MINI REVIEW
published: 09 July 2020
doi: 10.3389/fimmu.2020.01548

Role of Immune Dysregulation in
Increased Mortality Among a Specific
Subset of COVID-19 Patients and
Immune-Enhancement Strategies for
Combatting Through Nutritional
Supplements
Kosagi-Sharaf Rao 1 , Vaddi Suryaprakash 2 , Rajappa Senthilkumar 3 ,Senthilkumar Preethy 3 , Shojiro Katoh 4 , Nobunao Ikewaki 5,6 and Samuel J. K. Abraham 7,8,9*
Edited by:
Brandt D. Pence,
University of Memphis, United States
Reviewed by:
Juraj Majtan,
Independent Researcher, Bratislava,
Slovakia
Chunjian Qi,
Nanjing Medical University, China*Correspondence:
Samuel J. K. Abraham
drsam@nichimail.jp;
drspp@nichimail.jp
Specialty section:
This article was submitted to
Nutritional Immunology,
a section of the journal
Frontiers in Immunology
Received: 07 May 2020
Accepted: 12 June 2020
Published: 09 July 2020
Citation:
Rao K-S, Suryaprakash V,
Senthilkumar R, Preethy S, Katoh S,
Ikewaki N and Abraham SJK (2020)
Role of Immune Dysregulation in
Increased Mortality Among a Specific
Subset of COVID-19 Patients and
Immune-Enhancement Strategies for
Combatting Through Nutritional
Supplements.
Front. Immunol. 11:1548.
doi: 10.3389/fimmu.2020.01548

1
Centre for Neuroscience, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP),
Panama City, Panama, 2 Department of Urology, Yashoda Hospitals, Hyderabad, India, 3 The Fujio-Eiji Academic Terrain,
Nichi-In Centre for Regenerative Medicine, Chennai, India, 4 Edogawa Evolutionary Laboratory of Science, Edogawa Hospital,
Tokyo, Japan, 5 Department of Medical Life Science, Kyushu University of Health and Welfare, Nobeoka, Japan, 6 Institute of
Immunology, Junsei Educational Institute, Nobeoka, Japan, 7 The Mary-Yoshio Translational Hexagon, Nichi-In Centre forRegenerative Medicine, Chennai, India, 8 School of Medicine, Yamanashi University, Yamanashi, Japan, 9 GN Corporation Co.
Ltd., Kofu, Japan

Background: The COVID-19 pandemic has been causing varying severities of illness.
Some are asymptomatic and some develop severe disease leading to mortality acrossages. This contrast triggered us explore the causes, with the background that a vaccine
for effective immunization or a drug to tackle COVID-19 is not too close to reality. We
have discussed strategies to combat COVID-19 through immune enhancement, using
simple measures including nutritional supplements.
Discussion: A literature search on mortality-related comorbid conditions was
performed. For those conditions, we analyzed the pro-inflammatory cytokines, which
could cause the draining of the immune reservoir. We also analyzed the immune
markers necessary for the defense mechanism/immune surveillance against COVID-19,
especially through simple means including immune enhancing nutritional supplement
consumption, and we suggest strategies to combat COVID-19. Major comorbid
conditions associated with increased mortality include cardiovascular disease (CVD),
diabetes, being immunocompromised by cancer, and severe kidney disease with a senile
immune system. Consumption of Aureobasidium pullulans strain (AFO-202) beta 1,3-1,6glucan supported enhanced IL-8, sFAS macrophage activity, and NK cells’ cytotoxicity,which are major defense mechanisms against viral infection.
Conclusion:
People with co-morbid conditions who are more prone to
COVID-19-related deaths due to immune dysregulation are likely to benefit from

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consuming nutritional supplements that enhance the immune system. We recommend
clinical studies to validate AFO-202 beta glucan in COVID-19 patients to prove its efficacy
in overcoming a hyper-inflammation status, thus reducing the mortality, until a definite
vaccine is made available.
Keywords: COVID-19, co-morbidity, diabetes, hypertension, chronic kidney disease, immuno-compromised,nutritional supplement, AFO-202 beta glucan

INTRODUCTION

cytokines, including interleukin (IL)-1β, IL-1Rα, IL-2, IL-10,
fibroblast growth factor (FGF), granulocyte-macrophage colony
stimulating factor (GM-CSF), granulocyte-colony stimulating
factor (G-CSF), interferon-γ-inducible protein (IP10), monocyte
chemoattractant protein (MCP1), macrophage inflammatory
protein 1 alpha (MIP1A), platelet-derived growth factor (PDGF),
tumor necrosis factor (TNFα), and vascular endothelial growth
factor (VEGF). Furthermore, critically ill patients requiring
admission to the intensive care unit (ICU) were found to havemarkedly high concentrations of IL-2, IL-10, G-CSF, IP10, MCP1,
MIP1A, TNFα, and IL-6. Importantly, increased levels of IL-6
are also correlated with increased mortality. In severe COVID19, a reduction of natural killer cells—CD4+ and CD8+ T
lymphocytes—and IFN-γ expression in CD4+ cells have been
observed, along with hampered adaptive immune systems due tocytokine release syndrome, which can be attributed to the inverse
correlation of levels of IL-6, IL-10, and TNFα with lymphocyte
count (6–8). In another report, lymphopenia with drasticallyreduced numbers of CD4+ T cells, CD8+ T cells, B cells, andnatural killer (NK) cells was reported to be a common featurein patients with severe COVID-19, which was not observed in
milder cases. In addition, the numbers of CD4+ T cells, CD8+
T cells, B cells, and NK cells are normalized in patients who
have recovered or are convalescent. The exhaustion markers,
such as NKG2A, on cytotoxic lymphocytes, including NK cells
and CD8+ T cells, were increased in those with severe disease
and returned to normal levels after recovery from COVID19 (9). Increased neutrophil-to-lymphocyte ratio (NLR) andlow lymphocyte-to-C-reactive protein ratio (LCR), reflecting anenhanced inflammatory process, have been reported to suggest apoor prognosis in patients with severe COVID-19 (10).
Thus, in summary, in case of inflammatory pathway leading
to cytokine storm, pro-inflammatory factors such as IL-6, IL8, IL-1β, and GM-CSF and chemokines such as CCL2, CCL5, IP-10, and CCL3, together with reactive oxygen species havebeen attributed to cause acute respiratory distress syndrome(ARDS) leading to pulmonary fibrosis and death. In COVID19, high levels of serum pro-inflammatory cytokines (IFN-γ,
IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10,CXCL9, and IL-8) have been reported to be detected in cases withsevere disease compared to patients with uncomplicated SARS
(11). Also, continuous high levels of three cytokines (CXCL10,
CCL7, and IL-1 receptor antagonist) has been associated withincreased viral load, loss of lung function, lung injury, and afatal outcome (12). While suppression of this pro-inflammatory
cytokine storm is considered essential to combat COVID-19,
some cytokines such as Type-I interferon and IL-7 have beenfound to be beneficial. Several studies are being conducted to

