Paediatric Allergy and Clinical Immunology (As Applied to Atopic Disease): A Manual for Students and Practitioners of Medicine (Fourth Edition) 9781442653016

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PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY (as applied to Atopic Disease)

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CECIL COLLINS-WILLIAMS

Paediatric Allergy and Clinical Immunology (as applied to Atopic Disease) a manual for students and practitioners of medicine FOURTH EDITION

U N I V E R S I T Y OF TORONTO PRESS

© University of Toronto Press 1973 Toronto and Buffalo Printed in Canada ISBN 0-8020-2058-5 LC 72-94918

Contents

Preface / vii History taking / 3 Respiratory allergy in children / 12 Asthma / 12 Hay fever / 24 Allergic rhinitis / 26 Allergic bronchitis / 27 Symptomatic treatment of respiratory allergy / 27 Nasal smears / 28 Eczema (atopic dermatitis) / 32 Urticaria and angioedema / 38 Gastrointestinal allergy / 43 Drug hypersensitivity / 48 Penicillin sensitivity / 51 Drugs inducing hypersensitivity not involving allergic mechanisms / 55 Acute reactions to bee stings / 57 Indications for removal of tonsils and adenoids in the allergic child / 59 Immunization of the allergic child against infectious disease / 60 Preparation and maintenance of a dust-free environment / 62 Dosages of drugs useful in the care of allergic children / 65 Skin testing / 71 Hyposensitization therapy in atopic disease / 75 Prophylaxis of allergy / 82 Common mistakes in the care of the allergic patient / 83 The optimistic approach to the care of the allergic patient / 84 The four types of allergic reactions responsible for clinical hypersensitivity and disease / 85 Anaphylaxis in man / 87

vi C O N T E N T S

The immunoglobulins / 92 Immunoglobulin IgE (reagin) / 92 Immunoglobulin IgA / 95 The atopic constitution - pulmonary aspergillosis / 99 Bibliography / 102 Glossary / 104 Appendix A: Elimination diets /111 Milk-free diet / 112 Egg-free diet / 113 Wheat-free diet / 114 Wheat-egg-milk-free diet / 115 #1 Elimination diet (Rowe) / 117 #2 Elimination diet (Rowe) / 122 #3 Elimination diet (Rowe) / 125 #4 Elimination diet (Rowe) / 133 Cereal-free elimination diet (Rowe) / 134 Cereal-free and fruit-free elimination diet (Rowe) / 137 Appendix B: Immunological deficiency diseases / 141 Appendix C: Beta adrenergic blockade - Cyclic 3'5' AMP / 150 Appendix D: Pathophysiology of asthma / 158

Preface

This manual of paediatric allergy and clinical immunology as applied to atopic disease is not meant to be a complete textbook. It is presented as a quick reference for the medical student or practising physician to aid him in the investigation, diagnosis, and treatment of allergy in children and in understanding the basic underlying principles of atopic disease. It is based on procedures used at The Hospital for Sick Children in Toronto, Canada. Dr Cecil Collins-Williams, B.A., M.D., F.R.C.P.(C) is Head of the Allergy Division and Senior Staff Physician at The Hospital for Sick Children, Toronto, and Associate Professor of Paediatrics at the University of Toronto. ACKNOWLEDGMENTS

The author acknowledges the help given him by the Medical Publications Department of The Hospital for Sick Children, Toronto, in the preparation of the manuscript; and thanks Dr Paul Swyer for the use of the nomogram on page 20 and his help in preparing Section 10, p. 19; Dr Gerald Arbus for the use of his nomogram on page 21 and his help in preparing Section 10, p. 19; the Visual Education Department, The Hospital for Sick Children, for the preparation of figures on page 93 and in Appendices B, C, and D. The author is grateful to Lea and Febiger, Philadelphia, and to Albert Rowe Jr, M.D., for permission to publish the Rowe Diets in Appendix A; Blackwell Scientific Publications for their permission to publish Figure 5 and Table IX in Appendix B; Dr Margaret M. Wood for her help in preparation of the Cyclic AMP Charts in Appendix C; Dr Robert Orange for his advice in the preparation of Appendix C; and Dr Henry Levison, Chief of Respiratory Physiology, The Hospital for Sick Children, for writing Appendix D.

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PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY (as applied to Atopic Disease)

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History taking

Treat the whole patient, not just his allergy. On the following pages is the allergy history form used at The Hospital for Sick Children. At first glance this looks formidable, but after a little experience such a form can be completed in about twenty minutes, and it will give a clear picture of the allergic aspects of the patient's condition. A functional enquiry and a history directed to other complaints are required also. Remember that, when such a history is taken, it involves planning to embark on a long treatment programme, usually requiring three or more years. Such a programme cannot be started intelligently without a good history.

THE HOSPITAL FOR SICK CHILDREN ALLERGY SERVICE

DIAGNOSES (Mork Principal Diagnosis)

(1) (2) (3) (4) (5) (6)

ALLERGIC COMPLAINTS WITH AGE OF ONSET Yes

Age of onset

Wheezy breathing Cough Repeated colds Nasal discharge Post-Nasal drip Nasal obstruction Sneezing Itching of nose Itching of eyes Running eyes Red eyes Eczema (atopic) Dermatitis (contact) Urticaria Ang ¡oedema Failure to Thrive Feeding Problems

Additional notes about allergic complaints:-

No

SEVERITY Severe

Moderate

Mild

AGE OF DISAPPEARANCE (if still not present)

FOR EACH OF THE ALLERGIC COMPLAINTS, COMPLETE THE FOLLOWING;Yes

No

WHEEZY BREATHING [UMark if this section is not applicable (a) Is this wheezing typical of asthma i.e. an expiratory wheezing sound, whether with or without an accompanying head cold? If no, describe in detail (b) (i) Is there always or nearly always accompanying dyspnea? (ii) Seldom? (iii) Never? (c) (i) (ii)

•Mark one

Number of days attacks usually last Range in days

(d) (i) Have they ever necessitated hospitalization? (ii) How often? (iii) Date of last hospitaiization for asthma (e) Is there usually accompanying infection? Suggested by: (i) the patient appearing to have a cold? (¡i) low grade fever (101 or lower)? (iii) high fever (over 101)? (iv) tonsillitis, pharyngitis, purulent nasal discharge or otitis media observed by the physician? (v) has there ever been pneumonia confirmed by x-ray? (vi) colds in other members of the family?

Mark one

(f ) How many episodes in past 12 months? (g) Has there ever been chronic wheezing lasting as long as a month? (i) When? (¡i) How severe usually Severe with dyspnea Moderate Mild

•Mark one

(h) Additional notes

PERENNIAL ALLERGIC RHINITIS G Mark if this section is not applicable (a) Constant Intermittent (b) Severe Moderate Mild (c) Associated with mouth breathing Constant or almost constant Night only Day only (d) Associated with upper respiratory infections usually

Mark one Mark one

Mark one

Yes (e) Discharge if present is usually Watery Purulent

No

Mark one

(f ) Stuffiness of nose ¡s main symptom with little or no discharge (g) Additional notes

ATOPIC DERMATITIS

Q Mark if this section is not applicable

(a) Site(s) of onset (b) Areas which have been involved (c) Areas most commonly involved during the past year (d) Severity of rash Severe Moderate Mild (e) Severity of itching Severe Moderate Mild (f)

Ever secondarily infected? Often Rarely Never

Mark one

Mark one

Mark one

(g) Has patient ever been seen by a dermatologist? If so (i) When (ii)

Treatment prescribed

(h) Additional notes (including present and past treatment)

URTICARIA & ANGIOEDEMA D Mark if this section is not applicable (a) Acute (present under 3 months) Chronic (present over 3 months) (b) (i) (ii)

Constant? Number of episodes (if not constant)

(c) Distribution of lesions.

Mark one

Yes

(d) Appearance of lesions (i) Size Usual Shape (iii) Similar in size Vary greatly in size

No

Mark one

(e) Severity of itching (i) Severe (ii) Moderate (Hi) Mild

Mark one

(f) Additional notes

SYMPTOMS CAUSED BY: Wheezing 1. Exposure to house dust (sweeping, dusting, house cleaning) 2. Cellar 3. Smell of: food cooking (state food) paint turpentine floor cleaner furniture polish cosmetics perfumed soap tobacco smoke insect sprays 4. Cold ai r damp air wind exercise

5. Emotional upsets 6. Cats dogs birds horses other animals (specify)

Cough

Nasal

Eye

Eczema

SYMPTOMS CAUSED: (Mark ^ where indicated) Urticaria &/or G.I. Angiocdcma

SYMPTOMS CAUSED BY: 7. Foods (specify the food in each case) (Do not simply list previous skin tests) (a) foods known to cause symptoms (list in the appropriate column) (b) foods suspected of causing symptoms (list in the appropriate column)

8. Places visited other people's houses hotel motel farm barn stable 200

9. Other people's clothing fuzzy wool mohair angora fur

10. Contact with

(dermal allergy only) sheep's wool nylon rayon pure silk plastic other (specify)

11. Playthings:

stuffed toys glue paste plasticine chalk other (specify)

12. Flowers in house flower garden fresh cut grass tall grass and weeds

Wheezing

Cough

Nasal

Eye

SYMPTOMS CAUSED Urticaria &/or Ang ¡oedema Eczema

G.I.

SEASONAL INCIDENCE

SYMPTOMS WORSE IN Apr ¡I-May

June

Aug. 15-Frost

July-Aug. 15

Frost-1st April

Wheezing Coughing Nasal Eye

Urticaria & An g ¡oedema Eczema Other (specify) PATIENT'S HOME ENVIRONMENT AND ITS RELATIONSHIP TO ATTACK OR EXACERBATION House

Apartment

TYPE OF HEATING

Damp Place

Basement

Hot Air Oil

Hot Water Coal

AMOUNT OF DUST IN THE HOUSE METHOD OF CLEANING

PATIENT'S ROOM - OWN ROOM Pillow

Electronically Filtered Air

Wood A Great Deal

Dry Broom

Mop

Yes

Feather

Old Dwelling

Gas

Stove

Space Heater

Electric

Average Vacuum

New Dwelling

Very Little TYPE OF VACUUM

Bag Cylinder Water Filter

No

Rubber

Non Allergenic

Feather Comforter

Yes

No

Woollen Bedding

Yes

No

Mattress

Spring

Stuffed

Fluffy Toys

Yes

No

Favourite Blanket or Quilt

Yes

No

Rugs

Yes

No

Type.

Drapes

Yes

No

Type.

PETS OR ANIMALS IN THE HOUSE (specify type) PETS OR ANIMALS OUTSIDE & NEVER IN HOUSE (Specify type)

Rubber

UNUSUAL ENVIRONMENTAL FACTORS WHICH HAVE PRECIPITATED SYMPTOMS (Mark V) Painting Decorating Remodelling home or school Other (specify) PREVIOUS UNTOWARD REACTIONS TO DRUGS

Yes

No

DETAILED DESCRIPTION

DRUG

1. 2. 3. PREVIOUS SPECIFIC ALLERGY INVESTIGATION

Elsewhere

In HSC only?

If in HSC only mark "In HSC only" and do not complete (a) and (b) (a)

Skin-testing

Yes

By Whom 1 st

2nd.

3rd

Year

2nd

3rd

1st.

Positive Results: (b)

No

Foods

Dietary Instructions

Inhalants

Yes

No

Yes

No

Epidermals

Pollens

Details (c)

Hyposensitization

From Effect:

Nil

Month & Year Fair

Good

To

Month & Year

Excellent

Composition of the hyposensitizing solutions (if known) (d)

Benefits from environmental correction

DIETARY HISTORY Present diet (Given in detail) Listing:(a) Full diet minus the following: —

or (b) Only the following foods are allowed: —

Obvious improvement No Obvious improvement

Moulds

(circle)

(c) Foods which have caused definite symptoms and are still on the forbidden list. (State symptoms) (Do not list positive skin tests)

(d) Severe food dislikes (e) Stools:

Normal

Abnormal

(Specify)

PSYCHOLOGICAL BACKGROUND No significant details elicited Significant details elicited

(Specify)

Previous Investigations Which May Influence Diagnosis or Treatment e.g., High Sweat chlorides, (Specify) low gamma globulin Yes No FAMILY HISTORY OF ALLERGY (State relationship and allergy)

POSITIVE PHYSICAL FINDINGS

(Applies to O.P.D. only)

LABORATORY RESULTS (Applies to O.P.D. only for results at time of the initial work-up)

PRESCRIBED TREATMENT (Refers to O.P.D. only at time of the initial work-up) (a) Diet (b) Medications (c) Hyposensitization recommended at Clinic by family physician

Mark one

(d) Hyposensitization not recommended | | (e) Physiotherapy prescribed Yes |

|

No | |

Type prescribed

(f ) Composition of extract to be given by family physician

(g) Letter written to family physician Signature Print Name

M.D.

Respiratory allergy in children

ASTHMA DEFINITION

An allergic disease characterized by recurrent bouts of wheezy breathing with prolongation of expiration. AETIOLOGY

Foods: often the chief cause in small infants, and may be contributing factor at other ages Inhalants (e.g. house dust, feathers, animal hairs): the chief cause in most patients of any age Pollens: important cause in many patients, and the chief cause in some seasonal cases Moulds: contributory cause in many cases Bacteria: important in many cases AGE INCIDENCE

Can be any age. A typical attack may be seen as early as two weeks of age. Ten to fifteen per cent of children developing asthma do so in the first year of life. CLINICAL PICTURE

The asthmatic attack itself may be preceded by nasal discharge, sneezing, and coughing for several hours. Then the patient begins to wheeze', the wheezing becomes progressively worse and cyanosis may appear. On examination, in a severe attack, the patient is in acute distress, breathing is laboured, and the expiratory phase of respiration is prolonged noticeably. The

RESPIRATORY ALLERGY IN CHILDREN 13

accessory muscles of respiration are called into play. The chest is clear to percussion, unless complications are present, and may be hyperresonant if the attack has been prolonged. On auscultation sonorous rhonchi and sometimes sibilant rales are heard throughout the chest, particularly on expiration. DIFFERENTIAL DIAGNOSIS (most common ones are marked*) Infections

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Bronchitis, acute or chronic* Bronchiolitis* Bronchopneumonia* Laryngotracheobronchitis* Acute epiglottitis* Bronchiectasis* Whooping cough* Sino-bronchial syndrome* Retropharyngeal abscess Pulmonary abscess Tuberculous lymphadenopathy Tuberculous ulcération

Congenital Anomalies 13. 14. 15. 16.

Congenital laryngeal stridor* Double or right aortic arch Aberrant left subclavian artery Anomalous pulmonary artery

Tumours 17. 18. 19. 20. 21. 22. 23. 24. 25.

Adenoma, papilloma, or haemangioma of larynx, trachea, or bronchus Lymphosarcoma Leukaemia Hodgkin's disease Cystic hydroma Enlarged thymus Substernal goitre Hydatid cyst Congenital or acquired lung cysts

Miscellaneous Diseases Involving the Respiratory Tract 26. Foreign body in the larynx or at base of tongue 27. Foreign body in the lung*

14 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

Bronchostenosis Aspiration pneumonia* Cystic fibrosis of the pancreas* Pulmonary oedema or congestion Loeffler's syndrome Spontaneous pneumothorax Mediastinal emphysema Acute massive atelectasis Ayerza's disease Pulmonary fibrosis Inflammation of the respiratory tract resulting from gases and odours Congenital lobar emphysema Idiopathic pulmonary haemosiderosis Alveolar capillary block Pulmonary alveolar microlithiasis Pulmonary alveolar proteinosis Primary pulmonary obliterative vascular disease Hypersensitivity diseases of the lung caused by fungi and organic dusts

Other Miscellaneous Diseases 46. 47. 48. 49. 50. 51. 52. 53. 54.

Foreign body in the oesophagus Postencephalitic hyperpnoea Stridor due to cerebral palsy Recurrent laryngeal nerve paralysis Anaphylactic shock from injection Cardiac asthma Salicylate intoxication Uraemia Visceral larva migrans

Note that the term asthmatic bronchitis does not appear in the list. This is because the term is used loosely by many people to denote wheezing with infection, when no decision is made as to whether the primary condition is infection or allergy. It is extremely important for the proper care of the patient to determine whether he is suffering from allergy or from infection, or both. Therefore if the term asthmatic bronchitis is used at all, it should be confined to non-allergic wheezing due to infection and differentiated from allergic wheezing or asthma. At first glance, it would appear that the differential diagnosis of asthma is difficult. Actually most cases of wheezing can be diagnosed accurately by: 1. A careful history 2. A careful physical examination 3. X-ray of the chest 4. X-ray of the sinuses

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N 15

On occasion one might require: 1. Nasal smear 2. Bronchogram 3. Laryngoscopic examination 4. Bronchoscopic examination 5. Barium or lipiodol swallow 6. Fluoroscopy of the chest 7. WBC and smear 8. ECG 9. Sputum cultures 10. Tuberculin test 11. Biopsy of the lung 12. Sweat electrolytes 13. Pulmonary function studies Skin tests are used to reveal the aetiological factors in asthma, not to diagnose asthma. USUAL COURSE

Most commonly the asthmatic child will present with a history of repeated severe respiratory infections, often starting in infancy. As time goes on, asthmatic breathing is associated with this infection and the child has his attacks of asthma only when respiratory infection is present. Later on, the asthmatic attack occurs both with and without respiratory infection. In some cases the respiratory infection precipitates the attack of asthma because the patient suffers from bacterial allergy, or acts as a trigger mechanism lowering the patient's threshold to the substances to which he is allergic. In many cases both of these mechanisms operate at once. R E L A T I O N S H I P TO O T H E R

ALLERGIES

1. May be unassociated with other allergies 2. Many asthmatic children have constant allergic nasal discharge and cough between attacks 3. Many asthmatic children have a history of previous eczema and approximately two-thirds of the infants who suffer severe eczema later have respiratory allergy of which asthma is a common manifestation 4. Approximately one-quarter of children with hay fever have or subsequently will have asthma PATHOLOGY

1. Bronchospasm 2. Mucus in the lumen 3. Oedema of the wall of the bronchi and bronchioles

16 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

For For For For

symptomatic treatment between attacks, see page 65 treatment of the acute attack, see below skin testing, see page 71 hyposensitization therapy, see page 75

PROGNOSIS

Excellent if proper treatment is given. Over 90% do very well if treated adequately. To obtain a good result frequently requires three or more years of treatment. In the overall care of an allergic child, the skin tests form only a small fraction of the total, and all the care outlined, except for the skin tests, can be done quite adequately by the general practitioner if he will take the time and trouble to do so. TREATMENT OF THE ACUTE ASTHMATIC ATTACK

The following is the protocol now in use at The Hospital for Sick Children for treatment of the child in the acute asthmatic attack. The protocol may be modified to fit the needs of individual hospitals or treatment centres. 1. Epinephrine (1:1000) S/C In practice, 0.125-0.20 ml repeated in ten and again in another ten minutes is sufficient. Concurrent use of epinephrine and isoproterenol In general, it is unwise to use these two drugs within an hour of each other. Especially in the presence of hypoxaemia, these drugs given close together may be dangerous since they predispose to cardiac arrhythmia (C. Collins-Williams, R. Nizami, and C. Lamenza, 1969). If the patient is no longer responding to one of these drugs, the implication is that he requires more intensive therapy than is provided by either. He especially requires oxygen. Such patients should be given oxygen, preferably after a determination of the PaOz, and acid base balance should be restored immediately (see 10). 2. Oxygen Institute oxygen therapy with high humidity early. Acute asthmatics coming into Emergency should be given moist oxygen from the time of arrival via the 35% MixO-Mask with an oxygen flow of 8 litres per minute until ordered discontinued by the physician. The reason for this is that many acute asthmatics have a very low PaCh even though they do not look severely ill. Until the physician arrives, the 35% oxygen will not be harmful (100% oxygen may be harmful). However, before deciding to discontinue the oxygen the physician should bear in mind that clinical evaluation of low arterial oxygen is extremely difficult. The patient should not be left unat-

RESPIRATORY A L L E R G Y IN C H I L D R E N 17

tended while oxygen is being administered. Early in the acute asthmatic attack a low PaOz develops, usually before elevation of the PaCOz. The latter is a danger signal. However, PaCCh rising after oxygen therapy is begun is a further danger signal suggesting the need for assisted respiration. 3. IIV Fluids Intravenous fluids (2/3 glucose and 1/3 normal saline) should be started early if the patient is not taking fluids, is vomiting, or is very ill. Sufficient fluid to correct dehydration and electrolyte imbalance and provide maintenance therapy must be given. 4. Aminophylline Aminophylline preparations should be given (unless the patient is known to have an idiosyncrasy to aminophylline) intravenously in the I/V tubing (slowly) or flask, but not directly into the vein. In milder cases the drug may be given orally or rectally in the following doses: oral 5 mg/kg \ rectal 7 mg/kg > q 6-8 hours prn and reviewed after two doses I/V 3.5 mg/kg ) depending on the patient's condition 5. Solu-Cortef In all acutely ill cases, I/V hydrocortisone* should be started at once even though the effect will not be apparent for about six hours. For infants, use 200 mg stat into tubing; 200 mg q6h in flask to be delivered over six hours. For small children 2 to 5 years old, the initial and subsequent doses may be 250 mg; for the 5 to 10 year old, 300 mg; for the child over 10 years, 400 mg. Do not think of this as emergency treatment because improvement due to Solu-Cortef takes about six hours to appear. For very acutely ill cases, more frequent administration of hydrocortisone is suggested, 4 mg/kg body weight I/V every 140 minutes (J.V. Collins, P.W.R. Harris, T.J.H. Clark, and J. Townsend, 1970). This maintains a minimum plasma level of 11-hydroxy corticosteroids of 150 /¿g-%. Intravenous therapy with hydrocortisone should be supplemented with KC1 at the rate of 20 mEq of K to each litre of I/V fluid because large doses of intravenous corticosteroids induce hypokalaemia. Muscular weakness and faintness indicate the need for serum potassium level determinations. 6. Antibiotics If infection is present or suspected, always give an antibiotic, preferably not penicillin or ampicillin. Erythromycin by mouth is probably the drug of choice unless the patient is known to be sensitive to it. In the very ill patient, another antibiotic may be required, administered intramuscularly or intravenously. * Solu-Cortef® . The Upjohn Company of Canada, Don Mills, Ontario

18 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

7. Inhalation Therapy In an acute attack all patients should have inhalation therapy (administered by the Inhalation Therapy Department) consisting of isoproterenol HC1* q2h or less often depending on the patient's condition. The dosages of 1:200 solution isoproterenol HC1 recommended are: 2 to 5 years of age, 0.10 ml diluted to 2 ml in normal saline 5 to 10 years of age, 0.20 ml diluted to 2 ml in normal saline 10 to 15 years of age, 0.25 ml diluted to 2 ml in normal saline If the patient is not responding, other therapy must be considered. Do not persist with a form of therapy that is not producing an advantageous effect. Note For acutely ill patients who may later require attention in the Intensive Care Unit, the "Special Status Asthmaticus Routine" is ordered by special form (p. 25). This routinet includes inhalation therapy with a bronchodilator for 20 minutes, followed by breathing of humidified air (to liquefy secretions) for a further 20 minutes. Then the physiotherapist administers chest percussion to help remove the secretions, followed by breathing exercises to increase aeration of the lung. The physician who orders the treatment should complete the special order sheet and per sonally call Inhalation Therapy. This treatment is emergency treatment and an order in the order book is not sufficient. The inhalation therapist will notify Physiotherapy. The entire treatment will be carried out every six hours except when limitations of staff preclude treatments during the night. As mentioned in the Preface, this is the procedure followed at The Hospital for Sick Children. If this special routine is ordered, all other therapy except additional isoproterenol inhalations is continued. 8. Roentgenograms In all ill patients, take a chest roentgenogram and look at it immediately. Examine the patient frequently and, if there is any deterioration in his condition, repeat the chest roentgenogram, looking especially for pneumothorax or mediastinal emphysema. 9. Blood Gases In all ill patients, determine the blood PaCh, PaCCh, pH and base excess, on arterial blood if possible, because such samples reflect the acid-base status of the patient more accurately than venous samples. Use a heparinized syringe and a #25 gauge * Isuprel®. Winthrop Laboratories, Aurora, Ontario t Suggested by E. Warner Ahlgren, M.D., Physician Director of the Department of Respiratory Therapy, Children's Medical Center, Dallas, Texas, U.S.A.

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N

19

needle for radial artery puncture. In older patients, a small amount of local anaesthetic should be injected first. It may be possible to obtain a rapid result by having the Intensive Care Unit technician do the determinations on heel-prick blood, or it can be done by the attending physician in the 7G laboratory. Otherwise, determinations will be done by the regular laboratory, but in this case the house officer should personally take the sample to the laboratory and ask for the result as soon as possible. The tests are not worth doing unless the results are received and made use of immediately. Although arterial blood is preferable, relatively representative results for pH, pCU2 and base excess, but not pCh, may be obtained from venous blood, providing the peripheral circulation is reasonable. Be careful to mark the requisition either arterial or venous blood because the normal values (see Table I) differ. TABLE I Normal values of blood gases Arterial or arteriolized capillary pH PC02

pO2 Total CO2 Base excess

7.4 40 mm Hg 90 to 100 mm Hg 25 to 26 -2.3 to +2.3

Venous

7.35 45 mm Hg 50 to 60 mm Hg 25 to 29 -2.3 to +2.3

10. Correction of Acido sis Correction of acidosis is extremely important, not only because of the deleterious effects it has on the patient but also because medications, particularly adrenaline and digitalis, do not work effectively when the pH is very low. Sodium bicarbonate is given for two main reasons: (1) to correct a metabolic acidosis which may cause arterial spasm compromising pulmonary blood flow, and (2) to correct a metabolic acidosis when it occurs as a second pathologic acid-base disturbance concomitant with a respiratory acid-base disturbance. Correction may be carried out using either of the two attached nomograms, the Davenport nomogram from the Neonatal Research Unit modified by Dr Paul Swyer and Dr N. Aspin, or the in vivo acid-base nomogram devised by Dr Gerald Arbus. These may be used with either venous or arterial gas values to calculate the corrections required. The Modified Davenport Nomogram (Figure 1) Follow the patient's pCCh isobar from his present pH and pCCh up to desired pH, read the difference between the two pHs in mEq of HCCb". The difference in mEq x 0.3 x the patient's weight (kg) = the number of mEq of buffer needed. Since 7.5% sodium bicarbonate solution contains 0.9 mEq per ml, the number of ml of 7.5% NaHCCh required = the difference in mEq x 0.3 x the weight (kg). (In infants under one year of age, the

20 PAEDIATRIC ALLERGY AND CLINICAL I M M U N O L O G Y

Figure 1 The modified Davenport nomogram. Modified by N. Aspin and P.R. Swyer from H. Davenport, ABC of Acid Base Chemistry, 1958. N. M. Nelson and K.P. Riegel, Pediatrics, 43: 821, 1969

factor is 0.4 instead of 0.3.) Note that 0.3 is one-half the diffusion coefficient and is used in these calculations instead of 0.6 because it is safer to correct only one-half of the acid-base disturbance first, then repeat the blood gases and correct again. Example If the arterial or venous blood gas determinations are found to have a HCOs" level less than 15 mEq per litre, this should be corrected in the following manner: 25 mEq per litre minus the value found = base deficit in mEq per litre. The base deficit x 0.3 x the patient's body weight (kg) = one-half the total base deficit. After this correction the blood determination should then be repeated about every ten minutes and further corrections made until the blood values are near normal. From the functional point of view pH is the physiologically important parameter rather than the absolute level of the base deficit, and the dosage of bicarbonate for the treatment of acidosis may need modification to bring the pH to at least 7.25 to ensure a reasonable cellular environment. Persistently high levels of pCCh (>70 mm Hg) may require artificial ventilation for their correction. The shaded areas in Figure 1 represent the 95% confidence bands for chronic compensated respiratory acidosis and acute uncompensated respiratory acidosis.

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N 21

Figure 2 In vivo acid-base nomogram (G.S. Arbus, The Hospital for Sick Children, Toronto, Canada)

Dr Gerald Arbus's Nomogram (Figure 2) Shaded areas on the acid-base nomogram represent 95% confidence bands for the pathophysiological condition labelled. That is, 95% of all patients with the condition labelled would be expected to fall within the confines of the confidence band. Thus, if the values obtained from the laboratory fall outside the shaded area, by definition there must be at least two pathological acid-base disturbances. For example, a patient with a blood pH of 7.4, a pCOz of 22 mm Hg, and a bicarbonate of 12 mEq/1 would have two pathologic acid-base disturbances. Most likely these would be a combination of respiratory alkalosis and metabolic acidosis such as that seen in salicylate intoxication. In this case it is important to recognize that two pathological acid-base disturbances exist and that further monitoring of the blood is recommended since a further drop in plasma bicarbonate and blood pH may occur, necessitating alkaline therapy. Example 1 A patient appears in an asthmatic attack and his electrolytes $re pH 7.2, pCU2 70 mm Hg, plasma bicarbonate 27 mEq/1. If it is felt that correction of the acidosis should be employed to relieve pulmonary artery spasm and 7.37 is the pH one wishes to attain, then the nomogram tells us that we have to increase the

22 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

plasma bicarbonate 10 mEq/1 to 37 mEq/1. Assuming that bicarbonate distributes equally throughout the total body water, then the amount of bicarbonate to be added is 0.6 x the patient's weight in kilograms x 10 mEq/1. Note that Dr Arbus uses 0.6 x the patient's weight in kilograms because acidosis occurs throughout the total body water rather than simply in the extracellular fluid. This figure then gives a more representative value than 0.3 x body weight (kg) for the total bicarbonate deficit. However, if the physician feels that total correction to the desired level is not necessary, a proportion of the total bicarbonate deficit as calculated can be given. Example 2 A patient appears to have acute respiratory acidosis. However, the pH is 6.95, the pCCh is 70 mm Hg, the plasma bicarbonate is 15 mEq/1 and, therefore, the acid-base values do not fall within the confidence band for one pathologic acid-base disturbance, namely, acute respiratory acidosis. Thus, by definition, the patient has a second pathologic acid-base disturbance, most likely metabolic acidosis. Obviously the respiratory acidosis can only be corrected by adequate ventilation of the lungs. If it is felt that the patient should have complete correction of his metabolic acidosis at apCCh of 70 mm Hg, the plasma bicarbonate concentration should be raised to 27 mEq/1. The patient should therefore receive (12 mEq/1 x 0.6 x body weight in kilograms) mEq sodium bicarbonate. Example 3 A patient is thought to have chronic respiratory acidosis. However, his pH is 7.25, his pCCh is 70 mm Hg, and his plasma bicarbonate is 30 mEq/1. His acid-base values do not fall within the chronic respiratory acidosis confidence band and, therefore, he has a second pathologic acid-base disturbance, most likely metabolic acidosis. If after determining the cause of the metabolic acidosis, it is thought that he should be treated to the extent that his acid-base parameters fall within the band for chronic respiratory acidosis, he should receive (35-30 mEq/1 x 0.6 x body weight in kilograms) mEq sodium bicarbonate. 11. Intensive Care (a) If the patient is acutely ill, the staff physician in charge of the ward and the consulting allergist for the ward must be notified. At The Hospital for Sick Children the latter is a compulsory consultation and must be requested for all very acutely ill asthmatics. The member of Paediatric Consultants, if any, who admitted the patient should also be notified since he is interested and will also be in touch with the parents. (b) In general, sedation is not desirable. Restlessness may be partially due to air hunger. At times, light sedation with rectal chloral hydrate may be used. Paraldehyde is undesirable. Morphine, demerol, and barbiturates are definitely contraindicated unless the patient is on assisted respiration because these depress respiration. (c) A persistently low Pa Ch not responding to oxygen therapy by mask, a PaCCh > 65, or a PvCCh > 75 are real danger signals and suggest the need for controlled

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N 23

respiration. Such intervention will be decided by the staff physician in charge of the ward and the consulting allergist together, but they must be notified of the patient's condition long before this point is reached. Such a decision is based on the clinical condition as well as on blood gases. (d) Always consider the possibility of a foreign body as a cause of respiratory distress, particularly in a wheezing infant who is not responding to therapy. This is the only indication for bronchoscopic suction in status asthmaticus. Bronchoscopic suction, if necessary, is an emergency treatment and preparations must be made rapidly. The senior resident on the ward should make it his own responsibility to supervise the arrangements. In the Ear, Nose and Throat (ENT) operating room, the patient is under direct charge of the ENT staff surgeon. The pre-medication (if any) and anaesthetic agents are ordered and administered by the anaesthetist. Once the operation has been performed the patient is transferred to the recovery room or to the Intensive Care Unit. At this time, his medical care again becomes the responsibility of the staff physician from whose ward he came, and of the consulting allergist with the chief medical resident (rather than a member of the house staff from the ward) in direct charge. All orders from the medical service (from staff physician in charge of the ward, from the consulting allergist, or from other consultants) should be discussed with and written by one person, the chief medical resident, so that there is no confusion. (e) If assisted respiration is ordered, the anaesthetist will be in direct charge of the procedure, of inhalation therapy, and of the use of curare-like drugs. He, together with the staff physician, will control the patient's oxygen therapy and acid-base balance. The medical service is also responsible for seeing that all other necessary medications such as Solu-Cortef, antibiotics, and so forth are continued, and for discontinuing any that new conditions have made unnecessary. The ENT surgeon is also available for consultation, but again, to avoid confusion, should not act except in cases of great emergency without consulting the chief medical resident and the anaesthetist. Once the patient has improved, the various medications, assisted respiration, etc. will be discontinued after consultation between the anaesthesia and medical services, and the patient finally returned to the ward. (f) Close observation by the nursing service and house staff is very important, especially during the first 24 hours back on the ward. NOTES

1. If a patient goes directly from Emergency to the Intensive Care Unit without being assigned to a ward, the chief medical resident is in charge. The physician in charge of the Emergency Department is the staff physician in charge. The allergist on the emergency list for the Allergy Division is on call as allergy consultant.

24 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

2. Respiratory failure (J.J. Downes, D.W. Wood, T.W. Striker, and H.I. Leeks, 1966) is considered to be present when the patient satisfies at least three of the following criteria: (a) severe respiratory retractions, (b) barely audible wheezing and breath sounds, (c) minimal thoracic movement with hyperinflation, (d) depressed level of consciousness and lack of response to painful stimuli, (e) cyanosis in 40% oxygen. This picture is associated with a PaCCh above 65 mm Hg. 3. Respiratory arrest In general, it is undesirable to give I/V bicarbonate without first measuring the pH and PaCCh. In an emergency such as an acute asthmatic going into respiratory arrest, it is reasonable to give a dose of 1.5 mEq/kg body weight over a 15 to 30 minute period by syringe into the intravenous tubing, or else one-half of the total dose very quickly (over two minutes) and the other half over the next six hours. Dosage (based on 1.5 mEq/kg body weight) 1 year approximately 10 kg 15 mEq 17 ml of 7.5% NaHCOa 2 years approximately 12 kg 20 mEq 22 ml of 7.5% NaHCOs 5 years approximately 18 kg 27 mEq 30 ml of 7.5% NaHCOs 10 years approximately 33 kg 50 mEq 56 ml of 7.5% NaHCOs 15 years approximately 54 kg 80 mEq 90 ml of 7.5% NaHCOs Further adjustments may have to be made depending on the blood gases and the course of the attack. 4. Patients who require assisted respiration should have their ECG, central venous pressure, and arterial pressure monitored.

