Efficacy of short-course colchicine treatment in hospitalized patients with moderate to severe COVID-19 pneumonia and hyperinflammation: a randomized clinical trial

To our knowledge, this is the first study evaluating the clinical efficacy of colchicine in hospitalized patients with COVID-19 pneumonia and established hyperinflammation. In this randomized trial, adding colchicine to standard background therapy was not associated with a lower risk of CPAP/BiPAP use, ICU admission, need for invasive ventilation, or death.

When the study was designed, COVID-19 patients had poorer clinical outcomes early in the pandemic because steroids and heparins had not yet been included in standard treatment protocols. Nevertheless, most of the patients included in our trial received steroids and heparins, potentially explaining, at least in part, a lower than expected rate of the observed primary clinical endpoint. For this reason, the main analysis might have been underpowered. Moreover, the optimal dosage of colchicine in COVID-19 patients is still undefined. Remarkably, the proposed dose of colchicine was safe in our population with moderate to severe COVID-19 pneumonia.

The interaction of SARS-CoV-2 with macrophages promotes inflammasome assembly of protein nod-like receptor 3 (NLRP3), a pro-inflammatory complex that results in the release of several cytokines, including IL- 1β and IL-6. These pro-inflammatory cytokines induce neutrophil activation and infiltration in infected tissues which, in excess, worsen the clinical condition. Considering that colchicine was shown to inhibit NLRP3 inflammasome and neutrophil activation, it was considered a valid candidate as a potential treatment for COVID-1918.19. Two randomized clinical studies have previously suggested a beneficial effect of colchicine in hospitalized patients with COVID-19, recruiting only 72 and 105 patients, respectively. Specifically, Lopes et al. observed a reduction in the duration of hospitalization, while Deftereos et al. documented significant improvement in time to clinical deterioration in participants receiving colchicine11.20. However, the results remained uncertain because both trials had small sample sizes and low event rates. In contrast, the colchicine arm of the RECOVERY trial, a large randomized clinical trial, found no clinical benefit. Additionally, colchicine showed no beneficial effect on the need for mechanical ventilation or on 28-day mortality in a recent randomized clinical trial including 1279 patients hospitalized with COVID-19 pneumonia.21. Nevertheless, none of these previous studies focused on patients with COVID-19 pneumonia and established hyperinflammation, a subset of patients of particular interest to assess the effect of colchicine.

In the pre-specified subgroup analysis, overweight patients in the colchicine group showed a statistically significant lower prevalence of CPAP/BiPAP use, ICU admission, invasive ventilation, or death. Interestingly, in the scenario of SARS-CoV-2 infection, overweight and obesity are associated with a higher risk of hospitalization22 and progression to severe COVID23. However, since the RECOVERY and ECLA PHRI COLCOVID trials did not collect information on BMI12.21, this is the first clinical trial analyzing the effect of colchicine on overweight patients. Remarkably, excess macronutrients in adipose tissue predispose to releases of inflammatory mediators that participate in the cytokine storm aggravating COVID-192. Additionally, colchicine has previously been shown to significantly improve inflammatory markers in obese patients without significant medical disease.24. For all these reasons, overweight patients with COVID-19 pneumonia and established hyperinflammation might particularly benefit from colchicine treatment. In a post-hoc analysis, we found no difference in background treatment of overweight patients during hospitalization, including tocilizumab. On the other hand, the proposed dose and duration of colchine treatment might be insufficient to observe beneficial effects in obese patients. Thus, although attractive from a pathophysiological point of view, particular attention should be paid to the interpretation of this subgroup given its limited size. Therefore, the results should only be considered as hypothesis-generating and would require confirmation in further studies.

Colchicine had no beneficial effect on myocardial damage as measured by day 5 troponin release. However, given the stabilizing effect of colchicine on atherosclerotic plaques5.9, coronary patients would theoretically be the subgroup of patients most sensitive to colchicine. Given that coronary artery disease was present in only 6.7% of patients in the study, our cohort may not be appropriate to rule out a potentially protective role of colchicine on myocardial injury associated with COVID-19.

Our study has several limitations. As noted, the event rate was lower than expected, reducing the power of the primary analysis. Additionally, the absence of a placebo may introduce a performance bias that cannot be ruled out. However, this was partially mitigated by blinding of outcome assessment by an independent external clinical events committee. Despite the short-term colchicine treatment, a longer biological effect was expected because the half-life of the drug is approximately 60 h in leukocytes. Despite using a masked randomization scheme, which is a common method to mitigate allocation biases in baseline characteristics, our study showed differences between groups in terms of ferritin and d-dimer levels. during randomization. These differences in inflammatory markers could explain the higher rate of tocilizumab administration in the colchicine group during the hospital stay.

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