Colchicine for COVID-19: Hype or hope?

Published:November 12, 2021DOI:https://doi.org/10.1016/j.ejim.2021.11.011
      We appreciate the efforts of Schattner [
      • Schattner A.
      Colchicine-new horizons for an ancient drug.
      ] to summarize the evidence from randomized controlled trials regarding the efficacy and safety of colchicine for various emerging indications, which included coronavirus disease 2019 (COVID-19). The four randomized controlled trials [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ,
      • Deftereos S.G.
      • Giannopoulos G.
      • Vrachatis D.A.
      • et al.
      Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial.
      ,
      • Lopes M.I.
      • Bonjorno L.P.
      • Giannini M.C.
      • et al.
      Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
      ,
      • Mareev V.Y.
      • Orlova Y.A.
      • Plisyk A.G.
      • et al.
      Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study.
      ] summarized by Schattner [
      • Schattner A.
      Colchicine-new horizons for an ancient drug.
      ] which investigated the use of colchicine in patients with COVID-19 strongly suggesting a beneficial effect of the use of colchicine. Nevertheless, Schattner might have overlooked the recently published RECOVERY trial [
      RECOVERY Collaborative Group
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ] investigating the use of colchicine in patients with COVID-19 (available as a preprint during the time of his literature search), which is by far the largest randomized trial (n = 11,340) to report the effects of colchicine in patients with COVID-19. According to the RECOVERY trial [
      RECOVERY Collaborative Group
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ], the use of colchicine in patients with COVID-19 was not associated with reduction in 28-day mortality (rate ratio = 1•01; 95% confidence interval 0•93–1•10). In fact, the findings of the RECOVERY trial [
      RECOVERY Collaborative Group
      Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ] on colchicine had dampened the enthusiasm of further investigating the effects of colchicine in patients with COVID-19.
      The NLRP3 inflammasome, a multiprotein complex in macrophages, dendritic cells, and other non-immune cells, is a vital part of the innate immune system for antiviral host defenses. The aberrant activation of the NLRP3 inflammasome during the course of COVID-19 leads to the production of interleukin-1β, facilitating the formation of cytokine storms and the subsequent multiorgan injury. This is the rationale where colchicine, a well‐known NLRP3 inhibitor, has been repurposed for the treatment of COVID-19. Nevertheless, such beneficial effects of colchicine did not appear to translate into mortality benefits. It is likely that the proportion of enrolled patients with concurrent obesity and/or diabetes in the existing trials, who would have more pronounced activation of the NLRP3 inflammasome, was too low to allow detection of mortality benefits [
      • Bertocchi I.
      • Foglietta F.
      • Collotta D.
      • et al.
      The hidden role of NLRP3 inflammasome in obesity-related COVID-19 exacerbations: lessons for drug repurposing.
      ,
      • Lambadiari V.
      • Kousathana F.
      • Raptis A.
      • Katogiannis K.
      • Kokkinos A.
      • Ikonomidis I.
      Pre-existing cytokine and NLRP3 inflammasome activation and increased vascular permeability in diabetes: a possible fatal link with worst COVID-19 infection outcomes?.
      ]. In the trial by Tardif et al. [
      • Tardif J.C.
      • Bouabdallaoui N.
      • L'Allier P.L.
      • et al.
      Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
      ] in which the findings have been summarized by Schattner [
      • Schattner A.
      Colchicine-new horizons for an ancient drug.
      ], the participants had a median body mass index of 30.0 kg/m2. There was a significant reduction in the odds for a composite of death or hospitalization due to COVID-19 in colchicine users compared to non-colchicine users (odds ratio = 0.75; 95% confidence interval: 0.57–0.99). Besides, the pre-specified subgroup analysis reported that the odds for a composite of death or hospitalization due to COVID-19 was trended towards a significant effect in patients with concurrent diabetes receiving colchicine (odds ratio = 0.37; 95% confidence interval: 0.37–1.01).
      Besides the purported anti-inflammatory action of colchicine which has been discussed by Schattner [
      • Schattner A.
      Colchicine-new horizons for an ancient drug.
      ], colchicine could also suppress the formation of neutrophil extracellular traps (NETs) [
      • Kow C.S.
      • Hasan S.S.
      Colchicine as an adjunct to heparin for prophylaxis of venous thromboembolism in patients with COVID-19.
      ]. Colchicine stabilizes the cytoskeleton, thereby attenuating chromatin swelling and subsequent NET release from neutrophils. Interestingly, NETs have been found to contribute to immunothrombosis in patients with COVID-19, especially those with severe course of illness. Therefore, colchicine, being one of the anti-NETs therapeutics, could also be useful as an adjunct to anticoagulants for thromboprophylaxis in this patient population. Noteworthily, a recent systematic review and meta-analysis [
      • Sarwar M.
      • Ali Z.
      • Fatima M.
      • Sarfraz Z.
      • Sarfraz A.
      • Cherrez-Ojeda I.
      Colchicine, COVID-19 and hematological parameters: a meta-analysis.
      ], which aimed to determine the effects of colchicine on several inflammatory hematological biomarker levels among patients with COVID-19 noted that the use of colchicine relative to control treatment led to statistically significantly lower mean D-dimer level (standardized mean difference = −0.9; 95% confidence interval −1.22–−0.57), which is a sensitive marker of thrombosis.
      With the wisdom of hindsight, future randomized trials aiming to determine the effects of colchicine in patients with COVID-19 should focus on the population of patients with COVID-19 with concurrent obesity and/or diabetes, and preferably at the early (mild) stage of illness, in order to elicit its efficacy to prevent mortality and clinical deterioration. In addition, apart from evaluating its mortality benefits, there should be a concurrent evaluation of its efficacy for thromboprophylaxis (as an adjunct to anticoagulants) among patients with COVID-19. These trials should also be designed in a way that the treatment duration of colchicine is long enough (21 days or until discharge) to establish its therapeutic efficacy.

