Friday, 24 July 2020

C0vid-19 and V1tamin D : Virus and Humankind

C0vid-19 and V1tamin D : Virus and Humankind

Please excuse spelling mistakes: all will be revealed


I sometimes think that I am living in a dreamworld. Perhaps there has not been a pandemic; perhaps one morning I will wake up and all will be well. But unfortunately I must assume that what is going on around me is real, and my despair continues.


I cannot believe the continuing ignorance. I have been aware of the lack of scientific knowledge of the great majority of politicians, and also among society in general. What I am seeing and hearing now is a lack of scientific knowledge and understanding among professional scientists.


Just this morning (Tuesday July 21st) I had the misfortune to listen to BBC Radio 4. It is usually informative, during the Brexit campaign it was hilarious (very black comedy), but now it is just so sad and frustrating.




“The Virus” 

Every day there is a concentration on “The Virus”, as though there were just one, a destructive monster like Godzilla. Yes, perhaps we have been exposed to too much fiction. In Michael Crichton’s book “The Andromeda Strain” (1969) there was a sort of virus but not the DNA or RNA type that we know of. It caused havoc, and then one day the havoc suddenly stopped. “It” had mutated into something friendly, and all lived happily ever after. 






There is no question that deaths from Covid-19 are declining world-wide, whereas the number of cases is still increasing. In many countries, and certainly in Europe, deaths from Covid-19 have virtually stopped. The number of cases has declined but slower than deaths. It is in the Americas that the number of cases and deaths is still increasing, reflecting the origin of the pandemic in the Far East and spreading westwards.


In Switzerland we can see that the incidence, the number of new cases each day, declined but has now risen. The number of deaths has virtually come to an end and is not matching the increase of cases.






The same phenomenon is seen in Spain.





The persistence of new cases of Covid-19 is frustrating to public health officials, but it is perhaps the inevitable consequence of relaxing lockdown. People who have been isolated will obviously emerge and come into contact with the virus to which they have no immunity.  Widespread viruses cannot be killed, especially when they are inside the human host.


If the illness is only a mild upper respiratory tact infection (URTI), the number of cases is not of great consequence. It will contribute to the herd immunity that is so important for the future. The tragedy to be avoided is serious respiratory disease, or even death. We can see that is what is happening. The experience in Switzerland is matched in other countries. The increase in cases is not matched by an increase in deaths. The number of Covid-19 deaths is now extremely low, and the reason for this is the improvement of immunity of people, as we are now in the summer.


The time to develop Covid-19 infection is in the summer, when the sun is generating vitamin D. This is clear from the experience of Spain and Switzerland, and all other European countries. In the summer significant deaths are not occurring, but immunity is spreading and that is good. Vitamin D will lead to avoidance of serious illness and death from Covid-19, and as indicated by the UK chief scientific officer, take it throughout the winter. 


Mutation?

The suggestion made on BBC News this morning was that “the virus” is mutating into a more mild form. This has been the problem during the pandemic. “Science” and politics have been concentrating on the virus and not on humankind. This blinkered approach has led to far more deaths and serious illness than need have happened. It is not difficult to think it through from simple principles. I make the assumption that viruses do not have the capability to think. 


First, unlike the Andromeda Strain, there is not “a” Covid-19 virus. There are obviously very many trillions of virus copies. There could be a million inside each infected individual; I do not know the number but perhaps it could be estimated. Many are visible in tissues on electron microscopy. 


Multiple Covid-19 particles in lung tissue
Multiple Covid-19 viruses (blue stain) in lung tissue


With very rapid reproduction mutations will be frequent, and perhaps the same mutation on many occasions. We were told that the mutations identified at Birmingham University UK did not appear to be of great clinical significance, but they are being watched.


It is obvious that if they were all to mutate at the same time, and all with the same mutations, it would entail a remarkable level of co-ordination that even humankind could not achieve. Synchronous reproduction occurs in corals of the Great Barrier Reef, but that seems to be co-ordinated by an eternal agent – the Moon. 


