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.