Asthma and lower airway disease
Biomarker-based asthma phenotypes of corticosteroid response

https://doi.org/10.1016/j.jaci.2014.10.026Get rights and content
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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.

Key words

Asthma
inhaled corticosteroids
biomarker
clinical outcome
sputum eosinophils
urinary bromotyrosine
fraction of exhaled nitric oxide

Abbreviations used

ACQ
Asthma Control Questionnaire
AMP
Adenosine 5′-monophosphate
AUC
Area under the curve
BrTyr
Bromotyrosine
Feno
Fraction of exhaled nitric oxide
ICS
Inhaled corticosteroid
LOC
Loss of control
m/z
Mass/charge ratio
OR
Odds ratio
PC20AMP
Provocative concentration of adenosine 5′-monophosphate causing a 20% decrease in FEV1

Cited by (0)

Supported by Lottery Health New Zealand, the Dunedin School of Medicine, National Institutes of Health grants HL1034531 and HL109250, and Alfred Lerner Memorial Chair (to S.C.E.). S.C.E. is a Senior Fellow of the American Asthma Foundation. S.L.H. was partially supported by a gift from the Leonard Krieger Fund. Mass spectrometry instrumentation used for BrTyr analyses is housed within the Cleveland Clinic Lerner Research Institute Mass Spectrometry Facility, which is partially supported by a Center of Innovation Award by AB Sciex.

Disclosure of potential conflict of interest: S. L. Hazen reports grants from the National Institutes of Health (P01HL103453), nonfinancial support from Abbott, grants and personal fees from the Cleveland Heart Lab, personal fees from Esperion, grants from Foundation LeDucq, personal fees from Frantz Biomarkers, personal fees from Lilly, grants and personal fees from Liposcience, personal fees from Merck & Co, grants and personal fees from Pfizer, grants and personal fees from Procter & Gamble, personal fees from Siemens, and grants from Takeda Pharmaceuticals during the conduct of the study. In addition, S. L. Hazen has a patent with Cleveland Clinic and is partially supported by a gift from the Leonard Krieger endowment. The rest of the authors declare that they have no relevant conflicts of interest.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12606000531516, ACTRN12606000488505.