The outbreak of the ongoing COVID-19 pandemic started
at the end of 2019, in the city of Wuhan, China. COVID-19
has been attributed to a novel type of coronavirus, termed by
the WHO as the “novel coronavirus-2019” (SARSCoV-2). The
genome sequence of SARSCoV-2 is similar to those of severe
acute respiratory syndrome coronavirus (SARS-CoV) (∼79%
homology), whose outbreak occurred in 2002 and 2003, and of
Middle East respiratory syndrome coronavirus (MERS-CoV)(∼50% homology), whose outbreak occurred between 2012 and2019. Coronavirus is member of the family Coronaviridae andsubfamily Coronavirinae, which, based on genomic sequencing
and phylogenetic relationships, consists of four genera:
Alphacoronavirus, Betacoronavirus, Gammacoronavirus, andDeltacoronavirus. SARS-CoV-2 belongs to the Betacoronavirus
genus (1, 2).
As of 3 May 2020, there have been 3,356,205 confirmed
cases of COVID-19, including 238,730 deaths, reported to
the WHO (3). The incubation period of SARS-CoV-2 is
3–6 days, with the maximum being 14 days. The clinicalsigns and symptoms of COVID-19 include low to high fever,
non-productive cough, myalgia, dyspnea, fatigue, standard
or decreased leukocyte counts, and confirmed evidence ofpneumonia on chest radiography. Less common symptomsof SARS-CoV-2 infection include headache, abdominal pain,
dizziness, nausea, vomiting, and diarrhea. Regarding thetherapeutic aspects, no specific therapy is currently available
for COVID-19 (4). Patients with mild signs and symptoms
are treated with antibacterial drugs for pneumonia, including
azithromycin, fluoroquinolones, and amoxicillin. Anti-viral
agents such as viral methyltransferase inhibitor, nitazoxanide,
the nucleotide prodrug GS-5734 Remdesivir, ribavirin in
combination with lopinavir, interferon therapy, and convalescentplasma therapy are being tested for treating COVID-19. The casefatality rate (CFR) was reported to be between 2.3% (1,023 deaths
among 44,672 confirmed cases) in China up to 15.80% in the UK(4, 5). In particular, patients with co-morbid conditions are athigher risk of mortality from COVID-19 due to the conditions
compromising their immune system (4). Here, we present theimmune system implications of COVID-19 in the presence of
co-morbidities and ways to enhance immunity, with a focus on
nutritional supplements.

COVID-19 AND THE IMMUNE SYSTEM
A characteristic feature of COVID-19 infection is a proinflammatory status characterized by high levels of different

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study the effectiveness of IFN-α and IFN-β as drugs against
SARS-CoV-2. Since lymphopenia and lymphocyte exhaustion arehallmarks of COVID-19, IL-7—the major cytokine promoting
lymphocyte expansion and possibly reversal of T cell exhaustion
is considered to be restoring immune system homeostasis.
Intriguingly, in sera of patients with either mild or moderate oreven severe forms of COVID-19, IL-2, and IL-7, the cytokines
responsible for expansion and differentiation of various T cellsubsets are increased which could be speculated as an attempt by
the immune system to reverse lymphopenia and T cell exhaustion(13). A synopsis of pro-inflammatory cytokines which have to be
down-regulated and the beneficial immune-factors which have to
be enhanced to combat the COVID-19 are illustrated in Figure 1.

who were admitted to the hospital for COVID-19, 30% had
hypertension, and 12% had diabetes (18). The mechanisms
proposed for increased susceptibility of patients with diabetes
to COVID-19 include “(1) higher affinity cellular binding andefficient virus entry, (2) decreased viral clearance, (3) diminishedT cell function, (4) increased susceptibility to hyperinflammationand cytokine storm syndrome, and (5) presence of CVD” (19).
When the cytokine profile in diabetes was analyzed in relation to
COVID-19, the focus was again on IL-6, which was reported toplay a more deleterious role in COVID-19 infection (20).

IMMUNE SYSTEM IMPLICATIONS OFCHRONIC KIDNEY DISEASE AND
COVID-19

IMMUNE SYSTEM IMPLICATIONS OF
CARDIOVASCULAR DISEASES AND
COVID-19

Chronic kidney disease, particularly patients with end-stage renal
disease (ESRD) who are dependent on dialysis, are also in thehigh-risk category of acquiring severe disease and mortality
due to COVID-19. When the underlying immune profile wasanalyzed, it was observed that cytokines such as interleukin-1
beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), andIL-6 induce an inflammatory state, playing a significant rolein dialysis-related morbidity (21), again pointing to IL-6. In
another report, between 30 and 50% of hemodialysis patients had
elevated serum levels of inflammatory markers such as C-reactive
protein and IL-6 (22). Furthermore, CKD has been associatedwith increases in immune senescence (23) and inflammation
biomarkers (24).

The CFR of 2.3% in China was found to be elevated to 6.0% forpatients with hypertension, 7.3% for patients with diabetes, and10.5% for patience with CVD (14). Multiple studies have reported
that patients with underlying cardiovascular comorbidities areat higher risk of severe COVID-19 infection that requires ICU
care and of having complications like acute respiratory distresssyndrome (ARDS), which may result in death. The mechanism
has been attributed to reduced or impaired cardiovascularfunctional reserves in such CVD patients, which is worsenedby the myocardial infarction precipitated by COVID-19, leading
to increase myocardial demand, the worsening of ischemia andnecrosis or, an increase in metabolic demand, which leads toheart failure and death. COVID-19 infection indirectly causes
cardiac injury due to an overwhelming immune inflammatory
response and cytokine storm. Other proposed mechanisms
include SARS-CoV-2 viral invasion and direct damage of
cardiomyocytes, as well as myocardial injury arising from severe
hypoxia due to acute respiratory damage and also from anotherimportant process concerning angiotensin-converting enzyme 2(ACE2) which is expressed in the heart and which SARS-CoV2 uses as a receptor for entry into the cell (15). Among thecytokines that are elevated in the cytokine storm in COVID19, IL-6 is important because it is the most strongly associatedcytokine with coronary heart disease (CHD) (16). Interleukin-1b(IL-1b), tumor necrosis factor (TNF), and IL-17 have also beenreported to be effective targets that can reduce cardiovascular
progression (16).

