Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study

Abstract

Background Low serum levels of the anti-inflammatory club cell secretory protein (CC16) have been associated with an accelerated FEV1 decline in COPD. Whether low circulating CC16 precedes lung function deficits and incidence of COPD in the general population is unknown. Methods We used longitudinal data from adults who were COPD-free at baseline from the population-based TESAOD (N=960, mean follow-up: 14yrs), ECRHS-Sp (N=514, 11yrs) and SAPALDIA (N=167, 8yrs) studies. CC16 was measured in serum from baseline and associated with subsequent FEV1 decline and incidence of airflow limitation. To evaluate early life CC16 effects, we also measured circulating CC16 in samples from ages 4-6yrs to predict subsequent lung function in childhood in the CRS (N=427), MAAS (N=481), and BAMSE (N=231) birth cohorts. Findings In adults – after adjustment for sex, age, height, smoking status/intensity, pack-years, asthma, and initial FEV1 levels – baseline CC16 was inversely associated with subsequent decline of FEV1 in TESAOD (p=0.0014), ECRHS-Sp (p=0.023), and a similar trend was found in SAPALDIA (p=0.052). Low CC16 at baseline also predicted an increased risk for incident stage 2 airflow limitation (i.e., FEV1/FVC<70% plus FEV1 % predicted < 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 at age 4–6yrs was associated with subsequent FEV1 deficits up to age 16yrs (meta-analyzed estimate from adjusted models on birth cohorts: −68ml, p=0.0001). Results were confirmed among subjects who never smoked by age 16yrs (−71ml, p<0.0001). Interpretation Low serum CC16 is associated with subsequent slower growth and accelerated decline of lung function, and increased risk of developing stage 2 airflow limitation. Funding US National Heart, Lung, and Blood Institute and EU Seventh Framework Programme. For a complete list of other funding agencies, please refer to the acknowledgements section of the paper.

Urine Club Cell 16-kDa Secretory Protein and Childhood Wheezing Illnesses After Lower Respiratory Tract Infections in Infancy

“…13,14 Furthermore, urine levels of CC16 have been highly correlated to serum levels (which are less likely to be affected by some of these factors) in other studies using a similar instrument. 14,29,30 In the present study, similar results were obtained when analyzing urine CC16 with and without the creatinine correction, but there could still be residual confounding by the renal function and/or hydration status at the time of the urine sample. Third, there were a large number of values below the LOD.…”

“…21,22 In a recent large prospective study of children in three different countries, low serum levels of CC16 at 4-6 years of age were associated with decreased lung function by 16 years of age, although the outcome of asthma was not assessed. 29 To the authors' knowledge, this is the first study to examine the relationship between urine CC16 and the development of childhood wheezing illnesses.…”

“…The variables to be included in the multivariable models (infant's age, sex, and current exposure to SHS) were selected a priori based on published literature. 12,26,29,37 First-order interactions were tested for between urine levels of CC16 and each of the covariates mentioned above.…”

“…13,14 For instance, respiratory disorders that increase the epithelial permeability (e.g., acute respiratory distress syndrome, 16 exposure to proinflammatory agents, 17 or severe chest trauma 18 ) have been associated with higher serum levels of CC16. On the other hand, respiratory illnesses leading to small airway inflammation (e.g., asthma, [19][20][21][22][23][24] exposure to tobacco smoke, [25][26][27] or chronic obstructive pulmonary disease 25,[27][28][29] ) have been associated with lower serum levels of CC16.…”

Club cell protein (CC16) in plasma, bronchial brushes, BAL and urine following an inhaled allergen challenge in allergic asthmatics

“…Lower circulating levels are also seen in asthmatic subjects compared to healthy controls (Shijubo et al 1999b), as well as fewer CC16-positive epithelial cells in small airways (Shijubo et al 1999a). Lower levels of CC16 have also been linked to a more rapid decline of lung function in patients with COPD (Park et al 2013) and in the general population (Guerra et al 2015).…”