nutrients

Systematic Review
Does Evidence Exist to Blunt Inflammatory Response by
Nutraceutical Supplementation during COVID-19 Pandemic?
An Overview of Systematic Reviews of Vitamin D, Vitamin C,
Melatonin, and Zinc
Salvatore Corrao 1,2, * , Raffaella Mallaci Bocchio 2 , Marika Lo Monaco 2 , Giuseppe Natoli 2 , Attilio Cavezzi 3 ,
Emidio Troiani 4 and Christiano Argano 2

1 Department of Health Promotion Sciences, Maternal and Infant Care, Internal Medicine and Medical
Specialties, [PROMISE], University of Palermo, 90127 Palermo, Italy
2 COVID Unit, Department of Internal Medicine, National Relevance and High Specialization Hospital Trust
ARNAS Civico, Di Cristina, Benfratelli, 90127 Palermo, Italy; [email protected] (R.M.B.);
[email protected] (M.L.M.); [email protected] (G.N.); [email protected] (C.A.)
3 Eurocenter Venalinfa, 63074 San Benedetto del Tronto, Italy; [email protected]
4 Cardiology Unit, State Hospital, Social Security Institute, 20, 47893 Cailungo, Republic of San Marino;
[email protected]
* Correspondence: [email protected] or [email protected]; Tel.: +39-340-590-7183





 Abstract: More than one year has passed since the first cases of coronavirus disease 2019 (COVID-19)
Citation: Corrao, S.; Mallaci Bocchio,
caused by severe acute respiratory syndrome (SARS)-CoV-2 coronavirus were reported in Wuhan
R.; Lo Monaco, M.; Natoli, G.; (China), rapidly evolving into a global pandemic. This infectious disease has become a major public
Cavezzi, A.; Troiani, E.; Argano, C. health challenge in the world. Unfortunately, to date, no specific antivirals have been proven to
Does Evidence Exist to Blunt be effective against COVID-19, and although a few vaccines are available, the mortality rate is not
Inflammatory Response by decreasing but is still increasing. One therapeutic strategy has been focused on infection prevention
Nutraceutical Supplementation and control measures. In this regard, the use of nutraceutical supports may play a role against
during COVID-19 Pandemic? An some aspect of the infection, particularly the inflammatory state and the immune system function
Overview of Systematic Reviews of of patients, thus representing a strategy to control the worst outcomes of this pandemic. For this
Vitamin D, Vitamin C, Melatonin, and
reason, we performed an overview including meta-analyses and systematic reviews to assess the
Zinc. Nutrients 2021, 13, 1261.
association among melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers
https://doi.org/10.3390/nu13041261
using three databases, namely, MEDLINE, PubMed Central and the Cochrane Library of Systematic
Reviews. According to the evidence available, an intake of 50,000 IU/month of vitamin D showed
Academic Editor: Rosa Casas
efficacy in CRP. An amount of 1 to 2 g per day of vitamin C demonstrated efficacy both in CRP
Received: 12 March 2021 and endothelial function, and a dosage of melatonin ranging from 5 to 25 mg /day showed good
Accepted: 6 April 2021 evidence of efficacy in CRP, TNF and IL6. A dose of 50 mg/day of elemental zinc supplementation
Published: 12 April 2021 showed positive results in CRP. Based on the data reported in this review, the public health system
could consider whether it is possible to supplement the current limited preventive measures through
Publisher’s Note: MDPI stays neutral targeted nutraceutical large-scale administration.
with regard to jurisdictional claims in
published maps and institutional affil- Keywords: COVID-19; SARS-CoV-2; overview; systematic review; vitamin D; vitamin C; melatonin;
iations. zinc; inflammation; nutraceuticals

Copyright: © 2021 by the authors. 1. Introduction

Licensee MDPI, Basel, Switzerland. The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has rapidly spread
This article is an open access article worldwide. The clinical spectrum of SARS-CoV-2 severity may range from asymptomatic
distributed under the terms and to severe conditions, including acute respiratory distress syndrome and sometimes leading
conditions of the Creative Commons
to multiorgan failure. For most people, a piece of important information is to know how to
Attribution (CC BY) license (https://
strengthen the immune system to prevent SARS-CoV-2 infection to avoid the next waves of
creativecommons.org/licenses/by/
the deadly COVID-19 pandemic [1]. It is well known that the presence of chronic diseases
4.0/).

Nutrients 2021, 13, 1261. https://doi.org/10.3390/nu13041261 https://www.mdpi.com/journal/nutrients

Nutrients 2021, 13, 1261 2 of 19

may exacerbate the inflammatory response induced by coronavirus disease, increasing the
risk of severe disease and mortality. In this respect, systemic inflammation developing
in people with non-communicable diseases, such as diabetes, tends to exacerbate the
respiratory symptoms of infection [2]. Additionally, obesity and central adiposity represent
important risk factors for complications of COVID-19, especially in patients with impaired
heart and lung function [3]. Furthermore, the vascular damage frequent in diabetic patients
and people with hypertension increases the risk of these individuals being affected by
COVID-19 thrombotic complications. The latest report issued by WHO mentioned more
than 96 million confirmed cases and more than two million deaths worldwide [4]. To
reduce the risk of transmission of SARS-CoV-2, several preventive measures have been
advised for general public health, including hand and respiratory hygiene and safe food
practices (concerning raw animal products) to reduce the risk of transmission of SARS-
CoV-2 [5]. The use of both a correct life-style and nutraceutical supports of proven efficacy
may play a role against some aspect of the infection, thus representing a strategy to control
this epidemic. In the current situation, it is urgent to propose preventive health measures
to reduce the risk of COVID-19 infection in addition to an adequate vaccine diffusion
and/or effective antiviral drugs. In the COVID-19 pandemic, the importance of adequate
nutrition and eating habits has been widely emphasized, not only to reduce the impact of
the widely diffused non-communicable diseases that may cause more severe infections (e.g.,
diabetes and obesity) but also as a way to regulate the inflammatory state of patients. In
fact, underestimating the importance of nutrition for COVID-19 patients will significantly
affect the prognosis of these subjects [6]. Vitamins C and D and trace elements, including
zinc [7], may play a fundamental role in disease susceptibility and maintaining immune
system function [8]. In fact, COVID-19 is characterized by high levels of inflammatory
markers, including C-reactive protein (CRP) and increased levels of inflammatory cytokines
and chemokines [9,10]. Any nutritional/nutraceutical approach potentially useful to
regulate immune function may consequently be beneficial both in the early phase, when an
adequate immune reaction is fundamental, and in case of later cytokine storm, when the
hyper-reactive immunity may be detrimental. This overview aims to analyze the current
knowledge from systematic reviews of the relationship between nutraceutical supports
and the reduction in inflammatory response to formulate clinical recommendations and
highlight directions for future research during the COVID-19 pandemic. The influence of
nutraceutical compounds on inflammatory markers will be addressed.

