- Email: [email protected]
IMMUNOTHERAPY FOR ASTHMA
Letters to the editor IMMUNOTHERAPY FOR ASTHMA To the Editor: In their review of specific immunotherapy in children Sigman and Mazer1 do not clearly specify that this treatment is effective, safe, and is the only curative treatment for asthma. As regards the effectiveness, they discuss only twelve pediatric studies. Instead we have found 27/29 (93%) controlled pediatric studies (literature available on request) disclosing beneficial effects on the natural history with total remission of asthmatic symptoms in the children who regularly completed the immunotherapy cycle.2–5 We have treated 1443 children, aged 2 to 14 years, with immunotherapy.2–5 During 3 years we have prospectively observed 300 children with asthma due to Dermatophagoides pteronyssinus or pollen.2 We also have studied 39 children with monosensitization to Alternaria alternata, also treated for 3 years with allergenic extracts. Statistically significant differences were observed between children receiving immunotherapy and those treated only with drugs.2,3 In immunotherapy-treated children there was an 8.8-fold increase in IgG levels6 and a significant reduction in IgE levels. The authors comment briefly on the frequency of reactions to immunotherapy.1 We observed systemic reactions in 0.09% injections and only one case of shock (0.0016% of injections and in 0.089% of 1119 treatments).4 In studies of children with asthma/allergic rhinitis due to pollen,5 and Alternaria alternata3 we observed only local reactions treated with drug therapy. Among 300 children with asthma,2 only three children experienced urticaria (1.5%) and two wheezing (1%) (0.006% of treatments), caused by high dosage and eliminated with reduced doses. Our studies therefore confirm the effectiveness of immunotherapy in
VOLUME 80, JANUARY, 1998
children. In a recent study the rate of apparent systemic reactions was 2.6%.6 Sigman and Mazer stress several recommendations against performance of immunotherapy in children.1 The paper they cite7 emphasizes that children ⬍5 years of age have a significantly greater risk of systemic reactions.8 Several significant points were omitted2: (1) the children were subjected to a rush protocol, which is known to provoke more reactions, (2) the children had neither premedication nor preventive measures; the authors were conscious of the risks, therefore the patients were hospitalized for the first night of treatment, (3) the authors hypothesized that the hospitalization increased the rate of reactions because of its psychologic impact.8 Among the 47 fatal cases that occurred before 1973 and 1989 reported by Lockey et al9 and Reid et al10 there are seven children aged 7 to 18 years. In one case there was a known error of immunotherapy administration and an incorrect dose of epinephrine, in another a probable error of dosage and delay in the treatment, two patients did not wait in the doctor’s office, one had wheezing at time of injection and during the 24 to 48 previous hours, without known errors in 3/7. Therefore there is a rationale for using immunotherapy in children. ARNALDO CANTANI, MD, PHD GIOVANNA ARCESE, MD ANDREA DI RIENZO, MD PATRIZIA LUCENTI, MD Department of Pediatrics Allergy and Clinical Immunology Division University of Rome “La Sapienza” Rome Italy REFERENCES 1. Sigman K, Mazer B. Immunotherapy for childhood asthma: is there a ratio-
2. 3.
4.
5.
6.
7.
8.
9.
10.
nale for its use? Ann Allergy Asthma Immunol 1996;76:299 –305. Cantani A, Gagliesi D. Specific immunotherapy (SIT) in children. Allergy 1996;51:265– 6. Cantani A, Businco E, Maglio A. Alternaria allergy: a three-year controlled study in children treated with immunotherapy. Allergol Immunopathol 1988; 16:1– 4. Businco L, Zannino L, Cantani A, et al. Systemic reactions to specific immunotherapy in children with respiratory allergy: a prospective study. Pediatr Allergy Immunol 1995;6:44 –7. Cantani A, Businco E, Benincori N, et al. A three-year controlled study in children with pollinosis treated with immunotherapy. Ann Allergy 1984;53: 79 – 84. 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 –31. Ownby DR, Adinoff AD. The appropriate use of skin testing and immunotherapy in young children. J Allergy Clin Immunol 1994;94:662–5. Hejjaoui A, Ferrando R, Dhivert H, et al. Systemic reactions occurring during immunotherapy with standardized extracts. J Allergy Clin Immunol 1992; 89:925–33. Lockey RF, Benedikt LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79: 660 –77. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TAE. Survey of fatalities from skin testing and immunotherapy 1985–1989. J Allergy Clin Immunol 1993;92:6 –15.
