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The Role of Infection in Allergic Disease
The Role of Infection in Allergic Disease ABRAHAM H. EISEN, M.D., F.R.GP. (C)"
In common usage, allergic disease refers to bronchial asthma, allergic rhinitis, atopic dermatitis, and urticaria. Although the pediatrician sees a variety of allergic reactions to drugs, contactants, insects, cold, and heat, most of the clinical work involves bronchial asthma, allergic rhinitis, and atopic dermatitis. Accordingly, this discussion of the role of infection in allergic disease emphasizes and considers these conditions in detail. However, the term "allergic disease" is now far more inclusive than previously. In general, any pathologic or undesirable reaction resulting from an immunologic reaction (antigen-antibody union) may be considered allergic. Parallel to this broadened definition, the clinical allergist is being converted to the clinical immunologist, as is evident by the nature of postgraduate training, specialty examinations, and, indeed, by the content of this volume. In this connection, a discussion of the role of infection in allergic disease appropriately includes comments on the immunologic deficiency states, autoimmune and collagen disorders that the clinical immunologist is asked to see and to treat. Obviously, a detailed discussion of each of these latter subjects is beyond the scope of this article.
BRONClllAL ASTHMA
The central problem in allergic disease is bronchial asthma, a descriptive term that does not imply pathogenesis. In discussing the role From the Department of Allergy and Clinical Immunology, The Montreal Children's Hospital and the McGill University-Montreal Children's Hospital Research ~nstitute.
" Director, Department of Allergy and Clinical Immunology, and Assistant Physician, Department of Pediatric Medicine, The Montreal Children's Hospital. This work was supported in part by grants from the Medical Research Council of Canada, from the Conseil de la Recherche Medicale du Quebec, and from Mr. Nathan Steinberg, Montreal, Quebec.
Pediatric Clinics of North America-Vol. 16, No.1, February, 1969
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of infection in bronchial asthma, it is pertinent to know the type of asthma. Since we are largely ignorant of the pathogenesis of bronchial asthma, classifications are clinical and descriptive. Nevertheless some arrangement is necessary, and for each type of asthma described below the role of infection will be discussed separately. Children with bronchial asthma fall into three broad clinical groups. A minority of pediatric patients presenting with bronchial asthma have a distinct seasonal (pollinosis) or environmental (e.g., animal dander) pattern of wheezing corresponding to an extrinsic sensitivity. The second and much larger group of pediatric asthmatics present with perennial wheezing of variable severity. Typically, their symptoms are worse during the winter months and, especially in the very young, tend to recur in a cyclic pattern. These episodes begin, as the mother states, with a "cold." When asked to describe this cold, the following description is obtained: irritability and anorexia often preceding the attack, followed by rhinitis, cough, and then wheezing and respiratory distress. Some children have no apparent prodrome. Fever, if present at all, is low grade. On the other hand, occasional children may suddenly develop high temperatures which subside just as rapidly. There are other minor clinical variations, as, for example, mucus production, but, in general, this is the clinical picture. Examination of these children during an attack reveals congestion of the nasal mucosa, evidence of airway obstruction with indrawing, generalized wheezing and expiratory rhonchi, and occasional rales. Clinically, these signs are virtually identical with infection of the respiratory tract. Investigation of these patients for infection, however, is often unrewarding. Other members of the family may not have concurrent infection. The hemogram is usually normal. Culture of the nose and throat are negative for pathogens or reveal a heavy growth of normal flora. The roentgenogram of the chest demonstrates hyperinflation, with or without bronchopneumonia, and perhaps some increase in bronchovascular markings and bronchial wall thickening. Despite this, roentgenograms during an asymptomatic period may be interpreted as normal. Patients may lose weight during an acute episode, but the majority of children continue to grow and thrive despite repeated episodes. Consistent with this latter observation are normal stool pattern, normal values for sweat chloride, serum proteins, immunoglobulins, and renal, liver, and endocrine function. Similarly, allergic investigation of this group of asthmatics is often unrevealing. Smears of the nasal mucus reveal neutrophilia or epithelial cells, and skin tests are negative or show minor reactions to concentrated extracts of house dust. The problem facing the physician with this group of children is often stated succinctly by the mother: "How is it possible for my child to catch a fresh cold each month? No sooner is he well than he starts another
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episode." The physician attempting to work out the pathogenesis and treatment for this common problem may well ask himself the same question. Certainly the symptoms resemble infection of the respiratory tract, but the frequency and the cyclic characteristic are unique to this group of patients. The parents are usually provided with the following sort of explanation. "The child has bronchial asthma. At this time there are no apparent allergies. Rather the main problem seems to be repeated infection. The child wheezes with each infection because he has bacterial allergythat is, he is allergic to his own germs." The physician with experience will then suggest that with treatment most attacks will be reasonably well controlled and that, in general, the prognosis is good. Those physicians believing in the value of bacterial vaccine will add these injections to the treatment program. The third and largest group of children presenting with bronchial asthma have, to a variable degree, symptoms of both group one and group two. The reader will immediately recognize these groups corresponding to the classification of bronchial asthma into extrinsic, intrinsic, and mixed types. 26 Many pediatric patients begin with the second pattern of asthma and with time develop extrinsic sensitivities and end in group three. The tendency to cyclic episodes of rhinitis, cough, and wheeze usually disappears after 5 years of age, and attacks occur in a more random fashion.
THE ROLE OF INFECTION IN EXTRINSIC ASTHMA
Secondary Infection Patients with extrinsic sensitivity may develop secondary bacterial or viral infection, which aggravates and prolongs symptoms. The typical example is that of a child with seasonal (pollen) asthma who develops bacterial infection with bronchitis. Long after other patients with pollen symptoms have improved, this patient continues to be ill. Another example is the child seen in November or early December with bronchitis of 2 or 3 months' duration. History reveals a mild seasonal hay fever and asthma due to ragweed in the 2 or 3 preceding years. In the year seen, these mild symptoms recur and seem to be reasonably well controlled with symptomatic medication or, at least, are no worse than in previous years. Then, after the first upper respiratory infection once school begins, the patient develops persistent cough, wheeze, and bronchitis. One interprets these historical facts by suggesting that infection superimposed on a chronically congested respiratory mucosa results in an enhanced and prolonged response to an ordinary infection of the respiratory tract.
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Unusual Severity of Ordinary Infections The typical example in this case is the patient with animal dander sensitivity who has severe and prolonged respiratory infections. When the animal is removed, infections become milder and less frequent. In summary, the combination of infection and extrinsic sensitivity enhances and prolongs both allergic and infectious symptoms.
THE ROLE OF INFECTION IN INTRINSIC ASTHMA
It is difficult for the physician, as well as the unsophisticated mother, to distinguish clinically between symptoms of overt infection and those of allergic reaction without infection. This confusion has bred many theories. Some clinicians ascribe all the patients' symptoms to allergic reactions,lB and others state that symptoms are due primarily to infection. 1 Between these positions there exists every shade of opinion.
Direct Infection All physicians will agree that infection of the respiratory tract with bacterial or viral organisms does precipitate attacks of bronchial asthma. In this case one visualizes direct invasion of the respiratory mucosa by the infectious agent, and the ensuing inflammation in some way precipitates asthma. Direct infection is particularly common in infants. In these patients, infection with respiratory syncytial virus, adenovirus, Hemophilus influenzae type B, etc., may result in bronchiolitis, which occurs in both asthmatic and nonasthmatic children. However, there is the clinical impression that asthmatic infants react more intensely to the infection and develop bronchiolitis more frequently, and there is some objective proof for this impression. In one study 14 involving 357 children, 27 per cent of the infants wheezed. Among the children who wheezed with their viral infection, allergy was far more frequent (50 per cent) than in those who did not wheeze (17 per cent). The same authors found that wheezing in association with respiratory infection which occurred after the age of 18 months was far more common in the patient who was ultimately to be asthmatic. This particular role of infection, that is, direct infection of the respiratory mucosa, is a most common and most important cause of bronchial asthma. Secondary Bacterial Infection In this case the asthmatic episode begins with a viral infection and, because of impaired ventilation, accumulation of secretions, and poor ciliary action, bacterial infection supervenes to perpetuate and prolong the asthmatic attack.
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Distant Focus of Infection A distant focus of infection (otitis, pyelonephritis) may precipitate asthma, but this is rare in children. In my personal experience I have not been able to document a focus of infection in teeth, skin, gastrointestinal, or urinary tract as a cause of perennial wheezing. In the occasional child whose asthma improves after removal of the tonsils and adenoids, one can, perhaps, retrospectively imply removal of a distant focus, but this is debatable. Bronchial asthma due to pulmonary migration of parasites, in Loeffier's syndrome or in tropical eosinophilia, is also rare in children. It is intellectually stimulating and important to search for a distant focus of infection, but one must be satisfied with only the occasional case. Bacterial Allergy This vague term usually implies that type of bronchial asthma in which extrinsic sensitivity cannot be incriminated and in which symptoms appear related to infection. In this concept, asthma is not due to direct or secondary invasion of the respiratory tract, but rather to a hypersensitivity reaction resulting from the interaction between the organism or its product and the host. The term "infectious allergy" would seem to be more appropriate than the more restrictive term "bacterial allergy." It is interesting to recall that the delayed skin reaction to tuberculin was noted in 1882,31 and in many ways this observation initiated the study of hypersensitivity and allergy. After infection, the patient's skin and respiratory tract have an altered reactivity to bacterial and viral products. In fact, the capacity to develop a delayed hypersensitivity reaction is essential for immunologic competence, and all normal persons react in this fashion. In this connection, universal antigens (tuberculin, histoplasmin, mumps, Candida, streptococcal products) are used to test this function and indirectly to test for the presence of immunocompetent lymphocytes, which are thought to mediate the delayed hypersensitivity reaction. Similarly, immediate skin reactions with wheal and Hare may be induced with infectious antigens such as the polysaccharide from pneumococcus, Ascaris, and Trichinella. Using the analogy of immediate and delayed skin reactions, early investigators tested asthmatic patients with extracts of bacteria or with whole bacterial vaccines, searching for an immediate or delayed skin reaction in support of their clinical impression of bacterial allergy. Enthusiasm for these tests waned as the reactions in many cases were found to be irritative and not immunologic and, further, were found just as frequently in control patients.27 , 32 Despite the lack of an objective test, the concept of bacterial (infectious) allergy has gained some acceptance. What is the evidence for infectious allergy as a cause of bronchial asthma?