      Funding

      The publication of this article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      The authors report no conflict of interest.

      Reference

        • Schattner A.
        Colchicine-new horizons for an ancient drug.
        Eur J Intern Med. 2021; ([published online ahead of print, 2021 Oct 14])https://doi.org/10.1016/j.ejim.2021.10.002
        • Tardif J.C.
        • Bouabdallaoui N.
        • L'Allier P.L.
        • et al.
        Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
        Lancet Respir Med. 2021; 9: 924-932
        • Deftereos S.G.
        • Giannopoulos G.
        • Vrachatis D.A.
        • et al.
        Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the GRECCO-19 randomized clinical trial.
        JAMA Netw Open. 2020; 3e2013136
        • Lopes M.I.
        • Bonjorno L.P.
        • Giannini M.C.
        • et al.
        Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
        RMD Open. 2021; 7e001455
        • Mareev V.Y.
        • Orlova Y.A.
        • Plisyk A.G.
        • et al.
        Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study.
        Kardiologiia. 2021; 61: 15-27
        • RECOVERY Collaborative Group
        Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
        Lancet Respir Med. 2021; ([published online ahead of print, 2021 Oct 18]) (S2213-2600(21)00435-5)
        • Bertocchi I.
        • Foglietta F.
        • Collotta D.
        • et al.
        The hidden role of NLRP3 inflammasome in obesity-related COVID-19 exacerbations: lessons for drug repurposing.
        Br J Pharmacol. 2020; 177: 4921-4930
        • Lambadiari V.
        • Kousathana F.
        • Raptis A.
        • Katogiannis K.
        • Kokkinos A.
        • Ikonomidis I.
        Pre-existing cytokine and NLRP3 inflammasome activation and increased vascular permeability in diabetes: a possible fatal link with worst COVID-19 infection outcomes?.
        Front Immunol. 2020; 11557235
        • Kow C.S.
        • Hasan S.S.
        Colchicine as an adjunct to heparin for prophylaxis of venous thromboembolism in patients with COVID-19.
        Rheumatol Int. 2021; 41: 677-678
        • Sarwar M.
        • Ali Z.
        • Fatima M.
        • Sarfraz Z.
        • Sarfraz A.
        • Cherrez-Ojeda I.
        Colchicine, COVID-19 and hematological parameters: a meta-analysis.
        J Clin Lab Anal. 2021; ([published online ahead of print, 2021 Oct 28]): e24057