Immune Immunomodulation in Coronavirus Disease 2019 (COVID-19): Strategic Considerations for Personalized Therapeutic Intervention

Abstract

We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a "one size fits all" approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.

Keywords: COVID-19; cytokine storm; immune modulation; immunoparalysis; inflammation.

Figure 1.

Dynamic, heterogenous inflammatory processes subsequent to immune escape contribute to disease severity and tissue damage. Early, local inflammatory processes in the lung often result in an effective host response leading to pathogen clearance. In the event of escape of the virus from the immune system as the result of a suppressed or delayed immune response, there is unchecked viral replication. Increased viral load and direct tissue injury precipitate inflammatory processes, which lead to highly dynamic and variable local and systemic immune responses. Within the context of COVID-19–induced critical illness, including acute hypoxemic respiratory failure, systemic inflammation (A) and immunoparalysis (B) may occur independently or simultaneously (C). Systemic inflammation, including hypercytokinemia and hyperferritinemia, is common, but is not universally severe. Only a subset of patients have inflammatory biomarkers that are high enough to be consistent with MAS- or CRS-like presentations. Severe immune suppression (ie, immunoparalysis) may be characterized by decreased antigen-presenting capacity and decreased numbers of lymphocytes and NK cells. In sum, COVID-19–induced critical illness is a highly dynamic state with a temporally variable immunophenotype. Heterogeneity of the subsequent inflammatory responses in individual patients is common, and the use of immunomodulatory interventions likely needs to be based on the phase of the response and individual patient immunophenotype. Abbreviations: COVID-19, coronavirus disease 2019; CRS, cytokine release syndrome; MAS, macrophage activation syndrome; NK, natural killer.