LAMA improve tissue oxygenation more than LABA in patients with COPD.

Background The effect of bronchodilators is mainly assessed with forced expiratory volume in 1s (FEV1) in COPD. Their impact on oxygenation and lung periphery is less known. Objectives To compare the action of long-acting ß2-agonists (LABA-olodaterol) and muscarinic antagonists (LAMA-tiotropium) on tissue oxygenation in COPD, considering their impact on proximal and peripheral ventilation as well as lung perfusion. Methods FEV1, Helium slope (SHe) from a single-breath washout test (SHe decrease reflecting a peripheral ventilation improvement), frequency dependence of resistance (R5-R19), area under reactance (AX), lung capillary blood volume (Vc) from double diffusion (DLNO/DLCO) and transcutaneous oxygenation (TcO2) were measured before and 2 hours post-LABA (day 1) and LAMA (day 3) in 30 COPD patients (FEV1 54±18% pred; GOLD A 31%/B 48%/E 21%) after 5-7 days of washout, respectively. Results TcO2 increased more (p=0.03) after LAMA (11±12%from baseline, p<0001) compared to LABA (4±11%, p=0.06) despite a lower FEV1 increase (p=0.03) and similar SHe (p=0.98), AX (p=0.63) and R5-R19 decreases (p=0.37). TcO2 and SHe changes were negatively correlated (r=-0.47, p=0.01) after LABA, not after LAMA (r=0.10, p=0.65). DLNO/DLCO decreased and Vc increased after LAMA (p=0.04; p=0.01, respectively) but not after LABA (p=0.53; p=0.24). Conclusion LAMA significantly improved tissue oxygenation in COPD patients, while only a trend was observed with LABA. The mechanisms involved may differ between both drugs: LABA increased peripheral ventilation while LAMA increased lung capillary blood volume. Should oxygenation differences persist over time, LAMA could arguably become the first therapeutic choice in COPD.

Factors most strongly associated with breathlessness in a population aged 50-64 years.

Background: Breathlessness is a troublesome and prevalent symptom in the population, but knowledge of related factors is scarce. The aim of this study was to identify the factors most strongly associated with breathlessness in the general population and to describe the shapes of the associations between the main factors and breathlessness. Methods: A cross-sectional analysis was carried out of the multicentre population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) of adults aged 50 to 64 years. Breathlessness was defined as a modified Medical Research Council breathlessness rating ≥2. The machine learning algorithm extreme gradient boosting (XGBoost) was used to classify participants as either breathless or nonbreathless using 449 factors, including physiological measurements, blood samples, computed tomography cardiac and lung measurements, lifestyle, health conditions and socioeconomics. The strength of the associations between the factors and breathlessness were measured by SHapley Additive exPlanations (SHAP), with higher scores reflecting stronger associations. Results: A total of 28 730 participants (52% women) were included in the study. The strongest associated factors for breathlessness were (in order of magnitude): body mass index ( SHAP score 0.39), forced expiratory volume in 1 s (0.32), physical activity measured by accelerometery (0.27), sleep apnoea (0.22), diffusing lung capacity for carbon monoxide (0.21), self-reported physical activity (0.17), chest pain when hurrying (0.17), high-sensitivity C-reactive protein (0.17), recent weight change (0.14) and cough (0.13). Conclusion: This large population-based study of men and women aged 50-64 years identified the main factors related to breathlessness that may be prevented or amenable to public health interventions.

Exertional breathlessness related to medical conditions in middle-aged people: the population-based SCAPIS study of more than 25,000 men and women.

