The European respiratory journal. Supplement最新文献

{"title":"Antiviral CD8+ T-cell immune responses are impaired by cigarette smoke and in COPD","authors":"Jie Chen, Xinyuan Wang, Adrian Schmalen, S. Haines, Martin Wolff, Huan Ma, Huabin Zhang, M. Stoleriu, Johannes Nowak, M. Nakayama, M. Bueno, J. Brands, A. Mora, Janet S. Lee, S. Krauss‐Etschmann, A. Dmitrieva, M. Frankenberger, Thomas P.J. Hofer, E. Noessner, A. Moosmann, J. Behr, K. Milger, C. Deeg, C. Staab-Weijnitz, S. Hauck, H. Adler, T. Goldmann, K. Gaede, J. Behrends, I. Kammerl, S. Meiners","doi":"10.1183/23120541.lsc-2023.179","DOIUrl":"https://doi.org/10.1183/23120541.lsc-2023.179","url":null,"abstract":"Graphical abstract Main findings of the study. Cigarette smoke impairs virus-induced upregulation of the major histocompatibility complex (MHC) class I antigen presentation machinery resulting in reduced activation of antiviral CD8+ T-cells. Background Virus infections drive COPD exacerbations and progression. Antiviral immunity centres on the activation of virus-specific CD8+ T-cells by viral epitopes presented on major histocompatibility complex (MHC) class I molecules of infected cells. These epitopes are generated by the immunoproteasome, a specialised intracellular protein degradation machine, which is induced by antiviral cytokines in infected cells. Methods We analysed the effects of cigarette smoke on cytokine- and virus-mediated induction of the immunoproteasome in vitro, ex vivo and in vivo using RNA and Western blot analyses. CD8+ T-cell activation was determined in co-culture assays with cigarette smoke-exposed influenza A virus (IAV)-infected cells. Mass-spectrometry-based analysis of MHC class I-bound peptides uncovered the effects of cigarette smoke on inflammatory antigen presentation in lung cells. IAV-specific CD8+ T-cell numbers were determined in patients’ peripheral blood using tetramer technology. Results Cigarette smoke impaired the induction of the immunoproteasome by cytokine signalling and viral infection in lung cells in vitro, ex vivo and in vivo. In addition, cigarette smoke altered the peptide repertoire of antigens presented on MHC class I molecules under inflammatory conditions. Importantly, MHC class I-mediated activation of IAV-specific CD8+ T-cells was dampened by cigarette smoke. COPD patients exhibited reduced numbers of circulating IAV-specific CD8+ T-cells compared to healthy controls and asthmatics. Conclusion Our data indicate that cigarette smoke interferes with MHC class I antigen generation and presentation and thereby contributes to impaired activation of CD8+ T-cells upon virus infection. This adds important mechanistic insight on how cigarette smoke mediates increased susceptibility of smokers and COPD patients to viral infections. Extract COPD is characterised by progressive airflow limitation and alveolar destruction, resulting in reduced lung function and severely diminished quality of life [1]. >10% of the world's population are diagnosed with COPD, with a mortality that makes COPD the third leading cause of death globally [2]. Tobacco smoke consumption is one of the main risk factors for developing COPD [1]. Exacerbations of the disease with sudden decline in lung function are related to viral infections such as rhinovirus and influenza A virus (IAV) or bacteria [3, 4] and contribute to COPD progression [5, 6]. Tweetable abstract Cigarette smoke impairs virus-induced upregulation of the MHC class I antigen presentation machinery resulting in reduced activation of antiviral CD8+ T-cells. This may reduce viral clearance and increase susceptibility to viral exacerbations in COPD. https://bit.ly/43o","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89732903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis","authors":"F. Gafar, R. Wasmann, H. McIlleron, R. Aarnoutse, H. Schaaf, B. Marais, D. Agarwal, S. Antwi, N. D. Bang, A. Bekker, D. Bell, C. Chabala, Louise Choo, G. Davies, J. Day, R. Dayal, P. Denti, P. Donald, E. Engidawork, A. Garcia-Prats, D. Gibb, S. Graham, A. Hesseling, S. Heysell, Misgana I Idris, S. Kabra, A. Kinikar, A. H. Kumar, A. Kwara, R. Lodha, C. Magis-Escurra, Nilza Martinez, B. Mathew, V. Mave, E. Mduma, R. Mlotha-Mitole, S. Mpagama, A. Mukherjee, H. Nataprawira, C. Peloquin, T. Pouplin, G. Ramachandran, Jaya Ranjalkar, V. Roy, R. Ruslami, I. Shah, Yatish Singh, M. Sturkenboom, E. Svensson, S. Swaminathan, Urmilla