Principles in Nursing Practice in the Era of COVID-19 3030947394, 9783030947392

Citation preview

Principles in Nursing Practice in the Era of COVID-19 Amanda Bergeron Russell Perkins Emily Ingebretson Linda Holifield Editors

123

Principles in Nursing Practice in the Era of COVID-19

Amanda Bergeron  •  Russell Perkins Emily Ingebretson  •  Linda Holifield Editors

Principles in Nursing Practice in the Era of COVID-19

Editors Amanda Bergeron Center for Advanced Cardiopulmonary Therapies and Transplantation Memorial Hermann Houston, TX, USA

Russell Perkins Center for Advanced Cardiopulmonary Therapies and Transplantation Memorial Hermann Houston, TX, USA

Emily Ingebretson Center for Transplantation UC San Diego Health System San Diego, CA, USA

Linda Holifield Center for Advanced Cardiopulmonary Memorial Hermann Houston, TX, USA

ISBN 978-3-030-94739-2    ISBN 978-3-030-94740-8 (eBook) https://doi.org/10.1007/978-3-030-94740-8 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

In Wuhan, China, in late 2019, a pneumonia of unknown etiology was identified by Chinese authorities and reported to the World Health Organization (WHO). Later on, the etiology of the pneumonia would be identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus spread rapidly, causing a worldwide pandemic of coronavirus disease 2019 (COVID-19). Scientists, researchers, and medical professionals around the world have been working tirelessly since the beginning of the pandemic to develop processes for prevention and treatment modalities to control the highly contagious disease. Infection prevention and control practices are essential to the provision of safe and high-quality healthcare for patients with COVID-19. Just as transmission-based precautions must be applied in cases of tuberculosis or measles, similar practices must be implemented to prevent the transmission of SARS-CoV-2. Standard precautions, such as hand hygiene, have immense research to support their implementation across all settings in which healthcare is provided. Many studies, early in the pandemic, made it clear that limiting close contact between those infected with the virus and those not is essential to reducing transmission. From that early data, public health entities began recommending symptom screening, testing, and subsequent isolation as methods of isolating cases of infection. The incubation period of SARS-­ CoV-­2, which is defined as the time between exposure to the virus and development of symptoms, is 5–6 days on average, but it can be as long as 14 days. Given that infected people without symptoms can transmit the SARS-CoV-2 virus, it is essential to implement source control measures, such as face masks in public, physical or social distancing, hand hygiene, and adequate ventilation indoors. Along with these general measures, healthcare facilities must supply proper personal protective equipment to their employees, such as face masks, respirators, gowns, and gloves, as the virus is transmitted primarily through respiratory droplets, but can also become aerosolized during certain medical procedures. Testing for screening, diagnosis, and contact tracing is another paramount measure to reducing community infection burden. Finally, there are now vaccinations specific to SARS-CoV-2, which prevent severe COVID-19, thus reducing mortality and relieving strain on local healthcare entities, as fewer cases require hospitalization. The SARS-CoV-2 virus has revealed itself to have a variety of acute complications, especially in those critically ill with COVID-19. These complications include, but are not limited to, sepsis, acute respiratory distress syndrome, and shock. The v

vi

Preface

guidelines that exist to describe the classification, nature, and treatment of these complications have been derived from various other diseases; however, with some minor changes, they can be applied to the management of severe COVID-19. Management of oxygenation in those with COVID-19 infection is paramount to the treatment of these patients. Survival and morbidity are impacted by oxygenation and ventilation strategies. Hypoxia needs to be accurately assessed and measured, with management strategies targeted to clinical characteristics and patient response. Close monitoring at the bedside, coupled with prompt escalation of care, helps minimize poor outcomes. Once ventilation strategies have been maximized, use of more invasive management techniques, like ECMO, may need to be considered. Pharmacological management for this disease is an ever-developing field, with new products for treatment and prevention of severe disease becoming available regularly. Because of the varying strength of evidence in case studies and evaluation of real-world results, pharmacological agents used to treat and manage patients with COVID-19 can differ widely in both agents and dose used. At the start of the COVID-19 pandemic, the focus of medical care and treatment of the disease was in the acute phase of the illness; however, as time progressed, research revealed that various symptoms can persist for 4 or more weeks after the initial infection. Several terms have been coined to describe this syndrome, such as “long-COVID,” “chronic COVID syndrome,” “post-acute COVID-19 syndrome,” or “persistent post-COVID syndrome (PPCS).” In this patient population, symptoms persist, inhibiting the normal activities of daily living of the affected individuals, thus greatly affecting their quality of life. Nurses must also consider those patients who have recovered from severe COVID-19 and who deal with the long-­ term effects of hospitalization as well as those effects causing chronic organ dysfunction. Nurses should be able to recognize these long-term sequelae and be aware of the impacts on quality of life and mortality, as specialized post-acute care and rehabilitation are needed to assist patients who have recovered from the acute illness. Not only has the COVID-19 pandemic left lasting effects on the individuals who have contracted the disease, but it has also severely affected the mental health of both healthcare workers and the general public. Healthcare practitioners have been at the forefront of preventing and treating this disease while also living under the same social constraints as the public, which has led to increased burnout rates and decreased job satisfaction. Mandates, such as social quarantine, have had a significant psychological impact on the public, and compliance to preventative federal mandates varies in the general population. Along with this, social disparities in society and healthcare have become highly relevant during this pandemic. Populations with poor access to healthcare, and those distrustful of the systems in place, have been disproportionately affected by the disease and have decreased access to preventative vaccination and other prevention strategies. This book aims to provide a generalized overview of COVID-19 as it applies to the lives and professional practice of nurses. Because research on the disease is still very active, recommendations for prevention, treatment, and general considerations are apt to change rapidly. As with management guidelines for any disease, time and

Preface

vii

further scientific studies often reveal new strategies in treatment approach, problems with previous management methods, and considerations that were previously unconsidered. It is up to the educated consumer of these studies to determine their relevance to current disease management guidelines. Houston, TX, USA Houston, TX, USA  San Diego, CA, USA  Houston, TX, USA 

Amanda Bergeron Russell Perkins Emily Ingebretson Linda Holifield

Contents

1 History and Epidemiology������������������������������������������������������������������������   1 Linda Holifield 2 Prevention and Infection Control ������������������������������������������������������������  17 Emily A. Ingebretson 3 Manifestations of Coronavirus ����������������������������������������������������������������  55 Fidel Gonzalez 4 Pharmacological Management ����������������������������������������������������������������  67 Jigna Patel 5 Management of Oxygenation and Ventilation ����������������������������������������  97 Robin Miller 6 Systemic Complications���������������������������������������������������������������������������� 107 Russell Perkins 7 Long-Term Sequalae of COVID-19 Infection������������������������������������������ 127 Amanda Bergeron 8 Outpatient Management of COVID-19���������������������������������������������������� 141 Terri Alvarez 9 Implications for Pediatric Nursing Practice�������������������������������������������� 155 Jessica L. Peck, Renee Flippo, and Amee Moreno 10 Psychological and Sociological Effects ���������������������������������������������������� 171 Amanda Bergeron and Russell Perkins

ix

1

History and Epidemiology Linda Holifield

1.1

History and Epidemiology

In the year 2020, the world was stunned by the emergence of a novel coronavirus which quickly spread across the globe to become the most significant pandemic of the twenty-first century. The international committee of taxonomy of viruses named this novel virus SARS-CoV-2 and the disease that it causes is COVID-19. The COVID-19 pandemic has impacted a multitude of countries on every continent, causing a strain on healthcare systems and on the global economy. However, COVID-19 is not the only epidemic caused by a coronavirus, nor is it the only pandemic of this century. Viral infections are common sources of infectious disease and are the common culprits in major biological outbreaks [1]. Prior to the outbreak of COVID-19, there had been other viral epidemics. A disease epidemic occurs when there is an increase in the number of cases of a disease than what is normally expected in the population. A pandemic occurs when an epidemic spreads over multiple countries and continents. Other modern pandemics include the HIV/ AIDS, H1N1, and Zika virus. This chapter will discuss the epidemiology of SARSCoV-2, provide a timeline of events, and will discuss coronavirus virology based on what is currently known.

1.2

Timeline of Events

In late December 2019, a group of patients with pneumonia-like symptoms of unknown etiology were reported from Wuhan, Hubei Province, China [2]. The common link among these cases was that most of the patients either worked or lived in L. Holifield (*) Memorial Hermann Texas Medical Center, Houston, TX, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 A. Bergeron et al. (eds.), Principles in Nursing Practice in the Era of COVID-19, https://doi.org/10.1007/978-3-030-94740-8_1

1

2

L. Holifield

and around the local Huanan seafood wholesale wet market [2]. While the initial cause for the outbreak was unknown, the market was shut down and an investigation was initiated. At that time, there were 44 cases of pneumonia requiring hospitalization and the outbreak was limited to Wuhan city. Despite closing the wet markets in China, the virus continued to spread suggesting person-to-person transmission. Investigators ruled out a number of respiratory pathogens as the potential cause. By January 7, 2020, investigators had isolated the responsible virus and identified it as a novel coronavirus, a strain of coronavirus never before isolated in the population and thus with no existing immunity [3, 4]. The virus was tentatively named 2019 novel coronavirus (2019-n-CoV). On January 12, 2020, a Chinese laboratory announced that the complete genetic sequencing of SARS-CoV-2 was complete and the information made available to the WHO [3, 5]. On January 15th, the first case of COVID-19 was identified in the United States in Washington State in a gentleman with recent travel to Wuhan China. By January 30th, 2020, the WHO declared the COVID-19 epidemic as a public health emergency of international concern [5]. A Public Health Emergency of International concern (PHEIC) is defined as an extraordinary event with a public health risk to other countries through international spread of disease and requires a coordinated international response [6]. At that point, the WHO issued a number of requirements for all countries with regard to disease reporting, but it was especially noted that countries should be prepared to handle the containment of the disease; specifically, to anticipate the need for active surveillance, early detection, isolation, case management, contact tracing, and the prevention of further spread [7]. As SARS-CoV-2 continued to spread across the globe, the WHO continued to work with Chinese health officials and other international health agencies to establish research priorities and surveillance systems. On March 11, 2020, the WHO Director-General issued a statement declaring COVID-19 a pandemic [8]. At that time, the virus had spread to 114 countries across the globe. The Director-General called on all nations to prepare and be ready and to activate and scale up response mechanisms [9]. Just 2 days later, United States President Donald Trump declared a nationwide emergency. Shortly thereafter, on March 17th, the first human trial of the vaccine in the United States began [10]. April 9, 2020 signified the hundred-day mark since the beginning of the pandemic; there were over a million cases worldwide. As countries enacted shutdowns and travel restrictions, teams across the globe continued to work to learn more about the virus and discover methods of containment and treatment. In May of 2020, the WHO released a preliminary case definition for multisystem inflammatory syndrome in children after clusters of Kawasaki-like sequelae were seen in children [11]. In September of 2020, The United Nations opened the 75th session of the General Assembly, held virtually. At the forefront of the assembly was discussion of the Coronavirus pandemic and it’s sweeping effect on the well-being of the Nations. The WHO in conjunction with a number of international organizations described the harmful impact of the “infodemic”, the excessive amount of information available via a variety of media containing information about the pandemic which may or may not be accurate. International leaders called on civil leaders, media outlets, and social media

1  History and Epidemiology

3

platforms to take action against the spread of misinformation [12]. On December 11, 2020, the Food and Drug administration approved the first vaccine for distribution to individuals aged 16 and over in the United States [13]. Shortly thereafter, the first doses were administered to healthcare workers across the country.

1.3

Coronavirus Virology

The Coronaviruses (COVs) have been cited as the source organism in three major epidemics. Coronaviruses were first described in the 1960s as a virus with the ability to cause disease in humans. In November of 2002, there was an emergence of atypical pneumonia in the Guangdong Province of China. The responsible agent was identified as a novel coronavirus named SARS-CoV for the severe acute respiratory syndrome (SARS) that was associated with the infection. Over 8000 people were infected with a case fatality rate of 7% and the virus had spread to 29 countries [14, 15]. The epidemic of SARS was considered contained by July 2003 [14]. In 2012, another outbreak of a novel coronavirus was reported. The outbreak of acute respiratory syndrome originated in Saudi Arabia and spread rapidly throughout the Middle East. The virus was initially called novel coronavirus but was given the name Middle East respiratory syndrome coronavirus (MERS-CoV) [16]. Over 2000 people were infected with MERS-CoV with a case fatality rate of 34.4% and the virus had spread to 27 countries [14]. Coronaviruses are a large family of single-stranded RNA viruses [8]. Their name is derived from the crown-shaped spikes present on the surface which is seen on electron microscopy [2]. There are four main genera of coronavirus: alpha, beta, delta, and gamma. These are subclasses of virus and should not be confused with coronavirus variants which will be discussed later. In the Coronavirus family, there are seven common strains of virus that have been identified in human infections [17]. Of the seven strains of coronavirus, three have been identified as the source of epidemic level disease outbreaks among humans. These are: Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome (MERSCoV), and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The other common human coronaviruses are 229E, NL63, OC43, and HKU1. Among these strains, 229E and NL63 are alpha-coronavirus and OC43 and HKU1 along with SARS-CoV/MERSCoV/SARS-CoV-2 are all beta-­coronaviruses. When comparing the genetic sequencing among the coronaviruses, SARS-CoV-2 is 50% identical to MERS-CoV and 80% identical to SARS-CoV [2, 5]. However, there are seven domains in the genetic sequence that are used to identify a virus as a coronavirus, and along those domains, SARS-CoV and SARS-­CoV-­2 are 94.4% identical [5]. Coronaviruses are found in both animals and humans. They can cause zoonotic diseases which means that animals act as a vector or carrier for the virus and can spread virus from animals to humans ultimately causing disease in humans [17]. The SARS-CoV and MERS-CoV viruses are believed to have their origins in bats.

4

L. Holifield

These viruses spread to an intermediate host animal which were then transmitted to humans. In the case of SARS-CoV, the intermediate host was a palm civet (palm cat), and in MERS-CoV, a dromedary camel. In a similar manner, genetic sequencing has demonstrated that SARS-COV-2 has 96.2% similarity to bat coronaviruses which has led experts to believe that the SARS-CoV-2 has its origin in bats via an unknown intermediate host [18]. The belief in an intermediary host is based on two factors: first, the differences in sequences do not fit the timeline for the estimated mutation rate that the virus would need to undergo to arrive at its present coding, and two, there are genetic differences with the code for the spike protein which the virus needs to enter human cells [19]. Early in the pandemic, it was thought that Pangolins might have been the intermediate host based on the finding of coronaviruses in Malayan pangolins which had very similar genetic sequences at the spike protein, but that was ruled out as the intermediate host due to wider variation in the genetic sequencing [20]. Scientists continue to search for the intermediary host by doing retrospective sequencing of animal surveillance samples from China [21].

1.3.1 Variants of Concern The coronavirus, like all viruses, accumulates mutations in the nucleotide sequence over time. These mutations form variant strains of the virus. While most variants will have no impact on viral behavior or expression (phenotype), some mutations may cause changes to the way that the virus behaves in the form of increased transmissibility, atypical clinical course, decreased effectiveness of vaccine immunity or acquired immunity, decreased responsiveness to therapy, and failure of laboratory tests to detect virus [22]. Scientists and epidemiologists have been conducting genome sequencing and monitoring to identify any mutations to the virus since the initial sequencing of SARS-CoV-2 was completed. The reason for this surveillance is because the development of new variants is an expected phenomenon, and it is important to monitor for the mutations whose expression may lead to a more virulent strain than the original or wild-type strain. The World Health Organization (WHO) classifies the more concerning variants as either variants of interest (VOI) or variants of concern (VOC) [23]. In the United States, the Department of Health and Human Services established a SARS-CoV-2 Interagency Group (SIG) to monitor variant surveillance and they have further classified variants as: Variant Being Monitored (VBM), Variant of Interest (VOI), Variant of Concern (VOC), and Variant of High Consequence (VOHC) [41]. In addition to the scientific name given to each variant, the WHO has assigned Greek alphabet labels for variants of interest and concern to assist public discussion of the variant strains. A Variant of Interest is a variant that is suspected to have higher transmissibility, cause a more severe illness, bypass the immune response developed from either previous COVID-19 infection or vaccination (a phenomenon known as viral escape), or may evade traditional diagnostic testing [24]. When evidence accumulates that these are being observed in the population, then a variant becomes a Variant of Concern.

1  History and Epidemiology

5

Surveillance of variants can be done through genomic surveillance as well as through the detection of epidemiological signals and unexpected trends. Examples of surveillance indicators or alerts would be an increase or change in trends in number of cases (especially if skewed toward a group with specific shared characteristics such as age or gender), an increase in cases among health care workers, evidence of more severe illness than previously observed in the population, or an increase in hospitalizations or intensive care unit admissions [22]. Unexpected trends discovered during routine surveillance can indicate that something has changed in the behavior of the virus and should trigger an alert of variant behavior. As of 2021, the WHO has identified a number of Variants of Concern. A brief synopsis is given below of the most significant variants to date.

1.3.1.1 B.1.1.7 (Alpha) In December 2020, there was an unexpectant rise in cases in the United Kingdom which was attributed to the variant B.1.1.7, also known as the Alpha variant [25]. It has since spread to over 80 countries. The transmissibility rate is reported to be 43–90% higher in this strain than in the wild type [26]. The variant contains multiple mutations in its genome. Some of these mutations are in the spike protein which is the basis of some COVID-19 vaccines [27]. While there is some reduced efficacy of the vaccine and of monoclonal antibody therapy, the response to both has been generally effective in neutralizing the variant strain [28]. 1.3.1.2 B1.351 (Beta) The beta variant was detected in December of 2020 from the Republic of South Africa. Within a month of the variant’s identification, it became the dominant strain in South Africa [26]. It has now been found in over 40 countries. It is known to have a transmissibility rate that is 1.5 times higher than the original strain [28]. The risks for ICU admission and death have not been found to be significantly higher compared to non-variant cases [29]. With regard to treatment, there is some degree of escape from monoclonal antibodies [28]. With regard to the vaccine, the mRNA vaccines show some degree of protection after the second booster [29]. 1.3.1.3 P.1 (Gamma) The P.1 or Gamma variant has been circulating since 2020 when it was first identified from Brazilian passengers traveling to Japan [30]. This variant is extremely infections and is responsible for a surge of infections that struck the Brazilian Amazon, plunging the country into crisis [27]. The gamma variant is relatively refractory to monoclonal antibody treatments [29]. With regard to vaccines, there is reduced efficacy of the vaccine compared to the original strain, but still effective enough to provide protection in most vaccinated individuals [29]. 1.3.1.4 B.1.617.2 (Delta) Several variants emerged in India in December 2020 which led to a huge spike in the number of cases. Among those variants was B.1.617.2, also known as the Delta

6

L. Holifield

variant, which became rapidly dominant. It has spread to at least 124 countries and, at one point, was responsible for 90% of the new cases in France [25]. The Delta variant is reported to be more transmissible and have a higher risk for hospitalization and mortality than other variants of concern [26]. The variant did demonstrate escape from the activity of monoclonal antibody and convalescent plasma therapy [26]. However, the mRNA vaccine does show some degree of protection against the Delta variant [31]. As previously stated, the development of mutations is a natural part of viral evolution. Therefore, it is vital to continue close monitoring of the population for new variants and to monitor the spread of existing variants. The current vaccines available on the market show some protection against the current variants [30]. Increasing vaccination efforts across the world will also contribute to controlling the spread of the virus and therefore the pandemic.

1.4

Case Definition

The hallmark of every outbreak investigation is the case definition. This is a standardized definition used for public health surveillance in the identification of infected individuals. For COVID-19, the WHO has established three categories with criteria for suspected, probable, and confirmed cases of SARS-CoV-2 infection which are delineated below [32]. The clinical criteria are acute onset of fever and cough or acute onset of any three of the following: fever, cough, general weakness/fatigue, headache myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea, altered mental status. A suspected case of SARS-CoV-2 infection: 1. A patient who meets the clinical and epidemiological criteria. 2. A patient with severe acute respiratory illness (with history of fever and cough with onset in last 10 days and requiring hospitalization). 3. Asymptomatic person not meeting epidemiologic criteria with a positive SARS-­ CoV-­2 Antigen-rapid detection test. A probable case of SARS-CoV-2 infection: 1. A patient who meets clinical criteria and has either come into contact with a probable or confirmed case or is linked to a COVID-19 cluster. 2. A suspected case with chest imaging (radiography, CT, lung ultrasound) showing finding suggestive of COVID-19 disease. 3. A person with recent onset of loss of smell or loss of taste and the absence of any other identified cause. 4. Death in an adult with respiratory distress with no other identifiable cause. The patient was also a contact of a probable or confirmed case or linked to a COVID-19 cluster.

1  History and Epidemiology

7

A confirmed case of SARS-CoV-2 infection: 1. A person with a positive nucleic acid amplification test (NAAT). 2. A person with a positive SARS-CoV-2 Antigen RDT and meeting either the probable or suspect case criteria listed above. 3. An asymptomatic person with positive SARS-CoV-2 antigen-rapid detection test who is a contact of a probable or confirmed case.

1.5

Transmission

The ability to understand and quantify disease transmission is vital in controlling the spread of a disease. Transmissibility is the ability of a disease to be passed from one person or organism to another. When discussing the transmissibility of an infectious agent, a common term utilized is the reproduction number, R0, pronounced “R naught”. The reproduction number (R0) is a measure of infectivity that represents the number of people who can be infected by coming into contact with one sick person in a population that is neither immune nor vaccinated [18, 33]. If a disease outbreak has a reproduction number greater than 1, then it is expected that the spread will continue exponentially, whereas a disease with a reproduction number less than 1 is not expected to continue [33, 34]. The reproduction number is meant to estimate contagiousness based on complex mathematical modeling, which involves the infectious period, the mode of transmission, and the contact rate. In other words, the reproduction number is an estimate of contagiousness which takes into account both the biology of the virus and the patterns of human behavior that contribute to spread. Patterns of behavior vary widely among different countries. Therefore, the estimated value of the reproduction number in China or Europe may not accurately reflect the reproduction value in the United States. It is also not valid to compare reproduction number values among historic or emerging infections without recalculating this using the same modeling assumptions [35]. There has been much discussion in modern media about the reproduction number in relationship to COVID-19 in an attempt to anticipate the severity of the pandemic. It is very easy to misinterpret and misapply the reproduction number so that the true interpretation of the metric is distorted [35]. For example, obtaining an accurate count of the number of cases during an active outbreak is difficult under the best of circumstances. Even in modern times, there is rarely sufficient data collection systems in place to capture the early stages of an outbreak. As a result, the reproduction number is often estimated retrospectively. Determining the reproduction number for COVID-19 is particularly limited by asymptomatic spread [34]. Despite these limitations, the reproduction number of COVID-19 has still been used in common discussion and it is important to have a basic understanding of what it is and how it is used in discussions of epidemiology. Despite the limitations in determining the reproduction number, it has been repeatedly shown that the virus is highly transmissible, and the Centers for Disease

8

L. Holifield

Control consider the R0 of SARS-CoV-2 to be greater than 1 though the estimated value varies widely in the literature [36]. While initially associated with wet markets in China, several cases were quickly identified as having had no association with the wet markets [37]. This suggested that there must be an element of person-­ to-­person transmission. The pathophysiology behind the transmission of the virus is that SARS-CoV-2 uses an enzyme, angiotensin-converting enzyme 2 (ACE2), as an entry point into the body as a cellular entry receptor [18]. The ACE2 enzyme is highly expressed in the epithelial cells of the alveoli, trachea, and bronchi [18]. It is also highly expressed along the glandular cells of gastric, duodenal, and rectal epithelia [8]. SARS-CoV-2 binds to ACE2 with high affinity and acts as an entry receptor for the virus [8]. The spike protein on the virus merges with the viral envelope with the host cell membrane [18]. There have been several mechanisms of disease transmission that have been discussed and theorized to control the spread of the disease. The most discussed are mentioned below.

1.5.1 Animal Transmission Coronaviruses are zoonotic and can be transmitted from animal to human [1]. The initial cases of COVID-19 were associated with wet markets. Wet markets are open air markets that sell fresh meats and vegetables and may have live wild animals that are butchered on site [38]. To mitigate the spread of the virus, closing the wet markets in Wuhan was one of the very first interventions by the Chinese government. The origin of SARS-CoV-2 is believed to be bats, but the intermediate host has never been identified. In addition to the original animal host, there have been cases of infected Minks spreading the virus to humans [39]. There were two mink farms in the Netherlands that had infected workers, of which at least one was identified as developing the virus from the Minks [39, 40]. The virus is highly transmissible among the Mink population and several variants were identified from the samples taken [39]. One variant is responsible for a number of human infections in the Netherlands and Denmark [39]. Conversely, there is a risk of transmission from humans to animals. Coronaviruses are known to infect animals and while animals may act as a host to the virus, few of them will develop severe infection [41]. The pathophysiology of the viral infection is similar to animals in that the virus binds to the ACE2 receptors in animals [39]. Experimental inoculation has demonstrated that the virus does not replicate well in dogs and did not replicate at all in pigs, chickens, and ducks [39, 42]. It did, however, replicate efficiently in ferrets and cats [41, 42]. In April 2020, there was an outbreak of COVID-19 at the Bronx Zoo in New York City when eight big cats were infected with COVID-19. These cases were linked to a COVID-19 positive zookeeper [40]. Another notable zoo outbreak occurred at the San Diego Zoo where several western lowland gorillas tested positive for SARS-CoV-2 after they developed respiratory symptoms. It is thought that these animals were infected by a zoo staff member [39].

1  History and Epidemiology

9

While closing the wet markets in Wuhan was an important step in limiting exposure, future efforts and disease spread should be targeted toward regulating the markets and exotic animal farming rather than a complete ban as it will only encourage black market or illegal sales of wild animals [41].

1.5.2 Person-to-Person Person-to-person transmission is the predominate method of viral spread. This occurs through droplet particles carrying the virus. The symptomatic COVID-19 patient will experience cough and sneezing. This generates a viral cloud of thousands of viral droplets that range in sizes between 0.6 and 100 μm [43]. The droplet particles have the potential to evaporate and form smaller droplet nuclei depending on the temperature and humidity level of the environment. Warm moist air in the environment helps the viral cloud to remain airborne longer and extends the lifetime of the droplet rather than aid in its evaporation [43]. Droplet transmission occurs when a person comes in close contact (within 6 ft for at least 15 min) with an infected individual and is at risk for having their mucosae exposed to viral droplets [44, 45]. The smaller droplet nuclei contain lighter viral particles that may remain suspended in the air for a longer period and have the ability to cause airborne transmission. Studies have shown that transmission occurs through respiratory droplets and contact. However, airborne transmission is shown to be possible with aerosolizing procedures such as endotracheal intubation, bronchoscopy, administering nebulizers, to name a few [44]. According to studies, the viral load of SARS-CoV-2 is highest surrounding symptom onset and gradually declines [46]. Within 10 days of symptom onset, it is unlikely to recover viral samples capable of replication from patients with mild cases of COVID-19 [47]. People who have recovered from COVID-19 may have prolonged detection of viral RNA. In one investigation, researchers failed to isolate replication-competent virus from adults who persistently tested positive for COVID-19. In contrast, patients who are immunocompromised or who develop severe COVID-19 infection can demonstrate prolonged periods of infectivity from the virus [46]. Given these findings, infection control should rely on early detection and isolation. In addition, all preventative measures should be taken to prevent the spread of potentially infectious droplets.

