The potential role of Vitamin D (25(OH)D), Zinc, Selenium and Vitamin C supplementation in reducing morbidity and mortality in susceptible communities during the Covid-19 pandemic in South Africa. An overview of evidence.

Authors

  • Dr. David M Nye (MB.ChB. [UCT], MFHom [UK], Dip Hom [CEDH])
  • Dr. Anamika Jithoo (Mb.ChB, [UKZN],MPH [UCT], PhD(Med) [UCT])
  • Dr. Erika Drewes (MB.ChB[UFS], MMed.Fam.Med [UKZN])
  • Dr. Rene Jeannes (MTechHom. [UJ])
  • Dr. Julienne Fenwick (MB.ChB, [US])
  • Dr. Maria Theologides (BDS, [Wits], BscHon, [US], PDD [US], Msc. [US])

Initiated and endorsed by the South African Society of Integrative Medicine (SASIM)

Abstract

South Africa has a large population of undernourished and elderly people with significant co-morbidities. These factors have been shown in the current Covid-19 pandemic to be significant risk factors for increased morbidity and mortality in those who contract the virus. There are also a significant number of front-line workers, who have co-morbidities, putting them at increased risk while serving Covid-19 positive patients. As there is currently no known treatment for Covid-19, strengthening the individual immune systems of people may provide an effective intervention, which can reinforce and complement the Government’s current policy of sanitizing and distancing recommendations.

Scientific research demonstrates that several micronutrients in combination can have a significant effect on strengthening the immune system.1 We have selected four of the most prominent of these; Vitamin D, zinc, selenium and Vitamin C. All of these are considered to be deficient in many individuals, they are effective, they are non-toxic and they are cost-effective. This overview sets out to demonstrate that, together, they can be formulated into an inexpensive oral supplement, which can be distributed in the poorer communities, in old age homes, in diabetic clinics, in TB and HIV clinics, and to front-line health workers with co-morbidities. By strengthening the immune system of susceptible individuals, it is hoped that when Covid-19 is contracted, the illness will be less severe, with fewer hospital admissions and consequently lower mortality.

Please see Appendix for sample industry costings.

Background

The world is now in the grip of the COVID-19 epidemic. At the time of writing, there is no known treatment for Covid-19, making the immune response currently the only method of defence against infection. Immunocompetence is a direct function of nutritional status and micronutrient deficiencies can unfavourably affect the ability of a person to mount appropriate innate and adaptive immune responses. While we acknowledge the role played by many other factors in immunity, the one that can be addressed by a single public health intervention is improvement in nutritional status of high-risk groups.

Maintaining immunity via balanced nutrition is essential for prevention and management of viral infections.2 Since data regarding nutritional supplementation in Covid-19 are not yet available, this document aims to evaluate evidence from studies on specific micronutrients in the in the prophylaxis and treatment of viral infections, particularly those resulting in respiratory disease.

The benefit of Vitamin D and C, and trace elements zinc and selenium has been shown via immune modulating effects in viral respiratory infection, especially in deficient populations, the elderly, those with metabolic syndrome, cancer, diabetes and cardiovascular disease.

In South Africa large numbers of persons are vulnerable to severe COVID infection and even death. The numbers of elderly patients together with those with HIV, diabetes, tuberculosis and other chronic illnesses are well known. The current latitudinal spread of the countries that are worst effected by COVID-19 together with several epidemiological models, suggests that South Africa may experience a peak in infections during the winter months. Moreover, the South African economy can ill afford prolonged lock-down to curb the spread. Improved strategies to protect the vulnerable and to flatten the curve are needed. In his public address on the 9th of May 2020, Health Minister Zweli Mkhize, acknowledged that the weakness in South Africa’s COVID-19 response lies at the primary health care level. We would argue that strategic strengthening of the COVID-19-vulnerable sub-populations offers primary healthcare a practical tool that is evidence-based, effective, accessible and affordable.

Multiple studies have demonstrated that patients with chronic disorders are prone to Vitamin D (25(OH)D), Zinc, Selenium and Vitamin C insufficiency or deficiency.1,3,4 Multiple specific micronutrients have been shown to play vital synergistic roles at every stage of the complex immune response. Supplementation of these nutrients decreases the risks and incidence of viral infections. A large body of scientific evidence builds a rational case for increasing these nutrient levels in patients at risk, in order to prevent severe forms of Covid-19 disease and shorten duration of illness.

