Association between circadian rhythm alterations and the persistence of respiratory dysfunction in survivors of acute respiratory distress syndrome

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Background: The molecular basis of the potential link between circadian rest-activity rhythm and respiratory dysfunction in survivors of acute respiratory distress syndrome (ARDS) remains unexplored. Aim: To assess whether the circadian health (clinical and molecular) is associated with the persistence of pulmonary sequelae in survivors of COVID-19-induced ARDS. Methods: Longitudinal study including 89 survivors of COVID-19-induced ARDS. Pulmonary dysfunction was defined as a diffusing capacity (DLCO)<80% at 3 and 24 months post-discharge. The circadian rest-activity rhythm was analyzed at 3 months (7-day actigraphy). A panel of 15 clock genes was quantified in whole blood samples at 3- and 12-month visits (RT-qPCR). Results: Of the survivors with pulmonary dysfunction at 3 months post-discharge (n=45), 46.9% exhibited a DLCO<80% at 24 months. At 3 months, these patients showed alterations in circadian rest-activity rhythm variables (fragmentation and activity levels) and reduced expression levels of CRY1, BMAL1 and BMAL2. The reduced expression of these same genes persisted at 12 months. In the multivariable study (sPLS), a specific circadian rest-activity rhythm pattern was identified and associated with the persistence of respiratory sequelae at 24 months (GAM modeling). CRY1 expression levels at 3 months were also associated with this circadian rhythm pattern and with the persistence of respiratory sequelae, even after adjusting for confounders. Conclusion: The possible association between circadian rhythm alterations and the persistence of respiratory sequelae in ARDS survivors highlights a potential therapeutic target in these patients.

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