3.4  Moderate and severe infection: the hyperinflammatory syndrome
Between 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.
Earlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.
Dysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.
Immunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.