This document presents the scientific rationale for these four key nutrients. Practical recommendations have been drawn for both prophylactic and therapeutic nutritional interventions for Covid-19.

Vitamin D (25(OH)D)

25(OH)D has immunomodulatory and epigenetic effects. Multiple studies (randomized controlled trials, reviews and meta-analyses) found on Pubmed, Medline and Cochrane Databases have investigated the clinical effects of vitamin D supplementation. Many of these point to the therapeutic benefit of supplementation in preventing not only musculoskeletal illnesses but also reducing the risk of chronic illnesses, including some cancers, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and mortality.5

Definition of 25(OH)D insufficiency

The US Endocrine Society recommends that 25(OH)D deficiency be defined as a 25(OH)D level of 20 ng/mL or less, 25(OH)D insufficiency as 21 to 29 ng/mL, and vitamin D sufficiency as 30 ng/mL or greater for children and adults.5

Prevalence of 25(OH)D deficiency

It is well-known that 25(OH)D insufficiency and deficiency is common in patients with chronic illnesses such as HIV and TB and the elderly.5 South African data confirms low serum levels in our HIV and TB populations. There is a lack of existing data on the levels of 25(OH)D in the general population of South Africa.6 A small recent study reported 25(OH)D deficiency to be as high as 7% and insufficiency as high at 10% of 10-year-old children in South Africa. International studies have shown that patients on anti-retroviral and other chronic medications are known to have lower 25(OH)D levels.7,8 In critical care settings the prevalence of 25(OH)D insufficiency varies from 28% to 69%.9

A 2016 review article10, on the role and benefits of 25(OH)D supplementation in South Africa, concluded that enough local data is lacking and therefore it is not known to what degree 25(OH)D supplementation would be beneficial in our context. While this may be true when the role of 25(OH)D supplementation in the general population is debated, it is not the case in patients with known chronic illnesses and the elderly. The correction of low serum levels through supplementation has been shown to benefit thousands of patients with chronic diseases internationally. We infer that it would act in the same way in South African patients with chronic illnesses and risk factors.

Clinical evidence in respiratory infections

Several meta-analyses have found 25(OH)D protects patients against acute respiratory illnesses and is safe.8,11 Macrophages have a Vitamin-D Receptor (VDR), and when they ingest an infectious agent, such as tuberculosis bacillus, the toll-like receptors are activated, resulting in signal transduction to increase the expression of VDR and CYP27B1.

The roles of 25(OH)D in its protection against infections are three-fold:

  • It helps with barrier protection through maintaining tight junctions, gap junctions and adherens junctions.
  • It enhances innate immunity through the induction of anti-microbial peptides such as cathalicidin LL-37 and defensins (natural human antibiotics). Vitamin D has also been shown to, in part, decrease the cytokine storm associated with fulminating infections.
  • 25(OH)D can reduce the production of pro-inflammatory Th1 cytokines, such as tumor necrosis factor α and interferon γ.5,8

It has been shown that Covid-19 infections may induce pro-inflammatory and anti-inflammatory cytokines in affected patients. Some in vitro studies have demonstrated that the administration of 25(OH)D during infection attenuates the cytokine response by decreasing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. 25(OH)D promotes the induction of regulatory T cells thereby down-regulating the down-stream induction of NFkappaB and its inflammatory sequelae.12

Meta-analyses have shown the protective effects of 25(OH)D is best when patients are on weekly and daily supplementation regimens. Large bolus doses were not associated with protective effects.11

Why supplement 25(OH)D in the elderly?

Serum 25(OH)D concentrations tend to decrease with age, which may be an important factor to consider in the context of COVID-fatality rates. Less time that is spent in the sun and reduced production of vitamin D as a result of lower levels of 7-dehydrocholesterol in the skin are the most common reasons for low levels in the elderly.8 In addition, some pharmaceutical medications reduce 25(OH)D serum concentrations by activating the pregnane-X receptor. Such drugs include antiepileptics, antineoplastics, antibiotics, anti-inflammatory agents, antihypertensives, antiretrovirals, endocrine drugs, and some herbal medicines. Pharmaceutical drug use typically increases with age.