Thatte, S. Thee, T. Thomas, T. Tikiso, D. Touw, A. Turkova, T. Velpandian, L. M. Verhagen, J. Winckler, Hongmei Yang, V. Yunivita, K. Taxis, J. Stevens, J. Alffenaar","doi":"10.2139/ssrn.4161712","DOIUrl":"https://doi.org/10.2139/ssrn.4161712","url":null,"abstract":"Background Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. Methods We systematically searched MEDLINE, Embase and Web of Science (1990–2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration–time curve from 0 to 24 h post-dose (AUC0–24) and peak plasma concentration (Cmax) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0–24 and Cmax were assessed with linear mixed-effects models. Results Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0–24 were summarised for isoniazid (18.7 (95% CI 15.5–22.6) h·mg·L−1), rifampicin (34.4 (95% CI 29.4–40.3) h·mg·L−1), pyrazinamide (375.0 (95% CI 339.9–413.7) h·mg·L−1) and ethambutol (8.0 (95% CI 6.4–10.0) h·mg·L−1). Our multivariate models indicated that younger age (especially <2 years) and HIV-positive status were associated with lower AUC0–24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0–24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0–24 and slow acetylators had higher isoniazid AUC0–24 than intermediate acetylators. Determinants of Cmax were generally similar to those for AUC0–24. Conclusions This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring. Summary estimates and key determinants of anti-TB drug pharmacokinetics in children and adolescents were assessed from globally available data, advocating for dose adjustment or therapeutic drug monitoring in certain groups at risk of suboptimal exposures https://bit.ly/3Vzw4f0","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89802161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The causal relationship between gastro-oesophageal reflux disease and idiopathic pulmonary fibrosis: a bidirectional two-sample Mendelian randomisation study","authors":"C. Reynolds, F. Del Greco M, R. Allen, C. Flores, R. Jenkins, T. Maher, P. Molyneaux, I. Noth, J. Oldham, L. Wain, Jiyuan An, Jue-Sheng Ong, S. Macgregor, T. Yates, P. Cullinan, C. Minelli","doi":"10.1101/2022.08.31.22279411","DOIUrl":"https://doi.org/10.1101/2022.08.31.22279411","url":null,"abstract":"Background Gastro-oesophageal reflux disease (GORD) is associated with idiopathic pulmonary fibrosis (IPF) in observational studies. It is not known if this association arises because GORD causes IPF or because IPF causes GORD, or because of confounding by factors, such as smoking, associated with both GORD and IPF. We used bidirectional Mendelian randomisation (MR), where genetic variants are used as instrumental variables to address issues of confounding and reverse causation, to examine how, if at all, GORD and IPF are causally related. Methods A bidirectional two-sample MR was performed to estimate the causal effect of GORD on IPF risk and of IPF on GORD risk, using genetic data from the largest GORD (78 707 cases and 288 734 controls) and IPF (4125 cases and 20 464 controls) genome-wide association meta-analyses currently available. Results GORD increased the risk of IPF, with an OR of 1.6 (95% CI 1.04–2.49; p=0.032). There was no evidence of a causal effect of IPF on the risk of GORD, with an OR of 0.999 (95% CI 0.997–1.000; p=0.245). Conclusions We found that GORD increases the risk of IPF, but found no evidence that IPF increases the risk of GORD. GORD should be considered in future studies of IPF risk and interest in it as a potential therapeutic target should be renewed. The mechanisms underlying the effect of GORD on IPF should also be investigated. This bidirectional two-sample Mendelian randomisation study provides strong evidence that gastro-oesophageal reflux disease (GORD) increases the risk of idiopathic pulmonary fibrosis (IPF), but found no evidence that IPF increases the risk of GORD https://bit.ly/3Lde737","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81268946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic overlap between idiopathic pulmonary fibrosis and COVID-19.","authors":"Richard J Allen, Beatriz Guillen-Guio, Emma Croot, Luke M Kraven, Samuel Moss, Iain Stewart, R Gisli Jenkins, Louise V Wain","doi":"10.1183/13993003.03132-2021","DOIUrl":"10.1183/13993003.03132-2021","url":null,"abstract":"","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"223 