Rationale：IL-4 receptor (IL-4R)-mediated alternative activation of macrophage drives type 2 airway inflammation. Cadherin-26 (CDH26) upregulates epithelial type II IL-4R signaling in asthma. However, whether CDH26 contributes to type I IL-4R-mediated macrophage activation and the mechanism by which CDH26 upregulates IL-4R expression remains unknown. Objectives: To investigate whether CDH26 promotes macrophage alternative activation via suppressing IL-4Rα ubiquitination-proteasomal degradation. Methods: CDH26 expression in bronchoalveolar lavage cells of asthma patients was examined using quantitative PCR and immunostaining. Airway inflammation and macrophage activation were assessed in ovalbumin-sensitized and challenged macrophage-specific Cdh26-deficient mice. Mechanistic experiments included IL-4Rα degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis. Cdh26 siRNA encapsulated lipid nanoparticles were used to treat the mouse model. Measurements and Results: CDH26 expression was enhanced in bronchoalveolar lavage cells from patients with eosinophilic asthma and was localized to lung macrophages. Airway eosinophilia, mucus overproduction and macrophage alternative activation were significantly suppressed in ovalbumin-challenged macrophage-specific Cdh26-deficient mice compared to control mice. Cdh26 deficiency inhibits IL-4Rα expression and STAT6 phosphorylation in macrophages in vitro. Furthermore, CDH26 knockdown enhances whereas CDH26 overexpression suppresses IL-4Rα ubiquitination and proteasomal degradation. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4Rα and subsequent ubiquitination-proteasomal degradation. Cdh26 siRNA encapsulated lipid nanoparticles markedly alleviate airway inflammation, mucus overproduction and macrophage alternative activation in the mouse model. Conclusions: CDH26 interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, thereby amplifying IL-4R signaling in macrophages in asthma. CDH26 is a potential therapeutic target for asthma.
{"title":"Cadherin-26 drives macrophage alternative activation via suppressing STUB1-mediated IL-4Rα ubiquitination in asthma","authors":"Gongqi Chen, Shengchong Chen, Chunli Huang, Wei Gu, Huiru Jie, Lu Zhao, Weiqiang Kong, Jiali Gao, Yuchen Feng, Lingling Yi, Guohua Zhen","doi":"10.1101/2024.08.01.24311333","DOIUrl":"https://doi.org/10.1101/2024.08.01.24311333","url":null,"abstract":"Rationale：IL-4 receptor (IL-4R)-mediated alternative activation of macrophage drives type 2 airway inflammation. Cadherin-26 (CDH26) upregulates epithelial type II IL-4R signaling in asthma. However, whether CDH26 contributes to type I IL-4R-mediated macrophage activation and the mechanism by which CDH26 upregulates IL-4R expression remains unknown. Objectives: To investigate whether CDH26 promotes macrophage alternative activation via suppressing IL-4Rα ubiquitination-proteasomal degradation.\u0000Methods: CDH26 expression in bronchoalveolar lavage cells of asthma patients was examined using quantitative PCR and immunostaining. Airway inflammation and macrophage activation were assessed in ovalbumin-sensitized and challenged macrophage-specific Cdh26-deficient mice. Mechanistic experiments included IL-4Rα degradation and ubiquitination assay, CDH26 co-immunoprecipitation and mass spectrometry analysis. Cdh26 siRNA encapsulated lipid nanoparticles were used to treat the mouse model.\u0000Measurements and Results: CDH26 expression was enhanced in bronchoalveolar lavage cells from patients with eosinophilic asthma and was localized to lung macrophages. Airway eosinophilia, mucus overproduction and macrophage alternative activation were significantly suppressed in ovalbumin-challenged macrophage-specific Cdh26-deficient mice compared to control mice. Cdh26 deficiency inhibits IL-4Rα expression and STAT6 phosphorylation in macrophages in vitro. Furthermore, CDH26 knockdown enhances whereas CDH26 overexpression suppresses IL-4Rα ubiquitination and proteasomal degradation. Mechanistically, CDH26 directly interacts with STUB1 and suppresses the binding of STUB1 to IL-4Rα and subsequent ubiquitination-proteasomal degradation. Cdh26 siRNA encapsulated lipid nanoparticles markedly alleviate airway inflammation, mucus overproduction and macrophage alternative activation in the mouse model. Conclusions: CDH26 interacts with STUB1 and suppresses STUB1-mediated IL-4Rα ubiquitination-proteasomal degradation, thereby amplifying IL-4R signaling in macrophages in asthma. CDH26 is a potential therapeutic target for asthma.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141883956","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}
Pub Date : 2024-07-27DOI: 10.1101/2024.07.25.24309976
Ricardo Sales dos Santos, Ricardo Figueiredo, Juliana P Franceschini, César Augusto de Araújo Neto, Almério Machado, Bruno Hocchegger, Mario Claudio Ghefter, Ulisses Amancio Pereira Neto, Petrucio Abrantes Sarmento, Igor Barbosa Ribeiro, Daniel Augusto Xavier Carvalho, Felipe Passos, Caio Santos Holanda, Marcel Samuel Blech Hamaoui, Gustavo Borges da Silva Teles, Carolina Alves Neves, Helena Alves Costa Pereira, Jackline Pereira Leto, Adelmo de Souza Machado Neto, Audrey Cabral, Fernando Nunes Galvão de Oliveira, Clarissa Maria de Cerqueira Mathias, César Garcia Machado, Josiane Dantas Viana Barbosa, Marine Barbosa, Crislaine Gomes da Silva, Mariana Moreira de Silva, Lila Teixeira de Araújo, Alvaro A. Cruz
