Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• COVID-19

• Chronic Virus Reactivation

• PASC (long covid)

Main Findings

The authors present a longitudinal multi-omic (transcriptomics, metabolomics, proteomics), study of chronic viral reactivation in a cohort of >1,000 COVID-19 patients that were followed for 12 months post hospitalization. Viral reactivation during and after SARS-CoV-2 infection is shown for Herpesviridae, Enteroviridae, and Anelloviridae, as detected by RNA sequencing samples from 3 distinct body compartments (PBMCs, nasal swabs and endotracheal aspirates). Transcriptomic detection of EBV, CMV and HSV in patients during the acute phase of COVID-19 correlates with higher mortality in these patients. Multi-omic analysis highlights virus-specific immune signatures during acute SARS-CoV-2 infection, such as increase in IL-6 in EBV in PBCMs, CXCL10 in Herpesviridae in both PBMC and nasal compartments, TNF in HSV and CMV, or upregulation of cellular replication genes in Herpesviridae in PBMCs. Finally, the authors report a statistically significant association between detection of Anelloviridae transcripts during convalescent period and symptoms of Long COVID/PASC in patient reported outcome (PRO) groups.

Limitations & Suggestions

• The authors did not establish a full understanding of the link between COVID-19 and chronic viral reactivation. Is reactivation merely correlated with severe disease, or does/can it also contribute to a worse clinical outcome itself? Furthermore, from the study design, it is not clear if the chronic viral reactivation occurs prior to or after hospitalization due to COVID-19. However, the authors can, to a certain extent, circumvent this with the following approaches:

• As obtaining pre-hospitalization patient multi-omics data might not be feasible, the authors could turn to an animal model (such as humanized mouse model of Epstein-Barr virus infection that reproduces persistent infection, or employ murine COVID-19 infection models).

• Run a comparative analysis of viral activation with publicly available databases to compare rate of viral reactivation in this study (a hospital) with that of the public (community setting). This approach can give an idea on the likelihood of SARS-CoV-2 being the causative agent of chronic viral reactivation in this study.

• Most of the reactivated viruses are known causative agents of nosocomial infection. Therefore, it might be difficult to determine whether the viral reactivation is due to SARS-CoV-2 infection or hospital transmission. A way around this is to potentially investigate chronic viral reactivation in non-hospitalised COVID-19 patients as controls to determine if they will observe the same dynamics and kinetics of viral reactivation as seen in this study.

Significance/Novelty

Novelty: Reactivation of latent viruses following SARS-CoV-2 infection, based on detection of antibodies in saliva samples, has been reported already in 2022 (Apostolou et al., Front. Immunol 2022). However, the novelty here is that the authors used nucleic acid detection (for viral reactivation) in conjunction with multi-omics to create an atlas of viral reactivation during COVID-19 in hospitalized patients. The generated data can be used for the prognosis  of chronic viral reactivation and in the development of predictive models for COVID-19 related comorbidities.

Credit

Reviewed by Anonymous as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.