HAY FEVER DEFINITION

A seasonal disease characterized by one or more of: watery nasal discharge, nasal obstruction, sneezing, itching of the nose, watering of the eyes, and itching of the eyes and throat. In Ontario, hay fever occurs chiefly in August and September (ragweed), but also in May and June (grasses) and April and May (trees). AETIOLOGICAL AGENT

Pollen DIAGNOSIS

1. Clinical picture as described above 2. A history of allergy 3. Attacks occurring at the same season each year

Special Status Asthmaticus Routine at The Hospital for Sick Children

HSC No.

Patient's Name Ward

Date

Ordered by: TO INITIATE THIS TREATMENT NOTIFY INHALATION THERAPY Therapy to be given every six hours until discontinued. Stepl Topical medication (20 minutes IPPB) ml isoproterenol (1:200)

Isoproterenol dosage ( 2 - 5 years, 0.12ml) ( 5 - 10 years, 0.25 ml) (10 - 15 years, 0.50ml)

ml normal saline 5.0

ml total

Step 2 Humidification: 20 minutes aerosol by mask (normal saline) Type of nebulizer used to be decided by inhalation therapist Step3 Chest physiotherapy: Postural drainage and chest percussion by mechanical percussor (15 minutes) General Emphasis on the following areas:

Step 4 Breathing exercises (10 minutes) INHALATION THERAPY Time Date Instituted

Day1 Day 2 Day3

Day 4 Day5

Signature

PHYSIOTHERAPY Time Date Instituted

Signature

26 PAEDIATRIC A L L E R G Y AND C L I N I C A L I M M U N O L O G Y DIFFERENTIAL DIAGNOSIS

During the first season of the disease, hay fever may be confused with a common cold, otherwise there is seldom any confusion. For symptomatic treatment, see page 69 For skin testing, see page 71 For hyposensitization therapy, see page 75 PROGNOSIS

Excellent if properly treated. Again, a good result may not be achieved until the second or third season of treatment.

ALLERGIC

RHINITIS

DEFINITION

A recurrent or constant blocking of the nose, or a nasal discharge due to an allergen. AETIOLOGY

Same as for asthma DIAGNOSIS

1. Clinical picture as above 2. A history of allergy 3. Nasal smear, see page 28 D I F F E R E N T I A L DIAGNOSIS

1. Common cold 2. Chronic sinusitis 3. Hay fever For symptomatic treatment, see page 69 For skin testing, see page 71 For hyposensitization therapy, see page 75 PROGNOSIS

Most patients do well with prolonged (at least three years) treatment. Progress is usually slow. Some patients are highly resistant to treatment.

RESPIRATORY ALLERGY IN CHILDREN 27 ALLERGIC BRONCHITIS DEFINITION

Allergic bronchitis is due to allergens. The symptom is recurrent cough, with or without sputum. It is usually associated with allergic rhinitis or asthma but may occur alone as the only clinical manifestation of allergy. AETIOLOGY

Same as for asthma DIAGNOSIS

1. Clinical picture as above 2. A history of allergy 3. Nasal smear, see page 28 D I F F E R E N T I A L DIAGNOSIS

1. 2. 3. 4. 5.

Common cold Chronic sinusitis Infectious bronchitis (acute or chronic) Bronchiectasis Any local lesion of the throat, larynx, trachea, or bronchi resulting in a cough

For symptomatic treatment, see page 69 For skin testing, see page 71 For hyposensitization therapy, see page 75 PROGNOSIS

Excellent if properly treated (see page 65)

SYMPTOMATIC T R E A T M E N T OF RESPIRATORY ALLERGY In addition to the long-term treatment of respiratory allergy by hyposensitization procedures, it is important to give adequate symptomatic therapy in an attempt not only to make the patient more comfortable but also to prevent severe asthmatic attacks. In general it is better to become acquainted with a few medications suitable for treating each condition and to use them exclusively, rather than to try to remember the dosages and side-reactions of several dozen drugs. See "Dosages of Drugs Useful in the Care of Allergic Children" (p. 65).

28 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Every mother with an asthmatic child should have at least two medications on hand to administer as soon as the attack begins. By experience she will learn when to use them and can often prevent attacks completely or prevent them from becoming serious, thus making it unnecessary to send for the physician. Steroids are useful in the symptomatic treatment of allergic disease but are of limited value because of their side-effects. INDICATIONS FOR STEROIDS IN ASTHMA

1. Treatment of an acute attack 2. Long-term management of severe symptoms while waiting for anti-allergic treatment to become effective 3. For the occasional patient who does not respond to anti-allergic therapy. Steroids should not be used if other medications will give reasonable relief. They are only rarely indicated in respiratory allergy other than asthma. NASAL SMEARS The examination of the nasal smear for eosinophiles is of considerable value in the diagnosis of respiratory allergy, but in a clear-cut case of asthma or hay fever the diagnosis can be made on history alone. However, the nasal smear is extremely helpful in the diagnosis of allergic rhinitis, allergic bronchitis, and wheezing of uncertain aetiology. M E T H O D OF PREPARATION

The patient blows his nose into a piece of waxed paper and the secretion is transferred to a microscope slide and spread carefully in a thin film. If no secretion is available from blowing the nose, it may be swabbed with a cotton applicator. After drying in air, the smear is stained in the same manner as a blood film with Wright's or Giemsa stain or, even more quickly, with Hansel stain, which involves putting a few drops of the stain on a slide, leaving it for 20 seconds, adding an equal amount of distilled water, leaving for 20 seconds, washing in tap water, and then decolourizing with 95% alcohol for a few seconds. In most cases the smear can be interpreted easily but, as the number of eosinophiles decreases, more experience is required for a proper interpretation. A typical smear consists of mucus containing large numbers of cells which may be polymorphonuclear neutrophiles or eosinophiles. Generally, polymorphonuclear neutrophiles indicate an infective process in the nose and eosinophiles, an allergic process. If both are present in large numbers a combination of the two processes is indicated. There is no definite relationship between the numbers of eosinophiles in the nasal mucus and in the blood. Many factors influence the interpretation of a smear. 1. It is often impossible to draw conclusions from the examination of a single smear.

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N 29

2. Unless the staining is carefully done the cytoplasm of the polymorphonuclear neutrophiles may take on a pinkish hue, particularly in thick sections. They can be distinguished from eosinophiles by the lack of granularity in the cytoplasm. 3. The cells in the smear may be few, especially if the secretion is thin and watery. If these few cells are eosinophiles the smear is just as indicative of allergy as if the eosinophiles are present in large numbers. 4. Polymorphonuclear neutrophiles in the proportion of at least ten to every eosinophile may be present because the polymorphonuclear neutrophile response is always greater than the eosinophile response. In other words, if there are ten times as many polymorphonuclear neutrophiles as eosinophiles in a smear, the two responses may be regarded as equal. 5. The eosinophiles may be clumped together, particularly at the edge of the smear. If this is forgotten, large areas of the smear may show polymorphonuclear neutrophiles only. Clumps of eosinophiles are just as significant as scattered eosinophiles. 6. The eosinophiles in the nasal secretions of a patient with allergy may be temporarily depressed during an episode of acute infection. Therefore, during a true nasal infection, the nasal smear may consist entirely of polymorphonuclear neutrophiles. Once the infection has cleared, the eosinophiles return. In other words, although a smear that is positive for eosinophiles denotes nasal allergy (except as in 7), a smear that is negative for eosinophiles does not necessarily indicate an absence of allergy. 7. Eosinophiles may appear temporarily in considerable numbers in the nasal smear of the patient without allergy during recovery from a respiratory infection. If repeated smears are made it is found that these eosinophiles disappear rapidly whereas they tend to remain or increase in the smear of the allergic patient. This is the only way in which one may obtain a falsely positive smear, provided that the smear is properly made and stained. 8. The smear is most likely to be positive for eosinophiles if taken during an active phase of the respiratory allergy. For example, a patient with ragweed asthma alone may have large numbers of eosinophiles in his smear during the ragweed season but may have none the rest of the year. Similarly a patient with perennial asthma may have a symptom-free period during which his smear is free of eosinophiles. 9. The smear may become positive for eosinophiles early in the course of respiratory allergy before severe symptoms such as asthma or hay fever have developed. Similarly, the smear may remain positive late in the course of respiratory allergy after the acute symptoms have subsided as a result of specific hyposensitization therapy.

30 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

If these facts are borne in mind, the nasal smear becomes a valuable adjunct in the complete appraisal of the allergic patient. REFERENCES

Collins, J. V., Harris, P.W.R., Clark, T.J.H., and Townsend, J. Intravenous corticosteroids in treatment of acute bronchial asthma. Lancet, 2: 1047, 1970 Collins-Williams, C. The prognosis of asthma in children. Cañad. Med. Assoc. J., 82: 33, 1960 Collins-Williams, C., Nizami, R., and Lamenza, C. The use of isoproterenol in the treatment of the acute asthmatic attack with report of a case. J. Asthma Res., 7: 17, 1969 Downes, J.J., Wood, D.W., Striker, T.W., and Leeks, H.I. Diagnosis and treatment: advances in the management of status asthmaticus in children. Pediatrics, 38: 286, 1966 Hansel, F.K. The cytology of the secretions in allergy. Clinical Allergy, p. 408. St Louis: C.V. Mosby Company, 1953 Transactions of the World Asthma Conference, March 23-26, 1965, Eastbourne, England. The Chest and Heart Association, Tavistock House North, Tavistock Square, London, 1965 DR ARBUS'S NOMOGRAM Respiratory Acidosis, Acute Brackett, N.C., Jr., Cohen, J.J., and Schwartz, W.B. Carbon dioxide titration curve in normal man: effect of increasing degrees of acute hypercapnia on acid-base equilibrium. New Eng. J. Med., 272: 6, 1965 Respiratory Acidosis, Chronic Brackett, N.C., Jr., Wingo, C.F., Muren, O., and Solano, J.T. Acid-base response to chronic hypercapnia in man. New Eng. J. Med., 280: 124, 1969 Metabolic Acidosis, Acute and Chronic Albert, M.S., Dell, R.B., and Winters, R.W. Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann. Intern. Med., 66: 312, 1967 Elkinton, J.R. Clinical disorder of acid-base regulation, a survey of seventeen years' diagnostic experience. Med. Clin. N. Amer., 50: 1325, 1966 Lennon, E.J., and Lemann, J., Jr. Defense of hydrogen ion concentration in chronic metabolic acidosis. Ann. Intern. Med., 65: 265, 1966 Miller, B. The hydrogen ion concentration in arterial blood. Universitetsforlaget I Aarhus P. 11, 1959 Poppell, J.W., Vanamee, P., Roberts, K.E., and Randall, H.T. The effect of ventilatory insufficiency on respiratory compensations in metabolic acidosis and alkalosis. J. Lab. Clin. Med., 47: 885, 1956 Respiratory Alkalosis, Acute Arbus, O.S., Hébert, L.A., Levesque, P., Etsten, B., and Schwartz, W.B. Characterization and clinical application of the "significance band" for acute respiratory alkalosis. New Eng. J. Med., 280: 117, 1969 Metabolic Alkalosis, Acute and Chronic See Elkinton and Poppell et al. references above Goldring, R.M., Cannon, P.J., Heinemann, H.O., and Fishman, A.P. Respiratory adjustment to chronic metabolic alkalosis in man. J. Clin. Invest., 47: 188, 1968

R E S P I R A T O R Y A L L E R G Y IN C H I L D R E N 31 Relation between pH and H+ (7.10-7.50)* pH

H+ nanomoles/litre

7.20 7.39 7.40

60 41 40

7.41 7.50

39 30

Note that pH 7.40 corresponds to [H+] of 40 nM/1 and each deviation in pH of 0.01 corresponds to an opposite deviation in [H+] of 1 nM/1. * J.P. Kassirer and H.L. Bleich. Rapid estimation of plasma carbon dioxide tension from pH and total carbon dioxide content, New Eng. J. Med., 272: 1067, 1965

Eczema (ATOPic DERMATITIS)

Eczema or atopic dermatitis is an allergic condition of the skin which usually begins on the cheeks but may spread to any part of the body and may become generalized. It is characterized by vesiculation followed by oozing, crusting, and scaling, and is intensely itchy. Infantile eczema frequently lasts several months and then disappears, but it may continue into childhood. In older children the lesions are characteristically in the antecubital and popliteal fossae but may be on any part of the body in patches or generalized. In a small percentage of cases eczema persists into adult life. The distribution of lesions tends to follow the childhood pattern. Because of the great disability the condition can cause, intensive therapy from the onset is indicated. Before beginning treatment it is essential to differentiate eczema from the nonallergic dermatoses and from contact dermatitis, another allergic dermatosis. D I F F E R E N T I A L DIAGNOSIS OF THE "ECZEMAS" OF INFANCY AND CHILDHOOD*

Eczema must be differentiated from: The Non-Allergic Dermatoses 1. Seborrhoeic dermatitis, and its severe form, erythrodermia desquamativa (Leiner's disease) 2. Eczematoid fungus infections 3. Infectious eczematoid dermatitis 4. Nummular eczema 5. Circumscribed neurodermatitis * See L.W. Hill, 1956

ECZEMA(ATOPIC DERMATITIS) 33 The Allergic Dermatoses

6. Contact dermatitis 7. Atopic dermatitis, atopic erythroderma Seborrhoeic Dermatitis 1. Commoner before 4 months of age than later 2. Often begins with cradle cap, then involves intertriginous areas; may be generalized 3. Typical lesions are pink with yellowish scales 4. Usually little itching 5. Often associated with atopic dermatitis Eczematoid Fungus Infections 1. Usually caused by trichophyton or by candida albicans 2. May resemble atopic dermatitis 3. Lesions tend to be patchy, sharply marginated; small satellite lesions may form at margins, enlarge, and fuse with the other patches 4. Confirm diagnosis by culture Infectious Eczematoid Dermatitis 1. Low-grade bacterial infection and often bacterial sensitization are contributory or even primary causes of the eczema (not to be confused with secondarily infected eczema) 2. Usually sharply circumscribed patches 3. Usually chronic and thickened, often oozing or crusted 4. Must treat both eczema and infection Nummular Eczema 1. Usually after 1 year of age 2. Circular, coin-sized patches on extremities, trunk, and face 3. Patches may be few or many, patches may coalesce 4. Normal skin between patches 5. Patches are vesicular, ooze a little, and form crusts 6. Itching varies 7. May be associated atopic dermatitis Circumscribed Neurodermatitis 1. Irregularly shaped, usually small, thickened, itchy lichenified patches 2. Normal skin between the patches 3. Usually on neck, hands, arms, or legs 4. Never in infancy, rarely in children 5. Probably caused by primary itching, followed by long-continued rubbing and scratching

34 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

Contact Dermatitis 1. Appearance varies all the way from mild erythema to scaling to bullae 2. In chronic cases thickening may be present 3. Borders are not sharp 4. May closely resemble atopic dermatitis 5. Rash may spread far from area where the rash started 6. Diagnosis often suggested by history Atopic Dermatitis 1. Usually starts between 2 and 6 months 2. Usually starts on cheeks and soon spreads to limbs and neck; may be generalized 3. Vesiculation is most characteristic element, also erythema, maculation, papulation, and sometimes whealing; secondary changes from scratching, rubbing, infection, and crusting 4. Itchy 5. In older children characteristically in antecubital and popliteal fossae, wrists, and back of neck 6. About 58% develop respiratory allergy

TREATMENT

This falls into four categories: local treatment, dietary control, environmental correction, hyposensitization (in some patients). Most infants under two years of age with eczema can be adequately treated by local treatment, dietary control, and environmental correction without the use of skin testing. A. Local Treatment Since the child with eczema is extremely uncomfortable, local treatment is important and can be expected to give considerable relief. The medication used will depend on the condition of the skin at the time. 1. Thick crusted lesions Soak thoroughly with corn oil, then remove the scales with a fine comb twice daily. 2. Weeping lesions Apply a lotion of Domeboro powder (aluminum acetate) made by dissolving one powder in one pint of water q3h prn until weeping stops. The solution must be freshly prepared each day.

ECZEMA(ATOPIC DERMATITIS) 35

3. Dry scaling lesions (except on the scalp) Apply cream of 1% hydrocortisone in dermabase twice a day after removing the scales by rubbing briskly with a face cloth dipped in corn oil. The cream is preferable to the ointment for most patients. 4. Secondarily infected lesions Apply bacitracin or neosporin ointment locally; 3% vioform ointment locally; sulfa drugs, penicillin, etc. by mouth or by injection as indicated, but not locally (use only if infection is severe). 5. Chronic scaling lesions often occurring in the flexures Apply 3% vioform, 1% hydrocortisone cream b.i.d. May be irritating to any open lesions. 6. Scalp Apply 4% resorcin in vaseline to the scalp b.i.d. Remove scales with a fine comb. B. Dietary Control The diet should be "denatured," that is, consist of well-cooked foods, because heating renders most foods less allergenic. Depending on the age of the infant, the following foods may be used: Initially 1. Soybean preparations Then try (one at a time) 1. Rice cereal 2. Synthetic vitamin preparation with A, B, C, and D Then try (one at a time) 1. Barley cereal 2. Carrot 3. Squash 4. Applesauce 5. Banana 6. Lamb 7. Jello Then try (one at a time) 1. Oatmeal cereal 2. Other baby canned vegetables 3. Other baby canned fruits 4. Bacon Then try (one at a time) 1. Wheat cereals and other wheat products 2. Beef 3. Evaporated milk

36 PAEDIATRIC A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Then try (one at a time) 1. Raw or semi-raw foods such as raw fruits 2. Egg yolk (hard boiled) 3. Egg yolk (soft boiled) 4. Egg white (well cooked) Then try: Full diet with bottled milk. C. Environmental Correction 1. 2. 3. 4. 5. 6. 7.

Provide dust-free room Provide non-allergenic toys Remove animals or birds in household (if possible) Use dust removing appliances Avoid silk or sheep's wool in contact with skin Use smooth cotton clothing as far as possible Wash clothing in mild soap, not a detergent If the eczema does not respond to this therapy or if it persists beyond two years, skin testing should be undertaken. Skin testing is not nearly as useful for eczema as it is for respiratory allergy.

D. Hyposensitization 1. 2. 3. 4.

Rarely indicated under two years of age Often of value after two years of age Must use very low doses of extract or severe flare-ups may result Try all other measures before resorting to skin testing and hyposensitization

ADDITIONAL REMARKS

1. Foods are more important than other allergens in the aetiology of eczema up to the age of one year. Around the age of one to two years inhalants are equally important. After this, inhalants are more important than foods. Pollens are also of aetiological importance in some cases. 2. Childhood eczema almost always begins in infancy, chiefly during the first year. Therefore, infantile eczema should be treated carefully in an attempt to prevent its persisting into childhood. 3. Over 50% of infants with severe eczema subsequently develop respiratory allergy. Early evidence of respiratory allergy should be watched for and treated before severe manifestations such as asthma appear.

ECZEMA(ATOPIC DERMATITIS) 37 Immunization Procedures for Infants and Children with Eczema

1. Diphtheria toxoid } Tetanus toxoid > Pertussis vaccine )

as in non-allergic children

2. Poliomyelitis vaccine: use "penicillin-free" preparations 3. Vaccination for smallpox: withhold until the skin is clear for one year; meanwhile do not vaccinate other individuals in the same household 4. Do not give immunizing agents containing horse serum unless absolutely essential Indications for Use of Steroids in Children with Eczema 1. To control severe exacerbations 2. To give reasonable relief while waiting for anti-allergic therapy to become effective 3. To clear skin temporarily so that skin testing can be done 4. To treat exceptionally severe cases that have not responded to the usual methods of treatment REFERENCES

Collins-Williams, C. Eczema (atopic dermatitis) in infants and children. Cañad. Med. Assoc. J., 86: 406, 1962 Hill, L.W. The Treatment of Eczema in Infants and Children. St Louis; C.V. Mosby Company, 1956 Hill, L.W. Eczema. Brennemann's Practice of Pediatrics, vol. 4, chap. 46. Hagerstown, Maryland: W.F. Prior & Co. Inc., 1968 Lerner, M.R., and Lerner, A.B. Dermatologie Medications, 2nd ed. Chicago: Year Book Publishers, 1960 Ratner, B., Collins-Williams, C., and Untracht, S. Allergic dermal-respiratory syndrome in children. Amer. J. Dis. Child., 82: 666, 1951

Urticaria and angioedema

Diagnostically, urticaria and angioedema form one of the most difficult symptom complexes facing the allergist. The allergic causes are varied and in addition all urticaria and angioedema is not of allergic aetiology in all patients. Non-allergic urticaria and angioedema is much more common in adults than it is in children. FACTORS IN THE AETIOLOGY

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Bacterial infections Viral infections Fungus infections Infestations Drugs and chemicals Foods Contactants Inhalants Inhalation of odours Insect bites Endocrine factors Psychogenic factors Pollens Physical allergy Systemic disease Miscellaneous

The main hope of arriving at a true aetiological diagnosis for either acute or chronic urticaria is the history. History must involve searching questions concerning the sixteen possible aetiological factors mentioned above. Only by having an intimate knowledge of the possibilities can the physician take a proper history. For patients with acute recurrent urticaria or chronic urticaria not responding to

URTICARIA AND ANGIOEDEMA 39

medical treatment, allergy skin testing is a worthwhile tool to aid in the investigation. However, it must be realized that allergy skin tests often fail to pinpoint the cause and are definitely not as valuable as a good history. TABLE II Causes of urticaria and angioedema Classification

Subclassification

Examples

Bacterial infections

Acute

Pharyngitis Otitis Pyelitis Convalescence from scarlet fever

Focal

Teeth TonsilsNasopharynx Sinuses Gall bladder and biliary tract Appendix Urinary tract Prostate Anal fistula Infected sebaceous cyst Bronchiectasis

Viral infections

Post-smallpox vaccination

Fungus infections

Epidermophyton interdigitale Trichophyton infection of skin

Infestations

Drugs and chemicals

Helminths

Filariasis Schistosomiasis Ascariasis Oxyuriasis (enterobiasis vermicularis) Strongyloidiasis Ancylostoma duodenale Necator americanus Trichinella Tapeworm Echinococcus

Protozoa

Trypanosomiasis Malaria Amoebiasis (endamoeba histolytica) Trichomoniasis Giardia lamblia

Miscellaneous

Scabies

Medicinal drugs

See Table III (Brennemann reference also) Erythromycin Atropine ¿/-tubocurarine ACTH Tonics Vitamins Nose drops Laxatives Cold tablets Headache medicine Blood transfusion Tetanus toxoid Insulin Eye drops Suppositories Pantopaque®

Chemical agents in processed foods

Phenolphthalein in cake Food colours Sulphur dioxide

40 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY TABLE II (continued) Causes of urticaria and angioedema Classification

Subclassification

Examples

Foods Contactants

Soaps, powders, cosmetics, dyes, mouth washes, nail polish, wave set, lipstick, detergents, bubble baths, silk, caterpillars, dog saliva, cat saliva, pollen, mercury ointment, nettles (primary urticariogenic), filter tips on cigarettes, mercury amalgam fillings, food such as eggs and citrus fruits, potassium iodide, formaldehyde

Inhalants

Hair spray, perfumes, insect sprays, cottonseed, flaxseed, animal dander, castor beans, house dust, wheat flour, feathers

Osmylogenic

Paint, fish, formaldehyde, ammonia

Insect bites

Endocrine disturbances

Papular urticaria Anaphylactoid reactions Thyrotoxicosis Premenstrual urticaria

Psychogenic Pollens Physical

Urticarial dermographism Pressure urticaria Urticarial hypersensitivity to light (solar urticaria) Hypersensitivity to heat (a) General (cholinergic) due to heat, exercise, or emotional tension (b) Local (non-cholinergic) Cutaneous sensitivity to cold (a) Cryoglobulinaemia (b) Syphilitic paroxysmal cold haemoglobinuria (c) Essential cold urticaria

Systemic cause

Malignancy Lymphoma (Hodgkin's) Myelogenous leukaemia Loeffler's disease Periarteritis nodo sa Chronic ulcerative colitis Brucellosis Liver disease Rheumatoid states Obstructive jaundice Lupus erythematosis

U R T I C A R I A AND A N G I O E D E M A 41 TABLE II (concluded) Causes of urticaria and angioedema Classification

Subclassification

Examples Stevens-Johnson syndrome Amyloidosis Anthrax Coxsackie-A9 infection Mediterranean fever Multiple myeloma Raynaud's syndrome Syphilis

Miscellaneous

Child crying - on face only during newborn period Palpebral - prior to roseola infantum Foreign body acting as allergen, e.g. peanut in the nose Syphilis

TABLE III Investigations which should be done in all cases of urticaria (acute or chronic) 1. History, as indicated 2. Physical examination, especially for (a) Appearance and distribution of lesions (b) Other skin lesions, e.g. bullae, atopic dermatitis, scabetic burrows, etc. (c) Evidence of infection, acute or chronic 3. Discontinue all drugs including vitamins, tonics, etc. If medication must be given during the period of investigation, use drugs chemically unrelated to those the patient has been receiving recently TABLE IV Investigations which should be done in all cases of urticaria (acute or chronic) if indicated by history or other findings listed in Table III 1. White blood count and differential blood smear (urticaria per se rarely causes eosinophilia; a high eosinophile count suggests an infestation) 2. Sedimentation rate 3. Repeated urinalyses 4. X-rays of chest, sinuses, teeth, gall bladder and biliary tract, urinary tract 5. Culture of non-urticarial skin lesions (if present) for fungi 6. Warm stool specimens for ova and parasites 7. Examination of peripheral blood or fluid from enlarged lymph nodes for trypanosomes 8. Examination of blood smears for malaria 9. Penicillin skin tests with special testing material (see page 51) 10. Elimination diets, and/or food diary, and/or provocative food tests 11. Elimination of or change to other types of toilet materials, cosmetics, clothing, ointments; eliminate gum chewing 12. Patch tests (if history indicates contact allergy); read immediate and delayed reactions 13. Allergy skin tests 14. Psychiatric appraisal 15. Gentle stroking of the skin (for urticarial dermographism) (watch for delayed reactions at 3-6 hours) 16. Solar or ultraviolet light applications 17. Heat or infrared applications 18. Intradermal testing with mecholyl 19. Ice or cold water applications 20. Determination of cryoglobulins 21. Cold haemolysins 22. Cold agglutinins 23. Blood Wassermann or other test for syphilis 24. Special tests for systemic disease indicated by history 25. Examination for sarcoptes scabei in their burrows 26. Determination of serum inhibitor of Ci esterase 27. Skin biopsy

42 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY REFERENCES

Collins-Williams, C. Urticaria and angioedema. F. Speer (éd.), The Allergic Child. New York: Harper and Row, 1963 Collins-Williams, C. Urticaria and angioedema. Brennemann's Practice of Pediatrics, vol. 2, chap. 65. Hagerstown, Maryland: W.F. Prior and Co., Inc., 1968

Gastrointestinal allergy

Gastrointestinal allergy is defined as allergy involving the gastrointestinal tract, whether due to foods, inhalants, pollens, moulds, or drugs. Most often the allergen is a food. Gastrointestinal allergy must be differentiated from food allergy which is manifested anywhere in the body, producing asthma, urticaria, and so forth. PATHOLOGICAL PHYSIOLOGY

Spasm, oedema, increased or decreased gastrointestinal motility, increased secretion of mucus, petechiae, and ulcération. CLINICAL SYNDROMES

The clinical syndromes which may be seen in infants and children as a result of gastrointestinal allergy include (1) vomiting, (2) diarrhoea, (3) coeliac syndrome, (4) mucous stools, (5) colic, (6) abdominal pain, both acute and chronic, (7) intestinal bleeding, (8) cheilitis, (9) canker sores, (10) angioneurotic oedema of the lips, palate, and other parts of the gastrointestinal tract, (11) anorexia, and (12) constipation. All of these symptoms are common in infants and children and may have many causes other than allergy. The criteria for making a diagnosis of allergy will be discussed later. DIFFICULTIES IN DIAGNOSIS

Since many other diseases - both organic and functional - may produce the same manifestations as gastrointestinal allergy, a careful study of the patient is required to give the correct diagnosis. DIAGNOSTIC METHODS 1. History

This is very important. If, for example, nausea and vomiting occur every time a patient eats oysters, the diagnosis is almost certainly allergy to oysters and this is

44 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

even more certain if there is associated urticaria. In the older child or adult, diagnosis is more difficult if the suspected or offending food is one commonly used, such as milk or wheat. In the small infant, each new food may be implicated by correlating the time the food was introduced into the diet and the onset of the symptoms. The association of other allergies in the patient or in members of the patient's family may also point to the diagnosis. History may on occasion suggest inhalants, pollens, moulds, or drugs as the aetiological agents. 2. Physical Examination This is usually negative except in such conditions as coeliac syndrome where the physical findings may be characteristic. 3. Dietary Manipulation (a) Removal of a suspected food from the diet and its reintroduction later will give invaluable information if done in a systematic manner. (b) Elimination diets (see Rowe, 1944 and Appendix A). (c) Denatured diets (only well-cooked foods). (d) Test diets. Suspected foods are fed deliberately to see if they will provoke symptoms. (e) It is extremely important that the patient's diet be confined to foods whose composition is known. This involves insisting on packaged foods which are labelled with a list of constituents. 4. Food Diary In almost all cases of gastrointestinal allergy some combination of the above methods is sufficient to establish the diagnosis. In more difficult cases other methods may be used, such as keeping a detailed food diary and correlating it with symptoms. Sufficient tests should be undertaken to establish the diagnosis of gastrointestinal allergy when it exists or to rule it out when it does not exist. 5. Skin Tests Skin tests are of limited value in investigating gastrointestinal allergy since clinically important foods frequently give negative skin reactions. Occasionally, if the patient is not responding to treatment based on the other methods of diagnosis, it is worthwhile resorting to skin tests which may sometimes give important leads missed by other diagnostic methods. 6. Gastrointestinal Eosinophilia In diarrhoea of allergic origin eosinophiles may be found in the mucus in the stools. These are difficult to demonstrate, but if a small amount of the mucus is found and stained in the same manner as a blood smear, eosinophiles will be seen. The same is true of vomiting caused by gastrointestinal allergy. Mucus found in the vomitus frequently contains large numbers of eosinophiles.

G A S T R O I N T E S T I N A L A L L E R G Y 45

7. Effect of Antihistamines and Other Drugs Often adrenaline, the antihistamines, and occasionally other drugs may be of value in diagnosing gastrointestinal allergy. Almost 50% of patients with gastrointestinal allergy are benefited by these drugs. Some of the therapeutic value of these drugs, however, may be due to their atropine-like properties or sedative effect rather than to their antihistaminic activity. Hence, for diagnostic significance the patient must be helped by antihistamines, but not by belladonna and its related compounds or sedatives. 8. Roentgenographic Studies Roentgenographic studies may also be carried out to help in the diagnosis of gastrointestinal allergy. Such studies consist of examining the patient, using contrast media with and without the suspected food allergen in the medium. For example, a child with gastrointestinal allergy suffering from nausea, vomiting, epigastric distress, or abdominal cramps within a few minutes of ingesting small amounts of an offending food will have no abnormalities demonstrable on the X-ray plate. However, if the child is examined by fluoroscopy and the suspected food is added to the contrast medium, pylorospasm resulting in gastric retention or increased small intestinal segmentation will be seen. Other positive roentgenographic findings may be disturbances of peristalsis, spasm, or dilatation of the stomach or intestines. 9. Gastroscopy The administration of a food allergen may result in definite gastroscopic changes consisting of hyperaemia, oedema, and thickening of the rugal folds, diminished peristalsis, a greyish mucus clinging to the mucosa, as well as submucosal haemorrhages. A gastroscopy should be performed for comparison before administering the suspected food. 10. Sigmoidoscopy This may help in diagnosing allergic colitis. In this condition the mucosa appears reddened, oedematous, and covered with considerable mucus. DISCUSSION

The diagnosis of gastrointestinal allergy implies an antigen-antibody reaction, with the antibody fixed somewhere in the gastrointestinal tract and the antigen entering the body, usually in the form of food, or as inhalant, pollen, mould, or drug. Without skin tests, which can be clinically correlated with symptoms, it is obviously impossible to prove an antigen-antibody reaction in every patient in whom the diagnosis of gastrointestinal allergy is made. However, there are many reasons for thinking that such a reaction takes place. An infant may become sensitized to food by several means, permitting an antigen-antibody reaction to occur: (1) sensitization in utero;

46 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

(2) sensitization by breast milk; (3) occasional feedings of raw milk during the neonatal period; (4) raw foods taken during convalescence; (5) fad diets; (6) overfeeding; (7) excessive indulgence in seasonal or bizarre foods. The antibody may be fixed in any portion of the gastrointestinal tract which later becomes the shock organ. In addition, experimental work on people and animals has demonstrated that antigen-antibody reactions occur in the gastrointestinal tract. If the mucous membrane of the human rectum is passively sensitized and antigen is administered either rectally or orally, a reaction results at the sensitized site. Similar studies have been reported on the human ileum and colon. Similarly, symptoms may be induced by either oral or rectal administration of foods to patients suffering from gastrointestinal allergy. Thus, there are many ways in which the gastrointestinal tract may become sensitized, in other words, to have antibody fixed in it and for antigen-antibody reactions to occur in the gastrointestinal tract. By analogy, it may be concluded that such an antigen-antibody reaction is taking place in the gastrointestinal tract of an infant or child in whom a diagnosis of gastrointestinal allergy is made if all the following criteria are strictly observed. (1) The patient has a history compatible with the diagnosis of allergy. (2) The specific allergen, almost always a food in an infant, is identified. (3) Symptoms come on within a reasonable time, from a few hours to a day or two, after ingestion of that food. (4) Symptoms disappear within a reasonable time, usually a day or two or occasionally more, after excluding the food from the diet. (5) Symptoms return when the food is reintroduced. (6) The food is one that is commonly tolerated without difficulty by most people; this will exclude foods that frequently cause gastrointestinal irritation unrelated to allergy. (7) The diagnosis is supported by other allergic manifestations to the same allergen, for example, urticaria. (8) The diagnosis is supported by other known allergies in the same patient. (9) The diagnosis is supported by the positive findings in other special diagnostic procedures such as blood eosinophilia, gastrointestinal eosinophilia, positive X-ray findings compatible with allergy, gastric or sigmoidoscopic examination, the effects of drugs, and the results of skin tests. TREATMENT

The main treatment of gastrointestinal allergy is dietary control, that is, elimination of the food causing the reaction. It is important to remember that adequate diet must be provided for the infant or child, one that is complete in calories, carbohydrates, protein, fat, minerals, and vitamins. Therefore, food substitutes, especially the milk substitutes, must be used to replace important food elements removed from the diet. Some authorities favour oral hyposensitization with foods, but the majority feel that there is little or no value in this and that the food should be completely eliminated from the diet. Usually the patient will be able to eat the food again without difficulty in several months or a few years. If pollens, inhalants, or moulds are implicated, the treatment involves both environmental correction and hyposensitization by injection. Drugs causing a reaction must be avoided.

