Complement-associated microvascular injury in severely ill COVID-19 patients
It is currently unknown, why some patients with novel coronavirus SARS-CoV-2 infection develop mild symptoms while others progress to severe COVID-19 illness and multisystem organ failure with extremely high mortality rates. It is also unknown, why some patient populations, especially African Americans, are at higher risk to develop severe complications in response to SARS-CoV-2 infection. Recent autopsy data from New Orleans in 4 African American patients who succumbed to COVID-19 infection (Fox, Akmatbekov, Harbert, Li, Brown & Vander Heide, 2020) demonstrated diffuse alveolar damage and TMA associated with foci of alveolar hemorrhage in the lungs. One of the cases had extensive fibrin with degenerated neutrophils within the alveoli possibly representing neutrophil extracellular traps (NETs). RNA imaging in available samples demonstrated multinucleated cells within alveolar spaces with abundant RNA, likely representing virally infected cells similar to previously reported in post-mortem case from China (Xu et al., 2020). The most significant gross cardiac finding was cardiomegaly with right ventricular dilatation in all patients without evidence of myocarditis. Elevated B-type natriuretic peptide associated with right ventricular dilatation was documented at least in one case. The authors hypothesized that these finding might be consistent with recent observation by Chen et al hypothesizing that pericytes may be infected by the SARS-CoV-2 virus and cause capillary endothelial cell microvascular dysfunction which may cause individual cardiac cell necrosis (Chen, Li, Chen, Feng & Xiong, 2020) There were no documented secondary bacterial of fungal infections, although all these patients received antimicrobials during critical illness. Based on these findings, the authors concluded that effective therapy for these patients should include targeted therapy for TMA in addition to virus directed therapies.
Further studies showed complement-associated microvascular injury and thrombosis in critically ill SARS-CoV-2-infected patients. They found extensive deposits of the terminal complement complex C5b-9, C4d and MASP2 in small vessels of affected organs (Fox, Akmatbekov, Harbert, Li, Brown & Vander Heide, 2020; Magro et al., 2020). Co-localization of complement components C5b-9 and C4 with SARS-CoV-2 spike glycoprotein indicated viral invasion of vascular endothelial cells that had been also demonstrated by reports of electron microscopy showing viral inclusion structures in vascular endothelial cells in lungs, heart, kidney, gastrointestinal tract and the skin (Magro et al., 2020). A recent study from Wuhan identified strong staining for MBL, MASP-2, C4a C3b and C5b-9 in type I and type II alveolar epithelia cells, inflammatory cells, pneumocytes, and even in exudates in alveolar spaces with necrotic cell debris (Gao et al., 2020).
Pulmonary abnormalities in severely affected patients are largely restricted to the alveolar capillaries, presenting as TMA with some evidence of viral cytopathic changes in alveolar lining. It is known that the virus uses ACE2 receptor expressed by pneumocytes in the epithelial alveolar lining to infect the host, thereby most commonly causing lung injury, but ACE2 receptors are also widely expressed on vascular endothelial cells, so multiple organs can be affected (Ou et al., 2020). There is potential interaction of complement with coagulation pathways resulting in acutely progressive microthrombosis with fibrin deposition and highly elevated D-dimers (Figure 2). Regardless of the originating insult leading to TMA, complement-mediated vascular endothelial injury may respond to complement-modulating therapies and offers the opportunity to adopt current knowledge from other TMAs to COVID-19.