Effect of viral storm in patients admitted to intensive care units with severe COVID-19 in Spain: a multicentre, prospective, cohort study

Abstract

Background: The contribution of the virus to the pathogenesis of severe COVID-19 is still unclear. We aimed to evaluate associations between viral RNA load in plasma and host response, complications, and deaths in critically ill patients with COVID-19.

Methods: We did a prospective cohort study across 23 hospitals in Spain. We included patients aged 18 years or older with laboratory-confirmed SARS-CoV-2 infection who were admitted to an intensive care unit between March 16, 2020, and Feb 27, 2021. RNA of the SARS-CoV-2 nucleocapsid region 1 (N1) was quantified in plasma samples collected from patients in the first 48 h following admission, using digital PCR. Patients were grouped on the basis of N1 quantity: VIR-N1-Zero (<1 N1 copies per mL), VIR-N1-Low (1-2747 N1 copies per mL), and VIR-N1-Storm (>2747 N1 copies per mL). The primary outcome was all-cause death within 90 days after admission. We evaluated odds ratios (ORs) for the primary outcome between groups using a logistic regression analysis.

Findings: 1068 patients met the inclusion criteria, of whom 117 had insufficient plasma samples and 115 had key information missing. 836 patients were included in the analysis, of whom 403 (48%) were in the VIR-N1-Low group, 283 (34%) were in the VIR-N1-Storm group, and 150 (18%) were in the VIR-N1-Zero group. Overall, patients in the VIR-N1-Storm group had the most severe disease: 266 (94%) of 283 patients received invasive mechanical ventilation (IMV), 116 (41%) developed acute kidney injury, 180 (65%) had secondary infections, and 148 (52%) died within 90 days. Patients in the VIR-N1-Zero group had the least severe disease: 81 (54%) of 150 received IMV, 34 (23%) developed acute kidney injury, 47 (32%) had secondary infections, and 26 (17%) died within 90 days (OR for death 0·30, 95% CI 0·16-0·55; p<0·0001, compared with the VIR-N1-Storm group). 106 (26%) of 403 patients in the VIR-N1-Low group died within 90 days (OR for death 0·39, 95% CI 0·26-0·57; p<0·0001, compared with the VIR-N1-Storm group).

Interpretation: The presence of a so-called viral storm is associated with increased all-cause death in patients admitted to the intensive care unit with severe COVID-19. Preventing this viral storm could help to reduce poor outcomes. Viral storm could be an enrichment marker for treatment with antivirals or purification devices to remove viral components from the blood.

Funding: Instituto de Salud Carlos III, Canadian Institutes of Health Research, Li Ka-Shing Foundation, Research Nova Scotia, and European Society of Clinical Microbiology and Infectious Diseases.

Translation: For the Spanish translation of the abstract see Supplementary Materials section.

Figure 1

Virological and antibody profiles (A) Viral RNA load in plasma (copies of N1 mRNA per mL of plasma). (B) Prevalence of N-antigenaemia in each group. (C) Anti-SARS-CoV-2 S IgG concentrations in plasma. (D) Anti-SARS-CoV-2 S IgM concentrations in plasma. (E) Percentage of plasma binding inhibition of SARS-CoV-2 S protein to ACE2 receptor. Patients were distributed in two categories in each group (those with an inhibitory activity of 50% or greater and those with an inhibitory activity of less than 50%). N1=SARS-CoV-2 nucleocapsid region. AUC=area under the curve. ACE2=angiotensin-converting enzyme 2.

Figure 2

Complications and 90-day mortality by viral RNA N1 load group N1=SARS-CoV-2 nucleocapsid region.

Figure 3

Heat map showing biomarker concentrations by viral RNA N1 load group Results are provided as log 2 (median in each group divided by median in healthy controls). Differences in the concentrations of the biomarkers shown here were significant (p<0·05) for all the comparisons between the three groups (VIR-N1-Zero, VIR-N1-Low, and VIR-N1-Storm). N1=SARS-CoV-2 nucleocapsid region. IFN=interferon. GZB=granzyme B. TNF=tumour necrosis factor. ET=endothelin. CCL=C-C motif chemokine ligand. IL=interleukin. PD-L=programmed death-ligand. G-CSF=granulocyte colony-stimulating factor. CXCL=C-X-C motif chemokine ligand. PTX=pentraxin.

Figure 4

Biological responses and clinical outcomes in patients in the VIR-N1-Zero, VIR-N1-Low, and VIR-N1-Storm viral load groups N1=SARS-CoV-2 nucleocapsid region. PTX=pentraxin. Th1=T helper 1 cytokines. IFN=interferon. Ch=chemokines. IL=interleukin. PD-L=programmed death-ligand.