G A S T R O I N T E S T I N A L A L L E R G Y 47 REFERENCES

Collins-Williams, C. Gastrointestinal allergy in infancy. J. Pediat., 45: 337, 1954 Collins-Williams, C. Acute allergic reactions to cow's milk. Ann. Allerg., 13: 415, 1955 Collins-Williams, C. The incidence of milk allergy in pédiatrie practice. J. Pediat., 48: 39, 1956 Collins-Williams, C. Cow's milk allergy in infants and children. Int. Arch. Allerg., 20: 38, 1962 Collins-Williams, C. Gastrointestinal allergy in infancy and childhood. Harms, E. (éd.), Somatic and Psychiatric Aspects of Childhood Allergies. Almsford, N. Y., Pergamon, 1963 Collins-Williams, C., and Salama, Y. A laboratory study on the diagnosis of milk allergy. Int. Arch. Allerg., 27: 110, 1965 Rowe, A.H. Elimination Diets and the Patient's Allergies: A Handbook of Allergy, 2nd ed. Philadelphia: Lea & Febiger, 1944

Drug hypersensitivity

To understand abnormal reactions to drugs certain definitions are necessary. 1. Toxic reactions These are the result of a response to certain pharmacological properties of a drug. These reactions occur frequently in patients receiving medication either too frequently or in excess dosages. 2. Intolerance Symptoms of overdose following the usual therapeutic dose of the drug are referred to as intolerance. 3. Idiosyncrasy Some use idiosyncrasy as a synonym for drug allergy. It is a quantitative alteration in the response of an individual to the pharmacologie actions of a drug. Some patients experience the usual therapeutic or toxic effects of a drug at dosage levels either much less than or much greater than the usual quantity of medication required to give these effects. Idiosyncrasy is closely allied to drug intolerance and does not involve an immunologie mechanism. 4. Allergic reactions These occur in some persons after they receive an amount of drug which ordinarily would not cause any untoward reaction. Such a response manifests hypersensitivity, but the symptoms produced are not related to its pharmacological action, for example, asthma from aspirin denotes an antigen-antibody mechanism. 5. Drug hypersensitivity This term denotes mechanisms which are responsible for effects differing from pharmacological results of overdosage, and which are induced by therapeutic or sub-therapeutic amounts. This occurs only in a small percentage of exposed individuals. Allergy and other conditions such as platelet agglutination due to hypersensitivity to quinine -* thrombocytopenic purpura are also included. Many believe that most hypersensitivity reactions to drugs are the result of allergic mechanisms, but other immune reactions and also non-immune processes bring about lesions due to drug hypersensitivity.

DRUG H Y P E R S E N S I T I V I T Y 49

Note that 1,2, and 3 involve pharmacological reactions to the drugs; 4 and 5 involve non-pharmacological reactions to the drugs. The accepted concept of drug allergy is that a simple chemical such as aspirin is incapable of reacting as an antigen, but when it is introduced into the body it combines with certain body proteins to become a perfect antigen capable of producing allergic manifestations. CLINICAL MANIFESTATIONS

These are varied and include (1) asthma, (2) rhinitis, (3) angioneurotic oedema, (4) urticaria, (5) abdominal pain, (6) headaches, (7) purpura, (8) generalized skin rashes and dermatitis, (9) fixed drug eruptions, and (10) fever. Leucopenia, granulocytopenia, and thrombocytopenia have also been produced by drugs. Encephalitis, liver damage, and lens cataract have been described as effects of drug hypersensitivity. The evidence that drug eruptions in general are due to specific hypersensitiveness is: 1. Previous toleration of the drug by the patient 2. Recurrence of the symptoms on re-exposure to the drug 3. The difference between the reactions seen in the patient and the pharmacological response to the drug 4. The smaller dose usually required to produce eruptions as compared to the dose necessary for the pharmacological effect 5. The absence of similar effects in most persons even when large doses are given 6. The specificity of the reaction occasionally present 7. The production of identical symptoms by drugs with totally different pharmacological action. Many drugs commonly used today cause drug allergy. Probably one of the most frequent offenders is penicillin. Allergic reactions to penicillin occur in 1% to 5% of all patients receiving the drug. The type of sensitivity varies from mild skin rashes to severe anaphylactic reactions which are sometimes fatal. The most common skin manifestation is urticaria, beginning 10 to 14 days after the drug has been given and occasionally accompanied by a syndrome resembling serum sickness. However, other manifestations occur in the skin as well as oral lesions, asthma, vasomotor rhinitis, conjunctivitis, various collagen diseases, and fever. Other drugs frequently causing allergy include aspirin, morphine, barbiturates, sulphonamides, arsenic compounds, phenolphthalein, and many others. FIXED DRUG E R U P T I O N S

These occur as an allergic manifestation to a drug. If the same drug is given later, a similar eruption appears in the identical place on the skin. DIAGNOSIS OF DRUG A L L E R G Y

This is difficult since skin tests are usually negative, and the main clue in the diag-

50 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

nosis will come from the patient's history and and the physician's knowledge of what drugs are likely to produce allergic manifestations and what they are most likely to be. To confirm the diagnosis by administering the drug again is often dangerous. For example, if penicillin sensitivity is suspected, administering penicillin may produce fatal anaphylactic shock which, of course, is a most unsatisfactory way of confirming a diagnosis. REFERENCES

Alexander, H.L. Reactions with Drug Therapy. Philadelphia: W.B. Saunders Company, 1955 Levine, B.B. Immunochemical mechanisms of drug allergy. P. A. Miescher and HJ. MullerEberhard (eds.), Textbook of Immunopathology, vol. 1. New York: Gruñe and Stratton, 1968 Meyler, L. and Herxheimer, A. Side Effects of Drugs, vol. 6. Baltimore: Williams and Wilkins Company, and Amsterdam: Excerpta Medica Foundation, 1968 Meyler, L., and Peck, H.M. (eds.). Drug Induced Diseases, vol. 3. Amsterdam: Excerpta Medica Foundation, 1968 Napke, E. and Bishop, J. The Canadian drug adverse reaction reporting program. Cañad. Med. Assoc. J., 95: 1307, 1966

Penicillin sensitivity

Penicillin sensitivity will be described separately because of its tremendous importance. Penicillin is a widely used antibiotic and allergic reactions to it occur in about 1% to 5% of patients. It is estimated that more than 1000 anaphylactic deaths due to penicillin have occurred in the United States. Table Visa classification of allergic reactions to penicillin as proposed by Le vine et al. TABLE V* Allergic reactions to penicillin Immediate allergic reactions (occur 2 to 30 minutes after penicillin) Urticaria Hypotension or shock Laryngeal oedema Wheezing Accelerated urticaria! reactions (1 to 72 hours) Urticaria or pruritis Wheezing or laryngeal oedema Local inflammatory reactions Late allergic reactions (more than 72 hours) Morbilliform eruptions (occasionally occur as early as 18 hours after initiation of penicillin) Urticarial eruptions Erythematous eruptions Recurrent urticaria and arthralgia Local inflammatory reactions Some relatively unusual late reactions Immunohaemolytic anaemia Drug fever Acute renal insufficiency Thrombocytopenia * B.B. Levine, A.P. Redmond, H.E. Voss, and D.M. Zolov, 1967

52 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Once introduced into the body, penicillin has a complicated metabolism. The major pathway is: benzylpenicillin G —» benzylpenicillenic acid (which combines with tissue protein) —» benzylpenicilloyl-protein group (BPO), which is the benzylpenicilloyl haptenic determinant. In vitro approximately 95% of penicillin acts in this way. There are several minor pathways most of which are not known. One minor pathway is penicillin G —> penicillenic acid —> penamaldic acid (which combines with tissue protein) —» penamaldic acid-cystine disulphide, penicillenic acidcystine disulphide plus others. Other degradation products of benzylpenicillin are benzylpenicilloate and benzylpenilloate. Only a small proportion of penicillin, about 5%, takes the minor pathways. IgE M E D I A T E D

REACTIONS

Urticarial or anaphylactic (immediate reactions) are mediated by IgE. Le vine, who has done a major portion of the work on penicillin sensitivity, has never seen an anaphylactic reaction to penicillin in man that is not mediated by IgE. The possibility of such reactions may be predicted by the direct skin test or by the PrauznitzKustner reaction; the former is more reliable. One can test for the major determinant (BPO) and two of the minor determinants separately, although in practice the minor determinants are usually tested for as a group. Each of the three reagins (IgE immunoglobulins) is specific. It is possible to be sensitive to the minor determinants and not to the major determinant. The major reagin reacts with benzylpenicilloyl polylysine (BPL) and is usually tested for by the scratch method using 1 x 10~6 M solution. If the test is negative an intracutaneous test is done with 0.005 to 0.01 ml of the solution. One minor determinant reacts with pure benzylpenicillin G and is tested for using the two methods in a strength of 10,000 units per ml. The other minor determinant reacts with crystalline sodium benzylpenicilloate. To test for the minor determinants as a group one may use the minor determinant mixture, MDM, which is crystalline benzylpenicillin G in a concentration of 2 x 10~2 M, sodium benzylpenicilloate 1 x 10~2 M, benzylpenicilloate 1 x 10~2 M and sodium alpha benzylpenicilloyl-amine. Thus the testing is simplified by using BPL, the MDM, and the diluent control. If the patient is to receive semi-synthetic penicillin, he is also tested with penicilloyl polylysine and the MDM prepared from the semi-synthetic penicillin as well as with BPL and MDM. If, by this method there are no detectable reagins, regardless of a history of penicillin sensitivity, it is probably safe to give penicillin. A possible exception may be that reagins, not yet identified, will be detected. Theoretically, there could be another anaphylactic antibody, such as the IgG in the rat, that is not shown by such a skin test. Conversely, detectable reagins indicate a high probability of an immediate or an accelerated allergic reaction to penicillin and also predict that eosinophilia is apt to follow the use of penicillin. Negative skin tests, however, do not exclude the possibility of other reactions such as exanthems, Coombs positivity, or granulocytopenic reactions to penicillin, since these reactions are not mediated by reagins. Furthermore negative skin tests do not exclude the possibility of a late urticarial reaction, since production of reagin

P E N I C I L L I N S E N S I T I V I T Y 53

may begin some days or weeks after the initiation of penicillin therapy. Skin tests must be done with material freshly prepared from the powder which stays stable indefinitely. The ultimate way to prove the diagnosis in a child who must have penicillin is by the oral challenge with 10,000 units after skin testing is done. The following points are worth emphasizing: 1. Patients who are skin test positive to minor determinants are those with the highest risk of immediate (including anaphylactic) allergic reactions to penicillin. 2. Skin sensitivity to BPL appears to be related to accelerated or late penicillin reactions, although occasionally it may be related to immediate reactions. 3. Blood eosinophilia developed in the course of penicillin therapy is specifically associated with the presence of skin sensitizing antibodies and is not specifically associated with the presence of IgG or IgM antibodies. 4. Minor determinants mediating the immediate allergic reaction are most frequently detected by skin tests using sodium benzylpenicilloate. 5. Minor determinants mediating recurrent urticaria and arthralgia are more frequently determined by skin tests using sodium benzylpenicilloate. IgM AND IgG M E D I A T E D R E A C T I O N S

Other forms of antibody to penicillin are the IgM and the IgG circulating antibodies detectable by passive haemagglutination. Assays, however, can only measure the BPO since methods have not yet been developed for measuring the minor components. IgM and IgG antibodies are common in people who have had penicillin. The IgM in high titre suggests the possibility of a morbilliform eruption. The eruptions which may be morbilliform, maculopapular, or erythematous are evident during therapy and fade with some scaling between 3 and 21 days after the drug is discontinued. They are probably mediated by soluble toxic antigen-antibody complexes with IgM. IgM antibodies may also be of value in predicting the rare cases of agranulocytosis associated with penicillin. The benzylpenicilloyl specific IgG antibodies on the other hand are probably associated with the rare immunohaemolytic anaemia with Coombs positivity. The IgG antibodies also act as blocking antibodies, that is, they can compete with reagins for antigen and thus can prevent or modulate antigen-reagin binding and the subsequent specific release of histamine. In other words the IgG antibodies are frequently protective in nature. Although the haemagglutinating titre appears to be of no value in predicting immediate reactions or accelerated urticarial reactions to penicillin in skin test negative patients, IgG titres may be useful in judging immediate reactions in BPL positive patients. Since a high IgG antibody titre may block an immediate reaction, it may be useful in evaluating the patient's chance of having such a reaction.

54 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y DELAYED HYPERSENSITIVITY

Positive skin tests occur in a large number of patients after a skin test with 0.1 ml of 0.1 M benzylpenicillin solution injected intradermally. These tests may on occasion be useful in diagnosing interstitial nephritis, a rare complication of penicillin sensitivity. Why do all such patients not develop these reactions to penicillin? The reason depends on several factors: 1. The penicillin dose. The higher the dose the more likely an accelerated reaction. 2. The presence of IgG antibodies acting as blocking antibodies. 3. The binding affinity of the reagins. If the reagins are of low affinity, a relatively high concentration of antigen is required to initiate mediator response and release is more likely to occur slowly than suddenly. 4. Non-immunological factors such as tissue content of releasable mediators, blood vessel reactivity, and histaminase activity in the tissue may also be involved. REFERENCES

Bierman, C.W., and Van Arsdel, P.P., Jr. Penicillin allergy in children: the role of immunological tests in its diagnosis. J. Allerg., 43: 267, 1969 Bloomer, H.A., Barton, L.J., and Maddock, R.K., Jr. Penicillin-induced encephalopathy in urémie patients. J.A.M.A., 200: 121, 1967 Girard, J.P. Common antigenic determinants of penicillin G, ampicillin and the cephalosporins demonstrated in men. Int. Arch. Allerg., 33: 428, 1968 Kunz, M.L., Reisman, R.E., and Arbesman, C.E. Evaluation of penicillin hypersensitivity by two newer immunological procedures. J. Allerg., 40: 135, 1967 Le vine, B.B. Immunologie mechanisms of penicillin allergy. A haptenic model system for the study of allergic diseases of man. New Eng. J. Med., 275: 1115, 1966 Le vine, B.B., and Redmond, A. P. Minor haptenic determinant-specific reagins of penicillin hypersensitivity in man. Int. Arch. Allerg., 35: 445, 1969 Le vine, B.B., Redmond, A. P., Voss, H.E., and Zolov, D.M. Prediction of penicillin allergy by immunological tests. Ann. N.Y. Acad. Sci., 145: 298, 1967 Le vine, B.B., and Zolov, D.M. Prediction of penicillin allergy by immunological tests. J. Allerg., 43: 231, 1969 Rosh, M.S., and Shinefield, H.R. Penicillin antibodies in children. Pediatrics, 42: 342, 1968 Stewart, G.T. Clinical and epidemiologic impact of penicillins old and new. Pediat. Clin. N. Amer., 15(1): 13, 1968 Stewart, G.T., and McGovern, J.P. Penicillin Allergy: Clinical and Immunologie Aspects. American Lecture Series. Springfield, 111.: Charles C Thomas, 1970 Wicher, K., Reisman, R.E., and Arbesman, C.E. Allergic reaction to penicillin present in milk. J.A.M.A., 208: 143, 1969 Zolov, D.M., and Levine, B.B. Correlation of blood eosinophilia with antibody classes: studies with the penicillin hypersensitivity system. Int. Arch. Allerg., 35: 179, 1969

Drugs inducing hypersensitivity not involving allergic mechanisms

1. Primaquine Certain patients who develop haemolytic anaemia on the ingestion of certain drugs such as Primaquine have red cells deficient in the enzyme glucose6-phosphate dehydrogenase, an enzyme which is used in the metabolism of glucose. The trait is inherited as an X-linked recessive and occurs only in males. Sixteen variants of the enzyme have been established and there are other doubtful variants. These enzymes vary greatly in their percentage of normal activity. Some variants lead to drug-induced haemolytic anaemia and fever and some to apparently spontaneous haemolytic anaemia. Other agents that may cause haemolytic anaemia in Primaquine-sensitive individuals are: Sulphonamides Phenacetin Acetanilid Furadantin Antipyrine Probenecid Naphthalene

Pollen of fava plant Fava bean Para-amino salicylic acid Pamaquine Pentaquine Phenylhydrazine Menadione

2. Succinylcholine (Suxamethonium), a muscle relaxant used in anaesthesia, is rapidly destroyed by serum cholinesterase. Certain patients receiving this drug may develop prolonged apnoea, lasting from one to several hours. In about 50% of patients the altered response is on a genetic basis; these patients have alterations in cholinesterase because of mutations at the Ei locus. The acetylcholine at the neuromuscular junction is therefore not destroyed as rapidly as normal. This syndrome is a single enzyme defect, but four different phenotypes are involved, the usual, the intermediate, the atypical, and the silent. No anaesthetist should administer succinylcholine without first determining whether there is a history of any adverse reaction to succinylcholine in the patient or in his family.

56 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

3. Isoniazid, used in treating tuberculosis, is normally acetylated in the liver by the hepatic enzyme acetyltransferase in the metabolism of the drug. Slow inactivators are homozygous for a recessive gene believed to cause lack of this enzyme and are more likely to develop polyneuritis as a complication of isoniazid therapy. Therefore, this drug should not be used if the patient has any relative who has had an adverse reaction as a result of inability to acetylate this drug. The peripheral neuropathy is not allergic in aetiology. 4. Barbiturates and sulphonamides may precipitate porphyria where the condition is latent. Acute intermittent porphyria is caused by a dominant gene. The condition may remain latent without ever showing clinical symptoms. Presumably, these drugs may precipitate the symptoms of the disease in an unknown manner and must be avoided by patients and family members who have been demonstrated to carry the gene. 5. Sulphonamides Some patients having a rare haemoglobin mutation called Hemoglobin Zurich tend to have severe haemolytic reactions from sulphonamide drugs. During these episodes of haemolysis there is a high methemoglobin level. 6. Primary urticaria genie drugs can cause urticaria by acting directly on the mast cells in the skin as histamine liberators. Examples are atropine, morphine, codeine, thiamine, apresoline, priscoline, pilocarpine, curare, polymyxin B, quinine, stilbamidine, sodium desoxycholate, acetylsalicylic acid, and sodium salicylate. 7. Sedormid, quinidine, quinine In susceptible patients who develop thrombocytopenic purpura after ingesting one of these drugs, it can be shown that the serum of the patients, plus the drug in question, plus normal platelets in the presence of complement will lead to agglutination and subsequent lysis of platelets. The drug may attach to the surface of the platelet forming a hapten-platelet complex which then combines with antibody leading to agglutination and lysis. Although this is an antigen-antibody immune reaction it is obviously not allergic. REFERENCES

Evans, D.A.P. Pharmacogenetics. Amer. J. Med., 34: 639, 1963 Kalow, W. Pharmacogenetics: Heredity and the Response to Drugs. Philadelphia: W.B. Saunders Co., 1962 Steinberg, A.G., and Beam, A.G. Progress in Medical Genetics, vol. Ill, pp. 49-74. New York: Gruñe and Stratton Inc., 1964 Thompson, J.S., and Thompson, M.W. Genetics in Medicine. Philadelphia: W.B. Saunders Co., 1966

Acute reactions to bee stings

Allergy to stings from such insects as bees, yellow jackets, hornets, and wasps can cause a variety of symptoms. If the sting is on the arm, the entire limb may swell and be followed by generalized urticaria, dyspnoea with or without dysphagia, anaphylactic shock from which the patient may or may not recover. Since there is no way of knowing whether the next sting will result in death or not, anyone who has had an acute allergic reaction requires treatment. The patient is initially skin tested with an extract of the whole bodies of the four insects, not to see whether he is allergic, but to see what strength of hyposensitizing solution is safe for initial treatment. Skin tests are done using 1:100,000,000, 1:10,000,000, and 1:1,000,000 dilution. If none of these gives a positive reaction, treatment is then started according to the following schedule with 1:1,000,000 dilution. If one of these gives a positive reaction, treatment is started with a weaker solution than that which caused the positive reaction. DOSAGE S C H E D U L E USING S T I N G I N G I N S E C T E X T R A C T

The following is the schedule to be used: Dosage 1:1,000,000 0.05 cc, 0.10 cc, 0.20 cc, 0.40 cc 1:100,000 0.05 cc, 0.10 cc, 0.20 cc, 0.40 cc 1:10,000 0.05 cc, 0.10 cc, 0.20 cc, 0.40 cc 1:1,000 0.05 cc, 0.10 cc, 0.20 cc, 0.30 cc, 0.40 cc 1:100 0.05 cc, 0.075 cc, 0.10 cc, 0.15 cc, 0.20 cc, 0.30 cc, 0.40 cc 1:10 0.05 cc, 0.075 cc, 0.10 cc, 0.15 cc, 0.20 cc, 0.30 cc, 0.40 cc The injections should be given at 4-day intervals until the top dose tolerable to the patient is reached, possibly 0.40 cc of the 1:10 dilution, or less. When the patient reaches his maximum tolerance, the injections may be given every 3 weeks, and

58 P A E D I A T R I C ALLERGY AND C L I N I C A L I M M U N O L O G Y

should be continued for a total of 3 years in the hope that permanent immunization will be achieved. If there is any general or undue local reaction to an injection, subsequent doses should be smaller, and increased gradually. The patient should be kept in the office for 20 minutes after the injection so that if there is any reaction he can be treated with Adrenaline immediately. Because the next time the child is stung medical help may not be available immediately, the parents should have an emergency kit including: 1. Three 1-cc Tuberculin (disposable) syringes with 25 x 5/8 inch needles. The cellophane wrapping should be kept intact until it is to be used. 2. Three 1-cc ampoules of Adrenaline 1:1,000 for subcutaneous use 3. One 2-oz bottle of Actifed Syrup sealed with adhesive tape to prevent leakage 4. Six Prednisone 5-mgm tablets 5. Three Pleds for cleansing the skin 6. One teaspoon Use To treat such an acute reaction, the following medications may be used: 1. Two minims (0.12 ml) of Adrenaline subcutaneously 2. Actifed Syrup 1 teaspoon up to 10 years of age, 2 teaspoons after 10 years of age 3. Two 5-mgm Prednisone tablets 4. Adrenaline (2 minims) may be repeated 10 minutes after the first dose if symptoms'are still severe People who have suffered allergic reactions should be given directions for destroying such insects and their nests or habitats. DIRECTIONS FOR DESTROYING BEES, WASPS, YELLOW J A C K E T S , A N D H O R N E T S

The insects should be destroyed by spraying their nests or the eaves or cracks in the house where they live. Such treatment will eventually eliminate the insects although it may need to be repeated as often as once a week for a period of time. For spraying, use 0.5% Lindane or 2% Chlordane, in oil solution; for dusting, 5% Chlordane or 1% Lindane Powder may be used. The oily sprays should be administered by a hand sprayer, preferably a compressed air type. Thedustingpowders may be spread by meansofahand sprayer. The choice of the oil spray or the powder will depend on the nature of the place to be attacked. A combination of the two may be beneficial. The directions should be read carefully before using these preparations, which are poisonous to people and animals as well as to the insects. The insecticides mentioned may be obtained from a feed and seed dealer.

Indications for removal of tonsils and adenoids in the allergic child

Indications for removal of tonsils and adenoids (T & A) in the allergic child are identical with those in the non-allergic child. This should be done for the child with respiratory allergy who is having recurrent episodes of acute tonsillitis, recurrent attacks of otitis media associated with upper respiratory infections, or whose enlarged tonsils and adenoids obstruct breathing and the passage of solid food. However, a T&A should never be done in the hope that chronic symptoms caused by allergic disease will be relieved, because a T&A will not clear up the symptoms of allergic rhinitis or recurrent asthma if the latter is not precipitated by acute attacks of tonsillitis. Allergic children, in fact, are frequently made worse if a T&A is done without a specific indication.

Immunization of the allergic child against infectious disease

The allergic child is immunized against the first three diseases as is the non-allergic child. 1. Diphtheria 2. Tetanus 3. Pertussis 4. Poliomyelitis Because of the danger of producing or aggravating penicillin sensitivity, it is wise to use penicillin-free poliomyelitis vaccine (Connaught Laboratories in Toronto). 5. Smallpox Smallpox vaccination is contraindicated in the child with eczema because of the danger of his developing eczema vaccinatum, a very dangerous disease which could be fatal. It is inadvisable to vaccinate a child with eczema until his skin has been clear for a year in case the eczema returns while the vaccination is at its climax. The child with eczema should be kept away from others who have been vaccinated until their lesions have healed. 6. Measles Although measles vaccine should not be withheld from allergic children, vaccines prepared on chick embryo cell culture should not be used in children who are markedly sensitive to egg, chicken feathers, or chicken meat. If the child can eat eggs without symptoms he should be able to tolerate the vaccine. The eggsensitive child may be immunized with measles vaccine grown on canine renal cell culture, whereas the latter vaccine is contraindicated for the child who is sensitive to dog hair or dander. Examples of culture vaccine made from chick embryo tissue are Rúbeovax manufactured by Merck, Sharp & Dohme, and Lirugen manufactured by Pitman-Moore. Examples of measles vaccine made from canine renal cell

I M M U N I Z A T I O N A G A I N S T I N F E C T I O U S DISEASE 61

culture are Parke Davis Measles Vaccine and Philips Roxane Measles Vaccine. All of these are live attenuated virus vaccines. Connaught inactivated measles vaccine, grown on monkey kidney cell cultures, which may be combined in DPT Polio Measles vaccine, should not predispose eggsensitive or dog-sensitive children to allergic reactions. 7. Tetanus antitoxin for prophylaxis of tetanus in a patient who may not have had sufficient tetanus toxoid to immunize him actively The allergic person requires tetanus immune globulin of human source because of the danger of acute sensitivity reactions or serum sickness from horse serum. Such a product, called HuTet, is manufactured by Flint Laboratories. No previous sensitivity testing is necessary; danger of reaction is minimal because human serum protein is being injected.

Preparation and maintenance of a dust-free environment

Since most allergic children are either sensitive to house dust or likely to become sensitive if exposed to it in large quantities, it is important to remove house dust from their environment as much as possible. The various methods are listed below. The "General Directions" should be followed for all children. The "Special Directions" apply to children who are known to be acutely sensitive to house dust, or who have severe allergic symptoms. Each child is considered as an individual and how fully these recommendations should be followed depends on the severity of his symptoms and the resulting disability. G E N E R A L DIRECTIONS

1. The room should contain a minimum of furniture and other dust-collecting objects so that it can be cleaned thoroughly once a week, and less thoroughly every day. 2. The room and furniture that must be left in the room should be cleaned thoroughly. This includes cleaning the walls and ceiling, scrubbing the woodwork and floor, and cleaning the closets. The bed and springs must be thoroughly cleaned also, and if it is necessary to have another bed in the same room it must be cleaned in a similar manner. 3. The boxspring, mattress, and pillow should be sponge rubber, or be covered with an impervious covering such as Egyptian cotton or plastic sewn with French seams. These coverings can be home-made or purchased ready-made. 4. The bed clothing should consist of washable blankets, quilts, and spreads. No sheep's wool blankets, eiderdowns, or comforters should be used. If a sheep's wool blanket is considered necessary, it should be enclosed in a cotton blanket cover or pinned between cotton sheets so that the fluff cannot escape. Such coverings should be washed frequently.

P R E P A R A T I O N AND M A I N T E N A N C E OF DUST-FREE E N V I R O N M E N T

63

5. Only a washable cotton rug should be in the room. The drapes should also be washable. Both should be washed every week. 6. The contents of the clothes cupboard should be minimal. If it is necessary to store clothing in the cupboard, garment bags should be used and kept zippered, especially for woollen clothing. 7. Much dust may enter the room through the heating system. Heating by hot water or steam presents no difficulty. If the heating is by hot air from a modern furnace, thoroughly cleaning and replacing all filters in the furnace three or four times during the heating season should be sufficient. If, however, the heating is by hot air from an old furnace without filters, the hot air register into the room must be sealed and the room heated by other means, such as an electric heater or electric radiator. If this is impractical, several layers of cheesecloth (which must be washed frequently) over the hot air register will help greatly. 8. Toys, books, and ornaments in the room should be kept to a minimum. Allergic children should play with wooden, metal, or rubber toys. Ordinary fuzzy stuffed toys are not acceptable; fuzzy animals made of nylon or dacron and stuffed with sponge rubber are ideal. 9. If possible the child should dress and undress in another room to minimize dust in the bedroom. For the same reason the bedroom door should be kept closed when the room is not in use. 10. The house, and especially the patient's bedroom, should be vacuumed daily. It is better to remove dust by using the vacuum cleaner attachments rather than a dust cloth, preferably when the child is out of the house. Initially, making a bedroom dust-free requires considerable work, but it is relatively easy to maintain it day by day. It should be remembered that these precautions are taken not only to relieve present symptoms but also to try to prevent other and often more serious trouble in the future. SPECIAL D I R E C T I O N S

1. Allergex This comes in an aerosol can and is sold in drugstores as Allergex Aerosol. It is used to spray rugs and furniture, and to wash bedding and drapes; it acts as a dust inhibitor. It is easy to apply and one application lasts about a year. Two pints are usually sufficient for a whole house. 2. Fan with electric filter (for one room) Such a machine can be obtained commercially for the child's room. It will constantly circulate the air in the room and remove dust particles from the air as it passes through the machine (Honeywell, Trion, Micronaire). 3. Air conditioner with electric filter (for one room) This type of air conditioner

64 PAEDIATRIC ALLERGY AND C L I N I C A L I M M U N O L O G Y

is ideal for the child's bedroom since it removes most of the dust and pollen. It is most effective when the vents are closed since some pollen may enter the room with the vents open. Such an air conditioner is of tremendous value to a child sensitive to pollens or house dust. An ordinary (not electric) filter is unsatisfactory. Since models change from year to year, consult a reliable dealer before purchasing such an air conditioner. 4. Electronic air cleaner (for a whole house) These machines are inserted into the air circuit of forced hot air heating units, and thus clear most of the dust from the hot air supply to the whole house. They are quite expensive (e.g., Honeywell, Trion, Westinghouse). 5. Protective mask If it is necessary for the patient to be in a dusty environment for a short time a protective mask over the nose and mouth is helpful.

Dosages of drugs useful in the care of allergic children

The following dosages assume the child is of average weight for age and that there are no contraindications to the use of the drug. A rationale for the use of many of these drugs is given in Appendix C, Beta Adrenergic Blockade - Cyclic 3'5' AMP. TABLE VI Bronchodilators (oral and suppository) 6 mos. lyr

Tedral (q6h) Paediatric tablets Elixir (tsp) Isuprel sublingual tablets (10 mgm) q4h prn

1-2 yr *

i

Acet-aminophylline

gr 5 tabs (q6h) Child size suppos. with pentobarbital Ephedrine tablets (q6-8h) Quibron (2-3 x daily) Capsules Elixir Bethiodyl (tid-qid) Paediatric capsules Drops (in water) Paediatric suppositories (tid) Aminophylline (q6-8h) Tablets gr li Suppositories grl 3

y

i

2-3 yr

5-10 yr

10+ yr

1

2 2-4 1

3-4 yr

4-5 yr

i

i

H

lf-2

i

i

•J— 1

1

i

•J— 1

1

1-3

i

i

1

1

1 adult size

¿gr

¿gr

¿-|gr

¿-Jgr

i

i

1/16 gr ¿gr

i

15 mgm over 12 yr

under 100 Ib 1 over 100 Ib 2 1 tsp

*

i i

1¿ tsp

lí tsp

2 tsp

2 tsp-1 tbsp

1-2 tbsp

5 min

5 min

5 min

1

2

i i i i

i

0.5 ce 1

i adult size

1-1 -J-

1-2

2

i

1

1

* i

Note: These are the drugs available in Canada.

1.0 ce

66 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY TABLE VI (continued) Bronchodilators (oral inhalation) Epinephrine hydrochloride, (Medihaler-epi) Isoproterenol (Medihaler-iso) Isuprel mistometer

1:100 soin 0.15 mgm epinephrine per measured dose 1 deep inhalation - may repeat in one minute 2.0 mgm/ml 0.075 mgm isoproterenol per measured dose 1 deep inhalation - may repeat in one minute 1:400 or 125 meg per dose - one deep inhalation In one minute repeat if necessary May repeat in 10-30 minutes

Bronchodilators (injectables) Adrenaline 1:1,000 S/C

0.01 ml/kg/dose - maximum 0.5 ml 2 minims is usually sufficient for any age May repeat in 10 minutes 0.05-0.1 ml 1-5 yrs 0.1-0.3 ml 5-11 yrs (initial dose should not exceed 0.1 ml)

Sus-phrine 1 :200 S/C

Expectorants 6 mos.1-2 yr lyr

Potassium iodide (sat'd sol'n) q4h 1 min Syr. hydriodic acid q4h 15 min Organidin 4 x daily Solution (with liquids) Elixir Tablets Syr. Ipecac Expectorant (q3-4h) Emetic

2-3 yr

3-4 yr

4-5 yr

5-10 yr

10+ yr

1-2 min

2-3 min

2-3 min

3 min

3-10 min

5-10 min

20 min

20 min

i tsp

i tsp

1 tsp

1 tsp

1-2 drops

drops

2-3

3-4 drops

4-5 drops

5-10 drops

20 drops 1 tsp 2

i-1 3-6 drops

4-7 drops

5-8 drops

6-9 7-10 drops drops 5-10 ml 5-10 ml May repeat in 30 min.

2-3 yr

3-4 yr

4-5 yr

5-6 yr

6+ yr

1 tsp i

1 tsp i

1 tsp i

1 tsp i

1 tsp i

2 tsp 1

1 tsp i

1 tsp i

\

1 tsp

1 tsp i

1 tsp i

2 tsp 1

i tsp

i tsp

i tsp

i tsp

i tsp

1 tsp*

2-5 drops

Nasal decongestant - antihistamine combinations 4 mos.1-2 yr lyr

Sudafed(3-4x daily) Syrup 1 tsp Tablets ¿ Actifed (tid) Syrup 1 tsp Tablets \ Co-Actifed (4 x daily) Cough syrup *2 tsp 12+ yr.

Note: These are the drugs available in Canada.

DRUG DOSAGES FOR ALLERGIC CHILDREN 67 TABLE VI (continued) Antihistamines (other than oral) Chlor-Tripolon I/V (10 mg/ml) I/M or S/C (100 mg/ml) Phenergan Suppositories i, 25 &50mg) Benadryl hydrochloride Steri-vial (10 mg/ml) Ampoule (50 mg/ml) I/V or deep I/M

1 ml diluted for adults (for emergencies only) 5-10 mg (up to 20 mg) per injection for adults 3-5 yr 12.5 mg up to q!2h 5-10 yr 25 mg up to q8h over 10 yr 25-50 mg up to q8h Child 10-50 mg (1 mg/lb) Adult 10-50mg (give undiluted)

Tranquillizer Atarax Tablets 10 & 25 mg Syrup 10 mg/tsp

Children 6-10 yr 10 mg bid Adults 10-25 mg tid-qid Dose must be adjusted within these limits

Steroids (oral) Tablets (p.o) 1 to 3 tablets q6h depending on severity of symptoms; decrease to zero, preferably over the next few days, as symptoms improve Cortisone (25 mgm) Hydrocortisone (20 mgm) Prednisone (5 mgm) e.g., Delta-Cortef, Meticorten Methylprednisone (4 mgm) e.g., Medrol Triamcinalone (4 mgm) e.g., Aristocort, Kenacort Dexamethasone (0.75 mgm) e.g., Decadron, Deronil Beta-methyl-prednisolone (0.6 mgm) e.g., Celestone These products are available in tablets of different sizes and the above doses refer to size of tablet shown. Some of these products are available as a syrup.

