Correspondence
Immunotherapy for Asthma
N Engl J Med 1997; 336:1911-1913June 26, 1997
- Article
To the Editor:
The failure of the study by Adkinson et al. (Jan. 30 issue)1 to demonstrate a significant benefit of immunotherapy with a few allergens to a particular group of children with asthma does not negate the positive benefit demonstrated in numerous other studies. The meta-analysis by Abramson et al.2 suggests that 33 negative studies would be necessary to overturn the results that demonstrated significant odds of symptomatic improvement, decreased medication use, reduction in bronchial hyperreactivity, and improvement in forced expiratory volume in one second with immunotherapy.
Some of the patients may have been sensitive to allergens not included in treatment (or presumably in testing). These might include cockroach, other molds, and other tree and fall-weed pollens. Most allergist-immunologists are familiar with the wide variety of pollens at different seasons in their areas, and they test and treat with all the major pollens that have positive results on skin-prick testing. They would not expect improvement if they treated with only one type of allergen for the season. Adkinson et al. chose to limit the number of allergens in order to reach very high doses and perhaps threw out the baby with the bath water.
The authors themselves suggest caution in interpreting their results. The patients received maintenance treatment with free medications with close follow-up, and any participating children who did not comply were dropped from the study. I concur that allergy shots may be more useful in patients in the real world who tend to have lower levels of compliance with pharmacotherapy.
2 ReferencesBetty B. Wray, M.D.
American College of Allergy, Asthma and Immunology, Arlington Heights, IL 60005-44251
Adkinson NF Jr ,Eggleston PA ,Eney D , et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997;336:324-331
Full Text | Web of Science | Medline2
Abramson MJ ,Puy RM ,Weiner JM . Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med 1995;151:969-974
Web of Science | Medline
To the Editor:
In the study by Adkinson et al. the patients differed from people with asthma in the real world in two respects. All the patients, and their parents, volunteered for the study. Volunteers are generally far more interested in their disease and in adhering to lifestyle alterations likely to help it than are most patients with asthma. These volunteers were uncommonly likely to comply with prescribed management and also received unusually intense follow-up by the clinical research team. The compliance rate with medication was 93 percent.
The clinical improvement reported by Adkinson et al. in both the immunotherapy and placebo groups is similar to that achievable in less strongly motivated patients, followed less intensively, but with immunotherapy to supplement environmental controls and medications.1
Might it be most appropriate to conclude that for uncommonly motivated patients, coached and monitored by an allergy research team that checks closely for compliance with medications, adding immunotherapy probably will not make them much better?
1 ReferencesRobert E. Coifman, M.D.
Allergy and Asthma of South Jersey, Vineland, NJ 083601
Coifman RE . Dynamic approach to asthma. J Asthma 1983;20:45-52
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To the Editor:
The study by Adkinson et al. has important flaws. The placebo group received injections of histamine. Histamine is not an inert agent and is thus inappropriate for use in a placebo. Histamine has physiologic activity on the immune system, even at low doses,1 and has been used for therapy for several conditions.2 Therefore, failure to demonstrate a difference between the histamine group and the immunotherapy group could indicate that both treatments were active. In fact, this possibility is suggested by the observed decreases in medication-use scores and in methacholine sensitivity that occurred in both groups.
Each patient in the immunotherapy group was treated with only two to six inhalant allergens. The omission of many important perennial allergens from treatment, including animal danders, cockroach, penicillium, helminthosporium, and others, may have resulted in treatment with insufficient numbers of allergens to reduce the total allergy load significantly. Both the history and clinical testing frequently incriminate multiple allergic triggers of asthma in a single patient, and failure to treat enough of these triggers adequately is a very possible reason for the failure of any immunotherapy program.3
This study shows a large effort and commendable attention to detail, but unfortunately, the methods used do not exclude several large possible sources of error. Therefore, I believe that the authors' conclusion that immunotherapy was of no benefit in this study group may be invalid.
