Clinical Reviews in Allergy ~Copyright 1992 by The Humana Press Inc. 0731o8235/92/237-251/$3.00
Immunotherapy for Mold Allergy Hans-J rgen Mailing Laboratory of Clinical Allergology, State University Hospital, Copenhagen, Denmark
INTRODUCTION Immunotherapy was introduced in 1911 by Noon (1) as a result of the erroneous belief that allergy was caused by some toxins in pollens. The scientific background was the combined active and passive immunization against rabies, tetanus, and diphtheria that began in the latter part of the 19th century. When subcutaneous pollen extracts were administered to hay fever patients, a reduced sensitivity was observed by conjunctival challenge tests, and the patients reported diminished allergy symptoms. In spite of the rapidly widespread use of immunotherapy, the first controlled study by Bruun (2) in Denmark was not published until nearly 40 years after Noon's observations. Despite intensive research for more than 75 years, i m m u n o t h e r a p y is still largely based on empirical observations regarding diseases responding to treatment and safe dosage regimens. The international allergological societies have recognized that immunotherapy has to be approached in a highly scientific way. Recently the European Academy of Allergology and Clinical Immunology published a position paper on immunotherapy (3), and a status report on the same subject from the World Health Organization/ International Union of Immunological Societies (4) has been issued.
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Efficacy Parameters The exact immunological mechanism or mechanisms underlying the clinical efficacy of immunotherapy are still largely unknown. Several immunological phenomena have been demonstrated (5), but none show any convincing relation to the clinical efficacy, i.e., no parameter can predict the clinical efficacy in individual patients. The missing relation between clinical efficacy and immunological parameters may be caused by the fact that the clinical efficacy is determined by complicated interactions between different immunological parameters, which are not revealed by the evaluation of one single parameter. Conversely, the clinical efficacy may be caused by immunological phenomena varying from one patient to another, and with time.
Specificity Several studies have shown that immunotherapy can alter the allergen-specific hyperreactivity measured by, e.g., skin or challenge tests. A series of studies has clearly shown that, in patients with asthma, immunotherapy reduces bronchial sensitivity and enables patients to tolerate the inhalation of larger amounts of allergens than before the treatment (6). In asthmatics the clinical symptoms are caused by a combination of the inflammatory reaction elicited by the specific allergen and the nonspecific bronchial hyperreactivity (7). In this connection it should be noted that ongoing allergic inflammation increases the patient's symptoms as a result of specific (other allergens) and nonspecific (irritants, and the like) stimuli, so that the patient has more symptoms than those caused by the allergen-IgE interaction (8). When symptoms elicited by the allergen used for immunotherapy are reduced or eliminated, the patient's tolerance for other specific and nonspecific stimuli is increased, and the patient will have fewer symptoms (7).
Criteria for Evaluating Clinical Efficacy In the evaluation of the clinical efficacy of allergen immunotherapy, at least three points are of crucial importance: 1. The diagnostic procedures used to establish the specific diagnosis of allergy; Clinical Reviews in Allergy
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2. The quality of the allergen extract used for immunotherapy; and 3. The validity of the methods used to estimate the clinical efficacy. The clinical efficacy has been documented in clearly IgE mediated diseases only, indicating that authors presenting efficacy studies have to supply convincing data supporting that the patients are in fact IgE-allergic. The diagnosis of allergy is established by various diagnostic tests, and the validity of the tests has to be documented. The specific diagnosis represents a combination of clinical allergy symptoms oscillating in parallel with the allergen load and the demonstration of IgE reactivity, including an unequivocally positive challenge test in the relevant shock organ. Owing to insufficient quality, allergen extracts have until recently been the limiting factor in many immunotherapy studies. The use of well-characterized, qualitatively and quantitatively optimal allergen composition and stable extracts represents the only way to evaluate changes in in vivo and in vitro parameters and increases the probability of obtaining sufficient clinical results. The poor quality of allergen preparations used formerly indicates that clinical studies without a documented clinical efficacy have to be reevaluated, since the lack of efficacy may be a consequence of the use of improper allergen extracts. In the evaluation of the clinical efficacy of allergen immunotherapy, only placebo-controlled and double-blind studies have to be considered (9). Furthermore, only objective clinical parameters (clinical symptoms, drug consumption, and, in asthmatics, pulmonary-function monitoring) should be accepted, since no definite proof exists that any in vivo or in vitro tests correlate to clinical improvement (10). Patients should preferably record daily symptom-medication score for one season before immunotherapy in order to ensure that they really have clinical symptoms caused by the suspected allergen (to etablish a specific diagnosis) and that a possible clinical efficacy is not caused simply by variation between the placebo and the actively treated group in scoring disease severity and drug consumption. The patients may thus serve as their own controls. This very time-consuming way of performing clinical studies may be compensated for by valid conclusions based on fewer patients. Besides the ability to show a positive clinical efficacy of active immunotherapy, another advantage of this methodology is the estimation of
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deterioration of placebo-treated patients---a clinically rather relevant observation. In the evaluation of efficacy, only changes in symptoms and drug consumption that are relevant from a clinical point of view should be considered indicators of efficacy.
