Longitudinal multi-omics analysis of convalescent individuals with respiratory sequelae 6–36 months after COVID-19

Abstract

Background

Approximately 10–30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.

Methods

We prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.

Results

We performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.

Conclusions

These data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.