But synchronous mutation of trillions of virus DNA/RNA strands is would be a biochemical event of much greater complexity than shedding sperm and ova, even in response to an external agent. The chance of world-wide synchronous Covid-19 mutation would be similar to that of a two year old child when given a pencil and paper spontaneous writing the complete works of Shakespeare.


Think of evolution. In order to survive and prosper, a mutation must give an advantage to the virus. What would be the advantage of Covid-19 mutating into a milder form? Did Covid-19 realise that it was going to close down most air travel on the planet? Does it want to become milder so that air travel can resume? There would be no advantage to a virus that can already co-exist with its human host. The idea of Covid-19 mutating into something that makes us less ill is absurd. It is however the logical conclusion of those who think only of a virus and ignore humankind.


“The weather” and Covid-19

The second absurdity on BBC News this morning was a statement by another professor that the decrease in the number of cases per day since the peak in early April is because of improvement in the weather. Sorry, this in itself sounds to be reasonable, but he went on to say that the weather has become warmer and drier, and the virus does not like these conditions. The virus does not live in the external environment as it is not free-living. A virus can only live within the cells of the bodies of human and other animals (or even plants).


The fact that the Covid-19 pandemic in the northern hemisphere has declined since mid-April is nothing to do with the virus but everything to do with the human host. The professor talked about warmth and dryness, but he made not the slightest mention of the great controller, the Sun. The tilt of the Earth gives us seasons and the Sun gives us warmth.




The Sun and vitamin D

The Sun does more than that. For the past 1.5 billion years it has had an effect on plankton in the sea, splitting a molecule that plankton synthesis  It is 7-dehydro-cholesterol, a fundamental substance produced by all animal life. Since the Cambrian explosion 500 million years ago the Sun has had the same effect on land animals, including Homo sapiens during the past 300,000 years or thereabouts. I have explained in a previous post about the biology of vitamin D.


For one billion years the single advantage from the production of vitamin D was the absorption of UV light, thereby reducing any damaging effect on living tissues. It was only with the Cambrian explosion of life that evolution created an intracellular enzyme now named VDR (vitamin D receptor) that by chance had to be activated by vitamin D, thus giving vitamin D a metabolic function. The activation of VDR by vitamin D enabled the cascade of defensive immunity against pre-existing bacteria and viruses. It was possibly this defence that enabled the occurrence of the Cambrian explosion of complex animal life. 


Fossil from the Cambrian explosion


Immunity was the first and vitally important effect of vitamin D. The development of bones came much later in the evolutional story, the the bone forming cell the osteoblast (activated by Vitamin D /VDR) being derived from the defensive cell the macrophage. 


45,000 UK deaths

The ignorance of scientific advisors to the government concerning the vital immune functions of vitamin D is the main reason for the deaths of more than 45,000 people in the UK, the fourth highest number of deaths per million population in the world after San Marino and Belgium, and marginally behind Andorra. Some smaller nations have been hit very badly, the highest case incidence being Vatican City 12 cases in a population of 801 (14,981 cases per million) but fortunately no deaths.



Even this morning the ignorance persists. I would have expected that scientists would be reading into the subject of immunity and would have come across vitamin D. There are hundreds of references and many excellent review articles. It might be difficult for the non-scientist to follow many of them, but not for a professor of medical-scientific subjects.


The number of cases of Covid-19 could be controlled or delayed by isolation and lockdown, but this would not have controlled the number of deaths in the same way. The virus is easily transmitted, especially in overcrowded houses and localities. Vitamin D would not have prevented infection, but would have reduced the chance of the development of significant illness and death in those individuals infected.


Seasonal change and Covid-19

The decline of deaths since mid-April was the result of the inclination of the axis of the Earth changing the season in the northern hemisphere (where most people live) from winter into summer. At the latitude of the UK (London 51.5 degrees north) it is only during April that the mid-day Sun is more that 45 degrees above the horizon. It is then that the intensity of the Sun is strong enough for vitamin D to be produced (it is a physico-chemical production not a biochemical synthesis). 


You might be able to work this out from the Solar Location diagram shown below, the example being for London UK.

