Jayawardena 2020

Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 367e382
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews
journal homepage: www.elsevier.com/locate/dsx
Enhancing immunity in viral infections, with special emphasis on

COVID-19: A review
Ranil Jayawardena a, b, *, Piumika Sooriyaarachchi b, c, Michail Chourdakis d,
Chandima Jeewandara e, Priyanga Ranasinghe f
a
Department of Physiology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
b
School of Exercise and Nutrition Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
c
Health and Wellness Unit, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
d
Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of
Thessaloniki, University Campus, 4, Thessaloniki, Greece
e
National Center for Primary Care and Allergy Research, University of Sri Jayewardenepura, Sri Lanka
f
Department of Pharmacology, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
a r t i c l e i n f o a b s t r a c t
Article history: Background and aims: Balanced nutrition which can help in maintaining immunity is essential for pre-
Received 7 April 2020 vention and management of viral infections. While data regarding nutrition in coronavirus infection
Received in revised form (COVID-19) are not available, in this review, we aimed to evaluate evidence from previous clinical trials
12 April 2020
that studied nutrition-based interventions for viral diseases (with special emphasis on respiratory in-
Accepted 12 April 2020
fections), and summarise our observations.
Methods: A systematic search strategy was employed using keywords to search the literature in 3 key
medical databases: PubMed®, Web of Science® and SciVerse Scopus®. Studies were considered eligible if
they were controlled trials in humans, measuring immunological parameters, on viral and respiratory
infections. Clinical trials on vitamins, minerals, nutraceuticals and probiotics were included.
Results: A total of 640 records were identified initially and 22 studies were included from other sources.
After excluding duplicates and articles that did not meet the inclusion criteria, 43 studies were obtained
(vitamins: 13; minerals: 8; nutraceuticals: 18 and probiotics: 4). Among vitamins, A and D showed a
potential benefit, especially in deficient populations. Among trace elements, selenium and zinc have also
shown favourable immune-modulatory effects in viral respiratory infections. Several nutraceuticals and
probiotics may also have some role in enhancing immune functions. Micronutrients may be beneficial in
nutritionally depleted elderly population.
Conclusions: We summaries possible benefits of some vitamins, trace elements, nutraceuticals and
probiotics in viral infections. Nutrition principles based on these data could be useful in possible pre-
vention and management of COVID-19
© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction supplementation of these have shown positive impact on

enhancing immunity in viral infections. Vitamin A and D supple-
Considering the current pandemic of COVID-19 where no mentationhas increased the humeral immunity of paediatric pa-
effective preventive and curative medicine is available, a healthy tients following influenza vaccination [2]. High dose zinc
immune system is one of the most important weapons . There are supplementation has shown immune enhancement in patients
several vitamins and trace elements which are essential for the with torquetenovirus (TTV) [3]. Similarly, selenium supplementa-
normal functioning of the immune system [1]. Furthermore, tion has shown a positive response after an influenza vaccination
challenge [4]. In addition to micronutrients, several herbals and
probiotics also have shown effectiveness for treatment and pre-
* Corresponding author. Department of Physiology, Faculty of Medicine, Univer- vention of viral infections [5]. Moreover, several nutraceuticals and
sity of Colombo, Sri Lanka. probiotics have also shown a supportive role in enhancing immune
E-mail address: [email protected] (R. Jayawardena).
https://doi.org/10.1016/j.dsx.2020.04.015
1871-4021/© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.
368 R. Jayawardena et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 367e382
responses [6,7]. from each study: a) details of the study (study setting, year of
Malnutrition increases morbidity, mortality, and causes signifi- publication and study design), b) study population, sample size
cant economic impact on the health care systems, while the eco- (male/female) and age of the subjects in years, c) primary in-
nomic situation of a country influences all aspects of optimal tervention(s) and control group and d) details of the main antiviral/
nutrition care [8]. The increased risk of morbidity and mortality immunological outcomes reported. Outcomes evaluated were
caused by malnutrition is a result of the increased rate of infections, classified as a) Clinical response e incidence of disease, duration,
as well as by delayed recovery. Furthermore, infections increase the severity and symptoms or b) Immunological response e cellular
demand for several nutrients [9]. It is well-recognized that nutri- changes, serological response, and other relevant immunological
tion is a crucial factor in modulating immune homeostasis. Protein- phenomenon. These are reported in the relevant tables for vita-
energy malnutrition or even subclinical deficiencies of one micro- mins, minerals, nutraceutical and probiotics, for comparison of
nutrient may impair one’s immune responses [10]. Recently, Calder similar outcomes between interventions. The Jadad scale (0e5,
et al. has highlighted the importance of optimal nutritional status where <3 indicates poor quality) was used to assess the method-
to protect against viral infections [11] and Wu et al. has provided ological quality of the trials included in the review [14]. The Jadad
nutritional advices to reduce damages to the lungs from corona- scale score of each included study is reported in respective tables.
virus and other lung infections [12]. Acknowledging both these
valuable reviews, we used a systematic searching strategy and 3. Results
evaluated the highest quality evidence from clinical trials for both
the prevention and treatment of viral diseases by means of nutri- A diagram showing the details of studies included is shown in
tional interventions. Priority has been given for supplementation of Fig. 1. A total of 640 recorded were identified initially from PubMed,
vitamins, trace-elements, nutraceuticals and probiotics. Scopus and Web of Science databases. In addition, 22 studies were
In the light of the current pandemic of COVID-19, we wanted to included from other sources. After excluding duplicates and articles
evaluate the evidence on enhancing immunity in viral infections. that did not meet the inclusion criteria, we obtained 60 articles
Hence, this review mainly focuses on, influenza-like viral in- with full-texts which were read for further evaluation, where
fections; however, other studies on viral infections have also been another 17 were excluded as irrelevant. Overall, we included 43
included. Finally, practical recommendations have been drawn on articles of which 13 were on vitamins, 8 on minerals, 18 on nutra-
both preventive and therapeutic nutritional interventions for ceuticals and 4 on probiotics.
COVID-19.
3.1. Vitamins and multi-nutrient supplements
2. Methods
A summary of RCTs on vitamins and multi-nutrient supple-
This was conducted using a systematic search strategy and re- ments that are discussed below is presented in Table 1.
ported in adherence with the Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) guidelines [13]. 3.1.1. Vitamin A
PRISMA checklist is attached as a supplementary material. Vitamin A is a fat-soluble vitamin, which is crucial for main-
taining vision, promoting growth and development, and protecting
2.1. Search strategy epithelium and mucosal integrity in the body [15]. It is known to
play an important role in enhancing immune function, and having a
A comprehensive search of the literature was conducted in the regulatory function in both cellular and humoral immune re-
following databases; PubMed® (U.S. National Library of Medicine, sponses [15]. Vitamin A supplementation to infants has shown the
USA), Web of Science® (Thomson Reuters, USA) and SciVerse Sco- potential to improve antibody response after some vaccines,
pus® (Elsevier Properties S.A, USA) for studies published until 23rd including measles [15] and anti-rabies vaccination (2.1 times) [16].
March 2020. The search strategy is shown in Table A as a In addition an enhanced immune response to influenza virus
supplementary material. The cited references of retrieved articles vaccination has also been observed in children (2e8 years) who
and previous reviews were also manually checked to identify any were vitamin A and D-insufficient at baseline, after supplementa-
additional eligible studies. All citations were imported into a tion with vitamin A and D [2].
bibliographic database (EndNote X8; Thomson Reuters) and du-
plicates were removed. This search process was conducted inde- 3.1.2. Vitamin D
pendently by two reviewers (RJ and PR) and the final group of Vitamin D, another fat-soluble vitamin, that plays a vital role in
articles to be included in the review was determined after an iter- modulating both innate and adaptive immune responses [17].
ative consensus process. Epidemiological data has linked vitamin D deficiency to increased
susceptibility to acute viral respiratory infections [18]. Recent re-
2.2. Study selection, data extraction and quality assessment views evaluating possible mechanisms suggest that vitamin D plays
an important modulatory role of the innate immune responses to
Title, abstract and then full-text of all articles were screened for respiratory viral infections, such as Influenza A and B, parainfluenza
eligibility. Studies were considered eligible for data extraction if 1 and 2, and Respiratory syncytial virus (RSV) [19]. A systematic
they met the following inclusion criteria: RCTs in humans, review on the role of vitamin D in the prevention of acute respi-
measuring immunological parameters, on viral infection and res- ratory infections, which included 39 studies (4 cross-sectional
piratory infections, and only articles in English language. We studies, 8 case-control studies, 13 cohort studies and 14 clinical
excluded interventional studies conducted on HIV patients, due to trials), noted that observational studies predominantly report sta-
large body of evidence and not being directly related to respiratory tistically significant associations between low vitamin D status and
viral infections and studies on infants. Data were extracted from the increased risk of both upper and lower respiratory tract infections
included articles by one author (PS) by using a standardized form. A [20]. However, results from RCTs included in the above systematic
second author checked the accuracy of the data extracted (RJ), and review were conflicting, possibly, reflecting heterogeneity in dosing
discrepancies were corrected by the involvement of a third author regimens and baseline vitamin D status in study populations [20].
where necessary (PR). The following information was extracted Few RCT have been conducted subsequent to the above systematic
R. Jayawardena et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 367e382 369
Fig. 1. Flow of information through the different phases of a systematic review.
review. A study by Aglipay et al. on the effect of high-dose (2000 IU/ 3.1.3. Vitamin E
day) vs. standard-dose (400 IU/day) vitamin D supplementation on Vitamin E, a fat-soluble vitamin, is a potent antioxidant and has
viral upper respiratory tract infections did not show any significant the ability to modulate host immune functions [26]. Vitamin E
difference between the two group [21]. However, only about 1/3 of deficiency is known to impairs both humoral and cellular immunity
the study population had vitamin D levels <30 ng/ml. A recent RCT [26]. However, few studies have shown that vitamin E supple-
on the impact of vitamin D supplementation on influenza vaccine mentation might cause harmful effects on the incidence of infec-
response in deficient elderly person, showed that it promotes a tious disease. A study among 50e69 years old adult smokers
higher TGFb plasma level without improving antibody production, showed that vitamin E supplementation increases the risk of
and suggested that supplementation seems to direct the lympho- pneumonia [27]. Similarly, supplementation of vitamin E (200 IU/
cyte polarization toward a tolerogenic immune response [22]. day) did not have a statistically significant effect on lower respi-
Similarly in another RCT, a monthly high-dose (100,000 IU/month) ratory tract infections in elderly nursing home residents [28].
vitamin D supplementation reduced the incidence of acute respi- However positive effects of vitamin E have been observed in the
ratory infections in older long-term care residents, in comparison treatment of chronic hepatitis B in a small pilot RCT, where a
to a standard dose group (12,000 IU/month) [23]. It is evident that significantly higher normalization of liver enzymes and HBV-DNA
the role of vitamin D supplementation on antiviral immunity negativization, was observed in the vitamin E group [29]. Similar
against respiratory infections is likely to depend on the vitamin D results have been observed in a RCT in the paediatric population,
status of the individual. Furthermore, vitamin D has demonstrated where vitamin E treatment resulted in a higher anti-HBe serocon-
a beneficial effect in other viral infections, for example adding version and virological response [30].
vitamin D to conventional Peg-a-2b/ribavirin therapy for treat-
ment-naïve patients with chronic HCV genotype 1 infection 3.1.4. Vitamin C
significantly improved the viral response [24], and a similar effect Vitamin C is known as an essential antioxidant and enzymatic
has also been observed in patients with HCV genotype 2e3 [25]. co-factor for many physiological reactions in the body, such as
hormone production, collagen synthesis and immune potentiation
Table 1
Immunological effect of Vitamins and multi-nutrients.
Author; Nutrient Study Study Intervention; Purpose Significant anti-viral outcome

