Respiratory Research最新文献

{"title":"CHF6523 data suggest that the phosphoinositide 3-kinase delta isoform is not a suitable target for the management of COPD.","authors":"Mirco Govoni, Michele Bassi, Luca Girardello, Germano Lucci, François Rony, Rémi Charretier, Dmitry Galkin, Maria Laura Faietti, Barbara Pioselli, Gloria Modafferi, Rui Benfeitas, Martina Bonatti, Daniela Miglietta, Jonathan Clark, Frauke Pedersen, Anne-Marie Kirsten, Kai-Michael Beeh, Oliver Kornmann, Stephanie Korn, Andrea Ludwig-Sengpiel, Henrik Watz","doi":"10.1186/s12931-024-02999-5","DOIUrl":"10.1186/s12931-024-02999-5","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory condition. Given patients with COPD continue to experience exacerbations despite the availability of effective therapies, anti-inflammatory treatments targeting novel pathways are needed. Kinases, notably the phosphoinositide 3-kinases (PI3K), are thought to be involved in chronic airway inflammation, with this pathway proposed as a critical regulator of inflammation and oxidative stress response in COPD. CHF6523 is an inhaled PI3Kδ inhibitor that has shown positive preclinical results. This manuscript reports the results of a study of CHF6523 in patients with stable COPD (chronic bronchitis phenotype), and who had evidence of type-2 inflammation.</p><p><strong>Methods: </strong>This randomised, double-blind, placebo-controlled, two-way crossover study comprised two 28-day treatment periods separated by a 28-day washout. Patients (N = 44) inhaled CHF6523 in one period, and placebo in the other, both twice daily. The primary objective was to assess the safety and tolerability of CHF6523; the secondary objective was to assess CHF6523 pharmacokinetics. Exploratory endpoints included target engagement (the relative reduction in phosphatidylinositol (3,4,5)-trisphosphate [PIP₃]), pharmacodynamic evaluations such as airflow obstruction, and hyperinflation, and to identify biomarker(s) of drug response using proteomics and transcriptomics.</p><p><strong>Results: </strong>CHF6523 plasma pharmacokinetics were characterised by an early maximum concentration (C_max), reached 15 and 10 min after dosing on Days 1 and 28, respectively, followed by a rapid decline. Systemic exposure on Day 28 showed limited accumulation, with ratios < 1.6 for C_max and area under the curve from 0 to 12 h post-dose, and with steady state achieved on Day 20. Target engagement was confirmed by a significant 29.7% reduction from baseline in induced sputum PIP₃ (29.5% reduction vs. placebo; adjusted ratio 0.705 [0.580, 0.856]; p = 0.001), but this did not translate into an anti-inflammatory pharmacodynamic effect, as assessed through measures including biomarkers and multi-omics. Additionally, although CHF6523 was generally well-tolerated, 95.2% of patients reported cough as an adverse event, most mild to moderate and resolving within one-hour post-dose.</p><p><strong>Conclusions: </strong>These data, together with those from other PI3K inhibitors, suggest that PI3Kδ is not a suitable pathway for the management of COPD, as the achieved target engagement did not translate into any pharmacodynamic anti-inflammatory effect.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT04032535); posted 23rd July 2019.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"380"},"PeriodicalIF":5.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can switching from cigarettes to heated tobacco products reduce consequences of pulmonary infection?","authors":"Tariq A Bhat, Suresh G Kalathil, Noel J Leigh, Maciej L Goniewicz, Yasmin M Thanavala","doi":"10.1186/s12931-024-02992-y","DOIUrl":"10.1186/s12931-024-02992-y","url":null,"abstract":"<p><strong>Rationale: </strong>While tobacco industry data suggests that switching from combustible cigarettes to heated tobacco products (HTPs), like IQOS, may reduce the users' exposure to respiratory toxicants, it is not known if using HTPs impacts the outcomes of acute respiratory infections.</p><p><strong>Objectives: </strong>Does switching from cigarettes to HTPs improve responses to pulmonary infection.