Journal of Asthma, 26(2), 149-152 (1989)

MEETING REVIEW

Review of Pediatric/Adult Allergy and Clinical Immunology Conference

Toronto, Ontario, Canada July 15-17, 1988

Robert F. Lemanske, Jr.

The 11th National Conference on Pediatric/ Adult Allergy and Clinical Immunology was held in Toronto, Ontario, Canada from July 15 through July 17, 1988. This annual con- ference is sponsored by the Department of Pediatrics, Children’s Hospital of Buffalo. A variety of topics were presented in half-hour lecture formats followed by question and answer periods. Discussed below are high- lights of some presentations pertaining to the pathophysiology or the treatment of asthma.

Thomas B. Casale discussed “Neuropep- tides: Nature, Function and Relation to Aller- gic Disease.” Dr. Casale first reviewed airway innervation including fibers originating from parasympathetic, sympathetic, and nonadre- nergic and noncholinergic (NANC) systems. The NANC system is the least well known of the three but is considered by many in- vestigators to contribute, in part, to nervous system control of airway tone, in local reflex

arcs activated by tissue inflammation, and in the pathogenesis of airway hyperresponsive- ness. NANC is comprised of both nonadrener- gic inhibitory and noncholinergic excitatory systems. Vasoactive intestinal peptide and peptide histidine methionine/isoleucine are considered to be neurotransmitters of the nonadrenergic inhibitory system; substance P, neurokinins A and B, and calcitonin gene- related peptide are neurotransmitters in- volved with the noncholinergic excitatory system (1-3).

Peter F. Weller discussed “Eosinophils in Allergy and Inflammation.” Dr. Weller re- viewed the importance of the various granu- lar constituents including major basic pro- tein, eosinophil cationic protein, and eosinophil-derived neurotoxin. He discussed the presence of various cell surface receptors, including a low-affinity receptor for IgE anti- body and the ability of the eosinophil to

149 Copyright 0 1989 by Marcel Dekker, Inc.

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produce a variety of mediators which are believed to play an important role in asthma, including leukotriene C, (in contrast to leukotriene B, made by neutrophils) and platelet-activating factor. The contribution of the eosinophil to various disease processes in- cluding parasitic disease, asthma, allergic rhinitis, skin diseases (atopic dermatitis, scabies, cellulitis, etc.), and hypereosinophilic syndromes was also presented (4).

Robert F. Lemanske discussed “Airway Late Phase Reactions: Nature, Importance and Therapy.” Dr. Lemanske reviewed the pathogenesis of late-phase reactions in both the nose and the lung. Late-phase reactions develop as a consequence of allergen chal- lenge of these target organs and usually develop within 4 to 8 hr following resolution of the immediate response. Since late-phase reactions are felt to be a better model for the study of the pathogenesis of both allergic rhinitis and asthma than is the isolated im- mediate response, research in this area has been intense during the past decade. One common feature of late-phase reactions in both the upper and lower airway is the presence of tissue inflammation; in the nose, the basophil is felt to contribute whereas in the lung, the eosinophil appears to play a more prominent role. Continued study of the effects of various pharmaceuticals on the late response will hopefully lead to the develop- ment of more effective treatment modalities for both asthma and allergic rhinitis (5-7).

Dr. Lemanske also discussed “Nocturnal Asthma.’’ Asthmatic symptoms in general and more severe exacerbations of asthma leading to emergency room visits, hospitali- zation, and even death are much more fre- quent a t night. Compared to nonasthmatics, asthmatic patients tend to sleep less well, and to have more periods of wakefulness and ir- regular breathing. Interestingly, airway re- sponsiveness and cutaneous response to allergen challenge are both increased at night. Factors which have been demonstrated to play a role, at least in part, in nocturnal asthma include late-phase reactions, sleep stages, altered mucociliary clearance, airway cooling, and changes in circadian rhythms. Of these, circadian rhythms including decreased

cortisol levels, decreased catecholamine levels, increased parasympathetic tone, and increased histamine levels are felt to play a prominent role. Therapy for nocturnal asth- ma should be directed to better control of asthmatic symptoms in general (including the introduction of pharmaceuticals with demon- strable effects on decreasing airway hyper- reactivity including cromolyn sodium and topical corticosteroids) and attention to the use of sustained release bronchodilators in- cluding both theophylline and beta agonists (8, 9).

Peter Konig discussed “Aerosol Cromolyn: Present Status in Therapy of Asthma and Rhinitis.” Dr. Konig emphasized that the use of cromolyn as a first-line drug in the treat- ment of asthma has undergone a resurgence in the past few years. Following approval for use in asthma therapy in 1973, initial en- thusiasm for the drug waned as it was initial- ly marketed as a product to potentially reduce corticosteroid requirements in severe asthma and it clearly did not live up to that claim. With the recent introducton of newer delivery systems for the drug (nebulizer solution and metered dose inhalers), its low frequency of drug toxicity, its efficacy in exercise-induced asthma, and its potential to reduce airway hyperreactivity with prolonged administra- tion, have all contributed to cromolyn’s in- creasing popularity in the United States. Although one mechanism of action of cromolyn may involve mast cell stabilization, other mechanisms, still not well defined, no doubt are more important in its beneficial ef- fects (10).