 



As we have moved the winter into summer, our bodies have been producing more vitamin D and the effects of Covid-19 have diminished. It is the same every year in respect of a variety of illnesses, especially what we refer to as flu. Vitamin D production reaches its maximum per day in midsummer, which was month ago. Vitamin D production stops during September, but by then we should have produced sufficient vitamin D to last us until midwinter if not beyond. 




The bar chart shows the progressive decline of deaths per day in the UK since mid April when vitamin D production started. Superimposed is an illustration of vitamin D production during the summer months. 

 

What will happen during the decline of vitamin D production? Will Covid-19 return during the winter when our natural blood levels  of vitamin D diminish? It might happen but hopefully we will accumulate  adequate reserves during the summer, especially with the air now being so much cleaner. 


But we must make certain and maintain our vitamin D store by taking a supplement, 3,000 units per day or equivalent usually being adequate to establish optimal immunity. To check on adequacy it would be sensible to have blood level of vitamin D to be checked as we move into the winter.


The Chief Scientist recommends Vitamin D



I could hardly believe my eyes yesterday (Monday July 20th) when a few friends sent me emails of an article in the Times. It quoted the government chief scientist Sir Patrick Vallance stating that “millions of our population should take vitamin D to boost immunity and diminish the impact of Covid-19 so that our hospitals will not be overwhelmed”. This is the first time that “officials” have recommended vitamin D in this way. Is ignorance on the wane and is enlightenment on the ascendency? We can only hope so. By this statement the chief scientist over-ruled the very poor advice that he received from NICE last month. 


Lack of action

I have previously reported observations concerning Covid-19 and vitamin D status. These were reported from the Philippines, Indonesia, India, and Singapore. In summary they indicated that if a person’s blood level of vitamin D is greater than 30ng/ml (75nmol/L), the chance of serious or fatal illness from Covid-19 is less than 10%. If on the other hand the blood level is very low at less than 10ng/ml (25nmol/L) the chance of serious or fatal illness from Covid-19 is about 90%.


This should lead the average citizen to conclude that the choice of the preferable blood level of vitamin D is what might be called a “no brainer”. The high level is obviously preferable.


But this advice from the far East, where the pandemic originated, was ignored by our UK government and its advisors, and by the National Institute of Clinical and Health Care Excellence. We have watched while 45,000 of our fellow-citizens have died when many might have survived had they received an adequate dose of vitamin D supplement. 



At this time of national emergency and anticipated pandemic, the population could have been protected most simply by each receiving a single supplement of vitamin D 100,000 units by mouth as a drop of the oil on a piece of bread or directly on to the tongue. This could then have been repeated after a month or followed up by a daily smaller dose to. There is not the slightest danger from a single dose of 100,000 units. The alleged dangers in the recent NICE report were bogus.


Newcastle upon Tyne



Earlier this month we received a report from Newcastle upon Tyne that the observation studies of the Philippines and Indonesia have been repeated, this time in the UK. I must say that I had expected a large number of repeated studies as they would have been so simple to perform. Perhaps they have been performed, but if so the results are very slow to appear.


However the results from Newcastle are as follows.

Of patients with Covid-19 a blood vitamin D level less than 20ng/ml (50nmol/L) was found in:

90 out of 134 patients (67%)

and in 34 out of 42 (81%) on the ITU.





Covid-19 and vitamin D deficiency - more news from Indonesia 

I have just received a copy of a paper from the Duta Wacana Christian University Medical School, Indonesia.


This is a small study but the authors are to be congratulated on making a research effort. They tested blood vitamin D levels on 10 patients with Covid-19. The results (ng/ml) were: 20.5,12.4, 11.9, 11.6, 10.6, 10.1, 8.3, <8.1, <8.1, <8.1. 


It appears from other studies that a blood vitamin D level of greater than 30ng/ml (75nmol/L) is necessary for enabling optimal immunity. Therefore all these hospital patents were deficient. Less than 10ng/ml (25nmol/L) is considered to be dangerously low, and will possibly lead to bone disease (osteomalacia).


Five patients were male and five female  The age range was 14 to 65. The 14 year-old was a girl with blood vitamin D 8.3ng/ml.


