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Vitamin B12 Deficiency and COVID-19

COVID-19 Infection

  • The COVID-19 virus enters cells via ACE-2 receptors on cells

  • Expression of ACE-2 receptors is increased with the use of ACE-2 receptor blockers (ARBs)

  • Potentially the use of the ARBs could increase the uptake of COVID-19

  • This may explain why people on anti-hypertensive medication are more at risk of COVID-19 infections.

  • Risk factors for COVID-19 related deaths include increased signs of sepsis,  high blood pressure, heart disease CVD increase 10.6%, lung disease  7.3%, diabetes  6.3%, being immuno-suppressed  5.6% and blood clotting issues, however, the greatest risk is with increasing age.

  • In some regards, the death rate is more dependent upon the standard of health care than any thing else with death rates of only 1-2% in countries such as Israel and Australia, but as high as 11.8, 19 and 11.8% in Spain, France and Italy respectively  (as of 26/03/20). This is going to be catastrophic in Africa, where death rates from the flu are very high.

Potential increase in Infection with ACE inhibitors

Many of the anti-hypertensive medicines, including Captopril and enalapril, and also selenopril directly interact with ACE and inhibit their action. Potentially, though, the reduce activity of ACE would lead to an up-regulation of ACE by the cells, and hence provide more receptors for COVID-19 to bind to, thereby increasing the severity of the infection. Recently a new inhibitor selenoneine has been identified as a potential ACE inhibitor (Seko etal, 2019). Whilst this molecule, a selenium-containing imidazole, does contain Selenium, its action is completely different to that of dietary or supplemental Selenite, which is involved in production of Selenoproteins.

Vitamin B12 and the Production of Melatonin

Melatonin, together with vitamin D, stimulates neuronal stem cells to differentiate into oligodendrocytes, which are the cells in the brain that are responsible for myelination of the nerves in the brain. Melatonin is thus critically important in the young for neuronal development as the child grows and matures. Production of melatonin gradually starts to decline after puberty. To date there have been no fatalities due to COVID-19 in children under the age of 9, and there is a gradual increase in fatality rate with age, which is inversely  proportional to the drop in melatonin production with age (Gravid etal, 2007). One reason postulated for this is melatonin's unique ability to inhibit the activation of the inflammatory cascade. In this way destruction of mitochondrial energy production during the inflammatory response can be inhibited. In the lung, the site of COVID-19 infection, melatonin can thereby inhibit the acute respiratory distress syndrome, thereby reducing the damage to the lungs and thereby the need for intubation and mechanical ventilation of the lungs, with the associated damage (Wu etal, 2020). Melatonin has also been shown to be protective against multiple organ failure, circulatory failure, as well as preventing mitochondrial damage in experimental sepsis, and able to reduce lipid peroxidation, one of the indices of inflammation and mortality in human newborns with sepsis (Escames etal, 2006; Lopez etal 2006; Escames etal, 2005; Carillo-Vico etal, 2005; Srinivasan etal, 2010; Reiter etal, 2001; 2017; Biancatelli etal 2020) Melatonin has also been shown to modulate the inflammatory response through its modulation of Inflammasome activation (Favero etal, 2017)

 

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Melatonin levels as we aget

Grivas and Savvidou, 2007

COVID-19 fatality rate by age (China)

Production of melatonin is critically dependent upon maintaining sufficient levels of the methylating agent, S-Adenosylmethionine, a product of the methylation cycle, a cycle which is dependent on functional activity of methyl vitamin B12. Functional activity of vitamin B12 is in turn dependent upon functional vitamin B2, or more specifically FMN and FAD. Production of FMN and FAD, in turn is dependent upon intake of vitamin B2, Iodine, Selenium and Molybdenum. Deficiencies in any or all of these will lead to lower active vitamin B2 being present, and from there lower active methyl B12, and hence lower levels of melatonin. Potentially there is another reason for higher lethality in those with low melatonin, and that is the potential accumulation of the adrenalin pre-cursor- serotonin, leading to serotonin levels typically seen in serotonin syndrome, a syndrome that has been associated with acute pulmonary edema (Wu etal, 2015; Shah and Jain, 2016; Ferslew etal, 1998).