BACKGROUND: Breathlessness is common in the population and can be related to a range of medical conditions. We aimed to evaluate the burden of breathlessness related to different medical conditions in a middle-aged population. METHODS: Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study of adults aged 50-64 years. Breathlessness (modified Medical Research Council [mMRC] ≥ 2) was evaluated in relation to self-reported symptoms, stress, depression; physician-diagnosed conditions; measured body mass index (BMI), spirometry, venous haemoglobin concentration, coronary artery calcification and stenosis [computer tomography (CT) angiography], and pulmonary emphysema (high-resolution CT). For each condition, the prevalence and breathlessness population attributable fraction (PAF) were calculated, overall and by sex, smoking history, and presence/absence of self-reported cardiorespiratory disease. RESULTS: We included 25,948 people aged 57.5 ± [SD] 4.4; 51% women; 37% former and 12% current smokers; 43% overweight (BMI 25.0-29.9), 21% obese (BMI ≥ 30); 25% with respiratory disease, 14% depression, 9% cardiac disease, and 3% anemia. Breathlessness was present in 3.7%. Medical conditions most strongly related to the breathlessness prevalence were (PAF 95%CI): overweight and obesity (59.6-66.0%), stress (31.6-76.8%), respiratory disease (20.1-37.1%), depression (17.1-26.6%), cardiac disease (6.3-12.7%), anemia (0.8-3.3%), and peripheral arterial disease (0.3-0.8%). Stress was the main factor in women and current smokers. CONCLUSION: Breathlessness mainly relates to overweight/obesity and stress and to a lesser extent to comorbidities like respiratory, depressive, and cardiac disorders among middle-aged people in a high-income setting-supporting the importance of lifestyle interventions to reduce the burden of breathlessness in the population.

Respiratory symptoms, exacerbations and sleep disturbances are more common among participants with asthma and chronic airflow limitation: an epidemiological study in Estonia, Iceland and Sweden.

BACKGROUND: Chronic airflow limitation (CAL) is a hallmark of chronic obstructive pulmonary disease but is also present in some patients with asthma. We investigated respiratory symptoms, sleep and health status of participants with and without CAL with particular emphasis on concurrent asthma using data from adult populations in Iceland, Estonia and Sweden investigated within the Burden of Obstructive Lung Disease study. METHODS: All participants underwent spirometry with measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) before and after bronchodilation. CAL was defined as postbronchodilator FEV1/FVC below the lower limit of normal. IgE-sensitisation and serum concentrations of eosinophil-derived neurotoxin (S-EDN) were assessed in a subsample. The participants were divided into four groups: no self-reported doctor's diagnosed asthma or CAL, asthma without CAL, CAL without asthma and asthma and CAL: χ2 test and analysis of variance were used in bivariable analyses and logistic and linear regression when analysing the independent association between respiratory symptoms, exacerbations, sleep-related symptoms and health status towards CAL, adjusting for centre, age, sex, body mass index, smoking history and educational level. RESULTS: Among the 1918 participants, 190 (9.9%) had asthma without CAL, 127 (6.6%) had CAL without asthma and 50 (2.6%) had CAL with asthma. Having asthma with CAL was associated with symptoms such as wheeze (adjusted OR (aOR) 6.53 (95% CI 3.53 to 12.1), exacerbations (aOR 12.8 (95% CI 6.97 to 23.6), difficulties initiating sleep (aOR 2.82 (95% CI 1.45 to 5.48), nocturnal gastro-oesophageal reflux (aOR 3.98 (95% CI 1.79 to 8.82)) as well as lower physical health status. In these analyses, those with no asthma and no CAL were the reference group. The prevalence of IgE-sensitisation was highest in both asthma groups, which also had higher levels of S-EDN. CONCLUSION: Individuals with self-reported asthma with CAL suffer from a higher burden of respiratory and sleep-related symptoms, higher exacerbation rates and lower health status when compared with participants with asthma alone or CAL alone.

Biomarkers of chronic airflow limitation and COPD identified by mass spectrometry.

Rationale: COPD affects 300 million people worldwide and is the third leading cause of death according to World Health Organization global health estimates. Early symptoms are subtle, and so COPD is often diagnosed at an advanced stage. Thus, there is an unmet need for biomarkers that can identify individuals at early stages of the disease before clinical symptoms have manifested. To date, few biomarkers are available for clinical diagnostic use in COPD. Methods: We evaluated a panel of serum biomarkers related to inflammation and infection for their ability to discriminate between 77 subjects with chronic airflow limitation (CAL) and 142 subjects with COPD, versus 150 healthy subjects (divided into two control groups that were matched with regards to age, gender and smoking to CAL and COPD). Healthy subjects and CAL were from Burden of Obstructive Lung Disease (BOLD), a population-based study. CAL was defined by post-bronchodilatory forced expiratory volume in 1 s/forced vital capacity ratio <0.7 in the BOLD population. COPD subjects were from Tools for Identifying Exacerbations (TIE), a COPD patient cohort. Quantification of 100 biomarker candidates was done by liquid chromatography-tandem mass spectrometry. Results: Several protein-derived peptides were upregulated in CAL, compared to controls; most notably peptides representing histidine-rich glycoprotein (HRG), α1-acid glycoprotein (AGP1), α1-antitrypsin (α1AT) and fibronectin. Out of these, HRG-, AGP1- and α1AT-specific peptides were also elevated in the COPD cohort. Conclusion: HRG, AGP1 and α1AT biomarkers distinguish subjects with CAL and COPD from healthy controls. HRG and AGP1 represent novel findings.

