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New perspectives in allergic asthma Samuel O. Freedman, md,

frcp[c],

Major advances have recently been made in both the diagnosis and the treatment of allergic asthma. The radioallergosorbent test (RAST), which measures allergen specificity of IgE antibodies in vitro, offers as good results as direct skin tests for allergy, without the inconvenience, discomfort and risk for the patient of the latter. However, the RAST must be done in a radioisotope laboratory, and standardized extracts of test

allergens

are

lacking.

Several new drugs, administered by inhalation and relatively free from serious side effects, are highly effective in treating asthma. Disodium cromoglycate, believed to stabilize tissue mast cells, protects particularly against exercise- or antigen-induced bronchospasm, and often permits reduction or withdrawal of corticosteroid therapy. Some acetonides or esters of glucocorticoids, because of their greatly increased topical anti-inflammatory activity, are effective in doses too small to cause serious systemic side effects. With the most topically effective, beclomethasone dipropionate, systemic corticosteroid therapy can usually be reduced or withdrawn, but recovery of hypothalamic-pituitary-adrenal function may be delayed; the drug regimens should therefore overlap. La medecine a fait recemment de grands progres dans le diagnostic et le traitement de I'asthme allergique. Le test radioallergosorbant (RAST), qui permet de mesurer la specificite allergenique des anticorps IgE in vitro, From the division of clinical immunology and allergy, department of medicine, The Montreal General Hospital and McGill University, Montreal Presented at the annual meeting of the Canadian Society of Allergy and Clinical Immunology, London, Ont., June 1975 Reprint requests to: Dr. S.O. Freedman, Director, Division of clinical immunology and allergy, The Montreal General Hospital, 1650 Cedar Ave., Montreal, PQ H3G 1A4

facp

donne des resultats aussi bons que les cutireactions directes de I'allergie, sans en presenter les inconvenients, les malaises et le risque pour le malade. II faut admettre que le RAST doit etre fait dans un laboratoire de radioisotopes et que les extraits standardises des allergenes font defaut. D'autre part, plusieurs medicaments nouveaux, administres par inhalation et relativement exempts d'effets secondaires graves, se sont reveles tres efficace dans le traitement de I'asthme. Le cromoglycate disodique, que l'on croit susceptible de stabiliser les mastocytes tissulaires, protege particulierement contre les bronchospasmes provoques par I'effort ou par des antigenes, et permet souvent de reduire ou de suspendre la corticotherapie. Certains acetonides ou esters des glucocorticoides, en raison de leur activite anti-inflammatoire grandement augmentee, sont efficaces a des doses trop faibles pour entrainer de graves reactions secondaires systemiques. Celui d'entre eux avec le plus d'efficacite topique, le dipropionate de beclomethasone, permet habituellement de reduire ou d'arreter completement la corticotherapie, mais le retablissement fonctionnel de I'axe

hypothalamo-pituitaire-adrenal peut

retarde; les deux medications devraient done se chevaucher.

etre

The complex problem of asthma, with its multifactorial pathogenesis and varying clinical manifestations, has understandably led to many different diag¬ nostic procedures and treatments being advocated over the years. The recent development of serologic tests for measuring responses to allergens in vitro and the discovery of potent new drugs that are relatively free from serious side effects have led the most

optimistic investigators to proclaim a in the management of bron¬ chial asthma. In particular, the intro¬

new era

346 CMA JOURNAL/FEBRUARY 21, 1976/VOL 114

duction of highly effective new drugs has made hyposensitization therapy, which is inconvenient for the patient and is of doubtful value in allergic asthma, an increasingly less attractive alternative to the immunopharmacologic approach to asthma therapy. In vitro tests for