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First, there is the rare patient whose asthma improves dramatically after drainage of a purulent sinus or removal of infected tonsils and adenoids. Second, there is the ability to induce symptoms (asthma or rhinitis) 24 to 48 hours after an excessive subcutaneous dose of bacterial vaccine. This observation has been used most extensively in support of the diagnosis of bacterial ( infectious) allergy and the use of respiratory vaccines. 12 Third, there are patients with bronchial asthma who respond clinically to bacterial vaccine therapy. Fourth, there is the evidence that bronchial asthma may be induced with inhalations of bacterial extracts (Neisseria catarrhalis). This latter evidence is somewhat compromised by the irritant qualities of the extract. 16 The concept of infectious allergy as a cause of recurrent wheezing is an interpretive theory based on clinical impression with few objective data to support it. Treatment of bronchial asthma with bacterial vaccine must, of necessity, be empiric. This explains the spectrum of opinion on the subject of bacterial vaccine therapy, ranging from those who consider it essential10• 15 to those who consider it useless. 1 • 13 There are about equal numbers of articles for and against the value of bacterial vaccine in the literature. Testimonial and anecdotal studies tend to support the value of bacterial vaccine, while studies with attempts at scientific controls, in general, do not. Current Concepts. At this juncture the reader (forced to the more scientific side) may decide that infectious allergy is not a valid thesis and that bacterial vaccine is not a useful treatment. Recent studies suggest that it may be premature to reject the concept of infectious allergy as a cause of bronchial asthma, and some of these will be mentioned briefly. Ouellette and Reed23 first determined the bronchial sensitivity of patients with asthma to an inhalation of methacholine. They repeated these studies 24 to 48 hours after an injection of influenza virus vaccine and found a marked increase in bronchial sensitivity to the same dose of methacholine. Their results suggested that the host response to the virus particle had altered bronchial sensitivity and that this alteration was probably mediated through an endotoxin-like effect of the virus particle. Bacterial products can interfere with the workings of the autonomic nervous system, and endotoxin in particular can potentiate allergic reactions.so Partial beta adrenergic blockade has been demonstrated in patients with bronchial asthma, and infection may increase this blockade to allow unopposed parasympathetic response or nonspecific increased reactivity.sS The alteration of bronchial sensitivity by bacterial antigens has been amply demonstrated in mice, which ordinarily are resistant to
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inhalations of histamine. After an injection of pertussis vaccine, these mice become exquisitely sensitive to inhalation of histamine. Pertinent to this discussion is the finding that similar enhancement of bronchial sensitivity in mice to histamine can be produced by injecting them with propranolol, a potent beta adrenergic blockader.33 It is not the purpose of this article to discuss the mechanism of pertussis vaccine in mice, but rather to report early information on the role of infection in altering the autonomic nervous system in a manner that might lead to bronchial asthma. Some clinicians have insisted over the years that symptoms suggestive of infection in perennial asthma were not due to infection, but rather to allergic reactions. Indirect support for this contention comes from the work on the immunochemistry of house dust antigen. It has been shown that house dust shares common antigenic determinants with the endotoxin antigens of bacteria. 24 One can postulate that the dustsensitive patient, when infected, will react against the bacterial antigens with preformed antibodies and develop hypersensitivity reactions. By the same token, hyposensitization with house dust antigen may alter the immunologic and clinical response to subsequent infection, an observation rather common in clinical practice. Recent evidence suggests that it is not necessary to develop a specific antibody in order to develop a hypersensitivity reaction. Swedish workers have shown that the A protein isolated from staphylococcal cell walls will react with the Fc fragment of normal gamma globulin to produce a hypersensitivity-like reaction.29 Thus the patient with asthma (and an unstable bronchopulmonary tree), on acquiring staphylococcal infection, or, perhaps, with normal staphylococcal colonization, could develop hypersensitivity reactions when the polysaccharide antigen combines with the Fc fraction of the patient's normal gamma globulin. Therefore, infectious agents may play a role in bronchial asthma in ways other than by direct or secondary infection. Infection may alter, directly or indirectly (endotoxin), the autonomic nervous system, may provoke the host with antigens cross-reacting with extrinsic sensitivities, or may induce hypersensitivity reactions not mediated by antibodies. One could continue to speculate on other mechanisms, such as antigenantibody complex19 and release of pharmacologic mediators,S by which infection might result in bronchial asthma. The position to be emphasized in this discussion is that infection probably plays a fundamental role in so-called "intrinsic" asthma. At this time the mechanisms are not understood, but sufficient knowledge has accumulated to speculate on pathogenesis and to develop experiments to test current theories. Clinical Measures. From the clinical point of view there are two camps-those who consider bacterial vaccine treatment useless and those who believe strongly in bacterial allergy and use bacterial vaccine enthusiastically. Since the use of vaccine is controversial, a study was done
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( a) to determine the immunologic response of the patient to bacterial vaccine, and (b) to search for possible mechanisms for the delayed clinical teaction that is seen after -an excessive dose and is often used as the scientific rationale for the treatment. The results showed that the patient, just as the experimental animal, produced antibody to the major bacterial antigens. At the site of injection of the bacterial vaccine an inflammatory response was produced, and there were some features in the host response consistent with a small amount of endotoxin activity in the bacterial vaccine. The presence of multiple antibodies suggested a mechanism for the induction of clinical symptoms. It was reasoned that after injection of the vaccine, the bacterial cells are phagocytosed and broken down and that antibody combines with bacterial breakdown products to produce antigen-antibody complexes. Such antigen-antibody complexes (produced in antigen excess) are able to produce immunologic inflammation and theoretically to induce bronchial asthma. 19 Again, whether this is the, actual mechanism is not as important as the attempt to remove the discussion from the testimonial stage to the accumulation of factual data.
INFECTION IN MIXED TYPE ASTHMA
In this group of patients, infection plays a variable role, in some being of great importance, in others of minor importance. The mechanisms by which infection may precipitate asthma are similar to those discussed above for extrinsic and intrinsic asthma.
TREATMENT OF INFECTION IN BRONCIDAL ASTHMA
All patients suffering from bronchial asthma derive benefit from environmental measures and elimination diets when food sensitivity is a factor. Skillful administration of symptomatic medication is important in treating children; and it is useful to start medications early with the . prodromal symptoms. Antibiotics The use of antibiotics varies, and there are no hard rules. In general, antibiotics are used more frequently during the child's early attacks of cough and wheeze, as it is difficult to differentiate these attacks from respiratory infectwns. As the pattern of repeated wheezing develops and the diagnosis of 'asthma becomes apparent, most clinicians attempt to control the atfack with symptomatic medication. If the attack persists or if fever or evidence of bacterial infection develops, antibiotics are added. In some patients, experie~ce teaches that withholding of antibiotics re-
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suIts in an unduly prolonged attack or in the complication of otitis or bronchopneumonia, and in these patients antibiotics are started early. In other patients, antibiotics make no difference in the. clinic'al course and are not used. Ideally the choice of antibiotic is based on culture and sensitivity. However, this is not practical for patients having repeated episodes. Penicillin is probably the drug of choice (bactericidal, effective, economical), with the reservation that repeated courses may induce penicillin sensitivity. Repeated courses of tetracycline or chloramphenicol are contraindicated, especially in young children, because of the known side effects. 28 It is my practice to use erythromycin for 5 to 7 days for undifferentiated respiratory infections. When there is evidence of bacterial infection (tonsillitis, pharyngitis), penicillin is given in high doses orally. When otitis media or bronchopneumonia is present, ampicillin or penicillin and a sulfonamide (sulfisoxazole) are used to provide wider antibacterial activity. For persistent or severe infections, cultures of the nose and throat and sputum are obtained, and antibiotics are used on the basis of in vitro sensitivity. There is a wide variety of antibiotics available. These hold no particular advantage over penicillin, sulfonamides, ampicillin, or erythromycin for routine use. They are of great value in the rare patient infected with a resistant organism. As mentioned previously, often one .cannot document bacterial infection, and the use of antibiotic is empiric. With this background, it is the role of the clinician certainly to treat the patient for infection, but also to prevent drug abuse. Drug reactions can be reduced by adopting a somewhat conservative approach in the use and selection of drugs to treat infants and children requiring repeated courses of antibiotics over the years. There are occasional patients whose symptoms are so frequent and persistent that the clinician is tempted to use an~ibiotics prophylactically, usually during the winter months. However, prophylactic antibiotic is of no value and may lead to infection with resistant organisms.u Steroids are being used increasingly in the management of bronchial asthma. Antibiotics are used concurrently with steroids when infection is present. Antibiotics are not necessary simply because the patient is receiving short-term or maintenance steroids. Increased precautions and suspicion of infection, both overt and masked, are necessary in the patient on pharmacological doses of steroids. Bacterial Vaccine The decision to use bacterial vaccine cannot wait': for the research laboratory to deliver the answer. Practical decisions are required daily. I use the following routine: in patients with perennial asthma that appears related to respiratory infection and of sufficient severity to
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Bacterial Vaccine
ORGANISM
NUMBER OP ORGANISMS PER ML.
