TY  - JOUR
AB  - BACKGROUND: Muscle dysfunction in chronic obstructive pulmonary disease (COPD) represents a significant extrapulmonary manifestation. Yet, the role of muscle fat infiltration (myosteatosis) in paraspinal muscles remains incompletely characterized. This study investigated whether paraspinal myosteatosis and its distribution patterns are associated with COPD and pulmonary function. METHODS: Within the population-based KORA cohort, 214 participants underwent whole-body magnetic resonance imaging and pulmonary function testing. Paraspinal myosteatosis was quantified by chemical shift-encoded MRI at lumbar vertebra 3 (L3), from which proton density fat fraction (PDFF, in %) maps were derived. Intramyocellular (IMCL) and extramyocellular lipids (EMCL) were determined through voxel-based analysis using validated PDFF thresholds. COPD was defined spirometrically as FEV1/FVC below the lower limit of normal. Associations were examined using multivariable regression models adjusted for age, sex, smoking status, physical activity, and body mass index. RESULTS: Among participants (mean age 58.5 ± 5.8 years, 56.1% male), 24 (11.2%) had spirometrically defined COPD. Participants with COPD showed higher paraspinal PDFF (19.9 ± 7.0% vs. 18.3 ± 7.6%) and lower IMCL/EMCL ratios (1.0 ± 0.4 vs. 1.2 ± 0.6) compared to those without COPD. After adjustment, higher PDFF was independently associated with increased odds of COPD (OR 1.69, 95% CI: 1.01-2.84, p = 0.046), while a higher IMCL to EMCL ratio showed protective associations (OR 0.49, 95% CI: 0.24-1.00, p = 0.050). Both total paraspinal PDFF and EMCL were negatively associated with pulmonary gas exchange capacity (TLCO/VA: β=-0.19, 95% CI: -0.35-0.04, p = 0.016 and β=-0.18, 95% CI: -0.33-0.03, p = 0.022, respectively). Conversely, higher IMCL/EMCL ratios were associated with better gas exchange (TLCO/VA: β = 0.15, 95% CI: 0.01-0.29, p = 0.031). CONCLUSIONS: This population-based study demonstrates that while increased total paraspinal muscle fat content is associated with higher COPD risk, its compartmental distribution reveals distinct patterns: A higher proportion of IMCL relative to EMCL shows protective associations, potentially reflecting preserved type I oxidative muscle fiber characteristics. These findings suggest that muscle fat distribution patterns may serve as imaging markers of metabolic adaptation in COPD, offering new perspectives for disease monitoring and therapeutic approaches.
AU  - Diallo, T.D.*
AU  - Karrasch, S.
AU  - Jung, M.*
AU  - Peters, A.
AU  - Lorbeer, R.*
AU  - Schlett, C.L.*
AU  - von Krüchten, R.*
AU  - Bamberg, F.*
AU  - Rospleszcz, S.
AU  - Kiefer, L.S.*
C1  - 74931
C2  - 57761
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Paraspinal myosteatosis is associated with COPD: A cross-sectional MRI analysis from the population-based KORA cohort.
JO  - Respir. Res.
VL  - 26
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Human precision-cut lung slices (hPCLS) are a unique platform for functional, mechanistic, and drug discovery studies in the field of respiratory research. However, tissue availability, generation, and cultivation time represent important challenges for their usage. Therefore, the present study evaluated the efficacy of a specifically designed tissue preservation solution, TiProtec, complete or in absence (-) of iron chelators, for long-term cold storage of hPCLS. METHODS: hPCLS were generated from peritumor control tissues and stored in DMEM/F-12, TiProtec, or TiProtec (-) for up to 28 days. Viability, metabolic activity, and tissue structure were determined. Moreover, bulk-RNA sequencing was used to study transcriptional changes, regulated signaling pathways, and cellular composition after cold storage. Induction of cold storage-associated senescence was determined by transcriptomics and immunofluorescence (IF). Finally, cold-stored hPCLS were exposed to a fibrotic cocktail and early fibrotic changes were assessed by RT-qPCR and IF. RESULTS: Here, we found that TiProtec preserves the viability, metabolic activity, transcriptional profile, as well as cellular composition of hPCLS for up to 14 days. Cold storage did not significantly induce cellular senescence in hPCLS. Moreover, TiProtec downregulated pathways associated with cell death, inflammation, and hypoxia while activating pathways protective against oxidative stress. Cold-stored hPCLS remained responsive to fibrotic stimuli and upregulated extracellular matrix-related genes such as fibronectin and collagen 1 as well as alpha-smooth muscle actin, a marker for myofibroblasts. CONCLUSIONS: Optimized long-term cold storage of hPCLS preserves their viability, metabolic activity, transcriptional profile, and cellular composition for up to 14 days, specifically in TiProtec. Finally, our study demonstrated that cold-stored hPCLS can be used for on-demand mechanistic studies relevant for respiratory research.
AU  - Melo-Narváez, C.
AU  - Gölitz, F.*
AU  - Jain, E.
AU  - Gote-Schniering, J.*
AU  - Stoleriu, M.-G.
AU  - Bertrams, W.*
AU  - Schmeck, B.*
AU  - Yildirim, A.Ö.
AU  - Rauen, U.*
AU  - Wille, T.*
AU  - Lehmann, M.
C1  - 73404
C2  - 57049
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Cold storage of human precision-cut lung slices in TiProtec preserves cellular composition and transcriptional responses and enables on-demand mechanistic studies.
JO  - Respir. Res.
VL  - 26
IS  - 1
PB  - Bmc
PY  - 2025
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection. RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005). CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.
AU  - Buschulte, K.*
AU  - Kabitz, H.J.*
AU  - Hagmeyer, L.*
AU  - Hammerl, P.*
AU  - Esselmann, A.*
AU  - Wiederhold, C.*
AU  - Skowasch, D.*
AU  - Stolpe, C.*
AU  - Joest, M.*
AU  - Veitshans, S.*
AU  - Höffgen, M.*
AU  - Maqhuzu, P.N.
AU  - Schwarzkopf, L.
AU  - Hellmann, A.*
AU  - Pfeifer, M.*
AU  - Behr, J.*
AU  - Karpavicius, R.*
AU  - Günther, A.*
AU  - Polke, M.*
AU  - Höger, P.*
AU  - Somogyi, V.*
AU  - Lederer, C.W.*
AU  - Markart, P.*
AU  - Kreuter, M.*
C1  - 68996
C2  - 55177
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Hospitalisation patterns in interstitial lung diseases: Data from the EXCITING-ILD registry.
JO  - Respir. Res.
VL  - 25
IS  - 1
PB  - Bmc
PY  - 2024
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality. METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression. RESULTS: Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001). CONCLUSION: Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.
AU  - Buschulte, K.*
AU  - Kabitz, H.J.*
AU  - Hagmeyer, L.*
AU  - Hammerl, P.*
AU  - Esselmann, A.*
AU  - Wiederhold, C.*
AU  - Skowasch, D.*
AU  - Stolpe, C.*
AU  - Joest, M.*
AU  - Veitshans, S.*
AU  - Höffgen, M.*
AU  - Maqhuzu, P.N.
AU  - Schwarzkopf, L.
AU  - Hellmann, A.*
AU  - Pfeifer, M.*
AU  - Behr, J.*
AU  - Karpavicius, R.*
AU  - Günther, A.*
AU  - Polke, M.*
AU  - Höger, P.*
AU  - Somogyi, V.*
AU  - Lederer, C.W.*
AU  - Markart, P.*
AU  - Kreuter, M.*
C1  - 70177
C2  - 55455
TI  - Disease trajectories in interstitial lung diseases - data from the EXCITING-ILD registry.
JO  - Respir. Res.
VL  - 25
IS  - 1
PY  - 2024
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has the highest increased risk due to household air pollution arising from biomass fuel burning. However, knowledge on COPD patho-mechanisms is mainly limited to tobacco smoke exposure. In this study, a repeated direct wood smoke (WS) exposure was performed using normal- (bro-ALI) and chronic bronchitis-like bronchial (bro-ALI-CB), and alveolar (alv-ALI) lung mucosa models at air-liquid interface (ALI) to assess broad toxicological end points. METHODS: The bro-ALI and bro-ALI-CB models were developed using human primary bronchial epithelial cells and the alv-ALI model was developed using a representative type-II pneumocyte cell line. The lung models were exposed to WS (10 min/exposure; 5-exposures over 3-days; n = 6-7 independent experiments). Sham exposed samples served as control. WS composition was analyzed following passive sampling. Cytotoxicity, total cellular reactive oxygen species (ROS) and stress responsive NFkB were assessed by flow cytometry. WS exposure induced changes in gene expression were evaluated by RNA-seq (p ≤ 0.01) followed by pathway enrichment analysis. Secreted levels of proinflammatory cytokines were assessed in the basal media. Non-parametric statistical analysis was performed. RESULTS: 147 unique compounds were annotated in WS of which 42 compounds have inhalation toxicity (9 very high). WS exposure resulted in significantly increased ROS in bro-ALI (11.2%) and bro-ALI-CB (25.7%) along with correspondingly increased NFkB levels (bro-ALI: 35.6%; bro-ALI-CB: 18.1%). A total of 1262 (817-up and 445-down), 329 (141-up and 188-down), and 102 (33-up and 69-down) genes were differentially regulated in the WS-exposed bro-ALI, bro-ALI-CB, and alv-ALI models respectively. The enriched pathways included the terms acute phase response, mitochondrial dysfunction, inflammation, oxidative stress, NFkB, ROS, xenobiotic metabolism of AHR, and chronic respiratory disorder. The enrichment of the 'cilium' related genes was predominant in the WS-exposed bro-ALI (180-up and 7-down). The pathways primary ciliary dyskinesia, ciliopathy, and ciliary movement were enriched in both WS-exposed bro-ALI and bro-ALI-CB. Interleukin-6 and tumor necrosis factor-α were reduced (p < 0.05) in WS-exposed bro-ALI and bro-ALI-CB. CONCLUSION: Findings of this study indicate differential response to WS-exposure in different lung regions and in chronic bronchitis, a condition commonly associated with COPD. Further, the data suggests ciliopathy as a candidate pathway in relation to WS-exposure.
AU  - Upadhyay, S.*
AU  - Rahman, M.*
AU  - Rinaldi, S.*
AU  - Koelmel, J.P.*
AU  - Lin, E.Z.*
AU  - Mahesh, P.A.*
AU  - Beckers, J.
AU  - Johanson, G.*
AU  - Pollitt, K.J.G.*
AU  - Palmberg, L.*
AU  - Irmler, M.
AU  - Ganguly, K.*
C1  - 69816
C2  - 55263
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Assessment of wood smoke induced pulmonary toxicity in normal- and chronic bronchitis-like bronchial and alveolar lung mucosa models at air-liquid interface.
JO  - Respir. Res.
VL  - 25
IS  - 1
PB  - Bmc
PY  - 2024
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - After more than two years the COVID-19 pandemic, that is caused by infection with the respiratory SARS-CoV-2 virus, is still ongoing. The risk to develop severe COVID-19 upon SARS-CoV-2 infection is increased in individuals with a high age, high body mass index, and who are smoking. The SARS-CoV-2 virus infects cells of the upper respiratory tract by entering these cells upon binding to the Angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is expressed in various cell types in the lung but the expression is especially high in goblet and ciliated cells. Recently, it was shown that next to its full-length isoform, ACE2 also has a short isoform. The short isoform is unable to bind SARS-CoV-2 and does not facilitate viral entry. In the current study we investigated whether active cigarette smoking increases the expression of the long or the short ACE2 isoform. We showed that in active smokers the expression of the long, active isoform, but not the short isoform of ACE2 is higher compared to never smokers. Additionally, it was shown that the expression of especially the long, active isoform of ACE2 was associated with secretory, club and goblet epithelial cells. This study increases our understanding of why current smokers are more susceptible to SARS-CoV-2 infection, in addition to the already established increased risk to develop severe COVID-19.
AU  - Pouwels, S.D.*
AU  - van den Berge, M.*
AU  - Vasse, G.F.*
AU  - Timens, W.*
AU  - Brandsma, C.A.*
AU  - Aliee, H.
AU  - Hiemstra, P.S.*
AU  - Guryev, V.*
AU  - Faiz, A.*
C1  - 67810
C2  - 54288
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Smoking increases expression of the SARS-CoV-2 spike protein-binding long ACE2 isoform in bronchial epithelium.
JO  - Respir. Res.
