD activity at 30 to 70% that of the normal population) and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs

Reduce starting dose based upon activity score, followed by titration of dose based upon toxicityΔ or therapeutic drug monitoring (if available).

Activity score 1: Strong

Complete DPD deficiency and increased risk for severe or even fatal drug toxicity when treated with fluoropyrimidine drugs

Activity score 0.5: Avoid use of fluorouracil or fluorouracil prodrugbased regimens. In the event, based upon clinical advice, alternative agents are not considered a suitable therapeutic option, fluorouracil should be administered at a strongly reduced dose◊ with early therapeutic drug monitoring.§

DPYD poor metabolizer

recommendations

Activity score 1.5: Moderate

Activity score 1 or 1.5: Reduce dose by 50%.

Strong

Activity score 0: Avoid use of fluorouracil or fluorouracil prodrugbased regimens.

Assignment of likely DPD phenotypes based on DPYD genotypes, from CPIC Likely

Activity score¥

phenotype https://www.uptodate.com/contents/2824/print

Genotypes‡

Examples of

Alternative

genotypes†

designation:

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The high-risk genotype DPYD normal metabolizer

2

An individual carrying two normal-function alleles

[ = ];[ = ]

 

DPYD intermediate metabolizer

1 or 1.5

An individual carrying one normal-function allele plus one no-function allele or one decreasedfunction allele, or an individual carrying two decreasedfunction alleles

 

 

c.[1905+1G>A];[ = ]

*2A/normal

c.[1679T>G];[ = ]

*13/normal

c.[2846A>T];[ = ]

*9B/normal

c.[2846A>T]; [2846A>T]

*9B/*9B

c.[2846A>T]; [1129-5923C>G, c.1236G>A (HapB3)]¶¶

*9B/HapB3 with 1129-5923C>G

1.5

c.[1129-5923C>G, c.1236G>A (HapB3)];[ = ]¶¶

HapB3 with 11295923C>G/normal

1

c.[1129-5923C>G, c.1236G>A (HapB3)]/[1129-

HapB3 with 11295923C>G/HapB3 with 1129-5923C>G

1 1 1.5 1 1

5923C>G, c.1236G>A (HapB3)]¶¶ DPYD poor metabolizer

0 or 0.5 0.5 0.5

An individual carrying two nofunction alleles or an individual carrying one nofunction plus one decreasedfunction allele

0.5

 

 

c.[1679T>G]; [2846A>T]

*13/*9B

c.[1679T>G]; [1129-5923C>G,

*13/[1129-5923C>G, c.1236G>A (HapB3)]

c.1236G>A (HapB3)]¶¶ c.[1905+1G>A];

*2A/*9B

[2846A>T] 0.5

c.[1905+1G>A]; [1129-5923C>G,

*2A/[1129-5923C>G, c.1236G>A (HapB3)]

c.1236G>A (HapB3)]¶¶ 0 https://www.uptodate.com/contents/2824/print

c.[1679T>G];

*13/*13 67/91

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[1679T>G] 0

c.[1905+1G>A]; [1679T>G]

*2A/*13

0

c.[1905+1G>A];

*2A/*2A

[1905+1G>A] DPD: dihydropyrimidine dehydrogenase; fluoropyrimidines: fluorouracil, capecitabine, and tegafur; CPIC: Clinical Pharmacogenetics Implementation Consortium; c.[=]: sequence variant that does not confer heightened risk, refer to the Human Genome Variation Society (HVGS) website (http://varnomen.hgvs.org).

¶ Fluorouracil or capecitabine.

Δ Increase the dose in patients experiencing no or clinically tolerable toxicity in the first two cycles to maintain efficacy; decrease the dose in patients who do not tolerate the starting dose to minimize toxicities. ◊ If available, a phenotyping test (refer to UpToDate topic for further details) should be considered to estimate the starting dose. In the absence of phenotyping data, a dose of 3 days without improvement should be instructed to return for reevaluation. Worsening or persistent pain may indicate the development of a complication or the need to consider a different diagnosis. (See 'Worsening or persistent pain' above and "Evaluation of sore throat in children".)

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●

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We suggest not using systemic glucocorticoids for the symptomatic relief of throat pain in children and adolescents with acute pharyngitis (Grade 2C). Although low-dose glucocorticoids may modestly reduce the duration of pain compared with placebo, safe and effective alternatives (eg, acetaminophen, ibuprofen) are available without prescription or office visit. (See 'Glucocorticoids' above.) The use of glucocorticoids for upper airway obstruction in infectious mononucleosis is discussed separately. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Treatment'.)

●

We avoid probiotics, herbal therapies, homeopathic therapies, dietary supplements, or other complementary/alternative therapies in the treatment of sore throat in children and adolescents. They have not been proven to be effective and may be harmful. (See 'Alternative therapies' above.) Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Thompson M, Vodicka TA, Blair PS, et al. Duration of symptoms of respiratory tract infections in children: systematic review. BMJ 2013; 347:f7027. 2. Bisno AL. Acute pharyngitis: etiology and diagnosis. Pediatrics 1996; 97:949. 3. Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database Syst Rev 2013; :CD000023. 4. Thomas M, Del Mar C, Glasziou P. How effective are treatments other than antibiotics for acute sore throat? Br J Gen Pract 2000; 50:817. 5. Bradley CP. Taking another look at the acute sore throat. Br J Gen Pract 2000; 50:780. 6. Middleton DB, D'Amico F, Merenstein JH. Standardized symptomatic treatment versus penicillin as initial therapy for streptococcal pharyngitis. J Pediatr 1988; 113:1089. 7. Bisno AL. Acute pharyngitis. N Engl J Med 2001; 344:205. 8. Schmitt BD. Sore throat (pharyngitis). In: Instructions for Pediatric Patients, WB Saunders, P hiladelphia 1999. p.91. 9. Snellman L, Adams W, Anderson G, et al. Institute for Clinical Systems Improvement. Diagn osis and treatment of respiratory illness in children an adults. Updated January 2013. http s://www.icsi.org/guidelines__more/catalog_guidelines_and_more/catalog_guidelines/catalo g_respiratory_guidelines/respiratory_illness/ (Accessed on August 25, 2016). https://www.uptodate.com/contents/2875/print

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10. Weglowski J. An evidence-based approach to the evaluation and treatment of pharyngitis in children. Pediatr Emerg Med Pract 2011; 8:1. 11. Flurbiprofen: new indication. Lozenges: NSAIDs are not to be taken like sweets! Prescrire Int 2007; 16:13. 12. Ambroxol lozenges: new drug. Sore throat: better to just suck on hard candy. Prescrire Int 2009; 18:52. 13. Chenot JF, Weber P, Friede T. Efficacy of Ambroxol lozenges for pharyngitis: a meta-analysis. BMC Fam Pract 2014; 15:45. 14. Little P, Stuart B, Wingrove Z, et al. Probiotic capsules and xylitol chewing gum to manage symptoms of pharyngitis: a randomized controlled factorial trial. CMAJ 2017; 189:E1543. 15. Pierce CA, Voss B. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review. Ann Pharmacother 2010; 44:489. 16. Gehanno P, Dreiser RL, Ionescu E, et al. Lowest effective single dose of diclofenac for antipyretic and analgesic effects in acute febrile sore throat. Clin Drug Investig 2003; 23:263. 17. Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics in children. Clin Pharmacol Ther 1993; 53:593. 18. Bertin L, Pons G, d'Athis P, et al. Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. J Pediatr 1991; 119:811. 19. Benarrosh C. [Multicenter double blind study of tiaprofenic acid versus placebo in tonsillitis and pharyngitis in children]. Arch Fr Pediatr 1989; 46:541. 20. Eccles R, Loose I, Jawad M, Nyman L. Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. Pain Med 2003; 4:118. 21. Scottish Intercollegiate Guidelines Network. Management of sore throat and indications fo r tonsillectomy. Guideline No. 117. April 2010. http://www.sign.ac.uk/guidelines/fulltext/11 7/ (Accessed on August 30, 2016). 22. Moghal NE, Hegde S, Eastham KM. Ibuprofen and acute renal failure in a toddler. Arch Dis Child 2004; 89:276. 23. National Institute for Health and Care Excellence. Sore throat (acute): antimicrobial prescrib ing. January 2018. Available at: https://www.nice.org.uk/guidance/ng84 (Accessed on Janua ry 29, 2018). 24. Feder HM. Acute pharyngitis: fitting the drug to the bug. Contemp Pediatr 2001; 18:41. https://www.uptodate.com/contents/2875/print

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25. Watson N, Nimmo WS, Christian J, et al. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety. Int J Clin Pract 2000; 54:490. 26. Cingi C, Songu M, Ural A, et al. Effect of chlorhexidine gluconate and benzydamine hydrochloride mouth spray on clinical signs and quality of life of patients with streptococcal tonsillopharyngitis: multicentre, prospective, randomised, double-blinded, placebo-controlled study. J Laryngol Otol 2011; 125:620. 27. Cingi C, Songu M, Ural A, et al. Effects of chlorhexidine/benzydamine mouth spray on pain and quality of life in acute viral pharyngitis: a prospective, randomized, double-blind, placebo-controlled, multicenter study. Ear Nose Throat J 2010; 89:546. 28. Questions & Answers: Reports of a rare, but serious and potentially fatal adverse effect wit h the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mo uth www.fda.gov/Drugs/DrugSafety/ucm250029.htm (Accessed on August 03, 2012). 29. US Food and Drug Administration. Risk of serious and potentially fatal blood disorder prom pts FDA action on oral over-the-counter benzocaine products used for teething and mouth pain and prescription local anesthetics. Available at: https://www.fda.gov/Drugs/DrugSafet y/ucm608265.htm (Accessed on May 23, 2018). 30. Hopper SM, McCarthy M, Tancharoen C, et al. Topical lidocaine to improve oral intake in children with painful infectious mouth ulcers: a blinded, randomized, placebo-controlled trial. Ann Emerg Med 2014; 63:292. 31. Hess GP, Walson PD. Seizures secondary to oral viscous lidocaine. Ann Emerg Med 1988; 17:725. 32. Aertgeerts B, Agoritsas T, Siemieniuk RAC, et al. Corticosteroids for sore throat: a clinical practice guideline. BMJ 2017; 358:j4090. 33. Sadeghirad B, Siemieniuk RAC, Brignardello-Petersen R, et al. Corticosteroids for treatment of sore throat: systematic review and meta-analysis of randomised trials. BMJ 2017; 358:j3887. 34. de Cassan S, Thompson MJ, Perera R, et al. Corticosteroids as standalone or add-on treatment for sore throat. Cochrane Database Syst Rev 2020; 5:CD008268. 35. Chessman AW. Guideline: Experts recommend a single dose of oral steroids for pain relief in acute sore throat. Ann Intern Med 2018; 168:JC2. 36. Fernandes RM, Oleszczuk M, Woods CR, et al. The Cochrane Library and safety of systemic corticosteroids for acute respiratory conditions in children: an overview of reviews. Evid Based Child Health 2014; 9:733. https://www.uptodate.com/contents/2875/print

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37. Bereznoy VV, Riley DS, Wassmer G, Heger M. Efficacy of extract of Pelargonium sidoides in children with acute non-group A beta-hemolytic streptococcus tonsillopharyngitis: a randomized, double-blind, placebo-controlled trial. Altern Ther Health Med 2003; 9:68. 38. Mazzone A, Catalani M, Costanzo M, et al. Evaluation of Serratia peptidase in acute or chronic inflammation of otorhinolaryngology pathology: a multicentre, double-blind, randomized trial versus placebo. J Int Med Res 1990; 18:379. 39. Thamlikitkul V, Dechatiwongse T, Theerapong S, et al. Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis in adults. J Med Assoc Thai 1991; 74:437. 40. Spasov AA, Ostrovskij OV, Chernikov MV, Wikman G. Comparative controlled study of Andrographis paniculata fixed combination, Kan Jang and an Echinacea preparation as adjuvant, in the treatment of uncomplicated respiratory disease in children. Phytother Res 2004; 18:47. 41. Cáceres DD, Hancke JL, Burgos RA, et al. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine 1999; 6:217. 42. Brinckmann J, Sigwart H, van Houten Taylor L. Safety and efficacy of a traditional herbal medicine (Throat Coat) in symptomatic temporary relief of pain in patients with acute pharyngitis: a multicenter, prospective, randomized, double-blinded, placebo-controlled study. J Altern Complement Med 2003; 9:285. 43. Huang Y, Wu T, Zeng L, Li S. Chinese medicinal herbs for sore throat. Cochrane Database Syst Rev 2012; :CD004877. 44. Frye R, Bailey J, Blevins AE. Clinical inquiries. Which treatments provide the most relief for pharyngitis pain? J Fam Pract 2011; 60:293. 45. Sas D, Enrione MA, Schwartz RH. Pseudomonas aeruginosa septic shock secondary to "gripe water" ingestion. Pediatr Infect Dis J 2004; 23:176. 46. Newmaster SG, Grguric M, Shanmughanandhan D, et al. DNA barcoding detects contamination and substitution in North American herbal products. BMC Med 2013; 11:222. 47. Rodríguez-González M, Benavente Fernández I, Zafra Rodríguez P, et al. Toxicity of remedies for infantile colic. Arch Dis Child 2014; 99:1147. 48. Wille D, Hauri-Hohl M, Vonbach P, et al. Too much of too little: xylitol, an unusual trigger of a chronic metabolic hyperchloremic acidosis. Eur J Pediatr 2010; 169:1549.

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49. Aviner S, Berkovitch M, Dalkian H, et al. Use of a homeopathic preparation for "infantile colic" and an apparent life-threatening event. Pediatrics 2010; 125:e318. Topic 2875 Version 33.0

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GRAPHICS

Infectious causes of acute pharyngitis in children and adolescents  

Clinical syndrome

Clinical clues

Bacteria (requires antimicrobial therapy) Streptococcus,

Tonsillopharyngitis and scarlet fever

group A

Acute onset, fever, headache, abdominal pain, tonsillopharyngeal erythema and exudate, tender

(most common

anterior cervical lymph nodes

cause requiring antimicrobial therapy) Streptococcus, groups C and G

Tonsillopharyngitis and scarlatiniform rash

 

Neisseria

Pharyngitis

Oral-genital contact in sexually active

gonorrhoeae

adolescents

Fusobacterium

Jugular vein suppurative

Primarily affects adolescents and

necrophorum

thrombophlebitis (Lemierre

young adults, high fever (>39°C

syndrome)

[102.2°F]), rigors respiratory symptoms, unilateral neck swelling or pain

Arcanobacterium

Pharyngitis and scarlatiniform rash

haemolyticum Corynebacterium diphtheriae

More common in adolescents, rash occurs in approximately one-half

Diphtheria

Tightly adherent membrane in nose and throat, history of travel (particularly to former Soviet Union, Africa, or Asia), lack of immunizations

Tularemia

Ulcerative-exudative pharyngitis

Ingestion of poorly cooked wild animal meat or contaminated water

Atypical bacteria (may require specific therapy or infection control measures) Mycoplasma

Pneumonia, bronchitis, and

pneumoniae

pharyngitis

Adolescents and adults

Viruses that infect the pharynx directly Epstein-Barr virus

Infectious mononucleosis

(EBV)

Fever, severe pharyngitis, frequent exudates, anterior and posterior cervical lymphadenopathy, prominent constitutional symptoms

Cytomegalovirus

Infectious mononucleosis

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(CMV)

anterior and posterior cervical lymphadenopathy, prominent constitutional symptoms

Human

Primary HIV infection

Mononucleosis-like syndrome with

immunodeficiency

fever, weight loss, diffuse

virus (HIV)

adenopathy, rash, splenomegaly, lymphopenia

Herpes simplex virus types 1 and

Pharyngitis

2

Exudative or nonexudative tonsillopharyngitis in sexually active adolescents, ulcerative lip lesion in 10 to 40 percent of cases

Influenza A and B viruses

Influenza

Fever, cough, pharyngitis, headache, myalgia, seasonal epidemics

Enteroviruses

Herpangina and hand-foot-and-

Vesicles in posterior pharynx may be

(Coxsackie A)

mouth disease

accompanied by lesions on hands and feet

Adenovirus Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)*

Pharyngoconjunctival fever and

Conjunctivitis, tonsillopharyngeal

acute respiratory disease

erythema and exudates

Pharyngitis

Clinical features are variable; may

COVID-19 MIS-C

include fever, persistent cough, shortness of breath, gastrointestinal symptoms, cutaneous findings, epidemiologic link to individuals with SARS-CoV-2 infection

Viruses that cause nasopharyngitis (generally do not require specific therapy or infection control measures) Rhinovirus

Common cold

Nasal symptoms predominate

Coronaviruses,

Common cold

Nasal symptoms predominate

Bronchiolitis, common cold

Nasal symptoms predominate,

including SARSCoV-2* Respiratory syncytial virus Parainfluenza

seasonal epidemics Common cold, croup

Stridor, hoarseness, prominent nasal symptoms

This table is meant for use with UpToDate content on acute pharyngitis in children. Refer to UpToDate content for additional information (eg, indications for testing, management). COVID-19: coronavirus disease 2019; MIS-C: multisystem inflammatory syndrome in children. * SARS-CoV-2 requires strict infection control measures in health care settings and the community. https://www.uptodate.com/contents/2875/print

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Graphic 63398 Version 10.0

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Etiology of sore throat by age Cause Viral pharyngitis*

Infants and young children Respiratory viruses Herpangina (enterovirus)* SARS-CoV-2

Older children and adolescents Epstein-Barr virus (infectious mononucleosis)* Respiratory viruses* HIV Herpangina (enterovirus) HSV SARS-CoV-2

Bacterial pharyngitis

Group A Streptococcus

Group A Streptococcus*

Fusobacterium necrophorum and other

Neisseria gonorrhoeae

anaerobic bacteria (±Lemierre's syndrome¶ )

Other bacteriaΔ

Fusobacterium necrophorum and other anaerobic bacteria (±Lemierre's syndrome¶ ) Other bacteriaΔ

Other infections

Retropharyngeal abscess¶

Peritonsillar abscess¶

Lateral pharyngeal abscess¶

Retropharyngeal abscess¶

Epiglottitis¶

Lateral pharyngeal abscess¶ Epiglottitis¶

Miscellaneous conditions

Steven-Johnson syndrome

Psychogenic pharyngitis

Kawasaki disease

Referred pain

Behçet syndrome

Steven-Johnson syndrome

PFAPA syndrome

Kawasaki disease Behçet syndrome PFAPA syndrome

Traumatic injury

Foreign body

Irritation of the mucosa*

Chemical exposure HIV: human immunodeficiency virus; HSV: herpes simplex virus; SARS-CoV-2: severe acute respiratory coronavirus 2; PFAPA: periodic fever with aphthous stomatitis, pharyngitis, and adenitis. * Common causes of sore throat in children. ¶ Life-threatening causes of sore throat in children. Δ Other bacteria that can cause acute pharyngitis include group C and G Streptococcus, Arcanobacterium hemolyticum, Mycoplasma pneumoniae, Chlamydia pneumoniae, Francisella tularensis, https://www.uptodate.com/contents/2875/print

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Corynebacterium diphtheriae, and Neisseria gonorrhoeae. Graphic 60174 Version 18.0

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Contributor Disclosures Jan E Drutz, MD No relevant financial relationship(s) with ineligible companies to disclose. Teresa K Duryea, MD No relevant financial relationship(s) with ineligible companies to disclose. Mary M Torchia, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Dengue virus infection: Clinical manifestations and diagnosis Authors: Stephen J Thomas, MD, Alan L Rothman, MD, Anon Srikiatkhachorn, MD, Siripen Kalayanarooj, MD Section Editor: Martin S Hirsch, MD Deputy Editor: Keri K Hall, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Feb 23, 2021.

INTRODUCTION Dengue is a febrile illness caused by infection with one of four dengue viruses (DENV) transmitted by Aedes aegypti or Aedes albopictus mosquitoes during the taking of a blood meal [1-3]. Infection may be asymptomatic or present with a broad range of clinical manifestations including a mild febrile illness to a life-threatening shock syndrome. Numerous viral, host, and vector factors are thought to impact risk of infection, disease, and disease severity. There are four closely related but serologically distinct DENV types of the genus Flavivirus, called DENV-1, DENV-2, DENV-3, and DENV-4. There is transient cross-protection among the four types, which weakens and disappears over the months following infection; therefore, individuals living in a dengue-endemic area with all types co-circulating are at risk for infection with any and all DENV types. Issues related to clinical manifestations and diagnosis of DENV infection will be reviewed here. Issues related to epidemiology, pathogenesis, prevention, and treatment are discussed separately. (See "Dengue virus infection: Pathogenesis" and "Dengue virus infection: Prevention and treatment" and "Dengue virus infection: Epidemiology".)

CLASSIFICATION SCHEMES

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Overview — In 1997, the World Health Organization (WHO) published a classification scheme describing three categories of symptomatic DENV infection: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) [4]. (See 'WHO 1997 classification' below.) The WHO 1997 classification scheme is data driven and evidence based but has been criticized [5]. The term DHF suggests that hemorrhage is the cardinal manifestation of severe dengue; however, plasma leakage leading to intravascular volume depletion and potentially shock is the most specific feature of severe dengue and the focus of clinical management guidelines and algorithms [6,7]. In addition, some patients with severe illness requiring medical intervention do not meet all criteria for DHF. It is generally believed that use of the 1997 WHO definition for DHF underestimates the clinical burden of DENV infection [8]. In response to a wide call to reevaluate dengue disease classification, in 2009 the WHO published a revised classification scheme describing the following categories: dengue without warning signs, dengue with warning signs, and severe dengue [9] (see 'WHO 2009 classification' below). This scheme was proposed to emphasize early recognition of warning signs and thus optimize triage and management decisions. It has been adopted for case reporting and clinical management in many but not all countries. The sensitivity and specificity of the categories in the 2009 scheme for guiding clinical management of patients are not known. The 2009 classification has, in turn, been criticized for a lack of clarity in the criteria for severe dengue and for obscuring distinct disease phenotypes within each category [10]. Dengue classification schemes support a range of activities from clinical triage and treatment to epidemiologic and vaccine and drug studies. Each guideline has been evaluated by a number of groups, and the 2009 classification has not superseded the 1997 classification for all aspects of DENV infection [11-15]. The WHO issued additional documents on dengue management in 2011 and 2012 [16,17]. WHO 1997 classification — In 1997, the World Health Organization published a classification scheme describing three categories of symptomatic DENV infection: DF, DHF, and DSS [4]. (See 'Classification schemes' above.) Dengue fever — DF (also known as "break-bone fever") is an acute febrile illness defined by the presence of fever and two or more of the following but not meeting the case definition of dengue hemorrhagic fever [4] (see 'Dengue hemorrhagic fever' below): ●

Headache

●

Retro-orbital or ocular pain

●

Myalgia and/or bone pain

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●

Arthralgia

●

Rash

●

Hemorrhagic manifestations (eg, positive tourniquet test, petechiae, purpura/ecchymosis, epistaxis, gum bleeding, blood in emesis, urine, or stool, or vaginal bleeding)

●

Leukopenia

Dengue hemorrhagic fever — The cardinal feature of DHF is plasma leakage due to increased vascular permeability as evidenced by hemoconcentration (≥20 percent rise in hematocrit above baseline), pleural effusion, or ascites [4]. DHF is also characterized by fever, thrombocytopenia, and hemorrhagic manifestations (all of which may also occur in the setting of DF) [4]. (See 'Dengue fever' above.) In the setting of DHF, the presence of intense abdominal pain, persistent vomiting, and marked restlessness or lethargy, especially coinciding with defervescence, should alert the clinician to possible impending DSS [18]. (See 'Dengue shock syndrome' below.) The criteria for DHF comprise a narrow definition that does not encompass all patients with clinically severe or complicated dengue infections [5,19]. (See 'Classification schemes' above.) According to the guidelines, a DHF diagnosis requires all of the following be present: ●

Fever or history of acute fever lasting 2 to 7 days, occasionally biphasic

●

Hemorrhagic tendencies evidenced by at least one of the following:

• A positive tourniquet test – The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressures for 5 minutes. A test is considered positive when 10 or more petechiae per 2.5 cm (1 inch) square are observed. The test may be negative or mildly positive during the phase of profound shock. It usually becomes positive, sometimes strongly positive, if the test is conducted after recovery from shock.

• Petechiae, ecchymoses, or purpura. • Bleeding from the mucosa, gastrointestinal tract, injection sites, or other locations. • Hematemesis or melena. ●

Thrombocytopenia (100,000 cells per mm3 or less) – This number represents a direct count using a phase-contrast microscope (normal is 200,000 to 500,000 per mm3). In practice, for outpatients, an approximate count from a peripheral blood smear is acceptable. In

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healthy individuals, 4 to 10 platelets per oil-immersion field (100x; the average of the readings from 10 oil-immersion fields is recommended) indicates an adequate platelet count. An average of 3 platelets per oil-immersion field is considered low (ie, 100,000 per mm3). ●

Evidence of plasma leakage due to increased vascular permeability manifested by at least one of the following:

• A rise in the hematocrit equal to or greater than 20 percent above average for age, sex, and population.

• A drop in the hematocrit following volume-replacement treatment equal to or greater than 20 percent of baseline.

• Signs of plasma leakage such as pleural effusion, ascites, and hypoproteinemia. Dengue shock syndrome — DSS consists of DHF with marked plasma leakage that leads to circulatory collapse (shock) as evidenced by narrowing pulse pressure or hypotension ( table 1). For a diagnosis of DSS, all of the above four criteria for DHF must be present plus evidence of circulatory failure manifested by: ●

Rapid and weak pulse.

●

Narrow pulse pressure (20 mmHg [2.7 kPa]) or manifested by:

• Hypotension for age – Hypotension is defined to be a systolic pressure 80 mmHg (10.7 kPa) for those less than 5 years of age or 90 mmHg (12.0 kPa) for those greater than or equal to 5 years of age. Note that narrow pulse pressure is observed early in the course of shock, whereas hypotension is observed later or in patients who experience severe bleeding.

• Cold, clammy skin and restlessness. WHO 2009 classification — In 2009, the World Health Organization introduced a revised classification scheme consisting of the following categories: dengue without warning signs, dengue with warning signs, and severe dengue [9]. (See 'Classification schemes' above.) Dengue without warning signs — A presumptive diagnosis of dengue infection may be made in the setting of residence in or travel to an endemic area plus fever and two of the following [9]: https://www.uptodate.com/contents/3025/print

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Nausea/vomiting

●

Rash

●

Headache, eye pain, muscle ache, or joint pain

●

Leukopenia

●

Positive tourniquet test

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These clinical manifestations are described further above. (See 'Dengue fever' above.) Dengue with warning signs — Dengue with warning signs of severe infection includes dengue infection as defined above in addition to any of the following [9]: ●

Abdominal pain or tenderness

●

Persistent vomiting

●

Clinical fluid accumulation (ascites, pleural effusion)

●

Mucosal bleeding

●

Lethargy or restlessness

●

Hepatomegaly >2 cm

●

Increase in hematocrit concurrent with rapid decrease in platelet count

Issues related to plasma leakage are described further above. (See 'Dengue hemorrhagic fever' above.) Severe dengue — Severe dengue infection includes dengue infection with at least one of the following [9]: ●

Severe plasma leakage leading to:

• Shock • Fluid accumulation with respiratory distress ●

Severe bleeding (as evaluated by clinician)

●

Severe organ involvement:

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥1000 units/L • Impaired consciousness • Organ failure

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CLINICAL MANIFESTATIONS General principles — It is estimated that over 390 million DENV infections occur each year; approximately 96 million are clinically apparent [20]. Clinically apparent dengue infections are more common among adults [21]; among children, most dengue infections are asymptomatic or minimally symptomatic [22,23]. In one study including more than 3400 children in Southeast Asia and Latin America with acute febrile illness, dengue accounted for approximately 10 percent of cases; the incidence of virologically confirmed DENV infection was 4.6 and 2.9 episodes per 100 person-years, respectively, and the incidence of dengue hemorrhagic fever (DHF) was 2 seconds)

Very prolonged

Extremities

Warm, pink

Cool

Cold, clammy, mottled skin

Peripheral pulse volume

Good volume

Weak, thready

Feeble or absent

DHF: dengue hemorrhagic fever. * The World Health Organization has established the following grading system for severity of dengue hemorrhagic fever: DHF Grade I – Fever, hemorrhagic manifestation (positive tourniquet test), and evidence of plasma leakage. DHF Grade II – DHF Grade I plus spontaneous bleeding. DHF Grade III – DHF Grade I or DHF Grade II plus narrowing pulse pressure or hypotension. DHF Grade IV – DHF Grade III plus profound shock with undetectable blood pressure and pulse. Dengue shock syndrome consists of DHF Grade III and DHF Grade IV. ¶ Shock due to plasma leakage often presents with a narrow pulse pressure or elevated diastolic pressure with preserved systolic pressure, whereas shock due to bleeding often presents with hypotension or low systolic pressure. Other causes of shock must also be considered (such as hypoglycemia, excessive vomiting, or bacterial coinfection). https://www.uptodate.com/contents/3025/print

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Δ Pulse pressure is systolic pressure minus diastolic pressure. Modified from: Centers for Disease Control and Prevention. Dengue case management. Available at: http://www.cdc.gov/dengue/resources/dengue-clinician-guide_508.pdf (Accessed on September 15, 2016).

Graphic 109848 Version 2.0

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Rash in dengue fever

(A) Undifferentiated macular or maculopapular rash may occur over the face, thorax, abdomen, and extremities during the acute phase of dengue. The rash is typically macular or maculopapular and may be associated with pruritus. (B) Convalescent rash is characterized by confluent erythematous eruption with sparing areas of normal skin. It is often pruritic. The rash typically occurs within one to two days of defervescence and lasts one to five days.

Courtesy of Alan Rothman, MD.

Graphic 97534 Version 2.0

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Dengue virus infection

Maculopapular eruption on the back of a patient with dengue virus infection. Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.

Graphic 97996 Version 1.0

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Tourniquet test

Microvascular fragility may be demonstrated by a positive "tourniquet test"; this test is performed by inflating a blood pressure cuff on the arm to midway between systolic and diastolic blood pressures for five minutes. The pressure is released for at least one minute and the skin below the cuff is examined for petechiae. A finding of 10 or more petechiae in a one square inch area is considered positive. Courtesy of Siripen Kalayanarooj, MD.

Graphic 97567 Version 2.0

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Laboratory tests for diagnosis of dengue virus infection

Comparative merits of laboratory methods for diagnosis of dengue infection. Ig: immunoglobulin. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology. Peeling RW, Artsob H, Pelegrino JL, et al. Evaluation of diagnostic tests: Dengue. Nat Rev Microbiol 2010; 8:S30. Copyright © 2010. www.nature.com/nrmicro.

Graphic 113221 Version 1.0

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Dengue antibody response in primary and secondary infection

RNA: ribonucleic acid; NS1: nonstructural protein 1; Ig: immunoglobulin. Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Microbiology. Peeling RW, Artsob H, Pelegrino JL, et al. Evalua of diagnostic tests: Dengue. Nat Rev Microbiol 2010; 8:S30. Copyright © 2010. www.nature.com/nrmicro.

Graphic 113222 Version 1.0

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Approach to diagnostic testing for dengue and Zika virus infection in symptom individuals with risk for infection with both viruses

Specimen and test selection: Dengue and Zika virus NAATs, IgM antibody testing, and PRNTs should be pe NAATs also can be performed on plasma, whole blood, cerebrospinal fluid, or urine, and some antibody test plasma, whole blood, or cerebrospinal fluid. Laboratories might choose to perform dengue and Zika virus N testing simultaneously rather than sequentially, or to perform dengue virus nonstructural protein-1 testing NAAT. Indications to repeat assay(s): If the patient's illness has epidemiologic or clinical significance (eg, first cas area, new transmission mode, or unusual clinical syndrome), repeat a positive NAAT on newly extracted RNA specimen. For indeterminate IgM antibody test results, repeat IgM antibody testing or perform PRNT on the areas where PRNTs are not performed, report the indeterminate results and request a second serum specim testing. Interpretation of results: Dengue and Zika virus IgM antibodies can be detected in serum for months follo specific timing of infection cannot be determined. Data on the epidemiology of viruses known to be circulat exposure and clinical findings should be considered when interpreting the results of serologic diagnostic tes NAAT: nucleic acid amplification test; IgM: immunoglobulin M; PRNT: plaque reduction neutralization test. Reproduced from: Sharp TM, Fischer M, Muñoz-Jordán JL, et al. Dengue and Zika virus diagnostic testing for patients with a clinically c infection with both viruses. MMWR Recomm Rep 2019; 68:1. https://www.uptodate.com/contents/3025/print

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Graphic 121614 Version 2.0

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Interpretation of dengue and Zika virus diagnostic test results Dengue and Zika virus NAATs

Interpretation

Positive dengue virus assay, negative Zika virus

Acute dengue virus infection

assay Positive Zika virus assay, negative dengue virus

Acute Zika virus infection

assay Positive (both assays)

Acute dengue and Zika virus coinfection

Negative (both assays)

No evidence of dengue or Zika virus infection*

Dengue and Zika virus

Dengue

Zika

Nonpregnant

IgM antibodies

virus PRNT

virus PRNT

patients

≥10

5,000 U/L) are usually due to ischemic or drug-induced hepatitis. Other causes of massive elevations in AST include rhabdomyolysis and heat stroke. Differential diagnosis — Marked elevations in serum aminotransferase levels may be seen with: ●

Acetaminophen (paracetamol) toxicity

●

Idiosyncratic drug reactions

●

Acute viral hepatitis (hepatitis A, B, C, D, E; herpes simplex virus; varicella zoster virus; Epstein-Barr virus; cytomegalovirus [CMV]); other viral infections; or an acute exacerbation of chronic viral hepatitis (hepatitis B)

●

Alcoholic hepatitis

●

Autoimmune hepatitis

●

Wilson disease

●

Ischemic hepatitis

●

Budd-Chiari syndrome

●

Sinusoidal obstruction syndrome (veno-occlusive disease)

●

HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and occasionally acute fatty liver of pregnancy

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Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma)

●

Partial hepatectomy

●

Toxin exposure, including mushroom poisoning

●

Sepsis

●

Heat stroke

●

Muscle disorders (acquired muscle disorders [eg, polymyositis], seizures, and heavy exercise [eg, long distance running])

Evaluation of markedly elevated aminotransferases — For patients with marked elevations of serum aminotransferases, we obtain the following laboratory tests: ●

Acetaminophen level

●

Toxicology screen

●

Acute viral hepatitis serologies

• IgM anti-hepatitis A virus. • Hepatitis B surface antigen (HBsAg), IgM anti-hepatitis B core antigen (anti-HBc), antibody to HBsAg.

• Anti-hepatitis C virus antibody (HCV), hepatitis C viral RNA. • In some cases (based on patient history and risk factors): anti-herpes simplex virus antibodies, anti-varicella zoster antibodies, anti-CMV antibodies, CMV antigen, and, for Epstein-Barr virus, heterophile antibody. ●

Serum pregnancy test in women of childbearing potential who are not already known to be pregnant

●

Autoimmune markers (antinuclear antibodies, anti-smooth muscle antibodies, antiliver/kidney microsomal antibodies type 1, IgG)

●

Transabdominal ultrasonography with Doppler imaging to look for evidence of vascular occlusion (eg, Budd-Chiari syndrome)

Additional tests that are indicated in specific circumstances include: ●

Ceruloplasmin level and urinary copper quantitation in patients suspected of having Wilson disease. (See "Wilson disease: Clinical manifestations, diagnosis, and natural

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history", section on 'When to consider Wilson disease' and "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Diagnosis'.) ●

Hepatitis D virus antibodies in patients with acute or chronic hepatitis B. (See "Diagnosis of hepatitis D virus infection", section on 'Diagnosis of HDV infection'.)

●

Hepatitis E virus antibodies in patients who live in or travel to areas endemic for hepatitis E, such as Asia, Africa, the Middle East, and Central America, or in patients who are pregnant (because of the high rates of acute liver failure in pregnant women with hepatitis E). Additionally, cases of hepatitis E in the absence of foreign travel have been reported increasingly in developed countries [25,26] and in some cases of suspected drug-induced liver disease [27], and it is reasonable to test for antibodies to hepatitis E virus if no other cause for the elevated aminotransferases is found. (See "Hepatitis E virus infection", section on 'Diagnosis'.)

●

Urinalysis to look for proteinuria in women who are pregnant. (See "Preeclampsia: Clinical features and diagnosis", section on 'Definitions/diagnostic criteria'.)

●

Serum creatinine kinase or aldolase in patients with risk factors for or symptoms of muscle disorders.

If the above testing is negative, we typically proceed with a liver biopsy if the acute elevation of the serum aminotransferases fails to resolve or decline, or if the patient appears to be developing acute liver failure. If the elevation is less than five times the upper limit of normal and the patient appears well, we may follow the patient expectantly, checking liver tests every three to six months. Mild to moderate elevation — Mild to moderate elevations of the serum aminotransferases (less than 15 times the upper limit of normal) are often seen with chronic liver disease, although transient elevations may also be seen in patients with mild hepatic insults (eg, intake of nontoxic doses of acetaminophen). Differential diagnosis — Conditions associated with mild to moderate serum aminotransferase elevations include (

table 3):

●

Medication use

●

Chronic viral hepatitis (hepatitis B, C, D)

●

Alcoholic liver disease

●

Hemochromatosis

●

Nonalcoholic fatty liver disease

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●

Autoimmune hepatitis

●

Wilson disease

●

Alpha-1 antitrypsin deficiency

●

Congestive hepatopathy

●

Adult bile ductopenia

●

Malignant infiltration (most often breast cancer, small cell lung cancer, lymphoma, melanoma, or myeloma)

●

Muscle disorders (eg, subclinical inborn errors of muscle metabolism)

●

Thyroid disorders

●

Celiac disease

●

Adrenal insufficiency

●

Anorexia nervosa

●

Macro-AST (moderate elevations in plasma AST levels due to the presence ASTimmunoglobulin complexes, usually IgG) [28]

Evaluation of mildly or moderately elevated aminotransferases — The initial evaluation of patients with mildly to moderately elevated serum aminotransferases includes testing for chronic viral hepatitis, hemochromatosis, and nonalcoholic fatty liver disease (

table 4). The

majority of patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing will have alcoholic liver disease, steatosis, or steatohepatitis [29,30], and an initial evaluation directed toward likely causes of serum aminotransferase elevations can be cost-saving [29-32]. We typically start the evaluation with the following: ●

Hepatitis B: HBsAg, antibody to HBsAg, anti-HBc. (See "Hepatitis B virus: Screening and diagnosis".)

●

Hepatitis C: Anti-HCV. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

●

Hemochromatosis: Serum iron and total iron binding capacity (TIBC) with calculation of transferrin saturation (serum iron/TIBC). A transferrin saturation greater than 45 percent warrants obtaining a serum ferritin. Ferritin is less useful as an initial test because it is an acute phase reactant and therefore less specific than the transferrin saturation. A serum ferritin concentration of greater than 400 ng/mL (900 pmol/L) in men and 300 ng/mL (675 pmol/L) in women further supports (but does not confirm) the diagnosis of hemochromatosis. (See "Approach to the patient with suspected iron overload", section on 'Diagnosis'.)

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●

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Nonalcoholic fatty liver disease: The initial evaluation to identify the presence of fatty infiltration of the liver is radiologic imaging, usually ultrasonography, or possibly computed tomography (CT) or magnetic resonance imaging (MRI). Ultrasonography has a lower sensitivity than CT or MRI but is less expensive. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)

In a patient with a history of significant alcohol consumption, we generally do not obtain additional testing if the above tests are negative. For patients with liver test elevations less than five times the upper limit of normal, we typically recheck the liver tests in three to six months and only pursue the above workup if they remain elevated [2]. (See 'History' above.) If the initial evaluation fails to identify a likely source of the aminotransferase elevation, we test for the following: ●

Autoimmune hepatitis: Antinuclear antibodies, anti-smooth muscle antibodies, and antiliver/kidney microsomal antibodies, IgG (see "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation').

●

Wilson disease: Serum ceruloplasmin, evaluation for Kaiser-Fleisher rings, (see "Wilson disease: Clinical manifestations, diagnosis, and natural history", section on 'Initial evaluation').

●

Alpha-1 antitrypsin deficiency: Serum alpha-1 antitrypsin level; if indicated, alpha-1 antitrypsin phenotyping (see "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Evaluation and diagnosis').

●

Thyroid disorders: Thyroid-stimulating hormone, free T4 concentration, free T3 concentration (see "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Diagnosis of hyperthyroidism").

●

Celiac disease: Antibody screening with serum tissue transglutaminase antibodies [33] (see "Diagnosis of celiac disease in adults").

If the source of the liver test abnormalities is still unclear, we test for the following: ●

Adrenal insufficiency (in patients with symptoms associated with adrenal insufficiency, such as chronic malaise, anorexia, or weight loss): 8 AM serum cortisol and plasma corticotropin (ACTH), and a high-dose ACTH stimulation test (see "Clinical manifestations of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults").

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Muscle disorders (in patients with symptoms such exercise intolerance, muscle pain, or muscle weakness): Creatinine kinase or aldolase (see "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Clinical manifestations').

A liver biopsy is often considered in patients in whom all of the above testing has been unrevealing [34]. However, in some settings, the best course may be expectant observation. We suggest expectant observation in patients in whom the ALT and AST levels are less than five times the upper limit of normal and no chronic liver condition has been identified by the above noninvasive testing [2]. We use a conservative estimate for the upper limit of normal for aminotransferases (approximately 33 units/L for men and 25 units/L for women). In such patients, we will follow their liver biochemical and function tests every six months. This approach was supported by a preliminary study in which expectant clinical follow-up was found to be the most cost-effective strategy for managing asymptomatic patients with negative viral, metabolic, and autoimmune markers and chronically elevated aminotransferases [35]. A second small study also found that biopsy results rarely affected the management of such patients [36]. We suggest a liver biopsy in patients in whom the ALT and AST are persistently greater than twice the upper limit of normal, particularly if noninvasive testing suggests that advanced liver fibrosis is unlikely [34]. Occasionally, the biopsy will provide an unsuspected diagnosis or lead to a change in management [30]. In most cases, however, the biopsy proves reassuring to the patient and clinician by confirming that there is no evidence of serious or advanced liver disease. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

ELEVATED ALKALINE PHOSPHATASE Cholestasis may develop in the setting of extrahepatic or intrahepatic biliary obstruction ( table 5). In patients with cholestasis, the alkaline phosphatase is typically elevated to at least four times the upper limit of normal. The magnitude of the serum alkaline phosphatase elevation does not distinguish extrahepatic cholestasis from intrahepatic cholestasis. Lesser degrees of elevation are nonspecific and may be seen in many other types of liver disease, such as viral hepatitis, infiltrative diseases of the liver, and congestive hepatopathy. The gammaglutamyl transpeptidase (GGT) may also be elevated in the setting of cholestasis. However, elevated levels of serum GGT have been reported in a wide variety of other conditions. Patients with a predominantly cholestatic pattern typically undergo a right upper quadrant ultrasound to further characterize the cholestasis as intrahepatic or extrahepatic; the latter is suggested by biliary tract dilatation. (Related Pathway(s): Abnormal liver tests: Initial evaluation.) https://www.uptodate.com/contents/3576/print

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Confirming an elevated alkaline phosphatase is of hepatic origin — If a patient has an isolated elevation of the alkaline phosphatase, the first step in the evaluation is to confirm it is of hepatic origin, since alkaline phosphatase can come from other sources, such as bone and placenta (

algorithm 1). If, however, there are abnormalities in other liver chemistries or

markers of hepatic function, particularly an elevated bilirubin, confirmation is typically not required. To confirm that an isolated elevation in the alkaline phosphatase is coming from the liver, a GGT level or serum 5'-nucleotidase level should be obtained. These tests are usually elevated in parallel with the alkaline phosphatase in liver disorders but are not increased in bone disorders. An elevated serum alkaline phosphatase with a normal GGT or 5'-nucleotidase should prompt an evaluation for bone diseases. An elevated bone alkaline phosphatase is indicative of high bone turnover, which may be caused by several disorders including healing fractures, osteomalacia, hyperparathyroidism, hyperthyroidism, Paget disease of bone, osteogenic sarcoma, and bone metastases. We generally refer such patients to an endocrinologist for evaluation. Initial testing may include measurement of serum calcium, parathyroid hormone, 25-hydroxy vitamin D, and imaging with bone scintigraphy. (See "Bone physiology and biochemical markers of bone turnover", section on 'Markers of bone turnover' and "Clinical manifestations and diagnosis of Paget disease of bone", section on 'Clinical manifestations' and "Clinical manifestations, diagnosis, and treatment of osteomalacia", section on 'Diagnosis'.) Differential diagnosis — If the alkaline phosphatase elevation is isolated (ie, the other routine liver biochemical test levels are normal), is confirmed to be of hepatic origin, and persists over time, chronic cholestatic or infiltrative liver diseases should be considered (

table 5). The most

common causes include partial bile duct obstruction, primary biliary cholangitis (PBC), primary sclerosing cholangitis, and certain drugs, such as androgenic steroids and phenytoin. Infiltrative diseases include sarcoidosis, other granulomatous diseases, amyloidosis, and, less often, unsuspected cancer that is metastatic to the liver. Acute or chronic elevation of the alkaline phosphatase in conjunction with other liver biochemical abnormalities may be due to extrahepatic causes (eg, bile duct stones, primary sclerosing cholangitis, malignant biliary obstruction) or intrahepatic causes (eg, PBC, primary sclerosing cholangitis, infiltrative disease). (See 'Extrahepatic cholestasis' below and 'Intrahepatic cholestasis' below.) Rarely, an elevated alkaline phosphatase level is seen because of the presence of macro-alkaline phosphatase. Macro-alkaline phosphatase is due to the formation of complexes of alkaline https://www.uptodate.com/contents/3576/print

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phosphatase with immunoglobulins, which have reduced renal clearance compared with unbound alkaline phosphatase [37]. The clinical significance of these complexes is uncertain. Evaluation of elevated alkaline phosphatase — Testing in patients with an elevated alkaline phosphatase of hepatic origin typically starts with right upper quadrant ultrasonography to assess the hepatic parenchyma and bile ducts. The presence of biliary dilatation on ultrasonography suggests extrahepatic cholestasis, whereas the absence of biliary dilatation suggests intrahepatic cholestasis. However, ultrasonography may fail to show ductal dilatation in the setting of extrahepatic cholestasis in patients with partial obstruction of the bile duct or in patients with cirrhosis or primary sclerosing cholangitis, in which scarring prevents the intrahepatic ducts from dilating. The subsequent evaluation depends on whether ultrasonography suggests extrahepatic cholestasis or intrahepatic cholestasis. (See 'Extrahepatic cholestasis' below and 'Intrahepatic cholestasis' below.) Extrahepatic cholestasis — Although ultrasonography may indicate extrahepatic cholestasis, it rarely identifies the site or cause of obstruction. The distal bile duct is a particularly difficult area to visualize by ultrasonography because of overlying bowel gas. Potential causes of extrahepatic cholestasis include ( ●

table 5):

Choledocholithiasis (the most common cause) (see "Choledocholithiasis: Clinical manifestations, diagnosis, and management", section on 'Transabdominal ultrasound' and "Choledocholithiasis: Clinical manifestations, diagnosis, and management", section on 'Additional imaging (MRCP or EUS)').

●

Malignant obstruction (pancreas, gallbladder, ampulla, bile duct cancer, or metastasis to perihilar lymph nodes) (see "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Diagnostic approach' and "Gallbladder cancer: Epidemiology, risk factors, clinical features, and diagnosis", section on 'Diagnostic evaluation' and "Ampullary carcinoma: Epidemiology, clinical manifestations, diagnosis and staging", section on 'Diagnosis and staging' and "Clinical manifestations and diagnosis of cholangiocarcinoma").

●

Primary sclerosing cholangitis with an extrahepatic bile duct stricture (see "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis').

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Chronic pancreatitis (including autoimmune pancreatitis) with stricturing of the distal bile duct (see "Overview of the complications of chronic pancreatitis", section on 'Biliary obstruction').

●

AIDS cholangiopathy (see "AIDS cholangiopathy", section on 'Clinical suspicion and diagnosis').

If ultrasonography suggests obstruction due to a stone or malignancy, or if the onset of the cholestasis was acute, endoscopic retrograde cholangiopancreatography (ERCP) should be carried out to confirm the diagnosis and facilitate biliary drainage. If the cholestasis is chronic or ultrasonography shows biliary dilatation without an apparent cause or in patients who are at high risk for ERCP, magnetic resonance cholangiopancreatography (MRCP) or computed tomography (CT) should be obtained. In some cases, endoscopic ultrasonography may help identify an obstruction. ERCP can then be performed if there is evidence of an obstructing stone, stricture, or malignancy. If the results of ERCP or MRCP are negative for biliary tract disease, liver biopsy should be considered. (See "Overview of endoscopic retrograde cholangiopancreatography (ERCP) in adults", section on 'Patient selection'.) Intrahepatic cholestasis — There are numerous possible causes of intrahepatic cholestasis ( table 5), including drug toxicity, PBC, primary sclerosing cholangitis, viral hepatitis, cholestasis of pregnancy, benign postoperative cholestasis, infiltrative diseases, and total parenteral nutrition. In many cases, a possible cause can be identified based on the patient's history. If drug-induced cholestasis is suspected, elimination of the offending drug usually leads to resolution of cholestasis, although it may take months. If no cause is identified, additional testing is required. In patients with intrahepatic cholestasis, antimitochondrial antibodies (AMA), antinuclear antibodies, and antismooth muscle antibodies should be checked. If present, AMA are highly suggestive of PBC, and a liver biopsy may be considered to confirm the diagnosis. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Diagnosis'.) If AMA are absent, additional testing includes: ●

MRCP to look for evidence of primary sclerosing cholangitis (see "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis').

●

Testing for hepatitis A, B, C, and E (see 'Elevated serum aminotransferases' above).

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Testing for Epstein-Barr virus and cytomegalovirus (see "Infectious mononucleosis", section on 'Diagnosis' and "Overview of diagnostic tests for cytomegalovirus infection").

●

Pregnancy testing in women of child bearing potential who are not known to be pregnant (see "Intrahepatic cholestasis of pregnancy", section on 'Diagnosis').

If the above tests are negative and the alkaline phosphatase is persistently more than two times the upper limit of normal for more than six months, we obtain a liver biopsy. A liver biopsy may reveal evidence of an infiltrative disease (eg, sarcoidosis, malignancy) or other causes of cholestasis, such as vanishing bile duct syndrome and idiopathic adulthood bile ductopenia. If the alkaline phosphatase is less than two times the upper limit of normal, all of the other liver biochemical tests are normal, and the patient is asymptomatic, we suggest observation alone, since further testing is unlikely to influence management [36].

ISOLATED GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT) ELEVATION Elevated levels of serum GGT have been reported in a wide variety of clinical conditions, including pancreatic disease, myocardial infarction, renal failure, chronic obstructive pulmonary disease, diabetes mellitus, and alcoholism. High serum GGT values are also found in patients taking medications such as phenytoin and barbiturates. GGT is sensitive for detecting hepatobiliary disease, but its usefulness is limited by its lack of specificity. An elevated GGT with otherwise normal liver biochemical tests (including a normal alkaline phosphatase) should not lead to an exhaustive work-up for liver disease. We suggest GGT only be used to evaluate elevations of other serum enzyme tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or to support a suspicion of alcohol abuse in a patient with an elevated AST and an AST to ALT ratio of greater than 2:1). (See "Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5'-nucleotidase, gamma-glutamyl transpeptidase)".)

ISOLATED HYPERBILIRUBINEMIA The initial step in evaluating a patient with an isolated elevated hyperbilirubinemia is to fractionate the bilirubin to determine whether the hyperbilirubinemia is predominantly conjugated (direct hyperbilirubinemia) or unconjugated (indirect hyperbilirubinemia). An increase in unconjugated bilirubin in serum results from overproduction, impairment of uptake, or impaired conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased https://www.uptodate.com/contents/3576/print

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excretion into the bile ductules or leakage of the pigment from hepatocytes into serum. (See "Clinical aspects of serum bilirubin determination" and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".) (Related Pathway(s): Abnormal liver tests: Initial evaluation.) Unconjugated (indirect) hyperbilirubinemia — Unconjugated hyperbilirubinemia may be observed in a number of disorders (

table 6). These can be divided into disorders associated

with bilirubin overproduction (such as hemolysis and ineffective erythropoiesis) and disorders related to impaired hepatic uptake or conjugation of bilirubin (such as Gilbert disease, CriglerNajjar syndrome, and the effects of certain drugs). The evaluation typically involves evaluation for hemolytic anemia as well as obtaining a history to determine if the patient has Gilbert syndrome. In a patient with a history consistent with Gilbert syndrome (eg, the development of jaundice during times of stress or fasting), normal serum aminotransferase and alkaline phosphatase levels and mild unconjugated hyperbilirubinemia (20 mg/dL [342 micromol/L]) and neurologic impairment due to kernicterus. Crigler-Najjar type II is more common than type I. Patients live into adulthood with serum bilirubin levels that range from 6 to 25 mg/dL (103 to 428 micromol/L). Bilirubin UDP glucuronosyltransferase activity is typically present but greatly reduced. Bilirubin UDP glucuronosyltransferase activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. (See "Crigler-Najjar syndrome".)

Conjugated (direct) hyperbilirubinemia — An isolated elevation in conjugated bilirubin is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome. DubinJohnson syndrome and Rotor syndrome should be suspected in patients with mild hyperbilirubinemia (with a direct-reacting fraction of approximately 50 percent) in the absence of other abnormalities of standard liver biochemical tests. Normal levels of serum alkaline phosphatase and GGT help to distinguish these conditions from disorders associated with biliary obstruction. Differentiating between these syndromes is possible but clinically unnecessary due to their benign nature. In children, other inherited disorders caused by mutations in one of a variety of bile salt transporters may need to be considered [39]. (See "Inherited disorders associated with conjugated hyperbilirubinemia".) Patients with both conditions present with asymptomatic jaundice, typically in the second decade of life. The defect in Dubin-Johnson syndrome is altered hepatocyte excretion of bilirubin into the bile ducts, while Rotor syndrome is due to defective hepatic reuptake of bilirubin by hepatocytes [40].

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Abnormalities in tests of liver synthetic function, such as the prothrombin time and serum albumin level, are often seen in patients with chronic liver disease in conjunction with other liver test abnormalities. These patients should be evaluated according to the predominant pattern of liver test abnormalities. (See 'Patterns of liver test abnormalities' above.) However, isolated abnormalities in the prothrombin time or albumin are typically due to causes other than liver disease. The evaluation of these abnormalities is discussed elsewhere. (See "Clinical use of coagulation tests", section on 'Prothrombin time (PT) and INR' and "Overview of heavy proteinuria and the nephrotic syndrome" and "Protein-losing gastroenteropathy" and "Malnutrition in children in resource-limited countries: Clinical assessment".)

WHEN TO REFER TO A SPECIALIST Referral to a gastroenterologist or hepatologist should be considered for patients with unexplained, persistent liver biochemical test elevations (≥2 times the upper limit of normal for aminotransferases or 1.5 times the upper limit of normal for alkaline phosphatase) and for patients who are being considered for liver biopsy. We use a conservative estimate for the upper limit of normal for aminotransferases (approximately 30 units/L for men and 20 units/L for women) since the higher limits reported by many laboratories likely underestimate the degree of aminotransferase elevation. (See 'Aminotransferases' above.) If the liver tests normalize or remain mildly elevated (15 to 23 kg

>23 to 40 kg

>40 kg

60 mg/day

90 mg/day orally

120 mg/day

150 mg/day

orally divided

divided into 2 doses for 5 days

orally divided into 2 doses for

orally divided into 2 doses for

5 days

5 days

into 2 doses for 5 days ≥13 years

150 mg/day orally divided into 2 doses for 5 days

Baloxavir (Xofluza)Δ 40 mg tablet

≥12 years

80 mg tablet

Weight 40 to 80 kg – 40 mg orally as a single dose Weight ≥80 kg – 80 mg orally as a single dose

Peramivir (Rapivab)* 200 mg in 20 mL (10 mg/mL) in a single-use vial

6 months through 12 years 12 mg/kg per dose IV as a single dose (maximum dose 600 mg) ≥13 years 600 mg IV as a single dose

Zanamivir (Relenza)◊ 5 mg per inhalation

≥7 years

(Diskhaler)

2 inhalations (10 mg total per dose) twice daily for 5 days§

This table is meant for use with UpToDate content related to treatment of seasonal influenza in children. The choice of agent for treatment may vary with the age of the child and susceptibility patterns of circulating strains. Refer to UpToDate content for additional details, including indications for treatment and dosing recommendations for oseltamivir in infants younger than 1 year.

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IV: intravenously. * Dose adjustment is necessary for patients with renal insufficiency. ¶ When dispensing the oral suspension of oseltamivir, providers and pharmacists must take care to provide a dosing device that matches the units of measure on the prescription. Δ Baloxavir is available in Japan for the treatment of influenza in children 20 mm/h) and/or CRP (>10 to 20 mg/L [1 to 2 mg/dL]) is sensitive (approximately 95 percent) in cases of culture-proven osteomyelitis in https://www.uptodate.com/contents/6067/print

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children, but ESR and CRP are nonspecific [4-6]. Elevated ESR and/or CRP support the diagnosis of osteomyelitis but do not exclude other conditions in the differential diagnosis. ESR and CRP may be normal early in the infection in some patients, and repeat testing may be warranted within 24 hours in children in whom osteomyelitis is strongly suspected. CRP and, to a lesser extent, ESR also are important markers for evaluating the response to therapy. (See "Hematogenous osteomyelitis in children: Management", section on 'Response to therapy'.) Elevation of the white blood cell (WBC) count is neither a sensitive nor a specific indicator of osteomyelitis. In a 2012 systematic review of >12,000 patients, the WBC was elevated in only 36 percent [5]. However, the CBC and differential are helpful in evaluating other considerations in the differential diagnosis of children with bone pain (eg, vaso-occlusive crisis in sickle cell disease, leukemia). (See 'Differential diagnosis' below.) Radiographs — Radiograph(s) of the affected region(s) should be performed as the initial imaging study to exclude other causes of pain (eg, bone tumors and fractures) [3,7,8]. Radiographs are usually normal or inconclusive early in the course of osteomyelitis. Newborn infants are an exception to this general rule; radiographs are abnormal at the time of evaluation in most newborn and young infants who are ultimately found to have osteomyelitis [9,10]. For older children with suspected osteomyelitis and normal or inconclusive radiographs, MRI is usually indicated. (See 'Advanced imaging' below and 'Differential diagnosis' below.) Characteristic findings — Children with suspected osteomyelitis and characteristic abnormalities on initial radiographs are likely to have osteomyelitis (

table 1). They should

receive empiric antibiotic therapy pending further evaluation (microbiology and possibly additional imaging studies). (See "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy' and 'Microbiology' below and 'Advanced imaging' below.) Radiographic findings that are compatible with osteomyelitis include: ●

Evidence of periosteal new bone formation (periosteal reaction) (

●

Periosteal elevation (suggestive of periosteal abscess) (

●

Lytic lesions (

image 1A-B)

image 1D)

image 1C) or sclerosis, indicating subacute/chronic infection

However, these findings generally are not apparent at the onset of symptoms. The timing and typical sequence of radiographic changes of osteomyelitis varies depending on which bones are affected and the age of the patient. ●

Long bones – The typical sequence of radiographic changes in long bones of children is as follows [11,12]:

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• Approximately three days after symptom onset – Small area of localized, deep, softtissue swelling in the region of the metaphysis (

image 2)

• Three to seven days after symptom onset – Obliteration of the translucent fat planes interposed within muscle by edema fluid

• Ten to 21 days after symptom onset (7 to 10 days in neonates) – Evidence of bone destruction (osteopenia, osteolytic lesions), periosteal reaction, cortical thickening, periosteal elevation (due to subcortical purulence (

image 1A-D)); these lesions may

require surgical debridement or drainage (see "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery')

• One month or longer – Lytic sclerosis ●

Membranous, irregular bones – Bone destruction and periosteal elevation generally are apparent two to three weeks later than in long bones.

●

Pelvic bones – Radiographs usually are not useful in the diagnostic evaluation of osteomyelitis of the pelvis; in one large series, they were abnormal in only 25 percent of patients [13].

●

Vertebral osteomyelitis – In children with vertebral osteomyelitis, radiographs are normal at initial presentation in more than 50 percent of cases [14]. Initial abnormalities may include localized rarefaction of one vertebral plateau, followed by involvement of adjacent vertebrae. Marked destruction of bone, usually anteriorly, can occur, followed by anterior osteophytic reactions with bridging and bone sclerosis.

●

Discitis – The radiographic changes of discitis are first noted several weeks after the onset of symptoms, with the following sequence:

• Narrowing of the disc space two to four weeks after the onset of symptoms • Destruction of the adjacent cartilaginous vertebral end-plates • Herniation of the disc into the vertebral body In older children, anterior spontaneous fusion is common. Rarely, vertebral body compression or wedging is noted. Despite the delay in radiographic changes, findings suggestive of discitis often are apparent at the time of presentation (because of the indolent course). In one series, as an

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example, radiographic changes were present on initial evaluation in more than 70 percent of cases [14]. Normal radiographs — A normal radiograph early in the course (eg, within seven days of symptom onset) does not exclude osteomyelitis. Children with suspected osteomyelitis (eg, localized bone pain, limited function, elevated ESR or CRP) and normal initial radiographs generally should receive empiric antibiotic therapy pending additional imaging and the results of microbiologic studies. However, school-age children who are afebrile and have equivocal physical examination findings, and normal radiographs may occasionally be followed closely without antimicrobial therapy pending additional evaluation. (See "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy' and 'Advanced imaging' below and 'Microbiology' below.) Further imaging, usually with MRI or scintigraphy, should be performed as soon as possible in any child with suspected osteomyelitis whose initial radiographs are normal, regardless of whether antibiotic therapy is initiated (

image 3). (See 'Advanced imaging' below.)

Advanced imaging — Most children with suspected osteomyelitis undergo additional imaging with MRI, scintigraphy, computed tomography (CT), and/or ultrasonography (

table 2).

Indications for these imaging studies may include: ●

Confirmation of the diagnosis in children with normal initial radiographs

●

Further evaluation of abnormalities identified on radiographs (eg, bone destruction)

●

Evaluation of extension of infection (eg, growth plate, epiphysis, joint, adjacent soft tissues)

●

Guidance for percutaneous diagnostic and therapeutic drainage procedures (eg, needle aspiration, abscess drainage)

Magnetic resonance imaging — If it is available, MRI is the imaging modality of choice when imaging other than radiography is needed to establish the diagnosis of osteomyelitis (eg, early in the course) or to delineate the location and extent of bone and soft tissue involvement ( table 2) [3,7,8]. Intravenous contrast is not generally required but may help define intramedullary abscess or intramuscular abscesses [15]. Osteomyelitis is unlikely if MRI is negative. MRI is particularly useful in identifying and/or distinguishing: ●

Early changes in the bone marrow cavity (before changes in cortical bone are apparent on radiographs) [16]

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●

Pelvic osteomyelitis [17-19]

●

Involvement of the vertebral body and the adjacent disc in children with vertebral osteomyelitis

●

Areas that may require surgical drainage (eg, sinus tracts, intraosseous abscesses, subperiosteal or soft-tissue collections of pus) (

image 4) (see "Hematogenous

osteomyelitis in children: Management", section on 'Indications for surgery') ●

Involvement of the growth plate (

image 3) [20-22]

●

Contiguous septic arthritis (especially in the evaluation of young children with possible septic arthritis of the hip or femoral osteomyelitis)

●

Associated pyomyositis

●

Evidence of venous thrombosis

The major advantages of MRI compared with other imaging modalities include accurate identification of subperiosteal or soft-tissue collections of pus and avoidance of exposure to ionizing radiation [23]. In addition, the efficacy of MRI does not appear to be affected by diagnostic or surgical intervention. However, repeat MRI may be of limited value after surgical drainage because it can be difficult to distinguish between postsurgical changes and recurrent or persisting infection. Repeat MRI seldom leads to management changes in patients with clinical improvement. In a retrospective review of 60 cases of acute osteomyelitis, only 11 of 104 repeat MRIs resulted in a change in treatment; in all 11 cases, the CRP was persistently elevated or rising [24]. Disadvantages of MRI include a longer scanning time than CT and the need for sedation or general anesthesia for an adequate study in most young children, which may be a limiting factor in some institutions. MRI is less useful when multiple sites of involvement are suspected or there are no localized clinical findings. Finally, MRI is not always readily available. MRI demonstrates excellent anatomic detail and differentiation among soft tissue, bone marrow, and bone ( ●

image 5).

Areas of active inflammation show a decreased signal in T1-weighted images and an increased signal in T2-weighted images [25]. Fat-suppression sequences, including shorttau inversion recovery (STIR), decrease the signal from fat and are more sensitive for the detection of bone-marrow edema.

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The penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images (

image 6)) is characteristic of subacute

osteomyelitis and in one study was helpful in differentiating between indolent infections and neoplasms [26]. ●

The signal from infected bone marrow can be enhanced with intravenous gadolinium contrast [27], but this is seldom necessary for diagnostic purposes [15,28]. Because of the risk of nephrogenic systemic fibrosis, imaging with gadolinium should be avoided, if possible, in patients with moderate or advanced renal failure. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

MRI abnormalities in discitis include reduction of disc space, increased T2 signal in the adjacent vertebral end plates, and signal intensity changes in the intervening discs [14,16]. The sensitivity and specificity for the detection of bone involvement in children with suspected osteomyelitis with MRI are high (80 to 100 percent and 70 to 100 percent, respectively, in a 2012 systematic review) [5]. Given the high sensitivity, osteomyelitis is unlikely if the MRI is negative [7], although rare patients lack MRI abnormalities at the time of presentation. False-positive results may occur in patients with adjacent soft tissue infection; adjacent soft tissue infection can cause edema of the bone that may be interpreted as "consistent with osteomyelitis" but represents sympathetic inflammation rather than bone infection. False-positive MRI results also may occur in children with vitamin C deficiency [29-32]. (See 'Other noninfectious conditions' below.) Scintigraphy — We suggest scintigraphy (also known as radionuclide scanning or bone scan) when MRI is not available and imaging other than radiography is needed to establish the diagnosis of osteomyelitis (

table 2). Scintigraphy also may be useful when the area of

suspected infection cannot be localized or multiple areas of involvement are suspected. Scintigraphy is helpful early in the course, readily available, relatively inexpensive, and requires sedation less frequently than MRI in young children. However, it does not provide information about the extent of purulent collections that may require drainage (eg, intramedullary abscess, muscular phlegmon) [7]. Scintigraphy may be falsely negative if the blood supply to the periosteum is disrupted (eg, subperiosteal abscess) and during the transition between decreased and increased activity [33,34]. In addition, scintigraphy involves exposure to ionizing radiation [35]. The three-phase bone scan utilizing technetium 99m (99mTc) usually is performed as the initial nuclear medicine procedure in the evaluation of osteomyelitis. It consists of: https://www.uptodate.com/contents/6067/print

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●

A nuclear angiogram (the flow phase), obtained two to five seconds after injection

●

The blood pool phase, obtained 5 to 10 minutes after injection

●

The delayed phase, specific for bone uptake, obtained two to four hours after injection

Increased uptake of tracer in the first two phases can be caused by anything that increases blood flow and is accompanied by inflammation. Osteomyelitis causes focal uptake in the third phase; the intensity of the signal reflects the level of osteoblastic activity. Localization of a lesion near a growth plate can complicate interpretation. The sensitivity and specificity for the detection of bone involvement in children with suspected osteomyelitis with scintigraphy generally are high, but the range is wider than MRI (53 to 100 percent and 50 to 100 percent, respectively in a 2012 systematic review) [5]. Sensitivity is variable in neonates but appears to be lower than in older children [9,36,37]. Scintigraphy has been shown to have poor sensitivity (53 percent) in cases of osteomyelitis caused by methicillinresistant Staphylococcus aureus (MRSA) [7]. MRI generally is preferred if the results of the three-phase 99mTc bone scan are equivocal. Scintigraphy with inflammation imaging tracers (eg, gallium or indium) may be helpful but involve additional exposure to radiation. Computed tomography — MRI usually is preferred to CT in the evaluation of suspected osteomyelitis. However, CT better delineates changes in bone and may be preferred when significant bone destruction is identified on radiographs [16]. CT findings of osteomyelitis include increased density of bone marrow, periosteal new bone formation, and periosteal purulence. Other potential indications for CT may include: ●

Delineation of the extent of bone injury in chronic osteomyelitis or planning the surgical approach to debridement of devitalized bone (sequestra) (

●

image 7)

Lack of availability of MRI or contraindications to MRI

CT is less time consuming than MRI, and young children usually do not require sedation. However, CT exposes children to ionizing radiation. Ultrasonography — Ultrasonography usually is not helpful in the diagnosis of osteomyelitis. However, it can identify fluid collections associated with bone infections and may improve the success of percutaneous diagnostic and therapeutic drainage procedures [8,38,39].

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Ultrasonography findings consistent with osteomyelitis include fluid collection adjacent to the bone without intervening soft tissue, elevation of the periosteum by more than 2 mm, and thickening of the periosteum. (See "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis", section on 'Ultrasonography'.) Microbiology General principles — Isolation of a pathogen from bone, subperiosteal fluid collection, joint fluid, or blood or PCR detection of pathogens in bone, subperiosteal fluid collection, or joint fluid establishes a diagnosis of confirmed or probable osteomyelitis in children with compatible clinical and/or radiologic findings and speciation and susceptibility testing are essential for planning treatment. (See "Hematogenous osteomyelitis in children: Management", section on 'Antimicrobial therapy'.) With an increasing proportion of cases caused by antibiotic-resistant organisms (eg, community-associated MRSA) and previously unusual species (eg, Kingella kingae in young children), it is particularly important to collect specimens for culture from as many sites of infection as possible. It is preferable to obtain microbiologic specimens before administration of antibiotics, but this must be weighed against the potential for additional complications of ongoing bacteremia by S. aureus or other pathogens. If bone culture cannot be obtained immediately, decisions regarding immediate or delayed administration of antibiotics generally are made in consultation with the orthopedic surgeon. For children with signs of systemic illness (eg, fever, tachycardia), we provide antibiotic therapy immediately following blood culture. In a retrospective review of 250 cases of osteomyelitis, the rates of culture positivity were similar (approximately 74 percent) whether or not patients received antibiotics before cultures were obtained, although there was a tendency for cultures obtained by interventional radiology to more likely be positive if obtained within 24 hours of initiating antibiotic treatment [40]. In another retrospective study, operative cultures were positive in 42 of 50 children (84 percent) with osteomyelitis who received preoperative antibiotics [41]. Sites to culture — Specimens for culture should be obtained from blood and as many potential sites of infection as possible. An orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation of children with suspected osteomyelitis to assist in obtaining specimens for histopathology and/or culture and assessing the need for surgical intervention. In a retrospective review of 250 cases of osteomyelitis from a single institution, blood cultures were positive in 46 percent of cases in which they were obtained, cultures obtained in the operating room (OR, bone, subperiosteal abscess, adjacent https://www.uptodate.com/contents/6067/print

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septic arthritis) were positive in 82 percent, and cultures obtained in interventional radiology (IR) were positive in 52 percent [40]. OR/IR cultures were positive in 80 patients who had negative blood cultures; among these cases, results of OR/IR cultures prompted a change in antibiotic therapy in 68 (85 percent). It is important to inform the microbiology laboratory if less common or fastidious organisms (eg, K. kingae) are suspected because they may require specific media, growth conditions, or prolonged culture time ( ●

table 3) [42].

