TY  - JOUR
AU  - Heinrich, N.*
AU  - Ndjeka, N.*
AU  - Khosa, C.*
AU  - Howell, P.*
AU  - Kranzer, K.*
AU  - Vambe, D.*
AU  - Wasserman, S.*
AU  - Hoelscher, M.
C1  - 75186
C2  - 57830
TI  - endTB-Q results in the face of rising bedaquiline resistance.
JO  - Lancet Resp. Med.
PY  - 2025
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - There is a growing body of data describing the high burden of respiratory sequelae seen among tuberculosis survivors, including children, adolescents, and adults. This group of sequelae are known as post-tuberculosis lung disease and include parenchymal damage, airway disease, and pulmonary vascular disease. It is thought that approximately half of pulmonary tuberculosis survivors have ongoing structural pathology, lung function impairment, or respiratory symptoms after the resolution of active disease. Post-tuberculosis lung disease has been associated with adverse patient outcomes, including persistent symptoms and functional impairment, ongoing health seeking, and impacts on income and employment. There is still much to understand about the epidemiology and nature of post-tuberculosis lung disease, but in this Review we focus on strategies for prevention, diagnosis, and care to inform the ongoing work of tuberculosis-affected communities, health-care providers, researchers, and policy makers. We summarise recent data, highlight evidence gaps, and suggest key research priorities for those working in the field.
AU  - Meghji, J.*
AU  - Auld, S.C.*
AU  - Bisson, G.P.*
AU  - Khosa, C.*
AU  - Masekela, R.*
AU  - Navuluri, N.*
AU  - Rachow, A.
C1  - 73749
C2  - 57214
CY  - 125 London Wall, London, England
SP  - 460-472
TI  - Post-tuberculosis lung disease: towards prevention, diagnosis, and care.
JO  - Lancet Resp. Med.
VL  - 13
IS  - 5
PB  - Elsevier Sci Ltd
PY  - 2025
SN  - 2213-2600
ER  - 

TY  - JOUR
AU  - Stoecklein, S.*
AU  - Koliogiannis, V.*
AU  - Prester, T.*
AU  - Kolben, T.*
AU  - Jegen, M.*
AU  - Hübener, C.*
AU  - Hasbargen, U.*
AU  - Flemmer, A.*
AU  - Dietrich, O.*
AU  - Schinner, R.*
AU  - Dinkel, J.*
AU  - Fink, N.R.*
AU  - Muenchhoff, M.*
AU  - Hintz, S.*
AU  - Delius, M.*
AU  - Mahner, S.*
AU  - Ricke, J.*
AU  - Hilgendorff, A.
C1  - 66500
C2  - 52833
SP  - e36-e37
TI  - Effects of SARS-CoV-2 on prenatal lung growth assessed by fetal MRI.
JO  - Lancet Resp. Med.
VL  - 10
IS  - 4
PY  - 2022
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension. Methods: We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02951429, and is no longer recruiting. The 11-month safety follow-up is ongoing. Findings: Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI −11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group. Interpretation: Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil. Funding: F Hoffmann-La Roche.
AU  - Behr, J.
AU  - Nathan, S.D.*
AU  - Wuyts, W.A.*
AU  - Mogulkoc Bishop, N.*
AU  - Bouros, D.E.*
AU  - Antoniou, K.*
AU  - Guiot, J.*
AU  - Kramer, M.R.*
AU  - Kirchgaessler, K.U.*
AU  - Bengus, M.*
AU  - Gilberg, F.*
AU  - Perjesi, A.*
AU  - Harari, S.*
AU  - Wells, A.U.*
C1  - 60024
C2  - 49173
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 85-95
TI  - Efficacy and safety of sildenafil added to pirfenidone in patients with advanced idiopathic pulmonary fibrosis and risk of pulmonary hypertension: A double-blind, randomised, placebo-controlled, phase 2b trial.
JO  - Lancet Resp. Med.
VL  - 9
IS  - 1
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18?80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40?90% predicted, a diffusing capacity of the lung for carbon monoxide of 10?90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6?24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebocontrolled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32;Background Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. Methods We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Findings Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0.043); the result was similar when the model was stratified by diagnostic group (p=0.042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint.The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1.69 FVC % predicted (95% CI -0.65 to 4.03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3.53 FVC % predicted (95% CI 0.21 to 6.86) with imputation of deaths as prespecified, or 2.79 FVC % predicted (95% CI 0.03 to 5.54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. Interpretation In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. Funding German Center for Lung Research, Roche Pharma.
