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Background: The progressive course of pulmonary fibrosis (PPF) is observed with variable prevalence in different entities of fibrosing interstitial lung disease (fILD). PPF is characterised by worsening respiratory symptoms, declining lung function and increasing extent of fibrosis on high-resolution computer tomography. In Germany, data are limited on the characteristics and management of such patients. Methods/Design: INSIGHTS-ILD is a prospective observational longitudinal registry designed to describe characteristics, management and course of newly diagnosed (incident) and prevalent patients with fILD on the long term. The registry uses a non-probability sampling approach to collect data on characteristics, therapeutic interventions, health-related quality of life and health economic parameters. It is planned to include 900 patients in ambulatory care in about 30 expert sites over three years. The study has been initiated in December 2021, and currently (January 2023) follows 360 patients. Discussion: The registry is expected to provide much-needed data on the characteristics, management, and trajectories of patients fILD in Germany. The start of the study comes at a time when new treatment options are available for PPF. We hypothesize that PPF represents a broad clinical phenotype that is differentially influenced by inflammatory and fibrotic pathomechanisms that need to be treated with anti-inflammatory and/or anti-fibrotic treatment strategies. This registry will allow comparisons with other countries. Gap analyses based on current guidelines for management of these patients will be possible. Trial registration DRKS00027389 (registered on 7.12.2021), BfArM NIS 7562. [ABSTRACT FROM AUTHOR]

Background: The INSIGHTS-IPF registry provides one of the largest data sets of clinical data and self-reported patient related outcomes including health related quality of life (QoL) on patients with idiopathic pulmonary fibrosis (IPF). We aimed to describe associations of various QoL instruments between each other and with patient characteristics at baseline.Methods: Six hundred twenty-three IPF patients with available QoL data (St George's Respiratory Questionnaire SGRQ, UCSD Shortness-of-Breath Questionnaire SoB, EuroQol visual analogue scale and index EQ-5D, Well-being Index WHO-5) were analysed. Mean age was 69.6 ± 8.7 years, 77% were males, mean disease duration 2.0 ± 3.3 years, FVC pred was 67.5 ± 17.8%, DLCO pred 35.6 ± 17%.Results: Mean points were SGRQ total 48.3, UCSD SoB 47.8, EQ-5D VAS 66.8, and WHO-5 13.9. These instruments had a high or very high correlation (exception WHO-5 to EQ-5D VAS with moderate correlation). On bivariate analysis, QoL by SGRQ total was statistically significantly associated with clinical symptoms (NYHA; p < 0.001), number of comorbidities (p < 0.05), hospitalisation rate (p < 0.01) and disease severity (as measured by GAP score, CPI, FVC and 6-min walk test; p < 0.05 each). Multivariate analyses showed a significant association between QoL (by SGRQ total) and IPF duration, FVC, age, NYHA class and indication for long-term oxygen treatment.Conclusions: Overall, IPF patients under real-life conditions have lower QoL compared to those in clinical studies. There is a meaningful relationship between QoL and various patient characteristics.Trial Registration: The INSIGHTS-IPF registry is registered at Clinicaltrials.gov ( NCT01695408 ). [ABSTRACT FROM AUTHOR]

Background: Genome-wide association studies of Single Nucleotide Polymorphisms (SNPs) have identified 55 SNPs associated with lung function. However, little is known about the effect of copy number variants (CNVs) on lung function, although CNVs represent a significant proportion of human genetic polymorphism. To assess the effect of CNVs on lung function quantitative traits, we measured copy number at 2788 previously characterised, common copy number variable regions in 6 independent cohorts (n = 24,237) using intensity data from SNP genotyping experiments. We developed a pipeline for genome-wide association analysis and meta-analysis of CNV genotypes measured across multiple studies using SNP genotype array intensity data from different platform technologies. We then undertook cohort-level genome-wide association studies of CNV with lung function in a subset of 4 cohorts (n < =12,403) with lung function measurements and meta-analysed the results. Follow-up was undertaken for CNVs which were well tagged by SNPs, in up to 146,871 individuals. Results: We generated robust copy number calls for 1962 out of 2788 (70%) known CNV regions genome-wide, with 1103 measured with compatible class frequencies in at least 2 cohorts. We report a novel CNV association (discovery P = 0.0007) with Forced Vital Capacity (FVC) downstream of BANP on chromosome 16 that shows evidence of replication by a tag SNP in two independent studies (replication P = 0.004). In addition, we provide suggestive evidence (discovery P = 0.0002) for a role of complex copy number variation at a previously reported lung function locus, containing the rootletin gene CROCC, that is not tagged by SNPs. Conclusions: We demonstrate how common CNV regions can be reliably and consistently called across cohorts, using an existing calling algorithm and rigorous quality control steps, using SNP genotyping array intensity data. Although many common biallelic CNV regions were well-tagged by common SNPs, we also identified associations with untagged mulitallelic CNV regions thereby illustrating the potential of our approach to identify some of the missing heritability of complex traits. [ABSTRACT FROM AUTHOR]

