{"paper_id":"3ff98b8a-bc33-43f2-845f-0a60ef4ab325","body_text":"Association of Relative Telomere Length with Glucocorticoids Therapy in Critically Ill Patients with COVID-19 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Association of Relative Telomere Length with Glucocorticoids Therapy in Critically Ill Patients with COVID-19 Raquel Behar-Lagares, Óscar Martínez-González, Ángela Algaba-Calderón, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8713144/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background: Glucocorticoids (GCs) have proven to be a key therapy in mitigating the systemic inflammatory response in severe COVID-19. Relative telomere length (RTL) is recognized as a biomarker of cellular aging and biological stress, with its role in acute critical illnesses being of growing interest. Chronic exposure to GCs or stress are strongly associated with telomere shortening. This study aimed to explore the association of RTL ratios with GCs therapy. Methods: A prospective, longitudinal study involving patients over 18 years of age with severe SARS-CoV-2 pneumonia was designed. Patients were admitted to the ICU of a university hospital. GCs therapy was standardized to dexamethasone equivalent doses based on the RECOVERY study. Blood samples were obtained upon admission and at least one year after discharge to determine telomere length using the Cawthon method (qPCR). RTL ratio (one year/baseline RTL) associations with GCs were calculated using generalized linear models (GLM). Results: A significant association was found between RTL ratios and the duration of GCs therapy (p=0.007). The dexamethasone equivalent dose also showed a significant association with RTL ratios (p<0.001). These associations were particularly significant in the male population (dexamethasone equivalent: p=0.028; duration of therapy: p=0.001), with no significant associations observed in women. Conclusion: In critically ill patients with SARS-CoV-2 pneumonia, this study reveals a significant association between RTL, the length of GCs therapy, and the equivalent dose of dexamethasone, especially in males. Further studies are needed to determine the effect of GCs on RTL admitted to de ICU for other critical conditions. Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Telomere telomere shortening COVID-19 glucocorticoids critical illness Figures Figure 1 Figure 2 INTRODUCTION In the treatment of severe COVID-19, glucocorticoids (GCs) proved to be a key therapy in mitigating the systemic inflammatory response (1-2), with a considerable number of patients developing severe disease requiring admission to intensive care units (ICUs) (3). Telomeres are DNA-protein complexes located at the end regions of chromosomes. They are characterised by shortening with each cell division. Although telomerase, a specialised intracellular enzyme, works to partially rebuild telomeres by adding repeat units, telomeres continue to shorten with repeated cell divisions, leading to disruption of cell function and ultimately to cell senescence. Telomere length (TL) and telomerase activity (TA) are considered valuable biomarkers in the diagnosis and prognosis of various pathological conditions. Relative telomere length (RTL) has been recognised as a biomarker of cellular ageing and biological stress, and its role in the context of critical acute illnesses is of growing interest. In fact, shorter telomere length in leukocytes, particularly in CD8CD28- cells, is expected to be associated with an increased risk of infection and clinical disease (4-5). Environmental stressors and predictable life history events can have a strong impact on telomere dynamics (6-9). Chronic stress and exposure to GCs increase the risk of medical disorders, including cardiovascular and neuropsychiatric disorders, and contribute to accelerated ageing (10-11). In this context, GCs are the main hormonal mediators of allostasis (maintaining stability through change) and deserve specific attention due to their involvement in the stress response (12-13). Sex is another factor associated with RTL. On average, women have longer telomeres than men, regardless of age. This should be taken into account when investigating how different pathologies or drugs affect telomere length (14). The influence of sex on RTL in severe SARS-CoV-2 infection has previously been studied. A lower RTL has been linked to a higher chance of mortality in women following a diagnosis of COVID-19 (15). The present study explores the association between the duration and dose of GCs therapy administered to ICU patients with COVID-19 and changes in RTL from admission to at least one-year after hospital discharge. This study adds to the growing body of research on how telomere length is associated with the pathobiology of critical illnesses, including acute respiratory distress syndrome (ARDS), a severe condition that can be caused by COVID-19 (16). METHODS Study population and clinical data This prospective, longitudinal study included patients over 18 years of age with severe SARS-CoV-2 pneumonia, admitted to the intensive care unit (ICU) of the Hospital Universitario del Tajo (Aranjuez, Madrid, Spain) between August 2020 and April 2021, who agreed to participate in the study (or consent was given by their relatives in cases where they were unable to give consent). Patients were admitted to the ICU within the first 72 hours of hospital admission. Those receiving chronic GCs treatment before ICU admission were excluded from the study, as were those who refused to participate. Demographic data, comorbidities, treatments received during hospitalisation, and other data considered descriptive of the severity of the situation during ICU admission were collected, such as the need for invasive mechanical ventilation (IMV) and its length, high-flow nasal cannula (HFNC) therapy and its duration, length of stay (LOS) in the ICU, need for prone positioning, modified shock index (MSI) (17), shock index (SI) (18), sequential organ failure assessment (SOFA) index (19), and the use of vasoactive drugs. Clinical and epidemiological data were recorded using Research Electronic Data Capture (REDCap) (20). The study was approved by the Research Committee of Tajo University Hospital and the Ethics Committee of the Carlos III Health Institute (Madrid, Spain; PI 33_2020-v3). Informed consent to be included in the study was obtained from all patients or their representatives in cases where it could not be obtained from the patients themselves. Assessment of glucocorticoids treatment GCs treatment guidelines were considered from the start of treatment until its completion in the ICU or hospital ward. During this period, patients received different GCs treatment regimens. Since most treatments followed the RECOVERY study protocol, based on dexamethasone (1), and to facilitate the interpretation of results, all GCs treatments are shown as equivalents to dexamethasone doses, following those previously published by Mager, DE et al. (2). During the study period, patients received dexamethasone, hydrocortisone, methylprednisolone, prednisone, or a combination of thereof. The average equivalence of doses to 1 mg of dexamethasone was as follows: methylprednisolone 5 mg, hydrocortisone 25 mg, prednisolone or prednisone 6.25 mg. Telomere length assessment Peripheral blood samples were obtained upon admission to the ICU and at least one year after discharge. DNA was isolated from whole blood. Telomere length was determined using the Cawthon method, which uses quantitative polymerase chain reaction (qPCR) (21). This method calculates a telomere: single-copy gene (T:S) ratio as an index of average telomere length. For the analysis of changes in telomere length, the RTL ratio (RTL at follow-up / RTL at baseline) was used as previously described (22). Outcome The study assessed how the GCs dose, as well as the duration of GCs therapy during ICU admission, impacted RTL one-year post-discharge. Statistical analysis The clinical and epidemiological characteristics of the patients were summarised using standard descriptive statistics, such as the median [interquartile range] for continuous variables and the count (percentage, %) for categorical variables. Differences between groups were analysed using the Mann-Whitney test for continuous variables and the Chi-square test or Fisher's exact test for categorical variables. Associations of RTL ratios (dependent variable) with dexamethasone equivalent dose (as independent variable), duration of GCs therapy, and other relevant clinical covariates were calculated using generalised linear models (GLM) with a gamma distribution adjusted by the most significant variables following a stepwise model selection: age, sex, body mass index (BMI), time elapsed from discharge from the ICU to follow-up, ICU LOS, ionotropic/vasopressor therapy and smoking status at ICU admission. For this purpose, arithmetic mean ratio (AMR) and adjusted arithmetic mean ratio (aAMR) are shown. RESULTS Clinical and epidemiological characteristics of the cohort During admission to the ICU, 10 patients died, so no follow-up samples were obtained and they were excluded from further analysis. One patient undergoing chronic GCs treatment during follow-up was also excluded from the study. Finally, 49 patients were included in the analysis. The median age of the patients was 64.0 years, with a median body mass index (BMI) of 30.86 kg/m 2 , and 71.4% were male. A significant percentage of patients were obese (BMI > 30 kg/m 2 ), representing 41.7% of the cohort. The median duration of GCs therapy was 10.0 days. IMV was required in 75.5% of patients, with a median duration of 14.0 days. The median ICU LOS was 12.0 days. A significant difference was observed in the use of the prone position, which was more frequent in female (64.3%) than in male (28.6%) (p=0.046). Clinical and epidemiological characteristics of patients with COVID-19, stratified by sex, are shown in Table 1 . Table 1 . Clinical and epidemiological characteristics of patients with COVID‐19, stratified by gender. Statistics : Individual characteristics were summarized using standard descriptive statistics: median [interquartile range] for continuous variables and count (percentage %) for categorical variables. Differences between groups were tested using the Mann-Whitney test for continuous variables, and the Chi-square test (n≥5 %) and Fisher’s exact test (n<5 %) for categorical variables. Abbreviations: BMI, body mass index; ACE, angiotensin converting enzyme inhibitors; AIIRA, angiotensin II receptor antagonists; ICU, intensive care unit; ICU LOS, ICU length of stay; IMV, invasive mechanical ventilation; MSI, modified shock index; RTL, relative telomere length; SI, shock index, SOFA, sequential organ failure assessment. Demographics No. 49 14 (28.6%) 35 (71.4 %) Age (years %) 64.00 [56.00, 72.00] 63.00 [52.25, 72.75] 65.00 [57.50, 71.00] 0.833 BMI (kg/m 2 ) 30.86 [26.35, 35.16] 34.52 [28.01, 35.87] 29.39 [25.04, 33.06] 0.093 RTL 1.35 [1.16, 1.60] 1.41 [1.29, 1.79] 1.33 [1.15, 1.53] 0.206 Ethnicity Caucasian 40 (81.6 %) 10 (71.4 %) 30 (85.7 %) 0.484 Hispanic 6 (12.2 %) 3 (21.4 %) 3 (8.6 %) Arabian 2 (4.1 %) 1 (7.1 %) 1 (2.9 %) Other 1 (2.0 %) 0 (0.0 %) 1 (2.9 %) Comorbidities Non-smoker 28 (63.6 %) 11 (78.6 %) 17 (56.7 %) 0.341 Ex-Smoker 15 (34.1 %) 3 (21.4 %) 12 (40.0 %) Smoker 1 (2.3 %) 0 (0.0 %) 1 (3.3 %) Arterial hypertension 21 (42.9 %) 4 (28.6 %) 17 (48.6 %) 0.338 Obesity (BMI>30 %) 20 (41.7 %) 8 (57.1 %) 12 (35.3 %) 0.08 Diabetes 15 (30.6 %) 4 (28.6 %) 11 (31.4 %) 1 Therapy before hospitalization AIIRA 7 (14.3 %) 2 (14.3 %) 5 (14.3 %) 0.815 ACE 7 (14.3 %) 2 (14.3 %) 5 (14.3 %) 0.815 Anticoagulant therapy 4 (8.2 %) 1 (7.1 %) 3 (8.6 %) 1 Treatment during hospitalization Antibiotics 48 (98.0 %) 13 (92.9 %) 35 (100.0 %) 0.632 Azithromycin 23 (47.9 %) 8 (57.1 %) 15 (44.1 %) 0.615 Corticoids 46 (93.9 %) 13 (92.9 %) 33 (94.3 %) 1 Anticoagulants Dexamethasone equivalent dose (mg) 66.00 [60.00, 88.00] 79.00 [61.50, 93.00] 66.00 [54.00, 81.00] 0.072 Duration of corticosteroid therapy (days) 10.00 [9.00, 13.00] 10.50 [10.00, 13.00] 10.00 [9.00, 12.50] 0.292 Inotropic/vasopressor therapy 11 (22.4 %) 5 (35.7 %) 6 (17.1 %) 0.304 Therapeutic dose of enoxaparin (80-100mg/12h %) 6 (12.2 %) 1 (7.1 %) 5 (14.3 %) 0.836 Oxygen Therapy and Ventilator Support IMV 37 (75.5 %) 12 (85.7 %) 25 (71.4 %) 0.495 Duration of IMV (days) 14.00 [6.00, 23.00] 14.50 [9.50, 22.25] 9.00 [5.00, 27.00] 0.505 High-flow nasal cannulas 40 (81.6 %) 11 (78.6 %) 29 (82.9 %) 1.000 Duration of high-flow nasal cannula therapy (days) 2.00 [0.00-4.00] 1.00 [0.00, 4.50] 2.50 [1.00, 4.00] 0.466 ICU ICU LOS (days %) 12.00 [8.00, 26.00] 17.00 [12.75, 25.25] 11.00 [7.00, 24.00] 0.24 Prone position 19 (38.8 %) 9 (64.3 %) 10 (28.6 %) 0.046 SOFA index 4.00 [4.00, 11.00] 4.00 [4.00, 11.00] 4.00 [4.00, 11.00] 0.609 SI 0.56 [0.46, 0.62] 0.61 [0.55, 0.66] 0.53 [0.45, 0.59] 0.172 MSI 0.82 [0.66, 0.90] 0.87 [0.78, 1.01] 0.75 [0.65, 0.86] 0.16 Follow-up Follow-up visit (months %) 13.61 [12.16, 15.12] 14.68 [12.64, 15.22] 12.89 [12.12, 14.75] 0.184 Anticoagulant treatment 6 (12.2 %) 1 (7.1 %) 5 (14.3 %) 0.836 Association of RTL with GC therapy A significant association was found between the GCs duration of therapy and RTL ratio (aAMR: 0.98, 95% CI: 0.97-0.99, p= 0.007), especially in male population (aAMR: 0.98, 95% CI: 0.97-0.99, p= 0.001) (Table 2 & Figure 1). In male population, the equivalent dexamethasone dose showed a significant association with the RTL ratio (aAMR: 0.99, 95% CI: 0.98–0.99, p= 0.028). This association was not observed in female group (Table 2 & Figure 2). Table 2 . Association of RTL ratios with dexamethasone equivalent dose and the duration of corticosteroid therapy during ICU stay. Statistics : Associations were calculated using Generalized Linear Models (GLM) with a gamma distribution. Significant differences are shown in bold. Abbreviations : AMR, arithmetic mean ratio; aAMR, adjusted AMR; 95%CI, 95% of confidence interval; p, level of significance. Dexamethasone equivalent dose Duration of corticosteroid therapy Sex AMR (95%CI) p-value aAMR (95%CI) P-value AMR (95%CI) p-value aAMR (95%CI) p-value All 0.99 (0.99-1.01) 0.136 0.99 (0.99-1.01) 0.452 0.98 (0.97-0.99) 0.007 0.98 (0.97-0.99) 0.007 Male 0.99 (0.98-0.99) 0.008 0.99 (0.98-0.99) 0.028 0.98 (0.97-0.99) < 0.001 0.98 (0.97-0.99) 0.001 Female 1.01 (0.99-1.01) 0.840 1.01 (0.99-1.01) 0.840 0.99 (0.98-1.01) 0.984 0.99 (0.98-1.01) 0.984 Association of GCs therapy duration and dexamethasone equivalent dose with other relevant clinical covariates Longer duration of the GCs therapy was associated with BMI at baseline (AMR: 1.03, 95% CI: 1.01-1.05, p= 0.023), dexamethasone higher equivalent dose (AMR: 1.004, 95% CI: 1.003-1.005, p< 0.001), length of IMV (AMR: 1.02, 95% CI: 1.01-1.03, p=0.003), ICU LOS (AMR: 1.02, 95% CI: 1.01-1.03, p<0.001) and use of inotropic/vasopressor therapy (AMR: 1.86, 95% CI: 1.40-2.46, p<0.001). Variables associated with dexamethasone equivalent dose were length of IMV (AMR: 1.03, 95% CI: 1.01-1.05, p= 0.001), ICU LOS (AMR: 1.03, 95% CI: 1.01-1.04, p< 0.001), the need for inotropic/vasopressor therapy (AMR: 2.14, 95% CI: 1.18-3.88, p= 0.015), smoker status (AMR: 1.31, 95% CI: 1.01-1.69, p= 0.048) and baseline BMI (AMR: 1.04, 95% CI: 1.01-1.08, p= 0.055). DISCUSSION This study highlights the complex interaction between telomere length, GCs therapy, and clinical outcomes in critically ill patients with COVID-19. Our findings suggest a significant association between both the duration and total dose of GCs therapy, particularly in male, and the RTL ratio, showing a lower recovery of telomere length associated with longer duration of treatment and higher doses of GCs. The effect of GCs on telomeres shows differences according to sex, although the evidence is limited and depends on the biological and clinical context. Sex-specific differences in the effect of corticosteroids on telomere length are explained by molecular and hormonal mechanisms involving the interaction between GCs, oestrogens, and androgens. Oestrogens modulate telomerase activity via the oestrogen receptor alpha (ERα), stimulating TERT gene expression and increasing telomerase activity in haematopoietic cells and other tissues, which may partially counteract glucocorticoid-induced telomere shortening (23-24). However, the effect of oestrogens is tissue-dependent and may vary; in certain areas of the brain, oestrogen may reduce telomere length (25). Androgens also increase telomerase activity, mainly through their conversion to oestrogens via aromatase and activation of ERα, rather than through the direct androgen receptor. In men, elevated levels of dihydrotestosterone and oestradiol are associated with longer telomeres, suggesting a protective hormonal effect against telomeric damage by glucocorticoids (24, 26). To our knowledge, there is no evidence of a relationship between GCs, RTL, and sex in critically ill patients. Stress and oxidative damage are considered the main causes of telomere shortening. Telomeres are particularly sensitive to reactive oxygen species (ROS) produced by metabolic processes and immune cells (6, 10). Inflammation, which is a characteristic of severe COVID-19, is accompanied by an increase in ROS content (27). GCs, such as dexamethasone, can influence oxidative balance and telomerase activity, although their effect may vary depending on the dose and duration of exposure. Chronic exposure to GCs or stress are strongly associated with telomere shortening in multiple species, including rats, mice, and humans. Studies have shown that stress in rats leads to a significant reduction in telomere length in T cells and the dentate gyrus of the hippocampus, and exposure to corticosterone in mice produces similar reductions in the blood and brain (25). Furthermore, in patients with active Cushing's syndrome, a considerable reduction in telomere length was observed, correlating with the duration of hypercortisolism (10, 28). Despite the numerous stress factors present in critically ill patients, this study takes into account variables such as disease severity data, including IMV, the requirement for vasoactive drugs, and mortality prediction scores. We believe that the inclusion in the association model (GLM) of these variables is necessary to rule them out as possible confounding variables that affect the results and the influence of GCs on RTL. Our previously published findings on RTL shortening in patients with idiopathic pulmonary fibrosis (IPF) align with evidence that shorter leukocyte telomere lengths (LTL) are common in IPF and associated with lower survival (22). Interestingly, research also suggests that LTL may serve as a pharmacogenomic biomarker, identifying IPF patients at higher risk of adverse outcomes (including hospitalizations) when exposed to immunosuppressive drugs such as prednisone and azathioprine. This highlights the genetic vulnerability of patients with short telomeres to immunosuppression, a relevant finding given the widespread use of GCs in the treatment of severe COVID-19 (29). The observation of significant changes in telomere length, both increases and decreases, in critically ill ICU patients over short periods (mean 7.2 ± 2.5 days) suggests active dynamics in the context of severe disease (30). Although a previous study found no direct correlation between these changes and clinical outcomes, other studies have shown that shorter telomere length in peripheral blood leukocytes is associated with mortality and ARDS severity in critically ill patients (4, 15, 22). This supports the idea that telomeric dysfunction is intrinsically linked to the pathobiology of critical illness. It is important to highlight the possible reversibility of GCs-induced telomere shortening. In patients cured of Cushing's syndrome, telomere length approached that of healthy controls, and in neuronal cell lines, discontinuation of dexamethasone exposure allowed telomere length to recover (31). This reversibility raises the possibility that treatments aimed at reducing cortisol levels may not only influence telomere length but also potentially reverse cellular senescence. In addition, recent studies are evaluating different therapies for telomere length recovery in diseases associated with telomere shortening, generating new therapeutic possibilities (32-33). Study limitations The limited sample size reduces the statistical power for subgroup analyses, especially within the female group. Therefore, we stress that the specific findings are exploratory and hypothesis-generating, rather than definitive conclusions. However, the statistically significant differences observed are noteworthy, given the sample size constrains. Although preliminary due to the limited sample size, this study is valuable because it is, to our knowledge, the first to examine the association between GCs dose and duration and RTL reduction in critically ill patients with COVID-19, addressing an area that has not been sufficiently studied due to the difficulty in recruiting and following up on these patients. In addition to the limited sample size, the low proportion of women in the sample (28%) may have underestimated the effect of GCs on RTL. Although this study was prospective, which helps mitigate concerns about reverse causality (disease or treatment causing telomere shortening), future research with longer follow-up periods and measurement of telomerase activity is needed to fully establish the role of TL as a prognostic and risk stratification tool in critically ill patients, as well as to elucidate the mechanisms underlying these associations. Abbreviations AMR: Arithmetic mean ratio aAMR: Adjusted arithmetic mean ratio ARDS: Acute respiratory distress syndrome BMI: Body mass index GCs: Glucocorticoids GLM: Generalized linear models HFNC: High-flow nasal cannula ICU : Intensive care unit IMV: Invasive mechanical ventilation IPF: Idiopathic pulmonary fibrosis LOS: Length of stay LTL: Leukocyte telomere lengths MSI: Modified shock index qPCR: Polymerase chain reaction REDCap: Research Electronic Data Capture ROS: Reactive oxygen species RTL: Relative telomere length SI: Shock index SOFA: Sequential organ failure assessment TA: Telomerase activity TL: Telomere length CONCLUSIONS In critically ill patients with SARS-CoV-2 pneumonia, this study demonstrates a significant association between both the duration and equivalent dose of GCs therapy and RTL shortening, particularly evident in male population. Furthermore, GCs duration and use were significantly associated with markers of disease severity and progression, including the duration of IMV, ICU LOS, and the need for vasopressor therapy. These findings collectively highlight the intricate relationship between telomere dynamics and the clinical trajectory of severe COVID-19. Notably, the possible reversibility of GCs-induced telomere shortening, as suggested by previous research, opens promising new therapeutic avenues for potentially mitigating long-term cellular damage and improving outcomes in