Coronavirus disease 2019: investigational therapies in the prevention and treatment of hyperinflammation

Abstract

Introduction: The mortality of coronavirus disease 2019 (COVID-19) is frequently driven by an injurious immune response characterized by the development of acute respiratory distress syndrome (ARDS), endotheliitis, coagulopathy, and multi-organ failure. This spectrum of hyperinflammation in COVID-19 is commonly referred to as cytokine storm syndrome (CSS). Areas covered: Medline and Google Scholar were searched up until 15th of August 2020 for relevant literature. Evidence supports a role of dysregulated immune responses in the immunopathogenesis of severe COVID-19. CSS associated with SARS-CoV-2 shows similarities to the exuberant cytokine production in some patients with viral infection (e.g.SARS-CoV-1) and may be confused with other syndromes of hyperinflammation like the cytokine release syndrome (CRS) in CAR-T cell therapy. Interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha have emerged as predictors of COVID-19 severity and in-hospital mortality. Expert opinion: Despite similarities, COVID-19-CSS appears to be distinct from HLH, MAS, and CRS, and the application of HLH diagnostic scores and criteria to COVID-19 is not supported by emerging data. While immunosuppressive therapy with glucocorticoids has shown a mortality benefit, cytokine inhibitors may hold promise as 'rescue therapies' in severe COVID-19. Given the arguably limited benefit in advanced disease, strategies to prevent the development of COVID-19-CSS are needed.

Keywords: Coronavirus disease 2019 (COVID-19); cytokine release syndrome; cytokine storm syndrome; hemophagocytic lymphohistiocytosis; hyperinflammation.

Figure 1.

Clinical phases of COVID-19 and potential strategies for the prevention and treatment of hyperinflammation (‘cytokine storm’). Disease progression in COVID-19 can be categorized based on the severity of clinical signs and symptoms in addition to the development of objective imaging and laboratory abnormalities. A hyperinflammatory state – following an initial viral replication phase – can be present in patients with severe disease. Potential approaches to ameliorate COVID-19 include strategies to reduce binding of SARS-CoV-2 to its cognate receptors (not shown), antiviral therapy (e.g. remdesivir), and the prevention and treatment of hyperinflammation and immune-mediated end-organ damage. ARDS: acute respiratory distress syndrome. ARDS: acute respiratory distress syndrome. IFN: interferon. IL: interleukin. JAK: Janus kinase. TNF: tumor necrosis factor.

Figure 2.

Summary of key therapeutic strategies investigated for the prevention or treatment of COVID-19-CSS and ARDS. Model of an inflammatory feed-forward loop in immune cells (e.g. lung-infiltrating monocytes and macrophages) in response to SARS-CoV-2 infection that results in exuberant cytokine production and cytokine storm. Drugs currently investigated for the treatment or prevention of severe COVID-19 and their respective targets are shown. Catecholamine and cytokine feed-forward loops are shown in magenta and green, respectively. α-1 AR: α-1 adrenergic receptor. BTK: Bruton tyrosine kinase. C5: Complement factor 5. IFN: interferon. IKK: I kappa B kinase. IL: interleukin. IRAK: Interleukin-1 receptor-associated kinase. JAK: Janus kinase. NFκB: Nuclear Factor kappa-light-chain-enhancer of activated B cells. R: receptor. STAT: signal transducers and activators of transcription. TNF: tumor necrosis factor.