Dr. Konig also discussed “Aerosol Cortico- steroids: Present Status in Therapy of Asth- ma and Rhinitis.” In use for about 16 years, inhaled corticosteroids were introduced as of- fering a safer mode of administration than systemic corticosteroids and were generally considered second-line drugs to be used in pa- tients not controlled by first-line drugs such as theophylline, beta agonists, or cromolyn sodium. Dr. Konig emphasized that a number of changes in our thoughts regarding asthma, specifically that the mechanisms of airway obstruction include not only bronchospasm but tissue inflammation as well, have

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Review of Clinical Immunology Conference 151

resulted in the use of steroids much earlier in individual patient treatment programs. Further, there is increasing evidence that in- haled corticosteroids can decrease nonspecific bronchial hyperresponsiveness and it has been speculated that such an effect can perhaps improve the long-term prognosis of asthma. In Europe, more physicians treating adult asthmatics use inhaled corticosteroids than cromolyn; and in Great Britain, inhaled corticosteroids are more often used than either cromolyn or theophylline. On the other hand, some investigators consider that in- haled corticosteroids offer no major advan- tages over alternate-day prednisone. To fur- ther increase the confusion, a number of new inhaled corticosteroids are now available in the United States, and it is unclear whether triamcinolone or flunisolide present any ad- vantages over beclomethasone dipropionate, the older representative of the groups. Uncer- tainty also exists regarding the appropriate dose, dosing frequency, dosing interval, and delivery systems. Dr. Konig, while empha- sizing that physicians are still frequently afraid of using inhaled corticosteroids, resulting in dangerously undertreated pa- tients, also reinforced the fact that inhaled corticosteroids are not completely free of side effects and therefore should not be automati- cally substituted for all presently used first- line drugs without careful risk-benefit analysis (11, 12).

Anthony M. Yurchak discussed “Theophyl- line: Current Status as Antiasthmatic Therapy and Substitution Problems.” Dr. Yurchak stated that U S . marketing surveys indicate that theophylline products are pre- scribed three out of four times as first-line drugs in the treatment of asthma. Sustained- release products are the most popular because of improved compliance with twice (or even once a day) dosing schedules and their generally predictable dose-response relation- ships that can be monitored with in-office techniques. Although popular for these rea- sons, recent attention has focused on the fact that multiple side effects can occur in patients despite “therapeutic” blood levels (10-20 g/ml). This coupled with variability in theo- phylline clearance due to a multitude of

factors [concomitant drug administration (erythromycin, cimetidine, anticonvulsants), congestive heart failure, liver failure, food in- take, and morel has led to renewed interest in alternative methods of treatment in many patients. Two additional areas discussed in- cluded the relationship of clinical efficacy with serum concentration (75% of the max- imal bronchodilating potential of theophyl- line will occur with serum levels between 5 and 10 g/ml), and mechanisms of action of theophylline (only 5-10% of its activity in vivo is due to its phosphodiesterase activity; other mechanisms include adenosine receptor antagonist, anti-inflammatory activity, and enhancement of diaphragmatic contractility) (13).

Elliot F. Ellis discussed “TAO Therapy of Severe Asthma.” Troleandomycin (TAO) is a macrolide antibiotic and therefore related to erythromycin. Its favorable effects in the treatment of steroid-dependent asthma were first reported in 1959 and since then, its potential role in this regard has remained controversial. TAO interferes with hepatic metabolism of both theophylline and cor- ticosteroids, resulting in increased serum con- centrations. Thus, from the standpoint of the total oral steroid burden, it can be considered to be “steroid-sparing”; however, from the standpoint of biologic activity, it greatly pro- longs the half-life of the circulating drug, thereby substantially increasing the potential for steroid side effects unless the total dose and dosing interval are closely monitored. Protocols for the use of TAO in severe steroid- dependent asthmatic patients have been published (14).

Elliot Middleton, Jr . discussed “Allergy and Asthma in Pregnancy.” Dr. Middleton stated that asthma complicates approximately 1% of all pregnancies in the United States and went on to consider first, the effects of asthma on pregnancy and second, the effects of pregnan- cy on the course of asthma. Several studies of pregnant asthmatics have shown that there is an increase of preterm births, an increase of low birth weight, increased neonatal hy- poxia, increased neonatal mortality, and an increase in perinatal mortality. On the other hand, the effect of pregnancy on asthma may

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vary. Approximately one-third of all pregnant asthmatics improve during pregnancy, another third remain the same, and the final third may worsen. In general, severe baseline disease is likely to worsen during pregnancy but not always. The peak incidence of asthma flares occurs during the 24-36th weeks of gestation and, in general, there are fewer symptoms during the 37-40th weeks of gesta- tion. Dr. Middleton reviewed the potential benefits and risks of the use of various phar- maceuticals for asthma treatment during pregnancy. With the exception of epinephrine (which causes a decrease in uteroplacental blood flow), and the use of sympathomimetic bronchodilators during delivery (these agents can inhibit uterine muscular contraction), most agents (except for ipatropium bromide for which data is insufficient at present) are reasonably safe to use during pregnancy if used judiciously.

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O'Byrne PM, Dolovich J, Hargreave FE: Late asthmatic responses. A m Rev Respir Dis I36:704- 751, 1987. Douglas NJ: Asthma at night. Clin Chest Med

Barnes P J Nocturnal asthma: underlying mechan- isms and implications for therapy. Zmrnunol Allergy Prac 8:9-15, 1986. Shapiro GG, Konig P: Cromolyn sodium: a review. Pharmacotherapy 5156-170, 1985. Siegel SC: Corticosteroid agents: overview of cor- ticosteroid therapy. JAllergy Clin Zmmunol76(2 pt

Konig P Asthma: a pediatric pulmonary disease and a changing concept. Pediatr Pulmon 3:264-275, 1987. Grant JA, Ellis EF: Symposium-update on theophyl- line. J Allergy Clin Zrnmunol 78(4Xpt 2):669-675, 1986. Eltches RW, Rachelefsky GS, Katz RM, Mendoza GR, Siegel SC: Methylprednisolone and trolean- domycin in treatment of steroid-dependent asth- matic children. A m J Dis Child 139:264-268, 1985.

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