VL  - 24
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Microbiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial disease with pre- and postnatal origins including intra-amniotic infection as main risk factor. Recently, postnatal pathologic lung microbiota colonization was associated with BPD. The objectives of this prospective observational cohort study were to describe differences in bacterial signatures in the amniotic fluid (AF) of intact pregnancies without clinical signs or risk of preterm delivery and AF samples obtained during preterm deliveries and their variations between different BPD disease severity stages. METHODS: AF samples were collected under sterile conditions during fetal intervention from intact pregnancies (n = 17) or immediately before preterm delivery < 32 weeks (n = 126). Metabarcoding based approaches were used for the molecular assessment of bacterial 16S rRNA genes to describe bacterial community structure. RESULTS: The absolute amount of 16S rRNA genes was significantly increased in AF of preterm deliveries and detailed profiling revealed a reduced alpha diversity and a significant change in beta diversity with a reduced relative abundance of 16S rRNA genes indicative for Lactobacillus and Acetobacter while Fusobacterium, Pseudomonas, Ureaplasma and Staphylococcus 16S rRNA gene prevailed. Although classification of BPD by disease severity revealed equivalent absolute 16S rRNA gene abundance and alpha and beta diversity in no, mild and moderate/severe BPD groups, for some 16S rRNA genes differences were observed in AF samples. Bacterial signatures of infants with moderate/severe BPD showed predominance of 16S rRNA genes belonging to the Escherichia-Shigella cluster while Ureaplasma and Enterococcus species were enriched in AF samples of infants with mild BPD. CONCLUSIONS: Our study identified distinct and diverse intrauterine 16S rRNA gene patterns in preterm infants immediately before birth, differing from the 16S rRNA gene signature of intact pregnancies. The distinct 16S rRNA gene signatures at birth derive from bacteria with varying pathogenicity to the immature lung and are suited to identify preterm infants at risk. Our results emphasize the prenatal impact to the origins of BPD.
AU  - Staude, B.*
AU  - Gschwendtner, S.
AU  - Frodermann, T.*
AU  - Oehmke, F.*
AU  - Kohl, T.*
AU  - Kublik, S.
AU  - Schloter, M.
AU  - Ehrhardt, H.*
C1  - 68646
C2  - 54849
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Microbial signatures in amniotic fluid at preterm birth and association with bronchopulmonary dysplasia.
JO  - Respir. Res.
VL  - 24
IS  - 1
PB  - Bmc
PY  - 2023
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive form of fibrosing interstitial pneumonia with poor survival. This study provides insight into the epidemiology, cost, and disease course of IPF in Germany. METHODS: A cohort of incident patients with IPF (n = 1737) was identified from German claims data (2014-2019). Incidence and prevalence rates were calculated and adjusted for age differences compared with the overall German population. All-cause and IPF-related healthcare resource utilization as well as associated costs were evaluated per observed person-year (PY) following the initial IPF diagnosis. Finally, Kaplan-Meier analyses were performed to assess time from initial diagnosis to disease deterioration (using three proxy measures: non-elective hospitalization, IPF-related hospitalization, long-term oxygen therapy [LTOT]); antifibrotic therapy initiation; and all-cause death. RESULTS: The cumulative incidence of IPF was estimated at 10.7 per 100,000 individuals in 2016, 10.9 in 2017, 10.5 in 2018, and 9.6 in 2019. The point prevalence rates per 100,000 individuals for the respective years were 21.7, 23.5, 24.1, and 24.1. On average, ≥ 14 physician visits and nearly two hospitalizations per PY were observed after the initial IPF diagnosis. Of total all-cause direct costs (€15,721/PY), 55.7% (€8754/PY) were due to hospitalizations and 29.1% (€4572/PY) were due to medication. Medication accounted for 49.4% (€1470/PY) and hospitalizations for 34.8% (€1034/PY) of total IPF-related direct costs (€2973/PY). Within 2 years of the initial IPF diagnosis (23.6 months), 25% of patients died. Within 5 years of diagnosis, 53.1% of patients had initiated LTOT; only 11.6% were treated with antifibrotic agents. The median time from the initial diagnosis to the first non-elective hospitalization was 5.5 months. CONCLUSION: The incidence and prevalence of IPF in Germany are at the higher end of the range reported in the literature. The main driver for all-cause cost was hospitalization. IPF-related costs were mainly driven by medication, with antifibrotic agents accounting for around one-third of the total medication costs even if not frequently prescribed. Most patients with IPF do not receive pharmacological treatment, highlighting the existing unmet medical need for effective and well-tolerated therapies.
AU  - Kreuter, M.*
AU  - Picker, N.*
AU  - Schwarzkopf, L.
AU  - Baumann, S.*
AU  - Cerani, A.*
AU  - Postema, R.*
AU  - Maywald, U.*
AU  - Dittmar, A.*
AU  - Langley, J.*
AU  - Patel, H.R.*
C1  - 64627
C2  - 52354
TI  - Epidemiology, healthcare utilization, and related costs among patients with IPF: Results from a German claims database analysis.
JO  - Respir. Res.
VL  - 23
IS  - 1
PY  - 2022
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Early appropriate diagnosis and treatment of interstitial lung diseases (ILD) is crucial to slow disease progression and improve survival. Yet it is unknown whether initial management in an expert centre is associated with improved outcomes. Therefore, we assessed mortality, hospitalisations and health care costs of ILD patients initially diagnosed and managed in specialised ILD centres versus non-specialised centres and explored differences in pharmaceutical treatment patterns. METHODS: An epidemiological claims data analysis was performed, including patients with different ILD subtypes in Germany between 2013 and 2018. Classification of specialised centres was based on the number of ILD patients managed and procedures performed, as defined by the European Network on Rare Lung Diseases. Inverse probability of treatment weighting was used to adjust for covariates. Mortality and hospitalisations were examined via weighted Cox models, cost differences by weighted gamma regression models and differences in treatment patterns with weighted logistic regressions. RESULTS: We compared 2022 patients managed in seven specialised ILD centres with 28,771 patients managed in 1156 non-specialised centres. Specialised ILD centre management was associated with lower mortality (HR: 0.87, 95% CI 0.78; 0.96), lower all-cause hospitalisation (HR: 0.93, 95% CI 0.87; 0.98) and higher respiratory-related costs (€669, 95% CI €219; €1156). Although risk of respiratory-related hospitalisations (HR: 1.00, 95% CI 0.92; 1.10) and overall costs (€- 872, 95% CI €- 75; €1817) did not differ significantly, differences in treatment patterns were observed. CONCLUSION: Initial management in specialised ILD centres is associated with improved mortality and lower all-cause hospitalisations, potentially due to more differentiated diagnostic approaches linked with more appropriate ILD subtype-adjusted therapy.
AU  - Marijic, P.
AU  - Schwarzkopf, L.
AU  - Maier, W.
AU  - Trudzinski, F.*
AU  - Kreuter, M.*
AU  - Schwettmann, L.
C1  - 65967
C2  - 53007
TI  - Comparing outcomes of ILD patients managed in specialised versus non-specialised centres.
JO  - Respir. Res.
VL  - 23
IS  - 1
PY  - 2022
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - The original version of the article [1] unfortunately contained a mistake in Fig. 7. In this a western blot image (p38a/b, panel E in Fig. 7) from the 24 h PDE6D siRNA transfected group has been mistakenly duplicated from the 12 h PDE6D siRNA transfected group shown in Fig. 7D. We are deeply sorry for this mistake and would like to replace it with a blot from 24 h PDE6D siRNA transfected group. This change will not affect the results, discussion, and the general message of the manuscript. It has been corrected in this correction. The correct version of Fig. 7 is in this erratum.
AU  - Nikolova, S.*
AU  - Guenther, A.*
AU  - Savai, R.*
AU  - Weissmann, N.*
AU  - Ghofrani, H.A.*
AU  - Königshoff, M.
AU  - Eickelberg, O.
AU  - Klepetko, W.*
AU  - Voswinckel, R.*
AU  - Seeger, W.*
AU  - Grimminger, F.*
AU  - Schermuly, R.T.*
AU  - Pullamsetti, S.S.*
C1  - 64006
C2  - 52042
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Correction to: Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis.
JO  - Respir. Res.
VL  - 23
IS  - 1
PB  - Bmc
PY  - 2022
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Despite the well-known detrimental effects of cigarette smoke (CS), little is known about the complex gene expression dynamics in the early stages after exposure. This study aims to investigate early transcriptomic responses following CS exposure of airway epithelial cells in culture and compare these to those found in human CS exposure studies. METHODS: Primary bronchial epithelial cells (PBEC) were differentiated at the air-liquid interface (ALI) and exposed to whole CS. Bulk RNA-sequencing was performed at 1 h, 4 h, and 24 h hereafter, followed by differential gene expression analysis. Results were additionally compared to data retrieved from human CS studies. RESULTS: ALI-PBEC gene expression in response to CS was most significantly changed at 4 h after exposure. Early transcriptomic changes (1 h, 4 h post CS exposure) were related to oxidative stress, xenobiotic metabolism, higher expression of immediate early genes and pro-inflammatory pathways (i.e., Nrf2, AP-1, AhR). At 24 h, ferroptosis-associated genes were significantly increased, whereas PRKN, involved in removing dysfunctional mitochondria, was downregulated. Importantly, the transcriptome dynamics of the current study mirrored in-vivo human studies of acute CS exposure, chronic smokers, and inversely mirrored smoking cessation. CONCLUSION: These findings show that early after CS exposure xenobiotic metabolism and pro-inflammatory pathways were activated, followed by activation of the ferroptosis-related cell death pathway. Moreover, significant overlap between these transcriptomic responses in the in-vitro model and human in-vivo studies was found, with an early response of ciliated cells. These results provide validation for the use of ALI-PBEC cultures to study the human lung epithelial response to inhaled toxicants.
AU  - van der Does, A.M.*
AU  - Mahbub, R.M.*
AU  - Ninaber, D.K.*
AU  - Rathnayake, S.N.H.*
AU  - Timens, W.*
AU  - van den Berge, M.*
AU  - Aliee, H.
AU  - Theis, F.J.
AU  - Nawijn, M.C.*
AU  - Hiemstra, P.S.*
AU  - Faiz, A.*
C1  - 66087
C2  - 52644
TI  - Early transcriptional responses of bronchial epithelial cells to whole cigarette smoke mirror those of in-vivo exposed human bronchial mucosa.
JO  - Respir. Res.
VL  - 23
IS  - 1
PY  - 2022
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Little is known about how long-term weight gain affects the health perception of COPD patients. Objectives: The aim is to evaluate the long-term association of BMI change and health-related quality of life (HRQoL) in obese COPD patients. Methods: Claims and survey data from a COPD disease management program were used to match two groups of COPD patients with BMI ≥ 30 who have differing weight trajectories over a 5-year timespan via propensity score and genetic matching. EQ-5D-5L, including visual analog scale (VAS) and COPD Assessment Test (CAT), were used as outcomes of interest. Sociodemographic and disease-based variables were matched. Results: Out of 1202 obese COPD patients, 126 with a weight increase of four or more BMI points were matched separately with 252 (propensity score matching) and 197 (genetic matching) control subjects who had relatively stable BMI. For the EQ-5D-5L, patients with BMI increase reported significantly worse health perception for VAS and all descriptive dimensions except pain/discomfort. For the CAT, especially the perception of ability to complete daily activities and overall energy results were significantly worse. VAS differences reach the range of minimal important differences. Stopping smoking and already being in obesity class II were the most influential risk factors for BMI increase. Conclusion: Obese COPD patients who gain four or more BMI points over 5 years report significantly lower results in different dimensions of generic and disease-specific HRQoL than their peers with stable BMI. To improve real-world outcomes, tracking and preventing specific BMI trajectories could constitute a clinically relevant aspect of managing COPD patients.
AU  - Huber, M.B.
AU  - Schneider, N.
AU  - Kirsch, F.
AU  - Schwarzkopf, L.
AU  - Schramm, A.*
AU  - Leidl, R.
C1  - 62810
C2  - 51079
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Long-term weight gain in obese COPD patients participating in a disease management program: A risk factor for reduced health-related quality of life.
JO  - Respir. Res.
VL  - 22
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. Methods: We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. Results: When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. Conclusions: Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933.
AU  - Kellerer, C.*
AU  - Jörres, R.A.*
AU  - Schneider, A.*
AU  - Alter, P.*
AU  - Kauczor, H.U.*
AU  - Jobst, B.*
AU  - Biederer, J.*
AU  - Bals, R.*
AU  - Watz, H.*
AU  - Behr, J.*
AU  - Kauffmann-Guerrero, D.*
AU  - Lutter, J.