allergy The frequent finding of positive skin tests that are unrelated to clinical symp¬ toms, or of positive mucosal challenge tests in individuals who are skin-test negative, has led many allergists to conclude that direct skin testing is less than ideal as a method of identifying precisely the causative agent in allergic disease. Thus, the newer in vitro diag¬ nostic techniques, if their results can be proven to correlate with clinical symptoms, offer distinct advantages. Radioallergosorbent test (RAST) The RAST, the technique most wide¬ ly used to measure the allergen specifi¬ city of IgE antibodies, is the first prac¬ tical in vitro test for allergy.1 It is based on the antiglobulin test first described by Coombs, but modified because of a lack of suitable methods for coupling allergens to erythrocytes. In the RAST an excess of allergen is coupled to cyanogen-bromide-activated cellulose par¬ ticles. The complex is then incubated with the patient's serum, whereupon antibodies in the serum attach to the antigen-coated particles. The concen¬ tration of IgE in the serum is deter¬ mined by adding radiolabelled anti¬ bodies of animal origin directed against human IgE. The results ob¬ tained with the patient's serum are then compared with those obtained with standard sera of known IgE concentra¬ tion. For clinical purposes the findings are classified as negative (0), borderline (1), clearly positive (2), strongly posi¬ tive (3) or very strongly positive (4). The role of the RAST in the in¬ vestigation of patients with suspected allergic symptoms requires careful eva-

luation because it is the most promising advance in allergy diagnosis in over 50 years. As presently performed the RAST gives results that are qualitatively comparable to prick testing and superior to direct intradermal testing.2 In a study of 300 children with al¬ lergies due to a variety of inhalants an overall agreement of 83% between re¬ sults of RAST and prick testing was found.3 For the purified grass allergen rye group I, the correlation between skin testing and radioimmunoassay in

atopic dermatitis, suppressed activity or dermatographia. New

skin

re¬

pharmacologic agents Disodium cromoglycate The chromone compound khellin, de¬ rived from the seeds of Ammi visnaga, a plant that grows wild in the Eastern Mediterranean area, has long been known to relax smooth muscle and was used successfully in the 1940s to treat bronchial asthma. Unfortunately, in grass-sensitive patients was 97.5%, therapeutic doses khellin usually pro¬ with 93 for crude extract a % compared duces nausea and vomiting. of mixed grasses. In the 1960s disodium cromoglycate The choice of direct skin testing or (DSG), a synthetic chromone analogue the RAST as the initial diagnostic pro¬ that does not relax smooth muscle, was cedure in allergic patients thus becomes shown to inhibit the bronchoconstrica matter of selecting one of two alter¬ tion that normally follows the inhala¬ natives, neither of which is superior in tion of antigen a sensitized asth¬ providing quantitative data or in corre- matic subject,4 butbyonly if administered lating with biologic events. Direct skin before the antigen challenge. Although testing is carried out easily as an office understood, the action of procedure with simple, readily ob¬ incompletely this compound appears to be quite dif¬ tained materials, and results are avail¬ ferent from those of the adrenergic and able within minutes. On the other hand, bronchodilators and the methylxanthine tests for specific IgE antibodies will which have long been probably soon be widely accepted as a glucocorticoids, the mainstays in the management of valid alternative to skin testing, pos¬ bronchial asthma. sibly for no other reason than their It is thought that DSG convenience and lack of discomfort or stabilizes presently tissue mast cells against the risk for the patient. The RAST can degranulation caused by antigen-antibe performed within 1 or 2 days on reactions that take place at their small amounts of stored serum but only body cell surfaces, and thereby prevents the in specialized hospital or regional ra¬ release of substances that induce the dioisotope laboratories. Because it is asthmatic reaction.5 Exercise-induced commonly performed for a limited bronchospasm, common in asthmatic number of allergens, selected on the is often prevented when DSG basis of the allergy history, the RAST subjects, is inhaled immediately before exercise. is a better diagnostic approach than Therefore, it may be that exercise-in¬ "screening" with a large number of duced asthma is due to mechanical disdirect skin tests for minor hypersensi- ruption of unstable mast cells caused tivities of questionable clinical im¬ by increased lung movements during portance. exertion. One of the major problems of the DSG is poorly absorbed from the RAST is the lack of standardized ex- gastrointestinal tract and is therefore tracts with known and uniform charac¬ administered as a micronized powder teristics for coupling to the cellulose. delivered by a specially designed inThe solution is to use partially purified haler. The duration of the local ther¬ extracts of allergens, such as ragweed apeutic effect in the lung depends on antigen E or rye group I, but such the dose of DSG and the degree of preparations are available for only a antigen exposure. Low doses may pro¬ very small proportion of the hundreds tect for less than 2 hours, whereas a of allergens known to cause allergic full 20-mg dose protects for 5 to 6 respiratory disease. hours and sometimes up to 24 hours.6 The RAST appears to be the diag¬ However, the protective effect of DSG nostic procedure of choice in patients can be overwhelmed by heavy antigen for whom the skin test either is not challenge; then, by shortening the inter¬ feasible or yields unreliable results, vals between administration of DSG, such as those for whom in vivo testing the response to the drug may improve. In numerous clinical trials DSG has might be dangerous because of a his¬ tory of extreme sensitivity to allergens, been shown to be effective in treating such as fish, egg white, nuts or castor adults and children with extrinsic and beans, known to evoke severe systemic intrinsic asthma.7,8 The experimental reactions on direct skin testing; those protocols and criteria for patient se¬ from whom antihistaminics or drugs lection have varied greatly and are not with antihistaminic properties (e.g., strictly comparable, but in most pa¬ tranquillizers) cannot be withdrawn tients good results have been reported without risk; or those with severe in terms of symptoms, pulmonary func¬

