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Micronutrient status and immune function

Reducing illness from COVID-19 in vulnerable populations

Learning objectivesYou will learn:

• Micronutrient inadequacies and deficiencies are widespread; in times of critical illness, infections, and other stressors, micronutrient requirements can increase significantly

• Differences in susceptibility to and severity of respiratory and other infections, as well as non-communicable diseases, could be partly due to micronutrient levels that are insufficient for adequate immune and organ function

• Malnutrition adversely affects clinical outcomes in respiratory infections.

IntroductionMicronutrients are vitamins and specific minerals critical to the structure and functioning of numerous proteins, enzymes, physiological processes and signalling pathways within the body. Without these micronutrients, essential processes cease to function properly. Frequently, poor nutrient status is associated with inflammation and oxidative stress, which in turn can impact the immune system. This contributes to morbidity and, in cases of severe deficiency, mortality. An optimal immune response depends on adequate nutrition; although this should ideally be achieved through the consumption of a well-balanced and diverse diet, it can be difficult to accomplish for the general population. Indeed, it is generally accepted that nutrient inadequacies and deficiencies are widespread and, furthermore, that in times of critical illness, infections, and other stressors, micronutrient requirements can increase significantly.1-3

This report explores the potential role of nutrients that may exert anti-inflammatory, immunomodulatory and antithrombotic effects that could prevent or attenuate the inflammatory and vascular manifestations associated with COVID-19

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Micronutrient status and immune function

Micronutrient deficiencies and COVID-19As the novel coronavirus (SARS-CoV-2) pandemic continues to grip the world, several significant risk factors, including older age, male sex and the presence of comorbidities, are associated with higher risk of severe mor-bidity and mortality. Older people and those with comorbidities are also often the most at risk of undernutrition. Despite international efforts to identify a specific treatment for COVID-19, therapy remains supportive and is principally focused on optimising respira-tory function. However, the timely identifica-tion and correction of undernutrition has the potential to improve outcomes cost-effectively and may serve as a useful mitigation measure. It is important to consider that differences in susceptibility to, and severity of, COVID-19 could be partly due to micronutrient levels insufficient for adequate immune and organ

function. As such, it would be of benefit to COVID-19 patients if clinicians take this into consideration and test for potential micronu-trient insufficiencies; if indicated, supplement with adequate amounts to restore normal status and function.2,4,5

There is significant pseudoscience and misin-formation surrounding potential treatments and supplements to fight COVID-19 infec-tion. Importantly, there is currently no known effective treatment or mitigation strategy. This report explores the potential role of nutrients that may exert anti-inflammatory, immunomodulatory and antithrombotic effects that could prevent or attenuate the inflammatory and vascular manifestations associated with COVID-19.

The impact of nutritional status on immunity The importance of nutrition in immune function is well-established. The long-term, consistent adoption of a beneficial dietary pattern benefits human health. Conversely, an unhealthy diet and lifestyle are associated with low-grade inflammation and increased

oxidative stress, which could lead to the development of non-communicable diseases (NCDs) and an increased risk of infections (Figure 1). Furthermore, there is considerable evidence that food and nutrients affect how the immune system functions.6

Figure 1. Lifestyle factors affecting immune function during adulthood6

Hectic, stressful lifestyle

Fast food, energy-dense but

micronutrient-poor food

Low income, lack of fresh,

nutritious food

Sedentary lifestyle, obesity

Restricted diet

Prolonged, excessive exercise

Excessive alcohol consumption

Sleep disturbances/deprivation

Chronic stress (physical & psychological)

Pollution, cigarette smoke

Increased risk of infection

Suboptimal nutritional status

Poor diet

COMPROMISED IMMUNE FUNCTION

The risk of infection is also influenced by gender, early immune programming, vaccination history, pathogen exposure, specific health conditions and diseases.

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Micronutrient status and immune function

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The traditional Mediterranean diet has been found to have protective effects on immune health when it comes to allergic respiratory diseases and inflammatory conditions, and is synonymous with anti-inflammatory prop-erties that are beneficial against NCDs. A Western dietary pattern is characterised by high consumption of processed foods; it is linked to hyperglycaemia and advanced glyca-tion end-products associated with inflamma-tion, metabolic complications and chronic disease. Systemic inflammation is a common feature of NCDs and affects COVID-19 patient outcomes. Notably, hyperglycaemia is a risk factor associated with high mortality in patients with severe COVID-19 infection.5