AU  - Hapfelmeier, A.*
AU  - Magnussen, H.*
AU  - Trudzinski, F.C.*
AU  - Welte, T.*
AU  - Vogelmeier, C.F.*
AU  - Kahnert, K.*
C1  - 62990
C2  - 51187
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Prediction of lung emphysema in COPD by spirometry and clinical symptoms: Results from COSYCONET.
JO  - Respir. Res.
VL  - 22
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - INTRODUCTION: Treatments of interstitial lung diseases (ILDs) mainly focus on disease stabilization and relief of symptoms by managing inflammation or suppressing fibrosis by (in part costly) drugs. To highlight economic burden of drug treatment in different ILD-subtypes we assessed cost trends and therewith-associated drivers. METHODS: Using data from the German, observational HILDA study we estimated adjusted mean medication costs over 36-month intervals using one- and two-part Generalized Estimating Equation (GEE) regression models with a gamma distribution and log link. Next, we determined factors associated with costs. RESULTS: In Idiopathic pulmonary fibrosis (IPF) mean per capita medication costs increased from €1442 before to €11,000€ at the end of study. In non-IPF subtypes, the increase took place at much lower level. Mean per capita ILD-specific medication costs at the end of the study ranged between €487 (other ILD) and €9142 (IPF). At baseline, higher FVC %predicted values were associated with lower medication costs in IPF (-9%) and sarcoidosis (-1%). During follow up higher comorbidity burden escalated costs in progressive fibrosing ILD (PF-ILD) (+52%), sarcoidosis (+60%) and other ILDs (+24%). The effect of disease duration was not uniform, with cost savings in PF-ILD (-8%) and sarcoidosis (-6%), but increased spending in IPF (+11%). CONCLUSION: Pharmacological management of ILD, in particular of IPF imposes a substantial economic burden on the healthcare system. Strategies to reduce comorbidity burden and early treatment may reduce the impact of ILDs on the healthcare system.
AU  - Maqhuzu, P.N.
AU  - Kreuter, M.*
AU  - Bahmer, T.*
AU  - Kahn, N.*
AU  - Claussen, M.*
AU  - Holle, R.
AU  - Schwarzkopf, L.
C1  - 62763
C2  - 51051
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Cost drivers in the pharmacological treatment of interstitial lung disease.
JO  - Respir. Res.
VL  - 22
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Two antifibrotic drugs, pirfenidone and nintedanib, are licensed for the treatment of patients with idiopathic pulmonary fibrosis (IPF). However, there is neither evidence from prospective data nor a guideline recommendation, which drug should be preferred over the other. This study aimed to compare pirfenidone and nintedanib-treated patients regarding all-cause mortality, all-cause and respiratory-related hospitalizations, and overall as well as respiratory-related health care costs borne by the Statutory Health Insurance (SHI). Methods: A retrospective cohort study with SHI data was performed, including IPF patients treated either with pirfenidone or nintedanib. Stabilized inverse probability of treatment weighting (IPTW) based on propensity scores was applied to adjust for observed covariates. Weighted Cox models were estimated to analyze mortality and hospitalization. Weighted cost differences with bootstrapped 95% confidence intervals (CI) were applied for cost analysis. Results: We compared 840 patients treated with pirfenidone and 713 patients treated with nintedanib. Both groups were similar regarding two-year all-cause mortality (HR: 0.90 95% CI: 0.76; 1.07), one-year all cause (HR: 1.09, 95% CI: 0.95; 1.25) and respiratory-related hospitalization (HR: 0.89, 95% CI: 0.72; 1.08). No significant differences were observed regarding total (€− 807, 95% CI: €− 2977; €1220) and respiratory-related (€− 1282, 95% CI: €− 3423; €534) costs. Conclusion: Our analyses suggest that the patient-related outcomes mortality, hospitalization, and costs do not differ between the two currently available antifibrotic drugs pirfenidone and nintedanib. Hence, the decision on treatment with pirfenidone versus treatment with nintedanib ought to be made case-by-case taking clinical characteristics, comorbidities, comedications, individual risk of side effects, and patients’ preferences into account.
AU  - Marijic, P.
AU  - Schwarzkopf, L.
AU  - Schwettmann, L.
AU  - Ruhnke, T.*
AU  - Trudzinski, F.*
AU  - Kreuter, M.*
C1  - 63356
C2  - 51487
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Pirfenidone vs. nintedanib in patients with idiopathic pulmonary fibrosis: A retrospective cohort study.
JO  - Respir. Res.
VL  - 22
IS  - 1
PB  - Bmc
PY  - 2021
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background Body mass index (BMI) is an important parameter associated with mortality and health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD). However, informed guidance on stratified weight recommendations for COPD is still lacking. This study aims to determine the association between BMI and HRQoL across different severity grades of COPD to support patient management. Methods We use conjunct analysis of claims and survey data based on a German COPD disease management program from 2016 to 2017. The EQ-5D-5L visual analog scale (VAS) and COPD Assessment Test (CAT) are used to measure generic and disease-specific HRQoL. Generalized additive models with smooth functions are implemented to evaluate the relationship between BMI and HRQoL, stratified by COPD severity. Results 11,577 patients were included in this study. Mean age was 69.4 years and 59% of patients were male. In GOLD grades 1-3, patients with BMI of around 25 had the best generic and disease-specific HRQoL, whereas in GOLD grade 4, obese patients had the best HRQoL using both instruments when controlled for several variables including smoking status, income, COPD severity, comorbidities, emphysema, corticosteroid use, and days spent in hospital. Conclusion This real-world analysis shows the non-linear relationship between BMI and HRQoL in COPD. HRQoL of obese patients with mild to severe COPD might improve following weight reduction. For very severe COPD, a negative association of obesity and HRQoL could not be confirmed. The results hint at the need to stratify COPD patients by disease stage for optimal BMI management.
AU  - Huber, M.B.
AU  - Kurz, C.F.
AU  - Kirsch, F.
AU  - Schwarzkopf, L.
AU  - Schramm, A.*
AU  - Leidl, R.
C1  - 60483
C2  - 49476
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The relationship between body mass index and health-related quality of life in COPD: Real-world evidence based on claims and survey data.
JO  - Respir. Res.
VL  - 21
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. Methods We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. Results 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. Conclusion We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.
AU  - Kahnert, K.*
AU  - Föhrenbach, M.*
AU  - Lucke, T.*
AU  - Alter, P.*
AU  - Trudzinski, F.T.*
AU  - Bals, R.*
AU  - Lutter, J.
AU  - Timmermann, H.*
AU  - Söhler, S.*
AU  - Förderreuther, S.*
AU  - Nowak, D.*
AU  - Watz, H.*
AU  - Waschki, B.*
AU  - Behr, J.*
AU  - Welte, T.*
AU  - Vogelmeier, C.F.*
AU  - Jörres, R.A.*
C1  - 57979
C2  - 48084
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The impact of COPD on polyneuropathy: Results from the German COPD cohort COSYCONET.
JO  - Respir. Res.
VL  - 21
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BackgroundFibrotic interstitial lung disease (ILD) is often associated with poor outcomes, but has few predictors of progression. Daily home spirometry has been proposed to provide important information about the clinical course of idiopathic pulmonary disease (IPF). However, experience is limited, and home spirometry is not a routine component of patient care in ILD. Using home spirometry, we aimed to investigate the predictive potential of daily measurements of forced vital capacity (FVC) in fibrotic ILD.MethodsIn this prospective observational study, patients with fibrotic ILD and clinical progression were provided with home spirometers for daily measurements over 6 months. Hospital based spirometry was performed after three and 6 months. Disease progression, defined as death, lung transplantation, acute exacerbation or FVC decline >10% relative was assessed in the cohort.ResultsFrom May 2017 until August 2018, we included 47 patients (IPF n=20; non-IPF n=27). Sufficient daily measurements were performed by 85.1% of the study cohort. Among these 40 patients (IPF n=17; non-IPF n=23), who had a meanSD age of 60.7 +/- 11.3years and FVC 64.7 +/- 21.7% predicted (2.4 +/- 0.8L), 12 patients experienced disease progression (death: n= 2; lung transplantation: n=3; acute exacerbation: n=1; FVC decline >10%: n=6). Within the first 28days, a group of patients had high daily variability in FVC, with 60.0% having a variation >= 5%. Patients with disease progression had significantly higher FVC variability than those in the stable group (median variability 8.6% vs. 4.8%; p=0.002). Cox regression identified FVC variability as independently associated with disease progression when controlling for multiple confounding variables (hazard ratio: 1.203; 95% CI:1.050-1.378; p=0.0076).Conclusions Daily home spirometry is feasible in IPF and non-IPF ILD and facilitates the identification of FVC variability, which was associated with disease progression.
AU  - Veit, T.
AU  - Barnikel, M.
AU  - Crispin, A.*
AU  - Kneidinger, N.
AU  - Ceelen, F.
AU  - Arnold, P.
AU  - Munker, D.
AU  - Schmitzer, M.
AU  - Barton, J.
AU  - Schiopu, S.
AU  - Schiller, H. B.
AU  - Frankenberger, M.
AU  - Milger, K.
AU  - Behr, J.
AU  - Neurohr, C.*
AU  - Leuschner, G.
C1  - 60356
C2  - 49386
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Variability of forced vital capacity in progressive interstitial lung disease: A prospective observational study.
JO  - Respir. Res.
VL  - 21
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background Interstitial lung disease (ILD) is a heterogeneous group of mainly chronic lung diseases differing in disease course and prognosis. For most subtypes, evidence on relevance and outcomes of hospitalisations is lacking. Methods Using German claims data we investigated number of hospitalisations (zero-inflated-negative-binomial models providing rate ratios (RR)) and time to first hospitalisation (Cox proportional-hazard models providing hazard ratios (RR)) for nine ILD-subtypes. Models were stratified by ILD-related and non-ILD-related hospitalisations. We adjusted for age, gender, ILD-subtype, ILD-relevant comorbidities and ILD-medication (immunosuppressive drugs, steroids, anti-fibrotic drugs). Results Among 36,816 ILD-patients (mean age 64.7 years, 56.2% male, mean observation period 9.3 quarters), 71.2% had non-ILD-related and 56.6% ILD-related hospitalisations. We observed more and earlier non-ILD-related hospitalisations in ILD patients other than sarcoidosis. Medical ILD-treatment was associated with increased frequency and in case of late initiation, earlier (non-)ILD-related hospitalisations. Comorbidities were associated with generally increased hospitalisation frequency except for COPD (RR = 0.90) and PH (RR = 0.94) in non-ILD-related and for lung cancer in ILD-related hospitalisations (RR = 0.89). Coronary heart disease was linked with earlier (ILD-related: HR = 1.17, non-ILD-related HR = 1.19), but most other conditions with delayed hospitalisations. Conclusion Hospitalisations are frequent across all ILD-subtypes. The hospitalisation risk might be reduced independently of the subtype by improved management of comorbidities and improved pharmacological and non-pharmacological ILD therapy.
AU  - Wälscher, J.*
AU  - Witt, S.
AU  - Schwarzkopf, L.
AU  - Kreuter, M.*
C1  - 58768
C2  - 48304
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Hospitalisation patterns of patients with interstitial lung disease in the light of comorbidities and medical treatment - a German claims data analysis.
JO  - Respir. Res.
VL  - 21
IS  - 1
PB  - Bmc
PY  - 2020
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Early life exposure to tobacco smoke has been extensively studied but the role of second-hand smoke (SHS) for new-onset respiratory symptoms and lung function decline in adulthood has not been widely investigated in longitudinal studies. Our aim is to investigate the associations of exposure to SHS in adults with respiratory symptoms, respiratory conditions and lung function over 20 years.We used information from 3011 adults from 26 centres in 12 countries who participated in the European Community Respiratory Health Surveys I-III and were never or former smokers at all three surveys. Associations of SHS exposure with respiratory health (asthma symptom score, asthma, chronic bronchitis, COPD) were analysed using generalised linear mixed-effects models adjusted for confounding factors (including sex, age, smoking status, socioeconomic status and allergic sensitisation). Linear mixed-effects models with additional adjustment for height were used to assess the relationships between SHS exposure and lung function levels and decline.Reported exposure to SHS decreased in all 26 study centres over time. The prevalence of SHS exposure was 38.7% at baseline (1990-1994) and 7.1% after the 20-year follow-up (2008-2011). On average 2.4% of the study participants were not exposed at the first, but were exposed at the third examination. An increase in SHS exposure over time was associated with doctor-diagnosed asthma (odds ratio (OR): 2.7; 95% confidence interval (95%-CI): 1.2-5.9), chronic bronchitis (OR: 4.8; 95%-CI: 1.6-15.0), asthma symptom score (count ratio (CR): 1.9; 95%-CI: 1.2-2.9) and dyspnoea (OR: 2.7; 95%-CI: 1.1-6.7) compared to never exposed to SHS. Associations between increase in SHS exposure and incidence of COPD (OR: 2.0; 95%-CI: 0.6-6.0) or lung function (beta: - 49 ml; 95%-CI: -132, 35 for FEV1 and beta: - 62 ml; 95%-CI: -165, 40 for FVC) were not apparent.Exposure to second-hand smoke may lead to respiratory symptoms, but this is not accompanied by lung function changes.
