Dr. Sundeep Mishra in his exclusive COVID-19 series for M3 India details on the role of micronutrients and their supportive role in prevention and treatment of the infection. He also provides his opinion on herbal supplements being marketed as immunity boosters.

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Immunity both innate (1-3rd stage) and adaptive (3rd stage) may occur in all stages of COVID disease and is in essence protective in nature. However, with severe COVID infection, it can become over-reactionary and maladaptive; becoming more harmful than beneficial e.g. cytokine storm.

In the case of novel coronavirus, it seems that adaptive T-cell response may be more important (especially in mild/asymptomatic cases) than the generation of antibodies. In addition, it has now been found that the SARS-CoV-2 virus possesses a novel free fatty acid (FFA) binding pocket (LA binding) that could explain in part the viral effects of hyper-inflammation, immune modulation, and membrane structure.

LA binding can affect all the three (lipid metabolism) cell pathways, one related to energy homeostasis, one to biological membrane fluidity and elasticity, and the third to lipid cell signaling molecules. Furthermore, LA scavenging carried out by SARS-CoV-2 can result in a non-tissue-specific disruption of normal regulation of immune and inflammatory pathways. This could be how the current virus produces such harsh features of the disease. Thus a balanced immune response is essential for a favourable outcome. There could be several ways to improve immunity, both natural and therapeutic.

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Strategies to prevent COVID-19 infection

Prevention of COVID-19
Mechanism	Preventive Strategy
Viral infectivity	Chloroquine / Hydroxychloroquine
Viral load	Social distancing General hygiene like frequently washing hands Wearing of masks Wearing of gloves Steam inhalation Saline gargles
Host factors-immunomodulation	Nebulisation with PUL-042 Smoking cessation Diet rich in fruits and vegetables   Regular exercise Maintenance of healthy body weight Drinking in moderation, if at all Adequate sleep Minimising stress Micro-nutrients- Zinc, selenium, iron, copper, folic acid, and vitamins A, B6, C, and E Omega-3 polyunsaturated fatty acids Herbs and natural supplements

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PUL-042

PUL-042 is an agent used for nebulisation with potential immunostimulating activity. It consists of two TLR ligands: Pam2CSK4 acetate (Pam2) and an oligodeoxynucleotide M362, both TLR agonists. It binds to and activates TLRs on lung epithelial cells which induces them to produce peptides and reactive oxygen species (ROS) against any pathogens in the lungs, including coronavirus.

Furthermore, it initiates the innate immune system and activates macrophages, NK cells, B cells, and plasmacytoid dendritic cells; stimulates interferon-α production; and induces a T-helper 1 & 2 cells. It has been approved for experimental use by US-FDA for both prevention and early treatment of disease. In prevention, it can be used via the intranasal route for 10 days in those having been exposed to SARS-CoV-2 infection.

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Lifestyle measures

Many lifestyle measures can build up immunity against many infections including viral infections; smoking cessation, daily exercise, moderation in drinking, sleeping well, maintaining ideal body weight, stress reduction, a proper diet rich in fruits and vegetables, proper intake of micro-nutrients and herbal immune-modulators can all help.

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Micronutrients and immunity

There is evidence that deficiency of some micro-nutrients such as zinc, selenium, iron, copper, folic acid, and vitamins A, B6, C, and E can alter immune responses in vitro and in animals. The use of some of the micro-nutrients may be found beneficial in prevention from COVID-19.

Zinc

Zinc (Zn) is an essential micronutrient for human metabolism that catalyses more than 100 enzymes, facilitates protein folding, and helps regulate gene expression. Zn ions are closely involved in the normal development, differentiation, and function of immune cells. It is considered critical for generating both innate and acquired (humeral) antiviral responses. Zn deficiency has been associated with reduced antibody production, the depressed performance of the innate immune system (e.g. low NK cell activity), decreased cytokine production by monocytes, and the chemotaxis and oxidative burst of neutrophil granulocytes. Long term Zc deficiency results in thymic atrophy, altered hormones production, lymphopenia, and defective cellular- and antibody-mediated responses culminating in increased rates and duration of viral infections.

Multiple antiviral effects of Zn have been demonstrated in a variety of viral species, including several nidoviruses, for which SARS-CoV-2 belongs. Administration of Zn has a potential to enhance antiviral immunity, both innate and humoral, and to restore depleted immune cell function or to improve normal immune cell function especially in immune-compromised/elderly individuals. Zinc can also have synergistic beneficial action when co-administered with other anti-viral agents.