Evaluation of the Benefit of Immunotherapy A strictly scientific attitude regarding whether immunotherapy should or should not be added to the pharmacological treatment of asthma is hard to obtain. The use ofimmunotherapy is, however, rather based on emotional feelings or common practice. Immunot h e r a p y has some undeniable advantages over exclusively pharmacological treatment. Immunotherapy has the obvious advantage of regular consultations, implying a closer and more intensive observation of patients with severe disease. This is of special importance in attempting to increase monitoring to prevent undermedication of asthma, and enhances the possibilities of more intensive treatment during acute exacerbations. Another advantage of immunotherapy in the treatment of asthma is the fundamental interference of immunotherapy in the pathophysiological mechanisms responsible for asthma. The component of the IgE-mediated allergic reaction is the immediate earlyphase reaction followed by a delayed late-phase reactivity. During recent years, special attention has been focused on allergy and, especially, asthma as inflammatory diseases, and the severity of the disease is more closely related to the late-phase reaction than to the immediate reaction (11,12). The IgE-mediated early reaction triggers the long-lasting inflammatory response involving eosinophils, neutrophils, macrophages, and so on, which results in a smoldering clinical picture with persistence of symptoms well past the allergen exposure (13). The inflammatory response may evolve into a component of nonspecific bronchial hyperreactivity induced by specific allergen sensitization (14). Several immunotherapy studies have documented a reduction in severity and frequency of both the early (15-17) and the late asthmatic response induced by immunotherapy (18-20). Using the nose as a model for the lower respiratory tract, Creticos et al. (21) have demonstrated an immunotherapy-induced dose-dependent reduction in mediator release on nasal pollen challenge and a significant reduction in patient symptoms during the pollen season. Although still subject to discussion, the reduction in
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mediator release induced by immunotherapy may be the basis of the reduction in nonspecific hyperreactivity reported in some immunotherapy studies (22,23). Before initiating immunotherapy, several factors have to be carefully considered (9). A crucial point is whether allergen sensitization is of importance in exacerbations and in the overall severity of the allergic disease, and whether the overall severity warrants this type of treatment. Allergen avoidance should be implemented whenever possible. When only inadequate allergen extracts are available, immunotherapy should not be instituted. The risks and benefits of including immunotherapy in the treatment modalities of allergic diseases must be carefully balanced. UNCONTROLLEDSTUDIESOF MOLD IMMUNOTHERAPY Although mold allergy has been considered a clinically significant problem, the number of studies reporting a dinical efficacy of mold immunotherapy is rather small. The first case report on mold immunotherapy was published in 1932 by Cobe (24). A greenhouse worker developed a s t h m a from the mold Cladosporium fulvum, which grows on the leaves of tomato plants. Following a course of injections with an extract from a culture of the mold, remarkable clinical relief occurred. Bernton and Thom (25) studied the clinical role of Cladosporium in allergy. Four patients with perennial hay fever and asthma and positive skin test to Cladosporium were given subcutaneous injections with the mold extract. The results of the treatment were regarded by three patients as highly satisfactory in alleviating their distressing symptoms. In a personal communication, Feinberg (26) describes clinical results of primarily Alternaria immunotherapy to be as satisfactory as pollen treatment in 28 patients. In a study of clinical sensitivity to airborne molds, Pennington (27) describes the relation between skin sensitivity to Alternaria and other molds and clinical disease. Seventeen patients, probably of a population of 43 subjects (40%), experienced definite improvements after treatment with mold extracts. Several authors have applied emulsified mold allergens in injection treatment (28--31). Prince (32) reported a larger series of patients treated with various molds during 10-62 mo. The age of treated patients varied from 4 to 62 yr, 40% of patients were
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between 6 and 10 yr. Of the patients, 16% had bronchial asthma only, 30% suffered from nasal allergic disease, and 54% had both. Perennially occurring atmospheric molds appeared to be the major determinants for clinical symptoms, but other inhalant allergens, such as pollens, house dust, and animal epithelium, along with Hymenoptera and food allergens, were applied in the treatment. The patients were randomly placed in a high- and a low-dosage group. The results of injection t r e a t m e n t with mold allergens were classified as good if the patients experienced no symptoms whatsoever, or if occasional symptoms were clearly explained by exposure to nonmold allergens. A fair result was based on symptoms incompletely controlled much of the time. A good therapeutic result was reported by 84% of the patients receiving high dosage and by 62% of patients in the low-dosage group. A fair result was obtained by 14% in the high-dosage group and 32% of the low-dosage group. No improvement was observed in one patient in the high-dosage group and two patients in the low-dosage group. The author concluded that the clinical results of injection treatment with emulsified mold allergens range from satisfactory to good in most patients, and that the control of symptoms persists for longer periods after higher dosage is attained. Given these excellent results, it would have been of much scientific value if this study had included a placebo group and been conducted in a double-blind fashion, and if the evaluation of the clinical results had been prospective. Studying children with chronic intractable asthma, Tuchinda and Chai (33) investigated injection treatment with aqueous extracts of Alternaria, pollen, and house dust. Ten patients received high dosage, from 30,000 to 230,000 PNU (protein nitrogen units), and five patients treated with allergen doses from 1000 to 8000 PNU served as controls. Repeated bronchial challenges in the low-dose control group showed no change in bronchial sensitivity to specific allergens, contrary to decreased bronchial sensitivity in 80% of patients in the high-dosage group. The clinical result of the treatment was divided as follows: 1. Improvement, i.e., significant improvement of peak flow and decreased use of bronchodilator or steroid requirement; 2. No change, i.e., significant improvement in either peak flow or drug consumption; and 3. Worse, i.e., significant deterioration of both parameters.
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In the high-dose group, three patients experienced improvement, six patients had no change, and one had a deterioration. In the control, low-dose group the figures were 0, 3, and 2, respectively (difference not statistically significant, p = 0.22). Furthermore, three children clinically evaluated for a total of 12 mo ("four allergen seasons") showed no clinical or medication improvement. The reason for finding no clinical efficacy of immunotherapy in these children might be both the multisensitization and a significant part of symptoms not caused by allergen sensitization. An important conclusion from the study, however, is that the reduced sensitivity in bronchial challenge does not reflect a concordant reduction in clinical disease activity. In spite of the lack of correlation between decrease in bronchial sensitivity and clinical improvement, Goldstein and Chai (34) in 1981 published a retrospective study of the efficacy of rush immunotherapy in decreasing bronchial sensitivity to inhaled allergens in perennial childhood asthma. Immunotherapy was performed for a rather short period of time, i.e., from seven to 18 wk and with only modest doses (3000 to 6000 PNU as the total dose). In four out of nine patients treated with mold extracts, two showed a decrease in bronchial sensitivity, one patient showed no change, and one showed an increase. The clinical efficacy was not evaluated owing to the multiple nonallergic factors that contributed to the severity of their asthma. The argument for using only the bronchial sensitivity as an estimate of clinical efficacy was rather questionable, "that decreased bronchial sensitivity to an antigen to which the patient is exposed will mean that in the 'real world,' inhalation of that antigen will be less likely to cause bronchospasm than prior to the immunotherapy, thus benefitting the patient clinically" (34). Another study of the influence of mold immunotherapy on the bronchial challenge response was published by Metzger et al. (19). Ten asthmatic patients who by pretreatment bronchial challenge demonstrated a dual early and late asthmatic response, received at least 100,000 PNU ofAlternaria. All subjects showed a decrement in their late asthmatic response following immunotherapy; the early response was reduced significantly in only one subject. In a control group of 13 subjects undergoing six weekly challenges, the late asthmatic response remained unchanged. The clinical relevance of the reduced late response has, however, not been evaluated.