Why supplement 25(OH) in patients with chronic conditions?

Vitamin D supplementation has been shown to have beneficial effects in several observational studies of immunologic diseases, such as type 1 diabetes, MS, asthma, and allergic diseases.5 25(OH)D insufficiency is common in patients with HIV and the prevalence increased with co-infections with TB.10

Several observational studies have found that 25(OH)D supplemented patients with ischemic heart disease have fewer myocardial infarcts and coronary artery calcifications. A short course of 4000IU Vitamin D3 for 4 days was shown to successfully attenuate circulating pro-inflammatory cytokines after an acute myocardial infarct. Moreover, Vitamin D insufficiency of less than 30ng/mL was strongly associated with hypertension and metabolic syndrome.5

There is a large body of studies that demonstrates 25(OH)D insufficiency, especially in infancy, is associated with the development of auto-immune diseases. It is thought that Vitamin D suppresses autoimmune pathophysiology by regulating the differentiation and activity of CD4-T cells, resulting in a more balanced TH1/TH2 response. This favours less development of self-reactive T cells and auto- immunity.5,13

It is clear from the literature that 25(OH)D plays an important role in preventing the development and progression of these chronic conditions. Patients with these conditions are most at risk of Covid-19 fatality and 25(OH)D supplementation could play a preventative role in these patients.

Dose for supplementation

While it is true that sun exposure is important in the production of 25(OH)D, it may not be effective in patients with chronic conditions. The elderly have lower levels of 7-hydrocholesterol in the skin which would impair production. Anecdotally, in our practices we find 25(OH)D insufficiency and deficiency to be common in our urban adult populations.

We therefore recommend oral supplementation-based on the American Endocrinology Society recommendations:

Where serum levels are not known and patients are high risk for severe Covid-19, 1000IU-4000IU 25(OH)D3 daily has been shown to be safe and effective.

Where serum levels are known and deficient or insufficient, 25(OH)D3 can be supplemented at 5000IU-10000IU daily for 3 months at which serum measurements should be repeated.

It suggested that maintenance of a 25(OH)D level of 40 to 60 ng/mL is ideal (this takes into account assay variability) and that up to 100 ng/mL is safe.5

Safety

Supplementation of Vitamin D as recommended has been shown to be safe and not associated with adverse events.5,11

Zinc

Zinc is the second most abundant ion after iron in the body. Adequate intake through food sources, such as animal protein and vegetables, is important as the body does not store zinc. Zinc is an essential nutrient for all cellular processes and maintains immunological integrity through its role in cellular immunity and its anti-oxidant activity.14,15

In Southern Africa zinc deficiency is estimated to affect 15-25% of the population.16 Globally, zinc deficiency affects 17-20% of the world’s population.15 Zinc deficiency is especially common in low-income populations who rely on grains and vegetables for nutrition.14 This is because phytates, found in grains, are known to chelate zinc. In this chelate form, the body is unable to absorb zinc.17 Zinc deficiency is also common in the elderly and patients with chronic conditions such as Diabetes, HIV infection and Tuberculosis.14,15,18,19 Certain drugs deplete the body of zinc, such as ACE inhibitors, thiazide diuretics, and acid-reducing drugs.20

Deficiency is associated with increased susceptibility to a variety of infections and decreased immunity due to thymus atrophy.18
Zinc is required for normal immune system function; it affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes and is crucial for normal development and functioning of cells mediating nonspecific immunity such as neutrophils and natural killer cells.17

Clinical effects of zinc supplementation

Multiple clinical studies have confirmed the role of zinc supplementation in illness resolution. Zinc supplementation has been shown to reduce severity and duration of common cold (many of which are coronaviruses) when zinc is administered within 24 hours of the onset of symptoms. Prophylactic supplementation in children results in fewer colds.20

Preventive zinc supplementation in at-risk populations decreases acute lower respiratory tract infections and lowers all-cause mortality.16

Zinc for HIV

Zinc supplementation in patients with HIV, has demonstrated a four-fold reduction of immune failure. In another randomised control study, patients on anti-retroviral treatments (ARV) were given additional zinc supplementation while the control group received only anti-retroviral medication. The intervention group had increased CD4 counts, compared to the control group thus demonstrating the synergistic effect of zinc with the ARV.15,20

Elderly

A small study on the effects of zinc on an elderly population, demonstrated a significant partial restoration of thymic status measured by serum thymulin activity.18 In underdeveloped countries; zinc is of importance as risk of infections are heightened in contexts of poor sanitation and poor nutrition.