Neisseria catarrhalis Klebsiella pneumonia Diplococcus pneumonia Type I Diplococcus pneumonia Type II Diplococcus pneumonia Type III Diplococcus pneumonia Type V, VII, VIII, XIV Streptococcus hemolyticus Streptococcus other than hemolytic us Staphylococcus a l b u s · Staphylococcus aureus Corynebacterium diphtheroid Hemophilus influenzae
X 10·
5 5 2. 5 2. 5 2.5 2.5 5 5 25 25 10 10
justify injection treatment, and in whom extrinsic sensitivities cannot be determined after careful history, skin testing, and observation, bacterial vaccine is given. Using a stock heat-killed bacterial vaccine in a maximum concentration of 100 X 106 organisms per mI. (Table 1), a series of 15 weekly injections of increasing concentration is given and the maximum dose, 0.5 mI., or the maximum tolerated dose, which may be less, is continued every 2 to 3 weeks. The parents receive an explanation of the empirical nature of the treatment, and the patients are evaluated every 4 to 6 months. The most common error in this treatment is overdosage, and the parents and the treating physician often fail to recognize rhinitis, cough, and wheeze recurring within 48 hours after each injection. Patients who have not responded at the end of 1 year are occasionally carried on for 2, but in most patients treatment is discontinued. Patients who have improved at the end of 1 year are continued on treatment for another year or two and then treatment is discontinued. Bacterial vaccine is rarely given for more than 3 consecutive years. In my personal experience, autogenous vaccines have provided no particular advantage over stock vaccines. Miscellaneous Measures
Gamma Globulin. It is well documented that regular injections of gamma globulin are of no value in the management of bronchial asthma. 8 Further, there is recent evidence that gamma globulin regularly injected may not be entirely innocuous and may result in antibody to human gamma globulin (aggregated).17 Immunization. Patients with bronchial asthma should be immunized in the usual manner against smallpox, tetanus,diphtheria, pertussis, poliomyelitis, and measles. Although allergic children have a tendency to develop enhanced local and systemic response, this is not a contraindication. In the occasional child with severe systemic response (fever
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and toxicity), it is useful to give one quarter or one half the dose and repeat fractional injections until the total immunizing dose has been given. Immunization with tetanus toxoid should be kept current and, if passive immunization is necessary, human antitetanus globulin should be given. Horse antitetanus serum should be avoided. Live measles vaccine contains minimal amounts of egg antigen. Patients who are extremely sensitive to egg clinically should not be immunized. These patients should be given passive protection, either complete or partial, with gamma globulin upon exposure. For the usual allergy patient who may have a positive skin test to egg, but can tolerate a small amount of egg, measles vaccine can be given with the following precautions: a longacting antihistamine, approximately an hour before the injection, and observation of the patient in the office for at least an hour after the injection, with adrenalin available in the event of a reaction. Patients with bronchial asthma and atopic dermatitis should not be vaccinated against smallpox while there are active lesions on the skin. Vaccination of the patient with eczema is usually safe after the skin has been clear for 12 months. In epidemic years, prophylactic injections with Asian influenza vaccine are useful adjuncts. Since the vaccine contains minimal amounts of egg antigen, the same precautions mentioned above for measles vaccine should be taken. Patients with bronchial asthma may be given typhoid vaccine, when this is required for travel, and similar prophylactic injections of gamma globulin for protection against hepatitis, rubella, etc.
INFECTION IN SEASONAL ALLERGIC RHINITIS
In seasonal rhinitis, infection occurs mainly as a secondary phenomenon. Purulent sinusitis and conjunctivitis occur not infrequently during and especially after the season, and the anticipated relief at the end of the pollination season does not occur. Antibiotics, as well as symptomatic medication, are necessary to control these symptoms.
INFECTION IN PERENNIAL ALLERGIC RHINITIS
The symptoms of perennial allergic rhinitis are nasal obstruction, mouth breathing, rhinitis, and repeated upper respiratory infections. In some patients, significant extrinsic sensitivities can be incriminated, but not in others. In perennial rhinitis, infection tends to play the same role it does in bronchial asthma, that is, direct infection, secondary infection, and infectious allergy. In some ways, the concept of infectious allergy is better suited to the symptoms of allergic rhinitis with perennial con-
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gestion of the nasal mucosa and repeated upper respiratory infections because the organism (antigen) may be continuously present in the site of symptoms. In some cases, perennial nasal congestion is an obvious familial trait and the role of infection must be secondary. Nasal polyps are .not common in children and tend to develop in the teenager who has a long history of perennial rhinitis and repeated purulent infection. Many of these patients have associated asthma, and of these a small number are. exquisitely sensitive to aspirin; others have cystic fibrosis. The treatment· of infection in perennial allergic rhinitis follows the same pattern as that of bronchial asthma-that is, avoidance of the significant environmental and food sensitivities, symptomatic therapy, and antibiotics for bacterial infection. When respiratory infections are frequent and prolonged,a trial of bacterial vaccine is indicated. Indication for Tonsillectomy and Adenoidectomy The indications for removal of the tonsils and adenoids in allergic children are the same as they are in nonallergic children. These indications are repeated tonsillitis, peritonsillar abscess, obstruction of the nasopharynx, or unusual unilateral hypertrophy. The lymphoid tissue in the nasopharynx seems to hypertrophy earlier and to a greater extent in the allergic patient than in the nonallergic patient. This hypertrophy often leads to early adenoidectomy and, in some of these patients, lymphoid tissue regrows over the next 2 or 3 years. In general, removing large tonsils or adenoids simply because they are large will do little to affect the course of asthma or perennial rhinitis.
INFECTION.IN RECURRENT OTITIS MEDIA
Recurrent otitis media is a proplem seen commonly in allergic practice. The precise mechanism is. not understood, but present concepts suggest that the eustachian canal fails to' maintain equal pressure in the middle ear and in the nasopharynx. 7 Obstruction of the eustachian canal is followed by resorption of air from the middle ear and increase in negative pressure with accumulation of fluid in the middle ear. This fluid is close to serum in its composition. It is not known whether the fluid is actively secreted by the' mucosa or whether it is a transudate. 21 In some children the secretion is, mucoid and gluelike. The child presents with recurrent' otitis media, hearing loss' or variations of these symptoms. This condition occurs in children under 10 years of age and tends to improve during adolescence. . Although allergy and infection are often implicated in the pathogenesis of obstruction in the eustachian capal, in many patients significmit extrinsic sensitivities. cannot be demon~trated, nor is there evidence
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of acute or chronic infection. About half the patients referred to the allergist already have had tonsils and adenoids removed, and theoretically all mechanical obstruction has been overcome. This fact alone would suggest that simple removal of tonsils and adenoids is insufficient for control of this condition, and this observation has recently been documented. 22 Optimal treatment of recurrent otitis requires the- combined effort of pediatrician and otolaryngologist. These patients require allergic management with environmental and food avoidance, symptomatic therapy, and particularly early and vigorous treatment of infection. When indicated, removal of mechanical obstruction (adenoids), myringotomy, and insertion of tubes are necessary. Occasional patients, particularly those with repeated upper respiratory infection, seem to benefit from a course of bacterial vaccine treatment. -
INFECTION IN ATOPIC DERMATITIS
The pathogenesis of this common and distressing condition remains an enigma. There are obvious genetic and environmental factors. Many of these children develop bronchial asthma or allergic rhinitis as the skin spontaneously improves. In others, eczema and asthma coexist, often with a fascinating inverse relationship, so that the asthma is worse as the skin improves and the skin becomes worse when the asthma abates. Many infants have significant food sensitivities with immediate or, less frequently, delayed clinical reactions; others have no obvious sensitivities. In some patients, skin-fixed reagins to inhalants are present years before respiratory symptoms develop. Many of these patients have abnormal skin vasculature, others a significant eosinophilia. Ultimately all these facets will be fitted into a unified hypothesis. 9 Infection seems to playa secondary role in atopic dermatitis. Infection is not always clinically apparent and must be continuously suspected. When infection is present, pruritus is. usually increased in intensity, and similarly, increased -pruritus often l~ads to infection. Impetigo due to streptococcus and staphylococcus is a common complication, and an occasional poststreptococcal nephritis develops from such a skin infection. Secondary infection may be iatrogenic, particularly when occlusive dressings are used for prolonged periods. Mild infection responds to topical treatment with soaks and antibiotic creams; more widespread infection requirt{s systemic antibiotics. Atopic dermatitis may worsen during an ordinary upper respiratory infection. It is a long-standing clinical observation that after measles and other severe systemic diseases, the skin rriay clear for a variable period. The skin of patients with atopic dermatitis is notoriously susceptible to infection with vaccinia virus and herpes virus. Life-threat~n~ ing infections may occur from the inadvertenf vaccination of a patient
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with active atopic dermatitis or even a patient in proximity to another child with the condition. Atopic dermatitis is a definite contraindication to vaccination for smallpox. Fortunately, some treatment for generalized vaccinia is now available with methisazone5 and hyperimmune vaccinia gamma globulin.
