Covid-19 and Vitamin D: summary of evidence

Covid-19 & Vitamin D – summary of evidence

Most vitamin D supplements come
 from the oils extracted from sheep's wool

, 

The pre-Covid era

Before the Covid-19 pandemic started a great deal was known about the importance of vitamin D in defensive immunity, but the knowledge was not widespread.

In the early 20th century the identification of rickets led to the recognition of vitamin D in the metabolism of bones. At about the same time it was realised that rickets and tuberculosis co-existed in families more frequently than would be expected by chance. It was observed that UV light could heal tuberculosis of the skin, and later that sunlight could improve the outcome of  systemic tuberculosis. At this time in the first half of the 20th century the science of immunology had not been established.

In the second half of the 20th century the activation of vitamin D became understood. The hydroxylation in the liver of vitamin D as cholecalciferol to 25(OH)D creates the body’s storage form, which circulates in the blood and is available for immediate use. A second hydroxylation in the kidneys to 1,25(OH)D creates an active form in the blood and this is vital for the control of the blood concentration of ionised calcium, active on the bones and also on the kidney tubules and the intestine. 

The process of the immune reaction to infection became understood in the late 20th century. B- and T-lymphocytes had  been identified, controlling antibody production and tissue immunity respectively. It became clear that they need to be activated from their resting state by vitamin D. It is now also clear that they generate internally their own 1,25(OH)D obtained from 25(OH)D in the blood – as long as there is an adequate quantity of it. The existence of the intracellular vitamin D receptor (VDR) was also identified, and that 1,25(OH)D would activate it in an unlocking mechanism common to endocrine hormones. 

The emergence of cytogenetics led to the identification of the 1,25(OH)D–VDR dimer to activate what is now a surprisingly large number of genes (in excess of 1,000). Some of these generate even more VDR molecules, a positive feedback mechanism. But 1,25(OH)D can only be used once as after use it is deactivated into 24,25(OH)D. This vital metabolic control  prevents a damaging excess of 1,25(OH)D. However it means that a constant supply of 25(OH)D is essential during the escalation of defensive immunity in response to infection, so as to replace the 1,25(OH)D that has been deactivated. The need of vitamin D in defensive immunity is much greater than for the control of ionised calcium, a fact that is seriously under-appreciated. 

It had also been understood that the immediate and indiscriminate inflammatory process of the body can be seriously damaging. A major player in this is TNF-alpha, and it has been identified that 1,25(OH)D–VDR by gene modulation will suppress TNF-alpha production and thereby end the very damaging so-called cytokine storm.

The Covid-19 pandemic

At the beginning of 2020 there was great deal of understanding about the potential of vitamin D at a time of infection, but in our world in which health is far better than it has ever been, there have not been the opportunities to put vitamin D to the test. It had been considered that vitamin D would have a powerful preventative action against uncommon or new infections, but a clinical trial would involve enormous numbers of people and a long time-scale. A further problem was funding, as vitamin D being natural, it cannot be patented and it is of very little commercial value.

The pandemic of Covid-19 that appeared at the onset of 2020 involved a novel corona virus, generally of low pathogenicity. There was no natural immunity and so the necessity was for an optimal innate immune process, otherwise serious or even fatal disease could be anticipated. 

One approach during the pandemic has been to protect the population physically from the virus. Protection against an invisible virus causing respiratory infection was always going to be a major challenge, and so it has proved. Closing down education, worship, family lives, public transport, and much of the economy has been the result not of the virus itself but of our attempts to contain it, of very doubtful success. When we emerge from lockdown, the virus will still be waiting for us. It will not have gone away like the bombers in the blitz.

Another approach has been to identify the virus in structural detail and produce a vaccine to protect the world population. This is both very expensive but it is also time-consuming. It was never expected that a vaccine could be produced and tested for safety within at least a year. Testing for effectiveness would take even longer. The search for a vaccine can never start until the virus has emerged and spread to cause an epidemic.