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9130756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73828745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Update June 2022: management of hospitalised adults with coronavirus disease 2019 (COVID-19): a European Respiratory Society living guideline","authors":"N. Roche, M. Crichton, P. Goeminne, B. Cao, M. Humbert, M. Shteinberg, K. Antoniou, C. Ulrik, H. Parks, Chen Wang, T. Vandendriessche, J. Qu, D. Stolz, C. Brightling, T. Welte, S. Aliberti, A. Simonds, T. Tonia, J. Chalmers","doi":"10.1183/13993003.00803-2022","DOIUrl":"https://doi.org/10.1183/13993003.00803-2022","url":null,"abstract":"Since the identification of SARS-CoV-2 at the end of 2019, the coronavirus disease 2019 (COVID-19) pandemic has affected more than 410 million people worldwide and killed almost 6 million [1, 2]. The predecessors of COVID-19, i.e. the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) outbreaks, had been relatively self-limiting, preventing clinicians and researchers from establishing evidence-based specific therapeutic strategies [3]. Conversely, COVID-19 rapidly proved to be extremely fast spreading, which led stakeholders to encourage, guide, build or fund multidirectional therapeutic research strategies based on both repurposing and development of new agents [4–8]. In parallel, considerable efforts were directed at describing the disease and understanding the underlying mechanisms [9–13]. As a result, there has been a huge generation of evidence, as highlighted by the impressive number of COVID-19 publications (more than 200 000 since the end of 2019). As a consequence, it proved rapidly impossible for any clinician, researcher or decision-maker to gather and analyse all the corresponding literature to derive appropriate guidance [14]. The first step of such a process is to select the relevant high-quality research that can be used to answer the question(s) of interest [15]. Even if limiting the search to clinical trials, systematic reviews and meta-analyses, almost 4000 papers appear in the PubMed database, as of mid-February 2022. In June and July 2020, the European Respiratory Society (ERS) and the American Thoracic Society (ATS) released early guidance on several aspects of COVID-19 management (i.e. rehabilitation, palliative care and acute management); at that time, direct specific evidence was sparse or absent [16–18]. Simultaneously, the ERS launched a living guideline on the management of COVID-19. The format was that of a “short” guideline, as per ERS standards [19, 20], in that the purpose was to release the first iteration within 12 months. However, the number of PICO (Population, Intervention, Comparator, Outcomes) questions to be addressed (n=12) already exceeded markedly what the ERS considers as being feasible during such a short timeframe (i.e. n=1–2), which was a direct consequence of the high number of unanswered issues in the field of acute COVID-19 management, all corresponding to outstanding clinical needs. The first version of these guidelines was published in March 2021 and addressed the following potential therapeutic options: corticosteroids, interleukin (IL)-6 receptor antagonists, hydroxychloroquine, azithromycin and both combined, colchicine, lopinavir-ritonavir, remdesivir, interferon-β, anticoagulation and non-invasive ventilatory support [6, 21]. An update of the mortality meta-analyses for corticosteroids, hydroxychloroquine, azithromycin, remdesivir, anti-IL-6 monoclonal antibodies, colchicine, lopinavir/ritonavir and interferon-β was published in December 2021 [22]. The ERS C","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"119 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77464514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Benefit of monoclonal antibodies in early treatment of COVID-19 after lung transplantation: a retrospective analysis in two centres","authors":"J. Gottlieb, M. Kolditz, Nils Gade, T. Welte, N. Kneidinger","doi":"10.1183/13993003.00124-2022","DOIUrl":"https://doi.org/10.1183/13993003.00124-2022","url":null,"abstract":"Transplant recipients are at risk for poor outcomes from coronavirus disease 2019 (COVID-19) due to frequent medical comorbidities and presence of immunosuppression. Observational cohort studies suggest that patients after lung transplantation (LTx) with COVID-19 may have higher mortality in comparison to other solid organ transplant recipients. In a US retrospective analysis in