Published design; population; Control;
Year; Duration; Sample size (I/ Dose/Frequency
Country Jadad C);
score Male/Female;
Age (years)
Siddiqui Vitamin A C; Healthy IG: Vitamin A (100000 IU on 1st Study the role of Vitamin A Clinical: NA
et al. 30 days; participants; vaccine day and 100000 IU on in enhancing humoral Immunological: IG group had
[16] 0 points 20/20; the following day) immunity produced by anti- significantly greater (2.1 times)
2001; 30/10; CG: No placebo rabies vaccine serum anti-rabies titre than CG.
Pakistan 10e35 Both groups received anti-rabies
vaccine
Patel et al. Vitamin A and Vitamin D R, DB, PC; Healthy IG: Oral gummy (Vitamin A Study benefit of vitamin Clinical: NA
[2] 28 days; children; 20,000 IU and Vitamin D 2000 A&D supplements on Immunological: Higher antibody
2019; 2 points 39/40; IU), on days 0 and 28 humoral immune responses responses among children who
USA 33/46; CG: Oral gummy placebo, on following paediatric entered the study with
2e8 days 0 and 28 influenza vaccination insufficient or deficient levels of
Both groups received influenza RBP and 25-hydroxyvitamin D.
vaccine
Abu- Vitamin D R, C; Chronic IG: Vitamin D3 (2000 IU/day) Determine whether adding Clinical: Similar in both groups.
Mouch 48 hepatitis C with antiviral therapy Vitamin D improves HCV Immunological: Significantly
et al. weeks; (HCV) patients; CG: Antiviral therapy alone response to antiviral more IG patients were HCV-RNA
2011 [24]; 1 point 36/36; therapy negative (at week 4, 12 and 24).
Israel 39/33; Vitamin D supplementation was
18e65 strongly and independently
associated with sustained
virological response in
multivariate analysis.
Aglipay Vitamin D R, DB, C; Healthy IG: Vitamin D3 high dose (2000 Compare effects of high- Clinical: No significant
et al. 4e8 children; IU/day) dose vs. standard-dose difference in incidence of
[21] months; 349/354; CG: Vitamin D3 standard dose vitamin D supplementation wintertime upper respiratory
2017; 5 points 404/296; (400 IU/day) on prevention of viral upper tract infections in IG compared
Canada 1e5 respiratory tract infections to CG
among children Immunological: NA
Ginde et al. Vitamin D R, DB, PC; Elderly IG: High-dose group (Vitamin D3 Evaluate efficacy of high Clinical: IG had significantly
[23] 12 participants; 100,000 IU/month) dose monthly Vitamin D for lesser number of acute
2017; months; 55/52; CG: Standard-dose group (A prevention of acute respiratory infections than CG.
USA 5 points 45/62; Placebo, for participants taking respiratory infection in Immunological: NA
60 400e1000 IU/day as part of older long-term care
usual care or 12000 IU of residents
vitamin D3/month, for
participants taking <400 IU/day
as part of usual care)
Goncalves- Vitamin D R, DB, PC; Elderly IG: Vitamin D (6 doses 100,000 Study whether Vitamin D Clinical: NA
Mendes 3 participants IU, 1 vial/15 days) supplementation in Immunological: IG had a higher
et al. months; (Vitamin D CG: Placebo (6 doses, 1 vial/15 deficient elderly persons TGFb plasma level in response to
[22] 5 points deficient); days) could improve influenza influenza vaccination without
2019; 19/19 Both groups received influenza sero-protection and improved antibody response.
France Both genders vaccine immune response. Vitamin D seems to direct
˃65 lymphocyte polarization toward
a tolerogenic immune response.
Nimer and Vitamin D R, C; Chronic HCV IG: Vitamin D3 (2000 IU/day) Examine whether vitamin D Clinical: NA
Mouch 24 patients; with antiviral therapy improved viral response Immunological: Ninety-five
[25] weeks; 20/30; CG: Antiviral therapy alone and predicted treatment percent in IG were HCV RNA
2012; 1 point 31/19; outcome in patients with negative at week 4 and 12. At 24
Israel 18e65 HCV genotype 2e3. weeks sustained virological
response was significantly more
in IG. Logistic regression analysis
identified vitamin D supplement
as an independent predictor of
viral response.
Andreone Vitamin E R, C; Chronic IG: Vitamin E (300 mg twice Study the role of Vitamin E Clinical: NA
et al. 3 hepatitis B, daily) as a treatment for Chronic Immunological: Significantly
[29] months; (HBV) patients; CG: No treatment HBV higher complete response, HBV-
2001; 2 points 15/17; DNA negativization, alanine
Italy NM; aminotransferase normalization
I: 37 ± 15 observed in IG.
C: 42 ± 14
Fiorino Vitamin E R, C; Children with IG: Vitamin E (15 mg/kg/day) Evaluate the safety and Clinical: NA
et al. 12 chronic HBV; CG: No treatment efficacy of vitamin E for the Immunological: Significantly
[30] months; 23/23; treatment of paediatric more patients in IG had anti-HBe
2017; 3 points 34/12; HBeAg-positive chronic seroconversion and a virological
Italy 2e17 HBV response.
Hemila € Vitamin E and b-carotene R, DB, PC; Male IG: Three groups a) Vitamin E (a- Examine the effects of vita- Clinical: Vitamin E
and 5e8 participants tocopheryl acetate, 50 mg/day) min E and pneumonia risk supplementation had no effect
Table 1 (continued )