IMMUNE SYSTEM IMPLICATIONS OFCANCER AND OTHER FORMS OF
IMMUNOSUPPRESSION IN COVID-19
Among 1,590 cases with confirmed COVID-19, Liang et al.
found that 18 patients had a history of cancer. They concluded
that patients with cancer had a higher risk of COVID19 and poorer prognoses than those without cancer (25).
While overwhelming inflammation and cytokine-associated lunginjury are associated with the severity of COVID-19 in cancer
patients according to Liang et al. (26) and Xia et al. (27)pointed out that the blunted immune status, characterizedby overexpressed immunosuppressive cytokines, suppressedinduction of proinflammatory danger signals, impaired dendritic
cell maturation, and enhanced functional immunosuppressive
leukocyte populations, could be the actual underlying factors
exacerbating the severity of COVID-19 in cancer patients(26). Importantly, immunocompromised patients often present
atypical presentations of viral diseases such as COVID due tothe altered nature of the immune system (27). Among 10 kidneytransplant recipients on immunosuppression who tested positive
for SARS-CoV-2 by PCR, nine were admitted as in-patients,
three patients (30%) died, and five (50%) developed acute kidney
injury (28). A review of 89 studies on immune-suppressing or stimulating drugs showed no conclusive evidence on the benefitsof cytotoxic chemotherapy against COVID-19 infection (yet such
benefits were observed during in vitro studies) or against the use

IMMUNE SYSTEM IMPLICATIONS OF
DIABETES AND COVID-19
According to Yang et al. (17), among those studied who died
due to COVID-19, 22% had cerebrovascular diseases and 22%
had diabetes. A study of 1,099 patients with confirmed COVID19 showed that among 173 who had severe disease, 23.7%
had comorbid hypertension, 16.2% also had diabetes mellitus,
5.8% also had coronary heart disease, and 2.3% also had
cerebrovascular disease. In another study among 140 patients

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FIGURE 1 | Graphical representation of demarcating between the upregulated immune enhancement factors and downregulated pro-inflammatory factors, bothbeing beneficial effects of AFO-202 1-3,1-6 beta glucan, a biological response modifier (BRM).

whose downstream cascade controls viral infection along with
the induction of effective adaptive immune response. Innate
immune cells recognize a virus’s invasion through pathogenassociated molecular patterns (PAMPs), in the form of viralgenomic RNA or the intermediates during viral replication,
including dsRNA (30). This recognition event leads to thedownstream signaling cascade being activated, which culminatesin the expression of type I IFN and other pro-inflammatory
cytokines. This initial response comprises the first line defense
against viral infection at the entry site. For SARS-CoV and
MERS-CoV, the response to viral infection by type I IFN
is actually suppressed, which is closely associated with thedisease’s severity. SARS-CoV-2 also utilizes similar strategies
of dampening type I IFN response. Furthermore, dysregulated
type I IFN and inflammatory monocyte-macrophage influxes
are the main cause of lethal pneumonia. Hence, the proposed
immune combat strategies for COVID-19 involve suppressing of
the cytokine storm by employing antagonists of some key proinflammatory cytokines, increasing the beneficial cytokines suchas IL7, Type I IFN, along with treatment using anti-viral agents(30). While innate immune system–based strategies are key toof non-steroidal anti-inflammatory drugs (NSAIDs) and TNFα
blockades. While clear evidence existed of an association between
IL-6 peak levels and the severity of pulmonary complications,no evidence showed a beneficial impact of IL-6 inhibitors on
modulating COVID-19 (29). Thus, immunosuppression has beenreported to help with COVID-19, in lieu of the cytokine storm,
and a kidney-transplanted patient infected with SARS CoV2
manifested only mild disease (30), thus adding more prominence
to the fact that hyper-inflammation is the mechanism underlying
COVID-19 progression. This is a major research area open for
future perspectives.

IMMUNE STRATEGIES FOR COMBATTINGCOVID-19
Having outlined the immune system characteristics in COVID19 especially with co-morbidities, let us focus on the strategies
for equipping the immune system to fight COVID-19. Innate
immune response is highly critical for fighting viral infections
and is decidedly dependent on interferon (IFN) type I responses,

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is secreted extra-cellularly by Aureobasidium pullulans andis collected from the culture medium, without the needfor additional purification (44). Several studies have reported
beta glucan to be a powerful immune stimulator that can
activate macrophages and have positive immune actions on
B-lymphocytes, natural killer cells, and suppressor T cells in
the immune system (45–47). These actions are not direct but
rather due to beta glucan being a biological response modifier(BRM) to enhance immunity (44). This AFO-202 beta glucan
is also a biological response–modifier glucan (BRMG) whose
biological response modifier (BRM) properties are significantly
high (44) due to it being an exopolysaccharide without additional
purification steps, which may hamper this nature. As indicatedby Vetvicka and Vetvickova in their conclusions (38–40), since
the AFO-202 β-1,3-1,6-glucan is highly pure and active, it exerts
significant immunological actions. This AFO-202 beta glucan isrecognized by the immune system as a PAMP equivalent andhence exerts immunological actions. This AFO-202 β-1,3-1,6glucan is a soluble beta glucan that contains both high and low
molecular weight beta-glucan. High molecular beta-glucan (HBG) component has been found to stimulate the proliferationof lymphocytes with stronger effects. On the other hand, lowmolecular beta-glucan (L-BG) component reduces the levelsof the inflammatory biomarkers (majorly cytokines), stimulates
the cytokine and activates chemokine signaling pathways. In
addition, L-BG effectively binds to dectin-1 (β-glucan receptor),and possesses antagonistic actions such as reactive oxygen
production and cytokine synthesis from various immune cells
such as macrophages, dendritic cells and endothelial cell etc.
Since this AFO-202 beta-glucan contains both H-BG and LBG it possesses ability to regulate whole of immune response
for biological homeostasis (44). Beta-1,3/1,6-glucan derived fromyeast has been listed by the US-FDA under the generally
recognized as safe (GRAS) category (48). This AFO-202 Beta
Glucan has been subjected to genotoxicity test, single oral
administration test, 28-day or 90-day repeated dose study, longterm oral administration test (1 year) and has been certified tobe safe (49). Also, this AFO-202 beta glucan has been approvedby the Japanese Ministry of Health and available as a commercial
food supplement for human consumption since 1996 (44).
Dectin-1 is a type II transmembrane receptor and the main
beta glucan receptor involved in innate and adaptive immune
responses to foreign antigens and pathogens; it is also thereceptor for beta glucan as an immune function modulator(44). Dectin-1 cooperates with pattern-recognition receptors(PRRs) and Toll-like receptors (TLRs) in the innate immune
responses to beta glucan recognition. Ikewaki et al. reported
that this AFO-202 beta glucan induces the production of IL8 and sFas through cultured peripheral blood mononuclear
cells (PBMCs) and U937 cells but does not stimulate theproduction of IL-1β, IL-6, IL-12 (p70+40), IFN-γ, or TNF-α
and actually decreases IL-6 levels (44). The enhancement of
immune responses by AFO-202 β-1,3-1,6-glucan is associatedwith multiple signal transduction pathways involving several
phosphoenzymes such protein kinase C (PKC), protein kinase
A (PKA) inhibitor H-89 and protein tyrosine kinase (PTK) via
intracellular mechanism(s). AFO- 202 beta glucan was shown totherapeutics, an adaptive immune system holds the key to vaccine
development (31). We postulate that a simpler and more effective
approach will be nutritional intervention.

