Changes in lung function in European adults born between 1884 and 1996 and implications for the diagnosis of lung disease:a cross-sectional analysis of ten population-based studies

Background: During the past century, socioeconomic and scientific advances have resulted in changes in the health and physique of European populations. Accompanying improvements in lung function, if unrecognised, could result in the misclassification of lung function measurements and misdiagnosis of lung diseases. We therefore investigated changes in population lung function with birth year across the past century, accounting for increasing population height, and examined how such changes might influence the interpretation of lung function measurements. Methods: In our analyses of cross-sectional data from ten European population-based studies, we included individuals aged 20-94 years who were born between 1884 and 1996, regardless of previous respiratory diagnoses or symptoms. FEV1, forced vital capacity (FVC), height, weight, and smoking behaviour were measured between 1965 and 2016. We used meta-regression to investigate how FEV1 and FVC (adjusting for age, study, height, sex, smoking status, smoking pack-years, and weight) and the FEV1/FVC ratio (adjusting for age, study, sex, and smoking status) changed with birth year. Using estimates from these models, we graphically explored how mean lung function values would be expected to progressively deviate from predicted values. To substantiate our findings, we used linear regression to investigate how the FEV1 and FVC values predicted by 32 reference equations published between 1961 and 2015 changed with estimated birth year. Findings: Across the ten included studies, we included 243 465 European participants (mean age 51·4 years, 95% CI 51·4-51·5) in our analysis, of whom 136 275 (56·0%) were female and 107 190 (44·0%) were male. After full adjustment, FEV1 increased by 4·8 mL/birth year (95% CI 2·6-7·0; p<0·0001) and FVC increased by 8·8 mL/birth year (5·7-12·0; p<0·0001). Birth year-related increases in the FEV1 and FVC values predicted by published reference equations corroborated these findings. This height-independent increase in FEV1 and FVC across the last century will have caused mean population values to progressively exceed previously predicted values. However, the population mean adjusted FEV1/FVC ratio decreased by 0·11 per 100 birth years (95% CI 0·09-0·14; p<0·0001). Interpretation: If current diagnostic criteria remain unchanged, the identified shifts in European values will allow the easier fulfilment of diagnostic criteria for lung diseases such as chronic obstructive pulmonary disease, but the systematic underestimation of lung disease severity. Funding: The European Respiratory Society, AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi-Genzyme

Poverty, dirt, infections and non-atopic wheezing in children from a Brazilian urban center

BACKGROUND: The causation of asthma is poorly understood. Risk factors for atopic and non-atopic asthma may be different. This study aimed to analyze the associations between markers of poverty, dirt and infections and wheezing in atopic and non-atopic children. METHODS: 1445 children were recruited from a population-based cohort in Salvador, Brazil. Wheezing was assessed using the ISAAC questionnaire and atopy defined as allergen-specific IgE ≥ 0.70 kU/L. Relevant social factors, environmental exposures and serological markers for childhood infections were investigated as risk factors using multivariate multinomial logistic regression. RESULTS: Common risk factors for wheezing in atopic and non-atopic children, respectively, were parental asthma and respiratory infection in early childhood. No other factor was associated with wheezing in atopic children. Factors associated with wheezing in non-atopics were low maternal educational level (OR 1.49, 95% CI 0.98-2.38), low frequency of room cleaning (OR 2.49, 95% CI 1.27-4.90), presence of rodents in the house (OR 1.48, 95% CI 1.06-2.09), and day care attendance (OR 1.52, 95% CI 1.01-2.29). CONCLUSIONS: Non-atopic wheezing was associated with risk factors indicative of poverty, dirt and infections. Further research is required to more precisely define the mediating exposures and the mechanisms by which they may cause non-atopic wheeze

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P= 1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer(LC;P= 4.0 × 10−4), chronic obstructive pulmonary disease (COPD;P= 9.3 × 10−4), peripheral artery disease (PAD;P= 0.090) and abdominal aortic aneurysms (AAAs; P= 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49,P= 2.2 × 10−4), COPD (OR = 3.22,P= 2.9 × 10−4), PAD (OR = 3.47,P= 9.2 × 10−3) and AAA (OR = 6.44, P= 6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P= 6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation

Galactose-α-1,3-Galactose–Specific IgE Is Associated with Anaphylaxis but Not Asthma

Rationale: IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract

All-cause and cause-specific mortality by spirometric pattern and sex : a population-based cohort study