2. Materials and Methods

2.1. Eligibility Criteria
All meta-analyses and systematic reviews (SRs) regarding the association among
melatonin, vitamin C, vitamin D, zinc supplementation and inflammatory markers were
eligible for this overview.

2.2. Search Methods

On 22 September 2020, at 10:06 a.m. (GMT -5, Bethesta, MA, USA), a literature
search was performed, regarding MEDLINE, PubMed Central and the Cochrane Library of
Systematic Reviews (CLSR) and using the following search strings.

2.2.1. Melatonin
(“melatonin” [MeSH Terms] OR “melatonin” [All Fields] OR “melatonin s” [All Fields]
OR “melatonin” [All Fields] OR “melatonins” [ All Fields]) AND (“inflammatories” [All
Fields] OR “inflammatory” [All Fields] OR (“inflammation” [MeSH Terms] OR “inflam-
mation” [All Fields] OR “inflammations” [All Fields] OR “inflammation s “[All Fields])
OR” TNF “[All Fields] OR (“ interleukine “[All Fields] OR” interleukines “[All Fields] OR”
interleukins “[MeSH Terms] OR” interleukins “[All Fields] OR” interleukin “[All Fields])
OR (“ cytokin “[All Fields] OR” cytokine s “[All Fields] OR” cytokines “[MeSH Terms] OR”
Nutrients 2021, 13, 1261 3 of 19

cytokines “[All Fields] OR” cytokine “[All Fields] OR” cytokinic “[All Fields] OR” cytokins
“[All Fields])).

2.2.2. Vitamin C
(“ascorbic acid” [MeSH Terms] OR (“ascorbic” [All Fields] AND “acid” [All Fields])
OR “ascorbic acid” [All Fields] OR “ vitamin c “[All Fields] OR (“ ascorbate “[All Fields]
OR” ascorbates “[All Fields] OR” ascorbic “[All Fields]) OR (“ ascorbate “[All Fields] OR”
ascorbates “[All Fields] OR “ascorbic” [All Fields])) AND (“inflammation” [MeSH Terms]
OR “inflammation” [All Fields] OR “inflammations” [All Fields] OR “inflammation s” [All
Fields] OR (“inflammatories” [ All Fields] OR “inflammatory” [All Fields]) OR “TNF” [All
Fields] OR (“interleukine” [All Fields] OR “interleukines” [All Fields] OR “interleukins”
[MeSH Terms] OR “interleukins” [ All Fields] OR “interleukin” [All Fields]) OR (“cytokin”
[All Fields] OR “cytokine s” [All Fields] OR “cytokines” [MeSH Terms] OR “cytokines” [All
Fields] OR “cytokine” [All Fields] OR “cytokinic” [All Fields] OR “cytokins” [All Fields])).

2.2.3. Vitamin D
(“vitamin d” [MeSH Terms] OR “vitamin d” [All Fields] OR “ergocalciferols” [MeSH
Terms] OR “ergocalciferols” [All Fields] OR (“ergocalciferols “[MeSH Terms] OR” ergocal-
ciferols “[All Fields] OR” ergocalciferol “[All Fields]) OR (“ cholecalciferol “[MeSH Terms]
OR” cholecalciferol “[All Fields] OR” cholecalciferols “[All Fields] OR” colecalciferol “[All
Fields]) OR (“ calcitriol “[MeSH Terms] OR” calcitriol “[All Fields] OR” calcitriols “[All
Fields])) AND (“ inflammation “[MeSH Terms] OR” inflammation “[All Fields] OR “inflam-
mations” [All Fields] OR “inflammation s” [All Fields] OR (“inflammatories” [All Fields]
OR “inflammatory” [All Fields]) OR “TNF” [All Fields] OR (“interleukine” [All Fields]
OR “interleukines” [All Fields] OR “interleukins” [MeSH Terms] OR “interleukins” [All Fi
elds] OR “interleukin” [All Fields]) OR (“cytokin” [All Fields] OR “cytokine s” [All Fields]
OR “cytokines” [MeSH Terms] OR “cytokines” [All Fields] OR “cytokine” [ All Fields] OR
“cytokinic” [All Fields] OR “cytokins” [All Fields])).

2.2.4. Zinc
(“zinc” [MeSH Terms] OR “zinc” [All Fields]) AND (“inflammation” [MeSH Terms]
OR “inflammation” [All Fields] OR “inflammations” [All Fields] OR “inflammation s” [All
Fields] OR (“inflammatories” [All Fields] OR “inflammatory” [All Fields]) OR “TNF” [All
Fields] OR (“interleukine” [All Fields] OR “ interleukines “[All Fields] OR” interleukins
“[MeSH Terms] OR” interleukins “[All Fields] OR” interleukin “[All Fields]) OR (“ cytokin
“[All Fields] OR” cytokine s “[All Fields] OR “cytokines” [MeSH Terms] OR “cytokines”
[All Fields] OR “cytokine” [All Fields] OR “cytokinic” [All Fields] OR “cytokins” [All
Fields])).
Mesh terms were not used to search the CLSR.

2.3. Study Selection

Two reviewers (RMB and MLM) independently reviewed the titles, abstracts and
full texts for their potential inclusion against the eligibility criteria. Any disagreement
was resolved by discussion with a third reviewer (SC). In cases where information about
a study’s eligibility was limited or incomplete (for instance, when only an abstract was
accessible), the authors of the study were contacted to request the full text or further details.