Blood cultures – We recommend at least one, and preferably two, blood cultures be obtained before administration of antibiotics to children with osteomyelitis. Although less frequently positive than cultures from bone or adjacent abscesses, blood cultures may be the only positive source of identification of the pathogen [5,40,42,43].

●

Bone culture – Bone samples for culture, Gram stain, and histopathology should be obtained whenever possible [40,43]. Culture specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality) or open biopsy (particularly if surgery is required for therapeutic drainage and debridement). (See "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery'.)

●

Other cultures – Subperiosteal exudate, joint fluid, and pus from adjoining sites of infection should be obtained and sent for Gram stain and culture whenever possible, as directed by imaging studies [40]. Specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality). Injection of bone aspirates or periosteal collections into blood culture bottles is recommended to enhance recovery of K. kingae [44,45]. (See "Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Kingella kingae'.) Percutaneous needle aspiration is often successful in neonates with extensive soft-tissue and periosteal involvement and infants and young children with subperiosteal collections. Percutaneous techniques are less successful in older children and adolescents, who may require bone aspiration or drilling to obtain culture specimens. In such cases, the risk of epiphyseal damage and further destruction of bone must be weighed against the benefit of obtaining a specimen.

As reported in a 2012 systematic review of observational studies of osteomyelitis (during or after 2000), a pathogen is isolated from any culture (blood, tissue, pus) in approximately 50 https://www.uptodate.com/contents/6067/print

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percent of cases [5]. The yield of cultures of bone tissue or pus is greater than that from blood cultures (70 versus 40 percent). Other microbiologic studies — Other microbiologic studies may be helpful in the detection of specific pathogens. PCR (if available) can be particularly helpful for detecting K. kingae in purulent materials or bone specimens, particularly when Kingella-specific methods are used [46-48]. Histopathology — The diagnosis of osteomyelitis is confirmed in children who have histopathologic evidence of inflammation in a surgical specimen of bone (

picture 1A-C). An

orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation of children with suspected osteomyelitis to assist in obtaining specimens for histopathology and/or culture and assessing the need for surgical intervention. Histopathologic specimens may be obtained by percutaneous needle aspiration (which may be guided by ultrasonography, fluoroscopy, or other imaging modality) or open biopsy (particularly if surgery is required for therapeutic drainage and debridement). (See "Hematogenous osteomyelitis in children: Management", section on 'Indications for surgery'.) Response to empiric therapy — Improvement in constitutional symptoms and localized inflammation (eg, erythema, point tenderness) with empiric antimicrobial therapy helps to support the diagnosis of osteomyelitis, particularly in children in whom no pathogen is isolated. (See "Hematogenous osteomyelitis in children: Management", section on 'Response to therapy' and 'Probable osteomyelitis' below.) In children with normal MRI and/or scintigraphy, a lack of clinical response to empiric therapy and the results of blood cultures help to direct additional evaluation for other conditions in the differential diagnosis. (See 'Osteomyelitis unlikely (advanced imaging studies normal)' below and 'Differential diagnosis' below.)

DIAGNOSTIC INTERPRETATION Confirmed osteomyelitis — The diagnosis of osteomyelitis is confirmed by histopathologic evidence of inflammation in a surgical specimen of bone (

picture 1A-C) (if obtained) or

identification of a pathogen by culture or Gram stain in an aspirate or biopsy of bone or periosteal fluid collection [2]. Probable osteomyelitis — The diagnosis of osteomyelitis is probable in a child with compatible clinical, laboratory, and/or radiologic findings ( https://www.uptodate.com/contents/6067/print

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blood or joint fluid, or if cultures are negative, detection of S. aureus, S. pneumoniae, or K. kingae by polymerase chain reaction (PCR) in bone aspirates, subperiosteal collections, or synovial fluid. We also consider the diagnosis to be probable in a child with compatible clinical, laboratory, and radiologic findings and negative cultures and PCR if he or she responds as expected to empiric antimicrobial therapy. Given the potential morbidity of delayed treatment, children with probable osteomyelitis should be managed in the same manner as children in whom infection has been confirmed by isolation of an organism from bone or blood [49]. (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Complications' and "Hematogenous osteomyelitis in children: Management", section on 'Empiric parenteral therapy'.) The response to empiric antimicrobial therapy in children with culture-negative osteomyelitis directs the need for additional evaluation. (See "Hematogenous osteomyelitis in children: Management", section on 'Culture-negative osteomyelitis'.) Osteomyelitis unlikely (advanced imaging studies normal) — Osteomyelitis is unlikely if advanced imaging studies (usually magnetic resonance imaging or scintigraphy) are normal throughout the evaluation. The major considerations in the differential diagnosis and approach to continued evaluation and management depend upon the results of the blood culture and response to antimicrobial therapy: ●

Positive blood culture, improvement with empiric therapy – A source of infection other than osteomyelitis must be sought (see 'Other infections' below)

●

Positive blood culture, no improvement with appropriate therapy – Other sources of bacteremia and noninfectious conditions that may have predisposed the patient to bacteremia must be sought aggressively (see 'Differential diagnosis' below)

●

Negative blood culture, improvement with empiric therapy – The child may have a more superficial source of infection (eg, cellulitis); a shorter course of antimicrobial therapy may be warranted (see 'Other infections' below)

●

Negative blood culture, no improvement with appropriate therapy – A bacterial infection is unlikely; fungal and noninfectious causes of musculoskeletal pain should be sought; discontinuation of empiric antimicrobial therapy may be warranted (see 'Noninfectious conditions' below)

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The differential diagnosis of osteomyelitis includes infectious conditions, noninfectious conditions, and radiographic mimics (

table 4).

Other infections — Infections that do not involve bone may cause fever, pain, and tenderness overlying bone, mimicking hematogenous osteomyelitis. These infections usually are distinguished from osteomyelitis by imaging studies that lack the characteristic features of osteomyelitis (

table 1). (See 'Advanced imaging' above.)

Other infections that may share features of osteomyelitis (and may complicate or be complicated by osteomyelitis) include: ●

Septicemia (see "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants", section on 'Clinical manifestations' and "Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

●

Cellulitis (see "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Cellulitis and erysipelas')

●

Septic arthritis; approximately one-third of cases of osteomyelitis extend to the contiguous joint (as many as 75 percent in neonates) [50-53] (see "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Clinical features')

●

Deep abscesses (eg, psoas abscess) (see "Psoas abscess", section on 'Clinical manifestations')

●

Pyomyositis (see "Pyomyositis", section on 'Clinical manifestations')

●

Garré sclerosing osteomyelitis – Garré sclerosing osteomyelitis is characterized by rigid bony swelling at the periphery of the mandible and nonsuppurative sclerotic bone inflammation [54]. It has been reported at all ages [51]. Garré sclerosing osteomyelitis is thought to be triggered by odontogenic infection [55-57], but noninfectious causes of inflammation also may play a role.

Noninfectious conditions Chronic nonbacterial osteomyelitis — Chronic nonbacterial osteomyelitis (CNO; also called chronic recurrent multifocal osteomyelitis [CRMO]) is a chronic inflammatory bone disorder that primarily affects children. It is characterized by bone pain with insidious onset. The initial presentation is similar to that of osteomyelitis. Imaging may localize the areas of bony involvement and indicate the absence of features suggestive of chronic osteomyelitis, such as https://www.uptodate.com/contents/6067/print

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an abscess or sinus tract. Microbiologic and pathologic studies from bone biopsy specimens are generally necessary to differentiate CNO from infectious osteomyelitis. The evaluation and treatment of CNO are discussed in detail separately. (See "Chronic nonbacterial osteomyelitis (CNO)/chronic recurrent multifocal osteomyelitis (CRMO)".) Other noninfectious conditions — Several noninfectious conditions have clinical features that overlap with osteomyelitis. These include: ●

Malignancy – Tumor growth can cause bone pain, and some children with malignancies (particularly leukemia and Ewing sarcoma) have fever as part of their initial presentation. Unlike those with osteomyelitis, symptoms can be intermittent in children with cancer. Affected children also fail to respond to empiric antibiotic therapy. Osteomyelitis and cancer involving bone are usually differentiated with bone biopsy. (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Bone and joint pain' and "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children", section on 'Presentation' and "Clinical presentation, staging, and prognostic factors of the Ewing sarcoma family of tumors", section on 'Signs and symptoms' and "Bone tumors: Diagnosis and biopsy techniques".)

●

Bone infarction – Bone infarction secondary to hemoglobinopathy, especially in infants with dactylitis, can be particularly difficult to distinguish from osteomyelitis. Radiographs, scintigraphy, and MRI all show similar results in both conditions. Unlike bone disease with hemoglobinopathy, osteomyelitis does not respond to hydration and other supportive measures. (See "Acute and chronic bone complications of sickle cell disease".)

●

Vitamin C deficiency – Vitamin C deficiency (scurvy) may cause musculoskeletal pain and refusal to bear weight, particularly in children with autism spectrum disorder (the prevalence of which has increased since the early 2000s), intellectual disability, food aversion, or limited food preferences [29,30,32]. Additional findings of vitamin C deficiency, which do not always accompany the musculoskeletal findings, include petechiae, ecchymoses, bleeding gums, coiled hairs, and hyperkeratosis (

picture 2).

(See "Overview of water-soluble vitamins", section on 'Deficiency' and "Autism spectrum disorder: Terminology, epidemiology, and pathogenesis", section on 'Prevalence'.) ●

Gaucher disease – Children with Gaucher disease can have painful bone crises similar to those that occur in patients with sickle cell disease. During bone pain crises, ischemia can be detected by technetium bone scan. Radiographs of the distal femur may demonstrate deformities caused by abnormal modeling of the metaphysis that are characteristic of Gaucher disease. However, the possibility of osteomyelitis should be considered in febrile

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patients with Gaucher disease who do not improve with hydration and other supportive measures. (See "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Gaucher disease: Treatment", section on 'Skeletal disease'.) ●

Complex regional pain syndrome – Complex regional pain syndrome (CRPS) is an uncommon chronic condition that causes pain, swelling, and limited range of motion in the affected extremity. It frequently begins after an injury, surgery, or vascular event. Vasomotor instability and chronic skin changes also occur. CRPS may be distinguished from osteomyelitis by autonomic dysfunction and normal ESR/CRP. (See "Complex regional pain syndrome in children", section on 'Diagnosis'.)

●

Caffey disease – Caffey disease (infantile cortical hyperostosis) is an inherited disease that usually presents in early infancy with fever, subperiosteal bone hyperplasia, and swelling of overlying soft tissues. It is a rare disorder caused by a subset of mutations in the type 1 collagen gene COL191 [58] and is difficult to distinguish from osteomyelitis on initial presentation. Caffey disease can be distinguished from infectious osteomyelitis by bone biopsy and genetic testing. (See "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)

Radiographic mimics — Benign and malignant bone tumors and tumors involving bone can have radiographic appearance similar to osteomyelitis. The acute clinical features and response to antibiotics in children with osteomyelitis usually distinguish osteomyelitis from these conditions. However, bone biopsy can be performed if necessary for histopathologic differentiation. Bone lesions that can have radiographic appearance similar to osteomyelitis include (

table 4

): ●

Fibrous dysplasia (see "Nonmalignant bone lesions in children and adolescents", section on 'Fibrous dysplasia')

●

Osteoid osteoma and osteoblastoma (see "Nonmalignant bone lesions in children and adolescents", section on 'Bone-forming lesions')

●

Chondroblastoma and chondromyxoid fibroma (see "Nonmalignant bone lesions in children and adolescents", section on 'Cartilage-forming tumors')

●

Eosinophilic granuloma and other forms of histiocytosis

●

Osteosarcoma (see "Osteosarcoma: Epidemiology, pathology, clinical presentation, and diagnosis", section on 'Clinical presentation')

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SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Septic arthritis and osteomyelitis in children".)

SUMMARY AND RECOMMENDATIONS ●

The diagnosis of osteomyelitis is supported by a combination of clinical features suggestive of bone infection, an imaging study with abnormalities characteristic of osteomyelitis (

table 1), a positive microbiologic or histopathologic specimen, and/or a

response to empiric antimicrobial therapy. The diagnosis often is unclear at the initial evaluation. A high index of suspicion and monitoring of the clinical course are essential to establishing the diagnosis. An orthopedic surgeon and/or interventional radiologist should be consulted as early as possible in the evaluation to assist in obtaining specimens for culture and/or histopathology. (See 'Overview' above.) ●

Acute hematogenous osteomyelitis should be suspected in infants and children with findings suggestive of bone infection, including:

• Constitutional symptoms (irritability, decreased appetite or activity), with or without fever

• Focal findings of bone inflammation (eg, warmth, swelling, point tenderness) that typically progress over several days to a week

• Limitation of function (eg, limited use of an extremity; limp; refusal to walk, crawl, sit, or bear weight) Osteomyelitis should also be suspected in children who are found to have bacteremia or an imaging study with characteristic findings during the evaluation of other conditions (eg, fever, trauma). (See 'Clinical suspicion' above.) ●

The initial evaluation of children with suspected osteomyelitis includes complete blood count with differential, erythrocyte sedimentation rate, C-reactive protein, blood culture, and radiographs. (See 'Initial evaluation' above.)

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Radiographs may be sufficient to confirm a diagnosis of osteomyelitis. If needed, additional evaluation generally includes advanced imaging with magnetic resonance imaging (MRI) or scintigraphy. If it is available, MRI is preferred to scintigraphy in view of its higher degree of sensitivity and spatial resolution; however, scintigraphy may be better if symptoms are poorly localized or multiple areas of involvement are suspected, and can often be performed without the need for sedation (

table 1 and

table 2). (See

'Advanced imaging' above.) ●

Specimens for Gram stain and culture should be obtained from as many sites of infection as possible. Isolation of a pathogen from bone, periosteal collection, joint fluid, or blood is necessary for diagnosis and speciation and susceptibility testing are essential for planning for the prolonged treatment required for osteomyelitis. (See 'Microbiology' above.)

●

The diagnosis of osteomyelitis is confirmed by histopathologic evidence of inflammation in a surgical specimen of bone (

picture 1A-C) (if obtained) or identification of a

pathogen by culture or Gram stain in an aspirate or biopsy of bone or a periosteal fluid collection. (See 'Confirmed osteomyelitis' above.) The diagnosis is probable in a child with compatible clinical, laboratory, and/or radiologic findings (

table 1) in whom a pathogen is isolated from blood or joint fluid, or if cultures

are negative, detection of S. aureus, S. pneumoniae, or K. kingae by polymerase chain reaction (PCR) in bone aspirates, subperiosteal collections, or synovial fluid. We also consider the diagnosis to be probable in a child with compatible clinical, laboratory, and radiologic findings and negative cultures and PCR if he or she responds as expected to empiric antimicrobial therapy. (See 'Probable osteomyelitis' above.) Osteomyelitis is unlikely if advanced imaging studies (usually MRI or scintigraphy) are normal throughout the evaluation. (See 'Osteomyelitis unlikely (advanced imaging studies normal)' above.) ●

The differential diagnosis of osteomyelitis includes other infections, noninfectious conditions, and radiographic mimics (

table 4). (See 'Differential diagnosis' above.)

Use of UpToDate is subject to the Terms of Use. REFERENCES

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2. Krogstad P. Osteomyelitis. In: Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed, Cherry JD, Harrison G, Kaplan SL, et al (Eds), Elsevier, Philadelphia 2018. p.516. 3. Saavedra-Lozano J, Falup-Pecurariu O, Faust SN, et al. Bone and Joint Infections. Pediatr Infect Dis J 2017; 36:788. 4. Harris JC, Caesar DH, Davison C, et al. How useful are laboratory investigations in the emergency department evaluation of possible osteomyelitis? Emerg Med Australas 2011; 23:317. 5. Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and subacute paediatric osteomyelitis: a systematic review of the literature. J Bone Joint Surg Br 2012; 94:584. 6. Pääkkönen M, Kallio MJ, Kallio PE, Peltola H. Sensitivity of erythrocyte sedimentation rate and C-reactive protein in childhood bone and joint infections. Clin Orthop Relat Res 2010; 468:861. 7. Browne LP, Mason EO, Kaplan SL, et al. Optimal imaging strategy for community-acquired Staphylococcus aureus musculoskeletal infections in children. Pediatr Radiol 2008; 38:841. 8. Jaramillo D, Dormans JP, Delgado J, et al. Hematogenous Osteomyelitis in Infants and Children: Imaging of a Changing Disease. Radiology 2017; 283:629. 9. Wong M, Isaacs D, Howman-Giles R, Uren R. Clinical and diagnostic features of osteomyelitis occurring in the first three months of life. Pediatr Infect Dis J 1995; 14:1047. 10. Knudsen CJ, Hoffman EB. Neonatal osteomyelitis. J Bone Joint Surg Br 1990; 72:846. 11. Capitanio MA, Kirkpatrick JA. Early roentgen observations in acute osteomyelitis. Am J Roentgenol Radium Ther Nucl Med 1970; 108:488. 12. Overturf GD. Bacterial infections of the bones and joints. In: Infectious diseases of the fetus and newborn infant, 7th, Remington JS, Klein JO, Wilson CB, et al (Eds), Elsevier Saunders, P hiladelphia Vol 2011, p.296. 13. Mustafa MM, Sáez-Llorens X, McCracken GH Jr, Nelson JD. Acute hematogenous pelvic osteomyelitis in infants and children. Pediatr Infect Dis J 1990; 9:416. 14. Fernandez M, Carrol CL, Baker CJ. Discitis and vertebral osteomyelitis in children: an 18year review. Pediatrics 2000; 105:1299. 15. Averill LW, Hernandez A, Gonzalez L, et al. Diagnosis of osteomyelitis in children: utility of fat-suppressed contrast-enhanced MRI. AJR Am J Roentgenol 2009; 192:1232. 16. Saigal G, Azouz EM, Abdenour G. Imaging of osteomyelitis with special reference to children. Semin Musculoskelet Radiol 2004; 8:255. https://www.uptodate.com/contents/6067/print

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17. Connolly LP, Connolly SA, Drubach LA, et al. Acute hematogenous osteomyelitis of children: assessment of skeletal scintigraphy-based diagnosis in the era of MRI. J Nucl Med 2002; 43:1310. 18. Weber-Chrysochoou C, Corti N, Goetschel P, et al. Pelvic osteomyelitis: a diagnostic challenge in children. J Pediatr Surg 2007; 42:553. 19. McPhee E, Eskander JP, Eskander MS, et al. Imaging in pelvic osteomyelitis: support for early magnetic resonance imaging. J Pediatr Orthop 2007; 27:903. 20. Mazur JM, Ross G, Cummings J, et al. Usefulness of magnetic resonance imaging for the diagnosis of acute musculoskeletal infections in children. J Pediatr Orthop 1995; 15:144. 21. Pöyhiä T, Azouz EM. MR imaging evaluation of subacute and chronic bone abscesses in children. Pediatr Radiol 2000; 30:763. 22. Jaramillo D, Hoffer FA. Cartilaginous epiphysis and growth plate: normal and abnormal MR imaging findings. AJR Am J Roentgenol 1992; 158:1105. 23. Kan JH, Hilmes MA, Martus JE, et al. Value of MRI after recent diagnostic or surgical intervention in children with suspected osteomyelitis. AJR Am J Roentgenol 2008; 191:1595. 24. Courtney PM, Flynn JM, Jaramillo D, et al. Clinical indications for repeat MRI in children with acute hematogenous osteomyelitis. J Pediatr Orthop 2010; 30:883. 25. Guillerman RP. Osteomyelitis and beyond. Pediatr Radiol 2013; 43 Suppl 1:S193. 26. Shih HN, Shih LY, Wong YC. Diagnosis and treatment of subacute osteomyelitis. J Trauma 2005; 58:83. 27. Schmit P, Glorion C. Osteomyelitis in infants and children. Eur Radiol 2004; 14 Suppl 4:L44. 28. Kan JH, Young RS, Yu C, Hernanz-Schulman M. Clinical impact of gadolinium in the MRI diagnosis of musculoskeletal infection in children. Pediatr Radiol 2010; 40:1197. 29. Kinlin LM, Blanchard AC, Silver S, Morris SK. Scurvy as a mimicker of osteomyelitis in a child with autism spectrum disorder. Int J Infect Dis 2018; 69:99. 30. Harknett KM, Hussain SK, Rogers MK, Patel NC. Scurvy mimicking osteomyelitis: case report and review of the literature. Clin Pediatr (Phila) 2014; 53:995. 31. Gulko E, Collins LK, Murphy RC, et al. MRI findings in pediatric patients with scurvy. Skeletal Radiol 2015; 44:291. 32. Duggan CP, Westra SJ, Rosenberg AE. Case records of the Massachusetts General Hospital. Case 23-2007. A 9-year-old boy with bone pain, rash, and gingival hypertrophy. N Engl J Med 2007; 357:392.

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33. Allwright SJ, Miller JH, Gilsanz V. Subperiosteal abscess in children: scintigraphic appearance. Radiology 1991; 179:725. 34. Tuson CE, Hoffman EB, Mann MD. Isotope bone scanning for acute osteomyelitis and septic arthritis in children. J Bone Joint Surg Br 1994; 76:306. 35. The Alliance for Radiation Safety in Pediatric Imaging. www.imagegently.org (Accessed on S eptember 03, 2016). 36. Mok PM, Reilly BJ, Ash JM. Osteomyelitis in the neonate. Clinical aspects and the role of radiography and scintigraphy in diagnosis and management. Radiology 1982; 145:677. 37. Bressler EL, Conway JJ, Weiss SC. Neonatal osteomyelitis examined by bone scintigraphy. Radiology 1984; 152:685. 38. Hoffer FA, Emans J. Percutaneous drainage of subperiosteal abscess: a potential treatment for osteomyelitis. Pediatr Radiol 1996; 26:879. 39. Llewellyn A, Jones-Diette J, Kraft J, et al. Imaging tests for the detection of osteomyelitis: a systematic review. Health Technol Assess 2019; 23:1. 40. McNeil JC, Forbes AR, Vallejo JG, et al. Role of Operative or Interventional Radiology-Guided Cultures for Osteomyelitis. Pediatrics 2016; 137. 41. Ratnayake K, Davis AJ, Brown L, Young TP. Pediatric acute osteomyelitis in the postvaccine, methicillin-resistant Staphylococcus aureus era. Am J Emerg Med 2015; 33:1420. 42. Yeo A, Ramachandran M. Acute haematogenous osteomyelitis in children. BMJ 2014; 348:g66. 43. Zhorne DJ, Altobelli ME, Cruz AT. Impact of antibiotic pretreatment on bone biopsy yield for children with acute hematogenous osteomyelitis. Hosp Pediatr 2015; 5:337. 44. Yagupsky P. Kingella kingae: from medical rarity to an emerging paediatric pathogen. Lancet Infect Dis 2004; 4:358. 45. Centers for Disease Control and Prevention (CDC). Osteomyelitis/septic arthritis caused by Kingella kingae among day care attendees--Minnesota, 2003. MMWR Morb Mortal Wkly Rep 2004; 53:241. 46. Chometon S, Benito Y, Chaker M, et al. Specific real-time polymerase chain reaction places Kingella kingae as the most common cause of osteoarticular infections in young children. Pediatr Infect Dis J 2007; 26:377. 47. Verdier I, Gayet-Ageron A, Ploton C, et al. Contribution of a broad range polymerase chain reaction to the diagnosis of osteoarticular infections caused by Kingella kingae: description of twenty-four recent pediatric diagnoses. Pediatr Infect Dis J 2005; 24:692. https://www.uptodate.com/contents/6067/print

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48. El Houmami N, Minodier P, Dubourg G, et al. Patterns of Kingella kingae Disease Outbreaks. Pediatr Infect Dis J 2016; 35:340. 49. Lyon RM, Evanich JD. Culture-negative septic arthritis in children. J Pediatr Orthop 1999; 19:655. 50. Yagupsky P, Bar-Ziv Y, Howard CB, Dagan R. Epidemiology, etiology, and clinical features of septic arthritis in children younger than 24 months. Arch Pediatr Adolesc Med 1995; 149:537. 51. Perlman MH, Patzakis MJ, Kumar PJ, Holtom P. The incidence of joint involvement with adjacent osteomyelitis in pediatric patients. J Pediatr Orthop 2000; 20:40. 52. Pääkkönen M, Kallio MJ, Kallio PE, Peltola H. Shortened hospital stay for childhood bone and joint infections: analysis of 265 prospectively collected culture-positive cases in 19832005. Scand J Infect Dis 2012; 44:683. 53. Fox L, Sprunt K. Neonatal osteomyelitis. Pediatrics 1978; 62:535. 54. Panders AK, Hadders HN. Chronic sclerosing inflammations of the jaw. Osteomyelitis sicca (Garré), chronic sclerosing osteomyelitis with fine-meshed trabecular structure, and very dense sclerosing osteomyelitis. Oral Surg Oral Med Oral Pathol 1970; 30:396. 55. Tong AC, Ng IO, Yeung KM. Osteomyelitis with proliferative periostitis: an unusual case. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102:e14. 56. Kannan SK, Sandhya G, Selvarani R. Periostitis ossificans (Garrè's osteomyelitis) radiographic study of two cases. Int J Paediatr Dent 2006; 16:59. 57. Padwa BL, Dentino K, Robson CD, et al. Pediatric Chronic Nonbacterial Osteomyelitis of the Jaw: Clinical, Radiographic, and Histopathologic Features. J Oral Maxillofac Surg 2016; 74:2393. 58. Gensure RC, Mäkitie O, Barclay C, et al. A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest 2005; 115:1250. Topic 6067 Version 30.0

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GRAPHICS

Imaging abnormalities in osteomyelitis Imaging modality Plain radiograph*

Abnormal findings Deep soft tissue swelling (3 days after onset) Periosteal reaction or elevation (10 to 21 days after onset) Lytic sclerosis (≥1 month after onset)

Magnetic

Bone marrow inflammation (decreased signal in T1-weighted images; increased

resonance imaging

signal in T2-weighted images) Edema in marrow and soft tissues Penumbra sign (high-intensity-signal transition zone between abscess and sclerotic bone marrow in T1-weighted images) With gadolinium enhancement: absent blood flow, suggestive of necrosis or abscess

Three-phase bone scan

Focal uptake of tracer in the third phase (delayed phase)

Computed tomography

Increased density of bone marrow Cortex destruction Periosteal reaction (new bone formation) formation Periosteal purulence Sequestra (devitalized, sclerotic bone)

Ultrasonography

Fluid collection adjacent to bone without intervening soft tissue Thickening of periosteum Periosteal elevation

* The timing and typical sequence of radiographic changes may vary with the site of infection and age of the patient. References: 1. Browne LP, Mason EO, Kaplan SL, et al. Optimal imaging strategy for community-acquired Staphylococcus aureus musculoskeletal infections in children. Pediatr Radiol 2008; 38:841. 2. Jaramillo D, Treves ST, Kasser JR, et al. Osteomyelitis and septic arthritis in children: Appropriate use of imaging to guide treatment. AJR Am J Roentgenol 1995; 165:399. 3. Saigal G, Azouz EM, Abdenour G. Imaging of osteomyelitis with special reference to children. Semin Musculoskelet Radiol 2004; 8:255. 4. Schmit P, Glorion C. Osteomyelitis in infants and children. Eur Radiol 2004; 14 Suppl 4:L44. https://www.uptodate.com/contents/6067/print

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Graphic 96767 Version 3.0

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Acute osteomyelitis

Light micrograph of acute osteomyelitis of the tibia shows many disconnected bony trabeculae in a sea of inflammatory cells (red arrow) and a single multinucleated giant cell (black arrow). The surfaces of the trabeculae (white arrows) have a few undifferentiated, spindle-shaped connective tissue elements. There is little evidence of active bone formation or bone resorption. Courtesy of Jon Mader, MD.

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Early repair in acute osteomyelitis

Light micrograph in acute osteomyelitis of the tibial articular apparatus. The presence of whorls of chondrocytes (arrows) indicates early tissue repair in which multinucleated osteoclasts (dashed arrows) are actively remodeling the subchondral region. Bone (arrowhead) has replaced the mature lamellar structure, and the medullary spaces are largely filled with inflammatory cells and fibrin. Courtesy of Jon Mader, MD.

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Chronic osteomyelitis

Light micrograph of chronic osteomyelitis of the tibia. Against a background of inflammatory cells (arrow), there are thickened bony trabeculae (arrowhead) lined by plump osteoblasts, which are actively forming bone. The accumulation of small dark cells (lymphocytes; dashed arrows) represent sites of perivascular inflammation. Courtesy of Jon Mader, MD.

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Brodie abscess radiograph

Lateral (A) and frontal (B) radiographs of the right lower extremity demonstrate an ovoid lucent lesion in the medullary cavity of the proximal metadiaphysis of the tibia (arrows) with associated periosteal reaction (arrowheads). The lateral radiograph (A) also demonstrates irregular cortical lucency anteriorly suggesting an area of focal cortical disruption (dashed arrow). Reproduced with permission from: Abdulhadi MA, White AM, Pollock AN. Brodie abscess. Pediatr Emerg Care 2012; 28:1249. Copyright © 2012 Lippincott Williams & Wilkins.

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Progression of radiographic findings in a six-year-old boy with osteomyelitis of the fibula

(A) Plain radiographs (after one week of swelling and pain in the calf) were initially interpreted as normal. (B) A plain radiograph obtained four days after the initial films demonstrates periosteal reaction and cortical thickening. (C) T1 weighted magnetic resonance image with gadolinium demonstrates enhancement of the fibula marrow space and surrounding soft tissues. Courtesy of Marvin B Harper, MD.

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Osteomyelitis with subperiosteal abscess

Radiograph of the femur demonstrates periosteal elevation due to a subperiosteal abscess as the result of osteomyelitis. Courtesy of Marvin B Harper, MD.

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Lytic lucency in osteomyelitis

(A) Radiograph at the initial evaluation of a nine-year-old with fever and limp demonstrates a lytic lucency in the distal femoral metaphysis. (B, C) Axial and coronal magnetic resonance (MR) images delineate the area of osteomyelitis and adjacent marrow edema. Reproduced with permission from Jeanne Chow, MD. Children's Hospital-Boston, Copyright © Jeanne Chow, MD.

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Early osteomyelitis in a six-year-old with fever and ankle pain

Radiographs of the ankle (A) demonstrate deep soft tissue swelling (arrow) inferior to the medial malleolus. A technetium 99m bone scan shows increased uptake in the distal tibia in the blood flow (B) and bone uptake (C; four hour) phases. Courtesy of Marvin B Harper, MD.

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Osteomyelitis in a nine-year-old girl with knee pain and fever

(A) Plain radiographs of the knee are unremarkable. (B) T1 weighted MRI demonstrates marked decrease in signal intensity in the medial metaphysis and epiphysis of the distal femur. There is some involvement of the soft tissue. (C) These findings are more pronounced in a T1 weighted MRI with gadolinium. MRI: magnetic resonance imaging. Courtesy of Marvin B Harper, MD.

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Comparison of imaging modalities in children with osteomyelitis Modality Plain radiographs

Indications

Advantages

Baseline

Inexpensive

Excluding other

Easy to obtain

Disadvantages

conditions in differential diagnosis

Comments*

Abnormal findings

Sensitivity: 16 to 20 percent

usually not present at onset of

Specificity: 80 to 100 percent

symptoms, except in newborns

Monitoring disease progression

Normal radiograph at onset does not exclude osteomyelitis

MRI¶

Identify location and extent of

No radiation risk

Costly

disease

Less useful in

Sensitivity: 80 to 100

Demonstrates early changes

multifocal or poorly

percent Specificity: 70

adjacent structures for extension of

in the marrow cavity

localized disease

to 100 percent

infection (soft tissues, growth plate, epiphysis,

Improved

Requires more

Osteomyelitis

demonstration of

time than CT

joint)

subperiosteal abscess

Young children

unlikely if MRI is normal

Evaluation of

Demonstration

may require sedation or anesthesia

Repeat MRI seldom leads

of concomitant septic arthritis,

Not always available

to management

Evaluation of

difficult sites (eg, pelvis, vertebral bodies,

venous thrombosis, or pyomyositis

intervertebral discs) Planning surgical intervention Scintigraphy

changes in patients with clinical

 

improvement

   

Poorly localized symptoms (eg,

More useful than MRI in

Radiation exposure

Sensitivity: 53 to 100

young children who cannot verbalize)

multifocal or poorly localized

Does not provide

percent

Multifocal disease

disease

information about extent of purulent

to 100 percent

Demonstrates early changes Readily available

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collections that may require drainage

Specificity: 50

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May require

May be

less sedation than MRI

falsely negative if blood supply to periosteum is interrupted (eg, subperiosteal abscess)

CT

Evaluation of cortical

Less timeconsuming

Expensive

destruction, bone gas, and sequestrum

than MRI

Increased

Sensitivity: 67 percent

Does not

radiation exposure

Specificity: 50 percent

require sedation

Poor soft tissue contrast

Generally used only if

Delineating extent of bone

other studies are not possible or

injury in subacute/chronic osteomyelitis

inconclusive

Planning surgical interventions Evaluation of complications if MRI not available or contraindicated Ultrasonography

Evaluate fluid collections in

Inexpensive

adjacent structures (eg, joint,

burden

periosteum)

No radiation Noninvasive

Does not penetrate

Sensitivity: 55 percent

bone cortex

Specificity: 47 percent

Portable

Monitor abscess resolution or progression MRI: magnetic resonance imaging; CT: computed tomography. * Values for sensitivity and specificity are from: Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and subacute paediatric osteomyelitis: A systematic review of the literature. J Bone Joint Surg Br 2012; 94:584. ¶ Preferred imaging study when imaging other than plain radiographs are necessary to establish the diagnosis of osteomyelitis. https://www.uptodate.com/contents/6067/print

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References: 1. Dartnell J, Ramachandran M, Katchburian M. Haematogenous acute and subacute paediatric osteomyelitis: A systematic review of the literature. J Bone Joint Surg Br 2012; 94:584. 2. Faust SN, Clark J, Pallett A, Clarke NM. Managing bone and joint infection in children. Arch Dis Child 2012; 97:545. 3. Peltola H, Pääkkönen M. Acute osteomyelitis in children. N Engl J Med 2014; 370:352. 4. Yeo A, Ramachandran M. Acute haematogenous osteomyelitis in children. BMJ 2014; 348:g66.

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Magnetic resonance image distal femoral osteomyelitis and subperiosteal abscess

Axial (A) and coronal (B) magnetic resonance images (post gadolinium infusion) of a seven-year-old with distal femoral osteomyelitis and subperiosteal abscess. The abscess is posterior on the axial view (arrow) and medial to the distal femur on the coronal view (arrow). The pus is dark and surrounded by an enhancing rim. Courtesy of William Phillips, MD, Texas Children's Hospital.

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Magnetic resonance image demonstrating osteomyelitis

(A) The proximal shaft and metaphysis of the left tibia show an abnormal mottled appearance. (B) The marrow signal from the left tibia is abnormal. In addition, there is soft tissue inflammation surrounding the left tibia. Courtesy of Sheldon L Kaplan, MD. Texas Children's Hospital.

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Penumbra sign in osteomyelitis

Magnetic resonance imaging (MRI) scan shows the penumbra sign (a transitional zone with relatively high signal intensity between abscess and sclerotic bone marrow on T1-weighted MRI). Reproduced with permission from: Shih HN, Shih LY, Wong YC. Diagnosis and treatment of subacute osteomyelitis. J Trauma 2005; 58:83. Copyright © 2005 Lippincott Williams & Wilkins.

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Devitalized bone (sequestra) in a child with osteomyelitis and septic arthritis

Radiographic appearance of devitalized bone (sequestra) in anteroposterior and lateral radiographs (panels A and B, respectively) and computed tomography (panel C) in a 13-year-old boy who developed femoral osteomyelitis and septic arthritis of the knee as complications of methicillin-resistant Staphylococcus aureus septic shock. Courtesy of William A Phillips, MD.

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Clinical features associated with bacterial pathogens that cause acute hematogenous osteomyelitis in children  

Clinical features

Gram-positive bacteria Staphylococcus aureus

All ages; possible associated skin or soft tissue infection; MRSA may be associated with venous thromboembolism and pulmonary disease

Coagulase-negative staphylococci

Neonates in intensive care unit; children with indwelling vascular catheters (eg, for chronic hemodialysis)

Group A Streptococcus

More common in children younger than 4 years; may occur as a complication of concurrent varicella-zoster virus infection

Group B Streptococcus

Infants younger than 3 months (usually 2 to 4 weeks)

Streptococcus pneumoniae

Children younger than 2 years who are incompletely immunized; children older than 2 years with underlying medical conditions (eg, sickle cell disease, asplenia, splenic dysfunction, immunodeficiency, chronic heart disease, chronic lung disease, diabetes mellitus)

Actinomyces

May affect the facial bones, the pelvis, or vertebral bodies

Gram-negative bacteria Kingella kingae

Children 6 to 36 months; indolent onset; oral ulcers preceding musculoskeletal findings; may affect nontubular bones

Nonsalmonella gramnegative bacilli (eg,

Birth to 3 months; children with sickle cell disease; instrumentation of the gastrointestinal or urinary tract; immunocompromised host (eg,

Escherichia coli, Serratia)

CGD)

Haemophilus influenzae type b

Incompletely immunized children in areas with low Hib immunization rates

Bartonella henselae

Children with cat exposure; may affect the vertebral column and pelvic girdle; may cause multifocal infection

Pseudomonas aeruginosa

Injectable drug use

Brucella

Travel to or living in an endemic area; ingestion of unpasteurized dairy products

Mycobacterium tuberculosis

Birth in, travel to, or contact with a visitor from, a region endemic for M. tuberculosis

Nontuberculous mycobacteria

Surgery or penetrating injury; CGD; other underlying immunodeficiency; HIV infection

Salmonella species

Children with sickle cell disease or related hemoglobinopathies; exposure to reptiles or amphibians; children with gastrointestinal symptoms; children in resource-limited countries

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Polymicrobial infection  

More likely with direct inoculation (eg, penetrating trauma) or contiguous spread (eg, from skull, face, hands, feet)

MRSA: methicillin-resistant S. aureus; CGD: chronic granulomatous disease; Hib: H. influenzae type b. Graphic 96510 Version 9.0

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Differential diagnosis of osteomyelitis in children and adolescents Condition

Features that distinguish from osteomyelitis

Other infections Septicemia Cellulitis

MRI or scintigraphy studies lack abnormalities characteristic of osteomyelitis

Septic arthritis Deep abscess Pyomyositis Garré sclerosing osteomyelitis

Noninfectious conditions Chronic nonbacterial osteomyelitis

Multifocal lesions on imaging studies

(eg, CRMO)

Lack of response to antimicrobial therapy

Malignancy (eg, primary bone tumor, leukemia)

Intermittent symptoms Lack of response to antimicrobial therapy Characteristic histopathology

Bone infarction in patients with

Improvement with hydration and other supportive

hemoglobinopathy

measures

Vitamin C deficiency (scurvy)

Dietary history of limited vitamin C intake (eg, restricted feeding behavior in children with autism spectrum disorder) Petechiae, ecchymoses, bleeding gums, coiled hair, hyperkeratosis

Gaucher disease

Characteristic radiographic features Dysmorphic features on examination

Complex regional pain syndrome

Autonomic dysfunction Normal erythrocyte sedimentation rate, C-reactive protein

Caffey disease (infantile cortical

Characteristic histopathology

hyperostosis)

Radiographic mimics* Benign bone tumors: Fibrous dysplasia

Absence of acute symptoms

Osteoid osteoma

Lack of response to antimicrobial therapy

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Osteoblastoma

Characteristic histopathology

Chondroblastoma Chondromyxoid fibroma Langerhans cell histiocytosis

Characteristic histopathology

Malignant bone tumors: Osteosarcoma

Intermittent symptoms Lack of response to antimicrobial therapy Characteristic histopathology

MRI: magnetic resonance imaging; CRMO: chronic recurrent multifocal osteomyelitis. * Refer to UpToDate topics on benign bone tumors, Langerhans cell histiocytosis, and malignant bone tumors for additional information about the radiographic appearance of these conditions. Graphic 96520 Version 4.0

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Perifollicular abnormalities in scurvy

In this example, the perifollicular hyperkeratotic papules are quite prominent, with surrounding hemorrhage. These lesions have been misinterpreted as "palpable purpura," leading to the mistaken clinical diagnosis of vasculitis. Reproduced with permission from: Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol 1999; 41:895. Copyright © 1999 Elsevier.

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Contributor Disclosures Paul A Krogstad, MD No relevant financial relationship(s) with ineligible companies to disclose. Sheldon L Kaplan, MD Grant/Research/Clinical Trial Support: MeMed Diagnostics [Bacterial and viral infections];Merck [Staphylococcus aureus];Pfizer [Streptococcus pneumoniae]. Consultant/Advisory Boards: MeMed Advisory Board [Diagnostics bacterial and viral infections]. Other Financial Interest: Elsevier [Pediatric infectious diseases];Pfizer [PCV13]. All of the relevant financial relationships listed have been mitigated. William A Phillips, MD No relevant financial relationship(s) with ineligible companies to disclose. Mary M Torchia, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Tonsillectomy and/or adenoidectomy in children: Indications and contraindications Author: Ellen R Wald, MD Section Editors: Morven S Edwards, MD, Glenn C Isaacson, MD, FAAP Deputy Editor: Laurie Wilkie, MD, MS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Mar 18, 2021.

INTRODUCTION Tonsillectomy and adenoidectomy are among the most common surgical procedures performed in children. Adenotonsillectomy is often thought of, and most often carried out, as a single, combined operation; however, in assessing indications for surgery, the two components require consideration individually. The two major categories of indications for tonsillectomy and/or adenoidectomy include obstruction and recurrent infection [1]. The indications and contraindications for tonsillectomy and adenoidectomy are reviewed here. Preoperative and postoperative care, complications of adenotonsillectomy, and the conditions for which these procedures may be indicated are discussed in greater detail separately: ●

(See "Tonsillectomy and/or adenoidectomy in children: Preoperative evaluation and care".)

●

(See "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications".)

●

(See "Adenoidectomy in children: Postoperative care and complications".)

●

(See "Adenotonsillectomy for obstructive sleep apnea in children".)

●

(See "Treatment and prevention of streptococcal pharyngitis in adults and children".)

EPIDEMIOLOGY

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Tonsillectomy is among the most commonly performed operations in children. The frequency with which tonsillectomy is performed varies from country to country and region to region [24]. The variation appears to be related to differences in the medical practice of general practitioners, pediatricians, and otolaryngologists in the management of recurrent tonsillitis and other conditions affecting the upper airway [5]. Patient/family factors and preferences may also influence the decision [6]. In the United States, the number of tonsillectomies has declined progressively since the 1970s [7-9]. The estimated number of tonsillectomies (with or without adenoidectomy) performed in children 2 cm) or tender anterior cervical lymph nodes • Tonsillar exudate https://www.uptodate.com/contents/6296/print

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• Positive culture for group A beta-hemolytic streptococci ●

Apparently adequate antibiotic therapy administered for proven or suspected streptococcal episodes

●

Each qualifying episode confirmed by examination with the clinical features described in a clinical record at the time of occurrence or, if not fully documented, subsequent observance of two episodes of throat infection with patterns of frequency and clinical features consistent with the initial history

Tonsillectomy (with or without adenoidectomy) reduced the overall number and severity of subsequent episodes of throat infection in children who met these criteria. In the first year of follow-up, the mean number of moderate or severe episodes in the tonsillectomy group was 0.08 (3 episodes among 38 children) compared with 1.17 in the control group (41 episodes among 35 children); a similar benefit was seen in the second follow-up year. Third-year differences, although in most cases not statistically significant, also consistently favored the surgical groups. However, in each follow-up year, many subjects in the nonsurgical groups had fewer than three episodes of throat infection and most episodes among subjects in the nonsurgical groups were mild. The results described above provide support both for surgical and for nonsurgical management of children with recurrent tonsillitis who are severely affected. Treatment decisions for such children are best made on a case-by-case basis. The decision should take into account the potential adverse consequences of surgery, the values and preferences of the family, and other factors described elsewhere. (See 'General considerations' above and "Tonsillectomy (with or without adenoidectomy) in children: Postoperative care and complications".) Mildly or moderately affected children — We suggest not performing tonsillectomy in children who are mildly or moderately affected (ie, recurrent episodes that are less frequent or less severe in any respect than as described above for severely affected children) [20]. For such children, the benefits of surgery are modest and outweighed by the potential risks. However, tonsillectomy is a reasonable option in such children with recurrent group A streptococcal (GAS) pharyngitis complicated by one or more of the following: ●

Multiple antibiotic allergy/intolerance.

●

Peritonsillar abscess (PTA). (See 'Peritonsillar abscess' below.)

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A history of rheumatic heart disease or close contact with a person with a history of rheumatic heart disease. Support for this indication is found in a retrospective cohort study of 290 closely matched children with ≥3 documented episodes of GAS pharyngitis during the preceding year [25]. Compared with children who underwent tonsillectomy, those who did not were 3.1 times more likely to develop subsequent episodes of GAS pharyngitis over a mean follow-up of four years. (See 'Other conditions' below and "Acute rheumatic fever: Treatment and prevention", section on 'Prevention'.)

For most mildly or moderately affected children, episodes of recurrent infection can be treated with symptomatic care and antimicrobial treatment (as indicated). (See "Treatment and prevention of streptococcal pharyngitis in adults and children" and "Acute pharyngitis in children and adolescents: Symptomatic treatment", section on 'General management'.) The efficacy of tonsillectomy in moderately affected children was evaluated in a randomized trial of 328 children with recurrent throat infection despite adequate antibiotic therapy [20]. The history standards were less stringent than those used in the earlier trials described above for severely affected children regarding either frequency, clinical features, or documentation of previous infections. The study included two parallel trials. One trial compared adenotonsillectomy with nonsurgical management in patients with coexisting indications for adenoidectomy (eg, recurrent otitis media); the other was a three-way comparison of tonsillectomy, adenotonsillectomy, and nonsurgical management in patients who lacked indications for adenoidectomy. The following results were noted [20]: ●

In the first year of follow-up, the mean number of moderate or severe episodes in the combined surgical groups (tonsillectomy and adenotonsillectomy) was 0.14 compared with 0.35 in the combined control groups.

●

During each of the three years of follow-up, the incidence of throat infection was significantly lower in the surgical groups than in the corresponding control groups. Results in surgical subjects were similar to those of the trials for severely affected children, described above [19]. However, the proportions of control subjects who developed no moderate or severe episodes of throat infection in a given year ranged from 70 to 84 percent (compared with 34 and 41 percent of control subjects in the first and second years of follow-up in the trials of severely affected children).

●

The outcomes in children who underwent adenotonsillectomy were not more favorable than those in children who underwent tonsillectomy only.

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Subsequent clinical trials and observational studies in mildly and moderately affected children found that compared with watchful waiting, tonsillectomy modestly reduces the number of throat infections, sore throat days, school absences, and clinic visits, mainly in the short term (ie, 5 years of age) and, less commonly, primary bacterial peritonitis (usually as a complication of nephrotic syndrome) or obstruction due to adhesions from a prior surgery.

• Adolescents – Appendicitis and, less commonly, obstruction caused by adhesions from previous surgery or inflammation, perforated ulcer, or primary bacterial peritonitis. Among postmenarchal females, serious conditions within the reproductive tract that can cause abdominal pain include ovarian torsion, pelvic inflammatory disease with tubo-ovarian abscess, and ruptured ectopic pregnancy. Trauma — Abdominal trauma (typically sustained in motor vehicle crashes, auto-pedestrian collisions, or falls) can cause life-threatening injuries (such as solid organ injury or perforated viscus). Typical mechanisms include motor vehicle crashes, falls, and child abuse. However, a history of trauma may not be forthcoming for infants and children who have sustained inflicted injuries. (See "Pediatric blunt abdominal trauma: Initial evaluation and stabilization" and "Physical child abuse: Recognition", section on 'Visceral injuries'.) Although symptoms of abdominal injury typically occur immediately, they may be delayed with some injuries (such as left shoulder pain from a slowly expanding splenic hematoma, vomiting from obstruction as the result of a duodenal hematoma, or bowel perforation associated with a lap seatbelt injury). (See "Pediatric blunt abdominal trauma: Initial evaluation and stabilization", section on 'Specific injuries'.) Infection — Children with intra- and extra-abdominal infections may present with a primary complaint of abdominal pain. Common conditions that are associated with acute abdominal pain include viral gastroenteritis, systemic viral illness, streptococcal pharyngitis, lobar pneumonia, and urinary tract infections. Exacerbation of chronic condition — Acute abdominal pain may also represent an exacerbation of a chronic condition. Frequent causes of chronic or recurrent abdominal pain include constipation, functional abdominal pain, gastroesophageal reflux, and dietary intolerance. In one- to three-month-old infants, abdominal pain and fussiness may be signs of colic (although other etiologies should be excluded). Acute abdominal pain may also represent an exacerbation of a chronic condition in older children and adolescents, such as inflammatory bowel disease, abdominal migraine, or gastrointestinal dysmotility. https://www.uptodate.com/contents/6434/print

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(See "Causes of acute abdominal pain in children and adolescents", section on 'Common causes'.) Characteristics of abdominal pain — Infants and children younger than two years of age with abdominal pain usually cannot describe or localize pain. This limitation leads to both over and under attribution of symptoms to "abdominal pain." Parents may infer that the child has abdominal pain from symptoms such as drawing the legs up or inconsolability. The preschool child may be able to describe pain and other symptoms, although descriptions may not be consistently reliable. Above five years of age, children can typically characterize the onset, frequency, duration, and location of their symptom. Specific diagnoses may be associated with the following characteristic patterns of pain: ●

Appendicitis – Periumbilical, migrating to the right lower abdomen

●

Appendiceal rupture (early), ovarian torsion – Acute, severe, focal

●

Intussusception – Intermittent, colicky

●

Gastroenteritis – Diffuse or vague

●

Hepatitis and cholecystitis – Right upper quadrant

●

Gastritis, gastric ulcer disease – Epigastric

●

Pancreatitis – Steady periumbilical and/or subxiphoid pain, often radiating to the back

●

Renal stone – Flank pain radiating to mid to lower lateral abdomen

●

Constipation – Intermittent, often left sided

For children with localized peritoneal irritation (as with advanced appendicitis), pain can be aggravated by movement (such as, coughing, hopping, traveling in the car or walking). In comparison, patients with visceral pain may writhe with discomfort. Improvement in pain after a bout of emesis may occur with conditions localized to the small bowel [2]. Pain relief after a bowel movement suggests a colonic condition including chronic constipation, or bowel inflammation from a host of causes. Associated symptoms ●

Fever – In an observational series describing children evaluated for abdominal pain in outpatient settings, 64 percent had a history of fever [1]. Patients with appendicitis often have fever, which may be initially low grade. Most children with abdominal pain and fever, however, have infectious etiologies such as gastroenteritis, urinary tract infection, or pharyngitis [1,3]. Bacterial infections that may be associated with abdominal pain include:

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• Streptococcal pharyngitis (often with sore throat, headache, and vomiting), although children with viral pharyngitis can also have abdominal pain (see "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Clinical features')

• Urinary tract infections (sometimes with vomiting or, less often, diarrhea in younger children) (see "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Clinical presentation')

• Lower lobe pneumonia (usually with respiratory symptoms such as tachypnea or cough, but without abdominal tenderness on examination) [4] (see "Communityacquired pneumonia in children: Clinical features and diagnosis", section on 'Clinical presentation')

• Pelvic inflammatory disease (in postmenarchal, sexually active females) (see "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Clinical features') ●

Vomiting – Vomiting is frequently reported among children with abdominal pain. In the previously noted series, 42 percent of patients had a history of vomiting [1]. Children with vomiting and abdominal pain (particularly in the absence of diarrhea) should be carefully evaluated for life-threatening conditions such as bowel obstruction or appendicitis with peritonitis.

• Volvulus must be excluded as the cause of bilious emesis and apparent abdominal pain in a neonate (see "Intestinal malrotation in children", section on 'Clinical presentation')

• With intussusception, vomiting (initially nonbilious, but often becoming bilious as the obstruction progresses) may occur following episodes of pain (see "Intussusception in children", section on 'Clinical manifestations')

• Small bowel obstruction may develop as the result of many conditions, including postoperative or postinflammatory adhesions. Worldwide, ascaris infection is a common cause of small bowel obstruction (see "Ascariasis", section on 'Complications')

• Nausea and vomiting are typically present among children with appendicitis, ovarian and testicular torsion, pancreatitis, and severe inflammatory bowel disease (see "Acute appendicitis in children: Clinical manifestations and diagnosis", section on 'Clinical manifestations') https://www.uptodate.com/contents/6434/print

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Diarrhea – The following conditions can be associated with diarrhea (see "Approach to diarrhea in children in resource-rich countries"):

• Children with diarrhea and abdominal pain usually have viral gastroenteritis • Urinary tract infections can cause diarrhea • Children with appendicitis occasionally present with diarrhea (typically mucoid stools, rather than profuse, watery diarrhea)

• Children with intussusception may have bloody stools, sometimes mixed with mucus (currant jelly). In addition, intussusception may be preceded by viral gastroenteritis (particularly from adenovirus) (see "Intussusception in children", section on 'Clinical manifestations' and "Intussusception in children", section on 'Pathogenesis')

• Bloody diarrhea with abdominal pain suggests infectious enteritis, hemolytic uremic syndrome (HUS), Meckel's diverticulum, or inflammatory bowel disease (see "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children" and "Meckel's diverticulum", section on 'Clinical presentations' and "Clinical presentation and diagnosis of inflammatory bowel disease in children") Other symptoms that may suggest the etiology of abdominal pain include cough (pneumonia), sore throat (pharyngitis), dysuria (urinary tract infection), polyuria (diabetic ketoacidosis), and hematuria (urinary tract infection, urolithiasis, hemolytic uremic syndrome, immunoglobulin A vasculitis [IgAV; Henoch-Schönlein purpura (HSP)]). Past medical history ●

Bowel obstruction from adhesions can occur among children who have had abdominal surgery. (See "Causes of acute abdominal pain in children and adolescents", section on 'Adhesions with intestinal obstruction'.)

●

Children with Hirschsprung disease can develop complications such as obstruction and fulminant enterocolitis. (See "Emergency complications of Hirschsprung disease", section on 'Enterocolitis'.)

●

Cholecystitis may be the cause of abdominal pain for older adolescents or children with predisposing conditions such as sickle cell disease or cystic fibrosis. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Hepatobiliary disease' and "Overview of the clinical manifestations of sickle cell disease", section on 'Hepatobiliary complications'.)

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Abdominal pain may be the manifestation of vasoocclusive crisis (VOC) for children with sickle cell disease. Other emergency conditions should be considered as suggested by specific findings (such as peritoneal signs or focal right lower quadrant pain), by a pattern of pain that is not typical of VOC for this patient, or for a child whose symptoms do not improve with hydration and analgesia. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Acute painful episodes'.)

●

Children with diabetic ketoacidosis may have abdominal pain. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'Signs and symptoms'.)

●

Primary bacterial peritonitis may occur in children with nephrotic syndrome or may present in patients with chronic ascites (eg, chronic liver disease, portal vein obstruction, or chylous ascites). (See "Complications of nephrotic syndrome in children", section on 'Infection'.)

Physical examination — A comprehensive physical examination, including vital signs, a detailed abdominal examination, and a focused extra-abdominal examination are essential for the evaluation of the child with acute abdominal pain. Appearance — Appearance and hydration should be noted. Patients with hypovolemia (as with abdominal injury, volvulus, or intussusception) or peritonitis (as from perforated appendicitis) may have signs of poor perfusion (see "Assessment of systemic perfusion in children"). Children with peritonitis typically prefer to lie still, while those with biliary or renal colic may writhe in pain. Children with jaundice may have hepatitis or hemolysis. However, children with intussusception early in the course of their disease may appear quite well in between painful episodes of peristalsis. Vital signs — Abnormal vital signs may provide a clue to the diagnosis: ●

Fever suggests infection (such as gastroenteritis, urinary tract infection, pneumonia, or pharyngitis). Although many children with appendicitis are febrile, fever is neither sensitive nor specific for this condition [5].

●

Tachypnea can be a sign of respiratory illness (such as pneumonia) or hyperventilation with metabolic acidosis (causing deeper and sometimes rapid breathing in children with dehydration from gastroenteritis, diabetic ketoacidosis, peritonitis, or intestinal obstruction).

●

Hypotension in a child with acute abdominal pain can develop from intravascular volume loss (as with hemorrhage from injury, gastroenteritis, or capillary leak from bowel

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obstruction with volvulus or intussusception) or septic shock with peritonitis (as with perforated appendicitis). Abdominal examination — The abdomen should be examined when the child is quiet and cooperative, in a position of comfort (such as a caretaker's lap), and before more anxiety provoking or uncomfortable parts of the examination (such as ears and throat). (See "The pediatric physical examination: Chest and abdomen", section on 'Abdomen'.) The following features should be noted: ●

Distention may be the result of obstruction or a mass.

●

Bowel sounds may be decreased (as with an ileus in response to peritoneal irritation from appendicitis) or increased (as with gastroenteritis or bowel obstruction).

●

Pain may be localized with gentle palpation performed in all four quadrants. Considerations include:

• Children can be asked to point with one finger to the spot that hurts the most. • Reproducible focal tenderness suggests an intra-abdominal inflammatory process. • Serious causes of abdominal pain are less likely for otherwise healthy children who are not uncomfortable with deep palpation throughout the abdomen, who have no focal tenderness, and who have no extra-abdominal findings. ●

Among older children, tenderness can sometimes be localized to the abdominal wall by demonstrating that tenderness to palpation is exacerbated when the child lifts her head off of the table.

●

Percussive tenderness, rebound, and involuntary guarding are most often signs of peritoneal irritation (as with appendicitis or cholecystitis). Other findings that may be noted with percussion include increased tympany (as with distended bowel), dullness (as with a mass), and shifting dullness (as with ascites).

Rectal examination (to assess for local tenderness, mass, constipation, and hematochezia) may be considered as part of the evaluation for abdominal pain. However, it is uncomfortable and may be of low yield to identify serious conditions. For example, observational evidence suggests that rectal examination may have low utility either for diagnosing appendicitis among children with abdominal pain or for identifying injuries among trauma patients [3,6-10]. If performed, findings on rectal examination that should be noted include: https://www.uptodate.com/contents/6434/print

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Hard stool in the rectal vault supports the diagnosis of constipation but does not prove that this common condition is responsible for a given episode of acute abdominal pain.

●

Blood in the stool can be seen in a variety of conditions, including intussusception, inflammatory bowel disease, inflamed Meckel's diverticulum, dietary protein allergy, infectious enteritis, and constipation with anal fissure.

●

Uterine or adnexal tenderness or masses (suggesting a gynecologic source for abdominal pain) may rarely be noted on rectal examination.

General examination — Extra-abdominal findings on physical examination can provide important information regarding the cause of abdominal pain. ●

Pharyngeal erythema and/or exudate can be seen with pharyngitis.

●

Crackles (Rales), focal, decreased breath sounds, or egophony on auscultation of the chest are suggestive of pneumonia.

●

Muffled heart sounds or a rub may be seen with pericarditis, a gallop rhythm may occur in myocarditis, and tachycardia is typically a feature of both conditions.

●

Flank tenderness may be a sign of pyelonephritis or urolithiasis.

●

Tender scrotal swelling suggests testicular torsion or incarcerated hernia. A careful genitourinary examination should be performed among all males presenting with abdominal pain.

●

Bruising suggests trauma. Petechiae and/or purpura may be seen with IgAV (HSP) and can present with abdominal pain prior to presence of the characteristic rash.

●

The sandpapery erythematous rash with perioral sparing occurs with scarlet fever.

●

Jaundice may be observed in children with hepatitis, gall bladder disease with obstruction, or hemolysis (as with sickle cell disease).

Sexually active females with lower abdominal pain should generally receive bimanual pelvic examinations to look for signs of pelvic inflammatory disease, adnexal masses or cysts, uterine pathology, or ectopic pregnancy. (See "The gynecologic history and pelvic examination".) Ancillary studies — Children with abdominal pain who are otherwise healthy, well appearing, and have normal physical examinations typically do not require ancillary studies. Those whose

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repeat examinations continue to be unremarkable and who tolerate feeding can usually be discharged with reliable medical follow-up. Laboratory and radiographic studies should be performed when history and/or physical examination demonstrate focal findings or suggest concerning diagnoses (such as intraabdominal injury, appendicitis, bowel obstruction, or infection). The choice of tests should be based upon the age of the child and the diagnoses under consideration. Laboratory studies — Specific studies that may be considered include: ●

White blood cell count (WBC) – An elevated WBC suggests infection or inflammation (such as appendicitis), although a normal WBC does not exclude these processes (see "Acute appendicitis in children: Clinical manifestations and diagnosis", section on 'Laboratory testing'). WBC >20,000 suggests perforated appendicitis, appendiceal abscess, or lobar pneumonia [11,12].

●

Hematocrit – For children with bleeding, hematocrits that are initially normal establish baselines for serial measurements but may be misleading (eg, in situations of dehydration). Anemia with abnormal red cell morphology can be seen with hemoglobinopathies (sickling) and hemolytic uremic syndrome (microangiopathic changes). Children with hemolytic uremic syndrome also have thrombocytopenia. (See "Overview of the clinical manifestations of sickle cell disease" and "Clinical manifestations and diagnosis of Shiga toxin-producing Escherichia coli (STEC) hemolytic uremic syndrome (HUS) in children", section on 'Clinical and laboratory manifestations'.)

●

Serum chemistries – Among children with upper abdominal pain, abnormal liver enzyme tests, lipase or amylase measurements suggest hepatitis, cholecystitis, or pancreatitis, respectively. Metabolic acidosis can occur with dehydration, intestinal obstruction, peritonitis, or diabetic ketoacidosis (DKA). An elevated blood glucose in the setting of acidosis is also consistent with DKA. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis".)

●

A urine dipstick evaluation (for blood, nitrites, leukocyte esterase, glucose, ketones, and protein) should be obtained for most children with abdominal pain. A formal urinalysis should be sent when the dipstick is abnormal. Hematuria can occur with urolithiasis, IgAV (HSP), hemolytic uremic syndrome, and urinary tract infection (UTI). Pyuria usually indicates a UTI, but a small number of WBCs (10 to 20 WBCs/hpf) can be seen with appendicitis (presumably when inflammation irritates the bladder wall). Children with DKA have glucosuria and ketonuria. A child with nephrotic syndrome and bacterial peritonitis typically has proteinuria.

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Urine pregnancy testing should be performed for postmenarchal females with abdominal pain. (See "Clinical manifestations and diagnosis of early pregnancy", section on 'Urine pregnancy test'.)

●

Rapid streptococcal antigen testing or bacterial throat culture – Children with abdominal pain and pharyngeal findings should usually receive rapid screening tests and/or throat cultures for group A beta hemolytic Streptococcus. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis", section on 'Diagnosis'.)

Imaging — Imaging is an essential component of the evaluation of some children with acute abdominal pain who have concerning clinical features such as trauma, peritoneal irritation, signs of obstruction, masses, distension, or focal tenderness and/or pain. Children with a typical clinical presentation for acute appendicitis are likely to have appendicitis. In this circumstance, we encourage clinicians to consult a surgeon with experience caring for children prior to obtaining imaging studies. (See "Acute appendicitis in children: Clinical manifestations and diagnosis", section on 'Imaging'.) ●

Plain radiography – In most instances, plain images are not helpful for providing a specific diagnosis for abdominal pain. They may serve a limited role in some children as follows:

• Abdominal films may demonstrate signs of obstruction (such as air fluid levels, distended bowel, or sentinel bowel loops) or perforation (such as free air) (

image 1).

• Fluid-filled loops of small bowel can be seen with gastroenteritis. • A fecalith in the right lower quadrant of a child with abdominal pain suggests the diagnosis of appendicitis, although this finding is not frequently observed. (See "Acute appendicitis in children: Diagnostic imaging", section on 'Plain radiographs'.)

• Although not routinely indicated for the evaluation of functional constipation, children with acute abdominal pain due to constipation may have increased stool noted with abdominal radiography. The absence of at least moderate amounts of stool excludes this diagnosis as an explanation for acute abdominal pain. (See "Constipation in infants and children: Evaluation", section on 'Imaging'.)

• For children who may have midgut volvulus, an upper GI contrast series is the best examination for diagnosis (

image 2 and

image 3). (See "Intestinal malrotation in

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• Although obstruction or mass effect may be seen on plain film, ultrasound is the best diagnostic test for intussusception. In addition, contrast enema (air or barium) can diagnose and often reduce an intussusception (

image 4 and

image 5). (See

"Intussusception in children", section on 'Nonoperative reduction'.)

• A chest radiograph may reveal basilar pneumonia or signs of myocarditis (cardiomegaly) as the cause of abdominal pain. ●

Ultrasonography (US) – Because it has the advantage of no radiation exposure and can be performed at the bedside, ultrasonography may be useful for several conditions that cause abdominal pain in children including the following:

• Gallstones. • Genitourinary conditions (eg, ovarian torsion, ruptured ovarian cyst, and testicular torsion). (See "Ovarian and fallopian tube torsion", section on 'Ultrasound' and "Causes of scrotal pain in children and adolescents", section on 'Role of imaging' and "Evaluation and management of ruptured ovarian cyst", section on 'Laboratory findings'.)

• Intussusception (

image 6). (See "Intussusception in children", section on

'Ultrasonography'.)

• Appendicitis – US is the recommended imaging modality for children with atypical or equivocal findings, although the utility of US for diagnosing appendicitis depends upon the experience of the ultrasonographer, and may also vary based upon a child's body mass index (

table 2 and

image 7). (See "Acute appendicitis in children: Diagnostic

imaging", section on 'Imaging approach' and "Acute appendicitis in children: Diagnostic imaging", section on 'Test performance'.)

• As part of a focused abdominal sonography for trauma (FAST examination) in a trauma patient with blunt injury, a negative FAST examination by an experienced ultrasonographer may exclude significant intra-abdominal hemorrhage as the explanation for shock. (See "Trauma management: Approach to the unstable child", section on 'e-FAST (extended focused assessment with sonography for trauma)'.) ●

Computed tomography (CT) – CT is generally not used as the primary imaging modality for abdominal pain in children because of the risks of radiation exposure and the availability of alternative modalities that provide accurate imaging. The radiation exposure of an abdominal CT in children can be significant, although lower-dose imaging protocols

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can mitigate this risk. Alternative imaging modalities such as ultrasound or magnetic resonance imaging (MRI) can frequently provide equivalent or higher diagnostic certainty without radiation exposure. Sequential use of ultrasound prior to (or rather than) CT may reduce radiation exposure (eg, children with suspected appendicitis), especially in young children. When an abdominal CT is performed, the clinician should consider a focused examination as well as ensure that CT scanning energy parameters are appropriate for children in their institution. (See "Acute appendicitis in children: Diagnostic imaging", section on 'Focused CT' and "Acute appendicitis in children: Diagnostic imaging", section on 'CT scanning parameters'.) Computed tomography (CT) with contrast is useful for the evaluation of patients with acute abdominal pain when a wide variety of diagnoses are being considered (such as appendicitis [particularly complex], pancreatitis, intra-abdominal abscess, blunt abdominal trauma, and for the evaluation of an intra-abdominal mass). As an example, CT has high sensitivity and specificity for diagnosing appendicitis and is the most sensitive imaging test for pediatric nephrolithiasis. (See "Acute appendicitis in children: Diagnostic imaging", section on 'Test performance' and "Kidney stones in children: Clinical features and diagnosis", section on 'Imaging' and "Pediatric blunt abdominal trauma: Initial evaluation and stabilization", section on 'Abdominal and pelvic CT'.) Ultrasound is the primary imaging modality to assess for hydronephrosis among children with suspected nephrolithiasis but has limited ability to identify stones 5 years of age and often have predisposing conditions such as hemoglobinopathies or cystic fibrosis. Causes of pancreatitis among children include trauma, infection, structural anomalies, metabolic or genetic causes, and some medications (such as tetracycline, L-asparaginase, valproic acid, and steroids) [16,17]. (See "Clinical manifestations and diagnosis of chronic and acute recurrent pancreatitis in children", section on 'Further evaluation for the cause'.)

• Meckel's diverticulum may cause abdominal pain mimicking an acute abdomen, but is more typically associated with painless rectal bleeding. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Meckel's diverticulum'.)

• Perforation of a peptic ulcer is an unusual cause of abdominal pain and peritoneal irritation among children, particularly those 5 years

Adhesions*

Adhesions*

Adhesions*

Adhesions*

Necrotizing enterocolitis*

Foreign body ingestion*

Appendicitis*

Appendicitis* Diabetic ketoacidosis*

Volvulus*

Hemolytic uremic syndrome*

Foreign body ingestion*

Colic¶ Dietary protein allergy Testicular torsion

Hirschsprung disease*

Hemolytic uremic syndrome*

Incarcerated hernia*

Intussusception*

Intussusception*

Primary bacterial peritonitis*

Trauma (including inflicted injury)* Gastroenteritis¶ Viral illness¶ Dietary protein allergy Hepatitis Inflammatory bowel disease Meckel's diverticulum Sickle cell syndrome vasoocclusive crisis Toxin Tumor Urinary tract infection

Trauma (including inflicted injury)* Gastroenteritis¶ Viral illness¶ Pharyngitis¶ Constipation¶ Henoch Schönlein purpura Hepatitis Inflammatory bowel disease Intraabdominal abscess Meckel's diverticulum

Myocarditis, pericarditis* Perforated ulcer* Primary bacterial peritonitis* Trauma* Constipation¶ Gastroenteritis¶ Pharyngitis¶ Viral illness¶ Abdominal migraine Cholecystitis or cholelithiasis Familial Mediterranean fever Gastrointestinal dysmotility

Urinary tract infection

Henoch Schönlein purpura

Ovarian torsion

Hepatitis

Pancreatitis

Inflammatory bowel disease

Pneumonia Sickle cell syndrome vasoocclusive crisis Toxin Tumor https://www.uptodate.com/contents/6434/print

Hemolytic uremic syndrome*

Intraabdominal abscess Meckel's diverticulum Ovarian torsion 26/49

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Pancreatitis Pneumonia Acute porphyria (adolescents) Ruptured ovarian cyst Sickle cell syndrome vasoocclusive crisis Testicular torsion Urinary tract infection Urolithiasis * Life-threatening condition. ¶ Common condition. Graphic 65488 Version 10.0

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Emergency department evaluation of abdominal pain: Males and premenarcha females

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Bold text: Life-threatening conditions. Italic text: Common conditions. For more details regarding the diagnostic approach for specific conditions, refer to UpToDate topics on emergency evaluation of abdominal pain in children.

