Thursday, 22 October 2020

Covid-19 and Vitamin D: NICE fails us again


The UK National Institute for Health and Care Excellence.


The NICE report of June 29th 2020 informed us that:

"There is no evidence to support taking vitamin D supplements to specifically prevent or treat COVID-19."

By this time there had been several important observational studies that demonstrated an association between low blood levels of vitamin D and increased risk of critical or fatal Covid-19. It had also been identified during previous decades that vitamin D has a pivotal role in activating the defensive immunity cascade, a role that has evolved during the past 500 million years. The early studies undertaken had measured blood levels of vitamin D in what were "snapshot" observations, but very valuable. Later studies demonstrated that a high risk of critical or fatal Covid-19 is predicted by low blood levels of vitamin D. Clinical research has been added to laboratory scientific research, and the two must always work together.


June 29th

NICE was not impressed by the research, but NICE has a very narrow view. Its role has been to evaluate new medicines to see if they are safe and effective to incorporate into the NHS. To achieve this a randomised controlled trial (RCT) is necessary, funded by the pharmaceutical company concerned. 

But with vitamin D we are looking at something much more than a pharmaceutical product. We are concerned with a natural pre-hormone, cholecalciferol, that is produced in the body. It cannot be patented and no funding is automatically available for an RCT, which would always be very expensive if on large scale.

NICE is not orientated towards the evaluation of a very complex biological system such as defensive immunity, and this becomes clear on reading the NICE documents.


NICE is confused

In the statement "There is no evidence to support taking vitamin D supplements to specifically prevent or treat COVID-19" we see a good example of cryptic double-speak. Taking vitamin D supplements was not part of the evidence available to NICE at the time. The NICE comment was not appropriate. It also failed to acknowledge that a treatment for an infection or other disease cannot be undertaken in advance of its emergence.

An evaluation of "supplements" would have involved an RCT which had not at the time been undertaken. To set up such an RCT takes considerable time. A primary prevention trial involving normal people would necessitate very large numbers at prohibitively high cost to cover logistics, staffing, follow-up etc.This is beyond the scope even of vaccine evaluation. An RCT of patients with definite and serious Covid-19 infection would involve many fewer subjects and could be performed in any acute hospital. 

Ethical approval

For a clinical trial, ethical approval is essential, with informed consent being given by the subjects. With existing knowledge concerning the benefits of vitamin D in Covid-19, the main issue would be whether it would be ethical to withhold vitamin D from the control group of patients. Human sacrifice should not be part of clinical research. 

The main development of the RCT followed the serious side-effects produced by the drug thalidomide when given to expectant mothers. It is safety of a medicine that is arguably more important than its effectiveness, and this is to be assessed by the RCT. However, with vitamin D we know that it is very safe, with reversible overdose effects being the result of a rare disease (eg sarcoidosis) or a serious dosing error, such as mistaking milligrams for micrograms and giving 1000 times the intended dose. 100mcg  or 100µg is 4,000 units, but 100mg is 4,000,000 units and taking this would be a serious error. It is much safer to keep to international units rather than potentially confusing mass units.

NICE is single-minded. RCT is its currency. It would not be able to evaluate, for example, the relationship between cigarette smoking and lung cancer, and this would be outside its remit. Similarly it was not able to evaluate the relationship between vitamin D and Covid-19. The government had no other agency to turn to, and its Chief Scientist Sir Patrick Vallance and Chief Medical Officer Professor Chris Whitty remained silent on the subject. Silence was similarly maintained by the Royal College of Physicians, the traditional source of medical wisdom during the past 500 years.

We are dealing with a pre-hormone deficiency

NICE was answering the wrong question. The question or challenge posed to NICE in June 2020 was not concerned with vitamin D supplements. It was concerned with the observations that vitamin D deficiency is associated with an unfavourable and perhaps fatal outcome from Covid-19 infection. NICE should have declared itself not able to comment on this challenge, not able to evaluate the immunological disadvantages of vitamin D deficiency.

But the government and its advisors took the NICE report to indicate that vitamin D itself was of no value in the Covid-19 pandemic and so no action was taken. 

