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

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Summary

Background

Low concentrations of the anti-inflammatory protein CC16 (approved symbol SCGB1A1) in serum have been associated with accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). We investigated whether low circulating CC16 concentrations precede lung function deficits and incidence of COPD in the general population.

Methods

We assessed longitudinal data on CC16 concentrations in serum and associations with decline in FEV1 and incidence of airflow limitation for adults who were free from COPD at baseline in the population-based Tucson Epidemiological Study of Airway Obstructive Disease ([TESAOD] n=960, mean follow-up 14 years), European Community Respiratory Health Survey ([ECRHS-Sp] n=514, 11 years), and Swiss Cohort Study on Air Pollution and Lung Diseases in Adults ([SAPALDIA] n=167, 8 years) studies. Additionally, we measured circulating CC16 concentrations in samples from children aged 4–6 years in the Tucson Children's Respiratory Study (n=427), UK Manchester Asthma and Allergy Study (n=481), and the Swedish Barn/children, Allergy, Milieu, Stockholm, Epidemiological survey (n=231) birth cohorts to assess whether low CC16 concentrations in childhood were predictive for subsequent lung function.

Findings

After adjustment for sex, age, height, smoking status and intensity, pack-years, asthma, and FEV1 at baseline, we found an inverse association between CC16 concentration and decline in FEV1 in adults in TESAOD (4·4 mL/year additional FEV1 decline for each SD decrease in baseline CC16 concentration, p=0·0014) and ECRHS-Sp (2·4 mL/year, p=0·023); the effect in SAPALDIA was marginal (4·5 mL/year, p=0·052). Low CC16 concentration at baseline was also associated with increased risk of incident stage 2 airflow limitation (ratio of FEV1 to forced expiratory volume [FEV1/FVC] less than 70% plus FEV1 % predicted less than 80%) in TESAOD and ECRHS-Sp. In children, the lowest tertile of CC16 concentrations was associated with a subsequent FEV1 deficit of 68 mL up to age 16 years (p=0·0001), which was confirmed in children who had never smoked by age 16 years (−71 mL, p<0·0001).

Interpretation

Low concentrations of CC16 in serum are associated with reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population.

Funding

National Heart, Lung, and Blood Institute and European Union Seventh Framework Programme.

Introduction

Chronic obstructive pulmonary disease (COPD) is among the chronic diseases with the highest morbidity and mortality burdens worldwide.1 Development of this disease might be related to an accelerated decline in lung function during adult life, impaired lung function development during childhood, or a combination of these features.2 Although smoking is the main risk factor for an accelerated decline in lung function and the inception of COPD,3 not all smokers develop the disease and a notable proportion of cases are seen in never smokers. Apart from α1-antitrypsin deficiency, which is only seen in about 1% of all cases of COPD,4 there are no established biomarkers to identify adults at risk before disease onset or children who might be predisposed to lung function deficits in adult life.

CC16 (approved symbol SCGB1A1) is a homodimeric pneumoprotein that is mainly produced by club cells in the distal airways, but is measurable in circulation.5, 6, 7 Recurrent exposure to noxious environmental factors, such as cigarette smoke, results in chronically decreased numbers of club cells and concentrations of CC16 in serum.8, 9

Growing evidence suggests that CC16 has anti-inflammatory and antioxidative properties in the lungs,5, 6, 7 and might have a protective role against obstructive lung diseases.9 In most clinical studies,10, 11, 12, 13, 14, 15 reduced concentrations of CC16 in blood and airways have been associated with increased prevalence and severity of COPD. Additionally, low concentrations of CC16 in serum were associated with decline in forced expiratory volume in 1 s (FEV1) in patients with COPD in the ECLIPSE study16 and Lung Health Study.17 However, whether serum CC16 is a predictor of lung function trajectories and development of COPD in the general population is unknown.

Research in Context

Evidence before this study

Low circulating concentrations of CC16 have been linked to subsequent accelerated decline in forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD). These observations are in line with experimental evidence that supports anti-inflammatory and antioxidative effects of this molecule in the lungs. However, whether low circulating CC16 concentrations predict decline in lung function and incidence of COPD in the general population remains unknown. Whether effects of CC16 on subsequent lung function are already present in childhood, before exposure to cigarette smoking, is also unknown. We completed several PubMed searches with the search terms “CC16”, “CC10”, “CCSP”, “uteroglobin”, “Clara cell”, “Club cell”, “COPD”, “emphysema”, “chronic bronchitis”, “asthma”, and “lung function”, without language restrictions. Several cross-sectional studies linking circulating CC16 to asthma, COPD, and lung function and two clinical studies linking circulating CC16 to subsequent decline in FEV1 among patients with COPD were identified. We did not, however, find any previous prospective studies that assessed baseline circulating CC16 concentrations in relation to lung function growth or decline, or in relation to subsequent incidence of COPD in the general population. The date of our last search was Nov 28, 2014.

Added value of this study

In six population-based cohorts, three of adults and three of children, we found consistent relations between low circulating baseline concentrations of CC16 and accelerated decline in lung function and incidence of COPD in adults and subsequent lung function growth deficits in children up to age 16 years. These results remained significant after adjustment for other known risk factors and they cannot be explained only by residual confounding by smoking. Our study provides novel evidence that implicates low CC16 concentrations as an independent risk factor for lung function deficits and COPD.

Implications of all the available evidence

Our results indicate the possible value of CC16 for risk stratification. Longitudinal studies designed to investigate determinants of circulating CC16 concentrations and to model serial CC16 measurements are warranted to establish conclusively the potential of this molecule in informing prevention or treatment of COPD.

We did a prospective study of participants in six longitudinal studies to investigate whether baseline concentrations of circulating CC16 are associated with lung function decline and incidence of airflow limitation in adults. Additionally, we assessed the relation between low CC16 concentrations and lung function in childhood, before exposure to any effects from active smoking.

Section snippets

Participants

To assess the effects of CC16 concentration in adults, we used data from the Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD)18 as the main sample. We tested for replication of results with data from three Spanish centres in the European Community Respiratory Health Survey (ECRHS-Sp)19 and from the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA).20 For studies in children, we used data from the birth cohorts of the Tucson Children's Respiratory

Results

The TESAOD study population included 570 (59%) women, 553 (58%) ever smokers, and 89 (9%) participants with asthma. Mean age at baseline was 45 years and a mean FEV1 % predicted was 98%; baseline characteristics are presented in the appendix. Distributions of demographic and clinical characteristics were similar in the replication cohorts, although ECRHS-Sp had fewer women and SAPALDIA fewer smokers and participants with asthma (appendix). In a comparison of TESAOD participants included and

Discussion

In this study we found consistent associations between decreased circulating CC16 concentrations and reduced lung function in childhood, accelerated lung function decline in adulthood, and development of moderate airflow limitation in the general adult population. These findings are consistent with those from previous studies of patients with COPD, in whom lower baseline CC16 concentrations have been associated with steeper decline in FEV1.16, 17 That we found this association in people without

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