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.