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Review
Immunomodulatory role and
potential utility of various
nutrients and dietary components
in SARS-CoV-2infection
Muhammad Osama Yaseen
1
, Humzah Jamshaid
1,2
, Arifa Saif
1
, and Talib Hussain
1
1
Institute of Pharmaceutical Sciences, University of Veterinary & Animal Sciences, Lahore, Pakistan
2
Department of Pharmacy, Quaid-e-Azam University, Islamabad, Pakistan
Abstract: Recently, the outbreak of severe acute respiratory syndrome cornoavirus-2 (SARS-CoV-2), causing coronavirus disease 2019
(COVID-19), has become a great perturbation all around the globe and has many devastating effects on every aspect of life. Apart from the oxygen
therapy and extracorporeal membrane oxygenation, Remdesivir and Dexamethasone have been proven to be efficacious against COVID-19, along
with various vaccine candidates and monoclonal antibody cocktail therapy for Regeneron. All of these are currently at different stages of clinical
trials. People with weak immunity are more prone to a severe infection of SARS-CoV-2. Therefore, early and judicious nutritional supplementation
along with pharmacological treatment and clinician collaborations are critical in restituting the current situation. Nutritional supplements help in
acquiring strong immunity to prevent the progression of disease any further. Vitamin C, vitamin D, selenium, zinc and many other nutritional and
dietary supplements inhibit the production of inflammatory cytokines during a viral infection and prevents several unwanted symptoms of
infection. Many dietary components like citrus fruits, black elderberry, ginger, and probiotics have the ability to attack viral replication. These
supplements can also tame the overriding immune system during coronavirus infection. Keeping in view these facts, nutritional and dietary
supplements can be used along with other management modalities. These nutritional and dietary supplements are potential candidates to curb
the convulsive unfolding of novel COVID-19, in combination with other standard treatment protocols. In this review, various search engines were
used to exploit available literature in order to provide a comprehensive review on nutritional and dietary supplements with respect to the viral
infections. It will also provide a brief overview on some of the clinical trials that are in progress to assess the role of nutritional supplements,
either alone or in combination with other pharmacological drugs, in fight against COVID-19.
Keywords: Coronavirus, natural nutrients, mortal disease, immunity booster, health
Introduction
Taxonomically, coronaviruses are the member of the ortho-
coronavirinae sub-family, which is in the family of Coron-
aviridae and order Nidovirales. This sub-family includes
the genus alpha-coronavirus, beta-coronavirus, gamma-
coronavirus and delta-coronavirus [1]. These viruses previ-
ously caused zoonotic infections in mammals but the
outbreaks of Middle East respiratory syndrome-related
coronavirus (MERS-CoV) and severe acute respiratory syn-
drome-associated coronavirus (SARS-CoV) had shown the
lethal tendencies of these viruses, specifically when they
trespass a specie barrier from other mammals to humans.
Key features of all these viruses are the supremacy of noso-
comial transmissions and pathogenesis that is steered by
the amalgamation of virus replication in respiratory tract
and an atypical host immune response [2].
Recently, a beta-coronavirus named severe acute respira-
tory syndrome cornoavirus-2(SARS-CoV-2) is emerging as
a new zoonotic agent, causing coronavirus disease 2019
(COVID-19). This virus initially originated in China but
now it has become a great perturbation all around the globe
[3]. SARS-CoV-2is following the trajectories of SARS-CoV
and MERS-CoV with more devastating effects on every
aspect of life [4]. The incubation period of SARS-CoV-2is
approximately 5.2days, while the mortality phase after
the completion of incubation period ranges from 6to 41
days depending on the immunity of a specific individual
[5–7].
Viral infection initially triggers innate immunity, the
effectiveness of which depends upon the production and
downstream signaling of interferons. Interferon-1(IFN-1)
inhibits the replication of virus and activates the adaptive
immune response. Like other coronaviruses, envelop
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protein of SARS-CoV-2inhibits the synthesis and signaling
of interferons and lymphocytes. Chronic infection results in
cytokine-storm and exhaustion of T-cells, specifically CD8
+ cells, thus weaken the overall defense mechanism of the
human body. T-cell exhaustion cause overexpression of
inhibitory receptors which upon binding to ligand, cause
significant suppression of immune system by affecting
T-cells, B-cells and natural killer (NK) cells. There is also
a strong relation between the relevant subset of lympho-
cytes and inflammatory markers like C-reactive protein
(CRP), erythrocyte sedimentation rate (ESR), interleukin-
6(IL-6). Lymphopenia is also a major observation in
patients with severe COVID-19 [8,9]. Immunocompro-
mised patients or patients with comorbidities, are at
increased risk of having severe symptoms of COVID-19,
and studies have shown increased morbidity and mortality
of such patients due to SARS-CoV-2infection [10]. The
most prevailing symptoms after the onset of COVID-19 ill-
ness include cough, fatigue and fever, while some other
symptoms are lymphopenia, hemoptysis, dyspnea, diar-
rhea, headache and sputum production [11]. Several reports
claimed that person-to-person contact is the major trans-
mission route in the spread of this virus. It is believed to
be spreading mainly by direct contact either with the
infected person or with emitted droplets, primarily through
sneezing or coughing from an infected individual [12].