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PLACEBO-CONTROLLEDDOUBLE-BLIND IMMUNOTHERAPYSTUDIES Immunotherapy in Cladosporium Asthma The previous absence of proper, potent, and reliable mold extracts has been a major limiting problem in the specific treatment of mold-allergic patients. A new epoch in mold allergy was marked by the work of Aukrust on Cladosporium herbarum allergens. Using fractionation and quantitative immunoelectrophoretic techniques, he was able to purify and characterize antigens and allergens in Cladosporium extracts (35-37). The problems of reproducing all important allergens, however, are considerable (38).Simultaneous placebo-controlled double-blind immunotherapy studies in children (39) and adults (15) were initiated in 1982. The study in adults included 22 asthmatics with a well-documented asthma to Cladosporium (40). Randomization to treatment with placebo or Cladosporium was based on pretreatment Skin Prick Test (SPT) and Bronchial Provocation Test (BPT) reactivity. Retrospectively, it was shown that the patients in the two groups were comparable with respect to pretreatment severity of asthma, although a tendency to more severe disease was observed in the Cladosporium group, an observation reinforcing the clinical outcome. Using a clustered dose-increase schedule, four clusters, each consisting of five injections, were given. Immunotherapy was initiated with 10 BU (biological units), aiming at a top dose of 100,000 BU in the Cladosporium group. A solution of caramelized histamine with identical label and appearance was used as placebo. In consequence of both local and systemic side effects, the actively treated patients received only 3.7 injections/cluster compared with the placebo group (4.9 injections&luster) (p < 0.001) at the expense of one more visit. The top dose was only half of that intended, and a further reduction to 20% was necessary as a result of side effects. The clinical efficacy was investigated using the patient as his or her own control. Daily recording of symptom score, peak flow, and drug consumption was performed in 1981 for 10 consecutive weeks (pretreatment), and in 1982 (after 5-7 months of treatment) during the peak Cladosporium season. In order to minimize the risk of observing statistically significant but clinically irrelevant differences, only marked differences in the symptom-medication score
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were accepted. Regarding symptom score (score 0-3), only changes in the mean daily score exceeding one step, e.g., from score 2 to score 1, or changes exceeding 25 L/min in the mean daily peak flow were considered significant. Concerning medication score, a clinically relevant change was a difference of one therapeutic dose in the mean daily drug consumption. Based on this, the clinical efficacy was graded as improved, unchanged, or deteriorated. The overall clinical status was a combination of symptoms and drug consumption, and "improvement" was considered if an improvement in symptoms and/or medication score occurred. Complementary changes were regarded as "deterioration." For both scores, inverse changes or no changes were considered "unchanged." A clear tendency was observed with regard to a beneficial role of Cladosporium immunotherapy to both the symptom and medication score. However, only in the case of the combined scores did the difference reach statistically significant levels (Table 1). The Cladosporium spore count during the treatment season in 1982 was 2-3 times higher than that of the pretreatment season in 1981, explaining deterioration in asthma symptoms in 73% of the placebo-treated patients, contrary to only 18% in the Cladosporium group. Furthermore, this might justify the simplification of regarding unchanged asthma symptoms as evidence of clinical improvement. In that way a clinical efficacy was observed in 81% of Cladosporium-treated patients vs 27% in the placebo group (p = 0.01). The approach of comparing changes in symptom-medication score from the pretreatment season with those of the treatment season represents two clinically important advantages. First, it gives an opportunity to ensure that the patients in fact have allergic symptoms in relation to the causative allergen; second, it is the only way to ensure that treatment results in a reduction of clinical symptoms/ drug consumption. Finally, the error of showing a clinical efficacy simply caused by differences in the individual scoring of patients in the two groups was circumvented. In the pediatric study (39) 30 children aged 5-17 yr with a typical history of asthma starting or deteriorating in the Cladosporium season and positive diagnostic tests were investigated. The same purified and standardized preparation of Cladosporium as in the adult study was used for diagnostic procedures and immunotherapy. The two groups did not differ significantly regarding total medication and symptom scores during the 10-wk scoring period at pretreat-
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Mailing Table 1 Clinical Efficacy of Cladosporium I m m u n o t h e r a p y ~ Improved
Unchanged
Deteriorated
S y m p t o m score Placebo
0
Cladosporium
4
6 5 p = 0.07
5 2
4 4
6 2
Medication score Placebo
1
Cladosporium
5
p = 0.10 Total score Placebo
Cladosporium
1
2
8
5
4
2
p = 0.03
aEvaluated by changes in symptom, medication, and total score in a 10-wk period in 1982 compared with the corresponding period in 1981.
ment (1981) or at evaluation (1982). Only a comparison of the 2 wk with the highest spore counts in the 2 yr revealed a statistically significant difference (p < 0.01) in the medication score, but not in symptom score. The authors explain the lack of clinical improvement in the whole 10-wk observation period by asthma symptoms caused by several different allergens, infections, exercise, and other nonimmune mechanisms that would not be changed by treatment with one mold allergen only. The most probable explanation for the decrease in medication score, but not in symptom score, is that when their a s t h m a improves as a result of immunotherapy, patients reduce drug intake and tolerate symptoms similar to those present before immunotherapy.
Immunotherapy in Alternaria Allergy Horst et al. (41) succeeded in collecting 24 patients (5-56 yr of age) exclusively sensitive to Alternaria and Stemphylium with perennial symptoms ofrhinitis with or without asthma and exacerbations in summer and autumn. All patients showed a positive skinprick test, positive RAST, and positive nasal challenge to the Alternaria extract used for immunotherapy. A 2-d rush protocol was
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applied during dose increase, and maintenance treatment with 2000 BU continued for 1 yr. A histamine HC1 preparation was used as placebo. The clinical efficacy of immunotherapy was evaluated by patients' self-evaluation on a visual analog scale, and patients receiving active treatment rated its efficacy significantly higher than did the placebo group (76.5 _+27.9% vs 39.5 _+30.4%, respectively, p > 0.001). Based on daily symptom score for nasal, ocular, and bronchial symptoms and drug intake, a significant (p < 0.005) difference in favor of Alternaria treatment was found (0.84 +_0.93 in the Alternaria group vs 3.55 + 2.0 in the placebo group). Immunotherapy blunted the seasonal increase in symptom-medication scores observed in the placebo group.