Background Lung cancer is a highly aggressive disease that affected almost 2.2 million people worldwide and caused 1.8 million deaths in 2020. Smoking as well as being exposed to cancer-causing substances in the workplace are significant contributors to the chance of developing cancer. Developing countries encounter distinctive obstacles in the implementation of lung cancer screening because of extensive geographical and socioeconomic disparities. Objectives: our primary objective is to describe tomographic findings in a high-risk lung cancer population in limited resource Brazilian areas. The secondary objectives are to quantify the frequency of pulmonary nodules (especially those falling into Lung-RADS categories 3 and 4) as well as the occurrence of lung cancer; to describe and analyze the challenges related to lung cancer screening programs in the context of Brazilian public health system; to explain the pulmonary function pattern and clinical characteristics of individuals diagnosed with moderate or severe emphysema by low-dose computed tomography (LDCT); and to evaluate the commitment of Community Health Assistants in actively recruiting the high-risk population. Methods: This is a prospective cohort study. The study includes individuals in an age range of 50 to 80 years who are either current or former smokers and have a smoking history of at least 20 pack-years. They undergo LDCT with a planned follow up of 12 months. All adverse events are monitored and assisted. The classification of screening results is performed according to the Lung-RADS standards. Individuals classified in categories 3 and 4 receive additional diagnostic assessments and may have further testing. Expected results: we expect this study shows the feasibility and effectiveness of lung cancer screening in people in situation of social vulnerability within limited resource settings, providing vital knowledge to reduce mortality and improve health outcomes. The project will generate relevant knowledge to inform policies on lung cancer screening within the Brazilian public health system, emphasizing the necessity of timely identification and action in limited resource settings. Outcome: The study's dissemination plan includes a website, social media, and participation in scientific conferences. Approval from the ethics committee has been obtained, and rigorous mechanisms are in place to guarantee the privacy of the data.
{"title":"Mobile Lung Cancer Screening in Limited Resource Regions: The ProPulmão Project (BRELT3) Study Protocol","authors":"Ricardo Sales dos Santos, Ricardo Figueiredo, Juliana P Franceschini, César Augusto de Araújo Neto, Almério Machado, Bruno Hocchegger, Mario Claudio Ghefter, Ulisses Amancio Pereira Neto, Petrucio Abrantes Sarmento, Igor Barbosa Ribeiro, Daniel Augusto Xavier Carvalho, Felipe Passos, Caio Santos Holanda, Marcel Samuel Blech Hamaoui, Gustavo Borges da Silva Teles, Carolina Alves Neves, Helena Alves Costa Pereira, Jackline Pereira Leto, Adelmo de Souza Machado Neto, Audrey Cabral, Fernando Nunes Galvão de Oliveira, Clarissa Maria de Cerqueira Mathias, César Garcia Machado, Josiane Dantas Viana Barbosa, Marine Barbosa, Crislaine Gomes da Silva, Mariana Moreira de Silva, Lila Teixeira de Araújo, Alvaro A. Cruz","doi":"10.1101/2024.07.25.24309976","DOIUrl":"https://doi.org/10.1101/2024.07.25.24309976","url":null,"abstract":"Background Lung cancer is a highly aggressive disease that affected almost 2.2 million people worldwide and caused 1.8 million deaths in 2020. Smoking as well as being exposed to cancer-causing substances in the workplace are significant contributors to the chance of developing cancer. Developing countries encounter distinctive obstacles in the implementation of lung cancer screening because of extensive geographical and socioeconomic disparities. Objectives: our primary objective is to describe tomographic findings in a high-risk lung cancer population in limited resource Brazilian areas. The secondary objectives are to quantify the frequency of pulmonary nodules (especially those falling into Lung-RADS categories 3 and 4) as well as the occurrence of lung cancer; to describe and analyze the challenges related to lung cancer screening programs in the context of Brazilian public health system; to explain the pulmonary function pattern and clinical characteristics of individuals diagnosed with moderate or severe emphysema by low-dose computed tomography (LDCT); and to evaluate the commitment of Community Health Assistants in actively recruiting the high-risk population. Methods: This is a prospective cohort study. The study includes individuals in an age range of 50 to 80 years who are either current or former smokers and have a smoking history of at least 20 pack-years. They undergo LDCT with a planned follow up of 12 months. All adverse events are monitored and assisted. The classification of screening results is performed according to the Lung-RADS standards. Individuals classified in categories 3 and 4 receive additional diagnostic assessments and may have further testing. Expected results: we expect this study shows the feasibility and effectiveness of lung cancer screening in people in situation of social vulnerability within limited resource settings, providing vital knowledge to reduce mortality and improve health outcomes. The project will generate relevant knowledge to inform policies on lung cancer screening within the Brazilian public health system, emphasizing the necessity of timely identification and action in limited resource settings. Outcome: The study's dissemination plan includes a website, social media, and participation in scientific conferences. Approval from the ethics committee has been obtained, and rigorous mechanisms are in place to guarantee the privacy of the data.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141776907","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}
Pub Date : 2024-07-27DOI: 10.1101/2024.07.25.24310916
Rosemary E Maher, Urszula Cytlak-Chaudhuri, Saad Aleem, Peter J Barry, Daniel Brice, Eva Caamano-Gutierrez, Kimberley Driver, Edward Emmott, Alexander Rothwell, Emily Smith, Mark Travis, Dave Lee, Paul S McNamara, Ian Waller, Jaclyn A Smith, Andrew M Jones, Robert W Lord
Background: Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy. Methods: We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age- matched healthy controls. Results: Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function. Conclusions: Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.