SARS-CoV-2induces a two-phase immune response. The
first phase of non-severe incubation stage requires a respon-
sive immune system to exterminate the virus and prevent its
progression to a second severe phase. However, if such an
adaptive immune barrier is impaired then the virus will
proceed to a massive destructive phase, damaging tis-
sues and organs that is predominantly mediated by pro-
inflammatory granulocytes and macrophages [13]. Since
January 2020, it is still in the propagating phase and infect-
ing every class of humanity. Some case reports and random-
ized controlled trials have already been published in various
internationally reputed journals, citing reports on different
coping strategies worldwide. To date, Remdesivir and Dex-
amethasone has shown considerably promising response in
critically ill COVID-19 patients but none of these treatment
options have proven to be the ultimate answer for current
situation [14]. Several anti-COVID-19 neutralizing mono-
clonal antibodies, due to their concrete proof-of-concept,
have also been traversing through myriad clinical trials.
Among them, the most promising candidates are
REGN10933 and REGN10987 antibody cocktail, experi-
encing Phase-I and II multicentered clinical trials with esti-
mated enrollment of 2000 individuals [15,16]. Currently,
several leading vaccine candidates including Pfizer-
BioNTech (mRNA vaccine), Moderna (mRNA vaccine),
Oxford-AstraZeneca and CanSino (both are non-replicating
viral vector-based vaccines) have also shown promising,
efficacious and safe results in phase-II and III randomized
trials. These candidates have attained emergency used
authorization by FDA in several countries across the globe
[17]. Hopefully, at the end of year 2021, the availability of
potential vaccination candidate is obvious.
Therefore, the motivation behind this extensive review is
to exploit the available literature using different search
engines including PubMed, Google Scholar and Web of
Science to provide an empirical and cost-effective strategy
in the management of COVID-19, given the limited time
span. In order to accomplish this aim, this literature
evaluation was undertaken with the following objectives:
(a) to highlight the immunomodulatory role of nutritional
supplements and dietary components for the management
of COVID-19 patients, and (b) to assist guideline develop-
ment groups in making recommendations about the pro-
phylactic use of nutritional and dietary supplementations
in COVID-19 [18].
Nutrition and immunity
Role of nutrition-immunity-infection triad is widely known
due to complex mosaic of many diseases. Early reported
deaths from the COVID-19 were mostly of elderly people
who had weak immunity, which permitted the faster
progression and replication of virus in the host body after
it bypassed the host immune system [5]. Therefore,
COVID-19 is providing an option to further extend our
knowledge in implementing non-pharmacological modali-
ties and exploiting their utility in the current situation. With
a rapidly evolving pandemic situation each day, quality of
patient care has become utmost important. Early and judi-
cious nutritional intervention along with pharmacological
treatment and clinician collaborations are critical in resti-
tuting the current situation. All members of clinical force
must be concerned such as, dietitians; for performing nutri-
tion-based diagnosis and evidence-based interventions,
nurses; for conducting preliminary nutritional strategies
and implementing novel nutritional plans to promote
patient compliance, pharmacists; for evaluating nutrition-
drug interactions, and clinicians; for developing an overall
care plan [19]. In designing such interventions, optimal
dose, features of targeted populace including their genetic
background, health condition, and nutritional status must
be considered. Furthermore, reproducibility, clinically rele-
vant efficacy, and clinical endpoints for reliable evaluation
of clinically relevant efficacy must also be kept in mind [20].
It is essential that an individual must be of good health with
strong immunity. Until recently, the nutritional status of
patients has not been considered, which is an important
factor in developing a robust host immune system [21].
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Keeping in view all aforementioned realities, nutritional
supplementation could be considered as potential candi-
dates to curb the emergence of novel COVID-19. Figure 1
demonstrate the summary of possible immunomodulatory
actions provided by potential nutritional supplements and
dietary components. Figure 2describes importance of nutri-
tional supplements in developing strong immunity against
viral infectious diseases.
Potential nutritional
supplementation for COVID-19
It is clearly evident from the above-mentioned literature
that malnourishment is an important contributing factor
of poor immunity and it is considered as one of the major
risk factor in viral infections [22]. Moreover, the phenom-
ena of inflammatory mediator release start with the onset
of viral infection and these mediators are responsible for
poor nutrition uptake. This ultimately leads to infection
mediated anorexia which exacerbate the decline in immu-
nity [23]. Nutritional support has been recognized as an
empirical and cost-effective method in boosting immune
system and providing resistance against infectious diseases
[23]. Patient management through nutritional support is
very common in many industrialized countries where the
number of mortalities due to infectious diseases is less
and life expectancy is longer [23]. To narrow our discussion
in the light of SARS-CoV-2infection, nutritional supplemen-
tation could be beneficial along with other standard treat-
ment options in the management of COVID-19 patients.