the beginning of 2020, 78% of infected transplant patients were hospitalised and 19% died within 28 days [1]. Recently, both mortality and hospitalisation rate have declined in transplanted patients [2] and reduced mortality has been associated with vaccination [3]. Treatment with monoclonal antibodies was associated with improved survival in COVID-19 after lung transplantation (LTx). Age was a negative independent predictor of survival in this cohort of 133 COVID-19 cases after LTx. https://bit.ly/3kx5CBw","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81200528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoor microbiome, microbial and plant metabolites, chemical compounds, and asthma symptoms in junior high school students: a multicentre association study in Malaysia","authors":"Yu Sun, Mei Zhang, Zheyuan Ou, Yi Meng, Yang Chen, Ruqin Lin, J. Hashim, Z. Hashim, G. Wieslander, Qingsong Chen, D. Norbäck, Xi Fu","doi":"10.1183/13993003.00260-2022","DOIUrl":"https://doi.org/10.1183/13993003.00260-2022","url":null,"abstract":"Background Indoor microbial exposure is associated with asthma, but the health effects of indoor metabolites and chemicals have not been comprehensively assessed. Methods We collected classroom dust from 24 junior high schools in three geographically distanced areas in Malaysia (Johor Bahru, Terengganu and Penang), and conducted culture-independent high-throughput microbiome and untargeted metabolomics/chemical profiling. Results 1290 students were surveyed for asthma symptoms (wheeze). In each centre, we found significant variation in the prevalence of wheeze among schools, which could be explained by personal characteristics and air pollutants. Large-scale microbial variations were observed between the three centres; the potential protective bacteria were mainly from phyla Actinobacteria in Johor Bahru, Cyanobacteria in Terengganu and Proteobacteria in Penang. In total, 2633 metabolites and chemicals were characterised. Many metabolites were enriched in low-wheeze schools, including plant secondary metabolites flavonoids/isoflavonoids (isoliquiritigenin, formononetin, astragalin), indole and derivatives (indole, serotonin, 1H-indole-3-carboxaldehyde), and others (biotin, chavicol). A neural network analysis showed that the indole derivatives were co-occurring with the potential protective microbial taxa, including Actinomycetospora, Fischerella and Truepera, suggesting these microorganisms may pose health effects by releasing indole metabolites. A few synthetic chemicals were enriched in high-wheeze schools, including pesticides (2(3H)-benzothiazolethione), fragrances (2-aminobenzoic acid, isovaleric acid), detergents and plastics (phthalic acid), and industrial materials (4,4-sulfonyldiphenol). Conclusions This is the first association study between high-throughput indoor chemical profiling and asthma symptoms. The consistent results from the three centres indicate that indoor metabolites/chemicals could be a better indicator than the indoor microbiome for environmental and health assessments, providing new insights for asthma prediction, prevention and control. Natural metabolites (plant-derived flavonoids and isoflavonoids, and micro-organism-derived indole and derivatives) and synthetic chemicals in the indoor environment are important for the development of asthma symptoms. https://bit.ly/3wjfC8g","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84257714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomics in pulmonary medicine: extracting the most from your data","authors":"S. Reinke, R. Chaleckis, C. Wheelock","doi":"10.1183/13993003.00102-2022","DOIUrl":"https://doi.org/10.1183/13993003.00102-2022","url":null,"abstract":"The metabolome enables unprecedented insight into biochemistry, providing an integrated signature of the genome, transcriptome, proteome and exposome. Measurement requires rigorous protocols combined with specialised data analysis to achieve its promise. https://bit.ly/3yPiYkQ","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80308425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mycobacterium tuberculosis-specific CD4 T-cell scoring discriminates tuberculosis infection from disease","authors":"Andrej Mantei, Tim Meyer, M. Schürmann, C. Beßler, H. Bias, D. Krieger, T. Bauer, P. Bacher, J. Helmuth, H. Volk, D. Schürmann, A. Scheffold, C. Meisel","doi":"10.1183/13993003.01780-2021","DOIUrl":"https://doi.org/10.1183/13993003.01780-2021","url":null,"abstract":"Background