A controlled trial of immunotherapy for asthma in allergic children

Summary

Injections of allergens have been shown to be effective in the treatment of allergic rhinitis. Efficacy has also been shown in some studies of single-allergen models of asthma. This study was designed to look at the use of multiple-allergen injections for the treatment of children with severe, perennial asthma. Children were randomized to multiple-allergen injections vs. placebo, in addition to standard, modern medical therapy.

Methods

• Patients: Children were eligible if they were between 5 and 12 years old, had asthma for over one year (on regular medical therapy for at least six months), and were allergic (by skin tests, serum IgE and history). Refusal to part with furred pets was a reason for exclusion.

  Randomization was preceded by a prolonged (mean: 408 days) run-in phase, during which medications were adjusted, families were instructed and children underwent skin testing.
   

• Immunotherapy: Prior to randomization, up to seven treatment allergens were selected for each child, based on results of skin testing and RAST tests. Patients were then randomized to treatment with injections of increasing doses of allergens or of placebo (containing caramelized saline and histamine). Doses were increased towards a target dose, or to a lower dose if systemic reactions necessitated this. Once maintenance therapy dose was attained, it was given every 2 weeks for 24 months, then every 3 weeks until completion of the study.
   
• Asthma management and follow-up: Asthma medication adjustment (increases and decreases) took place according to a stepped-care algorithm, but the algorithm could be and frequently was overruled by the responsible clinicians. The steps in treatment were:
   
  • Step 1: bronchodilator as needed
  • Step 2: regular bronchodilator (theophylline or albuterol)
  • Step 3: combination of 2 or 3 drugs (theophylline, albuterol or cromolyn)
  • Step 4: inhaled beclomethasone or alternate-day methylprednisolone
  • Step 5: daily oral steroid, with tapering
     
• Outcomes: The primary outcome measured was the amount of medication needed to adequately control the patient's asthma, as measured on a 10-point ordinal scale (0 -- no medication; 10 -- high doses of oral steroids, etc.). Other outcomes included peak flow rates, asthma symptom scores, number of days on which steroids were required, number of contacts with health care providers and sensitivity to methacholine.

• Subjects: Of 350 children recruited, 121 were randomized (61 to immunotherapy, 60 to placebo), average age 9.2 years, 54% white, 45% black. At randomization 43% required steroids, the majority of these only inhaled steroids. The predominant sensitivity was to dust mites; the median number of extracts given was 6. The mean time from randomization to completion (or dropping out) was approximately 1000 days in both groups. 70% of children in the immunotherapy group received the full, target dose for at least 18 months. There were 8 dropouts in the immunotherapy group and 3 in the placebo group, none because of adverse effects.
   
• Outcomes: The mean medication scores decreased significantly from baseline to the last follow-up visit in both groups (from 5.0 to 3.8 in the placebo group; from 4.9 to 3.5 in the immunotherapy group), but this change was not significantly different between the groups. Partial or total remission (prn albuterol or no medication) occurred in 19 patients in the immunotherapy group and in 17 in the placebo group.

  A similar pattern was seen for most of the outcome measures -- an improvement between baseline and study end in both groups, but not much difference between the two groups. The immunotherapy group showed a significantly greater improvement in peak flow rate (from 81.9% of predicted to 84.4%, vs. a 1.4% decrease in the placebo group). There was also a trend towards greater improvement in the use of inhaled steroids (# of days in the previous 60 days decreased by 5.4 in the placebo group vs. a decrease of 10.1 in the immunotherapy group, but P only 0.26). Use of oral steroids, symptom scores, medical contacts and methacholine sensitivity showed no significant advantage for immunotherapy.

  Analyses of multiple subgroups showed a benefit approaching statistical significance for immunotherapy in the younger age group (less than 8.5 years) and in those with mild asthma.

  Antigen specific IgG antibody levels rose significantly in the treatment group, not in the placebo group, as expected.
   

• Adverse events: Systemic reactions to allergen injections occurred in 34 percent of the immunotherapy group and in 7 percent of the placebo group. There were 114 reactions, 52 of which were treated with adrenergic drugs.

