Publications

Background and objectives: Different factors (etiotypes) can lead to persistent airflow obstruction (PAO) across the lifetime, including genetic factors, abnormal lung development, cigarette smoking, traffic pollution exposure, respiratory infections and asthma. Here we explore the prevalence of PAO and associated etiotypes in the general population in different age bins.

Methods: We studied 664 individuals with PAO (FEV1/FVC post bronchodilation (post-BD) below the lower limit of normal (LLN)) and 11,522 with normal lung function (FEV1/FVC, FEV1 and FVC ≥ LLN and ≤ upper limit of normal (ULN) post-BD) included in the LEAD Study (NCT01727518), a general population cohort in Vienna (Austria). For analysis, participants were stratified in three age bins (<25, 25-<50 and ≥ 50 years of age).

Results: PAO occurred in 3.8 % in females and 5.6 % in males of the cohort, and it increased with age. Most participants with PAO (57.5 %) reported respiratory symptoms, indicating a high burden of disease. PAO was associated with male sex (25-<50 years), ever smoking (>50 years), increased number of pack years (25-<50 years, >50 years), not being breastfed (<25 years) and ever diagnosis of asthma (in all age bins). Etiotypes varied by age bins with cigarette smoking being the most prevalent one, often in combination with traffic pollution exposure.

Conclusion: In the general population PAO occurs in about 5 % of participants with a higher prevalence in older individuals. Etiotypes and associated factors for PAO accumulate with age.

Background: While long-term air pollution and noise exposure has been linked to increasing cardiometabolic disease risk, potential effects on body composition remains unclear. This study aimed to investigate the associations of long-term air pollution, noise and body composition.

Methods: We used repeated data from the LEAD (Lung, hEart, sociAl, boDy) study conducted in Vienna, Austria. Body mass index (BMI; kg/m²), fat mass index (FMI; z-score), and lean mass index (LMI; z-score) were measured using dual-energy x-ray absorptiometry at the first (t₀; 2011-ongoing) and second (t₁; 2017-ongoing) examinations. Annual particulate matter (PM₁₀) and nitrogen dioxide (NO₂) concentrations were estimated with the GRAMM/GRAL model (2015-2021). Day-evening-night (L_den) and night-time (L_night) noise levels from transportation were modeled for 2017 following the European Union Directive 2002/49/EC. Exposures were assigned to residential addresses. We performed analyses separately in children/adolescents and adults, using linear mixed-effects models with random participant intercepts and linear regression models for cross-sectional and longitudinal associations, respectively. Models were adjusted for co-exposure, lifestyle and sociodemographics.

Results: A total of 19,202 observations (nt₀ = 12,717, nt₁ = 6,485) from participants aged 6-86 years (mean age at t₀ = 41.0 years; 52.9 % female; mean PM₁₀ = 21 µg/m³; mean follow-up time = 4.1 years) were analyzed. Among children and adolescents (age ≤ 18 years at first visit), higher PM₁₀exposure was cross-sectionally associated with higher FMI z-scores (0.09 [95 % Confidence Interval (CI): 0.03, 0.16]) and lower LMI z-scores (-0.05 [95 % CI: -0.10, -0.002]) per 1.8 µg/m³. Adults showed similar trends in cross-sectional associations as children, though not reaching statistical significance. We observed no associations for noise exposures. Longitudinal analyses on body composition changes over time yielded positive associations for PM₁₀, but not for other exposures.

Conclusion: Air pollution exposure, mainly PM₁₀, was cross-sectionally and longitudinally associated with body composition in children/adolescents and adults. Railway/road-traffic noise exposures showed no associations in both cross-sectional and longitudinal analyses.

Background: Within-breath analysis of oscillometry parameters is a growing research area since it increases sensitivity and specificity to respiratory pathologies and conditions. However, reference equations for these parameters in White adults are lacking and devices using multiple sinusoids or pseudorandom forcing stimuli have been underrepresented in previous studies deriving reference equations. The current study aimed to establish reference ranges for oscillometry parameters, including also the within-breath ones in White adults using multi-sinusoidal oscillations.

Methods: White adults with normal spirometry, BMI ≤30 kg/m2, without a smoking history, respiratory symptoms, pulmonary or cardiac disease, neurological or neuromuscular disorders, and respiratory tract infections in the previous 4 weeks were eligible for the study. Study subjects underwent oscillometry (multifrequency waveform at 5-11-19 Hz, Resmon PRO FULL, RESTECH Srl, Italy) in 5 centers in Europe and the USA according to international standards. The within-breath and total resistance (R) and reactance (X), the resonance frequency, the area under the X curve, the frequency dependence of R (R5-19), and within-breath changes of X (ΔX) were submitted to lambda-mu-sigma models for deriving reference equations. For each output parameter, an AIC-based stepwise input variable selection procedure was applied.

Results: A total of 144 subjects (age 20.8-86.3 years; height 146-193 cm; BMI 17.42-29.98 kg/m2; 56% females) were included. We derived reference equations for 29 oscillatory parameters. Predicted values for inspiratory and expiratory parameters were similar, while differences were observed for their limits of normality.