INFECTION IN URTICARIA
In some children, urticaria develops coincident with or immediately after what appears to be a viral respiratory infection. Investigation for a specific ·cause, however, is unrevealing. These children tend to develop recurrent hives with each subsequent respiratory infection, and this state of affairs may last for months or years. Infection, food and drug sensitivity, and emotional factors are considered the usual causes of chronic urticaria. As a rule, infection cannot be implicated. While it is true that the rare case of chronic urticaria will improve after parasitic infestation is eradicated or carious teeth are removed or a urinary infection clears, most children with chronic urticaria cannot be shown to be infected.
INFECTION IN IMMUNOLOGIC DEFICIENCY STATES25
In the 17 years since the first case of congenital sex-linked agammaglobulinemia was published, a sufficient number and variety of these patients have been described to establish preliminary but useful classifications. The fundamental feature of these patients is their inability to control infection. As a consequence, investigation has provided great insight into the mechanisms of immunity. Important observations have been made on circulating immunoglobulins, on the immunoglobulins and antibody content in respiratory and mucosal secretions, ~n the thymus, the lymphocyte and the lymphoid system, on complement, on the leukocyte, and phagocytosis, and the list continues to grow. It is fair to say that these patients have done more for medical science than science has for them. . At this time the useful functions of the clinician are the early recognition of disease, the early institution of treatment, and the applicatio!1 of genetic knowledge for counseling. In specific IgG deficiency, replacement gamma glob~lin and antibiotics remain the accepted treatment. Transient,.-isolated IgM deficiency states do not require gamma globulin injections, but an extended course of antibiotic therapy may be helpful. Preliminary experimental attempts have been made to reconstitute these patients with syngeneic bone marrow cells and thymic grafts. In
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general, these attempts have been unsuccessful, but recent reports are more hopeful and suggest that successful reconstitution will be feasible.
INFECTION IN COLLAGEN DISORDERS
In rheumatoid arthritis, the search for infectious agents continues, and attention has focused on the pleuropneumonia-like organisms. 6 Rheumatoid factor has been noted during acute infections such as SBE20 and may be experimentally induced in a variety of ways, including repeated injections of bacterial cells. 12 The role of infection in systemic lupus erythematosus,4 in scleroderma, polymyositis, and systemic vasculitis remains an enigma, but the search continues. These patients are susceptible to secondary infection because of the underlying disease and steroid treatment.
INFECTION IN AUTOIMMUNE DISORDERS
In the so-called autoimmune diseases, the debate on etiology continues. At least in one group of these diseases, such as rheumatic fever, glomerulonephritis, and primary atypical pneumonia, the primary event is thought to be an infection followed by an autoimmune reaction between the antibody formed and the infecting antigen. In the diseases in which tissue antigenicity is altered (thyroid, heart), the primary event may be infection of these tissues, followed by an autoimmune reaction between antibody and altered tissue antigen. 2
SUMMARY
Infection plays a fundamental role in allergic disease. Infection is a common complication of allergic asthma and rhinitis. Infection probably plays an important role in intrinsic asthma, in perennial rhinitis, and in recurrent otitis media. The mflchanisms by which infection may affect allergic disease are mentioned. The treatment of infection, including the role of bacterial vaccine, is discussed.
REFERENCES 1. Aas, K., BerdaI, P., Henriksen, S;...IJ., and Gardborg, 0.: "Bacterial allergy" in childhood asthma and the effect of vaccine treatment. Acta. Paediat. Scand., 52:338-344, 1963. 2. Asherson, C. L.: Auto-immune disease.!. Brit. Med. J" 3:417-420, 1967.
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3. Austen, K. F.: Histamine and- other mediators of allergic reactions. In Samter, M., ed.: Immunologic Diseases. Boston, Little, Brown & Co., 1965, p. 211. 4. Bolman; H. R: Systemic lupus erythematosus. In Samter, M., ed.: Immunologic Diseases. Boston, Little, Browri & Co., 1965, p. 744. 5. Brainerd, H. D., Hanna, L., and Jawetz, E.: Methisazone in progressize vaccinia. New Eng. J. Med., 276:620-622, 1967. 6. Christiap, C. L.: Rheumatoid aithritis. In Samter, M., ed.: Immunologic Diseases. -."Boston,Little, Brown & Co.; 1965, p. 735. 7. Chronic serous otitis media in childhood: A new treatment: Clinical rounds. Clin. Pediat:, 3:718-727, 1964. 8. Crepea, S. B., and Friedlaender, S.: The use of gamma globulin in the treatment of intrinsic asthma. J. Allergy, 30:439-441, 1959. 9. Conference on infantile eczema. J. Pediat.; January 1965, part 2. 10. Crump, J.; Value of vaccine treatment in allergic respiratory conditions. PEDIAT. CUN. N. AMER., I:987~933, 1954. 11. Davis, S. D., and Wedgwo.od, R J.: Antibiotic prophylaxis in acute viral respiratory diseases. Amer. J. Dis. Child., 109:544-553, 1965. 12. Eisen, A. H.,_ and Bacal, H. L.: Immunologic response to bacterial vaccine. Int. Arch. Allergy, 31:14-24, 1967. 13. Fontana, V. J., Salanitro, A. S., Wolfe, H. I., and Moreno, F.: Bacterial vaccine and infectious asthma. J.A.M.A., 193:895--900, 1965. 14. Freeman, G., and Todd; R H.: The role of allergy in viral respiratory tract infections. Amer. J. Dis. Child., '104:330-334, 1962. 15. Gundy, J. E.: Acellular bacterial antigen complex (Hoffmann) in the treatment of children with recurrent respiratory' infections and infectious asthma. J. Pediat., 51:516-526, 1957: 16. Hampton, S. F., Johnson, M. C., and Galakatos, E.: Studies of bacterial hypersensitivity in asthma. 1. The preparation of antigens of Neisseria catarrhalis, the induction of asthma by -aerosols and the performance of skin and passive transfer tests. J. Allergy, 34:63-95, 1963. 17. Henney, C. S., and Ellis, E. F.: Antibody production to human 'Y G-globulin in acquired hypogammaglobulinemia. New Eng. J. Med., 278:1144-1146, 1968. 18. Horesh, A. J.: Allergy and infection. 6. The criteria-for judgment. J. Asthma Res., 5:89-113, 1967. 19. Ishizaka, K.: Gamma globulin and -molecular mechanisms in hypersensitivity reactions. Progr. Allergy, 7:32-106, 1963. 20. Messner, R. P., Laxdal, T., Quie, P. Q.; and Williams, R C.: Rheumatoid factors in subacute bacterial endocarditis-bacterium, duration of disease or genetic predisposition? Ann. Int. Med., 68:746-756, 1968. 21. Miller, C. F.: Eustachian tubal function in. normal and diseased ears. Arch. Otolaryng., 81:41-48,1965.' . 22. Murray, A. B., Anderson, D. 0.,_ Camhon, K. G., Moghadam, H. K., and Robinson, G. C.: A survey of hearing loss in Vancouver school children. 2. The association between secretory otitis media and enlarged adenoids, infection and nasal allergy. Canad. Med. Ass. J., 98:995-1001, 1968. 23. Ouellette, J. J., and Reed, C. E.: Increased response of asthmatic subjects to methacholine after influenza vaccine. J. Allergy, 36:558-563, 1965. 24. Peterson, R D" Wicklunds, P.-E., and G@od, R A.: Endotoxin activity of house dust extract. J. Allergy, 35: 134-142, 1964.. 25. Rosen, F. S., and Janeway, C. A.: The gamma globulins. 3. The antibody deficiency syndromes. New Eng. J. Med., 275:709-715, 769-775, 1966. 26. Sheldon, J. M., Lovell, R G., and Mathews, K. P.: A Manual of Clinical Allergy. 2nd .ed. Philadelphia, W. B. -Saunders Co., 1967, p. 95. 27. Sheldon, J. M., Lovell, R G., and Mathews, K. P.: A Manual of Clinical Allergy. 2nd ed. Philadelphia, W. B. Saunders Co., 1967, p. 24. 28. Shirkey, H. C., and Barba, W. P.: Drug therapy. In Nelson, W. E., ed.: Textbook of Pediatrics. 8th ed.l'hj.ladelphia, W. B. Sau~ders Co., 1964, p. 222. 29. Syoq~ist, J., Forsgren, A., Gustafson, G. T., and Stalenheim, G.: Biological importance of the Fe-region of gamma globulins. In Cold Spring Harbor Symposia on Quantitative Biology, Vol. 32: Antibodies, pp. 577-581, 1967.