This paper confirms previous reports that patients with Covid-19 infection serious enough to lead to hospital admission are likely to be deficient of vitamin D. Also that living close to the equator does not guarantee vitamin D. It is an observational study with no intervention.


Observation studies are powerful

Intervention studies are not always possible, and science starts with observations. Many of these are of immense practical value, and examples are:

  • vitamin D and Covid-19, 
  • ethnicity and Covid-19, 
  • atmospheric pollution and Covid-19, 
  • obesity and Covid-19,
  • elderly and Covid-19. 

Also:

  • cigarette smoking and lung cancer, 
  • cycle helmets and head injury,
  • hard hats on building sites,
  • life jackets when sailing,
  • blood alcohol levels and road traffic accidents, 
  • wearing of seat belts and outcome from road traffic accidents. 

The list could go on. RCTs are not always possible.


Using judgement

It is clear that however desirable, randomised controlled trials (RCTs) are not always possible in the human experiences of life and death. Those (like NICE and the Royal Society) who argue for RCT results before recommending vitamin D to prevent the escalation of Covid-19 to a critical or fatal condition seem not to understand this. They must be unaware of the Criteria of Sir Austin Bradford Hill in forming practical judgement, not just differing in their ivory towers. I have reviewed this subject in an earlier Blog post in August 2015.



Wasted opportunity

After more than 45,000 deaths, substantial scientific evidence, and several examples of observational evidence, It should be glaringly obvious that we should be giving vitamin D to the population,  as we could have done and should have done four months ago. On March 23rd we introduced lockdown having experienced 284 deaths. What a wasted opportunity. The number of UK deaths from Covid-19-19 was 45,000 four months later. How many of these deaths might have been avoided. I hope lessons will have been learned.


There has not been sufficient time since the pandemic began to conduct clinical trials of prevention of serious disease using vitamin D supplements. However BBC News this morning provided other aspects of Covid-19 and therapeutic developments. There was great enthusiasm.


Interferon beta-1α

First we heard news from Southampton about an interferon preparation for use in the very sick patients with Covid-19. Interferon came to my attention when I was a medical student. It had been observed (please note) that virus diseases appear just one at a time. It is as though a current infection somehow inhibits a second infection. It was proposed that this “interference” is produced by an anti-viral substance that one virus programs its host cells to manufacture so as to discourage any competitors. It became known as Interferon. It seemed to have great therapeutic potential but realising this over many years has been fraught with disappointments.



But perhaps its time has come. Interferon beta-1α is manufactured by Synairgen, a spin-off company from Southampton University. Initial trials (observational) of 50 hospital patients with Covid-19 are promising with a 79% reduction in death or the need for mechanical ventilation. This has led to great commercial success.




Will NICE demand that Interferon beta-1α is be subjected to an RCT before it can be released for general use?


The Oxford vaccine

The other exciting BBC News item this morning was that the Covid-19 vaccine being developed by Astra Zeneca and Oxford University is looking hopeful. It has been shown to produce an antibody response in human volunteers. The UK government has bought 80 million doses, the price not yet disclosed.


There will however be a snag. The volunteers will almost certainly be healthy young people, those for whom the pandemic has not posed a problem. They have good immunity, but the at-risk groups do not have good immunity. They are the elderly, the obese, those with black or Asian ethnicity, those with diabetes and other pre-existing conditions. How will they react? We know from previous experience that less than half of the elderly exhibit a response to a vaccine. 



Once again, will NICE insist on an RCT? A different RCT for each vaccine? Will NICE allow extrapolation from young healthy volunteers to frail elderly? 




There is a great deal of press coverage of vaccines, but almost complete silence concerning vitamin D, apart from the comment by Sir Patrick Vallance that does not seem to have been reported in other newspapers or radio broadcasts. We can see that there is big money in the development of pharmaceuticals, but there is no big money to be made from vitamin D. Perhaps it is in the interests of the impressive Big Pharma that silence concerning vitamin D is useful. 



Censorship

But now a book on the subject is becoming available. Or is it? 