Several vitamins (including vitamins A, B6, B12, C, D, E and folate) and trace elements (including zinc, iron, selenium, magnesium and

copper) play important and complementary roles in supporting both the innate and adap-tive immune systems (Table 1). Deficiencies in or suboptimal status of these micronutrients negatively affect immune function and can decrease resistance to infections. Depending on the deficient nutrient(s), a consequent decrease in the numbers of lymphocytes, impairment of phagocytosis and microbial killing by innate immune cells, altered production of cytokines, reduced antibody responses, and even impair-ments in wound healing are observed. These functional impairments are, presumably, what lead to the clinical immune-related manifesta-tions of deficiency. It is recommended that at a minimum, recommend daily allowances (RDAs) be attained for these nutrients while taking care not to exceed the tolerable upper intake levels (TULs).1

Table 1. The collective role of micronutrients in supporting the innate and adaptive immune systems

Innate immunity

• Development and maintenance of physical barriers

• Production and activity of antimicrobial proteins

• Growth, differentiation, and motility/chemotaxis of innate cells

• Phagocytic and killing activities of neutrophils and macrophages

• Promotion of, and recovery from, inflammation.

Adaptive immunity

• Lymphocyte differentiation, proliferation and homing

• Cytokine production

• Antibody production

• Generation of memory cells.

What is the role of vitamin C in immunity?

Vitamin C is a potent antioxidant and affects several aspects of immunity, including immu-nomodulatory properties (Figure 2).7 Vitamin C supports epithelial barrier function; growth and function of both innate and adaptive immune cells; and leukocyte migration to sites of infection. It enhances phagocytic capacity and oxidative killing by neutrophils, as well as antibody production. Its antioxi-dant properties make it extremely beneficial

to clearing harmful reactive oxygen species (ROSs) used by immune cells to deactivate viruses, but which also cause inflammation and harm to human cells, such as the lung damage associated with respiratory dis-ease. Vitamin C also acts as a cofactor for a number of biosynthetic and gene regulatory monooxygenase and dioxygenase enzymes, suggesting immune-modulating effects.1,3

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Micronutrient status and immune function

Vitamin C intervention trials have demonstrated a decrease in the duration and severity of upper respiratory tract infections, such as the common cold, and a significant decrease in the risk of infection when given prophylactically in people under enhanced physical stress

Severe respiratory infections, such as pneu-monia, are a common complication of severely depleted vitamin C status with its associated enhanced oxidative stress; and pneumonia is one of the most common causes of mortality in patients with severe vitamin C deficiency. This indicates an important link between vitamin C status and respiratory infections. It is not yet known if vitamin C deficiency is a cause and/or a consequence of severe infection, as the lat-ter results in enhanced requirements for the vitamin. The vitamin C status of patients and its association with COVID-19 outcomes has not yet been reported in the literature.2

Vitamin C intervention trials have demon-strated a decrease in the duration and severity of upper respiratory tract infections, such as the common cold, and a significant decrease in the risk of infection when given prophy-lactically in people under enhanced physical stress. According to a meta-analysis of eight randomised controlled trials in children, sup-plementation of vitamin C did not prevent infection of the upper respiratory tract but did reduce the duration of infection by 1.6 days. A different meta-analysis has reported a significant reduction in the risk of pneu-monia with vitamin C supplementation,

particularly in individuals with low dietary intakes. Although these data precede the novel SARS-CoV-2, a meta-analysis of 18 controlled trials of more than 2 000 patients showed a highly statistically significant reduc-tion in length of stay in intensive care and the duration of mechanical ventilation following oral administration of vitamin C in doses of 1-3g/day. Yet another study has found that intravenous administration of 1.5g vitamin C every six hours in septic patients with acute respiratory distress syndrome (ARDS) significantly decreased the mortality rate by 30% and increased the number of ICU-free and hospital-free days. As ARDS is a major complication of severe COVID-19, it is pos-sible that vitamin C supplementation may prove beneficial. Several studies are underway to evaluate the effects of vitamin C in the treatment of COVID-19.1-3,8

There is a dose-concentration relationship with vitamin C intake, whereby healthy individuals may not benefit from supple-mentation if the dietary intake of vitamin C is 200mg/day. However, this does not apply to all situations. In the case of patients with infections, vitamin C supplementation is useful as these patients have lower vitamin C levels caused by altered metabolism.5