critically ill patients. Further prospective studies are crucial to fully elucidate the underlying mechanisms, to determine the effect of GCs on RTL in critically ill patients admitted for other conditions, and to explore strategies for preserving telomere integrity and enhancing patient recovery. Declarations Ethical approval and consent to participate The study was approved by the Research Committee of Tajo University Hospital and the Ethics Committee of the Carlos III Health Institute (Madrid, Spain; PI 33_2020-v3). All patients or their relatives (if the patient was unable) received advance study information, had their data anonymised, signed informed consent, and could withdraw at any time. This study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki and the International Standards of Good Clinical Practice (ICH-GCP). Consent for publication Not applicable Availability of supporting data All data generated or analyzed during this study are included in this published article. The data supporting the findings of this study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant number COV20/1144 [MPY224/20] to AFR/MAJS) and Fundacion Universidad Alfonso X el Sabio (FUAX) – Santander (1.013.005). The study was also supported by CIBER – Consorcio Centro de Investigacion Biomedica en Red-(CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion and Union Europea – NextGenerationEU (CB21/13/00044). Authors contribution Funding acquisition: RB, AFR, and MAJS. Conceptualization: RB. Project administration: RB, OMG, AFR and MAJS. Patients’ selection and clinical data acquisition: RB, OMG, ÁAC, CMP, MAAF, MMA, MMP, JMP, YT, MNH. Data curation: RB, OMG, ÁAC, CMP, MAAF, MMA, MMP, JMP, YT, MNH. Sample preparation and analysis: JMP, MJMP, RBL, AVB, CRG. Statistical and computational analyses: RBL. Manuscript writing: RB. Critical revision and approval of the final manuscript: RB, AFR, MAJS, OMG, RBL. Acknowledgements The authors are grateful for the willingness of the patients who made this study possible. References RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693–704. doi:10.1056/NEJMoa2021436. Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol. 2003;43(11):1216–27. Kohler K, De Corte T, Greco M, Povoa P, Cecconi M, Ostermann M, De Waele J, Morris AC; UNITE-COVID investigators. The impact of intensive care strain on patients' outcomes—a multinational observational cohort (UNITE-COVID) study. Crit Care. 2025;29(1):329. Liu S, Wang C, Green G, Zhuo H, Liu KD, Kangelaris KN, et al. Peripheral blood leukocyte telomere length is associated with survival of sepsis patients. Eur Respir J. 2020;55(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31619475/ Moskaleva EY, Glukhov AI, Zhirnik AS, Vysotskaya OV, Vorobiova SA. Telomere length and telomerase activity as biomarkers in diagnostics and prognostics of pathological conditions. Biochem. 2025;90(6):700–24. Wang C, Wolters PJ, Calfee CS, Liu S, Balmes JR, Zhao Z, et al. Long-term ozone exposure is positively associated with telomere length in critically ill patients. Environ Int. 2020;141. Available from: https://pubmed.ncbi.nlm.nih.gov/32417614/ Cohen S, Janicki-Deverts D, Turner RB, Casselbrant ML, Li-Korotky HS, Epel ES, et al. Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults. JAMA. 2013;309(7):699–705. Østhus IBØ, Lydersen S, Dalen H, Nauman J, Wisløff U. Association of telomere length with myocardial infarction: a prospective cohort from the population-based HUNT 2 study. Prog Cardiovasc Dis. 2017;59(6):649–55. Newton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, et al. Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(3):336–47. Lee RS, Zandi PP, Santos A, Aulinas A, Carey JL, Webb SM, et al. Cross-species association between telomere length and glucocorticoid exposure. J Clin Endocrinol Metab. 2021;106(12):E5124–35. Angelier F, Costantini D, Blévin P, Chastel O. Do glucocorticoids mediate the link between environmental conditions and telomere dynamics in wild vertebrates? Gen Comp Endocrinol. 2018;256:99–111. Rodriquez EJ, Kim EN, Sumner AE, Nápoles AM, Pérez-Stable EJ. Allostatic load: importance, markers, and score determination in minority and disparity populations. J Urban Health. 2019;96:3–11. Eachus H, Ryu S. Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload. J Exp Biol. 2024;227. Gardner M, Bann D, Wiley L, Cooper R, Hardy R, Nitsch D, Martin-Ruiz C, et al. Gender and telomere length: systematic review and meta-analysis. Exp Gerontol. 2014;51:15–27. Virseda-Berdices A, Concostrina-Martinez L, Martínez-González O, Blancas R, Resino S, Ryan P, et al. Relative telomere length impact on mortality of COVID-19: sex differences. J Med Virol. 2023;95(1):1–7. Mayr FB, Yende S. Size matters! Peripheral blood leukocyte telomere length and survival after critical illness. Eur Respir J. 2020;55(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31949102/ Jouffroy R, Gille S, Gilbert B, Travers S, Bloch-Laine E, Ecollan P, et al. Relationship between shock index, modified shock index, and age shock index and 28-day mortality among patients with prehospital septic shock. J Emerg Med. 2024;66(2):144–53. King RW, Plewa MC, Buderer NMF, Knotts FB. Shock index as a marker for significant injury in trauma patients. Acad Emerg Med. 1996;3(11):1041–5. Vincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter prospective study. Crit Care Med. 1998;26(11):1793–800. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG, et al. The REDCap Consortium: building an international community of software platform partners. J Biomed Inform. 2009;42(2):377–81. Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009;37(3):e21. Virseda-Berdices A, Behar-Lagares R, Martínez-González Ó, Blancas R, Bueno-Bustos S, Brochado-Kith Ó, et al. Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery. Crit Care. 2024;28(1). Taheri M, Ghafouri-Fard S, Najafi S, Kallenbach J, Keramatfar E, Atri Roozbahani G, et al. Hormonal regulation of telomerase activity and hTERT expression in steroid-regulated tissues and cancer. Cancer Cell Int. 2022;22(1):258. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones acting on the TERT gene increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11):2236–43. Cleber Gama de Barcellos Filho P, Campos Zanelatto L, Amélia Aparecida Santana B, Calado RT, Rodrigues Franci C. Effects of chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats. Brain Res. 2021;1750:147152. Yeap BB, Knuiman MW, Divitini ML, Hui J, Arscott GM, Handelsman DJ, et al. Epidemiological and Mendelian randomization studies of dihydrotestosterone and estradiol and leukocyte telomere length in men. J Clin Endocrinol Metab. 2016;101(3):1299–306. Lin J, Epel E. Stress and telomere shortening: insights from cellular mechanisms. Ageing Res Rev. 2022;73:101507. Athanasoulia-Kaspar AP, Auer MK, Stalla GK, Jakovcevski M. Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality? Endocr Connect. 2018;7(11):1217–26. Luppi F, Kalluri M, Faverio P, Kreuter M, Ferrara G. Idiopathic pulmonary fibrosis beyond the lung: understanding disease mechanisms to improve diagnosis and management. Respir Res. 2021;22(1):1–16. Zribi B, Uziel O, Lahav M, Mesilati Stahy R, Singer P. Telomere length changes during critical illness: a prospective observational study. Genes (Basel). 2019;10(10):E760. Aulinas A, Ramírez MJ, Barahona MJ, Valassi E, Resmini E, Mato E, et al. Telomere length analysis in Cushing’s syndrome. Eur J Endocrinol. 2014;171(1):21–9. Townsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374(20):1922–31. Myers KC, Davies SM, Lutzko C, Wahle R, Grier DD, Aubert G, et al. Clinical use of ZSCAN4 for telomere elongation in hematopoietic stem cells. NEJM Evid. 2025;4(3). Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 11 May, 2026 Reviewers agreed at journal 06 May, 2026 Reviewers agreed at journal 22 Apr, 2026 Reviewers invited by journal 19 Apr, 2026 Editor invited by journal 30 Jan, 2026 Editor assigned by journal 28 Jan, 2026 Submission checks completed at journal 28 Jan, 2026 First submitted to journal 27 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {\"props\":{\"pageProps\":{\"initialData\":{\"identity\":\"rs-8713144\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":627959867,\"identity\":\"5e3cbdca-1eeb-4a47-aa27-57e4ebcbcdbd\",\"order_by\":0,\"name\":\"Raquel Behar-Lagares\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Health Institute Carlos III (ISCIII)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Raquel\",\"middleName\":\"\",\"lastName\":\"Behar-Lagares\",\"suffix\":\"\"},{\"id\":627959868,\"identity\":\"a14141d7-5009-46a7-870a-f4e70ddc2e59\",\"order_by\":1,\"name\":\"Óscar Martínez-González\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Óscar\",\"middleName\":\"\",\"lastName\":\"Martínez-González\",\"suffix\":\"\"},{\"id\":627959869,\"identity\":\"8cf8a971-fee6-446f-8586-779a8b77c48b\",\"order_by\":2,\"name\":\"Ángela Algaba-Calderón\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ángela\",\"middleName\":\"\",\"lastName\":\"Algaba-Calderón\",\"suffix\":\"\"},{\"id\":627959870,\"identity\":\"a6accc20-6fda-46eb-b156-a444b9b7cc2e\",\"order_by\":3,\"name\":\"Carmen Martín-Parra\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Carmen\",\"middleName\":\"\",\"lastName\":\"Martín-Parra\",\"suffix\":\"\"},{\"id\":627959871,\"identity\":\"c63e87dc-462b-4e88-9193-a92134a75059\",\"order_by\":4,\"name\":\"Mª Ángeles Alonso-Fernández\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mª\",\"middleName\":\"Ángeles\",\"lastName\":\"Alonso-Fernández\",\"suffix\":\"\"},{\"id\":627959872,\"identity\":\"399cdb80-d4f2-41f2-a124-463bd86a6165\",\"order_by\":5,\"name\":\"Madian Manso-Álvarez\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Madian\",\"middleName\":\"\",\"lastName\":\"Manso-Álvarez\",\"suffix\":\"\"},{\"id\":627959873,\"identity\":\"001a1622-4c1a-483a-b08b-af40690c8bca\",\"order_by\":6,\"name\":\"Mª José Mallol-Poyato\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Mª\",\"middleName\":\"José\",\"lastName\":\"Mallol-Poyato\",\"suffix\":\"\"},{\"id\":627959874,\"identity\":\"4ec14145-4ecd-4049-bdbf-35134af46b9e\",\"order_by\":7,\"name\":\"Jorge Molina-del Pozo\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Jorge\",\"middleName\":\"Molina-del\",\"lastName\":\"Pozo\",\"suffix\":\"\"},{\"id\":627959875,\"identity\":\"82b910d4-f4b4-4e89-9455-a6bef12c18ad\",\"order_by\":8,\"name\":\"Yolanda Torrejón-Pulido\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Yolanda\",\"middleName\":\"\",\"lastName\":\"Torrejón-Pulido\",\"suffix\":\"\"},{\"id\":627959876,\"identity\":\"9464a0d6-b750-45da-93fd-42c6514284b7\",\"order_by\":9,\"name\":\"Marta Navalón-Hernández\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Marta\",\"middleName\":\"\",\"lastName\":\"Navalón-Hernández\",\"suffix\":\"\"},{\"id\":627959877,\"identity\":\"eb74d291-1677-470e-8b1a-a45d4bac850a\",\"order_by\":10,\"name\":\"Ana Virseda-Berdices\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Health Institute Carlos III (ISCIII)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ana\",\"middleName\":\"\",\"lastName\":\"Virseda-Berdices\",\"suffix\":\"\"},{\"id\":627959878,\"identity\":\"14d6b149-adad-4881-95a1-5953d42fd341\",\"order_by\":11,\"name\":\"Cristina Rodríguez-Grande\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Health Institute Carlos III (ISCIII)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Cristina\",\"middleName\":\"\",\"lastName\":\"Rodríguez-Grande\",\"suffix\":\"\"},{\"id\":627959879,\"identity\":\"111807c3-db2e-42a5-a2d6-4727c3f9ec30\",\"order_by\":12,\"name\":\"María