AU  - Flexeder, C.
AU  - Zock, J.P.*
AU  - Jarvis, D.*
AU  - Verlato, G.*
AU  - Olivieri, M.*
AU  - Benke, G.*
AU  - Abramson, M.J.*
AU  - Sigsgaard, T.*
AU  - Svanes, C.*
AU  - Torén, K.*
AU  - Nowak, D.*
AU  - Jõgi, R.*
AU  - Martinez-Moratalla, J.*
AU  - Demoly, P.*
AU  - Janson, C.*
AU  - Gislason, T.*
AU  - Bono, R.*
AU  - Holm, M.*
AU  - Franklin, K.A.*
AU  - Garcia-Aymerich, J.*
AU  - Siroux, V.*
AU  - Leynaert, B.*
AU  - Dorado Arenas, S.*
AU  - Corsico, A.G.*
AU  - Pereira-Vega, A.*
AU  - Probst-Hensch, N.*
AU  - Urrutia Landa, I.*
AU  - Schulz, H.
AU  - Heinrich, J.
C1  - 55521
C2  - 46395
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Second-hand smoke exposure in adulthood and lower respiratory health during 20 year follow up in the European Community Respiratory Health Survey.
JO  - Respir. Res.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Evidence on the economic impact of chronic obstructive pulmonary disease (COPD) for third-party payers and society based on large real world datasets are still scarce. Therefore, the aim of this study was to estimate the economic impact of COPD severity and its comorbidities, stratified by GOLD grade, on direct and indirect costs for an unselected population enrolled in the structured German Disease Management Program (DMP) for COPD.Methods: All individuals enrolled in the DMP COPD were included in the analysis. Patients were only excluded if they were not insured or not enrolled in the DMP COPD the complete year before the last DMP documentation (at physician visit), had a missing forced expiratory volume in 1 s (FEV1) measurement or other missing values in covariates. The final dataset included 39,307 patients in GOLD grade 1 to 4. We used multiple generalized linear models to analyze the association of COPD severity with direct and indirect costs, while adjusting for sex, age, income, smoking status, body mass index, and comorbidities.Results: More severe COPD was significantly associated with higher healthcare utilization, work absence, and premature retirement. Adjusted annual costs for GOLD grade 1 to 4 amounted to (sic)3809 [(sic)3691-(sic)3935], (sic)4284 [(sic)4176-(sic)4394], (sic)5548 [(sic)5328-(sic)5774], and (sic)8309 [(sic)7583-9065] for direct costs, and (sic)11,784 [(sic)11,257-(sic)12,318], (sic)12, 985 [(sic)12,531-13,443], (sic)15,805 [(sic)15,034-(sic)16,584], and (sic)19,402 [(sic)17,853-(sic)21,017] for indirect costs. Comorbidities had significant additional effects on direct and indirect costs with factors ranging from 1.19 (arthritis) to 1.51 (myocardial infarction) in direct and from 1.16 (myocardial infarction) to 1.27 (cancer) in indirect costs.Conclusion: The findings indicate that more severe GOLD grades in an unselected COPD population enrolled in a structured DMP are associated with tremendous additional direct and indirect costs, with comorbidities significantly increase costs. In direct cost category hospitalization and in indirect cost category premature retirement were the main cost driver. From a societal perspective prevention and interventions focusing on disease control, and slowing down disease progression and strengthening the ability to work would be beneficial in order to realize cost savings in COPD.
AU  - Kirsch, F.
AU  - Schramm, A.*
AU  - Schwarzkopf, L.
AU  - Lutter, J.
AU  - Szentes, B.L.
AU  - Huber, M.B.
AU  - Leidl, R.
C1  - 57103
C2  - 47496
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Direct and indirect costs of COPD progression and its comorbidities in a structured disease management program: Results from the LQ-DMP study.
JO  - Respir. Res.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - The diagnosis of depression, a frequent comorbidity of chronic obstructive pulmonary disease (COPD), is often supported by questionnaires, such as the Patient Health Questionnaire 9 (PHQ-9). It is unknown to which extent its single questions are affected by the clinical characteristics of COPD patients.We addressed this question in 2255 GOLD grade 1-4 patients from the COSYCONET (COPD and Systemic Consequences - Comorbidities Network) COPD cohort. The dependence on COPD severity was assessed using symptoms, exacerbation risk (GOLD A-D; modified Medical Research Council dyspnoea scale (mMRC)), and frequent comorbidities as predictors of PHQ-9 results, while including age, gender, body mass index (BMI) and smoking habits as covariates.Symptoms and exacerbation risk were associated with depression in an additive manner, with mean elevations in the PHQ-9 sum score by 2.75 and 1.44 points, respectively. Asthma, sleep apnoea, gastrointestinal disorders, osteoporosis and arthritis were linked to increases by 0.8 to 1.3 points. Overall, the COPD characteristics contributed to the mean PHQ-9 score by increases from 4.5 or 5.2 to 6.3 points, respectively, when either taking GOLD A as reference or the absence of comorbidities. This finding was independent of the diagnosis of mental disorder or the intake of antidepressants. The presence of COPD led to an increase in the proportion of scores indicating depression from 12 to 22%. Single item analysis revealed homogenous effects regarding GOLD groups, but heterogeneous effects regarding GOLD grades.These findings indicate specific effects of COPD severity on the PHQ-9 depression score, especially symptoms and exacerbation risk, explaining the high prevalence of depression in COPD. Alternative explanations like an overlap of COPD severity and PHQ-9 items are discussed. Of note, we also found COPD treatment effects on depression scores.
AU  - von Siemens, S.M.
AU  - Jörres, R.A.*
AU  - Behr, J.*
AU  - Alter, P.*
AU  - Lutter, J.
AU  - Lucke, T.*
AU  - Söhler, S.*
AU  - Welte, T.*
AU  - Watz, H.*
AU  - Vogelmeier, C.F.*
AU  - Trudzinski, F.*
AU  - Rief, W.*
AU  - Herbig, B.*
AU  - Kahnert, K.*
C1  - 55491
C2  - 46261
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Effect of COPD severity and comorbidities on the result of the PHQ-9 tool for the diagnosis of depression: Results from the COSYCONET cohort study.
JO  - Respir. Res.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Alterations of cognitive functions have been described in COPD. Our study aimed to disentangle the relationship between the degree of cognitive function and COPD characteristics including quality of life (QoL). Data from 1969 COPD patients of the COSYCONET cohort (GOLD grades 1-4; 1216 male/ 753 female; mean (SD) age 64.9 +/- 8.4 years) were analysed using regression and path analysis. The DemTect screening tool was used to measure cognitive function, and the St. George's respiratory questionnaire (SGRQ) to assess disease-specific QoL. DemTect scores were < 9 points in 1.6% of patients and < 13 points in 12% when using the original evaluation algorithm distinguishing between < 60 or > =60 years of age. For statistical reasons, we used the average of both algorithms independent of age in all subsequent analyses. The DemTect scores were associated with oxygen content, 6-min-walking distance (6-MWD), C-reactive protein (CRP), modified Medical Research Council dyspnoea scale (mMRC) and the SGRQ impact score. Conversely, the SGRQ impact score was independently associated with 6-MWD, FVC, mMRC and DemTect. These results were combined into a path analysis model to account for direct and indirect effects. The DemTect score had a small, but independent impact on QoL, irrespective of the inclusion of COPD-specific influencing factors or a diagnosis of cognitive impairment. We conclude that in patients with stable COPD lower oxygen content of blood as a measure of peripheral oxygen supply, lower exercise capacity in terms of 6-MWD, and higher CRP levels were associated with reduced cognitive capacity. Furthermore, a reduction in cognitive capacity was associated with reduced disease-specific quality of life. As a potential clinical implication of this work, we suggest to screen especially patients with low oxygen content and low 6-MWD for cognitive impairment.
AU  - von Siemens, S.M.*
AU  - Perneczky, R.*
AU  - Vogelmeier, C.F.*
AU  - Behr, J.*
AU  - Kauffmann-Guerrero, D.*
AU  - Alter, P.*
AU  - Trudzinski, F.C.*
AU  - Bals, R.*
AU  - Grohé, C.*
AU  - Söhler, S.*
AU  - Waschki, B.*
AU  - Lutter, J.
AU  - Welte, T.*
AU  - Jörres, R.A.*
AU  - Kahnert, K.*
C1  - 57393
C2  - 47784
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - The association of cognitive functioning as measured by the DemTect with functional and clinical characteristics of COPD: Results from the COSYCONET cohort.
JO  - Respir. Res.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Idiopathic pulmonary fibrosis (IPF) is a rare disease with a median survival of 3-5 years after diagnosis with limited treatment options. The aim of this study is to assess the psychometric characteristics of the Short Form 36 Health Status Questionnaire (SF-36) in IPF and to provide disease specific minimally important differences (MID). Methods: Data source was the European IPF Registry (eurIPFreg). The psychometric properties of the SF-36 version 2 were evaluated based on objective clinical measures as well as subjective perception. We analysed acceptance, feasibility, discrimination ability, construct and criterion validity, responsiveness and test-retest-reliability. MIDs were estimated via distribution and anchor-based approaches. Results: The study population included 258 individuals (73.3% male; mean age 67.3 years, SD 10.7). Of them 75.2% (194 individuals) had no missing item. The distribution of several items was skewed, although floor effect was acceptable. Physical component score (PCS) correlated significantly and moderately with several anchors, whereas the correlations of mental component score (MCS) and anchors were only small. The tests showed mainly significant lower HRQL in individuals with long-term oxygen therapy. Analyses in stable individuals did not show significant changes of HRQL except for one dimension and anchor. Individuals with relevant changes of the health status based on the anchors had significant changes in all SF-36 dimensions and summary scales except for the dimension PAIN. PCS and MCS had mean MIDs of five and six, respectively. Mean MIDs of the dimensions ranged from seven to 21. Conclusion: It seems that the SF-36 is a valid instrument to measure HRQL in IPF and so can be used in RCTs or individual monitoring of disease. Nevertheless, the additional evaluation of longitudinal aspects and MIDs can be recommended to further analyse these factors. Our findings have a great potential impact on the evaluation of IPF patients. Trial registration: The eurIPFreg and eurIPFbank are listed in https://clinicaltrials.gov (NCT02951416).
AU  - Witt, S.
AU  - Krauss, E.*
AU  - Barbero, M.A.N.*
AU  - Müller, V.*
AU  - Bonniaud, P.*
AU  - Vancheri, C.*
AU  - Wells, A.U.*
AU  - Vasakova, M.*
AU  - Pesci, A.*
AU  - Klepetko, W.*
AU  - Seeger, W.*
AU  - Crestani, B.*
AU  - Leidl, R.
AU  - Holle, R.
AU  - Schwarzkopf, L.
AU  - Guenther, A.*
C1  - 55607
C2  - 46426
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Psychometric properties and minimal important differences of SF-36 in Idiopathic Pulmonary Fibrosis.
JO  - Respir. Res.
VL  - 20
IS  - 1
PB  - Bmc
PY  - 2019
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Purpose of Review Advances in technology have expanded telemedicine opportunities covering medical practice, research, and education. This is of particular importance in movement disorders (MDs), where the combination of disease progression, mobility limitations, and the sparse distribution of MD specialists increase the difficulty to access. In this review, we discuss the prospects, challenges, and strategies for telemedicine in MDs.Recent Findings Telemedicine for MDs has been mainly evaluated in Parkinson's disease (PD) and compared to in-office care is cost-effective with similar clinical care, despite the barriers to engagement. However, particular groups including pediatric patients, rare MDs, and the use of telemedicine in underserved areas need further research.Summary Interdisciplinary telemedicine and tele-education for MDs are feasible, provide similar care, and reduce travel costs and travel time compared to in-person visits. These benefits have been mainly demonstrated for PD but serve as a model for further validation in other movement disorders.