AU  - Behr, J.*
AU  - Prasse, A.*
AU  - Kreuter, M.*
AU  - Johow, J.*
AU  - Rabe, K.F.*
AU  - Bonella, F.*
AU  - Bonnet, R.*
AU  - Grohe, C.*
AU  - Held, M.*
AU  - Wilkens, H.*
AU  - Hammerl, P.*
AU  - Koschel, D.*
AU  - Blaas, S.*
AU  - Wirtz, H.*
AU  - Ficker, J.H.*
AU  - Neumeister, W.*
AU  - Schoenfeld, N.*
AU  - Claussen, M.*
AU  - Kneidinger, N.*
AU  - Frankenberger, M.
AU  - Hummler, S.*
AU  - Kahn, N.*
AU  - Tello, S.*
AU  - Freise, J.*
AU  - Welte, T.*
AU  - Neuser, P.*
AU  - Guenther, A.*
C1  - 63602
C2  - 51556
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 476-486
TI  - Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): A double-blind, randomised, placebo-controlled, phase 2b trial.
JO  - Lancet Resp. Med.
VL  - 9
IS  - 5
PB  - Elsevier Sci Ltd
PY  - 2021
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. Funding: US National Institutes of Health, Wellcome Trust.
AU  - Moll, M.*
AU  - Sakornsakolpat, P.*
AU  - Shrine, N.*
AU  - Hobbs, B.D.*
AU  - DeMeo, D.L.*
AU  - John, C.*
AU  - Guyatt, A.L.*
AU  - McGeachie, M.J.*
AU  - Gharib, S.A.*
AU  - Obeidat, M.*
AU  - Lahousse, L.*
AU  - Wijnant, S.R.A.*
AU  - Brusselle, G.*
AU  - Meyers, D.A.*
AU  - Bleecker, E.R.*
AU  - Li, X.*
AU  - Tal-Singer, R.*
AU  - Manichaikul, A.*
AU  - Rich, S.S.*
AU  - Won, S.*
AU  - Kim, W.J.*
AU  - Do, A.R.*
AU  - Washko, G.R.*
AU  - Barr, R.G.*
AU  - Psaty, B.M.*
AU  - Bartz, T.M.*
AU  - Hansel, N.N.*
AU  - Barnes, K.*
AU  - Hokanson, J.E.*
AU  - Crapo, J.D.*
AU  - Lynch, D.*
AU  - Bakke, P.*
AU  - Gulsvik, A.*
AU  - Hall, I.P.*
AU  - Wain, L.*
AU  - Soler Artigas, M.*
AU  - Jackson, V.E.*
AU  - Strachan, D.P.*
AU  - Hui, J.*
AU  - James, A.L.*
AU  - Kerr, S.M.*
AU  - Polasek, O.*
AU  - Vitart, V.*
AU  - Marten, J.*
AU  - Rudan, I.*
AU  - Kähönen, M.*
AU  - Surakka, I.*
AU  - SpiroMeta Consortium (Gieger, C.
AU  - Karrasch, S.
AU  - Rawal, R.
AU  - Schulz, H.
AU  - Zeggini, E.)
AU  - Deary, I.J.*
AU  - Harris, SE.*
AU  - Enroth, S.*
AU  - Gyllensten, U.*
AU  - Imboden, M.*
AU  - Probst-Hensch, N*
AU  - Lehtimäki, T.*
AU  - Raitakari, O.T.*
AU  - Langenberg, C.*
AU  - Luan, J.*
AU  - Wareham, N.*
AU  - Zhao, J.H.*
AU  - Hayward, C.*
AU  - Murray, A.*
AU  - Porteous, D.J.*
AU  - Smith, B.H.*
AU  - Jarvelin, M.R.*
AU  - Wielscher, M.*
AU  - Joshi, P.K.*
AU  - Kentistou, K.A.*
AU  - Timmers, P.R.*
AU  - Wilson, J.F.*
AU  - Cook, J.P.*
AU  - Lind, L.*
AU  - Mahajan, A.*
AU  - Morris, A.P.*
AU  - Ewert, R.*
AU  - Homuth, G.*
AU  - Stubbe, B.*
AU  - Weiss, S.*
AU  - Weiss, S.T.*
AU  - Silverman, E.K.*
AU  - Dudbridge, F.*
AU  - Tobin, M.D.*
AU  - Cho, M.H.*
C1  - 60055
C2  - 48959
SP  - 696-708
TI  - Chronic obstructive pulmonary disease and related phenotypes: Polygenic risk scores in population-based and case-control cohorts.