Ángeles Jiménez-Sousa\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Health Institute Carlos III (ISCIII)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"María\",\"middleName\":\"Ángeles\",\"lastName\":\"Jiménez-Sousa\",\"suffix\":\"\"},{\"id\":627959880,\"identity\":\"c407e651-9af5-4afd-a8e8-860914fc960a\",\"order_by\":13,\"name\":\"Amanda Fernández-Rodríguez\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Health Institute Carlos III (ISCIII)\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Amanda\",\"middleName\":\"\",\"lastName\":\"Fernández-Rodríguez\",\"suffix\":\"\"},{\"id\":627959881,\"identity\":\"55eb5e9b-3e55-4cc0-a940-fba227711198\",\"order_by\":14,\"name\":\"Rafael Blancas\",\"email\":\"data:image/png;base64,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\",\"orcid\":\"\",\"institution\":\"Hospital Universitario del Tajo\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Rafael\",\"middleName\":\"\",\"lastName\":\"Blancas\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2026-01-27 17:23:56\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-8713144/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-8713144/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":108010303,\"identity\":\"38ac6f2e-921e-4895-a5ee-f21abb7145ca\",\"added_by\":\"auto\",\"created_at\":\"2026-04-28 13:12:59\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":41006,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8713144/v1/370c215c90c9ffd13ffaa929.png\"},{\"id\":108009201,\"identity\":\"d92bd56e-f99d-4ba6-aef0-782bb604c076\",\"added_by\":\"auto\",\"created_at\":\"2026-04-28 13:09:51\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":40409,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003eSee image above for figure legend\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"floatimage2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8713144/v1/1e2842948c2a3f68d7eff6e7.png\"},{\"id\":108012440,\"identity\":\"f939cb85-0e4c-4aba-9d0c-81d11fc54682\",\"added_by\":\"auto\",\"created_at\":\"2026-04-28 13:15:40\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":421999,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8713144/v1/d0a55de4-1ada-4428-86b7-ab16b15e381e.pdf\"},{\"id\":108009200,\"identity\":\"26c179ad-bd5a-411d-ad9e-83007de3a240\",\"added_by\":\"auto\",\"created_at\":\"2026-04-28 13:09:51\",\"extension\":\"docx\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":13078,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Supplementarymaterial.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-8713144/v1/4e8fa6faf066091690a6c679.docx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Association of Relative Telomere Length with Glucocorticoids Therapy in Critically Ill Patients with COVID-19\",\"fulltext\":[{\"header\":\"INTRODUCTION \",\"content\":\"\\u003cp\\u003eIn the treatment of severe COVID-19, glucocorticoids (GCs) proved to be a key therapy in mitigating the systemic inflammatory response (1-2), with a considerable number of patients developing severe disease requiring admission to intensive care units (ICUs) (3).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTelomeres are DNA-protein complexes located at the end regions of chromosomes. They are characterised by shortening with each cell division. Although telomerase, a specialised intracellular enzyme, works to partially rebuild telomeres by adding repeat units, telomeres continue to shorten with repeated cell divisions, leading to disruption of cell function and ultimately to cell senescence. Telomere length (TL) and telomerase activity (TA) are considered valuable biomarkers in the diagnosis and prognosis of various pathological conditions. Relative telomere length (RTL) has been recognised as a biomarker of cellular ageing and biological stress, and its role in the context of critical acute illnesses is of growing interest. In fact, shorter telomere length in leukocytes, particularly in CD8CD28- cells, is expected to be associated with an increased risk of infection and clinical disease (4-5).\\u003c/p\\u003e\\n\\u003cp\\u003eEnvironmental stressors and predictable life history events can have a strong impact on telomere dynamics (6-9). Chronic stress and exposure to GCs increase the risk of medical disorders, including cardiovascular and neuropsychiatric disorders, and contribute to accelerated ageing (10-11). In this context, GCs are the main hormonal mediators of allostasis (maintaining stability through change) and deserve specific attention due to their involvement in the stress response (12-13).\\u003c/p\\u003e\\n\\u003cp\\u003eSex is another factor associated with RTL. On average, women have longer telomeres than men, regardless of age. This should be taken into account when investigating how different pathologies or drugs affect telomere length (14). The influence of sex on RTL in severe SARS-CoV-2 infection has previously been studied. A lower RTL has been linked to a higher chance of mortality in women following a diagnosis of COVID-19 (15).\\u003c/p\\u003e\\n\\u003cp\\u003eThe present study explores the association between the duration and dose of GCs therapy administered to ICU patients with COVID-19 and changes in RTL from admission to at least one-year after hospital discharge. This study adds to the growing body of research on how telomere length is associated with the pathobiology of critical illnesses, including acute respiratory distress syndrome (ARDS), a severe condition that can be caused by COVID-19 (16).\\u003c/p\\u003e\"},{\"header\":\"METHODS \",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eStudy population and clinical data\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis prospective, longitudinal study included patients over 18 years of age with severe SARS-CoV-2 pneumonia, admitted to the intensive care unit (ICU) of the Hospital Universitario del Tajo (Aranjuez, Madrid, Spain) between August 2020 and April 2021, who agreed to participate in the study (or consent was given by their relatives in cases where they were unable to give consent). Patients were admitted to the ICU within the first 72 hours of hospital admission. Those receiving chronic GCs treatment before ICU admission were excluded from the study, as were those who refused to participate.\\u003c/p\\u003e\\n\\u003cp\\u003eDemographic data, comorbidities, treatments received during hospitalisation, and other data considered descriptive of the severity of the situation during ICU admission were collected, such as the need for invasive mechanical ventilation (IMV) and its length, high-flow nasal cannula (HFNC) therapy and its duration, length of stay (LOS) in the ICU, need for prone positioning, modified shock index (MSI) (17), shock index (SI) (18), sequential organ failure assessment (SOFA) index (19), and the use of vasoactive drugs.\\u003c/p\\u003e\\n\\u003cp\\u003eClinical and epidemiological data were recorded using Research Electronic Data Capture (REDCap) (20).\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was approved by the Research Committee of Tajo University Hospital and the Ethics Committee of the Carlos III Health Institute (Madrid, Spain; PI 33_2020-v3). Informed consent to be included in the study was obtained from all patients or their representatives in cases where it could not be obtained from the patients themselves.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAssessment of glucocorticoids treatment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eGCs treatment guidelines were considered from the start of treatment until its completion in the ICU or hospital ward. During this period, patients received different GCs treatment regimens. Since most treatments followed the RECOVERY study protocol, based on dexamethasone (1), and to facilitate the interpretation of results, all GCs treatments are shown as equivalents to dexamethasone doses, following those previously published by Mager, DE et al. (2). During the study period, patients received dexamethasone, hydrocortisone, methylprednisolone, prednisone, or a combination of thereof. The average equivalence of doses to 1 mg of dexamethasone was as follows: methylprednisolone 5 mg, hydrocortisone 25 mg, prednisolone or prednisone 6.25 mg.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTelomere length assessment\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003ePeripheral blood samples were obtained upon admission to the ICU and at least one year after discharge. DNA was isolated from whole blood. Telomere length was determined using the Cawthon method, which uses quantitative polymerase chain reaction (qPCR) (21). This method calculates a telomere: single-copy gene (T:S) ratio as an index of average telomere length. For the analysis of changes in telomere length, the RTL ratio (RTL at follow-up / RTL at baseline) was used as previously described (22). \\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eOutcome\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study assessed how the GCs dose, as well as the duration of GCs therapy during ICU admission, impacted RTL one-year post-discharge.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStatistical analysis\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe clinical and epidemiological characteristics of the patients were summarised using standard descriptive statistics, such as the median [interquartile range] for continuous variables and the count (percentage, %) for categorical variables. Differences between groups were analysed using the Mann-Whitney test for continuous variables and the Chi-square test or Fisher\\u0026apos;s exact test for categorical variables. Associations of RTL ratios (dependent variable) with dexamethasone equivalent dose (as independent variable), duration of GCs therapy, and other relevant clinical covariates were calculated using generalised linear models (GLM) with a gamma distribution adjusted by the most significant variables following a stepwise model selection: age, sex, body mass index (BMI), time elapsed from discharge from the ICU to follow-up, ICU LOS, ionotropic/vasopressor therapy and smoking status at ICU admission. For this purpose, arithmetic mean ratio (AMR) and adjusted arithmetic mean ratio (aAMR) are shown.\\u003c/p\\u003e\"},{\"header\":\"RESULTS\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eClinical and epidemiological characteristics of the cohort\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eDuring admission to the ICU, 10 patients died, so no follow-up samples were obtained and they were excluded from further analysis. One patient undergoing chronic GCs treatment during follow-up was also excluded from the study. Finally, 49 patients were included in the analysis.\\u003c/p\\u003e\\n\\u003cp\\u003eThe median age of the patients was 64.0 years, with a median body mass index (BMI) of 30.86 kg/m\\u003csup\\u003e2\\u003c/sup\\u003e, and 71.4% were male. A significant percentage of patients were obese (BMI \\u0026gt; 30 kg/m\\u003csup\\u003e2\\u003c/sup\\u003e), representing 41.7% of the cohort. The median duration of GCs therapy was 10.0 days. IMV was required in 75.5% of patients, with a median duration of 14.0 days. The median ICU LOS was 12.0 days. A significant difference was observed in the use of the prone position, which was more frequent in female (64.3%) than in male (28.6%) (p=0.046).