Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood

Background - There is increasing evidence that wheezing during childhood may be a heterogeneous condition, and that different forms of wheezing may be associated with different risk factors and prognosis. The aim of this study was to determine if measures of airway lability and of atopy could identify distinct wheezing phenotypes during childhood. Methods - In a cohort of children followed from birth peak flow variability (n = 600) was evaluated and methacholine challenge responsiveness (n = 397) was measured at age 11 in relation to wheezing before the age of three, and at age six and 11 years total serum IgE and skin test reactivity to allergens were determined. Results - Neither positive peak flow variability nor methacholine hyperresponsiveness measured at age 11 were associated with wheezing occurring only during the first three years of life. Both methacholine hyperresponsiveness and positive peak flow variability were associated with wheezing at both ages six and 11 (OR 5.1 (95% CI 2.4 to 10.6) and 2.3 (1.2 to 4.5), respectively). In addition, positive peak flow variability was associated with wheezing up to the age of six but not at age 11 in non-atopic children (OR 2.9 (95% CI 1.0 to 8.8)). Methacholine hyperresponsiveness measured at age 11 was more frequently observed in boys (OR 2.1 (95% CI 1.2 to 3.5)) and was strongly associated with serum IgE levels measured at ages six and 11 (p < 0.001) and with positive skin test reactivity (OR 4.5 (95% CI 2.0 to 10.1)). Peak flow variability was unrelated to sex or markers of atopy (IgE and skin test reactivity). Conclusions - Methacholine responsiveness and peak flow variability assessed at age 11, together with markers, of atopy (IgE and skin test reactivity to allergens) identify three different wheezing phenotypes in childhood: 'transient early wheezing' limited to the first three years of life and unrelated to increased airway lability; 'non-atopic wheezing' of the toddler and early school years associated with positive peak flow variability but not with methacholine hyper-responsiveness; and 'IgE-associated wheeze/asthma' associated with persistent wheezing at any age and with methacholine hyperresponsiveness, peak flow variability, and markers of atopy.