JO  - Lancet Resp. Med.
VL  - 8
IS  - 7
PY  - 2020
SN  - 2213-2600
ER  - 

TY  - JOUR
AU  - Peters, A.
AU  - Künzli, N.*
AU  - Forastiere, F.*
AU  - Hoffmann, B.*
C1  - 56381
C2  - 47036
CY  - The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, Oxon, England
SP  - 650-652
TI  - Promoting clean air: Combating fake news and denial.
JO  - Lancet Resp. Med.
VL  - 7
IS  - 8
PB  - Elsevier Sci Ltd
PY  - 2019
SN  - 2213-2600
ER  - 

TY  - JOUR
AU  - von Mutius, E.
C1  - 53376
C2  - 44839
CY  - Po Box 211, 1000 Ae Amsterdam, Netherlands
SP  - 482-483
TI  - Childhood origins of COPD.
JO  - Lancet Resp. Med.
VL  - 6
IS  - 7
PB  - Elsevier Science Bv
PY  - 2018
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Asthma is the most prevalent chronic respiratory disease both in children and adults and resembles a complex syndrome rather than a single disease. Different methods have been developed to better characterise distinct asthma phenotypes in childhood and adulthood. In studies of adults, most phenotyping relies on biomaterials from the lower airways; however, this information is missing in paediatric studies because of restricted accessibility. Few patients show symptoms throughout childhood, adolescence, and adulthood. Risk factors for this might be genetics, family history of asthma and atopy, infections early in life, allergic diseases, and lung function deficits. In turn, a large proportion of children with asthma lose their symptoms during school age and adolescence. This improved prognosis, which might also reflect a better treatment response, is associated with being male and with milder and less allergic disease. Importantly, whether clinical remission of symptoms equals the disappearance of underlying pathology is unknown. In fact, airway hyper-responsiveness and airway inflammation might remain despite the absence of overt symptoms. Additionally, a new-onset of asthma symptoms is apparent in adulthood, especially in women and in the case of impaired lung function. However, many patients do not remember childhood symptoms, which might reflect relapse rather than true initiation. Both relapse and adult-onset of asthma symptoms have been associated with allergic disease and sensitisation in addition to airway hyper-responsiveness. Thus, asthma symptoms beginning in adults might have originated in childhood. Equivocally, persistence into, relapse, and new-onset of symptoms in adulthood have all been related to active smoking. However, underlying mechanisms for the associations remain unclear, and future asthma research should therefore integrate standardised molecular approaches in identical ways in both paediatric and adult populations and in longitudinal studies.
AU  - Fuchs, O.
AU  - Bahmer, T.*
AU  - Rabe, K.F.*
AU  - von Mutius, E.
C1  - 50764
C2  - 42744
CY  - Oxford
SP  - 224-234
TI  - Asthma transition from childhood into adulthood.
JO  - Lancet Resp. Med.
VL  - 5
IS  - 3
PB  - Elsevier Sci Ltd
PY  - 2017
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: Previous published analyses have focused on the effect of air pollution on asthma and rhinoconjunctivitis throughout early and middle childhood. However, the role of exposure to air pollution in the development of childhood and adolescent asthma and rhinoconjunctivitis remains unclear. We aimed to assess the longitudinal associations between exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence. Methods: We did a population-based birth cohort study of 14 126 participants from four prospective birth cohort studies from Germany, Sweden, and the Netherlands with 14-16 years of follow-up. We linked repeated questionnaire reports of asthma and rhinoconjunctivitis with annual average air pollution concentrations (nitrogen dioxide [NO2], particulate matter [PM] with a diameter of less than 2·5 μm [PM2·5], less than 10 μm [PM10], and between 2·5 μm and 10 μm [PMcoarse], and PM2·5 absorbance [indicator of soot]) at the participants' home addresses. We analysed longitudinal associations of air pollution exposure at participants' birth addresses and addresses at the time of follow-up with asthma and rhinoconjunctivitis incidence and prevalence in cohort-specific analyses, with subsequent meta-analysis and pooled analyses. Findings: Overall, the risk of incident asthma up to age 14-16 years increased with increasing exposure to NO2 (adjusted meta-analysis odds ratio [OR] 1·13 per 10 μg/m3 [95% CI 1·02-1·25]) and PM2·5 absorbance (1·29 per 1 unit [1·00-1·66]) at the birth address. A similar, albeit non-significant, trend was shown for PM2·5 and incident asthma (meta-analysis OR 1·25 per 5 μg/m3 [95% CI 0·94-1·66]). These associations with asthma were more consistent after age 4 years than before that age. There was no indication of an adverse effect of air pollution on rhinoconjunctivitis. Interpretation: Exposure to air pollution early in life might contribute to the development of asthma throughout childhood and adolescence, particularly after age 4 years, when asthma can be more reliably diagnosed. Reductions in levels of air pollution could help to prevent the development of asthma in children. Funding: The European Union.