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* The approach to imaging depends upon the suspected etiology. Refer to UpToDate pediatric content on imaging of the gall bladder, pancreas, kidneys, ovaries, and appendix. Graphic 57204 Version 5.0

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Emergency department evaluation of abdominal pain in postmenarchal girls

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Bold text: Life-threatening conditions. Italic text: Common conditions. For more details regarding the diagnostic approach for specific conditions, refer to UpToDate topics on eme evaluation of abdominal pain in children. ​ * The approach to imaging depends upon the suspected etiology. Refer to UpToDate pediatric content on im gall bladder, kidneys, ovaries, and appendix. Graphic 69041 Version 9.0

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Intussusception

Plain film of a child with intussusception shows small intestinal obstruction. Notable are a dilated small bowel and the absence of colonic gas. Courtesy of Nancy Fitzgerald, MD and Taylor Chung, MD.

Graphic 56921 Version 3.0

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Duodenum with "corkscrew" appearance in intestinal malrotation

On upper gastrointestinal contrast study, a "corkscrew" appearance of the duodenum is diagnostic of intestinal malrotation. Courtesy of Terry Buchmiller, MD.

Graphic 106316 Version 1.0

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Upper gastrointestinal contrast studies demonstrating the duodenal bulb

In the image on the left, the duodenal bulb is to left of the spine. In the image on the right, with malrotation, the duodenal bulb is overlying spine. Reproduced with permission from Carlo Buonomo, MD, Children's Hospital-Boston. Copyright © Carlo Buonomo, MD.

Graphic 77126 Version 2.0

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Intussusception

Barium contrast enema showing intussusception in mid-transverse colon (arrow); the patient is in a prone position. Courtesy of Nancy Fitzgerald, MD and Taylor Chung, MD.

Graphic 54310 Version 4.0

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Intussusception air contrast

(A) Air contrast enema showing intussusception in mid-transverse colon (arrow). (B) Air contrast enema in the same patient showing that the intussusception in mid-transverse colon has been reduced to the ascending colon. (C) Air contrast enema after successful reduction of the intussusception: post-evaluation film. Courtesy of Nancy Fitzgerald, MD and Taylor Chung, MD.

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Intussusception ultrasound

Ultrasonography shows a typical appearance of "coiled spring" pattern. Courtesy of Nancy Fitzgerald, MD and Taylor Chung, MD.

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Ultrasonographic signs of acute appendicitis Non-compressible tubular structure in the right lower quadrant Wall thickness >2 mm Overall diameter >6 mm Free fluid in the right lower quadrant Thickening of the mesentery Localized tenderness with graded compression Presence of a calcified appendicolith Graphic 61146 Version 2.0

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Ultrasound findings of appendicitis

These ultrasound images are taken from a patient with early appendicitis at surgery. They demonstrate important diagnostic findings of acute appendicitis without evidence for perforation or abscess formation: (A) A dilated tubular fluid-filled structure in the right lower quadrant with a blind-ending tip is identified, consistent with the appendix. (B) The appendix is dilated, measuring up to 1.2 cm in the transverse dimension. (C) There is a hyperechoic shadowing focus within the midportion of the appendix, consistent with an appendicolith. (D) There is increased echogenicity of the periappendiceal fat and hyperemia observed on color Doppler imaging. On further ultrasound imaging (not shown), there is trace free fluid noted in the right lower quadrant, and n periappendiceal abscess is identified. Courtesy of Mark I Neuman, MD, MPH.

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Radiograph of necrotizing enterocolitis in premature infants

Plain abdominal radiographs in premature infants with necrotizing enterocolitis. Left panel: There is marked abdominal distention due in part to dilated bowel loops, and bubbles of gas in the bowel wall due to extensive pneumatosis intestinalis (arrow). An orogastric tube is in place. Right panel: There is marked abdominal distention, pneumatosis intestinalis, and a suspicion of portal venous (arrow) and/or free intraperitoneal air. Graphic 78676 Version 4.0

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Frequencies of clinical features of children with Henoch-Schonlein purpura (HSP) at presentation and during their disease Taiwan[1] (percent)

Italy[2] (percent)

United States[3] (percent)

Purpura

100

100

100

Arthralgia/arthritis

43

74

82

Abdominal pain

58

51

63

18

18

33

Intussusception

0.4

0.6

 

Renal involvement

21

54

40

Edema

 

52

 

Encephalopathy

1

3

2

Orchitis

 

13

 

Recurrence

 

33

33

Clinical features

Gastrointestinal bleeding

References: 1. Chang WL, Yang YH, Lin YT, Chiang BL. Gastrointestinal manifestations in Henoch-Schönlein purpura: a review of 261 patients. Acta Paediatr 2004; 93:1427. 2. Chang WL, Yang YH, Wang LC, et al. Renal manifestations in Henoch-Schönlein purpura: a 10-year clinical study. Pediatr Nephrol 2005; 20:1269. 3. Trapani S, Micheli A, Grisolia F, et al. Henoch Schonlein purpura in childhood: epidemiological and clinical analysis of 150 cases over a 5-year period and review of literature. Semin Arthritis Rheum 2005; 35:143. 4. Saulsbury FT. Henoch-Schönlein purpura in children. Report of 100 patients and review of the literature. Medicine (Baltimore) 1999; 78:395.

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Skin manifestations of immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Purpuric papules (palpable purpura) and macules on the lower extremities. Graphic 72094 Version 8.0

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Selected identifiable causes of prolonged/excessive crying in an infant younger than four months of age Condition

Clinical features

General Drug ingestion or

History of medication administration

overdosage (eg, pseudoephedrine) Hunger/inadequate

Signs of hypovolemia or undernutrition (eg, sunken fontanelle, dry

feeding

mucous membranes, decreased subcutaneous fat, etc)

Neonatal abstinence

Maternal history of prenatal substance use or positive urine screen

syndrome

(maternal or fetal)

Skin Hair tourniquet of digit

Apparent on physical examination 

or penis  Open diaper pin poking

Apparent on physical examination

the skin, diaper rash Trauma (abusive or nonabusive)

Bruising, laceration 

Eyes Corneal abrasion or foreign body

May have photophobia, positive fluorescein examination

Glaucoma

Chronic or intermittent tearing, photophobia, corneal enlargement, corneal clouding, optic nerve cupping, ocular enlargement

Ears, nose, oropharynx Otitis media

Bulging tympanic membrane

Thrush

White plaques on the buccal mucosa, tongue, or palate

Cardiovascular Anomalous origin of the

Cardiomegaly, heart failure

left coronary artery  Heart failure

Feeding intolerance, tachycardia, poor perfusion, tachypnea

Supraventricular

Pallor, irritability, poor feeding, cyanosis, restlessness

tachycardia

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Constipation

Passage of hard stools

Gastroenteritis 

Vomiting, diarrhea

Gastroesophageal reflux 

Vomiting, poor weight gain, feeding refusal, gross or occult blood in the stool

Gastrointestinal

Vomiting (may or may not be bilious or forceful), gastrointestinal

obstruction (eg, pyloric stenosis, intussusception,

bleeding, forceful vomiting, abdominal tenderness, distension, rightsided sausage-shaped abdominal mass (intussusception),

volvulus)

palpable "olive" (pyloric stenosis) 

Inguinal hernia

Bulge in the groin area (may be intermittent), vomiting and abdominal distension may indicate incarceration

Genitourinary Meatal ulcer 

Apparent on examination

Ovarian torsion  

Feeding intolerance, vomiting, abdominal distension, fussiness/irritability

Testicular torsion

Acute testicular swelling and tenderness 

Urinary tract infection

Fever, suprapubic tenderness, poor feeding, poor weight gain

Urinary tract obstruction

Abdominal distension (due to enlarged bladder), difficulty voiding, poor urinary stream, straining or grunting during voiding

Skeletal Fracture

Decreased movement of extremity, asymmetric Moro reflex, localized swelling and crepitation, increased pain response with movement of the extremity

Osteomyelitis or septic

Fever, decreased movement of extremity, asymmetric Moro reflex,

arthritis

increased pain response with movement of the extremity

Neurologic Abusive head trauma

Seizures, respiratory difficulty or apnea, retinal hemorrhages, cutaneous bruising, associated injuries

Meningitis

Fever, bulging fontanelle, lethargy, irritability, meningismus (often not present in infants)

Neuromuscular disease,

Abnormal tone, muscular weakness

CNS disorder, metabolic disease  CNS: central nervous system. Data from: 1. Drug and Therapeutics Bulletin. Management of infantile colic. BMJ 2013; 347:f4102.

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2. Parker S, Magee T. Colic. In: The Zuckerman Parker Handbook of Developmental and Behavioral Pediatrics for Primary Care, 3rd ed, Augustyn M, Zuckerman B, Caronna EB (Eds), Lippincott Williams & Wilkins, Philadelphia 2011. p.182. 3. Roberts DM, Ostapchuk M, O'Brien JG. Infantile colic. Am Fam Physician 2004; 70:735.

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Contributor Disclosures Mark I Neuman, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Gary R Fleisher, MD No relevant financial relationship(s) with ineligible companies to disclose. Jan E Drutz, MD No relevant financial relationship(s) with ineligible companies to disclose. Melvin B Heyman, MD, MPH Equity Ownership/Stock Options: Amgen[IBD]. Grant/Research/Clinical Trial Support: AbbVie [IBD];Genentech [IBD];Janssen [IBD];Lilly [IBD];Pfizer [UC];Shire [IBD];Takeda [IBD]. Consultant/Advisory Boards: Certara [IBD];Gilead[IBD];Mahana [GI conditions]. All of the relevant financial relationships listed have been mitigated. James F Wiley, II, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation of sore throat in children Authors: Gary R Fleisher, MD, Andrew M Fine, MD, MPH Section Editors: George A Woodward, MD, Jan E Drutz, MD Deputy Editor: James F Wiley, II, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: May 20, 2022.

INTRODUCTION This topic will review conditions that can cause the symptom of sore throat. The discussion will include pertinent features of the history and physical examination and an algorithmic approach to common and life threatening conditions. The approach and treatment of children with infectious pharyngitis are discussed in more detail elsewhere. (See "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis" and "Acute pharyngitis in children and adolescents: Symptomatic treatment" and "Treatment and prevention of streptococcal pharyngitis in adults and children".)

DEFINITION Sore throat refers to any painful sensation localized to the pharynx or surrounding anatomy. The developmental ability of young children to identify and define their symptoms varies and the physician must pay careful attention to the patient and the caretaker in order to clarify the exact nature of the complaint. Sore throat can be the symptom of a disease process that does not directly affect the pharynx. Occasionally, young patients with dysphagia that results from disease in the area of the esophagus or with difficulty swallowing because of a neuromuscular disorder may verbalize these sensations as a sore throat or their symptoms may be interpreted by a caretaker as a sore throat.

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CAUSES The etiology of sore throat varies by age (

table 1) and can further be divided by conditions

that are life-threatening, common, or less common. Life-threatening conditions Epiglottitis — The incidence of epiglottitis, a well-appreciated cause of life-threatening upper airway infection, has declined significantly since the introduction of vaccination against Haemophilus influenzae type b. This disease manifests with a toxic appearance, high fever, stridor, and drooling. Sore throat occurs in many cases, but is only rarely the primary complaint. (See "Epiglottitis (supraglottitis): Clinical features and diagnosis".) Retropharyngeal abscess — Retropharyngeal abscesses can cause sore throat and usually occur in children less than four years of age. Other complaints include neck pain and fever. There may be difficulty swallowing and respiratory distress. The posterior location of the abscess makes it difficult to visualize on physical examination. Imaging is often required to confirm the diagnosis. (See "Retropharyngeal infections in children".) Lateral pharyngeal abscesses — Lateral pharyngeal abscesses produce symptoms similar to retropharyngeal infections but occur less often. High fever is common. Other signs include trismus and swelling below the mandible. Peritonsillar abscess — A peritonsillar abscess may complicate a previously diagnosed infectious pharyngitis or may be the initial source of a child's discomfort. This disease is most common in older children and adolescents. The diagnosis is evident from visual inspection, augmented occasionally by careful palpation. The abscess produces a bulge in the posterior aspect of the soft palate, deviates the uvula to the contralateral side of the pharynx, and has a fluctuant quality on palpation. (See "Retropharyngeal infections in children".) Infectious mononucleosis — Infectious mononucleosis can rarely cause airway obstruction from severe tonsillar hypertrophy. (See "Infectious mononucleosis", section on 'Complications including airway obstruction'.) Diphtheria — Diphtheria is a life-threatening but seldom encountered cause of infectious pharyngitis, characterized by a thick pharyngeal membrane and marked cervical adenopathy. (See "Epidemiology and pathophysiology of diphtheria".) Lemierre syndrome — This unusual infection is caused by Fusobacterium necrophorum [1] or mixed anaerobic flora and is associated with jugular venous thrombophlebitis and the https://www.uptodate.com/contents/6457/print

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dissemination of infection by septic emboli. Both children and adults with Lemierre’s syndrome almost always have pharyngitis at presentation [2,3]. It should be considered in the illappearing patient with neck pain, severe pharyngitis, and respiratory distress [4,5]. (See "Lemierre syndrome: Septic thrombophlebitis of the internal jugular vein".) Common conditions Viral pharyngitis — Infection is the most common cause of sore throat and the etiologic agents are usually respiratory viruses, of which a few cause a readily identifiable syndrome including ( ●

table 1):

Adenoviruses – Pharyngoconjunctival fever, a benign follicular conjunctivitis often accompanied by a febrile pharyngitis and cervical adenitis (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Eyes')

●

Coxsackie A viruses – Herpangina or hand, foot, and mouth disease ( picture 2 and

picture 1 and

picture 3) (common in infants and young children; decreases in

frequency as age increases) (see "Hand, foot, and mouth disease and herpangina") Herpes simplex virus usually causes stomatitis (discussed below). However, it may cause pharyngitis in the immunocompromised child, and rarely in the immunocompetent child. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Primary infection'.) Coronavirus disease 2019 (COVID-19) — Sore throat and pharyngeal erythema occur in tobramycin > amikacin > neomycin. Ototopical aminoglycoside drops have the potential to cause ototoxicity. These include gentamicin, tobramycin, and Cortisporin (which contains neomycin). However, there are few case reports of sensorineural hearing loss with the use of ototopical medication and, in those, it is not clear that the drops were the cause. The reason it is believed that these medications do not have their normal ototoxic effect is that the inflamed mucosa within the ear prevents significant drug penetration into the oval and round windows [78]. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)

●

Other oral antibiotics that can cause ototoxicity include erythromycin and tetracycline. These drugs have a more pronounced ototoxic effect in patients with impaired kidney function. (See "Tetracyclines".)

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Many chemotherapeutic agents are known to cause hearing loss. The worst ototoxicity occurs with cisplatin. Other commonly used agents with ototoxicity are fluorouracil, bleomycin, and nitrogen mustard.

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High-dose aspirin (6 to 8 g/day) or other salicylates can cause hearing loss, but this is reversible with discontinuation of the drug. In an observational study in men, regular use of standard-dose aspirin, acetaminophen, or nonsteroidal antiinflammatory drugs (NSAIDs; ≥2 times/week) was also associated with an increased risk of hearing loss, particularly in those less than 50 years old [79]. Similar findings were found in women for acetaminophen and ibuprofen, but not aspirin [80].

●

Phosphodiesterase 5 inhibitors stimulate downstream events in the cyclic guanosine monophosphate (cGMP) pathway thought to damage cochlear hair cells [81]. In a large population-based sample, sildenafil use was associated with hearing loss [82]. Hearing loss has also been reported with tadalafil or vardenafil [83].

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Antimalarial medications such as quinine and chloroquine may also cause sensorineural hearing loss and tinnitus but, similar to salicylates, these effects are usually reversible.

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Loop diuretics may cause temporary hearing loss and tinnitus [84].

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Cocaine, both intranasal and intravenous, has been associated with unilateral or bilateral sensorineural hearing loss in case reports [85].

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Heavy metals, including lead, mercury, cadmium, and arsenic, can all lead to hearing loss [86].

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Exposure to aromatic solvents, including toluene and styrene, may cause hearing loss due to cochleotoxic effects as well as alterations of the middle ear acoustic reflex [87].

Neurogenic — Several neurologic disorders may cause sensorineural hearing loss: ●

Cerebrovascular accident or transient ischemic attack. (See "Stroke: Etiology, classification, and epidemiology" and "Definition, etiology, and clinical manifestations of transient ischemic attack".)

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Arnold-Chiari malformations may stretch the auditory vestibular nerve, thereby causing hearing loss and/or vestibular complaints [88]. The malformation may be decompressed with restoration of hearing.

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Multiple sclerosis is another disease that can initially present as a sudden sensorineural hearing loss and/or vertigo [89] (see "Sudden sensorineural hearing loss in adults: Evaluation and management" and "Manifestations of multiple sclerosis in adults"). The hearing loss may be temporary or permanent.

●

Otosyphilis is a rare cause of sudden unilateral or bilateral sensorineural hearing loss. The hearing loss is sometimes accompanied by vertigo or tinnitus, and it may be reversible when promptly recognized and treated [90]. (See "Neurosyphilis".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hearing loss and hearing disorders in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given https://www.uptodate.com/contents/6844/print

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condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Age-related hearing loss (presbycusis) (The Basics)" and "Patient education: Ear wax impaction (The Basics)" and "Patient education: Ruptured eardrum (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Anatomy and physiology of hearing loss – Hearing loss may be due to outer, middle, or inner ear etiologies (

●

figure 1 and

table 1). (See 'Anatomy and physiology' above.)

Causes of conductive and sensorineural hearing loss – All outer and middle ear causes of hearing loss result in conductive hearing loss; nearly all inner ear causes result in sensorineural hearing loss (

table 1 and

table 2). (See 'Outer ear causes' above and

'Middle ear causes' above and 'Inner ear causes' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES

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84. Ding D, Liu H, Qi W, et al. Ototoxic effects and mechanisms of loop diuretics. J Otol 2016; 11:145. 85. Stenner M, Stürmer K, Beutner D, Klussmann JP. Sudden bilateral sensorineural hearing loss after intravenous cocaine injection: a case report and review of the literature. Laryngoscope 2009; 119:2441. 86. Prasher D. Heavy metals and noise exposure: health effects. Noise Health 2009; 11:141. 87. Campo P, Morata TC, Hong O. Chemical exposure and hearing loss. Dis Mon 2013; 59:119. 88. Weber PC, Cass SP. Clinical assessment of postural stability. Am J Otol 1993; 14:566. 89. Fischer C, Mauguière F, Ibanez V, et al. The acute deafness of definite multiple sclerosis: BAEP patterns. Electroencephalogr Clin Neurophysiol 1985; 61:7. 90. de Goffau MJ, Doelman JC, van Rijswijk JB. Unilateral sudden hearing loss due to otosyphilis. Clin Pract 2011; 1:e133. Topic 6844 Version 55.0

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GRAPHICS

Ear anatomy

The external auditory canal is a cylinder measuring approximately 2.5 cm in length and 7 to 9 mm in width, extending from the conchal cartilage of the auricle to the tympanic membrane. It is divided into a lateral (outer) cartilaginous portion that occupies approximately one-third of the canal, and a medial (inner) bony portion that occupies the other two-thirds. Their junction is termed the isthmus and is the narrowest region of the ear canal. The outer cartilaginous portion is lined by thicker skin with numerous adnexal structures, including cerumen glands (a modified apocrine type gland), sebaceous glands, and hair follicles. Cerumen is formed here. The inner osseous portion of the canal contains thin skin without subcutaneous tissue. The inferior tympanic recess is a small depression in the inferior medial aspect of the ear canal, adjacent to the tympanic membrane. Debris can collect in this area and cause or perpetuate infection. Adapted with permission from: Cantor RM, Emerg Med 1999; 31:40. Copyright Quadrant HealthCom, Inc, 1999.

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Cochlear and vestibular anatomy

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Causes of hearing loss Conductive Outer-ear causes

Sensorineural Inner-ear causes

Congenital microtia or atresia

Hereditary hearing loss

External otitis

Congenital viral infections

Trauma

Congenital malformations

Squamous cell carcinoma

Presbycusis

Exostosis

Meningitis

Osteoma

Thyrotoxicosis

Psoriasis

Viral cochleitis

Cerumen

Ototoxic drugs

Middle-ear causes

Otologic surgery

Congenital atresia or ossicular chain malformation

Meniere disease

Otitis media

Noise exposure

Cholesteatoma

Barotrauma

Otosclerosis

Penetrating trauma

Tympanic membrane perforation

Acoustic neuroma

Temporal bone trauma

Meningioma

Glomus tumors

Autoimmune disease Multiple sclerosis Cerebrovascular ischemia Arnold-Chiari malformation  Otosyphilis

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Exostosis of the external auditory canal

Exostoses are multiple benign bony growths of the external auditory canal that most commonly occur in individuals who have had repeated exposure to cold water. Reprinted with permission from Nikolas H Blevins, MD

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Occluding exostosis of the external auditory canal

Surgical intervention with removal of the exostosis is performed when the exostoses become so large that they occlude the canal, and infections begin to develop because of retained skin and cerumen. Reprinted with permission from Nikolas H Blevins, MD

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Ear polyp

Courtesy of Vaibhav Parekh, MD, MBA.

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Cholesteatoma of the middle ear

Cholesteatoma (arrow) is a growth of desquamated, stratified, squamous epithelium. Reprinted with permission from Nikolas H Blevins, MD.

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Tympanic membrane perforation

Tympanic membrane perforation with surrounding myringosclerosis. Courtesy of Nikolas H Blevins, MD.

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Jugulotympanic paraganglioma (glomus tympanicum) of the middle ear

Picture of a left tympanic membrane with a pulsating red mass occupying the inferior portion of the middle ear space. The rest of the tympanic membrane is normal. Reproduced with permission from: Bechara Y Ghorayeb, MD. www.ghorayeb.com.

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Main causes of sudden sensorineural hearing loss (SSNHL)* Infections Viral cochleitis associated with herpesviruses, parainfluenza virus, influenza, mumps, measles, rubella, or HIV; bacterial meningitis; Mycoplasma pneumoniae infection; Lyme disease; tuberculosis, syphilis, or fungal infection

Ototoxic drugs Aminoglycosides, vancomycin, erythromycin, loop diuretics, antimalarials, cisplatin, sildenafil, cocaine

Neoplasms Acoustic neurinoma; meningeal carcinomatosis; lymphoma, leukemia, or plasma cell dyscrasia

Trauma Head injury, barotraumas; noise exposure

Autoimmune disease Autoimmune inner ear disease; Cogan's syndrome; Susac syndrome; systemic lupus erythematosus; antiphospholipid antibody sydrome; rheumatoid arthritis; Sjögren's syndrome; relapsing polychondritis; vasculitides (polyarteritis nodosa, Behçet's syndrome, Kawasaki disease, granulomatosis with polyangiitis [Wegener's], temporal arteritis, or primary central nervous system vasculititis)

Vascular disorder Vertebrobasilar cerebrovascular accident or transient ischemic attack; cerebellar infarction; inner ear hemorrhage

Varied causes Meniere disease, otosclerosis; Paget disease; multiple sclerosis; sarcoidosis; hypothroidism; idiopathic SSNHL * In many of the conditions listed, SSNHL can be the presenting manifestation of the disease. Sometimes, both ears may be affected simultaneously. Reproduced with permission from: Schattner A, Halperin D, Wolf D, Zimhony O. Enteroviruses and sudden deafness. CMAJ 2003; 168:1421. Copyright © 2003 Canadian Medical Association.

Graphic 78516 Version 10.0

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A typical audiogram of noise-induced sensorineural hearing loss

A typical audiogram of early noise-induced sensorineural hearing loss. Hearing is normal through 2000 Hz. There is an abrupt drop at 4000 Hz with recovery at 8000 Hz. With additional injury over time, this "drop" generalizes to involve more frequencies and becomes more noticeable to the child.

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ANSI-1969: American National Standards Institute, standard reference threshold sound-pressure levels for audiometers; AC: air conduction; BC: bone conduction; L: left; C: center; R: right; Hz: Hertz; NML: normal; NEG: negative pressure; VOL: volume; ART: acoustic reflex threshold; CR: contralateral R; CL: contralateral L; SRT: speech reception threshold; DISCM: speech discrimination; dB: decibel; MCL: most comfortable listening (loudness) level; LCL: loudness comfort level. Graphic 67636 Version 8.0

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Longitudinal temporal bone fracture

Blunt trauma to the temporal parietal region, resulting in a line of fracture in the temporal bone (arrows). Courtesy of Peter C Weber, MD.

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Transverse temporal bone fracture

Blunt trauma to the occipital or frontal region, resulting in a line of fracture through the cochlea (arrow). Courtesy of Peter C Weber, MD.

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Acoustic neuroma

A right-sided acoustic neuroma of the eighth cranial nerve is evident in the cerebellopontine angle (arrow). Courtesy of Peter C Weber, MD.

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Contributor Disclosures Peter C Weber, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Daniel G Deschler, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Lisa Kunins, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation of hearing loss in adults Author: Peter C Weber, MD, FACS Section Editor: Daniel G Deschler, MD, FACS Deputy Editor: Lisa Kunins, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Mar 30, 2022.

INTRODUCTION Hearing loss is a common problem that everyone experiences from time to time. Most commonly it occurs when flying or traveling up a mountain, and a full sensation develops in the ears, leading to the feeling of wanting to pop the ears open in order to hear better. Diminished hearing also may occur during an ear infection. These causes of hearing loss are usually shortlived. The other extreme is the permanent sensorineural hearing loss that occurs with aging, which most people experience to some degree [1]. The evaluation of hearing loss in adults will be reviewed here. The etiology and treatment of hearing loss are discussed separately. (See "Etiology of hearing loss in adults" and "Hearing amplification in adults".)

CLASSIFICATION OF HEARING LOSS Hearing loss may be classified into three types [2]: ●

Sensorineural, involving the inner ear, cochlea, or the auditory nerve.

●

Conductive, involving any cause that in some way limits the amount of external sound from gaining access to the inner ear. Examples include cerumen impaction, middle ear fluid, or ossicular chain fixation (lack of movement of the small bones of the ear).

●

Mixed loss, which is a combination of conductive and sensorineural hearing loss.

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A number of abnormalities may lead to hearing loss of each type (

table 1). It is useful to

begin the evaluation by classifying the loss as sensorineural or conductive, since this helps focus the remainder of the patient assessment. Conductive hearing loss is usually related to abnormalities of the outer or middle ear; sensorineural hearing loss is related to inner ear pathology.

HISTORY Any patient complaining of hearing loss should have a full auditory history and examination performed. Important questions in the history include: ●

What was the onset and progression of the hearing loss?

●

How well can the patient understand spoken words?

●

Is the problem mainly with background noise (eg restaurants, parties) or is it just as bad in quiet settings?

●

Is there pain or drainage out of the ear associated with the hearing loss?

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Is there a history of significant trauma, including noise and barotrauma?

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Is there a history of major infections?

●

Is there a history of previous ear surgery?

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Is there associated tinnitus, vertigo, or disequilibrium?

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Is there a family history of hearing loss? There are a number of congenital and hereditary causes of hearing loss; presbycusis also can run in families.

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What medications are taken?

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Do headaches or visual disturbances occur before, during, or after episodes of hearing loss?

●

What medications, including over-the-counter drugs, is the patient taking?

●

History of other medical disorders such as diabetes, smoking, coronary artery disease, autoimmune diseases.

Patients with sudden hearing loss require urgent referral as treatment success is related to early initiation of treatment. (See "Sudden sensorineural hearing loss in adults: Evaluation and management".)

EXAMINATION The examination for some patients will involve only simple tests that can be performed in a primary care office. Many patients, however, will require formal audiologic testing or other https://www.uptodate.com/contents/6850/print

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specialized tests. Office hearing evaluation — There are a variety of methods used to test hearing in the office setting. These include a whispered voice test, tone-emitting otoscope, questionnaires, and tuning forks. A systematic review of the whispered voice test concluded that in four studies in adults the sensitivity for hearing impairment was 90 to 100 percent and the specificity was 70 to 87 percent [3]. To perform a whispered voice test, stand at arm's length behind the patient (to prevent lip reading) and mask hearing in one ear by occluding the ear canal and rubbing the tragus with a circular motion. Whisper a short sequence of letters and numbers and ask the patient to repeat them. Test the other ear in a similar manner. In addition to the whispered voice test, tone-emitting otoscopes and/or questionnaires are often used. In a randomized trial of screening strategies in 2305 veterans (mean age 61 years), fewer patients evaluated with a tone-emitting otoscope screened positive (19 percent versus 59 and 64 percent of patients evaluated with questionnaire and dual screening [questionnaire and otoscope], respectively) [4]. Hearing aid use one year after screening was 6 percent in the toneemitting otoscope group compared with 4 and 7 percent in the questionnaire and dual screening groups, respectively. Screening with the tone-emitting otoscope was the most efficient screening method, as the questionnaire led to unnecessary audiology evaluations with little added benefit in terms of hearing loss detection. Hearing status can be further assessed with tuning forks [5]. Patients who cannot hear a 256 Hz tuning fork but can hear a 512 Hz tuning fork have a hearing loss of approximately 10 to 15 dB; patients who cannot hear a 512 Hz tuning fork have an approximate loss of at least 20 to 30 dB. An ear that hears normally should have air conduction (sound waves traveling to the tympanic membrane and converted into sound in the inner ear) that is louder than bone conduction (sound transmitted via the vibration of the skull into the cochlea). The Weber and Rinne tests examine the relative adequacy of air and bone conduction of sound. Weber and Rinne tests — The Weber and Rinne tests can help direct the remainder of the evaluation, but should not be used as screening evaluations for hearing loss [5]. Weber test — The Weber tuning fork test is performed by pressing the handle of the tuning fork to the bridge of the forehead, nose, or teeth and asking the patient if the sound is louder in one ear or the other. The sound is heard equally in both ears in patients with normal hearing or symmetric hearing loss.

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Rinne test — The Rinne test allows comparison of sound when the tuning fork is placed on the mastoid bone behind the ear (bone conduction), versus when the tuning fork is held near the ear (air conduction) [6,7]. An abnormal result occurs when sound is at least equally loud or louder when the fork is placed on bone as compared with when it is held next to the ear (bone>air conduction). The Rinne test is considered normal when the vibrating fork placed near the ear is louder than when placed on the mastoid bone (air>bone conduction). One method for performing the Rinne test is to press the handle of the tuning fork to the mastoid bone and ask the patient to tell the examiner when the sound is no longer audible. At that point, the vibrating end of the tuning fork is placed near the external auditory canal (EAC). If the patient can again hear the tuning fork, the Rinne test is normal. Interpretation — The Weber and Rinne tests can then be used to help distinguish conductive from sensorineural hearing loss ( ●

table 2 and

figure 1):

In patients complaining of a unilateral decrease in hearing, the Weber test suggests sensorineural hearing loss if the sound lateralizes (is louder on) to the "good" side; conductive hearing loss is suspected if the sound lateralizes to the "bad" side.

●

An abnormal Rinne test, with bone>air conduction, is consistent with conductive loss, particularly if the Weber test also lateralizes to that side.

●

When the Weber test lateralizes to an ear in which the Rinne is normal, the Rinne test in the opposite ear should be performed. A normal Rinne test in the contralateral ear suggests sensorineural hearing loss in this contralateral ear (ie, the Weber lateralized to the normal ear). An audiogram is indicated in this situation.

The Weber test may be unreliable in some settings. In one study of 250 patients with sudden sensorineural hearing loss (SSNHL) confirmed by audiometry, the Weber test correctly identified sensorineural hearing loss in the affected ear in 78 percent; the Weber test did not lateralize in 21 percent (heard midline or not heard at all), and incorrectly lateralized in just 1 percent [8]. These results suggest that in the setting of sudden hearing loss, further evaluation for SSNHL is required when the Weber test does not lateralize. (See "Sudden sensorineural hearing loss in adults: Evaluation and management".) Conductive hearing loss on one side is indicative of external or middle ear disease (

table 1).

(See "Etiology of hearing loss in adults", section on 'Outer ear causes' and "Etiology of hearing loss in adults", section on 'Middle ear causes'.)

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Gradual sensorineural hearing loss on one side suggests an inner ear disorder such as Meniere disease or a vestibular schwannoma (acoustic neuroma). If confirmed by audiometry, the patient with progressive asymmetric sensorineural hearing loss that is not clearly attributed to Meniere disease should have an MRI or CT scan of the posterior fossa and internal auditory canal. (See "Meniere disease: Evaluation, diagnosis, and management" and "Vestibular schwannoma (acoustic neuroma)".) Examination of the ear — Patients with conductive hearing loss should have an examination of the auricle and EAC performed to look for blockage of the EAC. The tympanic membrane (TM) should be viewed to ensure that there is no middle ear abnormality such as fluid or TM perforations. Pneumoscopy — Pneumoscopy is also performed to evaluate mobility of the TM. Positive pressure that forces air into the EAC thereby pushing down the TM, is done first. The pressure is then released, with the subsequent negative pressure pulling the TM outwards. ●

A nonmobile TM may occur because of fluid in the middle ear cavity, a mass in the middle ear cavity, or a stiff or sclerotic TM.

●

A hypermobile TM may indicate ossicular chain disruption.

●

The TM may only move with negative pressure; this can be caused by retraction of the TM or middle ear with a blocked eustachian tube, resulting in negative middle ear pressure.

Formal audiologic assessment — Patients without an obvious etiology for hearing loss (such as external otitis or cerumen impaction) should undergo formal audiologic testing [9]. Formal audiologic assessment is performed by an audiologist in a soundproof environment. This evaluation provides very accurate and detailed information regarding a patient's hearing ability. The formal audiogram, with tympanogram and site of lesion testing, provides definitive information. Every audiologic workup should consist of a number of audiometric studies [10]. Pure tone, air, and bone conduction testing — Pure tone testing is commonly known as the audiogram. The patient is in a soundproof booth, and the audiologist assesses the sensitivity or ability to hear pure tone stimuli at the frequencies of 250, 500, 1000, 2000, 4000, and 8000 hz. The threshold for each stimulus is determined by finding the dB level at which the patient can detect the tone 50 percent of the time [11]. Hearing is tested with both air and bone conduction. Air conduction tests the ability to hear with ear phones via the normal mechanism of hearing: sound through the EAC, TM, and the middle ear system. Bone conduction is tested with a bone oscillator. The oscillator is placed on https://www.uptodate.com/contents/6850/print

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either mastoid and held in place, stimulating noise going into the skull and bypassing the middle ears by setting the fluid and cochlea in motion directly with bone vibration. Measuring and comparing both air and bone conduction may be helpful in determining the etiology of the hearing loss. Any difference between air and bone conduction thresholds is known as an air/bone gap; a gap is consistent with conductive hearing loss (

figure 2). In

addition, the specific pattern of bone conduction may provide further information about the etiology of the hearing loss. As an example, in otosclerosis, a notch may be observed at approximately 2000 Hz (“Carhart’s notch”), which represents a partial closure of the air-bone gap at this frequency [12]. Speech audiometry — Speech audiometry typically consists of two parts: the speech reception threshold (SRT) and the word discrimination score. ●

The SRT is the softest level at which a patient can correctly repeat 50 percent of presented spondee words. Spondee words are two-syllable words where each syllable is stressed, such as airplane, armchair, or pancake. SRT is recorded in decibels and serves as a crosscheck for the pure tone air conduction thresholds. The SRT is typically equal to the pure tone air conduction average, ± 6 dB [13]. The pure tone average is the average decibel score at 500, 1000, and 2000 hz.

●

The word discrimination score is the percentage of phonetically balanced words that a patient can correctly repeat at a given sensation level. Typically, testing is performed at 40 dB above the patient's SRT. This discrimination score serves two purposes: it can establish the prognosis for the use of a hearing aid, and it helps determine the site of the lesion. A poor discrimination score usually indicates significant neural degeneration; these individuals may not be good candidates for hearing aids, since the aid will amplify sound but may not allow the patient to understand what is being said.

Impedance audiometry — Impedance audiometry is performed in two parts: tympanometry and stapedial reflex testing [14,15]. ●

Tympanometry – Tympanometry is the “hard-copy” version of pneumoscopy. It is an objective measure of the changes in the acoustic impedance of the middle ear system in response to changes in air pressure. As the pressure increases during pneumoscopy, the eardrum is pushed medially; as negative pressure is placed, the eardrum protrudes laterally. The point of maximum compliance of the middle ear is identified; this indicates the current status of the air pressure in the middle ear. Five types of tympanograms can be seen (

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• Type A – Normal middle ear pressure • Type B – Little or no mobility, suggestive of fluid behind the TM • Type C – Negative pressure in the middle ear suggestive of a retracted TM • Type AS – A very stiff middle ear system that may be due to myringosclerosis or otosclerosis

• Type AD – A highly compliant TM usually seen in ossicular chain discontinuity ●

Stapedial reflex testing – Stapedial reflex testing may also be performed [16]. Further discussion of this test is beyond the scope of this review.

Other audiologic tests — Auditory brainstem response (ABR) testing is commonly done in infants to assess hearing but can also be done to assess hearing in adults who either cannot cooperate with a traditional hearing test, may have a functional component, or exhibit a unilateral sensorineural hearing loss and when further evaluation in lieu of an MRI is needed to assess for central pathology [17-19]. Other tests — Various metabolic abnormalities have been known to either cause or be associated with sensorineural hearing loss. Thus, an evaluation of an unexplained sensorineural hearing loss should involve a complete laboratory evaluation to include the following: ●

Measurement of blood sugar; small vessel disease as a result of diabetic vasculopathy can cause cochlear ischemia.

●

Complete blood count with differential; anemia or a white blood cell dyscrasia may lead to sensorineural hearing loss by an unknown mechanism that may involve decreased oxygenation, microblockage of vessels, or infection.

●

Thyroid stimulating hormone to rule out hyper or hypothyroidism.

●

Serologic test for syphilis.

●

Serologic tests for Sjogren's syndrome (ANA, RF, anti-Ro and anti-La) in patients who have dry eyes or dry mouth. (See "Neurologic manifestations of Sjögren's syndrome", section on 'Multiple cranial neuropathies'.)

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Patients with unexplained conductive hearing loss should have a CT scan of the temporal bone.

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Patients with unilateral, fluctuating, or unexplained asymmetric sensorineural hearing loss should have an MRI with gadolinium.

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Patients with loss other than presbycusis (hearing loss of aging) should be evaluated by an ENT.

●

Patients whose hearing loss is not improved by traditional hearing aids should be considered for evaluation by a center that performs various types of implants for hearing (eg, cochlear implants, Baha implants, or middle ear implants of various types).

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hearing loss and hearing disorders in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Age-related hearing loss (presbycusis) (The Basics)" and "Patient education: Ear wax impaction (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Initial office evaluation of patients with hearing loss – Patients with hearing loss may have conductive, sensorineural, or mixed hearing loss. Patients with hearing loss should undergo a directed history and examination (

table 1). The evaluation should include:

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• An office test of hearing (see 'Office hearing evaluation' above) • Weber and Rinne tests to distinguish conductive from sensorineural hearing loss ( figure 1 and ●

table 2) (see 'Weber and Rinne tests' above)

Physical examination in conductive hearing loss – Patients with conductive hearing loss (

table 1) should undergo physical examination of the auricle and external auditory

canal (EAC) looking for evidence of blockage to explain the hearing loss. (See 'Examination of the ear' above.) ●

Formal audiology testing if the cause is uncertain – Patients without an obvious etiology for hearing loss (such as external otitis or cerumen impaction) should undergo formal audiologic testing. (See 'Formal audiologic assessment' above.)

●

Additional testing may be warranted in some patients. (See 'Other tests' above.)

• Patients with an unexplained sensorineural hearing loss should have the following laboratory tests: blood sugar, complete blood count with differential, thyroidstimulating hormone, and serologic test for syphilis.

• Patients with progressive asymmetric sensorineural hearing loss should have an MRI with contrast, and those with unexplained conductive hearing loss a CT scan of the posterior fossa and internal auditory canal to exclude disorders such as vestibular schwannoma (acoustic neuroma).

• Patients with hearing loss where the etiology is unclear generally require referral to an otolaryngologist or ENT clinician; patients with sudden sensorineural hearing loss require urgent referral as treatment success is related to early initiation of treatment. Use of UpToDate is subject to the Terms of Use. REFERENCES

1. Cassel C, Penhoet E, Saunders R. Policy Solutions for Better Hearing. JAMA 2016; 315:553. 2. Uy J, Forciea MA. In the clinic. Hearing loss. Ann Intern Med 2013; 158:ITC4. 3. Pirozzo S, Papinczak T, Glasziou P. Whispered voice test for screening for hearing impairment in adults and children: systematic review. BMJ 2003; 327:967. 4. Yueh B, Collins MP, Souza PE, et al. Long-term effectiveness of screening for hearing loss: the screening for auditory impairment--which hearing assessment test (SAI-WHAT) randomized trial. J Am Geriatr Soc 2010; 58:427. https://www.uptodate.com/contents/6850/print

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5. Bagai A, Thavendiranathan P, Detsky AS. Does this patient have hearing impairment? JAMA 2006; 295:416. 6. Chole RA, Cook GB. The Rinne test for conductive deafness. A critical reappraisal. Arch Otolaryngol Head Neck Surg 1988; 114:399. 7. Burkey JM, Lippy WH, Schuring AG, Rizer FM. Clinical utility of the 512-Hz Rinne tuning fork test. Am J Otol 1998; 19:59. 8. Shuman AG, Li X, Halpin CF, et al. Tuning fork testing in sudden sensorineural hearing loss. JAMA Intern Med 2013; 173:706. 9. Paul BC, Roland JT Jr. An abnormal audiogram. JAMA 2015; 313:85. 10. Yueh B, Souza P, Collins P, Collins. Screening for auditory impairment: Which hearing aid tes ts? A randomized clinical trail. Department of Veterns Affairs, Seattle, WA 2001. 11. Rintelmann WF. Hearing Assessment, 2nd ed, Pro-Ed Inc, Austin 1990. 12. Foster MF, Backous DD. Clinical Evaluation of the Patient with Otosclerosis. Otolaryngol Clin North Am 2018; 51:319. 13. Durrant JD, Lovrinic JH. Bases of Hearing Science, 2nd ed, Williams & Wilkins, Baltimore 198 4. 14. Baldwin RL, Carmichael L. Practical tympanometry and stapedial reflex testing in office practice. Ala Med 1983; 53:8. 15. Wiley TL, Fowler C. Acoustic Immittance Measures in Clinical Audiology: A Primer, 1st ed, Th ompson, 1997. 16. Faleiros MC. [Importance of the stapedial reflex in the diagnosis of several pathologies]. Rev Laryngol Otol Rhinol (Bord) 2000; 121:345. 17. Metselaar M, Demirtas G, van Immerzeel T, van der Schroeff M. Evaluation of Magnetic Resonance Imaging Diagnostic Approaches for Vestibular Schwannoma Based on Hearing Threshold Differences Between Ears: Added Value of Auditory Brainstem Responses. Otol Neurotol 2015; 36:1610. 18. Johnson TA, Brown CJ. Threshold prediction using the auditory steady-state response and the tone burst auditory brain stem response: a within-subject comparison. Ear Hear 2005; 26:559. 19. Chien CH, Tu TY, Shiao AS, et al. Prediction of the pure-tone average from the speech reception and auditory brainstem response thresholds in a geriatric population. ORL J Otorhinolaryngol Relat Spec 2008; 70:366. Topic 6850 Version 31.0 https://www.uptodate.com/contents/6850/print

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GRAPHICS

Causes of hearing loss Conductive Outer-ear causes

Sensorineural Inner-ear causes

Congenital microtia or atresia

Hereditary hearing loss

External otitis

Congenital viral infections

Trauma

Congenital malformations

Squamous cell carcinoma

Presbycusis

Exostosis

Meningitis

Osteoma

Thyrotoxicosis

Psoriasis

Viral cochleitis

Cerumen

Ototoxic drugs

Middle-ear causes

Otologic surgery

Congenital atresia or ossicular chain malformation

Meniere disease

Otitis media

Noise exposure

Cholesteatoma

Barotrauma

Otosclerosis

Penetrating trauma

Tympanic membrane perforation

Acoustic neuroma

Temporal bone trauma

Meningioma

Glomus tumors

Autoimmune disease Multiple sclerosis Cerebrovascular ischemia Arnold-Chiari malformation  Otosyphilis

Graphic 53903 Version 4.0

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Interpreting Weber and Rinne tests: Conductive versus sensorineural hearing loss  

Weber lateralizes

Rinne test

Conductive loss Good ear

 

AC > BC

Bad ear

To bad ear

BC > AC

Good ear

To good ear

AC > BC

Bad ear

 

AC > BC*

Sensorineural loss

AC > BC: Air conduction better than bone conduction (normal Rinne). BC > AC: Bone conduction better than air conduction (abnormal Rinne). * For patients with severe sensorineural hearing loss, the patient may report bone conduction >air conduction because the sound is being sensed by the "good" (contralateral) ear. Graphic 74212 Version 9.0

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Evaluation of hearing loss, Weber and Rinne tests

Weber test: Place the base of a struck tuning fork on the bridge of the forehead, nose, or teeth. In a normal test, there is no lateralization of sound. With unilateral conductive loss, sound lateralizes toward affected ear. With unilateral sensorineural loss, sound lateralizes to the normal or betterhearing side. Rinne test: Place the base of a struck tuning fork on the mastoid bone behind the ear. Have the patient indicate when sound is no longer heard. Move fork (held at base) beside ear and ask if now audible. In a normal test, AC > BC; patient can hear fork at ear. With conductive loss, BC > AC; patient will not hear fork at ear. Graphic 58032 Version 11.0

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Audiogram conductive loss

Graphic 59939 Version 2.0

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Tympanograms in various diseases

Type A: Normal tympanic membrane (TM) mobility. Type B: Flat tympanogram associated with fluid or perforation (will have large volume). Type C: Negative middle ear pressure such as from a retracted TM. Type AS: Very stiff noncompliant TM associated with TM sclerosis or otosclerosis. Type AD: Hypermobile usually associated with ossicular discontinuity. Graphic 73425 Version 1.0

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Contributor Disclosures Peter C Weber, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Daniel G Deschler, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Lisa Kunins, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Causes of abdominal pain in adults Authors: Robert M Penner, BSc, MD, FRCPC, MSc, Mary B Fishman, MD Section Editors: Andrew D Auerbach, MD, MPH, Mark D Aronson, MD Deputy Editor: Lisa Kunins, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: May 10, 2021.

INTRODUCTION The evaluation of abdominal pain requires an understanding of the possible mechanisms responsible for pain, a broad differential of common causes, and recognition of typical patterns and clinical presentations. This topic reviews the etiologies of abdominal pain in adults. The emergency and non-urgent evaluation of abdominal pain of adults discussed elsewhere. (See "Evaluation of the adult with abdominal pain in the emergency department" and "Evaluation of the adult with abdominal pain".) Abdominal pain in pregnant and postpartum individuals and patients with HIV is discussed elsewhere. (See "Approach to acute abdominal/pelvic pain in pregnant and postpartum patients".)

PATHOPHYSIOLOGY OF ABDOMINAL PAIN ●

Neurologic basis for abdominal pain – Pain receptors in the abdomen respond to mechanical and chemical stimuli. Stretch is the principal mechanical stimulus involved in visceral nociception, although distention, contraction, traction, compression, and torsion are also perceived [1]. Visceral receptors responsible for these sensations are located on serosal surfaces, within the mesentery, and within the walls of hollow viscera. Visceral mucosal receptors respond primarily to chemical stimuli, while other visceral nociceptors respond to chemical or mechanical stimuli.

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The events responsible for the perception of abdominal pain are not completely understood, but depend upon the type of stimulus and the interpretation of visceral nociceptive inputs in the central nervous system. As an example, the gastric mucosa is insensitive to pressure or chemical stimuli. However, in the presence of inflammation, these same stimuli can cause pain [2]. The threshold for perceiving pain may vary among individuals and in certain diseases. (See "Evaluation of chronic non-cancer pain in adults", section on 'Definition of pain'.) ●

Localization – The type and density of visceral afferent nerves makes the localization of visceral pain imprecise. However, a few general rules are useful:

• Most digestive tract pain is perceived in the midline because of bilaterally symmetric innervation [1,3]. Pain that is clearly lateralized most likely arises from the ipsilateral kidney, ureter, ovary, or somatically innervated structures, which have predominantly unilateral innervation. Exceptions to this rule include the gallbladder and ascending and descending colons which, although bilaterally innervated, have predominant innervation located on their ipsilateral sides.

• Visceral pain is perceived in the spinal segment at which the visceral afferent nerves enter the spinal cord [4]. As an example, afferent nerves mediating pain arising from the small intestine enter the spinal cord between T8 to L1. Thus, distension of the small intestine is usually perceived in the periumbilical region. ●

Referred pain – Pain originating in the viscera may sometimes be perceived as originating from a site distant from the affected organ (

figure 1) [5-7]. Referred pain is usually

located in the cutaneous dermatomes sharing the same spinal cord level as the visceral inputs. As an example, nociceptive inputs from the gallbladder enter the spinal cord at T5 to T10. Thus, pain from an inflamed gallbladder may be perceived in the scapula ( figure 1). The quality of referred pain is aching and perceived to be near the surface of the body. In addition to pain, two other correlates of referred pain can be detected: skin hyperalgesia and increased muscle tone of the abdominal wall (which accounts for the abdominal wall rigidity sometimes observed in patients with an acute abdomen).

UPPER ABDOMINAL PAIN SYNDROMES Upper abdominal pain syndromes typically have characteristic locations: right upper quadrant pain (

table 1), epigastric pain (

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Right upper quadrant pain — Biliary and hepatic etiologies cause right upper quadrant pain syndromes. Biliary etiologies include ( ●

table 1):

Gallstones – Symptoms of biliary colic classically include an intense, dull discomfort located in the right upper quadrant, epigastrium, or (less often) substernal area that may radiate to the back (particularly the right shoulder blade). Patients may have associated nausea, vomiting, and diaphoresis. The pain generally lasts at least 30 minutes, plateauing within an hour. Patients have an unremarkable abdominal examination. (See "Overview of gallstone disease in adults", section on 'Biliary colic'.)

●

Acute cholecystitis – The clinical manifestations of acute cholecystitis include prolonged (more than four to six hours), steady, severe right upper quadrant or epigastric pain, fever, abdominal guarding, a positive Murphy's sign, and leukocytosis. (See "Acute calculous cholecystitis: Clinical features and diagnosis", section on 'Clinical manifestations'.)

●

Acute cholangitis – Acute cholangitis occurs when a stone becomes impacted in the biliary or hepatic ducts, causing dilation of the obstructed duct and bacterial superinfection. It is characterized by fever, jaundice, and abdominal pain, although this classic triad (known as Charcot's triad) occurs in only 50 to 75 percent of cases [8]. The abdominal pain is typically vague and located in the right upper quadrant. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

●

Sphincter of Oddi dysfunction – Sphincter of Oddi dysfunction can be a cause of biliary pain in the absence of gallstones or biliary inflammation. Typically the pain is located in the right upper quadrant or epigastrium and lasts from 30 minutes to several hours. (See "Clinical manifestations and diagnosis of sphincter of Oddi dysfunction".)

Hepatic etiologies include ( ●

table 1):

Hepatitis – Patients with acute hepatitis (eg, from hepatitis A, alcohol, or medications) may have fatigue, malaise, nausea, vomiting, and anorexia in addition to right upper quadrant pain. Other symptoms include jaundice, dark urine, and light colored stools. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Alcoholic hepatitis: Clinical manifestations and diagnosis", section on 'Signs and symptoms' and "Drug-induced liver injury", section on 'Clinical manifestations'.)

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Perihepatitis – The Fitz-Hugh-Curtis syndrome, or perihepatitis, is a cause of right upper quadrant pain in young females with pelvic inflammatory disease (PID). It occurs in approximately 10 percent of patients with acute PID. It is characterized by right upper quadrant pain with a distinct pleuritic component, sometimes referred to the right shoulder. (See "Pelvic inflammatory disease: Clinical manifestations and diagnosis", section on 'Perihepatitis'.)

●

Liver abscess – Liver abscess is the most common type of visceral abscess. Patients generally present with fever and abdominal pain. Risk factors include diabetes, underlying hepatobiliary or pancreatic disease, or liver transplant. (See "Pyogenic liver abscess", section on 'Epidemiology' and "Pyogenic liver abscess", section on 'Clinical manifestations'.)

●

Budd-Chiari syndrome – Budd-Chiari syndrome is technically defined as hepatic venous outflow tract obstruction, independent of the level or mechanism of obstruction, provided the obstruction is not due to cardiac disease, pericardial disease, or sinusoidal obstruction syndrome (veno-occlusive disease). As commonly used, the Budd-Chiari syndrome implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Symptoms include fever, abdominal pain, abdominal distention (from ascites), lower extremity edema, jaundice, gastrointestinal bleeding, and/or hepatic encephalopathy. There are a variety of causes, many of which are related to an underlying prothrombotic or hypercoagulable state (

table 4). (See "Budd-Chiari syndrome: Epidemiology, clinical

manifestations, and diagnosis", section on 'Clinical manifestations' and "Etiology of the Budd-Chiari syndrome", section on 'Etiology'.) ●

Portal vein thrombosis – Clinical manifestations of portal vein thrombosis vary depending on the extent of obstruction as well as the speed of development (acute or chronic). It is common in patients with cirrhosis and is associated with the severity of liver disease. Patients may be asymptomatic or have abdominal pain, dyspepsia, or gastrointestinal bleeding. (See "Acute portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations' and "Chronic portal vein thrombosis in adults: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)

Epigastric pain — Pancreatic and gastric etiologies often cause epigastric pain ( ●

table 2).

Acute myocardial infarction – Epigastric pain can be the presenting symptom of an acute myocardial infarction. Patients may have associated shortness of breath or

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exertional symptoms. (See "Angina pectoris: Chest pain caused by fixed epicardial coronary artery obstruction", section on 'History'.) ●

Pancreatitis – Both acute and chronic pancreatitis are associated with abdominal pain that often radiates to the back. Most patients with acute pancreatitis have acute onset of persistent, severe epigastric pain. The pain is steady and may be in the mid-epigastrium, right upper quadrant, diffuse, or, infrequently, confined to the left side. (See "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Clinical features'.) The two primary clinical manifestations of chronic pancreatitis are epigastric pain and pancreatic insufficiency. The pain is typically epigastric, is occasionally associated with nausea and vomiting, and may be partially relieved by sitting upright or leaning forward. (See "Chronic pancreatitis: Clinical manifestations and diagnosis in adults", section on 'Abdominal pain'.)

●

Peptic ulcer disease – Upper abdominal pain or discomfort is the most prominent symptom in patients with peptic ulcers. Patients most often have epigastric pain, but occasionally the discomfort localizes to one side. (See "Peptic ulcer disease: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

●

Gastroesophageal reflux disease – Most patients with gastroesophageal reflux disease (GERD) complain of heartburn, regurgitation, and dysphagia. However, some patients may also complain of epigastric and/or chest pain. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Clinical features'.)

●

Gastritis/gastropathy – Gastritis refers to inflammation in the lining of the stomach. Gastritis is predominantly an inflammatory process, while the term gastropathy denotes a gastric mucosal disorder with minimal to no inflammation. Acute gastropathy often presents with abdominal discomfort/pain, heartburn, nausea, vomiting, and hematemesis. Gastropathy may be caused by a variety of etiologies including alcohol and nonsteroidal antiinflammatory drugs (NSAIDs). (See "Acute hemorrhagic erosive gastropathy and reactive gastropathy", section on 'Acute hemorrhagic erosive gastropathy' and "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)

●

Functional dyspepsia – Functional dyspepsia is defined as the presence of one or more of the following symptoms: postprandial fullness, early satiation, and epigastric pain or burning, with no evidence of structural disease (including at upper endoscopy) to explain the symptoms. (See "Functional dyspepsia in adults".)

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Gastroparesis – Patients with gastroparesis can present with nausea, vomiting, abdominal pain, early satiety, postprandial fullness, bloating, and, in severe cases, weight loss. The most common causes are idiopathic, diabetic, or postsurgical (

figure 2). (See

"Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.) Left upper quadrant pain — Left upper quadrant pain is often related to the spleen (

table 3

). ●

Splenomegaly – Splenomegaly can cause left upper quadrant pain or discomfort, referred pain to the left shoulder, and/or early satiety. Splenomegaly has multiple causes ( table 5). (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)

●

Splenic infarction – Patients with splenic infarction classically present with severe left upper quadrant pain, though atypical presentations are common. Splenic infarction is associated with a variety of underlying conditions (eg, hypercoagulable state, embolic disease from atrial fibrillation, conditions associated with splenomegaly). (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Abscess and infarction'.)

●

Splenic abscess – Splenic abscesses are uncommon and typically are associated with fever and tenderness in the left upper quadrant. They may also be associated with splenic infarction. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Abscess and infarction'.)

●

Splenic rupture – Splenic rupture is most often associated with trauma. The patient may complain of left upper abdominal, left chest wall, or left shoulder pain (ie, Kehr's sign). Kehr's sign is pain referred to the left shoulder that worsens with inspiration and is due to irritation of the phrenic nerve from blood adjacent to the left hemidiaphragm. (See "Management of splenic injury in the adult trauma patient", section on 'History and physical examination' and "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Trauma/rupture'.)

LOWER ABDOMINAL PAIN SYNDROMES Lower abdominal pain syndromes (

table 6) often cause pain in either or both lower

quadrants. Females may have lower abdominal pain from disorders of the internal female reproductive organs (

table 7). (See 'Females' below.)

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Lower abdominal pain syndromes that are generally localized to one side include ( ●

table 6):

Acute appendicitis – Acute appendicitis typically presents with periumbilical pain initially that radiates to the right lower quadrant. It is associated with anorexia, nausea, and vomiting. However, occasionally patients present with epigastric or generalized abdominal pain. The pain localizes to the right lower quadrant when the appendiceal inflammation begins to involve the peritoneal surface. (See "Acute appendicitis in adults: Clinical manifestations and differential diagnosis", section on 'Clinical manifestations'.)

●

Diverticulitis – The clinical presentation of diverticulitis depends upon the severity of the underlying inflammatory process and whether or not complications are present. Left lower quadrant pain is the most common complaint in Western countries, occurring in 70 percent of patients. Right-sided diverticulitis is more common in Asian populations. The pain is usually constant and is often present for several days prior to presentation. Patients may also have nausea and vomiting. (See "Clinical manifestations and diagnosis of acute diverticulitis in adults", section on 'Clinical manifestations'.)

Abdominal pain from some genitourinary etiologies may be localized to either side ( ●

table 6):

Kidney stones – Kidney stones usually cause symptoms when the stone passes from the renal pelvis into the ureter. Pain is the most common symptom and varies from a mild to severe. Patients may have flank pain, back pain, or abdominal pain. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Clinical manifestations'.)

●

Pyelonephritis – Patients with pyelonephritis may or may not have symptoms of cystitis (dysuria, frequency, urgency, and/or hematuria). These patients also have fever, chills, flank pain, and costovertebral angle tenderness. (See "Acute simple cystitis in women", section on 'Clinical manifestations' and "Acute simple cystitis in men", section on 'Clinical manifestations'.)

Other etiologies of lower abdominal pain may not always be localized to one side ( ●

table 6):

Cystitis – Patients with cystitis may complain of suprapubic pain as well as dysuria, frequency, urgency, and/or hematuria. (See "Acute simple cystitis in women", section on 'Clinical manifestations' and "Acute simple cystitis in men", section on 'Clinical manifestations'.)

●

Acute urinary retention – Patients with bladder outlet obstruction leading to acute urinary retention present with the inability to pass urine. They may have associated lower

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abdominal and/or suprapubic pain or discomfort. (See "Acute urinary retention", section on 'Clinical presentation'.) ●

Infectious colitis – Patients with infectious colitis generally have diarrhea as the predominant symptom but may also have associated abdominal pain, which may be severe. Patients with Clostridioides difficile infection can present with an acute abdomen and peritoneal signs in the setting of perforation and fulminant colitis (

table 8). (See

"Clostridioides difficile infection in adults: Clinical manifestations and diagnosis", section on 'Clinical manifestations' and "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Stool tests for bacterial pathogens'.)

DIFFUSE ABDOMINAL PAIN SYNDROMES Abdominal pain syndromes may have diffuse, nonspecific, or variable patterns of pain ( table 9). ●

Obstruction – Severe, acute diffuse abdominal pain can be caused by either partial or complete obstruction of the intestines. Intestinal obstruction should be considered when the patient complains of pain, vomiting, and obstipation. Physical findings include abdominal distention, tenderness to palpation, high-pitched or absent bowel sounds, and a tympanic abdomen. There are many etiologies of obstruction (

table 10), with the

most common etiologies in adults being postoperative adhesions, malignancy related (eg, from colorectal cancer), and complicated hernias. Other less common etiologies include Crohn disease, gallstones, volvulus, and intussusception. (See "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults" and "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation' and "Intestinal malrotation in children" and "Gastric volvulus in adults" and "Cecal volvulus" and "Sigmoid volvulus".) ●

Perforation of gastrointestinal tract – Perforation of the gastrointestinal tract can present acutely or in an indolent manner. Patients complain of chest or abdominal pain to some degree. Sudden, severe chest or abdominal pain following instrumentation or surgery is very concerning for perforation. Patients on immunosuppressive or antiinflammatory agents may have an impaired inflammatory response, and some may have little or no pain and tenderness. Many patients will seek medical attention with the onset or worsening of significant chest or abdominal pain, but a subset of patients will present in a delayed fashion. (See "Overview of gastrointestinal tract perforation", section on 'Clinical features'.)

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Mesenteric ischemia – Acute mesenteric ischemia presents with the acute and severe onset of diffuse and persistent abdominal pain, often described as pain out of proportion to examination. Several features of the pain and its presentation may provide clues to the etiology of the ischemia and help distinguish small intestinal from colonic ischemia ( table 11). Chronic mesenteric ischemia may be manifested by a variety of symptoms including abdominal pain after eating ("intestinal angina"), weight loss, nausea, vomiting, and diarrhea. Ischemia that involves the celiac territory causes epigastric or right upper quadrant pain. Ischemia may be from either arterial or venous disease. (See "Overview of intestinal ischemia in adults" and "Chronic mesenteric ischemia" and "Mesenteric venous thrombosis in adults", section on 'Clinical presentations' and "Colonic ischemia", section on 'Clinical features'.) Patients with aortic dissection may have abdominal pain from mesenteric ischemia ( table 12). (See "Clinical features and diagnosis of acute aortic dissection", section on 'Clinical features'.)

●

Inflammatory bowel disease– Inflammatory bowel disease (IBD) is comprised of two major disorders: ulcerative colitis and Crohn disease. IBD is also associated with a number of extraintestinal manifestations (

table 13). (See "Definitions, epidemiology, and risk

factors for inflammatory bowel disease".)

• Ulcerative colitis – Patients with ulcerative colitis usually present with diarrhea which may be associated with blood. Bowel movements are frequent and small in volume as a result of rectal inflammation. Associated symptoms include colicky abdominal pain, urgency, tenesmus, and incontinence. (See "Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults", section on 'Clinical manifestations'.)

• Crohn disease – The clinical manifestations of Crohn disease are more variable than those of ulcerative colitis. Patients can have symptoms for many years prior to diagnosis. Fatigue, prolonged diarrhea with abdominal pain, weight loss, and fever, with or without gross bleeding, are the hallmarks of Crohn disease. (See "Clinical manifestations, diagnosis, and prognosis of Crohn disease in adults", section on 'Clinical features'.) ●

Viral gastroenteritis – Patients with viral gastroenteritis often have diarrhea accompanied by nausea, vomiting, and abdominal pain. (See "Acute viral gastroenteritis in adults", section on 'Clinical manifestations'.)

●

Spontaneous bacterial peritonitis – Spontaneous bacterial peritonitis most often occurs in cirrhotics with advanced liver disease with ascites. Patients present with fever,

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abdominal pain, and/or altered mental status. (See "Spontaneous bacterial peritonitis in adults: Clinical manifestations", section on 'Clinical manifestations'.) ●

Peritonitis in peritoneal dialysis patients – Peritonitis may develop in patients on peritoneal dialysis either from contamination during dialysis or catheter related infection. The most common symptoms and signs are abdominal pain and cloudy peritoneal effluent. Other symptoms and signs include fever, nausea, diarrhea, abdominal tenderness, rebound tenderness, and occasionally systemic signs (eg, hypotension). (See "Clinical manifestations and diagnosis of peritonitis in peritoneal dialysis", section on 'Clinical presentation'.)

●

Malignancy – Gastrointestinal malignancies may be associated with abdominal discomfort. These are discussed in detail in specific topics. As examples:

• Colorectal cancer – Patients with colorectal cancer may present with abdominal pain from partial obstruction, peritoneal dissemination, or perforation. (See "Clinical presentation, diagnosis, and staging of colorectal cancer", section on 'Clinical presentation'.)

• Gastric cancer – Patients with gastric cancer may have abdominal pain that is often epigastric pain. (See "Clinical features, diagnosis, and staging of gastric cancer", section on 'Clinical features'.)

• Pancreatic cancer – The most common symptoms in patients with pancreatic cancer are pain, jaundice, and weight loss. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Clinical presentation'.) Additionally, patients may have pain as part of pain syndromes related to malignancy ( table 14). (See "Overview of cancer pain syndromes", section on 'Tumor-related visceral pain syndromes'.) ●

Celiac disease – Patients with celiac disease may complain of abdominal pain in addition to diarrhea with bulky, foul-smelling, floating stools due to steatorrhea and flatulence. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Clinical manifestations'.)

●

Ketoacidosis – Patients with ketoacidosis (eg, from diabetes or alcohol) may have diffuse abdominal pain as well as nausea and vomiting. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis",

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section on 'Abdominal pain in DKA' and "Fasting ketosis and alcoholic ketoacidosis", section on 'Clinical presentation'.) ●

Adrenal insufficiency – Patients with adrenal insufficiency may have diffuse abdominal pain as well as nausea and vomiting. Patients with adrenal crisis may present with shock and hypotension. Patients with chronic adrenal deficiency may also complain of malaise, fatigue, anorexia, and weight loss. (See "Clinical manifestations of adrenal insufficiency in adults", section on 'Autoimmune primary adrenal insufficiency' and "Clinical manifestations of adrenal insufficiency in adults".)

●

Foodborne disease – A foodborne disease will typically manifest as a mixture of nausea, vomiting, fever, abdominal pain, and diarrhea. Toxin-mediated illnesses can occur within hours of ingestion, but bacterial colitis generally requires 24 to 48 hours to develop. Certain foods may be linked to particular pathogens (

table 15). (See "Causes of acute

infectious diarrhea and other foodborne illnesses in resource-rich settings", section on 'Clinical clues to the microbial cause'.) ●

Irritable bowel syndrome – Patients with irritable bowel syndrome (IBS) can present with a wide array of symptoms which include both gastrointestinal and extraintestinal complaints. However, the symptom complex of chronic abdominal pain and altered bowel habits remains the nonspecific yet primary characteristic of IBS. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Clinical manifestations'.)

●

Constipation – Constipation may be associated with abdominal pain. Diseases associated with constipation include neurologic and metabolic disorders; obstructing lesions of the gastrointestinal tract, including colorectal cancer; endocrine disorders such as diabetes mellitus; and psychiatric disorders such as anorexia nervosa ( may also be due to a side effect of drugs (

table 16). Constipation

table 17). (See "Etiology and evaluation of

chronic constipation in adults".) ●

Diverticulosis – Uncomplicated diverticulosis is often asymptomatic and an incidental finding on colonoscopy or sigmoidoscopy. Abdominal pain and constipation seen in patients with uncomplicated diverticulosis may be related to abnormal motility and visceral hypersensitivity rather than to the diverticula themselves. (See "Colonic diverticulosis and diverticular disease: Epidemiology, risk factors, and pathogenesis", section on 'Symptomatic uncomplicated diverticular disease'.)

●

Lactose intolerance – Symptoms of lactose intolerance include abdominal pain, bloating, flatulence, and diarrhea. The abdominal pain may be cramping in nature and is often

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localized to the periumbilical area or lower quadrants. (See "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and management", section on 'Clinical features'.)

LESS COMMON CAUSES Less common causes of abdominal pain include ( ●

table 18):

Abdominal aortic aneurysm – Most patients with abdominal aortic aneurysm (AAA) have no symptoms. When patients with a nonruptured AAA do have symptoms, abdominal, back, or flank pain is the most common clinical manifestation. Classically, ruptured AAA is associated with severe pain, hypotension, and a pulsatile abdominal mass, but patients may have variable presentations. (See "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Asymptomatic AAA' and "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Symptomatic (nonruptured) AAA'.)

●

Abdominal compartment syndrome – Abdominal compartment syndrome generally occurs in patients who are critically ill. Patients have a tensely distended abdomen. (See "Abdominal compartment syndrome in adults".)

●

Abdominal migraine – Recurrent abdominal pain may occur in patients with abdominal migraine [9]. These patients usually also suffer from typical migraine headaches, although occasional patients present with gastrointestinal symptoms only [10]. Abdominal migraines have also been linked to cyclic vomiting syndrome. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults" and "Cyclic vomiting syndrome", section on 'Association with migraines'.)

●

Acute hepatic porphyrias – The acute hepatic porphyrias, of which acute intermittent porphyria (AIP) is the most common, are a rare cause of abdominal pain. The presentation of AIP is highly variable and patients have nonspecific symptoms. Abdominal pain is the most common and often earliest symptom. (See "Porphyrias: An overview", section on 'Acute hepatic porphyrias (AHP)' and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis", section on 'Acute attacks'.)