Other examples

Much observational evidence was presented, but NICE was not tempted to comment. Its lack of vision means that, had it been established at the time, NICE would have rejected the careful observational data that led to the conclusion that cigarette smoking causes lung cancer. Consider setting up a double blind RCT of cigarette smoking. Similarly the relationship between alcohol consumption by car drivers and subsequent road traffic accidents would create a challenge to those who would insist on an RCT. 

There are other examples of hormone deficiency states. One is thyroid under-activity, which can be corrected easily by the use of thyroid hormone (thyroxine) supplements. This has never been subjected to an RCT, but by good fortune NICE had not been established when thyroid replacement therapy was introduced. Similarly Type 1 diabetes is a life-threatening deficiency of insulin, but insulin had never been subjected to an RCT. Was one really necessary? Also, cortisol replacement in Addison's disease was not subjected to an RCT. 

The absurdity of demanding an RCT for correction of vitamin D deficiency is obvious.

Safety

The most interesting example is that the use of a parachute when gravitationally challenged by jumping out of an airborne aircraft has never been subjected to an RCT. Nevertheless it has been accepted throughout the world as the sensible thing to do, as observation indicates that injuries are far fewer in those who use parachutes compared o those who (inadvertently) don't. NICE members might volunteer for an RCT should it be demanded. 

It is obvious to anyone with sense that observational studies are very valuable and RCTs have very limited use in the real world, especially when evaluating safety. It is safety that is the objective when correcting vitamin D deficiency. We are not dealing with a pharmaceutical agent.

NICE stated that it would not approve the use of vitamin D unless it was supported by a positive RCT. It was predictable that this might occur and cause some discomfort to NICE in forthcoming  months. "No evidence" might be found to be a serious error.

RCT from Córdoba

September 3rd 2020 saw the results of an RCT from Córdoba, Spain. This has been reviewed earlier. To summarise, 26 randomly allocated patients with Covid-19 pneumonia received standard care, and 50 received standard care plus Calcifediol. 

Calcifidiol is 25(OH)Vitamin D, a part activated form. It is produced naturally from vitamin D (derived from the skin or from the diet) on circulation through the liver. When we test blood vitamin D level it is 25(OH)D that is measured. It appears that the blood level of 25(OH)D increases much more quickly when Calcifidiol is given rather than vitamin D. This would be a great advantage in the seriously ill.

In the control group of 26, 13 (50%) required ICU support and 2 died. In the group receiving vitamin D as Calcifediol only 1 (2%) required ICU and there were no deaths. 

This result shows a dramatic benefit from vitamin D as Calcifediol. Putting this together with the large amount of existing evidence (15 studies) and underlying laboratory science, as an optimist and pragmatist I anticipated that it would be incorporated into clinical practice. The basis of this would be that vitamin D is readily available, cheap, and known to be very safe. There would be the opportunity to reduce critical and fatal Covid-19 with no downside. 

The choice would be as described by Pascal's wager.

But no official change took place. The NICE proclamation of June 29th was set in stone.


NICE Report September 2020

NICE had demanded an RCT of vitamin D, and here it was. NICE had to be stirred into action to review its position with new knowledge from Córdoba, Spain, and in response it published a new interim report at the end of September.

The title is:

Vitamin D supplementation for preventing intensive care admissions in people with COVID-19 associated pneumonia.

It set out to assess the paper from Córdoba, by Castillo et al. "Assess" meant destroy.

It started: [The study] "found that vitamin D supplementation in hospitalised adults with COVID-19 may reduce admission to intensive care". 

The word "may" is not appropriate: it demonstrated "does" reduce admission to intensive care.

"However, the study has many confounders so the results should be interpreted with caution."

"The clinical management of patients with COVID-19 should not be changed based on the results of this study."

The traditional method of clinical practice in the UK and elsewhere is that physicians would read original papers, discuss them with colleagues, assimilate them with previous knowledge, and then decide whether or not to incorporate them into clinical practice. This is no longer what happens: thinking and clinical judgement are no longer acceptable. What is written by NICE is effectively the law, as departures from NICE guidelines cannot be legally defended.

NICE stated that clinical practice should not be changed and at least officially it wasn't changed. But individual doctors might have broken the rules and given vitamin D or Calcifediol to help patients at risk. Was there any reason to deny a likely life-saving treatment from patients with serious Covid-19, apart from the dogma of NICE? 

