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Relationship between duration of asthma and asthma severity
Correspondence Relationship between duration of asthma and asthma severity To the Editor: Zeiger et al (Zeiger RS, Dawson C, Weiss S, Childhood Asthma Management Program Research Group. Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP). J Allergy Clin Immunol 1999;103:376-87) concluded that asthma duration is associated with lower lung function and greater methacholine responsiveness. This conclusion is seemingly in contradiction with our long-term study,1 which concluded that pulmonary function deteriorated over time in patients treated with bronchodilators only, whereas it actually improved in patients treated with anti-inflammatory drugs (cromolyn sodium or inhaled corticosteroids). Several facts are worth mentioning: (1) The effect of duration in the study of Zeiger et al was very small and the statistical significance is mainly due to the very large sample size (more than 1000 children). Thus, for methacholine responsiveness, duration of illness is only responsible for 1.25% of variance, and for FEV1 (prebronchodilator) the number is 3.1%. (2) The authors’ own data suggest that anti-inflammatory drugs have an effect on pulmonary function because patients previously receiving cromolyn sodium had a significantly higher FEV1 than those not receiving this drug. (3) Careful reading of the study’s methods published elsewhere2 reveals that cromolyn sodium and inhaled corticosteroids were discontinued 4 weeks before the methacholine test and 6 weeks before the spirometry measurements. Previous studies have clearly established that both nonsteroidal (cromolyn or nedocromil) and steroidal anti-inflammatory treatment improve both pulmonary function3,4 and bronchial hyperreactivity,4,5 but the effect disappears shortly after discontinuation of these drugs.4,6 Thus, as soon as 2 weeks after discontinuation of inhaled corticosteroids, the effect on FEV1 was significantly reduced4 and the effect on bronchial hyperreactivity was significantly reduced in one study4 and completely gone in another.7 Similar results were described with nonsteroidal anti-inflammatory drugs.6 In view of these facts, the study by Zeiger et al cannot exclude the possibility that patients treated with anti-inflammatory drugs do not have a progressive deterioration with time in pulmonary function and bronchial hyperreactivity, and therefore their conclusion is not that far from the conclusion of our study, namely, that only patients not treated with anti-inflammatory drugs deteriorate with time. Deterioration with duration of the disease is an important concept because it influences the continuing debate about the need for early intervention and the nature of that intervention in the prevention of the possibility of irreversible airway obstruction. Therefore it is very important that the correct conclusions are drawn from the study of Zeiger et al. Peter König, MD University of Missouri Health Sciences Center Hospital and Clinics Department of Child Health School of Medicine N708 Health Sciences Center One Hospital Drive Columbia, MO 65212 REFERENCES 1. König P, Shaffer J. The effect of drug therapy on long-term outcome of childhood asthma: a possible preview of the international guidelines. J Allergy Clin Immunol 1996;98:1103-11.
2. Childhood Asthma Management Program. The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Control Clin Trials 1999;20:91-120. 3. Smith JM, Devey GF. Clinical trial of disodium cromoglycate in treatment of asthma in children. BMJ 1968;2:340-4. 4. Verberne AAPH, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF, Dutch Paediatric Asthma Study Group. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997;156:688-95. 5. Hoag JE, McFadden ER. Long-term effect of cromolyn sodium on nonspecific bronchial hyperresponsiveness: a review. Ann Allergy 1991;66:53-63. 6. Bel EH, Timmers MC, Hermans J, Dijkman JH, Sterk PJ. The long-term effects of nedocromil sodium and beclomethasone dipropionate on bronchial responsiveness to methacholine in nonatopic asthmatic subjects. Am Rev Respir Dis 1990;141:21-8. 7. Simons FER, Canadian Beciomethasone Dipropionate-Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337:1659-65. 1/8/101787
Reply To the Editor: It is a pleasure to respond to Konig’s letter. Our article represents a cross-sectional analysis of CAMP baseline data obtained before randomization, not outcome data from the CAMP trial. In this baseline cross-sectional data analysis, we noted a small and consistent association of asthma duration with markers of asthma severity, including lower lung function, greater methacholine responsiveness, more asthma symptoms, and greater use of as-needed albuterol during a 4-week screening period. These adverse associations with asthma duration persisted after controlling for several potential confounding or modifying factors including age, sex, markers of atopy and inflammation, and prior inhaled antiinflammatory medication (cromolyn or inhaled corticosteroids).1 The magnitude of decline in percent of predicted prebronchodilator