3 ReferencesBruce R. Gordon, M.D.
American Academy of Otolaryngic Allergy, Silver Spring, MD 209101
Brune M ,Hellstrand K . Remission maintenance therapy with histamine and interleukin-2 in acute myelogenous leukaemia. Br J Haematol 1996;92:620-626
CrossRef | Web of Science | Medline2
Fischer AJ . Histamine in the treatment of vertigo. Acta Otolaryngol Suppl (Stockh) 1991;479:24-28
CrossRef | Medline3
Ohman JL Jr . Allergen immunotherapy: review of efficacy and current practice. Med Clin North Am 1992;76:977-991
Web of Science | Medline
To the Editor:
The study by Adkinson et al. found that treatment with multiple-allergen immunotherapy in polysensitized children with asthma is not efficient. These results are very interesting. However, the panel of allergens for which children were tested was not reported, nor the prevalence of some perennial allergens such as cockroach. Cockroach is an important perennial allergen in the pediatric population of North America. Because eviction of this allergen is difficult to obtain and no extract is available for immunotherapy, continuous exposure to it could maintain bronchial inflammation and explain the lack of efficacy of immunotherapy in these polysensitized patients. Moreover, one benefit of participation in this protocol was free asthma medications, and this could have led to a selection bias toward children of low socioeconomic status and thus more exposure to cockroach allergen. For all these reasons, more details would be appreciated on these aspects of the study and should be considered in interpreting the results.
Anne Des Roches, M.D.
Hôpital Sainte-Justine, Montreal, QC H3T 1C5, CanadaLouis Paradis, M.D.
Jean Paradis, M.D.
Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 3J4, CanadaTo the Editor:
In the study by Adkinson et al. the patients received mixtures of allergens, but mixing induces rapid degradation of allergens.1 Although changes in skin-test results and levels of specific IgG were observed, such changes do not preclude an effect of the composition of the allergen extract. If some allergens essential to the patient's sensitivity are degraded, immunotherapy is less effective. This comment is substantiated by the study itself, since when patients were receiving more than five allergens, there was strictly no effect of immunotherapy. . . .
1 ReferencesJean Bousquet, M.D.
François-Bernard Michel, M.D.
Hôpital Arnaud de Villeneuve, 34090 Montpellier, FranceHans-Jorgen Malling, M.D.
National University Hospital, 2200 Copenhagen, Denmark1
Nelson HS ,Ikle D ,Buchmeier A . Studies of allergen extract stability: the effects of dilution and mixing. J Allergy Clin Immunol 1996;98:382-388
CrossRef | Web of Science | Medline
To the Editor:
Figure 1 of the article by Adkinson et al. shows the medication scores for the immunotherapy group and the placebo group at randomization and at the last follow-up visit. The text states that Table 3 shows the mean change in scores between base line and the last follow-up visit. If base line is the time of randomization, there seems to be a discrepancy. Figure 1 shows the score for the immunotherapy group to be greater than that of the placebo group, and both appear to be greater than 5. Table 3 shows the base-line score for the placebo group to be 5, and the score for the immunotherapy group is only 4.9. Are the figure and table showing different data?
Joseph T. Marino, M.D.
6555 Coyle Ave., Carmichael, CA 95608To the Editor:
The report by Adkinson et al. concludes that immunotherapy may be of limited value in the management of asthma in allergic children, a position many allergists can accept on the basis of experience. But it is very important to point out that the study does not indicate that accurate diagnosis of the child's allergies is unimportant. Children can be much better protected from house dust, a moldy environment, or a cat when their reactivity is documented and the physician can focus the parents' attention on appropriate environmental-control measures. These avoidance techniques are very important in treating childhood asthma and were used in both the treated and the control groups in this study with excellent results. Specific diagnosis of allergy is an essential component of the successful treatment of children with asthma. Radioallergosorbent tests or skin tests can provide accurate assessment of allergy.
Vincent A. Marinkovich, M.D.