Table 1represents, evidence-based human studies of
numerous vitamins and crucial micronutrients as well as
their dosing protocols (used in the study) along with recom-
mended daily intake for viral infections. Several studies
have been conducted so far to evaluate the role of nutrition
in previously devastated viral infections. However, each of
these nutrients and dietary components is discussed briefly
in the following section. Along that, in detail, the reason or
linkage between the specific nutrient deficiency and
COVID-19 infection has also been discussed. Upon these
concrete literature evidence, NIH is conducting myriad of
clinical trials, globally, to assess the efficacy of various nutri-
tional supplements against COVID-19 infection, stated in
Table 2.
Vitamin C
The important and vital dietary component with renowned
role in boosting immunity is vitamin C. It has the ability to
strengthen the epithelial cell barrier protection and
enhance phagocytic activity, lymphocytic response and
release of immune mediators, which ultimately strengthen
a patient’s immune system [26]. Not only does it strengthen
the immunity, but also imparts weak anti-histaminic prop-
erties that has made the use of vitamin C in flu and lower
respiratory tract infections as a widely recommended pro-
phylactic treatment. The effectiveness of vitamin C in pre-
venting and alleviating the symptoms of viral respiratory
tract infections was evaluated by Gorton, H.C. et al., in a
controlled study and they recommended the use of vitamin
C as an adjuvant therapy for effective treatment of viral
infections [50]. Another review concluded that the use of
large doses of vitamin C could minimize the suffering and
duration of viral infections [51]. In high doses, vitamin C
act as prooxidant which reduces the release of pro-inflam-
matory mediators, enhance alveolar fluid clearance and
also act as an antioxidant in strengthening epithelial barrier.
Furthermore, the meta-analysis has transparently provided
evidence that high dose IV Vitamin C is quite beneficial in
the management of sepsis and septic shock during
COVID-19 [52]. Despite all these claims, the Australian
Government, after detailed review of previously conducted
randomized controlled trials, has suggested lack of solid
evidence for the effectiveness against SARS-CoV-2induced
pneumonia and acute respiratory distress syndrome [53].
Although the use of vitamin C in COVID-19 is still question-
able due to lack of concrete evidence and some repro-
ducibility problems but it is still a potential candidate in
fight against COVID-19. Globally, myriad randomized
controlled trials are enduring to assess the efficacy of IV
and oral Vitamin C in managing COVID-19 patients, stated
in Table 2.
Vitamin D
In addition to mineral regulation and homeostatic effect of
vitamin D, its crucial effect on inflammatory cytokines has
also been discovered. Vitamin D inhibits the production of
inflammatory cytokines during a viral infection and pre-
vents several unwanted symptoms of infection [54]. A ran-
domized clinical trial of vitamin D on patients infected by
influenza virus concluded that vitamin D provided a signif-
icant preventive effect against influenza virus and this
effect is mediated primarily by increased production of
defensin peptides in epithelial and monocytic cells [55].
Another double blind randomized clinical trial concluded
with remarks that daily vitamin D supplementation signifi-
cantly reduced the risk of acute respiratory tract infections
associated with specific pathogens such as syncytial virus
and rhinovirus [56]. However, a review of several
randomized controlled trials pointed out the lack of firm
evidence in support of its role in the improvement of
virus-related respiratory tract infection [57]. Therefore,
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several trials sponsored by NIH to assess the role of
vitamin D in viral infections are still in progress [58,59].
Vitamin D deficiency trigger multiple co-morbidities like
hypertension and diabetes mellitus, and the chance of
infection with SARS-CoV-2increases manifold with the
presence of these co-morbidities [60]. Due to its anti-
inflammatory role that could prevent certain undesirable
symptoms after a viral infection, it can also be used in the
symptomatic treatment of COVID-19. Moreover, as an
alternative to pharmacologic intervention, it can either be
used alone or in combination with high dose vitamin C
[59]. A review report published in November 2020, has
clearly stated the same conclusive comments about vitamin
D that despite its beneficial aspects, more concrete clinical
evidence is required to determine its utilization in COVID-
19 patients [61]. Recently, it has been determined by the
group of doctors, vitamin D level has high co-relation with
COVID-19 infection severity. Particularly, 62 among 63
Critically ill COVID-19 patients, requiring intensive care
facility, were found to be deficient of Vitamin D (levels
Table 1.Evidence-based studies of various nutritional supplements
Nutritional
supplement
Adaptive response with
supplementation
Clinical evidence
against viral infections
Dose administered for
anti-viral activity RDA*
Reported complications
at higher doses Reference
Vitamin C Elevate B-cells and
T-cells proliferation
Herpes Zoster infection
(HZV)
5 g/day for 3 alternate
days for post herpetic
neuralgia
100–200 mg Hemolytic anemia with
G6PD*** deficiency,
Renal damage, Diarrhea
[24–28]
Enhancement of
chemotaxis and
phagocytic activity of
macrophages
Influenza H1N1 virus 0.2 g/day or more for
influenza
Vitamin D Inhibits the production
of inflammatory
cytokines
Influenza virus 2,000 IU/day 300–10,000 IU Hypercalcemic
manifestation with
bradyarrythmias,
hypertension, mental
alterations (confusion,
apathy, psychosis) and
renal damage
(Dehydration,
nephrocalcinosis and
kidney failure)
[29–33]
Prevent the
development of
co-morbidities that
potentiate the risk of
COVID-19
Human
immunodeficiency
virus (HIV)
High dose regimen:
100,000 IU/month
Vitamin E Strengthen the activity
of NK cells
Influenzae virus 15 mg/kg/day 15 mg Increase oxidative stress [34–38]
Enhance humoral
immune response
Hepatitis B virus (HBV) Increase risk of ischemic
heart diseases
Vitamin A Enhance antibodies
production and
proliferation of
inflammatory cells
Serum antibody level
raise followed by:
200,000 IU 900 mcg RAE** Cutaneous toxicity:
Hyper-proliferation of
epidermal cells,
cutaneous erythema,
dryness and peeling of
skin
[39–41]
Measles virus (MV)
vaccine
Influenzae virus vaccine Systemic toxicity:
Teratogenic potential,
osteoporosis,
hypothyroidism,
reversible serum
creatinine elevation and
hypertriglyceridemia
Polio vaccine
Selenium Reduction in levels of
inflammatory markers.
