Sara Khanal1, Megan Webster2, Naiqian Niu1, Jana Zielonka1, Myra Nunez3, Geoffrey Chupp1, Martin D Slade1, Lauren Cohn1, Maor Sauler1, Jose L Gomez1, Robert Tarran2, Lokesh Sharma1, Charles S Dela Cruz1, Marie Egan4, Theresa Laguna3, Clemente J Britto5. 1. Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA. 2. Dept of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA. 3. Division of Pediatric Respiratory Medicine, University of Minnesota, Minneapolis, MN, USA. 4. Division of Pediatric Pulmonology, Allergy, Immunology, and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA. 5. Section of Pulmonary, Critical Care and Sleep Medicine, Yale University School of Medicine, New Haven, CT, USA Clemente.britto@yale.edu.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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 interleukin-1β and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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 interleukin-1β and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: 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.
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