Page 87 - Haematologica May 2022

Immunologic Dysregulation
Complement dysregulation is associated with severe COVID-19 illness
Jia Yu, Gloria F. Gerber, Hang Chen, Xuan Yuan, Shruti Chaturvedi, Evan M. Braunstein and Robert A. Brodsky
Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
ABSTRACT
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other comple- ment-mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alter- native pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complement- mediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell sur- face. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplifica- tion induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, sug- gesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dys- regulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.
Introduction
Complement has emerged as a potential driver of the pathogenesis of severe coro- navirus disease 2019 (COVID-19).1–3 Clinically, endothelial damage, systemic microvascular thrombosis and recalcitrant hypercoagulability observed in COVID- 19 mirror other disorders of complement regulation, such as atypical hemolytic ure- mic syndrome (aHUS) and catastrophic antiphospholipid antibody syndrome (CAPS).1–6 Autopsy studies showed microvascular thrombi and complement deposi- tion in the lungs and kidneys of patients with severe COVID-19.7,8 Several studies have demonstrated elevated levels of soluble C5a and C5b-9 in COVID-19 patients.9,10 Further, plasma C3a levels are higher in COVID-19 patients admitted to the intensive care unit (ICU) compared to non-ICU patients.11 A small number of patients treated with eculizumab, a monoclonal anti-C5 antibody, experienced rapid improvement in hypoxia and inflammatory markers.12,13 Three patients treated with an upstream complement C3 inhibitor demonstrated reduction in inflammatory markers and improved disease severity within 48 hours of treatment.14 Clinical trials of complement inhibitors in COVID-19 are ongoing (clinicaltrials gov. Identifier: NCT04355494, NCT04390464).
The complement system, a key component of the human innate immune response, is a collection of proteases, receptors and inhibitors that functions to elim- inate cellular debris, promote inflammation and defend against pathogens.15 The
Ferrata Storti Foundation
Haematologica 2022 Volume107(5):1095-1105
Correspondence:
ROBERT A. BRODSKY
brodsro@jhmi.edu
Received: May 17, 2021. Accepted: July 14, 2021. Pre-published: July 22, 2021.
https://doi.org/10.3324/haematol.2021.279155 ©2022 Ferrata Storti Foundation
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