An approach complementary to the others, would be to optimise the defensive immunity of the population by issuing vitamin D supplements. The advantages of this would be that vitamin D is well-known, it is very cheap, it is immediately available, and it is known to be perfectly safe in the doses required to maximise defensive immunity (about 4,000 units daily). It has also been established that many members of the population of most nations in temperate zones have blood levels of vitamin D less than what is considered to be optimal for immune purposes, less than 30ng/ml, 75nmol/L.

The pandemic of Covid-19 provided an opportunity to correct widespread vitamin D deficiency and at the same time to conduct a wide range of clinical trials with assessment of the clinical value of vitamin D.  Unfortunately with a few exceptions research bodies seem to have been asleep. The Covid-19 Therapeutics Accelerator (Bill & Melinda Gates Foundation plus Wellcome Foundation) refuses to fund any research relating to vitamin D.

Observations of the populations

There are certain patterns of deaths from Covid-19 in which vitamin D and its deficiency appear to be important.

Ethnicity

It has been clear from the early days of the pandemic in Europe and North America that in the UK, the USA, and Sweden people with melanin-rich skin, the black African and Asian minority ethnic groups (BAME), have had a particularly high death rate from Covid-19. Although it has been officially attributed to socio-economically disadvantage this is clearly not the case. 26 working doctors in the UK died as the result of Covid-19 and 25 of them were of black African or Asian ethnicity. They were obviously not socio-economically disadvantaged and the only thing they had in common was a melanin-rich skin. 

These deaths came to an abrupt end at the beginning May and this could have been result of mail-shots sent to BAME doctors by BPAIO (British Physicians of Asian and Indian Origin), advising them to take a vitamin D supplement. The government sent no such advice. 

The only explanation for the extreme level of excess deaths of BAME doctors was deficiency of vitamin D. BAME people living in the UK have been known to have low blood levels of vitamin D because of melanin-rich skin (melanin being nature’s very effective block of UV from the sun) and in addition they frequently exhibit sun-avoiding behaviour.

It has been demonstrated that in India deaths per million are only one tenth those in The UK. A person living in equatorial Africa will have a chance of dying from Covid-19 several hundred-fold less than his family member living in the UK. Surely socio-economic disadvantage is not so bad in the UK?

A report from SAGE, the UK government Scientific Advisory Group for Emergencies came to my attention on October 13th 2020. It was a long involved document trying to explain the high death rate from Covid-19 among the Africa and Asian minority people in the UK. Socio-economic factors were explored. It was stated: "....observational analysis and more causal genetic studies have not found a relationship between Vitamin D and Covid-19 disease, suggesting this is unlikely to be an important explanation". The obvious role of vitamin D deficiency being responsible for the higher susceptibility to serious and fatal Covid-19 disease in the BAME populations was dismissed without further consideration.

Seasonality

The impact of the pandemic of Covid-19 in the UK was during the latter part of May 2020. The peak of deaths was in early April, but after mid-April the deaths per day declined, as did did the number of cases each day. 

The phase of decline coincided with the time of the Spring equinox, after which the inclination of the sun (at 50 degrees north of the equator), enables the onset of vitamin D production by the action of the sun on the skin. It reaches a maximum at the summer solstice. The improvement in immunity following an increase in vitamin D production explains the decline of Covid-19 (and other illnesses) during the summer, and then the decrease of vitamin D production in September would explain the increase in cases during that month. This pattern was seen throughout Europe.

Latitude

There is a clear latitude gradient of Covid-19 deaths, low rates close to the equator and high rates in countries distant from the equator, such as the UK at more than 50 degrees north. In equatorial Africa deaths million has been in single figures, such as 5 per million in Nigeria and 2 per million in Rwanda. It has been suggested that this must be the result of a genetic factor. However, other than genetically determined melanin-rich skin, this cannot be true as people from equatorial Africa (ethnically) who now live in the UK have a death rate very much higher at about 1000 per million, 1.9 x the  UK average of 620 deaths per million.