背景：尽管临床症状有了明显改善，但有证据表明，接受 Elexacaftor/tezacaftor/ivacaftor (ETI) 治疗的囊性纤维化患者的气道炎症仍在持续。由于囊性纤维化是一种多系统疾病，全身免疫状况可反映肺部和其他器官的局部炎症。了解 ETI 治疗后的全身炎症可能会揭示重要的转化观点。本研究旨在描述全身炎症变化，并将这些变化与 ETI 治疗后观察到的有据可查的改善联系起来：我们对 57 名开始接受 ETI 治疗的 CF 受试者进行了一项单中心纵向研究。所有参与者均为 Phe508del 基因同型或 Phe508del 基因/微功能患者。研究人员采集了 ETI 治疗前和治疗后 3-12 个月的血液样本。分析包括基于质谱的蛋白质组学、多重免疫测定和流式细胞术检测外周免疫细胞计数和表型。对照样本由 29 名年龄匹配的健康对照者提供：结果：接受 ETI 治疗后，全身炎症有所减轻；但免疫特征仍与健康对照组不同。ETI 降低了中性粒细胞的数量，并与更成熟、炎症更少的表型以及与 CD206 表达增加相关的免疫清除状态有关。已知会影响中性粒细胞水平的细胞因子随着治疗的进行而减少。尽管接受了 ETI 治疗，但与健康对照组相比，中性粒细胞和单核细胞计数仍然升高。与 ETI 相关的全身炎症改善与肺功能之间没有明显关联：结论：尽管接受了 ETI 治疗，但 CF 患者仍有证据显示全身炎症持续存在，这可能会对呼吸系统和其他器官系统产生长期潜在的不利影响。
{"title":"The effect of highly effective modulator therapy on systemic inflammation in cystic fibrosis","authors":"Rosemary E Maher, Urszula Cytlak-Chaudhuri, Saad Aleem, Peter J Barry, Daniel Brice, Eva Caamano-Gutierrez, Kimberley Driver, Edward Emmott, Alexander Rothwell, Emily Smith, Mark Travis, Dave Lee, Paul S McNamara, Ian Waller, Jaclyn A Smith, Andrew M Jones, Robert W Lord","doi":"10.1101/2024.07.25.24310916","DOIUrl":"https://doi.org/10.1101/2024.07.25.24310916","url":null,"abstract":"Background: Despite significant clinical improvements, there is evidence of persisting airway inflammation in people with cystic fibrosis established on Elexacaftor/tezacaftor/ivacaftor (ETI) therapy. As CF is a multi-system disease, systemic immune profiles can reflect local inflammation within the lungs and other organs. Understanding systemic inflammation after ETI therapy may reveal important translational insights. This study aims to profile systemic inflammatory changes and relate these to the well-documented improvements observed with ETI therapy.\u0000Methods: We conducted a single-centre longitudinal study with 57 CF subjects initiating ETI therapy. All participants were Phe508del homozygous or Phe508del/minimal function. Blood samples were collected pre-ETI and 3-12 months post-therapy initiation. Analyses included mass spectrometry-based proteomics, a multiplex immunoassay, and flow cytometry for peripheral immune cell counts and phenotype. Controls samples were provided by 29 age- matched healthy controls.\u0000Results: Systemic inflammation reduced with ETI therapy; however, the immune profile remained distinct from healthy controls. ETI reduced neutrophil counts and was associated with a more mature, less inflammatory phenotype, as well as a shift toward an immune resolving state associated with increased CD206 expression. Cytokines known to influence neutrophil levels reduced with therapy. Despite ETI therapy, neutrophil and monocyte counts remained elevated compared to healthy controls. There was no obvious association between the ETI-related improvements in systemic inflammation and lung function.\u0000Conclusions: Patients with CF show evidence of persisting systemic inflammation despite ETI therapy, this may have long term potentially adverse effects on respiratory and other organ systems.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141777006","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}
Pub Date : 2024-07-24DOI: 10.1101/2024.07.22.24310787
Anthony K May, Anne E Holland, Jennifer A Alison, Kelcie Herrmann, Narelle S Cox
Objective: To characterize Pulmonary rehabilitation (PR) service delivery, investigate the impact of the pandemic on PR services, and describe centre-based PR (CBPR) and telerehabilitation with reference to PR essential components. Design: Online national cross-sectional survey. Setting: Australian PR services. Participants: Representatives of PR programs listed within the Lung Foundation Australia national database (n=295). Interventions: Not applicable. Main Outcome Measure(s): Availability of PR in CBPR and telerehabilitation settings. Results: 97% of Australian PR services (n=114/117) delivered CBPR, similarly to pre-COVID-19 pandemic availability (96%). 43% (n=50/116) of services delivered telerehabilitation, which was significantly less than availability during COVID-19 restrictions (74%; p<0.001). CBPR was primarily delivered in a group setting (99%; median (IQR) 7 (6-8) participants/group), and telerehabilitation primarily via individual telephone calls (94%). 39% of respondents report CBPR group size has reduced. PR essential components of initial centre-based assessments and individually prescribed/progressed endurance and resistance training were achieved by most CBPR and telerehabilitation programs. Staff training in delivery of telerehabilitation models was undertaken in 33% of services. Conclusions: PR essential components are generally met in current Australian programs. However, telerehabilitation services and CBPR program capacity have declined indicating reduced program capacity. Sustainability of effective PR programs is required to support access for people with chronic respiratory diseases.
