{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:29:00Z","timestamp":1767677340024,"version":"3.48.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>A significant proportion of COVID-19 Intensive Care Unit (ICU) survivors develop long-term respiratory complications, including pulmonary fibrosis. Telomere attrition, a marker of cellular senescence, has emerged as a potential biomarker for post-COVID-19 sequelae. This study investigated the association between peripheral blood relative telomere length (RTL) and long-term pulmonary outcomes in COVID-19 ICU survivors, with a specific focus on gender-specific differences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>ICU-admitted COVID-19 patients were followed for at least one year post-discharge. RTL was quantified from peripheral blood using monochromatic multiplex quantitative PCR (MMqPCR) at hospital admission and one-year post-discharge. Primary outcomes were respiratory symptoms and diffuse parenchymal lung disease (DPLD), assessed via imaging. Data were analyzed using gender-stratified generalized linear models, adjusted for clinical covariates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At one year, 43.8% of patients reported respiratory symptoms and 23.9% developed DPLD. A total of 73 ICU survivors were included, with 51 men and 22 women. At one year, 43.8% of patients reported respiratory symptoms and 23.9% developed DPLD. Longitudinal analysis showed significant RTL shortening in both men and women who underwent IMV (p=0.011 and p=0.016, respectively), and in men who needed pronation during their ICU stay (p=0.037). Regarding one-year symptoms, in women, repeated-measures analysis showed an association with persistent respiratory symptoms, particularly in those who needed pronation during their ICU stay [adjusted arithmetic mean ratio (aAMR)=0.73) (95%CI=0.60-0.90); p=0.003]. At follow-up, women who had undergone pronation and had shorter RTL continued to show a higher prevalence of symptoms [aAMR= 0.66 (0.58-0.76); p&amp;lt; 0.001]. In contrast, men with shorter RTL at one-year post-discharge had an association with the presence of DPLD [aAMR = 0.64 (0.50-0.81); p = 0.001]. This association in men was significant particularly among those who required IMV [aAMR= 0.61 (0.49-0.76); p&amp;lt; 0.001] or prone positioning [aAMR= 0.56 (0.44-0.71); p= 0.016].<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings underscore the role of telomere attrition as a sex-specific biomarker of aging-associated pulmonary vulnerability in the aftermath of critical COVID-19 illness. RTL may serve as a prognostic marker for long-term respiratory sequelae, potentially guiding risk stratification and individualized follow-up strategies in post-ICU COVID-19 survivors.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1681454","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:18:58Z","timestamp":1767676738000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gender-based differences in telomere attrition and long-term respiratory dysfunction in COVID-19 ICU survivors one year post-infection: implications for aging-associated pulmonary decline"],"prefix":"10.3389","volume":"16","author":[{"given":"Raquel","family":"Behar-Lagares","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Virseda-Berdices","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"\u00d3scar","family":"Mart\u00ednez-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Blancas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Manteiga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paula","family":"Mu\u00f1oz-Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda J.","family":"Mallol Poyato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Molina del Pozo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcela","family":"Homez-Guzm\u00e1n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda A.","family":"Alonso Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Salvador","family":"Resino","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Fern\u00e1ndez-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda \u00c1ngeles","family":"Jim\u00e9nez-Sousa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"95:103208","DOI":"10.1016\/j.jbi.2019.103208","article-title":"The REDCap consortium: Building an international community of software platform partners","volume":"7","author":"Harris","year":"2019","journal-title":"J BioMed Inform"},{"key":"B2","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1186\/s13054-024-05051-6","article-title":"Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery","volume":"28","author":"Virseda-Berdices","year":"2024","journal-title":"Crit Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"100164","DOI":"10.1016\/j.dajour.2023.100164","article-title":"An outliers detection and elimination framework in classification task of data mining","volume":"6","author":"Dash","year":"2023","journal-title":"Decision Analytics J"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.6775","article-title":"Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the new york city area","volume":"323","author":"Richardson","year":"2020","journal-title":"JAMA"},{"key":"B5","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0234765","article-title":"The prevalence of symptoms in 24,410 adults infected by the novel coronavirus (SARS-CoV-2; COVID-19): A systematic review and meta-analysis of 148 studies from 9 countries","volume":"15","author":"Grant","year":"2020","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01136-X","article-title":"Long COVID: a clinical update","volume":"404","author":"Greenhalgh","year":"2024","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2003448","DOI":"10.1183\/13993003.03448-2020","article-title":"Dyspnoea, lung function and CT findings 3 months after hospital admission for COVID-19","volume":"57","author":"Lerum","year":"2021","journal-title":"Eur Respir J"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.3331","article-title":"Four-month clinical status