Response: Thank you for your comments on our paper. As your letter points out, since the submission and publication of our review article, there have been further clinical trials in children that contribute to the emerging data on immunotherapy for children with asthma.1– 4 Those studies that attempt to address specific antigen sensitivity have been encouraging; others that have at-
213
tempted nonspecific immunotherapy have not had positive results.5 In spite of these highly suggestive trials, the majority of children continue to suffer from episodic asthma and viral triggers remain the important causative factor of acute exacerbations, regardless of atopic status. This has led all asthma treatment consensus statements to primarily stress anti-inflammatory therapy with careful environmental control a crucial adjunct. In a recent trial that examined the concurrent use of dust mite immunotherapy and inhaled steroids, Costa et al demonstrated that the intervention that was most crucial to asthma control was inhaled steroids.3 In spite of the very tantalizing data (including that presented in your letter) suggesting an important action of specific dust mite immunotherapy, its application to routine asthma therapy still remains to be defined.
214
Regarding the frequency of reactions, the data provided by the authors of the letter are indeed impressive and were not all available as we prepared our article. We would hope that the protocols now being developed to study immunotherapy for asthma would utilize similar designs as a model of safety. We believe that the definition of appropriate candidates for immunotherapy as a primary or adjunctive treatment for asthma is key, and further study is clearly necessary. BRUCE MAZER, MD KAREN SIGMAN, MD Division of Allergy and Clinical Immunology Montreal Children’s Hospital Montreal, Quebec Canada REFERENCES 1. Cantani A, Ragno V, Monteleone MA, et al. Enzyme-potentiated desensitiza-
2.
3.
4.
5.
tion in children with asthma and mite allergy: a double-blind study. J Invest Allergol Clin Immunol 1996;6:270 – 6. Hirokawa Y, Kondo T, Kobayashi I, Ohta Y. Rush immunotherapy with house dust extract in patients with mild extrinsic asthma. Tohoku J Exper Med 1996;178:371– 80. Costa JC, Placido JL, Silva JP, et al. Effects of immunotherapy on symptoms, PEFR, spirometry, and airway responsiveness in patients with allergic asthma to house-dust mites (D. pteronyssinus) on inhaled steroid therapy. Allergy 1996;51:238 – 44. Rose G, Arlian L, Bernstein D, et al. Evaluation of household dust mite exposure and levels of specific IgE and IgG antibodies in asthmatic patients enrolled in a trial of immunotherapy. J Allergy Clin Immunol 1996;97: 1071– 8. 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 –31.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
VOLUME 80, JANUARY, 1998
children. In a recent study the rate of apparent systemic reactions was 2.6%.6 Sigman and Mazer stress several recommendations against performance of immunotherapy in children.1 The paper they cite7 emphasizes that children ⬍5 years of age have a significantly greater risk of systemic reactions.8 Several significant points were omitted2: (1) the children were subjected to a rush protocol, which is known to provoke more reactions, (2) the children had neither premedication nor preventive measures; the authors were conscious of the risks, therefore the patients were hospitalized for the first night of treatment, (3) the authors hypothesized that the hospitalization increased the rate of reactions because of its psychologic impact.8 Among the 47 fatal cases that occurred before 1973 and 1989 reported by Lockey et al9 and Reid et al10 there are seven children aged 7 to 18 years. In one case there was a known error of immunotherapy administration and an incorrect dose of epinephrine, in another a probable error of dosage and delay in the treatment, two patients did not wait in the doctor’s office, one had wheezing at time of injection and during the 24 to 48 previous hours, without known errors in 3/7. Therefore there is a rationale for using immunotherapy in children. ARNALDO CANTANI, MD, PHD GIOVANNA ARCESE, MD ANDREA DI RIENZO, MD PATRIZIA LUCENTI, MD Department of Pediatrics Allergy and Clinical Immunology Division University of Rome “La Sapienza” Rome Italy REFERENCES 1. Sigman K, Mazer B. Immunotherapy for childhood asthma: is there a ratio-
2. 3.
