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.