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30. Szentivanyi, A., and Fishel, C. W.: Effect" of· bacterial products on responses to the allergic mediators. In Samter, M., ed.: Immunologic Diseases. Boston, . Little, Brown & Co., 1965, p. 226. 31. Vaughan, W. T., and Black, J. H.: Practice of Allergy. 2nd ed. St. Louis, C. V. Mosby Co., 1948, p. 26. 32. Vaughan, W. T., and Black, J. H.: Practice of Allergy. 2nd ed. St. Louis, C. V. Mosby, 1948, p. 729. .. ' . 33. Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade: New Eng. J. Med., 275:580-584, 1266. 2300 Tupper Street Montreal 108, Quebec
In common usage, allergic disease refers to bronchial asthma, allergic rhinitis, atopic dermatitis, and urticaria. Although the pediatrician sees a variety of allergic reactions to drugs, contactants, insects, cold, and heat, most of the clinical work involves bronchial asthma, allergic rhinitis, and atopic dermatitis. Accordingly, this discussion of the role of infection in allergic disease emphasizes and considers these conditions in detail. However, the term "allergic disease" is now far more inclusive than previously. In general, any pathologic or undesirable reaction resulting from an immunologic reaction (antigen-antibody union) may be considered allergic. Parallel to this broadened definition, the clinical allergist is being converted to the clinical immunologist, as is evident by the nature of postgraduate training, specialty examinations, and, indeed, by the content of this volume. In this connection, a discussion of the role of infection in allergic disease appropriately includes comments on the immunologic deficiency states, autoimmune and collagen disorders that the clinical immunologist is asked to see and to treat. Obviously, a detailed discussion of each of these latter subjects is beyond the scope of this article.
BRONClllAL ASTHMA
The central problem in allergic disease is bronchial asthma, a descriptive term that does not imply pathogenesis. In discussing the role From the Department of Allergy and Clinical Immunology, The Montreal Children's Hospital and the McGill University-Montreal Children's Hospital Research ~nstitute.
" Director, Department of Allergy and Clinical Immunology, and Assistant Physician, Department of Pediatric Medicine, The Montreal Children's Hospital. This work was supported in part by grants from the Medical Research Council of Canada, from the Conseil de la Recherche Medicale du Quebec, and from Mr. Nathan Steinberg, Montreal, Quebec.
Pediatric Clinics of North America-Vol. 16, No.1, February, 1969
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of infection in bronchial asthma, it is pertinent to know the type of asthma. Since we are largely ignorant of the pathogenesis of bronchial asthma, classifications are clinical and descriptive. Nevertheless some arrangement is necessary, and for each type of asthma described below the role of infection will be discussed separately. Children with bronchial asthma fall into three broad clinical groups. A minority of pediatric patients presenting with bronchial asthma have a distinct seasonal (pollinosis) or environmental (e.g., animal dander) pattern of wheezing corresponding to an extrinsic sensitivity. The second and much larger group of pediatric asthmatics present with perennial wheezing of variable severity. Typically, their symptoms are worse during the winter months and, especially in the very young, tend to recur in a cyclic pattern. These episodes begin, as the mother states, with a "cold." When asked to describe this cold, the following description is obtained: irritability and anorexia often preceding the attack, followed by rhinitis, cough, and then wheezing and respiratory distress. Some children have no apparent prodrome. Fever, if present at all, is low grade. On the other hand, occasional children may suddenly develop high temperatures which subside just as rapidly. There are other minor clinical variations, as, for example, mucus production, but, in general, this is the clinical picture. Examination of these children during an attack reveals congestion of the nasal mucosa, evidence of airway obstruction with indrawing, generalized wheezing and expiratory rhonchi, and occasional rales. Clinically, these signs are virtually identical with infection of the respiratory tract. Investigation of these patients for infection, however, is often unrewarding. Other members of the family may not have concurrent infection. The hemogram is usually normal. Culture of the nose and throat are negative for pathogens or reveal a heavy growth of normal flora. The roentgenogram of the chest demonstrates hyperinflation, with or without bronchopneumonia, and perhaps some increase in bronchovascular markings and bronchial wall thickening. Despite this, roentgenograms during an asymptomatic period may be interpreted as normal. Patients may lose weight during an acute episode, but the majority of children continue to grow and thrive despite repeated episodes. Consistent with this latter observation are normal stool pattern, normal values for sweat chloride, serum proteins, immunoglobulins, and renal, liver, and endocrine function. Similarly, allergic investigation of this group of asthmatics is often unrevealing. Smears of the nasal mucus reveal neutrophilia or epithelial cells, and skin tests are negative or show minor reactions to concentrated extracts of house dust. The problem facing the physician with this group of children is often stated succinctly by the mother: "How is it possible for my child to catch a fresh cold each month? No sooner is he well than he starts another
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episode." The physician attempting to work out the pathogenesis and treatment for this common problem may well ask himself the same question. Certainly the symptoms resemble infection of the respiratory tract, but the frequency and the cyclic characteristic are unique to this group of patients. The parents are usually provided with the following sort of explanation. "The child has bronchial asthma. At this time there are no apparent allergies. Rather the main problem seems to be repeated infection. The child wheezes with each infection because he has bacterial allergythat is, he is allergic to his own germs." The physician with experience will then suggest that with treatment most attacks will be reasonably well controlled and that, in general, the prognosis is good. Those physicians believing in the value of bacterial vaccine will add these injections to the treatment program. The third and largest group of children presenting with bronchial asthma have, to a variable degree, symptoms of both group one and group two. The reader will immediately recognize these groups corresponding to the classification of bronchial asthma into extrinsic, intrinsic, and mixed types. 26 Many pediatric patients begin with the second pattern of asthma and with time develop extrinsic sensitivities and end in group three. The tendency to cyclic episodes of rhinitis, cough, and wheeze usually disappears after 5 years of age, and attacks occur in a more random fashion.
THE ROLE OF INFECTION IN EXTRINSIC ASTHMA
Secondary Infection Patients with extrinsic sensitivity may develop secondary bacterial or viral infection, which aggravates and prolongs symptoms. The typical example is that of a child with seasonal (pollen) asthma who develops bacterial infection with bronchitis. Long after other patients with pollen symptoms have improved, this patient continues to be ill. Another example is the child seen in November or early December with bronchitis of 2 or 3 months' duration. History reveals a mild seasonal hay fever and asthma due to ragweed in the 2 or 3 preceding years. In the year seen, these mild symptoms recur and seem to be reasonably well controlled with symptomatic medication or, at least, are no worse than in previous years. Then, after the first upper respiratory infection once school begins, the patient develops persistent cough, wheeze, and bronchitis. One interprets these historical facts by suggesting that infection superimposed on a chronically congested respiratory mucosa results in an enhanced and prolonged response to an ordinary infection of the respiratory tract.
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Unusual Severity of Ordinary Infections The typical example in this case is the patient with animal dander sensitivity who has severe and prolonged respiratory infections. When the animal is removed, infections become milder and less frequent. In summary, the combination of infection and extrinsic sensitivity enhances and prolongs both allergic and infectious symptoms.
THE ROLE OF INFECTION IN INTRINSIC ASTHMA
It is difficult for the physician, as well as the unsophisticated mother, to distinguish clinically between symptoms of overt infection and those of allergic reaction without infection. This confusion has bred many theories. Some clinicians ascribe all the patients' symptoms to allergic reactions,lB and others state that symptoms are due primarily to infection. 1 Between these positions there exists every shade of opinion.
Direct Infection All physicians will agree that infection of the respiratory tract with bacterial or viral organisms does precipitate attacks of bronchial asthma. In this case one visualizes direct invasion of the respiratory mucosa by the infectious agent, and the ensuing inflammation in some way precipitates asthma. Direct infection is particularly common in infants. In these patients, infection with respiratory syncytial virus, adenovirus, Hemophilus influenzae type B, etc., may result in bronchiolitis, which occurs in both asthmatic and nonasthmatic children. However, there is the clinical impression that asthmatic infants react more intensely to the infection and develop bronchiolitis more frequently, and there is some objective proof for this impression. In one study 14 involving 357 children, 27 per cent of the infants wheezed. Among the children who wheezed with their viral infection, allergy was far more frequent (50 per cent) than in those who did not wheeze (17 per cent). The same authors found that wheezing in association with respiratory infection which occurred after the age of 18 months was far more common in the patient who was ultimately to be asthmatic. This particular role of infection, that is, direct infection of the respiratory mucosa, is a most common and most important cause of bronchial asthma. Secondary Bacterial Infection In this case the asthmatic episode begins with a viral infection and, because of impaired ventilation, accumulation of secretions, and poor ciliary action, bacterial infection supervenes to perpetuate and prolong the asthmatic attack.
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Distant Focus of Infection A distant focus of infection (otitis, pyelonephritis) may precipitate asthma, but this is rare in children. In my personal experience I have not been able to document a focus of infection in teeth, skin, gastrointestinal, or urinary tract as a cause of perennial wheezing. In the occasional child whose asthma improves after removal of the tonsils and adenoids, one can, perhaps, retrospectively imply removal of a distant focus, but this is debatable. Bronchial asthma due to pulmonary migration of parasites, in Loeffier's syndrome or in tropical eosinophilia, is also rare in children. It is intellectually stimulating and important to search for a distant focus of infection, but one must be satisfied with only the occasional case. Bacterial Allergy This vague term usually implies that type of bronchial asthma in which extrinsic sensitivity cannot be incriminated and in which symptoms appear related to infection. In this concept, asthma is not due to direct or secondary invasion of the respiratory tract, but rather to a hypersensitivity reaction resulting from the interaction between the organism or its product and the host. The term "infectious allergy" would seem to be more appropriate than the more restrictive term "bacterial allergy." It is interesting to recall that the delayed skin reaction to tuberculin was noted in 1882,31 and in many ways this observation initiated the study of hypersensitivity and allergy. After infection, the patient's skin and respiratory tract have an altered reactivity to bacterial and viral products. In fact, the capacity to develop a delayed hypersensitivity reaction is essential for immunologic competence, and all normal persons react in this fashion. In this connection, universal antigens (tuberculin, histoplasmin, mumps, Candida, streptococcal products) are used to test this function and indirectly to test for the presence of immunocompetent lymphocytes, which are thought to mediate the delayed hypersensitivity reaction. Similarly, immediate skin reactions with wheal and Hare may be induced with infectious antigens such as the polysaccharide from pneumococcus, Ascaris, and Trichinella. Using the analogy of immediate and delayed skin reactions, early investigators tested asthmatic patients with extracts of bacteria or with whole bacterial vaccines, searching for an immediate or delayed skin reaction in support of their clinical impression of bacterial allergy. Enthusiasm for these tests waned as the reactions in many cases were found to be irritative and not immunologic and, further, were found just as frequently in control patients.27 , 32 Despite the lack of an objective test, the concept of bacterial (infectious) allergy has gained some acceptance. What is the evidence for infectious allergy as a cause of bronchial asthma?