Tuberculosis

Zinc deficiency is common in patients with tuberculosis. Tuberculosis patients who have raised C-reactive Protein levels are prone to hypozincemia. Several small studies have demonstrated that zinc supplementation as part of tuberculosis treatment results in faster clearance of Acid Fast Bacilli on sputum and resolution of cavities on chest X-Ray.14

Safety and Toxicity

Zinc supplementation at physiological doses is regarded as safe. Large doses of more than 150mg per day will interfere with copper bioavailability and produce side effects. Zinc is rarely contra-indicated and only in cases of acute renal impairment and severe kidney damage.

For general prevention, it is advised to use 5-10mg per day. Studies on Tuberculosis and HIV infection utilized 15-20mg per day. 21

Selenium

Selenium is a vital trace element, widely studied, and known to have beneficial immune-related effects to decrease the cardiac effects of viral infections, as well as cancer modulation/prevention mechanisms.  Multiple studies across the world have shown that selenium deficiency can lead to various chronic illnesses and supplementation can help boost immunity in various ways. There is little data on our specific population’s selenium status to date, but some authors estimate deficiency risk in South Africa between 11 and 25%.22,23

Sources of Selenium (Se)

The soil is the source of Se; it enters the food chain through incorporation into vegetable protein as the amino acids selenocysteine and selenomethionine.

Effects of Selenium on immune function

Se deficiency depresses the effectiveness of immune cells generally, with diverse specific effects.

Supplementation with Se appears to boost cellular immunity by three mechanisms:

  • It up-regulates the expression of the T-cell high-affinity IL2 receptor12 and provides a vehicle for enhanced T-cell responses. Since the T-cell is a key component in providing B-cell help for antibody synthesis, this may explain the stimulatory effects of Se on antibody production. Age-related decreases in cellular immunity can be partially reversed by Se supplementation increasing responsiveness to IL-2.
  • It prevents oxidative-stress-induced damage to immune cells.
  • It alters platelet aggregation by decreasing the ratio of thromboxane to leukotriene production. Selenium deficiency has been associated with cardiomyopathy, atopic asthma, arthritis, coronary heart disease, psoriasis and certain neoplasms.24

Selenium and HIV

In AIDS patients, Se status is predictive of survival times. There is also the intriguing observation that virulent strains of influenza virus evolve in Se-deficient areas of China.25 Several studies have shown that Se deficiency is associated with lower CD4 counts, and faster disease progression in patients with HIV infection. Furthermore, HIV cardiomyopathy has been linked by several authors to Se deficiency.2527

Cardiac failure

Selenium deficiency has been linked to increased oxidative stress and has detrimental effects on patients with heart failure.28

The elderly

Se levels decline with aging. Studies have found that this decline is most strongly associated with cardiac diseases and obesity in the elderly. Se is an integral part of the glutathione peroxidase system and therefore the oxidative capacity of human metabolism.29

Cancer

Selenium has been associated with protective effects against several cancers, including thyroid cancer, prostate cancer, lung cancer and colorectal cancer.30 In a meta-analysis of the effects of selenium supplementation for cancer prevention, the authors concluded that Se supplementation is of benefit in patients who are at risk of Se deficiency.31 Due to its effects on prevention of oxidative stress, Se is useful in cancer therapies that increase oxidative stress such as surgery, chemotherapy and radiotherapy.21

