Robert N. Ross, PhD, Harold S. Nelson, MD, and Ira Finegold, MD

Transcription

1 EFFECTIVENESS OF SPECIFIC IMMUNOTHERAPY IN THE TREATMENT OF ASTHMA: A META-ANALYSIS OF PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES Robert N. Ross, PhD, Harold S. Nelson, MD, and Ira Finegold, MD This meta-analysis consisted of 24 prospective, randomized, double-blind controlled studies consisting of nine hundred sixty two (962) asthmatic patients with documented allergies in whom subcutaneous immunotherapy (SIT) (dust mite, cat, pollen) was deemed effective. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Immunotherapy was found to be effective in 17 (71%) of the 24 studies, ineffective in 4 (17%), and equal to in 3 (12%). SIT was deemed clinically effective in 9 (75%) of adult asthma studies and 7 (70%) of the pediatric asthma studies. Patients who received SIT showed improvement of their asthma symptoms (when compared to placebo) (OR 2.6, 76, 95% CI 2.22 to 3.42) pulmonary function (OR 2.87, 95% CI 1.82 to 4.52), protection against bronchial challenge (OR 1.81%, 95% CI 1.32 to 2.49), as well as a decreased need for medications (OR 2.00, 95% CI 1.46 to 2.72). Conclusion: Allergen specific subcutaneous immunotherapy is effective in treatment of allergen triggered asthma.

2 CLINICAL THERAPEUTICSWOL. 22, NO. 3,200O Effectiveness of Specific Immunotherapy in the Treatment of Asthma: A Meta-Analysis of Prospective, Randomized, Double-Blind, Placebo-Controlled Studies Robert N. Ross, PhD,I Harold S. Nelson, MD? and Ira Finegold, Mti Medical/Science Analytics, Brookline, Massachusetts, Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado, and 3Department of Medicine, St. Luke&Roosevelt Hospital, New York, New York ABSTRACT Background: Despite decades of positive experience with specific immunotherapy (SIT) in the treatment of asthma, outcomes associated with SIT have not been evaluated. Objective: This meta-analysis was conducted to compare the effects of SIT plus medical treatment with those of SIT without medical treatment in patients with asthma. Methods: All studies of SIT in patients with asthma published in English between the years 1966 and 1998 were identified through a MEDLINE@ search. All prospective, randomized, double-blind, placebo-controlled studies of SIT identified by the search were included in the meta-analysis. One author (R.N.R.) extracted data from these studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Results: Data were extracted from 24 identified studies of the clinical effectiveness of SIT in the treatment of asthma, involving 962 asthmatic patients with documented allergy. Immunotherapy was judged effective in 17 (71%) of the 24 studies, ineffective in 4 (17%), and equivocal in 3 (12%) (x2 = 15.25, df= 2, P = ). Symptoms of asthma were more likely to improve in patients who received SIT than in patients who received placebo (OR 2.76, 95% CI 2.22 to 3.42). Results also favored the immunotherapy group for improvement in pulmonary function (OR 2.87, 95% CI 1.82 to 4.52), protection against bronchial challenge (OR 1.81, 95% CI 1.32 to 2.49), and reduced need for medications (OR 2.00, 95% CI 1.46 to 2.72). Conch&on: The findings of this meta-analysis support the conclusion that SIT is effective in a population of patients with allergen-triggered asthma. Key words: immunotherapy, meta-analysis, asthma, allergy, effectiveness. (Clin Ther. 2000;22: ) Accepted for publication December 28, Printed in the USA. Reproduction in whole or part is not permitted /00/$

