Pub Date : 2025-04-16DOI: 10.1164/rccm.202408-1656oc
Pallavi P Balte,John S Kim,Yifei Sun,Nori Allen,Elsa Angelini,Alexander Arynchyn,R Graham Barr,Michael Blaha,Russell Bowler,Jeff Carr,Shelley A Cole,David Couper,Ryan T Demmer,Margaret Doyle,Mitchell Elkind,Raúl San José Estépar,Olga Garcia-Bedoya,Suresh Garudadri,Nadia N Hansel,Emilia A Hermann,Eric A Hoffman,Stephen M Humphries,Gary M Hunninghake,Robert Kaplan,Jerry A Krishnan,Andrew Laine,Joyce S Lee,David A Lynch,Barry Make,Kunihiro Matsushita,Will McKleroy,Yuan-I Min,Sneha N Naik,George O'Connor,Olivia O'Driscoll,Eyal Oren,Anna J Podolanczuk,Wendy S Post,Tess Pottinger,Elizabeth Regan,Annie Rusk,Mary Salvatore,David A Schwartz,Benjamin Smith,Daniela Sotres-Alvarez,Jason G Umans,Ramachandran S Vasan,George Washko,Sally Wenzel,Prescott Woodruff,Vanessa Xanthakis,Victor E Ortega,Elizabeth C Oelsner
RATIONALEIncreased risk of COVID-19 hospitalization and death has been reported among patients with clinical lung disease.OBJECTIVETo test the association of objective measures of pre-pandemic lung function and structure with COVID-19 outcomes in US adults.METHODSPre-pandemic obstruction (FEV1/FVC<0.70) and restriction (FEV1/FVC≥0.7, FVC<80%) were defined based on the most recent spirometry exam conducted in 11 prospective US general population-based cohorts. Severe obstruction was classified by FEV1<50%. Percent emphysema, percent high attenuation areas (HAA), and interstitial lung abnormalities (ILA) were defined on computed tomography (CT) in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020-2023, and classified as severe (hospitalized or fatal) or non-severe. Cause-specific hazards models were adjusted for socio-demographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status.MEASUREMENTS AND MAIN RESULTSAmong 29,323 participants (mean age, 67 years), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs normal, aHR=2.11;95%CI:1.02-1.27), restriction (vs normal, aHR=1.40;95%CI:1.12-1.76), and percent emphysema (highest vs lowest quartile, aHR= 1.64;95%CI:1.03-2.61), but not greater HAA or ILAs. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease.CONCLUSIONSPre-pandemic severe spirometric obstruction, spirometric restriction, and greater percent emphysema lung on CT were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
{"title":"Associations of Pre-Pandemic Lung Function and Structure with COVID-19 Outcomes: The C4R Study.","authors":"Pallavi P Balte,John S Kim,Yifei Sun,Nori Allen,Elsa Angelini,Alexander Arynchyn,R Graham Barr,Michael Blaha,Russell Bowler,Jeff Carr,Shelley A Cole,David Couper,Ryan T Demmer,Margaret Doyle,Mitchell Elkind,Raúl San José Estépar,Olga Garcia-Bedoya,Suresh Garudadri,Nadia N Hansel,Emilia A Hermann,Eric A Hoffman,Stephen M Humphries,Gary M Hunninghake,Robert Kaplan,Jerry A Krishnan,Andrew Laine,Joyce S Lee,David A Lynch,Barry Make,Kunihiro Matsushita,Will McKleroy,Yuan-I Min,Sneha N Naik,George O'Connor,Olivia O'Driscoll,Eyal Oren,Anna J Podolanczuk,Wendy S Post,Tess Pottinger,Elizabeth Regan,Annie Rusk,Mary Salvatore,David A Schwartz,Benjamin Smith,Daniela Sotres-Alvarez,Jason G Umans,Ramachandran S Vasan,George Washko,Sally Wenzel,Prescott Woodruff,Vanessa Xanthakis,Victor E Ortega,Elizabeth C Oelsner","doi":"10.1164/rccm.202408-1656oc","DOIUrl":"https://doi.org/10.1164/rccm.202408-1656oc","url":null,"abstract":"RATIONALEIncreased risk of COVID-19 hospitalization and death has been reported among patients with clinical lung disease.OBJECTIVETo test the association of objective measures of pre-pandemic lung function and structure with COVID-19 outcomes in US adults.METHODSPre-pandemic obstruction (FEV1/FVC<0.70) and restriction (FEV1/FVC≥0.7, FVC<80%) were defined based on the most recent spirometry exam conducted in 11 prospective US general population-based cohorts. Severe obstruction was classified by FEV1<50%. Percent emphysema, percent high attenuation areas (HAA), and interstitial lung abnormalities (ILA) were defined on computed tomography (CT) in a subset. Incident COVID-19 was ascertained via questionnaires, serosurvey, and medical records from 2020-2023, and classified as severe (hospitalized or fatal) or non-severe. Cause-specific hazards models were adjusted for socio-demographics, anthropometry, smoking, comorbidities, and COVID-19 vaccination status.MEASUREMENTS AND MAIN RESULTSAmong 29,323 participants (mean age, 67 years), there were 748 severe incident COVID-19 cases over median follow-up of 17.3 months from March 1, 2020. Greater hazards of severe COVID-19 were associated with severe obstruction (vs normal, aHR=2.11;95%CI:1.02-1.27), restriction (vs normal, aHR=1.40;95%CI:1.12-1.76), and percent emphysema (highest vs lowest quartile, aHR= 1.64;95%CI:1.03-2.61), but not greater HAA or ILAs. COVID-19 vaccination provided greater absolute risk reduction in these groups. Results were similar in participants without smoking, obesity, or clinical cardiopulmonary disease.CONCLUSIONSPre-pandemic severe spirometric obstruction, spirometric restriction, and greater percent emphysema lung on CT were associated with risk of severe COVID-19. These findings support enhanced COVID-19 risk mitigation for individuals with impaired lung health and warrant further mechanistic studies on interactions of lung function, structure, and vulnerability to acute respiratory illnesses. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"29 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-16DOI: 10.1164/rccm.202411-2173rl
Philipp Simon,David Petroff,Andrew J Simpkin,Tài Pham,Giacomo Bellani,John G Laffey,Hermann Wrigge
{"title":"Adjusting the P/F-Ratio for BMI in Acute Hypoxemic Respiratory Failure Mitigates but Does Not Eliminate the Obesity Paradox.","authors":"Philipp Simon,David Petroff,Andrew J Simpkin,Tài Pham,Giacomo Bellani,John G Laffey,Hermann Wrigge","doi":"10.1164/rccm.202411-2173rl","DOIUrl":"https://doi.org/10.1164/rccm.202411-2173rl","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"108 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202406-1198im
Rui Xu,Kaige Wang,Weimin Li,Dan Liu
{"title":"Argon Plasma Coagulation Combined with Human Fibrin Sealant under Medical Thoracoscopy in the Closure of Bronchopleural Fistula.","authors":"Rui Xu,Kaige Wang,Weimin Li,Dan Liu","doi":"10.1164/rccm.202406-1198im","DOIUrl":"https://doi.org/10.1164/rccm.202406-1198im","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"39 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDPatients with sickle cell disease hospitalised for acute chest syndrome (ACS) are at high risk of in situ pulmonary microthrombosis. We evaluated whether therapeutic anticoagulation could shorten ACS duration.METHODSTASC is a randomized, controlled, double-blind trial conducted in 12 French hospitals (December 2016-April 2021) in adult ACS patients with no initial thrombosis on chest computerised tomography with pulmonary angiogram. We randomised 172 patients (1:1) to receive either prophylactic or therapeutic doses of low-molecular-weight tinzaparin for 7 days. The primary efficacy outcome was time to ACS resolution. The primary safety outcome was major bleeding. Main secondary outcomes included parenteral opioids consumption, transfusion, mortality at hospital discharge, and hospital readmissions at 6 months.FINDINGSThe primary efficacy outcome, time to ACS resolution, analysed using a Cox model, was shorter with therapeutic anticoagulation than with prophylactic doses (hazard ratio 0.71; 95% CI: [0.51-0.99]; p=0.044). As a supplemental estimate, the restricted mean time to ACS resolution (over a 15-day horizon or discharge) was shorter with therapeutic doses (4.8±0.4 vs 6.1±0.5 days). The primary safety outcome (major bleeding) did not occur in either group. The cumulative dose of parenteral opioids was lower with therapeutic anticoagulation: (124 [80;272] vs 219 [65;378] mg morphine equivalent, difference: -96, 95%CI: -202 to -46, p=0.02). Other short- and long-term secondary outcomes were similar between groups.INTERPRETATIONIn adult patients with ACS, a therapeutic anticoagulation shortened ACS duration and reduced opioids consumption compared with prophylactic doses, without increasing bleeding risk. Clinical trial registration available at www.CLINICALTRIALSgov, ID: NCT02580773.
