Benefits of Nanocurcumin on Mortality in Patients with COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background:

The Coronavirus disease-2019 (COVID-19) pandemic continues, and the death toll continues to surge. This systematic review and meta-analysis aimed to determine the efficacy of nanocurcumin on mortality in patients with COVID-19.

Methods:

A systematic search was performed in PubMed, Embase, Cochrane Library, and clinicaltrials.gov up to November 2024, without language restrictions. Inclusion criteria: (1) inclusion of hospitalized patients with COVID-19 who are 18 years or older; (2) polymerase chain reaction positive for severe acute respiratory syndrome coronavirus-2; and (3) use of a randomized controlled design to make a comparison of nanocurcumin with placebo. The Cochrane risk-of-bias tool for randomized trials was used to assess the risk of bias. Studies were pooled to risk ratios (RRs) and standardized mean differences (SMDs), with 95% confidence intervals (CIs).

Results:

Six trials (enrolling 333 participants) met the inclusion criteria. Nanocurcumin therapy showed significant improvements on mortality (RR 0.47, 95% CI 0.25–0.88; p = 0.02), interleukin-6 (IL-6) (SMD −0.30, 95% CI −0.56 to −0.04; p = 0.02), tumor necrosis factor-α (TNF-α) (SMD −0.63, 95% CI −1.16 to −0.10; p = 0.02), and IL-1β (SMD −0.88, 95% CI −1.37 to −0.39; p = 0.0004).

Conclusions:

Nanocurcumin significantly reduced mortality, IL-6, TNF-α, and IL-1β in hospitalized patients with COVID-19. Given the lack of safety data and concerns about the risk of bias, the use of nanocurcumin in COVID-19 requires further research.

Keywords

mortality nanocurcumin COVID-19 meta-analysis

Introduction

The Coronavirus disease-2019 (COVID-19) pandemic is the worst pandemic in more than 100 years, causing numerous infections and deaths worldwide.¹ Despite the use of multiple drugs with different mechanisms, mortality from COVID-19 remains high, especially in older adults.² The mortality rate increases significantly with age, even up to 30% in patients aged 85 years or older.² Therefore, there is an urgent need for treatments, pharmacological or otherwise, that can reduce mortality. Curcumin is believed to possess a variety of therapeutic properties, including antiproliferative, antibacterial, antiviral, and anti-inflammatory activities, as well as the ability to modulate different signaling pathways.^3,4 The ability of curcumin to modulate numerous molecular targets involved in the process of viral infection in many organs (e.g., liver, cardiovascular system, and kidneys) makes it a possible option for the treatment of COVID-19.⁵ Compared with curcumin, nanocurcumin has enhanced biological and pharmacological capabilities, higher bioavailability, and its manufacturing method addresses the limitations of crude curcumin.^6,7

Several randomized controlled trials (RCTs) have assessed the effects of nanocurcumin in hospitalized patients with COVID-19, and their results differed. The aim of the present study, therefore, was to perform a systematic review and meta-analysis of RCTs in order to determine the efficacy of nanocurcumin on mortality in patients with COVID-19.

Methods

Data sources and search strategy

This systematic review and meta-analysis were based on the preferred reporting items for systematic reviews and meta-analyses statement.⁸ The protocol was previously registered in January 2024 in the PROSPERO database (Review register: CRD42024507300). The PubMed, Embase, Cochrane Library, and clinicaltrials.gov were searched for studies up to November 29, 2024.

Study selection

To be eligible for inclusion in the meta-analysis, studies had to meet the following criteria: (1) inclusion of hospitalized patients with COVID-19 who were 18 years or older; (2) polymerase chain reaction positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); and (3) use of a randomized controlled design to make a comparison of nanocurcumin with placebo. The search strings used for the databases were (“COVID-19” OR “SARS-CoV-2” OR “SARS-CoV-19” OR “novel coronavirus 2019” OR “novel coronavirus pneumonia”) AND (“nanocurcumin” OR “nano-curcumin”). The reference lists of any relevant review articles were also screened to identify studies that might have been missed in this search. No language restrictions were applied to our study selection process. The full search strategies for all databases are provided in Supplementary Table S1.