\\u003c/p\\u003e\\n\\u003cp\\u003eClinical and epidemiological characteristics of patients with COVID-19, stratified by sex, are shown in \\u003cstrong\\u003eTable 1\\u003c/strong\\u003e.\\u003c/p\\u003e\\n\\u003cp id=\\\"_Toc201657867\\\"\\u003e\\u003cstrong\\u003eTable\\u0026nbsp;\\u003c/strong\\u003e\\u003cstrong\\u003e1\\u003c/strong\\u003e. Clinical and epidemiological characteristics of patients with COVID‐19, stratified by gender.\\u003cstrong\\u003e\\u0026nbsp;Statistics\\u003c/strong\\u003e: Individual characteristics were summarized using standard descriptive statistics: median [interquartile range] for continuous variables and count (percentage %) for categorical variables. Differences between groups were tested using the Mann-Whitney test for continuous variables, and the Chi-square test (n\\u0026ge;5 %) and Fisher\\u0026rsquo;s exact test (n\\u0026lt;5 %) for categorical variables. \\u003cstrong\\u003eAbbreviations:\\u003c/strong\\u003e BMI, body mass index; ACE, angiotensin converting enzyme inhibitors; AIIRA, angiotensin II receptor antagonists; ICU, intensive care unit; ICU LOS, ICU length of stay; IMV, invasive mechanical ventilation; MSI, modified shock index; RTL, relative telomere length; SI, shock index, SOFA, sequential organ failure assessment.\\u003c/p\\u003e\\n\\u003ctable border=\\\"0\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"748\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDemographics\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eNo.\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e49\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e14 (28.6%)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e35 (71.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAge (years %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e64.00 [56.00, 72.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e63.00 [52.25, 72.75]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e65.00 [57.50, 71.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.833\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eBMI (kg/m\\u003c/strong\\u003e\\u003cstrong\\u003e\\u003csup\\u003e2\\u003c/sup\\u003e\\u003c/strong\\u003e\\u003cstrong\\u003e)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e30.86 [26.35, 35.16]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e34.52 [28.01, 35.87]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e29.39 [25.04, 33.06]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.093\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eRTL\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e1.35 [1.16, 1.60]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1.41 [1.29, 1.79]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e1.33 [1.15, 1.53]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.206\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eEthnicity\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eCaucasian\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e40 (81.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e10 (71.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e30 (85.7 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"4\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.484\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eHispanic\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e6 (12.2 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e3 (21.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e3 (8.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eArabian\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e2 (4.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1 (7.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e1 (2.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eOther\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e1 (2.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e0 (0.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e1 (2.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eComorbidities\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eNon-smoker\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e28 (63.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e11 (78.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e17 (56.7 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd rowspan=\\\"3\\\" valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.341\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eEx-Smoker\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e15 (34.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e3 (21.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e12 (40.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eSmoker\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e1 (2.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e0 (0.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e1 (3.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eArterial hypertension\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e21 (42.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e4 (28.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e17 (48.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.338\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eObesity (BMI\\u0026gt;30 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e20 (41.7 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e8 (57.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e12 (35.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.08\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eDiabetes\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e15 (30.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e4 (28.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e11 (31.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTherapy before hospitalization\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAIIRA\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e7 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e2 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e5 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.815\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eACE\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e7 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e2 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e5 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.815\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAnticoagulant therapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e4 (8.2 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1 (7.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e3 (8.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eTreatment during hospitalization\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAntibiotics\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e48 (98.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e13 (92.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e35 (100.0 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.632\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAzithromycin\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e23 (47.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e8 (57.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e15 (44.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.615\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eCorticoids\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e46 (93.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e13 (92.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e33 (94.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e1\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAnticoagulants\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eDexamethasone equivalent dose (mg)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e66.00 [60.00, 88.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e79.00 [61.50, 93.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e66.00 [54.00, 81.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.072\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eDuration of corticosteroid therapy (days)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e10.00 [9.00, 13.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e10.50 [10.00, 13.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e10.00 [9.00, 12.50]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.292\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eInotropic/vasopressor therapy\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e11 (22.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e5 (35.7 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e6 (17.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.304\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eTherapeutic dose of enoxaparin (80-100mg/12h %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e6 (12.2 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1 (7.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e5 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.836\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eOxygen Therapy and Ventilator Support\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eIMV\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e37 (75.5 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e12 (85.7 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e25 (71.4 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.495\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eDuration of IMV (days)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e14.00 [6.00, 23.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e14.50 [9.50, 22.25]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e9.00 [5.00, 27.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.505\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eHigh-flow nasal cannulas\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e40 (81.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e11 (78.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e29 (82.9 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e1.000\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eDuration of high-flow nasal cannula therapy (days)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e2.00 [0.00-4.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1.00 [0.00, 4.50]\\u003c/p\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e2.50 [1.00, 4.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.466\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eICU\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eICU LOS (days %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e12.00 [8.00, 26.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e17.00 [12.75, 25.25]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e11.00 [7.00, 24.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.24\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eProne position\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e19 (38.8 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e9 (64.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e10 (28.6 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.046\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eSOFA index\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e4.00 [4.00, 11.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e4.00 [4.00, 11.