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First, there is the rare patient whose asthma improves dramatically after drainage of a purulent sinus or removal of infected tonsils and adenoids. Second, there is the ability to induce symptoms (asthma or rhinitis) 24 to 48 hours after an excessive subcutaneous dose of bacterial vaccine. This observation has been used most extensively in support of the diagnosis of bacterial ( infectious) allergy and the use of respiratory vaccines. 12 Third, there are patients with bronchial asthma who respond clinically to bacterial vaccine therapy. Fourth, there is the evidence that bronchial asthma may be induced with inhalations of bacterial extracts (Neisseria catarrhalis). This latter evidence is somewhat compromised by the irritant qualities of the extract. 16 The concept of infectious allergy as a cause of recurrent wheezing is an interpretive theory based on clinical impression with few objective data to support it. Treatment of bronchial asthma with bacterial vaccine must, of necessity, be empiric. This explains the spectrum of opinion on the subject of bacterial vaccine therapy, ranging from those who consider it essential10• 15 to those who consider it useless. 1 • 13 There are about equal numbers of articles for and against the value of bacterial vaccine in the literature. Testimonial and anecdotal studies tend to support the value of bacterial vaccine, while studies with attempts at scientific controls, in general, do not. Current Concepts. At this juncture the reader (forced to the more scientific side) may decide that infectious allergy is not a valid thesis and that bacterial vaccine is not a useful treatment. Recent studies suggest that it may be premature to reject the concept of infectious allergy as a cause of bronchial asthma, and some of these will be mentioned briefly. Ouellette and Reed23 first determined the bronchial sensitivity of patients with asthma to an inhalation of methacholine. They repeated these studies 24 to 48 hours after an injection of influenza virus vaccine and found a marked increase in bronchial sensitivity to the same dose of methacholine. Their results suggested that the host response to the virus particle had altered bronchial sensitivity and that this alteration was probably mediated through an endotoxin-like effect of the virus particle. Bacterial products can interfere with the workings of the autonomic nervous system, and endotoxin in particular can potentiate allergic reactions.so Partial beta adrenergic blockade has been demonstrated in patients with bronchial asthma, and infection may increase this blockade to allow unopposed parasympathetic response or nonspecific increased reactivity.sS The alteration of bronchial sensitivity by bacterial antigens has been amply demonstrated in mice, which ordinarily are resistant to
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inhalations of histamine. After an injection of pertussis vaccine, these mice become exquisitely sensitive to inhalation of histamine. Pertinent to this discussion is the finding that similar enhancement of bronchial sensitivity in mice to histamine can be produced by injecting them with propranolol, a potent beta adrenergic blockader.33 It is not the purpose of this article to discuss the mechanism of pertussis vaccine in mice, but rather to report early information on the role of infection in altering the autonomic nervous system in a manner that might lead to bronchial asthma. Some clinicians have insisted over the years that symptoms suggestive of infection in perennial asthma were not due to infection, but rather to allergic reactions. Indirect support for this contention comes from the work on the immunochemistry of house dust antigen. It has been shown that house dust shares common antigenic determinants with the endotoxin antigens of bacteria. 24 One can postulate that the dustsensitive patient, when infected, will react against the bacterial antigens with preformed antibodies and develop hypersensitivity reactions. By the same token, hyposensitization with house dust antigen may alter the immunologic and clinical response to subsequent infection, an observation rather common in clinical practice. Recent evidence suggests that it is not necessary to develop a specific antibody in order to develop a hypersensitivity reaction. Swedish workers have shown that the A protein isolated from staphylococcal cell walls will react with the Fc fragment of normal gamma globulin to produce a hypersensitivity-like reaction.29 Thus the patient with asthma (and an unstable bronchopulmonary tree), on acquiring staphylococcal infection, or, perhaps, with normal staphylococcal colonization, could develop hypersensitivity reactions when the polysaccharide antigen combines with the Fc fraction of the patient's normal gamma globulin. Therefore, infectious agents may play a role in bronchial asthma in ways other than by direct or secondary infection. Infection may alter, directly or indirectly (endotoxin), the autonomic nervous system, may provoke the host with antigens cross-reacting with extrinsic sensitivities, or may induce hypersensitivity reactions not mediated by antibodies. One could continue to speculate on other mechanisms, such as antigenantibody complex19 and release of pharmacologic mediators,S by which infection might result in bronchial asthma. The position to be emphasized in this discussion is that infection probably plays a fundamental role in so-called "intrinsic" asthma. At this time the mechanisms are not understood, but sufficient knowledge has accumulated to speculate on pathogenesis and to develop experiments to test current theories. Clinical Measures. From the clinical point of view there are two camps-those who consider bacterial vaccine treatment useless and those who believe strongly in bacterial allergy and use bacterial vaccine enthusiastically. Since the use of vaccine is controversial, a study was done
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( a) to determine the immunologic response of the patient to bacterial vaccine, and (b) to search for possible mechanisms for the delayed clinical teaction that is seen after -an excessive dose and is often used as the scientific rationale for the treatment. The results showed that the patient, just as the experimental animal, produced antibody to the major bacterial antigens. At the site of injection of the bacterial vaccine an inflammatory response was produced, and there were some features in the host response consistent with a small amount of endotoxin activity in the bacterial vaccine. The presence of multiple antibodies suggested a mechanism for the induction of clinical symptoms. It was reasoned that after injection of the vaccine, the bacterial cells are phagocytosed and broken down and that antibody combines with bacterial breakdown products to produce antigen-antibody complexes. Such antigen-antibody complexes (produced in antigen excess) are able to produce immunologic inflammation and theoretically to induce bronchial asthma. 19 Again, whether this is the, actual mechanism is not as important as the attempt to remove the discussion from the testimonial stage to the accumulation of factual data.
INFECTION IN MIXED TYPE ASTHMA
In this group of patients, infection plays a variable role, in some being of great importance, in others of minor importance. The mechanisms by which infection may precipitate asthma are similar to those discussed above for extrinsic and intrinsic asthma.
TREATMENT OF INFECTION IN BRONCIDAL ASTHMA
All patients suffering from bronchial asthma derive benefit from environmental measures and elimination diets when food sensitivity is a factor. Skillful administration of symptomatic medication is important in treating children; and it is useful to start medications early with the . prodromal symptoms. Antibiotics The use of antibiotics varies, and there are no hard rules. In general, antibiotics are used more frequently during the child's early attacks of cough and wheeze, as it is difficult to differentiate these attacks from respiratory infectwns. As the pattern of repeated wheezing develops and the diagnosis of 'asthma becomes apparent, most clinicians attempt to control the atfack with symptomatic medication. If the attack persists or if fever or evidence of bacterial infection develops, antibiotics are added. In some patients, experie~ce teaches that withholding of antibiotics re-
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suIts in an unduly prolonged attack or in the complication of otitis or bronchopneumonia, and in these patients antibiotics are started early. In other patients, antibiotics make no difference in the. clinic'al course and are not used. Ideally the choice of antibiotic is based on culture and sensitivity. However, this is not practical for patients having repeated episodes. Penicillin is probably the drug of choice (bactericidal, effective, economical), with the reservation that repeated courses may induce penicillin sensitivity. Repeated courses of tetracycline or chloramphenicol are contraindicated, especially in young children, because of the known side effects. 28 It is my practice to use erythromycin for 5 to 7 days for undifferentiated respiratory infections. When there is evidence of bacterial infection (tonsillitis, pharyngitis), penicillin is given in high doses orally. When otitis media or bronchopneumonia is present, ampicillin or penicillin and a sulfonamide (sulfisoxazole) are used to provide wider antibacterial activity. For persistent or severe infections, cultures of the nose and throat and sputum are obtained, and antibiotics are used on the basis of in vitro sensitivity. There is a wide variety of antibiotics available. These hold no particular advantage over penicillin, sulfonamides, ampicillin, or erythromycin for routine use. They are of great value in the rare patient infected with a resistant organism. As mentioned previously, often one .cannot document bacterial infection, and the use of antibiotic is empiric. With this background, it is the role of the clinician certainly to treat the patient for infection, but also to prevent drug abuse. Drug reactions can be reduced by adopting a somewhat conservative approach in the use and selection of drugs to treat infants and children requiring repeated courses of antibiotics over the years. There are occasional patients whose symptoms are so frequent and persistent that the clinician is tempted to use an~ibiotics prophylactically, usually during the winter months. However, prophylactic antibiotic is of no value and may lead to infection with resistant organisms.u Steroids are being used increasingly in the management of bronchial asthma. Antibiotics are used concurrently with steroids when infection is present. Antibiotics are not necessary simply because the patient is receiving short-term or maintenance steroids. Increased precautions and suspicion of infection, both overt and masked, are necessary in the patient on pharmacological doses of steroids. Bacterial Vaccine The decision to use bacterial vaccine cannot wait': for the research laboratory to deliver the answer. Practical decisions are required daily. I use the following routine: in patients with perennial asthma that appears related to respiratory infection and of sufficient severity to
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Bacterial Vaccine
ORGANISM
NUMBER OP ORGANISMS PER ML.