AU  - Gehring, U.*
AU  - Wijga, A.H.*
AU  - Hoek, G.*
AU  - Bellander, T.*
AU  - Berdel, D.*
AU  - Brüske, I.
AU  - Fuertes, E.
AU  - Gruzieva, O.*
AU  - Heinrich, J.
AU  - Hoffmann, B.*
AU  - de Jongste, J.C.*
AU  - Klümper, C.*
AU  - Koppelman, G.H.*
AU  - Korek, M.*
AU  - Krämer, U.*
AU  - Maier, D.*
AU  - Melén, E.*
AU  - Pershagen, G.*
AU  - Postma, D.S.*
AU  - Standl, M.
AU  - von Berg, A.*
AU  - Antò, J.M.*
AU  - Bousquet, J.*
AU  - Keil, T.*
AU  - Smit, H.A.*
AU  - Brunekreef, B.*
C1  - 47456
C2  - 40538
SP  - 933-942
TI  - Exposure to air pollution and development of asthma and rhinoconjunctivitis throughout childhood and adolescence: A population-based birth cohort study.
JO  - Lancet Resp. Med.
VL  - 3
IS  - 12
PY  - 2015
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - BACKGROUND: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the general population. The lung expression quantitative trait loci (eQTLs) study mapped the genetic architecture of gene expression in lung tissue from 1111 individuals. We used a systems genetics approach to identify single nucleotide polymorphisms (SNPs) associated with lung function that act as eQTLs and change the level of expression of their target genes in lung tissue; termed eSNPs. METHODS: The SpiroMeta-CHARGE GWAS results were integrated with lung eQTLs to map eSNPs and the genes and pathways underlying the associations in lung tissue. For comparison, a similar analysis was done in peripheral blood. The lung mRNA expression levels of the eSNP-regulated genes were tested for associations with lung function measures in 727 individuals. Additional analyses identified the pleiotropic effects of eSNPs from the published GWAS catalogue, and mapped enrichment in regulatory regions from the ENCODE project. Finally, the Connectivity Map database was used to identify potential therapeutics in silico that could reverse the COPD lung tissue gene signature. FINDINGS: SNPs associated with lung function measures were more likely to be eQTLs and vice versa. The integration mapped the specific genes underlying the GWAS signals in lung tissue. The eSNP-regulated genes were enriched for developmental and inflammatory pathways; by comparison, SNPs associated with lung function that were eQTLs in blood, but not in lung, were only involved in inflammatory pathways. Lung function eSNPs were enriched for regulatory elements and were over-represented among genes showing differential expression during fetal lung development. An mRNA gene expression signature for COPD was identified in lung tissue and compared with the Connectivity Map. This in-silico drug repurposing approach suggested several compounds that reverse the COPD gene expression signature, including a nicotine receptor antagonist. These findings represent novel therapeutic pathways for COPD. INTERPRETATION: The system genetics approach identified lung tissue genes driving the variation in lung function and susceptibility to COPD. The identification of these genes and the pathways in which they are enriched is essential to understand the pathophysiology of airway obstruction and to identify novel therapeutic targets and biomarkers for COPD, including drugs that reverse the COPD gene signature in silico. FUNDING: The research reported in this article was not specifically funded by any agency. See Acknowledgments for a full list of funders of the lung eQTL study and the Spiro-Meta CHARGE GWAS.
AU  - Obeidat, M.*
AU  - Hao, K.*
AU  - Bossé, Y.*
AU  - Nickle, D.C.*
AU  - Nie, Y.*
AU  - Postma, D.S.*
AU  - Laviolette, M.*
AU  - Sandford, A.J.*
AU  - Daley, D.D.*
AU  - Hogg, J.C.*
AU  - Elliott, W.M.*
AU  - Fishbane, N.*
AU  - Timens, W.*
AU  - Hysi, P.G.*
AU  - Kaprio, J.*
AU  - Wilson, J.F.*
AU  - Hui, J.*
AU  - Rawal, R.