{"title":"Comparison of Prophylactic and Therapeutic Doses of Anticoagulation for Acute Chest Syndrome in Sickle Cell Disease: The TASC Randomized Clinical Trial.","authors":"Armand Mekontso Dessap,Anoosha Habibi,Jean-Benoît Arlet,Muriel Fartoukh,Laurent Guerin,Constance Guillaud,Damien Roux,Johanna Oziel,Stéphanie Ngo,Benjamin Carpentier,Marilucy Lopez-Sublet,Louis Affo,Giovanna Melica,Maryse Etienne-Julan,Isabelle Delacroix,François Lionnet,Gylna Loko,Daniel Da Silva,Marc Michel,Keyvan Razazi,Anaïs Charles-Nelson,Pablo Bartolucci,Ségolène Gendreau,Sandrine Katsahian,Bernard Maitre","doi":"10.1164/rccm.202409-1727oc","DOIUrl":"https://doi.org/10.1164/rccm.202409-1727oc","url":null,"abstract":"BACKGROUNDPatients with sickle cell disease hospitalised for acute chest syndrome (ACS) are at high risk of in situ pulmonary microthrombosis. We evaluated whether therapeutic anticoagulation could shorten ACS duration.METHODSTASC is a randomized, controlled, double-blind trial conducted in 12 French hospitals (December 2016-April 2021) in adult ACS patients with no initial thrombosis on chest computerised tomography with pulmonary angiogram. We randomised 172 patients (1:1) to receive either prophylactic or therapeutic doses of low-molecular-weight tinzaparin for 7 days. The primary efficacy outcome was time to ACS resolution. The primary safety outcome was major bleeding. Main secondary outcomes included parenteral opioids consumption, transfusion, mortality at hospital discharge, and hospital readmissions at 6 months.FINDINGSThe primary efficacy outcome, time to ACS resolution, analysed using a Cox model, was shorter with therapeutic anticoagulation than with prophylactic doses (hazard ratio 0.71; 95% CI: [0.51-0.99]; p=0.044). As a supplemental estimate, the restricted mean time to ACS resolution (over a 15-day horizon or discharge) was shorter with therapeutic doses (4.8±0.4 vs 6.1±0.5 days). The primary safety outcome (major bleeding) did not occur in either group. The cumulative dose of parenteral opioids was lower with therapeutic anticoagulation: (124 [80;272] vs 219 [65;378] mg morphine equivalent, difference: -96, 95%CI: -202 to -46, p=0.02). Other short- and long-term secondary outcomes were similar between groups.INTERPRETATIONIn adult patients with ACS, a therapeutic anticoagulation shortened ACS duration and reduced opioids consumption compared with prophylactic doses, without increasing bleeding risk. Clinical trial registration available at www.CLINICALTRIALSgov, ID: NCT02580773.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"23 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202407-1506oc
Shehabaldin Alqalyoobi,Jennifer A Smith,Manoj V Maddali,Janelle Vu Pugashetti,Chad A Newton,John S Kim,Angela L Linderholm,Ching-Hsien Chen,Shwu-Fan Ma,Swaraj Bose,Susan Murray,Ayodeji Adegunsoye,Mary E Strek,Christine Kim Garcia,Paul J Wolters,Fernando J Martinez,Imre Noth,Justin M Oldham
RATIONALEWhile idiopathic pulmonary fibrosis (IPF) has been widely studied, progressive non-IPF interstitial lung disease (ILD) remains poorly understood.OBJECTIVETo identify and validate proteomic biomarkers of non-IPF ILD survival.METHODSHigh-throughput proteomic data were generated using plasma collected as part of prospective registries at the Universities of California and Texas (discovery cohort, n=676) and PRECISIONS multi-omic study (validation cohort, n=616). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression, and those associated with TFS after adjustment for false discovery were advanced for validation cohort testing. Pathway analysis was performed to identify molecular pathways unique to non-IPF ILD and shared with IPF.MAIN RESULTSOf 2925 proteins tested in the discovery cohort, 73 were associated with TFS, with 44 showing sustained TFS association in the validation cohort. The top TFS-associated proteins were amphiregulin (HR 2.51, 95% CI 2.07-3.04), integrin subunit beta 6 (HR 2.46; 95% CI 1.95-3.10) and keratin 19 (HR 1.70, 95% CI 1.47-1.98). All but one validated biomarkers showed consistent TFS association across non-IPF ILD subtypes. Pathway analysis identified several molecular pathways shared with IPF, along with three pathways unique to non-IPF ILD.CONCLUSIONSWe identified and validated novel prognostic protein biomarkers in non-IPF ILD, most of which showed consistent association across non-IPF ILD subtypes. While most biomarkers and molecular pathways identified were previously linked to IPF, several were unique to non-IPF ILD, suggesting that unique biology may contribute to progressive non-IPF ILD.
{"title":"Proteomic Biomarkers of Survival in Non-IPF Interstitial Lung Disease.","authors":"Shehabaldin Alqalyoobi,Jennifer A Smith,Manoj V Maddali,Janelle Vu Pugashetti,Chad A Newton,John S Kim,Angela L Linderholm,Ching-Hsien Chen,Shwu-Fan Ma,Swaraj Bose,Susan Murray,Ayodeji Adegunsoye,Mary E Strek,Christine Kim Garcia,Paul J Wolters,Fernando J Martinez,Imre Noth,Justin M Oldham","doi":"10.1164/rccm.202407-1506oc","DOIUrl":"https://doi.org/10.1164/rccm.202407-1506oc","url":null,"abstract":"RATIONALEWhile idiopathic pulmonary fibrosis (IPF) has been widely studied, progressive non-IPF interstitial lung disease (ILD) remains poorly understood.OBJECTIVETo identify and validate proteomic biomarkers of non-IPF ILD survival.METHODSHigh-throughput proteomic data were generated using plasma collected as part of prospective registries at the Universities of California and Texas (discovery cohort, n=676) and PRECISIONS multi-omic study (validation cohort, n=616). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression, and those associated with TFS after adjustment for false discovery were advanced for validation cohort testing. Pathway analysis was performed to identify molecular pathways unique to non-IPF ILD and shared with IPF.MAIN RESULTSOf 2925 proteins tested in the discovery cohort, 73 were associated with TFS, with 44 showing sustained TFS association in the validation cohort. The top TFS-associated proteins were amphiregulin (HR 2.51, 95% CI 2.07-3.04), integrin subunit beta 6 (HR 2.46; 95% CI 1.95-3.10) and keratin 19 (HR 1.70, 95% CI 1.47-1.98). All but one validated biomarkers showed consistent TFS association across non-IPF ILD subtypes. Pathway analysis identified several molecular pathways shared with IPF, along with three pathways unique to non-IPF ILD.CONCLUSIONSWe identified and validated novel prognostic protein biomarkers in non-IPF ILD, most of which showed consistent association across non-IPF ILD subtypes. While most biomarkers and molecular pathways identified were previously linked to IPF, several were unique to non-IPF ILD, suggesting that unique biology may contribute to progressive non-IPF ILD.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"37 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202502-0452ed
Kelsey Hills-Dunlap,Marc Moss
{"title":"Beyond Binary: The Potential of Ordinal Outcomes in Critical Care Trials.","authors":"Kelsey Hills-Dunlap,Marc Moss","doi":"10.1164/rccm.202502-0452ed","DOIUrl":"https://doi.org/10.1164/rccm.202502-0452ed","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"114 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202502-0327le
Rui Zhang,Xi Xi Chen,Jian Ping Zhou,Qing Yun Li
{"title":"Assessing the Correlation Between Systemic Inflammation and GGO: Beyond a Single Indicator.","authors":"Rui Zhang,Xi Xi Chen,Jian Ping Zhou,Qing Yun Li","doi":"10.1164/rccm.202502-0327le","DOIUrl":"https://doi.org/10.1164/rccm.202502-0327le","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"23 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202501-0240ed
