To the Editors:
We read with interest the recent paper by van den Nieuwenhof et al. 1 who reported no statistically significant association of airway hyperresponsiveness (AHR) with asthma incidence over 14 yrs in 123 asymptomatic adolescents aged 10–22 yrs at baseline. They concluded that AHR is not a risk factor for the development of asthma in adulthood and that screening for AHR in adolescents to detect subjects at risk for asthma cannot be recommended. We similarly assessed the association between AHR at baseline and asthma incidence over 11.4 yrs among 172 asymptomatic children (44.2% with AHR (provocative dose causing a 20% fall in forced expiratory volume in one second <4 mg methacholine) at baseline) and 517 adults (31.7% with AHR at baseline) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) 2, 3. Asymptomatic adults were defined as those with a null symptomatic score according to Pekkanen et al. 4 over the previous 12 months. The score is based on asthma-like symptoms (wheeze with breathlessness, woken with chest tightness, attack of shortness of breath (SOB) at rest, attack of SOB after exercise, woken by attack of SOB) and is already used in the EGEA study 5 and, with a similar definition, in children. Asthma incidence was 14.0% in children and 8.3% in adults. Asymptomatic AHR appeared to be significantly related to asthma incidence both in children and adults. The association remained statistically significant after adjustment for age, sex and atopy at baseline (positive skin prick test to any of 11 allergens) and taking into account familial dependence in children (odds ratio (OR) 3.39, 95% confidence interval (CI) 1.09–10.53, n = 145) and in adults (OR 2.68, 95% CI 1.08–6.69, n = 377). The results were similar when considering subjects in the same age range (10–22 yrs) as those of van den Nieuwenhof et al. 1 (OR 3.16, 95% CI 1.23–8.14, n = 158) and remained after exclusion of atopics (OR 5.84, 95% CI 1.06–32.10, n = 89). The conclusions were similar (ORs always >2) when considering other definitions of asymptomatic subjects. When including any wheeze and chronic cough in the preceding list of symptoms, as van den Nieuwenhof et al. 1 did, AHR at baseline remained significantly associated with asthma incidence among children (OR 3.18, 95% CI 1.08–9.37, n = 142), adults (OR 2.84, 95% CI 1.08–7.42, n = 343), or those aged 10–22 yrs (OR 3.27, 95% CI 1.11–9.69, n = 149). Furthermore, when asymptomatic adult subjects where defined by the absence of chronic cough, chronic phlegm, dyspnoea or wheezing, as per Brutsche et al. 6 in the SAPALDIA study, AHR was also associated with asthma incidence (OR 2.40, 95% CI 1.06–5.49, n = 387).
Methacholine AHR was significantly related to asthma incidence in asymptomatic subjects from the EGEA study, whatever the association of symptoms used to define asymptomatic subjects in the previous 12 months and age range at baseline. Results were similar after adjusting for age, sex and atopy or restricting the analysis to those aged 10–22 yrs as in the study by van den Nieuwenhof et al. 1, and even when restricting the analysis to nonatopic subjects in that age range. Although no significant association of AHR with asthma incidence was shown in the study of van den Nieuwenhof et al. 1, it is interesting to note that the OR observed was >2 (2.20), an association of similar magnitude to the association observed in the EGEA study. The differences are likely to depend on the greater statistical power of the EGEA study, but could also relate to the design of the study, which includes families of asthmatics 2. Besides being of prognostic significance for asthma persistence 7, AHR appears to be predictive of asthma incidence among asymptomatic subjects. However, such statistical association is insufficient to conclude that screening for asthma among asymptomatic adolescents is worthwhile, an aspect which needs specific evaluation. The main interest lies in the understanding of various aspects of asthma expression. Specific determinants (hormonal, personal, occupational and general environmental) may explain the heterogeneity of asthma expression over the lifespan.
Large representative samples with repeated measurements are needed to clarify the temporality of symptoms, hyperresponsiveness and asthma diagnosis, as the expression of both symptoms and airway hyperresponsiveness are variable, in particular in the sensitive period of adolescence 7, 8.
The Epidemiological Study on the Genetics and Environment of Asthma (EGEA) Cooperative group comprises the following. Coordination: F. Kauffmann (INSERM U780, Villejuif, France); F. Demenais (genetics; INSERM U794, Paris, France); I. Pin (clinical aspects; INSERM U823, La Tronche, France). Respiratory epidemiology: M. Korobaeff, F. Neukirch (EGEA1, INSERM U700, Paris); I. Annesi-Maesano (INSERM U707, Paris); F. Kauffmann, N. Le Moual, R. Nadif, M.P. Oryszczyn (INSERM U780); V. Siroux INSERM U823, Grenoble, France). Genetics: J. Feingold (INSERM U393, Paris); M.H. Dizier (INSERM U535, Villejuif); E. Bouzigon, F. Demenais (INSERM U794, Paris); I. Gut, M. Lathrop (Centre National de Génotypage, Evry, France). Clinical centres: I. Pin, C. Pison (Grenoble); D Ecochard (EGEA1), F Gormand, Y Pacheco (Lyon, France); D Charpin (EGEA1), D Vervloet (Marseille, France); J Bousquet (Montpellier, France); A. Lockhart (EGEA1, Cochin, Paris); R. Matran (Cochin, Paris); E. Paty, P. Scheinmann (Paris Necker, France); A. Grimfeld, J. Just (Paris-Trousseau, France). Data and quality management: J. Hochez (INSERM ex-U155 (EGEA1)); N. Le Moual, C. Ravault (INSERM U780); N Chateigner (INSERM U794); J. Ferran (Grenoble).
Support statement
Supported by Agence Nationale de la Recherche (ANR)-Santé-Environnement et Santé-Travail, ANR- Collection d’Échantillons Biologiques de la Santé, Agence Française de Sécurité Sanitaire de l'Environnement et du Travail and Programme Hospitalier de Recherche Clinique Paris (all Paris, France).
Statement of interest
None declared.
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