AU  - Schulz, H.
AU  - Stubbe, B.*
AU  - Hayward, C.*
AU  - Polasek, O.*
AU  - Jarvelin, M.R.*
AU  - Zhao, J.H.*
AU  - Jarvis, D.*
AU  - Kähönen, M.*
AU  - Franceschini, N.*
AU  - North, K.E.*
AU  - Loth, D.W.*
AU  - Brusselle, G.G.*
AU  - Smith, A.V.*
AU  - Gudnason, V.*
AU  - Bartz, T.M.*
AU  - Wilk, J.B.*
AU  - O'Connor, G.T.*
AU  - Cassano, P.A.*
AU  - Tang, W.*
AU  - Wain, L.V.*
AU  - Artigas, M.S.*
AU  - Gharib, S.A.*
AU  - Strachan, D.P.*
AU  - Sin, D.D.*
AU  - Tobin, M.D.*
AU  - London, S.J.*
AU  - Hall, I.P.*
AU  - Paré, P.D.*
C1  - 46946
C2  - 39076
SP  - 782-795
TI  - Molecular mechanisms underlying variations in lung function: A systems genetics analysis.
JO  - Lancet Resp. Med.
VL  - 3
IS  - 10
PY  - 2015
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: Understanding the genetic basis of airflow obstruction and smoking behaviour is key to determining the pathophysiology of chronic obstructive pulmonary disease (COPD). We used UK Biobank data to study the genetic causes of smoking behaviour and lung health. Methods: We sampled individuals of European ancestry from UK Biobank, from the middle and extremes of the forced expiratory volume in 1 s (FEV1) distribution among heavy smokers (mean 35 pack-years) and never smokers. We developed a custom array for UK Biobank to provide optimum genome-wide coverage of common and low-frequency variants, dense coverage of genomic regions already implicated in lung health and disease, and to assay rare coding variants relevant to the UK population. We investigated whether there were shared genetic causes between different phenotypes defined by extremes of FEV1. We also looked for novel variants associated with extremes of FEV1 and smoking behaviour and assessed regions of the genome that had already shown evidence for a role in lung health and disease. We set genome-wide significance at p<5 × 10-8. Findings: UK Biobank participants were recruited from March 15, 2006, to July 7, 2010. Sample selection for the UK BiLEVE study started on Nov 22, 2012, and was completed on Dec 20, 2012. We selected 50 008 unique samples: 10 002 individuals with low FEV1, 10 000 with average FEV1, and 5002 with high FEV1 from each of the heavy smoker and never smoker groups. We noted a substantial sharing of genetic causes of low FEV1 between heavy smokers and never smokers (p=2·29 × 10-16) and between individuals with and without doctor-diagnosed asthma (p=6·06 × 10-11). We discovered six novel genome-wide significant signals of association with extremes of FEV1, including signals at four novel loci (KANSL1, TSEN54, TET2, and RBM19/TBX5) and independent signals at two previously reported loci (NPNT and HLA-DQB1/HLA-DQA2). These variants also showed association with COPD, including in individuals with no history of smoking. The number of copies of a 150 kb region containing the 5' end of KANSL1, a gene that is important for epigenetic gene regulation, was associated with extremes of FEV1. We also discovered five new genome-wide significant signals for smoking behaviour, including a variant in NCAM1 (chromosome 11) and a variant on chromosome 2 (between TEX41 and PABPC1P2) that has a trans effect on expression of NCAM1 in brain tissue. Interpretation: By sampling from the extremes of the lung function distribution in UK Biobank, we identified novel genetic causes of lung function and smoking behaviour. These results provide new insight into the specific mechanisms underlying airflow obstruction, COPD, and tobacco addiction, and show substantial shared genetic architecture underlying airflow obstruction across individuals, irrespective of smoking behaviour and other airway disease. Funding: Medical Research Council.
