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

Abstract

Background: 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.

Objective: Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.

Methods: 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.

Results: 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.

Conclusion: Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.

FIG 1

Kaplan-Meier plots by cluster of the cumulative probability of a first course of prednisone (A) or initiation of additional asthma controller therapies (beclomethasone or other; B) during the 4-year follow-up period of the CAMP trial.

FIG 2

Mean pulmonary function measurements for each phenotypic cluster evaluated over 48 months of follow-up. P values for between-cluster differences among all longitudinal measures were less than .0001, as calculated by using linear mixed-effects models.

FIG 3

Kaplan-Meier estimate by treatment group of the cumulative probability of prednisone use during 4 years of follow-up stratified by phenotypic cluster. B, Budesonide; N, Nedocromil.