4.
5.
6.
7.
8.
9.
10.
nale for its use? Ann Allergy Asthma Immunol 1996;76:299 –305. Cantani A, Gagliesi D. Specific immunotherapy (SIT) in children. Allergy 1996;51:265– 6. Cantani A, Businco E, Maglio A. Alternaria allergy: a three-year controlled study in children treated with immunotherapy. Allergol Immunopathol 1988; 16:1– 4. Businco L, Zannino L, Cantani A, et al. Systemic reactions to specific immunotherapy in children with respiratory allergy: a prospective study. Pediatr Allergy Immunol 1995;6:44 –7. Cantani A, Businco E, Benincori N, et al. A three-year controlled study in children with pollinosis treated with immunotherapy. Ann Allergy 1984;53: 79 – 84. 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 –31. Ownby DR, Adinoff AD. The appropriate use of skin testing and immunotherapy in young children. J Allergy Clin Immunol 1994;94:662–5. Hejjaoui A, Ferrando R, Dhivert H, et al. Systemic reactions occurring during immunotherapy with standardized extracts. J Allergy Clin Immunol 1992; 89:925–33. Lockey RF, Benedikt LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J Allergy Clin Immunol 1987;79: 660 –77. Reid MJ, Lockey RF, Turkeltaub PC, Platts-Mills TAE. Survey of fatalities from skin testing and immunotherapy 1985–1989. J Allergy Clin Immunol 1993;92:6 –15.
Response: Thank you for your comments on our paper. As your letter points out, since the submission and publication of our review article, there have been further clinical trials in children that contribute to the emerging data on immunotherapy for children with asthma.1– 4 Those studies that attempt to address specific antigen sensitivity have been encouraging; others that have at-
213
tempted nonspecific immunotherapy have not had positive results.5 In spite of these highly suggestive trials, the majority of children continue to suffer from episodic asthma and viral triggers remain the important causative factor of acute exacerbations, regardless of atopic status. This has led all asthma treatment consensus statements to primarily stress anti-inflammatory therapy with careful environmental control a crucial adjunct. In a recent trial that examined the concurrent use of dust mite immunotherapy and inhaled steroids, Costa et al demonstrated that the intervention that was most crucial to asthma control was inhaled steroids.3 In spite of the very tantalizing data (including that presented in your letter) suggesting an important action of specific dust mite immunotherapy, its application to routine asthma therapy still remains to be defined.
214
Regarding the frequency of reactions, the data provided by the authors of the letter are indeed impressive and were not all available as we prepared our article. We would hope that the protocols now being developed to study immunotherapy for asthma would utilize similar designs as a model of safety. We believe that the definition of appropriate candidates for immunotherapy as a primary or adjunctive treatment for asthma is key, and further study is clearly necessary. BRUCE MAZER, MD KAREN SIGMAN, MD Division of Allergy and Clinical Immunology Montreal Children’s Hospital Montreal, Quebec Canada REFERENCES 1. Cantani A, Ragno V, Monteleone MA, et al. Enzyme-potentiated desensitiza-
2.
3.
4.
5.
tion in children with asthma and mite allergy: a double-blind study. J Invest Allergol Clin Immunol 1996;6:270 – 6. Hirokawa Y, Kondo T, Kobayashi I, Ohta Y. Rush immunotherapy with house dust extract in patients with mild extrinsic asthma. Tohoku J Exper Med 1996;178:371– 80. Costa JC, Placido JL, Silva JP, et al. Effects of immunotherapy on symptoms, PEFR, spirometry, and airway responsiveness in patients with allergic asthma to house-dust mites (D. pteronyssinus) on inhaled steroid therapy. Allergy 1996;51:238 – 44. Rose G, Arlian L, Bernstein D, et al. Evaluation of household dust mite exposure and levels of specific IgE and IgG antibodies in asthmatic patients enrolled in a trial of immunotherapy. J Allergy Clin Immunol 1996;97: 1071– 8. 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 –31.
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY