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Despite numerous studies, the role of immunotherapy in the management of asthma remains controversial,1,2 and interpretation of published reports varies considerably, presumably because of personal bias. It is reasonable to think that there will be more variability in responses to immunotherapy because of uncontrolled factors that differ for people receiving the same therapy: degree of allergen exposure and environmental control; other allergenic sensitivities not incorporated into the treatment; and nonallergenic triggers of asthma, such as infection or exposure to chemical sensitizers. The specificity of individual allergens in the treatment as well as the dose regimen employed may influence outcomes. Therefore, any large treatment group is likely to include both responders and nonresponders, and the investigator must use objective criteria to define those who benefit and those who do not. Variable responsiveness of individual patients likely accounts for the inconsistency in the literature.
Immunotherapy has been established as efficacious treatment for allergic rhinitis triggered by seasonal pollens, dust mites and animal allergens, although in the case of animal allergens, some authors still consider it controversial.3-11 Controlled studies have demonstrated the efficacy of immunotherapy in asthma, and a meta-analysis12 of 20 prospective studies concluded that allergen immunotherapy was effective in reducing the number of symptoms, the requirements for medication and airway hyperresponsiveness. Although the meta-analysis12 focused on immunotherapy in adults, the same group of investigators is conducting an up-date of the systematic review of allergen-specific immunotherapy for asthma as part of the Cochrane collaboration.13 In asthmatic adults allergic only to ragweed aeroallergen, Creticos and colleagues14 found an improvement in the immunotherapy-treated group, in terms of peak expiratory flow (PEF) and medication use, during the first year compared with the control group, but these factors were similar for the 2 groups in the second year.
Recently, Sigman and Mazer15 reviewed 1966-1994 reports on immunotherapy in the management of asthma in children, but meta-analysis was not possible because of the heterogeneity of the studies. Most studies showed some beneficial effects of immunotherapy, either improvement of asthmatic symptoms or a decrease of bronchial reactivity to specific antigens. Trials using household dust-mite immunotherapy provided the most consistent evidence of benefit; immunotherapy for grass pollens and cat dander was of some benefit, but the number of supporting studies was very small. Trials of immunotherapy for mould or dog dander were few and provided no convincing evidence of effectiveness. The heterogeneity and small numbers of studies precluded making firm recommendations for the use of immunotherapy in children with asthma.
A MEDLINE search of 1995-1998 reports of conventional immunotherapy and childhood asthma yielded 4 studies16-19 with abstracts in English. Peroni and colleagues16 conducted a double-blind, placebo-controlled trial of immunotherapy with a standardized extract of Dermatophagoides pteronissinus in 23 asthmatic children, aged 7-14 years, residing at high altitude. After 12 months, the 2 groups showed comparable improvement in clinical features and lung function, and diminution of nonspecific and specific bronchial hyperreactivity. The children treated with immunotherapy, but not those receiving placebo, had decreased sensitivity to D. pteronissinus on skin tests. The authors concluded that immunotherapy was beneficial, but the benefit of allergen avoidance derived from living at high altitude was even greater, resulting in the absence of difference between the treatment groups.
Costa and colleagues17 studied 11 patients with asthma and household dust-mite allergy who received specific immunotherapy and inhaled glucocorticosteroids for 27 months, while 11 similar patients received inhaled glucocorticosteroids alone. Improvement in symptoms score, bronchodilator use and lung function was comparable in the 2 groups. The patients treated with immunotherapy and glucocorticosteroids experience faster improvement in bronchial hyperreactivity and PEF variability. After 18 months, patients in both groups stopped using inhaled glucocorticosteroids. This interruption was followed by impairment of all end points, which was more pronounced in the patients previously treated with glucocorticosteroids alone. The authors concluded that immunotherapy and inhaled glucocorticosteroids produced a faster improvement than glucocorticosteroids alone and led to a lower rate of relapse after interruption of therapy with inhaled glucocorticosteroids.
In a prospective 3-year study,18 300 children with asthma due to pollen or household dust-mites were randomly allocated to receive specific immunotherapy or not. Children receiving immunotherapy had significantly fewer days with asthma and drug use than those in the control group. In addition, the immunotherapy group had fewer asthma attacks and better quality of life than the control group.
Adkinson and colleagues19 conducted the largest randomized controlled trial of immunotherapy in children with asthma; this is also the first study to assess polyvalent immunotherapy using a double-blinded, placebo-controlled protocol. In the trial, 121 children with moderate-to-severe perennial asthma received subcutaneous injections of either a mixture of up to 7 aeroallergen extracts or placebo for 18 months or longer. In the first phase of the trial, the children were evaluated and their treatment was optimized. The patients were sensitized to 2-7 of the 14 allergens tested. The children visited the clinic every 2 weeks, kept asthma diaries, were monitored by PEF measurement and received asthma education. Medication was adjusted to achieve the best control of symptoms with the least medication; 57 patients required regular glucocorticosteroid therapy.
After 1 year, immunotherapy or placebo treatment began. The management regimen established in the first phase was continued. Symptom scores, medication use and bronchial hyperresponsiveness declined in both treatment and control groups, but there were no significant differences between the groups. The 2 groups also did not differ in the number of days on which oral glucocorticosteroids were used. Complete remission (cessation of all drug therapy) was similar for the 2 groups - 7.5% in the treatment group and 8% in the control group. Skin-test reactivity to treatment allergens decreased substantially in the immunotherapy group.
In this study, immunotherapy did not provide additional benefit over close and careful management of asthma. This leads to speculation that immunotherapy may fulfill a role when optimal, comprehensive management of asthma, such as that provided to the study population, is not feasible.
Safety
Multiple factors must be considered before immunotherapy is employed, because the risk of adverse reactions to treatment, although low,20,21 is significant and fatalities have occurred.22,23 The Mayo Clinic20 reported an incidence of reactions of 0.137% in 79 593 injections over 10 years: most were mild, all were responsive to treatment and there were no fatalities.
Immunotherapy should be restricted to patients in whom specific allergens are identified as playing a causative role in asthma and where the allergen cannot be avoided. Because of the increased risk of severe reactions, patients should not receive immunotherapy if they are taking a ß-adrenergic antagonist (this medication is also contraindicated in the presence of asthma), if their asthma is not clinically stable or if they have an accompanying respiratory tract infection. Neither should immunotherapy be initiated nor the dosage increased during pregnancy. Patients must remain under medical supervision for a minimum of 20 minutes after injection of the allergen, longer in the case of high-risk patients.24,25
Suggestions for future research
Recommendations
References
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(e) 0820-3946 (p)
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association. |
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