Steroids (parenteral) Depo-Medrol (40 mgm/cc) 1 cc for acute allergic episodes per week, I/M or more often if symptoms are very acute May use other therapy concomitantly ACTH 10 I. units q6h for infants Aqueous - I/M 15 I. units q6h for children 5 to 15 I. units for infants I/V 15 to 25 I. units for children Diluted in each case in 250ml of 5% glucose in D.W. over 8 hours S/C or I/M daily or q2 days Long-acting 20 to 40 units for infants 40 to 80 units for children Note: These are the drugs available in Canada.

68 PAEDIATRIC ALLERGY AND C L I N I C A L I M M U N O L O G Y TABLE VI (concluded) Steroids (I/V) Hydrocortisone e.g. Solu-Cortef

Infant

50 mgm stat into I/V tubing and 50 mgm in I/V flask to run in over the next 8 hours. Taper dose or switch to oral steroids as patient improves Small child 75 mgm and 75 mgm respectively Older child 100 mgm and 100 mgm respectively In emergency, Solu-Cortef in Mix-o-vial may be given undiluted over at least 30 seconds. Aminophylline Dosage Intravenous 3.5 mgm/kg body weight Oral 5 mgm/kg body weight Rectal 7 mgm/kg body weight Not oftener than q6h ; preferably q6-8h Toxicity Gastrointestinal Nausea, vomiting, haematemesis Nervous system Confusion, restlessness, excitement, insomnia, sensory disturbances such as light flashes and tinnitus, convulsions, unconsciousness, respiratory failure Kidney Diuresis, albuminuria, dehydration Symptoms of toxicity may appear after use of drug by any route. Intravenous route is dangerous and should be used only in emergencies. Do not order routinely, use only prn. Discontinue the drug if vomiting, an early sign of toxicity, occurs. Note: These are the drugs available in Canada.

TABLE VII Antihistaminic drugs and dosages for general use in hay fever* (Classification according to Textbook of Organic, Medicinal and Pharmaceutical Chemistry, 4th éd., C.O. Wilson and O. Grisvold (eds.) Lippincott and Company, 1962) Generic name (manufacturer)

Preparations available

Dosage

Benadryl

Diphenhydramine hydrochloride (Parke-Davis)

Capsules Kapseals Elixir

25 mg 50 mg 10 mg/4 ml

0.5 mg/lb (1 mg/kg) q6h (maximum 50 mg/dose)

II Ethylenediamine derivatives

Pyribenzamine

Tripelennamine (Ciba)

Tablets Elixir Lontabs

50 mg 20 mg/4 ml 100 mg

0.5mg/lb (1 mg/kg) q6h (maximum 50 mg/dose except for long-acting form) 100 mg Lontabs - adult -j- q!2h

III Propylamine derivatives

Chlor-Tripolon

Chlorpheniramine maléate (Schering)

Tablets Syrup Repetabs Repetabs

4 mg 2 mg/4 ml 8 mg 12 mg

6 to 12 years, ^ adult dose Adult: Tablets f Syrup 4 to 8 ml 3 to 4 times daily Repetabs -f hs or q8-10h during the day 8-mg repetabs may be used in children over 6 years

Polaramine

Dextrochlorpheniramine maléate (Schering)

Syrup Tablets Repetabs

2 mg/4 ml 2 mg 6 mg

Dimetane

Brompheniramine maléate (Robins)

Elixir Tablets Extentabs Extentabs

2 mg/4 ml 4 mg 8 mg 12 mg

Group

Common name

I Ethanolamine derivatives

6 to 12 years, \ adult dose Adult: Syrup 4 ml tid or qid Tablets f tid or qid Repetabs -f am and hs Infants : 1 ml syrup tid or qid Under 3 years: 0.05 mg/lb q6h (0. 1 mg/kg) 3 to 6 years : 4 ml Elixir 3 times daily 6 to 12 years: Elixir 4 to 8 ml 3-4 times daily í Tablets f 3-4 times daily Over 12 years: 1 tablet 3-4 times daily or 1 8-mg extentab morning and evening Adult: Tablets 1-2 tid or qid Extentab f q8-12h Flixir

These are the drugs available in Canada.

8 16 ml tiH r»r niH

TABLE VII (continued) Group

Common name

IV Phenothiazine Phenergan related structural compounds

Miscellaneous structures

Generic name (manufacturer)

Preparations available

Promethazine (Poulenc)

Tablets Tablets Tablets Syrup

10 mg 25 mg 50 mg 10 mg/4 ml

Tacaryl

Methdilazine hydrochloride (Mead Johnson)

Syrup Tablets

4 mg/4 ml 8 mg

Perazil

Chlorcyclizine hydrochloride (Burroughs Wellcome) Phenylephrine hydrochloride + Diphenylpyraline hydrochloride (Pitman-Moore)

Tablets

Novahistine

Novahistex

Forhistal

Phenylephrine hydrochloride + Diphenylpyraline hydrochloride (Pitman-Moore) Dimethpyrindene maléate (Ciba)

Note: These are the drugs available in Canada.

50 mg

Dosage 0.125 to 0.25 mg/lb (0.25 to 0.5 mg/kg) q6h Example : Adult 10 mg before meals or on retiring; Child 5 to 10 mg q8h Use lowest dose possible to relieve symptoms Over 3 years: Syrup 4 ml twice daily Tablets ^ twice daily (increasing to 3^4 time: daily if necessary) Adult: Tablets T bid Syrup 8 ml bid Increasing to 3-4 times daily if required < 8 years, \ tablet in morning and at bedtime > 8 years, 1 tablet in morning and at bedtime

Elixir: i to 1 year 2 ml q4h 1 to 6 years 4 ml q4h 6 to 12 years 8 ml q4h Capsules : 6 to 12 years ~r q4h Adults and children over 12 years: Elixir 4 ml = -J- NovaElixir 4 ml q4h histex tablet Singlet -7- q4-6h Singlet 20 mg + 2 mg Tablet 40 mg + 4 mg Tablet -f q8-12h Elixir

4 ml 5 mg + 1 mg Fortis capsules 10 mg -f- 1 mg

Lontabs 2 . 5 mg Tablets 1 mg Syrup 1 mg/5 ml Paediatric oral drops 0.5 mg/0.6ml

Adults and children over 6 years: Lontab 1 am and hs Tablet 1-2, 1 to 3 times daily Syrup 4-8 ml 1 to 3 times daily Under 6 years : Paediatric oral drops 0.25 mg (0.3 ml) to 0.5 mg (0.6 ml), 2 to 3 times daily

Skin testing

When an allergen enters the body by any route it may give rise to the 4 ' skin sensitizing" antibody which becomes fixed in the patient's skin. If, at a later date, allergen is introduced into the skin, the antigen and antibody will combine to produce an area of erythema or whealing. Allergy skin testing is based on this principle. The allergic patient is studied by history and physical examination and is then subjected to a series of skin tests during which certain allergens, considered to be of possible aetiological significance in his allergy, are introduced into his skin. Within 15-20 minutes an area of erythema or a wheal will appear at the sites if skinsensitizing antibody to the specific allergen is present. These tests are read as positive, those at which no reaction occurs as negative. The reactions must not be interpreted literally to the extent of saying that the patient is allergic to all allergens giving a positive reaction and not allergic to all allergens giving a negative reaction. After the allergen is introduced into the body, the patient may show allergic manifestations to it before skin-sensitizing antibody has developed and become fixed in the skin, that is, he may show a false-negative reaction. On the other hand, a patient may go through a brief phase of allergy when skin-sensitizing antibody to certain allergens may become fixed in his skin and remain long after all clinical symptoms have disappeared, that is, he may show a false-positive reaction. Also, a few patients, although extremely sensitive to some allergens clinically, persistently show negative skin reactions to those allergens. The natural train of events in an allergic child is for food allergies to appear in infancy (acquired either in utero or shortly after birth). By about six months of age such children frequently show positive skin tests with the foods. In the next year or two, after repeated exposure to dust, animal emanations, etc., the infant becomes allergic and shows positive skin reactions to these substances. In the next few years pollens have the same effect. If the child is first skin-tested at, say, eight years of age, he may with foods give positive reactions, many of which are falsepositive. More reliable results are obtained with inhalants and pollens since inhalant sensitivities, although tending to develop later, persist and increase in number.

72 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

From this discussion it should not be concluded that skin tests are of little value; they are indeed extremely valuable in the diagnosis of aetiological factors and in subsequent treatment. They have their limitations, however, in common with other laboratory procedures, and it is only by understanding these limitations that we can interpret skin tests intelligently. METHODS

The scratch method and the intracutaneous method are in common use. Scratch Testing Advantages 1. Relatively painless 2. Safe

Disadvantages 1. Time-consuming 2. Infants difficult to hold 3. Frequently negative in the presence of clinical sensitivity to inhalants, pollens, and moulds

Intracutaneous Testing Advantages 1. Speedy 2. More reliable than the scratch tests for testing sensitivity to inhalants, pollens, and moulds

Disadvantages 1. Constitutional reactions may result 2. Painful

WHY ARE SKIN TESTS DONE?

Although the history usually throws considerable light on what foods, inhalants, and pollens are of aetiological importance for a given patient, skin tests are necessary in order to confirm these findings and also to indicate other aetiological agents not detected in the history. Greater success attends the treatment of allergic children when skin testing is used in conjunction with other procedures. A diagnosis of allergy is based on the history, physical examination, and such laboratory procedures as blood counts, nasal smears, and roentgenograms. Skin tests are used to help identify the aetiological agents, never to diagnose allergy.

SKIN TESTING 73 IN WHAT PATIENTS SHOULD SKIN TESTING BE DONE?

In those patients whose symptoms are severe enough to merit a prolonged course of anti-allergic treatment. WHAT ALLERGENS SHOULD BE USED FOR SKIN TESTING?

Foods, inhalants, pollens, and moulds to which the patient is commonly exposed. The more complete the testing, the better is the expectation of successful treatment. The allergens most responsible for clinical allergy are house dust, grass pollen, and ragweed pollen, but many other allergens may be important and should be used for testing. SHOULD SKIN TESTS EVER BE REPEATED?

When a child has been skin-tested and has been treated along the lines indicated, considerable improvement should result. If not, the reason may be found by reexamining the history and also by making sure that the directions for treatment are being rigidly followed. For example, parents commonly fail to follow the directions for a dust-free room accurately. Sometimes an unusual or unsuspected environmental factor is responsible for the lack of improvement. It is worthwhile to visit the home of a patient who is not doing well. If improvement is not marked at the end of two years of treatment, which includes hyposensitization, the patient should be reassessed. The skin tests should be repeated only if they are likely to reveal new important aetiological factors. If a child who has been tested at two years because of mainly wintertime symptoms shows at review SVz years later a history of summertime symptoms as well, the skin tests should be repeated. On the other hand, if the patient has symptoms all year around and the original testing showed reactions with most of the common inhalants, epidermals, pollens, and moulds, there is seldom any point in repeating the skin tests. Changes in the method of hyposensitization may be more important than the detection of a few more allergens. Do not rush into repeating the skin tests unless there is a real hope that they will benefit the patient. PRACTICAL INTERPRETATION

After skin testing has shown positive reactions with a few foods, inhalants, pollens, and moulds, how are the results to be applied to the care of the patient? Bear in mind that some of the positive reactions are false-positives and that some allergens important aetiologically may have been missed because of false-negative reactions. 1. Always correlate the results of the skin tests with the history. False-negative

74 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

reactions can frequently be so detected because the parent has already reported certain foods or environmental factors causing difficulty. False-positive reactions can frequently be detected by the child's lack of symptoms when exposed to certain allergens. 2. At the onset of treatment, all foods implicated by the history or by skin tests should be excluded from the diet if at all possible. As soon as symptoms are well controlled, however, the foods may be added to the diet one at a time and left in the diet if they cause no symptoms. In this way most allergic children can soon be put back on a reasonable diet. As long as certain foods cause clinical symptoms they must be totally omitted from the diet but they are never omitted indefinitely just because of a positive skin test. 3. In the plans for control of the patient's environment and for his hyposensitization therapy, one should take into account the inhalants, pollens, and moulds implicated by the history and by positive skin tests. False-positive results can be identified by referring to the history; for example, if symptoms are confined to August, September, and October, a positive test with pollen from the maple tree, which pollinates in April and May, cannot be significant.

Hyposensitization therapy in atopic disease

People with atopic illness such as hay fever or asthma differ from so-called nonatopic people in that they readily form skin sensitizing antibody, or reagin, when exposed to allergens in their environment. The reagin becomes fixed in one or more shock organs and subsequent exposure to the corresponding allergen may result in clinical symptoms. In hay fever the shock organs are the nasal mucosa and/or the conjunctiva. In asthma the shock organ is the bronchial smooth muscle. The symptoms of allergic rhinitis may develop in the patient with reagin to house dust fixed in his nasal mucosa when he is exposed to house dust in his environment. The patient who is clinically allergic to inhalants such as dust and animal emanations, pollens, or moulds and who receives subcutaneous injections of these substances will usually develop a degree of immunity to them. If the injections are continued, the allergic symptoms will become progressively milder and may eventually disappear. Experiments using food as the hyposensitizing agent are quite unsatisfactory. Merely removing the aetiologically important foods from the diet is usually enough to "desensitize" the patient spontaneously over the next few years. Thereafter the foods are usually non-allergenic for him. Hyposensitization therapy is one of the most valuable tools in clinical medicine, but, unfortunately, it is one of the most badly used. If used properly over a period of two or three years, it will give good results in excess of 90%. Some patients require prolonged therapy over many years. Frequently, however, only 40% to 50% of the results are satisfactory for the following reasons: 1. Patients vary greatly in the dose of a particular allergen required to combat their symptoms satisfactorily. For example, one patient with ragweed hay fever will recover almost completely with repeated relatively small doses of ragweed allergen ; another will need moderate doses ; another will need extremely high doses. Unless this is considered by the physician, his results will often be poor. The treatment must be tailored to the patient, not to the disease. Using a standard dosage

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schedule and expecting that it will benefit all patients to the utmost is a great mistake. 2. Many patients react to large doses of extract, and are actually worse than they would be if their disease were untreated. Frequently, this situation is unrecognized by the physician. 3. In hyposensitizing children who have atopic dermatitis and respiratory allergy, it is frequently necessary to keep the dose of extract low since the dermatitis may flare up severely. Although improvement in the respiratory allergy is delayed, the doses can be rapidly increased as soon as the atopic dermatitis has cleared. Then the respiratory symptoms should be greatly relieved. 4. Frequently, the practising physician does not report all reactions to the allergist who has prescribed the treatment extract and who could effect the appropriate changes if he knew whether the patient was tolerating the injections well, whether the patient was having reactions because of overdosage, what time of the year the symptoms were more severe, how well the original symptoms were being controlled, and whether new symptoms had developed. Repeated injections of an unsuitable extract can be avoided. Is hyposensitization really necessary? Will a patient with respiratory allergy not improve just as quickly if he is medicated for symptoms and his environment is controlled? The answer is "no." In long-term follow-up studies of asthma, the course of the disease was prolonged in those patients who were not hyposensitized. Rackemanna and Edwards (1952) studied 449 patients who had had asthma in childhood, only a few of whom had been hyposensitized, and found that after 20 years of treatment only 31% were cured, 19% were relieved, and others were still suffering from some asthma and other allergies. The conclusion was that the age of cure depended on how promptly specific allergenic substances could be found and removed. In 239 patients whose onset of asthma had been at the age of 13 years plus, 45% still suffered from asthma after 20 years of treatment, 28% to a severe degree and 2Vz% with fatal results. Flensborg (1945) studied 298 patients whose asthma had been treated with dietary control and environmental correction but without hyposensitization and found that after 5 to 18 years from onset, in patients whose average duration of the disease was 7.4 years, 22% had had no attacks for a year, 18% were still having exertional dyspnoea, 55% were still having attacks, and 2% had died in status. Ryssing (1959) studied the same group of patients 14 years later (total follow-up period, 19 to 32 years) and found that about 55% were still suffering from asthma and another 2% had died as a result. Only 30% had become symptom-free. M E C H A N I S M S OF

HYPOSENSITIZATION

One of the major immunological mechanisms is the production of blocking anti-

HYPOSENSITIZATION

THERAPY IN ATOPIC DISEASE 77

body, an antibody of the IgG class, probably one of the main reasons for clinical improvement in the patient's condition resulting from hyposensitization. Hyposensitization with a specific allergen to which a patient is sensitive reduces the histamine release from that patient's basophiles on subsequent exposure to that allergen. This reduction can be demonstrated in samples of "buffycoat" taken before and after hyposensitization by adding the allergen to the buffycoat suspension and measuring the histamine released. This may be an important mechanism by which hyposensitization brings relief to the patient. The relative importance of the two mechanisms is unknown. Other mechanisms, as yet unknown, probably play a part also. C O N T R O L L E D STUDIES

Clinical studies with equally severe cases in similar age groups have revealed that the addition of hyposensitization to programmes of therapy leads to greater success with treatment than when hyposensitization is excluded. Sceptics always criticize such experiments as being influenced by the bias of the person performing them. More scientific control, however, can be achieved in studies of histamine release and bronchial provocation. Monitoring the duration and severity of symptoms in a large group of patients with ragweed hay fever during the period of hyposensitization has revealed that the greatest relief in symptoms is accompanied by the greatest decrease in histamine release. Patients who become asymptomatic may have no histamine at all released from the white cells on exposure to the ragweed allergen, although an allergen other than ragweed to which the patient is sensitive may still evoke a histamine response, indicating that the intracellular changes are specific for the allergen being used in the hyposensitization programme. Provocative bronchial testing is the second method of assessing the results of hyposensitization. For example, at various stages in his hyposensitization programme a patient sensitive to house dust inhales an aerosol consisting of a dilute solution of house dust and the degree of bronchospasm is measured. After the patient has been hyposensitized for about a year it takes a much greater concentration of house dust in the aerosol to bring on a similar degree of bronchospasm. METHOD

The patient is injected with solutions containing progressively larger amounts of the inhalants, pollens, and moulds considered aetiologically significant for him. The programme outlined for a given patient will vary with his age, his clinical symptoms, and the severity of those symptoms. The allergist must decide which allergens are to be included, whether singly or in combination, and what concentrations the patient will tolerate initially and be able to tolerate eventually. In general, the allergist should incorporate the important allergens (not foods) which cannot be avoided in the patient's environment, start with a weak solution which does not cause reactions (i.e., bring on the patient's symptoms), and gradually use stronger

78 PAEDIATRIC A L L E R G Y AND C L I N I C A L IMMUNOLOGY

solutions until the patient no longer reacts to the allergen in his environment. If reactions occur, the dose must be reduced to the level which did not cause reactions, kept at that level for a few months, and then gradually increased again. Initially injections should be given weekly for a year or more. The interval should then be gradually lengthened to every two weeks, every three weeks, and finally every four weeks. Some allergists favour concentrated extracts, some dilute, some multiple allergens , some a few allergens. This should not be confusing to the practising physician if he realizes that every patient requires an individual hyposensitizing programme which will give him optimal relief. With patients who are receiving hyposensitization therapy because of perennial symptoms such as asthma or perennial allergic rhinitis, my own method is to treat with multiple allergens, starting off with a single small dose (0.05 ml) of a 1:5000 weight/volume (w/v) concentration of the allergens incriminated by the history and/or skin tests. In the extract I include such allergens as house dust, kapok, feathers, ragweed, grass and tree pollens, and generally omit allergens which the patient should be able to avoid completely, such as cat hair, dog hair, and horse dander. These might be included in special circumstances, for example in the case of a child who lives on a farm and cannot avoid these allergens. Each week the dose is increased to a quantity the patient can safely tolerate without reaction, by increments of 0.05 ml, until a maintenance level, usually 0.25 ml, is reached. Weekly injections are maintained at that level until the supply of extract has been used. For the second series of weekly injections, a new extract is made containing greater concentrations of the allergens most offensive to the patient. For example, if house dust and ragweed particularly affect him, these allergens may be increased to a 1:500 w/v concentration each, and the other allergens left at 1:5000. Again the patient is started off on a small dose, which is later increased to 0.25 ml. For the third series of injections, the indicated allergens are again increased in strength. For some patients the ragweed pollen concentration may be increased to 1:40 w/v and the house dust concentration to 1:100. For others the concentration of grass pollen may be increased to 1:40. If the patient receiving such an extract shows great improvement, except during ragweed season, a separate programme may be started. An extract of ragweed pollen alone may be combined with the other injection or given separately in an aqueous solution of in an Allpyral ragweed suspension. The latter can be tolerated in very high doses, but should be given as an injection separate from the aqueous material if the patient is receiving other extracts. It is my practice to begin with a No. 1 strength containing 500 protein nitrogen units (PNU) of pollen per millilitre or 250 PNU of house dust per millilitre. The dose is increased from 0.1 to 0.2 to 0.3 up to 0.8 ml when No. 2 strength, 2500 PNU per millilitre for pollen and 1250 PNU per millilitre for house dust, is used. The dose starts at 0.1 and is increased to 0.6 in a similar progression. The next strength is 5000 PNU/ml for pollen, 2500 PNU/ml for house dust. The dose starts at 0.3, increasing to 0.4 to 0.5 to 0.6 ml per injection. For most patients this is as high as the dose goes. For the patient who still does not respond to this dose with good clinical improvement but who is not reacting to the injections, No. 4 strength, 10,000 PNU/ml for

H Y P O S E N S I T I Z A T I O N T H E R A P Y IN ATOPIC DISEASE 79

pollen, 5000 PNU/ml for house dust, is used with the same dosage schedule as for No. 3. For an occasional patient, No. 5 strength, which is 20,000 PNU/ml for pollen, 10,000 PNU/ml for house dust (the strengths made by the manufacturer of the extract), can be used up to a maximal dose of 0.5 cc. The patient is now receiving 10,000 PNU of pollen per injection or 5000 PNU of house dust as well as the previous extract containing multiple allergens, with the important ones in higher concentration. The Allpyral suspension is available for most allergens. House dust, ragweed, timothy, or timothy plus June grass and tree pollens are the most important allergens to consider using in this therapy. To fit a patient's special circumstances, mould, particularly alternaría and hormodendrum, or some other allergen may be included. No patient should be considered to have failed to respond to hyposensitization therapy unless he has been treated with the allergens thought to be causing his symptoms up to as high a concentration of them as he can tolerate for at least a year, initially at weekly, then at two-weekly, intervals. The patient receiving strength No. 3 should not be injected more often than every two weeks since the material is long-acting and reactions can occur if the dose is not absorbed. Most failures with hyposensitization therapy happen because the patient is not being treated with the correct allergens or is being treated with the correct allergens in an insufficient dose. This programme must, of course, be modified to fit the patient's particular circumstances. For instance, if the patient is allergic to ragweed but has no symptoms the remainder of the year, he can be given the ragweed suspension immediately in the doses described or he can be given aqueous ragweed to increasingly high doses. Positive skin tests may predict clinical allergies that will be manifest later in life. By avoiding, as much as possible, the allergens to which his tests reacted positively, the patient may prevent symptoms caused by these in the future. However, if as treatment goes on, the patient starts to have symptoms at other times of the year, such as during the grass pollen season, additional hyposensitization therapy should be included since the ragweed injections are specific for symptoms during the ragweed season (approximately August 15 to the first frost). D U R A T I O N OF T H E R A P Y

The child's degree of well being is the only criterion for deciding when to discontinue the injections. As soon as symptoms are controlled the injections may be reduced from once a week to every two weeks, every three weeks, then every four weeks, and finally discontinued. The interval should not be longer than four weeks. If the injections are discontinued prematurely, the symptoms may soon return to their former severity and the whole programme must be repeated. As a working rule, the injections should be continued until the patient has been asymptomatic for at least one year, preferably two years. DEFICIENCIES

Hyposensitization therapy may not work satisfactorily even in the hands of a well-

80 PAEDIATRIC ALLERGY AND C L I N I C A L I M M U N O L O G Y

trained allergist. Some patients are so acutely sensitive to common allergens such as house dust or ragweed and develop increasing sensitivity so rapidly on continuing exposure that they cannot tolerate sufficient doses of extract by injection to produce the immunological changes necessary for relief. Such patients may have to be treated for a prolonged period with very dilute extract. Fortunately most of these patients will eventually tolerate much higher doses of extract as they produce more blocking antibody. A patient may be acutely sensitive to many allergens not recognizable even from a good history and skin testing. For example, he may have multiple mould sensitivities which are very difficult to detect from his history and even if his skin tests react positively to many moulds, it is impossible to assess how important these positive skin tests are unless the facilities to test the patient by either provocative bronchial or provocative nasal testing depending on his symptoms are available. If such tests are possible, the patient can be treated using only the moulds that actually bring on symptoms, instead of being treated with the many moulds that produce positive skin tests, some of which may not be clinically significant. One of the greatest difficulties in hyposensitization is communication from the patient to his physician to the allergist who is designing the programme and who needs to know exactly what is going on in order to write the prescription for extract intelligently. REFERENCES

Natural History of Asthma Flensborg, E.W. Prognosis for bronchial asthma arisen in infancy, after non-specific treatment hitherto applied (investigation in fate of 298 asthmatic children). Acta Pediat., 33: 4, 1945 Johnstone, D.E. A study of the natural history of bronchial asthma in children. Amer. J. Dis. Child., 115: 213, 1968 Rackemann, F.M., and Edwards, M.C. Asthma in children. A follow-up study of 688 patients after an interval of twenty years. New Eng. J. Med., 246: 815, 858, 1952 Ryssing, E. Continued follow-up investigation concerning the fate of 298 asthmatic children. Acta Pediat., 48: 255, 1959 Histamine Release Bierman, C.W., Pierson, W.E., VanArsdel, P.P., Jr., and Cady, V.B. A quantitative study on the in vitro antigen-induced histamine release in grass-allergic children (abstract). J. Allerg.,43: 165, 1969 Ishizaka, T., Ishizaka, K., Johansson, S.G.O., and Bennich, H. Histamine release from human leukocytes by anti-gamma E antibodies. J. Immunol., 102: 884, 1969 Levy, D. A., Goldstein, E.O., and Lichtenstein, L.M. Laboratory assessment of the efficacy of immunotherapy for ragweed hay fever (abstract). J. Allerg., 43: 166, 1969 Lichtenstein, L.M., Norman, P.S., and Winkenwerder, W.L. Clinical and in vitro studies on the role of immunotherapy in ragweed hay fever. Amer. J. Med., 44: 514, 1968 Lichtenstein, L.M., Norman, P.S., and Winkenwerder, W.L. Immunologie and clinical studies of a single year of immunotherapy for ragweed hay fever (abstract). J. Allerg., 43: 180, 1969

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McCourtie, D.R.M., and Broder, I. Correlations between clinical severity, leukocyte sensitivity, and serum blocking activity in ragweed-sensitive persons (abstract). J. Allerg., 43: 166, 1969 Malley, A., and Harris, R.L., Jr. Passive sensitization of monkey lung fragments with sera of timothy-sensitive patients. Spectroflurometric analysis of histamine release. J. Immunol., 100: 915, 1968 (Abstracted in Rev. Allerg., 22: 703, 1968) Perelmutter, L., and Eisen, A. H. Studies on histamine release from leukocytes of penicillinsensitive individuals. Int. Arch. Allerg., 38: 104, 1970 Pruzansky, J.J., and Patterson, R. Immunologie changes during hyposensitization therapy. J.A.M.A., 203: 805, 1968 Van Metre, T.E., Lichtenstein, L.M., and Turk, A. Hay fever symptoms, blocking antibody levels, and leukocyte histamine release in patients receiving very high dosage immunotherapy with ragweed pollen extract (abstract). J. Allerg., 43: 180, 1969 Young, S.H., Zimmerman, R.E.P., and Smithwick, E.M. The in vitro response of human lymphocytes challenged by ragweed antigen. Pediatrics, 42: 976, 1968 Controlled Studies on Hyposensitization Johnstone, D.E. Study of the role of antigen dosage in the treatment of pollenosis and pollen asthma. Amer. J. Dis. Child., 94: 1, 1957 Johnstone, D.E., and Crump, L. Value of hyposensitization therapy for perennial bronchial asthma in children. Pediatrics, 27: 39, 1961 Johnstone, D.E., and Button, A. The value of hyposensitization therapy for bronchial asthma in children. A 14-year study. Pediatrics, 42: 793, 1968 Frankland, A.W. Preseasonal injection treatment in hay fever using aqueous extracts. Int. Arch. Allerg., 28: 1, 1965 Miller, A. A statistical review of double-blind studies on ragweed hay fever injection therapy. Ann. Allerg., 26: 339, 1968 Provocative Bronchial Testing Citron, K.M. The uses of bronchial sensitivity tests. Acta Allerg., 22: suppl. 8: 17, 1967 Colldahl, H. The importance of inhalation tests in the etiological diagnosis of allergic diseases of the bronchi and in the evaluation of the effects of specific hyposensitization treatment. Acta Allerg., 22: suppl. 8: 7, 1967 Engstrôm, I., and Kraepelien, S. Specific desensitization in bronchial asthma in childhood. ActaPediat., 46: 81, 1957 Hosen, H. House Dust Sensitivity. The use of provocative skin tests in selecting extracts for desensitization. J. Allerg., 39: 222, 1967 Pegelow, K.O., Colldahl, H., Ripe, E., Svanborg, N., Sundberg, B., and Werner, M. Bronchial sensitivity before and during specific hyposensitization. Acta Allerg., 22: suppl. 8: 47, 1967 Ryssing, E. The prognosis in allergy to house dust in asthmatic children elucidated by provocation experiments. Acta Pediat. Scand., 46: 419, 1957 Miscellaneous Collins-Williams, C., Edwards, H., Savage, H., Fremes, A., Cole, A., and Imrie, R. An analysis of the effect of various dosage schedules in hyposensitizing programs for allergic children. Ann. Allerg., 18: 92, 1960

Prophylaxis of allergy

There is no such thing as a "non-allergic person." Although only about 10% of people manifest major allergy (i.e., eczema, urticaria, hay fever, or asthma) some time in their lives, and 50% of people manifest either major allergy or minor allergy (allergic manifestations other than these included in major allergy) some time in their lives, these manifestations can come on at any age. Since any child is potentially allergic, it is intelligent to protect him from unnecessary risks which may bring on serious and perhaps prolonged allergic symptoms and even disability. This can be done by: 1. Breast feeding 2. Using evaporated cow's milk instead of bottled milk 3. Avoiding occasional feedings of cow's milk in the newborn period 4. Delaying the introduction of highly allergenic foods into the infant's diet, e.g., egg, fish, peanuts 5. Introducing foods singly so that the cause of allergic symptoms can be recognized 6. Introducing foods in a well-cooked (hypoallergenic) form 7. During intestinal upsets avoiding new, raw, or lightly cooked foods 8. Avoiding highly allergenic environment. No horseback riding for a highly allergic child 9. Maintaining dust-free room for an infant with eczema to minimize his chance of developing respiratory allergy 10. Avoiding highly allergenic medications such as penicillin unless there is a definite indication 11. Giving medications orally when possible 12. Restricting the diet of the pregnant woman who has had one allergic child 13. Treating allergic symptoms early before the disease (e.g., asthma) is far advanced 14. Treating hay fever early to prevent pollen asthma

Common mistakes in the care of the allergic patient

Although improvement in the allergic patient may be slow, it is progressive provided that: 1. The correct diagnosis is reached through adequate history and physical examination 2. The differential diagnosis is complete and the correct diagnosis made 3. The skin testing is adequate 4. Food allergies are recognized 5. The dosages for hyposensitization are given at appropriate intervals and in the appropriate amount and concentration 6. The hyposensitizing extracts contain the correct allergens 7. Hyposensitization is not discontinued too soon 8. New allergens are recognized 9. Symptomatic and general care (e.g., anaemia) are adequate 10. Foci of infection are removed 11. The environment is adequately controlled 12. The patient is not overtreated Oversights occur when the physician in charge does not adequately supervise the patient's progress. It is not enough to give the patient his injection each week, since all of the other factors listed must be supervised and treatment changed accordingly. Additional oversights may occur if the physician and consulting allergist do not communicate adequately. For example, if the patient is being hyposensitized only with house dust and other winter inhalants, and begins to have symptoms in the pollen seasons, the appropriate pollens must be added to his hyposensitizing programme. The consulting allergist must be informed of this change before he prescribes a new supply of hyposensitizing extract, otherwise the patient fails to receive the proper extract to help him in the pollen seasons.

The optimistic approach to the care of the allergic patient

If the physician consistently demonstrates an optimistic attitude toward his allergic patients - many of whom are difficult to treat- the results of treatment will be better. Regardless of the number of allergens, or the severity, duration, or number of symptoms, a good result is usually possible. If the practising physician learns the principles outlined in this book and applies them, he will have the gratification of seeing most of his acutely and chronically ill allergic patients make a satisfactory recovery.

The four types of allergic reactions responsible for clinical hypersensitivity and disease*

TYPE I (anaphylactic, reagin-dependent)

This reaction is initiated by allergen or antigen reacting with tissue cells passively sensitized (allergized) by antibody produced elsewhere. The reaction results from the release of pharmacologically active substances (vaso-active amines, e.g., histamine). TYPE II (cytotoxic)

This is initiated by antibody reacting with either (a) an antigenic component of a cell or tissue element, or (b) an antigen or hapten which has become intimately associated with a cell or tissue element. Complement is usually but not always necessary to effect the cellular damage. The antibody is usually of classical type, i.e., IgG or IgM. Examples of antibody reacting with an antigenic component of tissue cells are transfusion reactions, haemolytic disease of the newborn, autoallergic reactions in which antibodies against surface components of the cell may, in the presence of complement, produce specific cell damage. Examples of antibody reacting with antigen or hapten absorbed on, or combined with, tissue cells are the cytotoxic reactions in drug hypersensitivity, such as the generalized purpura from Sedormid, and the haemolytic anaemia resulting from the use of drugs with an affinity for the red cell. TYPE III (damage by toxic complexes)

This is initiated when antigen in the tissue spaces in high local concentration reacts with potentially precipitating antibody from the blood, forming micro-precipitates * Coombs, R.R.A., and Cell, P.G.H. in Clinical Aspects of Immunology, p. 580, P.G.H. Cell and R.R.A. Coombs (eds.). 2nd ed. Blackwell, 1968

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in and around the small vessels and causing secondary damage to cells (an example is the Arthus type reaction); or when antigen in excess reacts in the blood stream with potentially precipitating antibody, forming soluble circulating complexes which are deposited in the blood vessel walls or in the basement membrane and cause local inflammation (an example is serum sickness). TYPE IV (delayed tuberculin-type cell-mediated)

This is initiated essentially by the reaction of specifically modified mononuclear cells (actively allergized cells) containing a substance or mechanism capable of responding specifically to allergen deposited at a local site. The exact mechanism of this type of reaction is still uncertain, but it is manifested by the infiltration of cells at the antigen site without the precipitation of free antibody.