Background: Chronic airway obstruction (CAO) and restrictive spirometry pattern (RSP) are associated with mortality, but sex-specific patterns of all-cause and specific causes of death have hardly been evaluated. Objectives: To study the possible sex-dependent differences of all-cause mortality and patterns of cause-specific mortality among men and women with CAO and RSP, respectively, to that of normal lung function (NLF). Design: Population-based prospective cohort study. Methods: Individuals with CAO [FEV1/vital capacity (VC) &lt; 0.70], RSP [FEV1/VC ⩾ 0.70 and forced vital capacity (FVC) &lt; 80% predicted] and NLF (FEV1/VC ⩾ 0.70 and FVC ⩾ 80% predicted) were identified within the Obstructive Lung Disease in Northern Sweden (OLIN) studies in 2002–2004. Mortality data were collected through April 2016, totally covering 19,000 patient-years. Cox regression and Fine–Gray regression accounting for competing risks were utilized to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, body mass index, sex, smoking habits and pack-years. Results: The adjusted hazard for all-cause mortality was higher in CAO and RSP than in NLF (HR, 95% CI; 1.69, 1.31–2.02 and 1.24, 1.06–1.71), and the higher hazards were driven by males. CAO had a higher hazard of respiratory and cardiovascular death than NLF (2.68, 1.05–6.82 and 1.40, 1.04–1.90). The hazard of respiratory death was significant in women (3.41, 1.05–11.07) while the hazard of cardiovascular death was significant in men (1.49, 1.01–2.22). In RSP, the higher hazard for respiratory death remained after adjustment (2.68, 1.05–6.82) but not for cardiovascular death (1.11, 0.74–1.66), with a similar pattern in both sexes. Conclusion: The higher hazard for all-cause mortality in CAO and RSP than in NLF was male driven. CAO was associated with respiratory death in women and cardiovascular death in men, while RSP is associated with respiratory death, similarly in both sexes

All-cause and cause-specific mortality by spirometric pattern and sex : a population-based cohort study

Background: Chronic airway obstruction (CAO) and restrictive spirometry pattern (RSP) are associated with mortality, but sex-specific patterns of all-cause and specific causes of death have hardly been evaluated. Objectives: To study the possible sex-dependent differences of all-cause mortality and patterns of cause-specific mortality among men and women with CAO and RSP, respectively, to that of normal lung function (NLF). Design: Population-based prospective cohort study. Methods: Individuals with CAO [FEV1/vital capacity (VC) &lt; 0.70], RSP [FEV1/VC ⩾ 0.70 and forced vital capacity (FVC) &lt; 80% predicted] and NLF (FEV1/VC ⩾ 0.70 and FVC ⩾ 80% predicted) were identified within the Obstructive Lung Disease in Northern Sweden (OLIN) studies in 2002–2004. Mortality data were collected through April 2016, totally covering 19,000 patient-years. Cox regression and Fine–Gray regression accounting for competing risks were utilized to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, body mass index, sex, smoking habits and pack-years. Results: The adjusted hazard for all-cause mortality was higher in CAO and RSP than in NLF (HR, 95% CI; 1.69, 1.31–2.02 and 1.24, 1.06–1.71), and the higher hazards were driven by males. CAO had a higher hazard of respiratory and cardiovascular death than NLF (2.68, 1.05–6.82 and 1.40, 1.04–1.90). The hazard of respiratory death was significant in women (3.41, 1.05–11.07) while the hazard of cardiovascular death was significant in men (1.49, 1.01–2.22). In RSP, the higher hazard for respiratory death remained after adjustment (2.68, 1.05–6.82) but not for cardiovascular death (1.11, 0.74–1.66), with a similar pattern in both sexes. Conclusion: The higher hazard for all-cause mortality in CAO and RSP than in NLF was male driven. CAO was associated with respiratory death in women and cardiovascular death in men, while RSP is associated with respiratory death, similarly in both sexes

Galactose-alpha-1,3-galactose Specific IgE is Associated with Anaphylaxis but not Asthma.

RATIONALE: IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. OBJECTIVE: To evaluate the relationship between IgE antibodies to alpha-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. METHODS: Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide (eNO), questionnaires, and serum IgE antibody assays. The results were compared with control subjects as well as cohorts from the Emergency Department (ED) in Virginia (n=130), northern Sweden (n=963), and rural Kenya (n=131). MEASUREMENTS AND MAIN RESULTS: Patients in Virginia with high titer IgE antibodies to alpha-gal had normal lung function, low levels of eNO, and low prevalence of asthma symptoms. Among patients in the ED and children in Kenya, there was no association between IgE antibodies to alpha-gal and asthma (odds ratios 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r=0.83), and to asthma (p<0.001). CONCLUSIONS: These results provide: i) a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and ii) further evidence that the main allergens that are causally related to asthma are those that are inhaled