In this longitudinal study, we found that patients with longer ICU-LOS and those who required IMV had a greater shortening of the RTL during the first year after hospital discharge. Among those patients who required IMV, a trend toward a decreased RTL at one-year visit was also observed. In addition, patients who developed pulmonary fibrosis showed a deep reduction of RTL during the first year after hospital discharge, showing lower RTL at one-year visit than those who did not have pulmonary fibrosis. To our knowledge, our study is the first one showing an association between RTL shortening and clinical variables of hospitalization after more than one year of follow-up in COVID-19 patients admitted to the ICU.
A severe or fatal COVID-19 is more likely to occur at older ages, suggesting that age-related molecular pathways are involved in the severity of this disease (15). In this regard, several studies have shown an association between shorter telomeres and the need for hospitalization, greater severity, or even mortality in COVID-19 patients (8–10). However, limited studies have evaluated the change in telomere size once patients have been discharged from the hospital. Retuerto et al., after a median of 14 months of follow-up, observed that 35% of study participants had shortened telomere. They did not observe an association between RTL and hospital clinical outcomes, which could probably be due to the fact that its population was not homogeneous, with a mixture of disease severity. However, the patients who had a more severe disease also had the largest telomere shortening (12). The impact and, consequently, the implications of telomere shortening in COVID-19 patients admitted to the ICU are currently unknown.
In this study, patients with longer ICU-LOS shortened RTL during follow-up. This could probably be due to the critical exhaustion of the immune system after a long ICU stay, where the length of telomeres would reach a critical size, which would compromise the telomerase capacity to recover telomere length. Previous studies have demonstrated significant changes in leukocyte telomere size in critical patients during ICU stay (13, 16). However, to our knowledge, no studies have investigated the impact of ICU-LOS on the RTL after hospital discharge. Our findings highlight the need for follow-up of patients with longer ICU-LOS over time for future senescence-related complications.
Patients requiring IMV had a longer ICU-LOS and a worse prognosis (17). Overall, we found that, in critically ill COVID-19 patients, the need for IMV was related to a telomere shortening during follow-up, which may reflect lung damage and loss of functionality. To our knowledge, few studies have addressed this issue. Only Liang et al. showed telomere shortening in ICU patients requiring IMV, but it was evaluated solely two days after ICU discharge (16). Therefore, additional studies with longer follow-ups are needed to elucidate the impact of the IMV on decreasing RTL and its association with the post-COVID syndrome of patients admitted to the ICU.
In severe patients with worse evolution of ARDS, a prone position is recommended to improve oxygen saturation and reduce lung damage (18, 19). A prone position significantly reduces the rate of tracheal intubation and mortality (20), although there are also studies with contradictory results (21). Moreover, among intubated patients, responders to the prone position in terms of oxygenation show better survival than those who do not respond (22). Regarding evolution after discharge, our study showed that COVID-19 patients who required a prone position shortened telomere during follow-up. To our knowledge, these findings are the first to associate the prone position with reduced telomere size in COVID-19 patients during the first year after hospital discharge. Further studies with a longer follow-up would be needed to study whether telomere size evolves to more critical levels in this subgroup of patients.
COVID-19 patients develop fibrotic pulmonary sequelae (23–25). There is also an association between telomere shortening in immune cells and lung disease development, such as idiopathic pulmonary fibrosis (7, 26–28). In our study, while no significant differences in RTL were observed at baseline, those patients who experienced an RTL shortening during follow-up developed lung fibrosis. Similarly, patients with fibrotic pulmonary sequelae showed shorter RTL at the one-year visit compared to those without radiological abnormalities. To our knowledge, this is the first study assessing the RTL and fibrosis development during follow-up in ICU patients. Still, these findings are in concordance with previous studies in hospitalized patients. McGroder et al. showed that patients with shorter telomere size at hospitalization were more prone to develop fibrotic abnormalities in the lung 4 months later, but the telomere length dynamics were not addressed (29). Using a different approach (Quantitative telomere Fluorescence in situ Hybridization Q-FISH), Martínez et al. found loss of alveolar type II (ATII) cellularity and shorter telomeres in these cells in post-COVID-19 lung cancer patients. Authors suggested that ATII cell telomere reduction may trigger lung fibrosis development in post-COVID-19 patients (30), but these results were produced in a cancer background, and studies on non-lung cancer COVID-19 patients should be addressed. Similarly, Mulet et al., in a recent prospective study (31), described that this attrition could also be evaluated on peripheral blood cells, as COVID-19 patients with radiological signs of fibrosis had significant telomere shortening one year after leaving the hospital. However, this study involved only 19 patients, and the authors did not comment on how they measured telomere length. Retuerto et al. also observed that patients who shortened their peripheral blood leukocyte telomeres after discharge were more prone to show persistent radiographic abnormalities. However, this study was performed during the first pandemic wave, when the hospital admission criteria were exceptional.
Our study is the first to confirm these findings in ICU patients, which is a more homogeneous group that showed similar severity and received similar clinical strategies. However, further studies with a longer follow-up of COVID-19 patients would be needed to establish the role of RTL shortening on fibrotic pulmonary sequelae and vice versa.
Limitations
Several issues must be considered in order to interpret our data correctly. The sample size was limited as only patients with one-year visit were included in the study. This could have limited the power of the statistical analysis, and some significant associations may not have been detected. However, the statistical analysis used was appropriate to address this issue correctly. This study also has several strengths, such as the fact that all patients were recruited during the second and third pandemic waves, where the ICU admission criteria were similar, and the selected method of measuring telomere length. We measured RTL in whole blood, and its determination could be transferred to routine clinical practice. This study addressed a topic that has been scarcely studied until now in critical patients because the recruitment and follow-up of these patients are arduous. In addition, it should be noted that we analyzed RTL before initiating any mechanical ventilation.