The latitude expression applies to Asia and Africa, but it is not seen in Central and South America, where the number of deaths per million is very high. Ecuador is experiencing 680 deaths per million. This could be the result of a genetic factor in the indigenous population (perhaps VDR polymorphisms) which would give a low level of immunity. This might have been responsible for the extraordinarily high death rates that resulted in the decimation of indigenous populations (95% died)  following the arrival of European explorers and conquistadors. 

Clinical studies

The pandemic of Covid-19 gave the opportunity for many research studies but there have been surprisingly few. Much attention has been given to counting the number of cases and deaths, but not learning very much. There has been concentration on the virus but very little attention has been given to improving the immunity of the people. A problem is that it is not possible to measure “immunity” in normal medical practice, remembering that tissue immunity is more important than antibody-mediated immunity. 

There were two early studies, from the Philippines and from Indonesia, and these indicated a strong protective action of vitamin D against serious and fatal Covid-19. However the authenticity of these studies is in serious doubt. 

I was anticipating these studies being repeated in Europe but, simple as they were, unfortunately there seems to be very few. 

The following studies have appeared:

1. India

Severity of disease associated with blood level of vitamin D

>30ng/ml 62% severe disease

<30ng/ml 85% severe disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276229/

2. Singapore 

Vitamin D + vitamin B12 + Magnesium treatment.

26 Controls: 16 required oxygen therapy. 16  ITU admissions

17 Treated:    3  required oxygen therapy. No ITU admissions

DOI: 10.1016/j.nut.2020.111017

https://www.medrxiv.org/content/10.1101/2020.06.01.20112334v1.full.pdf

3. Germany, Saarland

Respiratory disease fatalities associated with blood level of vitamin D. Ages 50–75 years.

Vitamin D <12ng/ml = 21% deaths

Vitamin D 12–20ng/ml = 13.7% deaths

Vitamin D >20ng/ml = 9.4% deaths

In this group, the incidence of respiratory deaths (not Covid-19) was twice as high in those with lowest vitamin D.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468980/

4. Newcastle upon Tyne

Severity of Covid-19 (need for ICU treatment) and blood levels of vitamin D.

ITU compared to medical ward for Covid-19 treatment

ITU patients had lower blood levels of vitamin D.

Also tended to be younger

https://www.medrxiv.org/content/10.1101/2020.06.21.20136903v1

5. Spain (Córdoba)

Randomised Controlled Trial, using Calcidiol, 25(OH)D, part-activated vitamin D.

Admissions to hospital with Covid-19 pneumonia

27 Controls: 

13 (50%) needed intensive care

  2   (8%) died

50 treated with vitamin D

  1 (2%) needed intensive care

   no deaths

https://www.sciencedirect.com/science/article/pii/S0960076020302764

6. Bari

Mortality from Covid-19 as predicted by blood levels of vitamin D. 

81% had bood vitamin D <30ng/ml

=> 30ng/ml 5% died

<10ng/ml 50% died

http://www.societaitalianadiendocrinologia.it/public/pdf/hypovitaminosis_d_covid19.pdf

7. Chicago

Prediction of positive Covid-19 test based on blood vitamin D levels.

Vitamin D ≧ 20ng/ml: 317 people, 39 (12%)  positive 

Vitamin D < 20ng/ml: 172 people, 32 (19%)  positive 

A low level of vitamin D (<20ng/ml, 50nmol/L) predicted an increased (x1.77) risk of becoming Covid-19 positive. 

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157

8. Israel

Risk of Covid-19 infection predicted by blood level of vitamin D.

Vitamin D <30ng/ml = 28.6%

Vitamin D >30ng/ml = 14.2%

https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1.full.pdf

9. Iran

Mean vitamin D levels with Covid-19 infection and deaths.

Controls  30ng/ml

Covid-19  19ng/ml

Fatal Covid-19  8ng/ml

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455115/

10. Heidelberg 

A predictive non-interventional observational study of 185 hospital patients with Covid-10. 

Blood for vitamin D was taken on presentation and analysed retrospectively, allowing predictive analysis.

Blood level of vitamin D predicting critical Covid-19 and deaths.