AU  - Knüppel, L.
AU  - Heinzelmann, K.
AU  - Lindner, M.*
AU  - Hatz, R.*
AU  - Behr, J.*
AU  - Eickelberg, O.
AU  - Staab-Weijnitz, C.A.
C1  - 53412
C2  - 44679
CY  - 233 Spring St, New York, Ny 10013 Usa
TI  - FK506-binding protein 10 (FKBP10) regulates lung fibroblast migration via collagen VI synthesis.
JO  - Respir. Res.
VL  - 19
IS  - 1
PB  - Springer
PY  - 2018
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored.Methods: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA.Results: Low mu M concentrations of Nintedanib (1 mu M) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs.Conclusions: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.
AU  - Lehmann, M.
AU  - Buhl, L.
AU  - Alsafadi, H.N.
AU  - Klee, S.
AU  - Hermann, S.
AU  - Mutze, K.
AU  - Ota, C.
AU  - Lindner, M.*
AU  - Behr, J.*
AU  - Hilgendorff, A.
AU  - Wagner, D.E.
AU  - Königshoff, M.
C1  - 54324
C2  - 45510
CY  - Campus, 4 Crinan St, London N1 9xw, England
TI  - Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis.
JO  - Respir. Res.
VL  - 19
IS  - 1
PB  - Bmc
PY  - 2018
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Interstitial lung diseases (ILDs) are associated with a high burden of disease. However, data on the prognostic impact of comorbidities and comorbidity-related pharmaceutical treatments in patients with various ILDs remain sparse. METHODS: Using longitudinal claims data from a German Statutory Health Insurance Fund, we assessed comorbidity in ILD subtypes and associated drug treatments. Baseline comorbidity was assessed via the Elixhauser Comorbidity Index that was amended by ILD-relevant conditions. Drug treatment was assessed on the substance level using the ATC-codes of drugs prescribed at the time of ILD diagnosis. Subsequently, the comorbid conditions (main analysis) and pharmaceutical substances (secondary analysis) with a meaningful association to survival were identified for the complete ILD cohort and within the subtype strata. For this, we applied multivariate Cox models using a LASSO selection process and visualized the findings within comorbidomes. RESULTS: In the 36,821 patients with ILDs, chronic obstructive pulmonary disease (COPD), arterial hypertension, and ischaemic heart disease (IHD) were the most prevalent comorbidities. The majority of patients with cardiovascular diseases received pharmaceutical treatment, while, in other relevant comorbidities, treatment quotas were low (COPD 46%, gastro-oesophageal reflux disease 65%). Comorbidities had a clinically meaningful detrimental effect on survival that tended to be more pronounced in the case of untreated conditions (e.g. hazard ratios for treated IHD 0.97 vs. 1.33 for untreated IHD). Moreover, comorbidity impact varied substantially between distinct subtypes. CONCLUSIONS: Our analyses suggest that comorbid conditions and their treatment profile significantly affect mortality in various ILDs. Therefore, comprehensive comorbidity assessment and management remains important in any ILD.
AU  - Schwarzkopf, L.
AU  - Witt, S.
AU  - Waelscher, J.*
AU  - Polke, M.*
AU  - Kreuter, M.*
C1  - 53455
C2  - 44590
TI  - Associations between comorbidities, their treatment and survival in patients with interstitial lung diseases - a claims data analysis.
JO  - Respir. Res.
VL  - 19
IS  - 1
PY  - 2018
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: Patients with interstitial lung diseases (ILD) have impaired health-related quality of life (HRQL). Little is known about the applicability of the disease-specific King's Brief Interstitial Lung Disease questionnaire (K-BILD) and the generic EQ-5D-5L in a German setting. Methods: We assessed disease-specific (K-BILD) and generic HRQL (EQ-5D experience based value set (EBVS) and Visual Analog Scale (VAS)) in 229 patients with different ILD subtypes in a longitudinal observational study (HILDA). Additionally, we assessed the correlation of the HRQL measures with lung function and comorbidities. In a linear regression model, we investigated predictors (including age, sex, ILD subtype, FVC percentage of predicted value (FVC%pred), DLCO percentage of predicted value, and comorbidities). Results: Among the 229 patients mean age was 63.2 (Standard deviation (SD): 12.9), 67.3% male, 24.0% had idiopathic pulmonary fibrosis, and 22.3% sarcoidosis. Means scores were as follows for EQ-5D EBVS 0.66(SD 0.17), VAS 61.4 (SD 19.1) and K-BILD Total 53.6 (SD 13.8). K-BILD had good construct validity (high correlation with EQ-5D EBVS (0.71)) and good internal consistency (Cronbach's alpha 0.89). Moreover, all HRQL measures were highly accepted by patients including low missing items and there were no ceiling or floor effects. A higher FVC % pred was associated with higher HRQL in all measures meanwhile comorbidities had a negative influence on HRQL. Conclusions: K-BILD and EQ-5D had similar HRQL trends and were associated similarly to the same disease-related factors in Germany. Our data supports the use of K-BILD in clinical practice in Germany, since it captures disease specific effects of ILD. Additionally, the use of the EQ-5D-5L could provide comparison to different disease areas and give an overview about the position of ILD patients in comparison to general population.
AU  - Szentes, B.L.
AU  - Kreuter, M.*
AU  - Bahmer, T.*
AU  - Birring, S.S.*
AU  - Claussen, M.*
AU  - Waelscher, J.*
AU  - Leidl, R.
AU  - Schwarzkopf, L.
C1  - 53581
C2  - 44804
TI  - Quality of life assessment in interstitial lung diseases: A comparison of the disease-specific K-BILD with the generic EQ-5D-5L.
JO  - Respir. Res.
VL  - 19
IS  - 1
PY  - 2018
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Failure to attain peak lung function by early adulthood is a risk factor for chronic lung diseases. Previously, we reported that C3H/HeJ mice have about twice total lung capacity (TLC) compared to JF1/MsJ mice. We identified seven lung function quantitative trait loci (QTL: Lfnq1-Lfnq7) in backcross/intercross mice derived from these inbred strains. We further demonstrated, superoxide dismutase 3, extracellular (Sod3), Kit oncogene (Kit) and secreted phosphoprotein 1 (Spp1) located on these Lfnqs as lung function determinants. Emanating from the concept of early origin of lung disease, we sought to identify novel candidate genes for pulmonary function by investigating lung transcriptome in C3H/HeJ and JF1/MsJ mice at the completion of embryonic development, bulk alveolar formation and maturity. METHODS: Design-based stereological analysis was performed to study lung structure in C3H/HeJ and JF1/MsJ mice. Microarray was used for lung transcriptomic analysis [embryonic day 18, postnatal days 28, 70]. Quantitative real time polymerase chain reaction (qRT-PCR), western blot and immunohistochemical analysis were used to confirm selected differences. RESULTS: Stereological analysis revealed decreased alveolar number density, elastin to collagen ratio and increased mean alveolar volume in C3H/HeJ mice compared to JF1/MsJ. Gene ontology term "extracellular region" was enriched among the decreased JF1/MsJ transcripts. Candidate genes identified using the expression-QTL strategy include: ATP-binding cassette, sub-family G (WHITE), member 1 (Abcg1), formyl peptide receptor 1 (Fpr1), gamma-aminobutyric acid (GABA) B receptor, 1 (Gabbr1); histocompatibility 2 genes: class II antigen E beta (H2-Eb1), D region locus 1 (H2-D1), and Q region locus 4 (H2-Q4); leucine rich repeat containing 6 (testis) (Lrrc6), radial spoke head 1 homolog (Rsph1), and surfactant associated 2 (Sfta2). Noteworthy genes selected as candidates for their consistent expression include: Wnt inhibitor factor 1 (Wif1), follistatin (Fst), chitinase-like 1 (Chil1), and Chil3. CONCLUSIONS: Comparison of late embryonic, adolescent and adult lung transcript profiles between mouse strains with extreme TLCs lead to the identification of candidate genes for pulmonary function that has not been reported earlier. Further mechanistic investigations are warranted to elucidate their mode of action in determining lung function.
AU  - George, L.*
AU  - Mitra, A.*
AU  - Thimraj, T.A.*
AU  - Irmler, M.
AU  - Vishweswaraiah, S.*
AU  - Lunding, L.P.*
AU  - Hühn, D.*
AU  - Madurga, A.*
AU  - Beckers, J.
AU  - Fehrenbach, H.*
AU  - Upadhyay, S.*
AU  - Schulz, H.
AU  - Leikauf, G.D.*
AU  - Ganguly, K.*
C1  - 51705
C2  - 43411
CY  - London
TI  - Transcriptomic analysis comparing mouse strains with extreme total lung capacities identifies novel candidate genes for pulmonary function.
JO  - Respir. Res.
VL  - 18
IS  - 1
PB  - Biomed Central Ltd
PY  - 2017
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: An impairment of CO diffusing capacity has been shown in diabetic patients without lung disease. We analyzed how diffusing capacity in patients with COPD is affected by the concurrent diagnosis of diabetes. Methods: Data from the initial visit of the German COPD cohort COSYCONET were used for analysis. 2575 patients with complete lung function data were included, among them 358 defined as diabetics with a reported physician diagnosis of diabetes and/or specific medication. Pairwise comparisons between groups and multivariate regression models were used to identify variables predicting the CO transfer factor (TLCO%pred) and the transfer coefficient (KCO%pred). Results: COPD patients with diabetes differed from those without diabetes regarding lung function, anthropometric, clinical and laboratory parameters. Moreover, gender was an important covariate. After correction for lung function, gender and body mass index (BMI), TLCO%pred did not significantly differ between patients with and without diabetes. The results for the transfer coefficient KCO were similar, demonstrating an important role of the confounding factors RV%pred, TLC%pred, ITGV%pred, FEV1%pred, FEV1/FVC, age, packyears, creatinine and BMI. There was not even a tendency towards lower values in diabetes. Conclusion: The analysis of data from a COPD cohort showed no significant differences of CO transport parameters between COPD patients with and without diabetes, if BMI, gender and the reduction in lung volumes were taken into account. This result is in contrast to observations in lung-healthy subjects with diabetes and raises the question which factors, among them potential anti-inflammatory effects of anti-diabetes medication are responsible for this finding.
AU  - Kahnert, K.*
AU  - Lucke, T.*
AU  - Biertz, F.*
AU  - Lechner, A.*
AU  - Watz, H.*
AU  - Alter, P.*
AU  - Bals, R.*
AU  - Behr, J.*
AU  - Holle, R.
AU  - Huber, R.M.*
AU  - Karrasch, S.
AU  - Stubbe, B.*
AU  - Wacker, M.
AU  - Söhler, S.*
AU  - Wouters, E.F.M.*
AU  - Vogelmeier, C.*
AU  - Jörres, R.A.*
C1  - 50346
C2  - 42150
CY  - London
TI  - Transfer factor for carbon monoxide in patients with COPD and diabetes: Results from the German COSYCONET cohort.
JO  - Respir. Res.
VL  - 18
PB  - Biomed Central Ltd
PY  - 2017
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Alpha-1-Antitrypsin Deficiency (AATD) is an economically unexplored genetic disease. METHODS: Direct and indirect costs (based on self-reported information on healthcare utilization) and health-related quality of life (HRQL, as assessed by SGRQ, CAT, and EQ-5D-3 L) were compared between 131 AATD patients (106 with, 25 without augmentation therapy (AT)) and 2,049 COPD patients without AATD participating in the COSYCONET COPD cohort. The medication costs of AT were excluded from all analyses to reveal differences associated with morbidity profiles. The association of AATD (with/without AT) with costs or HRQL was examined using generalized linear regression modelling (GLM) adjusting for age, sex, GOLD grade, BMI, smoking status, education and comorbidities. RESULTS: Adjusted mean direct annual costs were €6,099 in AATD patients without AT, €7,117 in AATD patients with AT (excluding costs for AT), and €7,460 in COPD patients without AATD. AATD with AT was significantly associated with higher outpatient (+273%) but lower inpatient (-35%) and medication costs (-10%, disregarding AT) compared with COPD patients without AATD. There were no significant differences between groups regarding indirect costs and HRQL. CONCLUSION: Apart from AT costs, AATD patients tended to have lower, though not significant, overall costs and similar HRQL compared to COPD patients without AATD. AT was not associated with lower costs or higher HRQL. TRIAL REGISTRATION: NCT01245933.