Reduction in Viral load.
Human
Immunodeficiency virus
(HIV)
200 mcg/day 55 mcg Symptoms of selenium
toxicity (Hair loss, nail
discoloration, joint pain,
headache, GIT distress
and skin destruction)
[42–45]
Zinc Regulate both cellular
and humoral immune
response
Herpes Simplex Virus
(HSV)
150–300 mg
Polaprezinc/days
8–12 mg Lethargy, metal fume
fever, respiratory tract
irritation, GIT distress
and elevation in prostate
cancer risk
[46–49]
Hepatitis C virus (HCV) Zinc lozenges
Viral Rhinitis
*Recommended dietary allowances.
**Retinoic Acid Equivalent.
***Glucose-6-phosphate dehydrogenase.
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Table 2.Nutritional supplements under randomized controlled trials for COVID-19 and other viral infections
Nutrient registered
under trial
Trial Registration
No Current phase
Dosing intervention of
trial Type of trial Viral infection Reference
Vitamin C NCT04264533 Phase-II 12 g Vitamin C IVF twice
daily for 7 days
Triple blinded,
randomized controlled
trial
COVID-19 [92]
NCT04401150 Phase-III 50 mg/kg IV Vitamin C
every 6 hrs for 4 days
Quadruple blinded,
randomized controlled
trial
COVID-19 [93]
NCT04323514 –10 g of IV Vitamin C
+conventional
management strategies
Open labeled, non-
randomized single group
experiment
COVID-19 [94]
NCT04344184 Phase-II 50 mg/kg IV Vitamin C
every 6 hrs for 4 days
Quadruple blinded,
randomized controlled
trial
COVID-19 [95]
NCT04363216 Phase-II 0.3–0.9 g/kg daily for
6 days
Open labeled,
randomized controlled
trial
COVID-19 [96]
Vitamin D NCT04344041 Phase-III Single oral dose of
200,000 IU
Open labeled,
randomized controlled
trial
COVID-19 [97]
Vitamin C+Zinc NCT04342728 –4000 mg ascorbic acid
twice daily+50 mg Zinc
gluconate at bedtime
daily
Open labeled,
randomized controlled
trial
COVID-19 [98]
Oral supplemented
capsule comprising
Vitamin A, C, E,
Selenium and Zinc
NCT04323228 Phase-II 1500 mcg of Vitamin A,
250 mg Vitamin C, 90 mg
Vitamin E, 15 mcg of
Selenium and 7.5 mg of
Zinc
Double blinded,
randomized controlled
trial
COVID-19 [99]
Vitamin D
3
+Zinc NCT04351490 –15 mg twice daily Zinc
gluconate capsule+
2000 IU Vitamin D
3
for
2 months
Open labeled,
randomized controlled
trial
COVID-19 [100]
Zinc+Ribavirin
+ivermectin
+Nitazoxanide
NCT04392427 Phase-III –Single blinded,
randomized controlled
trial
COVID-19 [101]
Zinc+HCQ NCT04377646 Phase-III 15 mg Zinc daily for 2
months
Double blinded,
randomized controlled
trial
COVID-19 [102]
Zinc+Vitamin C
+Ivermectin+HCQ
NCT04446104 Completed 80 mg zinc+500 mg
Vitamin C for 42 days
Open labeled,
randomized controlled
trial
COVID-19 [103]
Zinc+HCQ+Azithromycin/
Doxycycline
NCT04370782 Completed 220 mg Zinc sulfate daily
for 5 days
Open labeled,
randomized controlled
trial
COVID-19 [104]
Zinc citrate HCQ+AZT
+Vitamin C+Vitamin
D
3
+Vitamin B
12
NCT04395768 Phase-II 30 mg Zinc citrate daily Double blinded,
randomized controlled
trial
COVID-19 [105]
Ivermectin+Doxycycline
+Zinc+Vitamin D
3
+
Vitamin C
NCT04482686 Phase-II –Triple blinded,
randomized control trial
COVID-19 [106]
Vitamin A based
compounds (All trans
retinoic acid and
isotretinoin)
NCT04396067 Phase-II Both were aerosolized
and given in a dose of
0.2–0.4 mg/kg/day for
14 days
Open labeled,
randomized controlled
trial
COVID-19 [107]
Vitamin D NCT00656929 Completed 2000 IU daily for
3 months
Double blinded,
randomized controlled
trial
Viral upper
respiratory
tract infection
[108]
Selenium NCT00197561 Phase-III 200 mcg PO once daily for
6 months
Quadruple blinded,
randomized controlled
trial
HIV-1 [109]
Vitamin E ––
200 IU daily Double blinded,
randomized controlled
trial
Respiratory
tract infection
[110]
Vitamin A+Influenzae
vaccine
NCT02649192 Phase-II 20,000 IU single dose at
time of vaccine
Quadruple blinded,
randomized controlled
trial
Prevention of
upper
respiratory
tract infection
[111]
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below 20 ng/ml). Furthermore, over expressed immune
system a cytokine syndrome in COVID-19 patients, was also
presented with lower levels of Vitamin D. Thus, findings of
this experimental study were highly suggestive for the
employment of vitamin D in management of COVID-19
[62].
Vitamin E
Natural killer (NK) cells, also known as large granular lym-