SIDE EFFECTS OF MOLD IMMUNOTHERAPY Immunotherapy, especially with mold extracts, has been assodated with a high frequency of systemic side effects (42). By the use of nonstandardized extracts, Pennington (27) reported side effects in six of 22 patients (27%): Most were mild and in many cases no treatment was necessary. In the study with emulsified mold allergens, Prince (32) registered local adverse reactions in 153 of 515 injections (30%) and systemic reaction in 63 injections (12%). No difference in the frequency of side effects was observed between the high-dose and the low-dose group, which might be a consequence of irritant substances, rather than the allergens eliciting the side effects. The rush-immunotherapy study in children (34) was complicated by two of 13 subjects reacting with mild wheezing (15%), implying discontinuation of treatment. One of these patients was later restarted and tolerated immunotherapy well. In another study of mold immunotherapy in children, Kaad and Ostergard (43) had to withdraw seven of 38 (18%) patients because of serious side effects clinically consistent with a type III reaction. These seven subjects all showed a two- to fourfold increase in circulating precipitating antibodies to the injected mold antigens. In a prospective study on the safety of immunotherapy in children with severe asthma, Ostergaard et al. (44) registered moderate to severe side effects in 21% of children treated with different allergen extracts. In the 106 patients experiencing side effects, 42% of the side effects were caused by mold injections. Four of 13 patients (31%) were withdrawn
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from immunotherapy withAlternaria, and nine of 13 patients (69%) with Cladosporium. Anaphylactic life-threatening reactions during maintenance dose were observed in six patients, and in four cases were caused by mold injections. In the studies with standardized and characterized extracts, the frequency of side effects seems to be a consequence of the aggressiveness of the dosage regimen. With the use of a rather modest maintenance dose of 2000 BU, Horst et al. (41) observed asthmatic reactions easily controlled by inhaled [3-2 agonists in only two of 13 patients treated according to a rush protocol (15%). In the pediatric Cladosporium study (39) aiming at a top dose of 100,000 BU, four of 16 patients (25%) experienced local reactions (>10 cm) during the first 10 mo of treatment, equivalent to 0.9 local reaction per 100 injections. A total of 45 systemic reactions were observed in 81% of the patients, corresponding to 10.2 side effects per 100 injections. The highest frequency of side effects in mold immunotherapy has been published by Malling et al. (15). However, this study was designed to administer the maximum tolerated allergen dose in a very aggressive dose-increase schedule. In other words, a dosage schedule was chosen that would result in systemic side effects in all p a t i e n t s . In t h a t way, the absolute u p p e r limit of allergen administration in i m m u n o t h e r a p y was explored. It is, however, important to differentiate between mild and severe life-threatening systemic reactions. All Cladosporium-treated patients observed systemic reactions. Only 5% of these were life-threatening and required hospitalization. All other systemic reactions (asthma) responded to topical administration of ~-2 agonists. Systemic reactions were observed with a constant frequency in the dose range 3000-300,000 BU; while delayed local reactions (>8 cm) reached a maximum in the dose range 10,000-100,000 BU. Delayed local reactions occurred in 58% of the Cladosporium clusters, and systemic reactions in 74%. The corresponding figures in the placebo group are 0 and 4%, respectively. Systemic side effects were not related to the score-estimated pretreatment severity of asthma. Subsequent studies, using both Cladosporium and Alternaria in the patients initially treated with placebo, have shown that the same maintenance dose and clinical efficacy could be reached with a slightly modified dose-increase schedule. This consists of only four injections/cluster, aiming at a top dose of 60,000 BU. This schedule reduced the number of sys-
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temic side effects from one in every five injections to one in every 50 injections (45). In that way the risk of systemic side effects is comparable to other high-dose immunotherapy studies.
RECOMMENDATIONSFOR MOLD ~MMUNOTHERAPY Although a clinical efficacy of mold immunotherapy has been demonstrated in three placebo-controlled double-blind studies, the number of patients included is rather small: A total of 40 patients have received active mold-allergen material. A number of recent reviews of allergen-specific immunotherapy (3,4,9,46) recommend some hesitation with regard to applying mold extracts for routine immunotherapy. Based on the recommendations from the Immunot h e r a p y Subcommittee of the European Academy of AUergology and Clinical Immunology (3), i m m u n o t h e r a p y with mold allergens should be instituted in clinical trials only. On the other hand, owing to the clinical efficacy of a few mold species, further research should focus on production of standardized extracts of other clinically relevant mold species, and immunotherapy trials with these allergens should be conducted.
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Noon, L. (1911), Lancet i, 1572-1573. Bruun, E. (1949), Acta Allergol. 2, 122-127. Malling, H.-J. ed. (1988), Allergy (Suppl. 6) 43, 1-33. Thompson, R. A. (ed.), Bousquet, J., Cohen, S., Frei, P. C., J~iger, L., Lambert, P. H., Lessof, M. H., Loblay, R. H., Malling, H.-J., Norman, P. S., de Weck, A. L., and Weeke, B. (1989), Allergy 44, 369-379. Filipp, G. (1982), Allergol. Immunopathol. 10, 305-318. Ohman, J. L., Findlay, S. R. and Leitermann, K. M. J. Allergy Clin. Immunol. 74, 230-239. Lichtenstein, L. M., Valentine, M. D., and Norman, P. S. (1984), Am. Rev. Resp. Dis. 129, 657-659. Larsen, G. L. (1985), J. Allergy Clin. Immunol. 76, 665-669. Ohman, J. L. (1989), J. Allergy Clin. Immunol. 84, 133-140. Dreborg, S. (1986), Clin. Allergy 16, 271-277. Cockcroft, D. W. (1983), Lancet ii, 253-255. Kaliner, M. M. (1984), J. Allergy Clin. Immunol. 73, 311-315.
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13. Creticos, P. S. (1989), J. Allergy Clin. Immunol. 83, 554-562. 14. Naclerio, R. M., Proud, D., Togias, A. G., Adkinson, N. F., Meyers, D. ~ ,
Kagey-Sobotka, A., Plaut, M., Norman, P. S., and Lichtenstein, L. M. (1985), N. Engl. J. Med. 313, 65-70. 15. Malling H.-J., Dreborg, S., and Weeke, B. (1986), Allergy 41,507-519. 16. Van Metre, T. E., March, D. G., Adkinson, N. F., Kagey-Sobotka, .4., Khattignavong, A., Norman, P. S., and Rosenberg, G. L. (1988), J. Allergy Clin. ImmunoL 82, 1055-1068.
