Immunopathology of Hyperinflammation in COVID-19

Abstract

The rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented public health crisis worldwide. Recent studies indicate that a hyperinflammatory syndrome induced by SARS-CoV-2 contributes to disease severity and mortality in COVID-19. In this review, an overview of the pathophysiology underlying the hyperinflammatory syndrome in severe COVID-19 is provided. The current evidence suggests that the hyperinflammatory syndrome results from a dysregulated host innate immune response. The gross and microscopic pathologic findings as well as the alterations in the cytokine milieu, macrophages/monocytes, natural killer cells, T cells, and neutrophils in severe COVID-19 are summarized. The data highlighted include the potential therapeutic approaches undergoing investigation to modulate the immune response and abrogate lung injury in severe COVID-19.

Figure 1

Disease mechanism of severe COVID-19 after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. SARS-CoV-2 primarily infects type 2 pneumocytes expressing the ACE2 receptor in alveoli. The active viral replication of SARS-CoV-2 causes the host cell to undergo pyroptosis and release viral nucleic acids and proinflammatory cytokines. These are recognized by pattern-recognition receptors on neighboring pneumocytes and resident alveolar macrophages, which trigger the production of proinflammatory cytokines and chemokines, including IL-1β, IL-6, IL-8, GM-CSF, TNF-α, IFN-γ, IP-10/CXCL10, MCP-1/CCL2, MIP-1α/CCL3, and MIP-1β/CCL4. Inflammatory monocytes, CD4⁺ and CD8⁺ T cells, neutrophils, and NK cells are then recruited to the lung parenchyma and interstitium. The monocyte-derived classic M1 macrophages and CD4⁺ T cells exacerbate inflammation by producing additional cytokines; a profibrotic subset of alternative M2 macrophages are also recruited to the lung. A proinflammatory feedback loop is established that triggers a circulating cytokine storm and leads to acute respiratory distress syndrome, septic shock, and hemophagocytic macrophages in reticuloendothelial organs. Direct invasion of ACE2⁺ endothelial cells by SARS-CoV-2 may also trigger an endotheliitis in the pulmonary vasculature. pBTK, phosphorylated Bruton's Tyrosine Kinase.