phocytes (LGL) and considered innate part of cellular
immunity, are primarily responsible for viral killing in the
human body [63]. Vitamin E deficiency is directly related
to poor activity of NK cells that can be improved through rig-
orous supplementation with tocopherols [64]. A random-
ized clinical trial claimed that supplementation with
vitamin E could reduce the incidence of age-related recur-
rent pneumonia [65]. However, more randomized con-
trolled trials with better models should be performed to
understand the immunomodulatory role of vitamin E in
viral infections.
Vitamin A
Another vital nutrient and important component of diet,
vitamin A, has an immunomodulatory function that is
evident from a review of various clinical trials [39]. By the
process of bio-oxidation, vitamin A transforms into retinoic
acid which is an essential factor for immune system regula-
tion. It has major role in maturation of T-cells and regulation
of dendritic cells, macrophages and B-cells. Moreover, it
shows anti-inflammatory effects by limiting interleukin-12
(IL-12) production and inhibiting interleukin-6induced T
helper-17 (Th17) production [66]. A review highlighted var-
ious other roles of vitamin A in support of building and
strengthening of immune system [67]. Another study
explained the role of vitamin A in production of antibody
against the viral infection [39]. Because of all these mecha-
nisms, its utility could be judiciously exploited in the current
situation and more evidence could be generated on its role
in viral infections. Due to protagonist nature of vitamin A
analogues in cellular immunity [68], NIH has recruited
Aerosolized 14 days therapy of All-trans Retinoic Acid
(ATRA) and isotretinoin at the dose of 0.2–0.4mg/kg/day
against COVID-19 patients, which is currently in Phase-II
clinical trial (mentioned in Table 2).
Zinc
Zinc also possesses antiviral activity and it is as renowned as
vitamin C for its role in development and maintenance of
immune cells of both adaptive and acquired immune
system [69,70]. Thymulin, a critical hormone for
T-lymphocytes maturation, is chiefly composed of zinc.
Figure 1. Possible immunomodulatory actions provided by potential nutritional supplements and dietary components.
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In addition, to the activation of cytokines; IL-2and INF-γ,it
is also found to be essential for macrophagial stimulation
and synthesis of IL-12 which is a biological sniper for
assassination of myriad of pathogens [71]. Recent meta-
analysis of 7randomized control trials concluded that the
use of zinc causes reduction in length and suffering of symp-
toms associated with common cold [72]. Zinc significantly
inhibit the RNA-polymerase activity of coronaviruses and
arteriviruses in-vitro, and their replication in cell culture
was blocked by zinc-ionophores [73]. Thus, it can be used
alone or in combination with high dose vitamin C in the
management of COVID-19 patients. Fortunately, zinc was
found to be the nutrient of interest against COVID-19,
mainly due to the fact that zinc ionophores was found to
exhibit significant inhibitory potential against several
RNA viruses. These zinc ions, in particular pyrithione,
blocks the vital RNA virus’s enzyme- RNA dependent
RNA polymerase. In support of this claim, various chemical
compounds like hinokitiol and pyrrolidine dithiocarba-
mate, with the potential to increase intracellular zinc
concentration, have been evaluated and presented with
considerable inhibition of RNA virus replication cycle. At
present, zinc was evaluated for COVID-19 patients, as an
adjuvant with standard treatment. The results were satis-
factory in terms of reduction in pulmonary inflammation
and surge in mucociliary clearance along with overall
immunity of patients. Furthermore, in its high doses, the
reduction in symptoms duration and severity were
also encountered, with in 24 hrs of treatment initiation
[74,75]. NIH, because of cherished evidence, has enrolled
zinc in multiple randomized controlled trials (mentioned
in Table 2), in combination with other treatment regimens
(antivirals, HCQ and ivermectin) and nutritional
supplementation including Vitamin C, Vitamin D
3
and
Vitamin B
12
[76].