PREVENTIVE AND THERAPEUTIC
NUTRITIONAL INTERVENTIONS FOR
COVID-19
Supplementation of Vitamins A and D enhances immune
response to influenza virus vaccination (32). Although Vitamin C
is widely believed to help prevent viral infections, especially thecommon cold, a literature review of 640 studies failed to identify
any conclusive evidence for Vitamin C prophylaxis in preventing
the common cold (33, 34). Supplementation with micronutrientshas mixed results. One RCT on 725 institutionalized elderly
patients showed that low-dose supplementation of zinc together
with selenium enhanced the humoral response after vaccination,in comparison to the control group (34), while in another RCT,
neither daily multivitamin-mineral supplementation nor vitamin
E (200 mg/day) showed a favorable effect on the incidence andseverity of acute respiratory tract infections in well-nourishednon-institutionalized elderly participants (35).
Nutraceuticals provide relief to people infected withencapsulated RNA viruses, such as influenza and coronavirus, byboosting their immune responses.
Beta-glucans are naturally occurring polysaccharides obtained
from different sources such as oats, barley, bacteria, yeast, algae,
and mushrooms. Beta-glucans derived from different sources
have variation in their structure which is responsible for their
specific biological properties (36). There have been nearly 7,000
publications reporting the immune-modulating effects of βglucans (37). The immuno-modulating properties depend on
the primary chemical structure of the β-glucans. β-glucans
derived from fungi and yeast consisting of a (1,3)-β-linked
backbone with small numbers of (1,6)-β-linked side chains,
are known specifically for their immune-modulating effects(37). Vetvicka and Vetvickova have published several studies(38–40) comparing the immunological properties of different
commercially available Beta Glucans in terms of effects on
phagocytosis, IL-2 production, antibody secretion, Superoxide
production, IFNγ production and inhibition of experimental
cancer models, with their studies concluding that (i) glucans
in general have strong stimulating effects on most aspectsof the immune system; (ii) There are significant differencesamong tested glucans; (iii) highly purified and highly active
glucans have strong and pleotropic effects stimulating all facetsof immunological reactions while poorly defined glucans have
only medium (if any) biological effects. Beta glucans such as
the pleuran from the mushroom Pleurotus ostreatus has beenreported to reduce the incidence of upper respiratory tract
infection (URTI) symptoms and could increase the number ofcirculating NK cells (41). Therefore, beta glucans could be vital
tools to fight against COVID-19 through the immune system.
We herein focus our discussion on a specific beta glucan:
a 1-3,1-6 beta glucan from a black yeast called Aureobasidium
pullulans AFO-202 strain (42, 43). This 1-3,1-6 beta glucan

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beneficial cytokines listed in the introduction section of themanuscript (11, 13), AFO-202 beta glucan through IL8 causes
activation, migration and chemotaxis of neutrophils for killingvirus-infected cells. This beta glucan also causes decrease of
CCL2 (Monocyte chemotactic protein 1; MCP-1) and decrease
of CXCL10 levels, as result of which there will be prevention ofchemoattraction for monocytes/macrophages, T-cells, NK cells,
and dendritic cells thereby suppressing immune response. In
addition, promotion of T-cell adhesion to endothelial cells andanti-tumor activity accompanied by enhancement of immune
responses occur. Increase of type-I IFN production by AFO202 beta glucan helps in killing virus-infected cells (44).
Further, increase of IL-7 production leads to development andsurvival of mature T-cells to maintain homeostasis. Activationof CD8+ (cytotoxic T-cells) helps in anti-viral immunity
while activation of CD4+ (mainly Th1-cells) and Treg cells
helps in regulatory immune response and suppression ofcytokine storm with severe inflammation. Activation of Bcells results in production of virus-specific antibodies (IgG,
IgM, and sIgA) for neutralization of virus toxicity (44).
Figure 1 illustrates the beneficial effects of the AFO-202 beta
glucan by upregulating the immune enhancement factors anddownregulating the pro-inflammatory factors, in COVID-19 in
a nutshell.
The regulatory immune profile enhanced by AFO-202 beta
glucan (35) will assist with immune modulation in patientswith cancer. For kidney transplant recipients and patients withimmune suppression, the NK cell– and macrophage-enhancing
activity will come to play in antiviral immunity (44) thereby
helping them to fight COVID-19.
Another interesting aspect is that gut microbiota can
influence the generation of innate memory and the functional
reprogramming of bone marrow progenitors, which can help
to protect against infections (57). Their dysbiosis also leads tovariety of immune-mediated inflammatory disorders (57). Beta
glucan’s beneficial effects in reducing diseases like CVD havealso been attributed to their action influencing gut microbiota(58), and the immune-modulation of beta glucans by acting
on gut microbiota can help to alleviate an inflammatory
immune profile (59), thereby leading to beneficial effects.
These advantages mean that the beta glucan should more
importance in fighting COVID-19, specifically in the presence ofchronic inflammation–associated comorbidities. Thus, for thoseat high risk who suffer from a wide range of comorbidities,
consumption of this food supplement—whose safety has been
proven by consumption over two decades (44, 48, 49)—will be
a prospective preventive option and even as a supportive choiceduring therapeutics in the fight against this deadly COVID19 pandemic.