2.4. Data Extraction, Coding and Analysis

Two authors (MBR and LMM) collected data from all included articles using a pre-
tested form and individuated duplicates, and prepared the flow-chart of excluded and
included studies (Figure 1). SC and CA independently verified the entire process.
 2.4. Data Extraction, Coding and Analysis
Two authors (MBR and LMM) collected data from all included articles using a pre-
Nutrients 2021, 13, 1261 4 of 19
tested form and individuated duplicates, and prepared the flow-chart of excluded and
included studies (Figure 1). SC and CA independently verified the entire process.

Figure
Figure 1. Flow
1. Flow diagram
diagram of theofstudy
the study selection
selection process.
process.

2.5.Quality
2.5. QualityAssessment
AssessmentofofIncluded
IncludedReviews
Reviews
Twoauthors
Two authors (RMB
(RMB andand
MLM)MLM) assessed
assessed the quality
the quality of theofincluded
the included systematic
systematic reviewsre-
byviews by A Measurement
A Measurement Tool to Checklist
Tool to Checklist Assess Systematic
Assess Systematic ReviewsReviews
(AMSTAR).(AMSTAR).
AMSTAR AM-
is
aSTAR is a comprehensive
comprehensive validated validated toolthe
tool to assess to assess the methodological
methodological quality of quality of SRs. It
SRs. It includes
11includes
domains,11 like
domains, like the
the a priori a priori
protocol protocol documentation,
documentation, scientific
scientific quality quality
and risk and risk
assessment
assessmentbias.
publication publication
Based on bias. Based on
AMSTAR AMSTAR evaluations,
evaluations, we ordered the we AMSTAR
ordered the AMSTAR
scores into
scores and
tertiles intoclassified
tertiles and
the classified the methodological
methodological quality of the quality of the single
single identified identified
reviews re-
in three
views in three
categories:
Nutrients 2021, 13, x FOR PEER REVIEW “high”categories: “high”
(8–11 points (8–11
out of 11), points out of(4–7
“moderate” 11),points)
“moderate” (4–7
and “low” points)
5 of(3 and
21or fewer
points
“low”(Figure 2). points (Figure 2).
(3 or fewer

Figure 2. A Measurement Tool to Checklist Assess Systematic Reviews (AMSTAR) assessment for
Figure 2. A Measurement Tool to Checklist Assess Systematic Reviews (AMSTAR) assessment for
each systematic review, sorted by year of publication. Colors are referred to scores: green is re-
each systematic
ferred review,
to “high scores” sorted
(8–11 by year
points) of publication.
and yellow Colors
to “moderate” (4–7are referred
points). No to scores: green
systematic reviewis referred
to “high
had scores”
a “low” (8–11 evaluation.
(<3 points) points) and yellow to “moderate” (4–7 points). No systematic review had a
“low” (<3 points) evaluation.
2.6. Dosage of Nutraceuticals
Data were extracted from each trial of the included systematic reviews/meta-anal-
yses, and they were tabulated according to the results of each trial. We did not tabulate
vitamin D dosage due to the great heterogeneity among trials.
Nutrients 2021, 13, 1261 5 of 19

2.6. Dosage of Nutraceuticals

Data were extracted from each trial of the included systematic reviews/meta-analyses,
and they were tabulated according to the results of each trial. We did not tabulate vitamin
D dosage due to the great heterogeneity among trials.

3. Results
No SR regarding the four compounds was of low quality.
The punctual evaluation is reported in the Supplementary Materials.
Regarding vitamin D (Table 1), several SRs were taken into consideration, and they
were heterogenous in different aspects: patient characteristics, type of treatment, end-points
and measured variables.
However, this heterogeneity enriched the final analysis. Nine SRs were included,
with a follow-up duration between 1,5 month and 3 years. The diabetic patients were
mostly represented, but different categories of patients were considered, including those
affected by HIV, obese, elderly or featuring a high cardiovascular risk. Six out of nine
SRs demonstrated a clear efficacy of CRP reduction. Only one SR showed a reduction in
interleukin-6 (IL6).
Table 2 shows the variable dosages used in each study, but an average of 50.000 units
of ergocalciferol monthly were administered to patients.
Regarding vitamin C (Table 3), four SRs showed an effective action on the endothelial
function and CRP reduction with an intervention duration between 1 day and 52 weeks.
The diabetic patients, subjects with chronic diseases and adult participants aged 18 years
and older were considered. Two out of four SRs proved to be effective in reducing CRP
levels. The other two SRs showed beneficial effects on endothelial function.
Nutrients 2021, 13, 1261 6 of 19

Table 1. Vitamin D: characteristics of the included systematic reviews.

Małgorzata
Omid Asbaghia Sheila A. FisherID (2019) Mingming Wanga Mohsen Mazidi EK Calton (2018) Tari Agbalalah Neng Chen (2014)
Study Yanting Yu (2018) [14] Jamka (2015)
(2019) [11] [12] (2019) [13] (2018) [15] [16] (2017) [17] [19]
[18]
PubMed,
PubMed-Medline,
PubMed, Scopus, ISI Central, Medline, ENBASE, PubMed, Cochrane, Scopus, the PubMed, Web of
Databases PubMed and the SCOPUS, Google SCOPUS and
Web of Science and PubMed and Web of EMBASE, and PubMed and Cochrane Science, and
searched Cochrane Library Scholar and Web of PubMed
Google Scholar Science Cochrane Library Medline Library and Cochrane library
Science
EMBASE
Articles included 8 8 14 13 24 9 29 13 10
Patients ≥ 60 years,
Patients with obesity, Patients with type
Healthy subjects and overweight and
type 2 diabetic, 2 and gestational Healthy subjects and
patients with obese, prediabetes,
HIV-infected, diabetes melli- patients with type 2
colorectal adenoma, non-alcoholic fatty
Patients with type1 non-diabetic chronic tus/prediabetic, diabetes, polycystic
type 2 diabetes liver disease, Obese and
Type of patients diabetes, Addison’s disease, Patients with Patients with type kidney disease cardiovascular ovary syndrome
mellitus, pregnancy, myocardial overweight
analyzed multiple sclerosis, asthma asthma 2 diabetes chronic fatigue disease, chronic women, obese
pregnancy with infarction, isolated subjects
and healthy subjects syndrome, kidney disease adults, coronary
gestational diabetes systolic
non-alcoholic fatty and artery disease
and polycystic ovary hypertension,
liver disease and overweight/obese patients
syndrome postmenopausal
healthy pregnant. participants
women.