Selenium
Selenium is another micronutrient with prominent anti-
inflammatory and anti-oxidative activity [77]. Deficiency
of selenium cause oxidative stress which leads to impaired
immunity and pathogenic viral mutations [78]. A study was
conducted to assess the effect of selenium level on the
production of inflammatory cytokines induced by viral
infections. This study highlighted the link of poor selenium
levels with high production of viral induced inflammatory
mediators in mice [79]. In a recent publication by Zheng
et al., the results were transparently demonstrating a strong
association between the selenium levels of population and
the COVID-19 patient curative rates by collecting and com-
paring the data of Chinese province- Hubei. Briefly, the
authors have reported an improved cure rates of COVID-19
cases in Enshi city of Hubei (36.4%), China, in contrast to
other cities of Hubei (13.1%) as well as other provinces. This
significantly higher cure rates of Enshi city population was
mainly associated with higher selenium dietary intake [80].
On the basis of this association, selenium in combination
with other multi-vitamins is undergoing a randomized con-
trol trial (currently in phase-II), and results are much
awaited.
Figure 2. Proposed mechanism of role of nutritional supplements in obtaining immunity against viral infectious diseases.
Ó2021 Hogrefe Int J Vitam Nutr Res (2021), 1–14
M. O. Yaseen et al., Nutrition’s based potential immunity in COVID-19 infection 7
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Vitamin B-complex and iron
Vitamin B family and Iron are very crucial in case of pneu-
monic and respiratory depressed patients [11]. Vitamin B
reduces the infiltration of neutrophils and has a strong
anti-inflammatory effect [81]. A case-controlled study con-
cluded that iron deficiency causes recurrent acute respira-
tory tract infection while severe deficiency could worsen
the symptoms [82]. There is very poor to no evidence
regarding the effectiveness of vitamin B and iron in viral
infections, but these two products could be valuable candi-
dates to manage bacterial induced infections as a result of
weak immunity caused by SARS-CoV-2.
Omega-3 fatty acids
Phospholipids of immune cells contains fatty acids, such as
large amount of arachidonic acid and low levels of long
chain n-3fatty acid [83]. Arachidonic acid, eicosapen-
taenoic acid (EPA) and docosahexaenoic acid (DHA) give
rise to eicosanoids, resolvins and docosanoids that regulate
the functions of T and B cells. Alteration in the composition
could affect the activity of immune functions such as anti-
gen presenting capability, phagocytosis and T-cell signaling
[84]. A randomized clinical trial was conducted on HIV
patients to evaluate the improvement in immune function
by supplementation with omega-3fatty acids. High CD-4
cell count was seen in the subjects when given supplements
rich in peptides and n-3fatty acids [85]. Polyunsaturated
fatty acids (PUFAs) successfully inhibited the in-vitro repli-
cation of HCV. However, mechanism of this action is not
known [86]. Therefore, it could be considered as a potential
candidate in COVID-19 and its role can further be assessed
by conducting suitable clinical trials.
Dietary fibers
The impact of dietary fiber on host immune system is evi-
dent from various studies [87–89]. Short-chain fatty acids
(SCFAs), a fermentation product of dietary fiber synergies
the immune response by acting on various immune cells.
A research on mice fed with SCFAs, showed improved
immune response against influenza A virus by augmenting
hematopoiesis of bone marrow that ultimately produced
large number of macrophages. Furthermore, it also reduced
airway inflammation in lungs and improved their function
[90]. Almond skin (Prunus dulcis) is considered beneficial
due to its high fiber content and presence of polyphenols.
It showed anti-HSV-2property in-vitro by inhibiting viral
replication and played an important role against viral infec-
tion by activating peripheral blood mononuclear cells that
released proinflammatory cytokines which are essential
for initial examination of virus effect [91].
Nutrients registered under NIH
randomized controlled trials for COVID-19
and other viral infections
Erstwhile mentioned literature is clearly demonstrating the
beneficial impacts of some nutrients towards immunity pro-
file which are crucial for enhancing the immune function
and managing viral infections. Supported by the scientific
evidence, NIH has enrolled some of those candidates in
randomized controlled trials for the evaluation of their
anti-viral activity as shown in Table 2.