{"title":"Telerehabilitation services have declined post-COVID-19","authors":"Anthony K May, Anne E Holland, Jennifer A Alison, Kelcie Herrmann, Narelle S Cox","doi":"10.1101/2024.07.22.24310787","DOIUrl":"https://doi.org/10.1101/2024.07.22.24310787","url":null,"abstract":"Objective: To characterize Pulmonary rehabilitation (PR) service delivery, investigate the impact of the pandemic on PR services, and describe centre-based PR (CBPR) and telerehabilitation with reference to PR essential components.\u0000Design: Online national cross-sectional survey.\u0000Setting: Australian PR services.\u0000Participants: Representatives of PR programs listed within the Lung Foundation Australia national database (n=295).\u0000Interventions: Not applicable.\u0000Main Outcome Measure(s): Availability of PR in CBPR and telerehabilitation settings.\u0000Results: 97% of Australian PR services (n=114/117) delivered CBPR, similarly to pre-COVID-19 pandemic availability (96%). 43% (n=50/116) of services delivered telerehabilitation, which was significantly less than availability during COVID-19 restrictions (74%; p<0.001). CBPR was primarily delivered in a group setting (99%; median (IQR) 7 (6-8) participants/group), and telerehabilitation primarily via individual telephone calls (94%). 39% of respondents report CBPR group size has reduced. PR essential components of initial centre-based assessments and individually prescribed/progressed endurance and resistance training were achieved by most CBPR and telerehabilitation programs. Staff training in delivery of telerehabilitation models was undertaken in 33% of services.\u0000Conclusions: PR essential components are generally met in current Australian programs. However, telerehabilitation services and CBPR program capacity have declined indicating reduced program capacity. Sustainability of effective PR programs is required to support access for people with chronic respiratory diseases.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141776908","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}
Pub Date : 2024-07-21DOI: 10.1101/2024.07.19.24310604
Colin E Swenson, William R Hunt, Candela Manfredi, Diana J Beltran, Jeong S Hong, Brian R Davis, Shingo Suzuki, Cristina Barillá, Andras Rab, Cynthia Chico, Joy Dangerfield, Ashleigh Streby, Elizabeth M Cox, Arlene Stecenko, Adrianna Westbrook, Rebecca Kapolka, Eric J Sorscher
Non-cystic fibrosis bronchiectasis (NCFB) is a disease characterized by abnormal dilatation of the airways, airflow obstruction, persistent cough, excessive sputum production and recurrent lung infections. NCFB exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically ≥60 mEq/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings. Based on a considerable body of evidence, we believe many patients with NCFB have disease likely to benefit from drugs such as elexacaftor/tezacaftor/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF, and has not been adequately tested or proposed for patients with NCFB, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFB. Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers – which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV1, sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFB to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit.
{"title":"Evaluating elexacaftor/tezacaftor/ivacaftor (ETI; Trikafta™) for treatment of patients with non-cystic fibrosis bronchiectasis (NCFB): a clinical study protocol","authors":"Colin E Swenson, William R Hunt, Candela Manfredi, Diana J Beltran, Jeong S Hong, Brian R Davis, Shingo Suzuki, Cristina Barillá, Andras Rab, Cynthia Chico, Joy Dangerfield, Ashleigh Streby, Elizabeth M Cox, Arlene Stecenko, Adrianna Westbrook, Rebecca Kapolka, Eric J Sorscher","doi":"10.1101/2024.07.19.24310604","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310604","url":null,"abstract":"Non-cystic fibrosis bronchiectasis (NCFB) is a disease characterized by abnormal dilatation of the airways, airflow obstruction, persistent cough, excessive sputum production and recurrent lung infections. NCFB exhibits clinical and pathological manifestations similar to key features of cystic fibrosis (CF) lung disease. In CF, pathogenesis results from dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), and diagnosis is made by demonstrating elevated sweat chloride concentrations (typically ≥60 mEq/L), two CFTR mutations known to be causal, multi-organ tissue injury, or combination(s) of these findings. Based on a considerable body of evidence, we believe many patients with NCFB have disease likely to benefit from drugs such as elexacaftor/tezacaftor/ivacaftor (ETI) that activate CFTR-dependent ion transport. ETI is currently prescribed solely for treatment of CF, and has not been adequately tested or proposed for patients with NCFB, many of whom exhibit decreased CFTR function. Accordingly, we are conducting a clinical trial of ETI in subjects carrying a diagnosis of NCFB. Participants will exhibit one disease-causing CFTR mutation and/or sweat chloride measurements of 30-59 mEq/L. Cutaneous punch biopsy or blood samples will be obtained for iPS cell differentiation into airway epithelial monolayers – which will then be tested for response to ETI. Each patient will be given CFTR modulator treatment for approximately four weeks, with monitoring of clinical endpoints that include FEV1, sweat chloride, quality of life questionnaire, and weight. The study will evaluate response of patients with NCFB to ETI, and test usefulness of iPSC-derived airway epithelial monolayers as a novel in vitro technology for predicting clinical benefit.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"336 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739091","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}
Pub Date : 2024-07-21DOI: 10.1101/2024.07.19.24310721
Tae Yoon Lee, John Petkau, Ariana Saatchi, Fawziah Marra, Stuart Turvey, Hannah Lishman, David M. Patrick, Jacquelyn J Cragg, Kate M Johnson, Mohsen Sadatsafavi