AU  - Karl, F.
AU  - Holle, R.
AU  - Bals, R.*
AU  - Greulich, T.*
AU  - Jörres, R.A.*
AU  - Karch, A.*
AU  - Koch, A.*
AU  - Karrasch, S.
AU  - Leidl, R.
AU  - Schulz, H.
AU  - Vogelmeier, C.*
AU  - Wacker, M.
C1  - 50951
C2  - 42555
TI  - Costs and health-related quality of life in Alpha-1-antitrypsin deficient COPD patients.
JO  - Respir. Res.
VL  - 18
IS  - 1
PY  - 2017
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Various factors may affect lung function at different stages in life. Since investigations that simultaneously consider several factors are rare, we examined the relative importance of early life, current environmental/lifestyle factors and allergic diseases on lung function in 15-year-olds. METHODS: Best subset selection was performed for linear regression models to investigate associations between 21 diverse early life events and current factors with spirometric parameters (forced vital capacity, forced expiratory volume in 1 s and maximal mid-expiratory flow (FEF25-75)) in 1326 participants of the German GINIplus and LISAplus birth cohorts. To reduce model complexity, one model for each spirometric parameter was replicated 1000 times in random subpopulations (N = 884). Only those factors that were included in >70% of the replication models were retained in the final analysis. RESULTS: A higher peak weight velocity and early lung infections were the early life events prevalently associated with airflow limitation and FEF25-75. Current environmental/lifestyle factors at age 15 years and allergic diseases that were associated with lung function were: indoor second-hand smoke exposure, vitamin D concentration, body mass index (BMI) and asthma status. Sex and height captured the majority of the explained variance (>75%), followed by BMI (≤23.7%). The variance explained by early life events was comparatively low (median: 4.8%; range: 0.2-22.4%), but these events were consistently negatively associated with airway function. CONCLUSIONS: Although the explained variance was mainly captured by well-known factors included in lung function prediction equations, our findings indicate early life and current factors that should be considered in studies on lung health among adolescents.
AU  - Luzak, A.
AU  - Fuertes, E.
AU  - Flexeder, C.
AU  - Standl, M.
AU  - von Berg, A.*
AU  - Berdel, D.*
AU  - Koletzko, S.*
AU  - Heinrich, J.
AU  - Nowak, D.
AU  - Schulz, H.
C1  - 51527
C2  - 43283
CY  - London
TI  - Which early life events or current environmental and lifestyle factors influence lung function in adolescents? - Results from the GINIplus & LISAplus studies.
JO  - Respir. Res.
VL  - 18
IS  - 1
PB  - Biomed Central Ltd
PY  - 2017
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: In the human lung, epithelial progenitor cells in the airways give rise to the differentiated pseudostratified airway epithelium. In mice, emerging evidence confers a progenitor function to cytokeratin 5 (KRT5(+)) or cytokeratin 14 (KRT14(+))-positive basal cells of the airway epithelium. Little is known, however, about the distribution of progenitor subpopulations in the human lung, particularly about aberrant epithelial differentiation in lung disease, such as idiopathic pulmonary fibrosis (IPF). METHODS: Here, we used multi-color immunofluorescence analysis to detect and quantify the distribution of airway epithelial progenitor subpopulations in human lungs obtained from healthy donors or IPF patients. RESULTS: In lungs from both, healthy donors and IPF patients, we detected KRT5(+)KRT14(-), KRT5(-)KRT14(+) and KRT5(+)KRT14(+) populations in the proximal airways. KRT14(+) cells, however, were absent in the distal airways of healthy lungs. In IPF, we detected a dramatic increase in the amount of KRT5(+) cells and the emergence of a frequent KRT5(+)KRT14(+) epithelial population, in particular in distal airways and alveolar regions. While the KRT14(-) progenitor population exhibited signs of proper epithelial differentiation, as evidenced by co-staining with pro-SPC, aquaporin 5, CC10, or MUC5B, the KRT14(+) cell population did not co-stain with bronchial/alveolar differentiation markers in IPF. CONCLUSIONS: We provide, for the first time, a quantitative profile of the distribution of epithelial progenitor populations in human lungs. We show compelling evidence for dysregulation and aberrant differentiation of these populations in IPF.
AU  - Smirnova, N.F.
AU  - Schamberger, A.C.
AU  - Nayakanti, S.
AU  - Hatz, R.*
AU  - Behr, J.*
AU  - Eickelberg, O.
C1  - 49106
C2  - 41635
CY  - London
TI  - Detection and quantification of epithelial progenitor cell populations in human healthy and IPF lungs.
JO  - Respir. Res.
VL  - 17
IS  - 1
PB  - Biomed Central Ltd
PY  - 2016
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - 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.
AU  - Wacker, M.
AU  - Jörres, R.A.*
AU  - Karch, A.*
AU  - Koch, A.*
AU  - Heinrich, J.
AU  - Karrasch, S.
AU  - Schulz, H.
AU  - Peters, A.
AU  - Gläser, S.*
AU  - Ewert, R.*
AU  - Baumeister, S.E.*
AU  - Vogelmeier, C.*
AU  - Leidl, R.*
AU  - Holle, R.
C1  - 49081
C2  - 41584
CY  - London
TI  - Relative impact of COPD and comorbidities on generic health-related quality of life: A pooled analysis of the COSYCONET patient cohort and control subjects from the KORA and SHIP studies.
JO  - Respir. Res.
VL  - 17
IS  - 1
PB  - Biomed Central Ltd
PY  - 2016
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rapid progressive fibro-proliferative disorder with poor prognosis similar to lung cancer. The pathogenesis of IPF is uncertain, but loss of epithelial cells and fibroblast proliferation are thought to be central processes. Previous reports have shown that BARD1 expression is upregulated in response to hypoxia and associated with TGF-β signaling, both recognized factors driving lung fibrosis. Differentially spliced BARD1 isoforms, in particular BARD1β, are oncogenic drivers of proliferation in cancers of various origins. We therefore hypothesized that BARD1 and/or its isoforms might play a role in lung fibrosis. METHODS: We investigated BARD1 expression as a function of TGF-β in cultured cells, in mice with experimentally induced lung fibrosis, and in lung biopsies from pulmonary fibrosis patients. RESULTS: FL BARD1 and BARD1β were upregulated in response to TGF-β in epithelial cells and fibroblasts in vitro and in vivo. Protein and mRNA expression studies showed very low expression in healthy lung tissues, but upregulated expression of full length (FL) BARD1 and BARD1β in fibrotic tissues. CONCLUSION: Our data suggest that FL BARD1 and BARD1β might be mediators of pleiotropic effects of TGF-β. In particular BARD1β might be a driver of proliferation and of pulmonary fibrosis pathogenesis and progression and represent a target for treatment.
AU  - André, P.*
AU  - Prele, C.M.*
AU  - Vierkotten, S.
AU  - Carnesecchi, S.*
AU  - Donati, Y.*
AU  - Chambers, R.C.*
AU  - Pache, J.*
AU  - Crestani, B.*
AU  - Barazzone-Argiroffo, C.*
AU  - Königshoff, M.
AU  - Laurent, G.J.*
AU  - Irminger-Finger, I.*
C1  - 47118
C2  - 39232
TI  - BARD1 mediates TGF-β signaling in pulmonary fibrosis.
JO  - Respir. Res.
VL  - 16
PY  - 2015
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations. Methods: We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, before and 5-6 weeks after an acute pulmonary exacerbation of COPD (n=9 subjects). Results: Unexpectedly, mucin concentration and mucin stability were highest at the start of the exacerbation and restored to baseline after 6 weeks. Consistent with these data, immunoblots and zymograms confirmed decreased NE concentration and activity and increased A1-PI at the start of the exacerbation. After recovery there was an increase in NE activity and a decrease in A1-PI levels. In vitro, protease inhibitor studies demonstrated that serine proteases played a key role in mucin degradation. Mucin stability was further enhanced upon treating with cigarette smoke condensate (CSC). Conclusion: There appears to be rapid consumption of secreted proteases due to an increase in antiproteases, at the start of a COPD exacerbation. This leads to increased mucin gel stability which may be important in trapping and clearing infectious and inflammatory mediators, but this may also contribute acutely to mucus retention.
AU  - Chillappagari, S.*
AU  - Preuss, J.*
AU  - Licht, S.*
AU  - Müller, C.*
AU  - Mahavadi, P.*
AU  - Sarode, G.
AU  - Vogelmeier, C.*
AU  - Guenther, A.*
AU  - Nahrlich, L.*
AU  - Rubin, B.K.*
AU  - Henke, M.O.
C1  - 46411
C2  - 37687
TI  - Altered protease and antiprotease balance during a COPD exacerbation contributes to mucus obstruction.
JO  - Respir. Res.
VL  - 16
IS  - 1
PY  - 2015
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Transposable elements (TEs) are a class of mobile genetic elements (MGEs) that were long regarded as junk DNA, which make up approximately 45% of the genome. Although most of these elements are rendered inactive by mutations and other gene silencing mechanisms, TEs such as long interspersed nuclear elements (LINEs) are still active and translocate within the genome. During transposition, they may create lesions in the genome, thereby acting as epigenetic modifiers. Approximately 65 disease-causing LINE insertion events have been reported thus far; however, any possible role of TEs in complex disorders is not well established. Chronic obstructive pulmonary disease (COPD) is one such complex disease that is primarily caused by cigarette smoking. Although the exact molecular mechanism underlying COPD remains unclear, oxidative stress is thought to be the main factor in the pathogenesis of COPD. In this review, we explore the potential role of oxidative stress in epigenetic activation of TEs such as LINEs and the subsequent cascade of molecular damage. Recent advancements in sequencing and computation have eased the identification of mobile elements. Therefore, a comparative study on the activity of these elements and markers for genome instability would give more insight on the relationship between MGEs and complex disorder such as COPD.
AU  - Sargurupremraj, M.
AU  - Wjst, M.
C1  - 27821
C2  - 32826
TI  - Transposable elements and their potential role in complex lung disorder.
JO  - Respir. Res.
VL  - 14
IS  - 1
PB  - Biomed Central
PY  - 2013
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough. METHODS: Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model. RESULTS: Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05). CONCLUSIONS: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.
AU  - Smit, L.A.*
AU  - Kogevinas, M.*
AU  - Antò, J.M.*
AU  - Bouzigon, E.*
AU  - Gonzalez, J.R.*
AU  - Le Moual, N.*
AU  - Kromhout, H.*
AU  - Carsin, A.E.*
AU  - Pin, I.*
AU  - Jarvis, D.*
AU  - Vermeulen, R.*
AU  - Janson, C.*
AU  - Heinrich, J.
AU  - Gut, I.*
AU  - Lathrop, M*
AU  - Valverde, M.A.*
AU  - Demenais, F.*
AU  - Kauffmann, F.*
C1  - 7948
C2  - 29929
TI  - Transient receptor potential genes, smoking, occupational exposures and cough in adults.
JO  - Respir. Res.
VL  - 13
PB  - BioMed Central
PY  - 2012
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Declined lung function is a risk factor for particulate matter associated respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). Carbon nanoparticles (CNP) are a prominent component of outdoor air pollution that causes pulmonary toxicity mainly through inflammation. Recently we demonstrated that mice (C3H/HeJ) with higher than normal pulmonary function resolved the elicited pulmonary inflammation following CNP exposure through activation of defense and homeostasis maintenance pathways. To test whether CNP-induced inflammation is affected by declined lung function, we exposed JF1/Msf (JF1) mice with lower than normal pulmonary function to CNP and studied the pulmonary inflammation and its resolution. METHODS: 5 μg, 20 μg and 50 μg CNP (Printex 90) were intratracheally instilled in JF1 mice to determine the dose response and the time course of inflammation over 7 days (20 μg dosage). Inflammation was assessed using histology, bronchoalveolar lavage (BAL) analysis and by a panel of 62 protein markers. RESULTS: 24 h after instillation, 20 μg and 50 μg CNP caused a 25 fold and 19 fold increased polymorphonuclear leucocytes (PMN) respectively while the 5 μg represented the 'no observable adverse effect level' as reflected by PMN influx (9.7 × 10E3 vs 8.9 × 10E3), and BAL/lung concentrations of pro-inflammatory cytokines. Time course assessment of the inflammatory response revealed that compared to day1 the elevated BAL PMN counts (246.4 × 10E3) were significantly decreased at day 3 (72.9 × 10E3) and day 7 (48.5 × 10E3) but did not reach baseline levels indicating slow PMN resolution kinetics. Strikingly on day 7 the number of macrophages doubled (455.0 × 10E3 vs 204.7 × 10E3) and lymphocytes were 7-fold induced (80.6 × 10E3 vs 11.2 × 10E3) compared to day1. At day 7 elevated levels of IL1B, TNF, IL4, MDC/CCL22, FVII, and vWF were detected in JF1 lungs which can be associated to macrophage and lymphocyte activation. CONCLUSION: This explorative study indicates that JF1 mice with impaired pulmonary function also exhibits delayed resolution of particle mediated lung inflammation as evident from elevated PMN and accumulation of macrophages and lymphocytes on day 7. It is plausible that elevated levels of IL1B, IL4, TNF, CCL22/MDC, FVII and vWF counteract defense and homeostatic pathways thereby driving this phenomenon.