Rapid and reliable diagnostic work-up of tuberculosis (TB) remains a major healthcare goal. In particular, discrimination of TB infection from TB disease with currently available diagnostic tools is challenging and time consuming. This study aimed at establishing a standardised blood-based assay that rapidly and reliably discriminates TB infection from TB disease based on multiparameter analysis of TB antigen-reactive CD4+ T-cells acting as sensors for TB stage-specific immune status. Methods 157 HIV-negative subjects with suspected TB infection or TB disease were recruited from local tertiary care hospitals in Berlin (Germany). Peripheral blood mononuclear cells were analysed for CD4+ T-cells reactive to the Mycobacterium tuberculosis antigens purified protein derivative and early secretory antigenic target 6 kDa/culture filtrate protein 10. The activation state of TB antigen-reactive T-cells, identified by surface expression of CD154, was evaluated according to the expression profile of proliferation marker Ki-67 and activation markers CD38 and HLA-DR. Using data from 81 subjects with clinically confirmed TB infection (n=34) or culture-proven pulmonary or extrapulmonary TB disease (n=47), 12 parameters were derived from the expression profile and integrated into a scoring system. Results Using the scoring system, our assay (TB-Flow Assay) allowed reliable discrimination of TB infection from both pulmonary and extrapulmonary TB disease with high sensitivity (90.9%) and specificity (93.3%) as was confirmed by Monte-Carlo cross-validation. Conclusion With low time requirement, ease of sample collection, and high sensitivity and specificity both for pulmonary and extrapulmonary TB disease, we believe this novel standardised TB-Flow Assay will improve the work-up of patients with suspected TB disease, supporting rapid TB diagnosis and facilitating treatment decisions. In a prospective study, a scoring system based on analysis of the activation state of tuberculosis (TB)-specific CD4+ T-cells was developed that allows reliable discrimination of TB infection and TB disease with high sensitivity and specificity https://bit.ly/3EFG4KX","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77818551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The paradox of immune checkpoint inhibition re-activating tuberculosis","authors":"Mohamed Ahmed, L. Tezera, P. Elkington, A. Leslie","doi":"10.1183/13993003.02512-2021","DOIUrl":"https://doi.org/10.1183/13993003.02512-2021","url":null,"abstract":"By attenuating T-cell activation, immune checkpoints (ICs) limit optimal anti-tumour responses and IC inhibition (ICI) has emerged as a new therapy for a broad range of cancers. T-cell responses are indispensable to tuberculosis (TB) immunity in humans. However, boosting T-cell immunity in cancer patients by blocking the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis can trigger re-activation of latent TB. This phenomenon appears to contradict the prevailing thought that enhancing T-cell immunity to Mycobacterium tuberculosis will improve immune control of this pathogen. In support of this anecdotal human data, several murine studies have shown that PD-1 deficiency leads to severe TB disease and rapid death. These observations warrant a serious reconsideration of what constitutes effective TB immunity and how ICs contribute to it. Through restraining T-cell responses, ICs are critical to preventing excessive tissue damage and maintaining a range of effector functions. Bolstering this notion, inhibitory receptors limit pathology in respiratory infections such as influenza, where loss of negative immune regulation resulted in progressive immunopathology. In this review, we analyse the mechanisms of ICs in general and their role in TB in particular. We conclude with a reflection on the emerging paradigm and avenues for future research. Immune checkpoint inhibition is employed as a host-directed therapy for cancer, but many reports have shown it can cause re-activation of latent TB. This observation warrants a reappraisal of protective TB immunity and drivers of re-activation. https://bit.ly/3vi2xu0","PeriodicalId":77419,"journal":{"name":"The European respiratory journal. Supplement","volume":"472 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77139239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}