The book that I have co-authored with David Anderson is now available from Apple as an eBook. It is almost available as a printed book, pre-ordered from:


https://www.ypdbooks.com/2147-vitamin-d-deficiency-and-covid-19-its-central-role-in-a-world-pandemic-YPD02419.html


But something strange has happened. Amazon refused to market this book. It was accepted by the distributor Kobo, but two days later it was withdrawn. The message from both was as follows:


Kobo have now removed the book from sale.

This book has not been published because the following elements are unacceptable by Kobo's publishing standards:

  • Content (general policy violation)
  • In the interest of public heath and safety, due to the extremely quickly changing nature of current events, Kobo is restricting the sale of Coronavirus-themed titles to certain vetted sources of information. We thank you for your understanding in our efforts to prevent the spread of misinformation during this pandemic. We reserve the right to revisit our current policy at a later date.


Clearly David Anderson and I are not “vetted sources of information”  and the hand of the censor has descended. The “misinformation” of the role of vitamin D in Covid-19 infection that we provide is to be withheld from the public.


Censorship by Amazon and Kobo is not undertaken by an employee having to read all the books. It will be an Artificial Intelligence task. The computer program will have been:


If Covid-19 and Vitamin D then Reject.


There is no explanation other than this. But the program must have been defined from “the top”. Who exactly? Why must vitamin D be kept out of the Covid-19 story? The book explains it.



The problem is that vitamin D is a natural product supplied by the sun. No company can patent it, and there is no money to be made. The financial investment of an RCT would be completely pointless. And so because of the single-minded policy of vaccine development, now irrelevant at least in Europe, 45,000 deaths in the UK have occurred. Many of them could have been prevented by the prior use of vitamin D.


Will evidence concerning vitamin D be excluded from retrospective investigations into the handling of the Covid-19 pandemic? Will all mention of vitamin D be erased from the history of the pandemic?


Another thing. There were 11,842 views of my Blog posted on May 8th, 16,925 for June 7, but only 1,126 for July 6th. Perhaps my popularity is waning, but perhaps there are blocks being applied to the Blog distribution. 


Deliberate spelling mistakes might be necessary to fool the commuter program.


Are the scales of justice indicating increasing evidence of the benefits of vitamin D? Or is justice being over-ruled?





Monday, 6 July 2020

C0vid-19 and Vitamn D : the UK NICE Report




NICE Report June 29th 2020


“Is there any evidence that vitamin D prevents or treats Covid-19?”


“Is there any evidence that vitamin D might be useful in the prevention  or treatment of Covid-19?”


These are very different questions. The first is factual and simple. Within the timescale of the pandemic, the specificity of the question to one particular virus means that the answer must be “No”. 


The second implies uncertainty and introduces judgement of a much wider range of evidence. The answer might be “Perhaps”, which would then require the balance of possible benefits (reduction of deaths) against possible dangers and costs of vitamin D before making a decision to use vitamin D within the population.


If you ask the wrong question you will get the wrong answer. The government asked NICE to answer the first question, as indicated in the objective at the opening of the NICE Report.


NICE:

“This evidence review sets out the best available evidence on vitamin D for preventing or treating COVID-19, or for the susceptibility to COVID-19 based on vitamin D status”.

During the pandemic of Covid-19 UK newspapers have carried small stories that vitamin D might be of help, but from official bodies there has been silence on this topic. Government officials must only give answers based on official policy or advisory bodies. They are not allowed to give personal opinions and this might lead people to think that they are more ignorant than is the case. It is not possible for the observer to distinguish between silence and ignorance.




There are however many clinical doctors and scientists who are knowledgeable about vitamin D. They are able to express opinions based on their knowledge, and they have been making their voices heard through unofficial channels, mainly social media. This has by-passed officialdom and it had led to an increase of vitamin D sales by a factor estimated to be 35. 

I have previously mentioned the deaths of 26 doctors from Covid-19 and that 25 of them were of black African or Asian ethnicity (BAME). They were not socio-economically disadvantaged, and the word got around that the reason for this tragedy was almost certainly vitamin D deficiency, to which they are very susceptible. The deaths of doctors suddenly stopped, the last on May 1st. The reason for this was probably because those who had not died had started to take vitamin D supplements. This could easily be investigated by questionnaire and I hope that is happening.