This study showed no significant benefit for allergen injections in the treatment of perennial asthma in children, over a period of 30 months. The others discuss several possible explanations. They rebut the possibilities that these patients did not have severe enough asthma to show an effect, that they were over-medicated or that the allergens used were not potent enough.

They note that this population was selected for compliance and received presumably optimal therapy for asthma; the results might be different in a less compliant or under-medicated group. They also note that immunotherapy might be beneficial earlier in the course of asthma, which is supported by the subgroup analysis that found an effect in younger patients with milder asthma. Further studies in this subgroup should be undertaken.

Comment

The subject of whether immunotherapy is effective in asthma has been visited frequently in the medical literature. In February 1996, a similar study by Creticos et. al. (1) was published in the NEJM. It evaluated adult asthmatics with ragweed sensitive asthma (single allergen therapy). It too showed no benefit (save a minimal improvement in peak flow). In an accompanying editorial (2), Peter Barnes stated that immunotherapy is no longer used for asthma in the United Kingdom, and that the treatment should be re-evaluated in the United States. In these days of managed medicine, with the clinical impression of allergists being that immunotherapy is still a useful adjunct in asthma therapy and criticisms that single allergen therapy is not as realistic as multiple allergen therapy, this study was undertaken.

This is a well designed trial. The choice of placebo ensures good blinding. Because allergen extracts are not strictly standardized and the children were on different combinations of extracts, they did not all receive the same microgram amounts of antigen. This cannot be avoided in a study involving multiple extract allergen immunotherapy.

As stated in the discussion, the authors selected for an extremely compliant population of children. This was accomplished by having a long run in time and a requirement to rid the home of furred pets (which would have eliminated at least half of my patients and may explain part of the decrease from 350 to 121 subjects). The subjects were seen every two weeks, and both groups saw an improvement in medication use and a significant improvement in bronchial hyperreactivity as measured by methacholine sensitivity. A significantly larger group of children on treatment had systemic reactions than those who received placebo.

This level of compliance is unrealistic in a standard allergy practice. When a person comes in for "allergy shots" on a weekly basis, he is likely to say, "hey, doc, I ran out of my medicine." or, "I have sinusitis". Often, he gets a peak flow measurement prior to his injection, and early intervention is possible before a flare. The routine of regular visits imprints the routine of asthma medication compliance. This, in large part, may be why the clinical impression of many allergists is that immunotherapy is effective in asthma. In addition, the asthma patient who visits an allergist (a specialist) may receive better care than one who isn't cared for by a specialist.

All in all the advent of routine inhaled steroids has revolutionized asthma care, and added a tool which was not available to the allergists of yore who still often use immunotherapy as a treatment.

February 13, 1997

Reader comments

Mon, 17 Feb 1997
From: "Engler, RJM" <renata@erols.com>

rjme
 
 

Cockroach antigen, (bla g I) is a significant perennial allergen in inner-city asthmatic children. It appears that cockroach sensitivity was not evaluated in these children. This, in fact,may be a flaw of the study. I'm not sure when cockroach immunotherapy with commercial antigen became routine. This study lasted a long time, and this antigen may not have been available for testing at the outset of the study.

As an indirect estimate, we can look at the study's subgroup analysis. About half of the subjects were from the inner cities. The remainder were from suburban areas, presumably a predominantly white population. Subgroup analyses did not appear to show any significant effect when blacks and whites were examined separately, which argues against this criticism.

You and the authors are in agreement that early intervention with immunotherapy may be more effective than later intervention. This too is seen in subgroup analysis which shows a trend towards improvement in younger children (which may be a marker for recent-onset of asthma). -- elj

Letters to the Editor about this article, from the NEJM website.

Topics include the failure to test and treat for cockroach allergy, and whether the results can be generalized to a less compliant population.
 

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References

2. Barnes P. Is immunotherapy for asthma worthwhile? N Engl J Med 1996;334:531.
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References related to this article from the NLM's PubMed database.

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