Data extraction and quality assessment

Two reviewers (W.S. and G.W.) independently screened articles according to the inclusion criteria. The reviewers (W.S. and G.W.) compared selected studies, and differences were resolved by involving a third reviewer (D.H.). Data tables were used to collect all relevant data from texts, tables, and figures of each included trial, including author, year of publication or last update posted, patient number and age, treatment category, and outcomes such as mortality, interleukin (IL)-6, tumor necrosis factor-α (TNF)-α, and IL-1β.

Risk of bias of included trials

Two reviewers (W.S. and G.W.) independently assessed the risk of bias using the Cochrane collaboration risk of bias tool for RCTs.^9,10 Five domains of bias (i.e., randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results) were evaluated and reported.

Outcomes

The primary outcome of this meta-analysis was mortality. Secondary outcomes were the change of IL-6, TNF-α, and IL-1β.

Data synthesis and statistical analysis

Meta-analyses were conducted where applicable; otherwise, outcomes were presented in narrative form. Data were analyzed using the RevMan Version 5.4.1 (The Cochrane Collaboration, 2020). Next, risk ratios (RRs) for discontinuous outcomes and standardized mean differences (SMDs) for continuous outcomes due to heterogeneity in measurement units, with corresponding 95% confidence intervals (CIs), were computed for individual trials. Chi-squared and Higgins I² tests were used to assess heterogeneity among included trials. We used a random-effects model. And a p-value <0.05 was taken to indicate statistical significance. The p-value of Egger’s linear regression test^11–13 (STATA version 12.0) was used to assess the presence of publication bias in included studies for each outcome.

Results

Study selection and characteristics

Of 58 trials recognized by the initial search, 18 were retrieved for more detailed assessment, and 6 trials^14–19 (5 in Iran, 1 in Iraq) were included in this meta-analysis (Fig. 1). Baseline characteristics of trials included in this meta-analysis are shown in Table 1. A total of 333 patients were included: 168 assigned to the nanocurcumin treatment group and 165 to the control group. The risk of bias results are summarized in Figure 2.

FIG. 1.

Flowchart for selection of studies.

FIG. 2.

Assessment on risk of bias for included RCTs. RCTs, randomized controlled trials.

Table 1.

Baseline Characteristics of Trials Included in Meta-Analysis

Study(Ref. #)	Year	Country	Standard treatment	Regimen/day	n	Age, years (SD)	Male, %	Diabetes, %	Hypertension, %	Fever, %	Cough, %	Dyspnea, %
Abbaspour-Aghdam et al.¹⁴	2022	Iran	Atorvastatin, bromhexine, azithromycin, protease inhibitors, corticosteroids	160mg d1–21	30	52.7 (8.6)	70	3.3	6.6	90	60	27
Abbaspour-Aghdam et al.¹⁴	2022	Iran		Placebo	30	52.4 (7.6)	76.6	6.6	3.3	97	67	23
Asadirad et al.¹⁵	2022	Iran	Lopinavir/ritonavir, interferon-β1a	240 mg d1–7	30	56 (14)	80	NR	NR	73	57	30
Asadirad et al.¹⁵	2022	Iran	Lopinavir/ritonavir, interferon-β1a	Placebo	30	50 (12)	80	NR	NR	80	40	27
Mohammad¹⁶	2023	Iraq	Dexamethasone, remdesivir	320 mg d1–21	27	51 (12)	59	22	NR	NR	NR	NR
Mohammad¹⁶	2023	Iraq	Dexamethasone, remdesivir	Placebo	24	47 (14)	54	33	NR	NR	NR	NR
Sadeghizadeh et al.¹⁷	2023	Iran	Hydroxychloroquine, sofosbuvir	140 mg d1–14	21	53 (19–72)*	62	15	19	90	71	48
Sadeghizadeh et al.¹⁷	2023	Iran	Hydroxychloroquine, sofosbuvir	Placebo	21	54 (18–83)*	71	18	24	86	57	38
Tahmasebi et al.¹⁸	2021	Iran	Atorvastatin, bromhexine	320 mg d1–21	40	54 (9)	60	NR	NR	53	55	33
Tahmasebi et al.¹⁸	2021	Iran	Atorvastatin, bromhexine	Placebo	40	54 (9)	60	NR	NR	58	55	33
Valizadeh et al.¹⁹	2020	Iran	Betaferon, bromhexine, atorvastatin	160 mg d1–14	20	53 (8)	75	10	5	95	60	25
Valizadeh et al.¹⁹	2020	Iran	Betaferon, bromhexine, atorvastatin	Placebo	20	51 (8)	80	5	5	100	55	20

