Colchicine Reduces Lung Injury in Experimental Acute Respiratory Distress Syndrome

Dupuis, Jocelyn; Sirois, Martin G.; Rhéaume, Éric; Nguyen, Quang Trinh; Clavet-Lanthier, Marie-Élaine; Brand, Geneviève; Mihalache-Avram, Téodora; Théberge-Julien, Gabriel; Charpentier, Daniel; Rhainds, David; Neagoe, Paul‐Eduard; Tardif, Jean‐Claude

doi:10.21203/rs.3.rs-43204/v1

Cited by 10 publications

(16 citation statements)

References 24 publications

(32 reference statements)

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“…19,20 Colchicine has previously been shown to reduce acute lung injury in an experimental model of acute respiratory-distress syndrome. 18 The risk of viral inflammatory pneumonitis therefore appears to be lowered by colchicine in patients with COVID-19. Reassuringly, there was no evidence of an increased risk of bacterial pneumonia in COLCORONA.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17] In an experimental model of acute respiratorydistress syn drome, colchicine was shown to reduce inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment. 18 Substantial clinical benefits of colchicine have also been reported in observational studies and two randomised controlled trials of patients admitted to hospital with COVID-19. [19][20][21][22] We did the COLchicine CORONAvirus SARS-CoV-2 (COLCORONA) trial in community-treated patients with COVID-19 to establish the effects of colchicine on complications, including hospital admission and death, as well as its safety and tolerability.…”

Section: Introductionmentioning

confidence: 93%

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Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial

Tardif

Bouabdallaoui

L’Allier

et al. 2021

The Lancet Respiratory Medicine

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228

243

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Background Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.Methods The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0•5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97•9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants. FindingsTrial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53•9% women; median age 54•0 years, IQR 47•0-61•0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4•7%) of 2235 patients in the colchicine group and 131 (5•8%) of 2253 patients in the placebo group (odds ratio [OR] 0•79, 95•1% CI 0•61-1•03; p=0•081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4•6%) of 2075 patients in the colchicine group and 126 (6•0%) of 2084 patients in the placebo group (OR 0•75, 0•57-0•99; p=0•042). Serious adverse events were reported in 108 (4•9%) of 2195 patients in the colchicine group and 139 (6•3%) of 2217 patients in the placebo group (p=0•051); pneumonia occurred in 63 (2•9%) of 2195 patients in the colchicine group and 92 (4•1%) of 2217 patients in the placebo group (p=0•021). Diarrhoea was reported in 300 (13•7%) of 2195 patients in the colchicine group and 161 (7•3%) of 2217 patients in the placebo group (p<0•0001).Interpretation In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to pr...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial

Tardif

Bouabdallaoui

L’Allier

et al. 2021

The Lancet Respiratory Medicine

Self Cite

228

243

View full text Add to dashboard Cite

show abstract

“…[11][12][13] In an experimental model of acute respiratory distress syndrome, colchicine was shown to reduce inflammatory lung injury and respiratory failure by interfering with leukocyte activation and recruitment. 14 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.…”

Section: Discussionmentioning

confidence: 99%

“…Colchicine has previously been shown to reduce acute lung injury in an experimental model of acute respiratory distress syndrome. 14 The risk of viral inflammatory pneumonitis might therefore be lowered by colchicine in patients with COVID-19. In contrast, there was no evidence of an increased risk of bacterial pneumonia in COLCORONA.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19

