Association Between Serum Club Cell Protein 16 (CC16) Levels and FEF₂₅–₇₅ in Asymptomatic Active Smokers: A Cross-Sectional Study

Abstract

Club cell protein 16 (CC16) is a marker of airway epithelial integrity that may reflect early smoking-related injury. Small-airway dysfunction can occur before respiratory symptoms or overt airflow obstruction. This study aimed to determine the association between serum CC16 levels and forced expiratory flow at 25–75% of forced vital capacity (FEF₂₅–₇₅) in asymptomatic active smokers and to examine associations with other spirometric parameters. This cross-sectional study included 86 asymptomatic active male smokers aged 20–60 years recruited from hospital security personnel in Makassar, Indonesia. Serum CC16 concentrations were measured using enzyme-linked immunosorbent assay, and pulmonary function was assessed by spirometry. Associations were evaluated using Spearman correlation, group comparisons, and multivariable linear regression adjusted for age, body mass index, and Brinkman Index. The median serum CC16 concentration was 6.27 ng/mL (IQR, 4.45–8.90), while mean FEF₂₅–₇₅ was 75.6% predicted (SD, 18.1). Participants with FEF₂₅–₇₅ <65% predicted had significantly lower CC16 levels than those with FEF₂₅–₇₅ ≥65% predicted (3.87 vs. 7.64 ng/mL; p<0.001). Serum CC16 was positively correlated with FEF₂₅–₇₅ (ρ=0.560, p<0.001), FEV₁ (ρ=0.335, p=0.002), and FEV₁/FVC (ρ=0.410, p<0.001), but not FVC (ρ=0.174, p=0.109). After adjustment, each 1-ng/mL increase in CC16 was associated with a 2.62-percentage-point higher FEF₂₅–₇₅ (β=2.621; 95% CI, 1.49–3.75; p<0.001). Lower serum CC16 levels are associated with impaired small-airway expiratory flow in asymptomatic active smokers, supporting CC16 as a potential biomarker of subclinical smoking-related airway injury.