Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications

Judie A Howrylak,Anne L Fuhlbrigge,Robert C Strunk,Robert S Zeiger,Scott T Weiss,Benjamin A Raby

doi:10.1016/j.jaci.2014.02.006

Abstract

Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored. Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma. We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication. We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo. Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.

Highlights

Recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored
It has been observed that subsets of asthmatic children respond differently to medications[6,7,8] and exhibit markedly different disease trajectories, with some children outgrowing their asthma by early adolescence and others having disease progression[9,10,11,12] or decreased lung function in adulthood.[13]
Author manuscript; available in PMC 2014 June 06. It is in this context that we present the results of a phenotype-based cluster analysis of asthmatic children aged 5 to 12 years who participated in the 48-month Childhood Asthma Management Program (CAMP) trial[3,23] and demonstrate that computational approaches can define meaningful clusters with both longitudinal consistency and differing responses to medical therapy

Summary

Methods

We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Study population The CAMP study design and primary outcomes have been described.[3,23] Subjects aged 5 to 12 years were eligible if they (1) had a history of mild-to-moderate persistent asthma defined by the presence of symptoms at least twice weekly, the use of an inhaled bronchodilator at least twice weekly, or the use of daily medication for asthma; (2) had greater than 7 days of symptoms or decreased peak expiratory flow rates during the 28-day run-in period when taking only albuterol as needed; (3) exhibited airway hyperresponsiveness to methacholine; and (4) had no other clinically significant conditions. The addition of beclomethasone dipropionate (168 μg twice daily; Vanceril, Schering-Plough, Kenilworth, NJ) was allowed if asthma control was inadequate.

Results

Discussion

Conclusion