of a cohort of patients after hospitalization for COVID-19","volume":"325","author":"Morin","year":"2021","journal-title":"JAMA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26368","article-title":"Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation","volume":"93","author":"Halpin","year":"2021","journal-title":"J Med Virol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0280567","article-title":"Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study","volume":"18","author":"Ribeiro Carvalho","year":"2023","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00479-2021","article-title":"Respiratory symptoms and radiological findings in post-acute COVID-19 syndrome","volume":"8","author":"Jutant","year":"2022","journal-title":"ERJ Open Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(21)00174-0","article-title":"3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study","volume":"9","author":"Wu","year":"2021","journal-title":"Lancet Respir Med"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18632\/aging.202463","article-title":"Shorter telomere lengths in patients with severe COVID-19 disease","volume":"13","author":"Sanchez-Vazquez","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.18632\/aging.104097","article-title":"Short telomeres increase the risk of severe COVID-19","volume":"12","author":"Froidure","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B16","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1167\/iovs.63.5.30","article-title":"Relative telomere length is associated with age-related macular degeneration in women","volume":"63","author":"Koller","year":"2022","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B17","doi-asserted-by":"publisher","first-page":"101056","DOI":"10.1016\/j.bbrep.2021.101056","article-title":"Shorter leukocyte telomere length is associated with severity of COVID-19 infection","volume":"27","author":"Dos Santos","year":"2021","journal-title":"Biochem Biophys Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"103485","DOI":"10.1016\/j.ebiom.2021.103485","article-title":"Shorter leukocyte telomere length is associated with adverse COVID-19 outcomes: A cohort study in UK Biobank","volume":"70","author":"Wang","year":"2021","journal-title":"EBioMedicine"},{"key":"B19","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s12916-025-03881-x","article-title":"Exploring DNA methylation, telomere length, mitochondrial DNA, and immune function in patients with Long-COVID","volume":"23","author":"Polli","year":"2025","journal-title":"BMC Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"2296","DOI":"10.3390\/biomedicines12102296","article-title":"Exploring the relationship between telomere length and cognitive changes in post-COVID-19 subjects","volume":"12","author":"Villar-Juarez","year":"2024","journal-title":"Biomedicines"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s11899-023-00720-9","article-title":"Diagnosis and management of pulmonary manifestations of telomere biology disorders","volume":"19","author":"Del Valle","year":"2024","journal-title":"Curr Hematol Malig Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2021-217031","article-title":"Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length","volume":"76","author":"McGroder","year":"2021","journal-title":"Thorax"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.arbres.2023.11.003","article-title":"Persistent pulmonary fibrotic sequelae in patients with telomere shortening one year after severe COVID-19","volume":"60","author":"Mulet","year":"2024","journal-title":"Arch Bronconeumol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204755","article-title":"Short telomeres in alveolar type II cells associate with lung fibrosis in post COVID-19 patients with cancer","volume":"15","author":"Martinez","year":"2023","journal-title":"Aging (Albany NY)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"5656","DOI":"10.1038\/s41467-022-32771-6","article-title":"Consequences of telomere dysfunction in fibroblasts, club and basal cells for lung fibrosis development","volume":"13","author":"Pineiro-Hermida","year":"2022","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1177\/0194599820934380","article-title":"Olfactory and oral manifestations of COVID-19: sex-related symptoms-A potential pathway to early diagnosis","volume":"163","author":"Biadsee","year":"2020","journal-title":"Otolaryngol Head Neck Surg"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1089\/jwh.2021.0411","article-title":"Sex-related differences in long-COVID-19 syndrome","volume":"31","author":"Pela","year":"2022","journal-title":"J Womens Health (Larchmt)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13089","article-title":"Clinical and epidemiological characteristics of 1420 European patients with mild-to-moderate coronavirus disease 2019","volume":"288","author":"Lechien","year":"2020","journal-title":"J Intern Med"},{"key":"B29","doi-asserted-by":"publisher","first-page":"16402","DOI":"10.20452\/pamw.16402","article-title":"COVID-19 and its long-term sequelae: what do we know in 2023","volume":"133","author":"Lippi","year":"2023","journal-title":"Pol Arch Intern Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.55430","article-title":"Sex differences in long COVID","volume":"8","author":"Shah","year":"2025","journal-title":"JAMA Netw Open"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109285","article-title":"Confronting our next national health disaster - long-haul covid","volume":"385","author":"Phillips","year":"2021","journal-title":"N Engl J Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"2024.02.29.24303568","DOI":"10.1101\/2024.02.29.24303568","article-title":"Sex differences in symptomatology and immune profiles of Long COVID","volume":"4","author":"Silva","year":"2024","journal-title":"medRxiv"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1590\/1518-8345.7353.4479","article-title":"Prevalent symptoms and characteristics of the Long COVID-19 population: a scoping