Once again there was silence from official bodies as the deaths of doctors did not fit in with usual sociological and racism explanation of excess BAME deaths. But under pressure, the government was obliged to ask official bodies to review a possible role of vitamin D.


SACN


The government obtains its advice on vitamin D from the Scientific Advisory Committee on Nutrition (SACN), which published its report on vitamin D in 2016. Vitamin D has little to do with nutrition and so the advice has been very weak. It identified that vitamin D is important for bone health, the avoidance of rickets, but little else. The role of vitamin D in immunity was mentioned only very briefly. The report recommended that a supplement of vitamin D  400units (10mcg) daily would be adequate for most who need it. In practice this dose will lead to a blood level of vitamin D adequate to prevent rickets (10–20ng/ml (25–50noml/L). 



It is thought by those that are knowledgeable about vitamin D that a dose of 4,000 units (100mcg)  per day is necessary to achieve a blood level of about 40ng/ml (100nmol/L), and this provides a necessary reserve of vitamin D for optimal immunity. SACN considers that a dose in excess of 4,000units in adults might be “dangerous”. It stated that that blood levels of vitamin D should not fall below 10ng/ml (25nmol/L) but did not suggest how the population should be screened for this.


NICE 


The government and the NHS also receive advice from NICE, the National Institute for Clinical and Health Care Excellence, or perhaps the National Institute for Counter-Education. It is a body for standardising investigations and treatments, providing menus that become a series of tick-boxes so that doctors can easily be judged by others, especially lawyers. It completely stifles innovation, and more importantly it makes unnecessary the traditional medical educational practice of reading important medical-scientific papers. Because of continuing research, NICE dogma might be out of date, but nevertheless set in stone and to be obeyed.


NICE was asked to review the possible need for vitamin D supplements in the prevention or treatment of Covid-19, and its eagerly awaited report was published on June 29th. There must have been many disappointed readers. It is difficult to reconcile with the report the fact that we are experiencing a pandemic that has put enormous strain on the hospitals, that has closed down universities and schools, that has caused considerable economic damage with increasing unemployment, and which has been responsible for 44,000 deaths in the UK. We cannot be proud of the fact that we have the fourth highest number of deaths per million population, after San Marino, Belgium and Andorra. 


Immunity in Ivory Towers


But those living in ivory towers appear to be immune. What is needed at a time of national emergency is a sense of pragmatism. “What on earth can we do to stop all these people from dying? Is there anything that might help without doing harm?” The NICE report makes dismal reading, a complete lack of pragmatism and a complete failure to take seriously 44,000 deaths. It is completely negative and totally destructive of the little evidence that it examined. What has medical science come to? We should be ashamed.


NICE restricts evidence




It starts off optimistically: “This evidence review sets out the best available evidence on vitamin D for preventing or treating COVID-19, or for the susceptibility to COVID-19 based on vitamin D status”.


Then : “A literature search of vitamin D for COVID-19 identified 187 references. These references were screened using their titles and abstracts and 7 full text references were obtained and assessed for relevance.”


Only five studies were selected for inclusion this Report. They are:


D’Avolio A, Avataneo V, Manca A et al. (2020) 25-Hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2. Nutrients 12(5):1359 

Fasano A, Cereda E, Barichella M et al. (2020) COVID-19 in Parkinson’s disease patients living in Lombardy, Italy. Movement Disorders 2 June [online ahead of print] 

Hastie CE, Mackay DF, Ho F et al. (2020) Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14(4): 561–5 

Ilie PC, Stefanescu S, Smith L (2020) The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clinical and Experimental Research May 6:1–4 [online ahead of print] 

Laird E, Rhodes J, Kenny RA (2020) Vitamin D and inflammation: potential implications for severity of COVID-19. Irish Medical Journal 113(5):81 

 All were deemed to be unsatisfactory and unsuitable to be worthy of “evidence”.  They were rejected for a number of reasons that included bias, failure to standardise for confounding variables, they were all observational and not interventional, they were not randomised controlled trials (RCT), adverse events from vitamin D were not recorded. The data were demolished to find that “There was no significant interaction between ethnicity and vitamin D deficiency.” This unique finding should have indicated to NICE that its methods were at fault.


