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

Introduction: Biomarkers 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. Methods: We 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. Results: Among circulating biomarkers, serum high sensitivity C-reactive protein (hsCRP) and serum amyloid A (SAA) correlated most strongly with each other (r_s = 0.85). Comparing sputum-based inflammation measurements, sputum neutrophil elastase and myeloperoxidase (MPO) were the most highly correlated (r_s = 0.88). Markers most strongly correlated with ppFEV₁ were serum hsCRP (r_s = -0.55), SAA (r_s =-0.58), and sputum neutrophil elastase (r_s = -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. Conclusions: Among 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.