tion test results and requirements for bronchodilator drugs and corticoster¬ oids. Because DSG inhibits the release of chemical mediators from mast cells, the drug should be most effective in treating patients with allergic asthma

and, indeed, many investigators report

better response in this group of pa¬ tients than in those with other forms of asthma. However, for obscure rea¬ sons, an unpredictable proportion of patients with nonallergic asthma will benefit from DSG therapy. Thus, there appear to be no rigid criteria for predicting whether a patient will benefit from treatment with DSG. In general, older patients with intrinsic asthma and patients with persistent bronchial infection are the least likely to respond, whereas patients with in¬ creased serum IgE values are more likely to respond well.9 A 1-month trial of prophylactic DSG is appropriate in the asthmatic patient who requires long-term corticosteroids or repeated short courses, or whose symptoms are not adequately controlled by moderate doses of conventional bronchodilators. a

In

steroid-dependent patients, daily ad¬

ministration of DSG frequently permits a reduction in the maintenance dose of corticosteroids, a change to alternate-

day therapy, or occasionally complete withdrawal of corticosteroid therapy. The steroid-sparing effect of DSG is most apparent in children and patients with demonstrable sensitivity to com¬ mon inhalant allergens. DSG also helps wean some patients from excessive de¬ pendence on adrenergic aerosols. Be¬ cause of its protective effect against exercise- or antigen-induced broncho¬ spasm, DSG is valuable for susceptible individuals immediately before athletic activity or transient exposure to an unavoidable allergen (e.g., before a patient allergic to horse dander enters a stable). On the other hand, the prophylactic use of DSG is not indicated for in¬ dividuals with mild or infrequent at¬ tacks of asthma, and it is of no benefit in the emergency management of se¬ asthma because it will not reverse

vere

existing bronchospasm and, indeed, worsen airway obstruction by mechanically irritating hyperreactive may

bronchi. DSG is free of serious side effects. Dry mouth, sore throat or increased wheezing due to mechanical irritation may follow inhalation of the powder. Maculopapular or urticarial skin eruptions, nausea and vomiting, and eosin¬

ophilic pneumonia occur occasionally.