Vitamin D <12ng/ml

Hazard Ratio for invasive ventilation = 6.12 in those with lowest vitamin D levels

Hazard Ratio for death  =14.73 in those with lowest vitamin D levels.

https://www.mdpi.com/2072-6643/12/9/2757

11. Boston

Blood level of vitamin D predicting Covid-19 infection.

191,779 people

Vitamin D levels known and Covid-19 infection documented

Lowest level of vitamin D 20ng/ml, 12% risk of Covid-19 infection

Highest level 50–60ng/ml, 6% risk

Good blood level of vitamin D reduces risk of Covid-19 infection by 50%

https://doi.org/10.1371/journal.pone.0239252

12. Tehran / Boston

Blood level of vitamin D predicting severity of disease and death from Covid-19.

Vitamin D ≥ 30ng/ml  32.8%

Vitamin D < 30ng/ml. 67.2%

16.3% of 235 subjects died

Vitamin D ≥ 30ng/ml  9.7% of deaths

Vitamin D < 30ng/ml 90.3% of deaths

Deaths reduced by 80% in this with good blood levels of vitamin D

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239799

13. Birmingham, UK

392 healthcare workers tested for Covid-19 and Vitamin D.

Vitamin D <12ng/ml (30nmol/L) in 61 (15.1%)

Vitamin D <12ng/ml 41 out of 61 (72%) developed Covid-19

Vitamin D =>12ng/ml 170 out of 331(51%) developed Covid-19

BAME

Vitamin D <12ng/ml 17 out of 18 (94%) developed Covid-19

Vitamin D =>12ng/ml 12 out of 23 (52%) developed Covid-19

https://www.medrxiv.org/content/10.1101/2020.10.05.20206706v1.full.pdf

14. Turkey

Association between blood vitamin D and severity of Covid-19.

149 Covid-19 patients. Mean vitamin D 15.2ng/ml

Severe/critical disease 102 (68.5%). 66.7% died. Mean vitamin D 10.1 ng/ml. 

Moderate disease 47 (31.5%). 2.1% died. Mean vitamin D 26.3% ng/ml

https://link.springer.com/article/10.1007/s12603-020-1479-0

15. Mexico

Paper in Spanish, just the abstract in English.

Observational "snapshot' study.

All patients admitted to hospital on account of Covid-19 dad blood vitamin D level below the ideal, with mean 16.54 ng/ml (40nmol/L).

Patients with blood vitamin D level less than 8ng/ml had a risk of death 3.68 times that of those with levels above this.

https://www.medigraphic.com/cgi-bin/new/resumen.cgi?IDARTICULO=93773

16. Russia, St Petersburg

Paper in Russian, just the abstract in English.

Observational "snapshot' study.

Moderate illness, mean vitamin D 16.7 ng/ml.

Severe illness, mean vitamin D 11.9 ng/ml.

Fatal illness, mean vitamin D 10.8 ng/ml.

DOI: 10.22625/2072-6732-2020-12-3-21-27

17. Rhône, France

Study in a home for the elderly, where the usual practice was to give residents vitamin D 80,000 units orally every three months, as they were all expected to be deficient. Not all had received vitamin D, enabling a predictive study.

Deaths from Covid-19:

Received vitamin D: 57 residents. 10 (17.5%) died.

Did not receive vitamin D: 9 residents. 5 (55.6%) died from Covid-19.

https://www.sciencedirect.com/science/article/pii/S096007602030296X?via%3Dihub

18. Santander, Spain

Observational study of 216 hospital patients with Civid-19 infection and 197 community matched controls.

19 of the patients were taking vitamin D before admission.

Hospital patients, mean Vit D 13.8ng/ml, 82.2% deficient

Community controls, mean Vit D 20.9ng/ml, 47.2% deficient

Vit D ≧ 20ng/ml. ICU 17.7%. Days in hospital mean 12

Vit D < 20ng/ml  ICU 27.2%. Days in hospital mean 8

No difference in severity scores or deaths rates.

The scores for those with blood levels >30ng/ml not recorded.