17. Bertelsen, A., Andersen, J. B., Christensen, J., Ingemann, L., Kristensen, T., and Ostergaard, P. A. A. (1989), Allergy 44, 330-335. 18. Warner, J. O., Price, J. F., Soothill, J. F., and Hey, E. (1978), Lancet ii, 912-915. 19. Metzger, W. J., Donnelly, A., and Richerson, H. B., (1983), J. Allergy Clin. Immunol. (abstract 121) 71,119. 20. Van Bever, H. P., Bosmans, J., De Clerck, L. S., and Stevens, W. J. (1988), Allergy 43, 378-385. 21. Creticos, P. S., Marsh, D. G., Proud, D., Kagey-Sobotka, A., Adkinson, N. F., Friedhoff, L., Naclerio, R. M., Lichtenstein, L. M., and Norman, P. S. (1989), J. Allergy Clin. Immunol. 84, 197-205. 22. Bousquet, J., Hejjaoui, A., and Michel, F.-B. (1990), J. Allergy Clin. Immunol. 86, 292-305. 23. Lilja, G., Sundin, B., Graff-Lonnevig, V., Hedlin, G., Heilborn, H., Norrlind, }C, Pegelow, K.-O., and Lcwenstein, H. (1989), J. Allergy Clin. Immunol. 83, 37-44. 24. Cobe, H. M. (1932), J. Allergy 3, 389. 25. Bernton, H. S. and Thorn, C. (1937), J. Allergy 8, 363-366. 26. Feinberg, S. M. (1937), J. Allergy 8, 368,369. 27. Pennington, E. S. (1941), J. Allergy 12, 388-402. 28. Berman, B. A. (1961), Ann. Allergy 19, 619-623. 29. Caplin, I., Bates, L., and Benton, T. (1962), Ann. Allergy 20, 95. 30. Forman, J. and Newport, N. M. (1963), Ann. Allergy 21,303-309. 31. Scherr, M.S. (1963),Ann. Allergy 21,388. 32. Prince, H. E. (1965), Ann. Allergy 23, 249-261. 33. Tuchinda, M. and Chai, H. (1973), J. Allergy Clin. Immunol. 51,131-138. 34. Goldstein, G. L. and Chai, H. (1981), Ann. Allergy 47, 333-337. 35. Aukrust, L. (1978), Arb. Paul Ehrlich Inst. 73, 56-64. 36. Aukrust, L. and Borch, M. (1979), Int. Arch. Allergy Appl. Immunol. 60, 68-79. 37. Landmark, E. and Aukrust, L. (1985), Int. Arch. Allergy Appl. Immunol. 78, 71-76. 38. Sward-Nordmo, M., Almeland, T.-L., and Aukrust, L. (1984), Allergy 39, 387-394. 39. Dreborg, S., Agrell, B., Foucard, T., Kjellman, N.-I. M., Koivikko, A., and Nilsson, S. (1986), Allergy 41, 131-140. 40. Malling, H.-J., Dreborg, S., and Weeke, B. (1986), Allergy 41, 57-67. 41. Horst, M., Hejjaoui, A., Horst, V., Michel, F.-B., and Bousquet, J. (1990)J. Allergy Clin. Immunol. 85, 460-472.
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42. Dreborg, S., Mosbech, H., and Weeke, B. (1988), Bailli~re's Clinical Immunology and Allergy (Denman, ,~ M., Kay, A. B., and Wright, R., eds.), vol. 2, Balli~re Tindall, London, pp. 245-258. 43. Kaad, P. H. and ~stergaard, P. A. & (1982), Clin. Allergy 12, 317-320. 44. ~stergaard, P. A. A., Kaad, P. H., and Kristensen, T. (1986), Allergy 41, 588-593. 45. Malling, H.-J. (1987), Allergol. Immunol. Clin. 2, 168. 46. Malling, H.-J. (1988), ISIAtlas Sci. 1, 215-219.
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Immunotherapy for Mold Allergy Hans-J rgen Mailing Laboratory of Clinical Allergology, State University Hospital, Copenhagen, Denmark
INTRODUCTION Immunotherapy was introduced in 1911 by Noon (1) as a result of the erroneous belief that allergy was caused by some toxins in pollens. The scientific background was the combined active and passive immunization against rabies, tetanus, and diphtheria that began in the latter part of the 19th century. When subcutaneous pollen extracts were administered to hay fever patients, a reduced sensitivity was observed by conjunctival challenge tests, and the patients reported diminished allergy symptoms. In spite of the rapidly widespread use of immunotherapy, the first controlled study by Bruun (2) in Denmark was not published until nearly 40 years after Noon's observations. Despite intensive research for more than 75 years, i m m u n o t h e r a p y is still largely based on empirical observations regarding diseases responding to treatment and safe dosage regimens. The international allergological societies have recognized that immunotherapy has to be approached in a highly scientific way. Recently the European Academy of Allergology and Clinical Immunology published a position paper on immunotherapy (3), and a status report on the same subject from the World Health Organization/ International Union of Immunological Societies (4) has been issued.
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Efficacy Parameters The exact immunological mechanism or mechanisms underlying the clinical efficacy of immunotherapy are still largely unknown. Several immunological phenomena have been demonstrated (5), but none show any convincing relation to the clinical efficacy, i.e., no parameter can predict the clinical efficacy in individual patients. The missing relation between clinical efficacy and immunological parameters may be caused by the fact that the clinical efficacy is determined by complicated interactions between different immunological parameters, which are not revealed by the evaluation of one single parameter. Conversely, the clinical efficacy may be caused by immunological phenomena varying from one patient to another, and with time.
Specificity Several studies have shown that immunotherapy can alter the allergen-specific hyperreactivity measured by, e.g., skin or challenge tests. A series of studies has clearly shown that, in patients with asthma, immunotherapy reduces bronchial sensitivity and enables patients to tolerate the inhalation of larger amounts of allergens than before the treatment (6). In asthmatics the clinical symptoms are caused by a combination of the inflammatory reaction elicited by the specific allergen and the nonspecific bronchial hyperreactivity (7). In this connection it should be noted that ongoing allergic inflammation increases the patient's symptoms as a result of specific (other allergens) and nonspecific (irritants, and the like) stimuli, so that the patient has more symptoms than those caused by the allergen-IgE interaction (8). When symptoms elicited by the allergen used for immunotherapy are reduced or eliminated, the patient's tolerance for other specific and nonspecific stimuli is increased, and the patient will have fewer symptoms (7).
Criteria for Evaluating Clinical Efficacy In the evaluation of the clinical efficacy of allergen immunotherapy, at least three points are of crucial importance: 1. The diagnostic procedures used to establish the specific diagnosis of allergy; Clinical Reviews in Allergy
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2. The quality of the allergen extract used for immunotherapy; and 3. The validity of the methods used to estimate the clinical efficacy. The clinical efficacy has been documented in clearly IgE mediated diseases only, indicating that authors presenting efficacy studies have to supply convincing data supporting that the patients are in fact IgE-allergic. The diagnosis of allergy is established by various diagnostic tests, and the validity of the tests has to be documented. The specific diagnosis represents a combination of clinical allergy symptoms oscillating in parallel with the allergen load and the demonstration of IgE reactivity, including an unequivocally positive challenge test in the relevant shock organ. Owing to insufficient quality, allergen extracts have until recently been the limiting factor in many immunotherapy studies. The use of well-characterized, qualitatively and quantitatively optimal allergen composition and stable extracts represents the only way to evaluate changes in in vivo and in vitro parameters and increases the probability of obtaining sufficient clinical results. The poor quality of allergen preparations used formerly indicates that clinical studies without a documented clinical efficacy have to be reevaluated, since the lack of efficacy may be a consequence of the use of improper allergen extracts. In the evaluation of the clinical efficacy of allergen immunotherapy, only placebo-controlled and double-blind studies have to be considered (9). Furthermore, only objective clinical parameters (clinical symptoms, drug consumption, and, in asthmatics, pulmonary-function monitoring) should be accepted, since no definite proof exists that any in vivo or in vitro tests correlate to clinical improvement (10). Patients should preferably record daily symptom-medication score for one season before immunotherapy in order to ensure that they really have clinical symptoms caused by the suspected allergen (to etablish a specific diagnosis) and that a possible clinical efficacy is not caused simply by variation between the placebo and the actively treated group in scoring disease severity and drug consumption. The patients may thus serve as their own controls. This very time-consuming way of performing clinical studies may be compensated for by valid conclusions based on fewer patients. Besides the ability to show a positive clinical efficacy of active immunotherapy, another advantage of this methodology is the estimation of
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deterioration of placebo-treated patients---a clinically rather relevant observation. In the evaluation of efficacy, only changes in symptoms and drug consumption that are relevant from a clinical point of view should be considered indicators of efficacy.