Country Jadad C);
score Male/Female;
Age (years)
Kaprio years; (smoked at least b) b-carotene (20 mg/day) in males who initiated on the risk of pneumonia in
[27] 3 points 5 cigarettes/day c) Both vitamin E and b-ca smoking at an early age participants with body weight in
2008; and initiated CG: Placebo a range from 70 to 89 kg.
Finland smoking at 20 Vitamin E increased the risk of
years); pneumonia in participants with
10,784/10,873; body weight <60 kg and in
Males only; participants with body weight
50e69 >100 kg. The harm of vitamin E
supplementation was restricted
to participants with dietary
vitamin C intake above the
median.
Immunological: NA
Meydani Vitamin E R, DB, PC; Elderly IG: Vitamin E (a-tocopherol, 200 Investigate effect vitamin E Clinical: IG did not have a
et al. 12 participants; IU) in soybean oil, one capsule/ supplementation on statistically significant incidence
[28] months; 231/220; day respiratory infections in of lower respiratory tract
2004; 5 points 113/338; CG: Placebo (4 IU of vitamin E) in elderly nursing home infections. However, a
USA 65 soybean oil, one capsule/day residents. protective effect was noted on
upper respiratory tract
infections, particularly the
common cold.
Immunological: NA
Girodon Multi-nutrient (Trace elements R, DB, PC; Elderly IG: Three groups a) Trace Effect of long-term daily Clinical: Correction of specific
et al. [zinc and selenium sulphide] or 2 years; participants; element: zinc sulphate and supplementation with trace nutrient deficiencies was
[33] vitamins [beta carotene, 4 points 182:180:181/ selenium sulphide (Zinc 20 mg, elements or vitamins in observed after 6 months and
1999; ascorbic acid, and vitamin E]) 182; Selenium 100 mg) immunity and incidence of was maintained for the first
France 185/540; b) Vitamins: ascorbic acid infections in year, during which there was no
5e103 (120 mg), beta carotene (6 mg), institutionalized elderly. effect of any treatment on
atocopherol (15 mg) delayed-type hypersensitivity
c) Trace element and vitamin skin response. Number of
CG: Placebo group (calcium patients without respiratory
phosphate and microcrystalline tract infections during the study
cellulose) was higher in groups that
received trace elements.
Immunological: Antibody titers
after influenza vaccine were
higher in groups that received
trace elements alone or
associated with vitamins,
whereas the vitamin group had
significantly lower antibody
titers.
Graat et al. Multi-nutrient (retinol, beta- R, DB, PC; Elderly IG: Three groups a) Study the effect of daily Clinical: Neither daily
[34] carotene, ascorbic acid, vitamin 15 participants; Multivitamin-Mineral, vitamin E and multivitamin- multivitamin mineral
2002; E, cholecalciferol, vitamin K, months; 163:164:172/ 2 capsule/day b) Vitamin E mineral supplementation supplementation at
Netherland thiamine, niacin riboflavin, 5 points 153 (200 mg), on acute respiratory tract physiological dose nor 200 mg of
pantothenic acid, pyridoxine, Both genders 2 capsule/day c) Multivitamin- infections in elderly. vitamin E showed a favourable
cyanocobalamin, zinc, selenium, 60 Mineral Plus vitamin E, 2 effect on incidence and severity
iron, copper magnesium, iodine, capsule/day of acute respiratory tract
calcium, phosphor, manganese, CG: Placebo (soybean oil), infections in well-nourished
chromium, molybdenum and 2 capsule/day non- institutionalized elderly
silicium) and Vitamin E individuals.
Immunological: NA
C e Controlled; CG e Control group; DB e Double blind; DNA e deoxyribonucleic acid; HBV e Hepatitis B virus; HBeAg e Hepatitis B e-antigen; e Hepatitis B HCV e Hepatitis C
virus; IG e Interventional group; IU e International units; NA e Not applicable; PC e Placebo controlled; R- Randomized; RNA e Ribonucleic acid; RBP e Retinol binding
protein; TGF e Transforming growth factor.
[31]. In-vivo animal studies in mice have shown that it is an reduce the incidence of common cold, which is most often caused
essential factor for the antiviral immune responses against the by viral infections [32].
influenza A virus (H3N2) through the increased production of
interferon-a/b, especially at the early stages of the infection [31].
However, our literature search was unable to identify RCTs exam- 3.1.5. Multi-nutrients supplements
ining the use of vitamin C for the treatment for specific viral in- As evident from the studies described above, micronutrient
fections. Furthermore, a systematic review and meta-analysis on deficiency suppresses immune functions by affecting the T-cell-
the role of vitamin C for preventing and treating the common cold, mediated immune response and adaptive antibody response, and
did not find any conclusive evidence to indicate that there is benefit leads to dysregulation of the balanced host response [1]. Selected
of using vitamin C mega-dose prophylaxis in the community to vitamins and trace elements support immune function by
strengthening epithelial barriers and cellular and humoral immune
responses. Supplementations with various combinations of trace- glutathione peroxidase activities, the cellular immune response
elements and vitamins have shown beneficial effects on the anti- was increased (increased IFN-g and other cytokines), with an
viral immune response. A RCT including 725 institutionalized earlier peak T-cell proliferation, and an increase in T-helper cells.
elderly patients, studying delayed-type hypersensitivity skin However, humoral immune responses were unaffected [40].
response, humoral response to influenza vaccine, and infectious Furthermore selenium supplemented subjects also showed a more
morbidity and mortality showed that low-dose supplementation of rapid clearance of the poliovirus.
zinc together with selenium provides an increase to the humoral A 12-week lasting RCT on healthy adults, with sub-optimal se-
response after vaccination in comparison to the control group [33]. lenium concentration (<110 ng/ml), supplemented with daily
Antibody titers after influenza vaccine were higher in groups that capsules of yeast enriched with selenium showed both beneficial
received trace elements alone or with vitamins, whereas the vita- and detrimental effects [4]. In this study the immune response to
mins only group had significantly lower antibody titers [33]. The flu vaccine (immune challenge) was assessed in selenium supple-
number of patients without respiratory tract infections during the mented and control groups. Selenium supplementation resulted in
study was higher in groups that received trace elements (zinc a dose-dependent increase in T-cell proliferation, IL-8 and IL-10.
sulphate and selenium sulfide) [33]. However in another RCT However, positive effects were contrasted by lower granzyme B
neither daily multivitamin-mineral supplementation nor vitamin E content of CD8 cells. Furthermore, mucosal flu-specific antibody
(200 mg/day) showed a favourable effect on incidence and severity responses were unaffected by selenium supplementation [4]. A
of acute respiratory tract infections in well-nourished non-insti- similar RCT lasting 12-weeks showed that selenium supplemen-
tutionalized elderly [34]. On the contrary, this study noted an tation significantly improves selenoprotein W (SEPW1) mRNA,
increased severity, illness-duration, number of symptoms and re- while after an influenza vaccination, a dose dependent increase in
striction of activity in the group supplemented with vitamin E. selenoprotein S (SEPS1) gene expression was observed [41].
Furthermore, selenium supplementation has also demonstrated
3.2. Trace elements effects on the delayed type hypersensitivity (DTH) skin response
[42]. In this study low-selenium yeast (control group) induced
A summary of RCTs on trace element supplements that are anergy in DTH skin responses and increased counts of NK cells,
discussed below is presented in Table 2. while DTH skin responses in the high-selenium (treatment) group
were normal, suggesting that selenium supplementation blocked
3.2.1. Zinc the induction of DTH anergy [42].
Zinc is an essential trace element which plays an important role
in growth, development, and the maintenance of immune function 3.2.3. Copper
[35,36]. Zinc deficiency has been associated with an increased Copper plays a crucial role in immunity by participating in the
susceptibility to infectious diseases, including viral infections. development and differentiation of immune cells [43]. In-vitro
Studies have shown that the zinc status of an individual is a critical studies have shown that copper demonstrates antiviral properties.
factor that can influence immunity against viral infections, with For example, thujaplicin-copper chelates inhibit replication of hu-
zinc-deficient populations being at increased risk of acquiring in- man influenza viruses [44], while intracellular copper has been
fections, such as HIV or HCV [35]. Few RCTs have evaluated the shown to regulate the influenza virus life cycle [45]. Turnlund et al.
effect of zinc supplementation on the immune response. A study by conducted a study to determine the effect of long-term high copper
Acevedo-Murillo et al. among 103 children (1 monthe5 years) with intake on indices of copper status, oxidant damage, and immune
pneumonia showed a statically significant clinical improvement function [46]. Their results showed that plasma ceruloplasmin ac-
(duration of illness, respiratory rate and oxygen saturation) in the tivity, benzylamine oxidase, and superoxide dismutase were
zinc supplemented group compared to placebo [37]. They also significantly higher when copper intake was 7.8 mg/day, in com-
demonstrated an increase in the cytokine response in Th1 pattern parison to 1.6 mg/day, indicating an improvement in antioxidant
(IL-2 and INF-g) only in the zinc group, with Th2 cytokines (IL-4 and status. However, the higher copper intake (7.8 mg/day) significantly
IL-10) being elevated or remaining high in both groups. Another reduced the percentage of circulating neutrophils, serum IL-2R and
RCT on oral supplementation of high-dose zinc (150 mg/day) after the antibody titer against the Beijing strain of influenza [46].
stem cell transplantation, demonstrated that it enhances thymic
function and the output of new CD4þ naïve T cells, helping to 3.2.4. Magnesium
prevent the reactivation of TTV [3]. However, a study by Provincial Magnesium plays an important role in controlling immune
et al. concluded that although prolonged supplementation with function by exerting a marked influence on immunoglobulin syn-
zinc (400 mg/day) or zinc þ arginine (4 d/day) in the elderly (age thesis, immune cell adherence, antibody-dependent cytolysis,
64e100 years) restores zinc plasma concentrations, it is ineffective Immunoglobulin M (IgM) lymphocyte binding, macrophage
in inducing or ameliorating the antibody response or number of response to lymphokines, and T helper-B cell adherence [47].
CD3, CD4 or CD8 lymphocytes after influenza vaccination [38]. Although some in-vitro and in-vivo studies suggests that magne-
sium is likely to play a role in the immune response against viral
3.2.2. Selenium infections [48], our literature search was not able to identify any
Selenium is another trace element that has a wide range of RCTs that demonstrated a beneficial effect of magnesium supple-
pleiotropic effects, ranging from antioxidant effects to anti- mentation on immunity against viral infections.
inflammatory properties [39]. Low selenium status has been asso-
ciated with an increased risk of mortality, poor immune function, 3.3. Nutraceuticals supplements
and cognitive decline, while a higher selenium concentration or
selenium supplementation has shown antiviral effects [39]. This Nutraceuticals are products that claim physiological benefit or
has been demonstrated in a study by Broome et al., who evaluated protection against a chronic disease. These products may range
whether an increase in selenium intake (50e100 mg/day) improves from isolated nutrients, herbal products, dietary supplements,
immune function in adults with marginal selenium concentration genetically engineered designer foods, specific diets, and processed
[40]. Selenium supplementation increased plasma selenium con- foods, such as cereals, soups, and beverages [49]. Some nutra-
centrations, and lymphocyte phospholipid and cytosolic ceuticals have shown promising results in enhancing immune
Table 2
Immunological effect of Minerals.
Author; Nutrient Study Study population; Intervention; Purpose Significant anti-viral outcome
Published design; Sample size (I/C); Control;
Year; Duration; Male/Female; Dose/Frequency
Country Jadad score Age (years)
Iovino Zinc R, C; Patients IG: Zinc sulphate Investigate a possible therapeutic effect of Clinical: NA
et al. [3] 100 days; undergoing 600 mg/day (150 mg of zinc in improving the immune Immunological: CD4þ naïve lymphocytes
2018; 1.5 points autologous stem elementary zinc/day) reconstitution after stem cell and T-cell receptor excision circles showed
Italy cell transplantation CG: No placebo transplantation. a significant increase only in the IG.
for multiple Both groups received Moreover, the load of Torquetenovirus,
myeloma; standard therapy increased at day þ100 only in the CG.
9/9;
12/6;
47-72;
Acevedo- Zinc R, TB, PC; Children with IG: Zinc sulphate (10 mg Evaluate immunomodulatory effect of zinc Clinical: Higher improvement in the
Murillo Throughout Pneumonia; for <1-year-old or 20 mg supplementation in children with clinical status, respiratory rate and oxygen
et al. hospital 50/53; otherwise) pneumonia younger than 5 years old. saturation was seen IG compared to CG.
[37] stay; 57/46; CG: Placebo (glucose, Immunological: An increase in Interferon-
2019; 5 points 1 (month) e 5 20 mg) g (IFNg) and Interleukin-2 (IL-2) after
Mexico treatment in the IG was observed.
Provinciali Zinc or R, C; Elderly IG: Two groups a) Zinc Evaluate whether oral supplementation Clinical: Supplementation increased zinc
et al. Zinc plus 60 days; participants; sulphate (400 mg/day) b) with zinc or zinc/arginine increases the plasma concentrations restoring the age-
[38] arginine 1 point 33:34/31; Zinc sulphate (400 mg/ antibody response to influenza vaccine or related impairment in zinc concentrations.
1998; Both genders; day) with Arginine (4 g/ modulates lymphocyte phenotype in Immunological: The antibody titre against
Italy 64e100 day) elderly subjects. influenza viral antigens was not increased
CG: No placebo in both IGs in comparison with subjects
All groups received receiving vaccine alone. The number of
influenza vaccine CD3, CD4 or CD8 lymphocytes was also not
affected in both IGs.
Ivory et al. Selenium R, DB, PC; Healthy IG: Four groups a) Measure both cellular and humoral Clinical: NA
[4] 12 weeks; participants with Selenium 50 mg/day immune responses to flu vaccine in Immunological: Selenium-yeast increased
2017; 5 points suboptimal b) Selenium 100 mg/day healthy older individuals with marginal Tctx-Antibody-dependent cellular
UK Selenium (plasma c) Selenium 200 mg/day Selenium status after Selenium cytotoxicity cell counts in blood before flu
level <110 ng/ml); (a-c as Selenium yeast supplementation. vaccination and a dose-dependent
84/35; tablet) d) Selenium increase in T cell proliferation, IL-8 and IL-
65/54; 50 mg/day 10 secretion after in vivo flu challenge.
50e64 as enriched onions with Positive effects were contrasted by lower
meals granzyme B content of CD8 cells.
CG: Two groups e) Yeast Selenium-onions also enhanced T cell
without added selenium proliferation after vaccination, IFNg and
f) Non-enriched onions IL-8 secretion, granzyme and perforin
with meals content of CD8 cells but inhibited TNF-a
synthesis. Onion on its own reduced the
number of NK cells in blood. Mucosal flu-
specific antibody responses were
unaffected by Selenium supplementation.
Broome Selenium DB, PC; Healthy IG: Two groups a) 50 mg Assess whether administration of small Clinical: Selenium supplementation
et al. 15weeks; participants; (non- of Selenium/day (as selenium supplements to healthy subjects increased plasma selenium concentrations
[40] 2 points smoking); sodium selenite) leads to functional changes in immune and the body exchangeable selenium pool.
2004; 44/22; b) 100 mg of Selenium/ status and the rates of clearance and Immunological: Selenium
UK 33/33; day (as sodium selenite) mutation of a picornavirus supplementation increased lymphocyte
20e47 CG: Placebo (soybean oil phospholipid and cytosolic glutathione
with no selenium) peroxidase activity. Selenium
supplements augmented cellular immune
response through an increased production
of interferon and other cytokines, an
earlier peak T cell proliferation, an
increase in T helper cells and more rapid
clearance of poliovirus. Humoral immune
responses were unaffected.
Goldson Selenium R, DB, PC; Healthy IG: Five groups a) Determine effect of different doses and Clinical: NA
et al. 12 weeks; participants (non- Selenium 50 mg/day forms of Selenium on gene expression of Immunological: There was a significant
[41] 4 points smoking); b) Selenium 100 mg/day selenoproteins (SEPW1, SEPS1, SEPR) and increase in SEPW1 mRNA in the Se-
2011; 18:21:23:17:18/20; c) Selenium 200 mg/day responses to an immune function enriched onion group compared with
UK Both genders; (a-c, as enriched yeast) challenge (influenza vaccine). unenriched onion group. SEPR and SEPW1
50e64 d) Non-enriched onions did not change significantly over the
e) Enriched onions duration of the supplementation period in
(50 mg/day) the CG or Selenium-yeast groups, except at
(d-e with meals) week 10 when SEPW1 mRNA levels were
CG: Placebo significantly lower in the 200 mg/day
Selenium-yeast group compared to the CG.
Levels of SEPS1 mRNA increased
significantly 7 days after the influenza
vaccine challenge, the magnitude of the
increase in SEPS1 gene expression was
(continued on next page)
Author; Nutrient Study Study population; Intervention; Purpose Significant anti-viral outcome
Published design; Sample size (I/C); Control;
Year; Duration; Male/Female; Dose/Frequency
Country Jadad score Age (years)
dose-dependent, with a significantly

