Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate-to-Severe Asthma

Abstract

Rationale: It is unclear why select patients with moderate-to-severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of undergoing a severe decline in lung function.Objectives: To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline.Methods: Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV₁% predicted. Categories of participant FEV₁ slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline.Measurements and Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV₁% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models (P < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV₁, exacerbation history, blood eosinophils and body mass index.Conclusions: Failure to improve the post-bronchodilator FEV₁ after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.

Keywords: corticosteroid sensitivity; exacerbations; longitudinal; lung function; severe asthma.

Figure 1.

Longitudinal lung function of adult participants in SARP III (Severe Asthma Research Program III) not using biologic therapies. Data shown were collected after the participants were given four puffs of albuterol and are represented as box-and-whisker plots. The sample sizes are shown in A, with ongoing accrual contributing to the lower numbers at Years 4 and 5. (A–C) The FEV₁% predicted (Pred) (A), FVC% Pred (B), and FEV₁/FVC% Pred (C). (D) The distribution of longitudinal slopes for individual participants shown as a violin plot of the frequency distribution, with stratification by sex and baseline severity.

Figure 2.

Lung function trajectories of adult participants of SARP III (Severe Asthma Research Program III) not using biologic therapies. (A) Histogram of the FEV₁ slope for each participant. As stated in the Methods, participants were classified into four slope categories, namely severe decline (>2% loss/yr), mild decline (2.0 to <0.5% loss/yr), no change (0.5% loss/yr to <1% gain/yr), and improvement (≥1% gain/yr), respectively, denoted by colors in this figure. (B) The annual FEV₁% Pred group mean data stratified by these categorical trajectories. The solid line represents the severe decline group, and the dotted line represents the mild decline group. The two dashed lines are the no change (gray) and improvement (green) groups, respectively. Partition analysis of each participant’s pattern of change allows for classification regarding change dominated by airflow limitation, airway closure, or a mixture of both. (C) Dominance pattern for each lung function category showing change over time. Pred = predicted.

Figure 3.

Linear models of the change in FEV₁% Pred over 4 years. The symbols represent data from individual participants, with colors denoting the lung-function-change category. (A) Univariable model for tdFEV₁ (P < 0.001). (B) Univariable model for the history of exacerbations in the 12 months before enrollment (P = 0.134). For both panels, the solid blue line and surrounding shading represents the model-fitted values and their 95% confidence intervals. PostTA = post–triamcinolone acetonide value; Pred = predicted; PreTA = pre–triamcinolone acetonide value; tdFEV₁ = triamcinolone-induced difference in the FEV₁ % Pred.

Figure 4.

Ordinal logistic models of the categorical lung function trajectory. (A) The probability of assignment to individual categories, with 95% confidence intervals included with the fit lines, derived through subtraction from the base univariable model for the tdFEV₁ (P < 0.001). (B) Multivariable ordinal logistic regression model of baseline predictors associated with the risk of severe decline. Baseline predictors are listed at the left of the figure, with the units of change shown in parentheses for continuous variables. The point-estimate limits and 95% CLs for the odds ratios in this model are shown graphically and numerically. BMI = body mass index; CL = confidence limit; Eos = eosinophils; PostTA = post–triamcinolone acetonide value; Pred = predicted; PreTA = pre–triamcinolone acetonide value; tdFEV₁ = triamcinolone-induced difference in the FEV₁ % Pred.