RATIONALE: Reducing asthma exacerbation frequency is an important criterion for approval of asthma therapies, but the clinical features of exacerbation prone asthma (EPA) remain incompletely defined.
OBJECTIVE: Describe the clinical, physiological, inflammatory and co-morbidity factors associated with EPA.

METHODS: Baseline data from the NHLBI Severe Asthma Research Program-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting ≥3 days. Patients were classified by their number of exacerbations in the past year - none, few (1-2) or exacerbation prone (≥3). Replication of a multivariable model was performed with data from the SARP 1+2 cohort.

MEASUREMENTS AND MAIN RESULTS: Of 709 subjects in the SARP-3 cohort, 294 (41%) had no exacerbations, and 173 (24%) were exacerbation prone in the prior year. Several factors normally associated with severity (asthma duration, age, sex, race, and socioeconomic status) did not associate with exacerbation frequency in SARP-3; bronchodilator responsiveness also discriminated exacerbation proneness from asthma severity. In the SARP-3 multivariable model, blood eosinophils, BMI and bronchodilator responsiveness were positively associated with exacerbation frequency [rate ratios (95%CI); 1.6 (1.2-2.1) for every log unit of eosinophils, 1.3 (1.1-1.4) for every 10 BMI units, and 1.2 (1.1-1.4) for every 10% increase in bronchodilatory responsiveness]. Chronic sinusitis and gastroesophageal reflux were also associated with exacerbation frequency [1.7 (1.4-2.1) and 1.6 (1.3-2.0)], even after adjustment for multiple factors. These effects were replicated in the SARP 1+2 multivariable model.

CONCLUSIONS: EPA may be a distinct susceptibility phenotype with implications for the targeting of exacerbation prevention strategies. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01760915.

Authors: Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, Castro M, Peters SP, Phipatanakul W, Aujla S, Bacharier LB, Bleecker ER, Comhair SA, Coverstone A, DeBoer M, Erzurum SC, Fain SB, Fajt M, Fitzpatrick AM, Gaffin J, Gaston B, Hastie AT, Hawkins GA, Holguin F, Irani AM, Israel E, Levy BD, Ly N, Meyers DA, Moore WC, Myers R, Opina MT, Peters MC, Schiebler ML, Sorkness RL, Teague WG, Wenzel SE, Woodruff PG, Mauger DT, Fahy JV, Jarjour NN, National Heart Lung and Blood Institute’s Severe Asthma Research Program-3 Investigators