1.5.3 Asymptomatic/Presymptomatic Transmission The incubation period is the time that it takes to develop disease after exposure to the virus. The mean incubation period is 5–6 days, but has been reported in the literature to have a range of 1–14 days after exposure [4]. Presymptomatic patients are individuals who are infectious before developing symptoms, while asymptomatic patients are individuals who are never symptomatic. These patients can generate

10

L. Holifield

large quantities of droplets through normal breathing patterns which can be very small in size [43]. The virus may be found in the respiratory tract anywhere from 1 to 3 days prior to symptom onset [48]. This method of spread is difficult to quantify because of the challenge of testing patients with no symptoms. There have been studies done which involve estimating infectious time based on exposures and there are studies done testing household contacts [48]. The transmission of the virus from asymptomatic and presymptomatic individuals is well-documented in the literature [48–50]. These studies have important implications as they highlight the importance of prevention in the form of social distancing and in taking added precautions for individuals with known exposures [48].

1.5.4 Vertical Transmission Vertical transmission refers to the transmission of a pathogen from a mother to her baby either before or immediately after birth. Maternal pneumonias are associated with severe adverse obstetrical outcomes and viral pneumonia is a cause of morbidity and mortality in pregnant women [51]. It is known from previous coronavirus epidemics that pregnant women are at a higher risk for severe illness, morbidity, and mortality [51]. During the COVID-19 pandemic, there have been case reports of pregnant women with viral infection and inflammation of the placenta [52]. The mechanism of transmission is less clear. There have been documented cases of high SARS-CoV-2 viral load in the placenta which could be explained by the expression of ACE2 receptors (the entry point for the virus) expressed in the placenta [53, 54]. However, placental transmission remains speculative and more clinical research needs to be performed [53]. Maternal COVID-19 infection is believed to be at low risk for transmission to the baby [45, 55]. Multiple review articles have noted that the incidence of vertical transmission from mother to baby was minimal and the neonatal outcomes generally favorable [51, 56–62]. In cases with evidence of vertical transmission, transmission does not appear to coincide with the severity of maternal illness [55, 62]. Another speculated form of transmission is through breast milk or while breastfeeding. In one review out of China, there was no evidence of viral particles found in the breast milk of an infected mother [56]. Current guidelines from the Centers of Disease Control are in support of breastfeeding and recommend that breastfeeding parents use hand hygiene before touching their child and expressing mild. If the lactating parent is suspected of having or is positive for COVID-19, the lactating parent should wear a mask anytime they are less than 6 ft from the child. A child who is being breastfed by someone with suspected or confirmed COVID-19 infection should be considered as a close contact and be quarantined for the duration of time prescribed for the lactating parent’s quarantine and their own time thereafter [63]. In summation, the majority of studies reviewed indicate low risk of vertical transmission, though all studies highlight the need to continue further research and to take all measures to protect this vulnerable population.

1  History and Epidemiology

1.6

11

Conclusion

Understanding the epidemiology of a pathogen is key to limiting the spread of an illness, especially in the setting of a novel pathogen in which no innate immunity or vaccination exists. The critical first step towards this understanding is establishing the case definition which allows for uniformity in data collection. Once that is elucidated, an investigation can begin to determine the nature of disease transmission to control the spread of the pathogen. Finally, continued disease surveillance and monitoring for changes in the nature of the pandemic is vital until a treatment or vaccine can be developed. During the COVID-19 pandemic, identification and isolation of infected individuals and social distancing provided a crucial stopgap in limiting the spread of the virus. This was achieved through the coordinated efforts of public health officials, scientists, health care providers, veterinarians, and wildlife researchers around the globe. Coordinated epidemiological investigations provided the information needed to slow the spread so that scientists had time to study the disease and develop treatments and vaccinations.

References 1. Meo SA, Alkowikan AM, Al-Khlaiwai Meo IM, Halepoto DM, Igbal M, Usmani AM, Hajjar W, Ahmed N (2020) Novel coronavirus 2019-nCoV: prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV.  Eur Rev Med Pharmacol Sci 24:2012–2019 2. Muralidar S, Ambi S, Sekaran S, Krishnan U (2020) The Emergence of COVID-19 as a global pandemic: understanding the epidemiology, immune response, and potential therapeutic targets of SARS-COV2. Biochemie 179:85–100 3. World Health Organization (2020, January 12) COVID-19 China. https://www.who.int/emergencies/disease-­outbreak-­news/item/2020-­DON233 4. World Health Organization (2020) Laboratory testing for SARS-CoV-2: Interim guidelines. WHO/2019-nCoV/laboratory/2020.6 5. Liu Q, Xu K, Wang X, Wang W (2020) From SARS to COVID-19: what lessons have we learned? J Infect Public Health 13:1611–1618 6. World Health Organization (ed) (2016) International Health Regulations (2005), 3rd edn. World Health Organization, Geneva. https://apps.who.int/iris/handle/10665/246107 7. World Health Organization (2000, January 30) Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of the novel coronavirus (2019-nCoV). https://www.who.int/news/item/30-­01-­2020-­statement-­on-­ the-­second-­meeting-­of-­the-­international-­health-­regulations-­(2005)-­emergency-­committee-­ regarding-­the-­outbreak-­of-­novel-­coronavirus-­(2019-­ncov) 8. Halaji M, Farahani A, Ranjbar R, Heiat M, Dehkordi FS (2020) Emerging coronaviruses: first SARS, second MERS and third SARS-CoV2. Epidemiological updates of Covid 19. Infez Med Suppl 1:6–17 9. World Health Organization (2020, March 11) WHO Director-General’s opening remarks at the media briefing on COVID-19. WHO Directhttps: //www.who.int/director-­general/ speeches/detail/who-­d irector-­g eneral-­s -­o pening-­r emarks-­a t-­t he-­m edia-­b riefing-­o n-­ covid-­19%2D%2D-­11-­march-­2020or-­General’s opening remarks at the media briefing on COVID-19 - 11 March 2020 10. Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, ­Doria-­Rose

12

L. Holifield

NA, Corbett KS, Morabito KM, O’Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH, mRNA-1273 Study Group (2020) An mRNA Vaccine against SARS-CoV-2  - preliminary report. N Engl J Med 383(20):1920–1931. https://doi.org/10.1056/NEJMoa2022483 11. World Health Organization (2020) Multisystem inflammatory syndrome in children and adolescents with COVID-19: scientific brief, 15 May 2020. World Health Organization. https:// apps.who.int/iris/handle/10665/332095. License: CC BY-NC-SA 3.0 IGO 12. World Health Organization (2020) COVID-19 pandemic: countries urged to take stronger action to stop spread of harmful information, 23 September 2020. https://www.who.int/news/ item/23-­09-­2020-­covid-­19-­pandemic-­countries-­urged-­to-­take-­stronger-­action-­to-­stop-­spread-­ of-­harmful-­information 13. Food and Drug Administration (2021) FDA News Release: FDA Approves First COVID-19 Vaccine. 2021, August 23. FDA Approves First COVID https://www.fda.gov/news-­events/ press-­announcements/fda-­approves-­first-­covid-­19-­vaccine-­19 Vaccine | FDA 14. Peeri N, Shresta N, Rahman MS, Zaki R, Tan Z, Bibi S, Baghbanzadeh M, Aghamohammed N, Zhang W, Haque U (2020) The SARS, MERS, and novel coronavirus (COVID-19) epidemics, the newest and biggest global health threats: What lessons have we learned? Int J Epidemiol. 49(3):717–726 15. Hui D, Zumla A (2019) Severe acute respiratory syndrome: historical, epidemiologic, and clinical features. Infect Dis Clin N Am 33(4):869–889. https://doi.org/10.1016/j.idc.2019.07.001 16. Zumla A, Hui DS, Perlman S (2015) Middle East respiratory syndrome. Lancet (London, England) 386(9997):995–1007. https://doi.org/10.1016/S0140-­6736(15)60454-­8 17. Rahman S, Montero M, Rowe K, Kirton R, Kunik F Jr (2021) Epidemiology, pathogenesis, clinical presentations, diagnosis and treatment of COVID-19: a review of current evidence. Expert Rev Clin Pharmacol 14(5):601–621. https://doi.org/10.1080/17512433.2021.1902303 18. Zhang X, Huang HJ, Zhuang DL, Nasser M, Yang M, Yang M, Zhu P, Zhao M (2020) Biological, clinical, and epidemiological features of COVID-19, SARS, and MERS and AutoDock simulation of ACE2. Infect Dis Poverty 9:99 19. Friend T, Stebbing J (2021) What is the intermediate host species of SARS-CoV-2? Futur Virol. https://doi.org/10.2217/fvl-­2020-­0390 20. Prince T, Smith SL, Radford AD, Solomon T, Hughes GL, Patterson EI (2021) SARS-CoV-2 infections in animals: reservoirs for reverse zoonosis and models for study. Viruses. 13(3):494. https://doi.org/10.3390/v13030494. PMID: 33802857; PMCID: PMC8002747 21. The World Health Organization (2020) WHO-convened Global Study of Origins of SARSCoV-2: China Part. 2021, April, 6. https://www.who.int/publications/i/item/who-­convened-­ global-­study-­of-­origins-­of-­sars-­cov-­2-­china-­part 22. World Health Organization (2021) Guidance for the surveillance of SARS-CoV-2 variants: Interim Guidance. 2021, August 9. https://www.who.int/publications/i/item/WHO_2019-­ nCoV_surveillance_variants 23. World Health Organization (2021) Tracking SARS-CoV-2 Variants. 2021, October 29. https:// www.who.int/en/activities/tracking-­SARS-­CoV-­2-­variants/ 24. Walensky RP, Walke HT, Fauci AS (2021) SARS-CoV-2 variants of concern in the United States— challenges and opportunities. JAMA 325(11):1037–1038. https://doi.org/10.1001/jama.2021.2294 25. Teyssou E, Delagrèverie H, Visseaux B, Lambert-Niclot S, Brichler S, Ferre V, Marot S, Jary A, Todesco E, Schnuriger A, Ghidaoui E, Abdi B, Akhavan S, Houhou-Fidouh N, Charpentier C, Morand-Joubert L, Boutolleau D, Descamps D, Calvez V, Marcelin AG, Soulie C (2021) The Delta SARS-CoV-2 variant has a higher viral load than the Beta and the historical variants in nasopharyngeal samples from newly diagnosed COVID-19 patients. J Infect 83(4):e1–e3. https://doi.org/10.1016/j.jinf.2021.08.027 26. Tian D, Sun Y, Zhou J, Ye Q (2021) The global epidemic of SARS-CoV-2 variants and their mutational immune escape. J Med Virol. https://doi.org/10.1002/jmv.27376. Advance online publication

1  History and Epidemiology

13

27. Burki T (2021) Understanding variants of SARS-CoV-2. Lancet (London, England) 397(10273):462. https://doi.org/10.1016/S0140-­6736(21)00298-­1 28. Boehm E, Kronig I, Neher RA, Eckerle I, Vetter P, Kaiser L, Geneva Centre for Emerging Viral Diseases (2021) Novel SARS-CoV-2 variants: the pandemics within the pandemic. Clin Microbiol Infect 27(8):1109–1117. https://doi.org/10.1016/j.cmi.2021.05.022 29. Choi JY, Smith DM (2021) SARS-CoV-2 variants of concern. Yonsei Med J 62(11):961–968. https://doi.org/10.3349/ymj.2021.62.11.961 30. Jogalekar MP, Veerabathini A, Gangadaran P (2021) SARS-CoV-2 variants: a double-­ edged sword? Exp Biol Med (Maywood, NJ) 246(15):1721–1726. https://doi.org/10.1177/ 15353702211014146 31. Li M, Lou F, Fan H (2021) SARS-CoV-2 Variants of Concern Delta: a great challenge to prevention and control of COVID-19. Signal Transduct Target Ther 6(1):349. https://doi. org/10.1038/s41392-­021-­00767-­1 32. The World Health Organization (2020) Public Health Surveillance for COVID-19: Interim Guidance. 2020, December 16. https://www.who.int/publications/i/item/who-­2019-­nCoV-­sur veillanceguidance-­2020.7 33. Locatelli I, Trächsel B, Rousson V (2021) Estimating the basic reproduction number for COVID-19  in Western Europe. PLoS One 16(3):e0248731. https://doi.org/10.1371/journal. pone.0248731 34. Li H, Burm Sw, Hong SW, Ghayda RA, Kronbichler A, Smith L, Koyanagi A, Jacob L, Lee KH, Shin JI (2021) A comprehensive review of coronavirus disease 2019: epidemiology, transmission, risk factors, and international responses. Yonsei Med J 62(1):1–11 35. Delamater PL, Street EJ, Leslie TF, Yang Y, Jacobsen KH (2019) Complexity of the basic reproduction number (R0). Emerg Infect Dis 25(1):1–4. https://doi.org/10.3201/eid2501.171901 36. Ke R, Romero-Severson E, Sanche S, Hengartner N (2021) Estimating the reproductive number R0 of SARS-CoV-2 in the United States and eight European countries and implications for vaccination. J Theor Biol 517:110621. https://doi.org/10.1016/j.jtbi.2021.110621 37. Riou J, Althaus CL (2020) Pattern of early human-to-human transmission of Wuhan 2019 novel coronavirus (2019-nCoV), December 2019 to January 2020. Euro Surveill 25(4):2000058. https://doi.org/10.2807/1560-­7917.ES.2020.25.4.2000058 38. Xiao X, Newman C, Buesching CD et  al (2021) Animal sales from Wuhan wet markets immediately prior to the COVID-19 pandemic. Sci Rep 11:11898. https://doi.org/10.1038/ s41598-­021-­91470-­2 39. Sharun K, Dhama K, Pawde AM, Gortázar C, Tiwari R, Bonilla-Aldana DK, Rodriguez-­ Morales AJ, de la Fuente J, Michalak I, Attia YA (2021) SARS-CoV-2 in animals: potential for unknown reservoir hosts and public health implications. Vet Q 41(1):181–201. https://doi. org/10.1080/01652176.2021.1921311 40. Oreshkova N, Molenaar RJ, Vreman S, Harders F, Oude Munnink BB, Hakze-van der Honing RW, Gerhards N, Tolsma P, Bouwstra R, Sikkema RS, Tacken MG, de Rooij MM, Weesendorp E, Engelsma MY, Bruschke CJ, Smit LA, Koopmans M, van der Poel WH, Stegeman A (2020) SARS-CoV-2 infection in farmed minks, the Netherlands, April and May 2020. Euro Surveill. 25(23):2001005. https://doi.org/10.2807/1560-­7917.ES.2020.25.23.2001005 41. Tiwari R, Dhama K, Sharun K, Iqbal Yatoo M, Malik YS, Singh R, Michalak I, Sah R, Bonilla-­ Aldana DK, Rodriguez-Morales AJ (2020) COVID-19: animals, veterinary and zoonotic links. Vet Q 40(1):169–182. https://doi.org/10.1080/01652176.2020.1766725 42. Shi J, Wen Z, Zhong G, Yang H, Wang C, Huang B, Liu R, He X, Shuai L, Sun Z, Zhao Y, Liu P, Liang L, Cui P, Wang J, Zhang X, Guan Y, Tan W, Wu G, Chen H, Bu Z (2020) Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science. 368(6494):1016–1020. https://doi.org/10.1126/science.abb7015 43. Salian VS, Wright JA, Vedell PT, Nair S, Li C, Kandimalla M, Tang X, Carmona Porquera EM, Kalari KR, Kandimalla KK (2021) COVID-19 transmission, current treatment, and future therapeutic strategies. Mol Pharm 18(3):754–771. https://doi.org/10.1021/acs. molpharmaceut.0c00608

14

L. Holifield

44. The World Health Organization (2020) Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations. 2020, March 29. https://www.who. int/news-­r oom/commentaries/detail/modes-­o f-­t ransmission-­o f-­v irus-­c ausing-­c ovid-­1 9-­ implications-­for-­ipc-­precaution-­recommendations 45. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC (2020) Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA 324(8):782–793. https://doi.org/10.1001/jama.2020.12839 46. Mendes Correa MC, Leal FE, Villas Boas LS, Witkin SS, de Paula A, Tozetto Mendonza TR, Ferreira NE, Curty G, de Carvalho PS, Buss LF, Costa SF, da Cunha Carvalho FM, Kawakami J, Taniwaki NN, Paiao H, da Silva Bizário JC, de Jesus JG, Sabino EC, Romano CM, Grepan R, Sesso A (2021) Prolonged presence of replication-competent SARS-CoV-2 in mildly symptomatic individuals: a report of two cases. J Med Virol 93(9):5603–5607. https://doi. org/10.1002/jmv.27021 47. Lutgring JD, Tobolowsky FA, Hatfield KM, Lehnertz NB, Sullivan MM, Martin KG, Keaton A, Sexton DJ, Tamin A, Harcourt JL, Thornburg NJ, Reddy SC, Jernigan JA (2021) Evaluating the presence of replication-competent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from nursing home residents with persistently positive reverse transcription polymerase chain reaction (RT-PCR) results. Clin Infect Dis. 2021:ciab436. https://doi. org/10.1093/cid/ciab436 48. Johansson MA, Quandelacy TM, Kada S, Prasad PV, Steele M, Brooks JT, Slayton RB, Biggerstaff M, Butler JC (2021) SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Netw Open 4(1):e2035057. https://doi.org/10.1001/jamanetworkopen.2020.35057 49. Tong ZD, Tang A, Li KF, Li P, Wang HL, Yi JP, Zhang YL, Yan JB (2020) Potential presymptomatic transmission of SARS-CoV-2, Zhejiang Province, China, 2020. Emerg Infect Dis 26(5):1052–1054. https://doi.org/10.3201/eid2605.200198 50. Chaw L, Koh WC, Jamaludin SA, Naing L, Alikhan MF, Wong J (2020) Analysis of SARS-­ CoV-­2 transmission in different settings, Brunei. Emerg Infect Dis 26(11):2598–2606. https:// doi.org/10.3201/eid2611.202263 51. Behforouz A, Ferdosian F, Bahrami R (2020) Vertical transmission of coronavirus disease 19 (COVID-19) from infected pregnant mothers to neonates: a review. Fetal Pediatr Pathol 39(3):246–250. https://doi.org/10.1080/15513815.2020.1747120 52. Vivanti AJ, Vauloup-Fellous C, Prevot S, Zupan V, Suffee C, Do Cao J, Benachi A, De Luca D (2020) Transplacental transmission of SARS-CoV-2 infection. Nat Commun 11(1):3572. https://doi.org/10.1038/s41467-­020-­17436-­6 53. Li M, Chen L, Zhang J, Xiong C, Li X (2020) The SARS-CoV-2 receptor ACE2 expression of maternal-fetal interface and fetal organs by single-cell transcriptome study. PLoS One 15(4):e0230295. https://doi.org/10.1371/journal.pone.0230295 54. Chaubey I, Vignesh R, Babu H, Wagoner I, Govindaraj S, Velu V (2021) SARS-CoV-2 in pregnant women: consequences of vertical transmission. Front Cell Infect Microbiol 11:717104. https://doi.org/10.3389/fcimb.2021.717104 55. Walker KF, O'Donoghue K, Grace N, Dorling J, Comeau JL, Li W, Thornton JG (2020) Maternal transmission of SARS-COV-2 to the neonate, and possible routes for such transmission: a systematic review and critical analysis. BJOG 127(11):1324–1336. https://doi. org/10.1111/1471-­0528.16362 56. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, Li J, Zhao D, Xu D, Gong Q, Liao J, Yang H, Hou W, Zhang Y (2020) Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet (London, England) 395(10226):809–815. https://doi.org/10.1016/S0140-­6736(20)30360-­3 57. Alzamora MC, Paredes T, Caceres D, Webb CM, Valdez LM, La Rosa M (2020) Severe COVID-19 during pregnancy and possible vertical transmission. Am J Perinatol 37(8):861–865. https://doi.org/10.1055/s-­0040-­1710050 58. Salem D, Katranji F, Bakdash T (2021) COVID-19 infection in pregnant women: review of maternal and fetal outcomes. Int J Gynaecol Obstet 152(3):291–298

1  History and Epidemiology

15

59. Schwartz DA, Graham AL (2020) Potential maternal and infant outcomes from (Wuhan) coronavirus 2019-nCoV infecting pregnant women: lessons from SARS, MERS, and other human coronavirus infections. Viruses 12(2):194. https://doi.org/10.3390/v12020194 60. Moore KM, Suthar MS (2021) Comprehensive analysis of COVID-19 during pregnancy. Biochem Biophys Res Commun 538:180–186. https://doi.org/10.1016/j.bbrc.2020.12.064 61. Diriba K, Awulachew E, Getu E (2020) The effect of coronavirus infection (SARS-CoV-2, MERS-CoV, and SARS-CoV) during pregnancy and the possibility of vertical maternal-fetal transmission: a systematic review and meta-analysis. Eur J Med Res 25(1):39. https://doi. org/10.1186/s40001-­020-­00439-­w 62. Huntley B, Huntley ES, Di Mascio D, Chen T, Berghella V, Chauhan SP (2020) Rates of maternal and perinatal mortality and vertical transmission in pregnancies complicated by severe acute respiratory syndrome coronavirus 2 (SARS-Co-V-2) infection: a systematic review. Obstet Gynecol 136(2):303–312. https://doi.org/10.1097/AOG.0000000000004010 63. National Centers for Disease Control and Prevention (2021) Care for Breastfeeding People: Interim Guidance on Breastfeeding and Breast Milk Feeds in the Context of COVID-19. 2021, June 17. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/care-­for-­breastfeeding-­women.html

2

Prevention and Infection Control Emily A. Ingebretson

2.1

General Infection Control Practices

One of the common themes of discussion in the early part of the COVID-19 pandemic was the transmissibility of the SARS-CoV-2 virus. It was an important public conversation as people worked to protect themselves from developing the disease. Understanding how and why infected individuals transmit the SARS-CoV-2 virus is of utmost importance when developing infection control measures and decreasing transmission. This was discussed in the previous chapter, so this chapter will elucidate the methods of reducing and preventing that transmission. For the sake of this section, we will be discussing prevention and infection control in healthcare settings, which are defined by the CDC as “places where healthcare is delivered and includes, but is not limited to, acute care facilities, long term acute care facilities, inpatient rehabilitation facilities, nursing homes and assisted living facilities, home healthcare, vehicles where healthcare is delivered (e.g., mobile clinics), and outpatient facilities, such as dialysis centers, physician offices and others” [1]. Anyone entering a healthcare facility should comply with any source control measures and hand hygiene practices that are required for the safety of the visitors, patients, and employees of the facility. Steps should be taken to improve adherence to these practices and measures, such as posting visual alerts (posters, signs, lights, and physical barriers requiring acknowledgement prior to passing), as well as providing conveniently located and adequate supplies at entrances and strategic locations throughout the facility. Signs may include warnings concerning level of infection risk, how and when to perform hand hygiene, and what constitutes a well-­ fitting form of source control, and they may be located in areas such as waiting E. A. Ingebretson (*) UC San Diego Health, San Diego, CA, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 A. Bergeron et al. (eds.), Principles in Nursing Practice in the Era of COVID-19, https://doi.org/10.1007/978-3-030-94740-8_2

17

18

E. A. Ingebretson

rooms, lounges, cafeterias, and elevators, along with patient care-specific areas. General infection control practices in a healthcare setting include physical distancing and screening, source control, ventilation, and hand washing.

2.1.1 Physical Distancing Both the World Health Organization and the Centers for Disease Control endorse the implementation of social or physical distancing to reduce person-to-person transmission of SARS-CoV-2. They recommend maintaining greater than 2 m or 6 ft of distance between people to reduce droplet spread of the infection [2, 3]. This practice should be implemented in healthcare settings of all varieties, including in break rooms, waiting rooms, and conference rooms within these facilities. Waiting rooms can be modified to include outdoor seating in order to accommodate the need for more space between potential patients, and patients can be encouraged to wait in their vehicles, rather than inside. Visual aids, such as signs and floor markers, encouraging physical or social distancing, can also serve as useful reminders for distance for those visiting and working at the facility. Telehealth Strategies can be used when reasonable and feasible to do so, to reduce the risk of SARS-CoV-2 transmission and potential infectious exposures among patients and healthcare providers. It is important that this mode of care should not interfere with the quality of patient care provided. Telehealth can include simple telephone correspondence as well as more advanced video communication. Providers must take care to implement this method of evaluation and treatment within the legal terms of their respective government, insurance, and healthcare agencies. An important consideration when using telehealth is the patients’ access to technology and internet or other connectivity, as well as their level of comfort in utilizing audio-video technology. There are several telehealth methods to allow patients and healthcare providers to connect. These include [4]: • Synchronous, in which patients and healthcare providers interact in real-time using audio-video on a computerized device. • Asynchronous, in which data, messages, or images are submitted by the patient at one point in time and then reviewed and addressed by a healthcare professional at another point in time. An example of this is the use of a ‘patient portal’, where patients can access their health information and communicate via direct messaging with their healthcare provider. • Remote patient monitoring, which allows a patient to send certain clinical measurements to their healthcare provider from a distance. An example of this is a remote electrocardiogram (ECG) event monitor, which collects ECG data from the patient and transmits that data to a remote data collection system that is visible by the healthcare team. Virtual methods of healthcare provision can be implemented if group care is required, such as group therapy, or the group can be broken into smaller sessions to

2  Prevention and Infection Control

19

allow for 6 ft/2 m distancing between patients. Depending on the level of spread in the community, it may be safer to cancel group care in favor of virtual sessions until risk of transmission falls to safer levels. Screening and Triaging potentially infected individuals using the aforementioned telehealth methods reduces potential exposures that may have occurred if the patient had arrived at a healthcare facility. Before an individual is tested for COVID-19, nurses can perform virtual screening questionnaires to guide future action for the individuals. Not only can virtual visitation screen for COVID-19 symptoms, but can also be used to provide low-risk urgent care for non-COVID conditions that may not need to be addressed in an in-person healthcare setting where risk of transmission may be higher. This provides the additional benefit of decreasing the volume of patients in healthcare facilities, thus reducing the strain on resources that can occur during times of high community infection transmission. Further information concerning screening can be found in the following section about screening. If patients are requesting or scheduling appointments to be evaluated for a possible SARS-CoV-2 infection, nurse-directed triage protocols are appropriate to determine the need for in-person versus virtual/home management. Thorough examples of triage tools and protocols can be found on the WHO [5] and the CDC [6] websites. The general goal of these tools is to determine the patients’ exposure level, personal risk factors, living arrangement, and severity of disease to guide the decision on whether care should be provided in a healthcare setting or can be managed at home with virtual follow-up care. In addition to patient care and management, virtual visitation is also recommended for visitors wishing to visit patients in a hospital, in order to reduce possible exposure episodes.