• 500 mg/d Ca • 650 IU/day vit D

citrate + • 2000 IU/day vit D • 200 IU/day vit D
200 IU/day • 4000 IU/day vit D • 6.000 IU/day vit D
vit D • 14,000 IU/day vit D • 25.000 IU/day vit 1000 IU/day to
400 IU/day to 200 IU/day to 4000 IU/weeks vit 400 IU/day to
Posology • 1000 mg/d Ca • 4000 IU/monthly vit 500 UI/day vit D D 7000 IU/day vit
11200 IU/day vit D 11200 IU/day vit D D 7000 IU/day vit D
citrate + D • 50.000 IU/week vit D
50,000 IU/day • 140,000 IU/monthly D
vit D vit D

Intervention
6 weeks–3 years 3–12 months 1,5–12 months 8–52 weeks 4 weeks–12 months 12–52 weeks 8–52 weeks 4–52 weeks 9–48 weeks
duration range
Nutrients 2021, 13, 1261 7 of 19

Table 1. Cont.

Omid Asbaghia Sheila A. FisherID Mingming Wanga Yanting Yu (2018) Mohsen Mazidi EK Calton (2018) Tari Agbalalah Małgorzata Jamka Neng Chen (2014)
Study
(2019) [11] (2019) [12] (2019) [13] [14] (2018) [15] [16] (2017) [17] (2015) [18] [19]
The effect of vitamin
D supplementation The effect of
To examine whether
in enhancing To assess the The effects of supplementation To evaluate the
The effect of vitamin or not the To evaluate the effect Causal links
absolute T correlations of vitamin D with vitamin D on association of
D–calcium supplementation of of vitamin D between vitamin D
regulatory cells vitamin D status supplementation on selected vitamin D
Endpoint co-supplementation vitamin D exhibits supplementation on status [25(OH)D]
(Treg) numbers in with asthma- related endothelial function inflammatory supplementation
on inflammatory anti-inflammatory C-reactive protein and systemic
patients with respiratory and inflammation in biomarkers in with circulating
biomarkers in adults benefits in T2DM (CRP) inflammation
inflammatory or outcomes. adults overweight and hs-CRP levels.
subjects
autoimmune obese subjects.
disease.
A significant
Planned
reducing effect of
meta-analysis was Vitamin D
vitamin D–calcium Vitamin D
not possible due to Vitamin D Vitamin D supplementation
co-supplementation supplementation
the heterogeneous supplementation supplementation did significantly
on serum CRP was associated with There was no effect
nature of the studies. significantly not influence on decreased the
concentrations in a protective effect of on the weighted
Nevertheless, in a decreased the The results indicated CRP (std. mean circulating hs-CRP
comparison with exacerbation in mean difference
trial of autoimmune circulating hs-CRP that the vitamin D differences −0.11; level by 1.08 mg/L
placebo. No patients with (WMD) of IL-6
disorders which concentration supplementation 95% CI (95% CI, −2.13,
significant effect of vitamin D [(WMD (95% No significant
measured the (standard mean significant decreased −0.27–0.04; p = 0.15), −0.03), with the
joint calcium and insufficiency confidence interval) change in both
proportion of Tregs, differences, −0.45 the hs-CRP level by TNF-α (std. mean evidence of
Result supplementation (vitamin D < 30 = 0.1, (−0.166, 0.366) endothelial and
a significant [95% CI −0.77 to 0.45 µg/mL, differences −0.13; heterogeneity.
with vitamin D on ng/mL) (RR: 0.76 pg/mL, p = 0.462)] inflammatory
difference was −0.14], p = 0.005). whereas the vitamin 95% CI Subgroup analysis
serum 95%Cl (0.61–0.95)). It or C-reactive protein markers (p > 0.05).
reported, with a No significant effect D supplementation −0.38–0.12; p = 0.31) suggested a higher
concentrations of was also (CRP)
higher percentage of of vitamin D did not influence the and IL-6 reduction of
IL-6 (WMD: −1.45, demonstrated an [(WMD = −0.324,
Tregs observed in supplementation on TNF-α and IL-6. concentrations (std. 2.21 mg/L (95% CI,
95% CI: −5.31, improvement of (−1.007, 0.359)
the vitamin D group IL-6 and TNF-α mean differences 0.1; −3.50, −0.92) among
2.41 pg/mL, p = 0.46) their FEV1% (FEV1% mg/L, p = 0.352)].
(at 12 weeks, mean plasma 95% CI −0.43–0.63; participants with
and TNF-α (WMD: < 80%) (MD: 8.3
6.4% (SD 0.8%) concentration. p = 0.71). baseline hs-CRP
−0.79, 95% CI: 95%Cl (5.95–10.64).
(vitamin D) vs. 5.5% level ≥5 mg/L.
−2.19, 0.61 pg/mL,
(1.0%) (placebo).
p = 0.26).
Vitamin D Supplementation
Vitamin D–calcium supplementation with vitamin D does
In T2DM subjects,
co-supplementation may increase Vitamin D Vitamin D Available The use of vitamin D not have a
vitamin D
has beneficial effect Treg/CD3 ratios in supplementation supplementation high-quality RCTs supplementation as significant influence Vitamin D
supplementation is
on serum CRP both healthy reduced the rate of had no impact on did not support a a therapeutic or on changes in the supplementation is
beneficial for the
Conclusions * concentrations. A individuals and asthma exacerbation, serum CRP, IL10, beneficial effect of preventative concentration of beneficial for the
reduction in hs-CRP
beneficial effect was patients with especially in patients and TNF-α, while cholecalciferol on measure for CVD is selected reduction in
but does not have a
not seen for IL-6 and autoimmune with vitamin D significantly systemic IL-6 and not supported by inflammatory circulating hs-CRP.
significant influence
TNF-α disorders and may insufficiency. increased serum IL6. CRP. evidence. biomarkers in the
on TNF-α and IL-6.
concentrations. increase Treg obese and
function. overweight subjects.