*Values are median and interquartile range.

NR, not reported; SD, standard deviation.

Mortality

Data on mortality were available from four RCTs (231 patients). Compared with the control conditions, the mortality was significantly lower in the nanocurcumin groups (RR 0.47, 95% CI 0.25–0.88; p = 0.02 [Fig. 3]), with a rate of 10.26% versus 23.68%. There was no significant heterogeneity (I² = 0%; p = 0.53). Egger’s test (p = 0.252) did not show evidence of publication bias.

FIG. 3.

Forest plot assessing the efficacy of nanocurcumin on mortality.

IL-6

Data on the change of IL-6 were available from five trials (235 patients). Compared with the control conditions, nanocurcumin treatment significantly reduced the serum level of IL-6 (SMD −0.30, 95% CI −0.56 to −0.04; p = 0.02 [Fig. 4A]). There was no significant heterogeneity (I² = 0%; p = 0.84). Egger’s test (p = 0.655) did not show evidence of publication bias.

FIG. 4.

Forest plot assessing the efficacy of nanocurcumin on (A) IL-6, (B) TNF-α, and (C) IL-1β. IL, interleukin; TNF, tumor necrosis factor.

TNF-α

The change of TNF-α was evaluated in four randomized studies (193 patients). Compared with the control conditions, nanocurcumin treatment significantly decreased the serum level of TNF-α (SMD −0.63, 95% CI −1.16 to −0.10; p = 0.02 [Fig. 4B]). There was significant heterogeneity (I² = 69%; p = 0.02). Egger’s test (p = 0.409) did not show evidence of publication bias.

IL-1β

Data on the change of IL-1β were available from four RCTs (193 patients). Compared with the control conditions, the use of nanocurcumin significantly reduced the serum level of IL-1β (SMD −0.88, 95% CI −1.37 to −0.39; p = 0.0004 [Fig. 4C]). There was significant heterogeneity (I² = 62%; p = 0.05). Egger’s test (p = 0.248) did not show evidence of publication bias.

Discussion

To our knowledge, this meta-analysis is the first designed specifically to evaluate the efficacy of nanocurcumin therapy on mortality in patients with COVID-19. Based on the present results, we observed that nanocurcumin significantly reduced mortality, IL-6, TNF-α, and IL-1β.

COVID-19 is caused by SARS-CoV-2 and has caused a global pandemic. Although most patients have mild symptoms, further development of acute respiratory distress syndrome (ARDS) has been reported in approximately 20% of hospitalized patients with a more severe clinical presentation.²⁰ The main causes of COVID-19-related deaths are respiratory failure, excessive inflammation, cytokine storm, or multiple organ failure.²¹ Therefore, there is an urgent need for safe, effective, and accessible treatment to stop disease progression and shorten hospital stays, thereby reducing mortality.