Mechanism of action

Zn possesses a variety of direct and indirect antiviral properties and as such it has a broad-spectrum antiviral activity:

1. Physical process
   1. can inhibit viral attachment to cell ► decreasing infectivity
   2. can uncoat virus ► decreasing infectivity
   3. stabilise cell membrane contributing to blocking the virus entry in cell
2. RNA replication
   1. may inhibit the RNA-dependent RNA polymerase activity and coronavirus replication of nidoviruses; SARS-CoV-2
3. Enhance action of CQ/ HCQ by altering intra-celluar pH

Prophylaxis with zinc

Zn deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, diabetes, malnutrition, alcoholism, inflammatory bowel disease, and mal-absorption syndromes. For prophylaxis, a dose of 50 mg of zinc is to be taken daily at bedtime.

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Selenium

Selenium is an essential trace element widely present in nature in many organic compounds, particularly in proteins in the form of intra- or inter-molecular disulfides bridges. Impacting the viral genetic apparatus directly and by neuromodulation indirectly, it plays a very important role in the defense against infectious diseases.

Mechanism of action

1. Direct anti-viral action:
   1. Selenium, in concert with vitamin E prevents the formation of free radicals. When the immune system kills the virus, damaged tissue and virus may undergo oxidation. It is actually the oxidised products which are responsible for many negative effects of the COVID disease. Free radicals prevent this oxidation.
   2. Deficiency of selenium can cause a rapid mutation of benign variants of RNA viruses to virulent forms so that a normally benign/mildly pathogenic virus becomes very dangerous.
2. Immunomodulation: It increases the proliferation of NK cells and T-lymphocytes.
3. Synergistic effect: It has a positive effect in combination with some vitamins D and E.
4. Anti-thrombotic effect: Selenium reduces the formation of thrombosis in the blood vessels by reducing the risk of blood clots formation due to formation of high-molecular polymer- parafibrin in patients with COVID-19. Thromboembolism is an important contributor of morbidity and mortality in sicker COVID-19 patients.

Clinical evidence and dose

In a Chinese analysis, it was found that in areas with high levels of selenium, infected patients were more likely to recover from the SARS-CoV-2 coronavirus. In the city of Enshi in Hubei Province, which has the highest selenium intake in China, the recovery rate was ~3 times higher than the average for all the other cities in Hubei Province.

Another study found that in 17 cities outside of Hubei, the higher the selenium level (measured in hair), the higher the recovery. Moreover, researchers found that the COVID-19 recovery rate was significantly associated with selenium status, as measured by the amount of selenium in hair. Furthermore, in Heilongjiang Province (where selenium intake is among the lowest in the world), the death rate from COVID-19 was ~5 times higher than the rest of China.

Many whole grains and dairy products (including milk & yogurt) and some fruits and vegetables contain selenium. Chicken, fish, shellfish, and eggs contain high amounts of selenium. It is a constituent in many multivitamin tablets. The recommended daily allowance for selenium in adults is 55µg/day.

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Iron

Iron is an essential nutrient for both host and the virus. While on one hand iron deficiency will impair host immunity, on the other hand, iron overload may cause oxidative stress leading to harmful viral mutations. Thus, an ideal iron balance is necessary. Iron deficiency is a risk factor for the development of recurrent acute respiratory tract infections.

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Vitamin C

Vitamin C is a water‐soluble vitamin, also known as ascorbic acid. Vitamin C is best known for its role as an antioxidant and in the synthesis of collagen in connective tissues.

Mechanism of action

• Antioxidant: Prevents oxidative damage caused by dead tissue and virus
• Immunemodulator: Supports the development of WBC
• Weak anti-histaminic: Provides relief from flu‐like symptoms such as sneezing, a runny or stuffy nose, and swollen sinuses
• Anti-inflammatory: Prevents damage to lungs and other organs due to inflammation (especially common in serious COVID-19)

Clinical evidence and dose

Vitamin C has been found to prevent coronavirus infection in animal studies. Human trials have also shown that vitamin C administration could prevent as also provide relief against both upper respiratory tract infection (URI) and lower respiratory tract infection (LRI). In serious diseases, it can act via inhibiting inflammation and symptoms associated with COVID-19. A dose of 100 to 200 mg/day should prove to be adequate to optimise cell and tissue levels for the reduction of chronic disease risks such as viral infections. Overall, there could be some benefit with supplementation of vitamin C with practically ‘no harm’ in recommended doses.

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Vitamin D

Vitamin D (Vit D) is both a nutrient and a hormone, synthesised in our body on exposure to sunlight and is essential for the maintenance of bone integrity in the body. Its deficiency is particularly common ~40% in the US population and is commonly present in bedridden, immobile people, elderly individuals (essentially those not exposed to sunlight) and especially in the winter season.

1. Immunomodulation: It stimulates the maturation of immune cells, modulates WBC by preventing them from releasing too many inflammatory cytokines. This could reduce the possibility of COVID-19-induced cytokine storm (one of the highest contributor of morbidity and mortality associated with COVID-19). It also helps in reducing the risk of LRTI and lung injury.
2. Direct antiviral activity: It increases the synthesis of cathelicidin.