Neisseria catarrhalis Klebsiella pneumonia Diplococcus pneumonia Type I Diplococcus pneumonia Type II Diplococcus pneumonia Type III Diplococcus pneumonia Type V, VII, VIII, XIV Streptococcus hemolyticus Streptococcus other than hemolytic us Staphylococcus a l b u s · Staphylococcus aureus Corynebacterium diphtheroid Hemophilus influenzae
X 10·
5 5 2. 5 2. 5 2.5 2.5 5 5 25 25 10 10
justify injection treatment, and in whom extrinsic sensitivities cannot be determined after careful history, skin testing, and observation, bacterial vaccine is given. Using a stock heat-killed bacterial vaccine in a maximum concentration of 100 X 106 organisms per mI. (Table 1), a series of 15 weekly injections of increasing concentration is given and the maximum dose, 0.5 mI., or the maximum tolerated dose, which may be less, is continued every 2 to 3 weeks. The parents receive an explanation of the empirical nature of the treatment, and the patients are evaluated every 4 to 6 months. The most common error in this treatment is overdosage, and the parents and the treating physician often fail to recognize rhinitis, cough, and wheeze recurring within 48 hours after each injection. Patients who have not responded at the end of 1 year are occasionally carried on for 2, but in most patients treatment is discontinued. Patients who have improved at the end of 1 year are continued on treatment for another year or two and then treatment is discontinued. Bacterial vaccine is rarely given for more than 3 consecutive years. In my personal experience, autogenous vaccines have provided no particular advantage over stock vaccines. Miscellaneous Measures
Gamma Globulin. It is well documented that regular injections of gamma globulin are of no value in the management of bronchial asthma. 8 Further, there is recent evidence that gamma globulin regularly injected may not be entirely innocuous and may result in antibody to human gamma globulin (aggregated).17 Immunization. Patients with bronchial asthma should be immunized in the usual manner against smallpox, tetanus,diphtheria, pertussis, poliomyelitis, and measles. Although allergic children have a tendency to develop enhanced local and systemic response, this is not a contraindication. In the occasional child with severe systemic response (fever
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and toxicity), it is useful to give one quarter or one half the dose and repeat fractional injections until the total immunizing dose has been given. Immunization with tetanus toxoid should be kept current and, if passive immunization is necessary, human antitetanus globulin should be given. Horse antitetanus serum should be avoided. Live measles vaccine contains minimal amounts of egg antigen. Patients who are extremely sensitive to egg clinically should not be immunized. These patients should be given passive protection, either complete or partial, with gamma globulin upon exposure. For the usual allergy patient who may have a positive skin test to egg, but can tolerate a small amount of egg, measles vaccine can be given with the following precautions: a longacting antihistamine, approximately an hour before the injection, and observation of the patient in the office for at least an hour after the injection, with adrenalin available in the event of a reaction. Patients with bronchial asthma and atopic dermatitis should not be vaccinated against smallpox while there are active lesions on the skin. Vaccination of the patient with eczema is usually safe after the skin has been clear for 12 months. In epidemic years, prophylactic injections with Asian influenza vaccine are useful adjuncts. Since the vaccine contains minimal amounts of egg antigen, the same precautions mentioned above for measles vaccine should be taken. Patients with bronchial asthma may be given typhoid vaccine, when this is required for travel, and similar prophylactic injections of gamma globulin for protection against hepatitis, rubella, etc.
INFECTION IN SEASONAL ALLERGIC RHINITIS
In seasonal rhinitis, infection occurs mainly as a secondary phenomenon. Purulent sinusitis and conjunctivitis occur not infrequently during and especially after the season, and the anticipated relief at the end of the pollination season does not occur. Antibiotics, as well as symptomatic medication, are necessary to control these symptoms.
INFECTION IN PERENNIAL ALLERGIC RHINITIS
The symptoms of perennial allergic rhinitis are nasal obstruction, mouth breathing, rhinitis, and repeated upper respiratory infections. In some patients, significant extrinsic sensitivities can be incriminated, but not in others. In perennial rhinitis, infection tends to play the same role it does in bronchial asthma, that is, direct infection, secondary infection, and infectious allergy. In some ways, the concept of infectious allergy is better suited to the symptoms of allergic rhinitis with perennial con-
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gestion of the nasal mucosa and repeated upper respiratory infections because the organism (antigen) may be continuously present in the site of symptoms. In some cases, perennial nasal congestion is an obvious familial trait and the role of infection must be secondary. Nasal polyps are .not common in children and tend to develop in the teenager who has a long history of perennial rhinitis and repeated purulent infection. Many of these patients have associated asthma, and of these a small number are. exquisitely sensitive to aspirin; others have cystic fibrosis. The treatment· of infection in perennial allergic rhinitis follows the same pattern as that of bronchial asthma-that is, avoidance of the significant environmental and food sensitivities, symptomatic therapy, and antibiotics for bacterial infection. When respiratory infections are frequent and prolonged,a trial of bacterial vaccine is indicated. Indication for Tonsillectomy and Adenoidectomy The indications for removal of the tonsils and adenoids in allergic children are the same as they are in nonallergic children. These indications are repeated tonsillitis, peritonsillar abscess, obstruction of the nasopharynx, or unusual unilateral hypertrophy. The lymphoid tissue in the nasopharynx seems to hypertrophy earlier and to a greater extent in the allergic patient than in the nonallergic patient. This hypertrophy often leads to early adenoidectomy and, in some of these patients, lymphoid tissue regrows over the next 2 or 3 years. In general, removing large tonsils or adenoids simply because they are large will do little to affect the course of asthma or perennial rhinitis.
INFECTION.IN RECURRENT OTITIS MEDIA
Recurrent otitis media is a proplem seen commonly in allergic practice. The precise mechanism is. not understood, but present concepts suggest that the eustachian canal fails to' maintain equal pressure in the middle ear and in the nasopharynx. 7 Obstruction of the eustachian canal is followed by resorption of air from the middle ear and increase in negative pressure with accumulation of fluid in the middle ear. This fluid is close to serum in its composition. It is not known whether the fluid is actively secreted by the' mucosa or whether it is a transudate. 21 In some children the secretion is, mucoid and gluelike. The child presents with recurrent' otitis media, hearing loss' or variations of these symptoms. This condition occurs in children under 10 years of age and tends to improve during adolescence. . Although allergy and infection are often implicated in the pathogenesis of obstruction in the eustachian capal, in many patients significmit extrinsic sensitivities. cannot be demon~trated, nor is there evidence
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of acute or chronic infection. About half the patients referred to the allergist already have had tonsils and adenoids removed, and theoretically all mechanical obstruction has been overcome. This fact alone would suggest that simple removal of tonsils and adenoids is insufficient for control of this condition, and this observation has recently been documented. 22 Optimal treatment of recurrent otitis requires the- combined effort of pediatrician and otolaryngologist. These patients require allergic management with environmental and food avoidance, symptomatic therapy, and particularly early and vigorous treatment of infection. When indicated, removal of mechanical obstruction (adenoids), myringotomy, and insertion of tubes are necessary. Occasional patients, particularly those with repeated upper respiratory infection, seem to benefit from a course of bacterial vaccine treatment. -
INFECTION IN ATOPIC DERMATITIS
The pathogenesis of this common and distressing condition remains an enigma. There are obvious genetic and environmental factors. Many of these children develop bronchial asthma or allergic rhinitis as the skin spontaneously improves. In others, eczema and asthma coexist, often with a fascinating inverse relationship, so that the asthma is worse as the skin improves and the skin becomes worse when the asthma abates. Many infants have significant food sensitivities with immediate or, less frequently, delayed clinical reactions; others have no obvious sensitivities. In some patients, skin-fixed reagins to inhalants are present years before respiratory symptoms develop. Many of these patients have abnormal skin vasculature, others a significant eosinophilia. Ultimately all these facets will be fitted into a unified hypothesis. 9 Infection seems to playa secondary role in atopic dermatitis. Infection is not always clinically apparent and must be continuously suspected. When infection is present, pruritus is. usually increased in intensity, and similarly, increased -pruritus often l~ads to infection. Impetigo due to streptococcus and staphylococcus is a common complication, and an occasional poststreptococcal nephritis develops from such a skin infection. Secondary infection may be iatrogenic, particularly when occlusive dressings are used for prolonged periods. Mild infection responds to topical treatment with soaks and antibiotic creams; more widespread infection requirt{s systemic antibiotics. Atopic dermatitis may worsen during an ordinary upper respiratory infection. It is a long-standing clinical observation that after measles and other severe systemic diseases, the skin rriay clear for a variable period. The skin of patients with atopic dermatitis is notoriously susceptible to infection with vaccinia virus and herpes virus. Life-threat~n~ ing infections may occur from the inadvertenf vaccination of a patient
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with active atopic dermatitis or even a patient in proximity to another child with the condition. Atopic dermatitis is a definite contraindication to vaccination for smallpox. Fortunately, some treatment for generalized vaccinia is now available with methisazone5 and hyperimmune vaccinia gamma globulin.