</p><p><strong>Methods: </strong>We conducted experiments in which 3 groups of mice were pre-exposed to cigarette smoke for 8 weeks, followed by 8-week exposure to (1) HTPs (tobacco product switching), (2) air (smoking cessation), or (3) continued exposure to cigarette smoke. Pulmonary bacterial clearance and surrogate markers of lung damage were assessed as study outcomes.</p><p><strong>Main results: </strong>Significantly compromised clearance of bacteria from the lungs post-acute challenge occurred in both the switching group and in mice continuously exposed to cigarette smoke. Bacterial clearance, inflammatory T-cell infiltration into the lungs, and albumin leak improved at 12 h post-acute challenge in the switching group compared to mice continuously exposed to cigarette smoke. Bacterial clearance, total lung immune-cell infiltration, inflammatory T-cell infiltration into the lungs, the content of total proteins in the BAL, and albumin leak measured post-acute challenge were compromised in the switching group compared to mice in the cessation group. Switching from cigarettes to HTPs did not improve lung myeloperoxidase and neutrophil elastase levels (markers for lung inflammation and damage), which, however, were significantly reduced in the cessation group.</p><p><strong>Conclusions: </strong>This study reveals only a modest improvement in respiratory infection outcomes after switching exposure from cigarettes to HTPs and significantly compromised outcomes compared to a complete cessation of exposure to all tobacco products.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"381"},"PeriodicalIF":5.8,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11491011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma genome-wide mendelian randomization identifies potentially causal genes in idiopathic pulmonary fibrosis.","authors":"Kun Zhang, Puyu Shi, Anqi Li, Jiejun Zhou, Mingwei Chen","doi":"10.1186/s12931-024-03008-5","DOIUrl":"https://doi.org/10.1186/s12931-024-03008-5","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF.</p><p><strong>Methods: </strong>We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results.</p><p><strong>Results: </strong>We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17-0.54, FDR_SMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDR_SMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDR_SMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDR_SMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDR_SMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDR_SMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDR_SMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDR_SMR = 0.013) was negatively correlated with the risk of IPF.</p><p><strong>Conclusions: </strong>This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"379"},"PeriodicalIF":5.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11490078/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial.","authors":"Henrik Watz, Anne-Marie Kirsten, Andrea Ludwig-Sengpiel, Matthias Krüll, Robert M Mroz, George Georges, Guido Varoli, Rémi Charretier, Mauro Cortellini, Andrea Vele, Dmitry Galkin","doi":"10.1186/s12931-024-02993-x","DOIUrl":"https://doi.org/10.1186/s12931-024-02993-x","url":null,"abstract":"<p><strong>Background: </strong>The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD.</p><p><strong>Methods: </strong>This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7-10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3.</p><p><strong>Results: </strong>Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate.</p><p><strong>Conclusions: </strong>In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05097014), registered 27th October 2021.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"378"},"PeriodicalIF":5.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-1307-5p enhances fibroblast transdifferentiation to exacerbate chronic obstructive pulmonary disease through regulating FBXL16/HIF1α axis.","authors":"Li-Peng Yao, Zheng-Kai Wang, Xin-Qing Jiang, Beier Jiang, Si-Jia Chen, Zhi-Dan Hua, Dan-Dan Gao, Quan Zheng, Sheng-Mei Zhu, Mao-Xiang Qian, Feng Zhang, Li-Feng Xu, Cheng-Shui Chen, Fang Lu","doi":"10.1186/s12931-024-03007-6","DOIUrl":"https://doi.org/10.1186/s12931-024-03007-6","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive chronic inflammatory lung disease which affects millions of people worldwide. Activated fibroblasts are observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition. In this study, we identified that miR-1307-5p expression was significantly increased in lung fibroblasts derived from COPD patients. Mechanistically, we found that upregulation of miR-1307-5p promoted TGF-β induced lung fibroblast activation and transdifferentiation. We also identified FBXL16 as a direct target for miR-1307-5p mediated myofibroblast activation in COPD. Knockdown of FBXL16 by siRNA prominently increased the expression of myofibroblast markers in MRC-5 fibroblasts after TGF-β administration. Ectopic expression of FBXL16 in MRC-5 counteracted miR-1307-5p agomir-induced fibroblast transdifferentiation. Furthermore, We found that miR-1307-5p promoted pulmonary fibroblast transdifferentiation through FBXL16 regulated HIF1α degradation. In general, our findings indicate that miR-1307-5p is important for COPD pathogenesis, and may serve as a potential target for COPD treatment.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"376"},"PeriodicalIF":5.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of different CPAP levels on ultrasound-assessed lung aeration and gas exchange in neonates.","authors":"Victor Sartorius, Barbara Loi, Laura Vivalda, Giulia Regiroli, Sofia De La Rubia-Ortega, Lucilla Pezza, Manon Midevaine, Shivani Shankar-Aguilera, Rafik Ben-Ammar, Daniele De Luca","doi":"10.1186/s12931-024-03010-x","DOIUrl":"https://doi.org/10.1186/s12931-024-03010-x","url":null,"abstract":"<p><strong>Background: </strong>Respiratory distress syndrome (RDS) and transient tachypnoea (TTN) are the two commonest neonatal respiratory disorders. The optimal continuous positive airway pressure (CPAP) to treat them is unknown. We aim to clarify the effect of different CPAP levels on lung aeration and gas exchange in patients with RDS and TTN.</p><p><strong>Methods: </strong>Prospective, observational, pragmatic, physiological cohort study. CPAP was sequentially increased from 4 to 6 and 8 cmH₂O and backwards, with interposed wash-out periods. Lung aeration was assessed with a validated neonatal lung ultrasound score. Gas exchange was non-invasively evaluated with transcutaneous monitoring. Ultrasound score and PtcO₂/FiO₂ ratio were the co-primary outcomes. PtcCO₂ and other oxygenation metrics were the secondary outcomes.</p><p><strong>Results: </strong>30 neonates with RDS and 30 with TTN were studied. Each CPAP increment significantly (overall always p < 0.001) improved both lung aeration and oxygenation, but the increase from 6 to 8 cmH₂O achieved a small absolute benefit. In RDS patients, the absolute improvements were small and the diagnosis of TTN was significantly associated with greater improvement of lung aeration (β= -1.4 (95%CI: -2.4; -0.3), p = 0.01) and oxygenation (β = 39.6 (95%CI: 4.1; 75.1), p = 0.029). Aeration improved in 16 (53.3%) and 27 (90%) patients in the RDS and TTN groups, respectively (p = 0.034). Lung aeration showed significant hysteresis in TTN patients. Secondary outcomes gave similar results.</p><p><strong>Conclusions: </strong>Increasing CPAP from 4 to 8 cmH₂O improves ultrasound-assessed lung aeration and oxygenation in RDS and TTN. The absolute improvements are small when CPAP is beyond 6 cmH₂O or for RDS patients.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"375"},"PeriodicalIF":5.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefit of dual bronchodilator therapy on exacerbations in former and current smokers with chronic obstructive pulmonary disease in real-world clinical practice: a multicenter validation study (TOReTO).","authors":"Yu-Ting Lai, Ying-Huang Tsai, Meng-Jer Hsieh, Ning-Hung Chen, Shih-Lung Cheng, Chi-Wei Tao, Yu-Feng Wei, Yao-Kuang Wu, Ming-Cheng Chan, Shih-Feng Liu, Wu-Huei Hsu, Tsung-Ming Yang, Ching-Lung Liu, Ping-Hung Kuo, Ming-Shian Lin","doi":"10.1186/s12931-024-02971-3","DOIUrl":"10.1186/s12931-024-02971-3","url":null,"abstract":"<p><strong>Background: </strong>Dual bronchodilator therapy, consisting of a long-acting beta-agonist (LABA) and a long-acting muscarinic antagonist (LAMA), has proven effective for patients with chronic obstructive pulmonary disease (COPD). However, it remains uncertain whether there are efficacy differences between current and former smokers with COPD. This study aims to explore the effectiveness of LABA/LAMA therapies in both these groups.