Background: Infant antibiotic use is associated with increased risk of asthma. We examined the population impact of antibiotic exposure in the first year of life on the burden of pediatric asthma in British Columbia, Canada, using simulation modeling. Methods: We performed a Bayesian meta-analysis of empirical studies to construct dose-response equations between antibiotic exposure in the first year of life and pediatric (<19 years of age) asthma. We used administrative health data to document trends in infant (< 1 year of age) antibiotic use in British Columbia during 2001 and 2018 (the study period). An independently developed microsimulation model of asthma was utilized to estimate asthma-related outcomes under three scenarios pertaining to the trends in antibiotic use during the study period: 1) observed trends, 2) flat trend in which the prescription rate remained at the 2001 value, and 3) intermediate trends midway between these two. We reported cumulative person-years with asthma, cumulative asthma incidence, and cumulative asthma exacerbations among the pediatric population during the study period. Results: There were 773,160 live births during the study period, with an average antibiotic prescription rate of 523 per 1,000 infants in the first year of life. The prescription rate decreased by 71.5% during the study period. In Scenario 1, there were 1,982,861 person-years with asthma, 183,392 asthma incident cases, and 383,072 exacerbations. Had the antibiotic exposure remained at the 2001 values (Scenario 2), there would have been additional 37,213 person-years with asthma, 10,053 asthma incident cases, and 23,280 exacerbations. Had the decline been half of the observed trend (Scenario 3), there would have been additional 20,318 person-years with asthma, 5,486 asthma incident cases, and 12,728 exacerbations. At least 80% of the excess burden in each outcome was attributable to the younger pediatric population of <10 years of age. Conclusions: The decline in infant antibiotic exposure has resulted in a substantial reduction in the burden of asthma in British Columbia. Such benefits should be considered when evaluating the value proposition of initiatives aimed at reducing unnecessary antibiotic exposure in early life.
{"title":"Impact analysis of infant antibiotic exposure on the burden of asthma: a simulation modeling study","authors":"Tae Yoon Lee, John Petkau, Ariana Saatchi, Fawziah Marra, Stuart Turvey, Hannah Lishman, David M. Patrick, Jacquelyn J Cragg, Kate M Johnson, Mohsen Sadatsafavi","doi":"10.1101/2024.07.19.24310721","DOIUrl":"https://doi.org/10.1101/2024.07.19.24310721","url":null,"abstract":"<strong>Background:</strong> Infant antibiotic use is associated with increased risk of asthma. We examined the population impact of antibiotic exposure in the first year of life on the burden of pediatric asthma in British Columbia, Canada, using simulation modeling. <strong>Methods:</strong> We performed a Bayesian meta-analysis of empirical studies to construct dose-response equations between antibiotic exposure in the first year of life and pediatric (<19 years of age) asthma. We used administrative health data to document trends in infant (< 1 year of age) antibiotic use in British Columbia during 2001 and 2018 (the study period). An independently developed microsimulation model of asthma was utilized to estimate asthma-related outcomes under three scenarios pertaining to the trends in antibiotic use during the study period: 1) observed trends, 2) flat trend in which the prescription rate remained at the 2001 value, and 3) intermediate trends midway between these two. We reported cumulative person-years with asthma, cumulative asthma incidence, and cumulative asthma exacerbations among the pediatric population during the study period. <strong>Results:</strong> There were 773,160 live births during the study period, with an average antibiotic prescription rate of 523 per 1,000 infants in the first year of life. The prescription rate decreased by 71.5% during the study period. In Scenario 1, there were 1,982,861 person-years with asthma, 183,392 asthma incident cases, and 383,072 exacerbations. Had the antibiotic exposure remained at the 2001 values (Scenario 2), there would have been additional 37,213 person-years with asthma, 10,053 asthma incident cases, and 23,280 exacerbations. Had the decline been half of the observed trend (Scenario 3), there would have been additional 20,318 person-years with asthma, 5,486 asthma incident cases, and 12,728 exacerbations. At least 80% of the excess burden in each outcome was attributable to the younger pediatric population of <10 years of age. <strong>Conclusions:</strong> The decline in infant antibiotic exposure has resulted in a substantial reduction in the burden of asthma in British Columbia. Such benefits should be considered when evaluating the value proposition of initiatives aimed at reducing unnecessary antibiotic exposure in early life.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739093","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}
Pub Date : 2024-07-19DOI: 10.1101/2024.07.18.24310648
Alexander T Moffett, Scott D Halpern, Gary E Weissman
Background: Women are more likely than men to report delays in the diagnosis of chronic obstructive pulmonary disease (COPD), though the etiology of these delays is unknown. We sought to test whether delays in COPD diagnosis persist after the performance of spirometry. Methods: We used the Optum Labs Data Warehouse to identify patients 18 years of age and older without a prior diagnosis of COPD, with a post-bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio of less than 0.7 on spirometry. We used a Cox proportional hazards model to compare the time to diagnosis after spirometry in men and women, adjusting for age, race, ethnicity, tobacco use, and post-bronchodilator FEV1/FVC. Results: The probability of receiving a COPD diagnosis after the performance of spirometry was lower among women than men (adjusted hazard ratio [aHR] 0.66, 95% confidence interval [CI] 0.50 to 0.88) Conclusion: In this retrospective cohort study of patients with spirometric evidence of obstruction, the time to diagnosis of COPD was greater among women than men. While previous vignette-based studies have found that gender differences in the diagnosis of COPD resolve with the performance of spirometry, we found that gender differences persist after spirometry has been performed. Clinicians were less likely to diagnose COPD in women even when spirometry supported this diagnosis.