AU  - Wain, L.V.*
AU  - Shrine, N.*
AU  - Miller, S.*
AU  - Jackson, V.E.*
AU  - Ntalla, I.*
AU  - Artigas, M.S.*
AU  - Billington, C.K.*
AU  - Kheirallah, A.K.*
AU  - Allen, R.P.*
AU  - Cook, J.P.*
AU  - Probert, K.*
AU  - Obeidat, M.*
AU  - Bossé, Y.*
AU  - Hao, K.*
AU  - Postma, D.S.*
AU  - Paré, P.D.*
AU  - Ramasamy, A.*
AU  - Mägi, R.*
AU  - Mihailov, E.*
AU  - Reinmaa, E.*
AU  - Melén, E.*
AU  - O'Connell, J.*
AU  - Frangou, E.*
AU  - Delaneau, O.*
AU  - UK Brain Expression Consortium (Lamina, C.
AU  - Rawal, R.
AU  - Wichmann, H.-E.)
AU  - Freeman, C.*
AU  - Petkova, D.*
AU  - McCarthy, M.*
AU  - Sayers, I.*
AU  - Deloukas, P.*
AU  - Hubbard, R.*
AU  - Pavord, I.D.*
AU  - Hansell, A.L.*
AU  - Thomson, N.C.*
AU  - Zeggini, E.*
AU  - Morris, A.P.*
AU  - Marchini, J.*
AU  - Strachan, D.P.*
AU  - Tobin, M.D.*
AU  - Hall, I.P.*
C1  - 47099
C2  - 39192
SP  - 769-781
TI  - Novel insights into the genetics of smoking behaviour, lung function, and chronic obstructive pulmonary disease (UK BiLEVE): A genetic association study in UK Biobank.
JO  - Lancet Resp. Med.
VL  - 3
IS  - 10
PY  - 2015
SN  - 2213-2600
ER  - 

TY  - JOUR
AU  - Grether, M.*
AU  - Eickelberg, O.
AU  - Mall, M.A.*
AU  - Rabe, K.F.*
AU  - Welte, T.*
AU  - Seeger, W.*
C1  - 42817
C2  - 35346
SP  - e13-e14
TI  - New metrics for translational research.
JO  - Lancet Resp. Med.
VL  - 2
IS  - 8
PY  - 2014
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - BACKGROUND: Eczema, rhinitis, and asthma often coexist (comorbidity) in children, but the proportion of comorbidity not attributable to either chance or the role of IgE sensitisation is unknown. We assessed these factors in children aged 4-8 years. METHODS: In this prospective cohort study, we assessed children from 12 ongoing European birth cohort studies participating in MeDALL (Mechanisms of the Development of ALLergy). We recorded current eczema, rhinitis, and asthma from questionnaires and serum-specific IgE to six allergens. Comorbidity of eczema, rhinitis, and asthma was defined as coexistence of two or three diseases in the same child. We estimated relative and absolute excess comorbidity by comparing observed and expected occurrence of diseases at 4 years and 8 years. We did a longitudinal analysis using log-linear models of the relation between disease at age 4 years and comorbidity at age 8 years. FINDINGS: We assessed 16 147 children aged 4 years and 11 080 aged 8 years in cross-sectional analyses. The absolute excess of any comorbidity was 1·6% for children aged 4 years and 2·2% for children aged 8 years; 44% of the observed comorbidity at age 4 years and 50·0% at age 8 years was not a result of chance. Children with comorbidities at 4 years had an increased risk of having comorbidity at 8 years. The relative risk of any cormorbidity at age 8 years ranged from 36·2 (95% CI 26·8-48·8) for children with rhinitis and eczema at age 4 years to 63·5 (95% CI 51·7-78·1) for children with asthma, rhinitis, and eczema at age 4 years. We did longitudinal assessment of 10 107 children with data at both ages. Children with comorbidities at 4 years without IgE sensitisation had higher relative risks of comorbidity at 8 years than did children who were sensitised to IgE. For children without comorbidity at age 4 years, 38% of the comorbidity at age 8 years was attributable to the presence of IgE sensitisation at age 4 years. INTERPRETATION: Coexistence of eczema, rhinitis, and asthma in the same child is more common than expected by chance alone-both in the presence and absence of IgE sensitisation-suggesting that these diseases share causal mechanisms. Although IgE sensitisation is independently associated with excess comorbidity of eczema, rhinitis, and asthma, its presence accounted only for 38% of comorbidity, suggesting that IgE sensitisation can no longer be considered the dominant causal mechanism of comorbidity for these diseases. FUNDING: EU Seventh Framework Programme.