●

Angioedema – Angioedema with abdominal pain may be caused by hereditary angioedema or related to angiotensin-converting enzyme (ACE) inhibitor therapy. It can present with recurrent episodes of abdominal pain, accompanied by nausea, vomiting, colicky pain, and diarrhea. (See "Hereditary angioedema: Epidemiology, clinical

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manifestations, exacerbating factors, and prognosis" and "ACE inhibitor-induced angioedema", section on 'Intestine'.) ●

Celiac artery compression syndrome – Celiac artery compression syndrome (also referred to as celiac axis syndrome, median arcuate ligament syndrome, and Dunbar syndrome) is defined as chronic, recurrent abdominal pain related to compression of the celiac artery by the median arcuate ligament. (See "Celiac artery compression syndrome".)

●

Chronic abdominal wall pain – Chronic abdominal wall pain usually refers to anterior cutaneous nerve entrapment syndrome. Pain associated with nerve entrapment is characteristically maximal in an area 60 years. Exogenous

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reinfection in a previously infected person may present with similar findings. (See 'Postprimary and reactivation tuberculosis' above.) ●

Endobronchial TB − Endobronchial TB may develop via direct extension to the bronchi from an adjacent parenchymal focus (usually a cavity) or via spread of organisms to the bronchi via infected sputum. It can occur in patients with primary TB or postprimary TB and was observed more frequently prior to the antituberculous therapy era. Symptoms may be acute or chronic; a barking cough has been described in approximately two-thirds of patients. (See 'Endobronchial tuberculosis' above.)

●

Patients with HIV infection − The clinical manifestations of TB in patients with HIV infection are influenced by the degree of immunosuppression. As immunity declines, extrapulmonary TB and disseminated TB are more common. Immune reconstitution inflammatory syndrome can occur with initiation of antiretroviral therapy in some individuals living with HIV and is associated with paradoxic worsening of TB. (See 'Patients with HIV infection' above.)

●

Pulmonary complications − Pulmonary complications of TB include hemoptysis, pneumothorax, bronchiectasis, extensive pulmonary destruction (including pulmonary gangrene), acute respiratory distress syndrome, septic shock, malignancy, venous thromboembolism, and chronic pulmonary aspergillosis. (See 'Complications' above.)

●

Differential diagnosis − The differential diagnosis for pulmonary TB is broad and includes other causes of chronic infection, inflammatory diseases, and malignancy. (See 'Differential diagnosis' above.) Use of UpToDate is subject to the Terms of Use.

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21. Pérez-Guzmán C, Vargas MH, Torres-Cruz A, Villarreal-Velarde H. Does aging modify pulmonary tuberculosis?: A meta-analytical review. Chest 1999; 116:961. 22. Mathur P, Sacks L, Auten G, et al. Delayed diagnosis of pulmonary tuberculosis in city hospitals. Arch Intern Med 1994; 154:306. 23. Bobrowitz ID. Active tuberculosis undiagnosed until autopsy. Am J Med 1982; 72:650. 24. Breen RA, Leonard O, Perrin FM, et al. How good are systemic symptoms and blood inflammatory markers at detecting individuals with tuberculosis? Int J Tuberc Lung Dis 2008; 12:44. 25. Lee P, Ho KK. Hyponatremia in pulmonary TB: evidence of ectopic antidiuretic hormone production. Chest 2010; 137:207. 26. Day JH, Charalambous S, Fielding KL, et al. Screening for tuberculosis prior to isoniazid preventive therapy among HIV-infected gold miners in South Africa. Int J Tuberc Lung Dis 2006; 10:523. 27. POPPIUS H, THOMANDER K. Segmentary distribution of cavities; a radiologic study of 500 consecutive cases of cavernous pulmonary tuberculosis. Ann Med Intern Fenn 1957; 46:113. 28. Farman DP, Speir WA Jr. Initial roentgenographic manifestations of bacteriologically proven Mycobacterium tuberculosis. Typical or atypical? Chest 1986; 89:75. 29. LENTINO W, JACOBSON HG, POPPEL MH. Segmental localization of upper lobe tuberculosis; the rarity of anterior involvement. Am J Roentgenol Radium Ther Nucl Med 1957; 77:1042. 30. Nachiappan AC, Rahbar K, Shi X, et al. Pulmonary Tuberculosis: Role of Radiology in Diagnosis and Management. Radiographics 2017; 37:52. 31. Miller WT, MacGregor RR. Tuberculosis: frequency of unusual radiographic findings. AJR Am J Roentgenol 1978; 130:867. 32. Marciniuk DD, McNab BD, Martin WT, Hoeppner VH. Detection of pulmonary tuberculosis in patients with a normal chest radiograph. Chest 1999; 115:445. 33. Im JG, Itoh H, Shim YS, et al. Pulmonary tuberculosis: CT findings--early active disease and sequential change with antituberculous therapy. Radiology 1993; 186:653. 34. Im JG, Itoh H, Han MC. CT of pulmonary tuberculosis. Semin Ultrasound CT MR 1995; 16:420. 35. Hoheisel G, Chan BK, Chan CH, et al. Endobronchial tuberculosis: diagnostic features and therapeutic outcome. Respir Med 1994; 88:593.

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36. Salkin D, Cadden AV, Edson RC. The natural history of tuberculous tracheobronchitis. Am Rev Tuberc 1943; 47:351. 37. Wilson NJ. Bronchoscopic observations in tuberculosis tracheobronchitis: Clinical and pathological correlations. Dis Chest 1945; 11:36. 38. MacRAE DM, HILTZ JE, QUINLAN JJ. Bronchoscopy in a sanatorium; a review of 522 consecutive bronchoscopies. Am Rev Tuberc 1950; 61:355. 39. AUERBACH O. Tuberculosis of the trachea and major bronchi. Am Rev Tuberc 1949; 60:604. 40. Siow WT, Lee P. Tracheobronchial tuberculosis: a clinical review. J Thorac Dis 2017; 9:E71. 41. Shim YS. Endobronchial tuberculosis. Respirology 1996; 1:95. 42. Kashyap S, Mohapatra PR, Saini V. Endobronchial tuberculosis. Indian J Chest Dis Allied Sci 2003; 45:247. 43. Chung HS, Lee JH. Bronchoscopic assessment of the evolution of endobronchial tuberculosis. Chest 2000; 117:385. 44. Jung SS, Park HS, Kim JO, Kim SY. Incidence and clinical predictors of endobronchial tuberculosis in patients with pulmonary tuberculosis. Respirology 2015; 20:488. 45. LINCOLN EM, HARRIS LC, BOVORNKITTI S, CARRETERO R. The course and prognosis of endobronchial tuberculosis in children. Am Rev Tuberc 1956; 74:246. 46. Frostad S. Lymph node perforation through the bronchial tree in children with primary tuberculosis. Acta Tuberc Scand 1959; 47:104. 47. Lee JH, Park SS, Lee DH, et al. Endobronchial tuberculosis. Clinical and bronchoscopic features in 121 cases. Chest 1992; 102:990. 48. Ip MS, So SY, Lam WK, Mok CK. Endobronchial tuberculosis revisited. Chest 1986; 89:727. 49. Seiden HS, Thomas P. Endobronchial tuberculosis and its sequelae. Can Med Assoc J 1981; 124:165. 50. Caglayan S, Coteli I, Acar U, Erkin S. Endobronchial tuberculosis simulating foreign body aspiration. Chest 1989; 95:1164. 51. Matthews JI, Matarese SL, Carpenter JL. Endobronchial tuberculosis simulating lung cancer. Chest 1984; 86:642. 52. Van den Brande PM, Van de Mierop F, Verbeken EK, Demedts M. Clinical spectrum of endobronchial tuberculosis in elderly patients. Arch Intern Med 1990; 150:2105. 53. So SY, Lam WK, Sham MK. Bronchorrhea. A presenting feature of active endobronchial tuberculosis. Chest 1983; 84:635.

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54. Williams DJ, York EL, Nobert EJ, Sproule BJ. Endobronchial tuberculosis presenting as asthma. Chest 1988; 93:836. 55. Hatipoğlu ON, Osma E, Manisali M, et al. High resolution computed tomographic findings in pulmonary tuberculosis. Thorax 1996; 51:397. 56. Shahzad T, Irfan M. Endobronchial tuberculosis-a review. J Thorac Dis 2016; 8:3797. 57. Albert RK, Petty TL. Endobronchial tuberculosis progressing to bronchial stenosis. Fiberoptic bronchoscopic manifestations. Chest 1976; 70:537. 58. SEGARRA F, SHERMAN DS, RODRIGUEZ-AGUERO J. Lower lung field tuberculosis. Am Rev Respir Dis 1963; 87:37. 59. Chang SC, Lee PY, Perng RP. Lower lung field tuberculosis. Chest 1987; 91:230. 60. Parmar MS. Lower lung field tuberculosis. Am Rev Respir Dis 1967; 96:310. 61. STEELE JD. THE SOLITARY PULMONARY NODULE. REPORT OF A COOPERATIVE STUDY OF RESECTED ASYMPTOMATIC SOLITARY PULMONARY NODULES IN MALES. J Thorac Cardiovasc Surg 1963; 46:21. 62. Stead WW. Tuberculosis among elderly persons: an outbreak in a nursing home. Ann Intern Med 1981; 94:606. 63. Pratt PC. Pathology of tuberculosis. Semin Roentgenol 1979; 14:196. 64. Zwirewich CV, Vedal S, Miller RR, Müller NL. Solitary pulmonary nodule: high-resolution CT and radiologic-pathologic correlation. Radiology 1991; 179:469. 65. Lee HS, Oh JY, Lee JH, et al. Response of pulmonary tuberculomas to anti-tuberculous treatment. Eur Respir J 2004; 23:452. 66. Kulkarni NS, Gopal GS, Ghaisas SG, Gupte NA. Epidemiological considerations and clinical features of ENT tuberculosis. J Laryngol Otol 2001; 115:555. 67. Agarwal R, Gupta L, Singh M, et al. Primary Laryngeal Tuberculosis: A Series of 15 Cases. Head Neck Pathol 2019; 13:339. 68. Benwill JL, Sarria JC. Laryngeal tuberculosis in the United States of America: a forgotten disease. Scand J Infect Dis 2014; 46:241. 69. Reis JG, Reis CS, da Costa DC, et al. Factors Associated with Clinical and Topographical Features of Laryngeal Tuberculosis. PLoS One 2016; 11:e0153450. 70. Rajasekaran V, Srividhya G. A clinical study on laryngeal manifestations of tuberculosis. Int J Otolaryngol 2017; 3:845. 71. Greenberg SD, Frager D, Suster B, et al. Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance). Radiology 1994; https://www.uptodate.com/contents/7026/print

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193:115. 72. Barnes PF, Bloch AB, Davidson PT, Snider DE Jr. Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 1991; 324:1644. 73. Berkowitz N, Okorie A, Goliath R, et al. The prevalence and determinants of active tuberculosis among diabetes patients in Cape Town, South Africa, a high HIV/TB burden setting. Diabetes Res Clin Pract 2018; 138:16. 74. Jones BE, Young SM, Antoniskis D, et al. Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection. Am Rev Respir Dis 1993; 148:1292. 75. Holmes CB, Wood R, Badri M, et al. CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr 2006; 42:464. 76. Yang Z, Kong Y, Wilson F, et al. Identification of risk factors for extrapulmonary tuberculosis. Clin Infect Dis 2004; 38:199. 77. Leeds IL, Magee MJ, Kurbatova EV, et al. Site of extrapulmonary tuberculosis is associated with HIV infection. Clin Infect Dis 2012; 55:75. 78. Naing C, Mak JW, Maung M, et al. Meta-analysis: the association between HIV infection and extrapulmonary tuberculosis. Lung 2013; 191:27. 79. von Reyn CF, Kimambo S, Mtei L, et al. Disseminated tuberculosis in human immunodeficiency virus infection: ineffective immunity, polyclonal disease and high mortality. Int J Tuberc Lung Dis 2011; 15:1087. 80. Shafer RW, Kim DS, Weiss JP, Quale JM. Extrapulmonary tuberculosis in patients with human immunodeficiency virus infection. Medicine (Baltimore) 1991; 70:384. 81. Hudson CP, Wood R, Maartens G. Diagnosing HIV-associated tuberculosis: reducing costs and diagnostic delay. Int J Tuberc Lung Dis 2000; 4:240. 82. Frye MD, Pozsik CJ, Sahn SA. Tuberculous pleurisy is more common in AIDS than in nonAIDS patients with tuberculosis. Chest 1997; 112:393. 83. Ansari NA, Kombe AH, Kenyon TA, et al. Pathology and causes of death in a group of 128 predominantly HIV-positive patients in Botswana, 1997-1998. Int J Tuberc Lung Dis 2002; 6:55. 84. Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005; 40:1500. 85. Rangaka MX, Wilkinson RJ, Glynn JR, et al. Effect of antiretroviral therapy on the diagnostic accuracy of symptom screening for intensified tuberculosis case finding in a South African https://www.uptodate.com/contents/7026/print

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HIV clinic. Clin Infect Dis 2012; 55:1698. 86. Keiper MD, Beumont M, Elshami A, et al. CD4 T lymphocyte count and the radiographic presentation of pulmonary tuberculosis. A study of the relationship between these factors in patients with human immunodeficiency virus infection. Chest 1995; 107:74. 87. Diagnostic Standards and Classification of Tuberculosis in Adults and Children. This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999. Am J Respir Crit Care Med 2000; 161:1376. 88. Lessnau KD, Gorla M, Talavera W. Radiographic findings in HIV-positive patients with sensitive and resistant tuberculosis. Chest 1994; 106:687. 89. Perlman DC, el-Sadr WM, Nelson ET, et al. Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG). Clin Infect Dis 1997; 25:242. 90. Padyana M, Bhat RV, Dinesha M, Nawaz A. HIV-Tuberculosis: A Study of Chest X-Ray Patterns in Relation to CD4 Count. N Am J Med Sci 2012; 4:221. 91. Johnston H, Reisz G. Changing spectrum of hemoptysis. Underlying causes in 148 patients undergoing diagnostic flexible fiberoptic bronchoscopy. Arch Intern Med 1989; 149:1666. 92. McGuinness G, Beacher JR, Harkin TJ, et al. Hemoptysis: prospective high-resolution CT/bronchoscopic correlation. Chest 1994; 105:1155. 93. Conlan AA, Hurwitz SS, Krige L, et al. Massive hemoptysis. Review of 123 cases. J Thorac Cardiovasc Surg 1983; 85:120. 94. Middleton JR, Sen P, Lange M, et al. Death-producing hemoptysis in tuberculosis. Chest 1977; 72:601. 95. Knott-Craig CJ, Oostuizen JG, Rossouw G, et al. Management and prognosis of massive hemoptysis. Recent experience with 120 patients. J Thorac Cardiovasc Surg 1993; 105:394. 96. Rasmussen V, Moore WD. Continued observations on hemoptysis. Edinburgh Med J 1869; 15:97. 97. THOMPSON JR. Mechanisms of fatal pulmonary hemorrhage in tuberculosis. Am J Surg 1955; 89:637. 98. Ramakantan R, Bandekar VG, Gandhi MS, et al. Massive hemoptysis due to pulmonary tuberculosis: control with bronchial artery embolization. Radiology 1996; 200:691.

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99. Muthuswamy PP, Akbik F, Franklin C, et al. Management of major or massive hemoptysis in active pulmonary tuberculosis by bronchial arterial embolization. Chest 1987; 92:77. 100. Corey R, Hla KM. Major and massive hemoptysis: reassessment of conservative management. Am J Med Sci 1987; 294:301. 101. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis: technical aspects and long-term results. Radiology 1985; 157:637. 102. Jean-Baptiste E. Clinical assessment and management of massive hemoptysis. Crit Care Med 2000; 28:1642. 103. Bobrowitz ID, Ramakrishna S, Shim YS. Comparison of medical v surgical treatment of major hemoptysis. Arch Intern Med 1983; 143:1343. 104. Yeoh CB, Hubaytar RT, Ford JM, Wylie RH. Treatment of massive hemorrhage in pulmonary tuberculosis. J Thorac Cardiovasc Surg 1967; 54:503. 105. Amirana M, Frater R, Tirschwell P, et al. An aggressive surgical approach to significant hemoptysis in patients with pulmonary tuberculosis. Am Rev Respir Dis 1968; 97:187. 106. Berry FB. Tuberculous pyopneumothorax with pyogenic infection. J Thorac Surg 1932; 2:139. 107. WILDER RJ, BEACHAM EG, RAVITCH MM. Spontaneous pneumothorax complicating cavitary tuberculosis. J Thorac Cardiovasc Surg 1962; 43:561. 108. Ihm HJ, Hankins JR, Miller JE, McLaughlin JS. Pneumothorax associated with pulmonary tuberculosis. J Thorac Cardiovasc Surg 1972; 64:211. 109. Aktoğu S, Yorgancioglu A, Cirak K, et al. Clinical spectrum of pulmonary and pleural tuberculosis: a report of 5,480 cases. Eur Respir J 1996; 9:2031. 110. Hussain SF, Aziz A, Fatima H. Pneumothorax: a review of 146 adult cases admitted at a university teaching hospital in Pakistan. J Pak Med Assoc 1999; 49:243. 111. Auerbach O, Lipstein S. Bronchopleural fistulas complication pulmonary tuberculosis. J Thorac Surg 1939; 8:384. 112. Rilance AB, Gerstl B. Bronchiectasis secondary to puomonary tuberculosis. Am Rev Tuberc 1943; 48:8. 113. Roberts JC, Blair LG. Bronchiectasis in primary tuberculosis. Lancet 1950; 1:386. 114. Rosenzweig DY, Stead WW. The role of tuberculosis and other forms of bronchopulmonary necrosis in the pathogenesis of bronchiectasis. Am Rev Respir Dis 1966; 93:769.

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115. COHEN AG. Atelectasis of the right middle lobe resulting from perforation of tuberculous lymph nodes into bronchi in adults. Ann Intern Med 1951; 35:820. 116. CURTIS JK. The significance of bronchiectasis associated with pulmonary tuberculosis. Am J Med 1957; 22:894. 117. Brock RC. Post-tuberculous broncho-stenosis and bronchiectasis of the middle lobe. Thorax 1950; 5:5. 118. Galdermans D, Verhaert J, Van Meerbeeck J, et al. Broncholithiasis: present clinical spectrum. Respir Med 1990; 84:155. 119. Bobrowitz ID, Rodescu D, Marcus H, Abeles H. The destroyed tuberculous lung. Scand J Respir Dis 1974; 55:82. 120. Palmer PE. Pulmonary tuberculosis--usual and unusual radiographic presentations. Semin Roentgenol 1979; 14:204. 121. Khan FA, Rehman M, Marcus P, Azueta V. Pulmonary gangrene occurring as a complication of pulmonary tuberculosis. Chest 1980; 77:76. 122. López-Contreras J, Ris J, Domingo P, et al. Tuberculous pulmonary gangrene: report of a case and review. Clin Infect Dis 1994; 18:243. 123. Sudarsan TI, Thomas L, Samprathi A, et al. Tuberculous ARDS is associated with worse outcome when compared with non-tuberculous infectious ARDS. J Crit Care 2021; 61:138. 124. Kethireddy S, Light RB, Mirzanejad Y, et al. Mycobacterium tuberculosis septic shock. Chest 2013; 144:474. 125. Brenner AV, Wang Z, Kleinerman RA, et al. Previous pulmonary diseases and risk of lung cancer in Gansu Province, China. Int J Epidemiol 2001; 30:118. 126. Liang HY, Li XL, Yu XS, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer 2009; 125:2936. 127. Falagas ME, Kouranos VD, Athanassa Z, Kopterides P. Tuberculosis and malignancy. QJM 2010; 103:461. 128. Danwang C, Bigna JJ, Awana AP, et al. Global epidemiology of venous thromboembolism in people with active tuberculosis: a systematic review and meta-analysis. J Thromb Thrombolysis 2021; 51:502. Topic 7026 Version 35.0

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GRAPHICS

Tuberculosis terminology Tuberculosis terminology is inconsistent in the literature[1] . The following terms refer to the clinical state in which there is evidence of specific cell-mediated immunologic response following exposure to Mycobacterium tuberculosis-derived protein antigens in solution (eg, positive TST and/or IGRA), in the absence of signs or symptoms of illness: Tuberculosis infection (newer term) Latent tuberculosis infection (older term) The following terms refer to presence of signs or symptoms reflecting illness due to M. tuberculosis: Tuberculosis disease (newer term) Active tuberculosis (older term) Active tuberculosis disease (older term) Active tuberculosis infection (older term) TST: tuberculin skin test; IGRA: interferon-gamma release assay. Reference: 1. Behr MA, Kaufmann E, Duffin J, et al. Latent Tuberculosis: Two Centuries of Confusion. Am J Respir Crit Care Med 2021; 204:142.

Graphic 132526 Version 3.0

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Hilar and mediastinal lymphadenopathy in primary tuberculosis

(A) Chest radiograph in an 18 year old patient shows prominent right hilum and widening of the right paratracheal stripe (arrows). (B, C) Contrast enhanced chest computed tomography demonstrates right hilar and paratracheal lymphadenopathy (arrows). Graphic 134475 Version 2.0

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Right middle lobe consolidation in a 29-year-old patient with primary tuberculo

(A) Chest radiograph shows homogeneous right middle lobe consolidation and enlarged right hilum. (B) CT scan demonstrates dense right middle lobe consolidation and focal convexity in the subcarinal region suggestive of lymphadenopathy (arrow). (C) Contrast enhanced CT demonstrates enlarged right hilar and subcarinal lymph nodes with low attenuation centers consistent with necrosis (dashed arrows). CT: computed tomography. Graphic 134476 Version 1.0

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Right upper lobe consolidation and cavitation in postprimary tuberculosis

(A) Chest radiograph shows poorly defined areas of consolidation and subtle small cavity in the right upper lobe. (B and C) Computed tomography images demonstrate two adjacent cavities, poorly defined opacities, and cavitating consolidation in the apical segment of the right upper lobe. Graphic 134478 Version 1.0

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Endobronchial spread of tuberculosis on chest radiograph and CT

(A) Chest radiograph shows poorly defined areas of increased opacity in the lung apices and innumerable bilateral small nodules involving mainly the upper lobes. (B) CT demonstrates bilateral apical cavities, ground-glass opacities, small areas of consolidation, and numerous centrilobular nodules. (C) CT at the level of the lower lobes shows numerous bilateral centrilobular nodules, characterized by measuring 2 to 4 mm in diameter, typically occurring in clusters, and being centered a few millimeters away from the pleura and interlobar fissures. CT: computed tomography. Graphic 134479 Version 1.0

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Tree-in-bud pattern in endobronchial spread of tuberculosis

Maximum-intensity projection computed tomography image of the right lung demonstrates branching linear and nodular opacities resulting in a tree-in-bud pattern (arrows). The patient did not have any consolidation or cavity. Graphic 134480 Version 1.0

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Tuberculoma

Computed tomography image in a smoker shows emphysema and irregular 2 cm diameter nodule in the apicoposterior segment of the left upper lobe. Core needle biopsy demonstrated tuberculosis. Graphic 134481 Version 1.0

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Chest radiograph - Tuberculosis and HIV

Chest radiograph showing asymmetric hilar and mediastinal adenopathy and non-confluent opacification left mid and lower zones. Common appearance of tuberculosis in patients with CD4 counts 38.5°C or >101.5°F), and a strategy discussed regarding plans in case a fever develops during travel or when visiting with family members or caregivers who may not be familiar with the routine. Adults should also have a clear plan for seeking medical attention for signs of infection. Fever should be considered a medical emergency requiring prompt medical attention, blood culture, and treatment with antibiotics. This important issue is discussed separately. (See "Evaluation and management of fever in children and adults with sickle cell disease".) Immunizations — Immunizations are a cornerstone of infection prevention in SCD. ●

Children with SCD should receive all routinely recommended childhood vaccines, including those against Streptococcus pneumoniae, seasonal influenza, Neisseria meningitidis, Haemophilus influenzae type B, and hepatitis B virus (

●

table 2) [11-16].

People with SCD have increased morbidity and mortality from COVID-19, and COVID-19 vaccination (including booster doses) is recommended.

●

Annual seasonal influenza vaccination should also be provided.

●

When feasible, antibiotic prophylaxis may be indicated for individuals with SCD who are household contacts of persons with these infections.

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Data from a large randomized trial of hydroxyurea use (the BABY HUG trial) are reassuring that the use of hydroxyurea does not interfere with the response to immunizations [17].

COVID-19 — People with SCD are immunosuppressed due to functional asplenia and have increased morbidity and mortality from COVID-19. Vaccination (including booster doses) is recommended; significant antibody responses have been reported [18,19]. (See "Prevention of infection in patients with impaired splenic function", section on 'COVID-19 vaccination'.) Pneumococcal disease — Vaccination has led to a decrease in the incidence of invasive pneumococcal disease in children with SCD [16,20,21]. In the United States, both a 13-valent pneumococcal conjugate vaccine (PCV13, which has replaced the 7-valent conjugate vaccine [PCV7]) and a 23-valent pneumococcal polysaccharide vaccine (PPSV23) are available. All children with SCD should be immunized with both PCV13 and PPSV23. (See "Pneumococcal vaccination in children".) Administration of both the conjugate and polysaccharide vaccine provides protection at the earliest possible age and subsequently broadens protection against most of the invasive pneumococcal serotypes [12]. The pneumococcal conjugate vaccine (PCV13 or, if not available, PCV7) can be administered as early as six weeks of age and elicits an effective immunologic response during the first two years of life. The pneumococcal polysaccharide vaccine (PPSV23) includes a greater number of serotypes but is not immunogenic in children younger than two years of age. Penicillin prophylaxis does not appear to interfere with an IgG response to immunization [14]. In the United States, we recommend administering both the conjugate and the polysaccharide vaccines using the American Academy of Pediatrics (AAP) guideline as follows (

table 3 and

table 4A-B) [22,23]: ●

The pneumococcal conjugate vaccine (PCV13) is administered as four doses before 23 months of age on the same schedule as is routinely given to all children. The first three doses are administered at two, four, and six months of age. The first dose can be given as early as six weeks of age. A minimum of four weeks between the three doses is acceptable. The fourth dose should be given at 12 to 15 months of age but at least two months after the third dose. Children who had been fully immunized with PCV7 should receive a supplemental dose of PCV13 [24].

●

The pneumococcal polysaccharide vaccine (PPSV23) is given as two doses: the first dose at 24 months of age (at least eight weeks after the last dose of PCV13). A second dose

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three to five years after the first dose of the pneumococcal polysaccharide vaccine also is recommended; this was used in clinical trials, and probably provides additional protection [25]. In patients younger than five years of age who did not receive the full complement of pneumococcal immunization based upon the above schedule, catch-up doses of vaccines should be given. The timing and number of doses depend upon the number of total doses of the conjugate and/or polysaccharide vaccines that have been given by five years of age [23]. (See "Pneumococcal vaccination in children".) Recommendations for functionally asplenic adults are presented separately. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.) Influenza — Annual seasonal influenza vaccination is recommended for all individuals with SCD. Vaccination should be administered annually at the start of the flu season, beginning at six months of age. Individuals with SCD should receive that inactivated vaccine rather than the liveattenuated vaccine because of the increased risk of severe or complicated infection (

table 5).

(See "Seasonal influenza in children: Prevention with vaccines" and "Seasonal influenza vaccination in adults".) Analysis of Healthcare Cost and Utilization Project (HCUP) 2003 to 2005 state inpatient data indicated that although children with SCD were hospitalized for influenza 56 times more often than those without SCD, neither the length nor cost of hospitalization differed [26]. Therefore, effective influenza vaccination may decrease the hospitalization rate by decreasing the number of febrile episodes that require evaluation and treatment. (See "Prevention of infection in patients with impaired splenic function", section on 'Vaccinations'.) Meningococcus — In the United States, early meningococcal vaccination is recommended for all asplenic children, including those with SCD. Details are included in the summary table for ages 2 months through 23 months (

table 6) and age 2 years (

table 7) and in a separate

topic review. (See "Meningococcal vaccination in children and adults", section on 'Immunization of persons at increased risk'.) Other standard vaccinations — Children with SCD should receive all standard childhood vaccinations, including those against hepatitis A and B; measles, mumps, and rubella; varicella; rotavirus; Haemophilus influenzae; tetanus, diphtheria, and pertussis; and poliovirus in countries where it is still endemic (

table 2). (See "Hepatitis B virus immunization in adults" and

"Standard immunizations for children and adolescents: Overview", section on 'Routine schedule' and "Rotavirus vaccines for infants" and "Prevention of Haemophilus influenzae type b infection" and "Poliovirus vaccination".) https://www.uptodate.com/contents/7114/print

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Most of these vaccinations should be updated periodically during adulthood, according to the recommendations of the Centers for Disease Control (

table 2) or other national regulatory

agency. Inactivated virus vaccines are preferred. (See "Standard immunizations for nonpregnant adults".) Prophylactic penicillin — Prophylactic penicillin should be given to all individuals with SCD at least until age five [8,27]. The dose from age three months to three years is 125 mg penicillin V orally twice daily, and at age three years this should be increased to 250 mg twice daily until the age of five [25,28]. (See "Prevention of infection in patients with impaired splenic function", section on 'Antibiotic prophylaxis'.) After the age of five years, some parents/caregivers, with consultation of their clinicians, elect to stop penicillin prophylaxis, while others will continue [29]. This is an important issue given the lifelong persistence of splenic dysfunction starting in late childhood and continuing through adulthood. Patients and families should be reminded that fever is a medical emergency for a patient with SCD, regardless of whether they are taking penicillin. Patients with penicillin allergies should receive prophylactic erythromycin BID. Other alternative antibiotic choices for penicillin-allergic individuals are discussed separately. (See "Prevention of infection in patients with impaired splenic function", section on 'Antibiotic prophylaxis'.) The benefit of prophylactic penicillin has been demonstrated in two large randomized trials [30,31]. A 2012 Cochrane review of these trials included data from 457 patients with SCD [32]. As compared with no treatment or placebo, penicillin prophylaxis was associated with a decreased risk of pneumococcal infection (odds ratio 0.37; 95% CI 0.16-0.86) and a decreased risk of death (odds ratio 0.11; 95% CI 0.01-2.11). Adverse effects were minimal. Further discussion of these trials and related issues, such as penicillin resistance and country-specific guidelines, is presented elsewhere. (See "Prevention of infection in patients with impaired splenic function", section on 'Antibiotic prophylaxis'.) A randomized trial directly evaluated the safety of stopping penicillin prophylaxis in 400 children with SCD who had received penicillin prophylaxis for at least two years immediately before their fifth birthdays and had received the 23-valent pneumococcal vaccine between two and three years of age, and again at the time of randomization (ie, had received optimal prophylaxis) [25]. The incidence of systemic pneumococcal infection during 3.2 years of followup was very low and not significantly different in those receiving placebo or continued penicillin prophylaxis (2 versus 1 percent). The decision of whether to continue antibiotic prophylaxis after age five must be made on a case-by-case basis. Based upon the above data, many pediatric clinicians elect to stop https://www.uptodate.com/contents/7114/print

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prophylaxis if the child has not had a prior severe pneumococcal infection or splenectomy and is receiving comprehensive care, including administration of the pneumococcal polysaccharide vaccine (PPSV23) [8,29]. However, others will continue penicillin prophylaxis through adulthood because of the lifelong risk of pneumococcal infection, including infection with pneumococcal disease with serotypes not included in the vaccines [33]. (See 'Pneumococcal disease' above.) Regardless of the decision, careful monitoring should be continued because fever is a lifethreatening condition among individuals with SCD. Pneumococcal sepsis does occur in children taking penicillin who have received the pneumococcal vaccine, and factors affecting adequacy of pneumococcal prophylaxis should be explored [34,35]. As an example, publicly insured children with SCD often receive inadequate antibiotic prophylaxis. In a review of Washington State and Tennessee Medicaid programs, the average SCD patient was dispensed only 148 days of prophylactic medication per year [36]. Efforts to improve penicillin access should therefore be investigated. (See "Evaluation and management of fever in children and adults with sickle cell disease".) Variant sickle cell syndromes — Compared with patients with SCD (ie, hemoglobin SS [HbSS]), those with variant sickle cell syndromes (hemoglobin SC, sickle cell-beta thalassemia) may have reduced susceptibility to serious infections, depending on the disease severity. The risk of infection is proportional to disease severity due to the resulting effect on splenic function. ●

HbSC – Those with HbSC disease are less likely to develop invasive bacterial infection than those with HbSS [37-39], because they maintain some splenic function during early childhood [40]. In addition, patients with HbSC who develop bacteremia are less likely to develop sepsis and septic shock [37,39]. Although there are case reports of fatal bacterial infection in children with HbSC disease [41], the risk of death due to overwhelming sepsis is significantly lower than that of patients with HbSS. While routine childhood immunizations and a clear plan for seeking medical therapy for any febrile episode are important, individuals with HbSC are not routinely prescribed prophylactic penicillin [39].

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Sickle cell-beta thalassemia – Among patients with sickle cell-beta thalassemia, severity of the disease varies with the production of hemoglobin A (Hb A), and management varies accordingly:

• Patients with sickle cell-beta0 thalassemia (HbS-beta0 thalassemia) have a clinical course similar to patients with HbSS disease, with development of functional asplenia early in childhood and a similar risk of invasive bacterial infection. As a result, their infection prevention strategy should be the same as those with HbSS, including

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immunizations, prophylactic penicillin, and empiric antibiotic therapy when they are febrile.

• Patients with sickle cell-beta+ thalassemia (HbS-beta+ thalassemia) produce variable amounts of Hb A and in general have less severe SCD complications, although limited data are available regarding their risk of infection [39]. In general, they are treated in a manner similar to those with HbSC.

INFECTION MANAGEMENT Infection is a frequent complication of SCD, and historically it has been the major cause of death in children. Fever may be the first indication of a serious bacterial infection, and as such should be considered a medical emergency. Patients should seek prompt medical attention and be rapidly evaluated for a temperature >38.5°C (101.5°F). The important issue of infection management in individuals with SCD is discussed in detail separately. (See "Evaluation and management of fever in children and adults with sickle cell disease".) ●

The evaluation should include a brief history for localizing symptoms and an abbreviated physical examination focused on hemodynamic stability, signs of localized or generalized infection, splenic size, and evidence of stroke. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Initial evaluation'.) During the COVID-19 pandemic, testing for SARS-CoV-2 infection is appropriate for any individual with SCD who presents with fever. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function", section on 'COVID-19 considerations'.)

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Blood cultures and complete blood count with differential and reticulocyte count should be obtained. Empiric parenteral antibiotics should be started as soon as possible, ideally within 60 minutes of triage. Evaluation for pneumonia is important [42]; however, antibiotics should not be delayed while awaiting chest radiography. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Empiric antibiotic therapy'.)

LEG ULCERS The clinical characteristics and natural history of skin ulcers in individuals with SCD differ from those seen in individuals with other hemolytic anemias. Severe pain at the wound site is https://www.uptodate.com/contents/7114/print

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disproportionately greater in SCD than in other populations. Animal models support this observation. The best approach to leg ulcers is prevention, which includes attention to properly fitting shoes and immediate treatment for early signs of skin injury. (See "Basic principles of wound management".) If a patient develops a leg ulcer, we routinely use lower extremity Doppler to evaluate for deep vein thrombosis (DVT). Forty-four percent of leg ulcers in patients with SCD are associated with a DVT, likely due to lower extremity edema [43]. In addition, since pulmonary hypertension is associated with the development of lower extremity ulcers, we evaluate for pulmonary hypertension with a transthoracic Doppler echocardiography and obtain a complete blood count (CBC), lactate dehydrogenase (LDH) level, and serum chemistries. We do not routinely evaluate for peripheral vascular disease with ankle brachial pressure index or for osteomyelitis, unless there is clinical suspicion. Management of large skin ulcers requires a multidisciplinary team. Although many systemic and local therapies have been examined, the mainstays of therapy are wound care, compression, and SCD-based therapy with hydroxyurea or chronic transfusion. Components of management may include the following [44-48]: ●

Immediate attention to the pain. Many providers use systemic opioids. Topical opioids also have been examined and found to relieve pain and facilitate healing [49,50]. Topical opioids also decrease local fluid extravasation.

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Local edema must be minimized with rest, lower extremity elevation, and compression bandages. In some cases diuresis is also appropriate. Coban compression may be more beneficial than Unna boots.

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We have found bedrest, though difficult to comply with, is essential for healing of large and/or recalcitrant ulcers [51,52].

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Therapeutic debridement is important to remove fibrotic tissue and stimulate healing. In general, we initially refer the patient to a wound care specialist for debridement, dressing changes and, if necessary, topical antibiotics [53]. Wet to dry dressings and Duoderm hydrocolloid dressings may also facilitate healing.

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Infections require treatment, but antibiotics are often not helpful and should be used appropriately.

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In our experience, repeated transfusion therapy accelerates wound healing and is often a core therapy [54]. Alternatively, hydroxyurea may be beneficial, even though hydroxyurearelated skin ulcers have been reported. Patients can be managed initially with hydroxyurea and transitioned to chronic transfusion, or treated with chronic transfusion initially, depending on other comorbidities and patient factors.

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Grafts may be necessary, but they have a very high failure rate and should be used conservatively [55].

These therapies are discussed in more detail separately. (See "Overview of treatment of chronic wounds".) In addition to the specific therapies listed above, many patients with SCD and skin ulcers have multiple other problems that impair wound healing, including malnutrition, vitamin D and nutritional deficiencies, pulmonary hypertension, and depression. These confounding factors also need to be addressed. There are multiple therapies that may be beneficial but remain unproven, including Apligraf (a skin equivalent), topical sodium nitrite 2% cream, RGD peptide dressings, and topical Timolol [56-59]. We do not routinely use these therapies, but rely on pain relief, bedrest, transfusion therapy, local wound care, and when necessary, consultation with chronic ulcer programs.

NUTRITION There are few prospective data regarding clinical benefit of nutritional interventions that can be used to guide nutritional management in patients with SCD. However, growing evidence suggests that these individuals have vitamin and micronutrient deficiencies that may influence the course of their disease [60-64]. We therefore use the following in our patients: ●

Folic acid is given to all individuals in an oral dose of 1 mg daily. However, some clinicians may reasonably omit folic acid supplementation for patients who have sufficient dietary intake, especially in settings where grains and cereals are routinely supplemented. Folate deficiency has been found in several observational studies of patients with SCD [63,65-68]. Increased folate consumption from ongoing hemolytic anemia is often proposed as a rationale for the use of folic acid in these patients. However, there are no data that folic acid supplementation increases the hematocrit in individuals with SCD; a randomized trial of folic acid supplementation in 117 children with SCD showed that compared with controls, those receiving folic acid did not show an improvement in hemoglobin levels or growth characteristics but did have a decrease in mean cell volume and less dactylitis [66].

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Despite this, we believe that the potential yet unknown benefit from folic acid supplementation outweighs the potential harms. ●

We use a daily multivitamin without iron for all of our patients. This replaces some of the vitamins and micronutrients commonly reported to be deficient in these individuals, including zinc, vitamin D, vitamin E, vitamin C, vitamin A, magnesium, selenium, carotenoids, and flavonoids [60-63]. Excessive iron stores and oxidative injury may contribute to the depletion of antioxidant vitamins.

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We screen all infants with SCD for risk factors for iron deficiency, including those not receiving transfusions, during the first two years of life. We also use laboratory screening at one year of age, as advised by the American Academy of Pediatrics (AAP). All children with SCD who have evidence of iron deficiency anemia should be treated because iron deficiency has a negative effect on neurodevelopment. (See "Iron deficiency in infants and children 18 years) with CRS with NP inadequately responsive to intranasal corticosteroids [125]. The approved dosing is based on serum total IgE and body weight, although the upper limit of serum IgE (1500 kU/mL) and the maximum dose of Xolair (600 mg every two weeks) are significantly higher for nasal polyps compared with asthma using a formula provided by the manufacturer. It is also used in the treatment of inadequately controlled moderate-tosevere asthma and chronic urticaria, as discussed separately. (See "Anti-IgE therapy".) ●

Mepolizumab – Mepolizumab (an anti-IL-5 monoclonal antibody preparation) reduces tissue eosinophilia by blocking the actions of IL-5 on eosinophil differentiation and survival. It was approved by the US FDA in July 2021 for add-on therapy for adults (>18 years) with CRS with NP inadequately responsive to intranasal corticosteroids, at a dose of 100 mg subcutaneously every four weeks [126]. Mepolizumab at this dose was studied in a randomized, multicenter, 52-week trial of 407 patients with recurrent and symptomatic CRS with NP despite ≥8 weeks of intranasal corticosteroid and at least one surgery to remove polyps in the previous 10 years [127]. By the end of the trial, both co-primary endpoints improved: endoscopic polyp score (adjusted difference in medians -0.73, 95% CI -1.11 to -0.34) and nasal obstruction score (-3.14, 95% CI -4.09 to -2.18). Mepolizumab is also approved for severe asthma. (See "Treatment of severe asthma in adolescents and adults", section on 'Mepolizumab'.)

Two additional biologic agents, benralizumab (an anti-IL-5 receptor monoclonal antibody preparation) [128,129] and reslizumab (an anti-IL-5 monoclonal) [130] are considered investigational for the treatment of CRS with NP, but both are available for severe asthma. Preliminary data are encouraging.

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Aspirin desensitization and therapy — Patients with the combination of CRS with NP, asthma, and aspirin/NSAID intolerance, a combination of features that is referred to as AERD, NERD, or Samter's triad, may be candidates for aspirin desensitization, followed by daily aspirin therapy. Note that aspirin therapy is not effective for patients with CRS with NP but without asthma or NSAID intolerance. Sinus surgery is often recommended prior to desensitization, because the presence of extensive polyp tissue is associated with more severe symptoms during desensitization, and because aspirin therapy slows the regrowth of polyps but minimally reduces existing polyps. In addition, sinus surgery would carry a lower risk of bleeding if pursued before the patient is taking aspirin. A beneficial effect of aspirin desensitization and daily aspirin therapy on NP had been noted by several groups as far back as 1983 [131-134]. In contrast to patients with aspirin intolerance, those with CRS and NP who tolerate aspirin without developing characteristic flushing and nasal/respiratory symptoms do not appear to benefit from daily aspirin therapy, at least at moderate doses [135]. Aspirin desensitization requires close monitoring for bronchospasm and is usually conducted by a specialist in drug desensitizations. This is reviewed in detail separately. (See "Aspirin-exacerbated respiratory disease" and "Diagnostic challenge and desensitization protocols for NSAID reactions".) Long-term aspirin therapy has been shown in retrospective studies to reduce upper and lower airway inflammation in some patients, although it is rarely sufficient as monotherapy. In addition, gastrointestinal side effects from daily oral aspirin therapy preclude long-term treatment in some patients, although preventative H2 antihistamines and proton pump inhibitors can be helpful. The initial maintenance dose of aspirin has traditionally been 650 mg twice daily, but studies recommend attempting to lower the dose to 325 mg twice daily for long-term maintenance [136]. (See "Aspirin-exacerbated respiratory disease: NSAID challenge and desensitization".) A topical preparation of intranasal lysine-aspirin is available in many countries (not in the United States). Regular intranasal therapy with this agent is being studied for the purpose of treating CRS with NP in aspirin-intolerant patients but cannot be recommended [1,137]. Maintenance therapies — Once symptoms have been controlled to a level acceptable to the patient, therapies to minimize inflammation should be initiated or continued without interruption. Maintenance therapies for CRS with NP include intranasal corticosteroids and a trial of antileukotriene agents. Other therapies are of uncertain benefit but may help certain patients.

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Intranasal corticosteroids — The mainstay of maintenance treatment is intranasal corticosteroids [138,139]. Several different intranasal corticosteroids have been shown either to reduce the size or prevent the regrowth of NP following surgical removal, including (in alphabetical order) beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide (

table 2). Systematic reviews and randomized trials have demonstrated that these agents are

effective, delivered either by intranasal spray [18,19,28,140] or intranasal instillation [44]. Intranasal corticosteroids may also be helpful in preventing the regrowth of nasal polyps following sinus surgery [140,141], although not all studies have demonstrated efficacy, and the effect may not be equal in all patient populations [46,142]. Specifically, polyp recurrence may be more difficult to prevent in patients with AERD or nonsteroidal anti-inflammatory drug (NSAID)exacerbated respiratory disease (NERD). In a randomized trial of 60 patients with AERD who had undergone sinus surgery and polypectomy, intranasal corticosteroids did not prevent polyp regrowth [46]. The protocol compared three treatments: saline irrigation (60 mL/nostril twice daily), saline irrigation followed by intranasal budesonide spray (64 mcg/nostril), and saline irrigation with aqueous budesonide (250 mcg/60 mL/nostril), all administered twice daily. Treatment was continued for one year. The primary outcome variable was change in quality of life on the Sino-Nasal Outcome Test (QOL-SNOT-21) at six months and one year. Patients in each arm of the study experienced an improvement in QOL-SNOT-21, but the improvement was waning by one year. There were no statistically significant differences between groups. Antileukotrienes — Antileukotriene agents may be used as an adjunct to intranasal corticosteroids in the treatment of CRS with NP [143-146]. We treat most patients with AERD with some form of long-term antileukotriene therapy. We usually administer a three-month trial of montelukast and continue it indefinitely in patients who experience clinical benefit. Small, randomized trials demonstrated modest benefit after one to two months of montelukast, either as monotherapy [143] or as adjunctive therapy to oral prednisolone and budesonide nasal spray [145]. The effect of antileukotriene agents is generally less than that of intranasal corticosteroids, but additive effects have been reported in some studies [147-149]. Antileukotriene agents may not benefit all patients CRS with NP. They may be more effective in those with concomitant asthma and aspirin intolerance (ie, the syndrome of AERD) [150]. It is unclear whether the 5-lipoxygenase inhibitor zileuton is any more effective than leukotriene D4 (LTD4) receptor blockers (eg, montelukast or zafirlukast). (See "Aspirin-exacerbated respiratory disease", section on 'Leukotriene-modifying agents'.) Therapies of uncertain benefit https://www.uptodate.com/contents/7534/print

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Antihistamines – One randomized, placebo-controlled trial examined the effect of cetirizine 20 mg once daily for three months as a treatment for 45 patients with residual or recurrent nasal polyps [151]. Both allergic and nonallergic patients were included. The use of intranasal corticosteroids was not mentioned, except to state that the study group had "tried topical steroids unsuccessfully." Inhaled corticosteroids for asthma were allowed up to 800 mcg per day. In this study, treatment with cetirizine had no effect on the number or size of nasal polyps or total nasal symptom scores. However, individual symptoms of rhinorrhea, sneezing, and nasal obstruction were improved on cetirizine treatment. Since there are no studies combining treatment with intranasal corticosteroids plus antihistamines (oral or intranasal), it is unclear whether antihistamines provide any additional benefit in patients already receiving intranasal corticosteroids. However, if persistent nasal symptoms are present despite use of intranasal corticosteroids, antihistamines may be worth trying.

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Topical antifungal agents – Evidence for a beneficial effect of topical antifungal agents is mostly lacking, and this treatment is not recommended in recent consensus documents [51,98]. In one author's experience (DLH) topical antifungal therapy (ie, either amphotericin B or itraconazole) has been beneficial in a subset of patients with CRS with or without NP. The author reserves this therapy specifically for patients who have failed a trial of intranasal corticosteroid irrigations and have persistent mucosal thickening and mucus production, with no evidence of bacterial infection.

INDICATIONS FOR SINUS SURGERY CRS is an inflammatory disorder of the sinonasal mucosa, and underlying structural abnormalities, such as septal deviation, do not occur with higher frequency in patients with CRS compared with controls [152]. Thus, surgery should not be the first intervention in most cases, with the possible exception of allergic fungal rhinosinusitis (AFRS) and for complications related to CRS. (See "Allergic fungal rhinosinusitis".) Functional endoscopic sinus surgery, known by the acronym FESS, is intended to restore physiologic sinus ventilation and drainage, which can facilitate the gradual resolution of mucosal disease. However, because FESS does not directly treat the underlying inflammatory disorder, sinus surgery must be followed by medical management to control inflammatory processes or symptoms will invariably return [153]. This is particularly true for surgical polypectomy. Polyps usually reaccumulate within a few years without medical maintenance therapy [153,154]. https://www.uptodate.com/contents/7534/print

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Indications for surgical intervention include the following: ●

Failure of medical treatment

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Restoration of sinus ventilation (ie, restoration of sinus ostial patency and removal of material from opacified sinuses)

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Improve penetration of topical medical therapies

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Debulking of severe polyposis (see 'Options for refractory disease' above)

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Bony erosion or extension of disease beyond the sinus cavities

In patients with both asthma and CRS, there is some evidence that medical management results in better long-term outcomes [7,155]. General effectiveness — A 2006 systematic review of FESS for CRS concluded that it was safe, although the procedures encompassed by that term did not clearly confer additional benefit over medical management [156]. However, this was based upon just three randomized trials. A 2017 systematic review and meta-analysis was designed to compare surgery with continued medical treatment in patients who have already received some medical therapy, defined in the review as at least three weeks of antibiotics, with or without topical and/or oral corticosteroids [157]. This analysis included five studies (no randomized trials) and patients self-selected to surgery or continued medical therapy. The authors concluded that among patients who are refractory to medical therapy, those with lower quality of life scores tended to choose surgery, while those with higher scores chose continued medical management. Those who underwent surgery attained relatively greater benefit from it during the ensuing year, compared to those who continued medical therapy. Another study prospectively followed a cohort of 59 adults (from a potential pool of 227) who had elected FESS for CRS, in order to assess whether improvements achieved as a result of surgery were durable [158]. The type of surgery performed and subsequent medical therapy was determined by the responsible surgeon. Approximately one-half of the cohort had nasal polyposis (NP) and data was collected through several validated survey tools. Mean follow-up was 10.9 years. Measures of quality of life and health utilization improved immediately and remained improved for most patients, although 17 percent required one or more revision surgeries, mostly due to recurrent NP. However, without the corresponding data on the remaining patients, it is difficult to draw firm conclusions about long-term outcomes overall [159,160]. Sinus ostial dilation (balloon ostial dilation) — Balloon ostial dilation (BOD) is a procedure in which the frontal, sphenoid, or maxillary sinus ostium is dilated using a balloon catheter. This procedure also goes by other names, including "balloon catheter sinusotomy," but "balloon https://www.uptodate.com/contents/7534/print

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ostial dilation" is the recommended terminology of the American Academy of OtolaryngologyHead and Neck Surgery [161]. The procedure does not involve surgical removal of tissue and can be performed in the office setting under local anesthesia. High quality data comparing BOD and FESS for the management of CRS are limited and mostly sponsored by manufacturers of the balloon catheters: ●

A 2011 systematic review of BOD for CRS identified only one study of 34 patients that met inclusion criteria and concluded that there was no convincing evidence supporting the use of this technique, compared with conventional surgical modalities, in the management of CRS refractory to medical treatment [162].

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Observational case series reported high success rates of BOD (85 percent or greater) with low rates of revision treatment (less than 10 percent of patients) in patients followed for 6 months [163] or 24 months [164].

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In a subsequent randomized, open-label, industry-sponsored trial, 92 subjects with uncomplicated CRS of the maxillary sinuses, with or without anterior ethmoid disease, were randomized to in-office BOD or FESS [165]. Patients with gross polyposis, AFRS, aspirin-exacerbated respiratory disease (AERD), previous surgery, or other complicating conditions were excluded. Primary endpoints were mean improvement in Sino-Nasal Outcome Test (SNOT-20) score at six months and need for postoperative debridement procedures. Both groups experienced significant clinical improvement and similar degrees of improvement in SNOT-20 scores (–1.67 and –1.6 points in the BOD and FESS groups, respectively, with –0.8 defined as a clinically meaningful improvement). Those treated with BOD required fewer postoperative debridement procedures to remove clots, scabs, crusts, and synechiae than those undergoing FESS, and the difference in number of debridement procedures was statistically significant. Thus, BOD was noninferior to FESS in this selected population without complicating disorders. Benefits were sustained at one year [166].

Although these reports are encouraging, the final decision regarding whether to perform BOD or FESS is considered the responsibility of the attending surgeon and must take into consideration the suitability of the case for BOD alone. Current technology does not allow the dilation of the ethmoid sinuses, where much of the more significant sinus disease is often located. "Hybrid" procedures involving BOD plus endoscopic sinus surgery have also been reported by some groups [164]. Alternatively, extensions of typical FESS may also be beneficial for extensive disease and include maxillary mega-antrostomy and frontal sinus drillouts which increase the maximal openings to the sinuses.

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A 2018 consensus statement report agreed on the following clinical conditions in which sinus ostial dilatation (SOD) may be beneficial [167]: ●

SOD can be appropriate as an adjunct procedure to FESS in patients with chronic sinusitis without nasal polyps

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There can be a role for SOD in patients with persistent sinus disease who have had previous sinus surgery

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There is a role for SOD in managing patients with recurrent acute sinusitis, as defined in the American Academy of Otolaryngology - Head and Neck Surgery (AAO HNSF) guideline, based on symptoms and the computed tomography (CT) evidence of ostial occlusion and mucosal thickening [168]

Studies of surgery in children — Both adenoidectomy and FESS have been performed in children with CRS, although neither has been formally studied, and the efficacy is not well defined. In most cases, surgery should be considered only after medical therapy has failed. Thus, decisions regarding surgery should be individualized according to the potential benefits and risks and the values and preferences of the family and child. ●

Adenoidectomy – In young children with CRS and adenoidal hypertrophy, adenoidectomy is often suggested before other interventions. Enlarged adenoids are proposed to prevent normal mucociliary clearance, act as a reservoir for bacteria, and serve as a platform for biofilm formation [169,170]. However, high level evidence addressing the efficacy of adenoid surgery in children with CRS is lacking. The available literature regarding adenoidectomy in children with CRS is reviewed separately. (See "Tonsillectomy and/or adenoidectomy in children: Indications and contraindications", section on 'Chronic sinusitis'.)

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FESS – A 2013 systematic review of the literature evaluating FESS for the treatment of CRS in children included 11 studies, with three prospective studies and no randomized, controlled trials [171]. Most studies reported subjective measures of improvement and serious complications were rare, but the overall quality of the evidence was low.

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Balloon catheter sinuplasty – Balloon catheter sinuplasty (BCS) has been reported in prospective cohorts of children with or without ethmoidectomy or adenoidectomy [172,173]. Although BCS can be used to restore patency to the maxillary, sphenoid, or frontal sinuses, studies in children have focused on restoring patency to the maxillary sinus. The procedure appears to be safe and to result in significant improvement in symptoms beyond that afforded by adenoidectomy alone but comparable in magnitude

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with that previously published from adenoidectomy plus maxillary lavage [174]. One study compared BCS with ethmoidectomy to FESS and reported similar overall results in both groups but less postoperative use of antibiotics in the BCS with the ethmoidectomy group [173]. Medical adjuncts to sinus surgery — Several medical treatments have been developed as adjuncts to sinus surgery. Glucocorticoid-eluting sinus implants — Mometasone-eluting sinus implants are approved by the US Food and Drug Administration to maintain the patency of the ethmoid or frontal sinus openings following endoscopic surgery [175,176]. The approved implants deliver 370 mcg of mometasone furoate from a biodegradable, bioabsorbable polymer matrix over 30 days. Several published studies and a meta-analysis have examined the utility of these devices [177181]. The meta-analysis included two randomized trials with a total of 143 patients and found that drug-eluting implants, compared with nondrug implants, significantly reduced postoperative interventions, lysis of adhesions, and the need for oral corticosteroids by 35, 51, and 40 percent, respectively [180]. Another study demonstrated that the implants could be inserted in-office into the ethmoid cavity for treatment of recurrent polyposis following endoscopic sinus surgery with resultant reduction in NP size, ethmoid sinus obstruction, and improvement in nasal obstruction symptom scores achieved for six months [182]. Glucocorticoid-impregnated nasal dressing — Another method of delivery of intranasal corticosteroid therapy is corticosteroid-impregnated dressing, although evidence in support of this approach is less robust. In a retrospective, case control study, 21 subjects with recurrent polypoid changes following surgery underwent placement of triamcinolone-impregnated (total dose 20 mg) absorbable nasal dressings in the middle meatus [183]. Patients with frank polyposis were not included. Compared with a control group of patients treated with oral methylprednisolone (24 mg initially, gradually reduced over six days and discontinued), improvements were similar at four and eight weeks. This approach represents another method of delivery of intranasal corticosteroid therapy, which should achieve high local concentrations while minimizing systemic exposure. The assistance of an otolaryngologist is required, and this technique should be studied further to better define optimal dose, duration of benefit, and patient selection. In a separate study using 20 mg per side of triamcinolone-impregnated dressings (equivalent to a daily dose of 17 mg prednisolone orally), serum cortisol was suppressed at day 2 after placement but had normalized by day 10 [184].

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Exacerbations of CRS may be precipitated by the following: ●

Discontinuation or reduction of medications

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Acute viral upper respiratory tract infections

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Heavy exposure to allergens

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Exposure to noxious inhalants

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Worsening of inflammation secondary to bacterial infection or (perhaps) fungal colonization

A bacterial infection should be suspected if the patient has increased symptoms persisting greater than 7 to 10 days, purulent nasal discharge, and/or increased facial pain or pressure. However, the frequency of bacterial infection during acute exacerbations of CRS remains unknown and largely unstudied. The situation is even more complex in patients who have had S. aureus, gram-negative rod, or drug-resistant bacterial infections in the past. In patients suspected of having uncomplicated bacterial infection, acute exacerbations of CRS are treated similarly to episodes of acute bacterial rhinosinusitis with a 10- to 14-day course of antibiotics. Repeated use of the same agent should be avoided, as there is risk of promoting a drug-resistant bacterial infection and perhaps greater fungal colonization. A culture from the sinus ostium should be obtained if an infection with S. aureus, gram-negative rods, or drugresistant bacteria is suspected. (See "Microbiology and antibiotic management of chronic rhinosinusitis".)

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic rhinosinusitis".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. https://www.uptodate.com/contents/7534/print

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Nasal polyps (The Basics)" and "Patient education: Chronic sinusitis (The Basics)" and "Patient education: Rinsing out your nose with salt water (The Basics)")

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Beyond the Basics topic (see "Patient education: Chronic rhinosinusitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

Definition – Chronic rhinosinusitis (CRS) is an inflammatory condition of the paranasal sinuses and linings of the nasal passages that lasts 12 weeks or longer. In most cases, the disorder cannot be cured, and the goal of therapy is to reduce symptoms and improve quality of life. (See 'Goals of therapy' above.)

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General approach for different types of CRS – Multiple therapies are utilized in the management of CRS, including intranasal saline, intranasal and oral corticosteroids, antibiotics, antileukotriene agents, biologics, and endoscopic sinus surgery. These are combined in various ways to manage specific subtypes of CRS. (See 'Overview of medical therapies' above.)

CRS without nasal polyposis ●

Initial therapies – For patients with CRS without nasal polyposis (NP), we suggest initial treatment with one to three months of a combination of intranasal saline (sprays or irrigations) and intranasal corticosteroids (Grade 2C). (See 'Initial therapy' above and 'Overview of medical therapies' above.)

●

Further interventions – For patients who do not achieve adequate relief with intranasal saline and corticosteroids, next steps depend upon available evaluation. If endoscopy can be performed to obtain material from the sinuses directly, we culture this to determine if infection is present and treat accordingly. If endoscopy is not available, we suggest an empiric course of oral corticosteroids plus oral antibiotics (Grade 2C). A representative regimen for adults is prednisone, 40 mg daily for five days, followed by 20 mg daily for five days plus two to four weeks of an antibiotic. An alternative approach is to initiate treatment with long-term, low-dose macrolide antibiotics (see 'Persistent symptoms'

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above and 'Oral corticosteroids' above). Empiric antibiotic selection is discussed separately. (See "Microbiology and antibiotic management of chronic rhinosinusitis", section on 'Empiric regimen selection'.) ●

Endoscopic sinus surgery – In patients in whom these medical treatments do not result in sufficient improvement in symptoms, we proceed to endoscopic sinus surgery. (See 'Endoscopic sinus surgery' above.)  

●

Maintenance therapy – Any successful intervention for CRS without NP must be followed by maintenance therapy, because without ongoing treatment, symptoms will eventually return in most patients. For maintenance therapy, we suggest intranasal corticosteroid nasal sprays and intranasal saline (Grade 2B). For patients with persistent or increasing symptoms despite consistent use of corticosteroid sprays, we suggest changing to corticosteroid instillations (

●

figure 1) (Grade 2C). (See 'Maintenance treatment' above.)

Treatment of underlying allergic rhinitis – Patients with underlying allergic rhinitis who have sneezing or nasal pruritus may benefit from additional therapies targeting that condition, including minimally sedating second-generation oral antihistamines, intranasal antihistamine sprays or antileukotriene agents (eg, montelukast), and/or allergen immunotherapy. (See "Pharmacotherapy of allergic rhinitis".)

●

Reasons for treatment failure – Potential explanations for refractory or recurrent symptoms include persistent sinus ostial obstruction, odontogenic sinusitis, problems with mucociliary clearance, incompletely treated sinus infection, underlying immunodeficiency, or mucous recirculation syndrome. (See 'Treatment failure' above.)

CRS with nasal polyposis ●

Initial therapies – For patients with CRS with NP, we suggest initial treatment with one to three months of a combination of intranasal saline (sprays or irrigations) and intranasal corticosteroids (Grade 2C). Patients with severe polyposis may not be able to use intranasal medications because the nasal passages are blocked. (See 'Initial therapy' above.)  

●

Short-term relief of severe congestion – For patients with CRS with NP who are seeking relief of nasal blockage or an impaired sense of smell, we recommend a course of oral corticosteroids initially to shrink nasal polyps (Grade 1B). A typical adult regimen is prednisone 40 mg for five days, followed by 20 mg daily for five days. Antibiotics are not recommended unless a concomitant infection is suspected. The benefit of oral

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corticosteroids is temporary, and this intervention must be followed by maintenance therapy. (See 'Oral corticosteroids' above.) ●

Endoscopic surgery or biologic agents – For patients in whom intranasal and oral corticosteroids fail to reduce polyp tissue sufficiently and the patient has persistent blockage or anosmia, we suggest either sinus surgery or therapy with a biologic agent (Grade 2B). The choice of approach depends upon availability, cost, and patient preference. Available biologics include dupilumab, omalizumab, and mepolizumab. (See 'Options for refractory disease' above.)

●

Maintenance therapy – Following reduction of polyps by oral corticosteroids or sinus surgery, maintenance therapy is necessary to help prevent regrowth of polyps. For patients who have relatively mild residual symptoms (eg, nasal patency and an intact sense of smell), we suggest intranasal corticosteroids (Grade 2B). Dilute corticosteroid sinus rinses are another treatment option. We advise patients to try these approaches initially, but if symptoms worsen despite consistent use, we change this to the concentrated corticosteroid instillations (

figure 1). (See 'Intranasal corticosteroids'

above and 'Maintenance therapies' above.) ●

Patients with AERD – Some patients with CRS with NP also have asthma and intolerance to aspirin (or other nonsteroidal anti-inflammatory drugs [NSAIDs]), a condition called aspirin-exacerbated respiratory disease (AERD). Options for these patients include aspirin desensitization and daily aspirin therapy, or dupilumab. Aspirin desensitization is a treatment option for these patients, but it requires access to an allergy specialist with experience in drug desensitizations and is often performed shortly after surgery to remove polyps. (See 'Aspirin desensitization and therapy' above and "Aspirin-exacerbated respiratory disease".) Use of UpToDate is subject to the Terms of Use.

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120. Treister AD, Kraff-Cooper C, Lio PA. Risk Factors for Dupilumab-Associated Conjunctivitis in Patients With Atopic Dermatitis. JAMA Dermatol 2018; 154:1208. 121. Verbruggen K, Van Cauwenberge P, Bachert C. Anti-IgE for the treatment of allergic rhinitis-and eventually nasal polyps? Int Arch Allergy Immunol 2009; 148:87. 122. Gevaert P, Omachi TA, Corren J, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol 2020; 146:595. 123. Le PT, Soler ZM, Jones R, et al. Systematic Review and Meta-analysis of SNOT-22 Outcomes after Surgery for Chronic Rhinosinusitis with Nasal Polyposis. Otolaryngol Head Neck Surg 2018; 159:414. 124. Gevaert P, Calus L, Van Zele T, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol 2013; 131:110. 125. US FDA approval letter: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2020/1 03976Orig1s5235ltr.pdf (Accessed on October 01, 2020). 126. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/761122Orig1s006;%2012 5526Orig1s018ltr.pdf (Accessed on July 30, 2021). 127. Han JK, Bachert C, Fokkens W, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med 2021; 9:1141. 128. Tsurumaki H, Matsuyama T, Ezawa K, et al. Rapid Effect of Benralizumab for Hypereosinophilia in a Case of Severe Asthma with Eosinophilic Chronic Rhinosinusitis. Medicina (Kaunas) 2019; 55. 129. Bachert C, Han JK, Desrosiers MY, et al. Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial. J Allergy Clin Immunol 2022; 149:1309. 130. Weinstein SF, Katial RK, Bardin P, et al. Effects of Reslizumab on Asthma Outcomes in a Subgroup of Eosinophilic Asthma Patients with Self-Reported Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol Pract 2019; 7:589. 131. Lumry WR, Curd JG, Zeiger RS, et al. Aspirin-sensitive rhinosinusitis: the clinical syndrome and effects of aspirin administration. J Allergy Clin Immunol 1983; 71:580. 132. Schapowal AG, Simon HU, Schmitz-Schumann M. Phenomenology, pathogenesis, diagnosis and treatment of aspirin-sensitive rhinosinusitis. Acta Otorhinolaryngol Belg 1995; 49:235. 133. Gosepath J, Schaefer D, Amedee RG, Mann WJ. Individual monitoring of aspirin desensitization. Arch Otolaryngol Head Neck Surg 2001; 127:316.

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134. Rozsasi A, Polzehl D, Deutschle T, et al. Long-term treatment with aspirin desensitization: a prospective clinical trial comparing 100 and 300 mg aspirin daily. Allergy 2008; 63:1228. 135. Świerczyńska-Krępa M, Sanak M, Bochenek G, et al. Aspirin desensitization in patients with aspirin-induced and aspirin-tolerant asthma: a double-blind study. J Allergy Clin Immunol 2014; 134:883. 136. Lee JY, Simon RA, Stevenson DD. Selection of aspirin dosages for aspirin desensitization treatment in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol 2007; 119:157. 137. Ogata N, Darby Y, Scadding G. Intranasal lysine-aspirin administration decreases polyp volume in patients with aspirin-intolerant asthma. J Laryngol Otol 2007; 121:1156. 138. Meltzer EO, Hamilos DL. Rhinosinusitis diagnosis and management for the clinician: a synopsis of recent consensus guidelines. Mayo Clin Proc 2011; 86:427. 139. Bachert C, Watelet JB, Gevaert P, Van Cauwenberge P. Pharmacological management of nasal polyposis. Drugs 2005; 65:1537. 140. Small CB, Hernandez J, Reyes A, et al. Efficacy and safety of mometasone furoate nasal spray in nasal polyposis. J Allergy Clin Immunol 2005; 116:1275. 141. Stjärne P, Olsson P, Alenius M. Use of mometasone furoate to prevent polyp relapse after endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg 2009; 135:296. 142. Dijkstra MD, Ebbens FA, Poublon RM, Fokkens WJ. Fluticasone propionate aqueous nasal spray does not influence the recurrence rate of chronic rhinosinusitis and nasal polyps 1 year after functional endoscopic sinus surgery. Clin Exp Allergy 2004; 34:1395. 143. Pauli C, Fintelmann R, Klemens C, et al. [Polyposis nasi--improvement in quality of life by the influence of leukotrien receptor antagonists]. Laryngorhinootologie 2007; 86:282. 144. Ragab S, Parikh A, Darby YC, Scadding GK. An open audit of montelukast, a leukotriene receptor antagonist, in nasal polyposis associated with asthma. Clin Exp Allergy 2001; 31:1385. 145. Stewart RA, Ram B, Hamilton G, et al. Montelukast as an adjunct to oral and inhaled steroid therapy in chronic nasal polyposis. Otolaryngol Head Neck Surg 2008; 139:682. 146. Schäper C, Noga O, Koch B, et al. Anti-inflammatory properties of montelukast, a leukotriene receptor antagonist in patients with asthma and nasal polyposis. J Investig Allergol Clin Immunol 2011; 21:51. 147. Wentzel JL, Soler ZM, DeYoung K, et al. Leukotriene antagonists in nasal polyposis: a metaanalysis and systematic review. Am J Rhinol Allergy 2013; 27:482.