ERS technical standard: Global Lung Function Initiative reference values for exhaled nitric oxide fraction (F ENO50 ).

BACKGROUND: Elevated exhaled nitric oxide fraction at a flow rate of 50 mL·s-1 (F ENO50 ) is an important indicator of T-helper 2-driven airway inflammation and may aid clinicians in the diagnosis and monitoring of asthma. This study aimed to derive Global Lung Function Initiative reference equations and the upper limit of normal for F ENO50 . METHODS: Available individual F ENO50 data were collated and harmonised using consensus-derived variables and definitions. Data collected from individuals who met the harmonised definition of "healthy" were analysed using the generalised additive models of location, scale and shape (GAMLSS) technique. RESULTS: Data were retrospectively collated from 34 782 individuals from 34 sites in 15 countries, of whom 8022 met the definition of healthy (19 sites, 11 countries). Overall, height, age and sex only explained 12% of the between-subject variability of F ENO50 (R2=0.12). F ENO device was neccessary as a predictor of F ENO50 , such that the healthy range of values and the upper limit of normal varied depending on which device was used. The range of F ENO50 values observed in healthy individuals was also very wide, and the heterogeneity was partially explained by the device used. When analysing a subset of data in which F ENO50 was measured using the same device and a stricter definition of health (n=1027), between-site heterogeneity remained. CONCLUSION: Available F ENO50 data collected from different sites using different protocols and devices were too variable to develop a single all-age reference equation. Further standardisation of F ENO devices and measurement are required before population reference values might be derived.

The Impact of Airway Obstruction on Feno Values in Asthma Patients.

BACKGROUND: Exhaled nitric oxide (Feno) is used as a marker of type-2 airway inflammation in asthma management. Studies with airway challenges demonstrated that a reduction in airway caliber decreases Feno levels. OBJECTIVE: To evaluate the impact of airway caliber reduction occurring spontaneously in patients with asthma on Feno values in daily clinical practice. METHODS: In this post hoc analysis, Feno, FEV1, and asthma control questionnaire scores were recorded on each visit for 120 (1073 visits) adult patients with asthma. Blood eosinophils were measured intermittently. The intraindividual relationship between Feno and FEV1 was evaluated via a linear mixed model. The determinants of the individual mean Feno were measured by a stepwise multivariate linear model including individual mean FEV1, inhaled corticosteroid dose, asthma control questionnaire score, and blood eosinophils. RESULTS: Variations in the negative Feno-FEV1 relationship within individuals at different times were significantly determined by the individual's mean FEV1. This relationship did not hold for individuals above the 75th and below the 25th quartiles. The best explanatory variables for individual mean Feno were FEV1 (+4.3 parts per billion/10%pred) and blood eosinophil count (+1 part per billion per 100 cells/mm3). DISCUSSION: In the presence of variable degrees of heterogeneous patterns of airway inflammation, airway caliber is shown to be an independent and significant determinant of Feno when measured in patients with asthma. We would propose a +4-parts-per-billion correction factor to the measured Feno value for each 10% reduction below 100% predicted FEV1. Doing this should improve the rigor of interpretation of Feno as an indicator of type-2 inflammation in patients with low FEV1.

Periodontitis is associated with airflow obstruction in the Malmö Offspring Dental Study.