Anaphylaxis in man

Anaphylaxis in man, though rare, is a constant hazard, since the physician uses so many things which can produce anaphylactic shock in his patient. SYMPTOMS

The symptoms, which usually appear within seconds or minutes of exposure to the inciting substance, include the following: 1. Sudden collapse with cardio-respiratory arrest (frequently fatal) 2. Sense of uneasiness and apprehension 3. Nausea 4. Diaphoresis 5. Pounding headache 6. Occasional intense throbbing in ears 7. Dyspnoea 8. Wheezing 9. Cyanosis 10. Circulatory collapse 11. Coma 12. Generalized convulsions 13. Severe generalized pruritis with urticaria and angioedema 14. Rhinorrhoea 15. Coughing 16. Vomiting and diarrhoea Anaphylaxis is difficult to diagnose because it is easily confused with syncope. Many patients faint when they are subjected to an injection or other traumatic procedure; placing the patient in a supine position is usually sufficient treatment. On the other hand anaphylactic shock is fatal in 10% of cases and therefore prompt diagnostic differentiation is important. Syncope, the more common condition, is characterized by:

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1. 2. 3. 4. 5. 6.

Pallor Perspiration A feeling of faintness Momentary unconsciousness Steady pulse and blood pressure Absence of more serious signs The need to differentiate between anaphylaxis and syncope can be avoided in most cases by having the patient lie down for injections, allergy skin tests, etc. Syncope rarely occurs if the patient is lying down.

AGENTS CAUSING

ANAPHYLAXIS*

1. Antimicrobials A. Antibiotics: penicillin, streptomycin, tetracyclines, chloramphenicol, erythromycin, vancomycin B. Chemotherapeutic drugs: para-aminosalicylic acid (PAS) 2. Biologicals A. Blood and blood fractions: foreign serums (antitoxins), heterologous gamma globulin B. Hormones: adrenocorticotrophic hormone (ACTH), insulin, relaxin, pitocin C. Vaccines: influenza, poliomyelitis, tetanus, pertussis, typhus, yellow fever, etc. 3. Enzymes: penicillinase, chymotrypsin 4. Local anaesthetics: cocaine, procaine, benzocaine, tetracaine, lidocaine 5. ^Salicylates 6. Antihistamines 7. Tranquillizers 8. Diagnostic agents: iodinated contrast media, sodium dehydrocholate, sulfobromophthalein, Congo red 9. Miscellaneous drugs: vitamins, heparin, sclerosing agents, iron 10. Others: insect stings, foods, cosmetics P R E V E N T I O N (fatal in 10% of cases)

1. 2. 3. 4. 5. 6.

Avoid unnecessary drug admininistration, for example, penicillin Avoid foreign sera, for example tetanus antitoxin Take a careful history of previous exposure to the particular therapeutic agent Take the patient's history of allergy Take the family's history of allergy Do not depend on a negative scratch, intradermal or conjunctival test. A general anaphylactic reaction can occur even when these tests are negative 7. Use the oral route for the drug whenever possible * Siegel, S.C., and Heimlich, E.M. (1962)

A N A P H Y L A X I S IN MAN 89

8. Administer a small amount of the agent, giving the full dose after a short observation period 9. Hyposensitize in selected cases, for example, insect-sting reactions 10. If you are in doubt, have patient remain for 20 minutes after the injection T R E A T M E N T AS USED AT THE HOSPITAL FOR SICK CHILDREN

Most Important Measures 1. Adrenaline (1:1000) S/C 0.01 ml/kg up to 0.50 ml. May repeat in 5 minutes. May inject 2/5 this amount I/V slowly by mixing it with withdrawn blood. If a vein cannot be entered, inject into the sublingual area 2. Tourniquet proximal to injection site in a limb 3. Patient has head down and is kept warm 4. Benadryl I/V (Steri-vial Benadryl hydrochloride 10 mg/rnl) May also be given deeply intramuscularly Give undiluted 1 mg/lb of body weight (Dosage for children 10-50 mg) or Chlor-Tripolon I/V (10 mg/ml) 1 ml (diluted) for adult. Draw the Chlor-Tripolon into a 10 cc syringe. Draw 5-10 ml of the patient's blood into the syringe (the blood acts as a diluent). Inject the mixture during 1 minute (proportionately smaller dose for child) 5. I/V Solu-Cortef 500-1000 mg from Mix-o-Vial run in (undiluted) over at least 30 seconds. May add similar amount to I/V fluids over next 8 hours. or Decadron injection I/V (2 ml or 5 ml vials with 4 mg/ml) 3-4 ml stat. Repeat as necessary 6. Oxygen by mask or tent Additional Measures 7. For shock (i) Isuprel parenteral (Winthrop) is available as a sterile aqueous solution of isoproterenol HCL (1:5000) containing 0.2 mg per ml, i.e. per ampoule. Empty 5 ampoules (total of 1.0 mg isoproterenol) into a 250-cc flask of 2/3 x Va (2/a glucose in distilled water plus Va normal saline). Administer intravenously at a rate to keep patient's clinical condition (especially blood pressure and pulse) satisfactory.

90 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

(Winthrop Product Information suggests 1 mg isoproterenol in 500 ml of fluid administered, after an initial 5 ml dose of solution, at a rate of 0.1 to 0.2 mg/hour - adult dose.) Although Isuprel is valuable in treating shock, it is not conclusively superior to the following two preparations in anaphylactic shock. (ii) (a) Aramine (metaraminol bitartrate) (10 mg/ml) I/M or S/C-2 mg to 10 mg (0.2-1.0 ml) I/V infusion-15 mg to 100 mg (1.5-10 ml) In 500 ml isotonic saline or 5% glucose solution, adjusting flow to maintain blood pressure. Direct I/V injection (in grave emergencies) 0.5 mg to 5 mg. (0.05 ml to 0.5 ml) 0.5 mg for infants under 10 kg, 1 mg for older children. (b) Levophed (1-norepinephrine) 4.0 ml of 0.2% solution in 1000 ml 5% glucose in normal saline by infusion. May run about 30-60 ml/hr, speed of infusion determined by effect on pulse and blood pressure. 8. Aminophylline I/V 3.5 mg/k 221b(10K)- 35mgO/ 2 gr) 44 Ib (20 K) - 70 mg (1 gr) 661b(30K)- 105mg(lV2gr) 88 Ib (40 K) - 140 mg (2 gr) 1101b(50K)-175mg(2V2gr) 9. Ephedrine sulphate S/C Infants: Vie - Vs gr Children: Vs - V4 gr Adults: 3/s gr 10. For generalized convulsions (a) Phénobarbital I/M V4 gr/10 Ib (maximum 3 gr) (b) Paraldehyde I/M-1 ml/10 Ib I/V-V2 ml/10 Ib diluted to 5% with I/V solution 11. Artificial respiration or cardiac arrest procedures. Start immediately indication arises. Send immediately for anaesthesiologist or cardiac arrest team or both. REFERENCES Downes, J.J. Treatment of anaphylactic shock. New Eng. J. Med., 276: 641, 1967 Duff, J.H., Scott, H.M., Peretz, D.I., Mulligan, G.W., and Maclean, L.D. The diagnosis and treatment of shock in man based on hemodynamic and metabolic measurements. J. Trauma 6: 145, 1966

A N A P H Y L A X I S IN MAN 91

Heimlich, E.M., and Siegel, S.C. Anaphy Iaxis. In: Brennemann's Practice of Pediatrics, vol. 2, chap. 66. W.F. Prior Co. Inc.: Hagerstown, Maryland, 1968 Kardos, G.G. Isoproterenol in the treatment of shock due to bacteremia with gram-negative pathogens. New Eng. J. Med., 274: 868, 1966 Maclean, L.D., Duff, J.H., Scott, H.M., and Peretz, D.I. Treatment of shock in man based on hemodynamic diagnosis. Surg. Gynec. Obstet., 120: 1, 1965 Sheffer, A.L. Medical intelligence. Current concepts. Therapy of anaphylaxis. New Eng. J. Med., 275: 1059, 1966 Siegel, S.C., and Heimlich, E.M. Anaphylaxis. Pediat. Clin. N. Arner., 9: 29, 1962 Siegel, S.C. Anaphylaxis. In: S.S. Gellis, and B.M. Kagan (eds.), Current Pédiatrie Therapy, pp. 880-883. Philadelphia: Saunders & Co., 1968 Speer, F. (éd.) The Allergic Child. New York: Hoeber Medical Division, Harper & Row, 1963 (See inside cover: Constitutional (Systemic, Anaphylactic) Reactions) Stafford, G. E. Anaphylactic reactions. In: F. Speer (éd.), The Allergic Child. New York: Hoeber Medical Division, Harper & Row, 1963 Toit Du, H.J., Pleissis Du, J.M.E., Dommisse, J., Rorke, M.J., Theron, M.S., and Villiers De, V.P. Treatment of endotoxic shock with isoprenaline. Lancet 2: 143, 1966

The immunoglobulins

To date, five immunoglobulins have been described: IgG, IgA, IgM, IgD, and IgE (see Table VIII). Each of these is made up of two light chains of amino acids (common to all the five immunoglobulins) and two heavy chains of amino acids each peculiar to its own immunoglobulin (see Fig. 3) IgE is important in understanding atopic disease and will be discussed in detail. IgA is important in understanding certain conditions which need to be considered in the differential diagnosis of atopic disease, and therefore, will be considered briefly. A detailed discussion of the three other immunoglobulins is beyond the scope of this book. IMMUNOGLOBULIN IgE (REAGIN)

For many years the substance in the skin presumed to be fixed to the cells of the TABLE VIII

Molecular weight Sedimentation coefficient Serum concentration mg% Paraprotein Placental transfer Reagin activity Blocking antibody Important in external secretions Antibody activity Half-life in serum Fix complement Sensitize human skin Valence

IgD

IgE

165,000 850,000 7 (up to 15) 19

+ 150,000 7

196,000 8

1,200 G myeloma + 0 +

200 300 A myeloma Macroglobulin 0 0 0 0 0 0

3 D myeloma 0 0 0

0.05 E myeloma 0 + 0

0

+ + 7 days 0 0 2

0 + 2.8 days 7 Ó 72

0 +

IgG

IgA

150,000 7

+

25 days + 0 2

IgM

0 + 10 days + 0 5

7

6 + 7

THE IMMUNOGLOBULINS

93

Figure 3 Diagrammatic formulae of the immunoglobulins

skin and responsible for the skin test positive to an allergen has been called a reagin or skin sensitizing antibody. The reagin has been titred in the serum of the allergic patient by the laborious process of injecting dilutions of the patient's serum into the skin of a normal recipient who does not react positively to a skin test with the suspected allergen. Challenging these sites with a standard amount of allergen and finding the point at which there is no longer a positive skin test gives an approximate, but reproducible, titre of the skin sensitizing antibody or reagin in the serum of the individual being investigated for allergy. Because of the difficulty of this test, other methods, such as isometric contraction of monkey ileum in the Schultz-Dale apparatus, have been developed. In this test, the monkey ileum is suspended in the allergic serum so that it becomes passively sensitized; after the monkey ileum has been attached to the Schultz-Dale apparatus, antigen is added and the contraction measured. A correlation exists between the extent of the contraction and the titration previously described. Similar methods have been developed using human appendix and monkey skin suspension, but such tests are laborious.

94 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

In 1966 Ishizaka and Ishizaka fractionated sera from two atopic patients by chromatography on DEAE cellulose and by gel filtration with Sephadex G-200 and found that the skin sensitizing activity in the fraction did not parallel the concentration of IgA or IgG in the patient's serum and eventually went on to show that the skin sensitizing activity was specifically related to a new immunoglobulin IgE. IgE, a unique protein having two light chains comparable to the other immunoblobulins and two heavy chains peculiar to itself, qualifies as a specific immunoglobulin, the fifth to be identified after the IgG, IgA, IgM, and IgD. On immunoelectrophoresis, IgE appears very close to IgA. It has kappa and lambda light chains, its own specific heavy chain, a sedimentation constant of 8.0, and a molecular weight about 196,000. It can be demonstrated to be fixed to the cells of the skin in all normal human beings. It is possible to obtain a positive Prausnitz-Kustner test with IgE containing only 10~6 to 10~5 micrograms of nitrogen, indicating that immunologically it is an extremely active protein. In atopic individuals IgE tends to be present in much higher concentration than in individuals who have not yet demonstrated any atopic reactions. IgE has also been demonstrated in monkeys and in dogs; it comes from plasma cells. In the human it apparently attaches itself to mediator releasing cells in the blood (basophiles), and in tissues (mast cells) and this is thought to be a cell surface phenomenon. When the specific allergen or antigen is directed against the specific IgE, the mediator, such as histamine, released from the granules of the living cells stimulates smooth muscle contraction, vasodilatation, increased capillary permeability, tissue oedema, and excessive secretion of mucus. Histamine is probably not the only mediator. The symptoms will depend on the tissue in which this release is effected. IgE or reaginic antibody can produce all of the immediate allergic reactions and complement is not involved. Later Johansson discovered a patient with an IgE multiple myeloma. He initially referred to the immunoglobulin as IgND and since then has determined specific antibodies against 14 different allergens, namely, the danders of the horse, dog, cat, cow, and rabbit; the pollens of birch, reed, daisy, and three types of grass; fungus mixture, shell fish, and house dust. He found a 96% agreement between the results from provocation tests on patients and the in vitro measurement of their specific antibody directed against the specific allergen. He also found serum levels significantly raised to over 700 nanagrams per ml in 63% of patients with allergic asthma compared with 5% of patients with non-allergic asthma; the average concentration was six times higher in the former group than in the latter. Raised serum levels were found in patients with asthma, hay fever, and eczema. Electron microscopy shows the IgE molecule to have a compact structure, presumably cylindrical and about 120Â in diameter and 40Â high. IgND has since been found to be identical with IgE. Thus, the atopic individual's response when exposed to allergens is now known. All individuals are potentially allergic in that they have IgE fixed in their skin. Certain individuals have a pronounced tendency - probably through heredity - to develop manifestations of atopic disease and do so by manufacturing specific IgE

THE I M M U N O G L O B U L I N S 95

antibodies directed against specific allergens. Subsequent exposure to such allergens then produces symptoms determined in part by the amount of specific IgE which they have developed to that antigen and by the tissue in which the specific IgE in concentrated. IMMUNOGLOBULIN

IgA

Serum immunoglobulin IgA, like the other immunoglobulins, has two heavy chains and two light chains, a molecular weight of 165,000, and an ultracentrifugal sedimentation co-efficient of 7S. Its function is unknown. Immunoglobulin IgA is important to the clinical allergist because of its presence as secretory IgA in the secretions of the respiratory tract where it is thought to help resist infection. The child who has repeated upper and lower respiratory infections, frequent coughs, mucus in the chest but no clearly defined perennial allergic rhinitis or asthma is one of the most difficult problems in paediatric allergy. Some of these children lack IgA in their respiratory secretions and must be distinguished from allergic children since their treatment is quite different. IgA is present in low concentrations in many body fluids, namely the colostrum, parotid, lachrymal, bronchial, prostatic, vaginal, and amniotic fluids and in bile and the small intestine. Except in the case of the amniotic fluid, the presence of IgA in these secretions is thought to be related to immunity at their respective mucous membrane sites. Secretory IgA is a polymer of IgA which has a sedimentation coefficient of 11S. The US IgA molecule consists of two immunochemical fractions: (1) two 7S IgA molecules identical with the IgA in the serum and (2) a protein called the transport piece or the secretory piece, which is a beta globulin with a molecular weight of 50,000. The secretory piece is found in the saliva of patients with agammaglobulinaemia or ataxia telangiectasia, who lack both serum and salivary IgA; and in the parotid fluid of the newborn - unassociated with salivary IgA normally absent at this age. The 1 IS IgA has antigenic determinants which are not present in normal serum even though it will react with anti-7S IgA because the two have common determinants. It is thought that the secretory piece is formed in the acinar cells adjacent to the collecting ducts of the salivary gland, whereas the IgA and other immunoglobulins in the saliva are formed in the plasma cells near the surface of the mucous membrane. The two units that make up the 1 IS IgA molecule then unite and are secreted onto the mucosa. That the IgA in the mucus of the respiratory tract is associated with immunity is evident in that individuals with ataxia telangiectasia who have no respiratory tract secretory IgA have recurrent and often severe respiratory infections. Individuals with even small amounts of IgA in their saliva are less likely to experience such difficulty. Also the accumulated evidence suggests that for many infections of the respiratory tract local antibodies, particularly those of the IgA variety, are more important for resisting infection than are circulating antibodies. Secretory IgA antibodies are also thought to be important in immunity of the gastrointestinal tract and possibly of the genitourinary tract.

96 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

On the other hand, extensive studies on healthy individuals reveal a small number (1 in 700 in Sweden) with no IgA detectable in their serum but with no increased incidence of respiratory infections. The clinical allergist, however, must separate such patients from the majority of allergic children who do have normal serum and respiratory tract IgA. Since the two conditions are not mutually exclusive, it is quite possible for a patient to be allergic and also be without IgA in his serum and respiratory tract. On the other hand, a patient may be ill because of the absent IgA and not require anti-allergic investigation or treatment. REFERENCES

Collins-Williams, C., Tkachyk, S.J., Toft, B., and Moscarello, M. Quantitative immunoglobulin levels (IgG, IgA and IgM) in children. Int. Arch. Allerg., 31: 94, 1967 Collins-Williams, C., Toft, B., Generoso, L., and Moscarello, M. Quantitative immunoglobulin levels (IgG, IgA and IgM) in children, determined by the Hyland immunoplate technique. Cañad. Med. Assoc. J., 96: 1510, 1967 Terry, W.D. Structural characteristics of human immunoglobulins. Postgrad. Med., 41: 133, 1967 West, C.D., Hong, R., and Holland, N.H. Immunoglobulin levels from the newborn period to adulthood and in immunoglobulin deficiency states. J. Clin. Invest., 41: 2054, 1962 Immunoglobulin IgE (Reagin) Berg, T., and Johansson, S.G.O. Immunoglobulin levels during childhood with special regard to IgE. Acta Paediat. Scand., 58: 513, 1969 Berg, T., and Johansson, S.G.O. IgE concentrations in children with atopic diseases: A clinical study. Int. Arch. Allerg., 36: 219, 1969 Memorandum drafted by Bennich, H.H., Ishizaka, K., Johansson, S.G.O., Stanworth, D.R., and Terry, W.D. Immunoglobulin E: A new class of human immunoglobulin. Immunology, 15: 323, 1968 Coombs, R.R.A., Hunter, A., Jonas, W.E., Bennich, H., Johansson, S.G.O., and Panzani, R. Detection of IgE (IgND) specific antibody (probably reagin) to castor-bean allergen by the red-cell-linked antigen-antiglobulin reaction. Lancet, 1: 1115, 1968 Frick, O.L., and Ishizaka, K. Association of IgE with reaginic activity in sera from grass pollen- and horse dander-sensitive individuals. J. Allerg., 45: 220, 1970 Ishizaka, K., and Ishizaka, T. Physiochemical properties of reaginic antibody. I. Association of reaginic activity with an immunoglobulin other than y A- or yG-globulin. J. Allerg., 37: 169, 1966 Ishizaka, K., Ishizaka, T., and Lee, E.H. Physiochemical properties of reaginic antibody. II. Characteristic properties of reaginic antibody different from human yA-isohemoagglutinin and yD-globulin. J. Allerg., 37: 336, 1966 Ishizaka, K., and Ishizaka, T. Physiochemical properties of reaginic antibody. III. Further studies on the reaginic antibody in yA-globulin preparations. J. Allerg., 38: 108, 1966 Ishizaka, K., Ishizaka, T., and Hornbrook, M.M. Physiochemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. J. Immunol., 97: 75, 1966 Ishizaka, K., Ishizaka, T., and Hornbrook, M.M. Physiochemical properties of reaginic antibody. V. Correlation of reaginic activity with yE-globulin antibody. J. Immunol, 97: 840, 1966 Ishizaka, K., Ishizaka, T., and Hornbrook, M.M. Allergen-binding activity of yE, yG and yA antibodies in sera from atopic patients. In vitro measurements of reaginic antibody. J. Immunol., 98: 490, 1967 Ishizaka, K., Ishizaka, T., and Terry, W.D. Antigenic structure of yE-globulin and reaginic antibody. J. Immunol., 99: 849, 1967

THE I M M U N O G L O B U L I N S 97

Ishizaka, K., Ishizaka, T. Identification of yE-antibodies as a carrier of reaginic activity. J. Immunol., 99: 1187, 1967 Ishizaka, K., and Ishizaka, T. Human reaginic antibodies and immunoglobulin E. J. Allerg., 42: 330, 1968 Ishizaka, K., and Ishizaka, T. The significance of immunoglobulin IgE in reaginic hypersensitivity. Ann. Allerg., 28: 189, 1970 Ishizaka, T., Ishizaka, K., Orange, R.P., and Austen, K.F. The capacity of human immunoglobulin E to mediate the release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung. J. Immunol., 104: 335, 1970 Johansson, S.G.O., and Bennich, H. Immunological studies of an atypical (myeloma) immunoglobulin. Immunology, 13: 381, 1967 Johansson, S.G.O. Raised levels of a new immunoglobulin class (IgND) in asthma. Lancet, 2: 951, 1967 Johansson, S.G.O. Serum IgND levels in healthy children and adults. Int. Arch. Allerg., 34: 1, 1968 Johansson, S.G.O., Mellbin, T., and Vahlquist, B. Immunoglobulin levels in Ethiopian preschool children with special reference to high concentrations of immunoglobulin E (IgND). Lancet, 1: 1118, 1968 Ogawa, M., Kochwa, S., Smith, C., Ishizaka, K., and Mclntyre, O.R. Clinical aspects of IgE myeloma. New Eng. J. Med., 281: 1217, 1969 Rowe, D.S., and Wood, C.B.S. The measurement of serum immunoglobulin E levels in healthy adults and children and in children with allergic asthma. Int. Arch. Allerg., 39: 1, 1970 Stanworth, D.R. IgE and reaginic antibodies. Proc. Roy. Soc. Med., 62: 33, 1969 Tada, T., and Ishizaka, K. Distribution of gamma E-forming cells in lymphoid tissues of the human and monkey. J. Immunol., 104: 377, 1970 Wide, L., Bennich, H., and Johansson, S.G.O. Diagnosis of allergy by an in-vitro test for allergen antibodies. Lancet, 2: 1105, 1967 IgA Bachmann, R. Studies on the serum gamma-A-globulin level. III. The frequency of Agamma-A globulinemia. Scand. J. Clin. Lab. Invest., 17: 316, 1965 Bellanti, J.A. Role of local gamma-A-immunoglobulins in immunity. Amer. J. Dis. Child., 115: 239, 1968 Bellanti, J., Sanga, R.L., Klutinis, B., Brandt, B., and Artenstein, M.S. Antibody responses in serum and nasal secretions of children immunized with inactivated and attenuated measles-virus vaccines. New Eng. J. Med., 280: 629, 1969 Bienenstock, J. The significance of secretory immunoglobulins. Cañad. Med. Assoc. J. 103: 39, 1970 Buckley, R.H., Lucas, Z.J., Hattler, B.G., Jr., Zmijewski, C.M., and Amos, D.B. Defective cellular immunity association with chronic mucocutaneous moniliasis and recurrent staphylococcal botryomycosis: Immunological reconstitution by allogenic bone marrow. Clin. Exp. Immunol., 3: 153, 1968 Buser, F., Butler, R., and DuPan, R.M. Susceptibility to infection and IgA deficiency in the infant. J. Pediat., 72: 29, 1968 Butler, W.T., Rossen, R.D., and Waldmann, T.A. The mechanisms of appearance of immunoglobulin A in nasal secretions in man. J. Clin. Invest., 46: 1883, 1967 Collins-Williams, C., Lamenza, C., and Kokubu, H. Deficiency of IgA in serum and respiratory secretions. Cañad. Med. Assoc. J., 99: 1069, 1968 Collins-Williams, C., Lamenza, C., and Nizami, R. Immunoglobulin IgA: A review of the literature. Ann. Allerg., 27: 225, 1969 Collins-Williams, C., Chiu, A.W., and Varga, E.A. The relationship of atopic disease and immunoglobulin levels with special reference to selective IgA deficiency. Clin. Allergy, 1: 381, 1971 Collins-Williams, C., Kokubu, H.L., Lamenza, C., Nizami, R., Chiu, A.W., Lewis-

98 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY McKinley, C., Comerford, T.A., and Varga, E.A. Incidence of isolated deficiency of IgA in the serum of Canadian children. Ann. Allerg., 30: 11, 1972 Editorial: Problems in developing a respiratory vaccine. New Eng. J. Med., 283: 1287, 1970 Haworth, J.C., and Billing, L. Concentration of gamma A-globulin in serum, saliva and nasopharyngeal secretions of infants and children. J. Lab. Clin. Med., 67: 922, 1968 Hobbs, J.R. Immune imbalance in dysgammaglobulinaemia type IV. Lancet, 1: 110, 1968 Rockey, J.H., Hanson, L.A., Heremans, J.F., and Kunkel, H.G. Beta-2A aglobulinemia in two healthy men. J. Lab. Clin. Med., 63: 205, 1964 Rosenberg, D. IgA deficiency and susceptibility to infection (Letter to Editor). J. Pediat., 73: 642, 1968 Rossen, R.D., Alford, R.H., Butler, W.T., and Vannier, W.E. The separation and characterization of proteins intrinsic to nasal secretion. J. Immunol., 97: 369, 1966 Smith, R.T. Gamma-A immunoglobulins and the concept of local immunity. Pediatrics, 43: 317, 1969 South, M.A., Cooper, M.D., Wollheim, F.A., Hong, R., and Good, R.A. The IgA system. I. Studies of the transport and immunochemistry of IgA in the saliva. J. Exp. Med., 123: 615, 1966 South, M.A., Warwick, W.J., Wollheim, F.A., and Good, R.A.: The IgA system. III. IgA levels in the serum and saliva of pédiatrie patients - evidence for a local immunological system. J. Pediat., 71: 645, 1967 Tomasi, T.B., Jr., Tan, E.M., Solomon, A., and Prendergast, R.A. Characteristics of an immune system common to certain external secretions. J. Exp. Med., 121: 101, 1965 Tomasi, T.B., Jr., and Bienenstock, J. Secretory immunoglobulins. Advances Immunol., 9: 1, 1968 Waldman, R.H., Wigley, F.M., and Small, P. A. Specificity of respiratory secretion antibody against influenza virus. J. Immunol., 105: 1477, 1970 West, C.D. Comment on IgA deficiency and susceptibility to infection. J. Pediat., 72: 153, 1968 Wigley, F.M., Fruchtman, M.H., and Waldman, R.H. Aerosol immunization of humans with inactivated parainfluenza type 2 vaccine. New Eng. J. Med., 283: 1250, 1970

The atopic constitution pulmonary aspergillosis

All human beings (except for those with the extremely rare dysgammaglobulinaemia) have immunoglobulin IgE and therefore are potentially capable of manifesting the signs and symptoms of atopic disease. In their lifetime, 10% of all people exhibit major allergy, such as asthma, hay fever, urticaria and/or angioedema and eczema. Another 40% manifest some minor allergy such as a drug or gastrointestinal one, both of which are thought to be IgE mediated. The other 50% may never demonstrate their capability of developing IgE mediated reactions although such a manifestation may occur later in life. Clinically it is convenient to divide people arbitrarily into two groups, atopic and non-atopic. The former have demonstrated (often early in life) a ready tendency to respond to foreign substances by producing IgE antibodies specifically directed against those substances, with resulting clinical allergic disease. These individuals should, therefore, be observed carefully by their physician when highly allergenic foods are introduced into their diet; when highly allergenic factors are introduced into their environment; when drugs are used; when they are being recommended for employment; when they are observed for new manifestations of allergy. The non-atopic group do not need such care, but it is important to remember that at any age a "non-atopic" individual may become "atopic." Pulmonary aspergillosis demonstrates the difference between a person with an atopic constitution and one with a non-atopic constitution. Aspergillus fumigatus is an opportunistic pathogenic fungus for man and the disease it will produce in him depends on whether he is atopic or not. In an atopic subject it can cause asthma, the fungus acting as an allergen in exactly the same way as ragweed, timothy pollen, and house dust act as allergens to produce asthma. Specific reaginic antibody against the aspergillus fumigatus is produced in the subjects with consequent manifestations of allergic disease; this in an example of Type I allergy as defined by Gell and Coombs. On the other hand, in the non-atopic subject exposed to the inhalation of large numbers of these spores acting as a source of antigen, a disease is produced called extrinsic allergic alveolitis, which has quite different clinical manifestations.

100 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

This disease, which could be produced in the majority of the population who have no obvious constitutional predisposition, is an example of Type III (Arthus) allergy. In Type I allergy the antibody is IgE and the allergen provokes a rapid reaction within minutes of the combination with this reagin on the surface of mast cells, leading to histamine and other tissue mediators being liberated to produce the clinical manifestations of asthma, with wheezing, and dyspnoea proportional to the wheezing, and generalized rhonchi with prolonged expiration. Type III, on the other hand, produces precipitating antibody which combines with antigen in moderate excess to form aggregates that fix complement. These aggregates are chemotactic for polymorphonuclear leucocytes that phagocytose them and are destroyed, liberating lysosomal enzymes with resulting extracellular digestion and tissue damage typical of the Arthus reaction. Several hours are required to produce this reaction. Type I reaction gives an immediate skin test, Type III a delayed skin test showing an oedematous reaction after three to four hours, maximal at seven to eight hours and resolving within 24 hours. In Type I allergy, clinical exposure leads to a rapid asthmatic reaction. The only characteristic roentgenographic changes show hyperinflation. Pulmonary function shows an obstructive defect reversible by isoprenaline. In Type III, systemic and pulmonary reactions develop after five or six hours. Wheezing may occur, but is not common. Fever, chills, malaise, and weight loss occur. Cough and dyspnoea are out of proportion to the rales. Roentgenographic changes include miliary infiltrations followed by diffuse fibrosis. Respiratory obstruction is not reversed by isoprenaline. It is possible in the Type I reaction to have the Type III Arthus reaction also where precipitin formation induced by more intensive antigenic stimulation produces allergic bronchopulmonary aspergillosis with both asthma and pulmonary eosinophilia, transient pulmonary infiltrations, and both types of skin tests. In the Type III reaction a mild immediate Type I allergy may develop against the particular antigen which is weaker and less frequent than any in the atopic subjects giving immediate skin reactions also. This demonstrates very well that patients who are clearly atopic in constitution may react differently to antigens from those who are non-atopic. With adequate stimulation the atopic individual can show the same manifestations as the nonatopic individual who can occasionally show atopic manifestations, although not usually to so severe a degree. Other examples of inhaled organic dust that can produce different pulmonary allergic diseases depending upon whether the subject is atopic or not (i.e., Type I or Type III reactions) are farmer's lung, where the source of antigen is mouldy hay; bagassosis, where the source is mouldy bagasse; mushroom worker's lung where the source is mushroom compost; fog-fever in cattle where the source is mouldy hay; suberosis where the source of antigen is mouldy oak-bark or cork dust; New Guinea lung where the source of antigen is mouldy thatch dust; maple bark pneumonitis where the source of antigen is mouldy maple bark; malt worker's lung where the source of antigen is mouldy barley or malt dust; bird fancier's lung where the source of antigen is pigeon, budgerigar, parrot, or hen droppings; pituitary

THE ATOPIC C O N S T I T U T I O N

101

snuff-taker's lung where the source of antigen is heterologous pituitary powder; wheat weevil disease where the source of antigen is infested wheat flour; and sequoiosis where the source of antigen is mouldy sawdust. These fungi and organic dusts similar to aspergillus fumigatus can produce the bronchial reaction in atopic subjects mediated by reaginic antibody with Type I reactions, but also in non-atopic subjects the alveolitis due to Arthus Type III reactions. REFERENCES Goldstein, G.B., and Yokoyama, M. Studies of the dual antibody response in allergic bronchopulmonary aspergillosis. J. Allerg., 46: 340, 1970 Henderson, A.H. Allergic aspergillosis: Review of 32 cases. Thorax, 23: 501, 1968 Henderson, A.H., English, M.P., and Vecht, RJ. Pulmonary aspergillosis: A survey of its occurrence in patients with chronic lung disease and a discussion of the significance of diagnostic tests. Thorax, 23: 513, 1968 Pepys, J., et al. Candida Albicans precipitins in respiratory disease in man. J. Allerg., 41: 305, 1968 Pepys, J. Hypersensitivity of the Lungs Due to Fungi and Organic Dusts. Monographs in Allergy, vol. 4. Basel, Switzerland: S. Karger, 1969 Slavin, R.G., Stanczyk, D.J., Lonigro, A.J., and Broun, G.O. Allergic bronchopulmonary aspergillosis - A North American rarity. Amer. J. Med., 47: 306, 1969 Slavin, R.G., Laird, T.S., and Cherry, J.D. Allergic bronchopulmonary aspergillosis in a child. J. Pediat., 76: 416, 1970 Slavin, R.G., Million, L., and Cherry, J. Allergic bronchopulmonary aspergillosis: Characterization of antibodies and results of treatment. J. Allerg., 46: 150, 1970 Warren, W.P., and Rose, B. Hypersensitivity bronchopulmonary aspergillosis. Dis. Chest, 55: 415, 1969 Young, R.C., Bennett, I.E., Vogel, C.L., Carbone, P.P., and De Vita, V.T. Aspergillosis: The spectrum of the disease in 98 patients. Medicine, 49: 147, 1970

Bibliography

ALLERGY Baer, R.L. Allergy Dermatoses Due to Physical Agents. Philadelphia: J.B. Lippincott, 1956 Fontana, V.J. Practical Management of the Allergic Child. New York: AppletonCentury-Crofts, Education Division, Meredith Corporation, 1969 Glaser, J. Allergy in Childhood. Springfield, 111.: Charles C Thomas, 1956 Hansel, F.K. Clinical Allergy. St. Louis: C.V. Mosby Co., 1953 Sheldon, J.M., Lovell, R.G., and Mathews, K.P. A Manual of Clinical Allergy. Philadelphia: W.B. SaundersCo., 1967 Sherman, W.B. Hypersensitivity. Mechanisms and Management. Philadelphia: W.B. SaundersCo., 1968 Speer, F. (éd.) The Allergic Child. New York: Harper and Row, 1963 Tuft, L., and Mueller, L. Allergy in Children. Philadelphia: W.B. Saunders Co., 1970 CLINICAL IMMUNOLOGY Ackroyd, J.F. (ed.) Immunological Methods. Oxford: Blackwell Scientific Publications, 1964 Boyd, W.C. Fundamentals of Immunology, 4th éd. New York: Interscience Publications, 1966 Criep, L.H. Dermatologie Allergy. Philadelphia: W.B. Saunders Co., 1967 Cell, P.O.H., and Coombs, R.R.A. Clinical Aspects of Immunology, 2nd ed. Oxford: Blackwell Scientific Publications, 1968 Gray, D.F. Immunology, 2nd ed. London: Edward Arnold Ltd., 1970 Humphrey, J.H., and White, R.G. Immunology for Students of Medicine, 3rd ed. Oxford: Blackwell Scientific Publications, 1970 Wesley, A.J., and Good, R.A. Immunobiology for Surgeons. Toronto: W.B. Saunders Co., 1970 GENERAL Government of Canada, Department of Agriculture. Weeds of Canada. Ottawa: Queen's Printer, 1963

BIBLIOGRAPHY 103 Government of Canada, Department of Forestry. Native Trees of Canada. Ottawa: Queen's Printer, 1963 Korting, G.W., Carth, W., and Carth, H.O. Diseases of the Skin in Children and Adolescents. Toronto: W.B. Saunders Co., 1970 Scarpelli, E.M. The Surfactant System of the Lung. Philadelphia: Lea & Febiger, 1968 Speer, F. Allergy of the Nervous System. Springfield, 111.: Charles C Thomas, 1970

Glossary

A knowledge of specific terminology is required to understand adequately the recent literature on allergy and related clinical immunology. Included are: AFFINITY: of an antigen for an antibody refers to the strength of the association between them and is expressed numerically as Ko, the average association constant at equilibrium, as shown in the equations Ab + H = AbH and Ko= (AbH)

(Ab)(H)

AGAMMAGLOBULINAEMIA: less than 100 mg gamma globulin per 100 ml serum. ALLELES: all alternative forms of a gene found at one locus. Any one chromosome bears only one alíele at one locus. Different alíeles usually determine the production of different polypeptides. ALLELE (DOMINANT): always expressed in the phenotype, whether homozygous or heterozygous. ALLELE (RECESSIVE): expressed only when homozygous. ALLELES (MULTIPLE): at many loci more than two different alíeles are known. ANAPHYLATOXIN: described in 1910, is generated when fresh normal serum reacts with an antigen antibody complex, with dextran and with other substances. This material is thus named because it can mimic anaphylaxis in a guinea pig. Its properties are: (1) Contracts smooth muscle and this can be blocked with an anti-histamine. (2) Enhances capillary permeability. (3) Degranulates mast cells in the guinea pig. (4) Increases the permeability of guinea pig skin. Fragments from C3 and C5 both fill the criteria for anaphylatoxin. ANTIBODIES (COMPLETE): will precipitate antigens in solution and agglutinate particles and cells carrying the specific antigen. ANTIBODIES (INCOMPLETE): normally fail to precipitate or agglutinate, although they combine firmly with antigen.

