SPLUNC1: a novel marker of cystic fibrosis exacerbations.

Acute pulmonary Exacerbations (AE) are episodes of clinical worsening in cystic fibrosis (CF), often precipitated by infection. Timely detection is critical to minimise morbidity and lung function declines associated with acute inflammation during AE. Based on our previous observations that airway protein Short Palate Lung Nasal epithelium Clone 1 (SPLUNC1) is regulated by inflammatory signals, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF.We enrolled CF participants from two independent cohorts to measure AE markers of inflammation in sputum and recorded clinical outcomes for a 1-year follow-up period.SPLUNC1 levels were high in healthy controls (n=9, 10.7 μg mL-1), and significantly decreased in CF participants without AE (n=30, 5.7 μg mL-1, p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6 μg mL-1, p=0.0034) regardless of age, sex, CF-causing mutation, or microbiology findings. Cytokines Il-1β and TNFα were also increased in AE, whereas lung function did not consistently decrease. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (HR: 11.49, Standard Error: 0.83, p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even one year after sputum collection (HR: 3.21, Standard Error: 0.47, p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE.In acute CF care, low SPLUNC1 levels could support a decision to increase airway clearance or to initiate pharmacological interventions. In asymptomatic, stable patients, low SPLUNC1 levels could inform changes in clinical management to improve long-term disease control and clinical outcomes in CF.