Eculizumab in patients with severe coronavirus disease 2019 (COVID-19) requiring continuous positive airway pressure ventilator support: Retrospective cohort study.

BACKGROUND: Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. METHODS: In this single-centre, academic, unblinded study two 900 mg eculizumab doses were added-on standard therapy in ten COVID-19 patients admitted from February 2020 to April 2020 and receiving Continuous-Positive-Airway-Pressure (CPAP) ventilator support from ≤24 hours. We compared their outcomes with those of 65 contemporary similar controls. Primary outcome was respiratory rate at one week of ventilator support. Secondary outcomes included the combined endpoint of mortality and discharge with chronic complications. RESULTS: Baseline characteristics of eculizumab-treated patients and controls were similar. At baseline, sC5b-9 levels, ex vivo C5b-9 and thrombi deposition were increased. Ex vivo tests normalised in eculizumab-treated patients, but not in controls. In eculizumab-treated patients respiratory rate decreased from 26.8±7.3 breaths/min at baseline to 20.3±3.8 and 18.0±4.8 breaths/min at one and two weeks, respectively (p<0.05 for both), but did not change in controls. Between-group changes differed significantly at both time-points (p<0.01). Changes in respiratory rate correlated with concomitant changes in ex vivo C5b-9 deposits at one (rs = 0.706, p = 0.010) and two (rs = 0.751, p = 0.032) weeks. Over a median (IQR) period of 47.0 (14.0-121.0) days, four eculizumab-treated patients died or had chronic complications versus 52 controls [HRCrude (95% CI): 0.26 (0.09-0.72), p = 0.010]. Between-group difference was significant even after adjustment for age, sex and baseline serum creatinine [HRAdjusted (95% CI): 0.30 (0.10-0.84), p = 0.023]. Six patients and 13 controls were discharged without complications [HRCrude (95% CI): 2.88 (1.08-7.70), p = 0.035]. Eculizumab was tolerated well. The main study limitations were the relatively small sample size and the non-randomised design. CONCLUSIONS: In patients with severe COVID-19, eculizumab safely improved respiratory dysfunction and decreased the combined endpoint of mortality and discharge with chronic complications. Findings need confirmation in randomised controlled trials.

The state of complement in COVID-19.

Hyperactivation of the complement and coagulation systems is recognized as part of the clinical syndrome of COVID-19. Here we review systemic complement activation and local complement activation in response to the causative virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their currently known relationships to hyperinflammation and thrombosis. We also provide an update on early clinical findings and emerging clinical trial evidence that suggest potential therapeutic benefit of complement inhibition in severe COVID-19.

C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19.

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.

The case of complement inhibitors.

Severe COVID-19 is characterized by lung and multiorgan inflammation and coagulation in the presence of overactivation of the complement system. Complement is a double edged-sward in SARS-Cov-2 infection. On one hand, it can control the viral infection in milder cases, on the other hand in cases with severe and prolonged infection massive complement activation occurs, which can intensify lung and systemic inflammation and promote a procoagulant and prothrombotic state. Several uncontrolled studies and controlled clinical trials with different complement inhibitors have been performed and others are ongoing. Results are promising in some but negative in others. Further studies are required to elucidate the benefit to risk profile of complement inhibitors in COVID-19 patients at different stages of the disease and to clarify the best targets in the complement cascade.

Case Report: Effects of Anti-SARS-CoV-2 Convalescent Antibodies Obtained With Double Filtration Plasmapheresis.

Passive antibody therapy has been used to treat outbreaks of viral disease, including the ongoing pandemic of severe respiratory acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) or COVID-19. However, the real benefits of the procedure are unclear. We infused a concentrated solution of neutralizing anti-SARS-CoV-2 antibodies obtained from a convalescent donor with a single session of double filtration plasmapheresis (DFPP) into a 56-year-old woman with long history of unremitting, severe COVID-19. She was unable to establish an adequate antiviral immune response because of previous chemotherapy, including the infusion of the anti-CD20 monoclonal antibody rituximab, administered to treat a diffuse large B-cell lymphoma. The disease promptly recovered despite evidence of no endogenous anti-SARS-CoV-2 antibody production. The observation that passive antibody therapy might prove particularly effective in immunodepressed COVID-19 patients requires evaluation in prospective randomized controlled trial.

The case of complement activation in COVID-19 multiorgan impact.

The novel coronavirus disease COVID-19 originates in the lungs, but it may extend to other organs, causing, in severe cases, multiorgan damage, including cardiac injury and acute kidney injury. In severe cases, the presence of kidney injury is associated with increased risk of death, highlighting the relevance of this organ as a target of SARS-CoV-2 infection. COVID-19-associated tissue injury is not primarily mediated by viral infection, but rather is a result of the inflammatory host immune response, which drives hypercytokinemia and aggressive inflammation that affect lung parenchymal cells, diminishing oxygen uptake, but also endothelial cells, resulting in endotheliitis and thrombotic events and intravascular coagulation. The complement system represents the first response of the host immune system to SARS-CoV-2 infection, but there is growing evidence that unrestrained activation of complement induced by the virus in the lungs and other organs plays a major role in acute and chronic inflammation, endothelial cell dysfunction, thrombus formation, and intravascular coagulation, and ultimately contributes to multiple organ failure and death. In this review, we discuss the relative role of the different complement activation products in the pathogenesis of COVID-19-associated tissue inflammation and thrombosis and propose the hypothesis that blockade of the terminal complement pathway may represent a potential therapeutic option for the prevention and treatment of lung and multiorgan damage.