AU  - Pinart, M.*
AU  - Benet, M.*
AU  - Annesi-Maesano, I.*
AU  - von Berg, A.*
AU  - Berdel, D.*
AU  - Carlsen, K.C.L.*
AU  - Carlsen, K.H.*
AU  - Bindslev-Jensen, C.*
AU  - Eller, E.*
AU  - Fantini, M.P.*
AU  - Lenzi, J.*
AU  - Gehring, U.*
AU  - Heinrich, J.
AU  - Hohmann, C.*
AU  - Just, J.*
AU  - Keil, T.*
AU  - Kerkhof, M.*
AU  - Kogevinas, M.*
AU  - Koletzko, S.*
AU  - Koppelman, G.H.*
AU  - Kull, I.*
AU  - Lau, S.*
AU  - Melén, E.*
AU  - Momas, I.*
AU  - Porta, D.*
AU  - Postma, D.S.*
AU  - Ranciere, F.*
AU  - Smit, H.A.*
AU  - Stein, R.T.*
AU  - Tischer, C.G.
AU  - Torrent, M.*
AU  - Wickman, M.*
AU  - Wijga, A.H.*
AU  - Bousquet, J.*
AU  - Sunyer, J.*
AU  - Basagana, X.*
AU  - Guerra, S.*
AU  - Garcia-Aymerich, J.*
AU  - Antò, J.M.*
C1  - 29309
C2  - 33766
SP  - 131-140
TI  - Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: A population-based cohort study.
JO  - Lancet Resp. Med.
VL  - 2
IS  - 2
PY  - 2014
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Early life influences are crucial for the development of distinct childhood asthma phenotypes, which are currently included under the term asthma syndrome. Improved characterisation of different childhood asthma phenotypes will help to elucidate specific underlying immune mechanisms-namely, endotypes. Besides genetics, epigenetics and environmental factors have an effect on innate and adaptive immune regulatory networks. Crucial determining factors for complex immune regulation and barrier function include family history of atopy, respiratory infections, microbiome, and nutrition. Recent diagnostic approaches, including biomarkers, might offer a unique opportunity to improve definitions of asthma sub-phenotypes, prediction of outcome, and treatment options, by referring to the underlying pathophysiology. For prevention and patient-individualised medicine, a multifactorial approach incorporating deep phenotyping and mathematical models for analysis to extend our present knowledge is needed.
AU  - Rädler, D.
AU  - Schaub, B.
C1  - 32055
C2  - 34958
CY  - Oxford
SP  - 647-656
TI  - Immune mechanisms and development of childhood asthma.
JO  - Lancet Resp. Med.
VL  - 2
IS  - 8
PB  - Elsevier Sci Ltd
PY  - 2014
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. Methods: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. Findings: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10-8). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10-8 (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10-9, after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. Interpretation: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. Funding: European Commission and the Wellcome Trust.
AU  - Rautanen, A.*
AU  - Mills, T.C.*
AU  - Gordon, A.C.*
AU  - Hutton, P.*
AU  - Steffens, M.*
AU  - Nuamah, R.A.*
AU  - Chiche, J.D.*
AU  - Parks, T.L.*
AU  - Chapman, S.J.*
AU  - Davenport, E.E.*
AU  - Elliott, K.S.*
AU  - Bion, J.F.*
AU  - Lichtner, P.
AU  - Meitinger, T.
AU  - Wienker, T.F.*
AU  - Caulfield, M.J.*
AU  - Mein, C.*
AU  - Bloos, F.M.*
AU  - Bobek, I.*
AU  - Cotogni, P.*
AU  - Sramek, V.*
AU  - Sarapuu, S.*
AU  - Kobilay, M.*
AU  - Ranieri, V.M.*
AU  - Rello, J.*
AU  - Sirgo, G.*
AU  - Weiss, Y.G.*
AU  - Russwurm, S.*
AU  - Schneider, E.M.*
AU  - Reinhart, K.*
AU  - Holloway, P.A.H.*
AU  - Knight, J.C.*
AU  - Garrard, C.S.*
AU  - Russell, J.A.*
AU  - Walley, K.R.*
AU  - Stüber, F.*
AU  - Hill, A.V.S.*
AU  - Hinds, C.*
C1  - 43015
C2  - 35969
CY  - Oxford
SP  - 53-60
TI  - Genome-wide association study of survival from sepsis due to pneumonia: An observational cohort study.
JO  - Lancet Resp. Med.