Conclusions: We derived reference equations with narrow confidence intervals for within-breath and whole-breath oscillatory parameters for White adults.

Rationale: Preserved ratio impaired spirometry (PRISm) is a recently recognized spirometric pattern defined by a ratio of forced expiratory volume in 1 second to forced vital capacity of at least 0.70 and a forced expiratory volume in 1 second <80% of reference. For unclear reasons, PRISm is associated with increased cardiovascular (CV) morbidity and mortality. Arterial stiffness is a major mechanism of CV disease, which can be measured by carotid-femoral pulse-wave velocity (cfPWV).

Objectives: We explored the hypothesis that cfPWV would be increased in individuals with PRISm and airflow limitation (AL).

Methods: We measured forced spirometry, lung volumes by body plethysmography, and cfPWV in 9,466 subjects recruited from the general population in the Austrian cross-sectional LEAD (Lung, Heart, Social, Body) study and tested the association of arterial stiffness with PRISm and AL by multivariable linear regression analysis. Individuals younger than 18 years were excluded from the study.

Results: Individuals with PRISm (n = 431; 4.6%) were of similar age to those with normal spirometry (n = 8,136; 85.9%) and significantly younger than those with AL (n = 899; 9.5%). Arterial hypertension, diabetes mellitus, coronary artery disease, heart failure, and peripheral arterial occlusive disease were significantly more common in individuals with PRISm than in those with normal lung function and similar to those with AL. There was a significant association between PRISm and arterial stiffness on bivariate linear regression analysis (crude model, β = 0.038; 95% confidence interval [CI], 0.016-0.058), which persisted after robust adjustment for clinical confounders upon multivariable analysis (final model, β = 0.017; 95% CI, 0.001-0.032). cfPWV was significantly higher in individuals with PRISm irrespective of the presence of established CV disease or pulmonary restriction. AL also showed a significant association with arterial stiffness on multivariable linear regression analysis (final model, β = 0.025; 95% CI, 0.009-0.042).

Conclusions: Arterial stiffness measured by cfPWV is increased in individuals with PRISm independent of CV disease and risk factors. The pathobiological mechanisms underlying this association deserve further research.

While neutralizing antibodies (nAbs) induced by monovalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations are primarily directed against the wildtype (WT), subsequent exposure to the Omicron variants may increase the breadth of the antibodies’ cross-neutralizing activity. Here, we analyzed the impact of an Omicron breakthrough infection (BTI) or a fourth monovalent mRNA vaccination on nAb profiles in people living with human immunodeficiency virus (PLWH). Using a multivariant surrogate virus neutralization test (sVNT), we quantified nAbs in 36 three-times vaccinated PLWH, of whom 9 acquired a serologically confirmed Omicron BTI, 8 received a fourth vaccine dose, and 19 were neither infected nor additionally vaccinated. While nAbs against WT and Delta increased after the BTI and a fourth vaccination, a significant increase against BA.1, BA.2, and BA.5 was only observed after the BTI. However, there was no significant difference in nAb concentrations between the samples obtained after the BTI and fourth vaccination. In contrast, nAb levels were significantly lower in PLWH, who were neither infected nor additionally vaccinated after three vaccinations. Thus, our study demonstrates the suitability of a multivariant sVNT to assess hybrid humoral immunity after Omicron BTIs in PLWH vaccinated against SARS-CoV-2.

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance-which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment-and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)-ceralasertib (ATR kinase inhibitor), durvalumab-olaparib (PARP inhibitor), durvalumab-danvatirsen (STAT3 antisense oligonucleotide) or durvalumab-oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab-ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6-7.4) versus 2.7 (1.8-2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1-20.3) versus 9.4 (7.5-10.6) months. Benefit with durvalumab-ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab-ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab-ceralasertib is under further investigation in immunotherapy-refractory NSCLC.

There is an association between body composition and lung function, assessed by spirometry, but the effects of body compartments on static lung volumes and its changes during lung growth remain to be explored. We aimed to investigate the association of appendicular lean mass, reflecting skeletal muscle mass, and fat mass on forced and static lung function measures in childhood and adolescence.

This study demonstrates the different effects of muscle and fat mass on forced expiratory and static lung volumes. Achieving and maintaining muscle mass in childhood and adolescence might become an important preventive strategy for lung health in adulthood.

Chronic cough is a common respiratory symptom with an impact on daily activities and quality of life. Global prevalence data are scarce and derive mainly from European and Asian countries and studies with outcomes other than chronic cough. In this study, we aimed to estimate the prevalence of chronic cough across a large number of study sites as well as to identify its main risk factors using a standardised protocol and definition.

The prevalence of chronic cough varied from 3% in India (rural Pune) to 24% in the United States of America (Lexington,KY). Chronic cough was more common among females, both current and passive smokers, those working in a dusty job, those with a history of tuberculosis, those who were obese, those with a low level of education and those with hypertension or airflow limitation. The most influential risk factors were current smoking and working in a dusty job.

Our findings suggested that the prevalence of chronic cough varies widely across sites in different world regions. Cigarette smoking and exposure to dust in the workplace are its major risk factors.

