Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations

Am J Respir Crit Care Med. 2017 Feb 1;195(3):302-313. doi: 10.1164/rccm.201602-0419OC.


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.

Objectives: To describe the clinical, physiologic, inflammatory, and comorbidity factors associated with EPA.

Methods: Baseline data from the NHLBI Severe Asthma Research Program (SARP)-3 were analyzed. An exacerbation was defined as a burst of systemic corticosteroids lasting 3 days or more. Patients were classified by their number of exacerbations in the past year: none, few (one to two), 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, body mass index, and bronchodilator responsiveness were positively associated with exacerbation frequency (rate ratios [95% confidence interval], 1.6 [1.2-2.1] for every log unit of eosinophils, 1.3 [1.1-1.4] for every 10 body mass index 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 registered with (NCT 01760915).

Trial registration: NCT01760915.

Keywords: bronchodilator reversibility; eosinophils; exacerbation-prone asthma; gastroesophageal reflux; sinusitis.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Albuterol / administration & dosage
  • Albuterol / therapeutic use*
  • Asthma / drug therapy
  • Asthma / epidemiology
  • Asthma / immunology
  • Asthma / physiopathology*
  • Biomarkers / analysis
  • Body Mass Index
  • Breath Tests
  • Bronchodilator Agents / administration & dosage
  • Bronchodilator Agents / therapeutic use*
  • Chi-Square Distribution
  • Child
  • Comorbidity
  • Disease Progression*
  • Disease Susceptibility
  • Drug Resistance / immunology*
  • Eosinophils / drug effects
  • Female
  • Humans
  • Immunoglobulin E / blood
  • Inflammation / etiology*
  • Male
  • Middle Aged
  • Nitric Oxide / analysis
  • Severity of Illness Index
  • Sex Distribution
  • Sputum / chemistry


  • Biomarkers
  • Bronchodilator Agents
  • Nitric Oxide
  • Immunoglobulin E
  • Albuterol

Associated data