Vitamin B12 and the inflammatory Response

Vitamin B12 has long been known to have a role in damping down the inflammatory response via several mechanisms

  • Scavenging of Nitric Oxide

  • Inhibition of NFkappaB, an important inflammatory mediator

More recently high dose intravenous Methyl B12 has been suggested as a safe and cost effective treatment for the Acute Respiratory Distress Syndrome, that is one of the major causes of death from COVID-19 (Wheatley, 2006; Manzanares and Hardy, 2010). If this is found to be true, then one would assume that daily topical administration of Methyl B12 in TransdermoilTM has the potential to greatly ameliorate the disease once caught, and to thereby dramatically reduce the mortality of the condition.

Selenium and the inflammatory Response

High dose sodium selenite given to patients with severe systemic inflammatory response syndrome, sepsis, and septic shock, was found to reduce mortality rate (Angstwurm etal, 2007). The virulence of several respiratory viruses was found to be increased in Selenium deficient mice (Beck etal, 2003). Selenium supplementation with 200 ug/day selenium has been found to reduce the viral load in HIV (Hurwitz etal, 2007). Recent data analysis from China has shown that the areas with the highest Selenium concentrations has lower death rates than those with low Selenium. Selenium potentially has many roles in protection. It is required as a cofactor by glutathione peroxidase, which is involved in inactivating inflammatory hydrogen peroxide. It is critical in the activation of vitamin B2, and in thereby in maintaining free glutathione inside the cells, and active B2 (as FMN and FAD) are both required to maintain the activity of methylB12, and so is involved in the production of melatonin. Levels of Selenium decline in the body with age, and are generally lower in males, due to the targeting of Selenium to the testes, hence potentially explaining the higher death rate in males than females of the same age.

Zhang etal, 2020

Resistance to COVID-19 in China has been reported to be correlated with regional Selenium status (Zhang etal, 2020, Rayman etal, 2020).

Part of the inflammatory cascade involves the activation of oxygen by NADPH Oxidase to generate the reactive oxygen species O2**, This in turn is further activated to generate hydrogen peroxide (H2O2). Under normal circumstances the H2O2 is then converted to hydroxide and then water by the Selenoprotein Glutathione-Peroxidase (GSHPx(Se).

In Selenium deficiency this reaction is reduced and so dangerous H2O2 would accumulate inside the cell and cause massive intracellular damage. Further, the reduction of oxidized glutathione (GSSG) requires the FAD-dependent enzyme glutathione reductase (GSH reductase). In Selenium deficiency activation of vitamin B2 is incomplete and hence levels of FMN and FAD would be lower inside the cell. This has the dual effect of reducing the activity of  GSH-reductase, but also, because of the requirement for FMN and FAD in the cycling of methyl B12, lack of FMN and FAD would lead to lower methylation and reduced production of GSH, through lower activity of the sulphation cycle in Methyl B12 deficiency.

Studies in which glutathione production has been inhibited have shown to result in very high levels of free radicals accumulating within cells (Kurniawan etal, 2020), further supporting the hypothesis that reduced GSHPx and GSH reductase activity can result in massively increased oxygen radical damage. Uncontrolled NADPH-oxidase have been shown to play a critical role in Hyperoxia-induced acute lung injury (Carnesecchi etal). Hyperoxia has also been shown to increase ROS production by human pulmonary artery endothelial cells (Parinandi etal, 2003). NADPH oxidase activity in inflammasomes has also been shown to be responsible for the production of pulmonary fibrosis, a feature of COVID-19 infections (Sun etal, 2015). Potentially hyperoxygenation of the lungs during Ventilator treatment could potentiate the ROS damage, particularly in those that are Selenium, or B12 deficient. This may explain the very high death rate (92%) in those over 65 who are placed on ventilators. Despite these associations, no Health expert has yet to suggest that populations supplement with Selenium.