Tardif

Bouabdallaoui

L’Allier

et al. 2021

Preprint

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BackgroundEvidence suggests the role of an inflammatory storm in COVID-19 complications. Colchicine is an orally administered, anti-inflammatory medication beneficial in gout, pericarditis and coronary disease.MethodsWe performed a randomized, double-blind trial involving non-hospitalized patients with COVID-19 diagnosed by polymerase chain reaction (PCR) testing or clinical criteria. The patients were randomly assigned to receive colchicine (0.5 mg twice daily for 3 days and once daily thereafter) or placebo for 30 days. The primary efficacy endpoint was the composite of death or hospitalization for COVID-19.ResultsA total of 4488 patients were enrolled. The primary endpoint occurred in 4.7% of the patients in the colchicine group and 5.8% of those in the placebo group (odds ratio, 0.79; 95.1% confidence interval (CI), 0.61 to 1.03; P=0.08). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 4.6% and 6.0% of patients in the colchicine and placebo groups, respectively (odds ratio, 0.75; 95% CI, 0.57 to 0.99; P=0.04). In these patients with PCR-confirmed COVID-19, the odds ratios were 0.75 (95% CI, 0.57 to 0.99) for hospitalization due to COVID-19, 0.50 (95% CI, 0.23 to 1.07) for mechanical ventilation, and 0.56 (95% CI, 0.19 to 1.66) for death. Serious adverse events were reported in 4.9% and 6.3% in the colchicine and placebo groups (P=0.05); pneumonia occurred in 2.9% and 4.1% of patients (P=0.02). Diarrhea was reported in 13.7% and 7.3% in the colchicine and placebo groups (P<0.0001).ConclusionAmong non-hospitalized patients with COVID-19, colchicine reduces the composite rate of death or hospitalization. (COLCORONA ClinicalTrials.gov number: NCT04322682)

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“…Furthermore, Deftereos et al [ 37 ], performed a randomized clinical trial with 105 COVID-19 patients on colchicine therapy compared with standard care control; found that colchicine is an effective agent in reducing ALI and cardiac injury in the early course of COVID-19 due to its potent anti-inflammatory effects. Likewise, Dupuis et al [ 38 ], described that colchicine is effective in the management of ALI and ARDS through reduction of pro-inflammatory CS and inhibition of cellular inflammasomes. Indeed, COVID-19 in FMF patients under colchicine therapy developed mild symptoms without radiological findings [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects

Al-Kuraishy

Al-Gareeb

Qusty

et al. 2021

Pulmonary Pharmacology & Therapeutics

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Coronavirus virus disease 2019 (COVID-19) is a viral infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), actually considered as a global pandemic. The entry-point for SARS-CoV-2 is angiotensin converting enzyme 2 (ACE2) and dipeptidyl peptidase 4 (DPP4), which are highly expressed in the lung. Among other complications, COVID-19leads to fatal pneumonia, acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) due to development of cytokine storm (CS). The pathogenesis of SARS-CoV-2 infection depends on the viral load and human innate/adaptive immune response that are required for viral elimination in the first phase of COVID-19. However, an exaggerated immune response in the second phase of COVID-19 results in immune overreaction and CS-induced ALI and ARDS. Thus, in view of these considerations, we report here a series of five patients with COVID-19 pneumonia who developed ALI. In addition to the supportive therapy, the patients received doxycycline in the first week and doxycycline plus colchicine in the second week. Following sequential therapy with doxycycline and/or colchicine in patients with COVID-19 pneumonia, the patients had reduction of disease severity and symptoms with better clinical and radiological outcomes. However, it is tough to confirm the link between this therapeutic combination and recovery from COVID-19 pneumonia, as it is a small case-series report. Nevertheless, this study gives a rational for large-scale prospective studies to evaluate the dual sequential effect of doxycycline and colchicine on the COVID-19 severity. This case-series illustrated that use of colchicine: doxycycline combination is linked with marked improvements in the clinical, laboratory and radiological outcomes in patients with COVID-19 pneumonia. However, we cannot sketch any definitive conclusion from our observation, despite we hypothesize that this combination therapeutic regimen may attenuate and treat COVID-19. Further, namely prospective, randomized, and controlled clinical studies are recommended in this regard.

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Colchicine Reduces Lung Injury in Experimental Acute Respiratory Distress Syndrome

Cited by 10 publications

References 24 publications

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial

Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19

Sequential doxycycline and colchicine combination therapy in Covid-19: The salutary effects

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