Correspondence

Clinical Efficacy of Grass-Pollen Immunotherapy

N Engl J Med 2000; 342:58-59January 6, 2000

Article

To the Editor:

The study by Durham et al. (Aug. 12 issue)1 of the clinical efficacy of grass-pollen immunotherapy has a complex design. According to the authors, the study is a randomized, double-blind, placebo-controlled study of the discontinuation of immunotherapy in patients with rhinitis. The authors conclude that “immunotherapy for grass-pollen allergy for three to four years induces prolonged clinical remission.”

The design of the study has a flaw that we believe invalidates their conclusion: it did not include a randomized group that received placebo to control for the spontaneous course of rhinitis. In 1988, patients were randomly assigned to receive immunotherapy for three or four years. In 1992, each of these patients was randomly assigned to one of two groups, an immunotherapy-maintenance group or a discontinuation group, which received placebo injections until 1995. In 1992, an open, nonplacebo control group was added so that symptoms could be monitored.

Rhinitis is a common disease, but little is known about its epidemiology2 or its spontaneous course. Clinical experience shows that there is great variation in the severity of rhinitis and its course. Often, seasonal rhinitis diminishes after some years of disease.

Without the use of a randomized placebo group, Durham et al. cannot show whether immunotherapy is better than a seven-year spontaneous course of grass-pollen rhinitis. The study design does, however, support the conclusion that patients who have received immunotherapy for three to four years will not be harmed by discontinuing the treatment.

Marianne Stubbe Østergaard, M.D., Ph.D.
Klaus Witt, M.D., Ph.D.
University of Copenhagen, 2200 Copenhagen N, Denmark

2 References

1
Durham SR, Walker SM, Varga E-M, et al. Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468-475
Full Text | Web of Science | Medline

2
International Rhinitis Management Working Group. International consensus report on the diagnosis and management of rhinitis. Allergy 1994;49:Suppl:1-34
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To the Editor:

In their discussion, Durham et al. state that other studies have suggested that immunotherapy has a long-term effect, and two of the six references they cite are about immunotherapy with mite extract. We think it is a mistake to consider all these papers together, since there is no evidence of the long-standing efficacy of immunotherapy with mite extract.

The two studies cited actually do not suggest the long-term efficacy of specific immunotherapy for mite allergy. Price et al.1 gave evidence of deterioration when treatment was stopped, since most of the children who received placebo after one year of active treatment had a relapse within months. Des Roches et al.2 showed that the duration of efficacy of immunotherapy with Dermatophagoides pteronyssinus extract after its cessation can be increased by a period of treatment longer than 36 months. Even in the patients in the study by Des Roches et al., the rate of relapse three years after the discontinuation of treatment was as high as 48 percent (vs. 62 percent in the group that received short-term treatment).

Bousquet et al.3 observed that about half the patients in their study had a recurrence of symptoms within six months after the treatment was discontinued. In the study by Van Bever and Stevens,4 one year after discontinuing a one-year course of mite immunotherapy, children had a recurrence of a late asthmatic reaction at the same level as before immunotherapy was started.

There is no evidence that immunotherapy modifies the natural history of nonseasonal, perennial, mite-allergy disease through childhood and into adult life. Results found in patients allergic almost exclusively to pollens are not representative of those in patients allergic to house-dust mite.

Giorgio Longo, M.D.
Egiolio Barbi, M.D.
University of Trieste, 34100 Trieste, Italy

4 References

1
Price JF, Warner JO, Hey EN, Turner MW, Soothill JF. A controlled trial of hyposensitization with adsorbed tyrosine Dermatophagoides pteronyssinus antigen in childhood asthma: in vivo aspects. Clin Allergy 1984;14:209-219
CrossRef | Medline

2
Des Roches A, Paradis L, Knani J, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy 1996;51:430-433
Web of Science | Medline

3
Bousquet J, Hejjaoui A, Michel FB. Specific immunotherapy in asthma. J Allergy Clin Immunol 1990;86:292-305
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4
Van Bever HP, Stevens WJ. Evolution of the late asthmatic reaction during immunotherapy and after stopping immunotherapy. J Allergy Clin Immunol 1990;86:141-146
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Author/Editor Response

The authors reply:

To the Editor: We agree with Drs. Longo and Barbi that evidence of long-term efficacy is less convincing for mite immunotherapy. The reason may relate to the heterogeneous nature of perennial rhinitis and asthma, of which allergy to mites is only one of the determinants. As compared with our study of grass pollen, however, two of the studies cited involved a much shorter treatment period (one year). Also, Des Roches et al.1 showed, in results consistent with our findings, that the duration of efficacy of immunotherapy with D. pteronyssinus after its cessation was increased by treatment for more than three years. Similarly, more than 90 percent of patients who receive five years of immunotherapy with Hymenoptera-venom extracts are afforded protection from a sting for five years after discontinuing treatment.2 These studies suggest that in selected patients, long-term protection results from an adequate duration of treatment (three to five years) with high-dose standardized vaccines, not from the particular allergen used.

In response to Drs. Østergaard and Witt, it is unlikely that the improvement could be explained by the natural history of hay fever. First, substantial decreases in seasonal symptoms (60 percent) and rescue medication (80 percent) occurred within the first year of our previous study, with no further reductions over the following six years, as might have been anticipated because of age-related changes in the patients. Second, we included a matched control group of patients who had never received immunotherapy; these patients had no decline in symptoms during the three-year period after treatment had been discontinued. The advantage of using such a control group could not have been foreseen at the outset of the study in 1988. Third, the spontaneous remission of symptoms of rhinitis has been reported in one study in only 8 percent of patients over a period of two to four years.3 Such small changes could not have accounted for our findings. Finally, the remission of hay fever is less likely when the onset of symptoms occurs after 20 years of age4 and when the disease lasts for more than five years.3 In the majority of our patients, symptoms developed in adulthood (mean age at onset of symptoms, 26 years for the maintenance group, 19 years for the discontinuation group, and 20 years for the control group), and the disease was of long duration (14, 18, and 17 years, respectively).

We conclude that long-term clinical efficacy after the discontinuation of grass-pollen immunotherapy is the result of long-lasting immunologic effects, as evidenced by the decreased allergen-specific late cutaneous responses and associated suppression of T-lymphocyte responses.

Stephen R. Durham, M.D.
Samantha M. Walker, R.N.
Eva-Maria Varga, M.D.
Imperial College School of Medicine, London SW3 6LY, United Kingdom

4 References

1
Des Roches A, Paradis L, Knani J, et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy 1996;51:430-433
Web of Science | Medline

2
The discontinuation of Hymenoptera venom immunotherapy. J Allergy Clin Immunol 1998;101:573-575
CrossRef | Web of Science | Medline

3
Broder I, Higgins MW, Mathews KP, Keller JB. Epidemiology of asthma and allergic rhinitis in a total community, Tecumseh, Michigan. IV. Natural history. J Allergy Clin Immunol 1974;54:100-110
CrossRef | Web of Science | Medline