The hallmark of Covid-19 is a hyperinflammatory response characterised by raised inflammatory markers (C-reactive protein, ferritin and D-dimers) and inflammatory cytokines and increased neutrophil-to-lymphocyte ratio. And, if this inflammatory response continues unabated, it can even be life-threatening. Hence, controlling this inflammatory response is key to improving prognosis.

Hospitalized covid-19 patients have a more aggressive inflammatory response than patients being treated at home. The cytokine storm has been majorly implicated in severity of disease resulting in acute respiratory distress (ARDS), pulmonary edema and multi-organ failure. Early intervention with an anti-inflammatory drug to suppress this inflammatory response, particularly in non-hospitalized patients, may prevent lung damage by controlling the cytokine storm thereby reducing the need for hospital admission. 

This hypothesis has been corroborated earlier by the STOIC trial published in April in The Lancet Respiratory Medicine, which showed that early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19. The results of recently published COLCORONA trial further support this premise. 

Colchicine has been explored as a potential treatment for Covid-19 because of its anti-inflammatory effects.

The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, which tested a range of potential treatments for COVID-19 has stopped recruiting patients for its colchicine arm due to lack of evidence about its beneficial effect. However, the GRECCO-19 randomized clinical trial done at 16 hospitals in Greece did show a significant clinical benefit with colchicine treatment in hospitalized patients with confirmed COVID-19. A significant improvement in time to clinical deterioration was observed in these patients (JAMA Netw Open. 2020;3(6):e2013136). Colchicine beneficial effects in moderate to severe Covid-19 patients were also evident in another study from the University of Sao Paulo in Brazil (RMD Open. 2021 Feb;7(1):e001455).

The COLCORONA trial is a randomized, double-blind, placebo-controlled, multicenter trial, which investigated the effect of colchicine on outcomes in Covid-19 non-hospitalized patients in terms of death or hospital admission. These patients had been diagnosed either by PCR testing or on the basis of clinical criteria. Patients were randomized to either oral colchicine (0·5 mg twice daily x 3 days and then once daily x for 27 days) or placebo.

The trial showed mixed results. The trial failed to show any advantage of colchicine in reducing reduce deaths or hospital admissions in patients who were undergoing home treatment for Covid-19 diagnosed on the basis of symptoms. But, in patients with RT PCR-confirmed COVID-19, a significant reduction in death or hospital admission was seen with colchicine as compared to placebo. Hospitalizations reduced by 25%, need for mechanical ventilation decreased by 50% and deaths by 44%.

The placebo group also reported a higher incidence of serious adverse events vs colchicine group (6.3% vs 4.9%) including pneumonia (4.1% vs 2.9%). 

Fewer pneumonia cases with colchicine suggest that colchicine was able to limit the progress of lung damage by preventing the cytokine storm associated with Covid-19, due to its anti-inflammatory activity, which also correlated with the fewer hospital admissions with colchicine.

Clark D Russell writes in an editorial published in The Lancet Respiratory Medicine this week, “COLCORONA supports the belief that there is a “window of opportunity” to intervene so as to derail the inflammatory trajectory of this disease, which has proved so lethal. These results also demonstrate that prevention of the inflammatory storm with colchicine can affect the evolution of COVID-19 disease leading to hospital admission.” 

Oral colchicine therefore can be a safe and inexpensive treatment option for Covid-19 outpatients who are at risk of developing complications. Initiating colchicine treatment right after the RT PCR confirmation of diagnosis of Covid-19 offers an opportunity to prevent the disease from becoming severe and even fatal. 

Sources

1. Exploiting an early immunological window of opportunity in COVID-19. Lancet Respir Med 2021. Published Online May 27, 2021.
2. Tardiff JC, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. The Lancet Respiratory Medicine, Published May 27, 2021.

Dr Shashank Joshi,

Member, COVID-19 Maharashtra State Task Force