Immunohematologic Biomarkers in COVID-19: Insights into Pathogenesis, Prognosis, and Prevention

Abstract

Coronavirus disease 2019 (COVID-19) has had profound effects on the health of individuals and on healthcare systems worldwide. While healthcare workers on the frontlines have fought to quell multiple waves of infection, the efforts of the larger research community have changed the arch of this pandemic as well. This review will focus on biomarker discovery and other efforts to identify features that predict outcomes, and in so doing, identify possible effector and passenger mechanisms of adverse outcomes. Identifying measurable soluble factors, cell-types, and clinical parameters that predict a patient's disease course will have a legacy for the study of immunologic responses, especially stimuli, which induce an overactive, yet ineffectual immune system. As prognostic biomarkers were identified, some have served to represent pathways of therapeutic interest in clinical trials. The pandemic conditions have created urgency for accelerated target identification and validation. Collectively, these COVID-19 studies of biomarkers, disease outcomes, and therapeutic efficacy have revealed that immunologic systems and responses to stimuli are more heterogeneous than previously assumed. Understanding the genetic and acquired features that mediate divergent immunologic outcomes in response to this global exposure is ongoing and will ultimately improve our preparedness for future pandemics, as well as impact preventive approaches to other immunologic diseases.

Keywords: COVID-19; SARS-CoV-2; biomarkers; immunophenotyping; multiomics; prevention.

Figure 1.

Summary of discussed biomarkers. Anticipatory (ie, pre-infection) and reactive (ie, post-infection) biomarkers of COVID-19 infection risk and outcomes are described. Among the characteristics creating risk for infection and poor outcomes prior to SARS-CoV-2 infection include being a chronic carrier of a multitude of different viruses (eg, Epstein-Barr virus and cytomegalovirus), genetic variants predisposing individuals to impaired immunologic responses, and chronic comorbid conditions (eg, aging, heart disease, metabolic disease). Interventions possible at this stage of biomarker include preventative strategies protecting at-risk populations including vaccine and mask utilization. While numerous reactive biomarkers have been identified as discussed in the manuscript, each provides varying levels of mechanistic insight or utility in adapting such biomarkers to large clinical populations (shown with x and y axes). Among the most promising biomarkers discussed include simple complete blood count parameters (eg, ALC, ANC, and RDW), soluble serologic factors such as cytokines and acute phase reactants, deep profiling of immunophenotypes (through flow cytometric analysis of immune surface receptor expression), and multi-omic analyses using proteomics, metabolomics, and immunophenotypes. Targeting these factors has been more aggressive during the pandemic with immunomodulatory agents (eg, anti-IL6, anti-IL1β agents) with varying levels of success. Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CRP, C-reactive protein; IFNα, interferon alpha; IL1β, interleukin-1 beta; IL6, interleukin-6; IL10, interleukin-10; Nuc. antigen, nuclear antigens; PLs, phospholipids; RDW, red blood cell distribution width; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.