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e4.00 [4.00, 11.00]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.609\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eSI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e0.56 [0.46, 0.62]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e0.61 [0.55, 0.66]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e0.53 [0.45, 0.59]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.172\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eMSI\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e0.82 [0.66, 0.90]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e0.87 [0.78, 1.01]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e0.75 [0.65, 0.86]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.16\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eFollow-up\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eFollow-up visit (months %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e13.61 [12.16, 15.12]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e14.68 [12.64, 15.22]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e12.89 [12.12, 14.75]\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.184\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 234px;\\\"\\u003e\\n \\u003cp\\u003eAnticoagulant treatment\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 159px;\\\"\\u003e\\n \\u003cp\\u003e6 (12.2 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 147px;\\\"\\u003e\\n \\u003cp\\u003e1 (7.1 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 148px;\\\"\\u003e\\n \\u003cp\\u003e5 (14.3 %)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 59px;\\\"\\u003e\\n \\u003cp\\u003e0.836\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAssociation of RTL with GC therapy\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eA significant association was found between the GCs duration of therapy and RTL ratio (aAMR: 0.98, 95% CI: 0.97-0.99, p= 0.007), especially in male population (aAMR: 0.98, 95% CI: 0.97-0.99, p= 0.001) (Table 2 \\u0026amp; Figure 1).\\u003c/p\\u003e\\n\\u003cp\\u003eIn male population, the equivalent dexamethasone dose showed a significant association with the RTL ratio (aAMR: 0.99, 95% CI: 0.98\\u0026ndash;0.99, p= 0.028). This association was not observed in female group (Table 2 \\u0026amp; Figure 2).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eTable 2\\u003c/strong\\u003e. Association of RTL ratios with dexamethasone equivalent dose and the duration of corticosteroid therapy during ICU stay. \\u003cstrong\\u003eStatistics\\u003c/strong\\u003e: Associations were calculated using Generalized Linear Models (GLM) with a gamma distribution. Significant differences are shown in bold. \\u003cstrong\\u003eAbbreviations\\u003c/strong\\u003e: AMR, arithmetic mean ratio; aAMR, adjusted AMR; 95%CI, 95% of confidence interval; p, level of significance.\\u003c/p\\u003e\\n\\u003ctable border=\\\"1\\\" cellspacing=\\\"0\\\" cellpadding=\\\"0\\\" width=\\\"740\\\"\\u003e\\n \\u003ctbody\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 61px;\\\"\\u003e\\n \\u003cp\\u003e\\u0026nbsp;\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"4\\\" valign=\\\"top\\\" style=\\\"width: 342px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDexamethasone equivalent dose\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd colspan=\\\"4\\\" valign=\\\"top\\\" style=\\\"width: 336px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eDuration of corticosteroid therapy\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 61px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eSex\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 114px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAMR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 108px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eaAMR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eP-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 95px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAMR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 57px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 117px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eaAMR (95%CI)\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 68px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003ep-value\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 61px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eAll\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 114px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.99-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e0.136\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 108px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.99-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e0.452\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 95px;\\\"\\u003e\\n \\u003cp\\u003e0.98\\u003c/p\\u003e\\n \\u003cp\\u003e(0.97-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 57px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e0.007\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 117px;\\\"\\u003e\\n \\u003cp\\u003e0.98\\u003c/p\\u003e\\n \\u003cp\\u003e(0.97-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 68px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e0.007\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 61px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eMale\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 114px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.98-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e0.008\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 108px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.98-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e0.028\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 95px;\\\"\\u003e\\n \\u003cp\\u003e0.98\\u003c/p\\u003e\\n \\u003cp\\u003e(0.97-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 57px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e\\u0026lt; 0.001\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 117px;\\\"\\u003e\\n \\u003cp\\u003e0.98\\u003c/p\\u003e\\n \\u003cp\\u003e(0.97-0.99)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 68px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003e0.001\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003ctr\\u003e\\n \\u003ctd valign=\\\"top\\\" style=\\\"width: 61px;\\\"\\u003e\\n \\u003cp\\u003e\\u003cstrong\\u003eFemale\\u003c/strong\\u003e\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 114px;\\\"\\u003e\\n \\u003cp\\u003e1.01\\u003c/p\\u003e\\n \\u003cp\\u003e(0.99-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e0.840\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 108px;\\\"\\u003e\\n \\u003cp\\u003e1.01\\u003c/p\\u003e\\n \\u003cp\\u003e(0.99-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 60px;\\\"\\u003e\\n \\u003cp\\u003e0.840\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 95px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.98-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 57px;\\\"\\u003e\\n \\u003cp\\u003e0.984\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 117px;\\\"\\u003e\\n \\u003cp\\u003e0.99\\u003c/p\\u003e\\n \\u003cp\\u003e(0.98-1.01)\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003ctd valign=\\\"bottom\\\" style=\\\"width: 68px;\\\"\\u003e\\n \\u003cp\\u003e0.984\\u003c/p\\u003e\\n \\u003c/td\\u003e\\n \\u003c/tr\\u003e\\n \\u003c/tbody\\u003e\\n\\u003c/table\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAssociation of GCs therapy duration and dexamethasone equivalent dose with other relevant clinical covariates\\u0026nbsp;\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eLonger duration of the GCs therapy was associated with BMI at baseline (AMR: 1.03, 95% CI: 1.01-1.05, p= 0.023), dexamethasone higher equivalent dose\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e(AMR: 1.004, 95% CI: 1.003-1.005, p\\u0026lt; 0.001), length of IMV (AMR: 1.02, 95% CI: 1.01-1.03, p=0.003), ICU LOS (AMR: 1.02, 95% CI: 1.01-1.03, p\\u0026lt;0.001) and use of inotropic/vasopressor therapy\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003e(AMR: 1.86, 95% CI: 1.40-2.46, p\\u0026lt;0.001).\\u003c/p\\u003e\\n\\u003cp\\u003eVariables associated with dexamethasone equivalent dose were length of IMV (AMR: 1.03, 95% CI: 1.01-1.05, p= 0.001), ICU LOS (AMR: 1.03, 95% CI: 1.01-1.04, p\\u0026lt; 0.001), the need for inotropic/vasopressor therapy (AMR: 2.14, 95% CI: 1.18-3.88, p= 0.015), smoker status (AMR: 1.31, 95% CI: 1.01-1.69, p= 0.048) and baseline BMI (AMR: 1.04, 95% CI: 1.01-1.08, p= 0.055).\\u0026nbsp;\\u003c/p\\u003e\"},{\"header\":\"DISCUSSION\",\"content\":\"\\u003cp\\u003eThis study highlights the complex interaction between telomere length, GCs therapy, and clinical outcomes in critically ill patients with COVID-19. Our findings suggest a significant association between both the duration and total dose of GCs therapy, particularly in male, and the RTL ratio, showing a lower recovery of telomere length associated with longer duration of treatment and higher doses of GCs.\\u003c/p\\u003e\\n\\u003cp\\u003eThe effect of GCs on telomeres shows differences according to sex, although the evidence is limited and depends on the biological and clinical context. Sex-specific differences in the effect of corticosteroids on telomere length are explained by molecular and hormonal mechanisms involving the interaction between GCs, oestrogens, and androgens.\\u003c/p\\u003e\\n\\u003cp\\u003eOestrogens modulate telomerase activity via the oestrogen receptor alpha (ER\\u0026alpha;), stimulating TERT gene expression and increasing telomerase activity in haematopoietic cells and other tissues, which may partially counteract glucocorticoid-induced telomere shortening (23-24). However, the effect of oestrogens is tissue-dependent and may vary; in certain areas of the brain, oestrogen may reduce telomere length (25).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAndrogens also increase telomerase activity, mainly through their conversion to oestrogens via aromatase and activation of ER\\u0026alpha;, rather than through the direct androgen receptor. In men, elevated levels of dihydrotestosterone and oestradiol are associated with longer telomeres, suggesting a protective hormonal effect against telomeric damage by glucocorticoids (24, 26).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eTo our knowledge, there is no evidence of a relationship between GCs, RTL, and sex in critically ill patients.\\u003c/p\\u003e\\n\\u003cp\\u003eStress and oxidative damage are considered the main causes of telomere shortening. Telomeres are particularly sensitive to reactive oxygen species (ROS) produced by metabolic processes and immune cells (6, 10). Inflammation, which is a characteristic of severe COVID-19, is accompanied by an increase in ROS content (27). GCs, such as dexamethasone, can influence oxidative balance and telomerase activity, although their effect may vary depending on the dose and duration of exposure. Chronic exposure to GCs or stress are strongly associated with telomere shortening in multiple species, including rats, mice, and humans. Studies have shown that stress in rats leads to a significant reduction in telomere length in T cells and the dentate gyrus of the hippocampus, and exposure to corticosterone in mice produces similar reductions in the blood and brain (25). Furthermore, in patients with active Cushing\\u0026apos;s syndrome, a considerable reduction in telomere length was observed, correlating with the duration of hypercortisolism (10, 28). Despite the numerous stress factors present in critically ill patients, this study takes into account variables such as disease severity data, including IMV, the requirement for vasoactive drugs, and mortality prediction scores. We believe that the inclusion in the association model (GLM) of these variables is necessary to rule them out as possible confounding variables that affect the results and the influence of GCs on RTL.