GLOSSARY 105 ANTIGEN: a substance stimulating the formation of antibodies and reacting with them. ANTIGENIC DETERMINANT: the constitution of atoms establishing the specificity of an antigen or the collection of atoms adequate to occupy the complete binding site on the antibody. ARTHUS REACTION: occurs only after at least three subcutaneous or intradermal injections of an antigen repeated at intervals of a few days. Moderate oedema within half an hour of the injection is followed within 4 to 6 hours by a typical pathological reaction consisting of exudation of fluid and blood cells into the tissues, arteriolar spasm, endothelial damage and formation of leucocyte thrombi. Requirements are adequate levels of circulating precipitating antibody and antigen excess. AUTOANTIBODIES: antibodies that react with the host's own tissues independently of what the antigen may be. The antigen may be native, that is, undenatured, or altered. The autoantibodies react with native antigen. CLONAL SELECTION THEORY (BURNET): plasma cell precursors of mesenchymal origin, probably from the thymus gland, are derived by random mutation into as many as 10,000 different forms or clones. Each clone is self-propagating and also carries the latent ability under antigenic stimulus to differentiate by a series of steps into plasma cells. Each of these plasma cells is capable of producing a single kind of antibody, so that the total antibody repertoire may provide responses to all possible antigens, including auto-antigens, homo-antigens, and hetero-antigens. CODON: a triplet of nitrogen-containing organic bases (purines or pyramidines) in a DNA or RNA molecule which provides genetic code information for a specific amino acid. CYTOGENETICS: the study of the relationship of the structure and function of the chromosomes to the genotype and phenotype of the individual. DUPLICATION: the presence of one extra piece of chromosome within a chromosome, or attached to a non-homologous chromosome by translocation, or as a separate fragment. FORSSMAN (HETEROPHILE) ANTIGEN: a group of antigens (polysaccharide and lipoid material) found widely distributed in various species of animal, in some plants and in some microorganisms. Because none is found in the rabbit, rabbits may be immunized with sheep RBC, which contain Forssman antigen, to produce Forssman antibodies. FORSSMAN (HETEROPHILE) ANTIBODY: a haemagglutinin or haemolysin produced in response to immunization with Forssman antigen. Sheep RBC agglutinins are Forssman antibodies. The heterophile titre is raised in man in infectious mononucleosis and in serum sickness. Animals and man have "natural" heterophile antibodies, possibly produced by exposure to microorganisms. FREUND'S ADJUVANT (COMPLETE): an oily mixture of Bayol F (17 parts), Arlacel A (3 parts), and dried mycobacterium butyricum (0.5 or 1.0 mg/ml) which on injection into an animal increases antibody formation, enhances delayed hypersensitivity, slows release of antibody, produces granulomata, and alters normal tissue. FREUND'S ADJUVANT (INCOMPLETE): the "complete adjuvant" without the mycobacterium butyricum.

106 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

GENES: segments of the DNA molecules on the chromosomes; perhaps 100,000 per cell. They direct the synthesis of polypeptides. GENETIC CODE: that information carried by the DNA and RNA molecules whereby the particular combination of bases in the codon controls the insertion of particular amino acids in equivalent places in a protein molecule. GENOTYPE: of an individual is his genetic constitution. HAPTEN: a relatively simple substance which in combination with a protein causes the formation of antibody directed against the hapten group. The unrelated carrier protein does not cross-react with the antibody in the absence of hapten. The hapten, uncoupled with the protein, will react with the antibody. HAPTENIC GROUP: a combination of a hapten plus a carrier. Antibodies are formed to all the antigenic determinants of the molecule. HETEROPHILE ANTIBODY (FORSSMAN): see Forssman (heterophile) antibody. HETEROPHILE ANTIGEN (FORSSMAN): see Forssman (heterophile) antigen. HETEROZYGOTE: (heterozygous individual) - two different alíeles are present. HISTOCOMPATIBILITY (TRANSPLANTATION) ANTIGENS: the antigens involved in transplantation reactions. A large number of antigenic groups are affected, each controlled by a separate genetic locus. The strength of the reaction in any given donor-host combination expresses the cumulative response of all those antigens possessed by the donor but not by the recipient. HOMOZYGOTE: (homozygous individual) -the members of a pair of alíeles are identical. HYPOGAMMAGLOBULINAEMIA: gamma globulin is deficient but is present in excess of 100 mg per 100 ml serum. IMMUNOLOGICALLY COMPETENT CELLS: interact with antigen and initiate an animal's response to primary immunization; or are cells that are fully qualified to undertake an immunological response. IMMUNOLOGICAL TOLERANCE: the specific modification of immunological responses in an animal so that it will no longer react immunologically when foreign cells are introduced. For example, if a highly inbred albino rat on the day of birth receives a large intravenous injection of bone marrow cells from an adult Fi donor and an Fi skin graft at 6 weeks of age, the graft will survive. LIGAND: a general term for either antigen or hapten. May be a protein, nucleic acid, polysaccharide, lipid, synthetic polypeptide, or small organic molecule. LOCUS: the precise position of a gene. The genes are arranged linearly along the chromosomes. MACROPHAGE MIGRATION INHIBITION TEST: in this test macrophages from the blood are put into a capillary tube and, if the antigen to which the cells have been sensitized is outside, migration of the macrophages from the tube is inhibited. If no specific antigen is present the macrophages migrate from the tube.

GLOSSARY 107 PASSIVE TRANSFER TEST: see Prausnitz-Kustner reaction. PHARMACOGENETICS: the special subject of biochemical genetics related to drug responses and their genetic modification. Of patients who respond abnormally (prolonged apnoea) to the muscle relaxant succinylcholine, 50% have an abnormal genotype causing the abnormal response, and this is not an allergic reaction. PHENOTYPE: of an individual is the manifestation of his genes in his physical, biochemical, and physiological traits. (Genotype and phenotype are frequently applied with a limited meaning to signify specific genes and traits.) PRAUSNITZ-KUSTNER REACTION: (passive transfer test) - (1) Serum (0.1 ml) from a patient suspected of being allergic to a given allergen is injected intracutaneously into the skin of the forearm of an individual who is known to be non-allergic to that allergen and who has a negative skin test to that allergen. (2) After 48 hours, the time necessary for the IgE to fix to the mast cells in the skin of the recipient, the site is injected with the allergen (0.02 ml of a 1:1000 dilution). As a control the allergen is injected in the same manner at another site. (3) A wheal and flare at the site of injection of the serum but not at the control site indicates that the donor's serum contained IgE against the allergen under test. PROPOSITUS : (proband or index case) - the family member whose abnormality first attracts the attention of an investigator. SHWARTZMAN PHENOMENON: (1) A bacterial filtrate is injected subcutaneously into a rabbit, causing a local accumulation of granulocytes. (2) Twenty-four hours later the rabbit is injected I/V with a challenging dose of either the same bacterial filtrate or a filtrate obtained from another bacterium (even though the latter is an unrelated substance). (3) Skin lesions occur at the site of the initial injection within a few hours of the I/V injection. (4) Only in the rabbit and man is the generalized Shwartzman phenomenon demonstrable. SPECIFICITY: of an antigen and antibody is manifest by selectivity. In high specificity in an antibody the molecule reacts with its homologous antigen selectively instead of reacting with other substances. Specificity is also related to the nature of the functional groups. A ligand Li containing the group X is said to have specificity X to a given antibody population if, and only if, that antibody reacts with Li and with some other ligand Lz containing the same group X. TACHYPHYLAXIS: a sensitized muscle can be desensitized through repeated exposure to the specific antigen. TRAIT: phenotypic expression of a gene. TRANSFER FACTOR: important in delayed hypersensitivity and associated with lymphocytes, although its origin is not established. Its yield varies directly with the sensitivity of the donor. It is non-protein with a molecular weight of about 10,000, and is stable at 37°C, but unstable at 56°. It passes into solution when living tuberculin-competent cells are soaked in tuberculin. It may function as an information molecule, probably an RNA fragment of low molecular weight. TRANSPLANTATION ANTIGENS - HISTOCOMPATIBILITY ANTIGENS: see Histocompatibility (transplantation) antigens.

108 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

VALENCY: refers to the number of functional groups of reactant (ligand or antibody) per molecule. Thus the valency of the ligand is the maximum number of antibody molecules that one molecule of ligand can bind at one time. Antibodies are almost always bivalent. Ligand valency varies widely from one to over 100.

APPENDICES

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Appendix A: Elimination diets

Elimination diets, which have been championed by Dr Albert Rowe,* can be extremely useful in diagnosing food allergy. When food allergy is suspected in the small infant it is easy to outline a simple elimination diet based on the infant's age, what foods he has been eating, and what foods have been clinically implicated. For example, a simple elimination diet for a five-month-old infant who has been receiving milk, mixed cereals, vegetables, and fruit, and who is suspected of having food allergy that causes diarrhoea, would consist of a soybean preparation, a watersoluble vitamin preparation, and rice cereal. However, in the older child who chooses from a wide variety of foods, it is better to use one of the standard elimination diets proposed by Dr Rowe. Six such diets, included in this appendix, are easy to use, if the physician remembers to stress the important points. 1. They should be used only in those patients whose symptoms are suspected of being caused by food allergy and whose symptoms are severe enough that the patient is willing to follow a strict diet for a period of two months to see if his symptoms are relieved. After the two-month period, additional foods are added to the diet, to observe whether the symptoms return. 2. It must be emphasized to the patient or to the parent that the diet is useless unless it is followed rigidly. Even small amounts of forbidden foods or beverages taken at bedtime or between meals destroy the value of the diet. 3. The patient must be given a copy of the diet with the recipes clearly stated so that he can follow them. 4. If a patient is clinically sensitive to one of the foods on the diet, that food and all recipes using it must be carefully removed from the diet. * We wish to acknowledge the kindness of Lea & Febiger in allowing us to use material from Dr Rowe's Elimination Diets.

112 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

5. After a reasonable diet trial of a two-month period, depending on the severity of the patient's symptoms, foods may be added to the diet one at a time until the implicated foods are detected. The best way to add a food is to give it in pure form daily for five days, leaving it in the diet only if it does not cause symptoms. If, however, the patient is not greatly improved, he may be returned to a full diet. If his symptoms increase, he will have to return to the diet and foods will be added systematically to determine the offenders. MILK-FREE DIET

To follow the milk-free diet only foods known to be free of milk are eaten. Care must be taken to avoid foods in the following list which often contain milk in a hidden form. Foods must be prepared in the home or only foods whose ingredients are labelled and which explicitly omit milk or milk products are to be used. The only absolute way is not to buy packaged foods whose ingredients are unlisted. If eating away from home order only foods you are quite sure are free of milk. Forbidden Foods 1. Milk and milk products including fresh whole milk, skimmed milk, cultured milk, buttermilk, cream, condensed milk, evaporated milk, dried milk, milk solids, casein, lactalbumin, butter, margarine (unless specifically stated on the label to be free of milk solids), curds, whey, malted milk, and cheese. 2. Beef, because of a cross-reaction between beef albumin and milk proteins, a person on a strictly milk-free diet should not eat any beef. 3. Sauces and gravies should be avoided since most white or cream sauces contain milk or milk products. 4. Soups: many canned and dehydrated soups contain milk or milk products and should not be consumed unless their ingredients are labelled. 5. Salad dressings often contain milk, cream, butter, margarine, or cheese. 6. Desserts such as cakes, cookies, puddings, and pie crusts contain or are brushed with milk or milk products. Desserts made with milk also include the blanc manges, custard, junket, ice cream, milk sherbets. These should be home made without milk, or purchased only if they are clearly labelled free of milk. 7. Meats, poultry, fish, and sea food, commercially prepared, may contain milk products. 8. Candies and sweets often contain milk or milk products. 9. Vegetables, creamed and scalloped, often contain milk or milk products.

A P P E N D I X A: E L I M I N A T I O N DIETS 113

10. Bread and breaded foods such as pancakes, waffles, crackers, rusks, doughnuts, and foods breaded with bread crumbs or cracker crumbs frequently contain milk products. Most commercial breads and rolls contain some milk, and should be eaten only if they are clearly labelled to be milk-free. 11. Beverages: many preparations of chocolate or cocoa contain milk or milk products. 12. Miscellaneous: foods dipped in milk batter, fried in butter or in margarine, creamed and scalloped foods, foods prepared with cheese (au gratin), rarebits, and prepared mixes for cakes, doughnuts, muffins, cookies, biscuits, pie crusts, and waffles frequently contain milk or milk products. EGG-FREE DIET

On an egg-free diet, the patient may eat only foods free of egg. He must avoid foods containing egg in a hidden form. Ideally, foods should be prepared in the home. However, before prepared food is taken home or eaten in a restaurant the ingredients must be known. It is best to buy no packaged foods that are not labelled with their ingredients. Forbidden Foods 1. Egg dishes with baked, creamed, devilled, scalloped, fried, scrambled, hard or soft cooked eggs, and egg drinks such as egg nog, egg sauces, egg meringue, and egg omelettes. 2. Salad dressings, with the exception of true French dressing, often include egg. Unless the ingredients of the dressing are clearly labelled it should not be purchased; a homemade substitute should be used. 3. Breads and breaded foods such as breads, muffins, waffles, gingerbreads, doughnuts, and griddle cakes often contain egg. Many commercial breads and rolls contain egg. Breads or rolls with a glossy surface must be suspected of having been brushed with egg white. No prepared mixes should be used in the home unless their listed ingredients indicate that all forms of egg are absent. 4. Baking powder often contains egg white or egg albumen and should not be used unless the ingredients are on the label. 5. Desserts such as custards, Bavarian creams, angel and sponge cakes, macaroons, whips, pie fillings, blanc manges, frostings, ice creams, sherbets, puddings, and cakes often contain egg. 6. Beverages may contain egg or one of its constituents. Some coffees have been

114 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

clarified with egg white or egg shell. Root beer sometimes contains egg to make it foam. A manufacturer will usually inform the parent or the physician of the presence of egg in the beverage. 7. Meats, poultry, fish, sea food, game, and often sausages, meat loaves, croquettes, and prepared meats contain egg as a binding agent. A patient sensitive to egg should avoid chicken although he may eat capon. 8. Sauces such as tartar and Hollandaise frequently contain egg. 9. Sweets: many purchased sweets contain egg and should not be eaten unless labelled as being egg-free. Many commercial candies such as jelly-beans are brushed with egg white to give them a lustre and therefore are on the banned list. 10. Soups such as alphabet, mock turtle, and egg noodle, and consommés, bouillons, and broths often contain egg. No canned soups should be eaten unless they are clearly labelled egg-free. 11. Miscellaneous foods such as french toast and fritters frequently contain egg and should not be eaten unless their ingredients are clearly labelled. W H E A T - F R E E DIET

Wheat and wheat products include white bread, cake, pastry, self-rising, whole wheat, all-purpose, cracked wheat, graham, enriched, entire wheat, and phosphated durum flours. They also include wheat, wheat germ, bran, farina, and semolina, as well as malt, bread crumbs, and cracker meal. To remain on a wheat-free diet, it is essential to avoid buying any packaged foods whose ingredients are not labelled. When eating away from home, it is essential to eat substitute foods known to be free of wheat. Forbidden Foods 1. Breads, white bread, rolls, biscuits, muffins, whole-wheat bread, graham bread, gluten bread, sweet rolls, doughnuts, Johnny cake, pancakes, waffles, pretzels, crackers, zwieback, and popovers. Wheat is also present in prepared mixes for waffles, biscuits, doughnuts, breads, rolls, pancakes, and muffins. It may also be present in breads listed as being rye, corn, soybean, potato, rice or in rolls or muffins and, therefore, it is not safe to eat any of these unless they are clearly labelled free of wheat. Wheat-free rye bread is readily available, but ordinary rye bread does contain wheat as confirmed on the label. Breaded foods also contain wheat products. 2. Desserts such as doughnuts, dumplings, commercial sherbets, ice creams, ice cream cones, pastry, cakes, cookies, pies, puddings, and custards frequently con-

APPENDIX A: E L I M I N A T I O N DIETS 115

tain wheat as do prepared mixes for cakes, ice creams, puddings, cookies, and pie crusts. Again it is essential to purchase only those whose ingredients are listed on the label. 3. Cereals often contain wheat and it is essential that the label be read carefully. 4. Salad dressings are often thickened with wheat flour. 5. Soups, especially creamed, contain wheat flour as do vegetable and meat soups, chowders, and bisques. 6. Sweets, especially commercial ones, contain wheat products and should not be eaten unless their ingredients are clearly labelled. 7. Beverages: coffee substitutes and similar beverages contain wheat products, as do malted drinks, beer, and ale. 8. Sauces and gravies are often thickened with wheat flour and should not be eaten in restaurants. They should be purchased only if their ingredients are clearly listed. 9. Meats, poultry, fish, seafood, and game -many fish or meat patties contain wheat products. Wheat products are frequently used for stuffing poultry and game. Swiss steak, chili con carne, and croquettes frequently contain wheat. 10. Vegetables must not be served with sauce thickened with wheat flour. 11. Miscellaneous foods including most dumplings, spaghetti, macaroni, mostaccioli, ravioli, soup rings, soup alphabets, vermicelli, as well as malt products, contain wheat. W H E A T - E G G - M I L K - F R E E DIET Wheat and Wheat Products

Flour such as wheat, bread, cake, pastry, self-rising, whole wheat, wheat, allpurpose, cracked wheat, graham, enriched, entire wheat, phosphated, as well as wheat, wheat germ, bran, farina and semolina, malt, bread crumbs, and cracker meal. Egg and Egg Products Dishes with baked, creamed, devilled, scalloped, fried, scrambled, hard or soft cooked eggs, egg drinks such as egg nog, egg sauces, egg meringue and egg omelettes.

116 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y Milk and Milk Products

Fresh whole milk, skimmed milk, cultured milk, buttermilk, cream, condensed milk, evaporated milk, dried milk, milk solids, casein, lactalbumin, butter, margarine (unless specifically stated on the label to be free of milk solids),curds, whey, malted milk and cheese. It is difficult to stay on a wheat-egg-milk-free diet unless all food is prepared in the home. The patient must use packaged foods whose ingredients are listed as not containing any of the three forbidden foods or their products. When eating away from home, the patient should eat only vegetables and meats without gravies or sauces, with fresh fruits as dessert. To avoid these three foods, the following must be eliminated: 1. Breads, muffins, biscuits, crackers, rolls, and breaded foods except those made at home without the three foods in them or commercial ones whose ingredients are clearly listed. 2. Egg dishes known to contain egg, including egg sauces, egg drinks, meringues, soufflés, and egg omelettes. 3. Fats and salad dressings except true French dressing and those made at home, and all butters and margarines. 4. Baking powders can be used only if they are clearly labelled free of egg or albumen. 5. Sauces and gravies such as tartar and hollandaise, cream and hard sauces, and sauces or gravies thickened with wheat flour are forbidden unless they are homemade. 6. Sweets: most hard candies are free of these products but no candies should be consumed unless the ingredients are on the label. 7. Meats, poultry, fish, seafood and game. All the following must be avoided: foods stuffed with bread or cracker stuffings, meat loaves, croquettes, Swiss steak, dealer-prepared or commercially prepared meats, chili con carne. A patient sensitive to milk may be sensitive to beef which should also be avoided. A patient sensitive to egg may also be sensitive to chickens which should be avoided, although capon is acceptable. 8. Vegetables, creamed and scalloped, may contain one or more of these products. 9. Beverages such as coffee substitutes may contain wheat products. Also to be avoided are: coffee cleared with egg white or egg shell; chocolate or cocoa unless

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made with water from milk-free and egg-free chocolate and cocoa preparations; root beer, malted drinks, beer, and ale. 10. Desserts including cakes, dumplings, fritters, macaroons, meringues, sherbets, pastries, doughnuts, mousses, ice cream cones, ice cream, Bavarian cream, custard, blanc mange; prepared mixes, frostings and puddings or cookies unless homemade without the three forbidden foods. Pies must be avoided unless they are made without any of these products. 11. Cereals must be checked for their ingredients because they frequently contain wheat or milk or both. 12. Soups that are creamed contain milk products, as do mock turtle soups, bouillons, broths, consommés, thickened soups or soups containing noodles, soup rings, or alphabets. Canned and dehydrated soups frequently contain wheat, egg or milk products, so that usually only homemade soup is suitable unless a clearly labelled commercial product is obtainable. 13. Miscellaneous: creamed and scalloped foods, fritters, timbales, rarebits, foods cooked in batter, French toast, malt products, dumplings, macaroni, ravioli, mostaccioli, spaghetti, vermicelli, alphabets in soup, and soup rings must all be avoided. #1 E L I M I N A T I O N DIET (ROWE)

Foods allowed (not even traces of other foods may be given) Rice Tapioca Rice biscuit Rice bread Lettuce Chard Spinach Carrot Sweet potato or yam Lamb Lemon Grapefruit Pear

Cane sugar Sesame oil Olive oil Salt Gelatin, plain or flavoured with lime or lemon Maple syrup or syrup made with cane sugar flavoured with maple Baking powder Cream of tartar Baking soda Vanilla extract Lemon extract

118 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

In addition the patient should receive Poly-Vi-Sol 0.3 cc daily and Sandoz calcium syrup 1 tablespoonful twice daily. Example Rice or tapioca may be served with fruit or fruit juice or with maple syrup Jams, preserves, or jellies of the prescribed fruits may be used on bread in place of butter Fruits may be moulded in gelatin Use olive oil for cooking The juices of the allowed fruits may be used as beverages Fruit Tapioca 21/2 cups canned fruit juice and water 4 tbsp. Minute tapioca l /2 cup sugar V4 tsp. salt

1 to IVz cups chopped or puréed pears 1 tbsp. lemon juice

Combine fruit juice and water, Minute tapioca, sugar, and salt in a saucepan and mix well. Bring mixture to a boil, stirring constantly. Remove from fire. Do not overcook. Cool, stirring occasionally. Mixture thickens as it cools. Fruit-Free Tapioca 3 cups water Va cup Minute tapioca Vs cup white sugar or 1 /2 cup brown sugar

1

U tsp. salt V2 tsp. maple flavouring or 1 tsp. vanilla extract, or 2 tsp. caramel flavouring

(The amount of brown sugar and flavouring may be varied to suit the individual taste.) Combine all ingredients in a saucepan. Bring mixture quickly to a full boil over direct heat, stirring constantly. Remove from fire. Do not overcook. Stir occasionally as it cools. Caramel Flavouring Cook sugar until it turns golden brown. When cool, add just enough water to dissolve the hard caramel. The resulting liquid may be kept in ajar and used at will for flavouring and colouring. Lamb Patties Ground lamb pressed into small patties. Broiled or fried. Fondant 2 cups sugar 1 /4 tsp. cream of tartar 1 cup boiling water

1

U tsp. salt /2 tsp. vanilla

l

Measure sugar and cream of tartar into a saucepan and add the boiling water. Stir

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over a low heat until sugar is dissolved. Do not let the candy boil until the sugar is dissolved and sugar crystals wiped down from the sides of the pan with a clean cloth. When the boiling point is reached, cover the kettle and boil vigorously for 5 minutes. Remove the cover, wipe off crystals from sides of the pan and continue cooking without stirring until the medium ball stage has been reached (240-242° F). When done, pour the candy at once into a cold, wet platter and let it stand until lukewarm. Sprinkle salt over the surface, add vanilla and beat until white and knead in the hands until smooth and creamy. Put fondant into a glass jar and cover. It will keep several weeks in a cool place. Use of Fondant: Put a portion of the fondant into the top part of a double boiler. Melt over hot but not boiling water until fondant softens. Colouring or flavouring is added at this stage. Lemon extract or lemon juice and grated lemon rind may be used. Drop fondant from the tip of a spoon onto wax paper. Marshmallows 2 cups sugar 3 /4 cup water 2 tbsp. gelatin

Vz tsp. salt 1 tsp. vanilla extract

Mix sugar and water and boil until the soft ball stage has been reached (234-238° F). Remove from the fire. Soften gelatin in */2 cup cold water. Pour the hot syrup over the softened gelatin and stir until dissolved. Let it cool partially, add vanilla and salt and beat it until the mixture is thick and white and will hold its shape. Pour into straight sided pans. When firm, cut into squares. Roll in sugar. Rice Bread 1 cup rice 3 tsp. baking powder 2 tbsp. oil

flour

1 tbsp. sugar /2 tsp. salt 3 /4 cup water l

Sift the dry ingredients. Add the water and fat. Bake in a loaf pan in a moderate oven, 350° to 375°F, for 45 to 50 minutes. Rice Fruit Pudding ll/2 cups cooked rice J /4 cup sugar l /2 tsp. salt

1 cup canned pears

Mix all ingredients together and bake in a moderate oven for 30 minutes. Serve warm with lemon sauce. Rice Pudding with Lemon I1/2 cups cooked rice l /4 cup sugar Vz tsp. salt

1 tbsp. lemon juice 2 tsp. grated lemon rind lemon sauce

120 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Mix all ingredients together. Serve with additional lemon sauce. Lemon Sauce Mix 2 tbsp. tapioca flour with 3/4 cup sugar, flattening all the lumps. Add all at once to 1 1 /2 cups rapidly boiling water, stirring vigorously. Boil for 2 minutes. Add 4 tbsp. lemon juice and 1 tsp. grated rind, with a sprinkle of salt. Rice Cup Cakes 2 /3 cup hot water I112 cups rice flour 2 level tbsp. olive oil 1 U cup sugar

1

/4 tsp. salt 3 level tsp. baking powder 1 tsp. vanilla

Pour hot water over half of the flour. Cream sugar and oil and add to the above mixture, beating well. Add the other ingredients, mixing well. Bake in muffin pans about 20 minutes in a fairly hot oven (400°F). Rice Cookies

3 cups rice flour

2 tsp. baking powder 1 cup sugar l /2 cup olive oil

1 lemon rind, grated

1 lemon -juice U cup water

1

Sift dry ingredients, cream thoroughly with oil. Add grated lemon rind and juice with just enough water to make a stiff dough and pat into shape. Sprinkle with sugar and bake in moderate oven for 5 to 7 minutes. Lemon Frosting 1 tbsp. grated lemon rind Dash of salt 2 tbsp. sesame oil

3 cups confectioner's sugar 2 tbsp. lemon juice 1 tbsp. water

Mix oil, salt, and lemon rind. Add fruit juice and water alternately with sugar, stirring well after each addition. Place bowl over hot water for a few minutes. Remove and spread over cake. This will cover a two-layer cake or 24 cup cakes. Lemon Marmalade Six lemons unpeeled. Slice very thin and cut crosswise into small pieces. Measure fruit. Add three times as much water. Boil about one hour or until tender. Replace liquid boiled away with water. Allow 3/4 cup sugar to each cup of fruit juice. Cook in two-cup lots to the jelly test (thick, reluctant drops from the spoon - about ten minutes). Pour into sterilized jelly glasses. Cover with paraffin. This makes eight 6 ounce glasses. Carrot Marmalade 5 large carrots 4 lemons

sugar water

A P P E N D I X A: E L I M I N A T I O N DIETS 121

Squeeze the lemons, removing the seeds, and set the juice aside. Grind lemons and carrots together. Add 8 cups of water to the pulp and boil for 30-45 minutes. Measure this mixture and to it add an equal quantity of sugar and the lemon juice. Boil briskly for an hour or until it jells. Pour into sterile glasses and seal with paraffin. Pear Butter Peel and core 1 gallon of fresh pears; put into kettle and add 2 cups water, boil slowly, when done put through a colander. To every four cups of pulp add 2 cups of sugar. Place on stove again and cook slowly until dark and very thick. Stir occasionally. A few minutes before removing, add juice of 1 lemon. Sterilize jars, rubbers and lids, fill and seal while hot. Baked Pears 6 medium sized pears l /2 cup water

1 cup sugar, white or brown

Wash the pears and remove blossom ends. Place in a baking dish, add sugar and water, cover and bake at 350° F for one hour or until pears are tender. Lemon Ice (Made in the refrigerator) 2 /3 cup sugar 2 cups water 1V2 tsp. plain unfavoured gelatin soaked in 3 tbsp. water

pinch of salt Va cup of lemon juice 1 tsp. grated lemon rind

Cook sugar and water together 3 minutes. Dissolve soaked gelatin in hot syrup. Add salt and lemon juice. Turn into the refrigerator tray and freeze until solid 1 inch from edge of tray. Scrape from the sides of the tray and transfer to a chilled bowl. Beat with a chilled rotary beater until fluffy and smooth. Return to tray and freeze again until firm. Scotch Broth 2 Ibs. shoulder lamb 2 quarts water Í U cup pearl tapioca

!

/2 cup diced carrots salt

Cut the meat into small pieces and boil until tender. Cool and strain. Separate the lean meat from the bones and return it to the broth, together with the tapioca and carrots. Simmer gently until tapioca is clear. French Dressing l /2 cup specified oil J /4 cup lemon juice Mix well before using on salads.

l

/2 tsp. salt 1 tsp. sugar

122 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Glazed Carrots 6 whole cooked carrots 2 tbsp. sesame oil

1 tbsp. sugar Vz cup water

Make a syrup of the sugar and water. Cook carrots in the syrup, turning often to prevent burning. Rice Biscuits To make rice biscuits, add 2 tbsps. water to 1 cup of Nabisco Rice Flakes, blend gently, press out on an oiled cookie sheet, cut with a sharp knife, and bake for 1(M2 minutes at 375° F. #2 E L I M I N A T I O N DIET (ROWE)

Foods allowed (not even traces of other foods may be given) Corn Pineapple Rye Peach Apricot Corn pone Prune Corn-rye muffin Rye bread Cane or beet sugar Ry-Krisp Corn oil Sesame oil Beets Salt Squash Gelatin, plain Asparagus or flavoured with pineapple Artichoke Karo corn syrup White vinegar Capon (no hens) Baking powder Bacon Baking soda Cream of tartar Vanilla extract In addition the patient should receive Poly-Vi-Sol 0.3 ml daily and Sandoz calcium syrup 1 tbsp. twice daily. Example Cornflakes served with fruit or fruit juice Cornmeal served with Karo syrup Jams, preserves, or jellies of the prescribed fruits may be used on the bread in place of butter Homemade capon broth Fruits may be moulded in gelatin Use corn oil for cooking The juices of the allowed fruits may be used as beverages.

APPENDIX A: E L I M I N A T I O N DIETS 123

Corn Pone 1 cup cornmeal l /2 tsp. salt

boiling water 1 tbsp. corn oil

Carefully pour enough water onto the cornmeal to make a stiff mixture, stirring constantly. Add the oil and mix well. Mould into oblong "pones" and fry in hot skillet with enough fat to prevent sticking. When brown on one side, turn and brown on the other side. Serve hot. Corn-Rye Muffins ll/3 cups cornmeal

2!/2 tsps. baking powder

2/3 cup rye flour

1 cup water

/4 cup sugar l /2 tsp. salt

3 tbsps. corn oil

1

Sift all the dry ingredients together, add the water and oil. Pour into well-greased muffin pans. Bake at 400° F for 30 minutes. Rye Bread 1/2 cups rye flour

3 tsps. baking powder 1 /2 tsp. salt

3 tbsp. specified oil

2

/3 cup water (more if necessary)

Sift dry ingredients, add the oil and blend with pastry mixer. Add water and stir until smooth. Put in tin and allow to stand for 15 minutes. Bake 45 minutes in moderate oven (350° F). Fondant 2 cups sugar l /4 tsp. cream of tartar 1 cup boiling water

1 l

U tsp. salt /2 tsp. vanilla

Measure sugar and cream of tartar into a sauce pan and add the boiling water. Stir over low heat until sugar is dissolved. Do not let the candy boil until the sugar is dissolved and the sugar crystals wiped down from sides of the pan with a clean cloth. When the boiling point is reached, cover the kettle and boil vigorously for 5 minutes. Remove the cover, wipe off crystals from sides of the pan and continue cooking without stirring until the medium ball stage has been reached (240-242°F). When done, pour the candy at once into a cold wet platter and let it stand until lukewarm. Sprinkle salt over the surface, add vanilla and beat until white and knead in the hands until smooth and creamy. Put fondant into a glass jar, and cover. It will keep several weeks in a cool place. Use of Fondant Put a portion of the fondant into the top part of a double boiler. Melt over hot but not boiling water until fondant softens. Colouring or flavouring is added at this stage. Chopped prunes or glazed pineapple may be used. Drop fondant from tip of a spoon onto waxed paper.