2.1.2 Source Control Measures Source control in respiratory disease refers to the containment or reduction of transmission of a disease by blocking secretions produced by coughing, sneezing, or talking. Specifically, source control for SARS-CoV-2 refers to well-fitting masks or respirators that cover a person’s mouth and nose [7]. Masks have been used for decades as a method to reduce transmission of respiratory infections. They were recommended as a public health tool even during the Spanish Flu Pandemic of 1918 [8]. Not only do masks and respirators prevent the transmission of respiratory particles from the wearer to others, but they also prevent the wearer from inhaling respiratory particles expelled by people around them. Studies have shown a reduction in the growth rate of COVID-19 cases when masks are used by the public [9–12]. Due to the varied symptom expression of persons infected with SARS-CoV-2, the WHO and the United States Center for Disease Control and Prevention (CDC) both recommend that every person above the age of two should don a mask or respirator when entering a healthcare facility [13, 14]. Both asymptomatic carriers and symptomatic individuals can transmit virus from themselves to others through respiratory droplets, and well-fitted masks can provide an effective barrier to infectious

20

E. A. Ingebretson

respiratory droplets passed from person to person. However, masks must be used as part of a comprehensive strategy implementing multiple preventive measures, including frequent hand hygiene, physical distancing when possible, respiratory etiquette, environmental cleaning, and disinfection. Cloth and surgical masks are most effective when they conform to the wearer’s face, so that air is mainly passing through the mask material rather than the gaps on the sides. Improving how well a mask fits can increase the mask’s effectiveness by decreasing the wearer’s exposure to others’ respiratory particles as well as by trapping those produced by the wearer. Masks should fit snugly around the nose and mouth, reducing air that is exhaled or inhaled from around the edge of the mask. There are various aspects of masks that may improve its fit to the wearer and can improve the efficiency of the mask from 38.5% for an unmodified mask, to as much as 80.2% [15]. Examples of appropriate modifications for improved fit are as follows [16]: • A nose wire that can help the mask conform to the bridge of the nose. • A mask with ties rather than ear loops can decrease air loss around the edges of a mask. • Tying the ear loops and tucking in the side pleats to seal the sides of the mask. • Using a rubberized mask-fitter over the top of the mask to seal the edges. • Wearing a cloth mask over top of a nylon mask can help seal the edges of the nylon mask better to the wearer’s face. • Fastening the facemask’s ear loops behind the wearer’s head with a clip or ear-guard. • Wearing a band of nylon hosiery over the mask to fit it to the face. Any strategies to improve mask fit should not interfere with the wearer’s ability to breathe or their vision. Further information concerning the use of masks and respirators as personal protective equipment (PPE) by healthcare providers in patient care settings can be found in the following section of this chapter. Facilities should be prepared to offer masks upon visitor, patient, or employee entrance, in case these groups forget or neglect to bring their own. Patients should be allowed to remove their source control when they are in their room alone with the door closed; however, if there are visitors or providers in the room with the patient, both parties should don masks. Healthcare providers and facility employees who encounter patients should be encouraged to wear their face mask the entire time they are in the healthcare facility, including in break rooms when not eating or drinking [13]. It is important to remember that COVID-19 can be asymptomatic and healthcare employees may be unaware of when they, themselves, have been infected. Therefore, maintaining source control precautions and physical distancing in community employee areas is prudent. Healthcare facilities may choose to provide staggered schedules for employee breaks in order to reduce the number of people attempting to use a break room or lounge at once and provide the opportunity for appropriate physical distancing, especially when unmasked. Upon leaving the healthcare facility or their

2  Prevention and Infection Control

21

patient care unit, healthcare providers and other patient-facing personnel should remove their respirator or face mask, perform hand hygiene, and put on a different mask. There are scenarios where masking is not recommended due to safety concerns. Children under the age of two may be at risk of injuring themselves if not closely monitored with a mask. Persons with disabilities or underlying conditions that preclude wearing a mask safely should not be made to wear a mask in case of potential harm. Anyone who is unconscious or incapacitated to the degree that they are unable to remove their mask without assistance should be assisted with the donning and doffing of their mask when appropriate [17]. If these parties are present and desire on-site visitation at a healthcare facility, they should be encouraged to use alternative methods such as virtual visitation to decrease the risk of transmission within the facility. It is imperative that healthcare providers and patient-facing personnel receive training by the healthcare facility on how to safely don and doff their facemask and disinfect any reusable equipment. For example, it is important that the public is educated on appropriate hand hygiene prior to and after contacting their face mask or respirator.

2.1.3 Hand Hygiene Fomite transmission is low, as described in previous chapters [18–20]. Surface transmission can be further decreased with appropriate hand hygiene. Though the exact contribution that hand hygiene has on the spread of coronaviruses between hosts is not fully known, appropriate hand washing has been proven time and again to decrease the transmission of infectious pathogens from one person to the next [21]. There are two methods of effectively performing hand hygiene. The first is thoroughly scrubbing the entirety of both hands with soap and water for at least 20 seconds, rinsing with water that flows from fingertips back to wrists, then drying with a clean towel, taking care not to touch the faucet handle with the clean hand afterward. The second method is applying alcohol-based hand rub with a solution of 80% ethanol or 75% isopropyl alcohol formulations and rubbing both hands thoroughly together until the alcohol has evaporated. This method has a higher level of compliance than soap and water washing, because it is generally more readily available. Alcohol-based hand rubs should be produced in accordance with WHO guidelines, or the United States Food and Drug Administration, if appropriate [22]. In general, hand hygiene should be completed before eating, after toileting, and when hands are visibly soiled. However, in the healthcare setting, it is important that hand hygiene be performed, additionally, prior to patient care, prior to performing an aseptic task, after handling bodily fluids, and after PPE (including gloves) removal. Additionally, hand hygiene should be performed when moving from working on a soiled body site to a clean body site on the same patient [23]. The application of gloves does not take the place of hand hygiene, but rather works in conjunction with it.

22

E. A. Ingebretson

2.1.4 Ventilation Hand hygiene can help reduce the risk of fomite transmission, while adequate air flow works in conjunction with physical distancing and source control to decrease the risk of transmission through inhalation. Adequate ventilation prevents the transmission of infectious droplets or particles by reducing their concentration in areas where high concentration is a risk. Infected respiratory particles in higher concentration increase the chance of those particles entering the respiratory system or contacting mucous membranes (such as the eyes) of a person in that area of high concentration. By applying ventilation strategies appropriately, a facility can dilute the concentration of respiratory particles in areas where infection and risk of transmission are high. The WHO and CDC both recommend implementing various strategies to improve ventilation in indoor settings, thus reducing transmission of SARS-CoV-2 in those areas [3, 24]. Ventilation engineering controls to reduce exposures to active SARS-CoV-2 virus in respiratory droplets include optimizing ventilation and indoor air quality in situations when exposure risk is high. Some of these controls are specifically related to improving air-handling systems, such as: • Ensuring appropriate direction of airflow from areas of low infectivity to areas of high infectivity [25]. • Increasing airflow by opening windows and using fans to exhaust the indoor air to the outdoors. • Utilizing portable air filtration systems which use high-efficiency particulate air filters (HEPA) when possible and reasonable. HEPA filters are produced to remove “at least 99.97% of dust, pollen, mold, bacteria and any airborne particles with a size of 0.3 microns” [26]. • Implementing alternative air cleaning systems such as ultraviolet (UV) germicidal irradiation systems. These systems can be placed within air ducts and apply UV energy radiation to air as a sterilizing mechanism [27]. This strategy may be the most expensive option for ventilation improvement, which limits its use in many healthcare settings. • Utilizing negative-pressure, airborne infection isolation rooms when available. These are rooms in which the air pressure in the room is lower than that outside of the room, thus causing air to flow from the hall into the room when the door is opened [28]. Outdoor triage areas are recommended for patients presenting with respiratory symptoms, because SARS-CoV-2 viral particles are more likely to spread from person to person indoors than outdoors, due to decreased level of air flow indoors. In the outdoors, a light wind can disperse potentially infectious particles to low concentrations, thus decreasing the risk of those particles entering the body of another person through mucous membranes.

2  Prevention and Infection Control

23

2.1.5 Other Environmental Controls Just as with any other bacterial, viral, or fungal infection, cleaning and disinfecting should occur on a regular basis in areas with individuals with COVID-19, as well as after the patient leaves the care area [29]. As much as possible, equipment that must be utilized for multiple patients should be cohorted to patients who are confirmed SARS-CoV-2-infected. If adequate equipment for this is not available, then thorough cleaning and disinfecting of the equipment according to manufacturer guidelines should occur in between each patient use. Facilities should develop protocols to support appropriate cleaning and disinfecting practices of equipment and rooms in areas where patients with COVID-19 are receiving care. Environmental services personnel are essential for the prevention of transmission of this virus. They should be provided the same level of PPE as HCP when working in patient care areas holding individuals infected with SARS-CoV-2.

2.2

Screening and Quarantine

Due to varied compliance with all the above preventative measures, SARS-CoV-2 continues to spread. Once an individual develops symptoms concerning COVID-19, further preventative measures to identify positive cases, and stifle transmission, are necessary. Prescreening, contact tracing, and quarantine are all components to further prevent confirmed positive cases in spreading the disease.

2.2.1 Screening Screening may not identify asymptomatic or presymptomatic patients; however, it remains a critical strategy in identifying individuals who could have COVID-19, thus allowing for appropriate implementation of safety precautions upon any in-­ person meeting. Patients coming in for in-person appointments that they have scheduled ahead should be screened for previous exposure or SARS-CoV-2 infection. A pre-appointment screening phone call or preadmission electronic documentation should include questions such as [6]: • Have you had any symptoms of COVID-19 (fever, chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea, vomiting, diarrhea) within the 10 days prior to your appointment? • Have you been diagnosed with SARS-CoV-2 infection within the past 10 days prior to your appointment? • Have you been in close contact with someone with suspected or confirmed SARS-CoV-2 infection within 14 days prior to your scheduled appointment?

24

E. A. Ingebretson

If patients can answer yes to any of these, they should reschedule their appointment or opt for telehealth visits if their needs are appropriate for this level of care. Additionally, if they are being screened on admission to a hospital, they should be placed in a single room and HCP should apply contact and droplet precautions until a test result can be obtained [30]. Reported fever can be measured as a temperature (greater than or equal to 100F) or recorded as a subjective fever. People may not subjectively feel a fever at lower thresholds, so they should be encouraged to actively measure their temperature at home or have their temperature taken upon arrival to the facility. Personnel in charge of screening should be aware of factors contributing to obtaining a reliable temperature measurement, such as ambient environment temperature, proper calibration of the thermometers, and proper usage and reading of the thermometers. Noncontact infrared thermometers have become popular during the COVID-19 pandemic due to their speed of measurement and contact-free delivery; however, it is important to follow the manufacturer instructions for use to ensure accurate readings are obtained. Location of the measurement taken and distance from that location are critical factors in obtaining true temperatures. Entrances and other points of entry into facilities should be limited to ensure all persons entering are appropriately screened and receive education on basic prevention measures. Healthcare facilities that cannot implement virtual screening methods such as pre-visitation phone screening should ensure a process is in place to screen all visitors, patients, and employees immediately upon entrance. Examples of these processes include individual screening by trained personnel and electronic monitoring systems in which employees report exposure and symptoms prior to arrival to the facility [31]. Anyone who does not pass the pre-entrance screening should be managed appropriately. Facility employees should not be allowed to enter and should be directed to their occupational health department for further instruction. Visitors should be restricted from entrance and referred to their PCP for further direction and evaluation. Patients should be placed in proper isolation or directed to waiting areas with appropriate transmission precautions in place. Symptom screening prior to facility entrance should be performed daily. Visitors and patient-facing facility personnel run the risk of carrying SARS-CoV-2 asymptomatically, so patients should be reevaluated for signs and symptoms of COVID-19 daily, even if staying more than 1 day, and further testing and isolation precautions implemented if assessment is consistent with COVID-19 [32]. Facilities may consider performing SARS-CoV-2 testing on all patients entering the facility for care, regardless of the presence or absence of symptoms or vaccination status, in order to identify asymptomatic or presymptomatic infection and apply transmission-based precautions in a timely fashion. This type of screening may be guided by the availability of tests and ease of processing results. The CDC recommends testing patients prior to admission to a healthcare facility and prior to elective procedures in order to reduce potential exposure of healthcare providers to SARS-­CoV-­2 [33].

2  Prevention and Infection Control

25

2.2.2 Contact Tracing Both the WHO and the CDC recommend contact tracing and self-isolation or quarantine as a method of prevention and identification of potential disease spread [34, 35]. Contact tracing is a method of breaking the chain of transmission of a disease. Studies early in the COVID-19 pandemic revealed patterns of spread in which clusters of infection developed among individuals in close contact with each other [36, 37]. Within a healthcare facility, proper contact tracing requires employees, patients, and visitors to provide information concerning their potential positive testing results in order for close contacts to be notified to monitor for symptoms and quarantine themselves, if needed. Transparency and accountability are key in implementing this method of infection control. Notification of potential exposures should be performed under the regulatory guidance of health information governing bodies in order to preserve the privacy of involved parties. If the resources are available, healthcare facilities should establish a contact tracing team to perform appropriate outreach to anyone entering the facility who has been in close contact to a confirmed case of COVID-19. Questions from the contact tracer should include those about the closeness of the contact, the timing on the infected individual’s symptom onset or positive test, in the case of asymptomatic individuals, and the use of PPE from both parties. In a large contact tracing study in Taiwan, contacts with a high-risk exposure did not develop infection if the exposure occurred 6 or more days after the infected person’s onset of infection [38]. Depending on the responses of the potentially exposed parties, testing and quarantine may be warranted. Contact tracers should be able to refer interviewees to appropriate testing or isolation guidelines, as well as appropriate healthcare follow-up.

2.2.3 Quarantine Isolation, or quarantine, was and is currently applied to those with active infection, as well as those in close contact with potentially infectious individuals. Though contact tracing and quarantine can be difficult due to the slightly variable time in which an infected individual begins to transmit live, active virus, it is a critical step in breaking chains of transmission [34]. Early in the COVID-19 pandemic, it became highly evident that asymptomatic and presymptomatic SARS-CoV-2-­infected individuals were able to transmit the virus to others. Somewhere between 20–40% of infected individuals are found to be able to transmit the virus before symptoms develop [39]. Because this virus has the potential to present as asymptomatic disease, quarantine following an exposure to a laboratory-confirmed positive contact is essential in decreasing the spread of the virus. The World Health Organization (WHO) encourages quarantine of close contacts because, by doing so, “potential secondary cases will already be separated from others before they develop symptoms or they start shedding virus if they are infected, thus preventing the opportunity for further onward spread” [40]. The CDC defines

26

E. A. Ingebretson

a close contact as any person within 6 ft of a person with confirmed or probable COVID-19 for 15 or more minutes over 24-h without appropriate source control [1]. Quarantine guidance for the general public is based on time from last contact and symptom progression. Close contacts should quarantine themselves for 14 days after the exposure, according to the WHO [41]. If symptoms develop, laboratory testing should be completed to determine the person’s COVID-19 status. If that test reveals a positive result, the person should continue to isolate themselves for a total of 10 days from their symptom onset, plus an additional 3 days after symptoms have ended [41]. Fourteen days of quarantine can be a daunting and impossible request for some populations, particularly the working class, therefore dissuading them from responding honestly to a contact tracer. For those who do not have access to testing, the CDC recommends a full 14 days of quarantine after an exposure; however, the risk of transmission post-quarantine is only from 1–10% if the individual only quarantines for a total of 10  days barring the development of symptoms [42]. If testing is readily available to the exposed individual and the individual is symptom free, the CDC allows for ending quarantine after day seven, given a negative test was obtained 48 h prior to the end of the 7-day quarantine. Using the 7-day strategy, the CDC reports an estimated risk of transmission of 5–12% [42]. Regardless of the application of the abbreviated 7-day quarantine, continued symptom monitoring and masking through day 14 should be performed to capture the small percentage of cases that may develop further than 7 days after exposure. This is because research has shown that the incubation period of SARS-CoV-2 is an average of 5–6 days, but can be as long as 14 days [43, 44]. Incubation period is the time between exposure to the virus and symptom onset. Infected Healthcare Professionals (HCPs) are recommended, by the CDC, to abide by a symptom-based method, rather than testing-based, to determine when it is acceptable for them to return to work, because prolonged quarantine time may place significant burden on the availability of staff in healthcare facilities, particularly at times of high viral spread, such as a pandemic [45]. Following a suspected or confirmed diagnosis of COVID-19, symptomatic HCP are separated into three groups of severity of illness. HCP with mild to moderate illness who are not severely immunocompromised can return to work if they fulfill three criteria as follows [46]: • Ten days have passed since the first appearance of symptoms. • Twenty-four hours have passed since their last fever, without the use of antipyretic medications. • Symptoms have improved. Asymptomatic, laboratory-tested positive HCP who are not severely immunocompromised can return to work if 10  days have passed since their first positive viral diagnostic test [46]. Testing is recommended to occur no earlier than 2 days after the exposure. HCP with severe to critical illness, or who are severely immunocompromised, are cleared to return to work if the same criteria as those with mild to moderate illness are true; however, the CDC recommends considering consultation

2  Prevention and Infection Control

27

with infection control experts for further guidance in this population, and the HCP may wait up to 20 days since their first symptoms appeared to return to work [46]. There is a chance that this severely immunocompromised population may produce replication-competent (meaning the virus is still viable) virus beyond even 20 days after symptom onset [46]. In these cases, with the guidance of an infectious disease expert, a testing-based strategy for when to return to work may be appropriate. The following are the criteria for symptomatic HCP to return to work using the test-­ based strategy [46]: • Resolution of a fever without the use of antipyretics and. • Improvement/resolution of symptoms. • Negative tests from at least two consecutive respiratory specimens collected at least 24 h apart. Asymptomatic HCP should have negative results from at least two consecutive viral diagnostic tests that are collected at least 24 h apart. The testing is not recommended earlier than 2 days after exposure, and if negative, again 5–7 days after the exposure [46]. If HCP have recovered from SARS-CoV-2 infection within the past 90  days, it is possible that some individuals may no longer be infectious while still having detectable virus from their prior infection [47]. This is a limitation to the application of a testing-based strategy for returning to work and ending isolation or quarantine and will be discussed later in the chapter under Ending Isolation Precautions at the Hospital. Table 2.1 is a simplified chart developed by the CDC to guide HCP on returnto-­work timing after a close contact exposure to an individual infected with SARS-­ CoV-­2 [46]: Previously Infected Individuals with Subsequent Exposures to someone with suspected or confirmed COVID-19 do not require repeat testing or quarantine for SARS-CoV-2 in the context of the new exposure if they fulfill the following criteria [48]: • Has recovered from viral test-confirmed infection and has already met criteria to end isolation and. • Is within the first 90 days following the onset of symptoms or their first positive SARS-CoV-2 viral test if they were asymptomatic and. • Is asymptomatic since the new exposure. If they meet the first two criteria but have developed new symptoms consistent with COVID-19 within 14 days of the new exposure, and an alternative cause of the symptoms cannot be readily identified, retesting for SARS-CoV-2 infection may be warranted [48]. If reinfection with SARS-CoV-2 cannot be ruled out, the person should be isolated as recommended above. Please refer to the section concerning isolation later in this chapter for discussion on when to end isolation precautions in COVID-19 patient cases.

28

E. A. Ingebretson

Table 2.1  Return to work timing after close contact exposure to COVID-19 Exposure Higher-risk: HCP who had prolonged close contact with a patient, visitor, or HCP with confirmed SARS-CoV-2 infection

Lower risk: HCP other than those with exposure risk described above

2.3

Personal protective equipment used HCP not wearing a respirator or facemask HCP not wearing eye protection if the person with SARS-CoV-2 infection was not wearing a cloth mask or facemask HCP not wearing all recommended PPE (i.e., gown, gloves, eye protection, respirator) while performing an aerosol-generating procedure N/A

Work restrictions for unvaccinated HCP Exclude from work for 14 days after last exposure Perform SARS-CoV-2 testing immediately (but not earlier than 2 days after the exposure) and, if negative, again 5–7 days after the exposure. Advise HCP to monitor themselves for fever or symptoms consistent with COVID-19 Any HCP who develops fever or symptoms consistent with COVID-19 should immediately contact their established point of contact (e.g., occupational health program) to arrange for medical evaluation and testing No work restrictions or testing Follow all recommended infection prevention and control practices, including monitoring themselves for fever or symptoms consistent with COVID-19 and not reporting to work when ill. Any HCP who develops fever or symptoms consistent with COVID-19 should immediately self-isolate and contact their established point of contact (e.g., occupational health program) to arrange for medical evaluation and testing

I nfection Control and Prevention in COVID-­ 19-­Positive Patients

There are various concerns when caring for patients with COVID-19. They all revolve around how to minimize the risk of transmission from the patient to those caring for and in the vicinity of the patient. This section of the chapter will discuss various types of PPE and when it should be applied, as well as patient isolation precautions to be instituted upon a patient testing positive for SARS-CoV-2 and when to end them.

2.3.1 Personal Protective Equipment When caring for a patient infected with SARS-CoV-2, HCP and other healthcare facility employees must protect themselves from the virus by applying personal protective equipment (PPE). The WHO and CDC both recommend implementing droplet and contact precautions when caring for COVID-19 patients and airborne

2  Prevention and Infection Control

29

precautions when there are aerosol generating procedures being performed [32]. Their recommendations are consistent with other national and international guidelines, such as those developed by the European Society of Intensive Care Medicine and Society of Critical Care Medicine [49] and by the Infectious Diseases Society of America [50]. Along with maintaining droplet and contact precautions when directly caring for patients with active COVID-19 infections, the WHO advises that health workers and caregivers in clinical areas should wear a medical mask for all activities and throughout the entire shift [13]. Additionally, the WHO recommends where aerosol-generating procedures are performed, HCP should wear a particle respirator. Other countries’ public health organizations, including the CDC [7] and the European Centre for Disease Prevention and Control, [51] recommend continuous N95 respirator use for any situation involving the direct care of COVID-19 patients. However, these organizations also state medical masks are an acceptable option in case of shortages of respirators. If scenarios exist in which PPE must be reused, facilities should develop maintenance policies and procedures for this, as recommended by their national public health entities. General recommendations for how to manage PPE shortages are contained in subsequent sections. Prior to PPE use, healthcare professionals should be trained and demonstrate full understanding of when to use PPE, what types of PPE are necessary for different situations, how to appropriately don and doff PPE, how to dispose of PPE appropriately, and the limitations of various types of PPE.

2.3.1.1 Masks and Respirators Masks and respirators are equipment used by the healthcare facility employee, visitors to the facility, and the patients, when possible, to reduce the risk of transmission of SARS-CoV-2. If healthcare providers are working in areas with high rates of infection, it is recommended that they consider wearing the same mask their entire shift in order to reduce the number of times the healthcare provider must touch their face and risk potential self-contamination [7]. Surgical or medical masks are recommended over cloth masks in areas of patient care because they are disposable unless they are unavailable due to shortages. If cloth masks are necessary, they should be well-fitted to the wearer, made with tightly woven, breathable fabric such as cotton, and have at least two layers of fabric [14]. Respirators provide the highest level of protection against inhalation of infectious respiratory particles in the air. If a patient has a suspected or confirmed diagnosis of COVID-19, the CDC recommends that all patient-facing personnel working with or near these patients should be provided N95 respirators or equivalent high-­level respirators for use [7]. N95s or an equivalent high-level respirator should be used for any procedure that may generate aerosolized respiratory particles, regardless of the patient’s confirmed COVID-19 status. Aerosol producing procedures include the following: open suctioning of airways, cardiopulmonary resuscitation (CPR), endotracheal intubation and extubation, non-invasive ventilation such as bilevel positive airway pressure (BiPAP) and continuous positive airway pressure (CPAP) machine use, bronchoscopies, high-flow nasal cannula device use, manual ventilation with

30

E. A. Ingebretson

bag-valve masks, and sputum induction for sampling [52]. They should also be used in any surgical procedure that may pose a higher risk for transmission, particularly when anatomic regions such as the nose, throat, or respiratory tract are involved. These respirators should also be used by healthcare personnel who are providing care in areas of substantial community transmission, as they are more likely to encounter asymptomatic or presymptomatic patients with active COVID-19. Types of respirators vary, but the filtration concept is the same across all types. Respirators are a type of personal protective equipment that covers at least the mouth and nose and filters hazardous airborne particles as air passes through the device and into the wearer’s respiratory system. They must be worn throughout the period of exposure to fully protect the wearer. Appropriate use of respirators requires training, fit testing, and medical clearance for use. If preparing to utilize reusable respirators, the facility should also provide cleaning, disinfecting, inspection, repair, and storage of the devices as recommended by the manufacturer. Powered Air-Purifying Respirators (PAPRs) are battery-powered air filtration systems that are worn as a full facepiece with the battery pack worn on the back or waist. The filtration system pulls air from the atmosphere through a filter and into the sealed mask, providing filtered air to the wearer. They are reusable and should be disinfected between uses per manufacturing recommendations [53]. Elastomeric Respirators are a type of reusable respirator that provide at least the same level of filtering protection as an N95 respirator. Some provide a higher level of filtration than even an N95. This respirator facepiece is made of rubber or a synthetic material that is easily disinfected for storage and reuse. They come in half and full-face coverage. They are equipped with replaceable filters. The filter itself cannot be removed and decontaminated, but rather must be discarded when it becomes damaged, soiled, or clogged [54]. N95 Respirators are a type of filtering facepiece respirator that are named as such due to their ability to filter 95% of airborne particulate matter [55]. They are the most common type of respirator and are designed to create a tight seal around the wearer’s nose and mouth. This sealed fit precludes the use of these respirators by personnel with facial hair that prevents a seal from being present. Breathing through N95s can require more effort, so some have been designed with an exhalation valve to allow for easier breathing. It should be noted that this type of valved mask should not be used in sterile procedures, nor as transmission-based precautions for COVID-19, as they may allow the respiratory particulate from the wearer to escape the mask [56]. Surgical N95 respirators are cleared by the FDA to be “single-use”, disposable items and should be discarded if they are damaged, soiled, or if breathing becomes difficult. The respirators should be discarded appropriately. This means removing them without touching soiled portions of the mask to your face, placing them in a plastic bag, and finally disposing of them. Hand hygiene should always be performed afterward prior to further patient care or contact with anything else [57]. The single-use aspect of these respirators may require modification in situations in which supply shortages exist.

2  Prevention and Infection Control

31

2.3.1.2 Eye Protection Goggles, safety glasses, face shields, and other protective eyewear are an important part of PPE due to the risk of droplets contacting and infecting the exposed mucous membranes of the eyes [32]. Eyewear should not interfere with the proper fit of respirators and should be removed and disinfected after exiting patient care areas, unless they are being utilized for extended periods of time. 2.3.1.3 Gloves Using gloves is recommended by the CDC and WHO in the setting of SARS-CoV-2 infections [32, 58]. They should be removed prior to leaving patient care areas and hand hygiene should be performed immediately after removal and after exiting the patient care area. Gloves do not need to be sterile unless performing sterile procedures in the setting of the care of patients with COVID-19. 2.3.1.4 Gowns Fluid-resistant isolation gowns should be utilized in the care of patients with COVID-19 to prevent the spread of SARS-CoV-2 from room to room on healthcare professional’s personal garments [32, 58]. They should be applied prior to entering patient care areas and prior to exiting the area. If disposable, disposal should be performed according to the healthcare facilities guidelines. If reusable, they should be contained in an appropriately designated container and laundered according to local or national public health guidelines.

2.3.2 Isolation Guidelines As discussed in the prior section, patients positive for SARS-CoV-2 infection or who have high suspicion of infection, as noted during the screening process, should be placed on contact and droplet precautions. This means anyone entering the room should don a face mask or respirator, gloves, a fluid-resistant gown, and eye protection [32]. If available to the facility, and depending on the level of transmission in the community, facilities should consider designating a separate area, unit, or temporary structure in which patients presenting with symptoms concerning for COVID-19 can be evaluated and receive care.

2.3.2.1 Ending Isolation Precautions at the Hospital Patients with COVID-19 should be kept on isolation precautions while at a healthcare facility or during home health care until deemed safe to remove them. The CDC makes their recommendations on terminating isolation based on disease severity classification as well as immunocompetency as defined by the National Institutes of Health [58, 59]. Mild To Moderate Illness or Asymptomatic patients, neither severely immunocompromised, should remain on isolation precautions until they are at least 10 days past their first appearance of symptoms and first positive viral diagnostic test, at

32

E. A. Ingebretson

least 24 h after their last fever without the use of antipyretics, and until their symptoms have improved [58]. Severe To Critical Illness and severely immunocompromised patients should remain on isolation precautions for at least 10 days and up to 20 days after the first appearance of symptoms, at least 24  h after their last fever without use of antipyretics, and after symptoms have begun to improve. For this patient population, the CDC recommends considering consultation with infectious disease specialists for guidance. According to studies from Korea, some recovered patients can continue to have detectable levels of SARS-CoV-2 RNA in their upper respiratory systems for up to 12 weeks after symptom onset; however, they were unable to isolate replication-­competent virus in just under half of those sampled [60]. It is unlikely that these patients will shed replication-competent virus for longer than 20  days after their initial symptom presentation; however, some studies have shown that severely immunocompromised patients may produce replication-competent virus beyond 20 days after symptom onset, or in asymptomatic carriers, the date of their first positive viral test [61, 62]. The WHO makes its recommendations on when to discontinue isolation on patients with COVID-19 based on symptom timing. Early in the pandemic, they recommended obtaining two negative PCR tests at least 24 h apart; however, this option is difficult in areas with limited resources, but is still used by some countries [63]. Their new recommendations are as follows [63]: • Symptomatic patients can be removed from isolation or quarantine 10 days after symptom onset, plus at least 3 additional days without symptoms, such as fever and respiratory symptoms. • Asymptomatic patients can be removed from isolation or quarantine 10  days after their first positive viral test for SARS-CoV-2. Of note, per the CDC, meeting the criteria for discontinuation of transmission-­ based isolation in the hospital is not a prerequisite to discharge home.

2.3.2.2 Prevention and Isolation for Home Care Those persons who were triaged to remain at home for home care during a SARS-­ CoV-­2 infection should continue to follow isolation guidelines as outlined above. If possible, they should remain in a bedroom that is isolated from other members of the household until isolation is discontinued. Additionally, they should attempt to isolate the use of a bathroom for only the infected individual’s use; however, if there is not a separate bathroom for this use, then care should be taken to disinfect the bathroom after each use. Caregivers and infected individuals are encouraged to each don a face mask and maintain excellent hand hygiene during contact time and contact time should be minimized as much as possible. If there are members of the household who are at increased risk of severe illness from COVID-19 (i.e., those with comorbid conditions, immunocompromised individuals, those over the age of 65 years), they should not take care of household members who have COVID-19

2  Prevention and Infection Control

33

and isolation from each other should be maintained as strictly as possible [64]. As discussed previously, for individuals with mild to moderate or asymptomatic infection, isolation and precautions can be discontinued 10 days after symptom onset or first positive viral test and after resolution of fever for at least 24 h without the use of antipyretic medications, and with improvement of other symptoms. Employees of home healthcare organizations should abide by the same prevention and isolation strategies as those recommended for healthcare facilities when caring for COVID-19 patients in their homes. Home healthcare organizations should provide all necessary PPE for safe healthcare administration by their employees.

2.3.3 Optimization of PPE During Times of Shortages Facilities should have thorough inventory of their PPE and understand their supply chain and utilization rate in order to maintain optimal availability of PPE for a safe work environment for their employees. Optimizing Prevention Strategies that were discussed previously in the chapter to reduce transmission rates within the healthcare facility is the first step. Optimize ventilation as discussed previously in the chapter with directional air flow using negative-pressure rooms or fans. Air should flow from clean to contaminated, along with appropriate filtration and exchange rates. Negative-pressure rooms (airborne infection isolation rooms) should be prioritized for patients with COVID-19 who are undergoing aerosol generating procedures or are on machinery that increases the production of respiratory aerosols. Room transfers should be minimized to reduce the transmission of the pathogen in the halls and from room to room. Room doors are to be kept closed except when entering or exiting the room and these times should be minimized, so clustered care is recommended. Curtains may be used as a physical barrier between patients in shared areas. Closed suctioning systems for airway suctioning for intubated patients maintain respiratory droplets within the ventilator circuit. Continue strict source control use with face masks or respirators to prevent the spread of respiratory droplets when talking, sneezing, or coughing, even if no symptoms of COVID-19 are present [65]. Limit Patients and Visitors going to the hospital and outpatient settings by implementing telemedicine visits, phone triage, and virtual visitation whenever possible. The CDC recommends home care, if possible, for patients with minimal symptoms, in order to reduce potential exposure within the healthcare facility and to optimize resource allocation at times when transmission rates are high and hospitals have reduced capacity [65]. Limit visitors to those essential for patients’ physical and emotional well-being. Encourage alternative communication such as video-call applications on cell phones or tablets. Postpone and reschedule appointments for non-acute visits for patients with signs and symptoms of COVID-19 or exposures as identified in phone or online screening tools. Nurse advice lines and telemedicine can reduce the need for face-to-face visits and help triage clients to the appropriate level of care, thus reducing hospitalized patients with suspected or confirmed

34

E. A. Ingebretson

SARS-CoV-2 infection or those with close contact with infected persons. By taking these actions, healthcare facilities may be able to optimize their PPE for when it is needed [65]. Encourage Essential Personnel Only to enter patient care areas with SARS-­ CoV-­2-infected individuals, in order to reduce the number of people requiring PPE [65]. Limiting face-to-face exposure by utilizing methods such as bundling or clustering care to minimize room entry and using video-call applications, telephones, or video monitoring when appropriate can also reduce PPE use. Cohort patients and/or HCP by grouping patients infected with the same organism to confine their care to one area and prevent contact with other patients and multiple HCPs. This strategy has been used as a tactic to manage outbreaks of multidrug-­resistant organisms in the past with success [66]. Cohorts are created based on clinical diagnosis and microbiologic confirmation when available, as well as mode of transmission and epidemiology. When single patient rooms are not available, it may minimize respirator use by HCPs to group patients with confirmed SARS-CoV-2 infection in the same room. If extended wear of respirators is implemented, assigning designated teams of HCPs to provide care for patients with suspected or confirmed SARS-CoV-2 infection could minimize respirator use and exposed HCPs [67]. Patients with confirmed SARS-CoV-2 infection should be contained in single patient rooms if available. If space is limited, patients with the same respiratory pathogen can stay in the same room. The facility should attempt to cohort patients to certain units and keep staffing contained to that patient population for their shift if at all possible [67]. This also reduces respirator and PPE use, as the staff for these units become more adept at protective equipment use and conservation. Attempts should be made to limit patient movement outside of their rooms for testing and procedures. If available to the facility, these should be performed in the room. Administrative Controls, such as decreasing the length of hospital stay for medically stable patients with an infectious diagnosis requiring respirator or PPE use can be another measure to reduce use. Suspected or confirmed SARS-CoV-2-infected patients should be discharged when they are medically stable and have an appropriate home environment to which to return. Respirators should be limited during training and fit testing, and facilities should consider implementing qualitative fit testing to decrease mask loss due to destruction (hole in mask) required during quantitative testing [67]. Qualitative testing also allows for more rapid fit testing of larger numbers of HCP.

2.3.4 Postmortem Guidance Upon the death of an individual from laboratory-confirmed COVID-19, the local health department should be notified to ensure appropriate documentation and specimen collection are completed. When preparing the remains of an expired patient, PPE should be applied as previously discussed in the care of COVID-19-positive patients. Particular care should be taken in the donning of adequate PPE if there is

2  Prevention and Infection Control

35

concern for splashing of fluids. Standard body bagging procedures as recommended by each healthcare facility should be followed; however, prudent judgement should be applied when determining if there is risk for puncture or tearing of the body bag and whether a second body bag should be used. Disinfectants that meet the criteria for use against SARS-CoV-2 should be applied to the outside of the body bag after the body has been bagged [68].

2.4

Testing

The process of testing individuals is thoroughly detailed by both the CDC and WHO [69]. Testing should occur in areas with closed doors. Proper PPE should be donned to protect the tester in case the patient is actively infected with SARS-CoV-2. The number of HCP and visitors in the room should be limited to reduce the number of people exposed. After testing, the room should be sterilized as recommended by local or national public health standards. If testing is not available nationally, testing should be referred to WHO-designated laboratories. Anyone with any symptoms of COVID-19 should be tested for SARS-CoV-19, regardless of vaccination status. Vaccination status shouldn’t affect the results of viral testing. People being tested for COVID-19 should be made aware of results as soon as possible and educated on what the results mean and how to proceed. If someone declines to be tested, and they show signs and symptoms of active COVID-19 or have had a high-risk exposure to the virus, they should be advised to quarantine for the aforementioned timeframe in order to reduce risk of transmission as much as possible. Upper respiratory samples are preferred for ambulatory patients and lower respiratory samples produced by endotracheal aspirate or bronchoalveolar lavage should be used in patients admitted to healthcare facilities with more severe respiratory disease (taking appropriate precautions for procedures producing aerosols) [70]. If a negative test is obtained via upper respiratory sampling in a person with a high index of suspicion for the disease, the WHO recommends verifying it with additional lower respiratory sampling, if possible. A negative test in someone without symptoms and no known exposure to the disease suggests a lack of infection, whereas positive viral diagnostic test results in a person with signs and symptoms consistent with COVID-19 would indicate that the person has the disease. Symptomatic individuals with a negative antigen test result should have confirmative testing done using nucleic acid amplification testing (NAAT), or if the initial test was NAAT of the upper respiratory system, the WHO recommends confirming with a NAAT of the lower respiratory system if possible. NAAT will be discussed below.

2.4.1 Categories of Tests There are two categories of tests which provide different levels of sensitivity in detecting SARS-CoV-2: viral tests and antibody tests. Viral tests search for

36

E. A. Ingebretson

portions of the virus in the sample taken from the patient, while antibody tests reveal if the patient has developed an immune response to the virus, indicating that there is either active or previous infection. These tests can be completed for two reasons: diagnostic testing and screening testing. Diagnostic testing is performed to determine if people with symptoms consistent with COVID-19, whether vaccinated or not, are actively infected. Diagnostic testing is also performed as a method of contact tracing, to diagnose individuals who have been exposed to the virus and require confirmation of transmission. Screening is performed to ensure unvaccinated employees, visitors, or patients are free from asymptomatic SARSCoV-2 infection [69]. An important aspect of testing is understanding the sensitivity and specificity of the tests being applied. These markers show whether a test is effective at producing a result that can be trusted. Sensitivity is the ability of a test to detect false-negative results. For example, a test that is very sensitive produces very few false-negative results. Specificity is the ability of a test to detect false-positive results. For example, a test that is specific has few false-positive results.

2.4.1.1 Viral Tests These tests detect active infection with SARS-CoV-2, by identifying portions of the virus that are present in the host, such as an antigen or viral ribonucleic acid (RNA). An antigen is a part of a pathogen that is recognized as foreign by the host’s immune cells, thus triggering a reaction to remove the antigen and its associated pathogen from the body. Viral RNA is the instruction by which viruses replicate and is contained in the body of a virus. It is important to understand the significance of time with viral testing. Negative test results simply define the negativity of the person’s COVID-19 status at the time of testing. If a person is tested too early, there may not be enough replicated virus to produce a positive test. Unvaccinated people who have a negative test are recommended by the CDC to quarantine for 14 days after the exposure or symptom onset or 7 days if no symptoms have been reported in daily monitoring and they have a negative viral test within the past 48  h [69]. Those fully vaccinated, who have had a confirmed or suspected exposure to someone with suspected or confirmed COVID-19, “should be tested three to five days after exposure and are to wear a mask in public indoor settings for 14 days or until they receive a negative test result” [71]. Nucleic Acid Amplification Testing (NAAT) is highly specific and sensitive and is performed on samples from the respiratory system, such as nasopharyngeal or saliva. It is a test for viral ribonucleic acid (RNA) to detect active or recently active infection. Research has recently shown that people, who have had an infection with SARS-CoV-2, are no longer symptomatic, and have passed the recommended quarantine time, may still test positive using this type of testing. At this state, the person may still be shedding the virus, but that virus is unlikely to be able to produce an infection by way of replication in the next person [47]. Most of these tests must be processed in a laboratory and can take up to 3 days to result [69]. There are some over-the-counter NAATs that are currently available and can result in 15–45 min.

2  Prevention and Infection Control

37

Antigen tests detect the presence of a very specific part of the virus, such as the protein spike on the outside of the virus. They are similarly specific, but less sensitive than most NAATs. These tests are often less expensive and provide faster results (within minutes) than NAATs. For this reason, they are good tests for screening applications to identify those who are likely to be contagious. Because of the lower sensitivity of these tests, they are not always reliable in ruling out infection, so if a patient is persistently symptomatic and had a negative antigen test, or if someone is asymptomatic and had a positive antigen test, it is recommended by the CDC to perform confirmatory NAAT [69].

2.4.1.2 Antibody Tests An antibody is a particle that the body’s immune system produces that recognizes specific antigens in an effort to tag them for removal or destruction. The body produces different types of antibodies, some lasting for years and some only lasting a couple weeks to months. Vaccination status may affect the results of this type of test. Because vaccinations utilize portions of the spike protein of the virus to generate an immune response in the form of antibody production, both previously exposed and COVID-19-vaccinated individuals can have positive antibody tests [69]. As of October 2021, research has revealed two antigens, or proteins, that are essential to SARS-CoV-2 function and are used for current antibody testing: the S protein and the N protein. The S protein has multiple forms, while the N protein is more conserved across all coronaviruses [72]. Current vaccines available for administration induce the antibodies to the S protein. Therefore, “the presence of antibodies to N protein indicates previous infection regardless of a person’s vaccination status, while presence of antibodies to S protein indicates either previous infection or vaccination” [72]. These tests shouldn’t be used to diagnose active or current infection in people, because the test may be administered prior to when the person mounts an immune response to the virus, and the tests may return positive in individuals who are no longer able to transmit the virus. However, they may be useful in helping to determine the etiology of complications arising from a previous SARS-CoV-2 infection, such as multisystem inflammatory syndrome, because they can reveal previous infection with the virus [72].

2.4.2 Administering Tests Testing is performed on both respiratory secretions and blood, depending on the type of test being administered. Respiratory secretions can be obtained by either the upper or lower respiratory tract and blood samples are obtained through peripheral venipuncture or capillary finger stick sampling. Upper Respiratory Tract samples are obtained from the nasopharynx or oropharynx. Nasopharyngeal is the preferred testing method for upper respiratory specimens, but the oropharyngeal route is acceptable if nasopharyngeal is not attainable. Only synthetic fiber swabs with plastic or wire shafts designed for sampling

38

E. A. Ingebretson

nasopharyngeal mucosa should be used for this type of testing, as wooden shafts or other varieties of swabs may contain substances that inactivate some viruses and can inhibit molecular tests [73]. The steps for collection are as follows [73]: • Tilt patient’s head back to 70°. • Gently insert the swab, holding the end of the shaft, through the nostril, parallel to the palate (not upwards) until resistance is encountered or the distance is equivalent to that of the ear to the nostril of the patient. • Gently roll the swab in that location and leave swab in place for several second to absorb secretions. • Remove the swab slowly while rotating it. • Both nostrils may be tested using the same swab if the swab is not saturated with fluid after the first nostril collection. • Place the swab, tip first, into the transport tube provided with the swab. • In the case of oropharyngeal testing, the swab should be inserted into the posterior pharynx and tonsillar areas, then rubbed over both tonsillar pillars and posterior oropharynx, while avoiding contact with the tongue, teeth, and gums. Lower Respiratory Tract samples are obtained through bronchoalveolar lavage, tracheal aspirate, pleural fluid, or lung biopsy. These specimens should only be collected on patients presenting with more severe disease, due to the technical skill and potential aerosol prevention equipment necessary [73]. For a sputum sample, the patient should be educated on the difference between a deep cough sputum sample and an oral secretions saliva sample. The patient should be guided to rinse their mouth with water and then practice a deep cough and expectorate the sputum directly into a sterile container, taking care not to scrape their mouth or tongue on the container to free the sputum from their mouth [73]. Two to three milliliters of fluid should be collected into a sterile, leak-proof, screw-cap collection cup or other type of sterile, dry container [73]. Antibody Tests are performed on blood samples, which should be obtained according to the test manufacturer’s recommendations and by a trained professional. Blood may be obtained by venipuncture or by capillary fingerstick.

2.4.3 Screening Testing can be used as a screening tool to reduce asymptomatic and presymptomatic transmission of SARS-CoV-2, as well as to monitor trends in infection rates in areas. The CDC states, “Serial testing of unvaccinated persons, regardless of signs or symptoms, is a key component to a layered approach to preventing the transmission of SARS-CoV-2. Screening allows early identification and isolation of persons who are asymptomatic, presymptomatic, or have only mild symptoms and who might be unknowingly transmitting virus” [69]. Point of care antigen tests may play an important role in this screening strategy, because of low cost and fast turnaround time. In these screening settings, a confirmatory NAAT is recommended

2  Prevention and Infection Control

39

in cases where the antigen test is positive, as the sensitivity of antigen tests is lower than that of the NAAT [69]. Frequent testing along with the basic prevention strategies mentioned previously in this chapter was shown to contribute to low COVID-19 case rates in university settings, according to a study by Bracis et al. [74]. For this reason, the CDC recommends testing one to two times per week for unvaccinated individuals working in healthcare facilities. This screening strategy implementation is best guided by the level of community transmission at the time. For example, during high levels of community transmission, unvaccinated individuals should be tested more frequently than during times of low community transmission [69]. At minimum, for unvaccinated individuals, screening testing should occur at least weekly during high community spread, because the incubation period for SARS-CoV-2 can be up to 14 days [69]. Those individuals undergoing asymptomatic, negative exposure screening testing do not need to isolate between tests and while waiting for results, but rather when their test is positive and they are awaiting the confirmatory NAAT results [69]. Viral testing is recommended for those who have been in close contact with individuals with COVID-19. The timing of this testing depends on vaccination status. For those who have been fully vaccinated, testing should occur 3–5 days after exposure [71]. For unvaccinated individuals with a known exposure, the CDC recommends immediate testing upon learning of the exposure. If that test is negative, the exposed individual should get tested again in 5–7 days, or immediately upon development of symptoms, if they develop [69]. Anyone exposed should abide by the quarantine recommendations discussed previously in this chapter. Most individuals who have a history test-confirmed COVID-19 do not need to retest within 90 days of the last positive test, due to the prolonged positivity that can occur, as reported by studies [60, 75]. This prolonged positivity does not mean that those individuals are able to spread replication-competent virus. Due to the occurrence of prolonged positivity in certain individuals, the CDC and WHO recommend a symptom-based, rather than testing-based strategy to determine the duration of quarantine or isolation, as previously discussed in this chapter [76].

2.4.4 Diagnosing Testing can also be performed as a diagnostic tool. People with signs and symptoms of SARS-CoV-2 infection should be tested. Negative test results using either NAAT or antigen testing in individuals without symptoms, but with a recent exposure, are evidence of no active infection; however, these results are highly dependent on the timing of the administered test [69]. Based on the time of specimen collection, the results could change, as viral load could be too low at the time of testing to be detected. If there is concern about the accuracy of an antigen test result, a confirmatory NAAT should be administered and considered definitive [69]. If a person is diagnosed with a SARS-CoV-2 infection, they should follow quarantine instructions as discussed previously in this chapter.

40

E. A. Ingebretson

Table 2.2  Application of NAATs versus antigen tests Intended Use Analyte detected Specimen types Sensitivity

Specificity Test complexity Turnaround time Cost/Test Advantages

Disadvantages

NAATs Detect current infection Viral ribonucleic acid (RNA)

Antigen tests Detect current infection Viral antigens

Nasal, nasopharyngeal, oropharyngeal, sputum, saliva Varies by test, but generally high for laboratory-based tests and moderate-­ high for point of care (POC) tests High Varies by test Most 1–3 days. Some could be rapid in 15 min. Moderate (~$75–$100/test) Most sensitive test method available. Short turnaround time for NAAT POC tests, but few available. Usually does not need to be repeated to confirm results.

Nasal, nasopharyngeal

Longer turnaround time for lab-based tests (1–3 days). Higher cost per test. A positive NAAT diagnostic test should not be repeated within 90 days, because people may continue to have detectable RNA after risk of transmission has passed.

Varies depending on the course of infection, but generally moderate-to-­ high at all times of peak viral load High Relatively easy to use Ranges from 15 min to 30 min. Low (~$5–$50/test) Short turnaround time (approximately 15 min). When performed at or near POC, allows for rapid identification of infected people, thus preventing further virus transmission in the community, workplace, etc. Comparable performance to NAATs in symptomatic persons and/or if culturable virus present when person is presumed to be infectious. May need confirmatory testing with NAATs. Less sensitive (more false-negative results) compared to NAATs, especially among asymptomatic people.

Table 2.2 was developed by the CDC, outlining screening and diagnostic testing and when to apply the different types of tests [69]:

2.5

Immunity

After exposure to the virus, or portions of the virus, the body produces a humoral immune response to fight the pathogen, eventually creating memory B-cells, which allow the body to more efficiently react and remove the virus from the body upon repeat infection [77]. Natural immunity is that acquired from exposure to the pathogen leading to active infection with the actual disease, rather than vaccine-induced immunity, which is acquired through exposure to inactive, antigenic portions of the pathogen that allow the body to mount an immune response without active infection

2  Prevention and Infection Control

41

and disease development [78]. In both forms of immunity, the body produces memory immune cells to allow for a more efficient immune response in the future, if the person is exposed to the pathogen again. Vaccines were created with the idea of memory immune cells in mind. They are made with some portion of inactivated virus that the body recognizes as foreign, creates antibodies against, then produces specific memory immune cells to prevent severe infection upon reexposure to the virus components in the form of actual virus in the future. Vaccinations are critical to controlling and preventing disease outbreaks. They prevent the vaccinated individual from developing the disease, thus reducing the risk of transmission. Vaccinations for SARS-CoV-2 were developed in late 2020 during the COVID-19 pandemic and utilized some of the most up to date vaccine technology developed at that time. According to the CDC, “from January through June 2021, COVID-NET data from laboratory-confirmed COVID-19-­ associated hospitalizations in adults ≥18 years of age, for whom vaccination status is known, showed 3% of hospitalizations occurred in fully vaccinated persons” [79]. Viruses are made of various components, the outer protein-coated body of the virus, which can be recognized by the host as an antigen, as well as messenger RNA (mRNA) on the inside of the virus, which carries the genetic code for replication [80, 81]. Previously, most of all vaccines contained either completely inactivated virus, weakened virus, or some key portion of the virus, such as the proteins that make up the outer body of the virus. However, the COVID-19 pandemic created an imminent opportunity to develop two new types of vaccine: mRNA containing and viral vector [82]. These vaccine varieties had been studied for decades prior to the COVID-19 pandemic and were finally applied to the development of SARS-CoV-2 vaccines. The benefit of these being their ability to be rapidly produced in a laboratory and on a larger scale than the previous types of vaccines [83]. Similar to other injectable vaccines, the COVID-19 vaccines are administered intramuscularly, commonly in the deltoid muscle of either arm. There are over 100 vaccines currently undergoing clinical and preclinical research. Russia developed their own adenovirus vector two-dose vaccine called Sputnik V and Sputnik Light that has not yet been approved by the WHO, while China has developed CoronaVac, an inactivated viral vaccine [84]. Others are in development in Iran, Kazakhstan, Uzbekistan, and India, among many other countries. The main CDC- and WHO-approved vaccines are discussed in the following section. All these vaccines should be applied for use as recommended by local public health authorities.

2.5.1 Messenger Ribonucleic Acid-Based Vaccines mRNA vaccines contain mRNA, in special vesicles, or capsules, that codes to produce an antigenic portion of the virus against which they are to be effective. These vesicles combine with the membrane of cells which contain their deoxyribonucleic acid (DNA) replicating machinery, thus emptying the mRNA contents of the vesicle into the cell and triggering that replication machinery to begin producing

42

E. A. Ingebretson

the antigenic protein of the virus encoded by the mRNA [83]. Once the mRNA produces the antigenic protein, it naturally degrades. The protein produced cannot cause an infection, but rather is the antigenic portion of the vaccine that allows the body to produce antibodies against, and thus memory immune cells. As of October of 2021, there are two mRNA-based vaccinations against SARS-­ CoV-­2: one produced by Pfizer and BioNTech, technically noted as BNT162B2, and one produced by Moderna, technically noted as mRNA-1273 [85, 86]. Both vaccines have been approved for administration by the CDC and the WHO.  The BNT162B2 vaccine, whose brand name is Comirnaty, is to be administered as two doses, at least 21 days apart. It is currently recommended by the CDC for people 12 years of age and older as of October 2021 [85]. The only population of people restricted from using these vaccines are those less than 12 years of age, as the vaccine is still under trials for clearance for this age group, and those who have severe allergic reactions to the vaccine or any ingredient in the vaccine. The Moderna mRNA-1273 vaccine is administered as two doses at least 28  days apart and is approved for people 18 years of age and older as of October 2021 [86]. Storage of these vaccines is one of the major obstacles for their worldwide administration. They must be stored in ultra-cold freezers that keep them at a range of temperatures from −90 degrees Celsius and −60 degrees Celsius, and only last 5 days for the Comirnaty vaccine and 30 days for the Moderna vaccine in the freezer [87, 88]. They are only viable after coming to room temperature in the unreconstituted state for 2 h [87, 88]. After reconstitution, they must be used in 6 h, or they are no longer effective [87, 88]. It is important that facilities preparing to administer these vaccines follow strict guidelines for storage, preparation, and administration, according to the manufacturer and local public health organizations, in order to reduce the risk of dose wasting. Efficacy of the mRNA vaccines was initially very high, but as time passed and the virus began to mutate, effectiveness began to wane. Initial efficacy of the Comirnaty vaccine against laboratory-confirmed infection with SARS-CoV-2 was determined to be 95% [89]. As time passed, at 6 months, clinical trials reported a decline in vaccine efficacy to 91.3% [90]. Similarly, vaccine effectiveness declined to 88%, as per a study conducted by Bernal and Andrews et al., as infection by new virus mutations, such as the delta variant, became more widespread [91]. Initial effectiveness in clinical trials of the mRNA-1273 vaccine at preventing laboratory-­confirmed COVID-19 infection was 94.1% [92]. With SARSCoV-2 mutating to different variants, such as the delta variant, further studies have shown that for both mRNA-based vaccines, effectiveness declines. One such study performed in a senior living facility showed that effectiveness for either mRNA vaccine was only 53.1% at preventing any infection, be it severe, mild, or asymptomatic [93]. Adverse Reactions of both mRNA-based vaccines include rare cases of myocarditis and pericarditis in young adults after the second dose. According to a study in Israel, this reaction occurred with the highest incidence in males, aged 16–29 years, and was mild or moderate in severity [94]. If an individual develops myocarditis or pericarditis after the first or second dose of the vaccine, experts are recommending

2  Prevention and Infection Control

43

deferring the second or subsequent doses until further safety data are available [95]. Among the less severe side effects of the vaccine are short-term pain, redness, and swelling at the injection site, as well as fatigue, headache, muscle aches, chills, fever, and nausea or vomiting which can occur a day or two after getting the vaccine [87, 88]. These generalized symptoms are considered “reactogenicity symptoms”, which are defined as side effects occurring within 7  days of getting vaccinated and are often signs that the body is mounting an immune response [87, 88]. These symptoms should resolve within a couple of days after symptom appearance. Lymphadenopathy of the neck and arm regions was reported by a smaller number of recipients in studies and developed 2–4 days after injection and endured for approximately 10 days [87, 88]. Serious events with the Comirnaty vaccine that resulted in hospitalization and death or were life-threatening were events such as appendicitis, acute myocardial infarction, and cerebrovascular accident. These events constituted 0.6% of the vaccine group and 0.5% of the placebo group in trials. Between the two groups, vaccinated and placebo, the rate of events was relatively balanced, and thus cannot be causally related to the vaccines [96]. Finally, a serious complication related to vaccine administration in general is shoulder injury related to improper location of vaccine administration, in which the vaccine is injected into the joint and causes pain and disability that require months of recovery [97].

2.5.2 Viral Vector The two main viral vector vaccines that have been approved by both the WHO and the CDC are the Ad26.COV2.S vaccine created by Janssen Pharmaceuticals (referred to as the Janssen vaccine for this section of the chapter) and the ChAdOx1 nCoV-2019 vaccine created jointly by AstraZeneca and the University of Oxford. These vaccines use different replication incompetent versions of the adenovirus that carries the DNA encoding for the creation of the spike protein antigen of the SARS-­ CoV-­2 [82]. The benefit of these vaccines over the mRNA-based vaccines is their ease of storage. The viral vector vaccines can be refrigerated for up to 3 months [98]. The Janssen vaccine also only requires one dose, while the Oxford/AstraZeneca vaccine requires two doses, like the mRNA-based vaccines. According to the CDC, the Janssen vaccine is approved for people 18  years and older, as is the Oxford/ AstraZeneca vaccine, which was approved by the WHO [99]. Efficacy of the Janssen vaccine is reported as 66.3% against symptomatic, laboratory-­confirmed COVID-19 at least 14  days after vaccination and 65.5% at least 28 days after vaccination. Efficacy against all-cause death was 75% [100]. The AstraZeneca vaccine has a reported efficacy of 72% against symptomatic SARS-­ CoV-­2 infection, according to WHO [99]. Longer dose intervals within the 4–12-­ week range of administration were associated with higher vaccine efficacy [99]. Some studies showed a higher level of neutralizing antibodies when the first dose of the AstraZeneca vaccine is followed by either Pfizer or Moderna vaccine. If this vaccine plan occurs, doses should be administered at least 14 days apart [99].

44

E. A. Ingebretson

Just as with the mRNA vaccines, efficacy of the viral vector vaccines dropped with the development of SARS-CoV-2 virus variants, such as the delta variant. The efficacy of the AstraZeneca vaccine against the delta variant of the virus reportedly decreased, in a study by Bernal and Andrews et al., from 74.5% to 67% [91]. Adverse Reactions after the Janssen vaccine include syncope, which reportedly occurred at a rate of eight in 100,000 doses of the vaccine. By comparison, the rate of fainting after the flu vaccine was 0.05 per 100,000 doses [101]. It is unclear what leads to this adverse event, but it is possibly related to anxiety surrounding the COVID-19 vaccine and could be related to preexisting fear of needles in those who chose to receive a one-dose vaccine over a two-dose vaccine. Similarly to the mRNA vaccines, reactogenicity symptoms can occur with the viral vector vaccines within 7 days of administration, resolving 2–3 days after their appearance [101]. There is a possible causal relationship between the viral vector vaccines and a rare syndrome of blood clotting combined with low platelet counts called thrombosis with thrombocytopenia syndrome (TTS), which occurs at a rate of about seven in one million doses, most commonly in women between the ages of 18 and 49 years old [101]. This can occur three to 30  days after administration of a second dose of the AstraZeneca vaccine, and the pathophysiology behind the reaction is still being investigated [99]. Because of this reaction, it is recommended that individuals taking aspirin or anticoagulants hold those medications prior to vaccination [95]. Guillain-Barre syndrome has been reported rarely following AstraZeneca vaccination, but based on current data, a causal relationship cannot be confirmed [95].

2.5.3 Candidates for Vaccination The CDC recommends that anyone within the appropriate age bracket for the vaccine being administered, and who does not have documented allergies to the ingredients in the vaccines, a recent exposure to someone with laboratory-confirmed COVID-19, or an active acute illness with SARS-CoV-2, or any other medical disease, should be offered a COVID-19 vaccine [95]. The timing of vaccination with a previous COVID-19 infection is discussed in the next section on Natural Immunity. Those who are unvaccinated in the community or in outpatient settings, with a known COVID-19 exposure, should wait to receive vaccination until their quarantine period has ended to avoid potentially exposing others during the vaccination visit [95]. Waiting through the quarantine period also prevents diagnostic confusion between possible vaccine adverse effects and symptoms of an active SARS-CoV-2 infection [95]. Both the CDC and the WHO endorse the safety of coadministration of the COVID-19 vaccine with other vaccines, such as the flu vaccine, if the vaccine injections are administered in different injection sites [95, 102]. Special populations, such as pregnant individuals or those who received monoclonal antibodies, are also recommended to receive a COVID-19 vaccination. For those persons who have received monoclonal antibodies or convalescent plasma for treatment of an active SARS-CoV-2 infection, the CDC recommends that vaccination should be deferred for at least 90 days post-therapy. This is based on the

2  Prevention and Infection Control

45

estimated half-life of these therapies and some evidence that suggests reinfection is uncommon within 90 days of infection [95]. Individuals who have experienced multisystem inflammatory syndrome (MIS) or myocarditis related to COVID-19 are also recommended by the CDC to wait until 90 days have passed since their diagnosis of MIS or until normal cardiac function has returned [95]. The American College of Obstetricians and Gynecologists (ACOG) recommends that “pregnant individuals be vaccinated against COVID-19. Given the potential for severe illness and death during pregnancy, completion of the initial COVID-19 vaccination series is a priority for this population” [103].

2.5.4 Natural Immunity Natural immunity, as discussed previously, is immunity conferred through active infection, leading to antibody and memory immune cell production. Though we do not yet have testing to determine adequate immunity to prevent further infection, there is evidence suggesting that antibody development following an active infection likely confers some degree of immunity from subsequent infection for at least 6 months [104, 105]. However, it is unknown yet how emerging viral variants may impact protection from, and prevention of, subsequent infection [106]. Seroreversion, which is the loss of previously detectable antibodies over time after antigen exposure, has been reported among persons with mild disease, while those with more severe disease reportedly develop a larger antibody response, achieving higher antibody titers with longer persistence [107, 108]. According to the CDC, research has shown that, “although neutralizing antibodies might not be detected among patients with mild or asymptomatic disease, the humoral immune response appears to remain intact even with loss of specific antibodies over time because of the persistence of memory B-cells” [72]. Lifelong immunity has yet to be seen with other endemic seasonal coronaviruses, such as the SARS-CoV-1 and Middle East Respiratory Syndrome (MERS-CoV) coronavirus; these coronaviruses have reportedly demonstrated measurable antibody for up to 2 years following infection [72]. The likelihood of reinfection with SARS-CoV-2 may increase with time after an initial infection, because of waning immunity and the possibility of exposure to viral variants [109–111]. An individual’s risk of reinfection depends not only on timing of previous infection, but also on the individual’s susceptibility, vaccination status, and the likelihood of reexposure to the virus. We do not currently have enough data to support the use of the antibody test to determine sufficient immunity against SARS-CoV-2 to prevent an active infection. There are various measurable antibodies produced by the body against different parts of the virus and the vaccine, and they have yet to be correlated to specific levels of immunity in the general population [72]. In light of this information, the CDC recommends that people who have had a prior SARS-CoV-2 infection get vaccinated, regardless of this previous infection, after they have recovered from their acute illness (if they were symptomatic) and at least 10 days after symptom onset and after resolution of fever [95].

46

E. A. Ingebretson

2.5.5 Booster and Supplemental Immunization After a primary series, or for the Janssen vaccine primary dose, of a COVID-19 vaccine, it may be appropriate to receive either a supplemental dose of the vaccine, or a booster dose of the vaccine after some time. The difference between the two types of additional vaccines is the rationale for administration. Supplemental doses are appropriate in immunocompromised individuals or those over the age of 65 years, because of the reduced vaccine effectiveness in these populations as evidenced by reduced antibody responses to the initial doses of vaccine [79, 112, 113]. Booster vaccination is common among various types of vaccinations, such as the flu vaccine, tetanus, diphtheria and pertussis vaccine, and the hepatitis B vaccine. Booster immunization is an important part of continued immunity, because as time increases after initial vaccination, and with the evolution of viral variants, vaccine effectiveness wanes [95, 114]. Research has shown that the Comirnaty vaccine shows a 6-month overall efficacy against infection of 91% and 97% against severe illness [115]. However, it was noted that efficacy decreased about six percentage points every 2 months greater than 7 days postvaccination, from 96% between 1 week and 2 months postvaccination, to 90% at 2–4 months postvaccination, to 84% between 4- and 6-months postvaccination [115]. As of October 2021, only the Comirnaty vaccine has been FDA-approved for booster vaccination and the booster dose should be given no earlier than 6 months after completion of the primary series [95]. However, both the Comirnaty and the Moderna vaccines have clearance to be administered as a supplemental vaccine to augment immunity in immunocompromised or elderly recipients with inadequate antibody response to the first dosing series [95]. The CDC recommends that supplemental vaccination doses should be administered at least 28 days after completing the primary two-dose series [95]. Ultimately, patients’ clinical team with knowledge about their entire clinical picture is best positioned to determine their need for supplemental vaccination; however, the CDC recommends consideration for supplemental vaccination in the following patients [95]: • Undergoing active treatment for malignancies. • Solid-organ transplant recipients receiving immunosuppressive therapy, including high-dose steroids. • Recipient of chimeric antigen receptor (CAR)-T-cell or hematopoietic stem cell transplant (within 2  years of transplantation or taking immunosuppression therapy). • Moderate or severe primary immunodeficiency, such as, but not limited to, DiGeorge syndrome or Wiskott-Aldrich syndrome. • Advanced or untreated HIV infection. Booster or supplemental vaccination holds the same level of risk for adverse events as the primary series, discussed previously in this chapter.

2  Prevention and Infection Control

47

2.5.6 General Vaccination Considerations After receiving any part of the COVID-19 vaccination series, individuals should be observed for at least 15 min to ensure anaphylaxis or allergic reaction does not occur [95]. If an allergic reaction or anaphylaxis occurs, the individual should be stabilized and is contraindicated to receive further vaccination with COVID-19 vaccines, unless otherwise directed and under strict healthcare supervision [95]. People are considered fully vaccinated at least 2 weeks following the receipt of the full series of whichever vaccine they receive [79]. Transmission between unvaccinated individuals remains the primary cause of continued spread of SARS-CoV-2. Because the vaccine limits viral replication in the upper and lower respiratory tracts, fully vaccinated individuals may have a lower risk of transmission; however, early evidence suggests that fully vaccinated individuals may still be able to transmit viable virus to others [79]. As previously discussed, vaccination is not 100% effective at preventing the development of mild illness, indicating that during times of high community spread, basic source control measures should continue to be implemented by vaccinated individuals in and out of healthcare facilities.

References 1. CDC (2019) Terminology | HCP | Infection Control Guidelines Library | CDC. https:// www.cdc.gov/infectioncontrol/guidelines/healthcare-­personnel/appendix/terminology.html. Accessed 30 Oct 2021 2. CDC (2020) Healthcare Workers. In: Centers for Disease Control and Prevention. https://www. cdc.gov/coronavirus/2019-­ncov/hcp/infection-­control-­recommendations.html. Accessed 30 Oct 2021 3. WHO (2020) Considerations for public health and social measures in the workplace in the context of COVID-19. https://www.who.int/publications-­detail-­redirect/WHO-­2019-­nCoV-­ Adjusting_PH_measures-­Workplaces-­2020.1. Accessed 30 Oct 2021 4. CDC (2020) Using Telehealth to Expand Access to Essential Health Services during the COVID-19 Pandemic. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/telehealth.html. Accessed 15 Aug 2021 5. WHO (2020) Algorithm for COVID-19 triage and referral : patient triage and referral for resource-limited settings during community transmission. WHO Regional Office for the Western Pacific. https://apps.who.int/iris/handle/10665/331915. Accessed 30 Aug 2021 6. CDC (2020) Phone Advice Line Tool. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/ phone-­guide/index.html. Accessed 30 Aug 2021 7. CDC (2021) Infection Control Guidance: Recommended routine infection prevention and control (IPC) practices during the COVID-19 pandemic: Implement Source Control Measures. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/infection-­control-­recommendations.html. Accessed 31 Aug 2021 8. Hauser C (2020) The Mask Slackers of 1918. https://www.nytimes.com/2020/08/03/us/mask-­ protests-­1918.html. Accessed 1 Sept 2021 9. Lyu W, Wehby GL (2020) Community use of face masks and COVID-19: evidence from a natural experiment of state mandates in the US. Health Aff (Millwood). 39(8):1419 10. Hatzius J, Struyven D, Rosenberg I. Face Masks and GDP. Updated June 29, 2020. https:// www.goldmansachs.com/insights/pages/face-­masks-­and-­gdp.html. Accessed July 8, 2020

48

E. A. Ingebretson

11. Karaivanov A, Lu SE, Shigeoka H, Chen C, Pamplona S (2021) Face masks, public policies and slowing the spread of COVID-19: evidence from Canada. J Health Econ 78:102475 12. Joo H, Miller GF, Sunshine G, Gakh M, Pike J, Havers FP et al (2021) Decline in COVID-19 hospitalization growth rates associated with statewide mask mandates  - 10 states, March-­ October 2020. MMWR Morb Mortal Wkly Rep 70(6):212–216 13. WHO (2020) Advice on the use of masks in the context of COVID-19. Interim guidance. https://www.who.int/publications/i/item/advice-­on-­the-­use-­of-­masks-­in-­the-­community-­ during-­home-­care-­and-­in-­healthcare-­settings-­in-­the-­context-­of-­the-­novel-­coronavirus-­ (2019-­ncov)-­outbreak. Accessed 5 Sept 2021 14. CDC (2020) Your guide to masks. https://www.cdc.gov/coronavirus/2019-­ncov/prevent-­ getting-­sick/about-­face-­coverings.html. Accessed 31 Aug 2021 15. Clapp PW, Sickbert-Bennett E, Samet JM, Berntsen J, Zeman KL, Anderson DJ et al (2021) Evaluation of cloth masks and modified procedure masks as personal protective equipment for the public during the COVID-19 pandemic. JAMA internal medicine. JAMA Intern Med 181(4):463–469 16. CDC (2021) Improve the Fit and Filtration of Your Mask to Reduce the Spread of COVID-19. https://www.cdc.gov/coronavirus/2019-­ncov/prevent-­getting-­sick/mask-­fit-­and-­filtration. html. Accessed 31 Aug 2021 17. CDC (2020) Who should or should not wear a mask. https://www.cdc.gov/coronavirus/2019-­ ncov/prevent-­getting-­sick/cloth-­face-­cover-­guidance.html. Accessed 31 Aug 2021 18. CDC (2021) Science Brief: SARS-CoV-2 and Surface (Fomite) Transmission for Indoor Community Environments. https://www.cdc.gov/coronavirus/2019-­ncov/more/science-­and-­ research/surface-­transmission.html. 5 Sept 2021 19. Goldman E (2020) Exaggerated risk of transmission of COVID-19 by fomites. Lancet Infect Dis 20:892–893 20. van Doremalen N, Bushmaker T, Morris DH et  al (2020) Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1. N Engl J Med 382:1564–1567 21. CDC. Guideline for Hand Hygiene in Health-Care Settings: Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. MMWR 2002;51(No. RR-16) 22. WHO (2010) Guide to Local Production: WHO-recommended Handrub Formulations. https://www.who.int/publications/i/item/WHO-­IER-­PSP-­2010.5. Accessed 10 Sept 2021 23. CDC (2021) When and how to perform hand hygiene. https://www.cdc.gov/handhygiene/ providers/index.html. Accessed 5 Sept 2021 24. CDC (2020) Ventilation in Buildings. https://www.cdc.gov/coronavirus/2019-­ncov/community/ventilation.html. Accessed 5 Sept 2021 25. CDC (2020) Directional airflow. https://www.cdc.gov/coronavirus/2019-­ncov/community/ ventilation.html#daf. Accessed 6 Sept 2021 26. EPA (2021) What is a HEPA filter?. https://www.epa.gov/indoor-­air-­quality-­iaq/what-­hepa-­ filter-­1. Accessed 6 Sept 2021 27. CDC (2020) Upper-Room Ultraviolet Germicidal Irradiation (UVGI). https://www.cdc.gov/ coronavirus/2019-­ncov/community/ventilation/UVGI.html. Accessed 6 Sept 2021 28. CDC (2020) Airborne infection isolation rooms. https://www.cdc.gov/coronavirus/2019-­ ncov/hcp/infection-­control-­recommendations.html#sourcecontrol. Accessed 6 Sept 2021 29. CDC (2017) Principles of Cleaning and Disinfecting Environmental Surfaces. https://www. cdc.gov/infectioncontrol/guidelines/environmental/background/services.html. Accessed 10 Sept 2021 30. CDC (2020) Triage of patients with suspected COVID-19 (no or limited community transmission). https://www.cdc.gov/coronavirus/2019-­ncov/hcp/non-­us-­settings/images/triage-­ sop-­appendix2.jpg. Accessed 15 Sept 2021 31. CDC (2020) Standard Operating Procedure (SOP) for Triage of Suspected COVID-19 Patients in non-US Healthcare Settings: Early Identification and Prevention of Transmission during Triage. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/non-­us-­settings/sop-­triage-­ prevent-­transmission.html. Accessed 7 Sept 2021

2  Prevention and Infection Control

49

32. World Health Organization (2021) Infection prevention and control during health care when coronavirus disease (COVID-19) is suspected or confirmed. https://www.who.int/ publications-­detail-­redirect/WHO-­2019-­nCoV-­IPC-­2021.1. Accessed 30 Aug 2021 33. CDC (2021) Overview of Testing for SARS-CoV-2 (COVID-19): Considerations for testing in different scenarios. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/testing-­overview. html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-­ ncov%2Fphp%2Ftesting%2Fexpanded-­screening-­testing.html. Accessed 7 Sept 2021 34. WHO (2021) Considerations for quarantine of contacts of COVID-19 cases. https://www. who.int/publications-­detail-­redirect/WHO-­2019-­nCoV-­IHR-­Quarantine-­2021.1. Accessed 30 Aug 2021 35. CDC (2020) Contact Tracing for COVID-19. https://www.cdc.gov/coronavirus/2019-­ncov/ php/contact-­tracing/contact-­tracing-­plan/contact-­tracing.html. Accessed 7 Sept 2021 36. WHO (2020) Considerations in the investigation of cases and clusters of COVID-19. https:// www.who.int/publications-­detail-­redirect/considerations-­in-­the-­investigation-­of-­cases-­and-­ clusters-­of-­covid-­19. Accessed 30 Aug 2021 37. WHO (2020) Global surveillance for COVID-19 caused by human infection with COVID-19 virus: interim guidance. https://www.who.int/publications/i/item/global-­surveillance-­for-­ covid-­19-­caused-­by-­human-­infection-­with-­covid-­19-­virus-­interim-­guidance. Accessed 30 Aug 2021 38. Cheng H, Jian S, Liu D, Ng T, Huang W, Lin H (2020) Contact tracing assessment of COVID-19 transmission dynamics in taiwan and risk at different exposure periods before and after symptom onset. JAMA Intern Med 180(9):1156–1163 39. Oran DP, Topol EJ (2020) Prevalence of asymptomatic SARS-CoV-2 infection a narrative review. Ann Intern Med 173(5):362–367 40. WHO (2020) Transmission of SARS-CoV-2: implications for infection prevention precautions. https://www.who.int/news-­room/commentaries/detail/transmission-­of-­sars-­cov-­2-­ implications-­for-­infection-­prevention-­precautions. Accessed 30 Sept 2021 41. WHO (2021) Contact tracing in the context of COVID-19: Interim guidance. https:// www.who.int/publications/i/item/contact-­tracing-­in-­the-­context-­of-­covid-­19. Accessed 30 Sept 2021 42. CDC (2021) Options to Reduce Quarantine Using Symptom Monitoring and Diagnostic Testing. https://www.cdc.gov/coronavirus/2019-­ncov/science/science-­briefs/scientific-­brief-­ options-­to-­reduce-­quarantine.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2 Fcoronavirus%2F2019-­ncov%2Fmore%2Fscientific-­brief-­options-­to-­reduce-­quarantine. html. Accessed 7 Sept 2021 43. Yu P, Zhu J, Zhang Z, Han Y (2020) A familial cluster of infection associated with the 2019 novel coronavirus indicating possible person-to-person transmission during the incubation period. J Infect Dis 221(11):1757–1761 44. Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR et al (2020) The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med 172(9):577–582 45. CDC (2021) Potential Exposure at Work. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/ guidance-­risk-­assesment-­hcp.html. Accessed 8 Sept 2021 46. CDC (2021) Return to Work Criteria for Healthcare Personnel with SARS-CoV-2 Infection. https://www.cdc.gov/coronavirus/2019-­n cov/hcp/guidance-­r isk-­a ssesment-­h cp.html. Accessed 8 Sept 2021 47. Owusu D, Pomeroy MA, Lewis NM et  al (2021) Persistent SARS-CoV-2 RNA shedding without evidence of infectiousness: a cohort study of individuals With COVID-19. J Infect Dis. https://doi.org/10.1093/infdis/jiab107 48. CDC (2021) Criteria for Investigating Suspected SARS-CoV-2 Reinfection. https://www.cdc. gov/coronavirus/2019-­ncov/php/invest-­criteria.html. Accessed 10 Sept 2021 49. Alhazzani W, Moller MH, Arabi YM, Loeb M, Gong MN, Fan E et al (2020) Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19). Crit Care Med 48(6):E440–E469

50

E. A. Ingebretson

50. Lynch JB, Davitkov P, Anderson DJ, Bhimraj A, Cheng VC, Guzman-Cottrill J et al (2020) Infectious diseases society of america guidelines on infection prevention for health care personnel caring for patients with suspected or known COVID-19. Clin Infect Dis. https://doi. org/10.1093/cid/ciaa1063 51. European Centre for Disease Prevention and Control (2020) Infection prevention and control and preparedness for COVID-19  in healthcare settings  - fourth update. https://www.ecdc. europa.eu/sites/default/files/documents/Infection-­prevention-­and-­control-­in-­healthcare-­ settings-­COVID-­19_4th_update.pdf. Accessed 30 Sept 2021 52. CDC (2020) Clinical Questions about COVID-19: Questions and Answers: Which procedures are considered aerosol generating procedures in healthcare settings?. https://www.cdc. gov/coronavirus/2019-­ncov/hcp/faq.html#Transmission. Accessed 23 Sept 2021 53. CDC (2020) Powered Air Purifying Respirators (PAPRs). https://www.cdc.gov/ coronavirus/2019-­ncov/hcp/ppe-­strategy/powered-­air-­purifying-­respirators-­strategy.html. Accessed 7 Nov 2021 54. CDC (2020) Elastomeric Respirators. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/ elastomeric-­respirators-­strategy/index.html. Accessed 23 Sept 2021 55. CDC (2021) The National Personal Protective Technology Laboratory: NIOSH-approved N95 Particulate Filtering Facepiece Respirators. https://www.cdc.gov/niosh/npptl/topics/respirators/disp_part/n95list1.html. Accessed 23 Sept 2021 56. NIOSH (2020) Filtering facepiece respirators with an exhalation valve: measurements of filtration efficiency to evaluate their potential for source control. By Portnoff L, Schall J, Brannen J, Suhon N, Strickland K, Meyers J. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2021-107. https://doi.org/10.26616/NIOSHPUB2021107 57. FDA (2021) N95 Respirators, Surgical Masks, Face Masks, and Barrier Face Coverings: General N95 Respirator Precautions. https://www.fda.gov/medical-­devices/personal-­protective-­ equipment-­infection-­control/n95-­respirators-­surgical-­masks-­and-­face-­masks. Accessed 25 Sept 2021 58. CDC (2021) Infection Control Guidance: Recommended infection prevention and control (IPC) practices when caring for a patient with suspected or confirmed SARS-CoV-2 infection. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/infection-­control-­recommendations. html. Accessed 7 Nov 2021 59. NIH (2021) COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. https://www.covid19treatmentguidelines.nih.gov/. Accessed 25 Sept 2021 60. Korea Centers for Disease Control and Prevention (2020) Findings from Investigation and Analysis of re-positive cases. https://www.cdc.go.kr/board/board.es?mid=a30402000000& bid=0030. Accessed 1 Oct 2021 61. Baang JH, Smith C, Mirabelli C, Valesano AL, Manthei DM, Bachman MA et  al (2021) Prolonged severe acute respiratory syndrome coronavirus 2 replication in an immunocompromised patient. J Infect Dis 223(1):23–27 62. Choi B, Choudhary MC, Regan J et al (2020) Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med 383(23):2291–2293. https://doi.org/10.1056/ NEJMc2031364 63. WHO (2020) Criteria for releasing COVID-19 patients from isolation: Scientific Brief. https://www.who.int/news-­r oom/commentaries/detail/criteria-­f or-­r eleasing-­c ovid-­1 9-­ patients-­from-­isolation. Accessed 25 Sept 2021 64. CDC (2021) Care for Patients at Home: Assess the suitability of the residential setting for home care. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/guidance-­home-­care.html. Accessed 31 Oct 2021 65. CDC (2020) Optimizing the Supply of PPE in Healthcare Facilities. https://www.cdc.gov/ coronavirus/2019-­ncov/hcp/ppe-­strategy/strategies-­optimize-­ppe-­shortages.html. Accessed 31 Oct 2021