Evaluation of the Benefit of Immunotherapy A strictly scientific attitude regarding whether immunotherapy should or should not be added to the pharmacological treatment of asthma is hard to obtain. The use ofimmunotherapy is, however, rather based on emotional feelings or common practice. Immunot h e r a p y has some undeniable advantages over exclusively pharmacological treatment. Immunotherapy has the obvious advantage of regular consultations, implying a closer and more intensive observation of patients with severe disease. This is of special importance in attempting to increase monitoring to prevent undermedication of asthma, and enhances the possibilities of more intensive treatment during acute exacerbations. Another advantage of immunotherapy in the treatment of asthma is the fundamental interference of immunotherapy in the pathophysiological mechanisms responsible for asthma. The component of the IgE-mediated allergic reaction is the immediate earlyphase reaction followed by a delayed late-phase reactivity. During recent years, special attention has been focused on allergy and, especially, asthma as inflammatory diseases, and the severity of the disease is more closely related to the late-phase reaction than to the immediate reaction (11,12). The IgE-mediated early reaction triggers the long-lasting inflammatory response involving eosinophils, neutrophils, macrophages, and so on, which results in a smoldering clinical picture with persistence of symptoms well past the allergen exposure (13). The inflammatory response may evolve into a component of nonspecific bronchial hyperreactivity induced by specific allergen sensitization (14). Several immunotherapy studies have documented a reduction in severity and frequency of both the early (15-17) and the late asthmatic response induced by immunotherapy (18-20). Using the nose as a model for the lower respiratory tract, Creticos et al. (21) have demonstrated an immunotherapy-induced dose-dependent reduction in mediator release on nasal pollen challenge and a significant reduction in patient symptoms during the pollen season. Although still subject to discussion, the reduction in
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mediator release induced by immunotherapy may be the basis of the reduction in nonspecific hyperreactivity reported in some immunotherapy studies (22,23). Before initiating immunotherapy, several factors have to be carefully considered (9). A crucial point is whether allergen sensitization is of importance in exacerbations and in the overall severity of the allergic disease, and whether the overall severity warrants this type of treatment. Allergen avoidance should be implemented whenever possible. When only inadequate allergen extracts are available, immunotherapy should not be instituted. The risks and benefits of including immunotherapy in the treatment modalities of allergic diseases must be carefully balanced. UNCONTROLLEDSTUDIESOF MOLD IMMUNOTHERAPY Although mold allergy has been considered a clinically significant problem, the number of studies reporting a dinical efficacy of mold immunotherapy is rather small. The first case report on mold immunotherapy was published in 1932 by Cobe (24). A greenhouse worker developed a s t h m a from the mold Cladosporium fulvum, which grows on the leaves of tomato plants. Following a course of injections with an extract from a culture of the mold, remarkable clinical relief occurred. Bernton and Thom (25) studied the clinical role of Cladosporium in allergy. Four patients with perennial hay fever and asthma and positive skin test to Cladosporium were given subcutaneous injections with the mold extract. The results of the treatment were regarded by three patients as highly satisfactory in alleviating their distressing symptoms. In a personal communication, Feinberg (26) describes clinical results of primarily Alternaria immunotherapy to be as satisfactory as pollen treatment in 28 patients. In a study of clinical sensitivity to airborne molds, Pennington (27) describes the relation between skin sensitivity to Alternaria and other molds and clinical disease. Seventeen patients, probably of a population of 43 subjects (40%), experienced definite improvements after treatment with mold extracts. Several authors have applied emulsified mold allergens in injection treatment (28--31). Prince (32) reported a larger series of patients treated with various molds during 10-62 mo. The age of treated patients varied from 4 to 62 yr, 40% of patients were
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between 6 and 10 yr. Of the patients, 16% had bronchial asthma only, 30% suffered from nasal allergic disease, and 54% had both. Perennially occurring atmospheric molds appeared to be the major determinants for clinical symptoms, but other inhalant allergens, such as pollens, house dust, and animal epithelium, along with Hymenoptera and food allergens, were applied in the treatment. The patients were randomly placed in a high- and a low-dosage group. The results of injection t r e a t m e n t with mold allergens were classified as good if the patients experienced no symptoms whatsoever, or if occasional symptoms were clearly explained by exposure to nonmold allergens. A fair result was based on symptoms incompletely controlled much of the time. A good therapeutic result was reported by 84% of the patients receiving high dosage and by 62% of patients in the low-dosage group. A fair result was obtained by 14% in the high-dosage group and 32% of the low-dosage group. No improvement was observed in one patient in the high-dosage group and two patients in the low-dosage group. The author concluded that the clinical results of injection treatment with emulsified mold allergens range from satisfactory to good in most patients, and that the control of symptoms persists for longer periods after higher dosage is attained. Given these excellent results, it would have been of much scientific value if this study had included a placebo group and been conducted in a double-blind fashion, and if the evaluation of the clinical results had been prospective. Studying children with chronic intractable asthma, Tuchinda and Chai (33) investigated injection treatment with aqueous extracts of Alternaria, pollen, and house dust. Ten patients received high dosage, from 30,000 to 230,000 PNU (protein nitrogen units), and five patients treated with allergen doses from 1000 to 8000 PNU served as controls. Repeated bronchial challenges in the low-dose control group showed no change in bronchial sensitivity to specific allergens, contrary to decreased bronchial sensitivity in 80% of patients in the high-dosage group. The clinical result of the treatment was divided as follows: 1. Improvement, i.e., significant improvement of peak flow and decreased use of bronchodilator or steroid requirement; 2. No change, i.e., significant improvement in either peak flow or drug consumption; and 3. Worse, i.e., significant deterioration of both parameters.