VL  - 3
IS  - 1
PB  - Elsevier Sci Ltd
PY  - 2014
SN  - 2213-2600
ER  - 

TY  - JOUR
AB  - Background: Ambient air pollution has been associated with restricted fetal growth, which is linked with adverse respiratory health in childhood. We assessed the effect of maternal exposure to low concentrations of ambient air pollution on birthweight. Methods: We pooled data from 14 population-based mother-child cohort studies in 12 European countries. Overall, the study population included 74 178 women who had singleton deliveries between Feb 11, 1994, and June 2, 2011, and for whom information about infant birthweight, gestational age, and sex was available. The primary outcome of interest was low birthweight at term (weight <2500 g at birth after 37 weeks of gestation). Mean concentrations of particulate matter with an aerodynamic diameter of less than 2·5 μm (PM2·5), less than 10 μm (PM10), and between 2·5 μm and 10 μm during pregnancy were estimated at maternal home addresses with temporally adjusted land-use regression models, as was PM2·5 absorbance and concentrations of nitrogen dioxide (NO2) and nitrogen oxides. We also investigated traffic density on the nearest road and total traffic load. We calculated pooled effect estimates with random-effects models. Findings: A 5 μg/m3 increase in concentration of PM2·5 during pregnancy was associated with an increased risk of low birthweight at term (adjusted odds ratio [OR] 1·18, 95% CI 1·06-1·33). An increased risk was also recorded for pregnancy concentrations lower than the present European Union annual PM2·5 limit of 25 μg/m3 (OR for 5 μg/m3 increase in participants exposed to concentrations of less than 20 μg/m3 1·41, 95% CI 1·20-1·65). PM10 (OR for 10 μg/m3 increase 1·16, 95% CI 1·00-1·35), NO2 (OR for 10 μg/m3 increase 1·09, 1·00-1·19), and traffic density on nearest street (OR for increase of 5000 vehicles per day 1·06, 1·01-1·11) were also associated with increased risk of low birthweight at term. The population attributable risk estimated for a reduction in PM2·5 concentration to 10 μg/m3 during pregnancy corresponded to a decrease of 22% (95% CI 8-33%) in cases of low birthweight at term. Interpretation: Exposure to ambient air pollutants and traffic during pregnancy is associated with restricted fetal growth. A substantial proportion of cases of low birthweight at term could be prevented in Europe if urban air pollution was reduced. Funding: The European Union.
AU  - Pedersen, M.*
AU  - Giorgis-Allemand, L.*
AU  - Bernard, C.*
AU  - Aguilera, I.*
AU  - Andersen, A.-M.N.*
AU  - Ballester, F.*
AU  - Beelen, R.M.J.*
AU  - Chatzi, L.*
AU  - Cirach, M.*
AU  - Danileviciute, A.*
AU  - van Eijsden, M.*
AU  - Estarlich, M.*
AU  - Fernández-Somoano, A.*
AU  - Fernández, M.F.*
AU  - Forastiere, F.*
AU  - Gehring, U.*
AU  - Grazuleviciene, R.*
AU  - Gruzieva, O.*
AU  - Heude, B.*
AU  - Hoek, G.*
AU  - de Hoogh, K.*
AU  - van den Hoven, E.H.*
AU  - Haberg, S.E.*
AU  - Jaddoe, V.W.V.*
AU  - Klümper, C.*
AU  - Korek, M.*
AU  - Krämer, U.*
AU  - Lerchundi, A.*
AU  - Lepeule, J.*
AU  - Nafstad, P.*
AU  - Nystad, W.*
AU  - Patelarou, E.*
AU  - Porta, D.*
AU  - Postma, D.*
AU  - Raaschou-Nielsen, O.*
AU  - Rudnai, P.*
AU  - Sunyer, J.*
AU  - Stephanou, E.*
AU  - Sorensen, M.*
AU  - Thiering, E.
AU  - Tuffnell, D.*
AU  - Varró, M.J.*
AU  - Vrijkotte, T.G.M.*
AU  - Wijga, A.*
AU  - Wilhelm, M.*
AU  - Wright, J.*
AU  - Nieuwenhuijsen, M.J.*
AU  - Pershagen, G.*
AU  - Brunekreef, B.*
AU  - Kogevinas, M.*
AU  - Stama, R.*
C1  - 27947
C2  - 32872
CY  - Oxford
SP  - 695-704
TI  - Ambient air pollution and low birthweight: A European cohort study (ESCAPE).
JO  - Lancet Resp. Med.
VL  - 1
IS  - 9
PB  - Elsevier
PY  - 2013
SN  - 2213-2600
ER  -