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

Raquel Behar-Lagares^1,2Ana Virseda-Berdices^1,2Oscar Martínez-González^3,4,5*Rafael Blancas^3,4,5Eva Manteiga⁶Paula Muñoz-García¹María José Mallol-Poyato⁷Jorge Molina-Del Pozo⁷Marcela Homez-Guzmán⁶María A Alonso-Fernández³Salvador Resino^1,2Amanda Fernández-Rodríguez^1,2*María Angeles Jiménez-Sousa^1,2

• ¹Instituto de Salud Carlos III, Centro Nacional de Microbiología, Majadahonda, Spain
• ²Centro de Investigacion Biomedica en Red Enfermedades Infecciosas, Madrid, Spain
• ³Critical Care Department, Hospital Universitario del Tajo, Aranjuez, Spain
• ⁴Fundacion para la Investigacion e Innovacion Biomedica del Hospital Universitario Infanta Sofia y Hospital Universitario del Henares, Madrid, Spain
• ⁵Universidad Alfonso X el Sabio, Villanueva de la Cañada, Spain
• ⁶Critical Care Department, Hospital Universitario Infanta Cristina, Parla, Spain
• ⁷Emergency Laboratory, Hospital Universitario del Tajo, Aranjuez, Spain

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. 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. 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< 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< 0.001] or prone positioning [aAMR= 0.56 (0.44-0.71); p= 0.016].