Severe COVID-19 versus multisystem inflammatory syndrome: comparing two critical outcomes of SARS-CoV-2 infection

Proposed disease pathways implicated in the coronavirus disease 2019 (COVID-19) spectrum and multisystem inflammatory syndrome (MIS). a) Mild–moderate COVID-19. In individuals without any risk factors, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces local tissue damage, triggering canonical antiviral interferon-α (IFN-α), with subsequent induction of CD4⁺ helper T-cell responses (T-helper 1 (Th1) and T follicular helper (Tfh)) that facilitate destruction of virally infected cells by CD8⁺ cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells, promote antibody responses for neutralisation of SARS-CoV-2, and the phagocytic clearance of apoptotic cells and neutralised virus by macrophages, leading to viral clearance and recovery. b) Severe COVID-19. Associated with immune-modulating risk factors and characterised by a hallmark of blunted canonical IFN-α expression. Impaired Th1 and Tfh responses, suboptimal humoral responses that promote antibody-dependent enhancement (ADE), lymphocyte exhaustion and impaired functions, and macrophage dysfunction, permit further viral replication to cause extensive tissue damage. Sensing of self-DNA damage in infected host cells by the adaptor molecular STING (stimulator of IFN genes) can activate NF-κB-mediated hyperinflammatory noncanonical IFN-β signalling to induce extensive pro-inflammatory cytokine release that further dysregulates lymphoid and myeloid compartments without activating antiviral responses, whilst generating a hyperinflammatory feedback loop. Superantigenic stimulation can also skew helper T-cell responses and enhance pro-inflammatory cytokine release. Resultant dysregulated inflammatory pathology is linked to coagulopathy, vasculopathy, multiorgan injury and failure. c) MIS. Typically affects previously healthy individuals without pre-existing comorbidities. Patients exhibit absent/low respiratory tract (RT) viral loads and lack severe respiratory illness, which may be due to fewer infected RT cells, but may possess intrinsic genetic susceptibility traits that cause harmful maladaptations of adaptive responses and trigger the activation of systemic hyperinflammation pathways upon SARS-CoV-2 infection. Abnormal CD4⁺ helper T-cell functions, dysregulated humoral responses and impaired lymphocyte cytolytic functions can potentiate viral spread to extrapulmonary tissues, activating hyperinflammatory pathways (e.g. STING-mediated late, noncanonical hyperinflammatory IFN-β signalling) to promote systemic autonomous loops of inflammation with hypercoagulation, vasculopathy and multiorgan involvement. GC: germinal centre; ISG: IFN-stimulated gene; ROS: reactive oxygen species.