AIM: To investigate the association between periodontitis and lung function in the Malmö Offspring Dental Study. MATERIALS AND METHODS: In all 1001 individuals (49.9% female, mean age: 44.6) from Malmö Offspring Dental Study were included. Periodontitis was assessed by a full-mouth examination protocol including bleeding on probing and classified according to the American Academy of Periodontology/Center for Disease Control definitions. Forced expiratory volume in 1 s (FEV1 ) and forced vital capacity (FVC) were expressed as absolute values and %predicted according to Global Lung Function Initiative reference values. FEV1 , FVC and FEV1 /FVC were analysed in relation to periodontal status using linear regression. RESULTS: Severe periodontitis was found in 7% of the population. Adjusted regression models showed significant associations between lung function and severe periodontitis with 2.1 unit lower FEV1 /FVC ratio (95% CI: -3.91, -0.23) and odds ratio (adjusted) of 2.56 (95% CI: 1.40, 4.75, p = .003) for airflow obstruction (FEV1 /FVC less than the lower limit of normal) if having severe periodontitis. Lower values of %predicted FEV1 and %predicted FVC, but not FEV1 /FVC, were found in individuals with >25% bleeding on probing. CONCLUSIONS: Severe periodontitis was associated with lower FEV1 /FVC ratio and airflow obstruction in the present cohort. More large-scale prospective studies and intervention studies are required for a comprehensive evaluation.

Gastroesophageal reflux and snoring are related to asthma and respiratory symptoms: Results from a Nordic longitudinal population survey.

AIM: To study if individuals with nocturnal gastroesophageal reflux (nGER) and habitual snoring are more likely to develop asthma and respiratory symptoms (i.e. wheeze, cough, chest tightness, breathlessness) than those without these conditions, and if these associations are additive. METHODS: We used data from the population-based prospective questionnaire study Respiratory Health in Northern Europe (RHINE) (11,024 participants), with data from 1999 and 2011. Participants with heartburn or belching after going to bed, at least 1 night/week, were considered to have nGER. Participants reporting loud snoring at least 3 nights/week were considered to have habitual snoring. Participants were grouped into four groups by their nGER and snoring status: "never"; "former"; "incident"; "persistent". Incident respiratory symptoms were analyzed among participants without respective symptom at baseline. RESULTS: Snoring and nGER were independently associated with incident asthma and respiratory symptoms. The risk of incident wheeze was increased in subjects with incident or persistent snoring (adjusted odds ratio (95 % CI): 1.44 (1.21-1.72)), nGER (2.18 (1.60-2.98)) and in those with both snoring and nGER (2.59 (1.83-3.65)). The risk of developing asthma was increased in subjects with incident or persistent snoring (1.44 (1.15-1.82)), nGER (1.99 (1.35-2.93)) and in those with both snoring and nGER (1.72 (1.06-2.77)). No significant interaction was found between snoring and nGER. A similar pattern was found for the incidence of all other respiratory symptoms studied, with the highest risk among those with both incident or persistent nGER and snoring. CONCLUSION: The risk of developing asthma and respiratory symptoms is increased among subjects with nGER and habitual snoring. These associations are independent of each other and confounding factors. Snoring and nGER together are additive on respiratory symptoms.

Device comparison study to measure nasal nitric oxide in relation to primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic respiratory disease characterized by chronic cough, recurrent respiratory infections, and rhinosinusitis. The measurement of nasal nitric oxide (nNO) against resistance has been suggested as a sensitive screening method. However, current recommendations argue for the use of expensive, chemiluminescence devices to measure nNO. This study aimed to compare nNO measurement using three different devices in distinguishing PCD patients from healthy controls and cystic fibrosis (CF) patients and to evaluate their diagnostic precision. The study included 16 controls, 16 PCD patients, and 12 CF patients matched for age and sex. nNO measurements were performed using a chemiluminescence device (Eco Medics CLD 88sp), and two devices based on electrochemical sensors (Medisoft FeNO+ and NIOX Vero) following standardized guidelines. Correlation estimation, Bland-Altman, ROC curve, and one-way ANOVA were used to assess device differences and diagnostic performance. Significantly lower nNO output values were observed in PCD and CF patients compared to controls during exhalation against resistance. The correlation analysis showed high agreement among the three devices. ROC curve analysis demonstrated 100% sensitivity and specificity at different cut-off values for all devices in distinguishing PCD patients from controls (optimal cut-offs: EcoMedics 73, Medisoft 92 and NIOX 87 (nl min-1)). Higher nNO output values were obtained with the Medisoft and NIOX devices as compared to the EcoMedics device, with a bias of-19 nl min-1(95% CI: -73-35) and -21 nl min-1(-73-31) accordingly. These findings indicate that all three tested devices can potentially serve as diagnostic tools for PCD if device specific cut-off values are used. This last-mentioned aspect warrants further studies and consideration in defining optimal cut-offs for individual device.