Clinical evidence and dose

Several reports suggest decreased vitamin D levels could be associated with higher numbers of COVID-19 cases and mortality. A recent study also suggested that vitamin D administration could protect against severe respiratory tract infections. Diets rich in vitamin D, such as those that include fatty fish, orange juice, cheese, and eggs yolks, can help prevent vitamin D deficiency, along with supplementing vitamin D. In case of vitamin D supplementation, a daily dose ~2000 IU for the middle-age adults and ~4000 IU for low vitamin D risk group is recommended.

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Vitamin B Complex

B vitamins are water‐soluble vitamins and work as part of co-enzymes, each vitamin having its own special function:

• Vitamin B2 (Riboflavin) plays a role in the energy metabolism of all cells and its deficiency occurs in the elderly. It functions by reducing the level of MERS‐CoV in human plasma
• Vitamin B3 (Nicotinamide) has anti-pathogenic activity via myeloid‐specific transcription factor, by inhibiting neutrophil infiltration into the lungs and a strong anti‐inflammatory effect during ventilator‐induced lung injury
• Vitamin B6 is needed in protein metabolism and it participates in over 100 reactions in body tissues and is an immune-modulator as well

Deficiency of B vitamins may weaken host immune response and thus they should be supplemented to individuals susceptible to developing COVID-19 as well as its treatment.

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Vitamin E

Vitamin E is a lipid‐soluble vitamin and plays an important role in reducing oxidative stress through binding to free radicals as an antioxidant. Its deficiency (along with deficiency of Vit D) is associated with infection of bovine coronavirus. Thus, its administration may help reduce damage caused by dead tissue and virus during COVID-19.

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Omega‐3 polyunsaturated fatty acids

Omega-3 fatty acid rich-fish oil (FO) is a common component of the fat milieu in the body long‐chain polyunsaturated fatty acids (PUFAs) are another common constituent of the diet which may also be helpful in COVID.

Mechanism of action

1. Anti-inflammatory: Balance the inflammatory response in the body.
2. Direct antiviral: Can attenuate virus replication via RNA export machinery (influenza); anti‐hepatitis C virus activity.
3. Immunomodulator: FO may reduce the auto-immune response by inhibiting the linoleic acid (LA) pathway operative in COVID-19, which is responsible for the cytokine storm. They act by modulating the levels of selected cytokines chemokines, and enzymes involved in antioxidant defense. Moreover, vitamin E acting in concert seems to exert selective effects on proliferative response and specific subsets and selected cytokines.

As a result of these multiple actions, omega‐3 including protectin D1 could be considered for one of the potential interventions of this novel virus, COVID‐19. Thus, instituting appropriate levels of FO 7 Vitamin E in diets may enhance and modulate the beneficial immune response.

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Herbs and natural supplements

Using herbs to treat infections including viral infections is not a novel idea. For thousands of years, herbs like licorice, ginger, and ephedra have been used to treat respiratory infections like the flu and pneumonia in the West and many herbs have been used in traditional oriental medicine for a variety of ailments including the common cold. Although some preparations have been found to alter some components of immune function and some even have potent anti-viral effects, thus far there is no verifiable clinical evidence that they actually bolster immunity so much so that they provide protection against corona infection and disease.

Forsythia has been used in the past for airway illnesses, swelling, fever, and other conditions. But there is no good scientific research to support any use. Licorice (nadyapaan) is another one of such remedies that officials in China have recommended for COVID-19. It prevents the replication of viruses (herpes) and therefore could be useful in coronavirus as well. However, it also has a major downside; It can activate ‘aldosterone hormone’ can induce hypertension (via fluid retention) and hypertension in itself a huge risk factor for COVID-19 complications.

The most important risk is that certain herbs, if misused, could boost the immune system even more and lead to “a cytokine storm,” one of the most dangerous complications of COVID-19. Charaka Samhita suggests following herbs for the common cold; sitopaladi, talisadi, abhrak bhasma, and mahasudarshan churna but their effects in COVID protection are unknown. Traditional Indian medicine suggests herbal tea (kada) composed of tulsi (holy basil, one or two leaves), ginger, cinnamon and cardamom ± mint but again there is no confirmatory evidence, although with this there seems ‘no harm.’

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Conclusions

While many micronutrients and herbals are positioned as effective immune-modulators based on their putative mechanism of action, it is better to be a bit cautious as of now because direct actions of these agents on the natural history of COVID-19 are still not known.

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To read other articles in this series, click

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Should I give chloroquine/hydroxychloroquine for prevention of COVID-19?

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Sundeep Mishra is a Professor of Cardiology.