greater response with higher Se
supplementation.
Hawkes Selenium R, DB, C; Health participants; IG: High selenium yeast Study whether an increased intake of Clinical: Supplementation increased
et al. 48 weeks; 42* tablet (Baker’s yeast with dietary selenium affects immune function selenium levels by 50%.
[42] 3 points NM; sodium selenite, 300 mg Immunological: Consumption of the low-
2009; 18e45 selenium/tablet) selenium yeast induced anergy in delayed
USA CG: Low selenium yeast type hypersensitivity (DTH) skin
tablet (Baker’s yeast responses and increased counts of Natural
without sodium selenite, killer (NK) cells and T lymphocytes
<1.3 mg/tablet) expressing both subunits of the high
affinity IL2R. DTH skin responses and
IL2R þ cells did not change in the high-
selenium group, suggesting Se
supplementation blocked induction of
DTH anergy. No differences between
groups in other leukocyte phenotypes,
serum immunoglobulins, or complement
factors.
Turnlund Copper C; Healthy I: Copper with meals Determine the effect of long-term high Clinical: NA
et al. 148 days; participants; 0e18 days - 1.6 mg per copper intake on indexes of copper status, Immunological: Ceruloplasmin activity,
[46] 1 point 9/10; day oxidant damage, and immune function benzylamine oxidase, and super-oxide
2004; 19:0; 19e129 days e 7 mg per dismutase were significantly higher at the
USA 38 ± 7 day end of the second period than at the end of
130e148 days - 7.8 mg the first. Polymorphonuclear cell count,
per day the percentage of white blood cells,
C: No placebo lymphocyte count, and IL2R were affected
by copper supplementation. Antibody titre
for the Beijing strain of influenza virus was
significantly lower in IG after
immunization than in CG.
* Group allocation not mentioned; C e Controlled; CD e Cluster of differentiation; CG e Control group; DTH e Delayed type hypersensitivity; IFN e Interferon; IG e
Intervention group; IL e Interleukin; MRU - Metabolic research unit; NK e Natural killer cells; NA e Not applicable; NM e Not mentioned; PC e Placebo controlled; R e
Randomized; TB e Triple blind; SEP e selenoproteins; TNF e Tumour necrosis factor.
function. A very recent study by McCarty et al. reported that certain infections taking into consideration the current epidemic of COVID-
nutraceuticals may help provide relief to people infected with 19. This comprehensive review reports evidence on several vita-
encapsulated RNA viruses, such as influenza and coronavirus by mins, particularly A, D and E, as well as few trace elements, such as
boosting immune responses [6]. Our study found 18 RCTs con- zinc and selenium. Furthermore, a large number of nutraceuticals
ducted on nutraceuticals as shown in Table 3 [50e67]. All studies, and several probiotics have also shown immune enhancing effects
except the prebiotic study, showed enhanced immune responses for either preventing or treating viral infections, especially
after treatment [52]. influenza-like illnesses.
Several vitamins are essential for the proper functioning of the
3.4. Probiotic supplements immune system [1]. A well balanced and varied diet is essential not
only to minimize vitamin deficiencies, but also to avoid unnec-
Probiotics are defined as live micro-organisms that confer a essary excess consumption or supplementation [74]. According to
health benefit to the host, including on the gastrointestinal tract, our findings, vitamin supplementation, especially vitamin D may
when administered in adequate amounts [68]. They also stimulate be beneficial in people who are either deficient or insufficient.
immune response by increasing the antibody production [69]. The Theoretically, vitamin E is a potent antioxidant and has an ability to
results of a meta-analysis by Kang et al. implied that probiotics have modulate the host immune functions. However, most of studies in
a modest effect in common cold reduction [7]. Our review found 4 our review reported adverse effects of vitamin E supplementation
studies on probiotics [70e73], where Lactobacillus and Bifido- on the immune response. Similarly, evidence does not support
bacterium strains have been used as treatments (Table 4). All these supplementation of vitamin E in cardiovascular disease and cancer
studies have found that probiotic supplementation either reduces prevention. In fact, high-dosage of vitamin E supplementation may
the severity or shortens the duration of infection. Three of these increase all-cause mortality. Similar to vitamins, several trace ele-
studies showed the efficacy of Lactobacillus for treatment of res- ments are essential for proper immune functions. A disrupted zinc
piratory tract infection of viral origin [70e72]. The remaining study homeostasis affects immune cells by several mechanisms leading
highlighted a significant association between Bifidobacterium and to abnormal lymphopiesis, disturbed intercellular communication
increased immune function and intestinal microbiota in elderly via cytokines, and poor innate host defense via phagocytosis and
[73]. oxidative burst [75]. Similarly selenium has a complex immuno-
logical mechanism but mainly through its incorporation into sele-
noproteins [76]. Currently nutraceuticals have received
4. Discussion
considerable interest for their properties in improve general health,
prevent diseases and delay ageing and increase life expectancy [77].
To the best of our knowledge, this is the first systematic review
Although cellular mechanism on immunomodulating effects of
reporting nutritional interventions to enhance immunity in viral
Table 3
Immunological effect of Nutraceuticals.
Author; Nutrient Study Study Intervention; Purpose Significant anti-viral outcomes