Reference values of serum total IgE in Uppsala - comparison over four decades.

Background: Total immunoglobulin E (IgE) analysis is a common tool in allergy diagnosis. Suggested reference values for IgE are divergent and sometimes based on outdated assay methods. We aimed to validate the published reference values (geometric mean [GM]: 13.2 kU/L, upper limit of normal [ULN], 114 kU/L) shown in an Uppsala cohort from 1974 using Phadebas IgE PRIST, and the suggested clinical threshold of 100 kU/L (Zetterström and Johansson 1981). Methods: Immunoglobulin E was measured in two Uppsala cohorts from 1997 (Blood bank) and 2011 to 2013 (the European community respiratory health survey part III [ECRHS III]) using ImmunoCAP™ Total IgE. For the reference value calculations, exclusion criteria were atopy (both cohorts), doctor's diagnosis of asthma and self-reported allergy (hay fever, rhinitis, rash) (only ECRHS III). Upper limit of normal was defined as mean + 2 standard deviations (SD) calculated using log-transformed values and back-transformation of the ULN prior to presentation. Common imputation methods for results below the assay range were evaluated. Results: The average GM was 14.2 kU/L (Blood bank, n = 63; imputation method range: 16.9-17.4 kU/L; ECRHS III, n = 113: 10.7-11.6 kU/L) and the overall mean ULN was 118 kU/L (Blood bank: 113-130 kU/L; ECRHS III: 104-128 kU/L). The clinical sensitivity and specificity of the 100 kU/L IgE threshold were 37.8 and 94.3% for atopy, 34.9 and 89.5% for doctor's diagnosis of asthma, and 24.5 and 97.3% for any self-reported allergy (ECRHS III). Conclusion: The calculated ULN values were similar between the cohorts. We conclude that the total IgE reference values shown for Uppsala subjects from 1974 are still valid and suitable also for the ImmunoCAP Total IgE assay. The 100 kU/L threshold for total IgE had a low sensitivity but high specificity for atopy, asthma, and allergy.

Isolated small airways obstruction predicts future chronic airflow obstruction: a multinational longitudinal study.

BACKGROUND: Chronic airflow obstruction is a key characteristic of chronic obstructive pulmonary disease. We investigated whether isolated small airways obstruction is associated with chronic airflow obstruction later in life. METHODS: We used longitudinal data from 3957 participants of the multinational Burden of Obstructive Lung Disease study. We defined isolated small airways obstruction using the prebronchodilator mean forced expiratory flow rate between 25% and 75% of the forced vital capacity (FVC) (FEF25-75) if a result was less than the lower limit of normal (

Factors important for health-related quality of life in men and women: The population based SCAPIS study.

INTRODUCTION: Health-related quality of life (HRQoL) is essential for human wellbeing, influenced by a complex interplay of factors, and is reported lower in women than men. We aimed to evaluate which factors were the most important for HRQoL in a middle-aged general population. METHODS: This was a cross-sectional, multi-centre study of 29,212 men (48%) and women (52%) aged 50-64 in the general population in Sweden. Physical and mental HRQoL (0-100) was assessed using the Short Form 12 questionnaire, and association was evaluated for 356 variables including demographics, lifestyle, symptoms, physiological measurements, and health conditions. Using machine learning, each variable´s importance for HRQoL was measured by an importance score, comparable to effect size, and summarised in 54 factors, in men and women separately. RESULTS: Men and women had similar mean and standard deviation (SD) scores for physical HRQoL (53.4 [SD 8.1] vs 51.4 [9.7]) and mental HRQoL (37.1 [5.0] vs 37.3 [5.4]). The most important factors for physical HRQoL were (importance score) physical activity (40), employment (36), pain (33), sleep (33), and sense of control (26). The most important factors for mental HRQoL were sense of control (18), physical activity (12), depression (12), pain (6), and employment (5). CONCLUSIONS: The factors important for HRQoL identified by this study are likely to be amenable to interventions, and our findings can support prioritising interventions. The identified factors need to be a target even before middle-age to lay the foundation for long and happy lives.

