© 2008 American Thoracic Society doi: 10.1164/rccm.200805-736ED
Airway Responsiveness in Teenagers Is Becoming Sexier
Beatrix Children's Hospital In 1959, Tiffeneau interpreted airway hyperresponsiveness (AHR) (l'hyperexcitabilité broncho-motorice) as an allergic reaction of the lung. His theory was that allergy preceded the development of enhanced airway responsiveness. Orie and de Vries subsequently demonstrated that there was a correlation between bronchial hyperresponsiveness to acetylcholine and histamine and between histamine and SO2, cold weather conditions, and fog, and that this airway characteristic is an important finding in the diagnosis of asthma. Since then, measurement of bronchial reactivity has become standardized and AHR has become a major criterion in the diagnosis and definition of asthma. In many epidemiological studies, methacholine challenge has become an important tool not only to establish the diagnosis of asthma but also to assess the severity of the disease. Asthma and wheeze are not only more prevalent in boys than in girls but the severity of asthma and wheeze is also greater in boys as reflected in hospital admissions (1). However, asthma becomes more prevalent from the age of about 12 to 16 years in females and a similar change is observed in severity of the disease, with increased mortality risk for females and the finding that women with asthma more frequently visit the emergency room for asthma exacerbations (2). In the Childhood Asthma Management Program Continuation Study (CAMPCS) published in this issue of the Journal (pp. 325–331), Tantisira and colleagues prospectively studied 1,041 children with mild to moderate asthma aged 5 to 12 years over a period of 8.6 ± 1.8 years, with methacholine challenges yearly (3). In this study, airway hyperreactivity to methacholine was found to decrease both in boys and in girls and the mean PC20 values were similar in both sexes until the age of about 11 years. The fascinating finding in this study is that, from puberty, the level of AHR remained fairly constant in females and was more severe than that present in males. These results confirm the previously described differences in asthma prevalence and asthma severity between sexes. In previous analyses that examined the evolution of sex differences in AHR from infancy through childhood and then into adulthood, greater AHR has been described in postpubertal females (4). One of the reasons for this finding has been claimed to be the technical differences in the execution of the test. Relevant factors involved in testing for AHR include the choice of the provocation agent, such as histamine, methacholine, adenosine–monophosphate; differences in delivery of the agent; the inhalation procedure was used; definition of the fall in FEV1; and the maximum dose of the agent delivered. It is still unclear why in early adulthood women are at increased risk of developing asthma and why they suffer from more severe disease. Airway responsiveness decreased in male children with asthma between Tanner stage 2 and 3, but remained at the same level in females studied at these developmental time points (3). These developmental periods are synchronous with increased production of hormones, such as estrogens, progesterone, androgens, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in females, whereas in boys the main hormone responsible for the bodily changes and sexual maturation is testosterone. In rabbits, testosterone relaxes precontracted airway smooth muscle via interactions with the epithelium and through nitric oxide–mediated pathways (5). Factors other than testosterone may also play a role in inducing the decrease in airway hyperreactivity that is found at puberty in boys (6). Differences exist between boys and girls in physical growth of the lungs from birth into adulthood, and such factors have been interpreted as possible causes for the sex-related switch in asthma prevalence and AHR during development (6,7). During puberty, there are differences between boys and girls in the growth of the airways as compared with lung parenchyma and airspaces (8). Furthermore, from the age of 16 years, females have smaller and narrower airways in proportion to lung volume than males of the same age (7). The underlying mechanism for this "dysanapsis" is not yet completely understood. In the CAMPCS (3), AHR was found to disappear at puberty in many individuals of both sexes. However, no information is available concerning the possible factors that may predict or influence the natural course of disease. It will be of interest to follow these children over time to see what happens with airway responsiveness and severity of asthma in adulthood. In our own follow-up study in a group of 101 children with asthma, we found that, between the ages of 20 to 30 years, airway responsiveness decreased (9). However, a limitation of our study was the high percentage of male subjects. When these subjects were between 30 and 40 years of age, a substantial increase in airway responsiveness was found, and only 25% of subjects were symptom free at that age (10). The cohort of subjects included in the CAMPCS should be followed for as long as possible since these individuals offer a unique opportunity that may provide insight in the natural course of asthma both in male and female subjects. FOOTNOTES Conflict of Interest Statement: J.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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