Country Jadad C);
score Male/Female;
Age (years)
Ahmed Polyphenol-enriched R, DB, PC; Healthy long- IG: Blueberryegreen tea- Study the protective effects of aClinical: NA
et al. [50] protein powder 17 days; distance polyphenol soy protein complex polyphenol-enriched protein Immunological: A significant
2014; 2 points runners; (PSPC) powder on exercise-induced difference in ability of serum from
USA 16/15; CG: Soy protein isolate, with non- susceptibility to viral infectionIG versus CG athletes to protect cells
Both genders; polyphenolic food in culture from killing by vesicular
19e45 40 g/day; 2 doses (20 g/morning, stomatitis virus following strenuous
20 g/lunch) exercise. Serum of subjects who
ingested PSPC significantly delayed
an exercise-induced increase in
virus replication.
Brull et al. Plant stanol ester R, DB, PC; Asthma IG: Plant stanol enriched soy- Evaluate in-vivo the plant stanol Clinical: NA
[51] 8 weeks; patients; based yogurts, 4 g esters effect on the immune Immunological: IG showed higher
2016; 3 points 29/29; CG: soy-based yogurt without response in asthma patient antibody titres against hepatitis A
Netherland 16/42; added plant stanol esters, 4 g virus post-vaccination. Substantial
18e70 4 g plant stanols/day reductions in plasma IgE, IL-1ß, and
TNF-⍺ shown in IG. Increase in
serum plant stanol concentrations
correlated significantly with
decrease in IL-13 and Th1 switch in
Th1/Th2 balance. No absolute
differences in cytokine production
between groups.
Bunout Prebiotic mixture R, SB, PC; Healthy IG: Prebiotic mixture (70% Study the effect of prebiotics on Clinical: NA
et al. [52] 28 elderly raftilose and 30% raftiline), 3 g the immune response to Immunological: No changes in
2002; weeks; participants; sachet vaccination in the elderly serum proteins, albumin,
Switzerland 4.5 20/23; CG: Maltodextrin powder, 3 g immunoglobulins, and secretory
points NM; sachet IgA. Antibodies against influenza B
70 6 g/day (Two 3 g sachets/day) increased significantly from weeks
0e8, with no significant differences
between groups. Antibodies against
influenza A did not increase. No
effects of prebiotics on IL-4 and INF
secretion by cultured monocytes
were observed.
De Luca Coenzyme Q 10, R, DB, PC; Patients with IG: Coenzyme Q 10 (12.5 mg), Study the ability of a nutraceutical Clinical: The nutraceutical induced
et al. [53] Vitamin E, Selenium 6 HPV skin vitamin E (12.5 mg), selenium mixture to accelerate recovery and significantly faster healing with
2012; aspartate, and L- months; warts; aspartate (12.5 mg), and L- inhibit recurrences of a chronic reduced incidence of relapses as
Italy methionine 2 points 36/32; methionine (50 mg), in soy muco-cutaneous DNA-virus compared to CG
36/32; phospholipids (147 mg) per infections Immunological: IG had decreased
I: 31.4 ± 9.7 capsule viral load and increased antiviral
C: 30.5 ± 9.6 CG: Soy phospholipids (147 mg) cytokine and peroxynitrite plasma
per capsule levels. Plasma antioxidant capacity
4 capsules/day was higher in IG versus CG.
Elsaid et al. Arabinoxylan rice R, DB, PC; Healthy IG: Sachets with Biobran/MGN-3 Study whether arabinoxylan rice Clinical: NA
[54] bran (Biobran/MGN- 1 month; elderly (500 mg), maltitol (1000 mg), bran (Biobran/MGN-3) could Immunological: IG had no effect on
2018; 3) 3 points participants; dextrin (200 mg), hydroxypropyl counteract this decline in NK/NKT the total percentage of NK cells,
Egypt 6/6; distarch phosphate (280 mg), and cell activity in elderly however IG had enhanced cytotoxic
6/6; tricalcium phosphate (20 mg). activity of induced NK cell
56 CG: Sachets with maltitol expression of CD107a, when
(1000 mg), dextrin (200 mg), compared with baseline values and
hydroxypropyl distarch with the CG.
phosphate (780 mg), and
tricalcium phosphate (20 mg)
1 sachet per day
McElhaney COLD-fx: Root extract R, DB, PC; Healthy IG: Extract from Panax Study efficacy of COLD-fX in the Clinical: Frequency and duration of
et al. [55] of North American 4 elderly quinquefolium, containing 90% prevention of respiratory acute respiratory infections during
2006; ginseng (Panax months; Participants; polyfuranosyl-pyranosyl- symptoms in community- the first two months was found
Canada quinquefolium) 5 points 22/21; saccharides, 200 mg/capsule dwelling adults similar in both groups. However,
21/22; CG: microcrystalline cellulose, during the last 2 months
65 200 mg/capsule significantly fewer subjects in the
2 capsules (400 mg/day) every COLD-fX group had acute
morning respiratory infections. The duration
of symptoms during the last 2
months was significantly shorter in
the COLD-fX group.
Immunological: NA
Moyad EpiCor: a dried R, DB, PC; Healthy IG: EpiCor: A Saccharomyces Determine if EpiCor taken daily Clinical: Subjects receiving EpiCor
et al. [56] Saccharomyces 12 participants cerevisiae fermentate, 500 mg/ reduces the incidence and experienced a statistically
(continued on next page)

