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 minimize the morbidity and lung function decline associated with acute inflammation during AE. We previously demonstrated that the airway protein Short Palate Lung Nasal epithelium Clone 1 (SPLUNC1) is regulated by inflammatory signals. Here, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF. We enrolled adult CF subjects 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 control sputum (n=9, 10.7µg/mL), and significantly decreased in CF subjects without AE (n=30, 5.7µg/mL, p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6µg/mL, 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 subjects with lower SPLUNC1 levels were much more likely to have an AE at 60 days (Hazard Ratio: 11.49, Standard Error: 0.83, p=0.0033). Low-SPLUNC1 stable subjects remained at higher AE risk even one year after sputum collection (Hazard Ratio: 3.21, Standard Error: 0.47, p=0.0125). SPLUNC1 was transcriptionally downregulated by inflammatory cytokines and degraded by proteases increased in sputum during AE. Our findings suggest that low sputum SPLUNC1 levels could detect subjects at increased risk of AE in order to guide early therapeutic interventions in CF.