Against the sheer scale of morbidity and death due to the ongoing coronavirus disease 2019 (COVID-19) pandemic, the urgency of identifying drugs and other measures that reduce these adverse outcomes is enormous.
A new study – involving an international team of researchers from Canada, the U.S. and Brazil – describes the results of colchicine in mitigating the inflammatory storm associated with COVID-19, illustrating the drug's potential for preventing a percentage of severe and critical cases.
The team has released their findings on the medRxiv* preprint server.
The role of inflammation in COVID-19
Evidence is building up that the so-called “cytokine storm” is key in triggering severe or critical COVID-19 disease by the associated severe and systemic inflammatory damage caused by high levels of circulating cytokines on multiple organs. Drugs that prevent or regulate inflammation could thus be helpful in reducing the risk of poor outcomes in this condition.
One such drug is the corticosteroid dexamethasone, which has been found to reduce mortality in COVID-19 patients on mechanical ventilation or supplemental oxygen. Another is tocilizumab, the IL-6 receptor antagonist, which seems to effectively reduce the chances of requiring mechanical ventilation in patients hospitalized for COVID-19 pneumonia.
The mechanism of severe inflammation may be via the viral activation of the NLRP3 inflammasome, an intracellular complex of inflammatory mediators. The resulting activation of multiple interleukins leads to a cascade of inflammation. Indeed, high IL-6 levels are a marker of poor outcome in COVID-19.
The ideal anti-inflammatory in this setting would be one that is readily available, cheap and orally administered, with a good safety profile, well-tolerated, and that prevents or modulates inflammasome activation. The researchers selected colchicine for their study.
Colchicine is a powerful anti-inflammatory agent used to treat gout, coronary disease, viral pericarditis and familial Mediterranean fever. It has been found to act by preventing the polymerization of the protein called tubulin, thus inhibiting inflammasome activation, proinflammatory chemokines, and cellular adhesion molecules.
In an earlier experiment, colchicine was found to prevent the activation and recruitment of leukocytes, and thus reduce inflammatory lung injury, and respiratory failure, in acute respiratory distress syndrome (ARDS).
In the current trial, called the COLchicine CORONAvirus SARS-CoV-2 (COLCORONA) trial, the researchers studied almost 4,500 non-hospitalized patients with COVID-19 who were randomly assigned to either colchicine or placebo for 30 days. All were 40 years or above, and had one or more high-risk features such as fever, diabetes, coronary heart disease, obesity, known respiratory disease, or a high neutrophil count accompanied by a low lymphocyte count. All had been diagnosed by one of three methods: polymerase chain reaction testing on a nasopharyngeal swab, close contact with a positive family member along with suspicious symptoms, or by a clinical algorithm if symptoms were present without other obvious cause.
Patients with kidney, neuromuscular, liver or inflammatory bowel disease were not eligible, along with those who had cancer or were already on colchicine.
The primary outcome they analyzed was the composite outcome of death or hospitalization following COVID-19.
The researchers found that 4.7% of the patients in the colchicine group died or were hospitalized, versus 5.8% in the placebo group. The odds of either outcome were therefore 21% lower in the group on colchicine. The odds of death were 44% lower, and for hospitalization 21% lower. The odds of requiring mechanical ventilation were 47% lower. None of these odds were statistically significant.
Of the total group, 4,100 patients or so had been diagnosed by PCR testing. This subgroup showed a significant reduction in the odds of hospitalization or death by 25%, as well as for hospitalization alone by 25%. The odds for death showed a trend towards reduction by 44%. The need for mechanical ventilation also showed a trend towards lower odds in the colchicine group, by 50%.
Overall, serious adverse events were lower in frequency in the colchicine group versus the placebo group, at 5% and 5%, respectively. The rates of adverse events related to the use of colchicine and placebo were 24% and around 16%, respectively. Serious gastrointestinal adverse events occurred at least once in almost a quarter and 15% of treatment and control group patients, respectively. Diarrhea was reported in 14% in the colchicine group, double that of the controls.
What are the implications?
The study thus shows a tendency towards lower rates of death and hospitalization due to COVID-19 within 30 days of initiating colchicine. The subgroup within which the diagnosis was made on the basis of PCR showed a statistically significant reduction in the primary endpoint. Treatment with colchicine reduced hospitalizations as well.
Colchicine was associated with a statistically insignificant reduction in the number of deaths and a strong trend towards lower requirement for mechanical ventilation in this subgroup. In men, and in diabetic patients, there was a strong trend towards a 40% reduction in combined deaths and hospitalizations. This may have been caused by the higher rate of disease-related events in these groups.
The study suggests that “among non-hospitalized patients with confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospitalization than placebo.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.