3 CLINICAL THERAPEUTICS INTRODUCTION Allergen immunotherapy is a technique by which increasing amounts of allergen extract are injected subcutaneously over a varying number of months to years to lessen clinical symptoms that arise on exposure to allergens. The efficacy of immunotherapy with allergen extracts has been argued in published articles.,2 The effectiveness of immunotherapy in the treatment of asthma is still being debated. Specific immunotherapy (SIT) for asthma has not readily lent itself to outcomes research for several reasons. SIT requires careful selection of patients because it is only effective in patients whose asthma has a significant allergic component. One component of asthma is not allergic; irrtants, viral infection, medications, exercise, and other nonallergic factors play a role in triggering asthma. However, even in patients whose asthma has a significant allergic component, the sequelae of chronic inflammatory processes in the airways may not be amenable to change by SIT. Precise identification of the allergens responsible for a patient s hypersensitivity is a necessary, but not always a straightforward, prerequisite for treatment. The symptoms of asthma do not always correlate closely with the course of seasonal allergens in the environment. This may be due to the ongoing presence of several persistent allergens (eg, molds, animal dander, dust-mite antigen) that overwhelm the effects of seasonal allergens (notably pollens of trees, grasses, and ragweed). The treatment period itself typically lasts 2 1 year. Such long-term, prospective studies are expensive and difficult to manage. They also raise ethical concerns about conducting a long-term, placebo-con- trolled trial, because considerable evidence already suggests at least some benefit from SIT in the treatment of asthma. Furthermore, a host of environmental factors (eg, seasonal variations in airborne pollen species and concentrations, perennial indoor levels of dust-mite allergen), as well as concomitant medications ordinarily taken by patients, can confound the findings attributed to SIT. Asthma itself is characterized by dramatic fluctuations in severity, so that it is sometimes difficult to draw causal relationships between exposure to SIT and clinical outcome. Despite decades of positive experience with SIT in the treatment of asthma in the United States and Europe, outcomes associated with SIT for asthma have not been evaluated and clinicians continue to question the effectiveness of SIT in these patients. Poor understanding of the underlying immunologic mechanisms, the lack of adequate controlled studies, and the perceived risk of anaphylaxis may be responsible for this uncertainty. In addition, in a recent controlled trial of SIT in asthmatic children, Adkinson and colleagues4 concluded that SIT was ineffective in the presence of intensive medical treatment. In another study of asthmatic adults, Creticos and colleagues5 concluded that immunotherapy was associated with only slight, temporary improvement in asthma symptoms. Medications for the rapid relief of bronchoconstriction and long-term modulation of chronic inflammation have taken precedence over SIT as the treatment of choice, thus relegating SIT to the management of patients with persistent asthma despite pharmacotherapy.s Nevertheless, survey articles and a recent meta-analysis have suggested that SIT is an effective treatment that alters the mechanism of asthma and is, therefore, an 330

4 R.N. ROSS ET AL. appropriate adjunct to environmental controls and pharmacotherapy. A meta-analysis of 20 double-blind, placebo-controlled, randomized trials conducted by Abramson and colleague@ showed that asthma symptoms (odds ratio [OR] 3.2, 95% CI 2.2 to 4.9) and bronchial hyperreactivity (OR 6.8, 95% CI 3.8 to 12.0) were more likely to be reduced in asthmatic patients receiving immunotherapy than in patients receiving placebo. Douglass and colleagues concluded from their review of placebocontrolled studies of the efficacy and safety of SIT that immunotherapy for pollen allergy reduces asthma symptoms and may improve pulmonary function. Bousquet and colleagues8,9 concluded from their review of the literature that, along with pharmacotherapy and environmental controls, SIT has a definite place in the treatment of allergic asthma. Bonifazi and Bilb O reviewed 34 double-blind, placebo-controlled studies using standardized allergen extracts: 15 studies of moldand pollen-allergic asthma, 7 of animaldander asthma, and 12 of dust-mite asthma. Significant reductions in symptom scores and drug use were observed with SIT. Bronchial reactivity to allergen was reduced, but results were statistically inconclusive. Mailing reported on 25 asthma studies and found a positive effect of immunotherapy in 5 of 6 grass-pollen studies, in 2 of 4 dust-mite studies, in 1 of 2 cat-dander studies, and in 1 of 2 mold (Cladosporium herbarum) studies. Of the 16 studies reporting symptom or medication scores, 4 showed high efficacy (improvement ~60%), 4 moderate efficacy (improvement 45% to 59%), 3 low efficacy (improvement 30% to 44%), and 5 no efficacy (improvement <30%). The following is a meta-analysis of the literature on the use of SIT in patients with allergen-triggered asthma. METHODS The medical literature on SIT was searched by means of the MEDLINE@ database for the years 1966 through 1998 using the following key words: asthma, allergen, immunotherapy, hyposensitization, study, and randomized. In addition to studies found by means of the computer-driven literature search, others were added from references cited in publications (eg, identified articles, book chapters). Full copies of all candidate articles were retrieved for analysis, and one author (R.N.R.) extracted data from these studies. None of the data were interpreted or recomputed. Only prospective, randomized, doubleblind, placebo-controlled studies were included in this meta-analysis. All study reports were full-length articles (no abstracts) published in English in refereed journals. Only studies of immunotherapy by injection were included; studies of oral, sublingual, or other routes of administration were excluded. Although the source of funding for the studies might have been a relevant factor, possibly introducing publication bias, information about sponsorship of the studies was generally not available. Statistical Analysis Because experimental designs varied considerably from one study to another, it was not possible to reduce the entire asthma SIT database to a single format for statistical analysis. ORs and 95% CIs were the primary outcome variables evaluated; they were calculated using a random-effects model for studies that permitted the extraction of numbers of patients with positive 331