Supplementation and toxicity

According to the latest studies, Selenium can be safely supplemented in the general population in the form of sodium selenite at 50-200 mcg taken orally once per day. In patients with chronic conditions such as HIV/AIDS, cancer, kidney failure and cardiovascular disease higher doses, 100-300ug are recommended.21 The risk of toxicity at these moderate levels is very low. Toxicity (selenosis) depends on the selenium compound and its solubility. Selenomethionine is 90% absorbed and is the naturally occurring form of selenium.21

Vitamin C

The power of Vitamin C (ascorbic acid or sodium ascorbate) to support the immune system and to treat infections has been known since the early 1940s due to the work of Klenner and Cathcart who successfully treated influenza and pneumonia with very high doses of Vitamin C using both oral and intravenous routes.32

Vitamin C’s role in prevention and treatment of common cold was proposed in 1971 by double Nobel Prize laureate Linus Pauling, who found that ascorbic acid in a daily amount of 1000 mg decreased the incidence of colds by 45% and the integrated morbidity by 63%.33

Following the strong evidence from studies published before 1970 that Vitamin C has beneficial effects against the common cold 33, and from the ≥2 g/day Vitamin C studies published between 1972 and 1975.34 Two controlled trials found a statistically significant dose–response, for the duration of common cold symptoms, with up to 6–8 g/day of vitamin C.

Evidence for the recommended daily allowance of vitamin C puts intake at 200mg per day and clinical scurvy occurs at an intake of 10mg per day. One survey of elderly hospitalised patients showed scurvy in 10 percent. The WHO has created advice on the prevention of vitamin C deficiencies in major emergencies. The Covid-19 pandemic can be considered as such, especially in areas where food security is poor and vulnerable groups are at high risk of deficiency.

Physiological effects

Vitamin C is an essential micronutrient for humans, with varied functions related to its ability to donate electrons, making it a potent antioxidant, which protects cells from oxidative damage during infection from increased oxidative stress.35

It is a cofactor for a family of biosynthetic and gene regulatory enzymes, and contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system.35,36 It is present in the respiratory epithelium, as an immune stimulating agent, resulting in reduction in symptoms of upper respiratory tract infections.4 By supporting epithelial barrier function against pathogens and promoting the oxidant scavenging activity of the skin, it protects against environmental oxidative stress.35

In addition vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis, phagocytosis, generation of reactive oxygen and nitrogen species, and ultimately microbial killing, in viral and bacterial infections.35,37 These processes lead to reduction in vitamin C levels during infections.37 Vitamin C is also essential for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis and potential tissue damage by the products of lipid peroxidation.35,38 Neutrophils produce reactive oxygen species by activating NADPH oxidase, in order to kill viruses and bacteria.39

While the role of Vitamin C in lymphocytes is less clear, it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects.35 Vitamin C was also shown to increase the production of interferon at the initial stage of influenza infection in animal studies.40

In addition, hydrogen peroxide (H2O2) production of high dose Vitamin C upon its oxidation may have direct viricidal effects.41

Effects on respiratory viral illnesses

Vitamin C deficiency results in impaired immunity and higher susceptibility to respiratory infections. In turn, infections significantly decrease Vitamin C levels due to enhanced inflammation and metabolic requirements.34 Furthermore, supplementation with Vitamin C appears to be able to both prevent and treat respiratory and systemic infections.35

A study using 1000mg Vitamin C hourly for 6 hours, then 1000mg 3 x daily, administered before or after the appearance of cold and flu symptoms, reported flu and cold symptoms in the test group decreased 85% compared with the control group.42

Three prophylactic trials recorded cases of community-acquired pneumonia and found a statistically significant (80% or greater) reduction in pneumonia incidence in the Vitamin C group. It is important to note that no adverse effects of Vitamin C administration were encountered in any of the trials, and that vitamin C has a very low potential for toxicity even in higher doses.36 Therefore prophylactic use of Vitamin C to prevent pneumonia should be considered in populations who have a high incidence of pneumonia, especially if dietary Vitamin C intake is low.34 This consideration is of particular importance regarding the reduction in incidence and severity of pneumonia from Covid-19 especially for high risk groups, in order to decrease morbidity and mortality.