* Author’s conclusions are reported.

Nutrients 2021, 13, 1261 8 of 19

Table 2. Vitamin D: summary of the principal characteristics of the included systematic reviews.

Pharmaceutical Drug Dose Follow-Up Efficacy Yes Efficacy No Study

Mohsen Mazidi
Paricalcitol 400 IU day 3 months CRP
(2018) [15]
Vitamin D1 e D2
Mohsen Mazidi
Ergocalciferol 50.000 IU/ month 12 weeks–6 months CRP
(2018) [15]
200–6.000 IU/day Yanting Yu (2018)
8–52 weeks CRP TNF-α e IL6
25.000–50.000 IU/week [14]
400 IU/day– CRP, IL10 e Mohsen Mazidi
4 weeks–12 months IL6
11,200 IU/day TNF-α (2018) [15]
Vitamin D3 Cholecalciferol FMD *, CRP, IL-6 Tari Agbalalah
4000 IU/week 8 weeks
e TNF-α (2017) [17]
Neng Chen (2014)
4000 IU/day 24 weeks hs-CRP **
[19]
Yanting Yu (2018)
≤4000 IU/day >12 weeks CRP TNF-α e IL6
[14]
* FMD = flow-mediated dilation (endothelial function parameters). ** hs-CRP = circulating high-sensitivity C-reactive protein.

Table 3. Vitamin C: characteristics of the included systematic reviews.

Maryam Safabakhsh Sedagh Jafamejad (2018) Ammar W. Ashor (2015) Ammar W. Ashor (2014)
Scheme 2019.
(2019) [20] [21] [22] [23]
PubMed, Scopus, ISI Web Scopus, Cochrane Library, MEDLINE, Embase, Medline, Embase,
Databases searched of Science e Google PubMed and Google Cochrane Library and Cochrane Library, and
Scholar Scholar Scopus Scopus
Articles included 11 12 46 44
Type of patients Diabetic Patients with chronic Adult participants >18
Adult participants
analyzed subjects/Nonsmokers diseases years
Posology 500 mg/day 250 mg/day–1 g/day 500–2000 mg/day 500 mg/day–1 g/day
Intervention duration
1 day–8 weeks 4–24 weeks 4–52 weeks 1 day–8 weeks
range
The effects of
The effects of antioxidant The effect of
The effect of vitamin C on supplementation with
vitamins C and E supplementation with
Endpoint reducing CRP or hs-CRP vitamin C on serum
supplementation on vitamin C on endothelial
level. C-reactive Protein (CRP)
endothelial function. function.
levels.
Significant improvements
Vitamin C could decrease
in endothelial function A beneficial effect of
CRP levels relative to
Supplementation with were observed in trials vitamin C on endothelial
placebo group
Results vitamin C significantly supplementing with function was found (SMD:
([WMD] = −0.73 mg/L:
lowered CRP among trials. vitamin C (500–2000 0.50, 95% CI: 0.34, 0.66,
95% CI: −1.30 to −0.15,
mg/d) (SMD: 0·25, 95% p < 0.001)
p = 0.013).
CI 0·02, 0·49, P 14 0·043)
Vitamin C
Vitamin C Supplementation with Supplementation with
supplementation might
Conclusions supplementation reduces vitamin C improves vitamin C improved
have a significant effect
serum CRP levels. endothelial function. endothelial function.
only on CRP reduction.

One or two grams of vitamin C per day resulted in the most applicable posology to
increase the efficacy of CRP reduction (Table 4).
Table 5 shows the characteristics of the included systematic reviews of melatonin. Two
SRs showed an effective action of this hormone in terms of reduction in IL-6, TNF-alpha
and CRP. The follow-up duration ranged between 4 months and 60 weeks. The two studies
considered subjects with chronic diseases and individuals affected by metabolic syndrome.
Nutrients 2021, 13, 1261 9 of 19

Table 4. Vitamin C: summary of the principal characteristics of the included systematic reviews.

Administration Dose Follow-Up Endpoint Efficacy Study

250 mg/day 8 weeks CPR Yes Biniaz 2014 [24]
Intravenous
300 mg/day 24 weeks CPR Yes Attallah 2006 [25]
1 g/day 10 days EF * Yes De Marchi 2012 [26]
1 g/day 4 days CRP Yes Colby 2011 [27]
Oral 1 g/day 4 weeks CRP Yes Modi 2014 [28]
Antoniades 2004 [29]
2 g/day 4 weeks EF * Yes
Tousoulis 2007 [30]
* Endothelial function (EF) measured by either forearm blood flow (FBF) or flow mediated dilation (FMD).

Table 5. Melatonin: characteristics of the included systematic reviews.

Zarezadeh M (2019) [31] Akbari M (2018) [32]

SCOPUS, PubMed, Cochrane Library, Cochrane Library, EMBASE, PubMed, and
Databases searched
Embase, Google Scholar Web of Science
Articles included 13 6
Type of patients analyzed Patients with chronic diseases Patients with metabolic syndrome
Posology 3 to 25 mg/day 6 to 10 mg/day
Intervention duration range From 4 to 60 weeks From 4 weeks to 14 months
To evaluate the effect of supplementation
To evaluate the effect of supplementation
with melatonin on inflammatory markers
Endpoint with melatonin on inflammatory biomarker
among subjects with MetS or related
levels
disorders.
Melatonin supplementation significantly
Melatonin supplementation significantly
decreased TNF-α and IL-6 levels
reduced C-reactive protein (SMD = −1.80;
[(WMD = −2.24 pg/mL; 95% CI −3.45,
95% CI −3.27, −0.32; p = 0.01; I2: 95.2) and
−1.03; p < 0.001; I2 = 96.7%, Pheterogeneity <
interleukin 6 (IL-6) concentrations
Results 0.001) and (WMD = −30.25 pg/mL; 95% CI
(SMD= −2.02; 95% CI −3.57, −0.47; p = 0.01;
−41.45, −19.06; p < 0.001, 2I = 99.0%;
I2: 91.2) among patients with MetS and
Pheterogeneity < 0.001)], respectively. The
related disorders; however, it did not affect
effect of melatonin on CRP levels was
TNF-α concentrations.
marginal.
Melatonin supplementation significantly
reduced TNF-α and IL-6 levels. The promising effect of melatonin
The supplementation with melatonin administration on reducing CRP and IL-6
Conclusions
improved the levels of TNF-α and IL-6 more among patients with metabolic syndrome
efficiently in studies, which were conducted and related disorders.
for ≥ 12 weeks and at a dosage ≥ 10 mg/day.