\\u003c/p\\u003e\\n\\u003cp\\u003eOur previously published findings on RTL shortening in patients with idiopathic pulmonary fibrosis (IPF) align with evidence that shorter leukocyte telomere lengths (LTL) are common in IPF and associated with lower survival (22). Interestingly, research also suggests that LTL may serve as a pharmacogenomic biomarker, identifying IPF patients at \\u0026nbsp;higher risk of adverse outcomes (including hospitalizations) when exposed to immunosuppressive drugs such as prednisone and azathioprine. This highlights the genetic vulnerability of patients with short telomeres to immunosuppression, a relevant finding given the widespread use of GCs in the treatment of severe COVID-19 (29).\\u003c/p\\u003e\\n\\u003cp\\u003eThe observation of significant changes in telomere length, both increases and decreases, in critically ill ICU patients over short periods (mean 7.2 \\u0026plusmn; 2.5 days) suggests active dynamics in the context of severe disease \\u0026nbsp;(30). Although a previous study found no direct correlation between these changes and clinical outcomes, other studies have shown that shorter telomere length in peripheral blood leukocytes is associated with mortality and ARDS severity in critically ill patients (4, 15, 22). This supports the idea that telomeric dysfunction is intrinsically linked to the pathobiology of critical illness.\\u003c/p\\u003e\\n\\u003cp\\u003eIt is important to highlight the possible reversibility of GCs-induced telomere shortening. In patients cured of Cushing\\u0026apos;s syndrome, telomere length approached that of healthy controls, and in neuronal cell lines, discontinuation of dexamethasone exposure allowed telomere length to recover (31). This reversibility raises the possibility that treatments aimed at reducing cortisol levels may not only influence telomere length but also potentially reverse cellular senescence. In addition, recent studies are evaluating different therapies for telomere length recovery in diseases associated with telomere shortening, generating new therapeutic possibilities (32-33).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eStudy limitations\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe limited sample size reduces the statistical power for subgroup analyses, especially within the female group. Therefore, we stress that the specific findings are exploratory and hypothesis-generating, rather than definitive conclusions. However, the statistically significant differences observed are noteworthy, given the sample size constrains.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAlthough preliminary due to the limited sample size, this study is valuable because it is, to our knowledge, the first to examine the association between GCs dose and duration and RTL reduction in critically ill patients with COVID-19, addressing an area that has not been sufficiently studied due to the difficulty in recruiting and following up on these patients. In addition to the limited sample size, the low proportion of women in the sample (28%) may have underestimated the effect of GCs on RTL.\\u003c/p\\u003e\\n\\u003cp\\u003eAlthough this study was prospective, which helps mitigate concerns about reverse causality (disease or treatment causing telomere shortening), future research with longer follow-up periods and measurement of telomerase activity is needed to fully establish the role of TL as a prognostic and risk stratification tool in critically ill patients, as well as to elucidate the mechanisms underlying these associations.\\u003c/p\\u003e\"},{\"header\":\"Abbreviations\",\"content\":\"\\u003cp\\u003eAMR:\\u0026nbsp;Arithmetic mean ratio\\u003c/p\\u003e\\n\\u003cp\\u003eaAMR: Adjusted\\u0026nbsp;arithmetic mean ratio\\u003c/p\\u003e\\n\\u003cp\\u003eARDS: Acute respiratory distress syndrome\\u003c/p\\u003e\\n\\u003cp\\u003eBMI: Body mass index\\u003c/p\\u003e\\n\\u003cp\\u003eGCs:\\u003cstrong\\u003e\\u0026nbsp;\\u003c/strong\\u003eGlucocorticoids\\u003c/p\\u003e\\n\\u003cp\\u003eGLM: Generalized linear models\\u003c/p\\u003e\\n\\u003cp\\u003eHFNC: High-flow nasal cannula\\u003c/p\\u003e\\n\\u003cp\\u003eICU\\u003cstrong\\u003e:\\u0026nbsp;\\u003c/strong\\u003eIntensive care unit\\u003c/p\\u003e\\n\\u003cp\\u003eIMV:\\u0026nbsp;Invasive mechanical ventilation\\u003c/p\\u003e\\n\\u003cp\\u003eIPF: Idiopathic pulmonary fibrosis\\u003c/p\\u003e\\n\\u003cp\\u003eLOS: Length of stay\\u003c/p\\u003e\\n\\u003cp\\u003eLTL:\\u0026nbsp;Leukocyte telomere lengths\\u003c/p\\u003e\\n\\u003cp\\u003eMSI:\\u0026nbsp;Modified shock index\\u003c/p\\u003e\\n\\u003cp\\u003eqPCR: Polymerase chain reaction\\u003c/p\\u003e\\n\\u003cp\\u003eREDCap: Research Electronic Data Capture\\u003c/p\\u003e\\n\\u003cp\\u003eROS: Reactive oxygen species\\u003c/p\\u003e\\n\\u003cp\\u003eRTL: Relative telomere length\\u003c/p\\u003e\\n\\u003cp\\u003eSI:\\u0026nbsp;Shock index\\u003c/p\\u003e\\n\\u003cp\\u003eSOFA: Sequential organ failure assessment\\u003c/p\\u003e\\n\\u003cp\\u003eTA:\\u0026nbsp;Telomerase activity\\u003c/p\\u003e\\n\\u003cp\\u003eTL: Telomere length\\u003c/p\\u003e\"},{\"header\":\"CONCLUSIONS\",\"content\":\"\\u003cp\\u003eIn critically ill patients with SARS-CoV-2 pneumonia, this study demonstrates a significant association between\\u0026nbsp;both the duration and equivalent dose of GCs therapy and RTL shortening, particularly evident in male population. Furthermore, GCs duration and use were significantly associated with\\u0026nbsp;markers of disease severity and progression, including the duration of IMV, ICU LOS, and the need for vasopressor therapy.\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eThese findings collectively highlight the intricate relationship between telomere dynamics and the clinical trajectory of severe COVID-19. Notably, the\\u0026nbsp;possible reversibility of GCs-induced telomere shortening, as suggested by previous research, opens\\u0026nbsp;promising new therapeutic avenues\\u0026nbsp;for potentially mitigating long-term cellular damage and improving outcomes in critically ill patients.\\u003c/p\\u003e\\n\\u003cp\\u003eFurther prospective studies are crucial to fully elucidate the underlying mechanisms, to determine the effect of GCs on RTL in critically ill patients admitted for other conditions, and to explore strategies for preserving telomere integrity and enhancing patient recovery.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003cp\\u003e\\u003cstrong\\u003eEthical approval and consent to participate\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe study was approved by the Research Committee of Tajo University Hospital and the Ethics Committee of the Carlos III Health Institute (Madrid, Spain; PI 33_2020-v3).\\u0026nbsp;\\u003c/p\\u003e\\n\\u003cp\\u003eAll patients or their relatives (if the patient was unable) received advance study information, had their data anonymised, signed informed consent, and could withdraw at any time.\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was conducted in accordance with the ethical principles set out in the Declaration of Helsinki and the International Standards of Good Clinical Practice (ICH-GCP).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConsent for publication\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eNot applicable\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAvailability of supporting data\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eAll data generated or analyzed during this study are included in this published article.\\u003c/p\\u003e\\n\\u003cp\\u003eThe data supporting the findings of this study are available from the corresponding author upon reasonable request.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eCompeting interests\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors declare that they have no competing interests.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eFunding\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThis study was supported by grants from Instituto de Salud Carlos III (ISCIII; grant number COV20/1144 [MPY224/20] to AFR/MAJS) and Fundacion Universidad Alfonso X el Sabio (FUAX) – Santander (1.013.005). The study was also supported by CIBER – Consorcio Centro de Investigacion Biomedica en Red-(CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion and Union Europea – NextGenerationEU (CB21/13/00044).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAuthors contribution\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eFunding acquisition: RB, AFR, and MAJS.\\u003cbr\\u003e\\u0026nbsp;Conceptualization: RB.\\u003cbr\\u003e\\u0026nbsp;Project administration: RB, OMG, AFR and MAJS.\\u003cbr\\u003e\\u0026nbsp;Patients’ selection and clinical data acquisition: RB, OMG, ÁAC, CMP, MAAF, MMA, MMP, JMP, YT, MNH.\\u003c/p\\u003e\\n\\u003cp\\u003eData curation: RB, OMG, ÁAC, CMP, MAAF, MMA, MMP, JMP, YT, MNH.\\u003cbr\\u003e\\u0026nbsp;Sample preparation and analysis: JMP, MJMP, RBL, AVB, CRG.\\u003cbr\\u003e\\u0026nbsp;Statistical and computational analyses: RBL.\\u003cbr\\u003e\\u0026nbsp;Manuscript writing: RB.\\u003cbr\\u003e\\u0026nbsp;Critical revision and approval of the final manuscript: RB, AFR, MAJS, OMG, RBL.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eAcknowledgements\\u003c/strong\\u003e\\u003c/p\\u003e\\n\\u003cp\\u003eThe authors are grateful for the willingness of the patients who made this study possible.\\u003c/p\\u003e\"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\n\\u003cli\\u003eRECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693\\u0026ndash;704. doi:10.1056/NEJMoa2021436.\\u003c/li\\u003e\\n\\u003cli\\u003eMager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol. 2003;43(11):1216\\u0026ndash;27.\\u003c/li\\u003e\\n\\u003cli\\u003eKohler K, De Corte T, Greco M, Povoa P, Cecconi M, Ostermann M, De Waele J, Morris AC; UNITE-COVID investigators. The impact of intensive care strain on patients\\u0026apos; outcomes\\u0026mdash;a multinational observational cohort (UNITE-COVID) study. Crit Care. 2025;29(1):329.\\u003c/li\\u003e\\n\\u003cli\\u003eLiu S, Wang C, Green G, Zhuo H, Liu KD, Kangelaris KN, et al. Peripheral blood leukocyte telomere length is associated with survival of sepsis patients. Eur Respir J. 2020;55(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31619475/\\u003c/li\\u003e\\n\\u003cli\\u003eMoskaleva EY, Glukhov AI, Zhirnik AS, Vysotskaya OV, Vorobiova SA. Telomere length and telomerase activity as biomarkers in diagnostics and prognostics of pathological conditions. Biochem. 2025;90(6):700\\u0026ndash;24.\\u003c/li\\u003e\\n\\u003cli\\u003eWang C, Wolters PJ, Calfee CS, Liu S, Balmes JR, Zhao Z, et al. Long-term ozone exposure is positively associated with telomere length in critically ill patients. Environ Int. 2020;141. Available from: https://pubmed.ncbi.nlm.nih.gov/32417614/\\u003c/li\\u003e\\n\\u003cli\\u003eCohen S, Janicki-Deverts D, Turner RB, Casselbrant ML, Li-Korotky HS, Epel ES, et al. Association between telomere length and experimentally induced upper respiratory viral infection in healthy adults. JAMA. 2013;309(7):699\\u0026ndash;705.