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148. Kieff DA, Busaba NY. Efficacy of montelukast in the treatment of nasal polyposis. Ann Otol Rhinol Laryngol 2005; 114:941. 149. Mostafa BE, Abdel Hay H, Mohammed HE, Yamani M. Role of leukotriene inhibitors in the postoperative management of nasal polyps. ORL J Otorhinolaryngol Relat Spec 2005; 67:148. 150. Micheletto C, Tognella S, Visconti M, et al. Montelukast 10 mg improves nasal function and nasal response to aspirin in ASA-sensitive asthmatics: a controlled study vs placebo. Allergy 2004; 59:289. 151. Haye R, Aanesen JP, Burtin B, et al. The effect of cetirizine on symptoms and signs of nasal polyposis. J Laryngol Otol 1998; 112:1042. 152. Bassichis BA, Marple BF, Mabry RL, et al. Use of immunotherapy in previously treated patients with allergic fungal sinusitis. Otolaryngol Head Neck Surg 2001; 125:487. 153. Gosepath J, Pogodsky T, Mann WJ. Characteristics of recurrent chronic rhinosinusitis after previous surgical therapy. Acta Otolaryngol 2008; 128:778. 154. Li Y, Zhang GH, Liu X, et al. Clinical prognostic factors of chronic rhinosinusitis after endoscopic sinus surgery. ORL J Otorhinolaryngol Relat Spec 2008; 70:113. 155. Senior BA, Kennedy DW, Tanabodee J, et al. Long-term impact of functional endoscopic sinus surgery on asthma. Otolaryngol Head Neck Surg 1999; 121:66. 156. Khalil HS, Nunez DA. Functional endoscopic sinus surgery for chronic rhinosinusitis. Cochrane Database Syst Rev 2006; :CD004458. 157. Patel ZM, Thamboo A, Rudmik L, et al. Surgical therapy vs continued medical therapy for medically refractory chronic rhinosinusitis: a systematic review and meta-analysis. Int Forum Allergy Rhinol 2017; 7:119. 158. Smith TL, Schlosser RJ, Mace JC, et al. Long-term outcomes of endoscopic sinus surgery in the management of adult chronic rhinosinusitis. Int Forum Allergy Rhinol 2019; 9:831. 159. Senior BA, Kennedy DW, Tanabodee J, et al. Long-term results of functional endoscopic sinus surgery. Laryngoscope 1998; 108:151. 160. Smith KA, Orlandi RR, Oakley G, et al. Long-term revision rates for endoscopic sinus surgery. Int Forum Allergy Rhinol 2019; 9:402. 161. The American Academy of Otolaryngology-Head and Neck Surgery website. http://www.ent net.org/Practice/Balloon-Dilation.cfm (Accessed on November 07, 2013). 162. Ahmed J, Pal S, Hopkins C, Jayaraj S. Functional endoscopic balloon dilation of sinus ostia for chronic rhinosinusitis. Cochrane Database Syst Rev 2011; :CD008515. https://www.uptodate.com/contents/7534/print

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163. Stankiewicz J, Tami T, Truitt T, et al. Transantral, endoscopically guided balloon dilatation of the ostiomeatal complex for chronic rhinosinusitis under local anesthesia. Am J Rhinol Allergy 2009; 23:321. 164. Weiss RL, Church CA, Kuhn FA, et al. Long-term outcome analysis of balloon catheter sinusotomy: two-year follow-up. Otolaryngol Head Neck Surg 2008; 139:S38. 165. Cutler J, Bikhazi N, Light J, et al. Standalone balloon dilation versus sinus surgery for chronic rhinosinusitis: a prospective, multicenter, randomized, controlled trial. Am J Rhinol Allergy 2013; 27:416. 166. Bikhazi N, Light J, Truitt T, et al. Standalone balloon dilation versus sinus surgery for chronic rhinosinusitis: a prospective, multicenter, randomized, controlled trial with 1-year followup. Am J Rhinol Allergy 2014; 28:323. 167. Piccirillo JF, Payne SC, Rosenfeld RM, et al. Clinical Consensus Statement: Balloon Dilation of the Sinuses. Otolaryngol Head Neck Surg 2018; 158:203. 168. Bhattacharyya N. Surgical treatment of chronic recurrent rhinosinusitis: a preliminary report. Laryngoscope 2006; 116:1805. 169. Coticchia J, Zuliani G, Coleman C, et al. Biofilm surface area in the pediatric nasopharynx: Chronic rhinosinusitis vs obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2007; 133:110. 170. Brietzke SE, Brigger MT. Adenoidectomy outcomes in pediatric rhinosinusitis: a metaanalysis. Int J Pediatr Otorhinolaryngol 2008; 72:1541. 171. Makary CA, Ramadan HH. The role of sinus surgery in children. Laryngoscope 2013; 123:1348. 172. Ramadan HH, McLaughlin K, Josephson G, et al. Balloon catheter sinuplasty in young children. Am J Rhinol Allergy 2010; 24:e54. 173. Thottam PJ, Haupert M, Saraiya S, et al. Functional endoscopic sinus surgery (FESS) alone versus balloon catheter sinuplasty (BCS) and ethmoidectomy: a comparative outcome analysis in pediatric chronic rhinosinusitis. Int J Pediatr Otorhinolaryngol 2012; 76:1355. 174. Sedaghat AR, Cunningham MJ. Does balloon catheter sinuplasty have a role in the surgical management of pediatric sinus disease? Laryngoscope 2011; 121:2053. 175. US FDA approval of Propel https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100044A.pdf (Accessed on May 08, 2017). 176. US FDA approval of Propel mini https://www.accessdata.fda.gov/cdrh_docs/pdf10/p100044 s018a.pdf (Accessed on May 08, 2017).

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177. Murr AH, Smith TL, Hwang PH, et al. Safety and efficacy of a novel bioabsorbable, steroideluting sinus stent. Int Forum Allergy Rhinol 2011; 1:23. 178. Forwith KD, Chandra RK, Yun PT, et al. ADVANCE: a multisite trial of bioabsorbable steroideluting sinus implants. Laryngoscope 2011; 121:2473. 179. Marple BF, Smith TL, Han JK, et al. Advance II: a prospective, randomized study assessing safety and efficacy of bioabsorbable steroid-releasing sinus implants. Otolaryngol Head Neck Surg 2012; 146:1004. 180. Han JK, Marple BF, Smith TL, et al. Effect of steroid-releasing sinus implants on postoperative medical and surgical interventions: an efficacy meta-analysis. Int Forum Allergy Rhinol 2012; 2:271. 181. Smith TL, Singh A, Luong A, et al. Randomized controlled trial of a bioabsorbable steroidreleasing implant in the frontal sinus opening. Laryngoscope 2016; 126:2659. 182. Forwith KD, Han JK, Stolovitzky JP, et al. RESOLVE: bioabsorbable steroid-eluting sinus implants for in-office treatment of recurrent sinonasal polyposis after sinus surgery: 6month outcomes from a randomized, controlled, blinded study. Int Forum Allergy Rhinol 2016; 6:573. 183. More Y, Willen S, Catalano P. Management of early nasal polyposis using a steroidimpregnated nasal dressing. Int Forum Allergy Rhinol 2011; 1:401. 184. Hong SD, Kim JH, Dhong HJ, et al. Systemic effects and safety of triamcinoloneimpregnated nasal packing after endoscopic sinus surgery: a randomized, double-blinded, placebo-controlled study. Am J Rhinol Allergy 2013; 27:407. Topic 7534 Version 34.0

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GRAPHICS

How to perform nasal irrigation Buffered normal saline nasal irrigation The benefits 1. Saline (saltwater) washes the mucus and irritants from your nose. 2. The sinus passages are moisturized. 3. Studies have also shown that a nasal irrigation improves cell function (the cells that move the mucus work better).

The recipe Use a one-quart glass jar that is thoroughly cleansed. You may use a large medical syringe (30 cc), water pick with an irrigation tip (preferred method), squeeze bottle, or Neti pot. Do not use a baby bulb syringe. The syringe or pick should be sterilized frequently or replaced every 2 to 3 weeks to avoid contamination and infection. Fill with water that has been distilled, previously boiled, or otherwise sterilized. Plain tap water is not recommended, because it is not necessarily sterile. Add 1 to 1½ heaping teaspoons of pickling/canning salt. Do not use table salt, because it contains a large number of additives. Add 1 teaspoon of baking soda (pure bicarbonate). Mix ingredients together and store at room temperature. Discard after 1 week. You may also make up a solution from premixed packets that are commercially prepared specifically for nasal irrigation.

The instructions Irrigate your nose with saline 1 to 2 times per day. If you have been told to use nasal medication, you should always use your saline solution first. The nasal medication is much more effective when sprayed onto clean nasal membranes, and the spray will reach deeper into the nose. Pour the amount of fluid you plan to use into a clean bowl. Do not put your used syringe back into the storage container, because it contaminates your solution. You may warm the solution slightly in the microwave, but be sure that the solution is not hot. Bend over the sink (some people do this in the shower), and squirt the solution into each side of your nose, aiming the stream toward the back of your head, not the top of your head. The solution should flow into one nostril and out of the other, but it will not harm you if you swallow a little. https://www.uptodate.com/contents/7534/print

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Some people experience a little burning sensation the first few times that they use buffered saline solution, but this usually goes away after they adapt to it. Adapted with permission from: Diseases of the Sinuses: Diagnosis and Management. Kennedy DW, Bolger WE, Zinreich SJ (Eds), BC Decker, Hamilton, Ontario 2001. Copyright © Kennedy DW, Zinreich SJ.

Graphic 71059 Version 16.0

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Glucocorticoid nasal sprays for treatment of rhinitis

Common Name

brand name(s) and strength

Generic available

Available

Usual

without a prescription (OTC)

adult dose per nostril

Lower age limit when used in children (years)*

U ped dos no

Second-generation (systemic bioavailability 20,000 cells/microL, mostly neutrophils) but negative synovial fluid cultures, a presumptive diagnosis of septic arthritis may be made. (See 'Interpreting synovial fluid test results' below and 'Differential diagnosis' below.) In addition, blood cultures (two sets) and, when indicated, radiographs, ultrasound, or imaging studies of the involved joint should be obtained. In the setting of septic arthritis due to organisms that commonly cause endocarditis (such as S. aureus, streptococci, or enterococci) with no clear predisposing cause, evaluation for endocarditis should be pursued. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".) Obtaining clinical specimens — Collection of synovial fluid and blood cultures should be performed prior to administration of antibiotics. If synovial fluid cannot be obtained with closed needle aspiration, the joint should be aspirated under radiographic guidance. Certain joints (such as the hip or sacroiliac joint) may require surgical arthrotomy, which may be accompanied by irrigation and drainage. The only definitive way to diagnose a septic joint is via synovial fluid culture. Synovial fluid should be sent for Gram stain, bacterial culture, white blood cell count with differential, and assessment for crystals (monosodium urate and calcium pyrophosphate crystal deposition crystals) with a polarizing microscope. Synovial fluid may be sent for culture in a sterile tube (ideally with an anticoagulant such as ethylenediaminetetraacetic acid [EDTA] to guard against clotting) and/or in blood culture bottles (aerobic and anaerobic) [37-40]. If blood culture bottles are used, synovial fluid also should also be sent in a sterile container to allow Gram stain microscopy. Use of blood culture bottles may increase the likelihood of recovering nonpathogenic skin contaminants; in such cases, culture results should be interpreted in the context of the Gram stain result. The use of blood culture bottles has no significant advantage when common causes of septic arthritis such as S. aureus is https://www.uptodate.com/contents/7666/print

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suspected [41] but may have advantages in detecting unusual organisms such as Kingella and Brucella [42]. Kingella kingae occurs more commonly in children than adults. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children".) Nucleic acid amplification tests such as polymerase chain reaction and other advanced diagnostic methods such as MALDI-TOF mass spectometry may be useful when routine cultures are negative and the suspicion for infection remains high; in infections due to N. gonorrhoeae cases (see "Disseminated gonococcal infection"); or cases in which prior treatment with antibiotics is suspected as having led to a spuriously negative routine culture. When positive, such test results need to be interpreted carefully and correlated with Gram stains and clinical and epidemiologic findings, because extremely small amounts of contaminating bacterial material can lead to a false-positive result [43]. Measurement of procalcitonin levels (in the serum and/or synovial fluid) has been proposed as tools for diagnosis of septic arthritis, particularly when synovial fluid is difficult to obtain or in patients with coexisting inflammatory arthritis. The sensitivity of serum procalcitonin level is relatively low (pooled sensitivity in 10 studies 0.54 [95% CI 0.41-0.66]), as is the negative likelihood ratio (0.49 [95% CI 0.38-0.62]); thus, such a test cannot be used to rule out septic arthritis. The specificity of serum procalcitonin is higher (pooled sensitivity in one meta-analysis 0.95 [95% CI 0.87-0.96]); thus a positive test may be useful occasionally in deciding if a difficult-to-access joint such as the hip or sacroiliac joint should be aspirated [44,45]. There are limited data to suggest that synovial fluid procalcitonin levels may be more predictive of septic arthritis than blood levels [46]; however, such testing is not needed if a culture is obtained at the time of joint aspiration. Other synovial fluid assays (such as synovial fluid lactate, glucose, C-reactive protein, polymerase chain reaction, or immunoassays) are not useful for diagnosis of septic arthritis [4749]. Synovial biopsy is rarely necessary, but may be indicated if there is evidence of concurrent contiguous osteomyelitis, in rare cases in which joint aspiration fails to provide a satisfactory sample for diagnostic testing, or when infection or coinfection with M. tuberculosis or other slow growing pathogens is a possibility. Interpreting synovial fluid test results — In the setting of septic arthritis, synovial fluid analysis typically demonstrates the following ( ●

table 2 and

algorithm 1) [11]:

Leukocyte count of 50,000 to 150,000 cells/microL (mostly neutrophils) [37]. The likelihood of septic arthritis increases as the synovial fluid leukocyte count increases [4,16]. High

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synovial fluid white blood cell counts can also occur in other conditions, so it is important to interpret the results of synovial fluid testing in the overall clinical context. (See 'Differential diagnosis' below.) ●

Gram stain is positive in some cases; the sensitivity is 30 to 50 percent [3]. False-positive results may reflect precipitated crystal violet and mucin in the synovial fluid, which can mimic the appearance of gram-positive cocci. False-negative results may occur if crystals are present or if clotting occurs [38,50].

●

Synovial fluid culture is positive in the more than 60 percent of patients with nongonococcal bacterial arthritis [51]. Negative synovial fluid cultures may occur in the setting of recent antimicrobial therapy or infection with a fastidious organism. In one retrospective study including 383 patients with suspected septic arthritis (of whom 82 patients received antibiotics prior to the initial synovial fluid analysis), a leukocyte count between 16,000 and 33,000 cells/microL with >90 percent neutrophils was strongly suggestive of septic arthritis [52].

Radiographic imaging — Radiographs of the involved joint should be obtained for evaluation of concurrent bone and joint disease; in addition, baseline radiography is often useful to guide subsequent management decisions. For joints that are difficult to examine (such as the hip or sacroiliac joint), computed tomography or magnetic resonance imaging are useful for detection of effusion. Nuclear imaging is not warranted for suspected septic arthritis. There are insufficient data to support a role for fluorodeoxyglucose-positron emission tomography scans in diagnosis of septic arthritis [53]. (See "Imaging techniques for evaluation of the painful joint".)

DIFFERENTIAL DIAGNOSIS The differential diagnosis of septic arthritis includes infectious as well as noninfectious illnesses (

table 3 and

table 4) [54]. (See "Monoarthritis in adults: Etiology and evaluation".)

Other causes of infection include septic bursitis and alternate infectious causes of arthritis: ●

Septic bursitis – Septic bursitis refers to inflammation of the bursa due to infection; the mechanisms for development of septic bursitis are the same as the mechanisms for development of septic arthritis. The diagnosis of septic bursitis is confirmed by culture of fluid from the affected bursa. (See "Septic bursitis".)

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Gonococcal arthritis – Gonococcal arthritis typically presents acutely in sexually active individuals with fever, chills, skin lesions, polyarthralgias, and tenosynovitis, evolving into a persistent monoarthritis or oligoarthritis. The diagnosis of disseminated gonococcal infection is made by identification of Neisseria gonorrhoeae (either through molecular testing or culture) via nucleic acid amplification testing or culture of a specimen of blood, synovial fluid or tissue, skin lesion, or other nonmucosal site. Culture requires processing on chocolate agar plates, Thayer-Martin medium, or other selective gonococcal medium; the organism cannot be cultured on routine culture media. (See "Disseminated gonococcal infection".)

●

Lyme disease – Lyme disease should be suspected in patients with an acute monoarthritis in the setting of epidemiologic exposure in an endemic area; erythema migrans rash, fever, and migratory arthralgias may occur weeks or months prior. The diagnosis is established via serologic testing. (See "Musculoskeletal manifestations of Lyme disease", section on 'Diagnosis of Lyme arthritis'.)

●

Tuberculous arthritis – Tuberculous arthritis should be suspected in patients with indolent presentation of persistent culture-negative oligoarthritis or monoarthritis, in the setting of relevant epidemiologic exposure. The sensitivity of synovial fluid Ziehl-Neelsen stain for detection of acid-fast bacilli is low; the diagnosis is established via synovial membrane histopathology and culture. (See "Bone and joint tuberculosis", section on 'Arthritis'.)

●

Viral causes of arthritis – Viral causes of arthritis typically present with polyarthritis; they include chikungunya, dengue fever, Zika virus, parvovirus, Ross River virus, Barmah Forest virus, and rubella. A number of other viruses including enterovirus, adenovirus, and alphaviruses may also cause arthritis. (See "Viruses that cause arthritis".)

●

Fungal arthritis – Fungal arthritis should be suspected in patients with indolent presentation of persistent culture-negative oligoarthritis or monoarthritis, in the setting of relevant epidemiologic exposure, penetrating trauma, or immunosuppression. Fungal causes of arthritis include sporotrichosis, coccidioidomycosis, candidiasis, and others [55]. The diagnosis is established via fungal stain and culture of synovial fluid or via synovial membrane histopathology and culture.

Noninfectious causes of arthritis include trauma and inflammatory arthritis: ●

Acute traumatic arthritis – Acute traumatic arthritis usually causes bloody synovial fluid and is generally associated with a history of significant trauma to the joint. (See "Overview of hemarthrosis", section on 'Traumatic'.)

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Crystal-induced arthritis (gout or pseudogout) – Manifestations of crystal-induced arthritis include monoarthritis and leukocytosis. Clues suggestive of gout include involvement of the first metatarsophalangeal joint, prior self-limited attacks of arthritis, and presence of tophi. The diagnosis of crystal-induced arthritis can be established by synovial fluid analysis demonstrating monosodium urate crystals of gout or calcium pyrophosphate dihydrate crystals of pseudogout. Concurrent crystal-induced and septic arthritis can occur [56]. In patients with concurrent gout and septic arthritis, the synovial fluid Gram stain may be negative; thus, cultures should be performed if concurrent infection is suspected [50]. The synovial fluid leukocyte count is often above 50,000/mm3 in gout and calcium pyrophosphate crystal deposition disease; therefore, this finding cannot be used to distinguish from septic arthritis [57]. (See "Clinical manifestations and diagnosis of gout" and "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)

●

Reactive arthritis or spondyloarthritis – Chronic inflammatory joint disease can present with a new swollen joint, simulating septic arthritis; this is especially common in the seronegative spondyloarthropathies such as reactive arthritis. Most patients with reactive arthritis have recent genitourinary or gastrointestinal signs or symptoms, conjunctivitis, or skin or mucus membrane lesions. Occasionally, patients with ankylosing spondylitis present with acute-onset hip arthritis that mimics septic arthritis. (See "Reactive arthritis" and "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)

●

Avascular necrosis – Avascular necrosis refers to damage of the bone vasculature leading to mechanical bone failure; it can occur in the context of a number of conditions. It usually occurs in the anterolateral femoral head, although it may also affect the femoral condyles, humeral heads, proximal tibia, vertebrae, and small bones of the hand and foot. It typically presents with localized pain. The diagnosis is established via radiographic imaging. (See "Clinical manifestations and diagnosis of osteonecrosis (avascular necrosis of bone)".)

●

Rheumatoid arthritis – Rheumatoid arthritis (RA) is typically a symmetric, chronic polyarthritis; however, acute or subacute exacerbation of one or a few joints can occur. The diagnosis may be difficult to establish because the clinical findings may be atypical; many patients with RA and superimposed septic arthritis present indolently (rather than acutely), often with little fever or leukocytosis. Conversely, RA itself may present with a "pseudoseptic arthritis" picture, including an explosive acute synovitis with a marked synovial fluid leukocytosis. The diagnosis of RA is established via clinical criteria

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summarized separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

TREATMENT Management of acute bacterial arthritis consists of joint drainage and antibiotic therapy ( algorithm 2 and

algorithm 3) [58].

Joint drainage — In general, patients with septic arthritis warrant joint drainage, since this condition represents a closed abscess. Approaches to joint drainage for management of septic arthritis in adults include needle aspiration, arthroscopic drainage, or arthrotomy (open surgical drainage). The choice of approach depends on clinical factors including the joint affected and the duration of infection. For septic arthritis of the knee, elbow, ankle, or wrist, the joint may be drained via needle aspiration or arthroscopy. For septic arthritis of the hip, shoulder, or difficult-to-access joint (such as the sternoclavicular joint), the joint should be drained by arthroscopy. In any joint, arthroscopy may facilitate more thorough irrigation [59-62]. In one retrospective series including 72 cases of septic knee arthritis and 25 cases of septic hip arthritis, aspiration and surgical drainage were equally effective; aspiration was associated with a shorter hospital stay (21 versus 33 days) [63]. Surgical drainage is warranted in the following circumstances [10,11,64-66]: ●

Adequate drainage cannot be achieved by needle aspiration or arthroscopy

●

Suspicion for penetrating trauma with a residual foreign body

●

Joint effusion persists after seven days of serial aspiration

Patients with severe infection may require repeated aspirations or arthroscopic irrigations, and in some cases, synovectomy [8]. Serial synovial fluid analyses should be performed; as infection is treated, these findings should demonstrate sterilization of the fluid and decreasing total white blood cell count. Adequacy of drainage may also be assessed clinically (based on improvement in fever curve, white blood cell count, joint swelling, and pain). Antibiotic therapy Initial approach — The initial choice of empiric antimicrobial therapy should cover the most likely pathogens. The approach below is supported by case series [4]; there are no randomized trials. https://www.uptodate.com/contents/7666/print

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If the initial Gram stain of synovial fluid demonstrates gram-positive cocci, empiric treatment with vancomycin (

table 5) should be administered (

algorithm 2) [67].

• Patients with septic arthritis due to methicillin-susceptible S. aureus should be treated with a beta-lactam agent such as cefazolin (2 g intravenously [IV] every eight hours), nafcillin or oxacillin (2 g IV every four hours), or flucloxacillin (2 g IV every six hours). Patients who are allergic to penicillin can be treated with vancomycin.

• Patients with septic arthritis due to methicillin-resistant S. aureus should be treated with vancomycin; if this is not feasible due to allergy or drug intolerance, reasonable alternative agents include daptomycin (6 mg/kg/day IV), linezolid (600 mg orally or IV twice daily), or clindamycin (600 mg orally or IV three times daily) [67]. ●

If the initial Gram stain of synovial fluid demonstrates gram-negative bacilli, treatment should be guided by risk for Pseudomonas infection (

algorithm 2):

• Patients with risk for Pseudomonas infection (eg, immunosuppressed patients and people who inject drugs [PWID]) warrant empiric coverage for Pseudomonas infection.

- For patients who have sepsis or septic shock, have neutropenia and bacteremia, have severe burns, or are in a setting where the incidence of resistance to the chosen antibiotic class is high (eg, >10 to 15 percent), we administer empiric therapy with a combination of two antipseudomonal agents from different antibiotic classes (eg, a beta-lactam with an aminoglycoside or a fluoroquinolone) ( table 6). (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Indications for combination therapy'.)

- For patients without any of these additional risk factors for mortality or resistant organisms, we administer empiric treatment with a single antipseudomonal agent (eg, ceftazidime 2 g IV every eight hours or cefepime 2 g IV every 8 to 12 hours).

• Patients with no risk factors for Pseudomonas infection warrant treatment with a thirdgeneration cephalosporin (eg, ceftriaxone 2 g IV once daily or cefotaxime 2 g IV every eight hours). Empiric antimicrobial therapy should be tailored to antimicrobial susceptibility data when available. ●

If the initial Gram stain of synovial fluid is negative but synovial fluid cell count is consistent with septic arthritis, the approach depends on individual clinical circumstances ( algorithm 3) [30]:

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• For immunocompetent patients without confounding factors (such as trauma), we suggest treatment with vancomycin.

• For patients with traumatic bacterial arthritis, we suggest treatment with vancomycin plus a third-generation cephalosporin (ceftriaxone or cefotaxime).

• For immunocompromised patients and PWID, we suggest treatment with vancomycin plus a cephalosporin with activity against Pseudomonas (ceftazidime or cefepime). For patients with septic arthritis associated with an animal bite, the approach to antibiotic selection is discussed separately. (See "Animal bites (dogs, cats, and other animals): Evaluation and management", section on 'Spectrum of therapy'.) The initial antibiotic regimen should be tailored to culture and susceptibility results when available. As an example, vancomycin should be discontinued in patients with staphylococcal or streptococcal infections that are susceptible to beta-lactam therapy. In some circumstances, parenteral therapy may be switched to oral therapy following debridement and finalization of microbiology data [68]. Considerations include pathogen susceptibility to an oral antimicrobial agent with good bioavailability and substantial barrier to use of outpatient parenteral therapy. We do not use oral therapy for treatment of septic arthritis in the context of S. aureus bacteremia, poor compliance, or gastrointestinal conditions that could interfere with absorption [69]. There is no role for intra-articular antibiotics, since systemic antibiotic therapy produces adequate drug levels in joint fluid. Furthermore, direct instillation of antibiotics into a joint may induce an inflammatory response and carries a risk of iatrogenic complications such as secondary infection [11]. Duration — The optimal duration of antimicrobial therapy for treatment of septic arthritis is uncertain. The approach below is supported by case series [4]. For patients with septic arthritis due to S. aureus in the setting of concomitant bacteremia (but no evidence of endocarditis), we administer parenteral therapy for four weeks. For patients with septic arthritis due to S. aureus in the absence of concomitant bacteremia or signs of endocarditis, we administer parenteral antibiotics for at least 14 days, followed by oral therapy for an additional 7 to 14 days. The choice of oral antibiotic regimen for completion of therapy depends on the pathogen:

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For septic arthritis due to methicillin-sensitive S. aureus, suitable choices include dicloxacillin (500 mg orally every six hours), flucloxacillin (500 mg orally every six hours), or cephalexin (500 mg orally every six hours). Patients who are allergic to penicillin can be treated with clindamycin (600 mg orally every eight hours).

●

For septic arthritis due to methicillin-resistant S. aureus, suitable choices include clindamycin, trimethoprim-sulfamethoxazole, doxycycline (or minocycline), linezolid (or tedizolid), and rifampin in combination with either ciprofloxacin or fusidic acid (

table 7).

For patients with septic arthritis due to organisms that are susceptible to oral agents with high bioavailability (such as a fluoroquinolone), we favor treatment with a short course (four to seven days) of parenteral therapy, followed by 14 to 21 days of oral therapy. Compliance and response to therapy should be monitored carefully in such cases. For patients with septic arthritis due to difficult-to-treat pathogens (such as P. aeruginosa or Enterobacter spp), longer courses of outpatient parenteral antibiotic therapy (eg, three to four weeks) may be necessary, especially if the response to therapy is slow or the patient is immunosuppressed. For patients with septic arthritis and contiguous osteomyelitis, a long (four to six week) course of antibiotics may be indicated. (See "Nonvertebral osteomyelitis in adults: Treatment".) For patients with septic arthritis in the setting of endocarditis, the duration of therapy is guided by the duration required for treatment of endocarditis. (See "Antimicrobial therapy of left-sided native valve endocarditis" and "Antimicrobial therapy of prosthetic valve endocarditis".) One randomized trial suggested two weeks of antibiotic therapy may be noninferior to four weeks of therapy after surgical drainage; however, of the 154 patients enrolled, most had septic arthritis of the wrist or hand (64 percent); only 1 hip infection and 14 knee infections were included [70]. Furthermore, there no cases of infection due to methicillin-resistant S. aureus, and more than two-thirds of patients had pathogens other than S. aureus.

OUTCOME In the United States, these were 13,700 hospital admissions for septic arthritis in 2012 [2]. Average length of stay was seven days and only 40 percent of patients were discharged home. Discharge to a rehabilitation or nursing facility, longer hospital stay, and worse outcome correlated with age >50 years, Medicaid and self-pay as primary payer, teaching hospital status,

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heart failure, and diabetes. There was a 3 percent mortality rate during the primary hospitalization. Unfortunately, there are few studies on the long-term joint outcome in patients with septic arthritis. In most, the functional outcome has depended on host factors (such as pre-existing joint disease), the virulence of the infecting organism, and duration of infection prior to initiation of therapy. In one study including 121 adults with septic arthritis, a poor joint outcome (as defined by the need for amputation, arthrodesis, prosthetic surgery, or severe functional deterioration) occurred in one-third of the patients; adverse prognostic factors included older age and preexisting joint disease [9]. The pathogen may also influence the outcome of treatment. In studies of septic arthritis due to S. aureus, poor joint outcomes have been observed in up to half of patients following completion of therapy [11,71]. In a three-year period, 93 patients with S. aureus arthritis were identified and 40 percent were methicillin-resistant S. aureus [72]. More than 90 percent of the cases were community acquired and 44 percent of the patients had diabetes mellitus. The inhospital mortality rate was 5.4 percent. In contrast, a study of patients with pneumococcal septic arthritis noted a return to baseline joint function (or only mild limitation of joint motion) following therapy in 95 percent of cases [29]. Mortality due to septic arthritis depends on comorbid conditions such as advanced age, renal or cardiac disease, and immunosuppression. The mortality rates in most series range from 10 to 15 percent [9]. Polyarticular septic arthritis, particularly when it is due to S. aureus or occurs in the presence of rheumatoid arthritis, has an extremely poor prognosis, with mortality rates as high as 50 percent [34]. Mortality due to septic pneumococcal arthritis was reported as 19 percent in one series [29]. In a series of 55 patients treated with arthroscopic lavage and antibiotics for septic arthritis of the knee, medical comorbidities, increased age, and multiple medication use had worse outcomes [73]. The outcome of septic arthritis in people who inject drugs (PWID) is worse than in most other patient groups. In a nation-wide series of septic knees, the proportion of patients with injection drug user-related septic arthritis increased from 5 percent in 2000 to 11 percent in 2013 [74]. PWID-related cases were more likely to require repeat surgical procedures, longer hospital stays, and had higher mortality rates.

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In one series including more than 500 adult cases of native joint septic arthritis in New Zealand between 2009 and 2014, large joint septic arthritis was associated with a higher rate of treatment failure than small joint septic arthritis (23 versus 12 percent) [16]. Adverse outcomes included death (5 percent), relapse (5 percent), reinfection (6 percent), and amputation (3 percent).

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Septic arthritis in adults".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topic (see "Patient education: Septic arthritis (The Basics)")

●

Beyond the Basics topics (see "Patient education: Arthritis (Beyond the Basics)" and "Patient education: Joint infection (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

Pathogenesis – Septic arthritis refers to infection in a joint. Most commonly, septic arthritis arises via hematogenous seeding. It may also develop as a result of direct inoculation of bacteria into the joint. Rarely, septic arthritis develops via extension of

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infection into the joint space from adjacent tissues. (See 'Introduction' above and 'Mechanism of infection' above.) ●

Microbiology – Septic arthritis is usually monomicrobial. Staphylococcus aureus (including methicillin-resistant S. aureus) is the most common cause of septic arthritis in adults ( table 1). Other gram-positive organisms such as streptococci are also important potential causes. Septic arthritis due to gram-negative bacilli generally occurs in older adults, patients with underlying immunosuppression, or intravenous drug users; it may also occur as a complication of trauma. Rarely, nonbacterial organisms, such as fungi, can cause septic arthritis. (See 'Microbiology' above.)

●

Clinical manifestations – Patients with septic arthritis usually present acutely with a single swollen and painful joint (ie, monoarticular arthritis); oligoarticular or polyarticular infection occurs in approximately 20 percent of patients. Joint pain, swelling, warmth, and restricted movement occur in most cases. Patients with septic arthritis are usually febrile; older patients may be afebrile. The knee is involved in more than half of cases; wrists, ankles, and hips are also affected commonly. (See 'Clinical manifestations' above.)

●

Approach to diagnosis – The diagnosis of septic arthritis should be suspected in patients with acute onset of at least one swollen, painful joint. Prior to administration of antibiotics, synovial fluid should be sent for Gram stain, bacterial culture, white blood cell count with differential, and assessment for crystals. In addition, blood cultures (two sets) and radiographs of the involved joint should be obtained. (See 'Diagnosis' above.)

●

Interpreting diagnostic tests – The diagnosis of septic arthritis is established based on synovial fluid analysis and culture (

algorithm 1 and

table 2). A definitive diagnosis is

made if synovial fluid Gram stain and/or culture is positive. If synovial fluid Gram stain and culture are negative, a presumptive diagnosis can be made based on purulence of the synovial fluid (leukocyte count >20,000 cells/microL, mostly neutrophils). (See 'Diagnosis' above.) ●

Management – Treatment of acute bacterial arthritis consists of joint drainage or debridement coupled with antibiotic therapy. (See 'Treatment' above.)

• Joint drainage or debridement – Approaches to joint drainage for management of septic arthritis include needle aspiration, arthroscopy, or arthrotomy (open surgical drainage). (See 'Joint drainage' above.)

• Empiric antibiotic selection – The choice of empiric antimicrobial therapy should cover the most likely pathogens (see 'Initial approach' above): https://www.uptodate.com/contents/7666/print

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- If the initial Gram stain of the synovial fluid shows gram-positive cocci, treatment consists of vancomycin (

algorithm 2).

- If the initial Gram stain of the synovial fluid shows gram-negative bacilli, treatment should be guided by risk for Pseudomonal infection (

algorithm 2). Patients with

risk for Pseudomonas infection (eg, immunosuppressed patients and people who inject drugs [PWID]) warrant empiric coverage for Pseudomonas infection. For patients who have sepsis or septic shock, have neutropenia and bacteremia, have severe burns, or are in a setting where the incidence of resistance to the chosen antibiotic class is high (eg, >10 to 15 percent), we suggest treatment a combination of two antipseudomonal agents from different antibiotic classes (eg, a beta-lactam with an aminoglycoside or a fluoroquinolone) (

table 6) (Grade 2C).

(See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".) For patients without any of these additional risk factors for mortality or resistant organisms, we suggest treatment with a single antipseudomonal agent (

table 6)

(Grade 2B). (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections".) For patients with no risk factors for Pseudomonas infection, treatment consists of a third-generation cephalosporin.

- If the initial Gram stain of synovial fluid is negative but synovial fluid cell count is consistent with septic arthritis, the approach depends on individual clinical circumstances (

algorithm 3).

For immunocompetent patients without confounding factors (such as trauma), we suggest treatment with vancomycin (Grade 2C). For patients with traumatic bacterial arthritis, we suggest treatment with vancomycin plus a third-generation cephalosporin (Grade 2C). For immunocompromised patients and PWID, we suggest treatment with vancomycin plus a cephalosporin with activity against Pseudomonas (ceftazidime or cefepime) (Grade 2C).

• Targeted antibiotic therapy – Once microbiology and susceptibility data are available, antibiotic therapy should be narrowed.

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• Duration of therapy – The duration of therapy is tailored to individual clinical circumstances as described above. (See 'Antibiotic therapy' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES

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30. Allison DC, Holtom PD, Patzakis MJ, Zalavras CG. Microbiology of bone and joint infections in injecting drug abusers. Clin Orthop Relat Res 2010; 468:2107. 31. Mikhail IS, Alarcón GS. Nongonococcal bacterial arthritis. Rheum Dis Clin North Am 1993; 19:311. 32. Ross JJ, Hu LT. Septic arthritis of the pubic symphysis: review of 100 cases. Medicine (Baltimore) 2003; 82:340. 33. Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis: review of 180 cases. Medicine (Baltimore) 2004; 83:139. 34. Dubost JJ, Fis I, Denis P, et al. Polyarticular septic arthritis. Medicine (Baltimore) 1993; 72:296. 35. Sapico FL, Liquete JA, Sarma RJ. Bone and joint infections in patients with infective endocarditis: review of a 4-year experience. Clin Infect Dis 1996; 22:783. 36. Hariharan P, Kabrhel C. Sensitivity of erythrocyte sedimentation rate and C-reactive protein for the exclusion of septic arthritis in emergency department patients. J Emerg Med 2011; 40:428. 37. Miller JM, Binnicker MJ, Campbell S, et al. A Guide to Utilization of the Microbiology Laboratory for Diagnosis of Infectious Diseases: 2018 Update by the Infectious Diseases Society of America and the American Society for Microbiology. Clin Infect Dis 2018; 67:e1. 38. Stirling P, Faroug R, Amanat S, et al. False-negative rate of gram-stain microscopy for diagnosis of septic arthritis: suggestions for improvement. Int J Microbiol 2014; 2014:830857. 39. Kortekangas P, Aro HT, Lehtonen OP. Synovial fluid culture and blood culture in acute arthritis. A multi-case report of 90 patients. Scand J Rheumatol 1995; 24:44. 40. Ike RW. Bacterial arthritis. Curr Opin Rheumatol 1998; 10:330. 41. She RC, Romney MG, Jang W, et al. Performance of the BacT/Alert Virtuo Microbial Detection System for the culture of sterile body fluids: prospective multicentre study. Clin Microbiol Infect 2018; 24:992. 42. Hughes JG, Vetter EA, Patel R, et al. Culture with BACTEC Peds Plus/F bottle compared with conventional methods for detection of bacteria in synovial fluid. J Clin Microbiol 2001; 39:4468. 43. Carter K, Doern C, Jo CH, Copley LA. The Clinical Usefulness of Polymerase Chain Reaction as a Supplemental Diagnostic Tool in the Evaluation and the Treatment of Children With Septic Arthritis. J Pediatr Orthop 2016; 36:167.

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44. Zhao J, Zhang S, Zhang L, et al. Serum procalcitonin levels as a diagnostic marker for septic arthritis: A meta-analysis. Am J Emerg Med 2017; 35:1166. 45. Imagama T, Tokushige A, Seki K, et al. Early diagnosis of septic arthritis using synovial fluid presepsin: A preliminary study. J Infect Chemother 2019; 25:170. 46. Saeed K, Dryden M, Sitjar A, White G. Measuring synovial fluid procalcitonin levels in distinguishing cases of septic arthritis, including prosthetic joints, from other causes of arthritis and aseptic loosening. Infection 2013; 41:845. 47. Tetreault MW, Wetters NG, Moric M, et al. Is synovial C-reactive protein a useful marker for periprosthetic joint infection? Clin Orthop Relat Res 2014; 472:3997. 48. Shu E, Farshidpour L, Young M, et al. Utility of point-of-care synovial lactate to identify septic arthritis in the emergency department. Am J Emerg Med 2019; 37:502. 49. Carpenter CR, Vandenberg J, Solomon M, et al. Diagnostic Accuracy of Synovial Lactate, Polymerase Chain Reaction, or Clinical Examination for Suspected Adult Septic Arthritis. J Emerg Med 2020; 59:339. 50. Stirling P, Tahir M, Atkinson HD. The Limitations of Gram-stain Microscopy of Synovial Fluid in Concomitant Septic and Crystal Arthritis. Curr Rheumatol Rev 2018; 14:255. 51. Goldenberg DL. Septic arthritis. Lancet 1998; 351:197. 52. Massey PA, Clark MD, Walt JS, et al. Optimal Synovial Fluid Leukocyte Count Cutoff for Diagnosing Native Joint Septic Arthritis After Antibiotics: A Receiver Operating Characteristic Analysis of Accuracy. J Am Acad Orthop Surg 2021; 29:e1246. 53. Palestro CJ. FDG-PET in musculoskeletal infections. Semin Nucl Med 2013; 43:367. 54. Long B, Koyfman A, Gottlieb M. Evaluation and Management of Septic Arthritis and its Mimics in the Emergency Department. West J Emerg Med 2019; 20:331. 55. Kohli R, Hadley S. Fungal arthritis and osteomyelitis. Infect Dis Clin North Am 2005; 19:831. 56. Papanicolas LE, Hakendorf P, Gordon DL. Concomitant septic arthritis in crystal monoarthritis. J Rheumatol 2012; 39:157. 57. Luo TD, Jarvis DL, Yancey HB, et al. Synovial Cell Count Poorly Predicts Septic Arthritis in the Presence of Crystalline Arthropathy. J Bone Jt Infect 2020; 5:118. 58. Sharff KA, Richards EP, Townes JM. Clinical management of septic arthritis. Curr Rheumatol Rep 2013; 15:332. 59. Thiery JA. Arthroscopic drainage in septic arthritides of the knee: a multicenter study. Arthroscopy 1989; 5:65.

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60. Stutz G, Kuster MS, Kleinstück F, Gächter A. Arthroscopic management of septic arthritis: stages of infection and results. Knee Surg Sports Traumatol Arthrosc 2000; 8:270. 61. Sammer DM, Shin AY. Comparison of arthroscopic and open treatment of septic arthritis of the wrist. J Bone Joint Surg Am 2009; 91:1387. 62. Johns BP, Loewenthal MR, Dewar DC. Open Compared with Arthroscopic Treatment of Acute Septic Arthritis of the Native Knee. J Bone Joint Surg Am 2017; 99:499. 63. Mabille C, El Samad Y, Joseph C, et al. Medical versus surgical treatment in native hip and knee septic arthritis. Infect Dis Now 2021; 51:164. 64. Hunter JG, Gross JM, Dahl JD, et al. Risk factors for failure of a single surgical debridement in adults with acute septic arthritis. J Bone Joint Surg Am 2015; 97:558. 65. Ho G Jr. How best to drain an infected joint. Will we ever know for certain? J Rheumatol 1993; 20:2001. 66. García-Arias M, Balsa A, Mola EM. Septic arthritis. Best Pract Res Clin Rheumatol 2011; 25:407. 67. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18. 68. Scarborough M, Li HK, Rombach I, et al. Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT. Health Technol Assess 2019; 23:1. 69. Seidelman J, Sexton DJ. Is Long-term Oral Therapy for Treatment of Bone and Joint Infections Ready for Prime Time? Clin Infect Dis 2021; 73:e2589. 70. Gjika E, Beaulieu JY, Vakalopoulos K, et al. Two weeks versus four weeks of antibiotic therapy after surgical drainage for native joint bacterial arthritis: a prospective, randomised, non-inferiority trial. Ann Rheum Dis 2019; 78:1114. 71. Weston VC, Jones AC, Bradbury N, et al. Clinical features and outcome of septic arthritis in a single UK Health District 1982-1991. Ann Rheum Dis 1999; 58:214. 72. Lin WT, Wu CD, Cheng SC, et al. High Prevalence of Methicillin-Resistant Staphylococcus aureus among Patients with Septic Arthritis Caused by Staphylococcus aureus. PLoS One 2015; 10:e0127150. 73. Kang T, Lee JK. Host Factors Affect the Outcome of Arthroscopic Lavage Treatment of Septic Arthritis of the Knee. Orthopedics 2018; 41:e184. 74. Oh DHW, Wurcel AG, Tybor DJ, et al. Increased Mortality and Reoperation Rates After Treatment for Septic Arthritis of the Knee in People Who Inject Drugs: Nationwide Inpatient Sample, 2000-2013. Clin Orthop Relat Res 2018; 476:1557. https://www.uptodate.com/contents/7666/print

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Topic 7666 Version 51.0

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GRAPHICS

Causes of infectious arthritis Organism

Clinical clues

Staphylococcus aureus

Healthy adults, skin breakdown, previously damaged joint (eg, rheumatoid arthritis), prosthetic joint

Streptococcal species

Healthy adults, splenic dysfunction

Neisseria gonorrhoeae

Healthy adults (particularly young, sexually active), associated tenosynovitis, vesicular pustules, late complement deficiency, negative synovial fluid culture and Gram stain

Aerobic gram-negative bacteria

Immunocompromised hosts, gastrointestinal infection

Anaerobic gram-negative bacteria

Immunocompromised hosts, gastrointestinal infection

Brucellosis

Zoonosis 

Mycobacterial species

Immunocompromised hosts, travel to or residence in an endemic area

Fungal species (Candida species, sporotrichosis, Cryptococcus, blastomycosis, coccidioidomycosis)

Immunocompromised hosts

Spirochete (Borellia burgdorferi)

Exposure to ticks, antecedent rash, knee joint involvement

Mycoplasma hominis

Immunocompromised hosts with prior urinary tract manipulation

Refer to separate UpToDate topic for discussion of viral causes of arthritis. Graphic 57688 Version 10.0

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Guide to interpretation of synovial fluid analysis

WBC: white blood cell; MSU: monosodium urate; CPPD: calcium pyrophosphate crystal deposition.

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* Septic arthritis is typically associated with synovial fluid white blood cell counts >20,000 cells/microL, but lower counts may be observed, especially for arthritis due to disseminated gonococcal infection. With most bacterial organisms, particularly Staphylococcus aureus, the synovial fluid white blood cell count is typically >50,000 cells/microL (and often >100,000 cells/microL). ¶ Crystal-induced arthritis may still be considered despite the absence of identified crystals; falsenegative results occur, especially with CPPD. Δ If treatment of crystal-induced arthritis does not result in clinical improvement, consider other inflammatory or infectious arthridites. Graphic 111452 Version 2.0

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Classification of joint fluid based on synovial fluid characteristics Noninflammatory

 

(such as osteoarthritis)

Inflammatory

(such as rheumatoid

Septic

Hemorrhagic

arthritis)

WBC count (cells/microL)

20,000*

Up to 1 WBC for every 1000 RBCs

Percent neutrophils

75%

50,000 cells/microL (and often >100,000 cells/microL). However, lower counts (in the inflammatory range) may be observed in the setting of septic arthritis, especially for disseminated gonococcal infection or if antibiotics were administered prior to joint fluid sampling. ¶ Hemorrhagic synovial fluid usually has 20,000 cells/microL (often termed "pseudoseptic"). In general, the higher the synovial fluid leukocyte count, the greater the concern for septic arthritis. Graphic 76506 Version 12.0

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Differential diagnosis of acute monoarthritis Infection

Tumor

Bacterial

Tenosynovial giant cell tumor (formerly pigmented villonodular synovitis)

Fungal Mycobacterial Viral Spirochete

Crystal induced Monosodium urate Calcium pyrophosphate dihydrate

Chondrosarcoma Osteoid osteoma Metastatic disease

Systemic rheumatic disease Rheumatoid arthritis Spondyloarthritis Systemic lupus erythematosus

Hydroxyapatite

Sarcoidosis

Calcium oxalate

Osteoarthritis

Lipid

Erosive variant

Hemarthrosis

Intraarticular derangement

Trauma

Meniscal tear

Anticoagulation

Osteonecrosis

Clotting disorders

Fracture

Fracture

Other

Pigmented villonodular synovitis

Plant thorn synovitis

Graphic 62597 Version 5.0

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Major causes of inflammatory polyarthritis Infectious arthritis Bacterial Lyme disease Bacterial endocarditis Viral Other infections Postinfectious (reactive) arthritis Rheumatic fever Reactive arthritis Enteric infection Other seronegative spondyloarthritides Ankylosing spondylitis Psoriatic arthritis Inflammatory bowel disease Rheumatoid arthritis Inflammatory osteoarthritis Crystal-induced arthritis Juvenile idiopathic arthritis Systemic rheumatic illnesses Systemic lupus erythematosus Systemic vasculitis Systemic sclerosis Polymyositis/dermatomyositis Adult-onset Still's disease Behçet syndrome Relapsing polychondritis Autoinflammatory disorders Other systemic illnesses Sarcoidosis Palindromic rheumatism Familial Mediterranean fever Malignancy Hyperlipoproteinemias Graphic 74266 Version 8.0

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Approach to patients with suspected septic arthritis and positive synovial fluid

This algorithm summarizes an approach to evaluation and management of patients with suspected septic a stain. Issues related to septic arthritis associated with animal bites are discussed separately (refer to UpToD related to septic bursitis (refer to UpToDate topic on septic bursitis).

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* Refer to UpToDate topic on disseminated gonococcal infection for details on treatment regimens. ¶ The duration of therapy for septic arthritis is tailored to individual clinical circumstances (refer to UpToDat discussion). Graphic 134805 Version 1.0

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Approach to patients with suspected septic arthritis and negative synovial fluid Gram stain

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This algorithm summarizes an approach to evaluation and management of patients with suspected septic arthritis and negative synovial fluid Gram stain. Issues related to septic arthritis associated with animal bites are discussed separately (refer to UpToDate topic on animal bites), as are issues related to septic bursitis (refer to UpToDate topic on septic bursitis). * With most bacterial organisms, particularly Staphylococcus aureus, the synovial fluid white blood cell count is typically >50,000 cells/microL (and often >100,000 cells/microL). However, lower counts may be observed in the setting of septic arthritis, especially for disseminated gonococcal infection or if antibiotics were administered prior to joint fluid sampling. ¶ If there is high suspicion for disseminated gonococcal infection (eg, tenosynovitis or dermatitis, evidence of urogenital, rectal or pharyngeal gonococcal infection), including empiric treatment for gonococcal infection is reasonable. Δ Refer to separate UpToDate topic on disseminated gonococcal infection for details on treatment regimens. ◊ The duration of therapy for septic arthritis is tailored to individual clinical circumstances (refer to UpToDate topic on septic arthritis for further discussion). Graphic 134806 Version 1.0

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Approach to vancomycin dosing for adults with normal kidney function* Loading dose (for patients with known or

Load 20 to 35 mg/kg (based on actual body

suspected severe Staphylococcus aureus infection)¶

weight, rounded to the nearest 250 mg increment; not to exceed 3000 mg). Within this range, we use a higher dose for critically ill patients; we use a lower dose for patients who are obese and/or are receiving vancomycin via continuous infusion.

Initial maintenance dose and interval

Typically 15 to 20 mg/kg every 8 to 12 hours for most patients (based on actual body weight, rounded to the nearest 250 mg increment). In general, the approach to establishing the vancomycin dose/interval is guided by a nomogram.Δ

Subsequent dose and interval adjustments

Based on AUC-guided (preferred for severe infection)[1] or trough-guided serum concentration monitoring.◊

AUC: area under the 24-hour time-concentration curve. * Refer to the UpToDate topic on vancomycin dosing for management of patients with abnormal kidney function. ¶ For patients with known or suspected severe S. aureus infection, we suggest administration of a loading dose to reduce the likelihood of suboptimal initial vancomycin exposure. Severe S. aureus infections include (but are not limited to) bacteremia, endocarditis, osteomyelitis, prosthetic joint infection, pneumonia warranting hospitalization, infection involving the central nervous system, or infection causing critical illness. Δ If possible, the nomogram should be developed and validated at the institution where it is used, to best reflect the regional patient population. Refer to UpToDate topic on vancomycin dosing for sample nomogram. ◊ Refer to the UpToDate topic on vancomycin dosing for discussion of AUC-guided and troughguided vancomycin dosing. For patients with nonsevere infection who receive vancomycin for 85 percent) will have nonspecific low back pain, meaning that the patient has back pain in the absence of a specific underlying condition that can be reliably identified [3-5]. For most of these individuals, episodes of back pain are self-limited. Patients who continue to have back pain beyond the acute period (four weeks) have subacute back pain (lasting between 4 and 12 weeks), and some may go on to develop chronic back pain (lasting >12 weeks) [6]. This discussion focuses on the initial treatment of nonspecific acute low back pain. The treatment of acute low back pain due to specific conditions is discussed in the appropriate topics. As examples: ●

Treatment for vertebral compression fracture (see "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment")

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Treatment for lumbosacral radiculopathy (see "Acute lumbosacral radiculopathy: Treatment and prognosis")

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Treatment for lumbar spinal stenosis (see "Lumbar spinal stenosis: Treatment and prognosis")

The evaluation of low back pain, occupational back pain, and management of patients with occupational, subacute (4 to 12 weeks), and chronic (>12 weeks) back pain are also discussed separately.

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●

(See "Evaluation of low back pain in adults".)

●

(See "Occupational low back pain: Evaluation and management".)

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(See "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment".)

●

(See "Subacute and chronic low back pain: Nonsurgical interventional treatment".)

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(See "Subacute and chronic low back pain: Surgical treatment".)

GENERAL APPROACH TO CARE The goal of care for patients with acute low back pain is short-term symptomatic relief, since most will improve within four weeks. (See 'Prognosis' below and "Evaluation of low back pain in adults", section on 'Risk assessment subacute back pain'.) We typically advise nonpharmacologic treatment with superficial heat. Massage, acupuncture, and spinal manipulation are other reasonable options depending upon patient preference and their cost and accessibility. There are no data demonstrating superiority of one modality over another [7]. For patients who prefer pharmacotherapy or in whom nonpharmacologic approaches are inadequate, we suggest a nonsteroidal antiinflammatory drug (NSAID) with or without a skeletal muscle relaxant rather than acetaminophen for pharmacologic therapy. (See 'Nonpharmacologic therapies' below and 'Pharmacotherapy' below.) This approach is consistent with the 2017 updated guideline of the treatment of acute, subacute, and chronic low back pain from the American College of Physicians [4]. We do not advise bed rest for patients with acute low back pain. Patients who are treated with bed rest have more pain and slower recovery than ambulatory patients [8]. Activity modification should generally be minimal, with patients returning to activities of daily living and work as soon as possible. If activity is painful or increases pain, we advise patients to do as much as they can and gradually increase activity as tolerated. We emphasize the importance of avoiding prolonged periods of inactivity. However, we do not routinely refer patients with acute low back pain for exercise or physical therapy, and instead reserve those services for patients not improving with initial treatment or with risk factors for developing chronic low back pain (eg, poor functional or health status, psychiatric comorbidities). (See 'Exercise and physical therapy' below.) Return-to-work recommendations should be individualized. For example, an office worker who has control over the pace of work, positioning while working, and/or work hours may be able to

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return to work promptly. However, those with physically demanding jobs may not be able to return to work immediately if light-duty options are not available. Return-to-work advice for patients with occupational low back pain is discussed elsewhere. (See "Occupational low back pain: Evaluation and management", section on 'Return-to-work assessment'.)

NONPHARMACOLOGIC THERAPIES Evidence of the effectiveness of nonpharmacologic therapies is generally of low to moderate quality [7]. The choice among these options depends upon patient preference and their cost and accessibility. Heat — Heat is often applied with the rationale that it may reduce muscle spasm. A 2006 systematic review including six studies of low back pain found moderate evidence that a heat wrap may reduce pain and disability for patients with pain of less than three months’ duration, although the benefit was small and short-lived [9]. Massage — There is no evidence that massage offers clinical benefits for acute low back pain [10]. However, a randomized trial found that compared with usual care, when massage was chosen by the patient, it was associated with increased patient satisfaction [11]. Acupuncture — Acupuncture may be a reasonable option for interested patients with access to an acupuncturist. The evidence of benefit in acute low back pain is limited. Randomized trials of acupuncture tend to be small and heterogeneous in methodology, and blinding is difficult. Systematic reviews of acupuncture for acute low back pain have found inconsistent results [12]. Acupuncture is safe with few side effects. (See "Acupuncture", section on 'Adverse events'.) There is more evidence to support the use of acupuncture in chronic low back pain. (See "Acupuncture", section on 'Low back pain'.) Spinal manipulation — Spinal manipulation is a form of manual therapy that involves the movement of a joint near the end of the clinical range of motion. Based upon the available evidence, spinal manipulation appears to confer modest improvements in pain and function. A 2017 systematic review and meta-analysis of spinal manipulative therapy for acute low back pain examined 26 randomized controlled trials [13]. Fifteen trials (1711 patients) provided moderate-quality evidence of improvement in visual analog pain scale, and 12 trials (1381 patients) showed moderate-quality evidence of improvement in function. Comparator groups were heterogeneous and included analgesics, https://www.uptodate.com/contents/7780/print

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exercise, and physical therapy. Minor transient adverse events such as increased pain, muscle stiffness, and headache were reported in 50 to 67 percent of patients. Serious adverse events (eg, worsening lumbar disc herniation, cauda equina syndrome) following spinal manipulation are rare. Integrating spinal manipulation into the therapeutic plan for individual patients should depend upon their preferences and access to this type of intervention. There is little evidence to guide the duration of therapy. Most clinical trials have evaluated courses of twice-weekly manipulation for two to three weeks. There are no data on selecting practitioner type (eg, chiropractor, osteopath, massage therapist, physical therapist). (See "Spinal manipulation in the treatment of musculoskeletal pain", section on 'Risks of spinal manipulation'.) Exercise and physical therapy — Exercise therapy includes both self-care exercises done by the patient and supervised exercises in the context of physical therapy. In general, we do not refer patients with acute low back pain for exercise or physical therapy. However, we selectively refer patients with risk factors for developing chronic low back pain (eg, poor functional or health status, psychiatric comorbidities) who may benefit from immediate education by a physical therapist on how to avoid recurrences, appropriate levels of activity, and exercises to begin after the acute phase [14]. (See 'Prognosis' below and "Exercise-based therapy for low back pain", section on 'Acute low back pain: No benefit from exercise therapy'.) Although some studies do show modest efficacy of exercise therapy in selected cases of acute low back pain (80 percent) had subacute or chronic rather than acute low back pain [14,22,23]. https://www.uptodate.com/contents/7780/print

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There is evidence to support exercise therapy for patients with subacute and chronic low back pain [15-17,24]. (See 'Prognosis' below and "Exercise-based therapy for low back pain", section on 'Proposed mechanisms of benefit'.) Other — Many other interventions have been suggested for acute low back pain with little or no evidence to support their use [10,11]. ●

Cold – Application of cold is often recommended for patients with acute back pain, with the rationale that it may help reduce edema. However, cold applied superficially does not penetrate far below the skin. A 2006 systematic review found only three studies evaluating cold for low back pain and was unable to find evidence of benefit [9].

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Muscle energy technique – The muscle energy technique is a treatment that involves alternating periods of resisted muscle contractions and assisted stretching. A 2015 systematic review of randomized trials found no evidence of effectiveness in patients with acute low back pain [19].

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Traction – There is no evidence that traction is beneficial for acute low back pain. A 2013 systematic review including 32 randomized trials of traction for low back pain (with or without sciatica) concluded that traction provides no benefits [25].

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Lumbar supports – There is no evidence to suggest that lumbar supports such as corsets or braces have therapeutic value for most patients with acute low back pain [26].

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Mattress recommendations – The role of type of mattress/firmness of sleep surface has not been studied in acute low back pain.

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Yoga – Studies on yoga and back pain have primarily focused on chronic low back pain. There is no evidence to support the use of yoga in acute low back pain. (See "Exercisebased therapy for low back pain", section on 'Choice of exercise: All programs are beneficial'.)

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Paraspinal injections – A variety of injections (eg, epidural spinal, trigger point, or facet join injections) have been advocated for patients with back pain. There is little evidence to support any type of injection for nonspecific acute low back pain. Injections for lumbosacral radiculopathy, spinal stenosis, and subacute and chronic low back pain are discussed elsewhere. (See "Subacute and chronic low back pain: Nonsurgical interventional treatment", section on 'Glucocorticoid and other injections' and "Lumbar spinal stenosis: Treatment and prognosis", section on 'Epidural injections' and "Acute

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lumbosacral radiculopathy: Treatment and prognosis", section on 'Options of limited utility'.)

PHARMACOTHERAPY Initial therapy — If pharmacotherapy is used, we suggest a trial of short-term (two to four weeks) systemic treatment with a nonsteroidal antiinflammatory drug (NSAID). Nonsteroidal antiinflammatory drugs — We start with systemic NSAID therapy in patients with acute low back pain without contraindications to this therapy. Many NSAID options exist ( table 1). We generally start with either ibuprofen (400 to 600 mg four times daily) or naproxen (250 to 500 mg twice daily). Doses should be decreased as tolerated. NSAIDs provide modest symptomatic relief for acute low back pain [27-29]. In a 2008 systematic review and meta-analysis of 11 randomized trials, global symptomatic improvement after one week was modestly greater for patients with acute low back pain treated with NSAIDs compared with placebo (risk ratio [RR] 1.19; 95% CI 1.07-1.35) [28]. NSAIDs were associated with more side effects compared with either placebo or acetaminophen. NSAIDs may have significant renal, gastrointestinal, and cardiovascular adverse effects and may be contraindicated in some patients. All NSAID toxicities are more common in older patients. The adverse effects of nonselective NSAIDs and cyclooxygenase (COX)-2 inhibitors are discussed elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.) Limited benefit of acetaminophen — Acetaminophen has historically been considered an option for first-line therapy for low back pain. However, evidence of efficacy has been mixed [28,30,31], and a 2016 Cochrane review concluded that there was high-quality evidence that acetaminophen showed no benefit compared with placebo in acute low back pain [32]. There is also evidence that the addition of acetaminophen to short-term NSAID therapy provides no further benefit [33]. Given that acetaminophen has clear risks and questionable benefit, we do not recommend it as either initial or supplemental therapy for the majority of patients with acute low back pain. However, in selected patients for whom there are no safe alternatives and acetaminophen is the least potentially harmful treatment, we believe it reasonable to consider a trial of acetaminophen as initial therapy. We use acetaminophen 650 mg orally every six hours as needed (maximum 3 grams per 24 hours) for most adults, although we would use a lower total https://www.uptodate.com/contents/7780/print

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daily dose for older adult patients, those with any hepatic impairment, and patients with other factors that predispose to hepatotoxicity (

table 1). (See "Acetaminophen (paracetamol)

poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Clinical factors that may influence toxicity'.) Hepatotoxicity is the primary concern with acetaminophen use; the risk of liver injury is doserelated, but the dose causing toxicity may vary from patient to patient. Many prescription analgesics and over-the-counter products contain acetaminophen, and the total dose of acetaminophen should be considered when patients are taking multiple medications. Other less common but possible adverse effects that have been associated with acetaminophen use include chronic kidney disease, hypertension, and peptic ulcer disease. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on 'Acetaminophen' and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension", section on 'Effects of acetaminophen on blood pressure' and "Unusual causes of peptic ulcer disease", section on 'Non-NSAID medications'.) Second-line therapy — For patients with pain refractory to initial pharmacotherapy, we suggest the addition of a nonbenzodiazepine muscle relaxant. In patients who cannot tolerate or have contraindications to muscle relaxants, combining systemic NSAIDs and acetaminophen is another option, though there are few data to support the use of this combination. Combination with muscle relaxants — Muscle relaxants are a diverse group of drugs with similar physiologic effects including analgesia and a degree of skeletal muscle relaxation or relief of muscle spasm. They include benzodiazepines, cyclobenzaprine, methocarbamol, carisoprodol, baclofen, chlorzoxazone, metaxalone, orphenadrine, and tizanidine. Patients who can tolerate the potential sedating effects of these medications may benefit from the addition of a nonbenzodiazepine muscle relaxant to initial pharmacotherapy with NSAIDs or acetaminophen. We generally do not start these medications as initial therapy, as they tend to have sedating side effects that limit patients' ability to work or drive. Risks of these agents increase with age, and these agents should be used with caution in older adults. Cyclobenzaprine is a reasonable first-choice drug. For patients who cannot tolerate the sedating effects of muscle relaxants during the daytime, NSAIDs or acetaminophen during the day with muscle relaxants before bedtime may be helpful. Benzodiazepines should not be used because they are not effective in improving pain or functional outcome [34], and there is potential for abuse.

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Efficacy – Muscle relaxants provide short-term, symptomatic relief for patients with acute low back pain. A 2003 systematic review found high-quality evidence that nonbenzodiazepine muscle relaxants are more effective than placebo for short-term relief of acute low back pain (RR 0.80, 95% CI 0.71-0.89) [35]. A subsequent 2021 meta-analysis including 17 randomized trials also found that nonbenzodiazepine muscle relaxants had a small benefit in reducing short-term pain, although the quality of the evidence was limited due to bias in the included trials [36]. Both analyses noted an increased risk of adverse effects from muscle relaxants (RR 1.6, 95% CI 1.2-2.0; and RR 1.5, 95% CI 1.14-1.98, respectively). There is some evidence that cyclobenzaprine, methocarbamol, carisoprodol, and tizanidine are more effective than other muscle relaxants [37,38]. Evidence on combination therapy with NSAIDs is mixed. A randomized trial in 197 patients with acute low back pain comparing treatment for one week with aceclofenac 100 mg twice daily with or without the addition of tizanidine 2 mg twice daily found improved pain relief and decreased functional impairment with combination therapy [39]. However, in other randomized trials, there was no benefit from the addition of a skeletal muscle relaxant to NSAID treatment [40-42]. There are no studies evaluating the combination of acetaminophen with muscle relaxants.

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Adverse effects – The primary adverse effects (sedation, dizziness) of muscle relaxants relate to their central nervous system and anticholinergic activity; these are more likely to be problematic in older patients. Dependence and abuse potential are concerns with benzodiazepines. Carisoprodol also has abuse potential, particularly in patients with a history of substance abuse [43]. (See "Drug prescribing for older adults".)

Refractory or severe pain — Evidence to support the use of opioids and tramadol in acute low back pain is limited. These agents should be reserved for patients who do not have adequate relief from or have contraindications to other agents. Opioids — Opioids have few benefits when added to NSAID therapy. If opioids are used for acute low back pain, the duration of therapy should be brief. We agree with a 2016 US Centers for Disease Control and Prevention (CDC) recommendation limiting duration of opioid therapy for acute pain to less than three days for most patients unless circumstances clearly warrant additional therapy. Even in those cases, more than seven days is rarely needed [44]. There are few data on the efficacy and safety of opioids for acute low back pain [45]. Most studies of opioids focus on chronic back pain and are not generalizable to acute back pain. One randomized trial in patients presenting to the emergency department with ≤2 weeks of acute, https://www.uptodate.com/contents/7780/print

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nontraumatic, nonradicular low back pain found no difference in pain or disability after seven days of naproxen alone compared with naproxen plus oxycodone/acetaminophen [41]. The appropriate opioid dosing regimen is unknown. One trial comparing scheduled dosing of opioids with as-needed dosing found better outcomes in the scheduled dosing group [46]. One strategy is to limit opioids to bedtime use to facilitate sleep and reduce the chances of developing dependence or tolerance. Adverse effects of opioids include sedation, confusion, nausea, and constipation. Respiratory depression is an issue at higher doses but rarely at the doses used for acute low back pain. As with all medications, older patients are more susceptible to side effects. Patients given combination drugs containing acetaminophen or NSAIDs should be advised not to use them concurrently with over-the-counter analgesics without carefully reviewing the contents with a health care professional. Misuse is a concern with opioids. Addiction and abuse are rare with short-term prescription for acute pain [47] but more common in patients using opioids for the treatment of chronic back pain [48,49]. Tramadol — Tramadol is an opioid agonist that also blocks reuptake of serotonin and norepinephrine [50]. We prescribe tramadol similarly to opioids, limiting regular use to a few days and total use to two weeks. Tramadol may have a lower risk of constipation and dependence than conventional opioids but carries the risk of serotonin syndrome, especially when combined with other serotonergic agents [50,51]. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Mixed-mechanism drugs: Tramadol and tapentadol' and "Use of opioids in the management of chronic non-cancer pain", section on 'Opioids'.) While randomized trials have shown that tramadol may be effective for chronic back pain, there are few data evaluating tramadol for acute low back pain [52-54]. Other medications — Drugs with limited or no evidence of effectiveness include: ●

Antidepressants – There is no evidence to support the use of antidepressants in treatment of acute low back pain. However, in patients with concurrent depression, we ensure that the depression is appropriately treated. (See "Unipolar major depression in adults: Choosing initial treatment".) These medications may be considered in the management of subacute or chronic back pain. (See "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Pharmacologic therapies'.)

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Systemic glucocorticoids – There is no evidence to support the use of systemic glucocorticoids in acute nonspecific back pain [7]. Small randomized trials in patients with nontraumatic back pain presenting to the emergency department comparing systemic steroids with placebo have found no benefits [55,56]. The use of systemic glucocorticoids for the treatment of acute lumbosacral radiculopathy is discussed elsewhere. (See "Acute lumbosacral radiculopathy: Treatment and prognosis", section on 'Systemic glucocorticoids'.)

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Antiepileptics – There is no evidence to support the use of antiepileptics in treatment of acute low back pain. These medications may be considered in the management of subacute or chronic back pain. (See "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Pharmacologic therapies'.)

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Topical agents – There is low-quality evidence that topical capsicum may provide immediate relief for patients with acute back pain [57]. There is no evidence to support the use of lidocaine patches in this setting.

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Herbal therapies – Though these treatments may be commonly used by patients, the evidence to support the use of herbal therapies for low back pain is limited. (See "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment", section on 'Pharmacologic therapies'.)

PATIENT EDUCATION Patient education is an important aspect of care. A 2015 systematic review of studies evaluating patient education for acute and subacute low back pain (eg, education on the benign nature and good prognosis of acute low back pain, advice to stay active) found moderate-quality evidence that, compared with usual care, patient education reduces acute low back pain-related primary care visits [58]. Our view is that patient education is necessary, but not sufficient, to result in improved outcomes. Education should include information about the causes of back pain, favorable prognosis, generally minimal value of diagnostic testing, activity and work recommendations, and when to contact a clinician for follow-up [59]. (See 'Information for patients' below.)

PROGNOSIS https://www.uptodate.com/contents/7780/print

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The prognosis for acute low back pain is excellent; only one-third of patients seek medical care at all [60]. Of those who present for care, 70 to 90 percent improve within seven weeks [61,62]. Recurrences are common, affecting up to 50 percent of patients within six months and 70 percent within 12 months [63,64]. Similar to the initial episode, recurrences have a favorable prognosis. Some patients with acute low back pain will go on to develop chronic low back pain. Estimates of the percentage of patients who develop chronic back pain vary. In one prospective cohort study of patients with acute back pain seen in primary care, chronic back pain was diagnosed in 20 percent of patients within two years of their initial visit [63]. However, other studies have suggested only 5 to 10 percent of patients with acute low back pain go on to develop chronic low back pain [64-66]. Predictors of disabling chronic low back pain at one year include maladaptive pain coping behaviors, functional impairment, poor general health status, presence of psychiatric comorbidities, or nonorganic signs [67,68]. Maladaptive coping behaviors include fear avoidance (avoiding usual or recommended activities because of fear that they will cause worsening pain or hinder recovery) and catastrophizing (negative beliefs about pain or illness leading to patients imagining the worst possible outcome). (See "Evaluation of low back pain in adults", section on 'Physical examination'.) Stratifying care in patients with acute low back pain based upon risk assessment for chronicity is not of proven benefit. While studies that have assessed such an approach showed improved outcomes for disability and lost work time, the majority of patients in these studies (>80 percent) had subacute or chronic rather than acute low back pain [14,22,23]. Further, a United States study showed no advantage of this approach, in contrast to similar studies in the United Kingdom [69].

PREVENTION Exercise interventions may have some value in preventing recurrences of low back pain. (See "Exercise-based therapy for low back pain", section on 'Subacute and chronic low back pain: Exercise is beneficial'.) There are few data to support other interventions, such as lumbar supports, smoking cessation, or weight loss, for the prevention of low back pain [26,70]. However, interventions such as smoking cessation or weight loss may be otherwise beneficial for health. There also is no https://www.uptodate.com/contents/7780/print

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evidence that spinal manipulation reduces the risk of recurrence of back pain [71]. Ergonomic interventions for the prevention of occupational low back pain are discussed elsewhere.

SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lower spine disorders" and "Society guideline links: Acute pain management".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Low back pain in adults (The Basics)" and "Patient education: Spinal stenosis (The Basics)" and "Patient education: Herniated disc (The Basics)")

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Beyond the Basics topic (see "Patient education: Low back pain in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS ●

The majority of patients improve; nonpharmacologic therapy preferred – Most patients with acute low back pain improve regardless of specific management. We typically suggest nonpharmacologic therapy with superficial heat (Grade 2C). Massage, acupuncture, and spinal manipulation are other reasonable options depending upon

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patient preference and their cost and accessibility. There are no data demonstrating the superiority of one modality over another. Bed rest is not advised, and activity modification should be kept to a minimum. (See 'General approach to care' above and 'Nonpharmacologic therapies' above.) ●

Most patients are not referred for physical therapy – We do not refer most patients with acute low back pain for exercise or physical therapy. However, we selectively refer patients with risk factors for developing chronic low back pain (eg, poor functional or health status, psychiatric comorbidities) who may benefit from immediate physical education by a physical therapist, although this is unproven. (See 'Exercise and physical therapy' above.)