124 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

Marshmallows 2 cups sugar 3 /4 cup water 2 tbsp. gelatin

l

/2 tsp. salt 1 tsp. vanilla extract

Mix sugar and water and boil until the soft ball stage has been reached (234-238°F). Remove from the fire. Soften the gelatin in lh cup cold water. Pour the hot syrup over the softened gelatin and stir until dissolved. Let it cool partially, add vanilla and salt and beat it until the mixture is thick and white and will hold its shape. Pour into straight sided pans. When firm, cut into squares, roll in sugar. Corn Crisps 1 cup cornmeal 1 tsp. salt 2 cups boiling water

1 tbsp. corn oil 1 tsp. sugar

Mix all together. Pour a very thin layer on a well-greased cookie sheet. Bake 15 minutes at 350°F. While warm, cut into strips and sprinkle with salt. Pineapple-Apricot Marmalade 4 cups apricot pulp - fruit cut in small pieces and packed solidly in the cup.

1 cup crushed pineapple -juice and pulp 3Vz cups sugar

Mix fruit and sugar and boil rapidly until thick - approximately 30 minutes. Seal in hot, sterile glasses. Capon Croquettes I1 ¡2 cups cooked capon, chopped l /2 tsp. salt

fine

1 cup capon broth (made at home) 2 tbsps. cornstarch

Cook the cornstarch in the capon broth for 6 minutes or until thick. Add the capon and salt. Chill and shape into croquettes. Roll in crushed cornflakes, fry in deep prescribed oil or bake in the oven for 30-45 minutes. Cornstarch Fruit Blanc Mange ll/2 cups fruit pulp and juice ll/2 cups water

4 tbsp. cornstarch 3 tbsp. sugar

Dissolve cornstarch in a little water. Heat the fruit pulp, water, and sugar. When almost boiling, add the cornstarch mixed in water. Continue cooking for 15 to 20 minutes in a double boiler. Pour into moulds and chill. Serve with fruit or pudding sauce. Clear Pudding Sauce l /2 cup sugar 1 tbsp. cornstarch Vs tsp. salt

1 cup boiling water 1 tsp. vanilla extract

A P P E N D I X A: E L I M I N A T I O N D I E T S 125

Measure sugar, cornstarch, and salt into a sauce pan. Mix well. Add boiling water slowly, stirring carefully to make a smooth sauce. Heat to boiling, stirring constantly until thickened, smooth, and clear. Add vanilla extract and serve hot. #3 E L I M I N A T I O N DIET (ROWE)

Tapioca White potato Breads made of any combination of soy, lima, and potato starch and tapioca flours Tomato Carrot Lima beans

String beans Peas

Beef Bacon Lemon Grapefruit

Peach Apricot

Cane sugar Sesame oil Soy bean oil Gelatin, plain or flavoured with lime or lemon Salt

Maple syrup or syrup made with cane sugar flavoured with maple Baking powder Baking soda

Cream of tartar Vanilla extract Lemon extract

In addition the patient should receive Poly-Vi-Sol 0.3 ml daily, and Sandoz calcium syrup 1 tbsp. twice daily. Example Tapioca served with fruit or fruit juice Jams, preserves or jellies made from constituents listed in the diet may be used on bread instead of butter Homemade beef broth Fruits may be moulded in gelatin Use soy bean oil or sesame oil for cooking The juices of the allowed fruits may be used as beverages.

126 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Fruit Tapioca 2l/2 cups canned fruit juice and water 4 tbsp. Minute tapioca l /2 cup sugar V4 tsp. salt

1 to IVz cups chopped or puréed apricots or peach 1 tbsp. lemon juice

Combine fruit juice and water, Minute tapioca, sugar, and salt in a sauce pan and mix well. Bring mixture to a boil, stirring constantly. Remove from fire. Do not overcook. Cool, stirring occasionally. Mixture thickens as it cools. Fruit-free Tapioca 3 cups water Vz tsp. maple flavouring or l /3 cup Minute tapioca 1 tsp. vanilla extract, or 1 /3 cup white sugar 2 tsp. caramel flavouring */4 tsp. salt (The amount of brown sugar and flavouring may be varied to suit the individual taste.) Combine all ingredients in a saucepan. Bring mixture to a full boil quickly over direct heat, stirring constantly. Remove from the fire. Do not overcook. Stir occasionally as it cools. Soy-potato Muffins or Bread 1 cup soy flour 1 cup potato starch flour

1 tsp. salt /2 cup soy oil

2 tbsp. baking powder 2 tbsp. white sugar 3

l

/4 to 1 cup water

Sift the soy flour once before measuring. Fill the measuring cup lightly and level off the surface with a knife blade. Sift all the dry ingredients together four times. Add the oil and water and beat well. Pour the batter into muffin pans which are well greased with soy oil. Bake in a moderate oven (350-375°F) for about 25-30 minutes. Makes 12 muffins. For bread, bake in a loaf pan at 350° F for 11U hours. If a moister texture is desired, decrease the potato starch flour to 3/4 cup. Soy-lima-potato Muffins or Bread

1 cup potato starch flour 3/4 cup soy bean flour 1/4 cup lima bean flour l

/2 cup sesame or soy oil

2 tbsp. sugar 1 cup water* 6 tsp. baking powder l

/2 tsp. salt

Sift flour, baking powder, and salt together three times. Blend the oil and sugar well. Add the sifted flour and the water alternately to the oil and sugar. Beat well and *Or 1 cup cooked tapioca (2 tsp. tapioca cooked in 1 cup of water. Add water after cooking to make one cup).

APPENDIX A: E L I M I N A T I O N DIETS 127

pour into muffin pans which have been well greased with sesame or soy oil. Bake at 375°F for about 25-30 minutes. Makes 12 muffins. Or bake in a loaf pan at 350°F to 375°Ffor 1V4 hours. Soy-potato Pancakes or Waffles To the recipe for soy-potato muffins, add */4 cup of extra water to make a thinner batter. Bake on a griddle or waffle iron well greased with soy oil. Serve with maple syrup or syrup made with brown and white sugar flavoured with maple or caramel. Lima Bean or Split Pea Soup 1 cup split peas or lima beans 2 tbsp. bacon fat diced bacon, crisp

1 qt. water salt

Cook the split peas or lima beans and salt until it forms a smooth purée. Before serving add the bacon fat and crisp fried bacon. Tomato Soup (with soy bean flour) 1 cup strained tomatoes, or juice 1 cup water

2 tbsp. soy bean flour 1 tsp. salt

Mix the soy bean flour thoroughly with some of the water, and add to the hot tomato juice and water. Boil for J /2 hour. This resembles a cream soup in consistency and flavour. Soy-potato Cup Cakes or Cake 1 cup soy flour 3/4 cup potato starch flour

5 tsp. baking powder 3 /4 cup sugar l /2 tsp. salt

1/2 cup soy oil 2 tsp. vanilla or

1 tsp. vanilla and 1 tsp. lemon extract /2-2/3 cup water

l

Sift soy flour once before measuring. Sift together all the dry ingredients four times. Mix the oil, sugar, and flavouring and to this add the flour and water alternately, beginning and ending with flour. Beat well. Pour into muffin or layer cake pans well greased with soy oil and bake at 375°F for 30 minutes. Makes 12 cup cakes or 2 small layers. Or bake in a loaf pan for 45-50 minutes. Variations Flavour with lemon extract and grated lemon rind or with maple flavouring. Add chopped apricots, substitute fruit juice for water. Fondant slightly thinned with water or fruit juice may be used for frosting. Soy-potato Cookies Follow the recipe for Soy-potato Cake. Decrease the water to make a stiff dough. Force through a cookie press onto a cookie sheet well greased with soy oil. Or a thinner batter can be dropped from a teaspoon onto a greased cookie sheet. Bake at 375-400°F for 10 or 15 minutes. A thicker dough can be rolled and be kept in the

128 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

refrigerator. Cut into thin slices and bake as desired. If kept in an air-tight container cookies will remain crisp. Soy Crackers 1 cup soy flour 1 tsp. baking powder ! /4 tsp. salt

2 tbsp. soy oil 1 tsp. sugar ! /3 cup water

Mix well all ingredients. Dough should be quite thin. Drop from a teaspoon onto a cookie sheet, well greased with soy oil. Bake at 350°F until dry and crisp. Sprinkle lightly with salt. These crackers will remain crisp if kept in a tightly covered container. Soy Cookies 1 cup soy flour 2 tsp. baking powder l /4 tsp. salt Va cup sugar

4 tbsp. soy oil 3 to 5 tbsp. water l /2 tsp. vanilla or lemon extract

Mix oil and sugar and add the flavouring. Sift soy flour once before measuring and sift twice more after adding baking powder and salt. Add flour to oil and sugar and sufficient water to make a stiff dough. Form into a roll and cut into cookies or force through a cookie press. With a softer dough, drop from a teaspoon onto a cookie sheet well greased with soy oil. Bake at 350°F for 15 minutes. Chopped apricots may be added or fruit juice may be substituted for water. Cookies will remain crisp if stored in an air-tight container. Soy-potato Pudding 4 level tbsp. soy flour 1 cup water 2 tsp. potato starch flour 3 tbsp. sugar

!

/4 tsp. salt U tsp. lemon extract 1 U tsp. vanilla extract 1

Cook the soy flour and water for 15 minutes in top of double boiler. Stir potato starch, sugar, and salt into boiling mixture until it thickens. Continue cooking for 20 minutes. Flavour with lemon and vanilla extracts or with maple or caramel. Serve with fruit sauce, maple or caramel syrup as desired. More sugar may be desired or a combination of white and brown sugar may be used. Caramel Frosting 2 /3 cup water 2 cups brown sugar

3 tbsp. soy oil 1 tsp. vanilla extract

Combine sugar and water. Stir slowly while bringing it to a boil. Boil hard, stirring occasionally until the syrup has reached the "soft-ball" stage (234°F). Remove from the fire, add soy oil and vanilla and allow to cool undisturbed until lukewarm. Beat the mixture until it gets thick and loses its lustre. Spread quickly over the cake.

APPENDIX A: E L I M I N A T I O N DIETS 129

Fondant 2 cups sugar l /4 tsp. cream of tartar 1 cup boiling water

*/4 tsp. salt Vz tsp. vanilla

Measure sugar and cream of tartar into a saucepan and add the boiling water. Stir over low heat until sugar is dissolved. Do not let the candy boil until the sugar is dissolved, and the sugar crystals have been wiped down from the sides of the pan with a clean cloth. When the boiling point is reached, cover the kettle and boil vigorously for 5 minutes. Remove the cover, wipe off crystals from sides of pan and continue cooking without stirring until the medium ball stage has been reached (240^242°F). When done, pour candy at once into a cold wet platter and let it stand until lukewarm. Sprinkle with salt, add vanilla, and beat until white, and knead in the hands until smooth and creamy. Put fondant into a glass jar and cover. It will keep several weeks in a cool place. Use of Fondant Put a portion of the fondant into the top part of a double boiler. Melt over hot but not boiling water until fondant softens. Colouring or flavouring is added at this stage. Drop fondant from tip of a spoon onto waxed paper. Panocha 2 tbsp. sesame or soy oil 1 cup water 2 cups brown sugar Vs tsp. soda 1 cup white sugar Heat the oil in a kettle, stir in sugars. Add water and soda and mix well with sugar. Wipe down sugar from sides of pan. Heat slowly to boiling, stirring until sugar is dissolved. Boil to 240°F, the medium ball stage (the ball holds its shape when lifted from cold water). Remove from stove, sprinkle a dash of salt over top and set aside to cool undisturbed until lukewarm. Beat until creamy. Turn into greased pans and cut into squares. Marshmallows 2 cups sugar 3 /4 cup water 2 tbsp. gelatin

1

/2 tsp. salt 1 tsp. vanilla extract

Mix sugar and water and boil until the soft ball stage has been reached 234-238°F. Remove from the fire. Soften the gelatin in Vz cup cold water. Pour the hot syrup over the softened gelatin, and stir until dissolved. Let it cool partially, add vanilla and salt and beat until the mixture is thick and white and will hold its shape. Pour into straight sided pans. When firm, cut into squares. Roll in sugar. Caramel Flavouring Cook sugar until it turns golden brown. When cool, add just enough water to dissolve the hard caramel. The resulting liquid may be kept in ajar and used at will for flavouring and colouring.

130 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Lemon Frosting 1 tbsp. grated lemon rind dash of salt 2 tbsp. sesame or soy oil

3 cups confectioner's sugar 2 tbsp. lemon juice 1 tbsp. water

Mix oil, salt, and lemon rind. Add fruit juice and water alternately with sugar, stirring well after each addition. Place bowl over hot water for a few minutes. Remove and spread over cake. This will cover a two-layer cake or 24 cup cakes. Cotlemade 1 quart apricots 1 quart lemons

sugar water

Slice lemons, including rind, very thin, discarding seeds. Barely cover with water and cook gently 1 hour. Add the apricots, halved and pitted, and cook another hour, stirring occasionally. Measure the fruit and add an equal quantity of sugar. Boil rapidly, stirring frequently until the jelly stage is reached. Seal in sterile glasses. This marmalade is rather tart. Grapefruit Marmalade 3 large grapefruit sugar

water

Cut the fruit very fine. Measure and cover with 2!/2 times as much water. Let it stand overnight and the next morning boil briskly for 20 minutes. Remove from the fire and measure, adding 1 cup of sugar to each cup of fruit. Stir well until sugar is dissolved and let stand several hours. Boil briskly until it jells. Pour into hot sterile glasses and seal. Carrot Marmalade 5 large carrots 4 lemons

sugar water

Squeeze the lemons, removing the seeds and set the juice aside. Grind lemons and carrots together. Add 8 cups of water to the pulp and boil for 30-45 minutes. Measure this mixture and to it add an equal quantity of sugar and the lemon juice. Boil briskly for an hour or until it jells. Pour into sterile hot glasses and seal with paraffin. Tomato Preserves Select firm, ripe tomatoes. Remove the skins, cut in slices and drain an hour or more. For each cup of tomatoes add a cup of sugar and boil until thick, stirring often. Sliced lemon may be added to the tomatoes while cooking. Lemon Ice (made in the refrigerator) 2 /3 cup sugar

2 cups water

A P P E N D I X A: E L I M I N A T I O N DIETS 131

ll/2 tsp. plain unflavoured gelatin soaked in 3 tbsp. water pinch of salt

Va cup lemon juice 1 tsp. grated lemon rind

Cook sugar and water together 3 minutes. Dissolve soaked gelatin in the hot syrup. Add salt and lemon juice. Turn into the refrigerator tray and freeze until solid 1 inch from edge of tray. Scrape from the sides of the tray and transfer to a chilled bowl. Beat with a chilled rotary beater until fluffy and smooth. Return to tray and freeze again until firm. Apricot Ice 2 /3 cup sugar IVz cups apricot nectar or puréed l /2 cup water apricots and juice pinch of salt 2 tbsp. lemon juice 1 1 /2 tsp. gelatin soaked in 3 tbsp. water 1 tsp. grated lemon rind, if desired Follow directions above for Lemon Ice Lemon Ice (Using a mechanical freezer) 1 cup sugar 3 cups water

Vz tsp. grated lemon rind /2 cup lemon juice

l

Boil sugar and water for 5 minutes. Remove from stove and cool. Add lemon juice and rind. Pour into the freezer can and freeze, using 6 or 8 parts of ice to 1 part of rock salt. This makes a little over 1 quart. Beef Broth 2 cups beef stock 4 tbsp. soy bean flour

salt to taste vegetables which are allowed

Mix the soy bean flour with part of the stock and add to the hot soup. Boil for 30 minutes. Diced carrots, lima beans, peas, or potatoes may be added as desired. Hamburg-vegetable Chowder 3 /4 to 1 Ib. ground beef 3 tbsp. specified oil 2 cups canned tomatoes 2 carrots - diced

2 cups cubed potatoes 1/4 cup pearl tapioca 2 tsp. salt IVz quarts water

Brown the meat in the fat; put all the ingredients in a kettle and simmer slowly for an hour. Tomato Jelly Ring 1 tbsp. gelatin l /2 cup tomato juice - cold 1 cup tomato juice - hot

V2 tsp. salt 1 tsp. sugar 1 tbsp. lemon juice

132 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Soften gelatin in Vz cup cold tomato juice. Add the hot tomato juice, salt, sugar, and lemon juice and stir until dissolved. Pour into a ring mould. When firm, unmould on a bed of lettuce and fill the centre with mixed vegetables which have been marinated in French dressing made with lemon juice and specified oil. Use only the vegetables allowed in the diet. Stuffed Tomato Salad Peel medium sized tomatoes, scoop out the centre, sprinkle with salt and let them stand upside down until well chilled. Fill the centres with the following: diced cooked carrots and small lima beans. French Dressing 1 /2 cup specified oil 1 /4 cup lemon juice

1

/2 tsp. salt 1 tsp. sugar

Mix well before using on salads. Tomato juice may be added for vegetable salads, or apricot juice for fruit salads. Tomato Sauce 2 cups strained tomato cooked down to 1 cup with the juice of 1 lemon, salt and sugar to taste. Lima Bean Casserole 1 cup dried lima beans 1 tsp. salt 2 tbsp. white sugar

2 cups tomatoes 3 slices bacon

Soak the lima beans overnight in 1 quart of water. Cook in the same water for 30 minutes. Drain. Mix lima beans with the other ingredients in a casserole and bake at 250° F until tender - about 2 hours. Glazed Carrots 6 whole cooked carrots 2 tbsp. sesame or soy oil

2 tbsp. sugar /2 cup water

1

Make a syrup of the sugar and water. Cook carrots in the syrup, turning often to prevent burning. Quick Sweet Rolls 2 cups flour, !/2 soy bean and */2 potato Vz cup sugar 6 tsp. baking powder 1 tsp. salt l /2 cup sesame oil Vz to 3/4 cup water Mix flour, salt, and baking powder; work in the shortening and the liquid to make a soft dough. Turn on a floured board, knead lightly for less thanl minute. Roll into an oblong sheet. Sprinkle with a filling made with 1U cup water, 2 tbsp. sesame or soy oil, 1/2 cup grapefruit marmalade. Roll up like a jelly roll. Cut into slices Vz inch thick and bake 15 minutes in a hot oven.

APPENDIX A: E L I M I N A T I O N DIETS 133

Baked Peach Tapioca Pudding l /3 cup Minute tapioca 4 tbsp. sugar i /2 tsp. salt

2 cups canned sliced peaches, drained 2Vz cups water and peach juice 1 tbsp. lemon juice

Combine ingredients in a baking dish. Mix thoroughly. Bake in a moderate oven (375°) for 30 minutes, stirring well every 10 minutes. Serve warm or cold. Apricots may be substituted for peaches. Lemon Sauce Mix 2 tbsp. tapioca flour with 3/4 cup sugar, flattening all the lumps. Add all at once to 1 1 /2 cups rapidly boiling water, stirring vigorously. Boil for 2 minutes. Add 4 tbsp. lemon juice and 1 tsp. grated lemon rind, with a sprinkle of salt. Golden Turkish Paste 1 cup well-drained cooked apricots 4 tbsp. plain gelatin l /2 cup apricot juice - cold 1 /2 cup apricot juice - hot

2 cups sugar 1 tsp. grated lemon rind 2 tbsp. lemon juice

Soften gelatin in cold apricot juice. Mix sugar with the hot juice, bring it to the boil. Add gelatin, lemon juice and rind and boil 20 minutes. Remove from the stove and add the mashed apricots. Mix well. Pour into a pan lined with wax paper. After it has set, cut into cubes. Roll in sugar. #4 E L I M I N A T I O N DIET (ROWE)

Milk Cream Plain cottage cheese Tapioca Cane sugar In addition the patient should receive Poly-Vi-Sol 0.3 ml daily. Fruit-free Tapioca 3 cups water Va cup Minute tapioca 1 /3 cup white sugar

l

/4 tsp. salt 2 tsp. caramel flavouring

(The amount of sugar and flavouring may be varied to suit the individual taste.) Combine all ingredients in a saucepan. Bring mixture quickly to a full boil over direct heat, stirring constantly. Remove from the fire. Do not overcook. Stir occasionally as it cools. Caramel Flavouring Cook white sugar until it turns golden brown. When cool, add just enough water

134 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

to dissolve the hard caramel. The resulting liquid may be kept in ajar and used at will for flavouring and colouring. CEREAL-FREE ELIMINATION DIET (ROWE)

Foods allowed Tapioca White potato Sweet potato or yam Soy bean potato bread Lamb Beef Capon Bacon Liver (calves, beef, or lamb) Lettuce Spinach Chard Carrots Beets

Artichoke Tomato Squash Asparagus Peas String beans Lima beans Lemon Grapefruit Pears Pineapple Peaches Apricots Prunes

Cane or beet sugar Salt Sesame oil Soy bean oil Milk-free oleomargarine Gelatin, plain Lime, lemon, or pineapple flavoured gelatin Maple syrup or syrup made with cane sugar flavoured with maple

White vinegar Vanilla extract Lemon extract Baking powder Baking soda Cream of tartar

While on this diet, the patient should receive Poly-Vi-Sol 0.3 ml daily and Sandoz calcium syrup 1 table spoonful twice daily. Fruit Tapioca 21/2 cups canned fruit juice & water 4 tbsp. Minute tapioca l /2 cup sugar l /4 tsp. salt

1 to ll/2 cups chopped or puréed apricots, pears, prunes, or pineapple 1 tbsp. lemon juice

Combine fruit juice and water, Minute tapioca, sugar, and salt in a sauce pan and mix well. Bring mixture to a boil, stirring constantly. Remove from fire. Do not overcook.,Cool, stirring occasionally. Mixture thickens as it cools. Soy-potato Muffins or Bread 1 cup soy flour 1 cup potato starch flour 1 tsp. salt 1 U cup soy oil

3 tbsp. baking powder 2 tbsp. white sugar IVs cups water

Measure flours lightly to 1 cup level in measuring cup. Sift dry ingredients once. Add water and beat 3 minutes. Add oil and beat one minute longer. Grease baking pan well with soy oil. Preheat oven to 350° F. Bake at 350° F for 10 minutes. Reduce

APPENDIX A: ELIMINATION DIETS 135

heat to 285° or 300° F and continue baking for 1 hr. 20 min. Bake muffins at 300-325° F for 25 to 30 mins. Makes 12 muffins. For pancakes or waffles, thin this batter with 1U cup of water. Soy-potato Cup Cakes or Cake 1 cup soy flour 3 /4 cup potato starch 3 tbsp. baking powder 3 /4 cup sugar 1 /2 tsp. salt

l

/4 cup soy oil 3 tsp. vanilla or 2 tsp. vanilla and 1 tsp. lemon extract 1 small cup water

Sift soy flour once before measuring. Sift well together all the dry ingredients. Add water to sifted dry ingredients. Mix well. Add oil and vanilla and beat for 2 minutes. Pour into muffin or layer cake pans well greased with soy oil and bake at 350° F for 30 minutes. Makes 12 cup cakes or 2 small layers. Or bake in a loaf pan for ll/2 hours at 300° F. Variations Flavour with lemon extract and grated lemon rind or with maple flavouring. Add chopped apricots, prunes, or pineapple. Substitute fruit juice for water. Use fondant slightly thinned with water or fruit juice for frosting. Lima Bean or Split Pea Soup 1 cup split peas or lima beans 2 tbsp. bacon fat Diced bacon, crisp

1 qt. water salt

Cook the split peas or lima beans and salt until it forms a smooth purée. Before serving add the fat and crisp fried bacon. Tomato Soup (with Soy Bean Flour) 1 cup strained tomatoes or juice 1 cup water

2 tbsp. soy bean flour 1 tsp. salt

Mix the soy bean flour thoroughly with some of the water and add to the hot tomato juice and water. Boil for 1/2 hour. This resembles a cream soup in consistency and flavour. Soy Ice Cream 2 cups soy milk (e.g. Mullsoy) l /4 cup white sugar 2 tbsp. brown sugar

2 tsp. gelatin 1 tbsp. potato starch 2 tsp. vanilla or lemon extract

Dissolve the gelatin in a little cold water. Bring to a boil the soy milk and sugar. Mix the potato starch in 1U cup cold water and add to the milk. Cook for 5 minutes. Remove from the flame and add the dissolved gelatin and flavouring. Cool and freeze in a mechanical freezer or refrigerator. If made in the refrigerator, remove

136 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

from the trays after it freezes and beat well. Refreeze. Serve with caramel sauce. Fruit or fruit juice may be added if it is in the diet. Fondant 2 cups sugar l /4 tsp. cream of tartar 1 cup boiling water

i/4 tsp. salt V2 tsp. vanilla

Measure sugar and cream of tartar into a sauce pan and add the boiling water. Stir over a low heat until sugar is dissolved. Do not let the candy boil until the sugar is dissolved and the sugar crystals wiped down from the sides of the pan with a clean cloth. When the boiling point is reached, cover the kettle and boil vigorously for 5 minutes. Remove the cover, wipe off the crystals from the sides of the pan and continue cooking without stirring until the medium ball stage has been reached (240 to 242° F). When done, pour the candy at once into a cold wet platter and let it stand until luke warm. Sprinkle salt over the surface, add vanilla and beat until white. Knead in the hands until smooth and creamy. Put fondant into a glass jar and cover. It will keep several weeks in a cool place. Use of fondant Put a portion of the fondant into the top part of a double boiler. Melt over hot, but not boiling, water until fondant softens. Colouring or flavouring is added at this stage. Lemon extract or lemon juice and grated lemon rind, chopped prunes or glaced pineapple may be used. Drop fondant from tip of a spoon onto waxed paper. Panocha 2 tbsp. sesame or soy oil 2 cups brown sugar 1 cup white sugar

1 cup water Vs tsp. baking soda

Heat the oil in a kettle, stir in sugars. Add water and soda and mix well with sugar. Wipe down sugar from sides of pan. Heat slowly to a boiling point, stirring until sugar is dissolved. Boil to 240° F, the medium ball stage (the ball holds its shape when lifted from cold water). Remove from stove, sprinkle a dash of salt over top, and set aside to cool undisturbed until lukewarm. Beat until creamy. Turn into greased pans and cut in shape of squares. Marshmallows 2 cups sugar 3 /4 cup water 2 tbsp. gelatin

Vz tsp. salt 1 tsp. vanilla extract

Mix sugar and water and boil until the soft ball stage has been reached (234 to 238° F). Remove from the fire. Soften the gelatin in l/2 cup of cold water. Pour the hot syrup over the softened gelatin and stir until dissolved. Let it partially cool, add

APPENDIX A: E L I M I N A T I O N DIETS 137

vanilla and salt and beat it until the mixture is thick and white and will hold its shape. Pour into straight sided pans. When firm, cut into squares. Roll in sugar. CEREAL-FREE, AND FRUIT-FREE E L I M I N A T I O N DIET (ROWE) (liquid, soft, puréed or minced)

1. Tapioca cooked with white sugar and with or without soy bean milk (Sobee or Mullsoy powder made up in the proportion of 1 tablespoon to 2 oz. of water) or with maple syrup or caramel flavouring 2. Soy-potato starch pudding flavoured with vanilla or caramel 3. White or sweet potato - boiled, baked, or riced, served with sesame or soy bean oil and salt 4. Lamb chops, roast, or tongue, minced or ground at first, cooked with salt but without butter or seasoning 5. Lamb "milk" 6. Soy bean purée - best made from canned cooked beans or from cooked soy bean flour (split pea purée may also be used) 7. Carrots, beets, peas, squash, artichokes (fresh cooked or canned), strained or puréed. Salt, soy bean or sesame oil may be added, but no butter or other ingredients 8. Breads made of soy, lima, potato, or tapioca flour. Maple syrup may be used in place of butter 9. Mullsoy or Sobee (1 tablespoon powder to 2 ozs. water) as a beverage 10. Salt 11. Beet or cane sugar Note that Poly-Vi-Sol 0.3 cc daily must be given, also Sandoz calcium syrup, 1 tablespoon daily. Note that this diet should be continued for 4 weeks. With improvement the liquid, puréed and minced diet may be replaced gradually with soft or regularly cooked foods. Additional foods may then be added, one every 7 days (under your physician's direction). The following may be tried: beef, bacon, rice, corn, spinach, asparagus, string beans, pears, peach, apricot, and grapefruit.

138 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

Caramel Flavouring Cook sugar until it turns golden brown. When cool, add just enough water to dissolve the hard caramel. The resulting liquid may be kept in ajar and used at will for flavouring and colouring. Soy-potato Pudding 4 level tbsp. soy flour 1 cup water 2 tsp. potato starch flour

3 tbsp. sugar l /4 tsp. salt Vz tsp. vanilla extract

Cook the soy flour and water for 15 minutes in top of double boiler. Stir potato starch, sugar and salt into boiling mixture until it thickens. Continue cooking for 20 minutes. Flavour with vanilla extract or with maple or caramel. May serve with maple or caramel syrup if desired. More sugar may be desired or a combination of white and brown sugar may be used. Note that if potato starch flour is not available, I1 ¡2 tbsp. of granulated tapioca may be used. Lamb "Milk" Strained lamb Oil (use one of soy bean or sesame) Ordinary table sugar Flour or starch (use one of potato or tapioca) Calcium carbonate (prescription not necessary, get 4 oz. from your druggist) Ordinary table salt Water

1 cup (8 oz.) 3 Va tablespoons 22/3 tablespoons 2 tablespoons 1 teaspoon Vz teaspoon 4 cups (32 oz.)

All measurements are level, using standard measuring cups and spoons. Heat water in the top of a double boiler until the water in the outer boiler starts boiling. Add the salt, sugar, and calcium carbonate. Mix the starch to a paste in one third cup of cold water and stir into the water in the top of the double boiler. Cook mixture for ten minutes in the top of the double boiler, stirring constantly to prevent lumping. Then add the strained meat and oil and make up to approximately 4 /s quart, if the total volume is less, make up with boiled water, mix thoroughly and cook for ten minutes longer, bottle and use as formula. Soy-potato Muffins or Bread I cup soy flour 1 cup potato starch flour 1 tsp. salt ! /2 cup soy oil

2 tbsp. baking powder 1 tbsp. white sugar 1 tbsp. brown sugar 3 /4 to 1 cup water

Sift the soy flour once before measuring. Fill the measuring cup lightly and level off the surface with a knife blade. Sift all the dry ingredients together four times.

APPENDIX A: ELIMINATION DIETS 139

Add the oil and water and beat well. Pour the batter into muffin pans which are well greased with soy oil. Bake in a moderate oven (350° to 375° F) for 25 to 30 minutes. Makes 12 muffins. For bread, bake in a loaf pan at 350° F for 1 1 /4 hours. If a moister texture is desired, decrease the potato starch flour to 3/4 cup. Soy-lima-potato Muffins or Bread 1 cup potato starch flour 3 /4 cup soy bean flour ! /4 cup lima bean flour l /2 cup sesame or soy oil

2 tbsp. sugar 1 cup water 6 tsp. baking powder J /2 tsp. salt

Sift flour, baking powder, and salt together three times. Blend the oil and sugar well. Add the sifted flour and the water alternately to the oil and sugar. Beat well and pour into muffin pans which have been well greased with sesame or soy oil. Bake at 375° F for 25 to 30 minutes. Makes 12 muffins. Or bake in a loaf pan at 350° to 375° F for 1V4 hours. Soy-potato Cup Cakes or Cake l 1 cup soy flour /2 tsp. salt 3 /4 cup potato starch flour Vz cup soy oil 5 tsp. baking powder 2 tsp. vanilla 3 /4 cup sugar or 1U cup brown and Vz to 2/3 cup water l /2 cup white sugar Sift soy flour once before measuring. Sift together all the dry ingredients four times. Mix the oil, sugar, and flavouring and to this add the flour and water alternately, beginning and ending with flour. Beat well. Pour into muffin or layer cake pans well greased with soy oil and bake at 375° F for 30 minutes. Makes 12 cup cakes or 2 small layers. Or bake in a loaf pan for 45 to 50 minutes. Soy-potato Cookies Follow the recipe for soy-potato cake. Decrease the water to make a stiff dough. Force through a cookie press onto a cookie sheet well greased with soy oil. Or a thinner batter can be dropped from a teaspoon onto a greased cookie sheet. Bake at 375° to 400° F for 10 or 15 minutes. A thicker dough can be rolled and kept in a refrigerator. Cut into thin slices and bake as desired. If kept in an air-tight container, cookies will remain crisp. Soy Cookies 1 cup soy flour 2 tsp. baking powder ! /4 tsp. salt l /3 cup sugar

4 tbsp. soy oil 3 to 5 tbsp. water ! /2 tsp. vanilla

140 PAEDIATRIC A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Mix oil and sugar and add the flavouring. Sift soy flour once before measuring and sift twice more after adding baking powder and salt. Add flour to oil and sugar and sufficient water to make a stiff dough. Form into a roll and cut into cookies or force through a cookie press. With a softer dough, drop from a teaspoon onto a cookie sheet well greased with soy oil. Bake at 350° F for 15 minutes. Chopped prunes or apricots may be added or fruit juice may be substituted for water. Cookies will remain crisp if stored in an air-tight container.

Appendix B: Immunological deficiency diseases

Since many atopic patients first present as recurrent respiratory infections, this interesting though rare group of diseases is important in the differential diagnosis. To understand these diseases, the physician must have a knowledge of the immunoglobulins responsible for humoral immunity; the thymus which is so important in the development of cellular immunity; and the development of the immune response. A diagram of the development of the immune response is shown in Figure 4.

Figure 4 The development of immune responses

THE IMMUNOGLOBULINS

To date, five immunoglobulins have been described, IgG, IgA, IgM, IgD, and IgE (see p. 92). Each of these is made up of two light chains of amino acids (common

142 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

to all the five immunoglobulins) and two heavy chains of amino acids each peculiar to its own immunoglobulin (see Fig. 3, p. 93). IgG and IgM contain the important humoral antibodies protective against bacterial and viral diseases. IgA is important for local immunity in external secretions, such as saliva, and in the tracheobronchial tree and intestinal tracts. IgE contains the antibodies important for atopic disease. To date some antibody activity has been demonstrated for IgD. A defect in pathway B leads to defects in producing some or all of IgG, IgA and IgM (Fig. 4). THE THYMUS

The thymus, located in the chest, undergoes rapid growth in embryonic life. It is the first organ to become lymphoid. It reaches its maximum relative size in the neonatal period (average 11 gm). Growth continues throughout childhood and the maximum absolute size is reached about the twelfth year (average 35 gm). Growth ceases in early adolescence and involution begins. In old age the thymus is smaller than at birth. The thymus is an important site of production of lymphocytes. There is no proof that they ever leave the thymus but they probably do. Thymic cells, probably nonlymphoid (e.g., reticulum or epithelial), appear to regulate lymphopoiesis, both in the thymus and in other lymphoid organs. Foreign antigens appear to be the major proliferative stimuli for peripheral lymphopoiesis, but they have no observable effect on thymic lymphopoiesis. The thymus is extremely sensitive to ionizing radiations, cortisol, sex steroids, and starvation, while the peripheral lymphoid tissues are much less sensitive. THYMECTOMY IN N E O N A T A L LIFE

Thymectomy in the neonatal life of almost all animals produces a severe immunological cripple. Such an animal can accept any skin graft. In most animals, however, the immunoglobulins are perfectly normal and in fact, levels may be higher than normal. This is due to a break in pathway A, whereas pathway B remains normal (Fig. 4). The thymus in the chicken is easily removed experimentally because it is located in the neck. BURSA OF FABRICIUS

The bursa is a blind, ovoid, sac-like structure connected by a stalk to the posterior wall of the cloaca in the fowl. It plays a major role in the immune response of the young fowl. The thymus is similar to the bursa structurally and functionally; they resemble one another in their epithelial derivation, their lymphoid nature, their growth during embryonic and early postnatal life, and their early involution. In the chicken, antibody production of immunoglobulins is controlled by the

APPENDIX B: IMMUNOLOGICAL DEFICIENCY DISEASES 143

Bursa of Fabricius whereas cellular immunity is controlled by the thymus, pathways B and A respectively. The two cell populations differ morphologically. The cells derived from the Bursa of Fabricius have more RNA than do the thymusinfluenced cells and the RNA is organized into ribosomes differently. The thymusinfluenced cells are smaller. These two cell populations can be manipulated separately by removing the thymus or the bursa at birth, a If the Bursa of Fabricius is removed at 17-19 days embryonic life gamma M will be produced in the mature chicken, but not gamma G. b If the bursa is removed at birth, neither gamma G nor gamma M will be produced, c If the bursa is removed at one week of age, both gamma G and gamma M are produced but the production is deficient. If the chicken is irradiated and the bursa removed at birth, immunoglobulin is not formed because pathway B is interrupted. If the chicken is irradiated at birth and the thymus removed, immunoglobulin levels are normal because pathway B is intact, but the animal now cannot reject a homograft because pathway A has been broken. Furthermore, if the white blood cells of such a chicken are injected into another chicken, they will not produce a graft versus host reaction. Great variation appears in the chicken depending on the age at which the bursa is removed from the embryo. If the appendix, Peyer's patches, and related lymphoid tissue are extirpated in the rabbit, the immunoglobulin production is defective, suggesting that in the rabbit this lymphoid tissue is comparable to the Bursa of Fabricius in the chicken, and this may also apply to other mammals. Thus the patient may suffer from a defect anywhere in pathway A or in pathway B or in both. The complexity is demonstrated in Table IX and Figure 5, showing that a great many different immunological deficiency diseases are possible. This is further complicated by the fact that resistance to infection depends not only on the immunoglobulins (pathway B) and cellular immunity (pathway A) but also on the skin, mucous membranes, polymorphonuclear leucocytes, complement, and interferon. Thus, a patient who shows a defect in his resistance to infection must be examined from all these points of view.