Iron and Resistance to Respiratory infections

Iron deficiency has been associated with an increased susceptibility to respiratory infections (Jayaweera etal, 2019; Stepan etal, 2018; Tansarli  etal 2013), and with a poorer outcome in patients with other respiratory infections, such as influenza A (H1N1)(Bai  etal, 2010;. Iron deficiency has also been associated with a poorer outcome for congestive heart failure, a potential complication of Coronavirus infection (Nickol etal, 2015). Iron supplementation has been shown to reduce morbidity due to upper respiratory infections (de Silva etal, 2003; Hurrell 2007). Persons using PPIs for treatment of obesity are known to have lower iron levels (Yu etal, 2017), and as such might be expected to have higher incidence of URTI. Iron is also essential for energy production and for carrying oxygen, hence a deficiency of iron could contribute to respiratory failure seen in COVID patients.

Zinc and Resistance to Respiratory infections

Along with iron, zinc deficiency has been associated with an increased incidence of acute respiratory infections (Bailey etal, 2015)

Vitamin B12 Deficiency and Energy metabolism

Vitamin B12 has a critical role in energy production through it's role in production of CoQ10, creatine, and its role in the production of the Krebs cycle enzyme, aconitase. Hence decreased levels of active B12 should be correlated with lower metabolic energy in Krebs may be associated with reduced energy production and as such may contribute to respiratory failure in COVID-19 patients.

Vitamin D Deficiency and Respiratory Infections

Studies have reported a consistent association between low serum concentrations of 25-OH-Vitamin D and susceptibility to acute respiratory tract infections (Martinez etal, 2017; Ginde etal, 2009; Joliffe etal, 2013). Vitamin D supplementation has also been shown to reduce mortality to respiratory tract infections, particularly in the elderly (Bjelakovic etal, 2011). Current suggestions are supplementation with 1000-4000 IU of vitamin D per day, with bolus supplementation (ie once per week) not recommended (Sizar etal 2020). It has been suggested that the heavy mortality observed following Coronavius infection may be associated with low vitamin D levels in countries such as Italy, and Scandinavia. Low vitamin D is also prevalent in the UK, with a rise in rickets being seen in children. Vitamin D has been shown to decrease the production of pro-inflammatory molecules, and as such may reduce the "cytokine storm" that is associated with the pathogenesis of COVID-19. Vitamin D has also been shown to be essential for immune function, and low vitamin D is associated with greater susceptibility to both bacterial and viral infections. VItamin D levels tend to decrease with age, as too vitamin D deficiency associated conditions such as diabetes and obesity, all three of which have been associated with mortality to COVID-19. In Ireland, 47% of people over 85 are deficient in vitamin D, with 27% of those over 70. Vitamin D deficiency is very common in the community with 42% of Americans deemed vitamin D deficient. Deficiency increases in black people (82%) and Hispanics (70%). The highest death rate in the US occurs in African-Americans. Despite the known protective effect of vitamin D, no health authority has yet to suggest that the population increase their vitamin D. This alone could half the death rate.

Death Rates from COVID-19

Death rates from COVID-19 vary greatly from country to country, with some recording death rates from infection as low as 0.4%, but others with death rates as high as 12%. Thus, whilst within a country the predisposing factors are high blood pressure, heart disease CVD ^ 10.6%, lung disease ^ 7.3%, diabetes ^ 6.3%, being immunosuppressed ^ 5.6% and blood clotting issues, and age, by far the biggest predisposing factor for the death is the country in which you live, which depending upon country can vary from a death rate of less than 0.6% to over 12%. Currently it is unknown why the rates vary, however, if these reasons could be identified it may go a long way to reducing the severity of the condition, which will be an essential component of dealing with the virus, particularly during the waiting period between now and the development of a vaccine. This will be more even more important if a successful vaccine is not developed. We have dedicated a separate page to a discussion of possible causes of the varying death rates..

