Review Protocol: Impact of Nano-Curcumin on Inflammatory markers and

clinical outcomes in COVID-19 Patients: A Systematic Review and Meta-

analysis.

Review Question:
In patients diagnosed with COVID-19, what is the effect of nano-curcumin
administration, compared to placebo or standard care, on clinical outcomes such as clinical
improvement, inflammatory marker levels, hospitalization duration, and mortality rates?
Search Strategy:
A comprehensive search was performed in May 2025 on following electronic
databases: PubMed, Embase, Scopus and Cochrane Library. Additional clinical trials were
searched on Clinical trials.gov.
We used following Medical Subject Headings terms (MESH) and keywords:

("nano-curcumin" OR "nanocurcumin" OR "curcumin nanoparticles" OR "cucumin nano

micelles") AND ("COVID-19" OR "SARS-CoV-2" OR "coronavirus") AND ("clinical trial"
OR "efficacy" OR "inflammatory markers" OR "hospitalization" OR "mortality")

No restrictions regarding race, place, sex, ethnicity, language, or dates were applied.
A manual search of relevant publications and their references will be conducted to identify
potential articles.

Eligibility Criteria

Population:

 Included
Patients of any age and sex with a laboratory-confirmed diagnosis of COVID-19 as
defined by standard diagnostic criteria at the time of study.
 Excluded
Studies involving animal models, in vitro experiments, or patients without laboratory-
confirmed COVID-19 diagnosis.

Intervention
  Included
Administration of Nano-Curcumin in any form and formulation
 Excluded
Studies using in combination with such investigational agents where the effect of
nano-curcumin cannot be isolated.

Comparison

 Included
Studies comparing nano-curcumin against placebo, standard care, or no treatment.
 Excluded
Studies comparing nano-curcumin with other experimental treatments (e.g.,
remdesivir, hydroxychloroquine) unless placebo/standard care is also included as a
control group.

Outcomes

 Included
Studies reporting on at least one of the following clinical outcomes:
– Clinical improvement or recovery
– Changes in inflammatory biomarkers (e.g., CRP, IL-6, TNF-α)
– Duration of hospitalization
– All-cause mortality
 Excluded
Studies that do not report on any of the predefined clinical outcomes

Study Design

 Included
– Randomized Controlled Trials (RCTs) plus observational studies if predefined
outcomes are present.

– Full-text or translation available in English

For trials which have a crossover design, only data from the first randomization
period will be considered due to concerns over carryover effects.
  Excluded
_ Case reports, reviews, commentaries, letter to editors, preprints, or unpublished data
– Conference abstracts without full data

Condition or Domain Being Studied:

The coronavirus pandemic of 2019 (COVID-19) is one of the most significant global
health challenges in recent history. Since its emergence in late 2019, it has caused more than
778 million confirmed cases and almost 7 million deaths around the world [1,2]. While the
global vaccination efforts and antiviral measures have mitigated much of the early
devastation, the burden is still considerable: from April to May 2025, over 150,000 new cases
and 1,100 deaths were reported worldwide within a 28-day period [1,2].

Beyond its acute respiratory manifestations, severe COVID-19 is strongly associated

with immune dysregulation marked by a cytokine storm, a hyper-inflammatory state
characterized by excessive release of pro-inflammatory cytokines such as IL-6 and TNF-α.
This uncontrolled immune response can precipitate acute respiratory distress syndrome
(ARDS), multi-organ failure, poor clinical outcomes, prolonged hospitalization, and
increased mortality [3,4].

Considering the pivotal role of inflammation in the pathogenesis of the disease, anti-
inflammatory approaches have been widely studied. Curcumin, a polyphenolic compound
obtained from Curcuma longa, has been shown to have excellent anti-inflammatory and
antioxidant actions. Nanoformulated curcumin has been developed to overcome its poor
bioavailability, and early clinical trials suggest it may improve clinical outcomes in COVID-
19 patients [5]. However, results remain varied, and the effectiveness and safety of this
treatment must be assessed by a rigorous synthesis of all studies available.

References:

1. World Health Organization. COVID-19 Cases, World. WHO Coronavirus (COVID-

19) Dashboard [Internet]. [cited on 2025 June 4]. Available from:
https://data.who.int/dashboards/covid19/cases
 2. World Health Organization. COVID-19 deaths. WHO COVID-19 dashboard
[Internet]. [cited 2025 Jun 4]. Available from:
https://data.who.int/dashboards/covid19/deaths
3. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ. COVID-19:
consider cytokine storm syndromes and immunosuppression. The Lancet [Internet].
2020 Mar 1;395(10229):1033–4. Available from: https://doi.org/10.1016/s0140-
6736(20)30628-0
4. Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science
[Internet]. 2020 Apr 17;368(6490):473–4. Available from:
https://doi.org/10.1126/science.abb8925
5. Ahmadi S, Mehrabi Z, Zare M, Ghadir S, Masoumi SJ. Efficacy of Nanocurcumin as
an Add-On Treatment for Patients Hospitalized with COVID-19: A Double-Blind,
Randomized Clinical Trial. International Journal of Clinical Practice [Internet]. 2023
Jul 28;2023:1–7. Available from: https://doi.org/10.1155/2023/5734675

Screening and Data extraction:

Only peer-reviewed papers with no deadline for publication will be included. Two

reviewers will independently go through titles and abstracts of retrieved articles to screen

articles against predetermined eligibility criteria. This will be followed by full-text screening

of included articles. If a trial is described in more than one publication, only the study with

the most comprehensive data will be listed. Finally, the same two reviewers will cross-check

the selected outcomes. A third reviewer will arbitrate the final judgement if there are any

disputes during the process. Reviewers will get in touch with the associated author to request

any missing or unclear data to be supplemented or clarified. Subsequently, the accuracy of

these data will be cross-checked by the same two reviewers. Any differences of opinion will

be settled by consensus or by having a third reviewer make a decision.

