The effect of curcumin on the risk of mortality in patients with COVID‐19: A systematic review and meta‐analysis of randomized trials

The coronavirus disease 2019 (COVID-19) pandemic is far from bygone, with the emergence of newer variations of concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While the worldwide vaccine rollout has progressed at a breakneck pace, the hunt for new safe, effective, and targeted treatments should continue in parallel due to the frequent occurrence of breakthrough cases. Curcumin is one such natural polyphenolic compound with multiple benefits, including antiviral, anti-inflammatory, anticoagulant, antiplatelet, and cytoprotective, which have been demonstrated to be advantageous in reducing the progression of several inflammatory illnesses (Rattis, Ramos, & Celes, 2021). The aforementioned effects have made curcumin one of the potential treatment options for patients with COVID-19. Since the pathophysiology of COVID-19 is known to involve life-threatening inflammatory reactions, cytokine storms, and coagulopathy, curcumin can be advantageous due to its antiinflammatory effects via the inhibition of inflammasome formation (Yin et al., 2018). In addition, curcumin also demonstrates antiviral effects via its ability to bind to the viral primary protease (Mpro) enzyme of SARS-CoV-2, which is required for viral replication. Curcumin also prevents viral attachment and passage into the host cell with great potency (Dourado et al., 2021). The ability of curcumin in inhibiting the virus-receptor interaction is in two ways, according to modeling studies: it inhibits both the spike protein and the ACE2 receptor (Manoharan et al., 2020). Previously in this journal, the findings of the randomized trial reported by Hassaniazad et al. (2021) suggest that curcumin can accelerate the recovery of acute inflammatory phase in patients with COVID-19 by modulating inflammatory immune responses. Nevertheless, the mortality benefits of curcumin in patients with COVID-19 were not investigated in the aforementioned trial. Several controlled trials have been performed to validate the mortality benefits of curcumin in patients with COVID-19, and we aimed to summarize their overall efficacy in terms of mortality reduction in a systematic review and meta-analysis. A systematic literature search with no language restriction was performed in multiple electronic databases, including PubMed, Cochrane Central Register of Controlled Trials, Google Scholar, Scopus, and preprint servers (medRxiv, Research Square, SSRN) to identify eligible studies published from inception to January 20, 2022. Two investigators (CSK and DSR) independently performed the literature screening to identify eligible studies. We adopted the following search strategy: (curcumin OR curcuma OR diferuloylmethane OR turmeric) AND (COVID-19 OR SARS-CoV-2 OR coronavirus). In addition, the reference lists of relevant articles were also reviewed to search for additional studies. Studies eligible for inclusion were randomized controlled trials that compared the mortality outcomes between the use and nonuse of curcumin (at any dose and in any dosage form) in patients with COVID-19. We excluded single-arm trials, randomized trials that did not report mortality outcomes, and randomized trials with zero mortality events in the intervention and control arms. The outcome of interest was all-cause mortality. Each included study was independently evaluated by two investigators (CSK and DSR), who also extracted the study characteristics. Study characteristics extracted included the first author's surname, year of publication, study design, the country where the trial was performed, mean/ median age of patients, the regimen of curcumin, the regimen of comparative agents, number of deaths in the intervention arm, and number of deaths in the control arm. Two investigators (CSK and SSH) assessed the risk of bias of the randomized trials included with Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2), which is a standardized method for assessing potential bias in reports of randomized interventions (Sterne et al., 2019). RoB 2 is structured into a fixed set of domains of bias, which includes “randomization”, “deviations from intervention”, “missing outcome data”, “measurement of the outcome”, and ‘selection of the reported results. A proposed judgement about the risk of bias arising from each domain is generated by an algorithm, where judgment can be “Low” or “High” risk of bias or express ‘Some concerns’. A random-effects model was used to estimate the pooled odds ratio for all-cause mortality with the use of curcumin relative to nonuse of curcumin, at 95% confidence intervals. We examined the heterogeneity between studies using the I statistics and the χ test, with 50% and significance at p < . 10, respectively, indicating substantial heterogeneity. All analyses were performed using Meta XL, version 5.3 (EpiGear International, Queensland, Australia). Our literature search yielded 764 records. After deduplication and application of the eligibility criteria, five relevant articles were shortlisted for inclusion through full-text examination. Of these, two studies were excluded since they reported no mortality events. Eventually, three randomized trials (Pawar et al., 2021; Tahmasebi et al., 2021; Valizadeh et al., 2020) were included for this meta-analysis, with a total of 260 patients with COVID-19. Details of the included trials are depicted in Table 1. Received: 4 February 2022 Revised: 27 March 2022 Accepted: 30 March 2022