Country Jadad C);
score Male/Female;
Age (years)
2008; cerevisiae fermentate weeks; recently capsule duration of colds or flu-like significant reduction in the
USA (modified yeast) 4 points vaccinated CG: identical placebo, 500 mg/ symptomatic features in healthy incidence and duration of colds or
for influenza; capsules individuals recently vaccinated flu.
52/64; 1 capsule (500 mg/day) every against seasonal influenza. Immunological: NA
50/66; morning
18e76
Muller et al. Broccoli sprout R, DB, PC; Healthy IG: BSH e a shake was about 200 g Study the effect of Broccoli sprouts Clinical: NA
[57] homogenates (BSH) 4 days; participants; (containing about 111 g of fresh and Live Attenuated Influenza Immunological: LAIV significantly
2016; 5 points 13/16; broccoli sprouts) daily Virus (LAIV) on Peripheral blood reduced NKT (day 2 and 21) and T
USA 10/19; CG: Similar dose of alfalfa sprout NK cells cell (day 2) populations. LAIV
I: 25.5 ± 1.5 homogenate (ASH) daily Decreased NK cell CD56 and
C: 27.6 ± 1.5 CD158b expression, while
significantly increasing CD16
expression and cytotoxic potential
(day2). BSH supplementation
further increased LAIV-induced
granzyme B production (day 2) in
NK cells compared to ASH and in
BSH group granzyme B levels
appeared to be negatively
associated with influenza RNA
levels in nasal lavage fluid cells.
Nabeshima Maoto R, C; Influenza IG: Maoto granules 2.5 g three Compare the efficacy of Maoto Clinical: No significant between-
et al. [58] (multicomponent 5 days; patients; times/day with neuraminidase inhibitors in group differences were found in
2012; formulation extracted 3 points 10/18 (8:10); CG: Oseltamivir 75 mg two times/ the treatment of seasonal total symptom score among three
Japan from four plants: 14/14; day (n ¼ 8) or Zanamivir 20 mg influenza groups.
Ephedra Herb, Apricot 20e64 two times/day (n ¼ 10) Immunological: Viral persistent
Kernel, Cinnamon rates and serum cytokine levels
Bark, and Glycyrrhiza (IFN-a, IL6, IL-8, IL-10, and TNF-a)
Root during the study period showed no
differences among 3 groups. Hence
the clinical and virological efficacy
of Maoto was similar to
neuraminidase inhibitor
Nantz et al. Aged Garlic Extract R, DB, PC; Healthy IG: AGE capsule 2.56 g/day Study the effect of aged garlic Clinical: After 90 days illness diary
[59] (AGE) powder 90 days; participants; CG: Placebo capsule extract on immune function and entries showed that the incidence of
2012; 5 points 56/56; 4 capsules/day the severity of cold and flu colds and flu, a secondary outcome,
USA 49/63; symptoms were not statistically different.
21e50 However, IG appeared to have
reduced severity and a reduction in
the number of days and incidences
where the subjects functioned sub-
optimally and the number of work/
school days missed due to illness.
Immunological: After 45 days of
consuming of AGE, gd-T cells and
NK cells were shown to proliferate
better compared to CG.
Nantz et al. Cranberry R, DB, PC; Healthy IG: Cranberry beverage (cranberry Evaluate ability of cranberry Clinical: In the IG, the incidence of
[60] polyphenols 10 participants; components from juice, filtered phytochemicals to modify illness was not reduced, however
2013; weeks; 22/23; water, sugar, natural flavors, citric immunity, specifically gd-T cell significantly fewer symptoms of
USA 5 points 14/31; acid, and sucralose), 450 ml/bottle proliferation illness were reported.
21e50 CG: Placebo beverage (color-Red Immunological: The proliferation
40 and Blue 1), calorie-, and index of gd-T cells in culture was
sweetener-matched beverage almost five times higher after 10
without cranberry components), weeks in IG compared to CG.
450 ml/bottle
1 bottle to be taken through the
day
Negishi Mekabu fucoidan R, DB, PC; Healthy IG: granules with 300 mg of MF Study immune response to Clinical: NA
et al. [61] (MF) (a sulphated 4 weeks; elderly and 300 mg of dextrin seasonal influenza vaccination Immunological: The IG had higher
2013; polysaccharide 5 points participants; CG: granules with 600 mg dextrin after supplementation of Fucoidan antibody titres against all 3 strains
Japan extracted from 35/35; only from seaweed contained in the seasonal influenza
seaweed) 6/64; Granules mixed with lunch and virus vaccine than the placebo
>60 taken daily group. In the IG, natural killer cell
activity tended to increase from
baseline 9 weeks after MF intake,
but not in CG.
Raus et al. Influenza IG: Echinaforce Hotdrink Clinical: Recovery from illness was
[62] patients; 3 days (5 5 ml), followed by comparable in both groups at days

Country Jadad C);
score Male/Female;
Age (years)
2015; Echinaforce Hotdrink R, DB, C; 203/217; (3 5 ml) on the following 7 days Compare a new echinacea 1, 5 and 10. Non-inferiority was
Germany (Echinacea purpurea 10 days; 210/210; CG: Oseltamivir 75 mg two times/ formulation with oseltamivir, in demonstrated for each day and
plant extract) 5 points 12e70 day for 5 days followed by 5 days the treatment of influenza overall. Echinaforce Hotdrink is as
of placebo effective as oseltamivir in early
treatment of clinically diagnosed
and virologically confirmed
influenza virus infections.
Immunological: NA
Roman AHCC (Active hexose R, C; Healthy IG: AHCC capsule 3 g/day To study immune response to Clinical: NA
et al. [63] correlated 3 weeks; participants; C:G No placebo used influenza vaccine with AHCC Immunological: Flow cytometric
2013; compound), a 2 points 14/15; supplementation. analysis of lymphocyte
USA Basidiomycetes 16/13; subpopulations revealed that AHCC
mushroom extract I: 60.8 ± 4.0 supplementation significantly
C: 57.8 ± 5.3 increased NKT cells and CD8 T cells
post-vaccination compared to CG.
Analysis of antibody production 3
weeks post-vaccination revealed
that AHCC supplementation
significantly improved protective
antibody titres to influenza B, while
the improvement was not
significant in the CG.
Thies et al. Five types of R, DB, PC; Healthy IG: oils rich in ALA, GLA, AA, DHA, Determine effect of dietary Clinical: NA
[64] capsulated oil blends 12 participants; or EPA plus DHA) Each capsule supplementation with oil blends Immunological: The fatty acid
2001; (parallel intervention) weeks; 38(ALA:8; contained 445 mg of the oil blend. rich in ALA, GLA, AA, DHA, or EPA composition of plasma
UK Flaxseed oil (ALA), 4 points GLA:7; 9 capsules/d plus DHA (fish oil) on the NK cell phospholipids changed significantly
Evening primrose oil AA: 8; DHA:8; CG: placebo oil (an 80:20 mix of activity of human peripheral blood in the GLA, AA, DHA, and fish oil
(GLA), Arachidonic FO:7)/8 palm and sunflower seed oils) mononuclear cells groups. NK cell activity was not
Acid (AA), 24/22; significantly affected by the placebo,
docosahexaenoic acid 55e75 ALA, GLA, AA, or DHA treatment.
(DHA) and Fish oil Fish oil caused a significant
(FO) reduction in NK cell activity that
was fully reversed by 4 weeks after
supplementation had ceased.
Tiralongo Elderberries R, DB, PC; Healthy IG: Elderberry capsules (300 mg of Determine if a standardised Clinical: Most cold episodes
et al. [65] (Sambucus nigra) 15e16 participants elderberry extracts) membrane filtered elderberry occurred in the CG; however, the
2016; days; (economy CG: Placebo capsules priming extract has beneficial effects, difference was not significant. CG
Australia 5 points class phase 2 capsules/day (600 mg/ respiratory, and mental health in participants had a significantly
passengers day) while travelling and overseas air travellers longer duration of cold episode days
travelling 3 capsules/day (900 mg/day) and the average symptom score
overseas); over these days was also
158/154 significantly higher. A significant
106/206; reduction of cold duration and
18 severity in air travellers with
elderberry capsule.
Immunological: NA
Yakoot & Spirulina platensis R, DB, C; Chronic IG: Spirulina 500 mg dry powder Study effects of Spirulina platensis Clinical: NA
Salem (cynobacterium) 6 hepatitis C extract capsule versus silymarin in the treatment Immunological: In Spirulina group 4
[66] months; patients; CG: Silymarin 140 mg capsule of chronic hepatitis C virus patients had a complete end of
2012; 5 points 30/29; One capsule 3 times/day infection. treatment virological response and
Egypt Both genders; 2 patients had partial response.
18e70 However, the difference was not
statistically significant at the end of
both 6 months.
Zunino Freeze-dried grape R, DB, Obese adults; IG: One packet with 46 g of grape Study influence of dietary grapes Clinical: NA
et al. [67] powder (Vitis vinifera) CO; 24/24; powder on Inflammation in obese adults Immunological: No difference was
2014; 9 weeks; 8/16; CG: One packet with 46 g, similar observed for the production of T-
USA 4 points 20e50 flavour with food starch and cell cytokines between groups. The
tapioca maltodextrin, two production of TNF-⍺ was increased
potassium salts and silicon in the supernatants from
dioxide lipopolysaccharide-activated
2 packets/day (morning and peripheral blood mononuclear cells
night) in IG. A modest increase in the
proliferation of the CD8 T-
lymphocyte population was
observed at 24h post-activation.
AA e Arachidonic acid; AGE e Aged garlic extract; AHCC e Active hexose correlated compound; ASH - Alfalfa sprout homogenate; BSH e Broccoli sprout homogenates; C e
Controlled; CD e Cluster of differentiation; CO e Cross-over; CG e Control group; DB e Double blind; DHA e Docosahexaenoic acid; DNA - Deoxyribonucleic acid; FO e Fish oil;
HPV e Human papilloma virus; IG e Interventional group; IgA e Immunoglobulin A; IgE e Immunoglobulin E; IL e Interleukin; INF e Interferon; LAIV e Live attenuated
influenza virus; MF e Mekabu fucoidan; NA e Not applicable; NK e Natural killer cells; NM e Not mentioned; PC e Placebo controlled; PSPC - Polyphenol soy protein complex;
R e Randomized; SB e Single blind; Th e T helper cells; TNF e Tumour necrosis factor.
Table 4
Immunological effect of Probiotics.

