Evaluation of airway and circulating inflammatory biomarkers for cystic fibrosis drug development

Abstract

IntroductionBiomarkers of inflammation in blood and sputum can play a critical role in anti-inflammatory drug development in cystic fibrosis (CF). The objectives of this analysis were to examine relationships between airway and systemic measurements of inflammation, associations between inflammatory biomarkers and FEV1, differences in airway and systemic inflammation by baseline covariates, reproducibility of serum biomarkers, and to assess the effects of freezing and delayed processing on sputum analyte measurements. MethodsWe analyzed baseline and serial concentrations of inflammatory markers in blood and induced sputum collected from individuals with CF ages 10 years and older who participated in a multicenter clinical trial. ResultsAmong circulating biomarkers, serum high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) correlated most strongly with each other (rs = 0.85). Comparing sputum-based inflammation measurements, sputum neutrophil elastase and myeloperoxidase (MPO) were the most highly correlated (rs = 0.88). Markers most strongly correlated with ppFEV1 were serum hsCRP (rs = -0.55), SAA (rs =-0.58), and sputum neutrophil elastase (rs = -0.53). Within-subject standard deviation was consistently lower than between-subject standard deviation for all serum biomarkers. Serum calprotectin and MPO had the highest ratio of between-to-within subject variability. Freezing and delayed sputum processing were not associated with significant differences in measurements of sputum neutrophil elastase, IL-1β, or MPO. ConclusionsAmong the biomarkers analyzed, serum hsCRP and sputum neutrophil elastase are promising candidates to include in CF anti-inflammatory clinical trials to avoid redundancy, minimize variation, and serve as correlates of lung disease severity and change.