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In the high-dose group, three patients experienced improvement, six patients had no change, and one had a deterioration. In the control, low-dose group the figures were 0, 3, and 2, respectively (difference not statistically significant, p = 0.22). Furthermore, three children clinically evaluated for a total of 12 mo ("four allergen seasons") showed no clinical or medication improvement. The reason for finding no clinical efficacy of immunotherapy in these children might be both the multisensitization and a significant part of symptoms not caused by allergen sensitization. An important conclusion from the study, however, is that the reduced sensitivity in bronchial challenge does not reflect a concordant reduction in clinical disease activity. In spite of the lack of correlation between decrease in bronchial sensitivity and clinical improvement, Goldstein and Chai (34) in 1981 published a retrospective study of the efficacy of rush immunotherapy in decreasing bronchial sensitivity to inhaled allergens in perennial childhood asthma. Immunotherapy was performed for a rather short period of time, i.e., from seven to 18 wk and with only modest doses (3000 to 6000 PNU as the total dose). In four out of nine patients treated with mold extracts, two showed a decrease in bronchial sensitivity, one patient showed no change, and one showed an increase. The clinical efficacy was not evaluated owing to the multiple nonallergic factors that contributed to the severity of their asthma. The argument for using only the bronchial sensitivity as an estimate of clinical efficacy was rather questionable, "that decreased bronchial sensitivity to an antigen to which the patient is exposed will mean that in the 'real world,' inhalation of that antigen will be less likely to cause bronchospasm than prior to the immunotherapy, thus benefitting the patient clinically" (34). Another study of the influence of mold immunotherapy on the bronchial challenge response was published by Metzger et al. (19). Ten asthmatic patients who by pretreatment bronchial challenge demonstrated a dual early and late asthmatic response, received at least 100,000 PNU ofAlternaria. All subjects showed a decrement in their late asthmatic response following immunotherapy; the early response was reduced significantly in only one subject. In a control group of 13 subjects undergoing six weekly challenges, the late asthmatic response remained unchanged. The clinical relevance of the reduced late response has, however, not been evaluated.
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PLACEBO-CONTROLLEDDOUBLE-BLIND IMMUNOTHERAPYSTUDIES Immunotherapy in Cladosporium Asthma The previous absence of proper, potent, and reliable mold extracts has been a major limiting problem in the specific treatment of mold-allergic patients. A new epoch in mold allergy was marked by the work of Aukrust on Cladosporium herbarum allergens. Using fractionation and quantitative immunoelectrophoretic techniques, he was able to purify and characterize antigens and allergens in Cladosporium extracts (35-37). The problems of reproducing all important allergens, however, are considerable (38).Simultaneous placebo-controlled double-blind immunotherapy studies in children (39) and adults (15) were initiated in 1982. The study in adults included 22 asthmatics with a well-documented asthma to Cladosporium (40). Randomization to treatment with placebo or Cladosporium was based on pretreatment Skin Prick Test (SPT) and Bronchial Provocation Test (BPT) reactivity. Retrospectively, it was shown that the patients in the two groups were comparable with respect to pretreatment severity of asthma, although a tendency to more severe disease was observed in the Cladosporium group, an observation reinforcing the clinical outcome. Using a clustered dose-increase schedule, four clusters, each consisting of five injections, were given. Immunotherapy was initiated with 10 BU (biological units), aiming at a top dose of 100,000 BU in the Cladosporium group. A solution of caramelized histamine with identical label and appearance was used as placebo. In consequence of both local and systemic side effects, the actively treated patients received only 3.7 injections/cluster compared with the placebo group (4.9 injections&luster) (p < 0.001) at the expense of one more visit. The top dose was only half of that intended, and a further reduction to 20% was necessary as a result of side effects. The clinical efficacy was investigated using the patient as his or her own control. Daily recording of symptom score, peak flow, and drug consumption was performed in 1981 for 10 consecutive weeks (pretreatment), and in 1982 (after 5-7 months of treatment) during the peak Cladosporium season. In order to minimize the risk of observing statistically significant but clinically irrelevant differences, only marked differences in the symptom-medication score
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were accepted. Regarding symptom score (score 0-3), only changes in the mean daily score exceeding one step, e.g., from score 2 to score 1, or changes exceeding 25 L/min in the mean daily peak flow were considered significant. Concerning medication score, a clinically relevant change was a difference of one therapeutic dose in the mean daily drug consumption. Based on this, the clinical efficacy was graded as improved, unchanged, or deteriorated. The overall clinical status was a combination of symptoms and drug consumption, and "improvement" was considered if an improvement in symptoms and/or medication score occurred. Complementary changes were regarded as "deterioration." For both scores, inverse changes or no changes were considered "unchanged." A clear tendency was observed with regard to a beneficial role of Cladosporium immunotherapy to both the symptom and medication score. However, only in the case of the combined scores did the difference reach statistically significant levels (Table 1). The Cladosporium spore count during the treatment season in 1982 was 2-3 times higher than that of the pretreatment season in 1981, explaining deterioration in asthma symptoms in 73% of the placebo-treated patients, contrary to only 18% in the Cladosporium group. Furthermore, this might justify the simplification of regarding unchanged asthma symptoms as evidence of clinical improvement. In that way a clinical efficacy was observed in 81% of Cladosporium-treated patients vs 27% in the placebo group (p = 0.01). The approach of comparing changes in symptom-medication score from the pretreatment season with those of the treatment season represents two clinically important advantages. First, it gives an opportunity to ensure that the patients in fact have allergic symptoms in relation to the causative allergen; second, it is the only way to ensure that treatment results in a reduction of clinical symptoms/ drug consumption. Finally, the error of showing a clinical efficacy simply caused by differences in the individual scoring of patients in the two groups was circumvented. In the pediatric study (39) 30 children aged 5-17 yr with a typical history of asthma starting or deteriorating in the Cladosporium season and positive diagnostic tests were investigated. The same purified and standardized preparation of Cladosporium as in the adult study was used for diagnostic procedures and immunotherapy. The two groups did not differ significantly regarding total medication and symptom scores during the 10-wk scoring period at pretreat-
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Unchanged
Deteriorated
S y m p t o m score Placebo
0
Cladosporium
4
6 5 p = 0.07
5 2
4 4
6 2
Medication score Placebo
1
Cladosporium
5
p = 0.10 Total score Placebo
Cladosporium
1
2
8
5
4
2
p = 0.03
aEvaluated by changes in symptom, medication, and total score in a 10-wk period in 1982 compared with the corresponding period in 1981.
ment (1981) or at evaluation (1982). Only a comparison of the 2 wk with the highest spore counts in the 2 yr revealed a statistically significant difference (p < 0.01) in the medication score, but not in symptom score. The authors explain the lack of clinical improvement in the whole 10-wk observation period by asthma symptoms caused by several different allergens, infections, exercise, and other nonimmune mechanisms that would not be changed by treatment with one mold allergen only. The most probable explanation for the decrease in medication score, but not in symptom score, is that when their a s t h m a improves as a result of immunotherapy, patients reduce drug intake and tolerate symptoms similar to those present before immunotherapy.
