Reduction of systemic inflammation by elexacaftor/tezacaftor/ivacaftor correlates with lung function improvement in cystic fibrosis.

Abstract

BACKGROUND Triple CFTR modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI) rapidly improves airway and systemic inflammation in people with cystic fibrosis (CF). However, longitudinal effects on systemic inflammation and their relationship to lung function remain unknown. METHODS In this prospective, observational, multicenter study, we analyzed peripheral blood neutrophil counts, C-reactive protein (CRP) and six pro-inflammatory serum cytokines in a cohort of 198 people with CF aged 6 years and older at baseline (BL) and follow-up visits 3, 12, and 24 months after initiation of ETI, compared to 74 age-matched healthy control participants (HCs). RESULTS Neutrophil counts and CRP, G-CSF, IL-1β, IL-6, and IL-8 were reduced to 71%, 40%, 41%, 63%, 46%, and 81% of median BL values after 3 months of therapy already (all p<0.05), whereas MCP-1 reached 82% of BL levels at 12 months only (p<0.05). Change from BL to 3 months correlated with improvements in percent predicted forced expiratory volume (ppFEV1) for all systemic inflammation parameters except IL-8 (Spearman's r: -0.17 to -0.42, p<0.05). All cytokines reached HC levels at or before 24 months. Decreased inflammation levels were sustained until 24 months for all parameters (p<0.05) except IL-6. CONCLUSIONS Our results demonstrate that ETI exerts rapid and sustained effects on systemic inflammation associated with lung function improvements in children, adolescents and adults with CF in a real-world, post-approval setting. However, our data also show that individual markers of systemic inflammation remain at levels above those of HCs, particularly in certain sub-groups, suggesting persistence or resurgence of residual systemic inflammation.