The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused well over 2.3 million deaths in a little over a year. A new preprint appearing on the medRxiv* server reports the potential utility of colchicine in treating SARS-CoV-2 infection and forestalling severe and life-threatening inflammation of the lungs and other organs.
Inflammation and mortality in COVID-19
Few, if any, fully effective therapies have been identified in this period to alleviate the intense and unregulated systemic inflammatory storm that occurs in a significant minority of COVID-19 patients. This hyperinflammatory process causes damage in the lungs, often leading to fatal multiorgan damage and/or acute respiratory distress syndrome (ARDS).
The antiviral drug remdesivir, and the glucocorticoid dexamethasone, have been used in many of these cases with some success, along with supplemental oxygen and mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
Emergency use authorization has also been granted by the US Food and Drug Administration (FDA) for therapeutic monoclonal antibodies, and for convalescent plasma. The former is approved for use in early disease, prior to severe COVID-19, in the presence of high-risk factors.
The current paper discusses the use of colchicine, an established immunomodulatory drug used in gout, rheumatic disease, and pericarditis. It is known to suppress neutrophil movement towards the site of inflammation in response to chemokines, as well as neutrophil activity at sites of vascular injury. Colchicine is also an inhibitor of inflammasome signaling and of active IL-1β production.
Earlier studies have shown mixed results for the beneficial effects of colchicine on COVID-19-related death or hospitalization. The most recent is the COLCORONA trial, a randomized controlled trial (RCT) involving almost 4,500 patients who were not hospitalized at the time of enrollment. The researchers found that the odds of death or hospitalization were reduced by 25%.
The current paper reports the results of a systematic review and meta-analysis of the use of this drug in COVID-19. It includes three RCTs and three observational retrospective studies. Five of them were reports of the effects of colchicine on patients not admitted to the intensive care unit (ICU), but the remaining one was based on ICU patients. Again, five examined the use of colchicine after hospitalization with COVID-19, and one examined its use after diagnosis but before hospitalization.
Across all six studies, including 5,000 patients, mortality was reduced by 75%, with the odds being reduced by 64%, in colchicine users. In the study on non-hospitalized patients, the odds were 44% lower.
For hospitalized non-ICU patients, the mortality odds were 75% lower, and the risk of death was reduced by 85%. In contrast, the risk was 60% lower in hospitalized ICU patients.
Pooling the observational studies, the risk of mortality was reduced by 75% and the odds by 80%. However, the RCTs failed to show a significant difference in mortality, though they did demonstrate a trend towards a beneficial effect with the use of colchicine.
ICU admission and mechanical ventilation
There was no observed difference in the rate of ICU admissions among patients with and without colchicine use. Nor was there a significant reduction in the risk of mechanical ventilation among the two groups.
What are the implications?
This first systematic review and meta-analysis show that while RCTs fail to show benefit from colchicine use, observational cohort studies indicate a lower risk of mortality with the use of this anti-inflammatory drug.
With observational studies, the relative risk ratios (RRRs), adjusted for known confounding factors, must be included for valid comparisons to be made. This is because the distribution of such factors cannot be assumed to be uniform in both cohorts, unlike RCTs.
The current analysis includes only RCTs and observational studies with adjusted RRRs, thus excluding many sources of bias. The researchers also analyzed mortality relative to study design, time of hospitalization, and ICU admission.
Further studies may reveal differential benefits for non-hospitalized and hospitalized patients, who are at different stages of the disease. Only one of these studies examined colchicine use in the former group. This showed that there was a reduction in both death and hospitalization.
A closer look at this study shows that this was largely because COVID-19 patients were not hospitalized as often, and not because the number of deaths in this group went down. In fact, both the colchicine and the placebo groups showed a very low number of deaths, at 5/2075 vs 9/2084, respectively.
However, the use of colchicine is still associated with a large reduction in the number of hospitalizations, which is a significant benefit. Among hospitalized (ICU and non-ICU) patients, too, the risk of death was lower in the colchicine group, relative to those not placed on colchicine.
Colchicine is a safe and well-tolerated drug, with a low cost, and thus offers the potential for a highly cost-effective intervention if used more generally in COVID-19 patients before hospitalization. However, the researchers point out the need for larger studies to examine the effects of this drug on COVID-19 outcomes, depending on the time of initiation.
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.