Published design; population; Control; Dose/
Year; Duration; Sample size Frequency
Country Jadad (I/C);
score Male/
Female;
Age (years)
Akatsu Probiotic R, DB, PC; Elderly fed IG: BB536 powder Study effects of supplementation Clinical: NA
et al. Bifidobacterium longum 12 weeks; by enteral 2 g/sachet with Bifidobacterium longum on Immunological: BB536 intake significantly
[73] (BB536) 5 points tube; CG: Placebo powder immune function and intestinal increased cell numbers of bifidobacteria in
2013; 23/22; (an internal matrix, microbiota in elderly faecal microbiota. There was a tendency
Japan 13; 32 consisting mainly of toward an increase of serum IgA in IG
>65 dextrin), 2 g/sachet compared with CG. BB536 intake did not
1 sachet two times/ significantly affect hemagglutination
day (4 g/day) inhibition titres in response to influenza
vaccine. NK cell activity decreased
significantly in CG but not in IG.
Berggren Probiotic lactobacilli R, DB, PC; Healthy IG: Probiotic sachet, Investigate whether consumption of Clinical: Incidence of acquiring one or
et al. Lactobacillus plantarum HEAL 12 weeks; participants; Lyophilised probiotic lactobacilli could affect more common cold episode, number of
[70] 9 (DSM 15312) and 4 points 137/135; lactobacilli and naturally acquired common cold days with common cold symptoms and
2011; Lactobacillus paracasei 92/180 maltodextrin, 1g infections in healthy subjects. total symptom score was reduced
Sweden 8700:2 (DSM 13434) 18e65y sachet significantly in IG. Reduction in pharyngeal
CG: Placebo powder symptoms was significant.
(maltodextrin), 1 g/ Immunological: Proliferation of B
sachet lymphocytes was significantly
1 sachet/day (1 g/ counteracted in IG in comparison with CG.
day)
Boge et al. Probiotic Actimel® R, DB, C; Healthy IG: Actimel® 100 g/ Investigate effect of regular Clinical: NA
[71] A fermented dairy drink with 13 weeks; elderly bottle consumption of probiotic drink Immunological: Titres against the
2009; probiotic strain 5 points participants; CG: a non- Actimel® on specific antibody influenza B strain increased significantly
France Lactobacillus casei 113/109; fermented control responses to influenza vaccination more in the IG. Significant differences in
DN-114001 (CNCMI-1518), 74/148 dairy product 100 g/ in healthy elderly. seroconversion between the groups by
combined with ferments in 70y bottle intended to treat analysis were still found 5
yoghurt, Streptococcus Two bottle/day months after vaccination.
thermophilus and (200 g/day)
Lactobacillus bulgaricus
de Vrese Probiotic bacteria R, DB, PC; Healthy IG: Tablet with Investigate the effect of long-term Clinical: Intake of probiotic had no effect
et al. Lactobacillus gasseri 3 and 5 participants; spray dried consumption of probiotic bacteria on incidence of common cold infections,
[72] PA 16/8, months (2 158/153; probiotic 5 107 cfu on viral respiratory tract infections but significantly shortened duration of
2006; Bifidobacterium longum winter/ Both plus vitamins and episodes by almost 2 days and reduced the
Germany SP 07/3, spring genders; minerals severity of symptoms.
Bifidobacterium bifidum periods); 18e67 CG: Tablet with Immunological: IG had a larger increase in
MF 20/5 3 points vitamin minerals cytotoxic T plus T suppressor cell counts
only and in T helper cell counts.
1 tablet/day
BB536 e Bifidobacterium longum 536; CG e Control group; DB e Double blind; IG e Interventional group; IgA e Immunoglobulin A; NA e Not applicable; NK e Natural killer
cells; PC e Placebo controlled; R e Randomized.
various nutraceuticals are not well understood, one of the possible conducted by El-Kader and Al-Jiffri, in 100 obese patients with
mechanism is anti-oxidant and anti-inflammatory activities of chronic HCV infection, identified that the mean values of white
nutraceuticals [77]. Our review has reported several beneficial blood cells, total neutrophil count, monocytes, CD3, CD4 and CD8
nutraceuticals, however it is important to note that the efficacy and lymphocytes were significantly decreased in the group that un-
safety of nutraceuticals depend on their ingredients, as well as derwent a weight loss program in comparison to the control group
various other factors including, methods of extraction [78]. Pro- [84].
biotics regulate the functions of systemic and mucosal immune A few limitations of this review shall be highlighted; first, a
cells and intestinal epithelial cells of the host to regulate immune meta-analysis has not been performed due to heterogenicity of
function [79], but not all probiotics demonstrate similar health studies, especially in relation to reported outcomes. Secondly, we
benefits [80], therefore, probiotic products should be carefully excluded a large quantum of research on supplementation of
selected depending on the clinical situation, in order to obtain the different nutrients for patients with HIV infection. However, we
relevant beneficial effect. believe including clinical trials on HIV may dilute the well-timed
In addition to micronutrients, obesity has long been associated message of this review, targeting respiratory infection, like
with higher risks of chronic non-communicable diseases. However, COVID-19. Furthermore, quality assessment using the Jadad scale
recent evidence suggests that it may also be associated with in- identified 13 studies (<30%) with a score <3 points, indicating poor
fectious diseases [81]. Very recent clinical findings of patients with methodological quality. However, these were not excluded, espe-
COVID-19 shows severity of the disease is independently associated cially since a meta-analysis was not performed for pooled esti-
with BMI 28 kg.m-2 (OR, 5.872; 95% CI, 1.595 to 21.621; P ¼ 0.008) mates. Furthermore, another 24 studies (>54%) had a score >3,
[82]. Translational data suggested that an alteration in the meta- indicating acceptable/good methodological quality. Finally,
bolic profile of T cells in obese individuals impairs the activation although exercise is one of the lifestyle changes that is known to
and function of these critical adaptive immune cells [83]. A RCT increase immunity and reduces viral infection [85], we consider
reviewing the effects of exercise on immune function beyond the COVID-19 pandemic. In the absence of specific prophylaxis or
scope of the present review. Same applies for other parameters that vaccination for this viral infection, below recommendation will be
can alter the immune capacity, e.g. stress [86]. Furthermore, a large helpful for prevention and treatment of patient with COVID-19.
quantum of in-vitro and in-vivo animal studies have been con-
ducted on antiviral effects of vitamins, trace elements and nutra- 4.1. Recommendations for prevention and treatment of viral
ceuticals against several viral diseases including influenza virus infections
[87,88]. However, it is difficult to draw conclusions on efficiency
and safety or derive recommendations for human use from these Recommendations are summarized in Table 5. In addition to
studies. Therefore, these require further exploration through well- basic hygienic practices, proper dietary and lifestyle behaviors are
designed human clinical trials, especially considering the current essential for prevention and treatment of respiratory viral diseases,
Table 5
Recommendations for prevention or treatment of viral infections.
Condition/ Prevention Treatment Dose Food sourcesa