{"title":"Gender Differences in the Diagnosis of Chronic Obstructive Pulmonary Disease after Spirometry","authors":"Alexander T Moffett, Scott D Halpern, Gary E Weissman","doi":"10.1101/2024.07.18.24310648","DOIUrl":"https://doi.org/10.1101/2024.07.18.24310648","url":null,"abstract":"Background: Women are more likely than men to report delays in the diagnosis of chronic obstructive pulmonary disease (COPD), though the etiology of these delays is unknown. We sought to test whether delays in COPD diagnosis persist after the performance of spirometry. Methods: We used the Optum Labs Data Warehouse to identify patients 18 years of age and older without a prior diagnosis of COPD, with a post-bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio of less than 0.7 on spirometry. We used a Cox proportional hazards model to compare the time to diagnosis after spirometry in men and women, adjusting for age, race, ethnicity, tobacco use, and post-bronchodilator FEV1/FVC. Results: The probability of receiving a COPD diagnosis after the performance of spirometry was lower among women than men (adjusted hazard ratio [aHR] 0.66, 95% confidence interval [CI] 0.50 to 0.88) Conclusion: In this retrospective cohort study of patients with spirometric evidence of obstruction, the time to diagnosis of COPD was greater among women than men. While previous vignette-based studies have found that gender differences in the diagnosis of COPD resolve with the performance of spirometry, we found that gender differences persist after spirometry has been performed. Clinicians were less likely to diagnose COPD in women even when spirometry supported this diagnosis.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739199","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}
Background: The respiratory rate (RR) is a critical vital sign controlled by not only metabolic factors but behavior while awake. The prevalence of obstructive sleep apnea (OSA) is remarkably high. Therefore, a non-constraining and non-contact respiratory monitor to measure the RR both while awake and asleep is preferable. Methods: A millimeter wave radar (MWR) device was used for RR monitoring of participants suspected of OSA while awake (supine before and after polysomnography [PSG], sitting, and positioned on both sides) and asleep. Apnea and hypopnea during 1 hour of sleep (AHI) by PSG was compared with 1 hour of respiratory events (REI) judged by MWR. Portable monitoring (PM) and percutaneous arterial O2 (SpO2) monitoring were done simultaneously. Results: Correlations between the RR by MWR and respiratory inductance plethysmography at PSG while awake in every measured position including the supine position before and after PSG were very high (r=0.92~0.99) (n=60). The REI by MWR were significantly correlated with AHI determined by PSG, PM, or SpO2 monitoring (p<0.001). Brand-Altman plot showed that the MWR for AHI monitoring was acceptable. Predicted AHI by MWR relative to PSG was almost the same as with PM or SpO2 monitoring. Conclusions: The developed MWR respiratory monitor was useful during wakefulness and sleep, including detection of apnea and hypopnea. This system can be useful in multiple medical settings such as critical care with and without sleep apnea, pandemic infection, elder care at home, etc.
{"title":"Non-contact and non-constraining monitoring of the respiratory rate including sleep disordered breathing using ultra-wideband radar","authors":"Kazuo Chin, Shigeaki Okumura, Daisuke Endo, Kazuma Nagata, Tatsuya Ito, Kimihiko Murase, Hironobu Sunadome, Mamiko Hoshi, Hisato Hiranuma, Yutaka Kozu, Susumu Sato, Toyohiro Hirai, Yasuhiro Gon, Takuya Sakamoto, Hirofumi Taki, Toshiki Akahoshi","doi":"10.1101/2024.07.08.24310110","DOIUrl":"https://doi.org/10.1101/2024.07.08.24310110","url":null,"abstract":"Background: The respiratory rate (RR) is a critical vital sign controlled by not only metabolic factors but behavior while awake. The prevalence of obstructive sleep apnea (OSA) is remarkably high. Therefore, a non-constraining and non-contact respiratory monitor to measure the RR both while awake and asleep is preferable.\u0000Methods: A millimeter wave radar (MWR) device was used for RR monitoring of participants suspected of OSA while awake (supine before and after polysomnography [PSG], sitting, and positioned on both sides) and asleep. Apnea and hypopnea during 1 hour of sleep (AHI) by PSG was compared with 1 hour of respiratory events (REI) judged by MWR. Portable monitoring (PM) and percutaneous arterial O2 (SpO2) monitoring were done simultaneously.\u0000Results: Correlations between the RR by MWR and respiratory inductance plethysmography at PSG while awake in every measured position including the supine position before and after PSG were very high (r=0.92~0.99) (n=60). The REI by MWR were significantly correlated with AHI determined by PSG, PM, or SpO2 monitoring (p<0.001). Brand-Altman plot showed that the MWR for AHI monitoring was acceptable. Predicted AHI by MWR relative to PSG was almost the same as with PM or SpO2 monitoring.\u0000Conclusions: The developed MWR respiratory monitor was useful during wakefulness and sleep, including detection of apnea and hypopnea. This system can be useful in multiple medical settings such as critical care with and without sleep apnea, pandemic infection, elder care at home, etc.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141567061","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}
Pub Date : 2024-07-08DOI: 10.1101/2024.07.08.24309593
Yalini G Guruparan, Thiyahiny S Navaratinaraja, Gowry Selvaratnam, Shalini Sri Ranganathan