Respiratory resistance (Rrs) and reactance (Xrs) measured by oscillometry and their intra-breath changes have emerged as sensitive parameters for detecting early pathological impairments during tidal breathing.
Abnormal oscillometry parameters are present in 1/5 of this adult population and are significantly associated with respiratory symptoms and disease. Our findings underscore the potential of oscillometry as a tool for detecting and evaluating respiratory impairments, even in individuals with normal spirometry.

The use of maintenance medication in patients with chronic obstructive pulmonary disease (COPD) in real life is known to deviate from recommendations in guidelines, which are largely based on randomized controlled trials and selected populations.
Using data from a large, close to real-life observational cohort, we identified factors linked to the use of various types of respiratory COPD medication. Overall, use was consistent with GOLD recommendations. Beyond this, we identified other correlates of medication use that may help us to understand and improve therapy decisions in clinical practice.

There is a significant heterogeneity in the definitions and nomenclature used for low lung function. The most widely used term, “restrictive spirometry” (RSP), is defined by the presence of a low vital capacity (FVC) with a preserved forced expiratory volume in 1 second (FEV1)/FVC ratio.
The LEAD (Lung, hEart, sociAl, boDy) Study; NCT01727518; http://clinicaltrials.gov) is a
single-centred longitudinal, observational, population-based cohort study. In the first study phase (2012 to 2016) a randomized stratified sample population (stratified by age, sex, and residential area) of 11,423 subjects (females 52.4%), aged 6-82 years, from Vienna and lower Austria has been investigated.

Restrictive lung function (RLF) is characterized by a reduced lung expansion and size. In the absence of lung volume measurements, restriction can be indirectly assessed with restrictive spirometric patterns (RSP) by spirometry.
Pre-bronchodilation lung function data of 8891 subjects (48.0% male, age 6–82 years) have been collected in the LEAD Study, a population-based study from Vienna, Austria. The cohort was categorized in the following groups based on the Global Lung Initiative reference equations: normal subjects, RLF (TLC <lower limit of normal (LLN)), RSP (FEV1/FVC ≥LLN and a FVC <LLN), RSP only (RSP with TLC ≥LLN). Normal subjects were considered those with FEV1, FVC, FEV1/FVC and TLC between LLN and ULN (upper limit of normal).
The prevalence of true restrictive lung function and RSP in the Austrian general population is lower than previously estimated. Our data confirm the need for direct lung volume measurement to diagnose true restrictive lung function.

Dyspnea is a commonly described symptom in various chronic and acute conditions. Despite its frequency, relatively little is known about the prevalence and assessment of dyspnea in general populations. The aims of this review were:

1. to estimate the prevalence of dyspnea in general adult populations;
2. to identify associated factors; and
3. to identify used methods for dyspnea assessment.

Dyspnea is a common symptom in adults in high-income countries. However, the high heterogeneity across studies and the lack of data from low- and middle-income countries limit the generalizability of our findings. Therefore, more research is needed to unveil the prevalence of dyspnea and its main risk factors in general populations around the world.

It is now well established that there are different life-long lung function trajectories in the general population, and that some are associated with better or worse health outcomes. Yet, the prevalence, clinical characteristics and risk factors of individuals with supranormal FEV or FVC values (above the upper-limit of normal [ULN]) in different age-bins through the lifetime in the general population are poorly understood.

To address these questions, we investigated the prevalence of supranormal FEV and FVC values in the LEAD (Lung, hEart, sociAl and boDy) study, a general population cohort in Austria that includes participants from 6 to 82 years of age.

Rationale Structural airway changes related to chroniccough (CC) are described in the literature, but so farreported data are rare and non-conclusive. Furthermore,they derive mainly from cohorts with small sample sizes.Advanced CT imaging not only allows airway abnormalitiesto be quantified, but also to count the number of visibleairways. The current study evaluates these airwayabnormalities in CC and assesses the contribution of CCin addition to CT findings on the progression of airflowlimitation, defined as a decline in forced expiratory volumein 1 s (FEV1) over time.

In the current publication that is part of the LEAD general population cohort, we aimed to examine the prevalence of asthma in the Austrian general population and better understand how differential asthma phenotypes present itself. Our findings reveal that the prevalence of asthma is 4.6%, which fit well with the global prevalence rates. Furthermore, asthma phenotypes were age-dependent: there was a shift from allergic to non-allergic asthma with increasing age, with a non-eosinophilc asthma being more prominent. Lastly, we observed that asthma has major association with body composition.

Restrictive lung function (RLF) is characterized by a reduced lung expansion and size, but in the absence of lung volume measurements, restriction can be indirectly assessed through spirometry with the restrictive spirometric patterns (RSP). In the current publication that is part of the LEAD Study, we evaluated the prevalence of RLF and RSP in the general population and determined factors influencing RLF and RSP. The prevalence of RLF and RSP in the general population are 1.1 and 4.4%, respectively. While RSP has a high negative predictive value, it has a low positive predictive value to define true RLF. In addition, we observed that body composition is an important determining factor of RLF and RSP. Overall, our data indicate the need to combine lung function and body composition trajectories.