Two authors will independently collect data in an electronic database pertaining to the

inclusion and exclusion criteria of each study, the demographics of the patients, the
predefined outcomes, details on the methodology of the study and any other relevant

information included in the study.

Measures of effect:

For continuous outcomes, the impact size will be the standardized mean difference,
represented by Cohen's d; for dichotomous outcomes, the effect size will be the risk ratio,
along with the appropriate 95% confidence intervals. Response and remission rates will be
considered for efficacy.

Risk of Bias and Meta-Bias Assessment

The risk of bias will be independently assessed by two reviewers for all included
studies. For randomized controlled trials (RCTs), the Cochrane Risk of Bias 2 (RoB 2) tool
will be applied, evaluating domains such as randomization process, deviations from intended
interventions, missing outcome data, measurement of the outcome, and selection of the
reported result. For non-randomized (observational) studies, the ROBINS-I (Risk Of Bias In
Non-randomized Studies - of Interventions) tool will be used. This assesses risk of bias
across seven domains: confounding, selection of participants, classification of interventions,
deviations from intended interventions, missing data, measurement of outcomes, and
selection of the reported result.

Conflicts shall be settled by discussion first, followed by arbitration with the advice of a third
author.

To assess potential meta-bias, particularly publication bias, funnel plots will be

generated if ≥10 studies are included in a meta-analysis. Egger’s regression test will be
performed to statistically assess small-study effects.

Strategy for data synthesis:

Statistical heterogeneity will be assessed using Higgins' I² statistic. I² values of <25%,

25–50%, and >50% will be interpreted as low, moderate, and high heterogeneity,
respectively. If substantial heterogeneity is detected (I² >50%) and justified by clinical or
methodological differences among studies, a random-effects model will be used. Otherwise, a
fixed-effect model will be considered appropriate. Review Manager (RevMan) Version 5.4.
The Cochrane Collaboration, 2020 will be used to compile and statistically analyze the
effectiveness data. The relative risk with 95% confidence intervals (CIs) will be used to
calculate dichotomous data, and the weighted mean difference (WMD) or standardized mean
difference (SMD) with 95% confidence intervals will be used to evaluate continuous data.
Forest plots of summary effect sizes will be used to present main findings. For all statistical
analyses, a two-sided p < 0.05 will be considered statistically significant.

If we judge that the included studies are too clinically heterogeneous to warrant a
formal meta-analysis, we will not perform a meta-analysis but instead present the results of
the included trials in a narrative format.

Analysis of subgroups or subsets:

Sensitivity and sub-group analysis will be carried out to find out sources of heterogeneity. If
the required data are available, subgroup analysis based on various control group types and
different comparators might be done, or sensitivity analysis will be done by doing reanalysis
by excluding studies having high risk of biases and without imputing data for missing
participants.

Contact details for further information:

Ahmad Ali Hussain –

Email: [email protected]

Organisational affiliation of the review:

Allama Iqbal medical college, Lahore, Pakistan

Department of Medicine, Jinnah Hospital Lahore, Pakistan

Review team members and their organisational affiliations:

1. Ahmad Ali Hussain, Allama Iqbal Medical College, lahore, Pakistan

2. Rameez Qasim, Allama Iqbal Medical College, lahore, Pakistan
3. Dr Bakhtawar Haseeb, Department of Medicine, Jinnah Hospital Lahore, Pakistan
4. Ali Hassan, Allama Iqbal Medical College, lahore, Pakistan
5. Ali Azlan, Allama Iqbal Medical College, Lahore, Pakistan
6. Sarosh Bushra, Al Aleem medical college, Lahore, Pakistan
7. Emad ul Islam Khan, Allama Iqbal Medical College, Lahore, Pakistan
 8. Anzil Adnan, Allama Iqbal medical college, Lahore, Pakistan
9. Faseeh Fatima, Allama Iqbal medical college, Lahore, Pakistan
10. Abdul Wasay, Allama Iqbal medical college, Lahore, Pakistan

Type and method of review:

Intervention, Systematic review, Meta-analysis

Anticipated or actual start date: 25 May 2025

Anticipated completion date: 5 July 2025

Funding sources/sponsors: None

Conflicts of interest: None known

Language: English

Country: Pakistan

Subject index terms:

COVID-19; SARS-CoV-2; Curcumin; Nanocurcumin

Stage of review at time of this submission:

Stage Started Completed

Preliminary searches Yes Yes

Piloting of the study selection process Yes Yes

Formal screening of search results Yes No

against eligibility criteria

Data extraction No No

Risk of bias (quality) assessment No No

Data analysis No No