There is much evidence that Vitamin C influences the immune system, but its effects may be apparent only in particular conditions. For example, it is possible that variation in Vitamin C intake does not influence the immune system in the ordinary Western population because of their relatively high dietary intake levels. However, vulnerable South African population subgroups that are elderly, have co-morbidities such as diabetes, heart disease, or those receiving suboptimal diets with insufficient dietary sources of Vitamin C would be target groups for high risk of pneumonia, in whom supplementation would be most beneficial.

Prophylactic prevention of infection requires dietary Vitamin C intakes that provide at least adequate, if not saturating plasma levels (i.e. 100–200 mg/day), which optimise cell and tissue levels. In contrast, treatment of established infections requires significantly higher doses of the vitamin to compensate for the increased inflammatory response and metabolic demand.35

Hunt et al, found that 200mg of vitamin C per day resulted in a decrease in deaths among severely ill, hospitalised patients with acute respiratory infections.43 Those supplemented with the vitamin fared significantly better than those on placebo with significant improvement in clinical scores, especially the severely ill, many of whom had very low plasma and white cell Vitamin C concentrations on admission.43

In patients hospitalised with pneumonia, Bancalari reported a decrease in the duration of illness in the vitamin C supplementation group, and Khan reported a decrease in the number of days for improvement in oxygen saturation and respiratory rate in the vitamin C supplementation group.44,45 The mean duration of hospital stay in those receiving vitamin C supplementation was also lower in 2 recent studies.46

Hypovitaminosis C and Vitamin C deficiency are very common in critically ill patients due to increased needs and decreased intake. Because Vitamin C has pleiotropic functions, deficiency can aggravate the severity of illness and hamper recovery.47 There are currently 2 large ongoing studies on the use of vitamin C in treatment of pneumonia, one of which is studying IV vitamin C in the treatment of Covid-19 pneumonia.

Dose and toxicity

The potential for toxicity and adverse events related to Vitamin C is very low even at high doses. In order for it to be safe for those elderly persons with potentially poor renal or liver function, diabetes, hypertension, oxalate stone formers, those on anticoagulation, aluminum containing compounds, we recommend a dose of a 1000mg daily, well below the upper limit of the RDA of 2000mg.21

Conclusion

The limited movements resulting from enforced quarantine and social isolation19, along with the significant economic hardship experienced by many South Africans, make it very difficult to obtain a balanced and varied diet. In other cases, it worsens an already malnourished state. Adequate micro-nutrients are essential for immune function, this function currently being the only defense against Covid-19. Vulnerable South Africans need support to decrease the mortality and morbidity related to Covid-19 infections. Micronutrients in the form of supplements are a valuable and safe means of assisting in inflammatory conditions and assisting the vulnerable immune system. Supplementation will also have a beneficial effect with regards to the seasonal flu and other viral and bacterial infections.

While the government is doing all it can to mitigate the effects of the epidemic in South Africa, there remain treatment-need gaps that still need to be addressed. This includes not only the management and course of milder Covid-19 infections, but also the design of supportive strategies to prevent mild infections from progressing to more severe forms of the disease. This applies especially to those patients who are most at risk such as the elderly, immuno-compromised and those with chronic illnesses. We propose that there exists strong evidence that provision of the above micronutrients for the next 6-12 months is a safe, effective and affordable strategy to mitigate the effects of severe Covid-19 infections and in so-doing limit disease severity, hospitalisation incidence and disease mortality.

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Appendix

Quotes for manufacturing

Multinutrient option:

  • Selenium 75mcg
  • Vitamin C 250mg
  • Vitamin D3 1000iu
  • Zinc 15mg
  • Magnesium 50mg

Above ingredients combined into a tablet.
30 tablets packed into a PET tub.
Cost price R12.00 per tub.
This can be produced by Coyne Healthcare. Coyne Healthcare has offered to sponsor 10 000 units as a starting point, totalling a donation of R120 000.

Vitamin C option:

  • Vitamin C 950mg per capsule

30 capsules packed into a plastic PET tub, costing R23.85 a unit.
This can be produced by Acupharm.

Efferflu Immune Booster:

  • Vitamin C 1000 mg
  • Echinacea purpurea 50 mg
  • Zinc lactate trihydrate 22,71 mg

A unit contains 20 effervescent tablets.
Pharmadynamics has donated 1000 units.