nutrient
Healthy Follow local food based dietary guideline [89] Initial nutritional screening using validated NA NA
nutritional assessment tool (e.g. NRS-2002) and
treat accordingly [100]
Malnutrition Those with protein-energy malnutrition require structured Refer to dieticians/nutritionist. Personalized NA NA
dietary advices focusing on increasing calories. Furthermore, dietary advices are required with support of
they may require MVM [90] ONS and MVM.
Obesity Follow caloric restricted dietary plan covering all major food Weight loss not advisable [83] NA NA
groups in adequate portions, under health specialist
supervision [81,82,92]
Diabetes Foods with low glycemic index, limit consumption of high fat Refer to dieticians/nutritionist. Personalized NA NA
and starchy or sugary foods, and choose lean protein variety dietary advices are required [102,103]
[93]
Energy intake No change Increase by 10% [101] NA NA
Multi- Supplementation may be effective for vulnerable population Supplementation may be effective for those P:1 x RDI NA
nutrients and those who have poor dietary practices [33,91] who have poor dietary intake before and during T: 1x RDI
the illness [91]
Vitamin A Supplementation may be effective [2,16] Supplementation may be effective [2,16] P:5000IU/ AS: Liver, eggs, milk, cheese
d V:Dark green leafy
T:20000IU/ vegetables, carrots, mangos,
d papayas, sweet potatoes
Vitamin D Supplementation may be effective especially those who are Measure serum vitamin status and treat P: 5000IU/ AS: Oily fish (salmon,
deficient and those who are in self-quarantine [21,23,97,98] accordingly [22,24,25,98]. d sardines), egg yolk, liver
T:10000IU/ V: Mushrooms
d
Vitamin E Supplementation may be harmful [27,28] Supplementation may be harmful [29,30,34] P:NR AS: Eggs, tuna, salmon
T:NR V: Wheat germ, sunflower
seeds, sunflower oil, almonds,
peanuts,
Vitamin C Supplementation unlikely to be beneficial [32] Supplementation may be effective [32] P:NR AS: liver, oyster
T:1 g/d V: citrus fruits, guava,
strawberries, pineapple,
broccoli, tomato,
Zinc Supplementation may be effective [35] Supplementation may be effective [3,37,38] P:20 mg/d AS: Oysters, beef, pork,
T:150 mg/ chicken
d V: Backed beans, cashews,
pumpkin seeds, almonds,
peas
Selenium Supplementation may be effective [4,40,41] Supplementation may be effective [4,42] P:50 mg/d AS: Turkey, eggs, pork,
T:200 mg/d chicken, milk
V: Brazilnuts, sunflower
seeds, Tofu, whole grain
cereals
Cooper Supplementation may be effective [46] Supplementation unlikely to be beneficial P:1.6 mg/d AS: Oysters, shellfish, organ
T:NR meats
V: wheat-bran cereals, whole-
grain products, seeds and
nuts
Magnesium Supplementation unlikely to be beneficial Supplementation unlikely to be beneficial P:NR AS: salmon, chicken, beef
T:NR V: Green leafy vegetables,
legumes, nuts, seeds, and
whole grains
Nutraceuticals Supplementation could be beneficial depending on the Supplementation could be beneficial depending Depend on Garlic, oily fish, cranberry
ingredient [50,54e57,59e61,63e65,67] on the ingredient [51,53,58,62,66] the juices, broccoli sprouts
product
Probiotics Supplementation could be beneficial depending on the strain Supplementation could be beneficial depending Depend on Yogurt, curd
[70e72] on the strain [7,70e72] the
product
a
Food sources are from USDA database, MVM - Multivitamin/mineral Supplements; ONS - Oral nutritional supplements; RDI: Recommended Daily Intake; NA: Not
applicable; NR: Not recommended; AS- Animal sources; V- Vegetarian sources.
such as COVID-19. Everyone including self-quarantine patients are assessment, they are all required to be tested for serum vitamin D
encouraged to follow food based dietary guidelines from their levels, and if facilities are available, it is recommended to assess
respective national governing bodies, in addition to recommenda- micronutrient deficiencies. According to serum vitamin D levels,
tions given below [89]. For example, everyone should consume at deficient or insufficient patients must receive therapeutic doses of
least five portions of fruit and vegetables each day and all main vitamin D according to local guidelines [98]. Other vitamin de-
meals should contain starchy carbohydrate preferably a wholegrain ficiencies also should be treated accordingly. MVM (1xRDI) can be
variety. Moreover, two to three portions of meat or equivalent (for recommended to most patients with viral infections especially
vegetarians: pulses and other suitable protein rich foods) should be those who have poor dietary intake during the illness [91]. Patients
included on a daily basis [89]. However, taking multi-vitamin- receiving intensive care facilities should be treated by a critical care
mineral (MVM) supplement for a short period at least during this dietician/nutritionist. Furthermore, some patients may need oral
pandemic many be beneficial, since achieving a well-balanced and nutrition supplement (ONS) to achieve recommended calories and
varied diet is difficult due to several logistics and financial diffi- protein intake. Resting energy expenditure increases by 10% during
culties during lockdowns or self-quarantine. Furthermore, those viral infection, which should be considered and energy intake
who are malnourished or at risk of malnutrition should take extra should be increased by 10% during the illness [101]. Among trace
precautionary care to improve their energy, protein and micro- elements, zinc (150mg/daily) and selenium (200 mg/daily) supple-
nutrient levels [90]. Ideally, a trained dietician or nutritionist mentation could be beneficial to improve immunity during viral
should prescribe diet, after taking into considering socio-economic infections [4,37]. Along with proper energy and nutritional intake,
factors. In addition to protein and energy malnutrition, the pres- several nutraceuticals and Lactobacillus containing probiotics can
ence of micronutrient deficiency should be identified early and be supplemented to improve the immunity of the patients with
corrected by therapeutic doses of the respective micronutrient. In viral infections [70,72]. Furthemore, it has been observed that pa-
the absence of the individual micronutrient deficiencies, every tients with diabetes have severe disease progression and higher
malnourished should take a MVM supplement [91]. On the other mortality [82] therefore it is recommended to provide a personal-
hand, a patient with excess body weight (BMI>25 kg m2) should ized diet with help of qualified nutritionist/dietician and hospital
lose at least 5% body weight over a period of 12 weeks to improve catering system [102]. Gupta et al. recently listed clinical consid-
their immunity [92]. Patients with diabetes mellitus require a var- eration for patients with diabetes with regards to COVID-19 [103].
ied and balanced diet to maintain blood glucose and enhance im-
mune functions [93], they should give priority to foods with low
5. Conclusion
glycemic index, limit consumption of high fat and starchy or sugary
foods, and choose lean protein variety [93].
For a viral disease like COVID-19, where no pharmacological
Furthermore, it is important to remember that micronutrient
strategies for prevention or treatment are presently available and
deficiencies such as Vitamin D and B12 are well documented in the
where the exact time of the ending of the alarming situation is
South Asian countries [94]. Micronutrient deficiencies are highly
unknown, nutritional strategies for enhancing immunity is some-
prevalent even in high-income countries, especially among
thing to be explored. In addition to treating malnutrition and
vulnerable populations such as infants, children, adolescents, dur-
weight reduction in obese healthy subjects, in this review we have
ing pregnancy and lactation and the elderly [95]. Those who have
highlighted the potential preventive and therapeutic application of
restricted dietary habits such as food allergies, vegetarian of any
few vitamins, trace elements, several nutraceuticals and probiotics.
subtype and those who have chronic diseases are also at a high risk
In the current global context with limited movements, it is difficult
for micronutrient deficiencies [96]. It is safe to consume MVM on a
to obtain a balanced and varied diet. Therefore, achieving recom-
daily basis to optimize nutritional needs and maintain satisfactory
mended amounts of calories and micronutrient will be a challenge
immune function in such circumstances [91]. With regards to the
and elective micronutrient supplementations may be beneficial
global vitamin D deficiency especially in the population of the
especially for vulnerable populations such as the elderly.
northern hemisphere during the winter, supplementation of
vitamin D (5000IU/daily) may be effective for both high risk e.g.
diabetes and obese individuals, and self-quarantined individuals Icmje form
[97]. Toxicity of vitamin D is rare and moderately high doses
(2000e5000 IU/daily) can be taken for years [98]. The common Not relevant since this is a review.
practice of taking high dose of vitamin C and E found to be ineffi-
cient to enhance immunity except vitamin E for viral hepatitis Funding
[32,34]. Nearly 1/5 of the world’s population is at risk of inadequate
zinc intake [99], hence we recommend the supplementation of zinc The authors received no external or internal funding for this
(20mg/daily) for optimal immune function [11]. Similarly, selenium study.
supplementation (50mg/daily) has shown beneficial effect for
enhancing immunity.
Authors’ contributions
Regarding nutraceuticals, many single and combined products
have shown effectiveness in enhancing immunity in viral infections
RJ devised the conceptual idea. RJ and PR searched databases. RJ,
including influenza. Depending on the availability; many nutra-
PS and PR were involved in retrieving data. RJ, PR and PS drafted the
ceuticals can be used to enhance immunity. Among over 20
manuscript. CJ provided immunological inputs. RJ and MC made
different products; garlic, oily fish, cranberry juices and broccoli
recommendation; MC revised the manuscript. All authors provided
sprouts are relatively readily available options [57,58,60,64]. Pro-
critical feedback on manuscript. All authors read and approved the
biotics have been effective for improving the immunity in general
final manuscript.
and Lactobacillus varieties can be recommended to prevent influ-
enza like viral infections [70,71].
Every patient who has been diagnosed with COVID-19 must be Ethics declarations
screened for malnutrition on admission using a validated nutrition
screening tool (e.g. NRS-2002) [100]. In addition to dietary Not applicable.
Declaration of competing interest viral infections. Preprints 2020:2020030199.

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 367e382

Contents lists available at ScienceDirect

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Enhancing immunity in viral infections, with special emphasis on

1. Introduction supplementation of these have shown positive impact on

Fig. 1. Flow of information through the different phases of a systematic review.

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcome

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcome

dose-dependent, with a signiﬁcantly

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcomes

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcomes

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcomes

Author; Nutrient Study Study Intervention; Purpose Signiﬁcant anti-viral outcome

Condition/ Prevention Treatment Dose Food sourcesa

Declaration of competing interest viral infections. Preprints 2020:2020030199.

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