Erythrocytes Reveal Complement Activation in Patients with COVID-19

Abstract

COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multi-organ failure characterized by respiratory insufficiency, arrhythmias, thromboembolic complications and shock. The mortality of patients hospitalized with COVID-19 is unacceptably high and new strategies are urgently needed to rapidly identify and treat patients at risk for organ failure. Clinical epidemiologic studies demonstrate that vulnerability to organ failure is greatest after viral clearance from the upper airway, which suggests that dysregulation of the host immune response is a critical mediator of clinical deterioration and death. Autopsy and pre-clinical evidence implicate aberrant complement activation in endothelial injury and organ failure. A potential therapeutic strategy warranting investigation is to inhibit complement, with case reports of successful treatment of COVID-19 with inhibitors of complement. However, this approach requires careful balance between the host protective and potential injurious effects of complement activation, and biomarkers to identify the optimal timing and candidates for therapy are lacking. Here we report the presence of complement activation products on circulating erythrocytes from hospitalized COVID-19 patients using flow cytometry. These findings suggest that novel erythrocyte-based diagnostics provide a method to identify patients with dysregulated complement activation.

Acquired decrease of the C3b /C4b receptor (CR1, CD35) and C4d deposits on Erythrocytes from ICU COVID-19 Patients

“…Using an anti C3d for checking direct antiglobulin test (DAT) positive COVID-19 patients A. Berzuini et al detected C3 in 12% only of their patients , confirming isolated C4d deposits only in many cases (Berzuini et al, 2020), as already observed on E in kidney transplant rejection (Golocheikine et al, 2010;Haidar et al, 2012), and SLE clinical flares (Manzi et al, 2004). The decrease of CR1/E density presented here, and the detection of virus spike, C3 or C4 fragment on E (Metthew Lam et al, 2020), among COVID-19 patients, are likely to be two aspects of the same phenomenon. Measuring complement fragment deposits gives a snapshot at a given time, whereas measuring CR1/E gives a picture of the patient's response to infection over a longer duration.…”

“…One paper reported on a decrease of CR1/E in patients during the SARS epidemic (Wang et al, 2005). We hypothesized that the major clinical crisis observed in COVID-19 disease might be induced by the immune response and could lead to a major consummation of CR1 on E. Evidence is accumulating on the role of the complement system in SARS (Gralinski et al, 2018) and now in COVID-19 (Risitano et al, 2020;Magro et al, 2020), as well as on immune-adherence on E in that disease (Metthew Lam et al, 2020). Covalent C4d deposits on E are present at low level in normal individuals.…”

Complement C3 vs C5 inhibition in severe COVID-19: Early clinical findings reveal differential biological efficacy

“…CP and LP activity have been implicated in SARS-CoV-2 pathogenesis through the interaction of the heavily glycosylated N protein with MASP-2 [ 15 ] and the colocalization of viral S protein, immune complexes and C4d on COVID-19 erythrocytes [ 45 ]. Moreover, the prominent presence of C4d and MASP-2 deposits in the microvascular endothelium of COVID-19 biopsies argues for a key role of these pathways [ 4 , 46 ] To date, it remains debated whether the AP contributes to dysregulated complement activation in COVID-19.…”

Coagulopathy, endothelial dysfunction, thrombotic microangiopathy and complement activation: potential role of complement system inhibition in COVID-19

“…Similarly, Magro et al did a histologic examination of the patients with COVID-19 and reported the presence of SARS-CoV-2 spike glycoproteins along with C4d and C5b-9 in the interalveolar septa and the cutaneous microvasculature [41]. The presence of complement activation products was detected on circulating erythrocytes in hospitalized patients with COVID-19 [42]. A recent preprint study reported that the highly pathogenic coronavirus N protein aggregated the lung injury caused by SARS-CoV-2, SARS-CoV, and MERS by binding to mannan-binding lectin-associated protease (MASP-2), a key serine protease that could directly activate the complement cascade.…”