Andrew J Admon,Christopher J Yarnell
{"title":"A New Target from a Target Trial Emulation: Allow Early Assisted Breathing.","authors":"Andrew J Admon,Christopher J Yarnell","doi":"10.1164/rccm.202501-0240ed","DOIUrl":"https://doi.org/10.1164/rccm.202501-0240ed","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"74 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Lower Immunoglobulin G Levels Increased Exacerbation Risk in COPD: New Insights for Clinical Practice.","authors":"Yen-Fu Chen,Jung-Yien Chien,Hao-Chien Wang,Chong-Jen Yu","doi":"10.1164/rccm.202411-2177le","DOIUrl":"https://doi.org/10.1164/rccm.202411-2177le","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"108 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-10DOI: 10.1164/rccm.202411-2231oc
Cori L Daines,Deepika Polineni,Elizabeth Tullis,Stefano Costa,Rachel W Linnemann,Marcus A Mall,Edward F McKone,Bradley S Quon,Felix C Ringshausen,Hiran Selvadurai,Jennifer L Taylor-Cousar,Nicholas J Withers,Gregory S Sawicki,Timothy Lee,Neil Ahluwalia,Jessica Morlando Geiger,Mark Jennings,Yaoyuan Vincent Tan,David Waltz,Bonnie Ramsey,Matthias Griese,
RATIONALEClinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one F508del allele.OBJECTIVESGiven the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed.METHODSIn this phase 3, open-label, single-arm extension study, participants with F508del-minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the F508del-F508del genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks.MEASUREMENTS AND MAIN RESULTSPrimary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV1 (ppFEV1), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV1 was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA.CONCLUSIONSDuring this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV1 suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. Clinical trial registration available at www.CLINICALTRIALSgov, ID: NCT03525574.
{"title":"Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Adults and Adolescents with Cystic Fibrosis and at Least One F508del Allele: A Phase 3, Open-Label Extension Study.","authors":"Cori L Daines,Deepika Polineni,Elizabeth Tullis,Stefano Costa,Rachel W Linnemann,Marcus A Mall,Edward F McKone,Bradley S Quon,Felix C Ringshausen,Hiran Selvadurai,Jennifer L Taylor-Cousar,Nicholas J Withers,Gregory S Sawicki,Timothy Lee,Neil Ahluwalia,Jessica Morlando Geiger,Mark Jennings,Yaoyuan Vincent Tan,David Waltz,Bonnie Ramsey,Matthias Griese,","doi":"10.1164/rccm.202411-2231oc","DOIUrl":"https://doi.org/10.1164/rccm.202411-2231oc","url":null,"abstract":"RATIONALEClinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one F508del allele.OBJECTIVESGiven the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed.METHODSIn this phase 3, open-label, single-arm extension study, participants with F508del-minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the F508del-F508del genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks.MEASUREMENTS AND MAIN RESULTSPrimary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV1 (ppFEV1), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV1 was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA.CONCLUSIONSDuring this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV1 suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. Clinical trial registration available at www.CLINICALTRIALSgov, ID: NCT03525574.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"5 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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