Stefano Guerra

Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study

BACKGROUND Together with smoking, the lung function attained in early adulthood is one of the strongest predictors of chronic obstructive pulmonary disease. We aimed to investigate whether lung function in early adulthood is, in turn, affected by airway function measured shortly after birth. METHODS Non-selected infants were enrolled at birth in the Tucson Childrens Respiratory Study between 1980 and 1984. We measured maximal expiratory flows at functional residual capacity (Vmax(FRC)) in 169 of these infants by the chest compression technique at a mean of 2.3 months (SD 1.9). We also obtained measurements of lung function for 123 of these participants at least once at ages 11, 16, and 22 years. Indices were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory flow between 25% and 75% of FVC (FEF25-75), both before and after treatment with a bronchodilator (180 microg of albuterol). FINDINGS Participants who had infant Vmax(FRC) in the lowest quartile also had lower values for the FEV1/FVC ratio (-5.2%, p<0.0001), FEF25-75 (-663 mL/s, p<0.0001), and FEV1 (-233 mL, p=0.001) up to age 22, after adjustment for height, weight, age, and sex, than those in the upper three quartiles combined. The magnitude and significance of this effect did not change after additional adjustment for wheeze, smoking, atopy, or parental asthma. INTERPRETATION Poor airway function shortly after birth should be recognised as a risk factor for airflow obstruction in young adults. Prevention of chronic obstructive pulmonary disease might need to start in fetal life.

Lung-Function Trajectories Leading to Chronic Obstructive Pulmonary Disease.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is thought to result from an accelerated decline in forced expiratory volume in 1 second (FEV1) over time. Yet it is possible that a normal decline in FEV1 could also lead to COPD in persons whose maximally attained FEV1 is less than population norms. METHODS We stratified participants in three independent cohorts (the Framingham Offspring Cohort, the Copenhagen City Heart Study, and the Lovelace Smokers Cohort) according to lung function (FEV1 ≥80% or <80% of the predicted value) at cohort inception (mean age of patients, approximately 40 years) and the presence or absence of COPD at the last study visit. We then determined the rate of decline in FEV1 over time among the participants according to their FEV1 at cohort inception and COPD status at study end. RESULTS Among 657 persons who had an FEV1 of less than 80% of the predicted value before 40 years of age, 174 (26%) had COPD after 22 years of observation, whereas among 2207 persons who had a baseline FEV1 of at least 80% of the predicted value before 40 years of age, 158 (7%) had COPD after 22 years of observation (P<0.001). Approximately half the 332 persons with COPD at the end of the observation period had had a normal FEV1 before 40 years of age and had a rapid decline in FEV1 thereafter, with a mean (±SD) decline of 53±21 ml per year. The remaining half had had a low FEV1 in early adulthood and a subsequent mean decline in FEV1 of 27±18 ml per year (P<0.001), despite similar smoking exposure. CONCLUSIONS Our study suggests that low FEV1 in early adulthood is important in the genesis of COPD and that accelerated decline in FEV1 is not an obligate feature of COPD. (Funded by an unrestricted grant from GlaxoSmithKline and others.).

MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine

To cite this article: Bousquet J, Anto J, Auffray C, Akdis M, Cambon‐Thomsen A, Keil T, Haahtela T, Lambrecht BN, Postma DS, Sunyer J, Valenta R, Akdis CA, Annesi‐Maesano I, Arno A, Bachert C, Ballester F, Basagana X, Baumgartner U, Bindslev‐Jensen C, Brunekreef B, Carlsen KH, Chatzi L, Crameri R, Eveno E, Forastiere F, Garcia‐Aymerich J, Guerra S, Hammad H, Heinrich J, Hirsch D, Jacquemin B, Kauffmann F, Kerkhof M, Kogevinas M, Koppelman GH, Kowalski ML, Lau S, Lodrup‐Carlsen KC, Lopez‐Botet M, Lotvall J, Lupinek C, Maier D, Makela MJ, Martinez FD, Mestres J, Momas I, Nawijn MC, Neubauer A, Oddie S, Palkonen S, Pin I, Pison C, Rancé F, Reitamo S, Rial‐Sebbag E, Salapatas M, Siroux V, Smagghe D, Torrent M, Toskala E, van Cauwenberge P, van Oosterhout AJM, Varraso R, von Hertzen L, Wickman M, Wijmenga C, Worm M, Wright J, Zuberbier T. MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. Allergy 2011; 66: 596–604.