\\u003c/li\\u003e\\n\\u003cli\\u003e\\u0026Oslash;sthus IB\\u0026Oslash;, Lydersen S, Dalen H, Nauman J, Wisl\\u0026oslash;ff U. Association of telomere length with myocardial infarction: a prospective cohort from the population-based HUNT 2 study. Prog Cardiovasc Dis. 2017;59(6):649\\u0026ndash;55.\\u003c/li\\u003e\\n\\u003cli\\u003eNewton CA, Zhang D, Oldham JM, Kozlitina J, Ma SF, Martinez FJ, et al. Telomere length and use of immunosuppressive medications in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2019;200(3):336\\u0026ndash;47.\\u003c/li\\u003e\\n\\u003cli\\u003eLee RS, Zandi PP, Santos A, Aulinas A, Carey JL, Webb SM, et al. Cross-species association between telomere length and glucocorticoid exposure. J Clin Endocrinol Metab. 2021;106(12):E5124\\u0026ndash;35.\\u003c/li\\u003e\\n\\u003cli\\u003eAngelier F, Costantini D, Bl\\u0026eacute;vin P, Chastel O. Do glucocorticoids mediate the link between environmental conditions and telomere dynamics in wild vertebrates? Gen Comp Endocrinol. 2018;256:99\\u0026ndash;111.\\u003c/li\\u003e\\n\\u003cli\\u003eRodriquez EJ, Kim EN, Sumner AE, N\\u0026aacute;poles AM, P\\u0026eacute;rez-Stable EJ. Allostatic load: importance, markers, and score determination in minority and disparity populations. J Urban Health. 2019;96:3\\u0026ndash;11.\\u003c/li\\u003e\\n\\u003cli\\u003eEachus H, Ryu S. Glucocorticoid effects on the brain: from adaptive developmental plasticity to allostatic overload. J Exp Biol. 2024;227.\\u003c/li\\u003e\\n\\u003cli\\u003eGardner M, Bann D, Wiley L, Cooper R, Hardy R, Nitsch D, Martin-Ruiz C, et al. Gender and telomere length: systematic review and meta-analysis. Exp Gerontol. 2014;51:15\\u0026ndash;27.\\u003c/li\\u003e\\n\\u003cli\\u003eVirseda-Berdices A, Concostrina-Martinez L, Mart\\u0026iacute;nez-Gonz\\u0026aacute;lez O, Blancas R, Resino S, Ryan P, et al. Relative telomere length impact on mortality of COVID-19: sex differences. J Med Virol. 2023;95(1):1\\u0026ndash;7.\\u003c/li\\u003e\\n\\u003cli\\u003eMayr FB, Yende S. Size matters! Peripheral blood leukocyte telomere length and survival after critical illness. Eur Respir J. 2020;55(1). Available from: https://pubmed.ncbi.nlm.nih.gov/31949102/\\u003c/li\\u003e\\n\\u003cli\\u003eJouffroy R, Gille S, Gilbert B, Travers S, Bloch-Laine E, Ecollan P, et al. Relationship between shock index, modified shock index, and age shock index and 28-day mortality among patients with prehospital septic shock. J Emerg Med. 2024;66(2):144\\u0026ndash;53.\\u003c/li\\u003e\\n\\u003cli\\u003eKing RW, Plewa MC, Buderer NMF, Knotts FB. Shock index as a marker for significant injury in trauma patients. Acad Emerg Med. 1996;3(11):1041\\u0026ndash;5.\\u003c/li\\u003e\\n\\u003cli\\u003eVincent JL, de Mendonca A, Cantraine F, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter prospective study. Crit Care Med. 1998;26(11):1793\\u0026ndash;800.\\u003c/li\\u003e\\n\\u003cli\\u003eHarris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG, et al. The REDCap Consortium: building an international community of software platform partners. J Biomed Inform. 2009;42(2):377\\u0026ndash;81.\\u003c/li\\u003e\\n\\u003cli\\u003eCawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009;37(3):e21.\\u003c/li\\u003e\\n\\u003cli\\u003eVirseda-Berdices A, Behar-Lagares R, Mart\\u0026iacute;nez-Gonz\\u0026aacute;lez \\u0026Oacute;, Blancas R, Bueno-Bustos S, Brochado-Kith \\u0026Oacute;, et al. Longer ICU stay and invasive mechanical ventilation accelerate telomere shortening in COVID-19 patients 1 year after recovery. Crit Care. 2024;28(1).\\u003c/li\\u003e\\n\\u003cli\\u003eTaheri M, Ghafouri-Fard S, Najafi S, Kallenbach J, Keramatfar E, Atri Roozbahani G, et al. Hormonal regulation of telomerase activity and hTERT expression in steroid-regulated tissues and cancer. Cancer Cell Int. 2022;22(1):258.\\u003c/li\\u003e\\n\\u003cli\\u003eCalado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones acting on the TERT gene increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114(11):2236\\u0026ndash;43.\\u003c/li\\u003e\\n\\u003cli\\u003eCleber Gama de Barcellos Filho P, Campos Zanelatto L, Am\\u0026eacute;lia Aparecida Santana B, Calado RT, Rodrigues Franci C. Effects of chronic administration of corticosterone and estrogen on HPA axis activity and telomere length in brain areas of female rats. Brain Res. 2021;1750:147152.\\u003c/li\\u003e\\n\\u003cli\\u003eYeap BB, Knuiman MW, Divitini ML, Hui J, Arscott GM, Handelsman DJ, et al. Epidemiological and Mendelian randomization studies of dihydrotestosterone and estradiol and leukocyte telomere length in men. J Clin Endocrinol Metab. 2016;101(3):1299\\u0026ndash;306.\\u003c/li\\u003e\\n\\u003cli\\u003eLin J, Epel E. Stress and telomere shortening: insights from cellular mechanisms. Ageing Res Rev. 2022;73:101507.\\u003c/li\\u003e\\n\\u003cli\\u003eAthanasoulia-Kaspar AP, Auer MK, Stalla GK, Jakovcevski M. Shorter telomeres associated with high doses of glucocorticoids: the link to increased mortality? Endocr Connect. 2018;7(11):1217\\u0026ndash;26.\\u003c/li\\u003e\\n\\u003cli\\u003eLuppi F, Kalluri M, Faverio P, Kreuter M, Ferrara G. Idiopathic pulmonary fibrosis beyond the lung: understanding disease mechanisms to improve diagnosis and management. Respir Res. 2021;22(1):1\\u0026ndash;16.\\u003c/li\\u003e\\n\\u003cli\\u003eZribi B, Uziel O, Lahav M, Mesilati Stahy R, Singer P. Telomere length changes during critical illness: a prospective observational study. Genes (Basel). 2019;10(10):E760.\\u003c/li\\u003e\\n\\u003cli\\u003eAulinas A, Ram\\u0026iacute;rez MJ, Barahona MJ, Valassi E, Resmini E, Mato E, et al. Telomere length analysis in Cushing\\u0026rsquo;s syndrome. Eur J Endocrinol. 2014;171(1):21\\u0026ndash;9.\\u003c/li\\u003e\\n\\u003cli\\u003eTownsley DM, Dumitriu B, Liu D, Biancotto A, Weinstein B, Chen C, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374(20):1922\\u0026ndash;31.\\u003c/li\\u003e\\n\\u003cli\\u003eMyers KC, Davies SM, Lutzko C, Wahle R, Grier DD, Aubert G, et al. Clinical use of ZSCAN4 for telomere elongation in hematopoietic stem cells. NEJM Evid. 2025;4(3).\\u003c/li\\u003e\\n\\u003c/ol\\u003e\"}],\"fulltextSource\":\"\",\"fullText\":\"\",\"funders\":[],\"hasAdminPriorityOnWorkflow\":false,\"hasManuscriptDocX\":true,\"hasOptedInToPreprint\":true,\"hasPassedJournalQc\":\"\",\"hasAnyPriority\":false,\"hideJournal\":false,\"highlight\":\"\",\"institution\":\"\",\"isAcceptedByJournal\":false,\"isAuthorSuppliedPdf\":false,\"isDeskRejected\":\"\",\"isHiddenFromSearch\":false,\"isInQc\":false,\"isInWorkflow\":false,\"isPdf\":false,\"isPdfUpToDate\":true,\"isWithdrawnOrRetracted\":false,\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true},\"keywords\":\"Telomere, telomere shortening, COVID-19, glucocorticoids, critical illness\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-8713144/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-8713144/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground:\\u003c/strong\\u003e Glucocorticoids (GCs) have proven to be a key therapy in mitigating the systemic inflammatory response in severe COVID-19. Relative telomere length (RTL) is recognized as a biomarker of cellular aging and biological stress, with its role in acute critical illnesses being of growing interest. Chronic exposure to GCs or stress are strongly associated with telomere shortening. This study aimed to explore the association of RTL ratios with GCs therapy.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods:\\u003c/strong\\u003e A prospective, longitudinal study involving patients over 18 years of age with severe SARS-CoV-2 pneumonia was designed. Patients were admitted to the ICU of a university hospital. GCs therapy was standardized to dexamethasone equivalent doses based on the RECOVERY study. Blood samples were obtained upon admission and at least one year after discharge to determine telomere length using the Cawthon method (qPCR). RTL ratio (one year/baseline RTL) associations with GCs were calculated using generalized linear models (GLM).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults:\\u003c/strong\\u003e A significant association was found between RTL ratios and the duration of GCs therapy (p=0.007). The dexamethasone equivalent dose also showed a significant association with RTL ratios (p\\u0026lt;0.001). These associations were particularly significant in the male population (dexamethasone equivalent: p=0.028; duration of therapy: p=0.001), with no significant associations observed in women.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion:\\u003c/strong\\u003e In critically ill patients with SARS-CoV-2 pneumonia, this study reveals a significant association between RTL, the length of GCs therapy, and the equivalent dose of dexamethasone, especially in males. Further studies are needed to determine the effect of GCs on RTL admitted to de ICU for other critical conditions.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Association of Relative Telomere Length with Glucocorticoids Therapy in Critically Ill Patients with COVID-19\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2026-04-28 12:55:53\",\"doi\":\"10.21203/rs.3.rs-8713144/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-05-11T09:07:58+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"79682696906064146221941373962973232387\",\"date\":\"2026-05-06T09:26:30+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"97541098883268945165950105817222323813\",\"date\":\"2026-04-22T19:03:00+00:00\",\"index\":\"hide\",\"fulltext\":\"\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2026-04-19T17:54:34+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvited\",\"content\":\"\",\"date\":\"2026-01-30T12:00:03+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2026-01-28T11:47:00+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2026-01-28T11:46:35+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Scientific Reports\",\"date\":\"2026-01-27T17:20:01+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"scientific-reports\",\"isNatureJournal\":false,\"hasQc\":true,\"allowDirectSubmit\":false,\"externalIdentity\":\"scirep\",\"sideBox\":\"Learn more about [Scientific Reports](http://www.nature.com/srep/)\",\"snPcode\":\"\",\"submissionUrl\":\"\",\"title\":\"Scientific Reports\",\"twitterHandle\":\"\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"stoa\",\"reportingPortfolio\":\"Scientific Reports\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":true}}],\"origin\":\"\",\"ownerIdentity\":\"2833e090-e3d0-4746-b523-a8d95a85219b\",\"owner\":[],\"postedDate\":\"April 28th, 2026\",\"published\":true,\"recentEditorialEvents\":[{\"type\":\"editorInvitedReview\",\"content\":\"\",\"date\":\"2026-05-11T09:07:58+00:00\",\"index\":146,\"fulltext\":\"\"},{\"type\":\"reviewerAgreed\",\"content\":\"79682696906064146221941373962973232387\",\"date\":\"2026-05-06T09:26:30+00:00\",\"index\":143,\"fulltext\":\"\"}],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"under-review\",\"subjectAreas\":[{\"id\":66839458,\"name\":\"Health sciences/Biomarkers\"},{\"id\":66839459,\"name\":\"Health sciences/Diseases\"},{\"id\":66839460,\"name\":\"Health sciences/Medical research\"}],\"tags\":[],\"updatedAt\":\"2026-04-28T12:55:53+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2026-04-28 12:55:53\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-8713144\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-8713144\",\"identity\":\"rs-8713144\",\"version\":[\"v1\"]},\"buildId\":\"XKTyCvWXoU3ODBz1xrDgd\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}