As SARS-CoV-2 continues to cause worldwide mortality, it has become increasingly important to define molecular markers that can identify individuals at risk of developing severe COVID-19, and even death. This could help in determining early preventive measures for improved patient outcomes. In a recent pre-print and therefore not yet peer-reviewed, CITF-funded researchers Drs. Daniel Kaufmann, Andrés Finzi and Nicolas Chomont from the Université de Montréal and the University of Montreal Hospital Research Centre (CRCHUM), along with their collaborators, used blood samples from hospitalized COVID-19 patients to measure the virus and various mediators of immunity. They found that the amount of virus in the blood can help identify patients who will succumb to COVID-19. This work was funded in part by the COVID-19 Immunity Task Force (CITF), in collaboration with the Canadian Institutes of Health Research (CIHR).
Many studies report advanced age and comorbidities as risk factors for severe COVID-19 disease, but there is also a wide range of molecular abnormalities associated with severe infection. From a clinical perspective, this becomes challenging as there is a need for a minimal set of blood markers that can be easily and rapidly used to identify the patients that are most at risk.
In this study, researchers collected blood samples from 144 hospitalised patients, 11 days after COVID-19 symptom onset. Some of these patients were in critical care requiring ventilation, while others had a less severe infection. Uninfected donors served as the control group. The research team tested the amount of SARS-CoV-2 RNA present in the blood, levels of antibodies targeting the virus, and cytokines (small proteins that are involved in immune cell signaling), as well as tissue and lung injury markers to see if they were associated with increased mortality. Patients were clinically followed for 60 days after symptom onset.
The authors found:
- The detection of SARS-CoV-2 in the blood was strongly associated with disease severity and mortality.
- Overall higher cytokine levels in the blood of COVID-19 patients compared with the uninfected group. These included pro-inflammatory cytokines including IL-6, GM-CSF, and TNFα.
- Markers of lung and vascular damage including RAGE and angiopoietin-2, which increased with disease severity. These markers were found to be positively correlated with the amount of virus present.
- Using an antibody-antigen assay, they found higher levels of SARS-CoV-2 IgM, IgA and IgG antibodies compared to uninfected individuals, but no difference between the critical and non-critical groups.
- Further assessment of SARS-CoV-2 antibodies revealed higher IgG antibodies and antibodies involved in Fc-mediated effector functions, associated with increased survival.
Using modelling, each of the identified biomarkers was measured to determine if they could be used to predict mortality. The amount of virus, certain tissue injury markers, and cytokine levels were found to be associated with an increased risk of mortality. Interestingly, at 11 days post symptom onset, combining the amount of viral genetic material (vRNA), age and sex was robust at determining who would die from COVID-19.
Taken together, these findings suggest that measuring the amount of vRNA in the blood can help identify patients at high risk of mortality, informing robust medical attention and treatments.
Brunet-Ratnasingham E, Anand SP, Gantner P, Moquin-Beaudry G, Dyachenko A, Brassard N, Beaudoin-Bussières G, Pagliuzza A, Gasser R, Benlarbi M, Point F, Prévost J, Laumaea A, Niessl J, Nayrac M, Sannier G, Boutin M, Descôteux-Dinelle J, Gendron-Lepage G, Goyette G, Bourassa C, Medjahed H, Orban C, Butler-Laporte G, Morrison D, Zhou S, Nakanishi T, Laurent L, Richard J, Dubé M, Fromentin R, Rébillard R-M, Arbour N, Prat A, Larochelle C, Durand M, Richards JB, Chassé M, Tétreault M, Chomont N, Finzi A, Kaufmann DE. Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality. medRxiv. 2021 Mar 20. DOI: 10.1101/2021.03.18.21253907