</p><p><strong>Methods: </strong>The TOReTO trial assessed lung function, symptoms, health status, the occurrence of exacerbations, clinically significant exacerbations, and the use of LABA/LAMA therapies. These therapies include Tio/Olo, umeclidinium/vilanterol (Umec/Vi), and umeclidinium/vilanterol (Umec/Vi) are used in patients with COPD. The study examined the differences in outcomes between current and former smokers. To balance the baseline characteristics, propensity score matching (PSM) was employed.</p><p><strong>Results: </strong>Data from 967 patients were collected. After PSM, the time to the first acute exacerbation in current smokers was analyzed separately for the three treatment groups and was significantly different between them (p = 0.0457). Among, there are differences in the occurrence of acute exacerbation between treatment and smoking status in Umec/Vi (p = 0.0114). There is no significant difference in the treatment of former smokers among the three different groups of LABA/LAMA fixed-dose combinations (p = 0.3079). COPD-related symptoms remained stable throughout the treatment period. There were no significant differences in symptom scores, including CAT and mMRC, among the three groups at the end of the study.</p><p><strong>Conclusions: </strong>The three fixed-dose combinations of LABA/LAMA showed no difference in reducing exacerbations in former smokers but did show differences in current smokers. This trend has clinical significance, and future research will be conducted to control influencing variables to validate this point. However, due to the non-randomized study design, these findings should be interpreted with caution.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"377"},"PeriodicalIF":5.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11487693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survival, morbidity, and quality of life in pulmonary arterial hypertension patients: a systematic review of outcomes reported by population-based observational studies.","authors":"Stefan Reinders, Eva-Maria Didden, Rose Ong","doi":"10.1186/s12931-024-02994-w","DOIUrl":"https://doi.org/10.1186/s12931-024-02994-w","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive summaries on real-world outcomes in pulmonary arterial hypertension (PAH)-a rare, incurable condition, are lacking. We conducted a systematic literature review to describe current survival, morbidity, and quality of life (QoL) outcomes in adult and pediatric PAH patients. We searched Medline and Embase electronic databases, clinicaltrials.gov, and encepp.eu entries, and grey literature to identify outcome estimates for right-heart catheterization-confirmed PAH patients from population-based observational studies (search date: 25 Nov 2021). Data were synthesized using a narrative approach and post-hoc subgroup meta-analyses were conducted to explore adult survival by region, disease severity, representativeness, and study period. The search yielded 7473 records. Following screening and full text review, 22 unique studies with 31 individual reports of outcomes were included. Studies were mostly national registries (n = 21), European (n = 13) and covering adults (n = 17); only six had systematic countrywide coverage of centers. Survival was the most frequently reported outcome (n = 22). Global adult 1-, 3-, and 5-year survival ranged from 85 to 99% (n = 15), 65 to 95% (n = 14), and 50 to 86% (n = 9), respectively. Subgroup meta-analysis showed that 1-, 3-, and 5-year survival in Europe was 90% (95% CI 86-94%; n = 8), 78% (95% CI 68-86%; n = 8), and 61% (95% CI 49-72%; n = 6), respectively; 1-year survival in North America was 88% (95% CI 83-93%; n = 3) and 3-year survival in Asia was 85% (95% CI 82-88%; n = 3). No difference in survival between regions was observed. Subgroup analysis suggested higher survival in patients with better baseline functional class; however, interpretation should be cautioned due to large subgroup heterogeneity and potential missingness of data.