TGF-β in human milk is associated with wheeze in infancy

Abstract Background Cytokines secreted in human milk might play important roles in newborn health and in the development of infant immune responses. We investigated the relationship of the concentration and dose of cytokines in human milk to infant wheeze at 1 year of age. Objective Our objective was to test whether the cytokines in milk could account for some of the apparent protective effect of breast-feeding against wheeze in the first year of life. Methods Data on breast-feeding and infant wheeze were collected prospectively from birth to 1 year from 243 mothers participating in the Infant Immune Study in Tucson, Arizona. Breast milk samples obtained at a mean age of 11 days postpartum were assayed by means of ELISA for concentrations of TGF-β1, IL-10, TNF-α, and the soluble form of CD14. The dose of each cytokine was assessed for a relationship with wheeze in bivariate and logistic regression analyses. Results Increasing duration of breast-feeding was significantly associated with a decreased prevalence of wheeze ( P = .039). There was wide variability in levels of each cytokine in milk, as well as variability between women in the amount of each cytokine produced. There was a significant inverse association between the dose of TGF-β1 received through milk with the percentage of wheeze ( P = .017), and the relationship was linear ( P = .006). None of the other cytokines showed a linear relationship with wheeze. In multivariate analyses the risk of wheeze was significantly decreased (odds ratio, 0.22; 95% CI 0.05-0.89; P = .034) with increasing TGF-β1 dose (long breast-feeding and medium-high TGF-β1 level compared with short breast-feeding and low TGF-β. Conclusion This analysis shows that the dose of TGF-β1 received from milk has a significant relationship with infant wheeze, which might account for at least some of the protective effect of breast-feeding against wheeze.

Chronic Bronchitis Before Age 50 Years Predicts Incident Airflow Limitation and Mortality Risk

Background: Previous studies on the relationship of chronic bronchitis to incident airflow limitation and all-cause mortality have provided conflicting results, with positive findings reported mainly by studies that included populations of young adults. This study sought to determine whether having chronic cough and sputum production in the absence of airflow limitation is associated with onset of airflow limitation, all-cause mortality and serum levels of C-reactive protein (CRP) and interleukin-8 (IL-8), and whether subjects’ age influences these relationships. Methods: 1412 participants in the long-term Tucson Epidemiological Study of Airway Obstructive Disease who at enrolment (1972–1973) were 21–80 years old and had FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity) ⩾70% and no asthma were identified. Chronic bronchitis was defined as cough and phlegm production on most days for ⩾3 months in two or more consecutive years. Incidence of airflow limitation was defined as the first follow-up survey with FEV1/FVC <70%. Serum IL-8 and CRP levels were measured in cryopreserved samples from the enrolment survey. Results: After adjusting for covariates, chronic bronchitis at enrolment significantly increased the risk for incident airflow limitation and all-cause mortality among subjects <50 years old (HR 2.2, 95% CI 1.3 to 3.8; and HR 2.2, 95% CI 1.3 to 3.8; respectively), but not among subjects ⩾50 years old (HR 0.9, 95% CI 0.6 to 1.4; and HR 1.0, 95% CI 0.7 to 1.3). Chronic bronchitis was associated with increased IL-8 and CRP serum levels only among subjects <50 years old. Conclusions: Among adults <50 years old, chronic bronchitis unaccompanied by airflow limitation may represent an early marker of susceptibility to the effects of cigarette smoking on systemic inflammation and long-term risk for chronic obstructive pulmonary disease and all-cause mortality.

Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort

Background Nocturia has been independently associated with cardiovascular morbidity and all-cause mortality, but such studies did not adjust for sleep-disordered breathing (SDB), which may have mediated such a relationship. Our aims were to determine whether an association between nocturia and cardiovascular morbidity exists that is independent of SDB. We also determined whether nocturia is independently associated with SDB. Methodology/Principal Findings In order to accomplish these aims we performed a cross-sectional analysis of the Sleep Heart Health Study that contained information regarding SDB, nocturia, and cardiovascular morbidity in a middle-age to elderly community-based population. In 6342 participants (age 63±11 [SD] years, 53% women), after adjusting for known confounders such as age, body mass index, diuretic use, diabetes mellitus, alpha-blocker use, nocturia was independently associated with SDB (measured as Apnea Hypopnea index >15 per hour; OR 1.3; 95%CI, 1.2–1.5). After adjusting for SDB and other known confounders, nocturia was independently associated with prevalent hypertension (OR 1.23; 95%CI 1.08–1.40; P = 0.002), cardiovascular disease (OR 1.26; 95%CI 1.05–1.52; P = 0.02) and stroke (OR 1.62; 95%CI 1.14–2.30; P = 0.007). Moreover, nocturia was also associated with adverse objective alterations of sleep as measured by polysomnography and self-reported excessive daytime sleepiness (P<0.05). Conclusions/Significance Nocturia is independently associated with sleep-disordered breathing. After adjusting for SDB, there remained an association between nocturia and cardiovascular morbidity. Such results support screening for SDB in patients with nocturia, but the mechanisms underlying the relationship between nocturia and cardiovascular morbidity requires further study. MeSH terms: Nocturia, sleep-disordered breathing, obstructive sleep apnea, sleep apnea, polysomnography, hypertension.

Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story: Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015.

MeDALL (Mechanisms of the Development of ALLergy; EU FP7‐CP‐IP; Project No: 261357; 2010–2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large‐scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy‐related diseases. To complement the population‐based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda.

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

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 Childrens 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.

Combined effects of parental and active smoking on early lung function deficits: a prospective study from birth to age 26 years

Background Cross-sectional reports have suggested that, among active smokers, previous exposure to parental smoking may increase susceptibility to development of chronic obstructive pulmonary disease. We assessed prospectively whether parental smoking enhances the effects of active smoking on early deficits of lung function in young adults. Methods We used data from the prospective birth cohort, the Tucson Childrens Respiratory Study. Maternal and paternal smoking was assessed via questionnaires completed by the parents at the time of the participants birth. Active smoking by participants was assessed via personal questionnaires completed at ages 16 (YR16), 22 and 26 years. Four groups were generated based on the combination of parental and active smoking. Lung function parameters, including forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, were assessed by spirometry before and after inhalation of 180 μg of albuterol at YR11, YR16, YR22 and YR26. Results Complete data were available for 519 participants. Pre-bronchodilator FEV1/FVC values did not differ at YR11, YR16 or YR22 by parental or active smoking. However, at YR26 participants with exposure to parental and active smoking had pre-bronchodilator FEV1/FVC levels that were, on average, 2.8% (0.9% to 4.8%; p=0.003) lower than participants who were not exposed to parental or active smoking. In contrast, subjects who were only exposed to active smoking or only exposed to parental smoking did not differ from those who were not exposed to either. Between YR11 and YR26, participants with exposure to parental and active smoking had the steepest decline in sex, age and height adjusted residuals of FEV1/FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25–75) and FEF25–75/FVC (all p values between 0.03 and <0.001). Conclusions Parental and active smoking act synergistically to affect early lung function deficits in young adulthood.

Pneumonia in childhood and impaired lung function in adults: a longitudinal study.

BACKGROUND: Diminished lung function and increased prevalence of asthma have been reported in children with a history of early lower respiratory illnesses (LRIs), including pneumonia. Whether these associations persist up to adulthood has not been established. METHODS: As part of the prospective Tucson Childrens Respiratory Study, LRIs during the first 3 years of life were ascertained by pediatricians. Spirometry was performed at ages 11, 16, 22, and 26 years. The occurrence of asthma/wheeze during the previous year was ascertained at ages 11, 13, 16, 18, 22, 24, 26, and 29 years. Longitudinal random effects models and generalized estimating equations were used to assess the relation of LRIs to lung function and asthma. RESULTS: Compared with participants without early-life LRIs, those with pneumonia had the most severe subsequent lung function impairment, with mean ± SE deficits of −3.9% ± 0.9% (P < .001) and −2.5% ± 0.8% (P = .001) for pre- and post-bronchodilator FEV1:FVC ratio from age 11 to 26 years, respectively. Pneumonia was associated with increased risk for asthma (odds ratio [OR]: 1.95; 95% confidence interval [CI]: 1.11–3.44) and wheeze (OR: 1.94; 95% CI: 1.28–2.95) over the same age range. Early non-pneumonia LRIs were associated with mildly impaired pre-bronchodilator FEV1 (−62.8 ± 27.9mL, P = .024) and FEV1:FVC ratio (−1.1 ± 0.5%, P = .018), and wheeze (OR: 1.37; 95% CI: 1.09–1.72). CONCLUSIONS: Early pneumonia is associated with asthma and impaired airway function, which is partially reversible with bronchodilators and persists into adulthood. Early pneumonia may be a major risk factor for adult chronic obstructive pulmonary disease.