How to rubbish a good trial: a lesson from NICE

The only way to stop vitamin D was to show that the RCT from Córdoba was of no value and could not be trusted to convey the truth. The attack was based on "confounders". This can always be done.

When an RCT is undertaken, the subjects entering the study are randomly allocated to either the control group or the special treatment group. Random allocation is to make certain that the two groups are as similar as possible in respect of factors that might influence the results. One would be age, and if the average age of one group was significantly different from the other group this might influence the result and cast doubt upon its truth. This is a confounder.

The RCT from Córdoba presented all the potential confounders and they can be seen in the table.  



It is then necessary to check differences for statical significance, this usually being summarised by a "p value". The smaller the p, the more likely is the significance of difference. NS means not significant.

Ideally the differences of the characteristics in the two groups should show almost complete overlap on the distribution curves, indicating no significant difference, as illustrated below left. But there might be a separation, indicting a significant difference.

The ideal is as in the first pair with means (averages) 14 and 18. Perfect matching cannot be expected and we can see this in the two columns above. But the second pair shows a degree of separation, with means 14 and 25. This not likely to be significant, but when the separation becomes greater, the "confounding" becomes greater. The p-value can be calculated from the caparisons, adjusting the means for the sample size and the spread of the data (variance), comparing two "standard errors" and reading off the p-value from a standard table.

In the Córdoba RCT, only one confounding variable showed a  statistically significant difference, and this was "a previous history of high blood pressure". 21.49% of the vitamin D treated groups had a history of high blood pressure, compared to 57.69% in the control group. This difference was statistically significant, with the control group put at a greater risk of serious illness than the vitamin D treated group. The question is, would this difference be so important that the study would be invalidated?

NICE decided that the results of the trial were invalid on the basis of an excess of subject with high blood pressure in the control group. We know that such people are at greater than average risk when experiencing Covid-19 infection, and this can be quantified. It is thought that people with previous high blood pressure have twice the risk of death as those without.

Let us adjust for this by dividing by two the unfavourable outcomes for the control group.


Let us ignore the death rates as the numbers are so small (1 versus 0),

We can see however that the adjusted ICU admission rate is 25% in the control group and 4% in the vitamin D treated group. This remains a very significant difference.

Correction in this way for a confounder is perfectly in order and it probably over-corrects.


Another criticism from NICE

The NICE report offered another criticism, that the paper did not make it clear if the ward doctors knew which patients had been given vitamin D on admission. If they did know, they might have kept the Calcifediol treated group away from intensive care, but that might have increased deaths. Ideally those not receiving Calcifediol should have been given a placebo, so as to "blind" the attending doctors. 

I quote from the Córdoba paper:

An electronically generated randomization 2:1 list was prepared by independent statisticians. The list was accessible only to nonmasked specialists in the study in an attempt to minimize observation bias. The patients' data were recorded in the hospital's electronic medical record, with blind access by the technical data collectors and the statistician who carried out the study.

Clinical research is very difficult to control and the researchers must do their best to avoid observation bias, as in this study. In retrospect it would have been better to give the control patients a dummy capsule, a placebo to minimise observation bias further.

Should this criticism invalidate the results of the trial? I think not.

The weight of evidence

The Córdoba study was not in isolation but it should be taken into consideration with other studies the results of which were available but which NICE chose to ignore.

NICE proposed to delay a decision on the value of a vitamin D supplement until more RCT results become available. When will this be? To reproduce the Córdoba trial would be simple, in a one or group of several UK hospitals. 

I am aware that the Chief Medical Officer Professor Chris Whitty has refused at least one major hospital permission to undertake such a study. Furthermore, The Bill & Melinda Gates Foundation / Wellcome Foundation consortium the Covid-19 Accelerator has refused funding for vitamin D related research.

What is happening to our long tradition of good quality clinical research?

But what are the staff in the UK hospitals to do in the meantime? Acting on the basis of the weight of evidence available at the time, and knowing that vitamin D at the doses given is perfectly safe, they should have accepted Pascal's wager and started to treat patients with Covid-19 pneumonia on the Córdoba protocol. The least they could have done would be to give patients with Covid-19 pneumonia the option of receiving vitamin D as Calcifediol, informing them of the possible dangers (zero) and the possible benefits, 25% rather than 2% risk of needing transfer to ICU.


Edict from NICE

Edict = an official order or proclamation issued by a person in authority.