induce DNA synthesis (cell proliferation) in PBMCs via Dectin1, CD11a CD54 (intercellular adhesion molecule-1; ICAM-1),
HLA-class II, TLR-2 and TLR-4 and also induces the productionof sFas. AFO-202 beta glucan stimulated U937 cells (a humanmonocyte-like cell line) inducing the production of sFas via
Dectin-1, but not TLR-2 or TLR-4. The production of sFas by thisbeta glucan can prevent the onset of apoptosis, which is regulatedby the Fas/FasL system, and can potentially downregulate
inflammatory responses (44). When explored, beta glucan in oneway human mixed lymphocyte reaction (MLR) assay systems
could activate suppressor cells—in particular, regulatory T cells(Treg)—and also induce the production of suppressive cytokines(44) which will be helpful in suppressing the cytokine storm
observed in COVID-19. While the immunological actions of
the AFO-202 beta glucan are evident and will have potential
use against COVID-19 infection by immunosuppressing proinflammatory cytokines, several studies have also reported that
this beta glucan can enhance immunity by increasing the levelsof cytotoxic cells such as NK cells and macrophages, which
will be the actual line of defense against the viruses. NK cell
activity was significantly increased by this beta glucan in patientswith Leishmania amazonensis infection (50). This beta glucan
had regulatory or enhancing properties on poultry non-specificcellular immunity in a study on Peking ducks (51) and may
enhance the immune response to avian influenza A H5 vaccine(52). This AFO-202 beta glucan increased the NK cell andmacrophage counts in cancer patients and elderly patients (53).
Glucan supplementation enhanced the immune response against
an influenza challenge in mice (54). In a study analyzing theefficacy of this AFO-202 beta glucan in protecting mice infectedwith a lethal titer of the A/Puerto Rico/8/34 (PR8; H1N1) strain
of influenza virus, the survival rate was significantly increasedby the beta glucan’s administration after a sublethal infectionof PR8 virus, and pre-treatment with beta glucan significantly
repressed the replication of the PR8 virus (55). Yeast (1,3)-(1,6)beta-glucan also reduced the severity of upper respiratory tract
infections in a double-blind, randomized, placebo-controlled
study (56).

AFO-202 BETA GLUCAN AND RELEVANCETO COVID-19 PATIENTS WITH
CO-MORBIDITIES
While AFO-202 beta glucan supplementation can be a potential
strategy to fight COVID-19 infection due to its immuneenhancing activity in terms of IFN-γ-increasing capability (44),whose suppression is characteristic of SARS-COv2 infection(31), its consumption should be emphasized for people withcomorbidities. IL-6 is the most commonly elevated cytokine
in cytokine storms from conditions involving chronic microinflammation, such as CVD, diabetes and CKD (12, 13, 17,18). This AFO-202 beta glucan decreases IL-6 levels (44). The
increase in sFAS, which helps in regulating the immune responseby immune suppression, will be highly valuable in regulating
the cytokine storms and hyper-inflammation associated with
COVID-19 (44). In regard to the pro-inflammatory andFrontiers in Immunology | www.frontiersin.org

LIMITATIONS IN CONSIDERING AFO-202
BETA GLUCAN TYPE OF NUTRITIONAL
SUPPLEMENTS IN COVID-19
Beta glucans in general are considered to have immune
modulatory effect which differs based on their source and6July 2020 | Volume 11 | Article 1548

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CONCLUSION

structure of each type of beta glucan; the AFO-202 beta
glucan due to its purity and other unique characteristics,
is considered relatively advantageous in terms of immune
enhancement and immuno-modulatory effects to be strategicallyefficient in tackling COVID-19 implications. Though, the AFO202 beta glucan has not yet been subjected to a clinical study
in COVID-19 positive patients, which is a limitation, before
such a study, variabilities among patients with COVID-19
due to inherent factors or acquired variations or individual
factors such as co-morbid conditions will have to be consideredto evaluate the efficacy of AFO-202 beta glucan. Because,
inherent factors such as genetic variation in terms of humanleukocyte antigen (HLA) polymorphisms (60), mutations in
ACE-2 gene (61), age, general health, and nutrition (62),acquired variations such as cross immunity provided by vaccines
like BCG vaccine (63) and Japanese encephalitis (JE) vaccine(64) and individual variations due to co-morbidities whichcause dysregulation, described in this manuscript, have beenreported to influence the variation in susceptibility of individuals
to COVID-19. Another limitation is on the exact stage ofpathophysiology until which the immune-enhancement or
immune-modulation mechanisms could play a role in tackling
COVID-19 and whether those mechanisms will come into playwhen hyper-inflammation leads to a cytokine storm settingin, causing respiratory illness and multi-organ dysfunction(65). Recently, thrombo-embolic complications culminating in
micro-or macrovascular stroke have been reported in somepatients with mild COVID-19 infection (66). Increased levels of
IL6 leading to secretion of vascular endothelial growth factor(VEGF) and reduction of E-cadherin expression contributing tovascular permeability by which SARS-CoV-2 invades endothelial
cells inducing an endothelial inflammation has been citedas the probable mechanism behind (67, 68). Thus, further
in-depth studies are warranted to evaluate the effects ofnutritional supplements such as the AFO-202 beta glucan
in such implications of different interacting pathways of theimmune system leading to thrombo-embolic manifestations
as well.

The immune system is a double-edged sword (69) that hasbalance between its primary activity of defense against foreign
pathogens, oncogenesis, and circulating cancer cells while
maintaining their limitations from overacting and ending up in a
hyperinflammatory status, which leads to severe cytokine storm
in COVID-19 patients. Although specific targeted molecules andagents that can act on each step of such an immune system may
be efficacious for providing beneficial effects they continue tohave adverse reactions. Given this background, broadly acting
non-harmful strategies are currently considered essential, giventhat the lack of a definitive vaccine to “complex” the COVID19 pandemic is threatening vulnerable populations with immune
dysregulation. Through this analysis, we have found that a provenprimary immune defense–improving and immune-modulation
oriented nutritional supplement such as the AFO-202 beta glucan
could be tried in these patients in a multi-centric study to prove
its efficacy. Its consumption as a food supplement has proven safe
for more than two decades.

