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

PLoS One. 2021 Dec 20;16(12):e0261113. doi: 10.1371/journal.pone.0261113. eCollection 2021.

Abstract

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.

Publication types

  • Controlled Clinical Trial
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • COVID-19 / mortality
  • COVID-19 / physiopathology
  • COVID-19 / therapy*
  • COVID-19 Drug Treatment
  • Case-Control Studies
  • Complement Membrane Attack Complex / analysis
  • Continuous Positive Airway Pressure*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Retrospective Studies
  • Thrombosis / drug therapy
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Complement Membrane Attack Complex
  • eculizumab

Grants and funding

The ASST Papa Giovanni XXIII in Bergamo (Italy) sponsored the trial, Brembo SpA (Curno, Bergamo, Italy) partially covered study costs by a liberal grant under the initiative "Progetto TrexUno" and Alexion Pharma Italy S.R.L. (Milan, Italy) freely supplied the study drug. Neither the sponsor nor the companies had any role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. All authors had full access to all the data in the study and accept responsibility to submit for publication. There was no additional funding received for this study. The funder provided support in the form of salaries for authors PR, FDM, LL, SS, LN, VP, LC and CC, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.