Aerosolized corticosteroids Prolonged oral administration of cor¬ ticosteroids with a relatively pure glucocorticoid action, such as prednisone, betamethasone or dexamethasone, leads

CMA JOURNAL/FEBRUARY 21, 1976/VOL 114 347

to serious side effects. The anti-inflammatory action of these agents is unequivocally beneficial in asthmatic individuals but their other effects are generally harmful. In particular, the suppression of hypothalamic-pituitaryadrenal (HPA) function makes the patient less able to respond to stress. This is especially dangerous when oral corticosteroid therapy is discontinued and recovery of adrenal function is incomplete. While corticosteroid therapy is essential for certain patients with severe chronic bronchial asthma, how to prevent or minimize serious side effects of long-term therapy is a major problem. Recently it has been found that certain acetonides or esters of glucocorticoids have greatly increased topical anti-inflammatory activity without increased systemic activity; examples are beclomethasone dipropionate, betamethasone valerate, triamcinolone acetonide and fluocinolone acetonide. Even though these corticosteroids are absorbed from the lung and gastrointestinal tract after inhalation, they are so active topically that they have a local therapeutic effect at doses too small to suppress HPA function or cause other systemic side effects. Beclomethasone dipropionate was chosen for most of the early clinical trials because it has the greatest topical activity and because the parent steroid, beclomethasone, appeared to have the least systemic activity in animals. Evidence for the therapeutic usefulness of beclomethasone dipropionate and other such topically active corticosteroids in the inhalation treatment of steroiddependent asthma is constantly accumulating. Beclomethasone dipropionate, 400 to 600 .g/d administered as an aerosol, was found to control effectively the symptoms of asthma and enable patients to reduce or even stop taking systemic steroids.'0 In at least 70% of patients from whom oral steroid therapy is withdrawn adrenal function recovers." The optimum therapeutic dosage for inhaled beclomethasone dipropionate depends on the severity of the asthma. Data from a controlled double-blind trial indicated that 400 . daily of this drug was effective and permitted at least a 50% reduction in the daily dose of prednisone in 62% of patients taking 15 mg/d orally or less of the latter, whereas 800 . daily of beclomethasone was required for optimum effect in those taking more than 15 mg of prednisone daily.'2 HPA function may be suppressed in some patients taking 2000 ,.g or more daily of inhaled beclomethasone; therefore, the daily dose should not be increased above 1000 ,.tg unless adrenal function is monitored regularly.'3

The greatest problem in managing steroid-dependent patients when systemic corticosteroids have been completely replaced by inhaled beclomethasone dipropionate is delayed recovery of HPA function. The risk of adrenal insufficiency after withdrawal of oral prednisone therapy can be greatly reduced if the prednisone and beclomethasone regimens are overlapped by 1 week and the daily dose of prednisone is reduced by 2.5 mg/wk when adrenal stimulation tests show normal function, and by 1 mg/mo when there is evidence of adrenal suppression. The patient should be instructed to inform his doctor immediately if his symptoms worsen suddenly or if symptoms suggesting adrenal insufficiency, such as nausea, abdominal pain or muscle weakness, develop. Temporary reinstitution of oral corticosteroid therapy is frequently necessary to treat acute exacerbations of asthma triggered by viral upper respiratory tract infections, because not enough inhaled beclomethasone can penetrate the smaller airways to control symptoms effectively. Severe allergic rhinitis or atopic eczema recurs in some patients receiving beclomethasone aerosol therapy when oral corticosteroid therapy is withdrawn. Oral candidiasis also occurs in some patients but is easily treated and rarely sufficiently troublesome to necessitate stopping therapy with the aerosol. In fact, the advantage gained by the patient when the oral corticosteroid therapy is reduced or discontinued probably far outweighs any of the complications outlined above. Hyposensitization therapy Although immunotherapy with pollen and other allergens has been advocated as effective treatment of allergic asthma since the early 1920s - and, indeed, was considered by many as the "raison d'etre.' of the clinical allergist - its acceptance as a therapeutic modality depended mainly on uncontrolled personal observations. It is only within the last 15 years that clinical trials designed to assess objectively the efficacy of immunotherapy, and in vitro studies designed to measure its immunologic effects, have raised doubts concerning the appropriateness of immunotherapy as a routine treatment. A series of rigidly controlled studies of therapy with pollen extract and placebo has demonstrated beyond reasonable doubt that immunotherapy provides substantial relief of symptoms in most patients with ragweed or grass hay fever.14 The relief is incomplete, however. Although control of symptoms is difficult to evaluate quantitatively, it seems to most observers that the degree