FEV1 of 0.9% per year of asthma duration was of a magnitude similar to that observed in a smaller cohort of untreated asthmatic children followed up for 5 years (1.3% annual decline) reported previously.2 We agree with Konig that prior anti-inflammatory treatment could be expected to affect measures of lung function during the phase of medication administration and for some uncertain time after discontinuation of the medication. For the purpose of enrollment into CAMP, a minimum withdrawal of anti-inflammatory medication was made 4 weeks before methacholine testing and 6 weeks before spirometry at randomization. Many patients did not take anti-inflammatory medication for longer periods, but this was not recorded. During this withdrawal of anti-inflammatory medication, as reported previously and referenced in the above letter (references 5-8), pulmonary function and bronchial hyperreactivity might decline if the benefit from such therapy was transient. We used multiple regression analysis to account for the potential confounding influences of prior anti-inflammatory therapy on lung function, responsiveness, and other markers on their relationship to asthma duration. As noted, after accounting for prior anti-inflammatory medication use in these regression analyses, asthma duration was found to be adversely and significantly associated with markers of asthma severity.1 Recent bivariate analysis of 557 participants not receiving any inhaled anti-inflammatory agents in the 6 months before CAMP revealed increasing duration of asthma associated with significantly lower prebronchodilator and postbron1115
2. Childhood Asthma Management Program. The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Control Clin Trials 1999;20:91-120. 3. Smith JM, Devey GF. Clinical trial of disodium cromoglycate in treatment of asthma in children. BMJ 1968;2:340-4. 4. Verberne AAPH, Frost C, Roorda RJ, van der Laag H, Kerrebijn KF, Dutch Paediatric Asthma Study Group. One year treatment with salmeterol compared with beclomethasone in children with asthma. Am J Respir Crit Care Med 1997;156:688-95. 5. Hoag JE, McFadden ER. Long-term effect of cromolyn sodium on nonspecific bronchial hyperresponsiveness: a review. Ann Allergy 1991;66:53-63. 6. Bel EH, Timmers MC, Hermans J, Dijkman JH, Sterk PJ. The long-term effects of nedocromil sodium and beclomethasone dipropionate on bronchial responsiveness to methacholine in nonatopic asthmatic subjects. Am Rev Respir Dis 1990;141:21-8. 7. Simons FER, Canadian Beciomethasone Dipropionate-Salmeterol Xinafoate Study Group. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. N Engl J Med 1997;337:1659-65. 1/8/101787
Reply To the Editor: It is a pleasure to respond to Konig’s letter. Our article represents a cross-sectional analysis of CAMP baseline data obtained before randomization, not outcome data from the CAMP trial. In this baseline cross-sectional data analysis, we noted a small and consistent association of asthma duration with markers of asthma severity, including lower lung function, greater methacholine responsiveness, more asthma symptoms, and greater use of as-needed albuterol during a 4-week screening period. These adverse associations with asthma duration persisted after controlling for several potential confounding or modifying factors including age, sex, markers of atopy and inflammation, and prior inhaled antiinflammatory medication (cromolyn or inhaled corticosteroids).1 The magnitude of decline in percent of predicted prebronchodilator FEV1 of 0.9% per year of asthma duration was of a magnitude similar to that observed in a smaller cohort of untreated asthmatic children followed up for 5 years (1.3% annual decline) reported previously.2 We agree with Konig that prior anti-inflammatory treatment could be expected to affect measures of lung function during the phase of medication administration and for some uncertain time after discontinuation of the medication. For the purpose of enrollment into CAMP, a minimum withdrawal of anti-inflammatory medication was made 4 weeks before methacholine testing and 6 weeks before spirometry at randomization. Many patients did not take anti-inflammatory medication for longer periods, but this was not recorded. During this withdrawal of anti-inflammatory medication, as reported previously and referenced in the above letter (references 5-8), pulmonary function and bronchial hyperreactivity might decline if the benefit from such therapy was transient. We used multiple regression analysis to account for the potential confounding influences of prior anti-inflammatory therapy on lung function, responsiveness, and other markers on their relationship to asthma duration. As noted, after accounting for prior anti-inflammatory medication use in these regression analyses, asthma duration was found to be adversely and significantly associated with markers of asthma severity.1 Recent bivariate analysis of 557 participants not receiving any inhaled anti-inflammatory agents in the 6 months before CAMP revealed increasing duration of asthma associated with significantly lower prebronchodilator and postbron1115