2  Prevention and Infection Control

51

66. CDC (2006) Infection Control: Management of Multidrug-Resistant Organisms in Healthcare Settings: Cohorting and other MDRO control strategies. https://www.cdc.gov/infectioncontrol/guidelines/mdro/prevention-­control.html. Accessed 30 Sept 2021 67. CDC (2020) Optimizing N95 Respirator Supplies: Conventional Capacity Strategies. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/infection-­control-­recommendations.html. Accessed 5 Sept 2021 68. CDC (2021) Postmortem Guidance: Handling and Transportation of Human Remains. https:// www.cdc.gov/coronavirus/2019-­ncov/hcp/guidance-­postmortem-­specimens.html. Accessed 31 Oct 2021 69. CDC (2021) Testing Overview. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/testing-­ overview.html. Accessed 27 Oct 2021 70. WHO (2020) Laboratory testing for coronavirus disease 2019 (COVID-19) in suspected human cases: Interim guidance. https://www.who.int/publications/i/item/10665-­331501. Accessed 30 Oct 2021 71. CDC (2021) Guidance for Fully Vaccinated People. https://www.cdc.gov/coronavirus/2019-­ ncov/vaccines/fully-­vaccinated-­guidance.html. Accessed 20 Oct 2021 72. CDC (2021) Antibody Testing Guidelines: Interim Guidelines for COVID-19 Antibody Testing in Clinical and Public Health Settings. https://www.cdc.gov/coronavirus/2019-­ncov/lab/ resources/antibody-­tests-­guidelines.html#ftn1. Accessed 5 Oct 2021 73. CDC (2021) Specimen Collection. https://www.cdc.gov/coronavirus/2019-­ncov/lab/ guidelines-­clinical-­specimens.html. Accessed 30 Oct 2021 74. Bracis C, Burns E, Moore M, Swan D, Reeves DB, Schiffer JT et  al (2021) Widespread testing, case isolation and contact tracing may allow safe school reopening with continued moderate physical distancing: a modeling analysis of King County, WA data. Infect Dis Model 6:24–35 75. Liu W, Chang S, Wang J, Tsai M, Hung C, Hsu C et al (2020) Prolonged virus shedding even after seroconversion in a patient with COVID-19. J Infect 81(2):318–356 76. Ending Isolation. Updated Sept. 14, 2021. https://www.cdc.gov/coronavirus/2019-­ncov/hcp/ duration-­isolation.html#assessment. Accessed Sept 30, 2021 77. Janeway C (2005) Immunobiology: the immune system in health and disease, 6th edn. Garland Science, New York 78. CDC (2021) Vaccines & Immunizations: Immunity Types. https://www.cdc.gov/vaccines/ vac-­gen/immunity-­types.htm. Accessed 7 Oct 2021 79. CDC (2021) COVID-19 Vaccines and Vaccination. https://www.cdc.gov/coronavirus/2019-­ ncov/science/science-­briefs/fully-­vaccinated-­people.html. Accessed 7 Oct 2021 80. antigen | Definition, Function, Types, & Facts | Britannica. https://www.britannica.com/science/antigen. Accessed 5 Nov 2021 81. Gelderblom HR (1996) Chapter 41: Structure and classification of viruses. In: Baron S (ed) Medical microbiology, 4th edn. University of Texas Medical Branch at Galveston, Galveston (TX). Available from: https://www.ncbi.nlm.nih.gov/books/NBK8174/ 82. HHS (2021) Vaccine Types. https://www.hhs.gov/immunization/basics/types/index.html. Accessed 10 Oct 2021 83. CDC (2021) mRNA Vaccines. https://www.cdc.gov/coronavirus/2019-­ncov/vaccines/ different-­vaccines/mrna.html. Accessed 5 Nov, 2021 84. RAPS (2021) COVID-19 vaccine tracker. https://www.raps.org/news-­and-­articles/news-­ articles/2020/3/covid-­19-­vaccine-­tracker. Accessed 1 Nov 2021 85. CDC (2021) Pfizer-BioNTech. https://www.cdc.gov/coronavirus/2019-­ncov/vaccines/ different-­vaccines/Pfizer-­BioNTech.html. Accessed 7 Nov 2021 86. CDC (2021) Moderna. https://www.cdc.gov/coronavirus/2019-­ncov/vaccines/different-­ vaccines/Moderna.html. Accessed 7 Nov 2021 87. CDC (2021) Pfizer-BioNTech COVID-19 Vaccine: Storage and Handling Summary. https:// www.cdc.gov/vaccines/covid-­19/info-­by-­product/pfizer/downloads/storage-­summary.pdf. Accessed 10 Nov 2021

52

E. A. Ingebretson

88. CDC (2021) Moderna COVID-19 Vaccine: Storage and Handling Summary. https://www. cdc.gov/vaccines/covid-­19/info-­by-­product/moderna/downloads/storage-­summary.pdf. Accessed 10 Nov 2021 89. Oliver S, Gargano J, Marin M et al (2020) The advisory committee on immunization practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine — United States, December 2020. MMWR Morb Mortal Wkly Rep 69:1922–1924. https://doi.org/10.15585/ mmwr.mm6950e2 90. Thomas SJ, Moreira ED, Kitchin N et al (2021) Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine through 6 months. N Engl J Med 385:1761–1773 91. Lopez Bernal J, Andrews N, Gower C et al (2021) Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 385:585–594 92. Oliver S, Gargano J, Marin M et al (2021) The advisory committee on immunization practices’ interim recommendation for use of moderna COVID-19 vaccine  — United States, December 2020. MMWR Morb Mortal Wkly Rep 69:1653–1656. https://doi.org/10.15585/ mmwr.mm695152e1 93. Nanduri S, Pilishvili T, Derado G, Soe MM, Dollard P, Wu H et al (2021) Effectiveness of Pfizer-BioNTech and Moderna vaccines in preventing SARS-CoV-2 infection among nursing home residents before and during widespread circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant - National Healthcare Safety Network, March 1-August 1, 2021. Morb Mortal Weekly Rep 70(34):1163–1166 94. Witberg G, Barda N, Hoss S et al (2021) Myocarditis after Covid-19 vaccination in a large health care organization. N Engl J Med. 385(23):2132–2139 95. CDC (2021) Vaccines & Immunizations: Interim Clinical Considerations. https://www. cdc.gov/vaccines/covid-­19/clinical-­considerations/covid-­19-­vaccines-­us.html. Accessed 5 Nov 2021 96. Pfizer and BioNTech (2020) Vaccines and Related Biological Products Advisory Committee Meeting: FDA Briefing Document: Pfizer-BioNTech COVID-19 Vaccine 97. Bancsi A, Houle SKD, Grindrod KA (2019) Shoulder injury related to vaccine administration and other injection site events. Can Fam Physician 65(1):40–42 98. CDC (2021) Janssen COVID-19 Vaccine (Johnson & Johnson): Storage and Handling Summary. https://www.cdc.gov/vaccines/covid-­19/info-­by-­product/janssen/downloads/janssen-­ storage-­handling-­summary.pdf. Accessed 29 Nov 2021 99. WHO (2021) Interim recommendations for the use of the ChAdOx1-S [recombinant] vaccine against COVID-19. https://www.who.int/publications/i/item/WHO-­2019-­nCoV-­vaccines-­ SAGE_recommendation-­AZD1222-­2021.1. Accessed 29 Nov 2021 100. Oliver SE, Gargano JW, Scobie H, Wallace M, Hadler SC, Leung J et al (2021) The advisory committee on immunization practices’ interim recommendation for use of Janssen COVID-19 vaccine - United States, February 2021. MMWR Morb Mortal Wkly Rep 70(9):329–332 101. CDC (2021) Johnson & Johnson’s Janssen. https://www.cdc.gov/coronavirus/2019-­ncov/ vaccines/different-­vaccines/janssen.html. Accessed 5 Nov 2021 102. WHO (2021) Coadministration of seasonal inactivated influenza and COVID-19 vaccines: Interim guidance. https://www.who.int/publications/i/item/WHO-­2019-­nCoV-­vaccines-­ SAGE_recommendation-­coadministration-­influenza-­vaccines. Accessed 5 Nov 2021 103. The American College of Obstetricians and Gynecologists (2021) COVID-19 Vaccines and Pregnancy: Key Recommendations and Messaging for Clinicians. https://www.acog.org/ covid-­19/covid-­19-­vaccines-­and-­pregnancy-­conversation-­guide-­for-­clinicians. Accessed 15 Nov 2021 104. Hall VJ, Foulkes S, Charlett A, Atti A, Monk EJM, Simmons R et al (2021) SARS-­CoV-­2 infection rates of antibody-positive compared with antibody-negative health-­care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet 397(10283):1459–1469 105. Lumley SF, O’Donnell D, Stoesser NE, Matthews PC, Howarth A, Hatch SB et al (2020) Antibody status and incidence of SARS-CoV-2 infection in health care workers. N Engl J Med 384:533–540

2  Prevention and Infection Control

53

106. Abdool Karim SS, de Oliveira T (2021) New SARS-CoV-2 variants – clinical, public health, and vaccine implications. N Engl J Med 384(19):1866–1868 107. Milani GP, Dioni L, Favero C, Cantone L, Macchi C, Delbue S et  al (2020) Serological follow-up of SARS-CoV-2 asymptomatic subjects. Sci Rep 10(1):20048 108. Rijkers G, Murk JL, Wintermans B, van Looy B, van den Berge M, Veenemans J et al (2020) Differences in antibody kinetics and functionality between severe and mild severe acute respiratory syndrome coronavirus 2 infections. J Infect Dis 222(8):1265–1269 109. Sabino EC, Buss LF, Carvalho MPS, Prete CA, Crispim MAE, Fraiji NA et al (2021) Resurgence of COVID-19  in Manaus, Brazil, despite high seroprevalence. Lancet 397(10273): 452–455 110. Harrington D, Kele B, Pereira S, Couto-Parada X, Riddell A, Forbes S et al (2021) Confirmed reinfection with severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) variant VOC-202012/01. Clin Infect Dis. https://doi.org/10.1093/cid/ciab014 111. Zucman N, Uhel F, Descamps D, Roux D, Ricard J (2021) Severe reinfection with South African severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant 501Y.V2. Clin Infect Dis. https://doi.org/10.1093/cid/ciab129 112. Khan N, Mahmud N (2021) Effectiveness of SARS-CoV-2 vaccination in a Veterans affairs cohort of patients with inflammatory bowel disease with diverse exposure to immunosuppressive medications. Gastroenterology 161(3):827–836 113. Gomes D, Beyerlein A, Katz K, et  al (2021) Is the BioNTech-Pfizer COVID-19 vaccination effective in elderly populations? Results from population data from Bavaria, Germany. medRxiv. https://www.medrxiv.org/content/10.1101/2021.08.19.21262266v1 114. CDC (2019) Vaccines for Your Children: Flu (Influenza). https://www.cdc.gov/vaccines/parents/diseases/flu.html. Accessed 29 Oct 2021 115. Thomas SJ, Moreira ED, Kitchin N, et  al (2021) Six Month Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine. medRxiv. https://www.medrxiv.org/content/10.110 1/2021.07.28.21261159v1

3

Manifestations of Coronavirus Fidel Gonzalez

3.1

Introduction

Small pox, Spanish flu, swine flu, Ebola, HIV/AIDS, and currently, COVID 19 have all wreaked havoc across the globe. According to the Oxford Dictionary, an epidemic is a large number of cases of a particular disease at the same time and in a particular area [1]. A pandemic is a disease that spreads across an entire country or worldwide [1]. Unfortunately, the world is currently experiencing the pandemic known as the novel coronavirus disease 2019 (COVID-19). This virus has caused mass panic, instilled fear in most of the world, crippled economies, basically shutdown the world, and placed immense strain on the healthcare system. Although we have got a vast amount of knowledge studying how to treat COVID-19, we are still learning and fighting every day to end this global pandemic. This chapter will discuss the signs and symptoms of COVID-19. The signs and symptoms of COVID-19 range from mild to severe. Much of the severity of symptoms depends on vaccination status and overall health. At the start of the COVID-19 pandemic, the elderly and people with multiple comorbidities were affected the most. However, the development and use of the COVID-19 vaccine has proven to be a good defense against this virus. The range of clinical symptoms varies from asymptomatic, pneumonia, acute respiratory distress syndrome (ARDS), and even death [2]. At first, COVID-19 was primarily known to attack the respiratory system, currently it is known to cause multisystemic destruction [2]. Regardless of symptomatology, the gold standard of diagnosing COVID-19 remains reverse transcription polymerase chain reaction (RT-PCR) positive for the viral RNA [3]. This chapter will be broken down by systems and

F. Gonzalez (*) Memorial Hermann, Houston, TX, USA e-mail: [email protected] © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 A. Bergeron et al. (eds.), Principles in Nursing Practice in the Era of COVID-19, https://doi.org/10.1007/978-3-030-94740-8_3

55

56

F. Gonzalez

Table 3.1  Symptoms by organ system Systemic

Cardiovascular

Respiratory

Neurological

Gastrointestinal

Hematological

Renal

• Fever • Headache • Myalgias • Chest Pain • Arrythmias • Myocardial infarction • Cardiogenic Shock • Cardiac Arrest • Cough • Dyspnea • Shortness of breath • Sputum production • Hypoxia • Respiratory Failure • ARDS • Headache • Confusion • Dizziness • Anosmia • Hyposmia • Dysgeusia • CVA • Guillain-Barre Syndrome • Nausea • Vomiting • Diarrhea • Anorexia • Abdominal Pain • Elevated liver enzymes • Lymphopenia • VTE, PE, or CVA • PT/PTT prolongation • Thrombocytopenia • Decreased Fibrinogen • AKI

Abbreviations: ARDS acute respiratory distress syndrome, CVA cerebrovascular event, VTE venous thromboembolism, PE pulmonary embolism, PT prothrombin time, PTT partial thromboplastin time. References [2–13]

will include some pathophysiologies behind the disease process. For reference, Table 3.1 will outline all symptoms by organ system.

3.2

General

Multiple studies reviewed regarding COVID-19 have mentioned a wide range of signs and symptoms related to the virus. The most commonly reported initial symptoms include fever, cough, dyspnea, fatigue, headache, and myalgia [4]. Initially, this disease was characterized by the triad fever, cough, and shortness of breath [4].

3  Manifestations of Coronavirus

57

Fever is the most common symptom observed in patients with COVID-19. Fever signals an organism’s response to a toxic substance that affects temperature regulation [4]. Fever can appear throughout the course of almost any infectious process; although it is a beneficial signaling process for an infectious invasion, it does require a significant increase in energy metabolism [4]. Fatigue is another frequently reported symptom among patients with COVID-19. Fatigue is related to the increase in viral load and to the immune response toward the infectious process. The insufficient energy production to meet the body’s metabolic demands relates fatigue to other COVID-19 related symptoms, for example dyspnea [4].

3.3

Respiratory

The most common body system affected by the SARS-CoV-2 virus is the pulmonary system [5]. Several retrospective studies have reported the following pulmonary manifestations, among COVID-19 patients, which include cough, shortness of breath, sputum production, respiratory failure, and ARDS [5]. Statistically, between 20% and 41% of all COVID-19 hospitalized patients will likely develop ARDS [6]. One of the most commonly reported respiratory symptoms is a cough. This symptom is also attributed to the transmission of the virus through respiratory droplets [4]. The cough reflex helps to improve the release of particles and secretions trapped in the airway, as a result of irritating mechanisms [4]. These mechanisms include accumulated secretions, postnasal drip, pathogens, and the basic inflammatory process [4]. In some patients, a cough can become excessive and has the potential to harm the airway mucosa [4]. Additional upper respiratory symptoms that have been reported include sneezing, nasal congestion, and sore throat [4]. Another commonly reported symptom among COVID-19 patients is dyspnea. The presence of dyspnea is also linked to a greater severity of the disease process and is a good predictor of ICU admissions [4, 7]. Patients who present with dyspnea usually present with other symptoms such as increased respiratory rate, speech tremor, weakened breath sounds, and dullness on lung percussion [4]. Statistically, the majority of patients who present with severe cases of COVID-19 have comorbidities such as cardiovascular disease, hypertension, or diabetes mellitus [4]. Hypoxia is a presenting symptom reported in patients who present with COVID-19 pneumonia [6]. Interestingly, the hypoxia is tolerated well by the patients, at first [6]. This is normally seen in the early stages of the disease process and is known as “silent hypoxia” [6]. This is also linked to atypical features of the ARDS syndrome associated with COVID-19 pneumonia [6]. Respiratory failure usually has a delayed onset of about a week after onset of symptoms [7]. Unlike typical ARDS, lung compliance is persevered, and hypoxia-driven tachypnea allows for high volumes and hypercapnia, which prevents the sensation of dyspnea [6]. This type of ARDS has a similar pathophysiological mechanism that is seen in hypobaric hypoxia at high altitudes [6]. A model was developed which includes two time-associated phenotypes based on severity of illness, patient comorbidities and physiological reserve, the time elapsed between disease onset and presentation to

58

F. Gonzalez

the hospital, and the host immune response [6]. The L-phenotype, seen in early stages, has high lung compliance, and the ventilation to perfusion ratio is low, but there is dysfunctional regulation of perfusion with hypoxic vasoconstriction [6]. At this stage, lung weight and lung recruitability are low with a small amount of non-­ aerated lung tissue [6]. This can develop into H-phenotype with decreased lung compliance secondary to edema, increased fraction of cardiac output perfusing the non-aerated tissue caused a right to left shunt, and increasing lung volume due to edema and consolidation and high recruitability [6]. Type L patients can remain stable, improve, or worsen and transition into type H [6]. This transition into type H is secondary to the evolution of COVID-19 pneumonia, but also injury caused by high stress ventilation [6]. It is well-established that the target of entry for SARS-CoV-2 is the angiotensin-­ converting enzyme-2 (ACE2) receptors [5]. ACE2 receptors are expressed in type I and II alveolar cells and airway epithelial cells and are considered the main functional receptor for the SARS-CoV-2 virus [5, 6]. ACE2 receptors are largely expressed on the apical side of type II alveolar epithelial cells in the alveolar space [6]. This large surface area is essentially a reservoir for viral binding and replication [6]. The virus enters these cells using cell-medicated endocytosis and starts a cascade of pro-inflammatory cytokines such as interleukin (IL)-1B, IL-6, and tumor necrosis factor (TNF) [5]. When SARS-CoV-2 binds to the ACE2 receptor, it reduces the expression of the ACE2 receptor [5]. The SARS-CoV-2 virus induces alveolar injury and induces inflammation [6].

3.4

Cardiovascular

Patients who have COVID-19 and underlying cardiovascular comorbidities, such as hypertension, diabetes, and cardiovascular disease, have been associated with adverse outcomes [6]. Obesity is also associated with a higher risk of adverse cardiovascular outcomes [6]. Cardiovascular manifestations of COVID-19 include chest pain, elevation of cardiac biomarkers, cardiac arrhythmia, heart failure, myocarditis, pericarditis, acute coronary syndrome, arterial and venous thromboembolism (VTE), cardiogenic shock, and even cardiac arrest [5, 8]. Presenting symptoms have ranged from mild chest pain with persevered ejection fraction to cardiovascular collapse. Severe cases of cardiovascular collapse have required the use of extracorporeal membrane oxygenation (ECMO) [7]. Myocardial injury is very common among patients with COVID-19 infection and correlates with disease severity [8]. Studies have defined myocardial injury as elevation of cardiac troponin markers, evidence of new electrocardiographic, or echocardiographic abnormalities [8]. Echocardiographic changes have been shown to have regional wall motion abnormalities or global hypokinesis [7]. Electrocardiographic changes may range from low voltage QRS complexes, ST elevations, or ST depression [7]. Elevated cardiac troponin markers correlate with disease severity and mortality [8]. Therefore, the pattern of the rise of cardiac troponin level is significant from a prognostic standpoint [8]. Cardiac troponin levels

3  Manifestations of Coronavirus

59

have been shown to continue to rise in patients who did not survive and generally stayed same in patients who have survived [8]. With these findings, it is important to monitor cardiac troponin markers frequently [8]. Viral infections, like COVID-19, can cause a systemic inflammatory response syndrome that can increase the possibility of plaque rupture and thrombus formation [8]; thus, resulting in an acute myocardial infarction or non-ST-elevation myocardial infarction [8]. Severe viral respiratory infections can also lead to decreased oxygen delivery to the myocardial muscle due to hypoxemia and vasoconstriction [8]. This supply and demand mismatch to the myocardial muscle can lead to myocardial injury, especially in patients with underlying coronary artery disease [8]. Prolonged hypoxemia results in reduced cellular capacity to metabolize aerobically, and therefore, cells switch to anaerobic metabolism [5]. Anaerobic metabolism produces an acidic state intracellularly due to lactic acid production [5]. This causes increased free radical production and destruction of phospholipid cell membranes [5]. Hypoxemia is also known to increase the influx of calcium ions, which may lead to cardiac myocyte apoptosis [5]. Although cardiac troponin markers are a good indicator of ischemia and infarction, it is not always sufficient in securing a diagnosis [8]. Diagnosis of acute myocardial infarction should be based on laboratory findings, electrocardiographic changes, signs and symptoms, and clinical judgment [8]. DIC has been shown to be catastrophic in patients with COVID-19. DIC is a marker of severe sepsis that can significantly worsen multiorgan damage through thrombosis, reduced perfusion, and bleeding [8]. DIC has been shown to cause thrombosis of the coronary arteries, focal necrosis of the myocardium, and severe cardiac dysfunction [8]. Myocardial infarction requires immediate intervention and treatment based on the updated Society of Cardiovascular Angiography and Interventions guidelines [8]. The disease process of COVID-19 causes a release of multiple cytokines and chemokines [8]. This cytokine release syndrome is also known as cytokine storm [8]. The process is caused by hyperinduction of pro-inflammatory cytokines including interleukin (IL)-1, IL-6, T helper 1 cytokine interferon-gamma, and tumor necrosis factor-alpha (TNF-α) [8]. It is believed that pro-inflammatory cytokines depress myocardial function, causing myocardial injury, through activation of the neural sphingomyelinase pathway and via nitric oxide-mediated blunting of beta-­adrenergic signaling [8]. Studies have shown plasma levels of IL-lβ, IL-2, IL-4, IL-6, IL-8, and TFN-α to be significantly higher in patients with COVID-19 [8]. Studies have also shown that non-survivors of COVID-19 have highly elevated levels of ferritin and IL-6, suggesting that cytokine release contributes to mortality [8]. Cardiac arrhythmias are another manifestation to watch out for in patients who present with COVID-19. Arrhythmias can present as an initial presentation of COVID-19 [8]. Regardless, new onset or progressive arrhythmias can indicate significant cardiac involvement [8]. A study conducted in Wuhan showed arrhythmias were more common among intensive care unit (ICU) patients at 44% and about 7% in non-ICU patients [8]. The same study showed patients with elevated cardiac

60

F. Gonzalez

troponin levels had a higher incidence of lethal arrhythmias such as hemodynamically unstable ventricular tachycardia or ventricular fibrillation [8]. Further information on cardiac manifestations can be found in Chap. 6, Systemic Complications.

3.5

Neurology

Neurological symptoms and manifestations, in COVID-19 patients, can be broken down into three different systems [9]. The three systems that can be affected by COVID-19 are the central nervous system (CNS), the peripheral nervous system, and the musculoskeletal system [9]. The most common general neurological symptoms reported among patients with COVID-19 include headache, confusion, dizziness, anosmia, and hyposmia [9, 10]. Similarly to other body systems, patients with more severe cases of COVID-19 tend to exhibit more abnormalities than patients with less severe infections [9]. Anosmia, hyposmia, and dysgeusia are considered to be the most common neurological symptom reported by patients with COVID-19 [10]. Anosmia is defined as the loss of sense of smell [10]. Hyposmia is defined as the reduced ability to smell [10]. Dysgeusia is defined as the loss of sense of taste [10]. Research shows that olfactory sensory neurons do not express ACE2 receptors, blocking SARS-CoV-2 from invading these cells [9]. On the other hand, olfactory epithelium cells express ACE2 receptors, and therefore are vulnerable to SARS-CoV-2 infection [9]. Resulting damage to the olfactory epithelium cells seems to be the cause of anosmia [9]. Patients who present with any of these symptoms should immediately be tested for COVID-19 because these symptoms occur early in the disease process and are considered useful diagnostic markers [9]. Prompt treatment can prevent severe cases of COVID-19. Another common symptom reported among patients with COVID-19 is myalgia [9]. Based on studies, the prevalence of myalgia greatly varies and ranges from 4% to 64% of patients [9]. Myalgia is considered to be caused by general inflammation and cytokine storm [9]. Headaches are also a commonly presented symptom among COVID-19 patients. Headaches have been classified into two different phases. The initial phase includes diffuse pain, which is moderate in intensity and is attributed to systemic viral infection [9]. The second phase usually occurs around 7–10  days postinfection and could include photophobia and neck stiffness [9]. Headaches in phase two are linked to cytokine storm [9]. Headaches are considered to be prodromal symptom [9]. Neurological complications that have occurred in patients with COVID-19 include encephalitis and Guillain-Barre syndrome [9, 10]. Although there is not a clear understanding of why these complications occur, ongoing research is being conducted [9, 10]. The most common etiology of encephalitis is viral infections [10]. Viral infections that cause encephalitis include Herpes simplex virus, Varicella zoster virus, cytomegalovirus, influenza virus, and respiratory viruses like SARS-­CoV-­2 [10]. The presence of SARS-CoV-2 found in CSF fluid confirms this neurological manifestation to be caused by the virus [9]. It has been

3  Manifestations of Coronavirus

61

proposed that encephalitis caused by SARS-CoV-2 is directly related to cytokine storm syndrome [10]. Guillain-Barre syndrome (GBS) is an inflammatory polyradiculoneuropathy associated with numerous infections [9]. Covid-19 patients who have GBS can present with various neurological symptoms ranging from lower limb weakness and paresthesia that can become progressively worse leading to generalized tetraparesis or tetraplegia [9, 10]. GBS is diagnosed based on MRI, spinal tap, and electrophysiological studies [9]. Specific case studies of COVID-19 patients with GBS presented with a demyelinating electrophysiological subtype acute inflammatory demyelinating polyneuropathy [9]. There are multiple proposed mechanisms by which SARS-CoV-2 enters the central nervous system [10]. Proposed mechanisms include direct infection injury, blood circulation pathway, neuronal pathway, and immune-mediated injury [5, 6, 9, 10]. Direct injury infection occurs by SARS-CoV-2 entering the brain tissue from the cribriform plate [10]. The cribriform plate is in close proximity to the olfactory bulb and this idea of direct spread could be supported by the presence of anosmia, hyposmia, and dysgeuia [10]. Another potential mechanism of entry is blood circulation pathway, which SARS-CoV-2 binds to the ACE2 receptor [5, 6, 9, 10]. ACE2 receptors are widely expressed throughout the body including airway epithelia, kidney cells, small intestine, lung parenchyma, vascular endothelium, and throughout the CNS [9]. ACE2 receptor expression throughout the CNS includes neurons, glial tissues, brain vasculature, astrocytes, ventricles, middle temporal gyrus, posterior cingulate cortex, and olfactory bulb [9, 10]. The viral spike protein interacts with ACE2 receptors in the neurons and glial cells of the brain, making the brain susceptible for neuroinvasion [9]. The presence of the virus in general circulation allows the virus entry into the cerebral circulation; as blood moves through the microvasculature of the brain, the viral spike protein interacts with the ACE2 receptors of the capillary endothelium [10]. Neuronal pathway is another mechanism of entry into the CNS. This is achieved by anterograde and retrograde transport with the help of motor proteins kinesins and dynein via sensory and motor nerve endings [9, 10]. One example includes afferent nerve endings of the vagus nerve from the lungs [10]. Immune-mediated injury is also a proposed mechanism of injury to the CNS. This proposed mechanism of injury involves a surge of inflammatory cytokines, which is also called cytokine storm syndrome [5, 6, 9, 10]. The main cytokine involved in this process is Interleukin-6 (IL-6) [10]. SARS-CoV-2 induces the production of IL-6 from glial cells, causing cytokine storm syndrome [10]. Leukocytes also release TNF, which is a pro-inflammatory cytokine that damages oligodendrocytes and neurons [9]. This causes a production of chemokines including CCL5, CXCL10, and CXCL11 [9]. The chemokines produced induce chemoattraction of activated T cell [9]. At the same time, astrocytes release CCL2, CCL5, and CXCL12, which are chemokines [9]. Chemokines CCL2, CCL5, and CXCL12 recruit more infected lymphocytes [9]. Ultimately, the cytokine storm syndrome causes a vicious cycle of neuroinflammation [9, 10].

62

3.6

F. Gonzalez

Hematology

The most commonly reported blood count abnormality is lymphopenia [2]. Lymphopenia is frequently reported and the absolute lymphocyte count is significantly lower in severe cases of COVID-19 [2]. Although the absolute lymphocyte count is low, patients with severe cases of COVID-19 may have higher total white cell counts [7]. A study conducted in Wuhan revealed patients with severe cases of COVID-19 having higher neutrophil counts, lower lymphocyte counts, higher neutrophil-­to-lymphocyte ratio, and lower percentages of monocytes, eosinophils, and basophils [2]. There is a reported reduction in CD4+ and CD8+ T lymphocytes, and patients with severe cases have been noted to have significantly decreased CD8+ lymphocytes, requiring ICU admission [2]. This decrease in CD4+ and CD8+ lymphocytes poses a great risk of bacterial infections [6]. Higher CD4+ and CD8+ lymphocyte counts have been correlated with improved clinical outcomes [2]. Lymphopenia is considered to be a cardinal laboratory finding with great prognostic indication [6]. Between 7 and 14 days of symptom onset, there is a surge in clinical manifestations with a pronounced increase in inflammatory mediators and cytokines, known as a “cytokine storm” [6]. Cytokine storm can also be referred to as cytokine release syndrome (CRS) [2, 6]. These pro-inflammatory markers include IL-lβ, IL-2, IL-4, IL-6, IL-10, TFN-α, and IFN-γ [2]. Lymphocytes express the ACE2 receptor on their surface, allowing SARS-CoV-2 to directly infect the lymphocytes [6]. Therefore, a cytokine surge could cause lymphocyte apoptosis [6]. Cytokine surge could also be associated with atrophy of the spleen, further impairing lymphocyte turnover [2, 6]. Several complex pathways have been implicated in the pathogenesis of COVID-19 cytokine storm including the Renin-Angiotensin-­ Aldosterone system (RAAS), JAK/STAT, and Complement activation pathways [2]. This surge in pro-inflammatory markers is also associated with Chimeric Antigen Receptor (CAR) T-cell therapy and HLH, which are both states of immune dysregulation and hyper-inflammation [2]. CRS is characterized by elevation of inflammatory markers and cytokines, notably IL-6, fever, hypotension, and respiratory distress following the infusion of CAR T cells or other immune therapies [2]. On the other hand, HLH is characterized by an uncontrolled activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages, resulting in hypercytokinemia and immune-mediated organ damage [2]. Most studies conducted on the management of COVID-19 patients have indicated an increase in thrombotic tendency [2, 6, 7]. Blood hypercoagulability is extremely common among patients with COVID-19 [6]. This hypercoagulability is even more pronounced in patients with severe cases of COVID-19 [6]. Patients with COVID-19 are at a higher risk for developing a venous thromboembolism (VTE) [2, 6, 7]. Patients with comorbidities have an increased risk of developing a VTE [6]. Endothelial cell damage due to the virus binding to the ACE2 receptors can also increase the risk of a VTE [6]. Elevated D-dimer level is a common laboratory finding noted among patients with severe COVID-19 infections [6]. D-dimer levels are also shown to gradually increase as the clinical presentation deteriorates [6]. D-dimer levels are not the only laboratory finding that is off, in regards to clotting

3  Manifestations of Coronavirus

63

or inability to clot. Other coagulopathic abnormalities include PT and PTT prolongation, increased fibrin degradation products, and severe thrombocytopenia [6]. A study done in France showed approximately one third of all COVID-19 patients had CT scan evidence of pulmonary embolism (PE) [2]. The other two thirds of patients, in the same French study, without PE had elevated D-dimers with a higher cut-off value of 2660  μg/L [2]. A Dutch study of ICU patient admitted with COVID-19 identified 31% incidence of thrombotic events [2]. These thrombotic events included PE, deep vein thrombosis (DVT), and ischemic strokes [2]. Due to the increased risk for VTE, prompt pharmacological thromboprophylaxis is highly recommended [6]. Other factors to help prevent VTE will be early ambulation, use of thrombo-­ embolus deterrent stockings, and the use of sequential compression devices.

3.7

Gastroenterology

Gastrointestinal (GI) manifestations seen in COVID-19 patients include nausea, vomiting, diarrhea, anorexia, and abdominal pain [11–13]. There has been an increasing recognition of GI symptoms among patients with COVID-19 [7]. Some patients have presented for treatment with only GI symptoms and tested positive for COVID-19 [7]. The underlying pathophysiological mechanism is believed to be the virus’s affinity to ACE2 receptors located in enterocytes of the ileum and colon [5–7]. ACE2 receptors are involved in inflammation mechanisms and could provide an explanation for the occurrence of diarrhea [6]. The incidence of liver injury is manifested by the elevation of alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, and hypoalbuminemia [11]. Liver dysfunction is primarily described in patients with severe COVID-19 infection [6]. There are several hypotheses regarding the cause of liver dysfunction. Liver dysfunction could be caused from the infection, sepsis, or hypoxia [6]. ACE2 receptors are located in hepatocytes and cholangiocytes and could be the cause of liver dysfunction [5–7, 11]. Liver dysfunction could also be caused by treatments used to treat the overall infection [6, 11]. These treatments include antibiotics, antipyretics, analgesics, and antiviral drugs [6, 11].

3.8

Nephrology

The renal system is another organ system that can be affected by COVID-19. Patients with COVID-19 have a higher incidence of developing acute kidney injury (AKI) [5]. AKI can occur in patients who have a history of chronic kidney disease, but can also affect patients with no prior history of renal impairment [5]. AKI is more commonly seen among ICU patients than non-ICU patients; however, AKI indicates severity of illness progression [5]. There are a couple of pathophysiological explanations regarding renal impairment, among COVID-19 patients [5]. ACE2 receptors are expressed in several cells

64

F. Gonzalez

such as podocytes, mesangial cells, epithelium of Bowman’s capsule, proximal cells brush border, and collecting cells [6]. SARS-CoV-2 has a higher affinity for the ACE2 receptor and could explain the higher prevalence of AKI.  The highly expressed ACE2 receptors in the renal system increase the susceptibility of the kidney to viral entry [5]. Another proposed mechanism of AKI is the significantly higher immune response to infection and multiorgan failure [5]. As previously discussed, SARS-CoV-2 induces the release of multiple inflammatory cytokines which are believed to be involved in the pathology of AKI [5]. Research has shown that COVID-19 ICU patients have higher levels of IL-lβ, IL-8, IFN-γ, and TFN-α [6]. The higher levels of cytokines suggest the uncontrolled systemic inflammatory response leading to kidney injury [6]. Other factors believed to contribute to renal impairment, in critically ill patients, include hypovolemia, rhabdomyolysis, hypoxemia, sepsis, and septic shock [5].

3.9

Conclusion

In conclusion, research has shown that this virus goes well beyond the respiratory system. SARS-CoV-2 has been shown to cause catastrophic damage to every body system. All patients who present to the hospital with signs and symptoms of COVID-19 should be tested immediately and treated with proper antiviral therapy. Prompt identification and treatment can help prevent patients from developing serious complications from COVID-19. Educating patients on proper hand hygiene, mask use, and vaccinations is also imperative to help prevent the spread of COVID-19.

References 1. Oxford Dictionary (2021) Oxford University Press 2. Agbuduwe C, Supratik B (2020) Haematological manifestations of COVID-19: from cytopenia to coagulopathy. Eur J Haemotol. https://doi.org/10.1111/ejh.13491 3. Jiang M, Zu Z, Schoepf U, Savage R, Zhang X, Lu G, Zhang L (2020) Current status of etiology, epidemiology, clinical manifestations and limitations of COVID-19. Korean J Radiol 21(10):1138–1149. https://doi.org/10.3348/kjr.2020.0526 4. Mesquita R, Junior L, Santana F, Farias de Oliveira T, Alcatara R, Arnozo G, Rodrigues da Silva Filho E, Galdino dos Santos A, Oliveira da Cunha E, Salgueiro de Aquino S, Freire de Souza C (2021) Clinical manifestations of COVID-19  in the general population: systemic review. Cent Eur J Med 133:337–382. https://doi.org/10.1007/s00508-­020-­01760-­4 5. Johnson K, Harris C, Cain J, Hummer C, Goyal H, Perisetti A (2020) Pulmonary and extra-pulmonary clinical manifestations of COVID-19. Front Med. https://doi.org/10.3389/ fmed/2020.00526 6. Gavriatropoulou M, Korompoki E, Fotiou D, Ntanasis-Stathopoulos J, Psaltopoulou T, Kastritis E, Terpos E, Dimopoulos M (2020) Organ-specific manifestations of COVID-19 infection. Clin Exp Med 20:493–506. https://doi.org/10.1007/s10238-­020-­00648-­x 7. Gulati A, Pomeranz C, Qamar Z, Thomas S, Frisch D, George G, Summer R, DeSimone J, Sundaram B (2020) A comprehensive review of manifestations of novel coronaviruses in the context of deadly COVID-19 global pandemic. Am J Med Sci 360:1

3  Manifestations of Coronavirus

65

8. Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, Chen Y, Han Y (2020) Cardiovascular manifestations and treatment considerations of COVID-19. Heart 106:1132–1141 9. Harapan B, Yoo H (2021) Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol 268:3059–3071. https://doi.org/10.1007/s00415/021/10406-­y 10. Ahmed M, Hanif M, Ali M, Haider M, Kherani D, Memon G, Karim A, Sattar A (2020) Neurological manifestations of COVID-19 (SARS-CoV-2): a review. Front Neurol. https://doi. org/10.3389/fneur.2020.00518 11. Su S, Shen J, Zhu L, Qiu Y, He J, Tan J, Iacucci M, Ng S, Ghosh S, Mao R, Liang J (2020) Involvement of digestive system in COVID-19: manifestations, pathology, management and challenges. Ther Adv Gastroenterol 13:1–12. https://doi.org/10.1177/175628420934626 12. Kopel J, Perisetti A, Gajendran M, Boregowda U, Goyal H (2020) Clinical insights into the gastrointestinal manifestations of COVID-19. Digest Dis Sci 65:1932–1939. https://doi. org/10.1007/s10620-­020-­06362 13. Dorrell R, Dougherty M, Barash E, Lichtig A, Clayton S, Jensen E (2021) Gastrointestinal and hepatic manifestations of COVID-19: a systemic review and meta-analysis. JGH Open. https:// doi.org/10.1002/jgh3.12456

4

Pharmacological Management Jigna Patel

4.1

Introduction

With the initial outbreak of the SARS-CoV-2 virus, researchers around the world have studied a variety of different medications of different categories in hopes to find a “cure”. Scientists have used the knowledge they have in pathophysiology and theorized how potential drugs could have an effect on the SARS-CoV-2 virus. The drugs include antivirals, antiparasitics, monoclonal antibodies, immunomodulators, and corticosteroids, among others. While some have shown potential benefits, studies have not shown benefits with many of these medications. At the time of this writing, remdesivir is the only medication in the United States that has been granted approval by the Federal Drug Administration (FDA), although several others have been granted Emergency Use Authorization (EAU). The current goal of medications used in COVID-19 treatment is to prevent severe illness and death, although studies still continue to find a curative treatment. Table  4.1 summarizes commonly used medications along with dosages, side effects, and important nursing considerations.

4.2

Antiviral Therapy

Many medications have been studied for their antiviral properties against the SARS-­ CoV-­2 virus, but not all of them have translated to efficacy beyond their laboratory or theoretical properties. Several, however, have been of some benefit in a variety of trial designs.

J. Patel (*) University of Texas Medical Branch Health, Galveston, TX, USA © The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 A. Bergeron et al. (eds.), Principles in Nursing Practice in the Era of COVID-19, https://doi.org/10.1007/978-3-030-94740-8_4

67

68

J. Patel

Table 4.1  Common medications used in COVID-19 Drug name Remdesivir [1, 2]

Dosages 200 mg IV once followed by 100 mg IV once daily × 4 days or until hospital discharge

Dexamethasone [3, 4]

6 mg IV or PO once daily for up to 10 days or until hospital discharge

Baricitinib [5]

Dose (1 mg–4 mg) based on eGFR, given up to 14 days or until hospital discharge,

Tofacitinib [6]

10 mg PO BID for up to 14 days or until hospital discharge (5 mg if eGFR 300 were randomized to receive 5 days of hydroxychloroquine or standard care. On day 6, time to clinical recovery was measured, defined as a return of body temperature and patient-reported cough relief, maintained for more than 72 h, and radiological changes on a chest computed tomography (CT) on day 6 compared to day 0. The inclusion criteria above define patients with mild disease and not on oxygen supplementation. Also of note, standard care in this study was defined as oxygen therapy, antiviral agents, antibacterial agents, and immunoglobulin, with or without corticosteroids. The investigators found that at day 6, 80.6% of patients in the hydroxychloroquine group compared to 54.6% in the control group had improved pneumonia [23]. Perhaps the largest trial conducted with hydroxychloroquine was the arm of the WHO Solidarity study, which randomized 954 patients to hydroxychloroquine and 906 patients in the control arm. Although not statistically significant, this trial found a slightly higher in-hospital mortality in the hydroxychloroquine arm [15]. The risks associated with hydroxychloroquine, specifically when combined with azithromycin, far outweighed any potential benefit [24, 25]. The safety studies conducted for hydroxychloroquine excluded patients with history of arrhythmias or corrected QT (QTc) interval prolongation at baseline and patients with structural heart disease or concomitant medications which may prolong QTc interval. In practice, this is not always possible, as many patients may have underlying arrythmias or QTc interval prolonging prior medications. The potential for cardiac toxicity and prolonged QTc interval, in the general population, although in some cases not statistically significant, and the lack of benefit in numerous studies, specifically RECOVERY and WHO Solidarity, made hydroxychloroquine fall out of favor early on in the pandemic [15, 19, 26, 27]. Many scientists speculated that earlier hydroxychloroquine administration may improve beneficial effects;

72

J. Patel

however, a randomized trial in nonhospitalized patients with COVID-19 when administered hydroxychloroquine within 1–2 days of symptom onset did not see a difference in severity of symptoms, but significantly increased adverse effects; 43% in the hydroxychloroquine group versus 22% in the placebo group [28]. Hydroxychloroquine is administered orally and can cause gastrointestinal upset (nausea, vomiting, and diarrhea) which can be managed if the medication is taken with food. Though cardiomyopathy has been reported in long-term use of this medication for rheumatic diseases, the only reported cardiovascular side effect of this medication for the duration of treatment for COVID-19 is QTc prolongation. It may be beneficial to monitor QTc regularly when administering other medications in conjunction with hydroxychloroquine that may prolong a patient’s QTc. Delayed hypersensitivity reactions of the skin may occur, but are reported as non-life-­ threatening. Severe hypoglycemia is a rarely reported side effect in patients with and without diabetes who take hydroxychloroquine. Because this medication was originally used for rheumatic diseases and malaria, there are some adverse reactions reported as time-related, such as skeletal muscle myopathy, retinopathy, and neuropsychiatric effects; however, due to the shorter treatment time for COVID-19, these side effects are less likely [29].

4.5

Lopinavir/ritonavir

Lopinavir/ritonavir is an antiretroviral combination product that The Federal Food and Drug Act (FDA) approved for the treatment of human immunodeficiency virus (HIV). Both agents are protease inhibitors, but ritonavir’s primary action is by inhibiting the Cytochrome P450 enzyme family, CYP3A4, to induce metabolism of lopinavir, increasing its plasma concentration. Lopinavir’s mechanism of action is inhibition of HIV-1 protease enzyme, preventing the cleavage of specific polyprotein precursors. The result is a noninfectious and immature viral particle incapable of further virulence [30]. In SARS-CoV-2 viral infections, it became a medication of interest because of its in vitro activity against SARS and MERS [31, 32]. A multicenter, retrospective matched cohort study in SARS and MERS found that when lopinavir/ritonavir was combined with ribavirin and corticosteroids, there was a reduction in mechanical ventilation requirements, need for rescue treatments with corticosteroids, viral loads, and mortality [33]. These positive findings led to the study of lopinavir/ritonavir in SARS-CoV-2 in a randomized, controlled, open-label trial in China. Patients in the treatment arm were given lopinavir/ritonavir 400 mg/100 mg tablets orally twice daily for 14 days, and the control group was given standard care. The primary outcome evaluated was time to clinical improvement, with secondary outcomes being mortality rate, and detection of viral RNA over a period of time. None of these outcomes were clinically significantly different between the study groups. In addition, the noted adverse effects of lopinavir/ritonavir were quite extensive, including QTc interval prolongation, hepatotoxicity, elevated cholesterol, hyperglycemia, skin rash, gastrointestinal (GI) effects, pancreatitis, and weight gain [34]. Lopinavir/ritonavir, being strong CYP3A4

4  Pharmacological Management

73

inhibitor, has also posed problems with significant drug-drug interactions [32, 33]. This protease inhibitor combination was also an antiviral arm studied on a larger scale in both RECOVERY and WHO Solidarity, both of which found no benefit in the treatment of COVID-19 [15, 19]. Lopinavir/Ritonavir is a combination drug trademarked under the name Kaletra in the United States and is available as a tablet and as an oral solution. The tablet formulation should not be broken or crushed and should be swallowed whole. The oral solution contains propylene glycol and ethanol and its use through polyurethane feeding tubes is contraindicated. As mentioned above, the side effects of Lopinavir/Ritonavir are extensive. In one study examining the effects of Lopinavir/ Ritonavir, 14% of the study population could not complete the 14-day drug course due to the side effects, namely, gastrointestinal upset [34]. Therefore, it may be difficult to maintain compliance with treatment. Liver function studies and a baseline electrocardiogram should be obtained prior to therapy initiation and should be routinely monitored during the course of the therapy.

4.6

Ivermectin

Ivermectin is an anthelmintic agent primarily used in animals for heartworm treatment and in humans for parasitic infections from animals, like strongyloidiasis. Ivermectin has been studied both in vitro and in vivo for COVID-19. The proposed mechanism of its activity against SARS-CoV-2 is the binding of ivermectin to the Imp α/β1 heterodimer. This blocks the SARS-CoV-2 viral protein from binding to this heterodimer, which is a necessary step to enter the nucleus for viral replication. Caly and colleagues studied ivermectin and its effect on viral load reduction in Vero-hSLAM cells. These are a nonhuman cell line used for biological studies, typically derived from the African Green Monkey [35]. The investigators found that they were able to reduce the viral RNA by 99.98% at 48 h, when they used an inhibitory concentration 50% (IC50) of 2.5 μM. IC50 is the minimum concentration needed to reduce viral load by 50%. This initial laboratory study was the basis for dose-­ finding pharmacokinetic studies and then actual human studies. Converting the concentration needed for this reduction in viral load would make 2.5  μM equal to 2190  in ng/mL.  Several pharmacokinetic studies investigated doses previously known to be safe in humans to see if they would meet the concentration requirements determined to reduce SAR-CoV-2 viral load by Caly and colleagues [35]. A 12 mg dose (150–200 μg/kg) studied by Krishna and colleagues yielded a maximum plasma concentration (Cmax) of 30 ng/mL, a study with 36 mg dose (550–700 μg/ kg) generated a Cmax of 96.2 ng/mL, and a study with 120 mg (1400–2000 μg/kg) produced a Cmax of 247.8 ng/mL [36–38]. Therefore, the concentration needed is 72 times the standard dose of ivermectin and 9 times the highest dose ever studied and deemed safe in humans [39]. Concerns with higher doses are that it may potentially cross the blood brain barrier and potentiate GABA neurotransmission, causing central nervous system depression. Human side effects with higher doses that are known are vomiting, echocardiogram (EKG) abnormalities, tachycardia, fluctuating

74

J. Patel

blood pressures, vomiting and drowsiness, ataxia, and visual disturbances [39]. Despite this, several studies have been conducted in humans for COVID-19, mainly at doses used for current indications in humans (200 μg/kg). A study of 280 patients evaluating ivermectin with usual care use or a control group receiving only usual care, conducted in four hospitals in Florida, found an improved mortality in the ivermectin group; however, there was a statistically significant higher number of patients who received corticosteroids in the ivermectin group. It was also retrospective in nature and was not randomized [40]. The Ivermectin in COVID-19 (ICON) study, a retrospective study in hospitalized COVID-19 patients found a reduced mortality in patients with on ivermectin compared to usual care. Once again, however, the ivermectin group had significantly more steroid use [41]. Ivermectin has been suggested to be helpful early on in treatment, and therefore, was studied in the outpatient population with mild to moderate disease. An open-label randomized study compared outpatient adults with positive SARS-CoV-2 results, who were randomized to ivermectin 200 μg/kg for one dose with standard of care versus standard of care alone. Standard of care for the investigators was antipyretics, cough suppressant and doxycycline 100 mg twice daily for 7 days. The primary outcome was time to resolution of symptoms, and they found no clinical benefit [42]. There are also other several non-randomized studies, with small sample sizes or no comparator groups, all leading to conflicting results [43–47]. Beltran Gonzalez and colleagues conducted a randomized placebo-controlled (RCT) trial looking at duration of hospitalization and found no difference, Lopez-Medina and colleagues investigated time to resolution of symptoms in a RCT and also found no difference in outcomes [48, 49]. One study found a reduced risk of death, but the study was only powered to detect a difference in clinical recovery within 45 days and the sample of each arm was only 30 patients [50]. Even the difference in viral clearance at 7 days was found to be insignificant in a randomized controlled trial with an extremely small sample of only 12 patients [51]. The majority of all these studies are preprint and have not been peer-reviewed. Many countries still have ongoing trials, in various stages; however, given the data for newer treatment modalities, the pharmacokinetic profile of the medication, and the need for toxic doses to make a difference with COVID-19, the repurposing of ivermectin is unlikely to be successful.

4.7

Other Antivirals

Favipiravir is also an RNA-dependent RNA polymerase inhibitor, with antiviral activity against influenza. It has not been approved for use in the United States, but is used in Japan for influenza; however, adverse reactions and drug interactions are of concern and are not well-established. Therefore, it has not been well-studied for COVID-19. Nitazoxanide is another anthelmintic approved for the use of diarrhea-­ associated Giardia lamblia or Cryptosporidium parvum. It has both antiviral properties, predicted to be via inhibition of viral cell entry, and anti-inflammatory properties by causing a reduction in cytokines, specifically interleukin (IL)-6 [52]. In vitro data suggest that its activity is not as selective for SARS-CoV-2 and was

4  Pharmacological Management

75

inferior to remdesivir [10]. SARITA-2, a double-blind, placebo-controlled trial, investigated viral clearance at day 7 and found a significant difference; however, it’s translation into clinical efficacy is yet to be established. The investigators found no difference in symptom resolution between the two groups [53]. Nitazoxanide is not a recommended treatment in the current IDSA or NIH guidelines [3, 14]. The WHO Solidarity trial studied interferon as one of its arms for the treatment of COVID-19; however, there was no improvement found in outcomes, and in fact, there was a non-statistically significant increased risk of mortality in the interferon group. This arm of the trial had 2050 patients in each, the study drug arm and the control group [15]. The newest antiviral medication which is showing promise, even in its initial investigation stage, is molnupiravir, an orally bioavailable prodrug which metabolizes to a β-D-N4-hydroxycytidine (NHC) analog. It has a similar mechanism to remdesivir and favipiravir in that it is an inhibitor of RNA-dependent RNA polymerase; however, it differs in that it does not simply delay chain termination, but causes lethal mutations in the viral RNA with each replication by incorporating itself into the RNA and increasing the frequency of G to A and C to U transition mutations [54–56]. NHC analogs have shown potent activity against SARS-CoV-1, MERS, and more recently, against SAR-CoV-2 [57]. Its activity is attributed to its ability to evade proofreading by viral 3′-5′ exoribonuclease (ExoN). This decreased proofreading sensibility was not observed with ribavirin or 5-fluorouracil, contributing to their inefficacy against the SARS-CoV-1, MERS [58]. Zhou and colleagues demonstrated this same potent mutagenesis in cell culture, but also studied its potential to target deoxyribonucleic acid (DNA) replication also, in Mammalian Cell Assay. They suggested, based on the common intermediate enzymes required for both RNA and DNA synthesis, ribonucleoside diphosphates, and 2’deoxyribonucleoside triphosphates, that there is a potential for the mutagenesis to occur in the host cells also. The caveat to this study is that it was conducted on diploid cells in an assay, which were in the process of replication, so its applicability would be to cells that are in replication only [59]. Sheahan and colleagues, however, found that there was increase in viral mutation, but not in host cell transcription genes [60]. Two phase I clinical trials (a human safety trial) for molnupiravir against SARS-CoV-2 have been conducted and shown to be safe at 28 days [61, 62]. A phase II/III clinical trial, MOVe-OUT, in its preliminary results released only in a press release, has shown an efficacy against the virus not seen with other polymerase inhibitors, including reduced hospitalizations by half. One of its primary outcomes is to look at adverse effect profile out approximately 7 months from drug administration [63]. It is also being studied in another phase III trial (MOVe-­ AHEAD) to determine its efficacy in postexposure prophylaxis, with no results released as of yet [64]. The anticipation of the final results from these studies, slated to be published later this year, may determine the course of future therapies, giving us another option for early treatment of COVID-19, and potentially for postexposure prophylaxis. In summary, the only antiviral currently approved based on the clinical trials to treat COVID-19 is remdesivir. The NIH guidelines recommend against the use of nitazoxanide, hydroxychloroquine, chloroquine, and lopinavir/ritonavir, and neither

76

J. Patel

recommend for or against ivermectin given the insufficient evidence to prove its efficacy and questionable safety [3].

4.8

Anti-SARS-CoV-2 Antibody Agents

When obtaining immunity from a SARS-CoV-2, there are essentially two main methods: adaptive immunity and passive immunity. Adaptive immunity is developed after an exposure to the antigen you need antibodies against (either by infection or vaccination). The initial activation of your immune system releases cytokines responsible for creating an increase in mature neutrophils, and lymphocytes, among other inflammatory mediators. The two main types of lymphocytes are T-cells and B-cells. T-cells can be further differentiated into CD4+ or CD8+ cells. CD8+ cells produce a direct cytotoxic effect to the antigen. CD4+ cells are called helper T-cells because of their 2 main functions: to produce more CD8+ cells and to produce virus-­ specific memory CD8+ cells, and B-cell antibody formation. CD8+ memory cells and B-cells are memory cells that store information about the antigen, making it a much faster process to manufacture and release antibodies specific for the antigen encountered [65]. Antibodies essentially either will be binding antibodies, whereby they bind to a pathogen and flag down the immune system, namely your macrophages, to destroy it, or neutralizing antibodies, which bind to the spike protein of SARS-CoV-2 and prevent its entry into the cell. These T-Cells, B-Cells, and antibodies have been found in the plasma of patients who have recovered from COVID-19 [66]. Also of note, neutralizing antibodies are highest in patients who have had severe COVID-19, possibly suggesting that they may play an important role in protection in the advanced immune response to COVID-19, after the initial immune response has failed [9]. Passive immunity would be the transfusion of these antibodies from a recovered patient (convalescent plasma), or monoclonal antibodies into the patients with active COVID-19 infections, who may not have enough of those antibodies in their own circulation.