Figure 2. Vitamin C and the immune system7

Vitamin C RDAs and TULs by life stage6

RDA M/F

TUL M/F

Children

4-8 years 25 650

9-13 years 45 1 200

14-18 years 75/651 800/ 1 800

Adults

>19 years 90/75 2 000

Innate immunity Adaptive immunity

Neutrophil uptake

Neutrophil migration

Neutrophil chemotaxis

Phagocytosis activity

Oxidant generation

NFkB signalling

NETosis formation

Natural killer cell generation

Natural killer cell proliferation

Cytotoxicity activity

Anti-tumoral activity

T cell proliferation

TH1 polarisation

TH17 polarisation

CTL activity

DTH response

B cell proliferation

Ab secretion

IgM, IgG, IgA

Macrophages activation

Phagocytosis activity

Clearance activity

DC uptake

Vit C

T Lymphocyte

B Lymphocyte

NKNeut

MQ

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Vitamin D deficiency increases the risk for respiratory infection; several recent meta-analyses have concluded that vitamin D supplementation can reduce the risk of respiratory tract infections, such as influenza, in both children and adults

How does vitamin D affect immune function?

Many immune cells have vitamin D receptors that affect their function after ligand binding, and as such vitamin D profoundly influences immunity (Figure 3). T-cell functioning is closely related to vitamin D. For example, it promotes differentiation of monocytes into macrophages and increases their kill-ing capacity, it modulates the production of inflammatory cytokines, and supports

antigen presentation. Vitamin D metabo-lites appear to regulate production of spe-cific antimicrobial proteins that directly kill pathogens, and are thus likely to help reduce infection including in the lungs. Vitamin D itself may exhibit antiviral effects by inter-fering with viral replication and through its immunomodulatory and anti-inflammatory properties.1,3,5,9

Vitamin D deficiency increases the risk for respiratory infection; several recent meta-analyses have concluded that vitamin D supplementation can reduce the risk of res-piratory tract infections, such as influenza, in both children and adults. Data from interven-tion trials are equivocal, as some studies of vitamin D have not shown any benefit. On balance, vitamin D supplementation has been found to be safe and, overall, it is protec-tive against acute respiratory tract infection.

In one meta-analysis, vitamin D therapy improved conditions in chronic obstructive pulmonary disease, although the COPD was not caused only by infection. Another review has reported on a reduced risk of COVID-19 infections and mortality, where older and male patients with pre-existing conditions and below-normal vitamin D levels had increasing odds of death, being almost 13 times as likely to succumb.1,3

Figure 3. Immunomodulatory effects of vitamin D9

Ada

ptiv

e im

mun

ity

syst

emIn

nate

imm

unit

y sy

stem

Decrease

Decrease

Decrease

Decrease

Decrease

Decrease

Increase

Increase

Increase

Increase

DC maturationAntigen

Th1 cytokine (IL2, INFy)

MΦ differentiation (IL1, IL6, TNFα)

Th2 cytokine (IL4, IL5, IL13, IL10)

Antimicrobial response (cathclicidin, defensinβ)

Immunoglobulins

Cytokines producction (IL6, IL12, TNFα, IL23)

Inflammation and autoimmunity

Antigen presentation

Suppression of helper T cells

Effects of vitamin D

IL10, TGFβ

IL17

Th1

Th2

Th17

Treg

B cell

T cell

TLR

DC

TLR

Macrophage

Monocyte

Vitamin D RDAs and TULs by life stage6

RDA M/F

TUL M/F

Children

4-8 years 15 75

9-18 years 15 100

Adults

19-50 years 15 100

Older age

>51 years 15-20 100

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Micronutrient status and immune function

Zinc

Zinc is critical to the development of both innate and adaptive immune cells, regulating proliferation, differentiation, maturation and functioning of leukocytes and lymphocytes. Zinc plays a signalling role in the modulation of inflammatory responses and is also an important cofactor for many enzymes. The

unchelated free form of zinc has direct anti-viral effects against many viruses including those involved in respiratory system pathol-ogy, through modulation of viral particle entry, fusion, replication and viral protein translation (Figure 4).1,3,10

Zinc deficiency is a serious public health problem worldwide. Poor zinc status signifi-cantly affects immune response, resulting in increased susceptibility to inflammatory and infectious diseases including tuberculo-sis and pneumonia. Those deficient in zinc, particularly children, are prone to increased diarrhoeal and respiratory morbidity. In elderly patients with low zinc status, mortal-ity due to pneumonia has been reported to be twice as high compared to individuals with normal zinc levels. Improved zinc status may reduce the risk of bacterial co-infection by improving mucociliary clearance and bar-rier function of the respiratory epithelium, as well as direct antibacterial effects against Streptococcus pneumoniae. Zinc status is also

tightly associated with risk factors for severe COVID-19 including ageing, immune defi-ciency, obesity, diabetes and atherosclerosis. In vitro experiments demonstrate that zinc inhibits SARS-CoV RNA polymerase.1,11