From the analysis of the included trials, a variety of employed dosages emerge
(Table 6); a daily dose from 5 to 25 mg daily has been reported, with similar efficacy.
Finally, we found only one SR of zinc supplementation summarizing 8 RCTs (Table 7).
The intervention duration ranged between 6 and 25 weeks. The hemodialysis patients were
considered.
Three RCTs had a positive effect on CRP reduction using 50 mg of elemental zinc daily
(Table 8).
Nutrients 2021, 13, 1261 10 of 19

Table 6. Melatonin: summary of the principal characteristics of the included systematic reviews.

Administration Dose Follow-Up Endpoint Efficacy Study

25 mg/day 26 weeks TNF and IL-6 Yes SanchezLopez A (2018) [33]
20 mg/day 12 weeks TNF Yes Lissoni P (1996) [34]
12 weeks Raygan et al. (2017) [35]
12 weeks CPR Yes Pakravan (2017) [36]
4 weeks Javanmard (2016) [37]
Oral 10 mg/day
26 weeks Forest CM (2007) [38]
60 weeks TNF and IL-6 Yes Celinski et al. (2014) [39]
4 weeks Cichoz-Lach et al. (2010) [40]
6 mg/day 6 weeks TNF and IL-6 Yes Mesri Alamdari (2015) [41]
5 mg/day 52 weeks CPR Yes Chojnacki C (2011) [42]

Table 7. Zinc: characteristics of the included systematic reviews.

Mousavi SM (2018) [43]

Databases searched PubMed, SCOPUS, and Google Scholar
Articles included 8
Type of patients analyzed Hemodialysis patients
Posology 50 mg/day
Intervention duration range 6–25 weeks
Effect of supplementation with zinc on plasma
Endpoint
CRP concentrations in adults
The results of the meta-analysis displayed a significant reduction in circulating CRP
Results levels (WMD: −1.68 mg/L; 95% CI: −2.4 to −0.9, p =< 0.001) following
supplementation with zinc.
Conclusions Supplementation with zinc markedly reduced plasma CRP concentration

Table 8. Dose finding according to single trial results for zinc.

Administration Dose Follow-Up Endpoint Efficacy Study

6 weeks Rashidi (2009) [44]
50 mg/day elemental zinc
Oral 8 weeks CPR Yes Tabrizi (2011) [45]
(220 mg zinc sulfate)
8 weeks Jamilian (2016) [46]

4. Discussion
Pathophysiological basis of nutraceutical supplementation during the COVID-19
pandemic.

4.1. Vitamin D
Recently, the use of cholecalciferol was proposed as a beneficial measure to reduce
the risk of COVID-19, in order to manage the pro-inflammatory milieu [47], and to reduce
virus-induced iron dysmetabolism [48]. Literature data show a scenario of a world epi-
demic of cholecalciferol deficiency [49], which reaches 80% in elderly people, who have
been shown to suffer from a higher COVID-19 mortality rate [50]. The intensity of the host
immune/inflammatory response has repercussions on the clinical severity and mortality
risk associated with viral diseases such as COVID-19, and this factor could be influenced
by vitamin D deficiency. Due to the low (20%) supply of cholecalciferol through dietary
consumption, the supplementation of this pro-hormone has been suggested as beneficial
Nutrients 2021, 13, 1261 11 of 19

in most chronic degenerative diseases. Specifically, active form calcitriol, a secosteroid

hormone, can exert immuno-modulatory/anti-inflammatory activities, playing a role in the
regulation of both innate and adaptive immunity; hence, in the COVID-19-related so-called
“Cytokine storm”, it is considered to be caused by the activation of the innate immune
system and with an excessively increased activation of the adaptive immunity [51,52]. With
regard to innate immunity, calcitriol can inhibit inflammatory T cell cytokines and Toll-like
receptors present on monocytes. Moreover, high doses of calcitriol supplementation result
in a significant reduction in IL-6 [53]. With regard to adaptive immunity, vitamin D also
reduces excessive proliferation and immunoglobulin production in B cells; furthermore,
it may suppress the differentiation of B cells into plasma cells [54]. Cholecalciferol can
reduce the risk of the common viral influenza enhancing the epithelium physical barrier
mechanism, as well as through the modulation of native and adaptive immunity [55]. In
addition, vitamin D is related to the preservation of adhesion junctions, tight and gap
junctions between epithelial cells, and their destruction represents the pathogenic mecha-
nism of viral upper respiratory tract infection [56,57]. Concerning COVID-19, it has been
hypothesized that the correction of vitamin deficiency suppresses CD26/DDP4, one of the
adhesion molecules through which the COVID-19 virus and COVID-MERS virus enter into
host cells [58–60]. Calcitriol could also directly affect SARS-CoV-2 infection through the
anti-microbial cathelicidin family of peptides, particularly LL-37 [18]. This peptide may
induce a viral membrane disruption via electrostatic interactions on the lipid envelopes
of viruses [18,19,61,62]. Cardiovascular thrombotic events have been associated with the
later stages of COVID-19, together with a high prevalence of pulmonary embolism, dis-
seminated intravascular coagulation, liver, myocardial and renal failure [63,64]. Calcitriol
was proven to exert some anticoagulant effects by upregulating the expression of anticoag-
ulant thrombomodulin and downregulating the expression of critical coagulation factor
in monocytes [65–67]. This virus-induced prothrombotic state is worsened in the case of
heme release in the blood stream, which results in an upregulation of NLRP3 inflamma-
some [68,69]. Finally, it can enhance the expression of antioxidant-related genes [26], and
increase the production of glutathione, thereby avoiding the use of ascorbic acid (vitamin
C), which results in an antimicrobial activity [70–72], reducing the production of free radi-
cals involved in inflammation which contribute to the pulmonary damage leading to the
development of acute respiratory distress syndrome (ARDS) [70]. Moreover, vitamin D
plays a crucial role in the reduction in proinflammatory cytokines, such as TNFα and IFNγ,
involved in the pathogenesis of ARDS through the stimulation of Th2 and inhibition of
Th1 [73–75]. Recently, a retrospective study has evaluated the clinical outcomes of 36 out of
91 COVID-19 patients receiving in-hospital high-dose cholecalciferol. During a follow-up
period of approximately two weeks, logistic regression statistical analysis indicated that
the positive effect of high-dose cholecalciferol on the combined endpoint was significantly
augmented with growing comorbidity burden [76]. Moreover, the intermediate form of
vitamin D Calcifediol was proposed as an additional treatment in COVID-19 patients, as
it could significantly reduce the need for ICU treatment [77]. A recent systematic review
and meta-analysis showed that low vitamin D serum levels were significantly associated
with a higher risk of COVID-19 infection [78]. Regarding the severity of the disease, an-
other systematic review highlights that subjects affected by severe COVID-19 present 65%
more vitamin D deficiency in comparison to individuals affected by mild COVID-19. In
addition, vitamin D deficiency was related to increased hospitalization and mortality from
COVID-19 [79].