$48 CMA JOURNAL/FEBRUARY 21, 1976/VOL 114

of illness in the average patient is reduced by no more than 50%. It is tempting to extrapolate to the management of pollen asthma the data showing that hay fever caused by certain plant pollens is partially relieved by immunotherapy at adequate dosage, but rigorous proof for the efficacy of immunotherapy in any form of asthma is presently lacking. The necessary doubleblind studies have not been conducted. Overall management of allergic asthma

The mainstays of ambulatory treatment in the majority of patients with allergic asthma are the oral administration or inhalation of p.-adrenergic agents (e.g., salbutamol) and the oral administration of aminophylline tablets to tolerance.'5 In patients who are resistant to conventional bronchodilator medication it seems reasonable to re. gard prophylactic disodium cromoglycate as the drug of first choice in view of its absolute safety and the chances of benefiting a high proportion of those with atopic asthma. If adequate control is still not achieved, the administration of inhaled topical corticosteroids on a maintenance basis or intermittent short courses of oral prednisone is indicated. References 1. WIDE L, BENNICH H, JOHANSSON SGO: Diag-

nosis of allergy by an in-vitro test for allergen antibodies. Lancet 2: 1105, 1967 2. BERG TLO, JOHAN5SON SGO: Allergy diagnosis with the radloallergosorbent test. J Allergy Clin Immunol 54: 209, 1974 3. HOFFMAN DR, HADDAD ZH: Diagnosis of multiple inhalant allergies in children by radioimmunoassay. Pediatrics 54: 151, 1974 4. ALTOUNYAN REC: Inhibition of experimental asthma by a new compound - disodium cromoglycate "Intal". Acta Allergol (Kbh) 22: 487, 1967 5. BROODEN RN, Ss'asosrr TM, AVERY GS: Sodium cromoglycate (cromolyn sodium): a review of its mode of action, pharmacology, therapeutic efficacy and use. Drugs 7: 164, 1974 6. KoLoTsuN BM, LEE CK, TOWNLEY RG: Duration and specificity of sodium cromolyn inhibition on aerosol challenge in asthmatic patients. J Allergy Clin Immunol 51: 87, 1973 7. Brompton Hospital/Medical Research Council collaborative trial: Long-term study of disodium cromoglycate in treatment of severe extrinsic or intrinsic bronchial asthma in adults. Br Med J 4: 383, 1972 8. HYDE JS, FLORO LD: Pros and cons of cromolyn sodium prophylaxis. A summary of experiences with 70 asthmatic children. Clin Pediatr (Phila) 12: 525, 1973 9. BRYANT DH, BURNS MW, LAZARUs L: New type of allergic asthma due to IgG "reaginic" antibody. Br Med J 4: 589, 1973 10. BROWN HM, STOREY G, GEORGE WHS: Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma. Br Med 1 1: 585, 1972 11. GADDIE J, PETRIE GR, RESO 1W, et Aerosol beclomethasone dipropionate

12.

13. 14. 15.

al: in

chronic bronchial asthma. Lancet 1: 691, 1973 Brompton Hospital/Medical Research Council collaborative trial: Double-blind trial comparing two dosage schedules of beclomethasone dipropionate aerosol in the treatment of chronic bronchial asthma. Lancet 2: 303, 1974 CHOO-KoNG YE, COOPER EJ, TRISE AE, et al: Beclomethasone dipropionate by inhalation in the treatment of airways obstruction. Br I Dis Chest 66: 101, 1972 LOWELL FC, FRANKLIN W: A double-blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N Engl I Med 273: 675, 1965 JACK D: Symposium on allergic lung disease. V. Selective drug treatments for bronchial asthma. Can Med Assoc 1 110: 436, 1974

New perspectives in allergic asthma.

tV .*¦¦.-.:: ;v''?^V:^&^^--A^V'Vu^i*-' ¦:'' New perspectives in allergic asthma Samuel O. Freedman, md, frcp[c], Major advances have recently bee...
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