AU  - Ganguly, K.
AU  - Upadhyay, S.
AU  - Irmler, M.
AU  - Takenaka, S.
AU  - Pukelsheim, K.
AU  - Beckers, J.
AU  - Hrabě de Angelis, M.
AU  - Hamelmann, E.*
AU  - Stöger, T.
AU  - Schulz, S.
C1  - 5569
C2  - 28806
SP  - 94
TI  - Impaired resolution of inflammatory response in the lungs of JF1/Msf mice following carbon nanoparticle instillation.
JO  - Respir. Res.
VL  - 12
PB  - BioMed Central Ltd.
PY  - 2011
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare lung disease characterised by progressive airflow obstruction. No effective medical treatment is available but therapy with sirolimus has shown some promise. The aim of this observational study was to evaluate sirolimus inprogressive LAM. METHODS: Sirolimus (trough level 5 - 10 ng/ml) was administered to ten female patients (42.4 ± 11.9 years) with documented progression. Serialpulmonary function tests and six-minute-walk-distance (6-MWD) assessments were performed. RESULTS: The mean loss of FEV1 was -2.30 ± 0.52 ml/day before therapy and a significant mean gain of FEV1 of 1.19 ± 0.26 ml/day was detected during treatment (p = 0.001). Mean FEV1 and FVC at baseline were 1.12 ± 0.15 l (36.1 ± 4.5%pred.) and 2.47 ± 0.25 l (69.2 ± 6.5%pred.), respectively. At three and six months during follow-up a significant increase of FEV1 and FVC was demonstrated (3 months ΔFEV1: 220 ± 82 ml, p = 0.024; 6 months ΔFEV1: 345 ± 58 ml, p = 0.001); (3 months ΔFVC: 360 ± 141 ml, p = 0.031; 6 months ΔFVC: 488 ± 138 ml, p = 0.006). Sirolimuswas discontinued in 3 patients because of serious recurrent lower respiratory tract infection or sirolimus-induced pneumonitis. No deaths and no pneumothoraces occurred during therapy. CONCLUSIONS: Our data suggest that sirolimus might be considered as a therapeutic option in rapidly declining LAM patients. However, sirolimusadministration may be associated with severe respiratory adverse events requiring treatment cessation in some patients. Moreover, discontinuation ofsirolimus is mandatory prior to lung transplantation.
AU  - Neurohr, C.*
AU  - Hoffmann, A.L.*
AU  - Huppmann, P.*
AU  - Herrera, V.A.*
AU  - Ihle, F.*
AU  - Leuschner, S.*
AU  - von Wulffen, W.
AU  - Meis, T.*
AU  - Baezner, C.*
AU  - Leuchte, H.*
AU  - Baumgartner, R.*
AU  - Zimmermann, G.*
AU  - Behr, J.*
C1  - 20
C2  - 29380
TI  - Is sirolimus a therapeutic option for patients with progressive pulmonary lymphangioleiomyomatosis?
JO  - Respir. Res.
VL  - 12
IS  - 1
PB  - BIOMED CENTRAL LTD
PY  - 2011
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - 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.
AU  - Schnabel, E.
AU  - Karrasch, S.
AU  - Schulz, S.
AU  - Gläser, S.*
AU  - Meisinger, C.
AU  - Heier, M.
AU  - Peters, A.
AU  - Wichmann, H.-E.
AU  - Behr, J.
AU  - Huber, R.M.
AU  - Heinrich, J.
C1  - 6443
C2  - 28697
TI  - High blood pressure, antihypertensive medication and lung function in a general adult population.
JO  - Respir. Res.
VL  - 12
PB  - Biomed Central Ltd.
PY  - 2011
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is an unresolved clinical issue. Phosphodiesterases (PDEs) are known therapeutic targets for various proliferative lung diseases. Lung PDE6 expression and function has received little or no attention. The present study aimed to characterize (i) PDE6 subunits expression in human lung, (ii) PDE6 subunits expression and alteration in IPF and (iii) functionality of the specific PDE6D subunit in alveolar epithelial cells (AECs). METHODOLOGY/PRINCIPAL FINDINGS: PDE6 subunits expression in transplant donor (n = 6) and IPF (n = 6) lungs was demonstrated by real-time quantitative (q)RT-PCR and immunoblotting analysis. PDE6D mRNA and protein levels and PDE6G/H protein levels were significantly down-regulated in the IPF lungs. Immunohistochemical analysis showed alveolar epithelial localization of the PDE6 subunits. This was confirmed by qRT-PCR from human primary alveolar type (AT)II cells, demonstrating the down-regulation pattern of PDE6D in IPF-derived ATII cells. In vitro, PDE6D protein depletion was provoked by transforming growth factor (TGF)-β1 in A549 AECs. PDE6D siRNA-mediated knockdown and an ectopic expression of PDE6D modified the proliferation rate of A549 AECs. These effects were mediated by increased intracellular cGMP levels and decreased ERK phosphorylation. CONCLUSIONS/SIGNIFICANCE: Collectively, we report previously unrecognized PDE6 expression in human lungs, significant alterations of the PDE6D and PDE6G/H subunits in IPF lungs and characterize the functional role of PDE6D in AEC proliferation.
AU  - Nikolova, S.*
AU  - Guenther, A.*
AU  - Savai, R.*
AU  - Weissmann, N.*
AU  - Ghofrani, H.A.*
AU  - Königshoff, M.
AU  - Eickelberg, O.
AU  - Klepetko, W.*
AU  - Voswinckel, R.*
AU  - Seeger, W.*
AU  - Grimminger, F.*
AU  - Schermuly, R.T.*
AU  - Pullamsetti, S.S.*
C1  - 4748
C2  - 28027
TI  - Phosphodiesterase 6 subunits are expressed and altered in idiopathic pulmonary fibrosis.
JO  - Respir. Res.
VL  - 11
PB  - BioMed Central Ltd.
PY  - 2010
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Atopic and non-atopic wheezing may be caused by different etiologies: while eosinophils are more important in atopic asthmatic wheezers, neutrophils are predominantly found in BAL samples of young children with wheezing. Both neutrophils as well as eosinophils may secrete matrix metalloproteinase 9 (MMP-9). Considering that MMP-9 plays an important role in airway wall thickening and airway inflammation, it may influence the development of obstructive airway phenotypes in children. In the present study we investigated whether genetic variations in MMP-9 influence the development of different forms of childhood asthma. METHODS: Genotyping of four HapMap derived tagging SNPs in the MMP-9 gene was performed using MALDI-TOF MS in three cross sectional study populations of German children (age 9-11; N = 4,264) phenotyped for asthma and atopic diseases according to ISAAC standard procedures. Effects of single SNPs and haplotypes were studied using SAS 9.1.3 and Haploview. RESULTS: SNP rs2664538 significantly increased the risk for non-atopic wheezing (OR 2.12, 95%CI 1.40-3.21, p < 0.001) and non-atopic asthma (OR 1.66, 95%CI 1.12-2.46, p = 0.011). Furthermore, the minor allele of rs3918241 may be associated with decreased expiratory flow measurements in non-atopic children. No significant effects on the development of atopy or total serum IgE levels were observed. CONCLUSIONS: Our results have shown that homozygocity for MMP-9 variants increase the risk to develop non-atopic forms of asthma and wheezing, which may be explained by a functional role of MMP-9 in airway remodeling. These results suggest that different wheezing disorders in childhood are affected differently by genetic alterations.
AU  - Pinto, L.A.*
AU  - Depner, M.*
AU  - Klopp, N.
AU  - Illig, T.
AU  - Vogelberg, C.*
AU  - von Mutius, E.*
AU  - Kabesch, M.*
C1  - 3230
C2  - 27295
TI  - MMP-9 gene variants increase the risk for non-atopic asthma in children.
JO  - Respir. Res.
VL  - 11
PB  - BioMed Central Ltd.
PY  - 2010
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - ABSTRACT: BACKGROUND: Allergen-containing subpollen particles (SPP) are released from whole plant pollen upon contact with water or even high humidity. Because of their size SPP can preferentially reach the lower airways where they come into contact with surfactant protein (SP)-D. Our previous work demonstrated that SP-D increases the uptake of SPP by alveolar macrophages. In the present study, we investigated the uptake of SPP in human primary epithelial cells and the potential modulation by SP-D. The patho-physiological consequence was evaluated by measurement of pro-inflammatory mediators. METHODS: SPP were isolated from timothy grass and subsequently fluorescently labelled. Human primary bronchial epithelial cells were incubated with SPP or polystyrene particles (PP) in the presence and absence of surfactant protein D. In addition, different sizes and surface charges of the PP were studied. Particle uptake was evaluated by flow cytometry and confocal microscopy. Soluble mediators were measured by enzyme linked immunosorbent assay or bead array. RESULTS: SPP were taken up by primary epithelial cells in a dose dependent manner. This uptake was coincided with secretion of Interleukin (IL)-8. SP-D increased the fraction of bronchial epithelial cells that bound SPP but not the fraction of cells that internalized SPP. SPP-induced secretion of IL-8 was further increased by SP-D. PP were bound and internalized by epithelial cells but this was not modulated by SP-D. CONCLUSIONS: Epithelial cells bind and internalize SPP and PP which leads to increased IL-8 secretion. SP-D promotes attachment of SPP to epithelial cells and may thus be involved in the inflammatory response to inhaled allergen.
AU  - Schleh, C.
AU  - Erpenbeck, V.J.*
AU  - Winkler, C.*
AU  - Lauenstein, H.D.*
AU  - Nassimi, M.*
AU  - Braun, A.*
AU  - Krug, N.*
AU  - Hohlfeld, J.M.*
C1  - 457
C2  - 27226
TI  - Allergen particle binding by human primary bronchial epithelial cells is modulated by surfactant protein D.
JO  - Respir. Res.
VL  - 11
PB  - BioMed Central Ltd.
PY  - 2010
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - 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.
AU  - Schnabel, E.*
AU  - Chen, C.M.*
AU  - Koch, B.*
AU  - Karrasch, S.*
AU  - Jörres, R.A.
AU  - Schäfer, T.*
AU  - Vogelmeier, C.*
AU  - Ewert, R.*
AU  - Schäper, C.*
AU  - Völzke, H.*
AU  - Obst, A.*
AU  - Felix, S.B.*
AU  - Wichmann, H.-E.
AU  - Gläser, S.*
AU  - Heinrich, J.
C1  - 5415
C2  - 27484
TI  - Regional differences in prediction models of lung function in Germany.
JO  - Respir. Res.
VL  - 11
PB  - BioMed Central Ltd.
PY  - 2010
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Asthma and allergy are complex multifactorial disorders, with both genetic and environmental components determining disease expression. The use of molecular genetics holds great promise for the identification of novel drug targets for the treatment of asthma and allergy. Genome-wide linkage studies have identified a number of potential disease susceptibility loci but replication remains inconsistent. The aim of the current study was to complete a meta-analysis of data from genome-wide linkage studies of asthma and related phenotypes and provide inferences about the consistency of results and to identify novel regions for future gene discovery. METHODS: The rank based genome-scan meta-analysis (GSMA) method was used to combine linkage data for asthma and related traits; bronchial hyper-responsiveness (BHR), allergen positive skin prick test (SPT) and total serum Immunoglobulin E (IgE) from nine Caucasian asthma populations. RESULTS: Significant evidence for susceptibility loci was identified for quantitative traits including; BHR (989 pedigrees, n = 4,294) 2p12-q22.1, 6p22.3-p21.1 and 11q24.1-qter, allergen SPT (1,093 pedigrees, n = 4,746) 3p22.1-q22.1, 17p12-q24.3 and total IgE (729 pedigrees, n = 3,224) 5q11.2-q14.3 and 6pter-p22.3. Analysis of the asthma phenotype (1,267 pedigrees, n = 5,832) did not identify any region showing genome-wide significance. CONCLUSION: This study represents the first linkage meta-analysis to determine the relative contribution of chromosomal regions to the risk of developing asthma and atopy. Several significant results were obtained for quantitative traits but not for asthma confirming the increased phenotype and genetic heterogeneity in asthma. These analyses support the contribution of regions that contain previously identified asthma susceptibility genes and provide the first evidence for susceptibility loci on 5q11.2-q14.3 and 11q24.1-qter.