Immunotherapy in Alternaria Allergy Horst et al. (41) succeeded in collecting 24 patients (5-56 yr of age) exclusively sensitive to Alternaria and Stemphylium with perennial symptoms ofrhinitis with or without asthma and exacerbations in summer and autumn. All patients showed a positive skinprick test, positive RAST, and positive nasal challenge to the Alternaria extract used for immunotherapy. A 2-d rush protocol was
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applied during dose increase, and maintenance treatment with 2000 BU continued for 1 yr. A histamine HC1 preparation was used as placebo. The clinical efficacy of immunotherapy was evaluated by patients' self-evaluation on a visual analog scale, and patients receiving active treatment rated its efficacy significantly higher than did the placebo group (76.5 _+27.9% vs 39.5 _+30.4%, respectively, p > 0.001). Based on daily symptom score for nasal, ocular, and bronchial symptoms and drug intake, a significant (p < 0.005) difference in favor of Alternaria treatment was found (0.84 +_0.93 in the Alternaria group vs 3.55 + 2.0 in the placebo group). Immunotherapy blunted the seasonal increase in symptom-medication scores observed in the placebo group.
SIDE EFFECTS OF MOLD IMMUNOTHERAPY Immunotherapy, especially with mold extracts, has been assodated with a high frequency of systemic side effects (42). By the use of nonstandardized extracts, Pennington (27) reported side effects in six of 22 patients (27%): Most were mild and in many cases no treatment was necessary. In the study with emulsified mold allergens, Prince (32) registered local adverse reactions in 153 of 515 injections (30%) and systemic reaction in 63 injections (12%). No difference in the frequency of side effects was observed between the high-dose and the low-dose group, which might be a consequence of irritant substances, rather than the allergens eliciting the side effects. The rush-immunotherapy study in children (34) was complicated by two of 13 subjects reacting with mild wheezing (15%), implying discontinuation of treatment. One of these patients was later restarted and tolerated immunotherapy well. In another study of mold immunotherapy in children, Kaad and Ostergard (43) had to withdraw seven of 38 (18%) patients because of serious side effects clinically consistent with a type III reaction. These seven subjects all showed a two- to fourfold increase in circulating precipitating antibodies to the injected mold antigens. In a prospective study on the safety of immunotherapy in children with severe asthma, Ostergaard et al. (44) registered moderate to severe side effects in 21% of children treated with different allergen extracts. In the 106 patients experiencing side effects, 42% of the side effects were caused by mold injections. Four of 13 patients (31%) were withdrawn
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from immunotherapy withAlternaria, and nine of 13 patients (69%) with Cladosporium. Anaphylactic life-threatening reactions during maintenance dose were observed in six patients, and in four cases were caused by mold injections. In the studies with standardized and characterized extracts, the frequency of side effects seems to be a consequence of the aggressiveness of the dosage regimen. With the use of a rather modest maintenance dose of 2000 BU, Horst et al. (41) observed asthmatic reactions easily controlled by inhaled [3-2 agonists in only two of 13 patients treated according to a rush protocol (15%). In the pediatric Cladosporium study (39) aiming at a top dose of 100,000 BU, four of 16 patients (25%) experienced local reactions (>10 cm) during the first 10 mo of treatment, equivalent to 0.9 local reaction per 100 injections. A total of 45 systemic reactions were observed in 81% of the patients, corresponding to 10.2 side effects per 100 injections. The highest frequency of side effects in mold immunotherapy has been published by Malling et al. (15). However, this study was designed to administer the maximum tolerated allergen dose in a very aggressive dose-increase schedule. In other words, a dosage schedule was chosen that would result in systemic side effects in all p a t i e n t s . In t h a t way, the absolute u p p e r limit of allergen administration in i m m u n o t h e r a p y was explored. It is, however, important to differentiate between mild and severe life-threatening systemic reactions. All Cladosporium-treated patients observed systemic reactions. Only 5% of these were life-threatening and required hospitalization. All other systemic reactions (asthma) responded to topical administration of ~-2 agonists. Systemic reactions were observed with a constant frequency in the dose range 3000-300,000 BU; while delayed local reactions (>8 cm) reached a maximum in the dose range 10,000-100,000 BU. Delayed local reactions occurred in 58% of the Cladosporium clusters, and systemic reactions in 74%. The corresponding figures in the placebo group are 0 and 4%, respectively. Systemic side effects were not related to the score-estimated pretreatment severity of asthma. Subsequent studies, using both Cladosporium and Alternaria in the patients initially treated with placebo, have shown that the same maintenance dose and clinical efficacy could be reached with a slightly modified dose-increase schedule. This consists of only four injections/cluster, aiming at a top dose of 60,000 BU. This schedule reduced the number of sys-
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temic side effects from one in every five injections to one in every 50 injections (45). In that way the risk of systemic side effects is comparable to other high-dose immunotherapy studies.
RECOMMENDATIONSFOR MOLD ~MMUNOTHERAPY Although a clinical efficacy of mold immunotherapy has been demonstrated in three placebo-controlled double-blind studies, the number of patients included is rather small: A total of 40 patients have received active mold-allergen material. A number of recent reviews of allergen-specific immunotherapy (3,4,9,46) recommend some hesitation with regard to applying mold extracts for routine immunotherapy. Based on the recommendations from the Immunot h e r a p y Subcommittee of the European Academy of AUergology and Clinical Immunology (3), i m m u n o t h e r a p y with mold allergens should be instituted in clinical trials only. On the other hand, owing to the clinical efficacy of a few mold species, further research should focus on production of standardized extracts of other clinically relevant mold species, and immunotherapy trials with these allergens should be conducted.
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42. Dreborg, S., Mosbech, H., and Weeke, B. (1988), Bailli~re's Clinical Immunology and Allergy (Denman, ,~ M., Kay, A. B., and Wright, R., eds.), vol. 2, Balli~re Tindall, London, pp. 245-258. 43. Kaad, P. H. and ~stergaard, P. A. & (1982), Clin. Allergy 12, 317-320. 44. ~stergaard, P. A. A., Kaad, P. H., and Kristensen, T. (1986), Allergy 41, 588-593. 45. Malling, H.-J. (1987), Allergol. Immunol. Clin. 2, 168. 46. Malling, H.-J. (1988), ISIAtlas Sci. 1, 215-219.
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