</p><p><strong>Short conclusion: </strong>This review describes current disease outcomes based on well-defined and representative PAH populations. There is an overall lack of follow-up data for morbidity and QoL outcomes; survival estimates for pediatric patients are scarce and may not be generalizable to the current treatment era, although publications from large pediatric registries became available after our search date. This study demonstrated a remaining unmet need world-wide to improve long-term prognosis in PAH in the current era.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"373"},"PeriodicalIF":5.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A genome-wide association study of adults with community-acquired pneumonia.","authors":"Eva Suarez-Pajes, Itahisa Marcelino-Rodriguez, Elisa Hernández Brito, Silvia Gonzalez-Barbuzano, Melody Ramirez-Falcon, Eva Tosco-Herrera, Luis A Rubio-Rodríguez, María Luisa Briones, Olga Rajas, Luis Borderías, Jose Ferreres, Antoni Payeras, Leonardo Lorente, Javier Aspa, Jose M Lorenzo Salazar, José Manuel Valencia-Gallardo, Nieves Carbonell, Jorge L Freixinet, Felipe Rodríguez de Castro, Jordi Solé Violán, Carlos Flores, Carlos Rodríguez-Gallego","doi":"10.1186/s12931-024-03009-4","DOIUrl":"https://doi.org/10.1186/s12931-024-03009-4","url":null,"abstract":"<p><strong>Background: </strong>Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).</p><p><strong>Methods: </strong>We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.</p><p><strong>Results: </strong>Six independent sentinel variants reached the genome-wide significance (p < 5 × 10^-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.</p><p><strong>Conclusions: </strong>We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"374"},"PeriodicalIF":5.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11484206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and evaluation of a questionnaire to capture environmental and occupational inhalational exposures in adults with fibrotic interstitial lung disease.","authors":"Aparna C Swaminathan, Molly McFatrich, Laura Mkumba, Lauren Wright, Carrie A Redlich, Laurie D Snyder, Bryce B Reeve, Divya Patel, Mridu Gulati","doi":"10.1186/s12931-024-03000-z","DOIUrl":"10.1186/s12931-024-03000-z","url":null,"abstract":"<p><strong>Background: </strong>Identification of exposures in patients with interstitial lung diseases (ILDs) is essential for diagnosis and management and can be facilitated through the use of exposure questionnaires. However, for most ILDs, a patient-focused questionnaire is lacking. Cognitive interviewing is a methodology used to evaluate sources of understanding and misunderstanding in a questionnaire and to provide evidence of content validity. We developed and refined a new exposure questionnaire for patients with fibrotic ILDs by using cognitive interviewing to establish its understandability and content validity.</p><p><strong>Methods: </strong>An exposure assessment questionnaire was developed by a multidisciplinary team. Cognitive interviews with 24 patients with fibrosing ILDs were conducted by trained interviewers over the phone or Zoom using a semi-structured interview guide. The questionnaire was amended based on the interviewers' interpretation of sources of misunderstanding. The revised questionnaire was tested in a second round of cognitive interviews with a different group of 24 patients.</p><p><strong>Results: </strong>Among the 48 patients who completed interviews, mean age was 61 years, 58.3% were male and 75.0% were white. Based on the first round of cognitive interviews, the multidisciplinary team modified the questions, organization, and instructions of the questionnaire to facilitate recall, adjust for exposures that were frequently misunderstood or required clarification, and focus on clinically relevant exposures. The revised questionnaire performed well in the second round of interviews.</p><p><strong>Conclusion: </strong>An exposure questionnaire, developed with input from patients, can be used to assess clinically relevant exposures in adults with fibrosing ILDs. This is the first questionnaire for all types of fibrosing ILD to have undergone content validation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"372"},"PeriodicalIF":5.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11481565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}