As we seen, any initiative taken by doctors was forbidden by NICE. To repeat:

"The clinical management of patients with COVID-19 should not be changed based on the results of this study."

This is staggering centralisation of power over the medical practitioners of the land, denying them the use of clinical judgement, and more importantly denying the patients a say concerning their treatment. "NICE knows best" is ultimate paternalism.

The doctors and other staff would want to do their best for their patients. But they have had to deny their patients a treatment that is known to be perfectly safe and which might be life-saving. Furthermore, the patients and their families were not given the opportunities to decide for themselves whether or not to take Calcifediol / Vitamin D, given the information that would be easily assimilated.


An ivory tower is a metaphorical place—or an atmosphere—where people are happily cut off from the rest of the world in favor of their own pursuits, usually mental and esoteric ones. 


NICE sits in a metaphorical ivory tower away from the sharp end of medical practice. There will never be blood on the floor of the NICE offices. 

But since the Córdoba results appeared on September 3rd until October 22nd there have been 2,803 deaths in the UK from Covid-19. This is a scandal and the occurrence of many of these deaths must be the responsibility of the myopia and intransigence of NICE.


This is NOT the floor of the NICE office




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


or from Amazon
eBook from iTunes 

 



Thursday, 15 October 2020

Covid-19 and Vitamin D – lessons from MICE


The main message is:
Use units and try to avoid micrograms, mcg, µg
more of this towards the end

The information below has been provided by my friend Dr David Anderson, former professor of endocrinology at the  University of Manchester and professor of medicine at the  Chinese University of Hong Kong.

David has now formed the Murine Institute of Clinical Excellence.



One international unit of vitamin D is the amount required each day for an immature mouse (weight 10 grams) to avoid rickets.

It has been demonstrated that an adult mouse of weight 30g requires 3 units of vitamin D each day. 

This achieves a blood level of 30 ng/ml (75 mol/L).

It has been demonstrated several times that this is the ideal minimum blood level for adult humans to avoid critical or fatal Covid-19.

Let us size up from a mouse to a human.

A 30g mouse to a 60kg human (or 60kg mouse!)

60kg = 60,000g. 

60,000 ÷ 30 = 2,000.

An adult human weighing 60kg is 2,000 times the weight of an adult mouse.

3 units x 2,000 = 6,000 units.

An adult human being weighing 60kg requires vitamin D 6,000 units daily. 

A child aged 10 weighing 30kg requires 3,000 units each day.

An obese adult weighting 100kg requires 10,000 units each day.






Units or micrograms?

Keep to units to avoid confusion.

Official semi-scientific organisations tend to use mass units, and so they would recommend for example 100 micrograms of vitamin D. 

This is a very small weight as 1 microgram = 1 millionth of a gram. 

100mcg of vitamin D is 4,000 units.

The immature mouse requires I unit per day, which is 100mcg divided by 4000, which is 1 millionth of a gram divided by 40, which is just 25 billionths of a gram.

This is a difficult number handle, and 1 unit is easier.

100 micrograms is abbreviated to 100mcg or 100µg.

Many people do not know about micrograms as such units do not appear in normal human life. There might thus be confusion with milligrams, one milligram (1mg) being one thousandth of a gram.

So, with vitamin D, 100mcg = 4,000 units,

but 100mg = 4,000,000 units.

Confusion between mcg / µg and mg can lead to a thousand times the correct dose of vitamin D being taken. This is how vitamin D excess can occur. It only occurs because of a major dosing error, and confusion of weight, 

Vitamin D excess certainly does not result from 4,000 units per day.

There are many manufacturers and many different capsule / tablet strengths. Just work out which one suits you best in terms of understanding how much vitamin D you will be taking.

Remember, the dose is not critical. If you have 5,000 unit capsules rather than 4,000 the difference is not important.

Also, a 4.000 unit capsule contains only 100 millionths of a gram of vitamin D. Most of the oil in the capsule will be olive oil. So no matter how much vitamin D is in a capsule, all the capsules tend to be the same size.

 Keep to units.



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


or from Amazon
eBook from iTunes 

 


Friday, 9 October 2020

Covid-19 and Vitamin D: summary of evidence

Covid-19 & Vitamin D – summaries 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

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




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,
  • 7 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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