Zinc supplements and lozenges are a popular remedy for fighting off colds and respira-tory illnesses. Compared to placebo, zinc significantly reduces symptom duration of the common cold, from 7.6 to 4.4 days, and may reduce the number of upper respira-tory infections in children. The data on zinc are mixed, but it has been suggested that a zinc intake of 30-50mg/day might aid in the control of RNA viruses such as influenza and coronaviruses.3,5,11

Figure 4. Influence of zinc during infection and inflammation10

Zinc RDAs and TULs by life stage6

RDA M/F

TUL M/F

Children

4-8 years 5 12

9-13 years 8 23

14-18 years 11/9 34

Adults

>19 years 11/8 40

Zinc supplementation

Zinc deficiency

Killing by zinc intoxication

Killing by zinc deprivation

Infla

mm

atio

n

Infe

ctio

n

Phagosome

M. tuberculosis

H. capsulatum

Phagosome

Golgi

Zn

Zn

Zn

Zn

Zn

ZnZn

Zn

ZnZn

ZnZnZn

M T

Zn Zn

ZnZnZn

Nucleus

TGFβ

IL-2

IL-6

IL-4

IL-1β

IL-1α

TNF-α

ZnZn

Zn

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Selenium deficiency can lead to reproducible genetic mutations and increased virulence of certain viruses

Selenium

Selenium plays a vital role in the antioxidant defence system, with its ability to quench ROSs. It is involved in T-lymphocyte prolif-eration and humoral immunity, especially in respect of immunoglobulin production. Human daily intake of selenium varies greatly depending on the geographical location of the soil in which food products are grown.

Poor serum selenium status is associated with decreased numbers of lymphocytes and albumin concentration, and correlates with increased C-reactive protein. Selenium deficiency can lead to reproducible genetic mutations and increased virulence of certain viruses, including coxsackievirus, poliovi-rus and influenza; passage of these viruses through a selenium-deficient animal causes mutation to a more virulent form that causes more severe pathology.1,12,13

Increased selenium intake by otherwise healthy subjects with relatively low concentra-tions of plasma selenium improves cellular immunity. In this context, selenium sup-plementation is used as an adjuvant therapy

for influenza. A population-based, retro-spective analysis of the association between the reported cure rates for COVID-19 and selenium status in China observed higher pathogenicity or mortality in the presence of selenium deficiency. The anti-inflammatory actions of selenium may be beneficial during hyper-inflammation, such as the COVID-19 cytokine storm. Of interest, a randomised trial in which patients critically ill with ARDS received sodium selenite showed no effects on overall survival, the duration of mechanical ventilation or intensive care stay.12,13

Depending on the chemical form used, selenium can be toxic to humans and sup-plementation should be considered with care, especially in subjects with diabetes. In general, organic selenium compounds are less toxic than inorganic ones, but doses vary greatly depending on the duration of expo-sure. It is generally believed, albeit not con-firmed, that toxic doses of selenite start from 600μg/day, although relatively high doses of up to 2000μg/day were reported to be well tolerated in patients with peritonitis.3,13

Does Echinacea have proven immunomodulatory and antiviral effects? Recent studies have shown that preparations derived from Echinacea purpurea, E. angusti-fola and E. pallida possess immunomodulat-ing properties and potent antiviral activities at non-cytotoxic concentrations, particularly against membrane-containing viruses such as all strains of human and avian influenza viruses that have been tested, as well as herpes simplex virus, respiratory syncytial virus and rhinoviruses. Randomised clini-cal trials on the common cold showed that volunteers receiving Echinacea preparations had fewer episodes and shorter duration of cold and other respiratory viruses, including beta-coronavirus strains. Beneficial actions of Echinacea in the treatment of viral respira-tory infections include:14,15

• A direct virucidal activity against sev-eral respiratory viruses; reversal of the

pro-inflammatory response of epithelial cells and tissues to different viruses

• Reduction in the excessive secretion of mucin by airway cells and tissues

• Lack of cytotoxic effects or disruption of tissue integrity by Echinacea in airway cell cultures or tissues, at practical antiviral concentrations

• Additional potentially positive effects on cellular gene expression

• Stimulation of the proliferation and func-tion of uninfected macrophages, and anti-cytokine effects on macrophage cell lines that are already stimulated with bacterial lipopolysaccharide or rhinoviruses, further supporting the theory that Echinacea preparations are immunomodulatory, ‘restoring’ normal immune functions instead of merely boosting capability.