review","volume":"33","author":"Prediger","year":"2025","journal-title":"Rev Lat Am Enfermagem"},{"key":"B34","doi-asserted-by":"publisher","first-page":"4015","DOI":"10.1038\/s41467-021-24265-8","article-title":"Lack of consideration of sex and gender in COVID-19 clinical studies","volume":"12","author":"Brady","year":"2021","journal-title":"Nat Commun"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac132","article-title":"Novel genes and sex differences in COVID-19 severity","volume":"31","author":"Cruz","year":"2022","journal-title":"Hum Mol Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.28368","article-title":"Relative telomere length impact on mortality of COVID-19: Sex differences","volume":"95","author":"Virseda-Berdices","year":"2023","journal-title":"J Med Virol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0000000000000863","article-title":"A clinical review of long-COVID with a focus on the respiratory system","volume":"28","author":"Daines","year":"2022","journal-title":"Curr Opin Pulm Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1186\/s12931-022-02163-x","article-title":"Pulmonary function and chest computed tomography abnormalities 6\u201312 months after recovery from COVID-19: a systematic review and meta-analysis","volume":"23","author":"Lee","year":"2022","journal-title":"Respir Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"e70289","DOI":"10.1002\/jmv.70289","article-title":"Metabolomic biomarkers of pulmonary fibrosis in COVID-19 patients one year after hospital discharge","volume":"97","author":"Botello-Marabotto","year":"2025","journal-title":"J Med Virol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.659339","article-title":"Molecular and biological mechanisms underlying gender differences in COVID-19 severity and mortality","volume":"12","author":"Wehbe","year":"2021","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"630","DOI":"10.3390\/biomedicines12030630","article-title":"Immunological similarities and differences between post-COVID-19 lung sequelae and idiopathic pulmonary fibrosis","volume":"12","author":"Gangi","year":"2024","journal-title":"Biomedicines"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1003469","article-title":"Biofunctional roles of estrogen in coronavirus disease 2019: Beyond a steroid hormone","volume":"13","author":"Wang","year":"2022","journal-title":"Front Pharmacol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"103590","DOI":"10.1016\/j.amsu.2022.103590","article-title":"Post COVID-19 pulmonary fibrosis; a meta-analysis study","volume":"77","author":"Hama Amin","year":"2022","journal-title":"Ann Med Surg (Lond)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1136\/bmjresp-2024-002538","article-title":"Pulmonary fibrosis followed by severe pneumonia in patients with COVID-19 infection requiring mechanical ventilation: a prospective multicentre study","volume":"11","author":"Kim","year":"2024","journal-title":"BMJ Open Respir Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4103\/atm.atm_7_23","article-title":"Post-COVID-19 pulmonary fibrosis: An ongoing concern","volume":"18","author":"Alrajhi","year":"2023","journal-title":"Ann Thorac Med"},{"key":"B46","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/s12016-022-08921-5","article-title":"Risk and protective factors for COVID-19 morbidity, severity, and mortality","volume":"64","author":"Zhang","year":"2023","journal-title":"Clin Rev Allergy Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.mayocp.2020.07.024","article-title":"COVID-19 and sex differences: mechanisms and biomarkers","volume":"95","author":"Haitao","year":"2020","journal-title":"Mayo Clin Proc"},{"key":"B48","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3390\/jcm11112999","article-title":"Health Perception among Female COVID-19 Patients. Comment on Fernandez-de-las-Penas et\u00a0al. Female Sex Is a Risk Factor Associated with Long-Term Post-COVID Related-Symptoms but Not with COVID-19 Symptoms: The LONG-COVID-EXP-CM Multicenter Study. J. Clin. Med. 2022, 11, 413","volume":"11","author":"Ayuso Garcia","year":"2022","journal-title":"J Clin Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(22)00127-8","article-title":"Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study","volume":"10","author":"Group","year":"2022","journal-title":"Lancet Respir Med"},{"key":"B50","doi-asserted-by":"publisher","first-page":"848","DOI":"10.3390\/ijerph20010848","article-title":"Prevalence and associated factors of post-COVID-19 syndrome in a Brazilian cohort after 3 and 6 months of hospital discharge","volume":"20","author":"Lapa","year":"2023","journal-title":"Int J Environ Res Public Health"},{"key":"B51","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1186\/s13148-023-01597-4","article-title":"Epigenetic age acceleration in surviving versus deceased COVID-19 patients with acute respiratory distress syndrome following hospitalization","volume":"15","author":"Bejaoui","year":"2023","journal-title":"Clin Epigenetics"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1901044","DOI":"10.1183\/13993003.01044-2019","article-title":"Peripheral blood leukocyte telomere length is associated with survival of sepsis patients","volume":"55","author":"Liu","year":"2020","journal-title":"Eur Respir J"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1177\/10998004221133395","article-title":"Changes in telomere length and indicators of oxidative stress in critically ill mechanically ventilated adults - A pilot study","volume":"25","author":"Liang","year":"2023","journal-title":"Biol Res Nurs"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681454\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T05:18:59Z","timestamp":1767676739000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1681454\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,6]]},"references-count":53,"alternative-id":["10.3389\/fimmu.2025.1681454"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1681454","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,6]]},"article-number":"1681454"}}