SARS-CoV-2 RNA viremia is associated with a sepsis-like host response and critical illness in COVID-19

Abstract

Background: Severe COVID-19 is characterized by clinical and biological manifestations typically observed in sepsis. SARS-CoV-2 RNA is commonly detected in nasopharyngeal swabs, however viral RNA can be found also in peripheral blood and other tissues. Whether systemic spreading of the virus or viral components plays a role in the pathogenesis of the sepsis like disease observed in severe COVID-19 is currently unknown. Methods: We determined the association of plasma SARS-CoV-2 RNA with the biological responses and the clinical severity of patients with COVID-19. 250 patients with confirmed COVID-19 infection were recruited (50 outpatients, 100 hospitalised ward patients, and 100 critically ill). The association between plasma SARS-CoV-2 RNA and laboratory parameters was evaluated using multivariate GLM with a gamma distribution. The association between plasma SARS-CoV-2 RNA and severity was evaluated using multivariate ordinal logistic regression analysis and Generalized Linear Model (GLM) analysis with a binomial distribution. Results: The presence of SARS-CoV-2 RNA viremia was independently associated with a number of features consistently identified in sepsis: 1) high levels of cytokines (including CXCL10, CCL-2, IL-10, IL-1ra, IL-15, and G-CSF); 2) higher levels of ferritin and LDH; 3) low lymphocyte and monocyte counts 4) and low platelet counts. In hospitalised patients, the presence of SARS-CoV-2 RNA viremia was independently associated with critical illness: (adjusted OR= 8.30 [CI95%=4.21-16.34], p < 0.001). CXCL10 was the most accurate identifier of SARS-CoV-2-RNA viremia in plasma (area under the curve (AUC), [CI95%], p) = 0.85 [0.80 0.89), <0.001]), suggesting its potential role as a surrogate biomarker of viremia. The cytokine IL-15 most accurately differentiated clinical ward patients from ICU patients (AUC: 0.82 [0.76 0.88], <0.001). Conclusions: systemic dissemination of genomic material of SARS-CoV-2 is associated with a sepsis-like biological response and critical illness in patients with COVID-19. RNA viremia could represent an important link between SARS-CoV-2 infection, host response dysfunction and the transition from moderate illness to severe, sepsis-like COVID-19 disease.

SARS-CoV-2 RNAemia and proteomic biomarker trajectory inform prognostication in COVID-19 patients admitted to intensive care

“…In our study, RNAemia was more frequent in ICU patients with type 2 diabetes and hypertension, two well-known risk factors for poor outcome in COVID-19. Using droplet digital PCR 15 RNAemia could be a consequence of severe disease or might contribute to poor outcome. Given that the SARS-CoV-2 entry receptor ACE2 is expressed on vascular cells, including endothelial cells, smooth muscle cells and pericytes of most organs 38,39 , and SARS-CoV-2 RNA was detected in lungs, pharynx, heart, liver, brain and kidneys of autopsy tissue 40 Furthermore, binding of C1q to NETs protects NETs from degradation by DNases in the circulation .…”

“…In this context, circulating SARS-CoV-2 RNA (RNAemia) has been highlighted as a promising prognostic biomarker in hospitalized COVID-19 patients, as it is associated with disease severity 7 and mortality [8][9][10] , with an estimated prevalence of 10% (95% CI 5-18%, random effects model) 7 . Further, we hypothesized that the acute and profound alterations in the innate and adaptive immune system in COVID-19 patients 3,[11][12][13] , especially in RNAemic patients [14][15][16][17][18] , will be accompanied by marked changes in the circulating proteome and interactome and that the proteome in COVID-19 patients will highlight mechanistically relevant signatures and trajectories, when compared to non-COVID-19 sepsis and healthy controls. Thus far, proteomics studies have focused on the determination of protein biomarkers of COVID-19 severity [19][20][21][22] , but have not assessed the longitudinal relationship between proteomic changes, RNAemia and 28-day mortality.…”

Mucosal Immunity in COVID-19: A Neglected but Critical Aspect of SARS-CoV-2 Infection

“…Although the COVID-19 pandemic has been ongoing now for several months, very little attention has been given to mucosal immunity in SARS-CoV-2 infection. Yet this virus primarily infects the mucosal surfaces of the respiratory tract (and possibly also the digestive tract) at least until advanced stages of the disease when viral RNA may become detectable in the circulation (1). The virus may also be acquired through the mouth, and at the conjunctival surface of the eye whence it drains into the nasal passages through the lacrimal duct.…”

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

“…19 Two cross-sectional studies using droplet-based dPCR reported higher rates of RNAaemia (42•4% and 74•1%) than did the qPCR studies above, and associated the presence and the level of RNAaemia with clinical severity. 8,9 Bermejo-Martin et al also observed correlation between RNAaemia and biomarkers of dysregulated host responses. 8 In this prospective, longitudinal, observational study of COVID-19 patients presenting to the Emergency Department (ED), we characterised relationships between SARS-CoV-2 RNAaemia and overall severity, clinical deterioration, and specific EPCs.…”

“…8,9 Bermejo-Martin et al also observed correlation between RNAaemia and biomarkers of dysregulated host responses. 8 In this prospective, longitudinal, observational study of COVID-19 patients presenting to the Emergency Department (ED), we characterised relationships between SARS-CoV-2 RNAaemia and overall severity, clinical deterioration, and specific EPCs. We used an array-based dPCR platform to maximise reliability and replicability, and to simplify potential clinical adoption of RNAaemia testing.…”