Background: Health-related quality of life (HRQL) is an important patient-reported outcome measure used to describe the burden of chronic obstructive pulmonary disease (COPD) which is often accompanied by comorbid conditions.Methods: Data from 2275 participants in the COPD cohort COSYCONET and from 4505 lung-healthy control subjects from the population-based KORA and SHIP studies were pooled. Main outcomes were the five dimensions of the generic EQ-5D-3 L questionnaire and two EQ-5D index scores using a tariff based on valuations from the general population and an experience-based tariff. The association of COPD in GOLD grades 1-4 and of several comorbid conditions with the EQ-5D index scores was quantified by multiple linear regression models while adjusting for age, sex, education, body mass index (BMI), and smoking status.Results: For all dimensions of the EQ-5D, the proportion of participants reporting problems was higher in the COPD group than in control subjects. COPD was associated with significant reductions in the EQ-5D index scores (-0.05 points for COPD grades 1/2, -0.09 for COPD grade 3, -0.18 for COPD grade 4 according to the preference-based utility tariff, all p < 0.0001). Adjusted mean index scores were 0.89 in control subjects and 0.85, 0.84, 0.81, and 0.72 in COPD grades 1-4 according to the preference-based utility tariff and 0.76, 0.71, 0.68, 0.64, and 0.58 for control subjects and COPD grades 1-4 for the experience-based tariff respectively. Comorbidities had additive negative effects on the index scores; the effect sizes for comorbidities were comparable to or smaller than the effects of COPD grade 3. No statistically significant interactions between COPD and comorbidities were observed. Score differences between COPD patients and control subjects were most pronounced in younger age groups.Conclusions: Compared with control subjects, the considerable reduction of HRQL in patients with COPD was mainly due to respiratory limitations, but observed comorbidities added linearly to this effect. Younger COPD patients showed a greater loss of HRQL and may therefore be in specific need of comprehensive disease management.Trial Registration: NCT01245933. [ABSTRACT FROM AUTHOR]

Background: Irisin, a recently discovered myokine, is assumed to be secreted by muscle cells in response to exercise and is involved in the regulation of energy metabolism by browning white adipose tissue cells. However, due to the fact that previous studies revealed conflicting results concerning the association between irisin and exercise, the aim of the present study was to investigate the potential relationship between irisin and exercise capacity in a population-based setting. Methods: From the population-based Study of Health in Pomerania (SHIP-TREND) 334 men and 406 women with irisin measurements were selected and a standardised symptom limited cardiopulmonary exercise test was used. Exercise capacity was quantified by oxygen uptake at anaerobic threshold (VO2@AT), peak exercise (peakVO2) and maximum power output at peak exertion. In addition, the oxygen pulse was assessed. ANOVA and multivariable linear regression analyses were performed stratified by sex and adjusted for age, weight, height and smoking. Results: In men, we observed inverse associations between irisin serum concentration and exercise capacity assessed by peakVO2 and maximum power output. In contrast, in women a trend towards a positive relationship between irisin and peakVO2 was detected, whereas none of the other parameters showed significant associations with irisin. Conclusion: Based on a large population sample, our results did not confirm the previous reported positive linkage between exercise and irisin. Thus the relationship needs further investigation in particular with respect to sex differences. [ABSTRACT FROM AUTHOR]