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Short-term NSAID therapy an option for some patients – For patients who prefer pharmacologic therapy or in whom nonpharmacologic approaches are inadequate, we suggest short-term (two to four weeks) treatment with a nonsteroidal antiinflammatory drug (NSAID) as initial therapy (Grade 2C) (

table 1). Acetaminophen is an acceptable

alternative option in patients with a contraindication to NSAIDs, although it has limited efficacy. (See 'Initial therapy' above.) ●

Addition of a skeletal muscle relaxant for patients with refractory pain – For patients with pain refractory to initial pharmacotherapy, we suggest the addition of a nonbenzodiazepine muscle relaxant (Grade 2C). In patients who cannot tolerate or have a contraindication to muscle relaxants, combining NSAIDs and acetaminophen is another option. (See 'Second-line therapy' above.)

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Limited role for opioids – Evidence to support the use of opioids and tramadol in acute low back pain is limited. We recommend reserving these agents for patients who do not have adequate relief from or have contraindications to other drugs (Grade 1C). If opioids are used, the duration of therapy should be limited to three to seven days. Tramadol should not be prescribed for more than two weeks. (See 'Refractory or severe pain' above.)

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Importance of patient education – Patient education is an important aspect of care. Education should include information about the causes of back pain, favorable prognosis, generally minimal value of diagnostic testing, activity and work recommendations, and when to contact a clinician. (See 'Patient education' above.)

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Reassess if persistent symptoms after four weeks of pharmacotherapy – Patients who do not improve after four weeks of pharmacotherapy should be reassessed. Some patients with acute low back pain will go on to develop chronic low back pain. Predictors of disabling chronic low back pain at one year include maladaptive pain coping behaviors,

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functional impairment, poor general health status, presence of psychiatric comorbidities, or nonorganic signs. (See 'Prognosis' above.) ●

Prevention – Exercise interventions may have some value in preventing recurrences of low back pain. (See 'Prevention' above.) Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. Deyo RA, Tsui-Wu YJ. Descriptive epidemiology of low-back pain and its related medical care in the United States. Spine (Phila Pa 1976) 1987; 12:264. 2. Cassidy JD, Carroll LJ, Côté P. The Saskatchewan health and back pain survey. The prevalence of low back pain and related disability in Saskatchewan adults. Spine (Phila Pa 1976) 1998; 23:1860. 3. Deyo RA, Weinstein JN. Low back pain. N Engl J Med 2001; 344:363. 4. Qaseem A, Wilt TJ, McLean RM, et al. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med 2017; 166:514. 5. Chou R, Qaseem A, Owens DK, et al. Diagnostic imaging for low back pain: advice for highvalue health care from the American College of Physicians. Ann Intern Med 2011; 154:181. 6. Chou R. In the clinic. Low back pain. Ann Intern Med 2014; 160:ITC6. 7. Chou R, Deyo R, Friedly J, et al. Nonpharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2017; 166:493. 8. Dahm KT, Brurberg KG, Jamtvedt G, Hagen KB. Advice to rest in bed versus advice to stay active for acute low-back pain and sciatica. Cochrane Database Syst Rev 2010; :CD007612. 9. French SD, Cameron M, Walker BF, et al. Superficial heat or cold for low back pain. Cochrane Database Syst Rev 2006; :CD004750. 10. Furlan AD, Giraldo M, Baskwill A, et al. Massage for low-back pain. Cochrane Database Syst Rev 2015; :CD001929. 11. Eisenberg DM, Post DE, Davis RB, et al. Addition of choice of complementary therapies to usual care for acute low back pain: a randomized controlled trial. Spine (Phila Pa 1976) 2007; 32:151.

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12. Liu L, Skinner M, McDonough S, et al. Acupuncture for low back pain: an overview of systematic reviews. Evid Based Complement Alternat Med 2015; 2015:328196. 13. Paige NM, Miake-Lye IM, Booth MS, et al. Association of Spinal Manipulative Therapy With Clinical Benefit and Harm for Acute Low Back Pain: Systematic Review and Meta-analysis. JAMA 2017; 317:1451. 14. Hill JC, Whitehurst DG, Lewis M, et al. Comparison of stratified primary care management for low back pain with current best practice (STarT Back): a randomised controlled trial. Lancet 2011; 378:1560. 15. Brennan GP, Fritz JM, Hunter SJ, et al. Identifying subgroups of patients with acute/subacute "nonspecific" low back pain: results of a randomized clinical trial. Spine (Phila Pa 1976) 2006; 31:623. 16. Fritz JM, Delitto A, Erhard RE. Comparison of classification-based physical therapy with therapy based on clinical practice guidelines for patients with acute low back pain: a randomized clinical trial. Spine (Phila Pa 1976) 2003; 28:1363. 17. Faas A. Exercises: which ones are worth trying, for which patients, and when? Spine (Phila Pa 1976) 1996; 21:2874. 18. Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of nonspecific low back pain. Cochrane Database Syst Rev 2005; :CD000335. 19. Franke H, Fryer G, Ostelo RW, Kamper SJ. Muscle energy technique for non-specific lowback pain. Cochrane Database Syst Rev 2015; :CD009852. 20. Schaafsma FG, Whelan K, van der Beek AJ, et al. Physical conditioning as part of a return to work strategy to reduce sickness absence for workers with back pain. Cochrane Database Syst Rev 2013; 8:CD001822. 21. Fritz JM, Magel JS, McFadden M, et al. Early Physical Therapy vs Usual Care in Patients With Recent-Onset Low Back Pain: A Randomized Clinical Trial. JAMA 2015; 314:1459. 22. Hill JC, Dunn KM, Lewis M, et al. A primary care back pain screening tool: identifying patient subgroups for initial treatment. Arthritis Rheum 2008; 59:632. 23. Foster NE, Mullis R, Hill JC, et al. Effect of stratified care for low back pain in family practice (IMPaCT Back): a prospective population-based sequential comparison. Ann Fam Med 2014; 12:102. 24. van Tulder MW, Malmivaara A, Esmail R, Koes BW. Exercise therapy for low back pain. Cochrane Database Syst Rev 2000; :CD000335. 25. Wegner I, Widyahening IS, van Tulder MW, et al. Traction for low-back pain with or without sciatica. Cochrane Database Syst Rev 2013; :CD003010. https://www.uptodate.com/contents/7780/print

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26. van Duijvenbode IC, Jellema P, van Poppel MN, van Tulder MW. Lumbar supports for prevention and treatment of low back pain. Cochrane Database Syst Rev 2008; :CD001823. 27. Agency for Healthcare Research and Quality (AHRQ). Noninvasive treatments for low back p ain. AHRQ Publication No. 16-EHC004-EF. February 2016. https://effectivehealthcare.ahrq.g ov/ehc/products/553/2178/back-pain-treatment-report-160229.pdf (Accessed on March 11, 2016). 28. Roelofs PD, Deyo RA, Koes BW, et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev 2008; :CD000396. 29. Machado GC, Maher CG, Ferreira PH, et al. Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis. Ann Rheum Dis 2017. 30. Williams CM, Maher CG, Latimer J, et al. Efficacy of paracetamol for acute low-back pain: a double-blind, randomised controlled trial. Lancet 2014; 384:1586. 31. Schreijenberg M, Lin CC, Mclachlan AJ, et al. Paracetamol is ineffective for acute low back pain even for patients who comply with treatment: complier average causal effect analysis of a randomized controlled trial. Pain 2019; 160:2848. 32. Saragiotto BT, Machado GC, Ferreira ML, et al. Paracetamol for low back pain. Cochrane Database Syst Rev 2016; :CD012230. 33. Friedman BW, Irizarry E, Chertoff A, et al. Ibuprofen Plus Acetaminophen Versus Ibuprofen Alone for Acute Low Back Pain: An Emergency Department-based Randomized Study. Acad Emerg Med 2020; 27:229. 34. Friedman BW, Irizarry E, Solorzano C, et al. Diazepam Is No Better Than Placebo When Added to Naproxen for Acute Low Back Pain. Ann Emerg Med 2017. 35. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev 2003; :CD004252. 36. Cashin AG, Folly T, Bagg MK, et al. Efficacy, acceptability, and safety of muscle relaxants for adults with non-specific low back pain: systematic review and meta-analysis. BMJ 2021; 374:n1446. 37. Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions. Am J Ther 2005; 12:151. 38. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage 2004; 28:140. 39. Pareek A, Chandurkar N, Chandanwale AS, et al. Aceclofenac-tizanidine in the treatment of acute low back pain: a double-blind, double-dummy, randomized, multicentric, https://www.uptodate.com/contents/7780/print

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comparative study against aceclofenac alone. Eur Spine J 2009; 18:1836. 40. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin 2005; 21:1485. 41. Friedman BW, Dym AA, Davitt M, et al. Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA 2015; 314:1572. 42. Friedman BW, Irizarry E, Solorzano C, et al. A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain. Ann Emerg Med 2019; 74:512. 43. Reeves RR, Carter OS, Pinkofsky HB, et al. Carisoprodol (soma): abuse potential and physician unawareness. J Addict Dis 1999; 18:51. 44. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain United States, 2016. MMWR Recomm Rep 2016; 65:1. 45. Abdel Shaheed C, Maher CG, Williams KA, et al. Efficacy, Tolerability, and Dose-Dependent Effects of Opioid Analgesics for Low Back Pain: A Systematic Review and Meta-analysis. JAMA Intern Med 2016; 176:958. 46. Fordyce WE, Brockway JA, Bergman JA, Spengler D. Acute back pain: a control-group comparison of behavioral vs traditional management methods. J Behav Med 1986; 9:127. 47. Compton WM, Volkow ND. Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend 2006; 81:103. 48. Martell BA, O'Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med 2007; 146:116. 49. Reid MC, Engles-Horton LL, Weber MB, et al. Use of opioid medications for chronic noncancer pain syndromes in primary care. J Gen Intern Med 2002; 17:173. 50. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004; 43:879. 51. Beakley BD, Kaye AM, Kaye AD. Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician 2015; 18:395. 52. Ruoff GE, Rosenthal N, Jordan D, et al. Tramadol/acetaminophen combination tablets for the treatment of chronic lower back pain: a multicenter, randomized, double-blind, placebo-controlled outpatient study. Clin Ther 2003; 25:1123. 53. Mullican WS, Lacy JR, TRAMAP-ANAG-006 Study Group. Tramadol/acetaminophen combination tablets and codeine/acetaminophen combination capsules for the https://www.uptodate.com/contents/7780/print

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management of chronic pain: a comparative trial. Clin Ther 2001; 23:1429. 54. Peloso PM, Fortin L, Beaulieu A, et al. Analgesic efficacy and safety of tramadol/ acetaminophen combination tablets (Ultracet) in treatment of chronic low back pain: a multicenter, outpatient, randomized, double blind, placebo controlled trial. J Rheumatol 2004; 31:2454. 55. Friedman BW, Holden L, Esses D, et al. Parenteral corticosteroids for Emergency Department patients with non-radicular low back pain. J Emerg Med 2006; 31:365. 56. Eskin B, Shih RD, Fiesseler FW, et al. Prednisone for emergency department low back pain: a randomized controlled trial. J Emerg Med 2014; 47:65. 57. Abdel Shaheed C, Maher CG, Williams KA, McLachlan AJ. Interventions available over the counter and advice for acute low back pain: systematic review and meta-analysis. J Pain 2014; 15:2. 58. Traeger AC, Hübscher M, Henschke N, et al. Effect of Primary Care-Based Education on Reassurance in Patients With Acute Low Back Pain: Systematic Review and Meta-analysis. JAMA Intern Med 2015; 175:733. 59. Atlas SJ, Deyo RA. Evaluating and managing acute low back pain in the primary care setting. J Gen Intern Med 2001; 16:120. 60. Carey TS, Evans AT, Hadler NM, et al. Acute severe low back pain. A population-based study of prevalence and care-seeking. Spine (Phila Pa 1976) 1996; 21:339. 61. Coste J, Delecoeuillerie G, Cohen de Lara A, et al. Clinical course and prognostic factors in acute low back pain: an inception cohort study in primary care practice. BMJ 1994; 308:577. 62. Cherkin DC, Deyo RA, Street JH, Barlow W. Predicting poor outcomes for back pain seen in primary care using patients' own criteria. Spine (Phila Pa 1976) 1996; 21:2900. 63. Mehling WE, Gopisetty V, Bartmess E, et al. The prognosis of acute low back pain in primary care in the United States: a 2-year prospective cohort study. Spine (Phila Pa 1976) 2012; 37:678. 64. Pengel LH, Herbert RD, Maher CG, Refshauge KM. Acute low back pain: systematic review of its prognosis. BMJ 2003; 327:323. 65. Koes BW, van Tulder MW, Thomas S. Diagnosis and treatment of low back pain. BMJ 2006; 332:1430. 66. Hazard RG, Haugh LD, Reid S, et al. Early prediction of chronic disability after occupational low back injury. Spine (Phila Pa 1976) 1996; 21:945. 67. Chou R, Shekelle P. Will this patient develop persistent disabling low back pain? JAMA 2010; 303:1295. https://www.uptodate.com/contents/7780/print

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68. Wertli MM, Eugster R, Held U, et al. Catastrophizing-a prognostic factor for outcome in patients with low back pain: a systematic review. Spine J 2014; 14:2639. 69. Cherkin D, Balderson B, Wellman R, et al. Effect of Low Back Pain Risk-Stratification Strategy on Patient Outcomes and Care Processes: the MATCH Randomized Trial in Primary Care. J Gen Intern Med 2018; 33:1324. 70. Lahad A, Malter AD, Berg AO, Deyo RA. The effectiveness of four interventions for the prevention of low back pain. JAMA 1994; 272:1286. 71. Cherkin DC, Deyo RA, Battié M, et al. A comparison of physical therapy, chiropractic manipulation, and provision of an educational booklet for the treatment of patients with low back pain. N Engl J Med 1998; 339:1021. Topic 7780 Version 60.0

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GRAPHICS

Nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen (paracetamol): Usual oral dosing for adults with pain or inflammation and selected characteristics Usual analgesic dose (oral)

Drug

Maximum dose per day

Selected characteristics

Nonselective NSAIDs* Acetic acids Diclofenac¶

50 mg every 8 to 12 hours

150 mg For rheumatoid arthritis, labeling in United States

Dosing for free-acid preparation differs from doses listed here for sodium or potassium salts; refer to Lexicomp drug monograph

permits up to 200 mg Approved maximum in Canada is 100 mg Etodolac

200 to 400 mg

1000 mg

every 6 to 8 hours

Relative COX-2 selectivity and minimal effect on platelet function at lower total daily dose of 600 to 800 mg

Indomethacin

25 to 50 mg every 8 to 12 hours

150 mg For rheumatologic conditions, labeling in United States permits up to 200 mg

Sulindac

150 to 200 mg every 12 hours

400 mg

Used for treatment of acute gout and certain types of headache Potent inhibitory effects on renal prostaglandin synthesis More frequently associated with CNS side effects (eg, headache, altered mental status) compared with other NSAIDs Rarely used More frequently associated with hepatic inflammation than other NSAIDs Metabolites implicated in the formation of renal calculi

Fenamates https://www.uptodate.com/contents/7780/print

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Meclofenamate

50 mg every 4 to

(meclofenamic

6 hours

acid)

400 mg

Used for treatment of dysmenorrhea Relatively higher incidence of GI side effects

or 100 mg three times daily up to 6 days for dysmenorrhea

Mefenamic

250 mg every 6

acid

hours

1000 mg

Used for treatment of dysmenorrhea; not indicated for treatment of chronic pain or inflammation Do not exceed 3 days (dysmenorrhea) to 7 days (acute pain) of use Less potent antiinflammatory effect

Nonacidic Nabumetone

1000 mg once to

2000 mg

twice daily

Relative COX-2 selectivity and minimal effect on platelet function at daily dose ≤1000 mg

Oxicams MeloxicamΔ

7.5 to 15 mg

15 mg

Long duration of effect; relatively

once daily

(conventional

slow onset

(conventional

tablet or ODT)

Relative COX-2 selectivity and

tablet or ODT) 5 to 10 mg once

minimal effect on platelet 10 mg (capsule)

function at lower daily dose of 7.5 mg

20 mg

Long-acting alternative for

daily (capsule) Piroxicam

10 to 20 mg once daily

treatment of chronic pain and inflammation poorly responsive to other NSAIDs Prescribing generally limited to specialists with experience in treatment of chronic pain and inflammation

Propionic acids Fenoprofen

200 mg every 4 to 6 hours or 400 to 600 mg every

3200 mg

More frequently associated with acute interstitial nephritis and nephrotic syndrome[1]

6 to 8 hours https://www.uptodate.com/contents/7780/print

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Flurbiprofen

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50 mg every 6

300 mg

 

hours or 100 mg every 8 to 12 hours IbuprofenΔ

400 mg every 4 to 6 hours or 600

3200 mg (acute), 2400 mg

Shorter-acting alternative to naproxen; useful in patients

to 800 mg every

(chronic)

without cardiovascular risks

6 to 8 hours Ketoprofen

50 mg every 6 hours or 75 mg

300 mg

 

every 8 hours Naproxen

Oxaprozin

Base: 250 to 500

Base: 1250 mg

Often preferred by UpToDate for

mg every 12

(acute); 1000 mg

treatment of acute or chronic

hours or 250 mg

(chronic); may

pain and inflammation in

every 6 to 8 hours

increase to 1500 mg during a

patients without relevant comorbidities or risks

disease flare

Higher dose (eg, 500 mg base twice daily) may have less

Naproxen

Naproxen

sodium: 275 to 550 mg every 12

sodium: 1375 mg (acute); 1100 mg

hours or 275 mg

(chronic); may

every 6 to 8

increase to 1650

hours

mg during a disease flare

1200 mg once daily

cardiovascular toxicity than comparable doses of other

NSAIDs;[2] refer to UpToDate topic review of cardiovascular effects of nonselective NSAIDs Naproxen sodium has a faster onset than naproxen base

1200 mg or 1800 mg depending on

Prolonged half-life (41 to 55 hours); requires several days of

body weight

treatment to reach full effect

(refer to Lexicomp drug monograph) Salicylate (acetylated) Aspirin

325 to 1000 mg every 4 to 6 hours

4000 mg

Not commonly used for chronic pain and inflammation High daily doses have been used as antiinflammatory therapy; such use is limited by toxicity Irreversibly inhibits platelet function Refer to appropriate clinical topics and Lexicomp drug monograph for other uses

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Salicylates (nonacetylated) Diflunisal

500 mg every 8

1500 mg

to 12 hours

No significant effect on platelet function at usual doses Relatively lower GI bleeding risk

Magnesium

1160 mg every 6

salicylate

hours

4640 mg

than other nonselective NSAIDs at usual doses May be tolerated at lower daily

Salsalate

1000 mg every 8

3000 mg

to 12 hours or

doses by adults with AERD or pseudoallergic reactions (eg, asthma, rhinosinusitis); refer to

1500 mg every

UpToDate topic reviews of

12 hours

allergic and pseudoallergic reactions to NSAIDs

COX-2 selective NSAIDs Celecoxib

200 mg daily or

400 mg

100 mg every 12 hours

Less risk of GI toxicity relative to nonselective NSAIDs; benefit negated by low-dose aspirin, which may require concurrent gastroprotection No effect on platelet function Cardiovascular and kidney risks are dose-related and may be similar to nonselective NSAIDs May be tolerated by patients with AERD or pseudoallergic reactions (eg, asthma, rhinosinusitis) who cannot take other NSAIDs; refer to UpToDate topic reviews of allergic and pseudoallergic reactions to NSAIDs

Etoricoxib (not available in the

30 to 60 mg once daily

United States)

60 mg (chronic pain and

May be associated with more frequent and severe dose-related

inflammation)

cardiovascular effects (eg, hypertension)

120 mg (acute pain for up to 8 days)

Other risks and benefits similar to celecoxib

Non-NSAID analgesic Acetaminophen (paracetamol)Δ

325 to 650 mg every 4 to 6 hours

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3000 mg 4000 mg in selected

Effective for noninflammatory pain; may decrease opioid requirements 23/26

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or 1000 mg every 6 hours up to three times per day

medically supervised patients Avoid or use a lower total daily dose (maximum 2000 mg) in older adults, patients at increased risk for hepatotoxicity (eg, regular alcohol use, malnourished),

Doses ≤2000 mg per day do not appear to increase risk of serious GI complications[3] Does not alter platelet function Can cause hepatotoxicity in chronic or acute overdose To avoid overdose, warn patients about acetaminophen content in combination prescription (eg, oxycodone-acetaminophen) and non-prescription (OTC) preparations

or with organ dysfunction NSAIDs are useful for treatment of acute and chronic painful and inflammatory conditions and may reduce opioid requirements. The indications for use of NSAIDs in specific disorders, adverse effects, and toxicities are presented in the relevant UpToDate topics including reviews of NSAID-associated adverse cardiovascular effects, gastroduodenal toxicity, acute kidney injury, etc. UpToDate contributors generally avoid use of NSAIDs, or use them with particular caution, in older adults and patients (regardless of age) with existing or increased risk for cardiovascular, GI, or kidney disease. Concurrent gastroprotection (eg, a proton pump inhibitor) may be warranted. For information on gastroprotective strategies, including use of selective COX-2 inhibitors and other options, refer to the UpToDate topic reviews of COX-2 selective NSAIDs and NSAIDs (including aspirin) and primary prevention of gastroduodenal toxicity. Short- to moderate-acting NSAIDs (eg, naproxen, ibuprofen) are preferred for most patients. Use the lowest effective dose for the shortest duration of time. For chronic inflammatory conditions, a trial of ≥2 weeks is advised to assess full efficacy. For patients who experience an inadequate response to an NSAID of one class, it is reasonable to substitute an NSAID of another class. Dosing in this table is for immediate-release preparations in patients with normal organ (eg, kidney) function. For treatment of acute pain, a loading dose of some NSAIDs may be used; refer to Lexicomp drug monographs. Drug interactions may be determined by use of the Lexicomp drug interactions program included within UpToDate. GI: gastrointestinal; AERD: aspirin-exacerbated respiratory disease; COX-2: cyclooxygenase, isoform 2; CNS: central nervous system; ODT: orally disintegrating tablet. * Nonselective NSAIDs reversibly inhibit platelet function, with some exceptions noted above. ¶ Also available as a topical agent. Δ Also available for parenteral use.

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References: 1. Murray MD, Brater DC. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annu Rev Pharmacol Toxicol 1993; 33:435. 2. Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomized trials. Lancet 2013; 382:769. 3. McCrae JC, Morrison EE, MacIntyer IM, et al. Long-term adverse effects of paracetamol – a review. Br J Clin Pharmacol 2018; 84:2218. Adapted from: Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All rights reserved.

Graphic 70067 Version 60.0

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Contributor Disclosures Christopher L Knight, MD No relevant financial relationship(s) with ineligible companies to disclose. Richard A Deyo, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Thomas O Staiger, MD No relevant financial relationship(s) with ineligible companies to disclose. Joyce E Wipf, MD No relevant financial relationship(s) with ineligible companies to disclose. Steven J Atlas, MD, MPH Equity Ownership/Stock Options: Stryker Corp. All of the relevant financial relationships listed have been mitigated. Lisa Kunins, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy



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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Evaluation of low back pain in adults Authors: Stephanie G Wheeler, MD, Joyce E Wipf, MD, Thomas O Staiger, MD, Richard A Deyo, MD, MPH, Jeffrey G Jarvik, MD, MPH Section Editor: Steven J Atlas, MD, MPH Deputy Editor: Lisa Kunins, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: May 26, 2022.

INTRODUCTION It is estimated that up to 84 percent of adults have low back pain at some time in their lives [1,2]. For many individuals, episodes of back pain are self-limited. Patients who continue to have back pain beyond the acute period (four weeks) have subacute back pain (lasting between 4 and 12 weeks) and may go on to develop chronic back pain (persists for ≥12 weeks) [3]. Rarely, back pain is a harbinger of serious medical illness. This discussion will focus on an approach to the initial evaluation, including diagnostic tests, of a patient presenting with low back pain in the primary care setting. The treatment of acute, subacute, and chronic low back pain are discussed separately. (See "Treatment of acute low back pain" and "Subacute and chronic low back pain: Nonpharmacologic and pharmacologic treatment" and "Subacute and chronic low back pain: Nonsurgical interventional treatment" and "Subacute and chronic low back pain: Surgical treatment".) (Related Pathway(s): Low back pain: Initial evaluation of an adult with acute, nontraumatic low back pain.)

TERMINOLOGY Several terms are used to describe conditions related to the back, based upon radiologic findings (eg, spondylosis), physical findings (radiculopathy), and symptoms (sciatica). These terms are defined in the table (

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table 1).

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EPIDEMIOLOGY In 2010, back symptoms were the principal reason for 1.3 percent of office visits in the United States [4]. Spinal disorders accounted for 3.1 percent of diagnoses in outpatient clinics. Prevalence — The prevalence of back pain has been estimated with surveys [1,5]. A 2012 systematic review estimated that the global point prevalence of activity-limiting low back pain lasting for more than one day was 12 percent and the one-month prevalence was 23 percent [6]. Other survey estimates of the prevalence of low back pain have ranged from 22 to 48 percent, depending on the population and definition [2,7-9]. For example, the 2002 National Health Interview Survey found that 26 percent of respondents reported low back pain lasting at least one day in the last three months [7]. Risk factors — Risk factors associated with back pain complaints include smoking, obesity, age, female sex, physically strenuous work, sedentary work, psychologically strenuous work, low educational attainment, Workers' Compensation insurance, job dissatisfaction, and psychologic factors such as somatization disorder, anxiety, and depression [2,8,10-15].

ETIOLOGIES Although there are many etiologies of low back pain (

table 2), the majority of patients seen

in primary care will have nonspecific low back pain. Nonspecific back pain — The vast majority of patients seen in primary care (>85 percent) will have nonspecific low back pain, meaning that the patient has back pain in the absence of a specific underlying condition that can be reliably identified [16-18]. Many of these patients may have musculoskeletal pain [3]. Most patients with nonspecific back pain improve within a few weeks. (See "Treatment of acute low back pain", section on 'Prognosis'.) Serious etiologies — Among patients who present with back pain to primary care settings, less than 1 percent will have a serious etiology (cauda equina syndrome, metastatic cancer, and spinal infection) [5,19]. Almost all patients with these conditions will have risk factors or other symptoms [18]. ●

Spinal cord or cauda equina compression – There are many causes of cauda equina syndrome, the most common being herniation of the intervertebral disc. In one systematic review, although based upon case reports and therefore subject to publication

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bias, cauda equina syndrome was caused by herniation of the intervertebral disc in 22.7 percent of cases, ankylosing spondylitis in 15.9 percent, lumbar puncture in 15.9 percent, trauma in 7.6 percent, malignant tumor in 7.2 percent, benign tumor in 5.7 percent, and infection in 5.3 percent [20]. While the incidence of cord compression in patients known to have cancer varies depending upon the cancer, among patients who are diagnosed with cord compression, it is the initial manifestation of malignancy in 20 percent [21]. Metastatic disease from any primary cancer can cause cord compression. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Epidemiology' and "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Pathophysiology'.) Pain is usually the first symptom of cord compression, but motor (usually weakness) and sensory findings are present in the majority of patients at diagnosis. Bowel and/or bladder dysfunction are generally late findings. Early diagnosis and treatment improves outcomes. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features' and "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Importance of early detection'.) ●

Metastatic cancer – The bone is one of the most common sites of metastasis. A history of cancer (excluding nonmelanoma skin cancers) is the strongest risk factor for back pain from bone metastasis [22]. Among solid cancers, metastatic disease from breast, prostate, lung, thyroid, and kidney cancers account for 80 percent of skeletal metastases. Approximately 60 percent of patients with multiple myeloma have skeletal lytic lesions present at diagnosis. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults", section on 'Epidemiology' and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Skeletal surveys'.) Pain is the most common symptom. In patients with a history of cancer, sudden, severe pain raises concern for pathologic fracture. Patients may also have neurologic symptoms from either spinal cord compression or spinal instability. Diagnostic imaging in the evaluation of osseous metastases in a patient with cancer and back pain is reviewed in detail elsewhere (

algorithm 1). (See "Epidemiology, clinical presentation, and diagnosis

of bone metastasis in adults", section on 'Clinical presentation'.) ●

Spinal epidural abscess – Spinal epidural abscess is a rare but serious cause of back pain. Initial symptoms (eg, fever and malaise) are often nonspecific; over time, localized back pain may be followed by radicular pain and, left untreated, neurologic deficits. Risk factors include recent spinal injection or epidural catheter placement, injection drug use, and other infections (eg, contiguous bony or soft tissue infection or bacteremia).

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Immunocompromised patients may also be at higher risk. Treatment of spinal epidural abscess is reviewed in detail elsewhere. (See "Spinal epidural abscess", section on 'Management'.) ●

Vertebral osteomyelitis – The majority of patients with vertebral osteomyelitis will present with back pain, which gradually increases over weeks to months [23]; fever may or may not be present. The intervertebral disc may also be become infected (discitis), and the clinical presentation (positional discomfort, pain to palpation, neurologic signs/symptoms) may vary depending upon the extent of the infection. (See "Vertebral osteomyelitis and discitis in adults", section on 'Clinical features'.) The incidence of vertebral osteomyelitis generally increases with age, and males are more commonly affected than females. Many cases are thought to be health care-related or postprocedural from hematogenous spread of bacteremia. Less specific risk factors include an immunocompromised state and injection drug use. (See "Vertebral osteomyelitis and discitis in adults", section on 'Epidemiology' and "Vertebral osteomyelitis and discitis in adults", section on 'Pathogenesis'.) Management of vertebral osteomyelitis is discussed in detail elsewhere. (See "Vertebral osteomyelitis and discitis in adults", section on 'Treatment'.)

Less serious etiologies — Less than 10 percent of patients who present in primary care settings with low back pain will have less serious but specific etiologies for their pain [19,24]; approximately 3 to 4 percent have symptomatic disc herniation or spinal stenosis. ●

Vertebral compression fracture – Approximately 4 percent of patients presenting in the primary care setting with low back pain will have a vertebral compression fracture [19]. While some produce no symptoms, other patients present with acute onset of localized back pain which may be incapacitating. There may be no history of preceding trauma. Risk factors for osteoporotic fracture include advanced age and chronic glucocorticoid use ( table 3). A history of an osteoporotic or traumatic fracture is a risk factor for subsequent fractures [25], which can be mitigated by pharmacologic therapy. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Clinical manifestations' and "Osteoporotic fracture risk assessment" and "Overview of the management of osteoporosis in postmenopausal women", section on 'Post-fracture'.)

●

Radiculopathy – Radiculopathy refers to symptoms or impairments related to a spinal nerve root. Damage to a spinal nerve root may result from degenerative changes in the vertebrae, disc protrusion, and other causes. The clinical presentations of lumbosacral

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radiculopathy vary according the level of nerve root or roots involved. Over 90 percent are L5 and S1 radiculopathies [26]. Patients present with pain, sensory loss, weakness, and/or reflex changes consistent with the nerve root involved; these are summarized in the table and discussed in more detail separately ( compression is shown in a figure (

table 4). Testing for lumbar nerve root

figure 1). Many patients with symptoms of acute

lumbosacral radiculopathy improve gradually with supportive care. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Pathophysiology and etiology' and "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Clinical presentations' and "Acute lumbosacral radiculopathy: Treatment and prognosis", section on 'Prognosis'.) Sciatica is a nonspecific term used to describe a variety of leg or back symptoms. Usually, sciatica refers to a sharp or burning pain radiating down from the buttock along the course of the sciatic nerve (the posterior or lateral aspect of the leg, usually to the foot or ankle) [27]. Most sciatica is attributable to radiculopathy at the L5 or S1 level from a disc disorder. ●

Spinal stenosis – Lumbar spinal stenosis is most often multifactorial. Spondylosis (degenerative arthritis affecting the spine), spondylolistheses, and thickening of the ligamentum flavum are the most common causes, typically affecting patients >60 years ( figure 2). (See "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis", section on 'Etiologies'.) Ambulation-induced pain localized to the calf and distal lower extremity resolving with sitting or leaning forward ("pseudoclaudication" or "neurogenic claudication") is a hallmark of lumbar spinal stenosis. Other symptoms of lumbar spinal stenosis can include back pain and sensory loss and weakness in the legs, though many patients may present with a normal neurologic exam. Symptoms of neurogenic claudication can usually be distinguished from vascular claudication (

table 5). Rare patients develop a cauda

equina syndrome. Patients often have symptoms only when active. Most patients with spinal stenosis related to osteoarthritis will have stable symptoms over time. A trial of conservative, nonsurgical treatment is the initial therapy for most patients [28]. (See "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis", section on 'Clinical presentation' and "Lumbar spinal stenosis: Treatment and prognosis", section on 'Prognosis' and "Lumbar spinal stenosis: Treatment and prognosis", section on 'Nonsurgical treatment'.) Other etiologies https://www.uptodate.com/contents/7782/print

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Ankylosing spondylitis – Among patients who present in primary care settings for back pain, it is estimated that approximately 0.5 percent will have ankylosing spondylitis [19,24]. It is most commonly diagnosed in men under the age of 40 years. (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Epidemiology'.) Almost all patients report back pain, which often has characteristics suggesting an inflammatory etiology (morning stiffness, improvement with exercise, pain at night) [3]. Patients may also have extraskeletal disease manifestations (eg, uveitis). (See "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Musculoskeletal symptoms and findings' and "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Extraarticular manifestations'.)

●

Osteoarthritis – Low back pain may be a symptom of osteoarthritis of the facet joints spine. Patients may also complain of hip pain, either from osteoarthritis of the hip or referred pain from the spine. Osteoarthritis most commonly presents in patients over the age of 40. Pain is typically exacerbated by activity and relieved by rest (

table 6).

Osteoarthritis can lead to spinal stenosis. (See "Clinical manifestations and diagnosis of osteoarthritis", section on 'Facet joint'.) ●

Scoliosis and hyperkyphosis – Back pain can be associated with scoliosis and hyperkyphosis. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Outcome' and "Hyperkyphosis in older persons", section on 'Other health-related consequences'.)

●

Psychologic distress – Psychologic distress (eg, depression or somatization) may contribute to the severity symptoms of low back pain or may be a cause of nonorganic back pain [3]. (See "Somatic symptom disorder: Epidemiology and clinical presentation", section on 'Clinical presentation'.)

●

Etiologies outside the spine – Low back pain may be a symptom of problems outside the back. Examples of other etiologies include pancreatitis, nephrolithiasis, pyelonephritis, abdominal aortic aneurysm, or herpes zoster [3,17]. Patients generally have other accompanying symptoms. (See "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Clinical features' and "Acute complicated urinary tract infection (including pyelonephritis) in adults", section on 'Clinical manifestations' and "Clinical features and diagnosis of abdominal aortic aneurysm", section on 'Clinical presentations'

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and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Clinical manifestations' and "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis", section on 'Clinical manifestations'.) There are also clinical entities that are possibly associated with low back pain symptoms: ●

Piriformis syndrome – The piriformis syndrome is thought by some to be a condition in which the piriformis muscle, a narrow muscle located in the buttocks, compresses or irritates the sciatic nerve [27,29,30].

●

Sacroiliac joint dysfunction – "Sacroiliac joint dysfunction," a term to describe pain in the region of the sacroiliac joint believed to be due to malalignment or abnormal joint movement, is a controversial topic. Diagnosing this condition is difficult due to the absence of an agreed upon “gold standard” [31]. Tests of pelvic symmetry or sacroiliac joint movement have been shown to have low intertester reliability [32-38], and provocative maneuvers such as fluoroscopically guided injections of the sacroiliac joint have been unreliable in diagnosis and treatment [37,39,40]. The sacroiliac joint may be a referred site of pain, including from a degenerative disc at L5-S1, spinal stenosis, or osteoarthritis of the hip.

●

Bertolotti's syndrome – Back pain in the setting of a transitional vertebra is known as "Bertolotti's syndrome." A transitional vertebra is a common finding on radiologic studies. It is a congenital anomaly with a naturally occurring articulation or bony fusion between the transverse processes of L5 and the sacrum. Estimates of prevalence of transitional vertebra range from 4 to 36 percent [41]. It remains unclear whether these individuals have a higher risk of back pain than those without such an anomaly. Generally, patients with Bertolotti's syndrome should initially be treated similarly as patients with nonspecific back pain. Whether and when surgical intervention is appropriate remains unclear.

INITIAL EVALUATION The clinical evaluation of low back pain includes a history and physical to evaluate for signs or symptoms that indicate need for immediate imaging and further evaluation. For most patients with acute back pain (50 years, unexplained weight loss, duration of pain >1 month, nighttime pain, and unresponsiveness to previous therapies [3]. Documented fevers, injection drug use, recent bacterial infection (particularly bacteremia), or recent epidural or spinal instrumentation increase the suspicion of spinal infection. (See "Spinal epidural abscess" and "Vertebral osteomyelitis and discitis in adults".) Physical examination — In general, the purpose of the physical examination is to identify features that suggest that further evaluation is indicated, rather than to make a primary diagnosis. The physical examination should include the following components: ●

Inspection of back and posture – Inspection of the patient on physical examination can reveal anatomic abnormalities such as scoliosis or hyperkyphosis (

table 1). (See

"Hyperkyphosis in older persons".) ●

Palpation/percussion of the spine – Palpation and/or percussion of the back is usually performed to assess vertebral or soft tissue tenderness. Vertebral tenderness is a sensitive, but not specific, finding for spinal infection, and may also be seen in patients with vertebral metastases and osteoporotic compression fracture [42]. (See "Vertebral osteomyelitis and discitis in adults", section on 'Symptoms and signs'.)

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Neurologic examination – Patients should have a neurologic examination including evaluation of the reflexes, strength, sensation, and gait. (See "The detailed neurologic examination in adults".)

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For patients suspected of having a radiculopathy, neurologic testing should focus on the L5 and S1 nerve roots (

table 4), since most clinically significant radiculopathies occur at

these levels. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Physical examination'.) ●

Straight leg raising – The straight leg raise and other maneuvers can be helpful in identifying whether symptoms are radicular in nature. These are described separately. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Maneuvers'.)

●

Nonorganic signs (Waddell's signs) – Patients with psychologic distress that is contributing to back pain symptoms may have associated inappropriate physical signs, also known as "Waddell's signs" (

table 7). These include patient overreaction during

physical examination, superficial tenderness, straight leg raise that improves when the patient is distracted, unexplainable neurological deficits (eg, nondermatomal distribution of sensory loss, sudden giving way or jerky movements with motor exam, inconsistency in observed spontaneous activity [dressing, getting off table]), and pain elicited by axial loading (pressing down on top of head, or rotating the body at hips or shoulders) [43]. The presence of multiple Waddell's signs suggests a psychologic component to a patient's pain, although they do not seem to be useful for predicting the ability to return to work or success of rehabilitation [3,44,45]. ●

Other – For patients with new or worsening urinary incontinence, we measure bladder post void residual (eg, by ultrasound) to differentiate overflow incontinence from urge and/or stress incontinence. If a patient's history strongly suggests malignancy, we evaluate as appropriate (eg, lymph node exam, breast exam, prostate evaluation). Other physical examination components (eg, hip examination or examination for peripheral vascular disease) should be performed based on the history. (See "Clinical features and diagnosis of lower extremity peripheral artery disease", section on 'Physical examination' and "Approach to the adult with unspecified hip pain", section on 'Diagnostic approach'.)

Laboratory studies — Most patients with acute low back pain do not require any laboratory testing. In some patients with suspected infection or malignancy, we use the erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) in addition to plain radiographs to determine the need for advanced imaging [22,46-48]. Because of its higher sensitivity, CRP may have similar or greater value than the ESR; however, CRP has not been similarly evaluated in the evaluation of low back pain. (See 'Risk assessment for acute back pain' below.)

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The ESR and CRP are also used in the diagnosis of ankylosing spondylitis. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Laboratory testing'.)

IMAGING Limited utility of imaging — Earlier use of imaging for low back pain without associated symptoms is not associated with improved outcomes but increases the use of invasive procedures and likely health care costs [49]. As examples: ●

A 2009 systematic review and meta-analysis of six trials that compared immediate imaging (lumbosacral spine magnetic resonance imaging [MRI], computed tomography [CT], or radiography) with usual care for patients with acute and subacute low back pain, without signs or symptoms of infection or malignancy, found no differences in short-term (up to three months) or long-term (6 to 12 months) outcomes for measures of patient pain or function [50].

●

In subsequent observational studies:

• In patients ≥65 years with back pain without radiculopathy, there were no differences in disability at one year for patients who received early imaging (within six weeks of the index visit) compared with those who did not [51].

• In a cohort study including 405,000 US Department of Veterans Affairs (VA) patients with nonspecific low back pain and no concerning features for malignancy or infection, imaging with lumbar MRI within six weeks of initial presentation was associated with a greater likelihood of back surgery (1.5 versus 0.1 percent), treatment with opioids (35 versus 29 percent), and greater costs (USD $8000 versus $5500) at one year [49]. Additionally, imaging exams often show abnormal findings in adults without low back pain, which makes it difficult to determine which imaging findings are clinically significant. As an example, disc herniations on MRI are seen in 22 to 67 percent of asymptomatic adults and spinal stenosis in 21 percent of asymptomatic adults over age 60 [52-54]. Osteoarthritis is also often seen on imaging but correlates poorly with symptoms [55]. In a study of 188 individuals 40 to 80 years old, 60 percent of males and 67 percent of females had facet joint osteoarthritic changes on lumbar CT scans; the prevalence of radiologic facet joint osteoarthritis increased with age, but there was no correlation with low back pain [56]. In addition, in a systematic review of 33 studies of asymptomatic adults, the prevalence of degenerative lumbar spine changes (identified on CT or MRI) increased with age [57]. Facet joint degeneration, for https://www.uptodate.com/contents/7782/print

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example, was observed among 9 percent of adults in their 30s and 83 percent of those in their 80s. Disc degeneration was observed in 52 percent of adults in their 30s and 96 percent of those in their 80s. Most findings had monotonic increases with each decade of age. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Neuroimaging' and "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis", section on 'Neuroimaging'.) Even when the radiographic findings are consistent with clinical presentation, the magnitude of radiographic findings does not necessarily correlate with clinical severity and outcome, and clinical improvement may not correlate with resolution of the radiographic defect [58,59]. As an example, in one follow-up of a trial of 283 patients with lumbar disk herniation and sciatica who had undergone surgery, MRI at one-year follow-up showed disk herniation in 35 and 33 percent of patients with favorable and unfavorable outcomes, respectively [59]. Some findings on MRI are clinically insignificant or of uncertain significance. These include: ●

Annular fissures (tears) – Annular fissures, colloquially termed tears, are separations between the annular fibers of the intervertebral disc or separations of annular fibers from their attachments to the vertebral bone. Several small studies found no correlation between the presence of annular fissure and back pain [60-62]. As an example, a prospective study of asymptomatic patients found that 38 percent had evidence of annular fissures at baseline [63]. Follow-up after three years showed that annular fissures were not associated with new back pain [60].

●

Schmorl's nodes – Schmorl's nodes, representing herniation of the nucleus pulposus into the adjacent end plate, can be seen in approximately 20 percent of MRI studies in patients without back pain (

image 1) [64]. Although Schmorl's nodes are associated with

degenerative changes in the lower back, they are not an independent risk factor for back pain [65]. ●

Modic changes – Modic changes (also known as degenerative endplate changes) are of unclear clinical significance. They refer to specific signal changes in the vertebral endplate and adjacent bone marrow on a spine MRI [66]. These changes occur in 6 to 10 percent of asymptomatic adults and are common in patients with back pain, with any type of Modic change typically reported in about 20 to 40 percent of patients [67,68]. The prevalence of Modic changes increases with age and appears to be associated with degenerative disc changes. A systematic review found only a small number of treatment studies involving patients with Modic changes and concluded that it is unclear whether the presence of

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these changes is helpful in guiding the selection of treatment options [69]. Additionally, the type of Modic change in a single patient may progress or regress over time [70]. Modalities — The main imaging modalities to evaluate back pain are spine MRI, CT, and plain radiographs. Initial imaging is not indicated in the majority of patients with low back pain. (See 'Indications for imaging' below.) ●

Advanced imaging – For most patients with low back pain who require advanced imaging, lumbar spine MRI is generally considered the best initial examination [71,72]. It provides axial as well as sagittal views and demonstrates discs, ligaments, nerve roots, and epidural fat, as well as the shape and size of the spinal canal. MRI is more sensitive and specific than plain radiographs for the detection of spinal infection and malignancy [19]. In patients where there is a suspicion for cancer, infection, or immunosuppression, MRI is performed without and with intravenous contrast to evaluate for underlying infection or mass. Enhancement with gadolinium also allows the distinction of scar from disc in patients with prior back surgery. In patients who require advanced imaging but cannot undergo MRI, we generally proceed with lumbar spine CT with contrast [72]. If iodinated contrast is contraindicated, CT without contrast is acceptable. Neither Tc-99m bone scan nor myelography are considered appropriate for the initial evaluation of patients with back pain. (See 'Infection' below and "Patient evaluation for metallic or electrical implants, devices, or foreign bodies before magnetic resonance imaging", section on 'Assessing implants, devices, or foreign bodies for MRI'.)

●

Plain radiographs – When plain radiographs are indicated, anteroposterior and lateral views of the lumbar spine are usually adequate. Oblique and spot views substantially increases the radiation dose and adds little new diagnostic information [73]. Flexionextension views may be helpful in patients for whom instability is a concern (eg, spondylolisthesis that worsens with flexion). Plain radiographs are a reasonable option for imaging in patients who have risk factors for malignancy [19], and they are often combined with the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) for evaluation (see 'Cancer' below and 'Cancer risk' below). Plain radiographs may also be an option for in patients with osteoporosis where the primary concern is detection of a compression fracture [74].

Indications for imaging — The majority of patients with low back pain of less than four weeks duration do not require imaging [17]. Most patients who present to primary care settings will have nonspecific pain without associated symptoms and will improve rapidly. (See 'Etiologies' https://www.uptodate.com/contents/7782/print

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above and "Treatment of acute low back pain", section on 'Prognosis'.) (Related Pathway(s): Low back pain: Initial evaluation of an adult with acute, nontraumatic low back pain.) Approximately one-quarter of patients 18 to 50 years of age with acute low back pain who underwent imaging exams had no identifiable indication for imaging [75]. Inappropriate lumbar imaging can lead to irrelevant findings and trigger additional costly studies, unneeded treatments, and unwarranted surgical interventions [76-78]. Joint guidelines from the American College of Physicians (ACP) and the American Pain Society explicitly recommend that "clinicians should not routinely obtain imaging or other diagnostic tests in patients with nonspecific low back pain" and reserve imaging for patients with severe or progressive neurologic deficits or when serious underlying conditions are suspected on the basis of history and physical examination [17,18]. Guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom advise clinicians to “not routinely offer imaging in a non-specialist setting for people with low back pain with or without sciatica” [79]. The ACP provides practical advice about when imaging studies should be considered in patients with acute low back pain (

table 8), and our recommendations below are consistent, with the

exception of imaging for suspected vertebral compression fracture. Avoiding imaging in acute low back pain has been identified as a recommendation in the American Board of Internal Medicine's "Choosing Wisely" campaign. Red flags — Some guidelines suggest "red flag" symptoms, which may identify patients at risk for a more dangerous cause of back pain and represent an indication for earlier imaging exams [5,17,18,80]. There are limited data to support the use of most of the red flags as an indication for early imaging [81]. Systematic reviews of studies that used one or more of these indications for imaging found that only a history of cancer has been shown to increase the probability of finding spinal malignancy [82,83]. Systematic reviews have found that the red flags associated with the highest post-test probability of a vertebral fracture were older age, prolonged use of corticosteroids, severe trauma, and presence of contusion or abrasion [82,84]. Risk assessment for acute back pain — Among patients seen in primary care, less than one percent will have a serious systemic etiology that requires evaluation with immediate advanced imaging (

algorithm 2). (See 'Serious etiologies' above and 'Modalities' above and 'Less

serious etiologies' above.) Neurologic deficits — Indications for imaging in the presence of neurologic symptoms depends upon the nature of the symptoms and the patient's risk factors for cancer and/or an infectious etiology of back pain ( https://www.uptodate.com/contents/7782/print

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Any patient with symptoms of spinal cord or cauda equina compression or progressive and/or severe neurologic deficits should have immediate MRI for further evaluation and urgent specialist referral. Such symptoms and signs include new urinary retention, urinary incontinence from bladder overflow, new fecal incontinence, saddle anesthesia, and significant motor deficits not localized to a single nerve root. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Magnetic resonance imaging of the spine' and "Spinal epidural abscess", section on 'Diagnosis'.)

●

Patients with radiculopathy attributable to a single nerve root level or with stable symptoms due to spinal stenosis do not need immediate imaging unless there is a risk of metastatic cancer or moderate to high risk of infection.

• Such patients (who have a risk of metastatic cancer or in whom there is moderate to high risk of infection) should undergo immediate MRI. (See 'Serious etiologies' above.)

• For all patients with radiculopathy attributable to a single nerve root level, we image with MRI if there is no improvement in symptoms after four to six weeks of conservative therapy. There is no indication to re-image patients with spinal stenosis symptoms if previous MRI was performed and symptoms are stable. (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis", section on 'Evaluation and diagnosis' and "Lumbar spinal stenosis: Pathophysiology, clinical features, and diagnosis", section on 'Diagnosis' and 'Radiculopathy or lumbar spinal stenosis' below.) Infection — For patients in whom there is a suspicion for spinal infection (including vertebral osteomyelitis or spinal epidural abscess), the evaluation should be guided by the degree of suspicion ( ●

algorithm 2).

Moderate to high clinical suspicion for infection – For patients with low back pain in whom there is moderate to high clinical suspicion for spinal infection, immediate MRI without and with contrast is indicated (

algorithm 2) [74].

Sign and symptoms of infection may include objective fever, tenderness to palpation (vertebral osteomyelitis), and neurologic symptoms (spinal epidural abscess). Risk factors for infection include:

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• Current or recent invasive epidural/spinal procedure • Current or recent endocarditis or bacteremia MRI is the most sensitive imaging modality for detecting spinal infection with sensitivity of 0.96 and specificity of 0.92 [19]. For patients who are unable to obtain an MRI, a CT scan is a useful alternative to evaluate for epidural abscess, while radionuclide scans are an option to evaluate for osteomyelitis. The evaluation and diagnosis of these conditions are discussed in detail separately. (See "Spinal epidural abscess", section on 'Diagnosis' and "Spinal epidural abscess" and "Vertebral osteomyelitis and discitis in adults", section on 'Suggested clinical approach' and "Vertebral osteomyelitis and discitis in adults", section on 'Radiographic imaging'.) ●

Lower concern for infection – When there is a lower level of concern for the possibility of an infectious cause of back pain, it is reasonable to first evaluate patients with ESR and/or CRP. Patients with an elevated ESR and/or CRP should be evaluated with MRI ( algorithm 2). (See "Spinal epidural abscess", section on 'Diagnosis' and "Vertebral osteomyelitis and discitis in adults", section on 'Suggested clinical approach'.) In patients with osteomyelitis or other spinal infection, the sensitivity of an elevated ESR is 0.76 to 0.95 and the sensitivity of an elevated CRP is 0.82 to 0.98 [3-5]. Infection is very unlikely in patients with an ESR 30 minutes. ¥ Further testing first involves revisiting the feasibility of CT pulmonary angiography. If CT pulmonary angiography is still not feasible then lower extremity compression ultrasonography with Doppler is appropriate. Graphic 113962 Version 1.0

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Evaluation of the nonpregnant adult with high probability of pulmonary embolism

CT pulmonary angiography is also called chest CT angiogram with contrast and is tailored for to evaluate the pulmonary arteries. A conventional chest CT with contrast is not adequate to exclude PE. PE: pulmonary embolism; CT: computed tomography. * We prefer the Wells criteria to determine the pretest probability of PE, although the modified Geneva score or clinical gestalt is also appropriate. Refer to UpToDate text for details. ¶ Feasibility requires adequate scanner technology. Also the patient must be able to lie flat, to cooperate with exam breath-holding instructions, have a body habitus that can fit into scanner, and no contraindications for iodinated contrast. Δ Repeat CT pulmonary angiography for more definitive results may be worthwhile if the factor causing poor image quality can be mitigated (eg, patient more capable of co-operating with positioning and breath-holding instructions). Repeat imaging is unlikely to prove useful if exam is nondiagnostic from factors such as scanner technology, body habitus, or indwelling metallic foreign bodies.

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◊ Feasibility requires a chest radiograph demonstrating clear lungs and a patient able to lie still for >30 minutes. § Further testing first involves revisiting the feasibility of CT pulmonary angiography. If CT pulmonary angiography is still not feasible then lower extremity compression ultrasonography with Doppler is appropriate. Graphic 113961 Version 1.0

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Pulmonary embolism severity index scores: Full and simplified Pulmonary embolism severity index (PESI) - Full Clinical feature

Points

Age

x (eg, 65)

Male gender

10

History of cancer

30

Heart failure

10

Chronic lung disease

10

Pulse ≥110/min

20

Systolic blood pressure 40 mmHg, hypotension requiring vasopressors, or clear evidence of shock). Importantly, these high-risk patients are a heterogeneous group [8] with the extremely unstable patients suffering cardiac arrest.

●

Hemodynamically stable PE is defined as PE that does not meet the definition of hemodynamically unstable PE. These patients are also a very heterogeneous group ranging from patients with small PE, stable BP, normal right ventricular size and function and normal biomarkers, with a normal simplified pulmonary embolism severity index (sPESI) ("low risk") to those patients with extensive emboli with tachycardia, right ventricular dysfunction, abnormal biomarkers, and borderline BP (ie, intermediate risk "submassive" PE). Based upon the European Society of Cardiology (ESC) guidelines [8], these patients have been categorized as "intermediate-low risk" (abnormal right ventricular function or elevated serum troponin) and intermediate-high risk (abnormal right ventricular function and elevated serum troponin).

Importantly, patients may become hemodynamically stable following resuscitation, or become unstable during the evaluation and early treatment period, both of which necessitate rapid redirection of therapeutic strategies. Hemodynamically stable — The majority of patients with PE are hemodynamically stable upon presentation [11]. The initial approach should focus upon general supportive measures while the diagnostic evaluation is ongoing; supportive measures include the following (see https://www.uptodate.com/contents/8265/print

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"Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism" and 'Hemodynamically stable patients' below): ●

Peripheral intravenous access with or without intravenous fluids (see 'Hemodynamic support' below)

●

Oxygen supplementation (see 'Respiratory support' below)

●

Empiric anticoagulation depending upon the clinical suspicion for PE, risk of bleeding, and expected timing of definitive diagnostic tests (see 'Empiric anticoagulation' below)

Hemodynamically unstable — A small percentage of patients with PE present with hemodynamic instability or shock (approximately 8 percent, ie, high-risk or "massive" PE). When patients with suspected PE present with hypotension, initial support should focus upon restoring perfusion with intravenous fluid resuscitation and vasopressor support, as well as oxygenation and, if necessary, stabilizing the airway with intubation and mechanical ventilation. (See 'Hemodynamic support' below and 'Respiratory support' below and "Overview of acute pulmonary embolism in adults", section on 'Nomenclature'.) ●

For most patients who become hemodynamically stable following resuscitation and in whom the clinical suspicion for PE is high, we prefer immediate anticoagulation with unfractionated heparin and prompt imaging for definitive diagnosis (usually computed tomographic pulmonary angiography [CTPA]). For patients with a moderate or low suspicion for PE, the use of empiric anticoagulation depends upon the timing of diagnostic testing. Diagnostic testing in patients with suspected PE is presented elsewhere. (See 'Empiric anticoagulation' below and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically stable patients'.)

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For patients with a high clinical suspicion for PE who are hemodynamically unstable (ie, systolic blood pressure 15 minutes, hypotension requiring vasopressors, or clear evidence of shock), and in whom transfer to radiology for a CTPA is considered unsafe, a portable perfusion scan can be done at some centers. When portable perfusion scanning or CTPA is not available or is unsafe, we prefer bedside echocardiography (transthoracic or transesophageal) to obtain a presumptive diagnosis of PE (right ventricle enlargement/hypokinesis, regional wall motion abnormalities that spare the right ventricular apex [McConnell's sign], or visualization of clot) prior to the empiric administration of systemic thrombolytic therapy (ie, reperfusion therapy). If bedside echocardiography is delayed or unavailable, the use of thrombolytic therapy as a lifesaving measure should be individualized; if not used, the patient should receive empiric

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anticoagulation. The initiation of anticoagulation should not be delayed while considering other, more aggressive interventional therapies. We suggest a similar approach for select patients with known PE whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high. (See 'Hemodynamically unstable patients' below.) For patients with suspected PE who remain hemodynamically unstable and the clinical suspicion is low or moderate, the approach to empiric anticoagulation should be the same as for patients who are hemodynamically stable; empiric thrombolysis is not justified in this population. The echocardiographic findings suggestive of PE and the diagnostic approach to hemodynamically unstable patients, as well as the indications for thrombolytic therapy and its alternative, embolectomy, are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Echocardiography' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Hemodynamically unstable patients' and 'Embolectomy' below and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Hemodynamically unstable patients (high risk)'.) Pulmonary embolism response teams — The decision to administer thrombolysis is strongly influenced by additional clinical factors. For example, while a patient with proven PEinduced shock who is unconscious requiring very high doses of pressors is a candidate for immediate intravenous thrombolytic therapy, a patient who has low blood pressure for 20 minutes but who is awake, alert, and comfortable, with low oxygenation requirement might be considered for anticoagulation alone, or a catheter-based interventional procedure. Thus, when feasible, it is prudent to adopt a multidisciplinary approach to facilitate management of hemodynamically unstable patients with PE as well as selected patients with intermediate-high risk PE; some centers have incorporated a "pulmonary embolism response team" (PERT) to facilitate the process [12-14]. There are limited data that describe the impact of PERT. One single center retrospective study examined outcomes in patients with PE before and after the implementation of PERT [15]. PERT was associated with a reduction in 30 day inpatient mortality (4.7 versus 8.5 percent), lower rates of major bleeding (8.3 versus 17 percent), shorter time to therapeutic anticoagulation (12.6 versus 16.3 hours), and decreased use of inferior vena cava filters (22.2 versus 16.4 percent). The mortality benefit was most pronounced in the subgroup of patients with intermediate- and high-risk PE (5.3 versus 10 percent), suggesting that this population derive the greatest benefit from PERT. There was also an increased use of https://www.uptodate.com/contents/8265/print

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thrombolytic and catheter-based strategies that did not reach statistical significance. In contrast, in another single-center study of 2042 patients, among which 165 were evaluated by PERT, there was no difference in the mortality between the pre-PERT and post-PERT implementation phases [16]. The 2019 European Society of Cardiology (ESC) guidelines have included a discussion of the utility of PERT and given it a Class IIa Level C recommendation [8]. Initial therapies Respiratory support — Supplemental oxygen should be administered to target an oxygen saturation ≥90 percent. Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of intubation and mechanical ventilation. Importantly, patients with coexistent right ventricle failure are prone to hypotension following intubation. Thus, in this population, it may be prudent to consult an expert in cardiovascular anesthesia and high plateau pressures should be avoided. The principles of intubation, mechanical ventilation, and extracorporeal membrane oxygenation (which has been used successfully in severely ill patients with refractory hypoxemia and/or hypotension), are discussed separately. (See "Induction agents for rapid sequence intubation in adults outside the operating room" and "Direct laryngoscopy and endotracheal intubation in adults" and "Extracorporeal membrane oxygenation (ECMO) in adults" and "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit", section on 'Indications'.) Hemodynamic support — The precise threshold that warrants hemodynamic support depends upon the patient's baseline blood pressure and whether there is clinical evidence of hypoperfusion (eg, change in mental status, diminished urine output). In general, we prefer small volumes of intravenous fluid (IVF), usually 500 to 1000 mL of normal saline, followed by vasopressor therapy should perfusion fail to respond to IVF. ●

Intravenous fluid – IVF is first-line therapy for patients with hypotension. However, in patients with right ventricular (RV) dysfunction, limited data suggest that aggressive fluid resuscitation is not beneficial, and may be harmful [17-21]. The rationale for limiting IVF administration comes from preclinical studies and one small observational study in humans, which reported that small volumes of IVF increase the cardiac index in patients with PE, while excessive amounts of IVF result in RV overstretch (ie, RV overload), RV ischemia, and worsening RV failure. The patient's volume status should be carefully assessed as this could influence the approach to fluid administration.

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Vasopressors – Intravenous vasopressors are administered when adequate perfusion is not restored with IVF. The optimal vasopressor for patients with shock due to acute PE is

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unknown, but norepinephrine is generally preferred (

table 1) [18,22-24]. Options

include:

• Norepinephrine – Norepinephrine is the most frequently utilized agent in this population because it is effective and less likely to cause tachycardia [18]. Other alternatives include dopamine and epinephrine, but tachycardia, which can exacerbate hypotension, can occur with these agents [22].

• Dobutamine – Dobutamine is sometimes used to increase myocardial contractility in patients with circulatory shock from PE. However, it also results in systemic vasodilation which worsens hypotension, particularly at low doses [23,24]. To mitigate this effect, we typically initially add norepinephrine to dobutamine; as the dose of dobutamine is increased, the effects of dobutamine-induced myocardial contractility exceed those of vasodilation, potentially allowing norepinephrine to be weaned off. Isoproterenol, amrinone, and milrinone have been investigated in animal models, but have not proven useful for hypotension due to acute PE [25,26]. Physiologic properties and use of vasopressors are discussed separately. (See "Use of vasopressors and inotropes".) Empiric anticoagulation — The administration of empiric anticoagulation depends upon the risk of bleeding, clinical suspicion for PE (calculator 1) (

table 2) and the expected timing of

diagnostic tests [5,21]. There is no optimal prediction tool for assessing bleeding risk in patients with PE. Similarly, while many experts propose use of the Wells score to assess the risk of PE, careful clinical judgment is acceptable and many experts use gestalt estimates, the details of which are discussed separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Determining the pretest probability of pulmonary embolism' and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Assessing the risk of bleeding'.) One strategy is shown below: ●

Low risk for bleeding – Patients without risk factors for bleeding (

table 3) have a three-

month bleeding risk of 6) • A moderate clinical suspicion for PE (eg, Wells score 2 to 6), in whom the diagnostic evaluation is expected to take longer than four hours https://www.uptodate.com/contents/8265/print

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• A low clinical suspicion for PE (eg, Wells score 3 percent) to high (>13 percent) risk of bleeding. In such patients, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio and the values and preferences of the patient. Additionally, use of these bleeding estimates should not preclude clinical judgment when making a decision to anticoagulate in this population. As an example, we might empirically anticoagulate a patient with moderate risk of bleeding if they have a high clinical suspicion for PE, severe respiratory compromise, or an expected delay for the insertion of a vena caval filter. Typically, menstruation, epistaxis, and the presence of minor hemoptysis are not contraindications to anticoagulation but should be monitored during anticoagulant therapy. (See 'Monitoring and follow-up' below.) The optimal agent for empiric anticoagulation depends upon the presence or absence of hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities (

table 4). As an example, low molecular weight

heparin (LMW heparin) may be chosen for patients with hemodynamically stable PE who do not have renal insufficiency in whom rapid onset of anticoagulation needs to be guaranteed (ie, therapeutic levels are achieved with four hours). While unfractionated heparin may be preferred by most experts in patients who are hemodynamically unstable in anticipation of a potential need for thrombolysis or embolectomy, LMW heparin is not contraindicated in this setting. Direct thrombin and factor Xa inhibitors should not be used in hemodynamically unstable patients. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".)

DEFINITIVE THERAPY

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Our approach — For patients in whom the diagnostic evaluation excludes pulmonary embolism (PE) (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism"), anticoagulant therapy should be discontinued if it was initiated empirically, and alternative causes of the patient's symptoms and signs should be sought (

algorithm 1A-B).

For patients in whom the diagnostic evaluation confirms PE, we suggest an approach that is stratified according to whether the patient is hemodynamically stable or unstable ( algorithm 1A-B). At any time, the strategy may need to be redirected as complications of PE or therapy arise. (See 'Hemodynamically stable patients' below and 'Hemodynamically unstable patients' below.) (Related Pathway(s): Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically stable adults and Pulmonary embolism (confirmed or suspected): Initial management of hemodynamically unstable adults.) Hemodynamically stable patients — Patients in this group are heterogeneous and have a wide range of presentations as well as variable risk of recurrence and decompensation; it includes those with low-risk, intermediate-low risk, and intermediate-high risk PE. We suggest the following approach for most hemodynamically stable (ie, normotensive) patients with low-risk and intermediate-low risk PE ( ●

algorithm 1A-B):

For those in whom the risk of bleeding is low, anticoagulant therapy is indicated. (See 'Anticoagulation' below.)

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For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, placement of an inferior vena cava (IVC) filter should be performed. (See 'Inferior vena cava filters' below and "Placement of vena cava filters and their complications".)

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For those in whom the risk of bleeding is moderate or high, therapy should be individualized according to the assessed risk-benefit ratio and values and preferences of the patient. As an example, a patient >75 years who is at risk of falling is not an ideal candidate for anticoagulation; anticoagulation may be considered if a vena cava filter cannot be placed (eg, inability to access the IVC due to extensive thrombus or tumor). (See 'Empiric anticoagulation' above.) It should be noted that when PE is proven and anticoagulation is contraindicated, an IVC filter is still indicated, whether the PE is small or extensive and even in the absence of residual deep venous thrombosis (DVT).

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For most hemodynamically stable patients, we recommend against thrombolytic therapy (eg, low risk patients).

Hemodynamically stable (ie, normotensive) patients with intermediate-risk/submassive PE who are anticoagulated, should be monitored closely for deterioration. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. Examples of such patients include those who have a large clot burden, severe RV enlargement/dysfunction, high oxygen requirement, and/or are severely tachycardic (

table 5). The details of such therapies are

discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Systemic infusion (full-dose thrombolytic)'.) Anticoagulation — Anticoagulant therapy is indicated for patients with PE in whom the risk of bleeding is low: ●

Initial anticoagulation – Initial anticoagulant therapy is administered as soon as possible to quickly achieve therapeutic anticoagulation. A detailed discussion of agent selection and patient selection for outpatient anticoagulation is presented separately. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)" and 'Outpatient anticoagulation' below.)

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Long-term anticoagulation (after discharge) – All patients are anticoagulated for a minimum of three months. Agent selection and duration of long-term anticoagulation in patients with PE and DVT are discussed in detail separately. (See "Venous thromboembolism: Anticoagulation after initial management".)

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Indefinite anticoagulation – Select patients with PE are candidates for indefinite anticoagulation. Patient selection depends upon the nature of the event (ie, provoked or unprovoked), the presence of risk factors (eg, transient or persistent), the estimated risk of bleeding and recurrence, as well as patient preferences and values (eg, occupation, life expectancy, burden of therapy), and trials that support a benefit. The rationale and indications for indefinite anticoagulation are described separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".) Outpatient anticoagulation — In select patients with PE, outpatient therapy can be

administered by giving the first dose of anticoagulant in the hospital or urgent care center, with the remaining doses given at home. The decision to treat as an outpatient should be made in the context of the patient's clinical condition, understanding of the risk-benefit ratio, and their https://www.uptodate.com/contents/8265/print

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preferences. Although the ideal candidate is poorly defined, guideline groups, several randomized trials, and meta-analyses suggest that, in patients with PE, outpatient anticoagulation is safe and effective in carefully selected patients with all of the following features [5,27-38]: ●

Low risk of death – defined as pulmonary embolism severity index (PESI) class I or II ( table 6), or simplified PESI (sPESI) score = 0 (see 'Prognostic models' below)

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No requirement for supplemental oxygen

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No requirement for narcotics for pain control

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No respiratory distress

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Normal pulse and blood pressure

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No recent history of bleeding or risk factors for bleeding (

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No serious comorbid conditions (eg, ischemic heart disease, chronic lung disease, liver or

table 3)

renal failure, thrombocytopenia, or cancer) ●

Normal mental status with good understanding of risk and benefits, are not needle averse (if low molecular weight [LMW] heparin chosen), and have good home support (eg, do not live alone, have access to a telephone and physician, can return to the hospital quickly if there is clinical deterioration)

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Absence of concomitant deep venous thrombosis (a high clot burden in the lower extremities may increase the risk of death or warrant additional therapy)

Support for outpatient therapy or early discharge following a brief inpatient stay is derived from randomized studies and meta-analyses with flawed methodology [9,31,33,35]. As examples: ●

One open label, multicenter trial randomly assigned 344 patients with symptomatic PE and a low risk of death (PESI I/II; (

table 6)) to receive either inpatient (intravenous

heparin followed by warfarin) or outpatient (subcutaneous low molecular weight heparin followed by warfarin) therapy [31]. Compared with inpatients, patients treated as an outpatient had a slightly higher rate of recurrent venous thromboembolism (VTE; 0.6 percent versus 0 percent) and major bleeding events (1.8 percent versus 0 percent) at 90 days that was not statistically significant. Mortality was no different between the groups (0.6 percent). The mean length of stay was 0.5 days for outpatients and 3.9 days for inpatients. https://www.uptodate.com/contents/8265/print

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A 2013 meta-analysis of 21 studies compared patients at low risk of death who were anticoagulated for PE as an outpatient (discharged within 24 hours) with patients who were treated as an inpatient and discharged after 72 hours (randomized and observational studies were included) [33]. Compared with inpatient anticoagulation, outpatient anticoagulation was not associated with a statistically significant difference in the rate of recurrent VTE (1.7 versus 1.2 percent) and mortality (1.9 versus 0.74 percent), or major bleeding events (0.97 versus 1 percent); However, although absolute rates of recurrent VTE and death were higher with outpatient treatment, there was significant population and therapeutic regimen heterogeneity among the included studies, limiting the interpretation of the results. A 2018 analysis of two randomized trials reported low quality evidence that there was no difference in 30- or 90-day mortality, major bleeding, or recurrence between low risk patients with acute PE who were treated as an inpatient or outpatient [39]. In a 2021 meta-analysis of 14 studies of patients with low-risk PE, there was no difference in the mortality or recurrence rate or rate of major bleeding among patients treated as an outpatient or inpatient [35].