Selenium RDAs and TULs by life stage6

RDA M/F

TUL M/F

Children

4-8 years 30 150

9-13 years 40 280

14-18 years 55 400

Adults

>19 years 55 400

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Micronutrient status and immune function

What are the implications of malnourishment for immunity in the elderly and patients with chronic disease? Malnourishment can occur for multifacto-rial reasons, including poor socioeconomic conditions, mental status and social status. Consequent on the social distancing require-ments of COVID-19, many people have lost livelihoods or are receiving reduced incomes. Those hit hardest are likely to be from finan-cially vulnerable groups that already consume cheaper food items of lower nutritional value.

Malnourishment can exacerbate an impaired immune system in the elderly, making them susceptible to infections; indeed, deficien-cies of calcium, vitamin C, vitamin D, folate and zinc are common among elderly popula-tions. Many elderly patients are unable to feed themselves adequately due to problems with chewing, physical disabilities, cognitive disturbance, psychosocial factors or frailty. Multicentre studies demonstrate that 23-60% of older patients in acute care settings and 40-50% of hospitalised polymorbid patients are malnourished. In addition to increased risk of malnourishment, the elderly are pre-disposed to NCDs and infections as a result

of the immunosenescence associated with ageing. The link between viral infection sever-ity and NCDs has been observed in infections such as influenza, and chronic and unresolved inflammation is implicated in the onset, pro-gression and development of NCDs. It is also thought that underlying systemic inflamma-tion may exacerbate COVID-19 infection.5,8,11

Malnutrition adversely affects clinical out-comes. Short-term effects of missing meals include not only fatigue, reduced immune function and increased risk of communicable diseases, but also a higher rate of complica-tions after these diseases lead to hospitali-sation. Complications, length of stay and mortality have been found to be significantly worse in untreated, nutritionally at-risk older or polymorbid in-patients, whereas those provided with nutritional support experience improved quality of life and reduced compli-cations. Of all predictors of mortality from influenza, only malnutrition and pneumonia are amenable to medical intervention.4,5

What are the complications of severe COVID-19 infection?

Many patients presenting to hospitals with COVID-19 infections have severe anorexia, inflammation and markers of malnutrition. These additional vulnerabilities may increase risks for respiratory failure, necessitating non-invasive ventilation. In severe cases, the most common complications are sepsis, ARDS, heart failure and septic shock. The inflammatory response plays a crucial role in the clinical manifestations of COVID-19. An extensive and uncontrolled release of proinflammatory cytokines and other immune-related stimuli that result in hyper-inflammation, termed the cytokine storm, presents clinically as systemic inflammation and multiple organ failure (Figure 5).3,5

Post SARS-CoV-2 entry, host factors trigger an immune response against the virus, which, if uncontrolled, may result in pulmonary tissue damage, functional impairment and

reduced lung capacity. Apart from respira-tory failure, other common features of critical COVID-19 patients include a sudden decline in the patient’s health status approximately two weeks after onset; infiltration of mono-cytes and macrophages into lung lesions; a decrease of lymphocytes such as natural killer cells in peripheral blood; extremely high levels of inflammatory response due to the proinflammatory cytokine storm; atrophy of the spleen and lymph nodes, along with reduced lymphocytes in lymphoid organs; hypercoagulability; thrombosis; and multiple organ damage. An early rise in serum levels of inflammatory cytokines has been observed in patients who end up with extensive lung damage and require intensive care. The coex-istence of NCDs in COVID-19 patients may aggravate and intensify their inflammatory pathology and increase the risk for adverse outcomes and mortality.5,15

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Key learnings

• Micronutrient requirements increase significantly in times of critical illness, infections and other stressors

• Several vitamins and trace elements play important and complementary roles in supporting both the innate and adaptive immune systems

• Vitamin C intervention demonstrates decreased duration and severity of upper respiratory tract infections and a significant decrease in risk of infection when given prophylactically in people under enhanced physical stress

• Vitamin D supplementation can be protective against respiratory tract infections

• Zinc status is tightly associated with risk factors for severe COVID-19 including ageing, immune deficiency, obesity, diabetes and atherosclerosis

• Reported cure rates for COVID-19 in China observed higher pathogenicity or mortality in the presence of selenium deficiency

• Echinacea possesses immunomodulating properties and potent antiviral activities at non-cytotoxic concentrations against respiratory and other viruses.

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Figure 5. COVID-19 infection - cytokine storm

DisclaimerThe views and opinions expressed in the article are those of the presenters and do not necessarily reflect those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by relevant control authorities.

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