AUTHOR CONTRIBUTIONS
NI, K-SR, SK, and SA contributed to conception and design of thestudy. RS performed the literature search and data analysis. SA
and SP drafted the manuscript. NI, K-SR, VS, and SA performed
critical revision of the manuscript. All authors contributed tomanuscript revision, read, and approved the submitted version.

ACKNOWLEDGMENTS
We thank Mr. Takashi Onaka, (Sophy Inc, Kochi, Japan), fornecessary technical clarifications and Ms. Eiko Amemiya (II Deptof Surgery, Yamanashi University) for her secretarial assistance.
K-SR is thankful to National Science System (SNI-62-2019) of
SENACYT, Panama for the support. SA is thankful to LICET(Loyola ICAM College of Engineering & Technology) and Prof.
Masaru Iwasaki for their support to research and advice.

REFERENCES

6. Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: Outcomes inhypertensive cohort and controversies with renin angiotensin system blockers.
Diabetes Metab Syndr. (2020) 14:283–7. doi: 10.1016/j.dsx.2020.03.016
7. Pedersen F, Ho YC. SARS-CoV-2: a storm is raging. J Clin Invest. (2020)
130:2202–5. doi: 10.1172/JCI137647
8. Li G, Fan Y, Lai Y, Han T, Li Z, Zhou P. Coronavirus infections
and immune responses. J Med Virol. (2020) 92:424–32. doi: 10.1002/jmv.
25685
9. Cao X. COVID-19: immunopathology and its implications for therapy. Nat
Rev Immunol. (2020) 20:269–70. doi: 10.1038/s41577-020-0308-3
10. Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-toC-reactive protein ratio in patients with severe coronavirus disease 2019
(COVID-19): A meta-analysis. J Med Virol. (2020) 25819. doi: 10.1002/jmv.
11. Sun X, Wang T, CaiD, Hu Z, Chen J, Liao H, et al. Cytokine storm intervention
in the early stages of COVID-19 pneumonia. Cytokine Growth Factor Rev.
(2020) 53:38–42. doi: 10.1016/j.cytogfr.2020.04.002
12. Vaninov N. In the eye of the COVID-19 cytokine storm. Nat Rev Immunol.
(2020) 20:277. doi: 10.1038/s41577-020-0305-6

1. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus
outbreak of global health concern. Lancet. (2020) 395:470–
3. doi: 10.1016/S0140-67362030185-9
2. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H. Genomic characterisationand epidemiology of 2019 novel coronavirus: implications forvirus origins and receptor binding. Lancet. (2020) 395:565–
74. doi: 10.1016/S0140-67362030251-8
3. World Health Organization. Coronavirus (COVID-19). (2020). Available
online at: https://covid19.who.int/ (accessed May 5, 2020).
4. Chakraborty C, Sharma AR, Sharma G, Bhattacharya M, Lee SS. SARS-CoV-2
causing pneumonia-associated respiratory disorder (COVID-19): diagnostic
and proposed therapeutic options. Eur Rev Med Pharmacol Sci. (2020)
24:4016–26. doi: 10.26355/eurrev_202004_20871
5. Centre for Evidence-Based Medicine. Global Covid-19 Case Fatality Rates.
(2020). Available online at: https://www.cebm.net/covid-19/global-covid-19case-fatality-rates/ (accessed May 5, 2020).

Frontiers in Immunology | www.frontiersin.org

7

July 2020 | Volume 11 | Article 1548

Rao et al.

Immune Enhancement to Combat COVID-19

34. Girodon F. Impact of trace elements and vitamin supplementation
on immunity and infections in institutionalized elderly patients:a randomized controlled trial. Arch Intern Med. (1999) 159:748–
54. doi: 10.1001/archinte.159.7.748
35. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E andmultivitamin-mineral supplementation on acute respiratory tract infections
in elderly Persons-A randomized controlled trial. JAMA. (2002) 288:715–
21. doi: 10.1001/jama.288.6.715
36. Akramiene D, Kondrotas A, Didziapetriene J, Kevelaitis E.
Effects of beta-glucans on the immune system. Medicina. (2007)
43:597–606. doi: 10.3390/medicina43080076
37. StierH,
Ebbeskotte
V,
Gruenwald
J.
Immune-modulatory
effects of dietary Yeast Beta-1,3/1,6-D-glucan. Nutr. J. (2014)
13:38. doi: 10.1186/1475-2891-13-38
38. Vetvicka V, Vetvickova J. Comparison of immunological effectsof commercially available β-glucans. Appl Sci Rep. (2014)
1:2. doi: 10.7243/2054-9903-1-2
39. Vetvicka V, Vetvickova J. Comparison of immunological effects ofcommercially available beta-glucans: part III. Int Clin Pathol J. (2016) 2:78–
83. doi: 10.15406/icpjl.2016.02.00046
40. Vetvicka V, Vetvickova J. Glucans and cancer: comparison ofcommercially available β-glucans - Part IV. Anticancer Res. (2018)
38:1327–33. doi: 10.21873/anticanres.12355
41. Bergendiova K, Tibenska E, Majtan J. Pleuran (β-glucan from
Pleurotus ostreatus) supplementation, cellular immune response andrespiratory tract infections in athletes. Eur J Appl Physiol. (2011)
111:2033–40. doi: 10.1007/s00421-011-1837-z
42. Dedeepiya VD, Sivaraman G, Venkatesh AP, Preethy S, Abraham SJ. Potential
effects of nichi glucan as a food supplement for diabetes mellitus andhyperlipidemia: preliminary findings from the study on three patients from
India. Case Rep Med. (2012) 2012:895370. doi: 10.1155/2012/895370
43. Ganesh JS, Rao YY, Ravikumar R, Jayakrishnan GA, Iwasaki M, Preethy S,
et al. Beneficial effects of black yeast derived 1-3, 1-6 Beta Glucan-Nichi
Glucan in a dyslipidemic individual of Indian origin–a case report. J Diet
Suppl. (2014) 11:1–6. doi: 10.3109/19390211.2013.859211
44. Ikewaki N, Fujii N, Onaka T, Ikewaki S, Inoko H. Immunologicalactions of Sophy beta-glucan (beta-1,3-1,6 glucan), currently available
commercially as a health food supplement. Microbiol Immunol. (2007)
51:861–73. doi: 10.1111/j.1348-0421.2007.tb03982.x
45. Brown GD, Gordon S. Fungal beta-glucans and mammalian immunity.
Immunity. (2003) 19:311–5. doi: 10.1016/S1074-7613(03)00233-4
46. Cramer DE, Allendorf DJ, Baran JT, Hansen R, Marroquin J, Li B, et al. Betaglucan enhances complement-mediated hematopoietic recovery after bonemarrow injury. Blood. (2006) 107:835–40. doi: 10.1182/blood-2005-07-2705
47. Ohno N, Furukawa M, Miura NN, Adachi Y, Motoi M, Yadomae T. Antitumor
beta glucan from the cultured fruit body of Agaricus blazei. Biol Pharm Bull.
(2001) 24:820–8. doi: 10.1248/bpb.24.820
48. FDA. GRAS Classification of Beta-1,3/1,6-Glucan or Beta-1,3(D)-Glucan.
(2020). Available online at: https://www.betaglucan.org/fdagras/ (accessed
June 6, 2020).
49. Ikewaki N, Sonoda T, Miyazawa Y, Onizuka S, Chikamori M. Serum levelsof β-1,3-1,6 glucan-specific antibodies and immune biomarkers in normal
individuals. J Kyushu Univ Health Welfare. (2018) 19:87–94.
50. Yatawara L, Wickramasinghe S, Nagataki M, Takamoto M, Nomura
H, Ikeue Y, et al. Aureobasidium-derived soluble branched (1,3-1,6)
beta-glucan (Sophy beta-glucan) enhances natural killer activity in
Leishmania amazonensis-infected mice. Korean J Parasitol. (2009)
47:345–51. doi: 10.3347/kjp.2009.47.4.345
51. Tang XY, Gao JS, Yuan F, Zhang WX, Shao,YJ, Sakurai F, et al. Effects ofSophy β-glucan on growth performance, carcass traits, meat composition,and immunological responses of Peking ducks. Poult Sci. (2011) 90:737–
45. doi: 10.3382/ps.2010-01008
52. Le T, Le T, Doan TH, Quyen D, Le KX, Pham V, et al. The adjuvant effectof Sophy β-glucan to the antibody response in poultry immunized by theavian influenza A H5N1 and H5N2 vaccines. J Microbiol Biotechnol. (2011)
21:405–11. doi: 10.4014/jmb.1011.11024
53. Ikewaki N. Results of oral consumption of AFO-202 Beta Glucan in elderly
volunteers and cancer patients through NK cell activity. Abstract presented at

13. Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T,
et al. Should we stimulate or suppress immune responses in COVID19? Cytokine and anti-cytokine interventions. Autoimmun Rev. (2020)
19:102567. doi: 10.1016/j.autrev.2020.102567
14. Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R,
et al. The anti-viral facet of anti-rheumatic drugs: lessons from COVID-19.
J Autoimmun. (2020) 111:102468. doi: 10.1016/j.jaut.2020.102468
15. Tan W, Aboulhosn J. The cardiovascular burden of coronavirus disease 2019
(COVID-19) with a focus on congenital heart disease. Int J Cardiol. (2020)
309:70–7. doi: 10.1016/j.ijcard.2020.03.063
16. Clarke R, Valdes-Marquez E, Hill M, Gordon J, Farrall M, Hamsten A, et al.
Plasma cytokines and risk of coronary heart disease in the PROCARDIS study.
Open Heart. (2018) 5:e000807. doi: 10.1136/openhrt-2018-000807
17. Williams JW, Huang LH, Randolph GJ. Cytokine circuits in cardiovasculardisease. Immunity. (2019) 50:941–54. doi: 10.1016/j.immuni.2019.03.007
18. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes
mellitus at increased risk for COVID-19 infection? Lancet Respir Med. (2020)
8:e21. doi: 10.1016/S2213-2600(20)30116-8
19. Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses,and diabetes mellitus. Am J Physiol Endocrinol Metab. (2020)
318:E736–41. doi: 10.1152/ajpendo.00124.2020
20. Maddaloni E, Buzzetti R. Covid-19 and diabetes mellitus: unveilingthe interaction of two pandemics. Diabetes Metab Res Rev. (2020)
e33213321. doi: 10.1002/dmrr.3321
21. Ferrey AJ, Choi G,Hanna RM, Chang Y, Tantisattamo E, Ivaturi K, et al. A caseof novel coronavirus disease 19 in a chronic hemodialysis patient presenting
with gastroenteritis and developing severe pulmonary disease. Am J Nephrol.
(2020) 51:337–342. doi: 10.1159/000507417
22. Pertosa G, Grandaliano G, Gesualdo L, Schena FP. Clinical relevance ofcytokine production in hemodialysis. Kidney Int Suppl. (2000) 76:S104–
11 doi: 10.1046/j.1523-1755.2000.07613.x
23. Jofré R, Rodriguez-Benitez P, López-Gómez JM, Pérez-Garcia R.
Inflammatory syndrome in patients on hemodialysis. J Am Soc Nephrol.
(2006) 17:S274–80. doi: 10.1681/ASN.2006080926
24. Crépin T, Legendre M, Carron C, Vachey C, Courivaud C, Rebibou
JM, et al. Uraemia-induced immune senescence and clinical outcomes inchronic kidney disease patients. Nephrol Dial Transplant. (2020) 35:624–
32. doi: 10.1093/ndt/gfy276
25. Liang W, Guan W, Chen R, Wang W, Li J, Xu K. Cancer patients in
SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. (2020)
21:335–7. doi: 10.1016/S1470-2045(20)30096-6
26. Xia Y, Jin R, Zhao J, Li W, Shen H. Risk of COVID-19 for patients with cancer.
Lancet. Oncol. (2020). 21:e180. doi: 10.1016/S1470-2045(20)30150-9
27. Guillen E, Pineiro GJ, Revuelta I, Rodriguez D, Bodro M, Moreno A,
et al. Case report of COVID-19 in a kidney transplant recipient: does
immunosuppression alter the clinical presentation? Am J Transplant. (2020).
doi: 10.1111/ajt.15874
28. Nair V, Jandovitz N, Hirsch JS., Nair G, Abate M, Bhaskaran M, et al.
COVID-19 in kidney transplant recipients. Am J Transplant. (2020).
doi: 10.1111/ajt.15967
29. Russell B, Moss C, George G, Santaolalla A, Cope A, Papa S, et al. Associations
between immune-suppressive and stimulating drugs and novel COVID19-a systematic review of current evidence. Ecancermedicalscience. (2020)
14:1022. doi: 10.3332/ecancer.2020.1022
30. Seminari E, Colaneri M, Sambo M, Gallazzi I, Di Matteo A, Silvia R, et al.
SARS Cov2 infection in a renal transplanted patients. A case report. Am J
Transplant. (2020). doi: 10.1111/ajt.15902
31. Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 andpotential vaccines: lessons learned from SARS and MERS epidemic. Asian Pac
J Allergy Immunol. (2020) 38:1–9. doi: 10.12932/AP-200220-0772
32. Patel N, Penkert RR, Jones BG, Sealy RE, Surman SL, Sun Y, et al. Baseline
serum vitamin A and D levels determine benefit of oral vitamin A&D
supplements to humoral immune responses following pediatric influenza
vaccination. Viruses. (2019) 11:907. doi: 10.3390/v11100907
33. Jayawardena R, Sooriyaarachchi P, Chourdakis M, Jeewandara C,
Ranasinghe P. Enhancing immunity in viral infections, with special
emphasis on COVID-19: a review. Diabetes Metab Syndr. (2020)
14:367–82. doi: 10.1016/j.dsx.2020.04.015