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A retrospective analysis of 1127 patients reported that the 14 day rate of adverse events (recurrent VTE, major bleeding, or death) was 3 percent for outpatients compared with 13 percent for inpatients and the three-month rate was 7 and 22 percent, respectively [40].

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In another randomized trial of 114 patients with PE who were discharged on rivaroxaban and were at low risk of death the LOS was significantly reduced in early discharge patients compared with those who were admitted (34 versus 5 hours) [41]. At three months, there were no bleeding events, recurrent VTE, or deaths.

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In a prospective analysis of 525 patients with PE who were discharged early and treated with rivaroxaban, only three patients (0.6 percent) developed symptomatic non-fatal VTE recurrence at three months follow-up and bleeding rates were low (1.2 percent) [42].

The ideal agent is unknown. Agent selection for outpatient anticoagulant therapy in patients with PE is similar to that for deep vein thrombosis. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Outpatient therapy'.) Despite the fact that outpatient anticoagulation has been shown to be safe, this practice may be uncommon. One retrospective review of 746 patients with PE who were potentially eligible for anticoagulation at home, reported that only 1.7 percent were treated at home and only 16 percent were discharged within two days [43]. However, clinician education may change this practice. As an example, in one trial of 1763 patients diagnosed with PE in the ED, an electronic intervention built into the electronic health record increased the number of patients who could https://www.uptodate.com/contents/8265/print

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be discharged to home (17 percent versus 28 percent) without increasing the risk of return visits to the ED, recurrent VTE, or mortality [44]. Patients with subsegmental PE — The increasing use of computed tomography (CT) has led to the increased diagnosis of incidental (asymptomatic) PE and small subsegmental PE (SSPE) (

figure 1).

One observational study reported that 15 percent of patients with symptomatic PE have SSPE [45]. The true proportion of patients with asymptomatic SSPE is unknown [46]. Although the clinical relevance of SSPE is unknown, a single subsegmental defect probably does not have the same clinical outcome as a single segmental or lobar PE or multiple SSPE. A retrospective review of 222 patients with PE, 36 percent of whom had SSPE, reported that 87 percent were systemically anticoagulated while the remaining were not anticoagulated due to bleeding or poor prognosis at the time of diagnosis [47]. Adverse events were similar between SSPE patients and patients with more proximal emboli. (See "Overview of acute pulmonary embolism in adults", section on 'Nomenclature'.) In patients with SSPE, the incidence of VTE recurrence is unclear but may be higher than that in the general population. While older retrospective studies suggested minimal recurrence, studies were flawed [48-50]. However, in the largest prospective study to date of 292 patients with isolated SSPE and no lower-extremity DVT who were managed without anticoagulation, the recurrence rate was 3.1 percent at 90 days, (ie, higher than the expected rate in the general population of approximately 1 percent or less) [51]. Rates were higher in those with multiple SSPEs compared with a single isolated PE (5.7 versus 2.1 percent) and higher in older patients compared with those younger than 65 years (5.5 versus 1.8 percent). No fatalities were reported. However, this study was stopped early for benefit, which may have influenced the results. Whether or not patients with SSPE should be anticoagulated is controversial [9,52]. Practice varies widely; some experts anticoagulate all patients with SSPE, regardless of whether or not symptoms are present, while other experts avoid anticoagulation in a minority of individuals (especially if a more convincing etiology is discovered on CT for the patients' symptoms) [45]. Our approach to anticoagulating patients with SSPE is the following: ●

We believe that most patients with SSPE should be anticoagulated similarly to those who present with symptomatic or large lobar defects [5,9]. This is particularly important when VTE is unprovoked and persistent risk factors for VTE such as active cancer and acute hospitalization with prolonged immobility, are present; defects are multiple; symptoms are

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present; and/or when patients have limited cardiorespiratory reserve. (See "Venous thromboembolism: Anticoagulation after initial management" and "Venous thromboembolism: Initiation of anticoagulation (first 10 days)".) The optimal duration of anticoagulation is unknown but similar to patients with segmental or lobar PE, patients with SSPE should be treated for a minimum of three months. Anticoagulant therapy beyond that period should be individualized, the details of which are discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation (first 10 days)" and "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation", section on 'Incidental small subsegmental PE without identifiable risk factors'.) ●

Experts also agree that a small subset of patients with a single small defect (ie, seen on one image) in whom there is no evidence of proximal lower extremity DVT or evidence of thrombus elsewhere (eg, upper extremity clot) may reasonably opt for no anticoagulation, provided the risk of recurrence is considered low and patients are monitored appropriately [9]. Additional findings that may support this decision include those in whom a false positive test is suspected, the absence of persistent risk factors, those with preserved baseline cardiorespiratory function, and/or those in whom a low pretest probability and normal Ddimer is present. When clinical surveillance is chosen, we suggest serial testing with bilateral proximal compression ultrasonography (CUS) of the lower extremities in two weeks to look for evidence of proximal thrombus. We also have a low threshold to repeat diagnostic imaging for PE should symptoms persist or recur. This strategy is based upon the rationale that serial CUS has been reported to be safe in patients with nondiagnostic testing for PE (eg, indeterminate or low probability ventilation perfusion scanning); details regarding this strategy are described separately. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Lowerextremity ultrasound with Doppler'.)

Inferior vena cava filter — In most patients, an inferior vena cava (IVC) filter is not necessary. For most patients with PE in whom anticoagulation is contraindicated, or patients in whom the risk of bleeding is unacceptably high, IVC filter should be placed. Similarly, an IVC filter is appropriate in patients who develop contraindications while on anticoagulation; however, placement in this population depends upon the planned duration of anticoagulation and risk of recurrence when anticoagulation is discontinued. Another more unusual indication for an IVC https://www.uptodate.com/contents/8265/print

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filter is recurrence despite therapeutic anticoagulation; a decision may be more difficult in patients who recur quickly after the onset of anticoagulation. Retrievable filters should be used such that once the contraindication has resolved, the filter can be removed and patients should be anticoagulated. The efficacy of IVC filters, their placement and complications, are presented separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Inferior vena cava filter' and "Placement of vena cava filters and their complications" and 'Inferior vena cava filters' below.) When contraindications to anticoagulation are present in acute PE, an IVC filter should be placed even in the absence of proven lower extremity thrombus. Thrombus may remain undetected in the pelvis or calf veins or clot can quickly reform in the leg veins after embolization. However, the decision to place an IVC filter, most of which are infrarenal, is modified in the following settings: ●

If the patient has confirmed extensive upper extremity thrombosis in the absence of lower extremity thrombosis, an IVC filter will not be effective; and a superior vena caval filter may be useful.

●

If the thrombus is in the renal vein (identified by the initial CT angiogram or during placement of the IVC filter), a suprarenal filter is appropriate.

Hemodynamically unstable patients — In patients with PE who are hemodynamically unstable or who become unstable due to recurrence despite anticoagulation, we suggest more aggressive therapies (ie reperfusion therapies) than anticoagulation including the following ( algorithm 1A-B): ●

Thrombolytic therapy is indicated in most patients, provided there is no contraindication ( table 7) (see "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Hemodynamically unstable patients (high risk)' and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Systemic infusion (full-dose thrombolytic)')

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Embolectomy is appropriate for those in whom thrombolysis is either contraindicated or unsuccessful (surgical or catheter-based) (see 'Embolectomy' below)

Reperfusion therapy

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Thrombolytic therapy — Systemic thrombolytic therapy is a widely accepted treatment for patients with PE who present with, or whose course is complicated by, hemodynamic instability. This therapy can be delivered more quickly than can be done via a catheter-based method; if there are no contraindications to systemic thrombolysis and the indication for reperfusion therapy is clear, the patient should not wait until an operator or catheterization service lab is available. Catheter-directed thrombus removal with or without thrombolysis can also be administered in select patients (eg, those at high risk of bleeding and those who have failed systemic thrombolysis). The indications, contraindications, agents, administration, and outcomes of systemic and catheter-directed thrombolysis are discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration" and 'Catheter-directed modalities' below.) For those in whom systemic thrombolysis is unsuccessful, the optimal therapy is unknown. Options include repeat systemic thrombolysis, catheter-directed thrombolysis, or catheter or surgical embolectomy, the choice of which is dependent upon available resources and local expertise. (See 'Embolectomy' below.) Embolectomy — Embolectomy is indicated in patients with hemodynamically unstable PE in whom thrombolytic therapy is contraindicated. It is also a therapeutic option in those who fail thrombolysis. Emboli can be removed surgically or using a catheter. The choice between these options depends upon available expertise, the presence or absence of a known diagnosis of PE, and the anticipated response to such therapies. As an example, when a patient has severe hemodynamic instability and standard dose thrombolysis is contraindicated, catheter-directed techniques may be preferred if the expertise is available. One advantage of this approach is that both diagnostic and therapeutic interventions can be applied simultaneously. Catheter-directed modalities — Several catheter-directed techniques are available. Studies have been limited by small sample size and the inclusion of heterogeneous populations (patients who are hemodynamically stable and unstable, patients with and without contraindications to thrombolysis) as well as the adjunctive administration of catheter-directed thrombolytic agents. Nearly all modern-day catheter-directed thrombolysis trials have utilized tissue plasminogen activator (tPA). None has been demonstrated to have superiority over the other, such that the choice of technique is institution-dependent; an absolute contraindication to a thrombolytic agent means that if a catheter-directed technique is utilized, a catheterdirected clot extraction (ie, embolectomy) can be used. In our experience, catheter-directed techniques are most commonly utilized in patients with intermediate-high risk PE, although there is some experience with high-risk PE. Options include: https://www.uptodate.com/contents/8265/print

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Ultrasound-assisted thrombolysis – Catheter-directed high frequency ultrasound can enable the thrombolytic agent to better penetrate the embolus. Without thrombolytics, the technique has no proven benefit. This is the technique that is best supported by clinical trial data which are discussed separately. (See "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Catheter-directed approaches' and "Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration", section on 'Catheter-directed thrombolytic therapy'.)

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Rheolytic embolectomy – Rheolytic embolectomy injects pressurized saline through the catheter's distal tip while macerated thrombus is aspirated through a catheter port [5358]. In a series of 16 patients with massive or submassive PE who underwent rheolytic embolectomy, resolution of symptoms and improvement in right ventricle dysfunction were achieved in all patients [57]. There were no in-hospital mortalities. Complications occurred in three patients (20 percent), two with acute kidney injury and one with an intraoperative cardiac arrest. Clinical success due to the intervention alone was unclear because two thirds of the cohort also received catheter-directed thrombolysis. Because the catheter is large, the major disadvantage of rheolytic devices is that a venous cut-down (venotomy) is often required for insertion, which increases the risk of bleeding at the insertion site. In addition, the release of adenosine from disrupted platelets can lead to bradycardia, vasospasm, and hypoxia; similarly, red blood cell fragmentation can result in hemoglobinuria. These and other side effects have led to a boxed warning from regulatory agencies.

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Rotational embolectomy – A rotating device at the catheter tip can be used to fragment the thrombus, while fragmented clot is continuously aspirated [59-63]. In a series of 18 patients with shock due to PE, clinical success was achieved in 16 cases (89 percent), defined as improvement in oxygenation and blood pressure. The remaining patients had complications (eg, hemorrhage) and one patient died from refractory shock [61]. Typically, rotational devices do not require venotomy.

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Suction embolectomy – Thrombus can be manually aspirated through a large-lumen catheter using an aspiration syringe and a hemostatic valve [64,65]. In one study of 63 patients with mostly hemodynamically unstable PE who underwent suction embolectomy, 88 percent had a clinically significant reduction in clot burden and pulmonary artery pressure [65]. Six percent of patients died and 14 percent had major bleeding. Clinical success due to the intervention alone was unclear because all patients also received catheter-directed thrombolysis.

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Technical difficulties with suction devices have limited their use but newer devices may be more successful [66]. As an example, in a study (FLARE), 106 patients with documented PE and RV dysfunction (ie, intermediate risk PE), aspiration thrombectomy with a newer device resulted in improvement in RV function and pulmonary artery pressure with a complication rate of only 4 percent [67]. There was one major bleed. More advanced catheters have been used for the removal of soft, fresh thrombi or for use during extracorporeal bypass. This applies most readily to large thromboemboli in the IVC, or right heart chambers. Such devices cannot easily access the pulmonary arteries to suction more distal emboli [68]. ●

Thrombus fragmentation – Mechanical disruption of the thrombus can be achieved by manually rotating a standard pigtail or balloon angioplasty catheter into the thrombus; small fragments move distally and thereby result in reduced pulmonary vascular resistance [60,69,70]. While older studies report improved hemodynamic indices with fragmentation alone, newer studies have reported efficacy when fragmentation is combined with angioplasty, aspiration, and catheter-directed thrombolysis [71]. Although rare, catheter-fragmentation can increase pulmonary vascular pressures likely via embolization of larger fragments into the distal branches of the pulmonary vascular bed [72,73]. Consequently, aspiration of fragments is frequently concurrently performed to deal with this complication.

Common to all catheter-assisted embolectomy techniques is the risk of pulmonary artery perforation; although rare, it can lead to pericardial tamponade and life-threatening hemoptysis, and is frequently catastrophic. Additional complications include hemorrhage and infection of venipuncture sites, cardiac arrest, and death, as well as device-specific adverse effects (listed above). Hemorrhagic side effects can be exacerbated by the co-administration of thrombolytic therapy. Surgical embolectomy — The usual indication for surgical embolectomy is hemodynamic instability due to acute PE for patients in whom thrombolysis (systemic or catheter-directed) is contraindicated, and is an option in those in whom thrombolysis has failed [74-77]. Additional indications may include echocardiographic evidence of an embolus trapped within a patent foramen ovale, or present in the right atrium, or right ventricle [78]. Surgical embolectomy is typically limited to large medical centers because an experienced surgeon and cardiopulmonary bypass are required. It has a high mortality, particularly in the older patient (2 to 46 percent) [74-77,79-87]. Proximal emboli are amenable to surgical removal (ie, right ventricle, main pulmonary artery [PA], and extrapulmonary branches of the PA), whereas distal thrombus generally is not amenable to surgery (eg, intrapulmonary branches of the PA). https://www.uptodate.com/contents/8265/print

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In a retrospective database study, there was no difference in 30-day mortality with the 257 patients who underwent surgical embolectomy compared with 1854 patients with PE who underwent thrombolysis (15 versus 13 percent) [88]. In an observational study of 40 patients with PE who had failed systemic thrombolysis, patients who underwent surgical embolectomy had fewer recurrent PE compared with patients who had repeat thrombolysis (0 versus 35 percent) [80]. In addition, there were fewer deaths and fewer major bleeding complications associated with surgical embolectomy, which did not achieve statistical significance. In another series of 115 patients who underwent surgical embolectomy, compared with patients who had stable PE, those with unstable PE had a higher operative mortality (10 versus 4 percent) and worse survival (75 versus 93 percent) [84]. Another retrospective series reported an in hospital mortality of only 2 percent and immediate improvement of right ventricle pressures that persisted at 30 months [77]. Transesophageal echocardiography (TEE) should be performed before or during embolectomy to look for extrapulmonary thrombi (eg, in the right atrium, right ventricle, or vena cava). In a series of 50 patients with PE, intraoperative TEE detected extrapulmonary thrombi in 13 patients (26 percent), which altered the surgical management of five patients (10 percent) [89]. Cardiac arrest upon presentation predicts mortality from surgical embolectomy [74,90-93]. In one study of 36 patients with shock due to acute PE, but without cardiac arrest, the operative mortality associated with surgical embolectomy was 3 percent [91]. In contrast, operative mortality was 75 percent among patients with acute PE who were resuscitated from a cardiac arrest and then underwent surgical embolectomy [91,92]. Complications include those associated with cardiac surgery and anesthesia, as well as embolectomy-specific complications such as perforation of the pulmonary artery and cardiac arrest. (See "Postoperative complications among patients undergoing cardiac surgery".) Special populations — In general, the initial approach to the treatment of PE as well as the treatment of life-threatening PE in special populations are similar to that in the general population (see 'Initial approach and resuscitation' above and 'Hemodynamically unstable patients' above). However, definitive therapy may differ in hemodynamically stable patients with malignancy, pregnancy, and heparin-induced thrombocytopenia. Patients with malignancy — In hemodynamically stable patients with malignancy and PE, LMW heparin and some of the direct oral anticoagulants, edoxaban and apixaban, are used as anticoagulants. The details of supporting trials are discussed separately. (See "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".) https://www.uptodate.com/contents/8265/print

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Patients who are pregnant — For most pregnant women with hemodynamically stable PE, adjusted-dose subcutaneous LMW heparin is the preferred agent for initial and long-term anticoagulation due to its favorable fetal safety profile (

table 8). Treatment of PE in

pregnancy is discussed in detail separately. (See "Use of anticoagulants during pregnancy and postpartum" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".) Patients with heparin-induced thrombocytopenia — For patients with PE and heparininduced thrombocytopenia (HIT), all forms of heparin are contraindicated (eg, unfractionated and LMW heparin). Immediate anticoagulation with a fast-acting non heparin anticoagulant (eg, argatroban) is indicated. The diagnosis and management of patients with HIT are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".) Inherited thrombophilias — In many cases, the presence of an inherited thrombophilia does not appreciably alter treatment decisions such as choice of an anticoagulant or duration of anticoagulation, but there may be specific circumstances in which the thrombophilia does affect management (eg, need for antithrombin [AT] administration in some individuals with AT deficiency). Details are presented in separate topic reviews: ●

Factor V Leiden – (See "Factor V Leiden and activated protein C resistance", section on 'Patients with VTE'.)

●

Prothrombin G20210A mutation – (See "Prothrombin G20210A", section on 'Patients with VTE'.)

●

Protein S deficiency – (See "Protein S deficiency", section on 'Patients with VTE'.)

●

Protein C deficiency – (See "Protein C deficiency", section on 'Thromboembolism management'.)

●

Antithrombin deficiency – (See "Antithrombin deficiency", section on 'VTE treatment (hereditary deficiency)'.)

Antiphospholipid syndrome — Considerations with treatment of VTE in patients with antiphospholipid syndrome (APS) are presented separately (eg, direct oral anticoagulants are generally not administered). (See "Management of antiphospholipid syndrome".)

ADJUNCTIVE THERAPIES Therapies that can be added as an adjunct to anticoagulation in patients with pulmonary embolism (PE) are discussed in the sections below.

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General medical — Patients with PE should always receive supportive care with analgesia, intravenous fluids, and oxygen, as clinically indicated (see 'Initial therapies' above). When present, pleuritic pain from PE is best treated with scheduled medications, usually acetaminophen or nonsteroidal antiinflammatories, and narcotics. The choice among these agents should be individualized. Failure to wean supportive therapies should prompt consideration of complications (eg, pneumonia or recurrence). Ambulation — Early ambulation does not promote embolization and, when feasible, should be encouraged in most patients with acute PE, once the patient is definitively treated. Typically, ambulation is limited by the need for postoperative bedrest, or by comorbidities including severe symptoms of concurrent deep venous thrombosis (DVT) or hypoxia, which can be treated with compression stockings and oxygen, respectively. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Ambulation'.) Elastic graduated compression stockings — Elastic graduated compression stockings (GCS) are not routinely used in patients with DVT to prevent post-thrombotic syndrome (PTS). Detailed discussion of the manifestations and treatment of post-thrombotic syndrome (PTS) and role of GCS in the prevention of PTS are discussed separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Compression stockings for the prevention of PTS' and "Post-thrombotic (postphlebitic) syndrome".) Inferior vena cava filters — In patients with acute PE, the primary indication for inferior vena cava (IVC) filter placement is when anticoagulation is contraindicated and when recurrent PE occurs despite therapeutic anticoagulation. However, it may be appropriate as an adjunct to anticoagulation in patients in whom another embolic event would be poorly tolerated (eg, poor cardiopulmonary reserve, or severe hemodynamic or respiratory compromise), although clinical data are lacking. Filters are not routinely placed as an adjunct in patients with PE. (See 'Management of recurrence on therapy' below.) Filter placement is also sometimes used in patients with recurrence despite therapeutic anticoagulation or in those with a high risk of recurrence in whom it is anticipated that anticoagulation may need to be discontinued because of bleeding. Examples include patients at moderate risk of bleeding who cannot receive fresh frozen plasma or red cells (eg, due to religious preference), and patients with metastatic malignancy who are at a high risk for both recurrence and bleeding. Although filters are not routinely placed as an adjunct in patients with PE, some experts place them in patients at risk of decompensation due to cardiorespiratory compromise. We agree that the adjunctive use of filters should not be routine, but placement may be individualized https://www.uptodate.com/contents/8265/print

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and should take into consideration the risk of recurrence and bleeding, patient preferences, institutional expertise, medical morbidities, and surgical complications. IVC filter placement in patients with contraindications to anticoagulation and filter complications are reviewed separately. (See "Placement of vena cava filters and their complications".) A femoral IV access line with a "built-in" IVC filter that can be opened when the line is placed and collapsed and removed when the line is removed has been found useful in high risk patients who cannot be treated with anticoagulants [94].

PROGNOSIS Morbidity and mortality — Prognosis from pulmonary embolism (PE) is variable. Accurate estimates have been limited by data that are mostly derived from older studies, registries, and hospital discharge records collected from heterogeneous populations of patients. As an example, a patient with a single, asymptomatic, subsegmental pulmonary embolism (SSPE) likely has a different prognosis than a patient with massive PE and shock. However, in general, if left untreated, PE is associated with an overall mortality of up to 30 percent compared with 2 to 11 percent in those treated with anticoagulation [1,4,50,95-101]. PE-related mortality may be decreasing with reported rates falling from 3.3 percent (2001 to 2005) to 1.8 percent (2010 to 2013) in one study and from 17 to 10 percent in another study [101,102]. Another study that derived data from the World Health Organization (WHO) mortality database reported a similar decrease in deaths from 12.8 per 100,000 to 6.6 per 100,000 between 2000 and 2015 [103]. Early — We consider early outcomes as those occurring within the first three months after the diagnosis of PE. The highest risk for events occurs within the first seven days; death and morbidity during this period are most commonly due to shock and recurrent PE. ●

Shock (ie, hemodynamic collapse) – Shock can be the initial presentation or an early complication of PE (8 percent of patients). It is the most common cause of early death, particularly in the first seven days, and when present, is associated with a 30 to 50 percent risk of death [97,98,104]. The high risk of death, which is greatest in the first two hours of presentation, is the rationale for the consideration of reperfusion therapy (thrombolytics/embolectomy) rather than anticoagulation. The risk remains elevated for 72 hours or more, such that close observation of this population, as well as those considered at risk of hemodynamic collapse (eg, right ventricle dysfunction), is prudent during hospitalization. (See "Approach to thrombolytic (fibrinolytic) therapy in acute

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pulmonary embolism: Patient selection and administration" and 'Embolectomy' above and 'Shock and right ventricular dysfunction' below.) ●

Recurrence – The risk of recurrence (deep venous thrombosis and PE) is greatest in the first two weeks, and declines thereafter. The cumulative proportion of patients with early recurrence while on anticoagulant therapy amounts to 2 percent at two weeks, and 6 percent at three months [105-107]. Factors including cancer and failure to rapidly achieve therapeutic levels of anticoagulation are major predictors of increased risk of recurrence during this period, the management of which is discussed below [108,109]. (See 'Management of recurrence on therapy' below.)

●

Pleuritic/alveolitis and pneumonia – In the one to two weeks following diagnosis, patients may deteriorate and develop worsening oxygenation, respiratory failure, hypotension, pain, and/or fever that suggests an evolving infarct and/or superimposed pneumonia. Although chest radiography may reveal collapse, atelectasis, or a pleural effusion to support the presence of an evolving infarct and/or superimposed pneumonia, these patients should undergo repeat definitive imaging (preferably with the original diagnostic imaging modality) to distinguish these diagnoses from recurrent PE. Patients without recurrence should be treated symptomatically with supplemental oxygen, analgesics, and intravenous fluids, and ventilation, vasopressors and/or antibiotics, as indicated.

●

Stroke – Prospective and retrospective studies have suggested an increased risk of stroke, thought to be due to paradoxical embolism via a patent foramen ovale (PFO), in patients with acute PE [110-114]. Prevalence rates of stroke have ranged from 7 to 50 percent (averaging 6.0

Moderate

2.0 to 6.0

Low

4.0

PE unlikely

≤4.0

DVT: deep vein thrombosis; PE: pulmonary embolism. Data from van Belle A, Buller HR, Huisman MV, et al. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006; 295:172.

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Risk factors for bleeding with anticoagulant therapy and estimated risk of major bleeding in low, moderate, and high risk categories Risk factors* Age >65 years Age >75 years Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Previous stroke Diabetes Anemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery¶ Frequent falls Alcohol abuse

Estimated absolute risk of major bleeding (%) Categorization of

Low risk◊ (0 risk

Moderate risk◊ (1

High risk◊ (≥2 risk

risk of bleedingΔ

factors)

risk factor)

factors)

Anticoagulation 0 to 3 months§ Baseline risk (%)

0.6

1.2

4.8

Increased risk

1

2

8

1.6§

3.2

12.8¥

0.3†

0.6

≥2.5

0.5

1

≥4

(%) Total risk (%)

Anticoagulation after first 3 months‡ Baseline risk (%/years) Increased risk

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(%/years) Total risk (%/years)

0.8**

1.6**

≥6.5

* The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, location and extent of metastatic disease, platelet count), (2) temporal relationships (eg, interval from surgery or a previous bleeding episode), and (3) how effectively a previous cause of bleeding was corrected (eg, upper-GI bleeding). ¶ Important for parenteral anticoagulation (eg, first 10 days), but less important for long-term or extended anticoagulation. Δ Although there is evidence that risk of bleeding increases with the prevalence of risk factors, this categorization scheme has not been validated. Furthermore, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past two days, severe thrombocytopenia). ◊ Compared with low risk patients, moderate risk patients are assumed to have a twofold risk and high risk patients an eightfold risk of major bleeding. § The 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy. We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with anticoagulation (refer to footnote ‡). ¥ Consistent with frequency of major bleeding observed by Hull et al in high risk patients[1] . ‡ We estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no extended anticoagulation. The relative risk of major bleeding during the first three months of therapy may be greater than during extended VKA therapy because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA therapy; (2) anticoagulant control will be less stable during the first three months; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the first three months of therapy. However, studies of patients with acute coronary syndromes do not suggest a ≥2.6 relative risk of major bleeding with parenteral anticoagulation (eg, UFH or LMWH) compared with control. † Our estimated baseline risk of major bleeding for low risk patients (and adjusted up for moderate and high risk groups as per footnote ◊). ** Consistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE. Reference: 1. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 1990; 322:1260.

Reproduced from: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S. Table used with the permission of Elsevier Inc. All rights reserved.

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Factors that influence agent selection for anticoagulation in patients with acute venous thromboembolism Factor

Preferred

Qualifying remarks

anticoagulant

Cancer

LMWH, factor Xa inhibitors

More so if: Just diagnosed, extensive VTE, metastatic cancer, very symptomatic; vomiting; on cancer chemotherapy.

Initial parenteral

Rivaroxaban;

VKA, dabigatran, and edoxaban require initial parenteral

therapy to be

apixaban

therapy.

Once daily oral therapy preferred

Rivaroxaban; edoxaban; VKA

 

Liver disease and

LMWH

DOACs contraindicated if INR raised because of liver

avoided

coagulopathy

disease; VKA difficult to control and INR may not reflect antithrombotic effect.

Renal disease and creatinine

VKA

DOACs and LMWH contraindicated with severe renal impairment. However, dosing of some DOACs can be renally

clearance 15 seconds Age >75 years Diabetic retinopathy SBP: systolic blood pressure; DBP: diastolic blood pressure; CPR: cardiopulmonary resuscitation. * The American College of Cardiology suggests that select patients with stroke may benefit from thrombolytic therapy within 4.5 hours of the onset of symptoms.

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Reproduced with permission from the American College of Chest Physicians. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S. Copyright © 2012.

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Use of heparins during pregnancy Heparin LMW heparin

Dose level Prophylactic*

Dose Enoxaparin 40 mg SC once daily Dalteparin 5000 units SC once daily

Intermediate¶

Enoxaparin 40 mg SC once daily, increase as pregnancy progresses to 1 mg/kg once daily Dalteparin 5000 units SC once daily, increase as pregnancy progresses to 100 units/kg once daily

Therapeutic

Enoxaparin 1 mg/kg SC every 12 hours Dalteparin 100 units/kg SC every 12 hours

Unfractionated

Prophylactic

5000 units SC every 12 hours

heparin

Intermediate¶

First trimester: 5000 to 7500 units SC every 12 hours Second trimester: 7500 to 10,000 units SC every 12 hours Third trimester: 10,000 units SC every 12 hours

Therapeutic

Can be given as a continuous IV infusion or an SC dose every 12 hours. Titrated to keep the aPTT in the therapeutic range.

Doses apply to pregnant women receiving heparin for venous thromboembolism prophylaxis. Therapeutic-dose level refers to doses used both for prophylaxis in individuals at especially high risk and for treatment of venous thromboembolism. This dosing table should not be used in women with prosthetic heart valves. Refer to the UpToDate topic on anticoagulant use in pregnancy for details of administration and monitoring. Refer to UpToDate topics on specific pregnant patient populations for other dosing recommendations (eg, prosthetic heart valve, atrial fibrillation, treatment of deep vein thrombosis or pulmonary embolism). LMW: low molecular weight; SC: subcutaneously; IV: intravenous; aPTT: activated partial thromboplastin time; ACCP: American College of Clinical Pharmacy; ACOG: American College of Obstetricians and Gynecologists.  * Prophylactic dosing may require modifications for extremes of body weight. ¶ Our "intermediate" dose level differs from that used in society guidelines (eg, ACCP, ACOG). Some clinicians prefer to use a different "intermediate" dose level such as enoxaparin 40 mg SC every 12 hours; however, this entails a significant increase in the number of injections over the course of the pregnancy. Graphic 91838 Version 9.0

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Contributor Disclosures Victor F Tapson, MD Grant/Research/Clinical Trial Support: Boston Scientific [PE treatment]; Janssen [VTE treatment/prophylaxis]; BMS [VTE treatment/prophylaxis]; Daiichi [PE treatment]; BiO2 [PE prophylaxis]; Genentech [PE treatment]. Consultant/Advisory Boards: Penumbra [PE treatment]; Thrombolex [PE treatment]; BiO2 [PE prevention]; BMS [PE treatment/prophylaxis]; Janssen [PE treatment/prophylaxis]. Speaker's Bureau: Janssen [VTE treatment/prophylaxis]. All of the relevant financial relationships listed have been mitigated. Aaron S Weinberg, MD, MPhil Consultant/Advisory Boards: Arena Pharmaceuticals [Venous thromboembolic disease]. All of the relevant financial relationships listed have been mitigated. Jess Mandel, MD No relevant financial relationship(s) with ineligible companies to disclose. Robert S Hockberger, MD, FACEP No relevant financial relationship(s) with ineligible companies to disclose. Geraldine Finlay, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Upper respiratory tract infections: Considerations in adolescent and adult athletes Authors: Carrie A Jaworski, MD, FAAFP, FACSM, David B Pyne, PhD, FACSM Section Editor: Francis G O'Connor, MD, MPH, FACSM Deputy Editor: Jonathan Grayzel, MD, FAAEM All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Oct 26, 2021.

INTRODUCTION Upper respiratory tract infections (URTIs) are common in athletes. The majority are self-limited viral infections. The evaluation and treatment of athletes with URTIs is typically the same as in the general population. However, there are specific considerations for medication choices in athletes and clinicians may be asked to determine when an athlete can return to play or competition. This topic will discuss the epidemiology, evaluation, and specific medication considerations in athletes with URTI. It will also discuss how to determine when an athlete can return to play after URTI.

ATHLETES WITH COVID-19 INFECTION The presentation and management of athletes infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not differ from the general population. A wide range of UpToDate topics covering all aspects of coronavirus disease 2019 (COVID-19) infection is available, including the following: (see "COVID-19: Questions and answers" and "COVID-19: Clinical features" and "COVID-19: Outpatient evaluation and management of acute illness in adults" and "COVID-19: Management in hospitalized adults" and "COVID-19: Evaluation and management of adults following acute viral illness" and "COVID-19: Vaccines"). https://www.uptodate.com/contents/13806/print

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Clinicians who manage athletes will find useful information in the topic devoted to return to play: (see "COVID-19: Return to sport or strenuous activity following infection").

TERMINOLOGY For the purposes of this topic, "athlete" refers to adolescents and adults who participate in both recreational and competitive sports. The term "upper respiratory tract infection" may be used to describe a variety of infections. For the purposes of this topic, URTIs include the illnesses listed below. Information regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is provided separately. (See 'Athletes with covid-19 infection' above.) ●

The common cold (see "The common cold in adults: Diagnosis and clinical features" and "The common cold in adults: Treatment and prevention" and "The common cold in children: Clinical features and diagnosis" and "The common cold in children: Management and prevention")

●

Infectious mononucleosis (see "Infectious mononucleosis")

●

Influenza (see "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in nonpregnant adults: Treatment" and "Seasonal influenza in children: Clinical features and diagnosis" and "Seasonal influenza in children: Management")

●

Pertussis (see "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis" and "Pertussis infection in adolescents and adults: Treatment and prevention")

●

Pharyngitis (see "Evaluation of acute pharyngitis in adults" and "Symptomatic treatment of acute pharyngitis in adults" and "Evaluation of sore throat in children" and "Group A streptococcal tonsillopharyngitis in children and adolescents: Clinical features and diagnosis" and "Acute pharyngitis in children and adolescents: Symptomatic treatment")

●

Sinusitis (see "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment" and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis" and "Acute bacterial rhinosinusitis in children: Microbiology and management")

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Upper respiratory tract infections (URTIs) are the most common type of infection in athletes [1,2]. In general, the incidence in athletes is the same as nonathletes. In the majority of cases, URTIs are self-limited viral infections [3]. Risk factors — There is little evidence that the incidence of URTI varies by sport. However, athletes in some sports are at higher risk for viral illnesses, such as influenza and infectious mononucleosis, as a consequence of close contact with teammates and opponents. URTIs are the most common cause of illness at national and international sporting competitions, likely related to increased exposure to pathogens during both travel and competition [1,4,5]. Risks associated with COVID-19 infection and spread are discussed separately. (See "COVID-19: Epidemiology, virology, and prevention" and "COVID-19: Questions and answers".) Athletes appear to be at greater risk of infection during the winter months [6]. This likely has to do with the seasonal variations of pathogens that cause URTIs (eg, influenza), as well as increased indoor crowding [3]. (See "Influenza: Epidemiology and pathogenesis".) A small number of athletes have problems with persistent or recurrent URTIs. Athletes at higher risk of developing URTIs are likely to include older adults and those with a history of recurrent or persistent illness [7]. The risk of illness may increase when an athlete is exposed to sleep disturbances, severe psychosocial stress, a major personal crisis, or an imbalance between psychological stress and recovery [8,9]. Relationship to exercise — The relationship between infection and exercise is poorly understood [10]. The risk of illness appears to increase with prolonged and/or intensive training, especially in susceptible athletes (eg, poorly-controlled asthmatics, those with chronic disease, those who are immunosuppressed, or those who have had a recent infection) [11]. However, most athletes can exercise, train, and compete with confidence, as acute exercise more likely improves rather than compromises immune competency [12]. A number of models have been developed to characterize relationships between the volume/intensity of exercise (and training) and risk of URTI. The J-curve model is based on evidence that moderately active individuals typically have a lower risk of URTI compared with sedentary individuals, but some highly trained athletes have a paradoxically heightened risk [13]. Another model is the open window theory, where the immune system is temporarily downregulated in the hours after strenuous exercise or training leading to a 'window' of opportunity for infections to become established [14].

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Effect on competition performance — Infections that coincide with the preparations for or actual competition may impair performance if the symptoms are moderate to severe. For example, the prolonged cough experienced by those with pertussis can hamper athletic performance [3]. Infections occurring early in the season well away from competition are unlikely to have substantial effects on competitive performance, unless a significant amount of training time is lost. In a retrospective study of 69 swimmers, mild infections (predominantly URTIs) lasting two or more days in the six weeks prior to international competition had little adverse effect on performance [15].

EVALUATION The evaluation of athletes for the various etiologies of upper respiratory tract infections (URTIs) is the same as for the general population. Evaluation and screening for coronavirus disease 2019 (COVID-19) will likely vary by sport and local conditions. (See 'Athletes with covid-19 infection' above.) Although it is not always necessary to obtain a white blood cell count (WBC) in the evaluation of URTI, exercise appears to affect WBC counts and function. The clinical importance of these changes is unclear. Prolonged endurance training can lead to leukopenia, but this is likely not pathologic. In one study including over 900 females and 1300 males in 14 sports, 16 percent of athletes who participated in aerobic sports (eg, cycling or the triathlon) had WBC counts that were below the normal reference range [16]. Also, acute exercise will typically increase the numbers of circulating leukocytes, but changes are transient and likely of little clinical significance. (See "Approach to the patient with neutrophilia", section on 'Stress/exercise'.)

MEDICATION CONSIDERATIONS In general, treatment strategies for upper respiratory tract illnesses (URTIs) in athletes should be the same as for nonathletes. There are some specific considerations for athletes regarding choice of antibiotics and adjunctive medications. Antibiotics — The same criteria should be used to determine if antibiotic treatment is necessary in athletes as in nonathletes. However, certain antibiotics have adverse effects that may have implications for athletes (

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table 1):

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Fluoroquinolones – When other options are available, we avoid prescribing fluoroquinolones in athletes because they are associated with tendinopathy and tendon rupture [17,18]. When fluoroquinolones are the best option for treatment, we monitor athletes for tendon pain. Any athlete that develops tendon pain while on fluoroquinolones should stop the medication and seek prompt evaluation. (See "Achilles tendinopathy and tendon rupture", section on 'Epidemiology and risk factors' and "Fluoroquinolones", section on 'Tendinopathy'.) In addition, fluoroquinolones are associated with photosensitivity and QT prolongation, which have specific implications for athletes [18]. In athletes that use fluoroquinolones, we recommend precautions such as sunscreen and protective clothing, particularly if they participate in outdoor sports. Some athletes are evaluated with an electrocardiogram (ECG) as part of clearance for participation. If an athlete needs ECG testing around the time of antibiotic therapy, it is reasonable to avoid the use of fluoroquinolones when possible. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Fluoroquinolones", section on 'QT interval prolongation' and "Fluoroquinolones", section on 'Other adverse effects'.)

●

Macrolides – The potential adverse effects of macrolides include QT prolongation. Some athletes are evaluated with an ECG as part of clearance for participation. If an athlete needs ECG testing around the time of antibiotic therapy, it is reasonable to avoid the use of macrolides when possible [18]. (See "Azithromycin and clarithromycin", section on 'QT interval prolongation and cardiovascular events' and "Fluoroquinolones", section on 'QT interval prolongation'.)

●

Tetracyclines and sulfonamides – Side effects of both of these antibiotics include photosensitivity. If these antibiotics are used, we recommend precautions such as sunscreen and protective clothing, particularly if athletes participate in outdoor sports [18]. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity' and "Tetracyclines", section on 'Allergic and skin reactions'.)

In addition, any antibiotic may have the following side effects that can affect athletes: ●

Antibiotic-associated diarrhea – Antibiotic-associated diarrhea is a common side effect that can impair an athlete's performance and increase the risk of dehydration. As with all patients, when possible, we choose narrow spectrum antibiotics and avoid extended courses [18]. Probiotics in the prevention of antibiotic-associated diarrhea are discussed elsewhere. (See "Probiotics for gastrointestinal diseases", section on 'C. difficile infection'.)

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Fatigue – Antibiotic use in athletes has been associated with fatigue and impaired performance; however, only limited evidence exists to substantiate this claim [18]. Determining if the fatigue is from illness versus the medication can be difficult. If there is concern that antibiotics may be causing fatigue, when possible, we time the antibiotic to avoid dosing around the time of competition or an important event (eg, stopping antibiotics for acne prophylaxis).

Medications used for symptom relief — Some medications used for symptom relief (adjunctive medications) may contain banned substances (eg, decongestants) and should be avoided (

table 1). The clinician should refer to the appropriate governing body based on the

athlete's sport for information about regulations on banned substances. These agencies include the World Anti-Doping Agency (WADA) (see prohibited substances list) and the International Olympic Committee (IOC) [19]. The National Collegiate Athletic Association (NCAA) has its own listing for American collegiate athletes [20]. (See "Use of androgens and other hormones by athletes", section on 'Banned drugs'.) Expectorants (eg, guaifenesin) are typically well-tolerated and can help to loosen and thin mucus production. Antihistamines, antitussives, and oral decongestants can have side effects that are harmful for athletes ( ●

table 1):

Use of first-generation antihistamines (eg, diphenhydramine) can increase risk of heat illness and dehydration due to anticholinergic effects. They can also cause sedation. Second-generation antihistamine formulations are less sedating but can still be dehydrating. Athletes may be more susceptible to injury when using sedating medications.

●

Some antitussives (eg, dextromethorphan) may cause fatigue and should be used with caution in athletes.

●

Oral decongestants are associated with a risk of dehydration and hyperthermia in athletes [3].

Bronchodilators may be needed for short-term relief of URI-associated bronchospasm. Occasional use of an inhaled, short-acting beta-agonist is usually all that is required. Athletes and coaches should note that beta-agonists are not permitted in some sports due to their potential ergogenic effects. If the need for treatment with such medications persists, they should check with the organizations that supervise drug testing for their sport. The management of exercise-related bronchoconstriction is discussed in greater detail separately. (See "Exercise-induced bronchoconstriction".) https://www.uptodate.com/contents/13806/print

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Medication and competition — Unless necessary, we do not start new medications one or two days prior to competition as side effects cannot always be predicted. Other medications we avoid in competition include (

table 1):

●

Antipyretics – These should not be used to mask fevers in order to allow participation.

●

Sedating medications – These may make the athlete more susceptible to injury from decreased alertness. (See 'Medications used for symptom relief' above.)

●

Adjunctive medications – Those that contain banned substances should not be used. (See 'Medications used for symptom relief' above.)

Some question exists whether antibiotics cause fatigue. When possible, we time the prescription of antibiotics as far from competition as possible. (See 'Antibiotics' above.)

CLEARANCE FOR SPORTS General participation — Athletes with mild, viral upper respiratory tract infections (URTIs) not involving coronavirus disease 2019 (COVID-19) or other highly contagious pathogens can continue to play as long as they feel able (

algorithm 1) [21]. Athletes may be more

susceptible to dehydration during or after a URTI. For this reason, we advise athletes to stay well-hydrated after returning to play, particularly if the athlete plans on participating in their sport/activity at high altitude or in adverse weather conditions [22]. Athletes with pre-existing conditions and/or moderate to severe illness (fever or systemic symptoms) may need to refrain from play until such symptoms have resolved. There may be particular considerations for return to play in specific situations. (See 'Special circumstances' below and 'Preventing spread of infection' below.) Criteria — Clinicians can use the "neck check" as a way to determine if athletes can return to play immediately or not ( ●

algorithm 1).

Passes the neck check – The "neck check" is a widely used screening method for determining appropriateness for participation in sports while ill [3]. Athletes may return to sport if their symptoms are all "above the neck" (eg, rhinorrhea or sore throat) [23]. If there are symptoms present "below the neck" (eg, fever, malaise, chest congestion, or gastrointestinal symptoms), athletes should be kept from participation until symptoms have resolved. Cough may be an "above" or "below" the neck symptom depending on its etiology. For example, if cough is from post-nasal drip, it is "above the neck," but if from pneumonia, it is "below the neck."

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Fever or systemic signs (presumed viral illness) – When fever or other systemic signs of illness are present from presumed viral illness, the athlete should refrain from exercise. Clearance is contingent on the athlete testing negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), afebrile, off antipyretics for a minimum of one day, well-hydrated, and feeling physically ready to return to sport. Athletes with viral illnesses should also refrain from exercise if he or she has unexplained sinus tachycardia. Unexplained sinus tachycardia may be the only sign of myocarditis, an uncommon complication of URTI caused by certain viruses (historically, the most common of which included coxsackie B virus, adenovirus, and Epstein-Barr virus (

table 2)).

Potential cardiac involvement of SARS-CoV 2 is discussed separately. (See "COVID-19: Cardiac manifestations in adults" and "COVID-19: Clinical manifestations and diagnosis in children".) Athletes with unexplained sinus tachycardia following viral URTI should be evaluated promptly if they develop symptoms or signs of myocarditis (

table 3). (See "Myocarditis:

Causes and pathogenesis", section on 'Viral or "idiopathic" myocarditis' and "Clinical manifestations and diagnosis of myocarditis in children", section on 'Clinical manifestations'.) ●

Bacterial illness – Athletes being treated for bacterial illnesses should be afebrile off antipyretics and on antibiotics for at least 24 hours prior to returning to activity. They should also be well-hydrated and feel physically ready to return to play.

Transition back to play — Transition back to play depends on the anatomic location, severity of illness, and resolution of symptoms [24]. Return to play following COVID-19 infection is discussed separately. (See "COVID-19: Return to sport or strenuous activity following infection".) ●

Returning after passing the "neck check" – If an athlete passes the "neck check," they should be counseled to initially attempt only 10 to 15 minutes of light exercise or training. If they feel well during this initial trial, they may proceed with exercise as tolerated. Anecdotally, some athletes report that light exercise provides symptomatic relief and an opportunity to clear the sinuses and airways of phlegm and mucus. If an athlete is not able to tolerate light exercise, they should rest and try again the following day.

●

Returning after non-COVID-19 fever or systemic illness – When the athlete returns to play, they should start with light activity and follow a graded return to play based on their response [9]. Typically, the sequence of training increments should be increasing frequency first, then duration, and finally, intensity of exercise. The exact time course will depend on the severity and duration of the underlying infection. A general rule is for every

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day missed due to illness, the athlete needs two to three days of graded return (eg, if an athlete misses two days of practice due to illness, they should gradually increase activity over four to six days until they are back to normal practice). Increments in training volume and intensity should be limited to approximately 10 percent at a time to avoid overexertion in the early phase of return. In certain situations, it may be appropriate to allow modified participation in sport while an athlete recovers from a URTI. For example, the athlete may be allowed to shoot free throws at basketball practice away from the team if they are afebrile but still recovering from "below the neck" symptoms. Return to competition — Clearance for competition is the same as for general sports participation. Athletes with mild viral URTIs can compete as long as they feel able. An athlete should be held from competition if they have fever or systemic signs of illness in order to prevent more significant illness and avoid the spread of disease. Fever, hypoxia, and dehydration are absolute contraindications to participation. Relative contraindications include the athlete not feeling physically able to participate and infection with an illness that is highly contagious (eg, influenza or pertussis). (See 'General participation' above and 'Influenza' below and 'Pertussis' below.) Special circumstances COVID-19 — Return to play following COVID-19 infection is discussed separately. (See "COVID19: Return to sport or strenuous activity following infection".) Infectious mononucleosis — Return to sports after infectious mononucleosis is discussed elsewhere. (See "Infectious mononucleosis", section on 'Return to sports'.) Underlying respiratory conditions — The athlete with poorly-controlled underlying respiratory conditions, such as asthma or chronic obstructive pulmonary disease, should seek the advice of their clinician before reinitiation of activity. (See "An overview of asthma management" and "Chronic obstructive pulmonary disease: Definition, clinical manifestations, diagnosis, and staging".) SCUBA diving — Athletes need to be clear of URTI symptoms for a minimum of 10 days prior to resuming SCUBA diving due to the risk of hypercarbia and lung injury/pneumothorax during ascent. It is also a contraindication to dive with ruptured tympanic membranes [25,26]. (See "Complications of SCUBA diving", section on 'Barotrauma'.)

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PREVENTION Preventing spread of infection — Upper respiratory tract infections (URTIs) are often very contagious and may spread through athletic teams quickly. Athletes with URTIs should follow precautions to help prevent spread of infection. Moreover, there are specific considerations to prevent the spread of infection for influenza and pertussis. General measures — Implementing simple precautions can minimize the spread of URTI among athletic teams [27]: ●

Hand hygiene can reduce transmission of organisms (

table 4). (See "Infection

prevention: Precautions for preventing transmission of infection", section on 'Hand hygiene'.) ●

All team members should be educated on the importance of coughing etiquette and disposal of soiled tissues. Patient information flyers are available from the Centers for Disease Control and Prevention. Sharing of personal items such as towels, drinks, and sporting equipment should be discouraged.

●

An athlete with infection should be isolated from team members and the general public when possible. This includes during meals, transport, and for competitions, at both accommodations and sporting venues. Some teams and sporting groups organize spare accommodations and separate meal rooms from the general public.

Influenza — Influenza infections are highly contagious and can spread quickly through a team's roster if left unattended. We test for influenza in athletes with an influenza-like illness who participate in competitive team sports. Rapid point-of-care analyzers can be used for this process [28]. If an athlete tests positive for influenza, prophylaxis for close contacts, particularly during competitions, may be reasonable to prevent further spread of the disease [29]. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Diagnosis' and "Seasonal influenza in children: Prevention with antiviral drugs" and "Seasonal influenza in children: Management", section on 'Antiviral therapy' and "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Seasonal influenza in nonpregnant adults: Treatment".) Those athletes with influenza should be isolated from others on the team and only allowed to return to participation after symptom resolution. The athlete must be afebrile off antipyretics for a minimum of one day, well-hydrated, and free of any myalgias or systemic symptoms. (See

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"Seasonal influenza in nonpregnant adults: Treatment", section on 'Infection prevention and control'.) Once an index influenza case has been confirmed, it remains important to test subsequent cases for both influenza and SARS-CoV-2, as symptoms are similar. Athletes should receive the influenza and COVID-19 vaccines to minimize the risks posed by these illnesses. (See 'Immunizations' below.) Pertussis — For athletes with confirmed pertussis, we agree with the American College of Chest Physicians recommendations that they be isolated for the first five days of antibiotic treatment [30]. Teammates and coaches should receive post-exposure prophylaxis. (See "Pertussis infection in adolescents and adults: Treatment and prevention" and "Pertussis infection in adolescents and adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.) Immunizations — Immunizations schedules should typically follow recommendations for the general population. For athletes, the timing of vaccine administration should be planned with the goal of minimizing any adverse effect on training and competition. (See "Standard immunizations for nonpregnant adults", section on 'Immunization schedule for nonpregnant adults'.) When possible, vaccines should be administered at the onset of a rest period from training and competition [31,32]. If vaccination within a training and/or competition period cannot be avoided, we administer the vaccine shortly after a competition to provide as long of a period of time until the next competition as possible. After immunizations, exercise intensity should be transiently decreased if an athlete feels unwell, or is inconvenienced by pain and soreness at or around the injection site. Side effects from inactivated vaccines can be expected within the first two days after vaccination, while side effects are typically seen approximately 10 to 14 days after receiving live attenuated vaccines [31]. It is essential to know the athlete's travel schedule during the season. Early preparation will allow time for the athlete to be immunized as appropriate. (See "Immunizations for travel".) Overtraining syndrome — Almost every athlete feels the effects of fatigue at some point in training and competition. However, some athletes may develop overtraining syndrome, which can lead to recurrent respiratory infections. Measures to prevent overtraining syndrome are discussed separately. (See "Overtraining syndrome in athletes", section on 'Clinical presentation' and "Overtraining syndrome in athletes", section on 'Prevention measures'.).

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Nutrition — Immune function can be compromised with micronutrient deficiencies (eg, zinc) in the general population, but this is less likely in trained athletes who consume a well-balanced diet. Some athletes struggle to maintain good dietary practices, and may benefit from nutritional supplementation [33]. However, adolescent athletes in particular may have limited or inaccurate knowledge and information about supplements [34]. Dietary review with a registered dietitian is useful in identifying athletes with poor dietary practices, and in developing sports-specific strategies. (See "Overview of dietary trace elements", section on 'Deficiency'.) There is little evidence to support the use of nutritional supplements (eg, vitamin supplements or probiotics) in preventing URTI in athletes [35]. Additionally, supplements may be contaminated with banned substances. (See "The common cold in adults: Treatment and prevention", section on 'Prevention'.)

SUMMARY AND RECOMMENDATIONS ●

Epidemiology – Upper respiratory tract infections (URTIs) are the most common type of infection in athletes. (See 'Epidemiology' above.)

●

COVID-19 infection – The presentation and management of athletes infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not differ from the general population. (See 'Athletes with covid-19 infection' above.)

●

Evaluation – The evaluation of athletes for the various etiologies of upper respiratory tract infections (URTIs) is the same as for the general population. (See 'Evaluation' above.)

●

Treatment – In general, treatment strategies and medications for upper respiratory tract illnesses in athletes should be the same as for nonathletes. There are some specific considerations for athletes regarding choice of antibiotics and medications used for symptom relief (

table 1). (See 'Antibiotics' above and 'Medications used for symptom

relief' above.) ●

Return to play – Athletes with mild viral URTIs not involving highly contagious or dangerous pathogens can continue to play and compete if they feel able (

algorithm 1).

Athletes with pre-existing conditions and/or moderate to severe illness (fever or systemic symptoms) may need to refrain from play until such symptoms have resolved. There may be particular considerations for return to play in certain situations. (See 'General participation' above and 'Special circumstances' above and 'Influenza' above and 'Pertussis' above.) https://www.uptodate.com/contents/13806/print

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Use of UpToDate is subject to the Terms of Use. REFERENCES

1. Mountjoy M, Junge A, Alonso JM, et al. Sports injuries and illnesses in the 2009 FINA World Championships (Aquatics). Br J Sports Med 2010; 44:522. 2. Edouard P, Junge A, Sorg M, et al. Illnesses during 11 international athletics championships between 2009 and 2017: incidence, characteristics and sex-specific and discipline-specific differences. Br J Sports Med 2019; 53:1174. 3. Jaworski CA, Rygiel V. Acute Illness in the Athlete. Clin Sports Med 2019; 38:577. 4. Engebretsen L, Soligard T, Steffen K, et al. Sports injuries and illnesses during the London Summer Olympic Games 2012. Br J Sports Med 2013; 47:407. 5. Soligard T, Steffen K, Palmer-Green D, et al. Sports injuries and illnesses in the Sochi 2014 Olympic Winter Games. Br J Sports Med 2015; 49:441. 6. Hellard P, Avalos M, Guimaraes F, et al. Training-related risk of common illnesses in elite swimmers over a 4-yr period. Med Sci Sports Exerc 2015; 47:698. 7. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA 2004; 292:1333. 8. Schwellnus M, Soligard T, Alonso JM, et al. How much is too much? (Part 2) International Olympic Committee consensus statement on load in sport and risk of illness. Br J Sports Med 2016; 50:1043. 9. Walsh NP. Recommendations to maintain immune health in athletes. Eur J Sport Sci 2018; 18:820. 10. Simpson RJ, Campbell JP, Gleeson M, et al. Can exercise affect immune function to increase susceptibility to infection? Exerc Immunol Rev 2020; 26:8. 11. Ekblom B, Ekblom O, Malm C. Infectious episodes before and after a marathon race. Scand J Med Sci Sports 2006; 16:287. 12. Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the Regulation of Immune Functions. Prog Mol Biol Transl Sci 2015; 135:355. 13. Nieman DC. Exercise, upper respiratory tract infection, and the immune system. Med Sci Sports Exerc 1994; 26:128. 14. Kakanis MW, Peake J, Brenu EW, et al. The open window of susceptibility to infection after acute exercise in healthy young male elite athletes. Exerc Immunol Rev 2010; 16:119.

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15. Pyne DB, Hopkins WG, Batterham AM, et al. Characterising the individual performance responses to mild illness in international swimmers. Br J Sports Med 2005; 39:752. 16. Horn PL, Pyne DB, Hopkins WG, Barnes CJ. Lower white blood cell counts in elite athletes training for highly aerobic sports. Eur J Appl Physiol 2010; 110:925. 17. Lewis T, Cook J. Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature. J Athl Train 2014; 49:422. 18. Fayock K, Voltz M, Sandella B, et al. Antibiotic precautions in athletes. Sports Health 2014; 6:321. 19. WADA Prohibited List. http://list.wada-ama.org/ (Accessed on September 26, 2021). 20. 2020-21 NCAA Banned Substances. Available at: http://www.ncaa.org/sport-science-institut e/topics/2020-21-ncaa-banned-substances (Accessed on September 26, 2021). 21. Metz JP. Upper respiratory tract infections: who plays, who sits? Curr Sports Med Rep 2003; 2:84. 22. Hoffman MD, Cotter JD, Goulet ÉD, Laursen PB. VIEW: Is Drinking to Thirst Adequate to Appropriately Maintain Hydration Status During Prolonged Endurance Exercise? Yes. Wilderness Environ Med 2016; 27:192. 23. Eichner E. Eichner, E. Infection, immunity, and exercise. What to tell patients? Phys Sportsmed 1993; 21:125. 24. Jansen van Rensburg A, Janse van Rensburg DCC, Schwellnus MP, et al. Days until return-toplay differ for sub-categories of acute respiratory tract illness in Super Rugby players: A cross-sectional study over 5 seasons (102,738 player-days). J Sci Med Sport 2021; 24:1218. 25. Divers Alert Network. http://diversalertnetwork.org/medical. (Accessed on September 26, 2 021). 26. Bove A. Medical evaluation for sport diving. In: Diving Medicine, 4th ed, Bove A, Davis J (Ed s), Saunders, Philadelphia 2004. p.519. 27. Schwellnus M, Janse van Rensburg C, Bayne H, et al. Team illness prevention strategy (TIPS) is associated with a 59% reduction in acute illness during the Super Rugby tournament: a control-intervention study over 7 seasons involving 126 850 player days. Br J Sports Med 2020; 54:245. 28. Tsalik EL, Henao R, Montgomery JL, et al. Discriminating Bacterial and Viral Infection Using a Rapid Host Gene Expression Test. Crit Care Med 2021; 49:1651. 29. Gundlapalli AV, Rubin MA, Samore MH, et al. Influenza, Winter Olympiad, 2002. Emerg Infect Dis 2006; 12:144. https://www.uptodate.com/contents/13806/print

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30. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 2006; 129:1S. 31. Gärtner BC, Meyer T. Vaccination in elite athletes. Sports Med 2014; 44:1361. 32. Hull JH, Schwellnus MP, Pyne DB, Shah A. COVID-19 vaccination in athletes: ready, set, go…. Lancet Respir Med 2021; 9:455. 33. Pyne DB, Verhagen EA, Mountjoy M. Nutrition, illness, and injury in aquatic sports. Int J Sport Nutr Exerc Metab 2014; 24:460. 34. Mettler S, Lehner G, Morgan G. Widespread Supplement Intake and Use of Poor Quality Information in Elite Adolescent Swiss Athletes. Int J Sport Nutr Exerc Metab 2022; 32:41. 35. Walsh NP, Gleeson M, Pyne DB, et al. Position statement. Part two: Maintaining immune health. Exerc Immunol Rev 2011; 17:64. Topic 13806 Version 14.0

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GRAPHICS

Medication considerations in athletes with URTIs Medication

Risks and implications

Our approach

Antibiotics Fluoroquinolones

Tendinopathy/tendon rupture

Avoid if possible, stop if symptoms of tendon pain arise

Photosensitivity

Emphasize use of sunscreen and protective clothing, particularly if participating in outdoor sports

Macrolides

QTc prolongation – May fail electrocardiogram (EKG)

Reasonable to avoid where possible if athlete will have

screening (if required for

electrocardiogram (EKG)

clearance for participation)

checked for clearance/eligibility

QTc prolongation – May fail EKG

Reasonable to avoid where

screening (if required for clearance for participation)

possible if athlete will have electrocardiogram checked for clearance/eligibility

Tetracyclines/sulfonamides

Photosensitivity

Emphasize use of sunscreen and protective clothing, particularly if participating in outdoor sports

Any antibiotic

Antibiotic-associated diarrhea –

Use narrow-spectrum

Decreased

antibiotics, avoid extended

performance/increased risk for

courses

dehydration Fatigue (possible) – Impaired

When possible, avoid dosing

performance

antibiotics (eg, prophylactic antibiotics for acne) around the time of competition

Medications used for symptom relief Expectorants

None

May be used

Antihistamines

Anticholinergic effects –

Advise to stay well-hydrated

Increased risk of dehydration/heat illness Sedation – Increased risk of

Avoid in competition

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Antitussives

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Fatigue – Increased risk of

Use with caution

injury Oral decongestants

Antipyretics

May contain banned substances

Avoid in competition

Dehydration/hyperthermia

Advise to stay well-hydrated

May mask a fever

Should not be used to mask fever in order to allow participation in competition

Graphic 102914 Version 2.0

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Determining when athletes can return to play after URTI*

URTI: upper respiratory tract infection. * For more severe and contagious illnesses (eg, coronavirus disease 2019 [COVID-19], influenza) and other specific circumstances (eg, immune compromised host), the criteria for return to play will differ from the general criteria presented here. Please refer to the UpToDate topic on upper respiratory tract infections in adolescent and adult athletes for further details. Graphic 103349 Version 3.0

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Causes of myocarditis Infectious causes Viral

Infectious causes (cont.) Spirochetal

Noninfectious causes Cardiotoxins

Adenovirus

Leptospirosis

Alcohol

Arbovirus

Lyme disease

Anthracyclines

Coxsackie B virus

Relapsing fever

Arsenic

Cytomegalovirus

Syphilis

Carbon monoxide

Dengue

Mycotic

Catecholamines

Echovirus

Aspergillosis

Cocaine

Epstein-Barr virus

Blastomycosis

Cyclophosphamide

Hepatitis B and C

Candidiasis

Heavy metals (copper,

Herpesvirus

Coccidioidomycosis

HIV

Cryptococcosis

Influenza A and B

Histoplasmosis

Mumps

Mucormycosis

Parvovirus

Nocardia

Poliomyelitis

Sporotrichosis

Rabies Rubella Rubeola Vaccinia (smallpox vaccine) Varicella Variola Yellow fever

Bacterial Actinomycosis Bartonella Brucellosis Chlamydia Cholera https://www.uptodate.com/contents/13806/print

Rickettsial Q fever Rocky mountain spotted fever Typhus

Protozoal Amebiasis Chagas disease (South American trypanosomiasis) Leishmaniasis Malaria Sleeping sickness (African trypanosomiasis)

lead, iron) Radiation

Hypersensitivity reactions Antibiotics (penicillins, cephalosporins, sulfonamides) Clozapine Diuretics (thiazide, loop) Dobutamine Insect bites (bee, wasp, spider, scorpion) Lithium Methyldopa Snake bites Tetanus toxoid Vaccinations (eg, vaccinia, coronavirus mRNA vaccines)

Systemic disorders Celiac disease Collagen-vascular 19/23

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Clostridial Diphtheria

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Toxoplasmosis

Helminthic

diseases Granulomatosis with polyangiitis

Gonococcal

Ascariasis

Haemophilus

Echinococcosis

Legionella

Filariasis

Meningococcal

Paragonimiasis

ulcerative colitis)

Mycoplasma

Schistosomiasis

Kawasaki disease

Pneumococcal

Strongyloidiasis

Sarcoidosis

Psittacosis

Trichinosis

Thyrotoxicosis

Hypereosinophilia Inflammatory bowel disease (Crohn disease,

Salmonella Staphylococcal Streptococcal Tetanus Tuberculosis Tularemia Graphic 56995 Version 9.0

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Clinical features of myocarditis Excessive fatigue or exercise intolerance Chest pain Unexplained sinus tachycardia S3, S4, or summation gallop Abnormal electrocardiogram Abnormal echocardiogram New cardiomegaly on chest radiograph Atrial or ventricular arrhythmia Partial or complete heart block, new-onset bundle branch block New-onset or worsening heart failure Acute pericarditis Cardiogenic shock Sudden cardiac death Respiratory distress/tachypnea Hepatomegaly Graphic 66776 Version 5.0

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Hand-hygiene technique When decontaminating hands with an alcohol-based hand rub, apply product to palm of one hand and rub hands together, covering all surfaces of hands and fingers, until hands are dry. Follow the manufacturer's recommendations regarding the volume of product to use. When washing hands with soap and water, wet hands first with water, apply an amount of product recommended by the manufacturer to hands, and rub hands together vigorously for at least 20 seconds, covering all surfaces of the hands and fingers. Rinse hands with water and dry thoroughly with a disposable towel. Use towel to turn off the faucet. Liquid, bar, leaflet, or powdered forms of plain soap are acceptable when washing hands with soap and water. When bar soap is used, small bars of soap and soap racks that facilitate drainage should be used. Multiple-use cloth towels of the hanging or roll type are not recommended for use in health care settings. Data from:  1. Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report 2002; 51(RR-16):1. 2. Centers for Disease Control and Prevention. When & How to Wash Your Hands. Available at: http://www.cdc.gov/handwashing/when-how-handwashing.html (Accessed on October 11, 2019).

Graphic 77676 Version 7.0

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Contributor Disclosures Carrie A Jaworski, MD, FAAFP, FACSM No relevant financial relationship(s) with ineligible companies to disclose. David B Pyne, PhD, FACSM Consultant/Advisory Boards: Human Kinetics Publishers [sports physiology]. All of the relevant financial relationships listed have been mitigated. Francis G O'Connor, MD, MPH, FACSM No relevant financial relationship(s) with ineligible companies to disclose. Jonathan Grayzel, MD, FAAEM No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Nasal obstruction: Diagnosis and management Author: Neil Bhattacharyya, MD, FACS Section Editor: Daniel G Deschler, MD, FACS Deputy Editor: Lisa Kunins, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Jan 11, 2022.

INTRODUCTION Nasal and sinus complaints are among the most common reasons for visits to primary care clinicians, otolaryngologists, and allergists. Although some clinicians consider nasal obstruction to imply a blockage within the nasal cavity, nasal obstruction is most commonly defined as a patient symptom manifested as a sensation of insufficient airflow through the nose [1]. Nasal obstruction may be the cardinal presenting symptom of many common disease processes, such as rhinitis, sinusitis, septal deviation, adenoid hypertrophy, and nasal trauma. This topic will focus on the clinical manifestations, evaluation, and treatment of nasal obstruction in adults. Specific etiologies of nasal symptoms and other conditions associated with symptomatic nasal obstruction are discussed separately: ●

(See "Etiologies of nasal symptoms: An overview".)

●

(See "An overview of rhinitis".)

●

(See "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis".)

●

(See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis".)

●

(See "Tumors of the nasal cavity".)

●

(See "Cancer of the nasal vestibule".)

●

(See "Nasal trauma and fractures in children and adolescents".)

RISK FACTORS

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The risk factors for nasal obstruction relate directly to the underlying etiology. Several common risk factors for nasal obstruction include a history of atopy, recurrent sinusitis, nasal trauma, nasal surgery, having household pets, exposure to poor air quality, and a family history of nasal polyposis [2-4]. Nasal obstruction commonly accompanies many other comorbid conditions including asthma and obstructive sleep apnea [5].

PATHOGENESIS The pathogenesis of nasal obstruction may be related to abnormalities occurring with any of the anatomic structures and functions within the nose. Normal nasal anatomy and function are discussed elsewhere. (See "Etiologies of nasal symptoms: An overview", section on 'Nasal anatomy and function'.) Nasal obstruction may be generally divided into mucosal and structural causes (

table 1). The

nasal mucosa is a complex tissue that is subject to local and systemic insults, leading to nasal obstruction. Examples of mucosal causes of nasal obstruction include bacterial sinusitis, nasal polyps, and soft tissue turbinate hypertrophy due to allergic rhinitis. There is also a normal, cyclical pattern of turbinate mucosal swelling, which alternates between sides of the nasal septum at intervals of two to five hours, referred to as the nasal cycle [6]. Disruption of the nasal cycle can contribute to nasal obstruction. Airflow through the nose is limited structurally by the width of the nasal cavity. The nasal cavity includes the anterior nasal cartilaginous structures as well as the borders of the bony piriform aperture ( airway (

figure 1 and

figure 2). The nasal valve is the narrowest portion of the human

figure 3) [7]. Collapse of any of the structures making up the nasal cavity can lead to

nasal obstruction. Examples of other structural causes include nasal septal deviation (cartilaginous or bony), bony inferior turbinate hypertrophy, concha bullosa formation (air in the middle turbinate), benign and malignant tumors, and choanal atresia or stenosis. The underlying pathogenesis of nasal obstruction may be multifactorial. As an example, it is common to have compensatory mucosal hypertrophy of the inferior turbinate on the side opposite a deviated nasal septum [8,9].

CLINICAL MANIFESTATIONS The most common clinical manifestations of nasal obstruction are the subjective sensation of congestion, stuffiness, fullness, or blockage within the nose. Of note, patients often use the https://www.uptodate.com/contents/14609/print

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term “congestion” to describe a variety of nasal symptoms, and it is important to distinguish nasal congestion from symptoms such as excessive mucus or sinus pressure or fullness [10]. It is common for symptoms of nasal etiology to wax and wane with respect to daily time course, body position, seasonality, and exposures to environmental stimuli. For example, difficulty sleeping due to nasal obstruction symptoms is a common complaint, as the inferior turbinates may engorge in the supine position. Patients may report being able to sleep on one side only, as contralateral sleeping causes increased nasal obstruction. In fact, nasal obstruction is a risk factor for poor sleep quality, independent of obstructive sleep apnea [11,12]. Difficulty breathing is a less common complaint, which can occur due to nasal disease on one or both sides of the nose. Patients will often report additional symptoms that may suggest the underlying etiology of nasal obstruction. In the case of rhinosinusitis, these symptoms include facial congestion, facial pain or pressure, dysosmia, anterior rhinorrhea, postnasal discharge, cough, pruritic conjunctivitis, sneezing, or throat irritation/itching. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Clinical manifestations'.) The degree of nasal obstruction, as measured objectively by acoustic rhinometry, peak nasal airflow, or rhinomanometry, may not correlate with the patient's subjective degree of nasal obstruction [13]. As an example, minimal changes in objectively measured nasal patency may be experienced as substantially bothersome for an individual patient. (See 'Other testing' below.) The natural history of nasal obstruction may vary based upon the underlying etiology. As examples, structural abnormalities such as nasal septal deviation or bony inferior turbinate hypertrophy typically worsen slowly over time. Mucosal abnormalities, such as those caused by seasonal allergies or noxious stimuli, typically fluctuate in duration and severity [14]. (See "Etiologies of nasal symptoms: An overview" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Clinical manifestations'.)

