Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality

Abstract

Despite advances in COVID-19 management, it is unclear how to recognize patients who evolve towards death. This would allow for better risk stratification and targeting for early interventions. However, the explosive increase in correlates of COVID-19 severity complicates biomarker prioritisation. To identify early biological predictors of mortality, we performed an immunovirological assessment (SARS-CoV-2 viral RNA, cytokines and tissue injury markers, antibody responses) on plasma samples collected from 144 hospitalised COVID-19 patients 11 days after symptom onset and used to test models predicting mortality within 60 days of symptom onset. In the discovery cohort (n=61, 13 fatalities), high SARS-CoV-2 vRNA, low RBD-specific IgG levels, low SARS-CoV-2-specific antibody-dependent cellular cytotoxicity, and elevated levels of several cytokines and lung injury markers were strongly associated with increased mortality in the entire cohort and the subgroup on mechanical ventilation. Model selection revealed that a three-variable model of vRNA, age and sex was very robust at identifying patients who will succumb to COVID-19 (AUC=0.86, adjusted HR for log-transformed vRNA=3.5; 95% CI: 2.0-6.0). This model remained robust in an independent validation cohort (n=83, AUC=0.85). Quantification of plasma SARS-CoV-2 RNA can help understand the heterogeneity of disease trajectories and identify patients who may benefit from new therapies.

Convalescent plasma for hospitalized patients with COVID-19: an open-label, randomized controlled trial

“…In animal models of COVID-19, mutation of monoclonal antibodies leading to loss of Fc-mediated function, but sparing the neutralizing function, abrogated the protective effect of the antibody [22][23][24][25] . In cohort studies of severe COVID-19, low Fc-mediated function, but not neutralization, was associated with mortality 26,27 .…”

COVID-19 virtual patient cohort suggests immune mechanisms driving disease outcomes

“…Further, the inflammation marker C can also be applied to patient data, similar to other proposed metrics (e.g. CytoScore [68]).…”

“…Models by design require simplifying complex dynamics to highlight critical underlying structures, which should then be experimentally or clinically verified. For instance, some unmodeled cytokines have overlapping function and cellular sources to those explicitly modelled here; thus, model predictions may be representative of broader synergistic effects [68] and other cytokines could also be targets of interest. Also, as this work is focused on acute, primary infections, our model does not account for antibody production and we chose not to explore questions related to vaccination efforts nor the potential for cross-reactivity given exposure to other seasonal coronaviruses.…”

Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset

“…However, we note that results as obtained in this study are very similar to those observed in larger cross-sectional and longitudinal studies. 3,5,6 Furthermore, although we successfully used our ADCC assay to show the importance of Fc-mediated effector functions of neutralizing Abs to protect from lethal SARS-CoV-2 challenges in K18-hACE2 transgenic mice 42 and as an immune correlate for survival in acutely infected individuals, 43 our assay uses cells constitutively expressing the Spike proteins and not bona fide SARS-CoV-2-infected cells.…”