Potential dietary components
for COVID-19
Black elderberry
Sambucus nigra, also known as European elderberry or
black elderberry, is known for its immune boosting effects
due to the presence of bioactive compound, anthocyanin,
which improves the postprandial antioxidant activity in
healthy human [112] and binds to the virion thus inhibiting
its action against host cells [113]. Moreover, it also increases
the production of several anti-inflammatory cytokines that
could prevent the suffering from a viral disease [114]. A
recent meta-analysis is conducted to check the activity of
black elderberry in common colds and influenza virus that
primarily effect the upper respiratory tract. This study sug-
gested black elderberry as an effective non-pharmacologi-
cal approach against viral infection as well as bacterial
super-infection during a viral ailment, specifically influenza
virus, that may otherwise lead to severe pneumonia [115].
Another small-scale randomized study revealed the use of
elderberry against Influenza A and Influenza B virus as safe
and cost-effective approach [116]. The extract of Sambucus
nigra successfully inhibited the infectious bronchitis coron-
aviruses at the early stages of in-vitro viral replication [117].
Garlic
Allium sativum has been used for treating not only bacterial,
protozoal and viral infections, but also for improved activity
of cardiovascular and immune system for decades [118]. It
has been used since the times of World War I (WWI) to treat
pneumonia [119]. Investigations uncovered that the active
compound, thiosulfinates, in fresh extract of garlic is
responsible for effective viricidal activity against common
cold, influenza A/B and herpes simplex infections. The viri-
cidal effect maybe due to its immunomodulatory effects
that increase the activity of NK cells [120]. Garlic has been
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very effective in reducing the severity and duration of symp-
toms, and also prevent the recurrence of viral infections by
strengthening the immune system [121]. However, one sys-
temic review emphasized the need of further investigations
for conclusive evidence to use garlic prophylactically or for
the treatment of infection [122]. Similarly, another in-vitro
study assessing the activity of garlic-based lectins failed to
prove the activity of garlic against SARS-CoV [123].
Ginger
Zingiber officinale is widely used spice due to its high efficacy
for many pharmacological purposes. Its anti-inflammatory
activity is mainly accredited to the inhibiting of LPS-derived
PGE2production [124]. It successfully inhibits the pro-
teases of several viruses in-vitro which are crucial for repro-
ductive cycle of most viruses [125]. Antiviral activity of
ginger against respiratory syncytial virus is mainly attribu-
ted to the stimulation of interferon-βcells, inhibition of viral
attachment and internalization [126]. Ginger potentially
inhibited the SARS-CoV-2PLpro homology models when
docked in-silico [127]. However, its activity against SARS-
CoV-2could further be assessed by designing better in-vitro
models and conducting randomized controlled trials based
on such models.
Fennel flower
Black cumin seeds (Nigella sativa), commonly called fennel
flower, have been traditionally used in folk medicine for
many diseases since pre-historic times. The active con-
stituent “thymoquinone”, increased the plasma level of
macrophages and CD-4T-helper against cytomegaloviral
infection on in-vitro models [128]. It also possesses antiox-
idative property which is responsible for the synergistic
effect in fight against viral infections [129]. In-silico molec-
ular docking revealed that Nigellidine, an active con-
stituent, successfully inhibited the SARS-CoV-2as
compared to other drugs under clinical test [130]. Nigella
sativa successfully decreased the coronavirus load in-vitro
owing to its interference with gene regulation that is essen-
tial for replication of coronaviruses [131].
Citrus fruits
A study on fluid extract of Citrus reticulate (Mandarin
orange) claimed the antiviral activity against respiratory
syncytial virus due to poly-methoxylated flavones “tan-
geretin”and “nobiletin”[132]. Another study performed
on essential oils of leaves and fruits of Fortunella margarita
(Citrus margarita) against avian influenza A virus showed
greater antiviral potential of fruit oil with 80% virus
inhibition as compared to its leaves, due to the presence of
“α-terpineol”in fruit. Similar effects were observed with
volatile oils of Curcuma zedoaria and Hypericin perforatum
attributed to the presence of “curcumenol”and “hypericin”
respectively [133]. This could be a potent candidate in fight
against SARS-CoV-2, if checked through properly designed
in-vitro and in-vivo studies.
Senna leaves tea
Senna belongs to family Leguminosae which is traditionally
used in various pathogenic diseases due to its medicinal
properties. It contains several compounds that are pharma-
cologically effective against many viruses and helps in the
enhancement of immune related functions of the patient
[134]. The active ingredient “Flavonoids”has antioxidant,
anti-inflammatory and antiviral activities. Moreover, these
activities can be enhanced with concurrent use of vitamin C
[135]. “Alkaloids”in the Senna leaves mitigate cough and
fatigue of the patient while “saponins”and “phenols”boost
the immune function and provide antioxidant properties
respectively [134,135]. Aqueous extract of Senna has
increased leucocytic count as well as the number of macro-
phages in in-vivo rabbit models [136]. “Aloe emodin”,an
anthraquinone found in Senna, has shown inhibitory effect
against influenza virus and HSV [137,138]. It has potential to
block the 3C-like protease enzyme of SARS-CoV and MERS-
CoV by binding specifically at S1,S2and S3sites of the pro-
tease enzyme [139,140]. In an in-silico model, Flavonoids
interacted with SARS-CoV-2spike protein which is respon-
sible for viral internalization, thereby stopping the virus
entry into host cell [141]. As Senna is rich in active com-
pounds like vitamin C, phenols, anthraquinones, vitamin
A, carotenoids and flavonoids; therefore, its aqueous
extract/tea can be used in the management of COVID-19.