4.9

Convalescent Plasma

Convalescent plasma is essentially derived from donated plasma from patients who have recovered from COVID-19. Since patients may each produce different amounts of antibodies, the time at which the antibody levels begin to fall in the plasma differs individually, and because the differentiation of virus-neutralizing antibodies from binding antibodies is not an easy process, the studies conducted on convalescent plasma for COVID-19 have not been positively conclusive. In a large observational trial, investigators described mortality rates based on high, medium, and low antibody titers with predetermined cutoffs for each titer group. They reported a lower 30-day mortality rate as the antibody titers increased, with 29.6%, 27.4%, and 22.3 in the lower titer, medium titer, and high titer groups, respectively. When subgroup analyses were conducted, this significance was not reproducible in patients

4  Pharmacological Management

77

who received mechanical ventilation before the plasma infusion and was only seen in patients who were not mechanically ventilated prior to infusion [67]. In other open-label, placebo-controlled studies, there was also no difference in mortality found with the infusion of convalescent plasma [68, 69]. These studies did not base their statistical calculations on antibody titer tiers; however, the mean antibody titer in one of them was noted to be higher than the antibody titer in the “high titer” group from Joyner and Colleagues [68]. Only one placebo-controlled study found a significant difference in mortality, specifically in patients aged greater than 75 years when transfused with convalescent plasma within 72 h of symptom onset [70]. While research on the use of convalescent plasma is ongoing, the National Institutes of Health COVID-19 Treatment Guidelines Panel have made several recommendations against the use of Convalescent Plasma in treating COVID-19 [71]. Specifically, they recommend against the use of low titer COVID-19 convalescent plasma which is no longer authorized for use under the Food and Drug Administration’s Emergency Use Authorization (EUA) for convalescent plasma. As of February 2021, the FDA revised the EUA to limit its use to high-titer COVID-19 convalescent plasma and only for the treatment of hospitalized patients early in the disease course or hospitalized patients with impaired immunity [72].

4.10 Monoclonal Antibodies Monoclonal antibodies are synthetic neutralizing antibodies, and also have direct cytotoxic and phagocytic activity against SARS-CoV-2 [73]. The advantage to monoclonal antibodies is that they can be produced in larger and more predictable quantities, since manufacturing of the antibodies is not reliant on post-infected individuals to donate their plasma. They are also highly specific for the S1 domain of the receptor binding protein (RBD) [9]. This is the part of the spike protein for SARS-CoV-2, which allows the virus to bind to the host cell receptor. When monoclonal antibodies bind to this domain, they block the entry into the host cell. There are currently four combination antibodies studied, and three single antibodies studied. The two combinations that are most commonly administered are bamlanivimab with etesevimab and casarivimab with imdevimab. Bamlanivimab has been studied as monotherapy compared to placebo in the BLAZE 5 (NCT04701658), ACTIV-2 (NCT04518410), and ACTIV-3 (NCT04501978) trials and in combination with etesevimab in the BLAZE-1 (NCT04427501) [74], BLAZE-2 (NCT04497987) [75], and BLAZE-3 (NCT04427501) [76] trials. The combination significantly reduced the rate of hospitalization or death by any cause a day 29  in high-risk patients, including symptoms resolution, whereas in non-high-risk patients, it reduced hospitalizations and emergency room visits significantly, but did not affect symptom resolution [76]. On February 9, 2021, the FDA gave an emergency use authorization (EUA) for bamlanivimab with etesevimab in patients over the age of 12  years, weighing >40 kg, with high-risk criteria and mild to moderate COVID-19 within 10  days of symptom onset, at a dose of 700  mg/1400  mg IV once over at least 60 min with a 1-h post-dose observation period. High-risk criteria are described as

78

J. Patel

age greater or equal to 65  years, medical history of diabetes mellitus, receiving immunosuppressant therapy, chronic kidney disease, or a body mass index (BMI) of 35 kg/m2 or more; in addition, if the patient is over 55 years with cardiovascular disease, hypertension or chronic obstructive lung disease (COPD), asthma, or other lung diseases. For patients between 12 and 17 years, it was approved for patients who have a BMI in the 85th percentile or more for their age and gender, have been diagnosed with sickle cell disease, congenital or acquired heart disease, neurodevelopmental disorders, asthma, or other chronic respiratory diseases requiring daily medication for control, and anyone dependent on any type of medical technology for survival [7]. Bamlanivimab monotherapy was also studied in non-vaccinated or previously infected nursing home residents and staff who had exposure to one or more cases of SARS-CoV-2  in the home, in one arm of the BLAZE-2 trial. Bamlanivimab significantly reduced the incidence of symptomatic COVID-19 (SARS-CoV-2 positivity in addition to worsening disease severity within 21 days of exposure) [75]. This trial is expected to be submitted for an EUA for bamlanivimab use in postexposure prophylaxis for SARS-CoV-2. In the REGN-CoV trial, casirivimab and imdevimab were studied as a combination and the preliminary results have found that the antibody combination can reduce the viral load, specifically in patients who had a very high viral load (greater than 106 copies/mL) at the time of infusion or who were serum antibody-negative (seronegative), signifying that their immune system had not yet generated antibodies [77]. Based on the findings of this trial, the FDA issued an EUA for casirivimab and imdevimab combination also on November 21, 2020, with the same use criteria as bamlanivmab and etesivimab [8]. The dose approved is 2400  mg (1200  mg/1200  mg casirivimab/ imdevimab, respectively) intravenous over 1  h, with a 1-h observation time. The RECOVERY trial also had a study arm investigating casirivimab and imdevimab. They found a reduction in 28-day mortality and a reduction in progression to mechanical ventilation in hospitalized patients with SARS-CoV-2 who were seronegative [78]. Other monoclonal antibody combinations currently being studied are cilgavimab and tixagevimab, and BRII-196 and BRII-198. Cilgavimab and tixagevimab combination is derived from the B cells of convalescent patients after SARS-CoV-2 infection, in the phase II ACTIV-2 (NCT04518410) and phase III PROVENT (NCT04625725) trials showing promising results, as reported in the Astra-Zeneca press release, for prevention of symptomatic COVID-19 with one intramuscular injection [79]. BRII-196 and BRII-198 were also studied in ACTIV-2 as a phase III trial. Brii Biosciences, the company behind BRRI-196-BRII-198, submitted an application to the FDA for an EUA on October 9, 2021, after ACTIV-2 results showed a 78% reduction in hospitalization and death when given to patients with positive SARS-CoV-2 viral detection who were not hospitalized within 10 days of symptom onset [80]. The timing of the data collection for this portion of ACTIV-2 was January to July 2021, when various SAR-CoV-2 variants had been spreading rampantly around the globe. Although full trial publication is pending, the number of hospitalizations and deaths prevented by this monoclonal antibody combination, stratified by variant type, will be evaluated for EUA by the FDA. The company has conducted an in vitro study with a pseudovirus which proposes the combination has

4  Pharmacological Management

79

activity against the most common variants of concern, including Alpha, originated in the United Kingdom (B1.1.17), Beta, originated in South Africa (B.1.351), Delta, originally found in India, (B.1.617.2), Epsilon, originally isolated in California (B.1.429), and Gamma, originated in Brazil (P.1), Lambda (C.37), and Mu (B.1.621) [9, 80]. Three monoclonal antibodies are being investigated as single therapy. These are sotrovimab, regdanvimab, and TY027, the former of which was granted EUA by the FDA on May 26, 2021, based on interim data from the phase I, II, and III trials showing an 85% reduction in hospitalization and death. This EUA is granted with the same use criteria as the others mentioned [81]. Of all the monoclonal antibodies studied so far, the FDA has granted an EUA for bamlanivimab/etesivamab, casirivimab/imdevimab, and sotrovimab; however, not all of them have equal coverage of the many variants that are of concern. Bamlanivimab has retained activity against the alpha variant, but has been shown to have a 5–ten fold reduction in activity against the Delta and Epsilon variants, and has very little activity against Beta and Gamma variants [82–84]. Sotrovimab has been found to be active against Alpha, Beta, Gamma, and Epsilon variants, but has not been studied in the Delta variant [82, 83, 85, 86]. Casirivimab/imdevimab are active against all current variants of interest [82, 87]. For additional nursing considerations regarding administration of monoclonal antibodies, refer to the discussion in Chap. 8, Outpatient management of COVID-19.

4.11 Immunomodulators The initial phase of the COVID-19 disease is viral replication. Symptoms at this stage can be none to mild, including sneezing, fevers, cough, rhinitis, and general fatigue or body aches [88]. In about 81% of adult patients, this is where the worsening of disease halts, and they recover via the activation of the immune system by local inflammation signaling the innate immune system, and the virus is eliminated. However, in the remaining 19%, viral replication can continue and spiral out of control, leading to moderate to severe disease. As replication continues, creating local epithelial inflammation and cellular debris to form in the lung tissue, an inflammatory cascade is initiated in which the body continues to produce more inflammatory mediators and cytokines. This creates more cellular debris and the patient enters a stage of hyperinflammation, starting the process of what is known as a cytokine storm, ending with lung fibrosis and scarring [88]. Inflammation is a good thing in infection; it allows the mobility of cytokines that signal the production and release of the T-helper cells (CD4+) and the cytotoxic cells (CD8+) that we discussed earlier. It also signals macrophages and other mediators to help eliminate the virus and develop immunity for the host. However, when talking about cytokine storm, this inflammation is an unchecked hyper response and can be damaging to the body, as it is classically characterized by a reduction in CD4+ cells and an increase in CD8+ and natural killer (NK) cells [89]. Specifically, this inflammation in the lungs begins as neutrophils and macrophages exudate, reduce alveolar surfactant, and as a result, reduce alveolar patency and gas exchange. Cytokine storm also

80

J. Patel

causes vascular inflammation, disseminated intravascular coagulation (DIC), hypotension, largely fluctuating heart rate, and shock [88, 90]. Other hyperinflammatory characteristics of this stage have also been compared to hemophagocytic syndrome (HPS) or macrophage activation syndrome (MAS) [91]. HPS is a similar disorder in which an abundant production of cytotoxic T-cells and NK cells causes damage to multiple organs systems in the body. Clinically, patients may have fever, increased inflammatory markers (IL1B, IL-2, IL-6, IL-7, G-CSF1, TNF-a, and a few others), splenomegaly, coagulopathy, neurological dysfunction, cytopenias, and hemophagocytosis. The difference with traditional HPS described in the literature and COVID-19 is that splenomegaly is not a typical sign of COVID-19, and some of these other signs and symptoms may or may not be present in certain patients with COVID-19. MAS typically develops in patients with other underlying autoimmune diseases; however, its effects are also similar to some seen with severe COVID-19 disease [92]. Immunomodulators have been studied to address each aspect of this potentially devastating inflammation caused by SARS-CoV-2.

4.12 Corticosteroids Corticosteroids have a broad mechanism of immunomodulatory effects. They suppress adhesion of neutrophils to endothelial cells at the initialization of the inflammatory cascade, reduce the extravasation of plasma, the carrier to inflammatory mediators, through intracellular junctions, and also reduce gene expression; directly, by glucocorticoid receptors binding to glucocorticoid-responsive elements (GRE), and indirectly, by interacting with other transcription factors such as activator protein 1 and Nuclear Factor (NF)-κβ [91]. NF-κβ signaling is complex, but has been associated with the development of immunity and inflammation, among others [93]. Steroids also increase the production of anti-inflammatory markers by effects on second messenger cascades [91]. Corticosteroids have been controversial in COVID-19 for several reasons. The first being that it is known that steroids can reduce your innate immunity, and the second, because this immune modulation early in the disease when inflammation is minimal may actually potentiate viral replication, as has been seen with the use of steroids and other viruses, such as SARS and MERS [94, 95]. These data from similar viruses led to hesitancy to use corticosteroids early on in the pandemic, and it was not until the publication of the RECOVERY trial data [96], first released as a press release in June 2020, that corticosteroids became part of recommended standard therapy for moderate to severe COVID-19 [3, 14]. It is still not recommended in early disease, however, as the potential to propagate viral replication is still present, but now we have evidence to prove that there is also no benefit of steroids in early COVID-19 [96]. The RECOVERY trial’s dexamethasone arm was a highly powered, randomized controlled trial. The investigators concluded that dexamethasone at 6 mg daily, administered either orally or IV, for up to 10 days reduced 28-day mortality in patients requiring oxygen support; by 12.3% points (age-adjusted) for patients receiving mechanical ventilation; and by 4.2% points (age-adjusted) in patients requiring

4  Pharmacological Management

81

noninvasive ventilation. Patients who were not requiring oxygen support had no evidence of benefit from dexamethasone therapy, and there was potential for harm as the therapy had side effects such as hyperglycemia [96]. Steroids have been used in another severe respiratory disease for decades, including Acute Respiratory Distress Syndrome (ARDS), formerly known as Adult Respiratory Distress Syndrome. The severe stage of COVID-19 is almost always associated with ARDS; therefore, corticosteroids being beneficial in patients on mechanical ventilation were a reasonable therapy to investigate. ARDS, first described in 1967, is characterized by a progressive hypoxemia from respiratory failure with various causes, from pneumonia, to aspiration, and trauma [97]. The most commonly accepted definition of ARDS is using the Berlin criteria, requiring all the following: 1. Timing of worsening respiratory symptoms within 1 week of clinical insult. 2. Chest X-ray showing bilateral opacities not completely attributed to pleural effusions, lobar collapse, or nodules. 3. Respiratory failure that is not completely attributed to cardiac failure or fluid overload. In addition, patients must have a risk factor for developing ARDS, such as pneumonia, sepsis, or pancreatitis, and a study such as echocardiogram to rule out hydrostatic edema, and PaO2/FiO2 (PF) ratio of ≤300  mmHg [98]. The definition of ARDS severity is based on the following measured parameters: • Mild ARDS: PF ratio >200 to ≤300 mmHg with PEEP or CPAP ≥5 cm H2O. • Moderate ARDS: PF ratio >100 to ≤200 mmHg with PEEP or CPAP ≥5 cm H2O. • Severe ARDS: PF ratio ≤100 mmHg with PEEP or CPAP ≥5 cm H2O. Steroids have been studied in ARDS for their potential to act on the proliferative and fibrotic phases of the disease for decades with mixed results [99–102]. More recently, a meta-analysis [103] of randomized controlled trials was conducted for corticosteroid use in ARDS, mostly with methylprednisolone or hydrocortisone, and the analysis determined that all-cause mortality was significantly lower as was the duration of mechanical ventilation, and there was a significant increase in ventilator-­free days in the corticosteroid group, even after a sensitivity analysis to remove the trials with a high potential for bias. A subgroup analysis also found that 60-day mortality was significantly higher in patients started on systemic corticosteroids 14 days or greater after the diagnosis of ARDS [103]. The authors concluded that although steroids may decrease mortality and ventilation duration, caution must be used to extrapolate as the doses and choice of agent in the trials are variable, and much of the initial experience with steroids has been in observational trials. Of note, this study was published in March, 2020, prior to the RECOVERY trial, and also did not include any trials on ARDS secondary to SARS-CoV-2 specifically. In the summer of 2020, a randomized controlled trial for the use of dexamethasone in ARDS secondary to COVID-19 was conducted, which found an improved 28-day ventilator-­free survival rate in patients in the dexamethasone arm, compared to

82

J. Patel

standard care [104]. This study is important to analyze for two reasons: first, the investigators did not have a previous comparator group to base their power calculations on; therefore, although the calculated sample size was a total of 290 patients, prior to the first interim analysis, they decided to increase the same size to a total of 350 patients, based on the Pitman Asymptotic relative efficiency [105]; second, the trial was terminated early as the results from the RECOVERY trial had been finalized, and the data and safety monitoring committee for the trial felt it would be unethical to continue the trial with such strong evidence pointing in favor of dexamethasone in RECOVERY [96]. The total number of patients enrolled was 299; therefore, despite the trial being terminated early, there was some evidence that dexamethasone in ARDS from COVID-19 was beneficial [104]. The dose used in this trial was 20 mg daily for 5 days, followed by 10 mg daily for 5 days, the same as used in the DEXA-ARDS trial by Villar and colleagues [106]. The DEXA-ARDS trial found a significant reduction in 28-day ventilator-free days as well, although this study was statistically underpowered secondary to a sharp decline in enrollment after 2017. Since it was an underpowered study, the authors concluded that dexamethasone may reduce duration of mechanical ventilation and mortality in patients with ARDS [106]. Several other studies have investigated methylprednisolone in COVID-19 also, and many have found a reduction in mortality; however, the trial design of RECOVERY makes a very strong argument for dexamethasone 6  mg daily for 10 days. Society of Critical Care Medicine (SCCM) guidelines for ARDS recommend methylprednisolone 1 mg/kg (or equivalent dose of another steroid) in early ARDS (within 7 days of symptom onset) and 2 mg/kg methylprednisolone or equivalent in ARDS with symptom onset greater than 6 days. They recommend following with a slow taper over following 6–14 days [107]. Despite all the different literature for steroid use in the various study populations, the current NIH guidelines for the Therapeutic Management Hospitalized Patients with COVID-19 recommend using dexamethasone 6 mg daily for 10 days in patients requiring oxygen supplementation, based on the evidence of the RECOVERY trial [3]. Patients who receive corticosteroid therapy should be monitored closely for adverse effects such as peptic ulcer disease, hyperglycemia, secondary infections, psychiatric/behavioral changes, and avascular necrosis. In addition, systemic corticosteroid may increase the risk of opportunistic fungal infections or reactivation of latent infections into active disease. There have been some cases of strongyloidiasis reported in COVID-19 patients being treated with corticosteroids [4]. It is important to monitor patients for evidence of any opportunistic infection.

4.13 Tocilizumab Tocilizumab is a monoclonal antibody which inhibits IL-6 receptor activity, reducing further inflammatory mediators. In 2017, the FDA approved tocilizumab for the treatment of cytokine storm, more formally known as cytokine release syndrome secondary to T-cell engaging therapy, which may cause severe and life-threatening

4  Pharmacological Management

83

proinflammatory conditions [108]. As COVID-19 was observed to have characteristics similar to cytokine storm in severe cases, early on in the pandemic, interest to study tocilizumab in this population grew. Initial data were derived from case studies from China in the early phase of the pandemic. There are six peer-reviewed observational studies for tociluzumab [109–114] and six major peer-reviewed randomized controlled trials [115–120]. Gupta and colleagues published a retrospective observational study of patients who received tocilizumab within 48 h of ICU admission for COVID-19-related critical illness, but had been hospitalized for no more than 7 days prior. They observed in-hospital death, a 30-day mortality rate, and infection rate among patients who received tocilizumab and those who did not. They reported that patients who received tocilizumab within 48 h had a mortality rate of 28.9% versus 40.6% in patients who did not. Thirty-day mortality was also lower in the tocilizumab group [109]. The main thing to note in this study, and another example of why randomized controlled trials are always important after initial observational trials, was that the tocilizumab group was more likely to receive corticosteroids, was younger, and had fewer comorbidities, although they did have more severe hypoxemia. Also, the comparator group used standard care, but may have received tocilizumab, only greater than 48 h after ICU admission. The study did not require elevation in inflammatory markers or specific diagnostic criteria for cytokine storm to be included. It has been demonstrated in a well-designed, statistically powered, prospective trial that corticosteroids improve mortality, so this may have affected the reason for the improved mortality in these patients [96]. As such, there are multiple limitations to these studies; biases, no comparator groups, and small sample sizes make these studies difficult to implement in practice; however, they do set the stage for more robust randomized controlled trials. In the RECOVERY trial [115], patients, who were positive for SARS-CoV-2, were hypoxic with an SpO2 ≤ 92% or requiring oxygen supplementation, and had a C-reactive protein (CRP) level ≥ 75 mg/L, were randomized to tocilizumab 8 mg/kg IV given once. All patients in this trial whether randomized to standard care or tocilizumab were no more than 14 days from symptom onset and no more than 5 days since hospitalization. The primary outcome of 28-day mortality was reached in only 31% of patients in the tocilizumab group, compared with 35% of patients in the standard care group, which was statistically significant, as were the outcomes of improved rate of discharge from the hospital and reduced risk of progression to mechanical ventilation and death, for patients who were not mechanically ventilated at the time of tocilizumab administration [115]. The benefits of this trial were seen in addition to corticosteroid use, as a similar number of patients received steroids in the both arms. The REMAP-CAP trial published just ahead of RECOVERY showed similar results, with their primary outcome being respiratory and cardiovascular support-­free days up to 21 days [116]. The patients were included if they were receiving respiratory or cardiovascular support at the time of randomization. Patients were randomly assigned to receive tocilizumab 8  mg/kg over 60  min once within 24  h of ICU admission compared to standard care. REMAP-CAP did not include inflammatory marker cutoffs, but instead chose to study the clinical endpoint of organ

84

J. Patel

support-­free days for the respiratory and cardiovascular system [116]. COVACTA, a multicenter, randomized, double-blinded, placebo-controlled phase III clinical trial, in contrast, found no difference in their primary outcome of clinical status at day 7 in the 7-category ordinal scale [117]. This trial was published just after the initial results of the RECOVERY steroid arm were released, and therefore, a majority of patients did not receive corticosteroids. In fact, more people received steroids in the usual care arm than in the tocilizumab arm, but this was unlikely to make a difference in outcomes, as there was no mortality difference observed. The investigators did find a potential decreased ICU length of stay and time to hospital discharge in patients who were not mechanically ventilated at the time they received tocilizumab. Rosas and colleagues also found that fewer patients progressed to mechanical ventilation [117]. The remaining three randomized controlled trials did not find a difference in clinical outcomes with the use of tocilizumab; however, one was an open-labeled trial in which the usual care group received corticosteroids twice as much as the tocilizumab group [120] and the remaining two trials were in patients requiring significant amounts of oxygen and found no difference in rates of mechanical ventilation or death [118, 119]. The current NIH guidelines for COVID-19 management recommend considering tocilizumab in combination with dexamethasone in patients requiring noninvasive ventilation, or invasive ventilation or extracorporeal membrane oxygenation (ECMO) if oxygen requirements are increasing rapidly, and have a CRP >75 mg/L and within 24 h of ICU admission, as this is where both RECOVERY and REMAP-CAP found a significant benefit [3]. Tocilizumab is administered intravenously over 60 min and should be infused through a dedicated IV line without other agents infusing at the same time. If repeated dosing is required, they should be administered at least 8 h apart. If the medication appears opaque or there is discoloration visible, the dose should not be administered. The most commonly noted adverse effects of this medication are increased serum cholesterol in adults, constipation, neutropenia, increased serum transaminases, and hypersensitivity reactions to the infusion [121]. There is a less than 10% chance of developing deep vein thrombosis, hypertension, peripheral edema, and septic shock. If neutropenia or thrombocytopenia occurs, the dose interval or dose amount may require modification. Significant hepatic injury has been documented, so if a patient is taking another hepatotoxic drug concurrently to this medication, liver function testing should be performed regularly, and treatment interruption or dose modification may be required. Hypersensitivity reactions may occur as early as the first dose, so medications for treatment of this type of reaction should be readily available when administering the medication. If a hypersensitivity reaction is noted, the treatment should be discontinued immediately. As this medication suppresses the activity of certain parts of the immune system, patients receiving the medication may be at increased risk for severe opportunistic infections or reactivation of infections such as that of herpes zoster or tuberculosis. This medication also affects the person’s defenses against malignancies. Concomitant use of tocilizumab with other biological disease-modifying antirheumatic drugs should be avoided due to the increased risk of infection [121].

4  Pharmacological Management

85

4.14 Sarilumab Sarilumab is another IL-6 inhibitor that may have potential benefit in COVID-19 also; however, it is currently in a global phase II/III study [122] and has only really been studied in REMAP-CAP as a subcutaneous dosing [116]. Therefore, at this time, it is only recommended if tocilizumab is not available [3].

4.15 Baricitinib A Janus Kinas (JAK) pathway inhibitor, baricitinib, is proposed to have anti-­ inflammatory properties and antiviral properties. This intracellular signaling pathway, activated by cytokine receptor signaling, allows the intracellular JAK family to phosphorylate and activate signal transducers and activators of transcription (STATs); these then regulate gene expression within the cell. Baricitinib’s anti-­ inflammatory properties come from the inhibitor of this JAK-STAT signaling cascade, preventing T-cell differentiation and proliferation and the elevation of other proinflammatory cytokines [123]. Its antiviral properties are associated with the inhibition of AP2-associated protein kinase 1(AAK1) interaction with cyclin G-associated kinase (GAK). This interaction allows the endocytosis of the virus into the nucleus, creating the release of more hyperinflammatory mediators [124]. Having said this, it is important to note that the inhibition of this pathway also reduced gene expression of erythropoiesis, myelopoiesis, and platelet production and can have innate viral immunomodulatory effects, reducing the innate immune response [123]. The two main trials for baricitinib that have been conducted are ACTT-2 [125] and COV-BARRIER [5], the latter of which is a preprint and has not yet been peer-­ reviewed. ACTT-2 was a randomized double-blind placebo-controlled trial, in which all patients received remdesivir for ≤10 days and were randomized to receive either baricitinib 4 mg daily for up to 14 days or placebo. The primary outcome was time to recover from day one to day 29. The remdesivir with baricitinib group recovered 1 day faster than the group with remdesivir alone, which was a statistically significant finding; the greatest improvement being in the patients who were on supplemental oxygen or noninvasive ventilation. Their median time to recovery was 10 days compared to the placebo counterparts, who recovered at a median time of 18 days. Other baseline characteristics that resulted in a slightly better recovery were patients between the ages of 40 and 65 years, males compared with females, and non-Hispanic or Latino patients. Adverse events in this study were similar between the two groups and included hyperglycemia, lymphopenia, anemia, and acute kidney injury. Patients who received glucocorticoids did, however, have more serious or nonserious new infections than those who did not; 25.1% compared to 5.5%, respectively [5]. Given this information and the more robust data for the benefit of glucocorticoids, many practitioners preferred to use remdesivir with dexamethasone, and baricitinib was used primarily in patients who had contraindications

86

J. Patel

to or adverse effects with dexamethasone. COV-BARRIER [5], which has not yet been peer-reviewed, was designed to study baricitinib with and without what is now standard of care. The study included only patients requiring supplemental oxygen, but not mechanical ventilation or ECMO at baseline. Approximately 80% of all patients received glucocorticoids, of which 90% was dexamethasone. The primary endpoint was the progression of disease (progression to high-flow nasal cannula, mechanical ventilation, ECMO, or death) by Day 28. The primary outcome was measured in all patients, and a separate report was generated for patients who did not receive steroids. Investigators found that the proportion of patients who progressed by day 28 were not significantly different between the groups. Among the key secondary outcomes, however, there was a significantly reduced all-cause mortality (38.3% reduction) in patients treated with baricitnib in addition to standard care compared with placebo, the highest benefit being in patients on noninvasive ventilation, with or without steroid use, without remdesivir use at baseline, and although significant for any duration of treatment, more so in those with disease duration of 100 beats/ min, severe pain or pressure in chest, severe shortness of breath, hypotension (systolic blood pressure