P185 Prospective randomized observational study validating biomarkers for association with future pulmonary exacerbations in people with cystic fibrosis

Airway inflammation underlies pulmonary exacerbations in cystic fibrosis (CF). We tested multiple inflammatory molecules previously studied to validate specific biomarkers and pathways as potential causes of CF pulmonary exacerbations. We prospectively observed inflammatory sputum biomarkers in randomly selected adolescents and adults from multiple CF Centers to derive Cox proportional hazards models of time to next pulmonary exacerbation. We adjusted for clinical confounders and mediators, and tested sensitivity to anti-inflammatory, antibiotic and ivacaftor treatments. We measured 24 inflammatory markers among 114 individuals representative of US patients with CF [December 8, 2014 to January 16, 2016; 46% male, mean age 28 years (SD 12), mean percent predicted forced expiratory volume in 1 s (FEV1%) 70 (SD 22)] and followed to next exacerbation or up to 2.65 years. Age, sex, pre-enrollment exacerbation numbers and total white cell counts confounded models while FEV1% mediated biomarker effects. FDR analysis identified ten plausibly causal biomarkers for time to next exacerbation. Results were insensitive to anti-inflammatory, antibiotic and ivacaftor treatments with no signs of nonrandom bias due to missingness. Receptor for advanced glycation end-products (RAGE) axis, protease-antiprotease imbalance and oxidative stress injury mechanisms plausibly cause CF pulmonary exacerbations. FEV1% mediated and obscured specific biomarker effects that explain exacerbations. These findings suggest that antagonist combinations may interrupt multiple networked inflammatory pathways and exacerbations when treatments targeting a single biomarker may be incompletely effective. Further development of novel anti-inflammatory treatments should focus on combined RAGE axis, protease-antiprotease imbalance and oxidant stress antagonists to interrupt inflammation leading to new pulmonary exacerbations.