5 CLINICAL THERAPEUTICS and negative outcomes. Secondary outcome variables were comparisons of pretreatment and posttreatment means and comparisons of baseline and treatment means. Outcomes are summarized in this analysis in 2 ways. Counting studies in which SIT was judged by the investigators to be effective, ineffective, or equivocal is a simple measure of the investigators judgment regarding the clinical effectiveness of SIT. This approach gives equal weight to each study in the present analysis, disregarding differences in sample size. Therefore, the second approach in the present analysis was to count the number of patients with various outcomes of interest. RESULTS Study Selection Using the combination of the MED- LINE@ search and manual identification, 58 candidate articles on immunotherapy and asthma were identified and retrieved, of which 24 (41%) met all the criteria for inclusion in the meta-analysis.4~5~12-3 As shown in Table I, 962 patients were represented in the 24 studies: 514 received SIT and 448 did not (comparison patients). Twelve studies5s ,33 included only adults (n = 301), 10 studies4,21-29 included only children (n = 529), and 2 studies30* did not restrict the age of the patients (n = 132). Of the 24 studies included in this analysis, 18 (75%) reported obtaining the patients written informed consent and 6 (25%) 16~19,21,23.26,28 were silent on this issue. Given the significance of asthma among the serious childhood diseases, a relatively low number of controlled studies involved children. One group of investigators reported parental resistance to involving their asthmatic children in a randomized, placebo-controlled trial.34 However, children comprised 255% of the patients in the studies included in the meta-analysis. Specific Allergens As shown in Table II, the most commonly administered specific allergen extract was dust-mite antigen. Dermatophagoidespteronyssinus was administered in 7 studies, Dermatophagoides farinae in 2 studies, and a combination of D pteronyssinus and D farinae in 3 studies. Cat dander (4 studies), grass pollen (2 studies), and C herharum (2 studies) were the next most frequently administered specific allergens. Outcomes It was not possible to directly compare all 24 studies included in the meta-analysis Table I. Studies included in the meta-analysis, by age group. Age Group No. (%) of Studies Treatment Group (n) Comparison Group (n) Total Reference No. Adults 12 (50) (31) 5, 12-20,32,33 Children 10 (42) (55) 4,21-29 All ages 2 (8) (14) 30,31 Total 24 (100) ( 100) 332

6 R.N. ROSS ET AL. Table II. Allergens administered during specific immunotherapy. Antigen Extract No. of Studies Reference No. Dermatophagoides pteronyssinus 7 12, 17, 19, 27, 29, 30, 32 Dermatophagoides farinae 2 15,24 D pteronyssinus + D farinae 3 4, 28, 33 House dust 1 21 Ragweed pollen 1 5 Grass pollen 2 16, 18 Cat dander 4 13,20,25,31 Dog dander 1 26 Cladosporium herbarum 2 14,22 Assorted allergens 1 23 Table III. Summary of investigators conclusions concerning effectiveness of specific immunotherapy in controlling asthma symptoms. No. (%) of Studies Age Group Effective Ineffective Equivocal Total Adults References Children References All ages References Total 9 (75) 1 (8) 2 (17) 12 (100) 12-14, 16, 18-20,32, ,17 7 (70) 3 (30) 0 10 (100) 21-23,25-27,29 4, 24, 28 1 (50) 0 1 (50) 2 (100) (71) 4 (17) 3 (12) 24 (100) x2 = 15.25, df= 2, P = because of the variety of research designs used. Therefore, the available data are summarized in separate tables for general conclusions (Table III), changes in asthma symptoms (Table IV), effects on pulmonary function (Table V), outcomes of challenge studies (Table VI), and changes in medication use (Table VII). Because the emphasis in this meta-analysis is on evidence of clinical effectiveness, the tables summarize findings by the numbers of patients with positive or negative outcomes. Other findings are discussed in the text. General Conclusions of the Studies As shown in Table III, the investigators concluded that a course of immunotherapy was effective in controlling asthma symptoms in 17 (71%) of the 24 studies, ineffective in 4 (17%), and equivocal in 3 (12%)(x2 = 15.25, df= 2, P = ). The investigators conclusions were independent of the age of the study population. Immunotherapy was judged clinically effective in 9 (75%) of the 12 studies of adult asthma, 7 (70%) of the 10 stud- 333