INFECTION IN URTICARIA
In some children, urticaria develops coincident with or immediately after what appears to be a viral respiratory infection. Investigation for a specific ·cause, however, is unrevealing. These children tend to develop recurrent hives with each subsequent respiratory infection, and this state of affairs may last for months or years. Infection, food and drug sensitivity, and emotional factors are considered the usual causes of chronic urticaria. As a rule, infection cannot be implicated. While it is true that the rare case of chronic urticaria will improve after parasitic infestation is eradicated or carious teeth are removed or a urinary infection clears, most children with chronic urticaria cannot be shown to be infected.
INFECTION IN IMMUNOLOGIC DEFICIENCY STATES25
In the 17 years since the first case of congenital sex-linked agammaglobulinemia was published, a sufficient number and variety of these patients have been described to establish preliminary but useful classifications. The fundamental feature of these patients is their inability to control infection. As a consequence, investigation has provided great insight into the mechanisms of immunity. Important observations have been made on circulating immunoglobulins, on the immunoglobulins and antibody content in respiratory and mucosal secretions, ~n the thymus, the lymphocyte and the lymphoid system, on complement, on the leukocyte, and phagocytosis, and the list continues to grow. It is fair to say that these patients have done more for medical science than science has for them. . At this time the useful functions of the clinician are the early recognition of disease, the early institution of treatment, and the applicatio!1 of genetic knowledge for counseling. In specific IgG deficiency, replacement gamma glob~lin and antibiotics remain the accepted treatment. Transient,.-isolated IgM deficiency states do not require gamma globulin injections, but an extended course of antibiotic therapy may be helpful. Preliminary experimental attempts have been made to reconstitute these patients with syngeneic bone marrow cells and thymic grafts. In
THE
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general, these attempts have been unsuccessful, but recent reports are more hopeful and suggest that successful reconstitution will be feasible.
INFECTION IN COLLAGEN DISORDERS
In rheumatoid arthritis, the search for infectious agents continues, and attention has focused on the pleuropneumonia-like organisms. 6 Rheumatoid factor has been noted during acute infections such as SBE20 and may be experimentally induced in a variety of ways, including repeated injections of bacterial cells. 12 The role of infection in systemic lupus erythematosus,4 in scleroderma, polymyositis, and systemic vasculitis remains an enigma, but the search continues. These patients are susceptible to secondary infection because of the underlying disease and steroid treatment.
INFECTION IN AUTOIMMUNE DISORDERS
In the so-called autoimmune diseases, the debate on etiology continues. At least in one group of these diseases, such as rheumatic fever, glomerulonephritis, and primary atypical pneumonia, the primary event is thought to be an infection followed by an autoimmune reaction between the antibody formed and the infecting antigen. In the diseases in which tissue antigenicity is altered (thyroid, heart), the primary event may be infection of these tissues, followed by an autoimmune reaction between antibody and altered tissue antigen. 2
SUMMARY
Infection plays a fundamental role in allergic disease. Infection is a common complication of allergic asthma and rhinitis. Infection probably plays an important role in intrinsic asthma, in perennial rhinitis, and in recurrent otitis media. The mflchanisms by which infection may affect allergic disease are mentioned. The treatment of infection, including the role of bacterial vaccine, is discussed.
REFERENCES 1. Aas, K., BerdaI, P., Henriksen, S;...IJ., and Gardborg, 0.: "Bacterial allergy" in childhood asthma and the effect of vaccine treatment. Acta. Paediat. Scand., 52:338-344, 1963. 2. Asherson, C. L.: Auto-immune disease.!. Brit. Med. J" 3:417-420, 1967.
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3. Austen, K. F.: Histamine and- other mediators of allergic reactions. In Samter, M., ed.: Immunologic Diseases. Boston, Little, Brown & Co., 1965, p. 211. 4. Bolman; H. R: Systemic lupus erythematosus. In Samter, M., ed.: Immunologic Diseases. Boston, Little, Browri & Co., 1965, p. 744. 5. Brainerd, H. D., Hanna, L., and Jawetz, E.: Methisazone in progressize vaccinia. New Eng. J. Med., 276:620-622, 1967. 6. Christiap, C. L.: Rheumatoid aithritis. In Samter, M., ed.: Immunologic Diseases. -."Boston,Little, Brown & Co.; 1965, p. 735. 7. Chronic serous otitis media in childhood: A new treatment: Clinical rounds. Clin. Pediat:, 3:718-727, 1964. 8. Crepea, S. B., and Friedlaender, S.: The use of gamma globulin in the treatment of intrinsic asthma. J. Allergy, 30:439-441, 1959. 9. Conference on infantile eczema. J. Pediat.; January 1965, part 2. 10. Crump, J.; Value of vaccine treatment in allergic respiratory conditions. PEDIAT. CUN. N. AMER., I:987~933, 1954. 11. Davis, S. D., and Wedgwo.od, R J.: Antibiotic prophylaxis in acute viral respiratory diseases. Amer. J. Dis. Child., 109:544-553, 1965. 12. Eisen, A. H.,_ and Bacal, H. L.: Immunologic response to bacterial vaccine. Int. Arch. Allergy, 31:14-24, 1967. 13. Fontana, V. J., Salanitro, A. S., Wolfe, H. I., and Moreno, F.: Bacterial vaccine and infectious asthma. J.A.M.A., 193:895--900, 1965. 14. Freeman, G., and Todd; R H.: The role of allergy in viral respiratory tract infections. Amer. J. Dis. Child., '104:330-334, 1962. 15. Gundy, J. E.: Acellular bacterial antigen complex (Hoffmann) in the treatment of children with recurrent respiratory' infections and infectious asthma. J. Pediat., 51:516-526, 1957: 16. Hampton, S. F., Johnson, M. C., and Galakatos, E.: Studies of bacterial hypersensitivity in asthma. 1. The preparation of antigens of Neisseria catarrhalis, the induction of asthma by -aerosols and the performance of skin and passive transfer tests. J. Allergy, 34:63-95, 1963. 17. Henney, C. S., and Ellis, E. F.: Antibody production to human 'Y G-globulin in acquired hypogammaglobulinemia. New Eng. J. Med., 278:1144-1146, 1968. 18. Horesh, A. J.: Allergy and infection. 6. The criteria-for judgment. J. Asthma Res., 5:89-113, 1967. 19. Ishizaka, K.: Gamma globulin and -molecular mechanisms in hypersensitivity reactions. Progr. Allergy, 7:32-106, 1963. 20. Messner, R. P., Laxdal, T., Quie, P. Q.; and Williams, R C.: Rheumatoid factors in subacute bacterial endocarditis-bacterium, duration of disease or genetic predisposition? Ann. Int. Med., 68:746-756, 1968. 21. Miller, C. F.: Eustachian tubal function in. normal and diseased ears. Arch. Otolaryng., 81:41-48,1965.' . 22. Murray, A. B., Anderson, D. 0.,_ Camhon, K. G., Moghadam, H. K., and Robinson, G. C.: A survey of hearing loss in Vancouver school children. 2. The association between secretory otitis media and enlarged adenoids, infection and nasal allergy. Canad. Med. Ass. J., 98:995-1001, 1968. 23. Ouellette, J. J., and Reed, C. E.: Increased response of asthmatic subjects to methacholine after influenza vaccine. J. Allergy, 36:558-563, 1965. 24. Peterson, R D" Wicklunds, P.-E., and G@od, R A.: Endotoxin activity of house dust extract. J. Allergy, 35: 134-142, 1964.. 25. Rosen, F. S., and Janeway, C. A.: The gamma globulins. 3. The antibody deficiency syndromes. New Eng. J. Med., 275:709-715, 769-775, 1966. 26. Sheldon, J. M., Lovell, R G., and Mathews, K. P.: A Manual of Clinical Allergy. 2nd .ed. Philadelphia, W. B. -Saunders Co., 1967, p. 95. 27. Sheldon, J. M., Lovell, R G., and Mathews, K. P.: A Manual of Clinical Allergy. 2nd ed. Philadelphia, W. B. Saunders Co., 1967, p. 24. 28. Shirkey, H. C., and Barba, W. P.: Drug therapy. In Nelson, W. E., ed.: Textbook of Pediatrics. 8th ed.l'hj.ladelphia, W. B. Sau~ders Co., 1964, p. 222. 29. Syoq~ist, J., Forsgren, A., Gustafson, G. T., and Stalenheim, G.: Biological importance of the Fe-region of gamma globulins. In Cold Spring Harbor Symposia on Quantitative Biology, Vol. 32: Antibodies, pp. 577-581, 1967.
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30. Szentivanyi, A., and Fishel, C. W.: Effect" of· bacterial products on responses to the allergic mediators. In Samter, M., ed.: Immunologic Diseases. Boston, . Little, Brown & Co., 1965, p. 226. 31. Vaughan, W. T., and Black, J. H.: Practice of Allergy. 2nd ed. St. Louis, C. V. Mosby Co., 1948, p. 26. 32. Vaughan, W. T., and Black, J. H.: Practice of Allergy. 2nd ed. St. Louis, C. V. Mosby, 1948, p. 729. .. ' . 33. Zaid, G., and Beall, G. N.: Bronchial response to beta-adrenergic blockade: New Eng. J. Med., 275:580-584, 1266. 2300 Tupper Street Montreal 108, Quebec