Background Currently inhaled corticosteroids (ICS) alone, or in combined with inhaled long- acting beta2-agonist (LABA) is recommended for chronic asthma. Objective This study aimed to assess the effectiveness of inhaled therapies in a cohort of adult patients with asthma who were receiving treatment in a tertiary hospital in the Northern Sri Lanka. Methods A prospective cohort study was carried out among adult patients with asthma on inhaled medications for at least three months. Participants were followed up for six months with two follow-up interviews three months apart. Primary outcome measure was asthma control which was assessed by a locally validated asthma control patient-reported outcome measure (AC-PROM). Secondary outcome measures were use of short-acting beta2-agonists, number of nebulisations and number of hospitalisations. Chi-squared test was used to determine the significance of differences in outcome measures between the two groups. Logistic regression was performed to determine the association between asthma control and socio-demographic factors. A p-value ≤ 0.05 was considered statistically significant. Results Data from 1094 participants were analysed. Majority were females (73%) and belonged to age group >60 years (60%). Ratio between ICS monotherapy and combined therapy with ICS and LABA (ICS/LABA) was 3:1. A progressive improvement in asthma control was observed in both groups which was significant in those on ICS monotherapy (p<0.001). A significant reduction was also observed in overuse of short-acting beta2-agonist (p<0.001) and number of nebulisations (p=0.027) in participants on ICS monotherapy. No significant association between asthma control and socio-demographic factors was found in either group. Conclusions Both ICS monotherapy and ICS/LABA were effective. However, treatment package comprising regular ICS plus non-pharmacological approaches would be more realistic and cost-effective treatment strategy in the local context. Considering the low availability and current economic status of Sri Lanka, ICS/LABA could be reserved for poorly controlled asthma.
{"title":"Effectiveness of inhaled therapies in asthma among adults in Northern Sri Lanka, a low and middle-income country: A prospective observational study","authors":"Yalini G Guruparan, Thiyahiny S Navaratinaraja, Gowry Selvaratnam, Shalini Sri Ranganathan","doi":"10.1101/2024.07.08.24309593","DOIUrl":"https://doi.org/10.1101/2024.07.08.24309593","url":null,"abstract":"Background Currently inhaled corticosteroids (ICS) alone, or in combined with inhaled long- acting beta2-agonist (LABA) is recommended for chronic asthma.\u0000Objective This study aimed to assess the effectiveness of inhaled therapies in a cohort of adult patients with asthma who were receiving treatment in a tertiary hospital in the Northern Sri Lanka. Methods A prospective cohort study was carried out among adult patients with asthma on inhaled medications for at least three months. Participants were followed up for six months with two follow-up interviews three months apart. Primary outcome measure was asthma control which was assessed by a locally validated asthma control patient-reported outcome measure (AC-PROM). Secondary outcome measures were use of short-acting beta2-agonists, number of nebulisations and number of hospitalisations. Chi-squared test was used to determine the significance of differences in outcome measures between the two groups. Logistic regression was performed to determine the association between asthma control and socio-demographic factors. A p-value ≤ 0.05 was considered statistically significant.\u0000Results Data from 1094 participants were analysed. Majority were females (73%) and belonged to age group >60 years (60%). Ratio between ICS monotherapy and combined therapy with ICS and LABA (ICS/LABA) was 3:1. A progressive improvement in asthma control was observed in both groups which was significant in those on ICS monotherapy (p<0.001). A significant reduction was also observed in overuse of short-acting beta2-agonist (p<0.001) and number of nebulisations (p=0.027) in participants on ICS monotherapy. No significant association between asthma control and socio-demographic factors was found in either group. Conclusions Both ICS monotherapy and ICS/LABA were effective. However, treatment package comprising regular ICS plus non-pharmacological approaches would be more realistic and cost-effective treatment strategy in the local context. Considering the low availability and current economic status of Sri Lanka, ICS/LABA could be reserved for poorly controlled asthma.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"58 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141567063","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}
Pub Date : 2024-06-27DOI: 10.1101/2024.06.27.24309566
Shuyuan Yang, Lap Ah Tse
Rationale Preserved ratio impaired spirometry (PRISm), defined as an impaired forced expiratory volume in one second (FEV1) with a preserved ratio of FEV1 to forced vital capacity (FVC), is associated with increased risk of airflow obstruction (AFO) and mortality in the general population. However, evidence is limited among the individuals with silicosis, an old occupational disease with an ongoing outbreak in some developed countries. Objectives To investigate the association of PRISm with the risk of mortality and incident AFO in a cohort of workers with silicosis. Methods A total of 4315 workers aged 18-80 years and diagnosed with silicosis at the Pneumoconiosis Clinic, Tuberculosis and Chest Service during 1981-2019 were enrolled in this study and followed up for a median of 12.3 years till 31 December 2019. Spirometry was included in the diagnostic examination of silicosis and follow-up reassessments. Lung function categories of participants were classified as normal spirometry (FEV1/FVC ≥ 0.7, FEV1 ≥ 80% predicted), PRISm (FEV1/FVC ≥ 0.7, FEV1 < 80% predicted), and AFO (FEV1/FVC < 0.7). The hazard ratio (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusting for age, body mass index, tuberculosis history, smoking, and radiographic characteristics. Measurements and Main Results During the follow-up period, a total of 2399 (55.6%) subjects died, 1359 of whom died from respiratory-related diseases, and 780 subjects developed AFO. Subjects with PRISm had significantly increased multivariable-adjusted risk of all-cause death (adjusted HR=1.63, 95% CI 1.44-1.85) and respiratory-related mortality (adjusted HR=1.74, 95% CI 1.48-2.05) as compared with the those with normal spirometry. Besides, there was a higher risk of developing AFO in subjects with PRISm than in those with normal spirometry (adjusted HR=1.46, 95% CI 1.22-1.75). No significant interaction was observed between PRISm and smoking status in the risk of all-cause mortality and incident AFO. Conclusions PRISm is significantly associated with increased all-cause and respiratory-related mortality and a greater risk of progression to AFO among the individuals with silicosis.