Background: Thyroid dysfunction has been described to be linked to a variety of cardiovascular morbidities. Through this pathway thyroid function might also be associated with cardiorespiratory function and exercise capacity. So far only few patient-studies with small study populations investigated the association between thyroid dysfunction and exercise capacity. Thus, the aim of our study was to investigate the association of serum thyroid-stimulating hormone (TSH) levels with lung function and cardiopulmonary exercise testing (CPET) in the general population. Methods: Data from the two independent cross-sectional population-based studies (Study of Health in Pomerania [SHIP] and SHIP-Trend-0) were pooled. SHIP was conducted between 2002 and 2006 and SHIP-Trend-0 between 2008 and 2012. Participants were randomly selected from population registries. In total, 4206 individuals with complete data were available for the present analysis. Thyroid function was defined based on serum TSH levels. Lung function was evaluated by forced expiratory volume in 1 s and forced vital capacity. CPET was based on symptom limited exercise tests on a bicycle in a sitting position according to a modified Jones protocol. Associations of serum TSH levels with lung function and CPET parameters were analysed by multivariable quantile regression adjusted for age, sex, height, weight, use of beta blockers, smoking status, and physical activity. Results: Serum TSH levels, used as continuously distributed variable and categorized according to the clinical cut-offs 0.3 and 3.0 mIU/L or according to quintiles, were not consistently associated with parameters of lung function or CPET. Conclusions: Our results suggest that thyroid dysfunction is not associated with lung function and cardiopulmonary exercise capacity in the general population. [ABSTRACT FROM AUTHOR]

Aims: To assess the cross-sectional association between exercise capacity, gas exchange efficiency and endothelial function, as measured by flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of the brachial artery, in a large-scale population-based survey. Methods: The study population was comprised of 1416 volunteers 25 to 85 years old. Oxygen uptake at anaerobic threshold (VO2@AT), peak exercise (peakVO2) and ventilatory efficiency (VE vs. VCO2 slope and VE/VCO2@AT) were assessed on a breath-by-breath basis during incremental symptom-limited cardiopulmonary exercise. FMD and NMD measurements at rest were performed using standardised ultrasound techniques. Results: Multivariable logistic regression analyses revealed a significant association between FMD and ventilatory efficiency in current smokers but not in ex-smokers or non-smokers. There was no association between FMD and VO2@AT or peak VO2. In current smokers, for each one millimetre decrement in FMD, VE/VCO2@AT improved by -3.6 (95% CI -6.8, -0.4) in the overall population [VE vs. VCO2 slope -3.9 (-7.1, -0.6)]. These results remained robust after adjusting for all major influencing factors. Neither exercise capacity nor ventilatory efficiency was significantly associated with NMD. Conclusion: In current smokers, FMD is significantly associated with ventilatory efficiency. This result may be interpreted as a potential clinical link between smoking and early pulmonary vasculopathy due to smoking. [ABSTRACT FROM AUTHOR]

Background: Little is known about the influencing potential of specific characteristics on lung function in different populations. The aim of this analysis was to determine whether lung function determinants differ between subpopulations within Germany and whether prediction equations developed for one subpopulation are also adequate for another subpopulation. Methods: Within three studies (KORA C, SHIP-I, ECRHS-I) in different areas of Germany 4059 adults performed lung function tests. The available data consisted of forced expiratory volume in one second, forced vital capacity and peak expiratory flow rate. For each study multivariate regression models were developed to predict lung function and Bland- Altman plots were established to evaluate the agreement between predicted and measured values. Results: The final regression equations for FEV1 and FVC showed adjusted r-square values between 0.65 and 0.75, and for PEF they were between 0.46 and 0.61. In all studies gender, age, height and pack-years were significant determinants, each with a similar effect size. Regarding other predictors there were some, although not statistically significant, differences between the studies. Bland-Altman plots indicated that the regression models for each individual study adequately predict medium (i.e. normal) but not extremely high or low lung function values in the whole study population. Conclusions: Simple models with gender, age and height explain a substantial part of lung function variance whereas further determinants add less than 5% to the total explained r-squared, at least for FEV1 and FVC. Thus, for different adult subpopulations of Germany one simple model for each lung function measures is still sufficient. [ABSTRACT FROM AUTHOR]