Honey
Honey has been widely used by many civilizations and gen-
erations as food and also as medicine to treat many human
pathological conditions [142]. Studies have reported the
topical use of honey to treat skin infections and for wound
healing [143–145]. Selected studies on oral use of honey
demonstrate its efficacy for symptomatic treatment of var-
ious diseases like hepatitis A/B, type 2diabetes, risk factors
for cardiovascular disease, gastric issues, common cold,
diarrhea, upper respiratory tract infections, nocturnal
cough and sleep disorders [146–149]. Antimicrobial effect
of honey is attributed to its high sugar concentration, low
pH, osmotic effect and constituents like phenolic acid,
flavonoids, hydrogen peroxide and antioxidants, while
immunomodulatory effect is due to increased release of
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anti-inflammatory cytokines [142]. These factors reduce
the severity and duration of infection, maintain the integrity
of epithelial cells, cause stimulation of granulation and
angiogenesis as well [150]. When studied in comparison
with available pharmacological antiviral drug “acyclovir”,
honey showed least to no deleterious effects in treating
infection of herpes simplex virus [151]. Since the infection
of SARS-CoV-2proliferate due to protease enzyme present
in the viral structure, a recent in-silico study showed strong
binding of constituents of honey to the active site of pro-
tease, making it a potential candidate for further in-vitro
and in-vivo studies to check it’s efficacy against SARS-
CoV-2[152].
Probiotics
Probiotics are microorganisms, that impart positive health
impact to the host when administered in sufficient amount
[153,154]. Lactobacillus is the most common probiotic, con-
sumed majorly in the form of yogurt and improve host
immunity against various infectious diseases [155]. It
increases the production and activity of interlukin-12,
macrophages and natural killer cells which ultimately
strengthen the immune system and provide anti-influenza
activity [156]. An in-vitro study proved the effective antivi-
ral activity of lactobacillus against coronavirus; however,
the mechanism of this action is still unknown [157].
Other miscellaneous dietary
components
Ketogenic diet
γδ T cells act as first line of defense that actively respond to
the viral invasion in human body [158]. A study conducted
on mice to check the effects of ketogenic diet on immune
system during influenza A virus. The ketogenic diet showed
improved immune response of body against Influenza A
virus and increased γδ T cells to improve the integrity of
epithelial cells of lungs [159]. It also decreases the cytokine
storm and scavenge reactive oxygen species, providing an
anti-inflammatory and anti-oxidant effect [160].
Conclusion
In this short review, we summarized the possible supportive
nutritional interventions, alternative to standard pharma-
cological management of COVID-19, keeping in view the
current literature on COVID-19 and previously performed
nutritional treatments on SARS-CoV, MERS-CoV and other
viral infections. Furthermore, several important clinical tri-
als, assessing the efficacy of these supportive nutritional
supplementation in COVID-19 infection, has also been dis-
cussed and represented systematically in Table 2. Inade-
quate nutritional status leads to poor host immune
response against a specific viral infection as can be seen in
many human studies as well as animal studies. As it is evi-
dent from the literature that nutritional supplements along
with conventional pharmacological interventions could be
beneficial in management of previously devastating pan-
demics related to viral infections. Therefore, we suggest
that nutritional supplements should be considered as pro-
phylactic measure to curb the emergence of SARS-CoV-2
infection along with other preventive measures. These
nutritional supplements can either be used alone for
patients with mild symptoms or can be used in combination
with other antiviral regimens. To further assess the role of
nutritional management, numerous models of human ran-
domized controlled trials utilizing specific dosage of these
nutrients and their combination with other treatment
options are under way to substantiate the benefits of nutri-
tional supplementation against SARS-CoV-2.
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History
Received October 2, 2020
Accepted May 11, 2021
Published online June 8, 2021
Acknowledgement
We would like to thank Dr. Maqbool Ali for reviewing and his
valuable input to this review.
Conflict of interest
The authors declare that there are no conflicts of interest.
ORCID
Talib Hussain
https://orcid.org/0000-0003-3508-8666
Dr. Talib Hussain
Institute of Pharmaceutical Sciences
University of Veterinary and Animal Sciences
Shaikh Abdul Qadir Jillani Road
Lahore, Pakistan
talib.hussain@uvas.edu.pk
Int J Vitam Nutr Res (2021), 1–14 Ó2021 Hogrefe
14 M. O. Yaseen et al., Nutrition’s based potential immunity in COVID-19 infection
https://econtent.hogrefe.com/doi/pdf/10.1024/0300-9831/a000715 - Talib Hussain <talib.hussain@uvas.edu.pk> - Tuesday, June 08, 2021 2:45:50 AM - IP Address:111.68.105.210
