Abstract
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.
Footnotes
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Conflict of interest: Dr. Khanal has nothing to disclose.
Conflict of interest: Dr. Webster has nothing to disclose.
Conflict of interest: Dr. Niu has nothing to disclose.
Conflict of interest: Dr. Zielonka has nothing to disclose.
Conflict of interest: MNunez has nothing to disclose.
Conflict of interest: Dr. Chupp reports other from Genentech, other from Astra Zeneca, other from Sanofi - Regeneron, other from GSK, other from TEVA, other from Boehringer-Ingelheim, other from Circassia, outside the submitted work; .
Conflict of interest: Dr. Slade has nothing to disclose.
Conflict of interest: Dr. Cohn reports other from Genentech, other from Novartis, other from Astra-zeneca, other from GlaxoSmithKline, other from Regeneron, other from Pieris, other from Sanofi, outside the submitted work; .
Conflict of interest: Dr. Sauler has nothing to disclose.
Conflict of interest: Dr. Gomez has nothing to disclose.
Conflict of interest: Dr. Tarran reports other from Eldec Pharmaceuticals, outside the submitted work; In addition, Dr. Tarran has a patent Peptide inhibitors of Ca2+ channels pending, a patent PEPTIDE INHIBITORS OF SODIUM CHANNELS with royalties paid, and a patent Regulation of sodium channels by PLUNC proteins with royalties paid.
Conflict of interest: Dr. Sharma has nothing to disclose.
Conflict of interest: Dr. Dela Cruz has nothing to disclose.
Conflict of interest: Dr. Egan has nothing to disclose.
Conflict of interest: Dr. Laguna reports grants from National Institutes of Health, grants from Cystic Fibrosis Foundation, other from Vertex Physician Advisory Board, outside the submitted work; .
Conflict of interest: Dr. Britto has nothing to disclose.
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