Background: Around 50% of critical COVID-19 survivors present lung ailments one year after hospital discharge. The biological pathways implicated in the long-term abnormalities are unknown.

Aim: To identify molecular mechanisms associated with the persistence of lung dysfunction in post-critical COVID-19 patients one year after hospital discharge using microRNA (miRNA) profiling.

Methods: Longitudinal study including 119 survivors admitted to ICU due to COVID-19 (March-December 2020) without previous pulmonary disease. A pulmonary evaluation was performed 3 and 12 months after hospital discharge. Circulating miRNAs were quantified using RT-qPCR in plasma samples collected at 3 months. KEGG, GO and tissue enrichment analyses were conducted.

Results: At 3 months 84% of the survivors showed lung dysfunction [diffusion capacity (DLCO)<80%]. Diffusion impairment was observed in 55.4% of patients who completed the follow-up. Random forest modelling identified three miRNAs associated with the persistence of respiratory sequelae: miR-9-5p, miR-222-3p, and miR-486-5p. The bioinformatic analyses based on these miRNAs reported an enrichment in pathways of apoptosis, angiogenesis, coagulation, inflammation, senescence, fibrosis, and viral infection. The miRNAs were highly expressed in the lung.

Conclusions: We described a subset of mechanistic pathways involved in the persistence of lung dysfunction in critical COVID-19 survivors, which may contribute to the development of novel therapeutic approaches.

Funding: ISCIII(FI21/00187,CP20/00041,COV20/00110)_UNESPA_Fundación Francisco Soria Melguizo_La Marató(202108?30/?31).