Frontiers in Immunology | www.frontiersin.org

8

July 2020 | Volume 11 | Article 1548

Rao et al.

Immune Enhancement to Combat COVID-19

reason for relatively lower mortality rate in some Countries. Arch Acad Emerg
Med. (2020) 8:e54. doi: 10.22037/aaem.v8i1.683.g806
65. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features,
Evaluation and Treatment Coronavirus (COVID-19) [Updated 2020 May 18].
In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing (2020)
66. Fara MG, Stein LK, Skliut M, Morgello S, Fifi JT, Dhamoon MS.
Macrothrombosis and stroke in patients with mild Covid-19 infection. J
Thromb Haemost. (2020). doi: 10.1111/jth.14938
67. Steinack C, Hage R, Benden C, Schuurmans MM. SARS-CoV-2 andnorovirus co-infection after lung transplantation. Transplantology. (2020)
1:16–23. doi: 10.3390/transplantology1010002
68. Tanaka T, Narazaki M, Kishimoto T. Immunotherapeutic implicationsof IL-6 blockade for cytokine storm. Immunotherapy. (2016) 8:959–
70. doi: 10.2217/imt-2016-0020
69. Shahabi nezhad F, Mosaddeghi P, Negahdaripour M, Dehghani Z,
Farahmandnejad M, Moghadami M, et al. Therapeutic approaches
for COVID-19 based on the dynamics of interferon-mediated immune
responses. Preprints. (2020) 2020030206. doi: 10.20944/preprints202003.0
206.v128th Annual Meeting of Japanese Society for Parenteral and Enteral Nutrition(2013).
54. Vetvicka V, Vetvickova J. Glucan supplementation enhances the immune
response against an influenza challenge in mice. Ann Transl Med. (2015)
3:22. doi: 10.3978/j.issn.2305-5839.2015.01.08
55. Muramatsu D, Iwai A, Aoki S, Uchiyama H, Kawata K, Nakayama Y, et al. βGlucan derived from Aureobasidium pullulans is effective for the preventionof influenza in mice. PLoS ONE. (2012) 7:e41399. doi: 10.1371/journal.pone.0
04139956. Dharsono T, Rudnicka K, Wilhelm M, Schoen C. Effects of yeast (1,3)-(1,6)beta-glucan on severity of upper respiratory tract infections: a double-blind,randomized, placebo-controlled study in healthy subjects. J Am Coll Nutr.
(2019) 38:40–50. doi: 10.1080/07315724.2018.1478339
57. Elson CO, Alexander KL. Host-microbiota interactions in the intestine. Dig
Dis. (2015) 33:131–6. doi: 10.1159/000369534
58. Wang Y, Ames NP, Tun HM, Tosh SM, Jones PJ, Khafipour E. High molecularweight barley β-glucan alters gut microbiota toward reduced cardiovasculardisease risk. Front Microbiol. (2016) 7:129. doi: 10.3389/fmicb.2016.00129
59. Raa
J. Immune
modulation
by non-digestible
andnonabsorbable beta-1,3/1,6-glucan. Microb Ecol Health Dis. (2015)
26:27824. doi: 10.3402/mehd.v26.27824
60. Nguyen A, David JK, Maden SK, Wood MA, Weeder BR, Nellore A, et al.
Human leukocyte antigen susceptibility map for SARS-CoV-2. J Virol. (2020)
JVI.00510–20. doi: 10.1128/JVI.00510-20
61. Stawiski EW, Diwanji D, Suryamohan K, Gupta R, Fellouse
FA,
Sathirapongsasuti
JF,
et
al.
Human
ACE2
receptorpolymorphisms predict SARS-CoV-2 susceptibility. bioRxiv. (2020)
2020.04.07.024752. doi: 10.1101/2020.04.07.024752x
62. Zabetakis I, Lordan R, Norton C, Tsoupras A. COVID-19: the inflammation
link and the role of nutrition in potential mitigation. Nutrients. (2020)
12:E1466. doi: 10.3390/nu12051466
63. Rajarshi K, Chatterjee A, Ray S. BCG vaccination strategy forpreventaion against COVID-19: Hype or Hope? Preprints. (2020)2020040351. doi: 10.20944/preprints202004.0351.v1
64. Katoh S, Obayashi T, Ganesh JS, Iwasaki M, Preethy S, Abraham SJ. Crossprotection induced by encephalitis vaccines against COVID-19 might be a

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Conflict of Interest: K-SR is an employee of INDICASAT AIP, Panama. NI is an
employee of Kyushu University of Health and Welfare, Institute of Immunology,
Junsei Educational Institute, Nobeoka, Miyazaki, Japan. VS is an employee of
Yashoda Hospital, India. RS and SP are employees of NCRM, India. SK is a facultyof EELS & employee of Edogawa Hospital, Japan. SA is a faculty in Yamanashi
University, EELS, Edogawa Hospital, Japan & NCRM, India, as well as shareholder
in GN Corporation, Japan which in turn is a shareholder in the manufacturing
company of the AFO-202 Beta Glucan.
Copyright © 2020 Rao, Suryaprakash, Senthilkumar, Preethy, Katoh, Ikewaki and
Abraham. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction inother forums is permitted, provided the original author(s) and the copyright owner(s)are credited and that the original publication in this journal is cited, in accordancewith accepted academic practice. No use, distribution or reproduction is permitted
which does not comply with these terms.

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