Abstract
Complement activation contributes to lung dysfunction in coronavirus disease 2019 (COVID-19). We assessed whether C5 blockade with eculizumab could improve disease outcome. 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. 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. 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.
Highlights
As observed in other experimental and human forms of coronavirus lung infection [1,2], dramatic respiratory dysfunction [3] and dismal outcomes [4] of Severe-Acute-Respiratory-Syndrome Coronavirus-2 (SARS-CoV-2) 2019, or COVID-19 [3,5], are largely mediated by overwhelming release of pro-inflammatory cytokines [6] and uncontrolled complement activation [7,8]
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
Researchers who wish to inquire about access to individual participant data that underlie the results reported in this article shall submit a proposal to the Laboratory of Biostatistics of the Department of Renal Medicine of the Istituto di Ricerche Farmacologiche Mario Negri IRCCS (RenMedBiostatistics@marionegri.it)
Summary
As observed in other experimental and human forms of coronavirus lung infection [1,2], dramatic respiratory dysfunction [3] and dismal outcomes [4] of Severe-Acute-Respiratory-Syndrome Coronavirus-2 (SARS-CoV-2) 2019, or COVID-19 [3,5], are largely mediated by overwhelming release of pro-inflammatory cytokines (cytokine storm) [6] and uncontrolled complement activation [7,8]. Endothelial injury and microangiopathic lesions similar to those observed in the hemolytic uremic syndrome (HUS) [9,10] and deposits of C5b-9 in lung and skin vessels [10], as well as in glomeruli and tubuli [11] of patients dying of COVID-19 confirm that complement activation, in particular of the terminal pathway, may have a key pathogenic role in COVID-19 [12]. Initial case series and explorative studies showed encouraging effects of C5 blockade in patients with COVID-19 [15–17], even in combination with the JAK1/2 inhibitor ruxolitinib [16]. Based on this background we planned to add two 900 mg eculizumab doses on best supportive therapy in ten patients with COVID-19 who required Continuous-PositiveAirway-Pressure (CPAP) ventilator support and compared their outcomes with outcomes of similar contemporary controls who received the same supportive therapy, but no eculizumab. We assessed whether C5 blockade with eculizumab could improve disease outcome
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