High prevalence of interstitial lung abnormalities in middle-aged never-smokers.

Background: Interstitial lung abnormalities (ILA) are incidental findings on chest computed tomography (CT). These patterns can present at an early stage of fibrotic lung disease. Our aim was to estimate the prevalence of ILA in the Swedish population, in particular in never-smokers, and find out its association with demographics, comorbidities and symptoms. Methods: Participants were recruited to the Swedish CArdioPulmonary BioImage Study (SCAPIS), a population-based survey including men and women aged 50-64 years performed at six university hospitals in Sweden. CT scan, spirometry and questionnaires were performed. ILA were defined as cysts, ground-glass opacities, reticular abnormality, bronchiectasis and honeycombing. Findings: Out of 29 521 participants, 14 487 were never-smokers and 14 380 were men. In the whole population, 2870 (9.7%) had ILA of which 134 (0.5%) were fibrotic. In never-smokers, the prevalence was 7.9% of which 0.3% were fibrotic. In the whole population, age, smoking history, chronic bronchitis, cancer, coronary artery calcium score and high-sensitive C-reactive protein were associated with ILA. Both ILA and fibrotic ILA were associated with restrictive spirometric pattern and impaired diffusing capacity of the lung for carbon monoxide. However, individuals with ILA did not report more symptoms compared with individuals without ILA. Interpretation: ILA are common in a middle-aged Swedish population including never-smokers. ILA may be at risk of being underdiagnosed among never-smokers since they are not a target for screening.

Impulse oscillometry indices in relation to respiratory symptoms and spirometry in the Swedish Cardiopulmonary Bioimage Study.

Background: Impulse oscillometry (IOS) is sensitive in detecting lung function impairment. In small studies, impaired IOS relates better to respiratory symptoms than spirometry. We studied how IOS related to spirometry and respiratory symptoms in a large population of individuals (n=10 360) in a cross-sectional analysis. Methods: Normal values for IOS and spirometry were defined in healthy, never-smoking individuals, aged 50-64 years, from the Swedish CArdioPulmonary bioImage Study (n=3664 for IOS and 3608 for spirometry). For IOS, abnormal values for resistance at 5 Hz (R5) and at 20 Hz and area of reactance were defined using the 95th percentile. Abnormal reactance at 5 Hz for IOS and abnormal conventional spirometry indices (forced expiratory volume in 1 s (FEV1), forced and slow vital capacity and their ratios) were defined using the 5th percentile. Results: Abnormal IOS parameters were found in 16% of individuals and were associated with increased odds ratios for nearly all respiratory symptoms when adjusted for age, gender and smoking. In individuals with normal spirometry, abnormal IOS resistance was related to cough and dyspnoea, while abnormal reactance was related to wheeze. In these individuals, the combination of abnormal R5 with abnormal reactance resulted in approximately two-fold higher likelihood for having cough, chronic bronchitis and dyspnoea, even when further adjusting for FEV1, expressed as % predicted. Conclusions: Abnormal IOS is related to increased respiratory burden in middle-aged individuals with normal spirometry, especially when resistance and reactance parameters are combined. The different relationships between respiratory symptoms and reactance and resistance warrant further research.

Impact of long-term exposure to ambient ozone on lung function over a course of 20 years (The ECRHS study): a prospective cohort study in adults.

Background: While the adverse effects of short-term ambient ozone exposure on lung function are well-documented, the impact of long-term exposure remains poorly understood, especially in adults. Methods: We aimed to investigate the association between long-term ozone exposure and lung function decline. The 3014 participants were drawn from 17 centers across eight countries, all of which were from the European Community Respiratory Health Survey (ECRHS). Spirometry was conducted to measure pre-bronchodilation forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) at approximately 35, 44, and 55 years of age. We assigned annual mean values of daily maximum running 8-h average ozone concentrations to individual residential addresses. Adjustments were made for PM2.5, NO2, and greenness. To capture the ozone-related change in spirometric parameters, our linear mixed effects regression models included an interaction term between long-term ozone exposure and age. Findings: Mean ambient ozone concentrations were approximately 65 µg/m³. A one interquartile range increase of 7 µg/m³ in ozone was associated with a faster decline in FEV1 of -2.08 mL/year (95% confidence interval: -2.79, -1.36) and in FVC of -2.86 mL/year (-3.73, -1.99) mL/year over the study period. Associations were robust after adjusting for PM2.5, NO2, and greenness. The associations were more pronounced in residents of northern Europe and individuals who were older at baseline. No consistent associations were detected with the FEV1/FVC ratio. Interpretation: Long-term exposure to elevated ambient ozone concentrations was associated with a faster decline of spirometric lung function among middle-aged European adults over a 20-year period. Funding: German Research Foundation.

