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

Abstract

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 www.clinicaltrials.gov (NCT 01760915).

Trial registration: ClinicalTrials.gov NCT01760915.

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

Figure 1.

Classification of asthma exacerbation frequency in the Severe Asthma Research Program (SARP)-3 baseline cohort. The frequency of asthma exacerbations was determined from self-reported number of oral corticosteroid (OCS) courses for asthma in the past 12 months on a medication history intake questionnaire, modified for 37 participants by questionnaire responses on a separate allergy and asthma history intake form. These 37 reported zero exacerbations but also reported intubations for asthma or OCS courses received at unscheduled doctor or emergency department visits for breathing problems, and were therefore reclassified as having had one exacerbation. A post hoc sensitivity analysis demonstrated that exclusion of these subjects did not affect the results. Because scheduled monthly steroid injections for asthma could not be separated from steroid injections received for exacerbations, four participants were excluded from analysis. An additional participant was excluded with a reported hospitalization for breathing problems with no reported OCS use. ED = emergency department; ICU = intensive care unit; NIH = National Institutes of Health.

Figure 2.

Unadjusted models of exacerbation frequency by measures of lung function. Negative binomial models were used to generate regression curves with the fitted numbers of exacerbations on the y-axis. The line is the fitted value and the shading is the 95% confidence interval with regression lines overlaid from children (dashed line, lighter gray) and adults (solid line, darker gray). Significance testing refers to the slope of the model in the log scale for exacerbations with prealbuterol FEV₁ z scores and maximum postalbuterol reversibility in A and B, respectively. Severity stratified mean and SE values of bronchodilator responsiveness are also shown with further stratification by age (C) or exacerbation categories (D) (None = 0, Few = 1 to 2, and Prone = 3 or more exacerbations). GLI = Global Lung Initiative.

Figure 3.

Unadjusted models of exacerbation frequency by measures of type 2 inflammation. Negative binomial models were used to generate regression curves with the fitted numbers of exacerbations on the y-axis. The line is the fitted value and the shading is the 95% confidence interval with regression lines overlaid from children (dashed line, lighter gray) and adults (solid line, darker gray). Significance testing refers to the slope of the model in the log scale for exacerbations. Blood eosinophils, sputum eosinophil percents, exhaled nitric oxide (Fe_NO), and total IgE values are shown in A–D, respectively. Each panel has regression lines overlaid from children (dashed line) and adults (solid line).

Figure 4.

Exacerbation-prone asthma in adults associates with eosinophilic inflammation despite lower measures of atopy. The percent of subjects with the designated categorical measure of type 2 inflammation is stratified by age and exacerbation category. Significance testing reflects the age-stratified trend across all three categories of exacerbation frequency.

Figure 5.

Selected comorbidities associated with exacerbation frequency. The percent of subjects with chronic sinusitis (A) and gastroesophageal reflux disease (GERD) (B) are stratified by categories of exacerbation frequency and by age. Significance testing reflects the age-stratified trend across all three categories of exacerbation frequency.