Figure 5 Taken from Clinical Aspects of Immunology (Fig. 19.8) by P.G. Gell and R.R.A. Coombs (eds.). Oxford and Edinburgh: Blackwell Scientific Publications, 1968, with the kind permission of the publisher. A functional or syndrome classification of the immunity deficiency states, based on the current con­ cept of the duality of specific immunity. Examples of non-specific mechanisms are indicated, but defects are not included. All patients with defects of specific immune mechanisms, whatever the structural or aetiological type, can be classified into defect syndromes, defect groups (according to quantitative or Figure 5 See facing page mechanism), for caption and defect class. There is reason to believe that most, if not qualitative defects of each all, of the eleven parameters (numbered in the figure) on which the defect classes are defined vary inde­ pendently in these patients, providing 11—4 x 10 combinations. 7

APPENDIX B: I M M U N O L O G I C A L DEFICIENCY DISEASES 145 TABLE IX* Deficiency states of specific immunity Deficient mechanism Humoral immunity

Possible basic defect Gastrointestinal lymphoid tissue deficiency, or disturbance or loss of function, etc.

2. Cellular immunity deficiency syndrome

Cellular immunity

Thymus dependent lymphoid tissue deficiency or disturbance of function

Isolated thymus dysplasia

3. 1 and 2

land 2

Perhaps 1 and 2 Perhaps a more profound thymus deficiency

Lymphopenic hypogammaglobulinaemia Ataxia telangiectasia

4. 1 and 2 and neutropenia

All reticular structures

Reticular dysgenesis

Reticular dysgenesis

Syndrome 1. Antibody deficiency syndrome

Example diseases Hypogammaglobulinaemia in boys Dysgammaglobulinaemia Nephrotic syndrome

* From Clinical Aspects of Immunology, P.O. Gell, and R.R.A. Coombs (eds.), Oxford: Blackwell Scientific Publications, 1968 Note that the first syndrome is characterized by a predominance of bacterial infections at multiple sites but not abnormal susceptibility to virus disease. The immunoglobulins are deficient. The second syndrome presents as a deficieny of cellular immunity often appearing as a delayed type allergy with recurrent or progressive viral or monilial infections. Immunoglobulin concentrations are normal. The incidence of bacterial infections is normal. Lymphopenia is present. The third syndrome is a combination of the first two - hypogammaglobulinaemia plus the cellular immunity deficiency syndrome. This combined syndrome is commoner than the isolated cellular defect (second syndrome). These patients have an abnormal susceptibility to bacterial, viral, and Candida infections. It usually begins early in life and is rapidly fatal. These three syndromes frequently overlap. In the fourth syndrome (very rare) a severe form of combined (humoral and cellular) immunity deficiency plus gross neutropenia, aplastic anaemia, and thrombocytopenia occurs. Infections start early in life and are rapidly fatal.

146 PAEDIATRIC ALLERGY AND C L I N I C A L IMMUNOLOGY

ANTIBODY DEFICIENCY SYNDROMES These are classified in Table X. DEFINITIONS

Agammaglobulinaemia: Less than 100 mg gamma globulin per 100 ml serum Hypogammaglobulinaemia: Gamma globulin is deficient but greater than 100 mg per 100 ml serum Dysgammaglobulinaemia: A deficiency of one or more immunoglobulins, G, M or A, the others being quantitatively normal For example: IgG IgA IgM

Agammaglobulinaemia Dysgammaglobulinaemia Dysgammaglobulinaemia Dysgammaglobulinaemia Dysgammaglobulinaemia Dysgammaglobulinaemia Dysgammaglobulinaemia

1 2 3 4 5 6

+ .+ +

+ + + -

- (e.g., Bruton's disease) + + - (e.g., Wiskott-Aldrich syndrome) — + (e.g., normal or ataxia telangiectasia)

However the normalcy of the total quantity of any immunoglobulin does not indicate that a disease is not present, since each of the immunoglobulins has subclasses which may not be present in normal amounts. IgG

IgG1 (2b We)

IgA IgM

At least two subclasses At least five subclasses

IgG2 (2aNe) IgG3 (2cVi) IgG4 (2dGe)

78% of total 13% of total 6% of total 3% of total

IgG IgG IgG IgG

Diseases associated with deficiencies in subclasses have not been well classified. E X A M P L E S OF S Y N D R O M E S W H I C H HAVE B E E N D E S C R I B E D

1. Bruton's congenital sex-linked agammaglobulinaemia Bruton's agammaglobulinaemia is a defect in the antibody-producing cells occurring only in males. Symptoms appear at 5 to 6 months and result in early death. These patients lack plasma cells and the germinal follicles are absent. The tonsils and adenoids are also absent. The thymus is normal morphologically. Although the response may be feeble, these patients always have the ability to reject a homograft since only pathway B is destroyed.

APPENDIX B: IMMUNOLOGICAL DEFICIENCY DISEASES 147 TABLE X* Classification of diseases associated with deficieny of immunological mechanism and lack oTcirculating antibodies I.

Agammaglobulinaemia-hypogammaglobulinaemia 1. Congenital sex-linked recessive 2. Congenital sporadic (non sex-linked recessive) 3. Adult (acquired) primary hypogammaglobulinaemia associated with deficiencies of other immunoglobulins 4. Adult (acquired) hypogammaglobulinaemia secondary to blood dyscrasia 5. Acquired agammaglobulinaemia associated with increased concentration of other immunoglobulins 6. Transient hypogammaglobulinaemia in infancy

II. Hypogammaglobulinaemia associated with generalized hypoproteinaemia 1. Primary failure of protein fabrication 2. Nephrotic syndrome or nephrosis 3. Starvation, malnutrition, and vitamin deficiency 4. Severe burns, weeping skin diseases with extensive protein loss 5. Generalized hypoproteinaemia secondary to protein loss into the gut (a) Primary exudative enteropathy (b) Exudative enteropathy associated with heart disease (c) Exudative enteropathy associated with inflammatory disease of the intestine III. Dysgammaglobulinaemia IV. Specific immunologie unresponsiveness or tolerance 1. Immunologie paralysis, immunologie tolerance, and protein overloading (a) Intentionally produced in man with homologous cells (b) Occurring with response to early or overwhelming infection * R.A. Good, W.D. Kelly, J. Rôtstein, and R.L. Vareo, 1962, p. 187

2. Swiss-type agammaglobulinaemia Serious infections begin in the first week of life. Both sexes are affected because of an autosomal recessive inheritance. Patients with this syndrome show a defect in both the antibody-producing cells and in the thymus-influenced cells and are subject to overwhelming virus infections such as vaccinatum gangrenosum. Delayed hypersensitivity, homograft rejection and antibody synthesis are absent because in such a patient both pathways A and B are interrupted, that is, the defect exists at the lymphoid stem cell stage. Attempts to cure these patients by thymus graft are ineffective because only pathway A can be restored. If these patients are injected with peripheral lymphoid cells from an immunologically competent donor they can be restored to normal since they can now reject a graft and can respond to antigens with manufacture of immunoglobulin. However such patients will die as a result of a graft versus host reaction. Theoretically, if such a patient could be given matched lymphocytes completely compatible with the recipient one might be able to restore this individual to normal since the graft versus host reaction would not occur.

148 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

3. Myeloma This is a plasma cell disease having no defect in the cell-mediated immunity because pathway A is not affected. (In chronic lymphatic leukaemia, however, a defect is present in both types of immunity because the disease is produced at the stem cell level, thus interrupting both pathways A and B.) 4. DiGeorge's syndrome In this syndrome the third and fourth pharyngeal pouches, where the thymus normally begins to grow at the sixth embryonic week, fail to develop. Thus the thymus is absent (thymic aplasia) or rudimentary; the parathyroids are absent. These patients do have normal immunoglobulins and plasma cells but, lacking a thymus, they have a defect in route A. They can be cured by transplanting embryonic thymus. 5. Pure thymic alymphoplasia This is another example of a defect in route A. The thymus is aplastic as in Swiss-type agammaglobulinaemia. 6. Wiskott-Aldrich syndrome In this sex-linked recessive syndrome, the patient is deficient in antibody and has eczema characteristic of atopic dermatitis, thrombocytopenia, and increased susceptibility to infection causing death in infancy. It occurs only in males. Serum IgA and IgG are usually normal. Serum IgM is usually deficient. Function of the thymus-dependent system of lymphocytes is deficient. The patients have lymphopenia and in some of them IgA and IgE have both been elevated. 7. Dysgammaglobulinaemia with nodular lymphoid hyperplasia of the intestine (Heremans) These patients lack IgA and IgM and have moderate depression of IgG and a sprue-like syndrome. 8. Ataxia telangiectasia This is another form of combined defect of cellular and humoral immunity, consisting of progressive disturbance of cerebellar function, dementia, telangiectasia of the conjunctiva and the area around the eyes, and abnormal susceptibility to infection. IgA levels are usually well below normal.IgG may be low or normal but the serum IgM is usually normal. It is inherited as an autosomal recessive. REFERENCES Claman, H.N., Hartley, T.F., and Merrill, D. Hypogammaglobulinaemia, primary and secondary: Immunoglobulin levels (gamma G, gamma A, gamma M) in one hundred and twenty-five patients. J. Allerg., 38: 215, 1966 Collins-Williams, C., Tkachyk, S.J., Toft, B., and Moscarello, M. Quantitative immunoglobulin levels (IgG, IgA and IgM) in children. Int. Arch. Allerg., 31: 94, 1967 Collins-Williams, C., Toft, B., Generoso, L., and Moscarello, M. Quantitative immunoglobulin levels (IgG, IgA and IgM) in children, determined by the Hyland immunoplate technique. Cañad. Med. Assoc. J. 96: 1510, 1967 Collins-Williams, C., Lamenza, C., and Kokubu, H. Deficiency of IgA in serum and respiratory secretions. Cañad. Med. Assoc. J. 99: 1069, 1968

A P P E N D I X B: I M M U N O L O G I C A L D E F I C I E N C Y DISEASES 149

Collins-Williams, C., Lamenza, C., and Nizami, R. Immunoglobulin IgA. A review of the literature. Ann. Allerg., 27: 225, 1969 Good, R.A., Kelly, W.D., Rôtstein, J., and Vareo, R.L. Immunological Deficiency Diseases. In: P. Kallos and B.H. Waksman (eds.), Progress in Allergy, VI, p. 187. Basel: S. Karger, 1962 Janeway, C.A. Progress in immunology. Syndromes of diminished resistance to infection. J. Pediat., 72: 885, 1968 Miller, M. E., and Hummeler, K. Thymic dysplasia ("Swiss Agammaglobulinemia"). II. Morphologic and functional observations. J. Pediat., 70: 737, 1967 Rosen, F.S., and Janeway, C.A. The gamma globulins. III. The antibody deficiency syndromes. New Eng. J. Med., 275: 709, 769, 1966 Sell, S. Immunological deficiency diseases. Arch. Path., 86: 95, 1968 Soothill, J.F. Immunity Deficiency States. In: P.O. Gell and R.R.A. Coombs (eds.), Clinical Aspects of Immunology, 2nd ed. Oxford: Blackwell Scientific Publications, 1968

Appendix C: Beta adrenergic blockade - Cyclic 3'5' AMP*

Many drugs are used to treat asthma. The important sympathomimetic drugs other than epinephrine are isoproterenol - known as isoprenaline or Isuprel - and metaproterenol, known as orciprenaline or Alupent. Disodium cromoglycate is known as Intal. Xanthines, steroids, and diethylcarbamazine or Hetrazan are also used. To understand the reason for this vast array of drugs a description of the action of Cyclic 3'5' AMP and beta adrenergic blockade is necessary (Fig. 6).

Figure 6 Formation of cyclic 3'5' AMP by adenyl cyclase

Cyclic 3'5' AMP (adenosine 3'5' monophosphate) is an enzyme mediating the action of a number of hormones and regulating the release of most, if not all, of the others (Frick 1969; Sutherland 1970; Szentivanyi 1968). It is formed by the action of adenyl cyclase on adenosine triphosphate. The beta adrenergic receptor is the functional subunit of adenyl cyclase present in all mammalian tissues except the non-nucleated erythrocyte. As a general rule, adenyl cyclase in any given tissue is acted on by hormones affecting that tissue. In almost all tissues studied the enzyme has been associated with cell membranes. Its role here will be described only in relation to asthma in the human. The key to all figures is shown in Figure 7. The beta adrenergic receptor, the functional subunit of adenyl cyclase, enhances * Rationale of recent advances in drug therapy in the treatment of asthma

APPENDIX C: BETA ADRENERGIC BLOCKADE 151

the breakdown of adenosine triphosphate (ATP) to Cyclic 3'5' AMP which then follows the normal pathway to Cyclic 5' AMP. Cyclic 3'5' AMP acts by causing many changes within the cell (Fig. 8). The change most important to the asthma patient is the relaxation of smooth muscle in the bronchioles. Phosphodiesterase, a naturally occurring enzyme, enhances the breakdown of Cyclic 3'5' AMP. Adenyl cyclase is important in relation to the alpha and beta adrenergic receptors which when stimulated cause opposite effects, the beta adrenergic receptors tending to produce bronchodilation and the alpha adrenergic receptors bronchoconstriction. The balance between these two systems is delicate. According to the beta adrenergic blockade theory, the basic defect in asthmatics is a deficiency, malfunction, or blockade of the beta adrenergic receptor.

Figure 7 Symbols used in subsequent figures to represent the various stimuli, pathways, and effects

Now let us consider the pathophysiology of Cyclic 3'5' AMP (Fig. 9). The usual pathway for antigen-antibody reactions causing asthma is stimulation of the release of histamine and slow reacting substance of anaphylaxis (SRS-A) particularly which produce smooth muscle contraction, an effect opposite to that exerted by the beta adrenergic receptor. Cyclic 3'5' AMP itself inhibits the release of histamine and SRS-A (Orange et al. 1971) and in addition causes smooth muscle relaxation in the bronchi. At the same time emotional upsets, exercise, cold air, and other non-specific stimuli are known to bring on wheezing in asthmatics. These stimuli are considered to act because of beta adrenergic blockade with loss of stimuli normally producing smooth muscle relaxation in the bronchi. Now, with this background, let us examine the drugs used in the treatment of asthma (Fig. 10). The corticosteroids in addition to their other pharmacological effects enhance the action of naturally occurring epinephrine. Epinephrine is a potent stimulant to the beta adrenergic receptors and therefore enhances the formation of Cyclic 3'5' AMP. Isoproterenol also is a potent stimulator of beta adrenergic receptors. Theophylline increases the concentration of Cyclic 3'5' AMP, by inhibiting phosphodiesterase which enhances the breakdown of Cyclic 3'5' AMP to the inactive Cyclic

152 PAEDIATRIC ALLERGY AND C L I N I C A L I M M U N O L O G Y

Figure 8 Normal physiology of cyclic 3'5' AMP

5' AMP (Orange and Austin 1971). For this reason, theophylline has a synergistic effect with both isoproterenol and epinephrine. In other words, if theophylline is given with either isoproterenol or epinephrine, the combined effect is greater than the sum of their separate effects. Disodium cromoglycate (Intal) acts at an entirely different site, preventing the release of histamine and SRS-A following an antigen-antibody reaction (Orr 1970). Diethylcarbamazine (Hetrazan), another drug which has been advocated for the treatment of asthma, may act similarly (Orange and Austin 1967; 1971). While epinephrine or isoproterenol may be given in an emergency, for continuing

Figure 9 Pathophysiology of cyclic 3'5' AMP

APPENDIX C: BETA ADRENERGIC BLOCKADE 153

Figure 10 Drugs used in the treatment of asthma

control theophylline compounds should be added for their synergistic effect. Disodium cromoglycate also may be used in addition to epinephrine, theophylline, and the corticosteroids because it acts at a different site. On the other hand, experimental work on animals suggests that disodium cromoglycate is anti-synergistic with isoproterenol, so that the two drugs used together may have an effect less than the sum of their effects used singly (Orange: personal communication). An asthmatic may overuse isoproterenol. In proper doses it stimulates the beta adrenergic receptors producing broncho relaxation (Fig. 11). In excess the breakdown product of isoproterenol, 3-methoxyisoproterenol, inhibits the beta adrenergic receptors producing broncho-constriction. In short, the medication given to help the patient may ultimately make him worse (Collins-Williams et al. 1969). Epinephrine stimulates the alpha adrçnergic receptor but to a lesser degree than the beta adrenergic receptor. Norepinephrine stimulates the alpha adrenergic receptor only and, given to an asthmatic would make his attack more severe (Goodman and Oilman 1970). Two other drugs are indicated, propranolol, a betaadrenergic blocking agent, which inhibits the effects of epinephrine and isoproterenol on beta adrenergic stimulation, and phenoxybenzamine, an alphaadrenergic blocking agent, which inhibits the action of epinephrine and norepinephrine on alpha adrenergic receptors (Goodman and Oilman 1970). To treat asthmatics logically with the new drugs available the physician must understand the action of these two types of blocking agents. At this point, let us look more closely at each of the drugs used in the treatment of asthma. Epinephrine stimulates the beta adrenergic receptors powerfully, increasing the vital capacity and decreasing the residual air in the lungs. But

154 P A E D I A T R I C A L L E R G Y AND C L I N I C A L I M M U N O L O G Y

Figure \ \ Additional drugs acting on the beta adrenergic receptor

although the airway obstruction is relieved, the lowered PAUZ generally remains static indicating that the ventilation-perfusion disturbance is unconnected. The relief given by this drug is largely due to the action on the beta receptor resulting in relaxed bronchial smooth muscle, but is also partly due to stimulation of the alpha receptor producing constriction of the bronchial mucosal vessels which reduces congestion and oedema (Goodman and Oilman 1970). Later on in the attack, the action of the epinephrine in reducing the bronchial secretion may adversely affect the patient's condition because the mucous plugs become viscid and difficult to dislodge. Isoproterenol has practically no effect on the alpha receptor (Goodman and Oilman 1970), but unfortunately for the asthmatic, by acting on the beta receptor it acts on the heart muscle as well as on the smooth muscle of the bronchi. So while the drug makes the patient feel better because the bronchial muscles relax, it does not raise the low PAUZ and in many instances may even depress it. Alveolar ventilation is increased but the lack of improvement in PAUZ indicates the increased ventilation must be going to alveoli already overventilated relative to bloodflow. For this same reason the PACCh may fall (Palmer and Diament 1967; Gazioglu et al. 1969; 1971) and were it the only measurement made the physician may be misled. Other hazards are associated with the use of isoproterenol. Cardiac arrhythmia is a frequent side effect of isoproterenol. In animals large repeated doses may lead to myocardial necrosis or to cardiac arrest following exertion (Goodman and Oilman 1970). Serious arrhythmias occasionally occur in asthmatics. Also, overuse of isoproterenol may irritate the air passages and induce intractable asthma (Van Metre 1969; Reisman 1970). The great increase in mortality from asthma in the early 1960s has been attributed to the overuse of isoproterenol. With the recognition of

APPENDIX C: BETA ADRENERGIC BLOCKADE 155

this association, use of the drug has declined and so has the mortality rate (CollinsWilliams et al. 1969). Epinephrine with isoproterenol makes cardiac arrhythmia or cardiac arrest even more likely. So, it is unsafe to use these drugs within an hour of each other, particularly if isoproterenol has been used in excess or the attack is so severe that the patient is anoxic (Collins-Williams et al. 1969). Metaproterenol, also a powerful bronchodilator because it stimulates the beta adrenergic receptor, has less effect on the heart. It is used in much larger doses than isoproterenol and it is more stable in the body and therefore can be given by mouth. When inhaled, metaproterenol acts promptly and is as efficient as isoproterenol. Its effect lasts up to 6 hours (Chervinsky and Belinkoff 1969). Theophylline has been used for many years and shows a remarkable ability to relax the smooth muscle of the bronchi, especially if the bronchi have been constricted as in an asthmatic attack (Goodman and Oilman 1970). Aminophylline, which is 85% theophylline and 15% ethylenediamine, is one of the most effective bronchodilating agents known. Since its route of action differs from that of epinephrine and isoproterenol and it is synergistic with each it can be used with them. The corticosteroids, of great value in the treatment of an acute asthmatic episode, act by enhancing the effect of naturally occurring epinephrine to stimulate the beta adrenergic receptor. However, the side effects and disadvantages of using steroids for long-term therapy are well known. Disodium cromoglycate acts at the mast cell membrane to uncouple the histamine release process from the antigen-antibody trigger mechanism. It prevents the release of histamine and SRS-A following an antigen-antibody reaction. Since disodium cromoglycate has a different site of action from the other drugs listed it can be used in conjunction with them, although it may be slightly antisynergistic with isoproterenol. Diethylcarbamazine or Hetrazan advocated for treating filariasis was found to benefit asthmatics during an attack (Malien 1965). Other observers disagree (Benner and Lowell 1970). Experimentally the drug inhibits the antigen-induced release of histamine and SRS-A from human lung sensitized with atopic serum and is synergistic with epinephrine and isoproterenol (Orange et al. 1971; Ishizaka et al. 1971). Phenylephrine, a powerful alpha receptor stimulant with little effect on the beta receptors of the heart has been added to isoproterenol aerosol. Because phenylephrine slows the heart, decreases cardiac output and increases total peripheral resistance, it is reported to enhance bronchodilator response with few side actions on the heart (Maeda et al. 1971). There are two additional drugs suggested but not yet available for the treatment of asthma. They have interesting therapeutic possibilities based on the division of the beta receptor into the beta 1 and beta 2 receptors (Lands et al. 1967) (Fig. 12). The first drug is practolol which might take the place of propranolol in the Cyclic 3'5' AMP figures because it is a beta adrenergic receptor blocking drug. However, unlike propranolol, it is predominantly cardioselective and only about 1/150 as active in antagonizing the epinephrine-induced relaxation of isolated guinea pig

156 PAEDIATRIC ALLERGY AND CLINICAL IMMUNOLOGY

Figure 12 The betai and betaz adrenergic receptors

trachéal rings (Grieco and Pierson 1971). Practolol might be a useful adjunct to bronchodilator therapy because it reduces the undesirable tachycardia and palpitation which follow the use of aerosol isoproterenol without hindering the beneficial action of the drug on the bronchi. In addition, practolol prevents the fall in PAUZ after isoproterenol administration, but does so without diminishing its bronchodilator action, a feature which can be extremely important in the severely ill patient with status asthmaticus. The second drug, salbutamol, appears to act primarily on the beta 2 receptor and therefore is a powerful bronchodilator with little action on the heart (Milner and Ingram 1971). For this reason salbutamol should be theoretically more effective than isoproterenol or metaproterenol. The prostaglandins, even though not a part of the Cyclic AMP story, because their action is not mediated through beta adrenergic stimulation, may become important in the treatment of asthma because they profoundly affect isolated human bronchial muscle. Prostaglandins Ei (PGEi) and £2 (PGEi) relax isolated bronchial muscle whereas prostaglandins F2«(PGF2a) contracts it (Collier 1971). In addition, PGEi and isoprenaline, when administered by aerosol to asthmatics, produce comparable results although the PGEi produces no change in blood pressure or pulse rate and has no effect on normal controls (Cuthbert 1969; 1971). An understanding of the alpha, beta 1 and beta 2 adrenergic receptors, Cyclic AMP and the theory of beta adrenergic blockade in asthmatics, has greatly increased our knowledge of asthma and given us an insight into the symptomatic treatment of this distressing disease. REFERENCES Benner, M., and Lowell, F.C. Failure of diethylcarbamazine citrate (Hetrazan) in the treatment of asthma. J. Allergy, 46: 29, 1970 Chervinsky, P., and Belinkoff, S. Comparison of metaproterenol and isoproterenol aerosols: Spirometric evaluation after two months' therapy. Ann. Allergy, 27: 611, 1969 Collier, H.OJ. Introduction to the actions of kinins and prostaglandins. Proc. R. Soc. Med., 64: 1, 1971 Collins-Williams, C., Nizami, R., and Lamenza, C. The use of isoproterenol in the treatment of the acute asthmatic attack with report of a case. J. Asthma Res., 7: 17, 1969 Cuthbert, M.F. Effect on airways resistance of prostaglandin Ei given by aerosol to healthy and asthmatic volunteers. Brit. Med. J., 4: 723, 1969 Cuthbert, M.F. Bronchodilator activity of aerosols of prostaglandins Ei and Ez in asthmatic subjects. Proc. R. Soc. Med., 64: 15, 1971 Frick, O.L. Mediators of atopic and anaphylactic reactions. Pediat. Clin. North Amer., 16: 95, 1969

APPENDIX C: BETA ADRENERGIC BLOCKADE 157 Gazioglu, K., Condemi, JJ. and Kaltreider, N. Response of blood gas tensions and diffusing capacity to isoproterenol in asthmatic subjects. J. Allergy, 43: 176, 1969 Gazioglu, K., Condemi, J.J., Hyde, R.W., and Kaltreider, N.L. Effect of isoproterenol on gas exchange during air and oxygen breathing in patients with asthma. Amer. J. Med. 50: 185, 1971 Goodman, L.S., and Gilman, A. The Pharmacological Basis of Therapeutics, 4th ed. Toronto: Collier-MacMillan, Canada Ltd., 1970 Grieco, M.H., and Pierson, R.N., Jr. Mechanism of bronchoconstriction due to beta adrenergic blockade: Studies with practolol, propranolol and atropine. J. Allergy, 48: 143, 1971 Ishizaka, T., Ishizaka, K., Orange, R.P., and Austen, K.F. Pharmacologie inhibition of the antigen-induced release of histamine and slow reacting substance of anaphylaxis (SRS-A) from monkey lung tissues mediated by human IgE. J. Immunol., 106: 1267, 1971 Lands, A.M., Arnold, A., McAuliff, J.P., Luduena, P.P., and Brown, T.G., Jr. Differentiation of receptor systems activated by sympathomimetic amines. Nature, 214: 597, 1967 Maeda, Y., Sawai, M., Ooka, Y., Inoue, T., Kajiura, A., Horiguchi, T., and Naruko, S. Phenylephrine added to an isoproterenol aerosol: A double-blind study in asthmatic patients. Ann. Allergy, 29: 475, 1971 Malien, M.S. Treatment of intractable asthma with diethylcarbamazine citrate. Ann. Allergy, 23: 534, 1965 Milner, A.D., and Ingram, D. Bronchodilator and cardiac effects of isoprenaline, orciprenaline and salbutamol aerosols in asthma. Arch. Dis. Child., 46: 502, 1971 Orange, R.P. Personal communication Orange, R.P., and Austen, K.F. Slow reacting substance of anaphylaxis. In: Advances in Immunology, vol. 10, F.J. Dixon, Jr. and H.G. Kunkel (eds.). New York: Academic Press, 1967 Orange, R.P., and Austen, K.F. Immunological release of the chemical mediators of anaphylaxis. In: Identification of Asthma. Ciba Foundation Study Group #38; R. Porter and J. Birch (eds.). Edinburgh: Churchill Livingstone, 1971 Orange, R.P., Austen, W.G., and Austen, K.F. Immunological release of histamine and slow-reacting substance of anaphylaxis from human lung. I. Modulation by agents influencing cellular levels of cyclic 3',5'-adenosine monophosphate. J. Exp. Med., 134: suppl. 136s-148s. 1971 Orr, T.S.C. Disodium cromoglycate. Proceedings of the 7th International Congress of Allergology, Florence, 17 October, 1970 Palmer, K.N.V., and Diament, M.L. Effect of aerosol isoprenaline on blood-gas tensions in severe bronchial asthma. Lancet, 2: 1232, 1967 Reisman, R.E. Asthma induced by adrenergic aerosols. J. Allergy, 46: 162, 1970 Sutherland, E.W. On the biological role of cyclic AMP. J.A.M.A., 214: 1281, 1970 Szentivanyi, A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy, 42: 203, 1968 Van Metre, T.E., Jr. Adverse effects of inhalation of excessive amounts of nebulized isoproterenol in status asthmaticus. J. Allergy, 43: 101, 1969

Appendix D: Pathophysiology of asthma DR H. LEVISON*

The basic functional disturbance in asthma is bronchospasm which interferes with the movement of air in and out of the lungs and requires much greater force for a given ventilatory volume. Both the elastic resistance and the flow resistance of the lung are greatly increased. As a result, the lungs are "suffer," that is, the pulmonary compliance is reduced. The mechanical resistance to airflow is increased so that the energy requirements for breathing rise. The physiological events which take place in an acute asthmatic attack can be shown schematically.

* Chief of Respiratory Physiology, Hospital for Sick Children, Toronto, Assistant Professor of Paediatrics, University of Toronto

APPENDIX D: PATHOPHYSIOLOGY OF ASTHMA 159 PULMONARY FUNCTION TESTS (Table XI) Symptom-Free Period

The abnormalities of pulmonary function in this period depend on the duration of the disease. Lung volumes The vital capacity and total lung capacity are usually normal; however, the functional residual capacity/total lung capacity ratio is usually increased indicating hyperinflation (Fig. 13). Timed vital capacities The expiratory flow rates are usually normal, however, the maximal mid-expiratory flow rates may be low indicating peripheral airway obstruction (Fig. 13). Airway resistance As measured in the body plethysmograph the airway resistance is usually normal. A number of patients who are asymptomatic, and who have no evidence of bronchospasm on physical examination often show gross abnormalities of pulmonary function.

Figure 13

160 P A E D I A T R I C ALLERGY AND C L I N I C A L I M M U N O L O G Y

Arterial blood gases In our laboratory 50% of asymptomatic asthmatics have lower than normal arterial oxygen tension levels; arterial carbon dioxide tension is normal. During Asthmatic Attack Lung volumes The vital capacity and total lung capacity are decreased. The functional residual capacity and residual volume, and their ratios to total lung capacity are greatly increased. Hyperinflation of the lungs displaces the diaphragm caudally and its movement becomes less efficient. Overinflation of the lungs, within certain limits, puts the expiratory muscles in a better position to perform additional expiratory work and tends to increase the diameter of the airways (Fig. 13). Timed vital capacities All the measurements of expiratory flow (forced expiratory volume in one second (FEVi), maximal mid-expiratory flow rate (MMEF), are reduced. The maximal inspiratory flow rate (MMIF) is also reduced (Fig. 13). Airway resistance Airway resistance is greatly increased. Gas exchange At the beginning of an attack the arterial oxygen tension begins to fall; however, the arterial carbon dioxide tension may be low or normal, as the asthmatic attack gets worse. Hypoxaemia increases and the arterial carbon dioxide tension increases. The patient now has hypoxaemia and hypercapnia and respiratory acidosis. With the progressing hypoxaemia, other abnormalities of respiratory gas exchange are noted. There is an increase in physiological dead space, abnormalities in the regional distribution of ventilation and perfusion. This inequality of ventilation-perfusion ratios is manifested by increased alveolar-arterial gradiants for oxygen and carbon dioxide. The diffusing capacity during a severe attack of asthma is usually low, however, returning to within normal limits on recovery. This reduction in diffusing capacity is caused by a reduction in alveolar ventilation that TABLE XI Pulmonary functional changes in asthma in the symptom free state and during an attack

Vital capacity Residual volume Functional residual capacity Total lung capacity Maximum mid-expiratory flow rate Forced expiratory volume 1 second Airway resistance Arterial oxygen tension Arterial carbon dioxide tension

Symptom free

Acute attack

N Î Î N Nor j N N N N

i Î Î Nor i 1 1 1 1 4 early fíate

APPENDIX D: PATHOPHYSIOLOGY OF ASTHMA 161

occurs with bronchial obstruction. Cardiac function may be impaired by asthma. Hypoxaemia leads to an increase in pulmonary artery pressure and this in turn increases the work load on the right ventricle and induces heart failure. Heart failure, in turn, aggravates the impairment of gas exchange. RESPIRATORY SYMBOLS

VC MMIF MMEF FEVi 1C ERV FRC RV TLC

Vital capacity Maximal mid-inspiratory flow rate Maximal mid-expiratory flow rate Forced expiratory volume 1 second Inspiratory capacity Expiratory reserve volume Functional residual capacity Residual volume Total lung capacity

REFERENCES

Featherby, E.A., Weng, T.-R., and Le vison, H. Measurement of response to isoprenaline in asthmatic children. Arch. Dis. Child., 44: 382, 1969 Kamel, M., Weng, T.-R., Featherby, E.A., Jackman, W.S., and Le vison, H. Relationship of mechanics of ventilation to lung volumes in children and young adults. Scand. J. Resp. Dis., 50: 125, 1969 Weng, T.-R., and Levison, H. Standards of pulmonary function in children. Amer. Rev. Resp. Dis., 99: 879, 1969 Weng, T.-R., and Levison, H. Pulmonary function in children with asthma at acute attack and symptom-free status. Amer. Rev. Resp. Dis., 99: 719, 1969 Weng, T.-R., Featherby, E.A., Gould, J., and Levison, H. Relative sensitivity of methods for measuring airway resistance in asthmatic children. Ann. Allerg., 27: 565, 1969 Weng, T.-R., Langer, H.M., Featherby, E.A., and Levison, H. Arterial blood gas tensions and acid-base balance in symptomatic and asymptomatic asthma in childhood. Amer. Rev. Resp. Dis., 101: 274, 1970