Nutritional Support for Dealing with COVID-19

Vitamin A. Vitamin A was originally thought of as the anti-infective vitamin, and vitamin A deficiency has been implicated in the severity of diarrhoea and measles. Supplementation with vitamin A has reduced the morbidity and severity of a range of infectious diseases including HIV, malaria, measles and measles-related pneumonia (Semba 1999). The ability to generate an immune response to inactivated bovine coronavirus vaccines is compromised in calves with low vitamin A (Lee etal, 2013).

Vitamin C. Vitamin C has been shown to support immune function and to be able to protect against coronavirus infections (Hemila 2003). Vitamin C is also essential for the formation of hydroxyproline, an essential amino acid for the production of high tensile collagen. Lack of vitamin C, could potentially lead to alveolar collapse, due to "weak" collagen.

Vitamin D. Vitamin D has known immune functions including stimulation of maturation of immune cells, but also in activation of several proteins in Krebs cycle. Decreased vitamin D levels in calves has been reported to increase susceptibility of calves to bovine Coranavirus (Nonnecke etal, 2014). Potentially the greatly reduced vitamin D levels in the population due to the adoption of high SPF cosmetics, could increase the morbidity and mortality to coronavirus. Activation of vitamin D requires adequate amounts of iron, activated vitamin B2 (FAD), vitamin B12 and folate. Interestingly, vitamin D levels were very low in Italy, one of the countries with the highest death rate from COVID-19 (Giustina etal, 2020; Garami 2020). Potentially doubling the vitamin D levels in the population could have a much more beneficial effect than any of the molecules currently under study to aid in reducing the inflammatory storm.

Selenium. Selenium has an important role in the body, not only in anti-oxidant defense but also in the activation of vitamin B2, and then the activation of vitamin B6, vitamin K and also for vitamin A. High dose sodium selenite has been found to reduce viral loads, and to reduce mortality in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Selenium is also a vital mineral for the activation of vitamin B2 .

Vitamin B2. Activation of vitamin B12, vitamin B6, vitamin A and vitamin K are all dependent upon functional vitamin B2.

Vitamin B12. High dose vitamin B12 has the potential to increase melatonin levels, and to also have a beneficial effect as far as modulation of the immune response. Vitamin B12 has also been demonstrated to inhibit the RNA-polymerase activity of the nsp12-protein from COVID-19 (Narayanan and Nair 2020)

Iron. Iron deficiency has been associated with an increased susceptibility to respiratory infections (Jayaweeraetal, 2019)High dose vitamin B12 has the potential to increase melatonin levels, and to also have a beneficial effect as far as modulation of the immune response.

Melatonin. There is the potential to give melatonin to increase the resistance to COVID-19. Doses of 3, 6 and 10 mg, have been given to patients in ICU, were found to be safe. Further doses of 1 g per day have been given for a month with no effect (Zhang etal 2020)..

General. Some general information on nutrition and fight COVID-19 has been summarized by Zhang and Liu (2020). Unfortunately, as long as the medical profession refuses to accept the importance of minerals such as Selenium, and vitamins D, B12 and B2 and iron in increasing the resistance to viral infections and in controlling the severity of infections, they will never recommend supplements as a preventative option against infection.

Mechanism of invasion of COVID-19

Video of the mechanism behind severe systemic inflammatory response syndrome with COVID-19

https://www.youtube.com/watch?v=PWzbArPgo-o

Review of Statistics on outbreak in China

See https://www.worldhealth.net/news/risk-factors-covid-19-related-death-identified/

Co-morbidities raise the risk of death from Corona. Thus, in China the death rate in those with no co-morbidities was 0.9%, but was much higher for those with Cardiovascular disease (10.5%), diabetes (7.3%), Chronic respiratory diseases (such as COPD, 6.3%), Hypertension (6.0%) and cancer (5.6%). In many countries, including the US, many people in the population have at least one underlying health condition (US, 60%).

