Biomarker-based asthma phenotypes of corticosteroid response

Abstract

Background: Asthma is a heterogeneous disease with different phenotypes. Inhaled corticosteroid (ICS) therapy is a mainstay of treatment for asthma, but the clinical response to ICSs is variable.

Objective: We hypothesized that a panel of inflammatory biomarkers (ie, fraction of exhaled nitric oxide [Feno], sputum eosinophil count, and urinary bromotyrosine [BrTyr] level) might predict steroid responsiveness.

Methods: The original study from which this analysis originates comprised 2 phases: a steroid-naive phase 1 and a 28-day trial of ICSs (phase 2) during which Feno values, sputum eosinophil counts, and urinary BrTyr levels were measured. The response to ICSs was based on clinical improvements, including a 12% or greater increase in FEV1, a 0.5-point or greater decrease in Asthma Control Questionnaire score, and 2 doubling dose or greater increase in provocative concentration of adenosine 5'-monophosphate causing a 20% decrease in FEV1 (PC20AMP). Healthy control subjects were also evaluated in this study for comparison of biomarkers with those seen in asthmatic patients.

Results: Asthmatic patients had higher than normal Feno values, sputum eosinophil counts, and urinary BrTyr levels during the steroid-naive phase and after ICS therapy. After 28-day trial of ICSs, Feno values decreased in 82% of asthmatic patients, sputum eosinophil counts decreased in 60%, and urinary BrTyr levels decreased in 58%. Each of the biomarkers at the steroid-naive phase had utility for predicting steroid responsiveness, but the combination of high Feno values and high urinary BrTyr levels had the best power (13.3-fold, P < .01) to predict a favorable response to ICS therapy. However, the magnitude of the decrease in biomarker levels was unrelated to the magnitude of clinical response to ICS therapy.

Conclusion: A noninvasive panel of biomarkers in steroid-naive asthmatic patients predicts clinical responsiveness to ICS therapy.

Keywords: Asthma; biomarker; clinical outcome; fraction of exhaled nitric oxide; inhaled corticosteroids; sputum eosinophils; urinary bromotyrosine.

Figure 1. Changes in biomarkers in asthmatics treated with ICS

The percent of asthmatics that decrease biomarkers with ICS treatment for 28 days proportionately shown by size of colored circles [blue, F_ENO; green, sputum eosinophils; red, urinary BrTyr], and percent of asthmatics that do not have decrease in either of the two biomarkers in each panel is shown by the black circles.

Figure 2

ROC analysis describes ability of each biomarker i.e F_ENO, sputum eosinophils and urinary BrTyr to classify asthmatics who respond to inhaled corticosteroid as measured by 2 out of 3 clinical outcomes (≥12% increase in FEV₁ and/or ≥0.5 point decrease in ACQ and/or ≥2 doubling dose increase in PC₂₀AMP).

Figure 3

ORs and 95% Cl for the association between a high level of biomarker (F_ENO ≥ 35ppm; sputum eosinophils ≥ 3%, BrTyr ≥ 0.45 ng/mg Cr) or biomarker combination [F_ENO AND BrTyr] and two positive clinical outcomes in response to ICS. Results shown represent the ORs (filled circles) and 95% Cl (lines) of having a steroid response versus having no steroid response. Asterisk indicates P<0.05 as determined by likelihood-ratio χ² test.