Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19
Authors: Bermejo-Martin Jesús F. , González-Rivera Milagros , Almansa Raquel , Micheloud Dariela , Tedim Ana P. , Domínguez-Gil Marta , Resino Salvador , Martín-Fernández Marta , Ryan Murua Pablo , Pérez-García Felipe , Tamayo Luis , Lopez-Izquierdo Raúl , Bustamante Elena , Aldecoa César , Gómez José Manuel , Rico-Feijoo Jesús , Orduña Antonio , Méndez Raúl , Fernández Natal Isabel , Megías Gregoria , González-Estecha Montserrat , Carriedo Demetrio , Doncel Cristina , Jorge Noelia , Ortega Alicia , de la Fuente Amanda , del Campo Félix , Fernández-Ratero José Antonio , Trapiello Wysali , González-Jiménez Paula , Ruiz Guadalupe , Kelvin Alyson A. , Ostadgavahi Ali Toloue , Oneizat Ruth , Ruiz Luz María , Miguéns Iria , Gargallo Esther , Muñoz Ioana , Pelegrin Sara , Martín Silvia , García Olivares Pablo , Cedeño Jamil Antonio , Ruiz Albi Tomás , Puertas Carolina , Berezo Jose Ángel , Renedo Gloria , Herrán Rubén , Bustamante-Munguira Juan , Enríquez Pedro , Cicuendez Ramón , Blanco Jesús , Abadia Jesica , Gómez Barquero Julia , Mamolar Nuria , Blanca-López Natalia , Valdivia Luis Jorge , Fernández Caso Belén , Mantecón María Ángeles , Motos Anna , Fernandez-Barat Laia , Ferrer Ricard , Barbé Ferrán , Torres Antoni , Menéndez Rosario , Eiros José María , Kelvin David J. 
Published: December 2020

Background

COVID-19 can course with respiratory and extrapulmonary disease. SARS-CoV-2 RNA is detected in respiratory samples but also in blood, stool and urine. Severe COVID-19 is characterized by a dysregulated host response to this virus. We studied whether viral RNAemia or viral RNA load in plasma is associated with severe COVID-19 and also to this dysregulated response.

Methods

A total of 250 patients with COVID-19 were recruited (50 outpatients, 100 hospitalized ward patients and 100 critically ill). Viral RNA detection and quantification in plasma was performed using droplet digital PCR, targeting the N1 and N2 regions of the SARS-CoV-2 nucleoprotein gene. The association between SARS-CoV-2 RNAemia and viral RNA load in plasma with severity was evaluated by multivariate logistic regression. Correlations between viral RNA load and biomarkers evidencing dysregulation of host response were evaluated by calculating the Spearman correlation coefficients.

Results

The frequency of viral RNAemia was higher in the critically ill patients (78%) compared to ward patients (27%) and outpatients (2%) (p < 0.001). Critical patients had higher viral RNA loads in plasma than non-critically ill patients, with non-survivors showing the highest values. When outpatients and ward patients were compared, viral RNAemia did not show significant associations in the multivariate analysis. In contrast, when ward patients were compared with ICU patients, both viral RNAemia and viral RNA load in plasma were associated with critical illness (OR [CI 95%],p): RNAemia (3.92 [1.183–12.968], 0.025), viral RNA load (N1) (1.962 [1.244–3.096], 0.004); viral RNA load (N2) (2.229 [1.382–3.595], 0.001). Viral RNA load in plasma correlated with higher levels of chemokines (CXCL10, CCL2), biomarkers indicative of a systemic inflammatory response (IL-6, CRP, ferritin), activation of NK cells (IL-15), endothelial dysfunction (VCAM-1, angiopoietin-2, ICAM-1), coagulation activation (D-Dimer and INR), tissue damage (LDH, GPT), neutrophil response (neutrophils counts, myeloperoxidase, GM-CSF) and immunodepression (PD-L1, IL-10, lymphopenia and monocytopenia).

Conclusions

SARS-CoV-2 RNAemia and viral RNA load in plasma are associated with critical illness in COVID-19. Viral RNA load in plasma correlates with key signatures of dysregulated host responses, suggesting a major role of uncontrolled viral replication in the pathogenesis of this disease.