Covid-19 without Vit D supplement, 197: 50 (25.4%) needed ICU, 20 (10.4%) died

Covid-19 with Vit D supplement, 19:  1 (5.3%) needed ICU,  2 (10.5%) died.

Taking vitamin D before the illness gave an advantage.

The records of patients with blood vitamin D levels >30ng/ml would have been a great advantage to the information gained from this study (as in other studies). 

Overall surprisingly low blood levels of vitamin D in Spain, mean blood level 20.9ng/ml (52nmol/L) in controls. >30ng/ml is regarded as ideal.

https://beta.ctvnews.ca/national/health/2020/10/27/1_5162396.html

(19.) Heidelberg 2

Same study, more data

A predictive non-interventional observational study of 185 hospital patients with Covid-10. 

Blood for vitamin D was taken on presentation and analysed retrospectively, allowing predictive analysis.

93 inpatients, 92 outpatients

Mean vitamin D levels 16.6 ng/ml (41.5nmol/L)

Hazard ratios for ICU ventilation:

Vit D <20ng = 5.75, <12ng = 6.12

Hazard ratios for ICU death:

Vit D <20ng = 11.27, <12ng = 14.73

A very significant hazard ratio for low blood levels of vitamin D.

https://www.mdpi.com/2072-6643/12/9/2757

These studies that have appeared suggest not just that vitamin D is very important in the escalation of defensive immunity in response to infection, but also that the blood level of vitamin D is a good surrogate for the measure of immunity. 

The studies indicate that a blood level of more than 30ng/ml (75nmol/L) is a level that indicates protection against serious or fatal Covid-19 infection. A target level of 40ng/ml (100nmol/L) would appear to be appropriate, and to achieve this vitamin D in a daily supplement of 4,000 units is effective, perfectly safe, and costs about £12 per year.

Interpretations

There are three dimensions to vitamin D in respect of Covid-19:

• The importance of vitamin D as judged by its blood level and the association of vitamin D deficiency with unfavourable outcome and death.
• The importance of vitamin D as judged by its blood value and its prediction of unfavourable outcome and death with vitamin D deficiency.
• The favourable effect of giving a vitamin D supplement in the prevention of an unfavourable outcome.

In the above list there were:

• 8 association studies,
• 8 prediction studies
• 2 supplement studies (one randomised controlled)

There is an aspect to association studies in that vitamin D is consumed during the defensive immune response to serious infection. It is to be expected that a lower blood level of vitamin D will be found after or during a severe or critical Covid-19 infection, but the important thing is that if the blood level is found to be less than 10ng/ml (25nmol/L) at that time, it must have been at a critically low level before the disease. Similarly, if the blood level is above 30ng/ml (75nmol/L) in advance of disease, then it will not fall to critically low levels and death is unlikely.

The official nay-sayers of vitamin D, those who wish to suppress the information and keep it hidden from the public, will say that there are no good studies of the benefits of vitamin D supplements. In saying this they avoid mentioning the clearly demonstrated temporal associations between vitamin D deficiency and unfavourable outcome from Covid-19, the importance of and the predictive value of the blood level of vitamin D in respect of Covid-19. 

Also, there is no official acknowledgement of the importance of blood levels of vitamin D in predicting the outcome from Covid-19. Would it not be sensible to check blood levels of vitamin D within the population? We are tested at regular intervals for blood pressure, blood glucose and HbA1c, haemoglobin, kidney and liver function. Why not add vitamin D? It is an easily correctable risk indicator for Covid-19 and its unfavourable outcomes.

Avoiding the glaringly obvious is becoming an art among those in charge of public health. The response of the NHS website team tells us in response to the important study from Spain was,"Well there is only one study." Ignoring this study is negligent. How many similar studies has the NHS commissioned? I hear of two UK proposals whose funding applications were rejected. 

The negative response of NICE to the study from Spain will be analysed in the next Blog post.

We must act on the best evidence available.

Vitamin D deficiency and Covid-19 : its vital importance in a world pandemic

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