理论依据肺活量保留比值受损（PRISm）是指一秒钟用力呼气容积（FEV1）受损，但 FEV1 与用力呼吸容量（FVC）的比值保持不变，它与普通人群气流阻塞（AFO）和死亡风险的增加有关。方法1981-2019年期间，共有4315名年龄在18-80岁之间、在肺尘埃沉着病门诊、肺结核和胸科被诊断患有矽肺病的工人被纳入本研究，并随访至2019年12月31日，随访时间中位数为12.3年。肺活量测定包括在矽肺诊断检查和随访复查中。参与者的肺功能类别分为肺活量正常（FEV1/FVC ≥ 0.7，FEV1 ≥ 80% 预测值）、PRISm（FEV1/FVC ≥ 0.7，FEV1 < 80% 预测值）和 AFO（FEV1/FVC < 0.7）。在随访期间，共有 2399 例（55.6%）受试者死亡，其中 1359 例死于呼吸系统相关疾病，780 例受试者出现 AFO。与肺活量正常的受试者相比，PRISm受试者的全因死亡（调整后HR=1.63，95% CI 1.44-1.85）和呼吸相关死亡（调整后HR=1.74，95% CI 1.48-2.05）的多变量调整风险明显增加。此外，与肺活量正常者相比，PRISm 患者发生 AFO 的风险更高（调整后 HR=1.46，95% CI 1.22-1.75）。结论PRISm与矽肺患者的全因死亡率和呼吸系统相关死亡率升高有明显关系，而且矽肺患者发展为AFO的风险更大。
{"title":"Association of preserved ratio impaired spirometry with mortality and airflow obstruction in the silicotics: a longitudinal cohort study","authors":"Shuyuan Yang, Lap Ah Tse","doi":"10.1101/2024.06.27.24309566","DOIUrl":"https://doi.org/10.1101/2024.06.27.24309566","url":null,"abstract":"Rationale\u0000Preserved ratio impaired spirometry (PRISm), defined as an impaired forced expiratory volume in one second (FEV1) with a preserved ratio of FEV1 to forced vital capacity (FVC), is associated with increased risk of airflow obstruction (AFO) and mortality in the general population. However, evidence is limited among the individuals with silicosis, an old occupational disease with an ongoing outbreak in some developed countries.\u0000Objectives\u0000To investigate the association of PRISm with the risk of mortality and incident AFO in a cohort of workers with silicosis.\u0000Methods\u0000A total of 4315 workers aged 18-80 years and diagnosed with silicosis at the Pneumoconiosis Clinic, Tuberculosis and Chest Service during 1981-2019 were enrolled in this study and followed up for a median of 12.3 years till 31 December 2019. Spirometry was included in the diagnostic examination of silicosis and follow-up reassessments. Lung function categories of participants were classified as normal spirometry (FEV1/FVC ≥ 0.7, FEV1 ≥ 80% predicted), PRISm (FEV1/FVC ≥ 0.7, FEV1 < 80% predicted), and AFO (FEV1/FVC < 0.7). The hazard ratio (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusting for age, body mass index, tuberculosis history, smoking, and radiographic characteristics.\u0000Measurements and Main Results\u0000During the follow-up period, a total of 2399 (55.6%) subjects died, 1359 of whom died from respiratory-related diseases, and 780 subjects developed AFO. Subjects with PRISm had significantly increased multivariable-adjusted risk of all-cause death (adjusted HR=1.63, 95% CI 1.44-1.85) and respiratory-related mortality (adjusted HR=1.74, 95% CI 1.48-2.05) as compared with the those with normal spirometry. Besides, there was a higher risk of developing AFO in subjects with PRISm than in those with normal spirometry (adjusted HR=1.46, 95% CI 1.22-1.75). No significant interaction was observed between PRISm and smoking status in the risk of all-cause mortality and incident AFO.\u0000Conclusions\u0000PRISm is significantly associated with increased all-cause and respiratory-related mortality and a greater risk of progression to AFO among the individuals with silicosis.","PeriodicalId":501074,"journal":{"name":"medRxiv - Respiratory Medicine","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141509655","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}
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