DIAGNOSIS The evaluation of a patient with nasal symptoms involves a detailed history and physical examination. Some patients may require further evaluation involving nasal endoscopy or diagnostic imaging. This section provides a general approach to the patient with nasal obstruction. The differential diagnosis of nasal obstruction is broad and includes both structural causes (congenital https://www.uptodate.com/contents/14609/print

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abnormalities, acquired diseases, tumors) and mucosal causes (medication-induced, infectious, and inflammatory conditions) (

table 1). Diagnostic criteria for specific etiologies of nasal

obstruction are discussed elsewhere. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Chronic nonallergic rhinitis", section on 'Diagnosis' and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis and evaluation' and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Diagnosis' and "Etiologies of nasal symptoms: An overview" and "Congenital anomalies of the nose".) History — Clinicians should focus on several key features of the clinical history: ●

Location – Whether symptoms are unilateral (suggesting structural causes) or bilateral (suggesting mucosal causes)

●

Time course – Temporal course of the nasal symptoms, including diurnal and seasonal variation suggesting an allergic process

●

Triggers – Allergic stimuli and airborne exposures (eg, cigarette smoke, particulate matter, pets, chemicals)

●

Symptoms of rhinosinusitis – Facial pain or pressure, nasal congestion, dysosmia, headache, purulent nasal discharge

●

Symptoms suggesting malignancy – Facial deformity, cranial nerve dysfunction (eg, facial numbness), and unexplained epistaxis

●

Intranasal drug use – Intranasal cocaine or overuse of topical nasal decongestant, such as oxymetazoline or phenylephrine

●

Oral medications – Oral contraceptives, antithyroid medication, antihypertensive medication, antidepressants, and benzodiazepines

●

Trauma – History of nasal trauma or previous nasal surgery, particularly rhinoplasty

●

Medical history – Granulomatosis with polyangiitis, cystic fibrosis (associated with nasal polyposis), sarcoidosis, syphilis, and asthma

Physical examination — The physical examination of the nose is of primary importance in identifying or confirming the cause of nasal obstruction [7]. Most of the underlying causes of nasal obstruction can be determined based on a thorough examination of the nose, nasal cavity, and the nasopharynx [15]. External examination — The external nasal contour is examined with close attention to any bony and cartilaginous deformities, looking for evidence of prior trauma, the structural integrity of the nasal tip, and indentation or depression of the surrounding nasal bones. In older patients, deterioration or hypertrophy of the cartilage in the nasal tip may contribute to nasal obstruction. The examiner should manually elevate the nasal tip to a neutral (rather than https://www.uptodate.com/contents/14609/print

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exaggerated) position and assess for improvement of nasal airflow. Airflow improvement suggests disease of the cartilage of the nasal tip. The clinician should also examine airflow both during shallow and deep inspiration. Early collapse of nasal patency suggests nasal valve incompetence. The Cottle maneuver is an additional physical examination maneuver to assess nasal valve competency [7]. The Cottle maneuver is performed by retracting the cheek laterally, which pulls the upper lateral cartilage away from the septum and widens the internal nasal valve angle. If the patient’s symptoms are relieved with this maneuver, the cause of nasal obstruction is likely related to the nasal valve. Palpation of the neck is also important to detect cervical lymphadenopathy, particularly if nasal malignancy is suspected. Anterior rhinoscopy — Anterior rhinoscopy can be performed with a nasal speculum or with an otoscope, along with a bright light source to improve visualization. Examination of the nose is conducted with the patient's head tilted back and the clinician sitting directly opposite. To reduce patient discomfort and steady the head, the examiner should position the outer ulnar aspect of the palm not holding an instrument against the patient's forehead; the thumb of that hand is used to elevate the tip of the nose. This procedure allows for optimal visualization of each vestibule, the nasal turbinates, septum, and mucosal surfaces (

picture 1).

The assessment should start at the level of the naris, looking for mucosal abnormalities, patency, and collapse of the soft tissues with respiration (

figure 4) [16]. Normal mucosal

surfaces are pink, and the vestibules are patent and easily visible to the level of the middle turbinates (

picture 2). The septum should be midline, although a slight deviation may be

normal. Anterior rhinoscopy provides assessment of the size and caliber of the inferior turbinates and the position of the anterior to mid-nasal septum. Although there are no strict definitions for normal size of the nasal cavity, clinicians should assess the overall dimensions of the nasal cavity relative to the septum and the turbinates while identifying septal deviation, significant inferior turbinate hypertrophy, and possible contact between mucosal surfaces ( picture 3). Occluded nasal passageways caused by boggy, red nasal mucosa may develop as a result of allergies, nonallergic rhinitis, or overuse of nasal decongestants. Ulcerated, friable mucosa may indicate granulomatous disease. Polyps at the level of the middle turbinate or mid-nasal cavity may be visible (

picture 4). Identification of purulent nasal discharge is helpful in identifying

cases of rhinosinusitis [17].

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Nasal endoscopy — Posterior nasal structures are best visualized with nasal endoscopy. Fiberoptic nasal endoscopy is a diagnostic tool with a high diagnostic yield but is typically available only to otolaryngologists. Patients in whom the etiology of nasal obstructive symptoms is unclear after initial evaluation, or in whom symptoms persist after initial treatment for a presumptive cause, should be referred for endoscopy. After preparation of the nose with topical decongestant and/or topical anesthetic spray, a rigid or flexible endoscope is used to directly examine the middle meatus, posterior aspects of the nasal cavity, and the nasopharynx to identify polyps, posterior turbinate hypertrophy, middle and posterior nasal septal deviations, adenoid hypertrophy, nasal tumors, choanal atresia, and purulent discharge draining posteriorly in rhinosinusitis (

picture 5 and

picture 6) [18].

Diagnostic imaging — Diagnostic imaging to assess both mucosal disorders and anatomical deformities is indicated when the diagnosis is not clear based upon the history and physical examination alone. Computed tomography (CT) scan of the nose and paranasal sinuses is the primary diagnostic imaging modality [15]. Plain film radiography lacks the sensitivity and specificity required in the diagnostic evaluation of nasal obstruction [15]. Magnetic resonance imaging (MRI), which allows for more detailed soft tissue assessment compared with CT, is generally a secondary study and is indicated for better characterization of nasal tumors [7]. Examples of abnormal CT findings include air-fluid levels in acute bacterial rhinosinusitis ( image 1), bony narrowing in choanal atresia ( image 3), and nasal septal deformities (

image 2), stenosis of the pyriform aperture (

image 4). Although an anatomic abnormality may

be seen on CT scan, the etiology of obstruction may not be apparent. As an example, any cause of inferior turbinate hypertrophy can lead to nasal obstruction, including allergic rhinitis (both seasonal and perennial), nonallergic rhinitis, rhinitis medicamentosa, and other medicationinduced rhinitis. In general, more useful clinical information is obtained from the history, physical exam, and, in certain cases, fiber-optic nasal endoscopy than imaging [17]. In general, imaging is not recommended as a first-line diagnostic intervention in most cases of clinically diagnosed allergic rhinitis or septal deviation [19,20]. Other testing — Several other tests can be performed to help characterize nasal obstruction. The data supporting the use of these measurements are somewhat controversial and results can be less than definitive. Thus, these tests are usually ordered under select clinical situations after specialist evaluation. ●

Allergy testing should be considered in patients with chronic and/or seasonal symptoms, given the high prevalence of allergic rhinitis and its contribution to nasal obstruction. It should be particularly considered in patients with concurrent asthma.

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Acoustic rhinometry is a simple, noninvasive measure of cross-sectional area of the nasal cavity longitudinally along the nasal passageway.

●

Peak nasal airflow is a noninvasive measure indicating peak nasal airflow in liters per minute achieved during maximal forced nasal inspiration.

●

Rhinomanometry is a computerized, functional assessment of airflow.

●

Mucosal biopsy is indicated for cases of suspected malignancy and may be helpful in the diagnosis of infection or inflammatory disease.

TREATMENT The treatment of nasal obstruction should target the underlying etiology. This section will focus on treatments of several causes of nasal obstruction, including nasal polyposis, nasal vestibulitis, nasal septal deviation, mucoceles, and nasal valve abnormalities. Treatments for other specific causes are discussed separately. (See "Congenital anomalies of the nose" and "Chronic rhinosinusitis: Management" and "Tonsillectomy and/or adenoidectomy in children: Indications and contraindications", section on 'Nasal obstruction' and "Nasal trauma and fractures in children and adolescents", section on 'Management' and "Snoring in adults", section on 'Nasal patency' and "Cancer of the nasal vestibule", section on 'Treatment' and "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".) Pharmacologic therapy is generally used as first-line treatment for mucosal causes of nasal obstruction. Nasal glucocorticoid sprays are first-line therapy for several mucosal etiologies of nasal obstruction (eg, rhinitis, nasal polyposis), and may often be used empirically as a trial of therapy [15]. Topical nasal glucocorticoid sprays are strongly recommended in patients with a clinical diagnosis of allergic rhinitis [20]. Clinicians should be alert to epistaxis occurring with topical nasal steroid sprays and consider otolaryngology referral if this persists. Some structural causes (eg, adenoidal hypertrophy) can be treated with pharmacologic therapy initially and referred for surgical treatment if medication response is inadequate. Other structural causes of nasal obstruction are less likely to respond to pharmacologic treatment, and surgery is the initial therapy [21,22]. As an example, choanal atresia usually requires transnasal puncture or palatal repair with subsequent stenting (

picture 7 and

picture 8). Malignancy of the nasal

cavity usually requires radiation therapy in combination with surgical resection. The etiology of nasal obstruction may be multifactorial, and treating more than one condition may be required for effective management of nasal obstruction. A combination of both nasal septal deviation and turbinate hypertrophy leading to nasal obstruction is common. Medical https://www.uptodate.com/contents/14609/print

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treatment of the turbinate hypertrophy component, possibly due to allergic rhinitis, may provide only partial relief depending on the degree of contribution of the individual elements. Similarly, surgical treatment may only provide partial relief, with pharmacologic treatment of comorbid allergic rhinitis needed to fully relieve symptoms. The majority of cases of nasal obstruction are effectively treated with a combination of pharmacologic and surgical therapy. However, nasal symptoms may wax and wane and it is not uncommon for nasal obstruction to recur if allergic stimuli are encountered again or if structural abnormalities recur after treatment. Such failure may occur months or even years after initial therapy but generally responds well to another course of treatment. Mucosal disorders Nasal polyps — Glucocorticoids are the mainstay of management of nasal polyposis [23]. Additional therapies include the treatment of underlying allergies, treatment with antileukotriene agents, anti-IgE monoclonal antibody therapy, and surgery for refractory disease. The treatment of nasal polyposis is reviewed in detail elsewhere. (See "Chronic rhinosinusitis: Management", section on 'CRS with nasal polyposis'.) Nasal vestibulitis — Treatment of nasal vestibulitis consists of the application of warm compresses and mupirocin nasal ointment twice daily for five days, or oral antibiotics if the infection appears to be widespread [24]. In some cases, the nasal vestibulitis may also reflect a local dermatitis, and empiric therapy with a low-potency topical nasal steroid (eg, 1% hydrocortisone ointment) in conjunction with the antibiotic ointment for a brief period may be additionally effective. (See "Etiologies of nasal symptoms: An overview", section on 'Nasal vestibulitis'.) Rhinosinusitis — Multiple therapies are utilized in the management of acute and chronic rhinosinusitis, including intranasal saline, topical and systemic glucocorticoids, antibiotics, antileukotriene agents, antifungals, and surgery. These treatments are combined in various ways to manage the different subtypes of rhinosinusitis. (See "Chronic rhinosinusitis: Management" and "Uncomplicated acute sinusitis and rhinosinusitis in adults: Treatment".) Rhinitis — Management of allergic rhinitis combines allergen avoidance and pharmacologic therapy. Intranasal glucocorticoids are the most effective single therapy for allergic rhinitis in patients with significant or persistent symptoms. Oral antihistamines can also be helpful for nasal obstruction in patients with persistent allergic rhinitis. (See "Pharmacotherapy of allergic rhinitis".)

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Patients with chronic nonallergic rhinitis are less responsive to pharmacologic therapy than those with allergic rhinitis. However, intranasal glucocorticoids and the topical antihistamine azelastine are useful in treating the total symptom-complex of chronic nonallergic rhinitis. (See "Chronic nonallergic rhinitis", section on 'Management'.) Medication-induced — Nasal obstruction caused by medication use generally resolves with termination of the offending medication (

table 1) [25]. In addition, an intranasal

glucocorticoid can help reduce nasal symptoms that persist soon after discontinuation. (See "An overview of rhinitis", section on 'Nasal decongestant sprays' and "An overview of rhinitis", section on 'Systemic medications'.) Structural disorders — In general, structural disorders are most effectively treated with surgical intervention [26]. In addition, external nasal dilator strips may be helpful in cases in which the soft tissues around the lateral external nose collapse, either unilaterally or bilaterally, during regular or moderate inspiration. Nasal septal deviation — Septoplasty is the definitive treatment in patients with nasal obstruction due to septal deviation. Reported rates of long-term efficacy vary, but one study reported that septoplasty was successful in reducing nasal symptoms in up to 89 percent of patients [27]. Mucoceles — Nasal and sinus mucoceles are effectively treated with endoscopic sinus surgery [28-31]. Nasal valve abnormalities — Nasal valve collapse generally requires surgical intervention [15,32,33]. Correction of nasal valve weakness usually involves cartilage grafts to buttress and support the existing cartilage. External nasal dilator strips and nasal clips, which are applied at night, may relieve symptoms and serve as an alternative to surgery in some patients [34].

REFERRAL Patients presenting with symptoms or signs of potentially serious nasal or sinus disease should be referred to an otolaryngologist (ie, facial deformity/swelling, diplopia, ocular proptosis, facial numbness, cranial nerve dysfunction, and unexplained epistaxis). Patients with structural causes of nasal obstruction should be also referred, as these conditions generally require specialized diagnostic equipment (eg, nasal endoscopy) and surgical treatment. Further evaluation and management of mucosal causes of nasal obstruction depend on individual clinician experience with a particular disorder. It is reasonable to start medical https://www.uptodate.com/contents/14609/print

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therapy (eg, intranasal glucocorticoids) for most mucosal disorders and refer to an allergist or otolaryngologist if nasal obstruction persists despite empiric therapy.

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) ●

Basics topics (see "Patient education: Deviated septum (The Basics)" and "Patient education: Nasal polyps (The Basics)")

SUMMARY AND RECOMMENDATIONS ●

Underlying causes of nasal obstruction include both mucosal disorders (medicationinduced, infectious, and inflammatory conditions) and structural abnormalities (congenital deformities, acquired diseases, tumors) (

table 1). (See "Etiologies of nasal symptoms:

An overview" and 'Pathogenesis' above.) ●

The evaluation of a patient with nasal symptoms involves a detailed history and physical examination. Some patients may require further evaluation involving nasal endoscopy or diagnostic imaging. (See 'Diagnosis' above.)

• The history should include a description of nasal symptoms, potential triggers, intranasal drug use, oral medication use, previous trauma or surgery, and pertinent medical history. (See 'History' above.)

• Most of the underlying causes of nasal obstruction can be identified with a thorough examination of the external nose, nasal cavity, and the nasopharynx. Anterior https://www.uptodate.com/contents/14609/print

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rhinoscopy and/or nasal endoscopy should be used for better visualization of internal nasal structures. (See 'Physical examination' above.)

• In cases where the diagnosis is not clear based upon the history and physical examination, computed tomography (CT) scan may be helpful in assessing for mucosal disorders and anatomic deformities. Plain film radiography lacks the sensitivity and specificity required in the diagnostic evaluation of nasal obstruction. (See 'Diagnostic imaging' above.) ●

The treatment of nasal obstruction should specifically target the underlying etiology. Pharmacologic therapy, particularly intranasal glucocorticoids, is generally used as firstline therapy for mucosal causes of nasal obstruction (eg, rhinitis, nasal polyposis). Many structural causes of nasal obstruction do not respond to medical treatment and require surgical intervention (eg, nasal septal deviation, nasal valve abnormalities). (See 'Treatment' above.)

●

Patients presenting with symptoms or signs of potentially serious nasal or sinus disease should be referred to an otolaryngologist (ie, facial deformity, cranial nerve dysfunction, and unexplained epistaxis). Patients with structural causes of nasal obstruction should be also referred, as these conditions generally require surgical intervention. (See 'Referral' above.) Use of UpToDate is subject to the Terms of Use.

REFERENCES

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6. Baraniuk JN, Kim D. Nasonasal reflexes, the nasal cycle, and sneeze. Curr Allergy Asthma Rep 2007; 7:105. 7. Chandra RK, Patadia MO, Raviv J. Diagnosis of nasal airway obstruction. Otolaryngol Clin North Am 2009; 42:207. 8. Akoğlu E, Karazincir S, Balci A, et al. Evaluation of the turbinate hypertrophy by computed tomography in patients with deviated nasal septum. Otolaryngol Head Neck Surg 2007; 136:380. 9. Jun BC, Kim SW, Kim SW, et al. Is turbinate surgery necessary when performing a septoplasty? Eur Arch Otorhinolaryngol 2009; 266:975. 10. McCoul ED, Mohammed AE, Debbaneh PM, et al. Differences in the Intended Meaning of Congestion Between Patients and Clinicians. JAMA Otolaryngol Head Neck Surg 2019; 145:634. 11. Storms W. Allergic rhinitis-induced nasal congestion: its impact on sleep quality. Prim Care Respir J 2008; 17:7. 12. Udaka T, Suzuki H, Fujimura T, et al. Chronic nasal obstruction causes daytime sleepiness and decreased quality of life even in the absence of snoring. Am J Rhinol 2007; 21:564. 13. Lam DJ, James KT, Weaver EM. Comparison of anatomic, physiological, and subjective measures of the nasal airway. Am J Rhinol 2006; 20:463. 14. Bellanti JA, Wallerstedt DB. Allergic rhinitis update: Epidemiology and natural history. Allergy Asthma Proc 2000; 21:367. 15. Fraser L, Kelly G. An evidence-based approach to the management of the adult with nasal obstruction. Clin Otolaryngol 2009; 34:151. 16. Wittkopf M, Wittkopf J, Ries WR. The diagnosis and treatment of nasal valve collapse. Curr Opin Otolaryngol Head Neck Surg 2008; 16:10. 17. Bhattacharyya N, Lee LN. Evaluating the diagnosis of chronic rhinosinusitis based on clinical guidelines and endoscopy. Otolaryngol Head Neck Surg 2010; 143:147. 18. Hamdan AL, Sabra O, Hadi U. Prevalence of adenoid hypertrophy in adults with nasal obstruction. J Otolaryngol Head Neck Surg 2008; 37:469. 19. Ardeshirpour F, McCarn KE, McKinney AM, et al. Computed tomography scan does not correlate with patient experience of nasal obstruction. Laryngoscope 2016; 126:820. 20. Seidman MD, Gurgel RK, Lin SY, et al. Clinical practice guideline: Allergic rhinitis. Otolaryngol Head Neck Surg 2015; 152:S1. 21. Corey CL, Most SP. Treatment of nasal obstruction in the posttraumatic nose. Otolaryngol Clin North Am 2009; 42:567. https://www.uptodate.com/contents/14609/print

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22. Tan BK, Lane AP. Endoscopic sinus surgery in the management of nasal obstruction. Otolaryngol Clin North Am 2009; 42:227. 23. Newton JR, Ah-See KW. A review of nasal polyposis. Ther Clin Risk Manag 2008; 4:507. 24. Rambur B, Winbourn MW. Recognizing nasal vestibulitis in the primary care setting. Nurse Pract 1994; 19:22, 25. 25. Varghese M, Glaum MC, Lockey RF. Drug-induced rhinitis. Clin Exp Allergy 2010; 40:381. 26. van Egmond MMHT, Rovers MM, Hannink G, et al. Septoplasty with or without concurrent turbinate surgery versus non-surgical management for nasal obstruction in adults with a deviated septum: a pragmatic, randomised controlled trial. Lancet 2019; 394:314. 27. Gandomi B, Bayat A, Kazemei T. Outcomes of septoplasty in young adults: the Nasal Obstruction Septoplasty Effectiveness study. Am J Otolaryngol 2010; 31:189. 28. Caylakli F, Yavuz H, Cagici AC, Ozluoglu LN. Endoscopic sinus surgery for maxillary sinus mucoceles. Head Face Med 2006; 2:29. 29. Brachlow A, Schwartz RH, Bahadori RS. Intranasal mucocele of the nasolacrimal duct: an important cause of neonatal nasal obstruction. Clin Pediatr (Phila) 2004; 43:479. 30. Devars du Mayne M, Moya-Plana A, Malinvaud D, et al. Sinus mucocele: natural history and long-term recurrence rate. Eur Ann Otorhinolaryngol Head Neck Dis 2012; 129:125. 31. Soon SR, Lim CM, Singh H, Sethi DS. Sphenoid sinus mucocele: 10 cases and literature review. J Laryngol Otol 2010; 124:44. 32. O'Halloran LR. The lateral crural J-flap repair of nasal valve collapse. Otolaryngol Head Neck Surg 2003; 128:640. 33. Hajem H, Botter C, Al Omani M, et al. Pyriform Aperture Enlargement for Internal Nasal Valve Obstruction in Adults: Systematic Review and Surgical Classification. Otolaryngol Head Neck Surg 2021; 165:745. 34. Kiyohara N, Badger C, Tjoa T, Wong B. A Comparison of Over-the-Counter Mechanical Nasal Dilators: A Systematic Review. JAMA Facial Plast Surg 2016; 18:385. Topic 14609 Version 35.0

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GRAPHICS

Etiology of nasal obstruction Mucosal Inflammatory Rhinosinusitis (may also have infectious etiology) Rhinitis, allergic and non-allergic Nasal polyps Granulomatosis with polyangiitis (Wegener's) Sarcoidosis Histiocytosis X

Infectious HIV Syphilis Tuberculosis Nasal vestibulitis

Medication Antithyroid medications Antihypertensive medications Alpha-blockers Angiotensin-converting enzyme (ACE) inhibitors Beta-blockers Calcium channel blockers Hydralazine Some antidepressants Benzodiazepines Erectile dysfunction agents (phosphodiesterase 5-inhibitors) Estrogen and progesterone Nonsteroidal antiinflammatory drugs (NSAIDs) Rhinitis medicamentosa (rebound nasal congestion with intranasal decongestants such as oxymetazoline or neosynephrine)

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Congenital abnormalities (eg, pyriform aperture stenosis, choanal atresia) Acquired abnormalities Enlarged adenoids Foreign bodies Septal disorders (eg, septal perforation due to intranasal cocaine, septal deviation due to trauma) Nasal valve abnormalities Mucoceles

Tumors (eg, inverted papilloma, squamous cell carcinoma, adenoid cystic carcinoma, olfactory neuroblastoma) Graphic 79359 Version 6.0

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External anatomy of the nose

Anatomical structures of the nose. Graphic 56105 Version 3.0

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Anatomy of the lateral wall of the nasal cavity and the nasopharynx

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Nasal valves

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Nasal polyposis

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Internal examination of the nose

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Anterior rhinoscopy

Normal nasal examination by anterior rhinoscopy. Inf: inferior; Turb: turbinate. Graphic 73166 Version 2.0

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Anterior rhinoscopy with septal deviation

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Nasal polyps in nostril

Nasal polyps appear as glistening, gray or white, mucoid masses in the nasal cavities. Courtesy of Glenis Scadding, MD and Peter Andrews, BSc, FRCS.

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Endoscopic view of choanal atresia

mt: middle turbinate; it: inferior turbinate; ns: nasal septum; a: atresia "plate." Courtesy of Glenn C Isaacson, MD, FAAP, FACS.

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Endoscopic image of purulent drainage from the middle meatus in a patient with acute bacterial rhinosinusitis

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CT of acute bacterial rhinosinusitis

Acute bacterial rhinosinusitis. Coronal image from a CT of the paranasal sinuses showing mucosal edema (arrows) and thick secretions (asterisks). CT: computed tomography. Graphic 68163 Version 4.0

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CT image of choanal atresia

Axial CT image of choanal atresia. Note the bony narrowing of the posterior nose. CT: computed tomography. Courtesy of Glenn C Isaacson, MD, FAAP, FACS.

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Pyriform aperture stenosis

Axial CT image documenting the small nasal opening of pyriform aperture stenosis. CT: computed tomography. Courtesy of Ellen S Deutsch, MD.

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Axial CT of congenital nasal septal deformity

CT: computed tomography. Courtesy of Glenn Isaacson, MD, FAAP, FACS.

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Transpalatal choanal atresia repair

Note reflected palatal flap and endotracheal tube stent in nasopharynx. Courtesy of Glenn C Isaacson, MD, FAAP, FACS.

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Nasal stenting after transnasal choanal atresia repair

Nasal stenting after transnasal choanal atresia repair. Courtesy of Glenn C Isaacson, MD, FAAP, FACS.

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Contributor Disclosures Neil Bhattacharyya, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Daniel G Deschler, MD, FACS No relevant financial relationship(s) with ineligible companies to disclose. Lisa Kunins, MD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Constipation in the older adult Author: Satish SC Rao, MD, PhD, FRCP Section Editors: Nicholas J Talley, MD, PhD, Kenneth E Schmader, MD Deputy Editor: Shilpa Grover, MD, MPH, AGAF All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Jun 15, 2022.

INTRODUCTION Constipation is a common complaint in older adults. It has a major impact on healthcare costs in the United States because it results in several office visits, specialty referrals, hospital admissions, and surgical procedures [1]. It also affects health-related quality of life [2,3]. This topic will review the clinical approach to the diagnosis and management of constipation in the older adult. The approach to diagnosis and management of constipation in children and adults in general are presented separately. (See "Constipation in infants and children: Evaluation" and "Chronic functional constipation and fecal incontinence in infants, children, and adolescents: Treatment" and "Etiology and evaluation of chronic constipation in adults" and "Management of chronic constipation in adults".)

DEFINITION OF CONSTIPATION The term constipation is variably defined by patients and physicians [4]. According to the Rome IV criteria, functional constipation is defined as any two of the following features: straining, lumpy hard stools, sensation of incomplete evacuation, use of digital maneuvers, sensation of anorectal obstruction or blockage with 25 percent of bowel movements, and decrease in stool frequency (less than three bowel movements per week) [5]. The above criteria must be fulfilled for the last three months with symptom onset six months prior to diagnosis, loose stools should rarely be present without the use of laxatives, and there must be insufficient criteria for a diagnosis of irritable bowel syndrome. https://www.uptodate.com/contents/16133/print

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EPIDEMIOLOGY AND RISK FACTORS Studies have reported that the prevalence of constipation in the older adult ranges from 24 to 50 percent [6-14]. Laxatives are used daily by 10 and 18 percent of community dwelling older adults and 74 percent of nursing home residents [11,15-18]. In addition to age, risk factors for chronic constipation include female gender, physical inactivity, low education and income, concurrent medication use, and depression [10,19]. One study showed that older adults who consume fewer calories and meals are also more likely to suffer from constipation [20]. Comorbid illnesses and nursing home residence are other risk factors for constipation.

PATHOPHYSIOLOGY Constipation in the older adult may be due to primary colorectal dysfunction or secondary to several etiologic factors (

table 1). The etiology of constipation in older patients is often

multifactorial. Primary colorectal dysfunction — Primary colorectal dysfunction can be further categorized into three broad subtypes: Slow transit constipation — Slow transit constipation (STC) is characterized by prolonged delay in stool transit throughout the colon. This could be due to a primary dysfunction of colonic smooth muscle (myopathy) or neuronal innervation (neuropathy) or secondary to dyssynergic defecation [21]. Dyssynergic defecation — Dyssynergic defecation (DD) is caused by difficulty with bowel movement or inability to expel stool from the anorectum. Many of these patients may also have prolonged colonic transit time (

table 2) [22].

Irritable bowel syndrome — Irritable bowel syndrome with predominant constipation (IBS-C) is characterized by abdominal pain with altered bowel habits. These patients may or may not have slow colonic transit or dyssynergia, and many have visceral hypersensitivity [20]. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".) Secondary causes for constipation — Conditions associated with constipation include endocrine or metabolic disorders, neurologic disorders such as Parkinson's disease and stroke, myogenic disorders, and medications (

table 1). Opioid induced constipation is common in

those suffering from chronic or cancer-related pain [23,24]. https://www.uptodate.com/contents/16133/print

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Chronic idiopathic constipation — Chronic idiopathic constipation or functional constipation is a common condition affecting the GI tract with an estimated global prevalence of 14 percent [25]. This functional disorder is defined as the infrequent, persistently difficult passage of stools or seemingly incomplete defecation, which does not meet IBS criteria [26]. These patients usually do not have any physiological abnormality. (See "Etiology and evaluation of chronic constipation in adults", section on 'Definition of constipation'.)

CLINICAL MANIFESTATIONS Constipation is characterized either by unsatisfactory defecation, infrequent stools, or difficulty with stool passage. In older adults, constipation may be associated with fecal impaction and overflow fecal incontinence. Fecal impaction can cause stercoral ulceration, bleeding, and anemia.

EVALUATION The first step in evaluation of constipation in older adults is to exclude secondary causes of constipation. This can often be accomplished with a thorough history and physical examination followed by undertaking the tests outlined below. History — It is important to elicit a thorough history noting the onset and duration of constipation. (See "Etiology and evaluation of chronic constipation in adults", section on 'History'.) Alarm symptoms (hematochezia, positive fecal occult blood test, obstructive symptoms, acute onset of constipation, severe persistent constipation that is unresponsive to treatment, weight loss ≥10 pounds, a change in stool caliber, family history of colon cancer or inflammatory bowel disease) should be specifically noted as these will indicate the need for more extensive evaluation. Comorbid issues such as immobility, chronic medical problems, and a medication list should be reviewed [27]. Concurrent psychosocial problems such as social isolation, decreased mobility, poor nutrition, and lack of independence should also be addressed as they can contribute to constipation [28,29]. Physical examination — A comprehensive physical examination should be performed that includes a rectal exam to palpate for hard stool, assess for masses, anal fissures, hemorrhoids, sphincter tone, push effort during attempted defecation, prostatic hypertrophy in males, and https://www.uptodate.com/contents/16133/print

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table 3). This is described in detail separately. (See

"Etiology and evaluation of chronic constipation in adults", section on 'Physical examination'.) Laboratory testing — A comprehensive metabolic panel, complete blood count, and thyroid function tests can identify metabolic conditions that may be causative as well as secondary anemia that will indicate further evaluation. We recommend routine laboratory testing in older adults with constipation. However, American College of Gastroenterology guidelines state that in patients with chronic constipation without alarm symptoms or signs (hematochezia, weight loss ≥10 pounds, family history of colon cancer or inflammatory bowel disease, anemia, positive fecal occult blood tests, acute onset of constipation in older adults, and severe persistent constipation that is unresponsive to treatment), there are inadequate data to make a recommendation about the routine use of laboratory tests [30]. Imaging — There are limited data to support the role of imaging in the evaluation of constipation in the older adult [30,31]. Endoscopy — A colonoscopy allows for direct visualization of the colon to exclude mucosal lesions (eg, solitary rectal ulcer syndrome, inflammation, malignancy) and should be performed in patients if they have alarm symptoms and also as indicated for colorectal cancer screening. (See "Etiology and evaluation of chronic constipation in adults", section on 'Endoscopy' and "Tests for screening for colorectal cancer", section on 'Colonoscopy'.) Physiologic testing — Specialized tests of colorectal function described below may prove useful in defining pathophysiology [23,32]. These tests are generally reserved for patients with chronic constipation who do not respond to therapy with lifestyle and dietary modifications and a trial of bulk forming and osmotic laxatives. (See "Etiology and evaluation of chronic constipation in adults", section on 'Motility studies' and "Etiology and evaluation of chronic constipation in adults", section on 'Colon transit studies' and "Etiology and evaluation of chronic constipation in adults", section on 'Defecography'.)

MANAGEMENT The first step in the treatment of chronic functional constipation is lifestyle and dietary modification. Bulk laxatives are recommended in patients who do not respond to lifestyle and dietary modification. A trial of osmotic laxatives should be considered in patients not responding to bulk laxatives. In patients who fail a trial of osmotic laxatives, colon secretagogues (lubiprostone) should be considered. Stimulant laxatives are efficacious, but chronic use should be avoided as the long-term safety in older adults is not known. Stool https://www.uptodate.com/contents/16133/print

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softeners and suppositories (glycerin or bisacodyl) have limited clinical efficacy. Enemas should only be used to prevent fecal impaction in patients with several days of constipation. Opioid antagonists may have a role in treatment of narcotic-induced constipation and paralytic ileus. In patients with dyssynergic defecation, biofeedback therapy may be helpful. Lifestyle modification — General measures such as increased fluid intake and exercise are suggested to treat constipation, but there is little evidence to support this [33]. In a small study of healthy volunteers, consumption of extra fluid was not associated with an increase in stool output [34]. It is advisable to encourage patients to establish a regular pattern of bowel movement. Most patients who have a normal bowel pattern usually empty stools at approximately the same time every day [35]. This fact suggests that the initiation of defecation is in part a conditioned reflex. Colonic motor activity is more active after waking and after a meal [36]. Thus, the optimal time for bowel movement is usually within the first two hours after waking and after breakfast. Other general measures include timed toilet training that consists of educating patients to attempt a bowel movement at least twice a day, usually 30 minutes after meals, and to strain for no more than five minutes [23]. Diaphragmatic breathing and posture may also impact defecation dynamics and ease of defecation. Measures include sitting up, leaning forward and raising the feet 8 to 12 inches above the ground. Diet and fiber — Fiber increases stool bulk, which causes colonic distention and promotes stool propulsion. A daily fiber intake of 20 to 25 g/day is generally recommended. The effects of fiber on bowel movements may take several weeks. Bloating and flatulence is a common problem with increased fiber intake [37]. (See "Management of chronic constipation in adults", section on 'Fiber'.) Laxatives — Laxative usage in the older adults should be individualized keeping in mind the patient's history (cardiac and renal comorbidities), drug interactions, cost, and side effects ( table 4) [38]. Bulk forming laxatives — Bulk forming laxatives include psyllium husk (eg, Metamucil), methylcellulose (eg, Citrucel), calcium polycarbophil (eg, FiberCon), and wheat dextrin (eg, Benefiber) (

table 4). They are natural or synthetic polysaccharides or cellulose derivatives

that primarily exert their laxative effect by absorbing water and increasing fecal mass. These laxatives are effective in increasing the frequency and softening the consistency of stool with a minimum of adverse effects. They may be used alone or in combination with an increase in dietary fiber.

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Despite substantial anecdotal clinical experience indicating benefit for bulk forming laxatives, objective evidence regarding the effectiveness is inconsistent. A systematic review found evidence that psyllium increases stool frequency in patients with chronic constipation but found insufficient evidence for other forms of fiber including calcium polycarbophil, methylcellulose, and bran [30]. Another review found evidence supporting the efficacy and safety of calcium polycarbophil, but poor evidence supporting the use of psyllium and methylcellulose [39]. One study showed that dried plums (prunes) were more effective than psyllium as first line therapy in the treatment of mild to moderate constipation [40]. A study showed that a fruit-based mixed soluble fiber (eg, Suprafiber) was as effective as psyllium, more palatable and caused less bloating [41]. Osmotic laxatives — A trial of osmotic laxatives should be considered in patients not responding to bulking agents [38]. Low-dose polyethylene glycol (PEG) (17 g/day) has been demonstrated to be efficacious and well tolerated in older patients [42,43]. However, high-dose PEG (34 g/day) is associated with abdominal bloating, cramping, and flatulence, and older adults may be more susceptible to these side effects [44]. Lactulose increases stool frequency, decreases the severity of constipation symptoms, and reduces the need for other laxatives in older adult patients compared with placebo. However, in one study, lactulose was less effective than low-dose PEG and also had a higher incidence of flatus [42]. Sorbitol was shown to be as efficacious as lactulose in a four-week study of constipated older adult patients and was less expensive and better tolerated [45]. Saline laxatives such as magnesium hydroxide have not been examined in older adults, and should be used with caution because of the risk of hypermagnesemia. Stimulant laxatives — Stimulant laxatives affect electrolyte transport across the intestinal mucosa and enhance colonic transport and motility. In one study, senna, the stimulant laxative, in combination with fiber was associated with improved stool consistency, frequency, and ease of stool passage when compared with lactulose in older nursing home residents, and appeared equally well tolerated [46]. Bisacodyl was evaluated in a randomized, double-blind, placebo-controlled, parallel-group study in which patients were randomized to bisacodyl (10 mg) or placebo for four weeks. The mean number of complete spontaneous bowel movements (CSBMs) per week, the number of https://www.uptodate.com/contents/16133/print

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spontaneous bowel movements (SBMs), constipation-associated symptoms, and quality of life were significantly improved in the bisacodyl group compared to placebo [47]. Treatment with bisacodyl was also well tolerated. However, the long-term safety of stimulant laxatives has not been established. Stool softeners, suppositories, and enemas — Stool softeners (docusate), suppositories (glycerin or bisacodyl), and enemas, although widely used, have limited clinical efficacy [28,39]. Glycerin or bisacodyl suppositories can be used in institutionalized older adults with dyssynergic defecation to help with rectal evacuation. Enemas (tap water, soapsuds) should be used only as needed for constipation in the older adult, ie, after several days of constipation in order to prevent fecal impaction. Adverse effects include rectal mucosal damage with soapsuds enemas. It is advisable not to use sodium phosphate enemas for the treatment of constipation in older adults. In a retrospective series, the use of sodium phosphate enemas in older adults (mean age 80 years, only one of whom was younger than age 70 years) was associated with complications including hypotension and volume depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe hypocalcemia, renal failure, and EKG changes (prolonged QT interval) [48]. In January 2014, the US Food and Drug Administration (FDA) issued a safety announcement regarding electrolyte abnormalities and severe dehydration with the use of a single dose of over the counter sodium phosphate that was larger than recommended or with more than one dose in 24 hours [49]. The FDA stated that individuals at higher risk for potential adverse effects when the recommended dose is exceeded include individuals older than 55 years, patients with dehydration, bowel obstruction, or inflammation, and patients with kidney disease or on medication that may affect renal function [50]. Other therapies for chronic constipation — Several agents have been studied or are undergoing further studies for the treatment of chronic constipation. These include colonic secretagogues, opioid antagonists, and 5HT4 receptor agonists. Colonic secretagogues — Lubiprostone is an oral bicyclic fatty acid that activates the type 2 chloride channels on the intestinal epithelial cells, thus secreting chloride and water into the gut lumen [23]. In two phase III studies of four weeks duration, lubiprostone 24 mcg twice daily significantly enhanced bowel movement frequency and relieved other constipation-related symptoms compared with placebo [51,52]. In a subgroup analysis, lubiprostone also demonstrated efficacy in older patients. It is best reserved for patients with severe constipation in whom other approaches have been unsuccessful.

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Linaclotide and plecanatide are guanylate cyclase C receptor (GCC) agonists that stimulates intestinal fluid secretion and transit [53,54]. In two large phase 3 trials of patients with chronic constipation, the linaclotide treated groups (both 145 micrograms and 290 micrograms) had significantly higher rates of three or more complete spontaneous bowel movements (CSBM) per week and an increase in one or more CSBMs from baseline during at least 9 out of 12 weeks as compared with placebo (145 micrograms: 21 and 16 percent, 290 micrograms: 19 and 21 percent, versus placebo: 3 and 6 percent). The most common and dose-related adverse event was diarrhea that led to discontinuation of treatment in 4 percent of patients in both linaclotide-treated groups [55]. In a subsequent randomized trial that included older adult patients, lower dose of linaclotide (72 micrograms daily) were also effective in improving constipation [56]. (See "Management of chronic constipation in adults", section on 'Guanylate cyclase-C receptor agonists'.) Opioid antagonists — Peripherally acting mu opioid receptor antagonists, alvimopan and methylnaltrexone, or naloxegol or naldemedine, may have a role in treatment of opioid-induced constipation and alvimopan for paralytic ileus [57]. [58,59]. As these opioid receptor antagonists act peripherally and do not cross the blood brain barrier, they do not impair the analgesic effects of opioids. 5HT(4) receptor agonists — Serotonin (5HT) is a key regulator of gastrointestinal motility. Prucalopride is a selective high affinity 5HT4 receptor agonist. In a dose of 1 and 4 mg once daily, prucalopride has been shown to be superior to placebo in 4- and 12-week trials, and safe and well tolerated in patients age 65 years or older [60,61]. In clinical trials, prucalopride 2 mg provided comparable efficacy to 4 mg and it is therefore the widely used dosage in clinical practice. The dose of prucalopride can be titrated up based on clinical response. Biofeedback — Biofeedback therapy is a painless, noninvasive means of cognitively retraining the pelvic floor and the abdominal wall musculature to facilitate evacuation. Patients are guided to improve control of these muscles by electromyographic surface electrodes on an anal plug and an abdominal wall surface electrode. For patients with pelvic floor dysfunction, especially dyssynergic defecation, rectal hyposensitivity, or rectal mucosal intussusception, biofeedback therapy should be considered. Randomized controlled trials have evaluated the efficacy of biofeedback therapy in the treatment of dyssynergic defecation and concluded that biofeedback is consistently superior to laxatives, standard therapy, sham therapy, placebo, and diazepam [62-65]. Home biofeedback therapy was as effective as office biofeedback therapy [66]. (See "Management of chronic constipation in adults", section on 'Biofeedback'.) https://www.uptodate.com/contents/16133/print

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FECAL IMPACTION Constipation plays an important role in the development of fecal impaction and incontinence in older and institutionalized adults. Fecal impaction results largely from the person's inability to sense and respond to the presence of stool in the rectum. Decreased mobility and lowered sensory perception are common causes of fecal impaction. Diagnosis — The diagnosis of fecal impaction is confirmed by performing a digital rectal examination. The impacted stool is not necessarily hard, but the key to the diagnosis of fecal impaction is in finding a copious amount of stool in the rectum. It is important to note that fecal impactions can occur in the proximal rectum or sigmoid colon, and a digital rectal examination will be nondiagnostic. If the clinical suspicion for a fecal impaction is high, an abdominal radiograph should be obtained to detect fecal loading in the absence of a rectal impaction. Management — In the absence of a suspected perforation or massive bleeding, the management of fecal impactions involves disimpaction and colon evacuation, followed by the implementation of a maintenance bowel regimen to prevent recurrent impactions. We suggest digital disimpaction to fragment a large fecal bolus to facilitate its passage through the anal canal. Subsequently a warm-water enema with mineral oil may be administered to soften the impaction and assist emptying of stool from the rectum and distal colon. Once the distal colon has been partially emptied with disimpaction and enemas, polyethylene glycol (PEG) may be administered orally or by a nasogastric tube. If the above measures fail, local anesthesia to relax the anal canal and pelvic floor muscles, together with abdominal massage, can help to pass the stool bolus. In rare cases, it may be necessary to use a colonoscope with a snare to fragment fecal material in the distal colon. In such cases, a mineral oil enema prior to the colonoscopy may help to soften the stool bolus. If such measures fail or if there is significant abdominal tenderness suggestive of an impending perforation or ischemia, surgery may be necessary. Following management of an acute impaction, it is important to identify and eliminate potential causes of constipation. This includes discontinuing medications that cause or exacerbate constipation. For the institutionalized adult, improving availability of toileting and/or providing assistance is necessary to prevent constipation. Regular use of medications that treat constipation in the older adult is discussed above. (See 'Laxatives' above.)

SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/16133/print

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Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Constipation".)

SUMMARY AND RECOMMENDATIONS ●

Constipation is defined as any two of the following features: straining, lumpy hard stools, sensation of incomplete evacuation, use of digital maneuvers, sensation of anorectal obstruction or blockage with 25 percent of bowel movements, and decrease in stool frequency (less than three bowel movements per week). (See 'Definition of constipation' above.)

●

Constipation in the older adult may be due to functional chronic constipation or secondary to other etiologic factors. Primary colorectal dysfunction consists of three overlapping subtypes: slow transit constipation, dyssynergic defecation, and irritable bowel syndrome with constipation. Secondary causes of constipation should be excluded with a thorough history and physical examination followed by diagnostic testing. (See 'Pathophysiology' above and 'Evaluation' above.)

●

The first step in the treatment of chronic functional constipation is with lifestyle and dietary modification. A daily fiber intake of 20 to 25 g/day is generally recommended. (See 'Lifestyle modification' above and 'Diet and fiber' above.)

●

Laxative usage in the older adults should be individualized based on the patient's history, comorbidities, drug interactions, and side effects. We suggest bulk laxatives as the first line of therapy in older patients with chronic constipation who do not respond to dietary and lifestyle modification (Grade 2B). Osmotic laxatives can be used in patients not responding satisfactorily to bulking agents. We suggest a trial of low-dose polyethylene glycol (PEG) as it has been demonstrated to be efficacious and well tolerated in older adults. Lactulose is less effective than low-dose PEG and also had a higher incidence of flatus. Sorbitol has shown to be as efficacious as lactulose, less expensive, and better tolerated. Saline laxatives such as magnesium hydroxide have not been examined in older adults, and should be used with caution because of the risk of hypermagnesemia. (See 'Laxatives' above.)

●

Stool softeners (docusate), suppositories (glycerin or bisacodyl), and enemas have limited clinical efficacy. Suppositories (glycerin or bisacodyl) and enemas should only be used in

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specific clinical scenarios. (See 'Stool softeners, suppositories, and enemas' above.) ●

In patients over the age of 70 years being treated with enemas for constipation, we suggest that patients receive warm water enemas rather than sodium phosphate enemas (Grade 2C). The use of sodium phosphate enemas in older adults has been associated with complications including hypotension and volume depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe hypocalcemia, renal failure, and EKG changes (prolonged QT interval).

●

Lubiprostone, a type 2 chloride channels activator, and both linaclotide, and plecanatide guanylate cyclase agonists, significantly enhance bowel movement frequency and relieve other constipation-related symptoms. (See 'Other therapies for chronic constipation' above.)

●

Peripherally acting mu opioid receptor antagonists, methylnaltrexone, naloxegol, and naldemedine may have a role in treatment of opioid-induced constipation. (See 'Other therapies for chronic constipation' above.)

●

Biofeedback therapy is a painless, noninvasive means of cognitively retraining the pelvic floor and the abdominal wall musculature. Randomized controlled trials have established the efficacy of biofeedback therapy in the treatment of dyssynergic defecation. (See 'Biofeedback' above.) Use of UpToDate is subject to the Terms of Use.

REFERENCES

1. https://www.chpa.org/OTCsCategory.aspx (Accessed on April 20, 2020). 2. Glia A, Lindberg G. Quality of life in patients with different types of functional constipation. Scand J Gastroenterol 1997; 32:1083. 3. Koloski NA, Jones M, Wai R, et al. Impact of persistent constipation on health-related quality of life and mortality in older community-dwelling women. Am J Gastroenterol 2013; 108:1152. 4. Drossman DA, Sandler RS, McKee DC, Lovitz AJ. Bowel patterns among subjects not seeking health care. Use of a questionnaire to identify a population with bowel dysfunction. Gastroenterology 1982; 83:529. 5. Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016.

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6. Talley NJ, O'Keefe EA, Zinsmeister AR, Melton LJ 3rd. Prevalence of gastrointestinal symptoms in the elderly: a population-based study. Gastroenterology 1992; 102:895. 7. Talley NJ, Fleming KC, Evans JM, et al. Constipation in an elderly community: a study of prevalence and potential risk factors. Am J Gastroenterol 1996; 91:19. 8. Wald A, Scarpignato C, Mueller-Lissner S, et al. A multinational survey of prevalence and patterns of laxative use among adults with self-defined constipation. Aliment Pharmacol Ther 2008; 28:917. 9. Sandler RS, Jordan MC, Shelton BJ. Demographic and dietary determinants of constipation in the US population. Am J Public Health 1990; 80:185. 10. Everhart JE, Go VL, Johannes RS, et al. A longitudinal survey of self-reported bowel habits in the United States. Dig Dis Sci 1989; 34:1153. 11. Whitehead WE, Drinkwater D, Cheskin LJ, et al. Constipation in the elderly living at home. Definition, prevalence, and relationship to lifestyle and health status. J Am Geriatr Soc 1989; 37:423. 12. Donald IP, Smith RG, Cruikshank JG, et al. A study of constipation in the elderly living at home. Gerontology 1985; 31:112. 13. Harari D, Gurwitz JH, Avorn J, et al. Bowel habit in relation to age and gender. Findings from the National Health Interview Survey and clinical implications. Arch Intern Med 1996; 156:315. 14. Choung RS, Locke GR 3rd, Schleck CD, et al. Cumulative incidence of chronic constipation: a population-based study 1988-2003. Aliment Pharmacol Ther 2007; 26:1521. 15. Ruby CM, Fillenbaum GG, Kuchibhatla MN, Hanlon JT. Laxative use in the communitydwelling elderly. Am J Geriatr Pharmacother 2003; 1:11. 16. Harari D, Gurwitz JH, Avorn J, et al. Constipation: assessment and management in an institutionalized elderly population. J Am Geriatr Soc 1994; 42:947. 17. Talley NJ. Definitions, epidemiology, and impact of chronic constipation. Rev Gastroenterol Disord 2004; 4 Suppl 2:S3. 18. Primrose WR, Capewell AE, Simpson GK, Smith RG. Prescribing patterns observed in registered nursing homes and long-stay geriatric wards. Age Ageing 1987; 16:25. 19. Stewart WF, Liberman JN, Sandler RS, et al. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features. Am J Gastroenterol 1999; 94:3530. 20. Towers AL, Burgio KL, Locher JL, et al. Constipation in the elderly: influence of dietary, psychological, and physiological factors. J Am Geriatr Soc 1994; 42:701. https://www.uptodate.com/contents/16133/print

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21. Whitehead W, Wald A, Diamant N, et al. Functional disorders of the anus and rectum. Gut 1999; 45:55. 22. Rao SS, Welcher KD, Leistikow JS. Obstructive defecation: a failure of rectoanal coordination. Am J Gastroenterol 1998; 93:1042. 23. Rao SS, Go JT. Update on the management of constipation in the elderly: new treatment options. Clin Interv Aging 2010; 5:163. 24. Liu JJ, Brenner DM. Opioid-Related Constipation. Gastroenterol Clin North Am 2022; 51:107. 25. Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol 2011; 106:1582. 26. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology 2006; 130:1480. 27. Sharma A, Kurek J, Morgan JC, et al. Constipation in Parkinson's Disease: a Nuisance or Nuanced Answer to the Pathophysiological Puzzle? Curr Gastroenterol Rep 2018; 20:1. 28. Bouras EP, Tangalos EG. Chronic constipation in the elderly. Gastroenterol Clin North Am 2009; 38:463. 29. Iovino P, Chiarioni G, Bilancio G, et al. New onset of constipation during long-term physical inactivity: a proof-of-concept study on the immobility-induced bowel changes. PLoS One 2013; 8:e72608. 30. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol 2005; 100 Suppl 1:S1. 31. Park SY, Khemani D, Nelson AD, et al. Rectal Gas Volume Measured by Computerized Tomography Identifies Evacuation Disorders in Patients With Constipation. Clin Gastroenterol Hepatol 2017; 15:543. 32. Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol 2016; 13:295. 33. Lindeman RD, Romero LJ, Liang HC, et al. Do elderly persons need to be encouraged to drink more fluids? J Gerontol A Biol Sci Med Sci 2000; 55:M361. 34. Chung BD, Parekh U, Sellin JH. Effect of increased fluid intake on stool output in normal healthy volunteers. J Clin Gastroenterol 1999; 28:29. 35. Heaton EA. The call to stool and its relationship to constipation: A community study. Eur J Gastroenterol Hepatol 1994; 6:145. 36. Rao SS, Kavelock R, Beaty J, et al. Effects of fat and carbohydrate meals on colonic motor response. Gut 2000; 46:205. https://www.uptodate.com/contents/16133/print

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37. Gallagher P, O'Mahony D. Constipation in old age. Best Pract Res Clin Gastroenterol 2009; 23:875. 38. Locke GR 3rd, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: guidelines on constipation. Gastroenterology 2000; 119:1761. 39. Ramkumar D, Rao SS. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol 2005; 100:936. 40. Attaluri A, Donahoe R, Valestin J, et al. Randomised clinical trial: dried plums (prunes) vs. psyllium for constipation. Aliment Pharmacol Ther 2011; 33:822. 41. Erdogan A, Rao SS, Thiruvaiyaru D, et al. Randomised clinical trial: mixed soluble/insoluble fibre vs. psyllium for chronic constipation. Aliment Pharmacol Ther 2016; 44:35. 42. Attar A, Lémann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999; 44:226. 43. Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005; 100 Suppl 1:S5. 44. Garlehner G, Jonas DE, Morgan LC, et al. Drug class review on constipation drugs, Oregon Health & Science University, Portland, OR 2007. 45. Lederle FA, Busch DL, Mattox KM, et al. Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose. Am J Med 1990; 89:597. 46. Passmore AP, Davies KW, Flanagan PG, et al. A comparison of Agiolax and lactulose in elderly patients with chronic constipation. Pharmacology 1993; 47 Suppl 1:249. 47. Kamm MA, Mueller-Lissner S, Wald A, et al. Oral bisacodyl is effective and well-tolerated in patients with chronic constipation. Clin Gastroenterol Hepatol 2011; 9:577. 48. Ori Y, Rozen-Zvi B, Chagnac A, et al. Fatalities and severe metabolic disorders associated with the use of sodium phosphate enemas: a single center's experience. Arch Intern Med 2012; 172:263. 49. FDA warns of possible harm from exceeding recommended dose of over-the-counter sodiu m phosphate products to treat constipation. Available at: http://www.fda.gov/Drugs/DrugS afety/ucm380757.htm (Accessed on January 08, 2014). 50. Mendoza J, Legido J, Rubio S, Gisbert JP. Systematic review: the adverse effects of sodium phosphate enema. Aliment Pharmacol Ther 2007; 26:9. 51. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008; 103:170. https://www.uptodate.com/contents/16133/print

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52. Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci 2010; 55:1090. 53. Lembo AJ, Kurtz CB, Macdougall JE, et al. Efficacy of linaclotide for patients with chronic constipation. Gastroenterology 2010; 138:886. 54. Miner PB Jr, Koltun WD, Wiener GJ, et al. A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation. Am J Gastroenterol 2017; 112:613. 55. Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011; 365:527. 56. Schoenfeld P, Lacy BE, Chey WD, et al. Low-Dose Linaclotide (72 μg) for Chronic Idiopathic Constipation: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Am J Gastroenterol 2018; 113:105. 57. Wild J, Webster L, Yamada T, Hale M. Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy: A Subgroup Analysis of Patients ≥ 65 Years of Age. Drugs Aging 2020; 37:271. 58. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med 2014; 370:2387. 59. Crockett SD, Greer KB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology 2019; 156:218. 60. Quigley EM, Vandeplassche L, Kerstens R, Ausma J. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2009; 29:315. 61. Müller-Lissner S, Rykx A, Kerstens R, Vandeplassche L. A double-blind, placebo-controlled study of prucalopride in elderly patients with chronic constipation. Neurogastroenterol Motil 2010; 22:991. 62. Rao SS, Seaton K, Miller M, et al. Randomized controlled trial of biofeedback, sham feedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007; 5:331. 63. Chiarioni G, Whitehead WE, Pezza V, et al. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology 2006; 130:657. 64. Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology 2005; https://www.uptodate.com/contents/16133/print

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129:86. 65. Heymen S, Scarlett Y, Jones K, et al. Randomized, controlled trial shows biofeedback to be superior to alternative treatments for patients with pelvic floor dyssynergia-type constipation. Dis Colon Rectum 2007; 50:428. 66. Rao SSC, Valestin JA, Xiang X, et al. Home-based versus office-based biofeedback therapy for constipation with dyssynergic defecation: a randomised controlled trial. Lancet Gastroenterol Hepatol 2018; 3:768. Topic 16133 Version 27.0

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GRAPHICS

Causes of secondary constipation Cause

Example

Organic

Colorectal cancer, extraintestinal mass, postinflammatory, ischemic, or surgical stenosis

Endocrine or metabolic

Diabetes mellitus, hypothyroidism, hypercalcemia, porphyria, chronic renal insufficiency, panhypopituitarism, pregnancy

Neurologic

Spinal cord injury, Parkinson disease, paraplegia, multiple sclerosis, autonomic neuropathy, Hirschsprung disease, chronic intestinal pseudoobstruction

Myogenic

Myotonic dystrophy, dermatomyositis, scleroderma, amyloidosis, chronic intestinal pseudo-obstruction

Anorectal

Anal fissure, anal strictures, inflammatory bowel disease, proctitis

Drugs

Opiates, antihypertensive agents, tricyclic antidepressants, iron preparations, antiseizure medications, anti-Parkinsonian agents (anticholinergic or dopaminergic), barium

Diet or lifestyle

Low-fiber diet, dehydration, inactive lifestyle

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Criteria for dyssynergic defecation A. Patients must satisfy the diagnostic criteria for functional chronic constipation (Rome III) and B. Patients must demonstrate dyssynergia during repeated attempts to defecate Dyssynergic or obstructive pattern of defecation (types 1-4) is defined as: Paradoxical increase in anal sphincter pressure (anal contraction) or Less than 20 percent relaxation of the resting anal sphincter pressure or Inadequate propulsive forces observed with manometry, imaging, or EMG recordings and One or more of the following criteria during repeated attempts to defecate: Inability to expel an artificial stool (50 mL water-filled balloon) within 1 minute A prolonged colonic transit time (ie, greater than five markers [>20 percent marker retention]) on a plain abdominal radiograph taken 120 hours after ingestion of one sitzmark capsule containing 24 radiopaque markers Inability to evacuate or ≥50 percent retention of barium during defecography Reproduced from: Rao SSC. Dyssynergic defecation and biofeedback therapy. Gastroenterol Clin N Am 2008; 37:569. Table used with the permission of Elsevier Inc. All rights reserved.

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Components of the technique and expected findings with a detailed digital rectal examination Exam component

Technique

Findings and grading of response(s)

I. Inspection of the anus and surrounding tissue  

Place patient in the left lateral position

Skin excoriation, skin tags, anal

with hips flexed to 90°. Inspect

fissure, scars or hemorrhoids

perineum under good light.

II. Testing of perineal sensation and the anocutaneous reflex  

Stroke the skin around the anus in a

Normal: Brisk contraction of the

centripetal fashion, in all four

perianal skin, the anoderm and the

quadrants, by using a stick with a

external anal sphincter

cotton bud

Impaired: No response with the soft cotton bud, but anal contractile response seen with the opposite (wooden) end Absent: No response with either end

III. Digital palpation and maneuvers to assess anorectal function Digital

Slowly advance a lubricated and

Tenderness, mass, stricture, or stool

palpation

gloved index finger into the rectum

and the consistency of the stool

and feel the mucosa and surrounding muscle, bone, uterus, prostate and pelvic structures Resting tone

Assess strength of resting sphincter

Normal, weak (decreased), or

tone

increased

Squeeze maneuver

Ask the patient to squeeze and hold as long as possible (up to 30 seconds)

Normal, weak (decreased), or increased

Pushing and

In addition to the finger in the rectum,

bearing down maneuver

place a hand over the patient's abdomen to assess the push effort. Ask the patient to push and bear down as if to defecate.

1. Push effort: Normal, weak (decreased), excessive 2. Anal relaxation: Normal, impaired, paradoxical contraction 3. Perineal descent: Normal, excessive, absent

Reproduced from: Tantiphlachiva K, Rao P, Attaluri A, Rao SSC. Digital rectal examination is a useful tool for identifying patients with dyssynergia. Clin Gastroenterol Hepatol 2010; 8:955. Table used with the permission of Elsevier Inc. All rights reserved.

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Medications for treatment of constipation Medication

Usual adult dose

Onset of action

Side effects

Bulk-forming laxatives* Psyllium

Up to 1 tablespoon (≅3.5 grams

12 to 72 h

fiber) 3 times per day Methylcellulose

Up to 1 tablespoon (≅2 grams

12 to 72 h

fiber) or 4 caplets (500 mg fiber

Impaction above strictures, fluid overload, gas and bloating

per caplet) 3 times per day Polycarbophil

2 to 4 tabs (500 mg fiber per tab)

24 to 48 h

per day Wheat dextrin¶

1 to 3 caplets (1 gram fiber per caplet) or 2 teaspoonsful (1.5

24 to 48 h

gram fiber per teaspoon) up to 3 times per daily

Surfactants (softeners) Docusate sodium

Docusate calcium

100 mg 2 times per day

240 mg 1 time per day

24 to 72

Well tolerated, but less

hours

effective than other

24 to 72 hours

agents. Use lower dose if administered with another laxative. Contact dermatitis reported.

Osmotic agents Polyethylene glycol

8.5 to 34 grams in 240 mL (8

(macrogol)

ounces) liquids

Lactulose

10 to 20 grams (15 to 30 mL)

24 to 48

Abdominal bloating,

every other day. May increase up to 2 times per day.

hours

flatulence

30 grams (120 mL of 25%

24 to 48

Abdominal bloating,

solution) 1 time per day

hours

flatulence

One suppository (2 or 3 grams)

15 to 60

Rectal irritation

per rectum for 15 minutes 1 time per day

minutes

2 to 4 level teaspoons

0.5 to 3

Watery stools and

(approximately 10 to 20 grams) of

hours

urgency; caution in

Sorbitol Glycerin (glycerol)

Magnesium sulfate

1 to 4 days

Nausea, bloating, cramping

granules dissolved in 8 ounces

renal insufficiency

(240 mL) of water; may repeat in

(magnesium toxicity)

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4 hours. Do not exceed 2 doses per day. Magnesium citrate

200 mL (11.6 grams) 1 time per

0.5 to 3

day

hours

10 to 30 mg as enteric coated

6 to 10

tabs 1 time per day

hours

10 mg suppository per rectum 1

15 to 60

time per day

minutes

2 to 4 tabs (8.6 mg sennosides per tab) or 1 to 2 tabs (15 mg

6 to 12 hours

Melanosis coli

24 to 48

Nausea, diarrhea

Stimulant laxatives Bisacodyl

Senna

Gastric irritation Rectal irritation

sennosides per tab) as a single daily dose or divided twice daily

Other Lubiprostone

24 micrograms 2 times per day

hours Linaclotide

145 micrograms 1 time per day

12 to 24

Diarrhea, bloating

hours Plecanatide

3 mg 1 time per day

12 to 24 hours

Diarrhea

Prucalopride

2 mg per day

6 to 12

Nausea, headache,

hours

diarrhea

All doses shown are for oral administration unless otherwise noted. Phosphate containing laxatives are not recommended. Mineral oil (enema and oral liquid) laxatives are not generally recommended except as enema following disimpaction (refer to UpToDate content). * Initiate at one-half or less of dose shown and gradually increase as needed to minimize gas and bloating. Administer with 180 to 360 mL (6 to 12 ounces) water or fruit juice. Do not administer within 1 hour of other medications. Fiber content per dose may vary. Consult individual product label.

¶ US trade name Benefiber. Courtesy of Arnold Wald, MD. Additional data from: Lexicomp Online. Copyright © 1978-2022 Lexicomp, Inc. All Rights Reserved.

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Contributor Disclosures Satish SC Rao, MD, PhD, FRCP Patent Holder: Home biofeedback device[Constipation, dyssynergic defecation ]. Grant/Research/Clinical Trial Support: Covidien [Gastroparesis];Forest Laboratories [IBS];Salix Pharmaceuticals [IBS];Synergy Pharmaceuticals [IBS, constipation];Vibrant [Constipation]. Consultant/Advisory Boards: Bayer [Constipation];In Control Medical [Biofeedback];Ironwood Pharmaceuticals [Constipation];Neurogut inc [Constipation]. All of the relevant financial relationships listed have been mitigated. Nicholas J Talley, MD, PhD Patent Holder: Biomarkers of irritable bowel syndrome [Irritable bowel syndrome];Mayo Clinic [Dysphagia questionnaire];Mayo Clinic [Bowel Disease questionnaire];Nepean Dyspepsia Index [Dyspepsia];Nestec [Irritable bowel syndrome];Singapore Provisional Patent [BDNF Tissue Repair Pathway]. Grant/Research/Clinical Trial Support: Allakos [Gastric eosinophilic disease];NHMRC Centre for Research Excellence in Digestive Health [NHMRC Investigator grant]. Consultant/Advisory Boards: Allakos [Gastric eosinophilic disease];Anatara Life Sciences, Brisbane [IBS/IBD];ARENA Pharmaceuticals [Abdominal pain];Aviro Health [Digestive health];Bayer [Inflammatory bowel syndrome];BluMaiden [Microbiome Ad Board];Cadila Pharmaceuticals [CME];Censa [Diabetic gastroparesis];Danone [Probiotic];Dr Falk Pharma [Eosinophilia];Glutagen [Celiac disease];International Foundation for Functional Gastrointestinal Disorders [Advisory board, functional GI disorders];Intrinsic Medicine [Human milk oligosaccharide];IsoThrive [Esophageal microbiome];Planet Innovation [Gas capsule, inflammatory bowel syndrome];Progenity Inc [Intestinal capsule];Rose Pharma [IBS];SanofiAventis [Probiotic];Takeda [Gastroparesis];twoXAR [Inflammatory bowel syndrome drugs];Viscera Labs [Inflammatory bowel syndrome, diarrhea]. Other Financial Interest: Elsevier textbook royalties. All of the relevant financial relationships listed have been mitigated. Kenneth E Schmader, MD No relevant financial relationship(s) with ineligible companies to disclose. Shilpa Grover, MD, MPH, AGAF No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy

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Official reprint from UpToDate®

www.uptodate.com © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The common cold in children: Management and prevention Author: Diane E Pappas, MD, JD Section Editor: Morven S Edwards, MD Deputy Editor: Mary M Torchia, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: May 2022. | This topic last updated: Apr 25, 2022.

INTRODUCTION The common cold is an acute, self-limiting viral infection of the upper respiratory tract characterized by variable degrees of sneezing, nasal congestion and discharge (rhinorrhea), sore throat, cough, low grade fever, headache, and malaise. The management and prevention of the common cold in children will be discussed here. The epidemiology, clinical features, and diagnosis of the common cold in children and the common cold in adults are discussed separately. (See "The common cold in children: Clinical features and diagnosis" and "The common cold in adults: Diagnosis and clinical features" and "The common cold in adults: Treatment and prevention".)

CAREGIVER EDUCATION The common cold is usually a mild and self-limiting viral illness, usually caused by rhinoviruses. Caregiver education is the mainstay of management [1,2] and is recommended by the American Academy of Pediatrics [3], the United Kingdom's National Institute for Health and Care Excellence [4-6], and British Thoracic Society guidelines for the assessment and management of cough in children [7]. Antiviral therapy is not available for the viruses that cause the common cold with the exception of influenza virus. The clinical features of influenza and treatment of influenza with antiviral https://www.uptodate.com/contents/16629/print

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agents are discussed separately. (See "Seasonal influenza in children: Management", section on 'Antiviral therapy'.) Expected course of illness — In infants and young children, the symptoms of the common cold usually peak on day 2 to 3 of illness and then gradually improve over 10 to 14 days ( figure 1) [8,9]. The cough may linger in a minority of children but should steadily resolve over three to four weeks. In older children and adolescents, symptoms usually resolve in five to seven days (longer in those with underlying lung disease or who smoke cigarettes) [10-12]. Indications for re-evaluation — Re-evaluation may be warranted if the symptoms worsen (eg, difficulty breathing or swallowing, high fever) or exceed the expected duration. Worsening or persistent symptoms (eg, persistent cough) may indicate the development of complications or the need to consider a diagnosis other than the common cold (eg, acute bacterial sinusitis, pneumonia, pertussis). (See "The common cold in children: Clinical features and diagnosis", section on 'Complications' and "The common cold in children: Clinical features and diagnosis", section on 'Differential diagnosis'.) Supportive care — We generally recommend one or a combination of the following interventions as first-line therapy for children with the common cold [3,13-18]. Although most of these interventions have not been studied in randomized trials, they are relatively inexpensive and unlikely to be harmful [14,16,19]. ●

Maintaining adequate hydration – Maintaining adequate hydration may help to thin secretions and soothe the respiratory mucosa [16].

●

Ingestion of warm fluids – Ingestion of warm liquids (eg, tea, chicken soup) may have a soothing effect on the respiratory mucosa, increase the flow of nasal mucus, and loosen respiratory secretions, making them easier to remove [15,16,20]. The warmed liquids should be appropriate for the age of the infant or child. (See "Introducing solid foods and vitamin and mineral supplementation during infancy", section on 'When to initiate complementary foods' and "Dietary recommendations for toddlers, preschool, and schoolage children", section on 'Dietary composition'.)

●

Topical saline – Topical saline may be beneficial, is inexpensive, and is unlikely to be harmful or impede recovery. The application of saline to the nasal cavity may temporarily remove bothersome nasal secretions, improve mucociliary clearance, and lead to vasoconstriction (decongestion) [21]. Side effects may include mucosal irritation or nosebleed.

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In infants, topical saline is applied with saline nose drops and a bulb syringe (

table 1).

In older children, a saline nasal spray or saline nasal irrigation (eg, squeeze bottle, neti pot, or nasal douche) may be used. It is important that saline irrigants be prepared from sterile or bottled water; cases of amebic encephalitis associated with nasal irrigation prepared from tap water have been reported [22]. (See "Free-living amebas and Prototheca", section on 'Epidemiology'.) The Centers for Disease Control and Prevention provides information about safe methods for nasal irrigation. A 2015 systematic review of five randomized trials (including 544 children and 205 adults) concluded that nasal saline irrigation may be beneficial in relieving upper respiratory infection symptoms [23]. Different outcome measures precluded pooling of results. In the largest trial, nasal saline irrigation modestly improved symptoms, decreased use of other therapies, decreased recurrence of symptoms, and decreased school absence [24]. ●

Humidified air – A cool mist humidifier/vaporizer may add moisture to the air to loosen nasal secretions, although this treatment is not well studied [17,25,26]. It is important to counsel caregivers who use cool mist humidifiers to clean the humidifier after each use according to the manufacturer's instructions to minimize the risk of infection or inhalation injury [27-29]. We do not recommend the inhalation of steam or heated humidified air as a treatment for nasal symptoms in children with the common cold. Inhalation of heated humidified air or steam does not reduce symptoms and may result in burns [30,31]. A 2017 systematic review of six randomized trials (387 participants) evaluating the effects of inhalation of heated humidified air on symptoms of the common cold found the benefits to be inconsistent [32]. A randomized trial including 899 patients (≥3 years) that was not included in the systematic review found that advice to use steam inhalation did not reduce symptoms of acute respiratory infection [33]. The World Health Organization suggests that neither steam nor cool mist therapy be encouraged in the management of a cough or cold [16].

Over-the-counter medications — Over-the-counter (OTC) products for symptomatic relief of the common cold in children include antihistamines, decongestants, antitussives, expectorants, mucolytics, antipyretics/analgesics, and combinations of these medications (

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table 2).

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Children