7 CLINICAL THERAPEUTICS Table IV. Changes in asthma symptoms in response to specific immunotherapy, based on available data. Immunotherapy Comparison Outcome Outcome (n = 324) (n = 336) Odds Reference Asthma Symptom Pos Neg Pos Neg Ratio 95% CI No. Adults Asthma symptoms 12 Asthma symptoms 4 Daytime asthma symptoms 5 Daytime breathlessness 8 Total s.oo* s.oo* I Children Asthma symptoms 48 Asthma symptoms 8 Asthma symptoms 23 Exertion wheeze 20 Height and weight for age 8 Total * * * * All ages Asthma symptoms 25 Symptoms, cat-dander exposure 9 Symptoms, dog-dander exposure 4 Exercise tolerance 14 Nonspecific tolerance of environment 14 Total 66 Total * Jl I * Pos = improved; Neg = not improved. P < ies of pediatric asthma, and 1 (50%) of the 2 studies in asthmatic patients of all ages. Change in Symptoms As summarized in Table IV, asthma symptoms improved in 202 (62%) of 324 patients receiving immunotherapy versus 76 (23%) of 336 comparison patients, whereas 122 (38%) of the patients receiving immunotherapy did not improve versus 260 (77%) of the comparison patients (OR 2.76, 95% CI 2.22 to 3.42). Results were comparable for studies involving adults (OR 2.77, 95% Cl 1.88 to 4.07) and children (OR 2.2 1,95% Cl 1.73 to 2.82). 334

8 R.N. ROSS ET AL. Table V. Changes in pulmonary function in adult patients in response to specific immunotherapy, based on available data. Immunotherapy Outcome Comparison Outcome (n = 105) (n = 61) Odds Reference Pulmonary Function Pos Neg Pos Neg Ratio 95% Cl No. Airways conductance % Evening PEFR Morning PEFR PEFR FEV, l Lung volume l MMEF * Total * Pos = improved; Neg = not improved; PEFR = peak expiratory flow rate; FEV, = forced expiratory volume in 1 second; MMEF = maximal mid-expiratory flow. *P < Table VI. Results of challenge studies after specific immunotherapy, based on available data. Immunotherapy Comparison Outcome Outcome Odds Reference Challenge Study Pos Neg Pos Neg Ratio 95% CI No. Bronchial challenge Cat dander Histamine Ragweed pollen Dog dander Cladosporium Dermatophagoides Total Cutaneous reactivity Dermatophagoides Cat dander Cladosporium Cutaneous reactivity Total (n = 128) (n=90) (n = 66y8 (n = 52; * I.27 24* * 3.19* * 2.69* * ot * * * Pos = improved; Neg = not improved. *Children. +Adults. ral1 ages. 335

9 CLINICAL THERAPEUTICS Table VII. Effects of specific immunotherapy on concomitant medication use, based on available data. Immunotherapy Comparison Outcome Outcome (n = 161) (n = 169) Odds Reference Outcome Pos Neg Pos Neg Ratio 95% CI No. Daytime inhaler score * Nighttime inhaler score 8 I * Medication score Medication use Bronchodilator use * I Medication use * l.llji.70 Cromolyn sodium use Inhaled corticosteroid use Total * I s Pos = improved; Neg = not improved. P < Adults. Children. SAlI ages. These findings are borne out by pretreatment and posttreatment findings. Compared with patients not treated with SIT, asthma symptom scores of patients treated with SIT improved (P < 0.001),i6 patients required less medication (P < 0.05),18 improvement persisted for 1 year (P = 0.009) but not through year 2 (P = 0. lo),5 and pulmonary function improved (P < 0.05)25 after exposure. SIT did not reduce nasal symptoms significantly.18,25 Pulmonary Function As summarized in Table V, pulmonary function improved in 74 (70%) of 105 patients receiving SIT versus 15 (25%) of 61 comparison patients, whereas 3 1 (30%) of the patients receiving SIT did not improve versus 46 (75%) of the comparison patients (OR 2.87, 95% CI 1.82 to 4.52). This general finding of improved pulmonary function is borne out by pretreatment and posttreatment comparisons, in which morning peak expiratory flow rate (PEFR) and both immediate and late asthmatic responses were found to improve in patients receiving SIT. Both immediate and late asthmatic responses improved in the patients receiving SIT compared with those receiving placebo.27 Morning PEFR was improved in the SIT group in 1 study,5 but PEFR did not improve in the other studies. 15,25,28 Challenge Studies As summarized in Table VI, 2 types of challenge studies are reported in the literature: bronchial challenge and cutaneous reactivity. Results favored the immunotherapy group for protection against 336