AU  - Denham, S.*
AU  - Koppelman, G.H.*
AU  - Blakey, J.*
AU  - Wjst, M.
AU  - Ferreira, M.A.*
AU  - Hall, I.P.*
AU  - Sayers, I.*
C1  - 3498
C2  - 25804
TI  - Meta-analysis of genome-wide linkage studies of asthma and related traits.
JO  - Respir. Res.
VL  - 9
PB  - Biomed Central
PY  - 2008
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - There is growing epidemiological evidence that short-term and long-term exposure to high levels of air pollution may increase cardiovascular morbidity and mortality. In addition, epidemiological studies have shown an association between air pollution exposure and respiratory health. To what extent the association between cardiovascular mortality and air pollution is driven by the impact of air pollution on respiratory health is unknown. The aim of this study was to investigate whether respiratory health at baseline contributes to the effects of long-term exposure to high levels of air pollution on cardiovascular mortality in a cohort of elderly women.
AU  - Schikowski, T.*
AU  - Sugiri, D.*
AU  - Ranft, U.*
AU  - Gehring, U.
AU  - Heinrich, J.
AU  - Wichmann, H.-E.
AU  - Krämer, U.*
C1  - 5841
C2  - 24438
TI  - Does respiratory health contribute to the effects of long-term air pollution exposure on cardiovascular mortality?
JO  - Respir. Res.
VL  - 8
PB  - BioMed Central
PY  - 2007
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Spherical monodisperse ferromagnetic iron oxide particles of 1.9 microm geometric and 4.2 microm aerodynamic diameter were inhaled by seven patients with primary ciliary dyskinesia (PCD) using the shallow bolus technique, and compared to 13 healthy non-smokers (NS) from a previous study. The bolus penetration front depth was limiting to the phase1 dead space volume. In PCD patients deposition was 58+/-8 % after 8 s breath holding time. Particle retention was measured by the magnetopneumographic method over a period of nine months. Particle clearance from the airways showed a fast and a slow phase. In PCD patients airway clearance was retarded and prolonged, 42+/-12 % followed the fast phase with a mean half time of 16.8+/-8.6 hours. The remaining fraction was cleared slowly with a half time of 121+/-25 days. In healthy NS 49+/-9 % of particles were cleared in the fast phase with a mean half time of 3.0+/-1.6 hours, characteristic of an intact mucociliary clearance. There was no difference in the slow clearance phase between PCD patients and healthy NS. Despite non-functioning cilia the effectiveness of airway clearance in PCD patients is comparable to healthy NS, with a prolonged kinetics of one week, which may primarily reflect the effectiveness of cough clearance. This prolonged airway clearance allows longer residence times of bacteria and viruses in the airways and may be one reason for increased frequency of infections in PCD patients.
AU  - Möller, W.
AU  - Häußinger, K.*
AU  - Ziegler-Heitbrock, L.
AU  - Heyder, J.
C1  - 3561
C2  - 23447
SP  - 1-8
TI  - Mucociliary and long-term particle clearance in airways of patients with immotile cilia.
JO  - Respir. Res.
VL  - 7
PY  - 2006
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: ADAM33, the first asthma candidate gene identified by positional cloning, may be associated with childhood asthma, lung function decline and bronchial hyperresponsiveness. However, replication results have been inconclusive in smaller previous study populations probably due to inconsistencies in asthma phenotypes or yet unknown environmental influences. Thus, we tried to further elucidate the role of ADAM33 polymorphisms (SNPs) in a genetic analysis of German case control and longitudinal populations. Methods: Using MALDI-TOF, ten ADAM33 SNPs were genotyped in 1,872 children from the International Study of Asthma and Allergy in Childhood (ISAAC II) in a case control setting and further 824 children from the longitudinal cohort Multicentre Study of Allergy (MAS). In both populations the effects of single SNPs and haplotypes were studied and a gene environment analysis with passive smoke exposure was performed using SAS/Genetics. Results: No single SNP showed a significant association with doctor's diagnosis of asthma. A trend for somewhat more profound effects of ADAM33 SNPs was observed in individuals with asthma and BHR. Haplotype analyses suggested a minor effect of the ADAM33 haplotype H4 on asthma (p = 0.033) but not on BHR. Associations with non atopic asthma and baseline lung function were identified but no interaction with passive smoke exposure could be detected. Conclusion: The originally reported association between ADAM33 polymorphisms and asthma and BHR could not be confirmed. However, our data may suggest a complex role of ADAM33 polymorphisms in asthma ethiology, especially in non atopic asthma. © 2006 Schedel et al; licensee BioMed Central Ltd.
AU  - Schedel, M.*
AU  - Depner, M.*
AU  - Schoen, C.*
AU  - Weiland, S.K.*
AU  - Vogelberg, C.*
AU  - Niggemann, B.*
AU  - Lau, S.*
AU  - Illig, T.
AU  - Klopp, N.
AU  - Wahn, U.*
AU  - von Mutius, E.*
AU  - Nickel, R.*
AU  - Kabesch, M.*
C1  - 2827
C2  - 24043
SP  - 1-12
TI  - The role polymorphisms in ADAM33, a disintegrin and metalloprotease 33, in childhood asthma and lung function in two German populations.
JO  - Respir. Res.
VL  - 7
IS  - 91
PY  - 2006
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - The vitamin D prophylaxis of rickets in pregnant women and newborns may play a role in early allergic sensitization. We now asked if an already diseased population may have inherited genetic variants in the vitamin D turnover or signalling pathway. Serum levels of calcidiol (25-OH-D3) and calcitriol (1,25-(OH)2-D3) were retrospectively assessed in 872 partipants of the German Asthma Family Study. 96 DNA single base variants in 13 different genes were genotyped with MALDI-TOF and a bead array system. At least one positive SNP with
      	a TDT of p < 0.05 for asthma or total IgE and calcidiol or calcitriol was seen in IL10, GC, IL12B, CYP2R1, IL4R, and CYP24A1. Consistent strong genotypic association could not be observed. Haplotype association were found only for CYP24A1, the main calcidiol degrading enzyme, where a frequent 5-point-haplotype was associated with asthma (p = 0,00063), total IgE (p = 0,0014),
      	calcidiol (p = 0,0043) and calcitriol (p = 0,0046). Genetic analysis of biological pathways seem to be a promising approach where this may be a first entry point into effects of a polygenic inherited vitamin D sensitivity that may affect also other metabolic, immunological and cancerous diseases.
AU  - Wjst, M.
AU  - Altmüller, J.
AU  - Faus-Kessler, T.
AU  - Braig, C.
AU  - Bahnweg, M.
AU  - André, E.
C1  - 3069
C2  - 23795
SP  - 1-11
TI  - Asthma families show transmission disequilibrium of gene variants in the vitamin D metabolism and signalling pathway.
JO  - Respir. Res.
VL  - 7
PY  - 2006
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background: According to the hygiene hypothesis, infections in early life protect from allergic diseases. However, in earlier studies surrogate measures of infection rather than clinical infections
      	were associated with decreased frequencies of atopic diseases. Exposure to infection indicating sub-clinical infection rather than clinical infection might protect from atopic diseases. Objective: to investigate whether exposure to acute respiratory infections within pregnancy and the first year of life is associated with atopic conditions at age 5–14 years and to explore when within pregnancy and the first year of life this exposure is most likely to be protective. Methods: Historical cohort study: Population level data on acute respiratory infections from the routine reporting system of the former German Democratic Republic were linked with individual data from consecutive surveys on atopic diseases in the same region (n = 4672). Statistical analyses included multivariate logistic regression analysis and polynomial distributed lag models. Results: High exposure to acute respiratory infection between pregnancy and age one year was
      	associated with overall reduced odds of asthma, eczema, hay fever, atopic sensitization and total IgE. Exposure in the first 9 months of life showed the most pronounced effect. Adjusted odds ratio's for asthma, hay fever, inhalant sensitization and total IgE were statistical significantly reduced up to around half. Conclusion: Exposure to respiratory infection (most likely indicating sub-clinical infection) within
      	pregnancy and the first year of life may be protective in atopic diseases development. The postnatal period thereby seems to be particularly important.
AU  - Zutavern, A.
AU  - von Klot, S.
AU  - Gehring, U.*
AU  - Krauss-Etschmann, S.
C1  - 3294
C2  - 23799
SP  - 81
TI  - Pre-natal and post-natal exposure to respiratory infection and atopic diseases development: A historical cohort study.
JO  - Respir. Res.
VL  - 7
PY  - 2006
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - BACKGROUND: Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+ T cells accumulate in pediatric ILD and are related to disease severity. METHODS: Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+ and CXCR3+ T cells were quantified by flow-cytometry. RESULTS: CCR2+ T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+ T cells in bronchoalveolar lavage fluid compared to non-fibrotic children. CONCLUSION: The results indicate that pulmonary CCR2+ T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies.  
AU  - Hartl, D.*
AU  - Griese, M.*
AU  - Nicolai, T.*
AU  - Zissel, G.*
AU  - Prell, C.*
AU  - Reinhardt, D.*
AU  - Schendel, D.J.
AU  - Krauss-Etschmann, S.
C1  - 4796
C2  - 22915
SP  - 93-104
TI  - A role for MCP-I/CCR2 in interstitial lung disease in children.
JO  - Respir. Res.
VL  - 6
PY  - 2005
SN  - 1465-9921
ER  - 

TY  - JOUR
AB  - Background Lung function and exacerbations of chronic obstructive pulmonary disease (COPD) have been associated with short-term exposure to air pollution. However, the effect of long-term exposure to particulate matter from industry and traffic on COPD as defined by lung function has not been evaluated so far. Our study was designed to investigate the influence of long-term exposure to air pollution on respiratory symptoms and pulmonary function in 55-year-old women. We especially focused on COPD as defined by GOLD criteria and additionally compared the effects of air pollution on respiratory symptoms by questionnaire data and by lung function measurements. Methods In consecutive cross sectional studies conducted between 1985–1994, we investigated 4757 women living in the Rhine-Ruhr Basin of Germany. NO2 and PM10 exposure was assessed by measurements done in an 8 km grid, and traffic exposure by distance from the residential address to the nearest major road using Geographic Information System data. Lung function was determined and COPD was defined by using the GOLD criteria. Chronic respiratory symptoms and possible confounders were defined by questionnaire data. Linear and logistic regressions, including random effects were used to account for confounding and clustering on city level. Results The prevalence of COPD (GOLD stages 1–4) was 4.5%. COPD and pulmonary function were strongest affected by PM10 and traffic related exposure. A 7 μg/m3 increase in five year means of PM10 (interquartile range) was associated with a 5.1% (95% CI 2.5%–7.7%) decrease in FEV1, a 3.7% (95% CI 1.8%–5.5%) decrease in FVC and an odds ratio (OR) of 1.33 (95% CI 1.03–1.72) for COPD. Women living less than 100 m from a busy road also had a significantly decreased lung function and COPD was 1.79 times more likely (95% CI 1.06–3.02) than for those living farther away. Chronic symptoms as based on questionnaire information showed effects in the same direction, but less pronounced. Conclusion Chronic exposure to PM10, NO2 and living near a major road might increase the risk of developing COPD and can have a detrimental effect on lung function.  
AU  - Schikowski, T.*
AU  - Sugiri, D.*
AU  - Ranft, U.*
AU  - Gehring, U.
AU  - Heinrich, J.
AU  - Wichmann, H.-E.
AU  - Krämer, U.*
C1  - 2544
C2  - 23601
SP  - 152
TI  - Long-term air pollution exposure and living close to busy roads are associated with COPD in woman.
JO  - Respir. Res.
VL  - 6
PY  - 2005
SN  - 1465-9921
ER  -