Circulating mast cell progenitors increase during natural birch pollen exposure in allergic asthma patients.

BACKGROUND: Mast cells (MCs) develop from a rare population of peripheral blood circulating MC progenitors (MCps). Here, we investigated whether the frequency of circulating MCps is altered in asthma patients sensitized to birch pollen during pollen season, compared to out of season. METHODS: Asthma patients were examined during birch pollen season in late April to early June (May), and out of season in November-January. Spirometry measurements, asthma and allergy-related symptoms, asthma control questionnaire (ACQ), and asthma control test (ACT) scores were assessed at both time points. The MCp frequency was determined by flow cytometry in ficoll-separated blood samples from patients with positive birch pollen-specific IgE, and analyzed in relation to basic and disease parameters. RESULTS: The frequency of MCps per liter of blood was higher in May than in November (p = .004), particularly in women (p = .009). Patients that reported moderate to severe asthma symptoms (<.0001), nose or eye symptoms (p = .02; p = .01), or reduced asthma control (higher ACQ, p = .01) had higher MCp frequency in May than those that did not report this. These associations remained significant after adjusting for sex and BMI. The change in asthma control to a lower ACT score in May correlated with an increase in MCp frequency in May (p = .006, rho = 0.46). CONCLUSIONS: The data suggest that the frequency of MCps increases in symptomatic patients with allergic asthma. Our results unravel a link between asthma symptoms and circulating MCps, and bring new insight into the impact of natural allergen exposure on the expansion of MCs.

Fathers' preconception smoking and offspring DNA methylation.

BACKGROUND: Experimental studies suggest that exposures may impact respiratory health across generations via epigenetic changes transmitted specifically through male germ cells. Studies in humans are, however, limited. We aim to identify epigenetic marks in offspring associated with father's preconception smoking. METHODS: We conducted epigenome-wide association studies (EWAS) in the RHINESSA cohort (7-50 years) on father's any preconception smoking (n = 875 offspring) and father's pubertal onset smoking < 15 years (n = 304), using Infinium MethylationEPIC Beadchip arrays, adjusting for offspring age, own smoking and maternal smoking. EWAS of maternal and offspring personal smoking were performed for comparison. Father's smoking-associated dmCpGs were checked in subpopulations of offspring who reported no personal smoking and no maternal smoking exposure. RESULTS: Father's smoking commencing preconception was associated with methylation of blood DNA in offspring at two cytosine-phosphate-guanine sites (CpGs) (false discovery rate (FDR) < 0.05) in PRR5 and CENPP. Father's pubertal onset smoking was associated with 19 CpGs (FDR < 0.05) mapped to 14 genes (TLR9, DNTT, FAM53B, NCAPG2, PSTPIP2, MBIP, C2orf39, NTRK2, DNAJC14, CDO1, PRAP1, TPCN1, IRS1 and CSF1R). These differentially methylated sites were hypermethylated and associated with promoter regions capable of gene silencing. Some of these sites were associated with offspring outcomes in this cohort including ever-asthma (NTRK2), ever-wheezing (DNAJC14, TPCN1), weight (FAM53B, NTRK2) and BMI (FAM53B, NTRK2) (p < 0.05). Pathway analysis showed enrichment for gene ontology pathways including regulation of gene expression, inflammation and innate immune responses. Father's smoking-associated sites did not overlap with dmCpGs identified in EWAS of personal and maternal smoking (FDR < 0.05), and all sites remained significant (p < 0.05) in analyses of offspring with no personal smoking and no maternal smoking exposure. CONCLUSION: Father's preconception smoking, particularly in puberty, is associated with offspring DNA methylation, providing evidence that epigenetic mechanisms may underlie epidemiological observations that pubertal paternal smoking increases risk of offspring asthma, low lung function and obesity.