10 R.N. ROSS ET AL. both bronchial challenge and cutaneous reactivity. Following bronchial challenge, 80 (62%) of 128 patients receiving SIT improved versus 31 (34%) of 90 comparison patients (OR 1.81, 95% CI 1.32 to 2.49); following cutaneous reactivity testing, 32 (48%) of 66 patients receiving SIT improved versus 15 (27%) of 55 comparison patients (OR 1.83, 95% CI 1.44 to 2.34). Use of Medications The effect of the combination of immunotherapy and the following medications was investigated: inhaled bronchodilators used daytime and nighttime, cromolyn sodium, beclomethasone, and inhaled corticosteroids. Data summarized in Table VII show a significant reduction in the use of medications associated with SIT, based on patients diaries and a standardized scale used by the investigators: 78 (48%) of 161 patients receiving SIT were able to reduce their use of concomitant medication versus 41 (24%) of 169 comparison patients (OR 2.00, 95% CI 1.46 to 2.72). Adverse Reactions to Treatment Of the 24 studies included in this analysis 812~15~17,21-24~27 were silent on the issue of adverse reactions to treatment. Of the remaining 16 studies, methods for defining, quantifying, and reporting adverse reactions to treatment were too diverse to permit pooling of data. In general, local reactions were observed frequently, and systemic reactions were observed regularly, but infrequently. All reactions to treatment resolved easily. Taking the placebo-controlled studies with the best reporting of adverse reac- tions to treatment,4v5*25 31 (29%) of 107 patients in the actively treated group versus 11 (10%) of 110 patients in the placebo group experienced some form of systemic adverse reaction (OR 2.90, 95% CI 1.54 to 5.46). Systemic reactions included urticaria, worsening asthma, facial edema, and rhinoconjunctivitis. Symptoms resolved quickly, either spontaneously or with medication. Large local reactions at the injection site were reported in -25% of the patients in the meta-analysis,25,26 but in as many as 48% of patients in 1 study.29 These reactions to treatment resolved easily. DISCUSSION Asthma is a complex disease with a variable course and episodic nature. Its clinical presentation is the final common pathway of many intrinsic and extrinsic factors, making studies of the outcome of asthma treatment difficult to conduct. Studies with acceptable statistical power would require larger patient samples than are usually included in such prospective, double-blind, placebo-controlled studies. A meta-analysis provides an estimate of outcomes by pooling results of smaller studies. The findings of the present meta-analysis support the effectiveness of immunotherapy in patients with asthma and documented allergy. The investigators concluded that SIT was more effective than placebo in 71% of the studies. The strongest response was in the reduction of asthma symptoms; however, reductions also were observed in response to bronchial challenge and use of medications, and pulmonary function improved. These are conservative estimates of effectiveness, because greater changes may 337