Review of Statistics on outbreak in Great Britain

The progression of the disease can lead to a critical point in which a decision must be made as to whether to admit the patient to critical care. See an explanation of the virus and who it infects and kills from a summary of UK Data

Coranavirus Vaccine

Many researchers are of the belief that there is every reason to believe that it should be possible to develop a coronavirus vaccine for humans, as many individuals who have been infected with the virus recover, and over 90% of those infected in China have now recovered. Further, it is known that passive immunity gained from bovine colostrum will protect calves against bovine coronavirus, if the titre is high enough (Bok etal, 2018). Recently Moderna has generated an mRNA vaccine against COVID-19. Best estimates for a vaccine to be on the market are still 18 months. Potential problems for the vaccine would be lack of immunogenicity in all persons. Thus, even for well established viral vaccines such as Hepatitis B, even after 3 injections there is less than a 90% seroconversion rate. Similarly, vaccine effectiveness for the common flu vaccine is only 19-60%, however, this is to a continually evolving flu virus, with effectiveness higher the higher the similarity of the vaccine to the current flu virus. Whether COVID-19 will do that, is not known (https://www.cdc.gov/flu/vaccines-work/effectiveness-studies.htm ). Recently an analysis has been performed looking at the immunological response to hepatitis B vaccine (Yang etal, 2016), where the data looked very similar to that observed for the current COVID-19 outbreak. Thus, the vaccine was much more effective in the young, with protection more effective in females than males, and less effective in those with concomitant diseases, with a BMI >25 or those who smoked.

Other Strategies

Several alternative strategies are possible which would potentially ameliorate the condition and reduce mortality

  • Antivirals - currently none seem to be working.

  • Peptide mimetics. Small peptides, that either mimic the binding site on ACE2, could potentially neutralize the viral binding protein, and reduce infectivity. These can be produced at large scale, however, it would not be possible to deliver these orally so that would need to be administered by injection, or via technologies such the TransdermOil™ technology.

  • Anti-scabies treatment. A group in Melbourne Australia has found that a single dose of the drug Ivermectin could stops SARS-COV2 virus in culture (Caly etal, 2020)

Comparison to Flu

It would seem useful to compare Coronavirus to the Flu. The annual burden of Flu in the US since 2010 has been between 9,300,000 to 45,000,000. Of these there were 140,000 to 810,000 hospitalizations with an annual death rate of 12,000 to 61,000 (CDC). Claims are that Coronavirus is different to flu in that the death rates for flu are in both the young and old. Globally, however, death rates go up for flu. <65 years - 0.1 to 6.5 per 100,000; 65-74 years 2.9-44.0 per 100,000 and for over 75, 17.9 to 223.5 per 100,000 (0.234%) (Iuliano etal, 2018). it is not known if susceptibility to COVID-19 is related to blood type, however, it has been shown in many studies that susceptibility to Influenza virus is, with type B and AB being much less able to generate effective antibody responses to Influenza A. Preliminary studies from China suggest that susceptibility to COVID-19 may be slightly higher in type A blood types. These data support the general concept that one's ability to fight the infection is affected by one's genetics (see section above on Vaccine).

Testing

Currently the majority of tests for Coronavirus test whether you have a detectable amount of the virus. The results of the test are being widely misunderstood to mean that the person does not have the virus, whereas this may not be true. All the test means is that at the time of testing the person being tested had undetectable amounts of the virus. It does not mean that if you tested the same person 4 or 5 hours later, they would still test negative for the virus.

Research

Spike Proteins See Link

References

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Phage Display 20976998-selection-sars-coronavirus-specific-cell-epitopes-phage-peptide-library-screening-evaluation-immunological-effect-epitope-based-peptides-mice

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Vitamin D to be added to M&S bread https://www.bbc.com/news/uk-32941923

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