Curcumin is an antiviral agent that fights a wide range of viruses, including herpes simplex virus, hepatitis C virus, human papillomavirus, human immunodeficiency virus, and respiratory influenza virus, through multiple molecular mechanisms.²² Among the multiple effects of curcumin, inhibition of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is mainly associated with its therapeutic effect.²³ Curcumin may exert its anti-inflammatory effects in COVID-19 mainly through the inhibition of NF-κB signaling and subsequent molecular cascades.⁵ Curcumin has immunomodulatory, anti-inflammatory, antifibrotic, and protective effects on lung tissues and is therefore promising for the treatment of COVID-19, especially in the inflammatory phase.²⁴ Expression of pro-inflammatory cytokines IL-1, IL-6, and TNF-α is mainly associated with COVID-19-related cytokine storm, ARDS, organ damage, and pulmonary fibrosis.^4,25 The inhibitory effect of curcumin on these inflammatory cytokines is associated with NF-κB inhibition.²⁶ Curcumin has been confirmed as a “generally recognized as safe” compound by the Food and Drug Administration,²⁷ and it is stated not to have any toxic effect.²⁸ The adequate daily intake value of curcumin is 0–3 mg/kg. It has been shown that an intake of curcumin up to 12 g per day has no harmful effects on healthy individuals.²⁹ Potential adverse effects have been documented and include diarrhea, headache, rash, and yellow stool,²⁹ but no serious adverse effects have been reported to date.

One limitation of using curcumin as a therapeutic agent is its poor bioavailability. It is poorly absorbed, undergoes rapid metabolism, and is subsequently eliminated from the body quickly.³⁰ Several formulations have been developed to enhance its bioavailability. For instance, the combination of curcumin with piperine, the main active ingredient in black pepper, has been associated with a 2000% increase in curcumin bioavailability.³¹ Nano-formulations of curcumin improve its solubility in aqueous solutions³² and enhance its concentration in the blood.³³ A previous RCT showed that short-term (7-day) curcumin–piperine supplementation significantly decreased serum aspartate aminotransferase and C-reactive protein (CRP) levels and increased hemoglobin levels in patients with COVID-19 admitted to the ICU.³⁴ However, another RCT showed that 14-day cosupplementation of curcumin and piperine failed to reduce liver enzymes, blood glucose levels, kidney function parameters, and CRP in COVID-19 outpatients.³⁵ In addition to efficacy, nanocurcumin has demonstrated favorable safety and tolerability in RCTs.^36,37

This study met most of the methodological criteria recommended for systematic reviews and meta-analyses.³⁸ However, some limitations need to be considered when interpreting the results of this study. First, some included trials had small sample sizes, which may have reduced the power of the results. Second, potential differences in treatment regimens between the two groups may have an impact on the prognosis. Third, the dose of nanocurcumin varied between studies. Fourth, data on adverse events were missing in the included studies. Finally, this meta-analysis was not patient-level, so the results should be considered provisional.

Conclusions

Treatment with nanocurcumin reduced mortality, IL-6, TNF-α, and IL-1β in hospitalized patients with COVID-19. Given the lack of safety data and concerns about the risk of bias, the use of nanocurcumin in COVID-19 requires further research.

Authors’ Contributions

All authors, led by D.H., were involved in the concept and protocol design of the meta-analysis. W.S. and G.W. screened the titles and abstracts and extracted data from the articles. W.S. was primarily responsible for statistical analyses. G.W. was primarily involved in the interpretation of the quality data. All authors contributed to interpreting the results. W.S. and D.H. accessed and verified the data. All authors contributed to the writing of the article and approved its submission. D.H. was responsible for the decision to submit the article.

Footnotes

Author Disclosure Statement

None of the authors has a conflict of interest to declare.

Funding Information

This research was supported by The Key Research and Development Projects of Shaanxi Province (Grant No. 2023-YBSF-064). The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the article, or in the decision to publish the results.

Availability of Data and Materials

Extracted data are available on request to the corresponding author.

Supplemental Material

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