11 CLINICAL THERAPEUTICS have been masked by the use of concomitant medications. Appropriate patient selection is an essential aspect of SIT. Obviously, if the allergic component of asthma is outweighed by the irreversible results of chronic inflammatory processes (remodeling of the airways), the effects of immunotherapy will be minimal. Creticos and colleagues screened the diary cards of 1000 patients to identify 90 patients with clear seasonal asthma and symptoms that were temporally associated with the local ragweedpollen season. The true proportion of asthmatic patients with underlying allergy is probably greater than their findings suggest, however, because the risk of asthma correlates more closely with sensitivity to indoor than to outdoor allergens. The National Institutes of Health (NIH) Global Initiative for Asthma and the Canadian Society of Allergy and Clinical Immunology3s concluded that immunotherapy may be considered in IgE-mediated asthma when patients symptoms are not well controlled by standard drug regimens and by avoidance of known allergens. According to the NIH Expert Panel Report 2, Guidelines for the Diagnosis and Management of Asthma, 6 allergen immunotherapy may be considered for asthma patients when (1) there is clear evidence of a relationship between symptoms and exposure to an unavoidable allergen to which the patient is sensitive, (2) symptoms are persistent, and (3) pharmacologic control of the asthma is difficult. The safety of allergen immunotherapy has remained a concern. Cook and Farias37 reviewed the literature on the 47 fatalities that were clearly attributed to immunotherapy over the past 40 years, with systemic reactions to immunotherapy oc- curring in 0.3% to 15.0% of patients undergoing treatment. Their conclusion is that allergen immunotherapy is generally regarded as a well-tolerated form of therapy. Although severe systemic reactions occur with some regularity and fatalities do occur, asthma itself can be fatal and immunotherapy should be considered whenever pharmacotherapy and avoidance of allergens fail to control the disease adequately. The present meta-analysis has certain necessary limitations. It would have been informative, for example, to determine the onset, duration, and magnitude of the therapeutic effect associated with immunotherapy. Unfortunately, the studies included in the database did not permit such an analysis. Finally, it is uncertain whether metaanalyses provide a reliable substitute for large clinical trials. Cappelleri and colleagues * found agreement between large trials and meta-analyses of smaller trials in 90% of cases when the meta-analysis pooled data on ~1000 patients. The total number of patients pooled in the present analysis is slightly ~1000, and the number of patients represented in each of the subanalyses is considerably less. The method is thus imperfect, but it is the best method available given the limitations of the data. LeLorier and colleagues39 called attention to potential dangers of oversimplifying complex clinical issues by summarizing the findings of several smaller studies. However, these critical reviewers of metaanalyses point out that a meta-analysis merits more confidence when the results consistently show a positive outcome. The findings of the present meta-analysis are, in fact, mostly on the same side of the nodifference line and in agreement with clinical experience. 338

12 R.N. ROSS ET AL. CONCLUSIONS Results of this meta-analysis suggest that SIT can be effective in the treatment of carefully selected patients with allergentriggered asthma and may be considered for patients with documented allergy whose asthma symptoms are not controlled by standard drug regimens. ACKNOWLEDGMENT This study was funded by an unrestricted grant from the American College of Allergy, Asthma, and Immunology, Arlington Heights, Illinois. Address correspondence to: Robert N. Ross, PhD, Medical/Science Analytics, 16 Windsor Road, Brookline, MA REFERENCES Norman PS. Immunotherapy for nasal allergy. J Allergy Clin Immunol. 1988;8 1: Weber RW. Immunotherapy with allergens. JAMA. 1997;278: Bousquet J, Lackey RF, Malling H-J. WHO position paper. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. Allergy. 1998;53(Suppl): I-42. Adkinson NF, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med. 1997;336: asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med. 1995; 151: Douglass JA, Thien CK, O Hehir RE. Immunotherapy in asthma. Thorax. 1997; 52(Suppl 3):S22-S29. Bousquet J, Michel FB. Specific immunotherapy in asthma: Is it effective? J Allergy Clin Immunol. 1994;94: l-l Bousquet J, Demoly P, Chanez P, Michel FB. Immunotherapie specifique des allergies respiratoires. Bull Acad Nat1 Med. 1997;8: Bonifazi F, Bile MB. Efficacy of specific immunotherapy in allergic asthma: Myth or reality? Allergy. 1997;52: Malling H-J. Immunotherapy as an effective tool in allergy treatment. Allergy. 1998;53: Bousquet J, Calvayrac P, Guerin B, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. I. In vivo and in vitro parameters after a short course of treatment. J Allergy Clin Immunol. 1985;76: Haugaard L, Dahl R. Immunotherapy in patients allergic to cat and dog dander. I. Clinical results. Allergy. 1992;47: Mailing H-J, Dreborg S, Weeke B. Diagnosis and immunotherapy of mould allergy. V. Clinical efficacy and side effects of immunotherapy with Cludosporium herbarum. Allergy. 1986;4 1: Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med. 1996;334: Newton DA, Maberley DJ, Wilson R. House dust mite hyposensitization. Br J Dis Chest. 1978;72: Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in 16 Ortolani C, Pastorello E, Moss RB, et al. Grass pollen immunotherapy: A single 339

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