key: cord-0759805-uh8ag7hb
authors: Ram-Mohan, Nikhil; Kim, David; Rogers, Angela J; Blish, Catherine A; Nadeau, Kari C; Blomkalns, Andra L; Yang, Samuel
title: Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19
date: 2021-12-25
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab646
sha: 12ae3780070b95041812cfc72ceb7a23322bd202
doc_id: 759805
cord_uid: uh8ag7hb

Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, worst disease severity, and length of symptoms.

The determinants of coronavirus disease 2019 (COVID-19) severity and extrapulmonary complications have now been well studied, and RNAemia (viral RNA in blood) has emerged as an important factor [1, 2] . Much less is known about the determinants of postacute sequelae of COVID-19 (PASC), the persistence or development of new symptoms after the acute phase of infection, recently reported to affect as many as 87.4% of COVID-19 patients [3, 4] , primarily those with with moderate or worse severity [5, 6] . Recent evidence has suggested persistent clotting protein pathology with elevated levels of antiplasmin [7] and nonclassical monocytes [8] in patients with PASC. Discovery of SARS-CoV-2 S1 protein in these nonclassical monocytes and fragmented SARS-CoV-2 RNA in peripheral blood mononuclear cells in a PASC patient 15 months postinfection further exhibited the persistence of viral particles [8] . Given the importance of RNAemia in disease severity and its persistence in the blood, we describe the relationship between RNAemia at presentation and postacute symptoms at least 4 weeks after symptom onset.

We studied the clinical trajectories of 127 patients enrolled in the institutional review board-approved (eP-55650) Stanford Hospital Emergency Department (ED) COVID-19 Biobank between April and November 2020 with completed follow-ups. We assessed symptoms and severity (based on a modified World Health Organization scale) [1] on the date of enrollment (median = 4, range = 0-14 days after symptom onset) and at least 4 weeks after symptom onset (median = 35, range = 28-75 days) as per the current Centers for Disease Control and Prevention definition of PASC (https://www.cdc.gov/coronavirus/2019ncov/hcp/clinical-care/post-covid-conditions.html).

We measured SARS-CoV-2 RNAemia at the time of enrollment using the definitions of our earlier study [1] . We compared the proportions of initially RNAemic and non-RNAemic patients with persistent or new symptoms in the postacute phase using a 2-sample chi-square test with continuity correction. We estimated the association between RNAemia at enrollment and PASC at follow-up in a logistic model controlling for worst severity within 30 days of enrollment, patient demographics (age and gender), presence of any symptom at enrollment (anxiety, dizziness, fatigue, hair loss, palpitations, rash, insomnia, chest pain, chills, cough, decrease in sense of taste, fever, nausea/vomiting/diarrhea, headache, loss of smell, myalgia, new confusion, shortness of breath), and durations of symptoms. We also compared the median number of PASC symptoms for RNAemic and non-RNAemic patients using the Wilcoxon rank-sum test with continuity correction. We performed all analyses in R (version 4 (Figure 1) , with 76.5% (13/17) of initially RNAemic patients symptomatic in the postacute phase, compared with 39.7% (25/63) of non-RNAemic patients (difference, 36.8%; 95% CI, 9.5%-65.0%; P = .01544). This difference was due almost entirely to persistent or new respiratory symptoms (difference in proportions, 36.1%; 95% CI, 14.4%-57.7%; P = .0003601).

To our knowledge, this study describes the first reported association between SARS-CoV-2 RNAemia and PASC. RNAemia at presentation was associated with new or persistent symptoms at least 28 days after symptom onset independent of initial patient severity, and the association was strongest among patients with moderately severe clinical presentations requiring hospital admission. This finding adds to the growing literature on SARS-CoV-2 RNAemia's role in disease severity and extrapulmonary complications in the acute phase of illness, as well as the association between hospitalization and PASC [1, 2, 5, 6] . The incidence of PASC was lower in this single-center study than in reports from Italy and the United Kingdom [3, 4] , but similar to that reported in a recent study from the United States [9] . The potential contributions of patient characteristics, study methodologies, and viral variants to these discrepancies merit further study. Though the mechanisms underlying RNAemia's contributions to multisystem pathology in both the acute and postacute phases, when persistent, remain to be elucidated, mounting evidence for its predictive value suggests that testing for SARS-CoV-2 RNAemia at presentation may help guide the triage, management, and prognosis of COVID-19.

SARS-CoV-2 RNAemia predicts clinical deterioration and extrapulmonary complications from COVID-19

Massachusetts Consortium for Pathogen Readiness. SARS-CoV-2 viral load is associated with increased disease severity and mortality

Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent symptoms in patients after acute COVID-19

Patient outcomes after hospitalisation with COVID-19 and implications for follow-up: results from a prospective UK cohort

Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study

Population-based estimates of post-acute sequelae of SARS-CoV-2 infection (PASC) prevalence and characteristics

Persistent clotting protein pathology in long COVID/ post-acute sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

Persistence of SARS CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection

Sixty-day outcomes among patients hospitalized with COVID-19

The authors would like to thank the additional author members of the Stanford COVID-19 Biobank Study Group Financial support. This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (Grants R01AI153133, R01AI137272, and 3U19AI057229 -17W1 COVID SUPP #2) and a donation from Eva Grove.Potential conflicts of interest. Yang is a Scientific Advisory Board member of COMBiNATi, Inc. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.