4.2. Vitamin C
The biomedical literature supports the role of ascorbic acid (AA) (vitamin C) in immu-
nity regulation, anti-infective and anti-NLRP3 (namely, cytokine storm) activity [80–84]. In
fact, this essential compound intervenes in a number of fundamental biochemical pathways
of cell metabolism, including mitochondria functionality. These organelles undergo a high
degree of oxidative stress and mitophagy during COVID-19 degenerative processes [85].
Nutrients 2021, 13, 1261 12 of 19

Vitamin C was shown to prevent mitochondrial membrane depolarization and to combat

mitochondrial DNA oxidative stress and cell toxicity, thus regulating fission and fusion
processes [86,87]. Of interest, in the context of COVID-19-related hypoxia, AA interacts
with hemoglobin to maintain heme iron in ferrous state, which is the only form to bind oxy-
gen [88]. This exclusive beneficial activity on hemoglobin metabolism is best achieved by
combining the supplementation of oral (L-AA) and intravenous AA [48,89,90] Overall, clin-
ical data have previously highlighted a significant role for AA among patients in ICU, with
sepsis, pneumonia, multiorgan failure and ARDS [91]. Similarly, vitamin C immunomod-
ulatory, anti-viral and anti-inflammatory properties have been repeatedly demonstrated
in infective diseases [72,80,92,93]. The combination of these beneficial biochemical fea-
tures has led several centers to assess high-dose AA supplementation as a complementary
therapy in COVID-19 patients [91,94,95]. A few preliminary clinical studies on vitamin
C in critical COVID-19 patients have shown some improvements in the oxygenation and
interleukin-6 level, though a lower benefit for the mortality rate has been reported [96–98].
Conversely, a more pronounced effect of vitamin C in combination with quercetin and
bromelain seems to be effective, in terms of the prevention of COVID-19 infection in health-
workers [99]. Ongoing clinical trials will likely provide more evidence on the possible
efficacy of vitamin C in COVID-19 patients. A randomized clinical trial is analyzing the
efficacy and safety of high-dose vitamin C in combination with Chinese medicine in the
treatment of moderate and severe COVID-19 [100]. An uncontrolled longitudinal study is
attempting to evaluate the efficacy and safety of 10 g of vitamin C intravenously in addition
to conventional therapy in hospitalized patients with COVID-19 [101].

4.3. Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a multifunctional hormone which is
secreted mostly by the pineal gland and maximally at nighttime; [102] its secretion is ex-
tremely high in infants and adolescents, much lower in the elderly. Basically, this molecule
helps to regulate many other hormones and maintains the body’s circadian rhythm. Mela-
tonin is significantly involved in the complex network of psycho-neuroendocrine immunol-
ogy (PNEI), stress management and aging mechanisms [103]; furthermore, this compound
interacts with cortisol and with a series of immunity and inflammasome pathways, which
have been shown to derange in COVID-19 [104]. This molecule has been repeatedly con-
sidered a potentially useful compound in COVID-19 patients [48,105–107]. In fact, in these
cases, it may reduce the documented extremely high mitochondria oxidative stress, namely,
in lung cells [108], while conferring a general antioxidant action [42]. Melatonin was
also recognized as a relevant modulator of innate and adaptive immune reactions [109]
and specifically of the inflammasome NLRP3 [110,111], the latter being a hyperactivated
pathway in COVID-19 patients, contributing to the so-called “cytokine storm”. This inflam-
masome downregulation also results in a reduction in pulmonary hypertension, which
typically occurs in the critical stages during Sars-Cov-2 infection [112]. Lastly, melatonin is
known to interact with CD147, a favorite Sars-Cov-2 cell receptor which is diffused in cell
walls, erythrocyte and endothelium specifically. This specific feature has been regarded as a
protective mechanism against a few pathologic pathways which may occur during COVID-
19, such as hemoglobin denaturation, iron accumulation, hypoxia, cardiomyocytes injury
and hypercoagulability [104,106,113]. Very preliminary clinical data correlate the better
survival rate of COVID-19 intubated patients with melatonin exposure [114]; similarly, a
small randomized clinical trial has shown a statistically significant improvement in clinical
and instrumental findings in a group of patients treated additionally with melatonin, with
a more rapid hospital discharge and return to baseline health [115]. A deregulation of
tryptophan (precursor of melatonin) production has been demonstrated in COVID-19,
which led a few authors to postulate the need of a greater supplementation with this
hormone [116]. Of great interest, a recent multidrug repurposing study on 26,779 subjects
affected by COVID-19 elucidated that higher melatonin levels were significantly associ-
ated with a 28% and 52% reduced likelihood of a SARS-CoV-2 infection in the general
Nutrients 2021, 13, 1261 13 of 19

population and in African Americans, respectively [117]. The combination of the potential
and demonstrated beneficial activities of melatonin, which is currently being investigated
in a series of specific clinical trials, may pave the way to a greater employment of this
compound in this pandemic [118].

