Role of Viral Storm in Critical COVID-19 Illness: A Prospective Cohort Multicentric Study

Abstract

Background: The physiopathology of the critical COVID-19 illness is unclear. The cytokine storm theory has been challenged by the evidence. In contrast, the potential role of the virus is still under discussion.

Methods: plasma from 836 COVID-19 patients collected in the first 48 hours following ICU admission was profiled for viral N1-RNA load using digital PCR. Patients were classified as VIR-N1-Zero (no viral RNA in plasma), VIR-N1-Low (< 2747 copies N1/mL) and VIR-N1-Storm (> 2747 copies N1/mL). A multivariate Cox-regression analysis evaluated their odds for 90-day mortality.

Findings:  VIR-N1-Storm patients (34%) were the most severe (94% needed invasive mechanical ventilation, IMV, 41% developed acute renal failure, 65% secondary infections and 64% anemia), and had the highest 90-day mortality (52%). 66% of the VIR-N1-Storm patients showed N-antigenemia. They showed a poor response of SARS-CoV-2 S IgM/IgG antibodies, but presented the highest levels of biomarkers of inflammation, immunosuppression, endothelial and tissue damage. In contrast, VIR-N1-Zero (18%) were the least severe patients (IMV:54%, acute renal failure: 23%, secondary infections: 32%, anemia: 39%), and those with the lowest mortality (17%). Compared to VIR-N1-Storm, VIR-N1-Zero patients showed an adjusted HR [95% CI], p of (0·52 [0·32 - 0·83], 0·006) for 90-day mortality. VIR-N1-Zero exhibited the strongest antibody response, and the mildest alterations in the levels of biomarkers. VIR-N1-Low patients (48%) had intermediate biological features and mortality (26%) (0·58 [0·45 - 0·76], < 0·001).

Interpretation: Patients presenting at the ICU with a massive presence of viral RNA in blood (viral storm) are those showing the deepest dysregulation of the host response and the highest mortality, denoting that uncontrolled viral replication is a major contributor to the most severe forms of critical COVID-19 illness. Viral storm could serve as a predictive enrichment tool for trials testing antivirals in these patients.

Funding Information: This work was supported by awards from the Instituto de Salud Carlos III: FONDO - COVID19, COV20/00110, CIBERES, 06/06/0028 (AT), Proyectos de Investigación en Salud, PI19/00590 (JFBM), Miguel Servet, CP20/00041 (DdG), Sara Borrell, CD018/0123 (APT), PFIS, FI20/00278 (AdF). We also received funds from: Programa de donaciones "estar preparados"; UNESPA (Madrid, Spain) and from the Canadian Institutes of Health Research (CIHR OV2 – 170357 (DJK/JFBM), Research Nova Scotia, Li-Ka Shing Foundation (DJK) and finally by a Research Grant 2020 from ESCMID (APT). COV20/00110, PI19/00590, CP20/00041, CD018/0123, FI20/00278 were co-funded by European Regional Development Fund (ERDF) European Social Fund (ESF), "A way to make Europe"/"Investing in your future").

Declaration of Interests: JFBM, AT, FB, RA and APT have a patent application on SARS-CoV-2 antigenemia as a predictor of mortality in COVID-19. The remaining authors declare no conflicts of interest regarding this work.

Ethics Approval Statement: The study received the approval by the Institution’s Internal Review Board (Comité Ètic d’Investigació Clínica, registry number HCB/2020/0370). Participant hospitals obtained the respective local ethics committee approval. We reported results in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study was performed in full compliance with the Declaration of Helsinki and national and international law on data protection. Informed consent was obtained from each patient or legal representative.