90 Middlefield Rd., Menlo Park, CA 94025Author/Editor Response
The authors reply:
To the Editor: Dr. Wray suggests that the meta-analysis of 20 asthma-immunotherapy studies by Abramson et al. demonstrated efficacy that outweighs our negative results. Most of the trials Abramson et al. analyzed dealt with single allergens, seasonal disease models, or both.1 We do not dispute the protective benefit of immunotherapy in selected cases, but our study demonstrates that it is not clinically indicated in children with well-managed moderate to severe perennial asthma.
Drs. Wray and Coifman express concern that the patients selected for our study were highly compliant and therefore not representative of typical immunotherapy patients. Although this may be true, we do not believe it explains our negative results, since there was still much symptomatic disease after stabilization at base line and multiple disease markers improved significantly in both groups during the study. If immunotherapy had been effective in these subjects, the study design was sufficient to have shown it.
Another concern expressed is that there were critical omissions of important aeroallergens, especially cockroach. In mid-study we performed cockroach skin testing and home-dust analysis for cockroach allergens for 87 of the 121 subjects.2 Only 20 children had positive cockroach skin tests and bedroom Bla g I levels >1 unit per gram. If the omission of cockroach or any other locally important allergen is essential for a successful outcome of immunotherapy, then much of the immunotherapy currently administered for asthma in the United States must be considered suspect.
Dr. Gordon objects that histamine has biologic effects and should not have been used in our placebo solutions. Diluents containing 1 to 10 μg of histamine per milliliter have been used in numerous controlled studies of immunotherapy with positive outcomes.3,4 It would be surprising if small doses of histamine injected intradermally weeks apart ameliorated asthma symptoms, and we would welcome any evidence that this is the case.
Dr. Bousquet and colleagues point to evidence that allergen mixtures may lead to autodegradation of important allergens, thereby rendering them impotent. In our study we observed pronounced IgG-antibody responses and altered skin-test reactivity, suggesting that, at least for most allergens, substantial biologic potency remained. The work of Litwin et al.5 shows that enzyme degradation of ragweed may actually convey advantages for immunotherapy.
The apparent discrepancy in base-line medication scores between Table 3 and Figure 1 reflects the fact that median levels are shown in Figure 1, whereas the scores in Table 3 are means.
We heartily agree with Dr. Marinkovich's assertion that accurate diagnosis of allergy in children with allergic asthma is indispensable to proper environmental control and patient education. Irrespective of the issue of immunotherapy, we believe that every child with asthma deserves and will benefit from comprehensive allergy evaluation and management.
5 ReferencesN. Franklin Adkinson, Jr., M.D.
Peyton A. Eggleston, M.D.
Johns Hopkins University School of Medicine, Baltimore, MD 212241
Abramson MJ ,Puy RM ,Weiner JM . Is allergen immunotherapy effective in asthma? A meta-analysis of randomized controlled trials. Am J Respir Crit Care Med 1995;151:969-974
Web of Science | Medline2
Sarpong SB ,Hamilton RC ,Eggleston PA ,Adkinson NF Jr . Socioeconomic status and race as risk factors for cockroach allergen exposure and sensitization in children with asthma. J Allergy Clin Immunol 1996;97:1393-1401
CrossRef | Web of Science | Medline3
Van Metre TE Jr ,Adkinson NF Jr ,Amodio FJ , et al. A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. J Allergy Clin Immunol 1982;69:181-193
CrossRef | Web of Science | Medline4
Sundin B ,Lilja G ,Graff-Lonnevig V , et al. Immunotherapy with partially purified and standardized animal dander extracts. I. Clinical results from a double-blind study on patients with animal dander asthma. J Allergy Clin Immunol 1986;77:478-487
CrossRef | Web of Science | Medline5
Litwin A ,Pesce AJ ,Fischer T ,Michael M ,Michael JG . Regulation of the human immune response to ragweed pollen by immunotherapy: a controlled trial comparing the effect of immunosuppressive peptic fragments of short ragweed with standard treatment. Clin Exp Allergy 1991;21:457-465
CrossRef | Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Stefan Zielen, Peter Kardos, Enzo Madonini. (2010) Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: A randomized controlled trial. Journal of Allergy and Clinical Immunology 126:5, 942-949
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