4.4. Zinc
The transition metal zinc (Zn), after iron, is the second most abundant trace metal in
the human body, and it is essential for multiple cellular functions, including the preser-
vation of immune health, playing a critical role in antiviral immunity. Zn also acts as an
anti-inflammatory agent and functions as an antioxidant, membrane stabilizer. Of interest,
Zn deficiency can lead to immunodeficiency and severe lymphopenia, which is caused
by a corresponding decrease in developing B cells in the bone marrow; furthermore, Zn
potentiates a type-I Interferon (IFN) effect. Marked neutrophilia is detected in severe
COVID-19 patients. Zn gluconate supplementation, inhibiting the NFkB-dependent tran-
scription of inflammatory genes, is able to reduce airway neutrophil infiltration and TNF-α
release. Zn supplementation may be able to reduce inflammatory cytokines (IL-6 and
IL-1β), enhancing the protective type-I IFN response in COVID-19 [119]. Zn inadequacy
and deficiency are predicted to affect about 30% of the world population, in particular
in the elderly; hence, the protective role of zinc supplementation against infection in the
elderly population has been proposed [120]. Zn-deficient individuals experience increased
susceptibility to pathogens, as well as some degree of ageusia and anosmia, emerging
symptoms in COVID-19 patients [121,122]. Interestingly, coronavirus RNA polymerase
activity appears to be inhibited by zinc [123], which could confer this metal a role in pre-
venting coronavirus entry into cells [124] and reducing coronavirus virulency [125]. To
date, scarce and contrasting clinical data on Zn supplementation efficacy on COVID-19
are available and particularly in the outpatient setting. A retrospective study including
141 individuals affected by COVID-19 in the general practice setting showed that zinc in
combination with low-dose hydroxychloroquine was associated with significantly fewer
hospitalizations [126]. On the contrary, in a recent randomized clinical trial of ambula-
tory COVID-19 patients, the administration of high-dose zinc gluconate or zinc gluconate
combined with ascorbic acid did not significantly reduce the durability of symptoms in
comparison with standard of care as well as hospitalizations and deaths [127].

4.5. Evidence
Regarding vitamin D, our review highlights a wide range of SRs, with different
dosages and in different populations. The follow-up was between 1.5 months and 3 years.
Different groups of patients were considered, including patients affected by diabetes, HIV,
obese, elderly or featuring a high cardiovascular risk. Considering that different dosages
of vitamin D (Table 2) showed a similar efficacy in CRP, the intake of 50,000 IU/month
seems to be the proper dosage in terms of advantage and efficacy; moreover, this dose
is in agreement both with the suggested dosage to reduce inflammatory activation and
with the recommendations that advise not to exceed 4000 IU/day, chronically. Regarding
vitamin C, our review identified four high-quality SRs. The intervention duration ranged
from 1 day to 52 weeks Different categories of patients were considered, including diabetic
patients, subjects with chronic diseases and adult participants aged 18 years and older. The
analysis of each single trial (Table 4) suggests that the effective dose is between 1 to 2 g per
day both for CRP and endothelial function. Due to the impracticability of the intravenous
administration within the community medicine policy, oral intake is recommended. With
reference to melatonin, our review highlighted two SRs, both of high quality at AMSTAR
evaluation. The follow-up duration ranged from 4 months to 60 weeks. The two studies
considered subjects with chronic diseases and metabolic syndrome.
Melatonin seems to show good evidence of efficacy regarding the reduction in CRP,
TNF and IL6, with a dosage ranging from 5 to 25 mg/day (Table 7). However, the proper
daily dose should be tailored to the age and clinical conditions of the patent, in order
Nutrients 2021, 13, 1261 14 of 19

to avoid possible adverse effects, such as drowsiness. Literature data on zinc show a
lower strength of evidence, in comparison to the other compounds. We found only one
SR with an intervention duration between 6 and 25 weeks. The hemodialysis patients
were included. The analysis of this single study (Table 8) showed positive results in CRP.
A dosage of 50 mg/day of elemental zinc supplementation was proposed to achieve an
adequate efficacy.

5. Conclusions
According to the selected systematic reviews, vitamin C, vitamin D, melatonin and
zinc nutraceuticals have anti-inflammatory actions. Hence, their large-scale utilization
seems to represent a useful and viable approach during the COVID-19 pandemic. Adequate
doses should be employed, following the most referenced literature data. Of importance,
since no specific drug or other therapeutic or preventive measure has proven to be beneficial
against the progression of COVID-19, this nutraceutical approach could have a role within
a community-based medicine. However, it is to be highlighted that, to date, no systematic
review has demonstrated a specific preventive effectiveness of these compounds in COVID-
19, and many clinical trials are ongoing. In view of this missing evidence, further research is
necessary and desirable to obtain more data on the employment of these natural molecules
as a prevention and/or treatment in the COVID-19 pandemic. Other future clinical trials
should be designed to assess the clinical benefits of each nutraceutical and/or of the
combination of two or more of them. Nevertheless, it might be more useful to implement a
therapeutic supplementation campaign for measuring the effects on the global population.
Observational studies (a design before–after study or cluster quasi-experimental study),
primarily focusing on outcomes such as hospital rates and mortality, would be useful to
preliminarily assess the efficacy of these compounds. Overall, the possible support of the
national health systems would be instrumental to guarantee an adequate provision of these
nutraceuticals to the population. On the basis of the reported data in this review, public
health systems, and subsequently the World Health Organization, could somehow take into
account the possibility to complement current limited preventative measures/interventions
with targeted nutraceutical large-scale administration.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/nu13041261/s1, Assessment of each systematic review by the AMSTAR tool.
Author Contributions: Conceptualization, S.C. and C.A.; methodology, S.C., G.N. and C.A.; software,
G.N.; validation, S.C. and C.A.; formal analysis, R.M.B. and M.L.M.; investigation, R.M.B., M.L.M. and
C.A.; resources, R.M.B. and M.L.M.; data curation, G.N., R.M.B. and M.L.M.; writing—original draft
preparation, C.A.; writing—review and editing, S.C., A.C. and E.T.; visualization, G.N.; supervision,
S.C.; project administration, C.A. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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