Background: Cardiopulmonary exercise testing (CPET) has become increasingly important as a routine procedure in daily clinical work. So far, it is generally accepted that an individualized exercise protocol with exercise duration of 6 to 12 minutes is preferable to assess maximal exercise performance. The aim of this study was to compare an individualized NYHA adapted exercise protocol with a fixed standard protocol in patients with severe pulmonary arterial hypertension. Methods: Twenty-two patients (17 female, 5 male; mean age 49 ± 14 yrs) underwent symptom limited CPET on a bicycle. On two consecutive days each subject performed a stepwise CPET according to a modified Jones protocol (16 Watt per minute stages) as well as an individualized NYHA adapted protocol with 5 or 10 Watt/min stages in a randomized order. Oxygen uptake at peak exercise (peakVO2) and anaerobic threshold (VO2AT), maximal ventilation (VE), breathing reserve (VE/MVV), ventilatory efficiency (VE vs. VCO2 slope), exercise time, maximal power and work rate were assessed and compared between both protocols. Results: Comparing both, adapted NYHA protocol and standardized Jones protocol, we found significant differences in maximal power (56.7 ± 19 W vs. 74 ± 18 W; p < 0.001) and exercise time (332 ± 107 sec. vs. 248 ± 72 sec.; p < 0.001). In contrast, no significant differences were obvious comparing both protocols concerning work rate, VE, VE/MVV, peakVO2, VO2AT and VE vs. VCO2 slope. Conclusion: Variations of incremental step size during CPET significantly affect exercise time and maximal power, whereas relevant parameters for clinical judgement and prognosis such as oxygen uptake, ventilation and ventilatory efficiency remain unchanged. These findings have practical implications for the exercise evaluation of patients with pulmonary hypertension. To reach maximal results for ventilation, oxygen uptake and gas exchange an individualization of incremental step size appears not to be mandatory. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) is a severe rheumatic disease of the interstitial tissue, in which heart and lung involvement can lead to disease-specific mortality. Our study tests the hypothesis that in addition to established prognostic factors, cardiopulmonary exercise testing (CPET) parameters, particularly peak oxygen uptake (peakVO2) and ventilation/carbon dioxide (VE/VCO2)-slope, can predict survival in patients with SSc.Subjects and Methods: We retrospectively assessed 210 patients (80.9% female) in 6 centres over 10 years with pulmonary testing and CPET. Survival was analysed with Cox regression analysis (adjusted for age and gender) by age, comorbidity (Charlson-Index), body weight, body-mass index, extensive interstitial lung disease, pulmonary artery pressure (measured by echocardiography and invasively), and haemodynamic, pulmonary and CPET parameters.Results: Five- and ten-year survival of SSc patients was 93.8 and 86.9%, respectively. There was no difference in survival between patients with diffuse (dcSSc) and limited cutaneous manifestation (lcSSc; p = 0.3). Pulmonary and CPET parameters were significantly impaired. Prognosis was worst for patients with pulmonary hypertension (p = 0.007), 6-min walking distance < 413 m (p = 0.003), peakVO2 < 15.6 mL∙kg- 1∙min- 1, and VE/VCO2-slope > 35. Age (hazard ratio HR = 1.23; 95% confidence interval CI: 1.14;1.41), VE/VCO2-slope (HR = 0.9; CI 0.82;0.98), diffusion capacity (Krogh factor, HR = 0.92; CI 0.86;0.98), forced vital capacity (FVC, HR = 0.91; CI 0.86;0.96), and peakVO2 (HR = 0.87; CI 0.81;0.94) were significantly linked to survival in multivariate analyses (Harrell's C = 0.95). This is the first large study with SSc patients that demonstrates the prognostic value of peakVO2 < 15.6 mL∙kg- 1∙min- 1 (< 64.5% of predicted peakVO2) and VE/VCO2-slope > 35. [ABSTRACT FROM AUTHOR]

Background: Several studies showed that blood pressure and lung function are associated. Additionally, a potential effect of antihypertensive medication, especially beta-blockers, on lung function has been discussed. However, side effects of beta-blockers have been investigated mainly in patients with already reduced lung function. Thus, aim of this analysis is to determine whether hypertension and antihypertensive medication have an adverse effect on lung function in a general adult population.Methods: Within the population-based KORA F4 study 1319 adults aged 40-65 years performed lung function tests and blood pressure measurements. Additionally, information on anthropometric measurements, medical history and use of antihypertensive medication was available. Multivariable regression models were applied to study the association between blood pressure, antihypertensive medication and lung function.Results: High blood pressure as well as antihypertensive medication were associated with lower forced expiratory volume in one second (p=0.02 respectively p=0.05; R2: 0.65) and forced vital capacity values (p=0.01 respectively p=0.05, R2: 0.73). Furthermore, a detailed analysis of antihypertensive medication pointed out that only the use of beta-blockers was associated with reduced lung function, whereas other antihypertensive medication had no effect on lung function. The adverse effect of beta-blockers was significant for forced vital capacity (p=0.04; R2: 0.65), while the association with forced expiratory volume in one second showed a trend toward significance (p=0.07; R2: 0.73). In the same model high blood pressure was associated with reduced forced vital capacity (p=0.01) and forced expiratory volume in one second (p=0.03) values, too.Conclusion: Our analysis indicates that both high blood pressure and the use of beta-blockers, but not the use of other antihypertensive medication, are associated with reduced lung function in a general adult population. [ABSTRACT FROM AUTHOR]