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.

Regulation of human immune cell cytokine production in vivo is not well understood due in part to limitations on imposing experimental conditions. We proposed that life-imposed conditions (pregnancy, birth, age, gender), combined with large sample size, repeat sampling, and family-based recruitment would serve to reveal peripheral blood cell-derived cytokine patterns reflective of in vivo regulation regarding Th1/Th2 balance and familial correlation. Mononuclear cells were obtained from 483 trios in the Tucson Infant Immune Study: from mothers pre- and postpartum, infants at birth and at 3 mo, and fathers. Con A/PMA-stimulated supernatants were assayed by ELISA for IFN-γ, IL-4, IL-13, IL-5, and IL-10 and allergen-stimulated supernatants for IFN-γ, IL-4, and IL-13. Mitogen-stimulated prepartum samples were not globally Th2 biased, differing from postpartum only by a modestly reduced IFN-γ:IL-5 ratio. Prepartum samples actually produced less IL-10 and IL-13 although more IL-5 than paternal samples. Newborns were also not globally Th2 biased, with mitogen stimulation producing ~10-fold less IL-4, IL-5, and IFN-γ than adults but only 2- to 3-fold less IL-13 and IL-10. Despite these group differences, all cytokines showed marked positive intraindividual correlations (all p < 0.001). Allergen stimulation gave results consistent with a lack of global Th2 bias. Mitogen stimulation revealed parent-child and parent-parent correlations. Thus, rather than a global Th2 bias, cytokine production in pregnant mothers and newborns appears regulated so as to maintain a relative balance among the cytokines, with the nature of the balance differing in mothers and infants and with production influenced by familial factors that include shared environment.

Background While it has been postulated that allergic disease is associated with a predominance of Th2 cells, whether IgE levels and asthma might differ in their relations with early life cytokine production is not known. Objective To assess relations between first year adaptive immune cytokine production with asthma and total IgE levels through age 5 years in a non-selected birth cohort. Methods Mitogen (ConA/PMA) stimulated IL-4, IL-5, IL-13 and IFN-γ were measured in supernatants from cord and peripheral blood mononuclear cells at birth, 3 months and 12 months. Total serum IgE and physician-diagnosed active asthma were assessed at 1, 2, 3 and 5 years. Longitudinal models that adjust for both Th1 and Th2 cytokine production were used to determine relations of outcomes. Results Relations of cytokines with total IgE and asthma were strikingly different. Total IgE through age 5 years was positively associated with 12-month IL-4 (p < 0.001), IL-5 (p < 0.001) and IL-13 (p = 0.02) levels when adjusted for IFN-γ, and inversely associated with 12-month IFN-γ after IL-4 adjustment (p = 0.01). Active asthma through age 5 was positively associated with 3-month IL-13 adjusted for IFN-γ (Odds ratio (OR) = 2.6, p <0.001), and inversely associated with 3-month IFN-γ adjusted for IL-13 (OR = 0.5, p = 0.001). These relations were strongest for non-atopic asthma. Conclusion Total IgE and active asthma through age 5 are associated with adaptive cytokine production in early life, though relations vary temporally and with regard to the relative importance of individual cytokines.

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Background YKL-40 is a chitinase-like protein that, in cross-sectional clinical studies, has been associated with severe asthma and COPD in smokers. Aim To determine the longitudinal relation of circulating YKL-40 to levels and lung function decline in the general population. Methods We used longitudinal data from up to 12 surveys from the population-based TESAOD study which was conducted in Tucson, Arizona between 1972-1996. In cross-sectional analyses, we also used data from 3 Spanish centers of the multicenter ECRHS study (ECRHS-Sp). Serum YKL-40 was measured at baseline in TESAOD and in survey 2 in ECRHS-Sp using ELISAs. Multivariate linear regression was used to test associations of serum YKL-40 to concomitant lung function. In TESAOD, random coefficients models were used to test associations of serum YKL-40 to subsequent decline of lung function. Results Data on YKL-40 and lung function were available from 1088 TESAOD and 854 ECRHS-Sp adult participants (59% and 51% females; respectively). In adjusted multivariate meta-analyses, being in the highest YKL-40 quartile was associated cross-sectionally with significant deficits in FEV1 and FVC %predicted. In adjusted longitudinal analyses, TESAOD participants in the top YKL-40 quartile had an FEV1 decline that was 5 ml/yr (p=0.05) faster than subjects in the third quartile, 5 ml/yr (p=0.02) faster than subjects in the second quartile, and 10 ml/yr (p<0.001) faster than subjects in the lowest YKL-40 quartile. These longitudinal effects were particularly strong in smokers and absent in never smokers. After adjusting for covariates, as compared with the other three quartiles combined the top YKL-40 quartile was associated with a 9 ml/yr (p=0.001) faster FEV1 decline among smokers, while no significant effects were found among never smokers (2 ml/yr, p=0.35). Conclusions Circulating YKL-40 is associated with levels and decline of lung function in the general population and may be a biomarker of susceptibility to the long-term effects of cigarette smoking.