Ignoring Science


The statement was made: “It has been hypothesised [my emphasis] that vitamin D may also have a role in the body’s immune response to respiratory viruses. In vitro studies suggest that vitamin D metabolites could [my emphasis] modulate immune and inflammatory responses.” 

This is great insult to the large quantity of high quality cytogenetic research work that has been undertaken during the last forty years. The immune role of vitamin D was “hypothesised” in the early years of the 20th century. Now that we are in the 21st century we can see that it has been demonstrated in great detail. In its highly selective Report, we can see that NICE far from being a scientific body is completely ignorant of, or has completely avoided science, but perhaps this is to be expected of a body that is dominated by nutritionists with no direct responsibility for the care of the sick who depend on immune processes.

Pragmatism

Research must be the art of the possible. Sir Ernest Rutherford, for example, was not one to say “Rather than perform experiments to look for sub-atomic particles, we must wait until better technology becomes available in the future”. Rutherford was a great scientist and inevitably a great pragmatist, like other scientists of the enlightenment. NICE has however retreated from the enlightenment into the shadows of science.


The five papers reviewed by NICE are contemporary with the pandemic. They were inevitably pragmatic and inevitably very short-term. The investigators should be congratulated on their work, for which it was not possible for them to spend a year or more planning. They seized the opportunities that were available, and good for them. For their work to be "critically" destroyed is a disgrace.

Dangers of vitamin D? What nonsense!

It is very difficult to find medical research that is absolutely conclusive, but much of it adds to the weight of evidence. Many people (I for one) have made their personal decisions whether to not to take vitamin D in an attempt to prevent serious or fatal Covid-19. It is a balance of risk: what are the potential benefits of taking vitamin D? Avoiding serious or fatal Covid-19. What are the potential dangers? None.

But the obvious safety of vitamin D is avoided in the NICE report. We know that by June 29th 2020 there had been world-wide 508,803 deaths from Covid-19, but as far as I can determine no deaths from vitamin D. The Report quotes:

“The BNF [British National Formulary] states that common or very common side effects with vitamin D supplements are abdominal pain, headache, hypercalcaemia, hypercalciuria, nausea and skin reactions. Uncommon side effects are decreased appetite, constipation, thirst and vomiting.”

What does “common or very common” mean? We use such terms to imply frequency. I conducted a short survey among family and friends. On average they regard “common" as about 60% and “very common” as about 75%, “uncommon” as about 20%.

I have checked the 2015 edition of the BNF and it states for Ergocalciferol, and referred back to for all other vitamin D preparations:


Side-effects

Symptoms of overdosage [my emphasis] include anorexia, lassitude, nausea and vomiting, diarrhoea, constipation, weight loss, polyuria, sweating, headache, thirst, vertigo, and raised concentrations of calcium and phosphate in plasma and urine.


BNF Pages 703–704

https://rudiapt.files.wordpress.com/2017/11/british-national-formulary-69.pdf


The clinical features of overdose listed by the BNF and of normal dose by NICE seem to be features of the very rare hypercalcaemia (too high a blood level of calcium). Whatever the cause, an excessive dose of vitamin D supplement is close to the bottom of the list. To call them “common” side-effects of vitamin D is absurd. Such a statement should be quantitative and should only be made by comparing people taking a vitamin D supplement with similar people not taking it. Anyone can experience “abdominal pain, headache, nausea, skin reactions, decreased appetite, constipation, thirst and vomiting” whether taking vitamin D or not.

The eyes of NICE remained closed. The absence of science (and perhaps truth) from the NICE Report is again both obvious and alarming.

The science of vitamin D and immunity

The NICE Report ignored many studies concerning the protective effects of vitamin D from the most serious effects of infections, including Covid-19. Those papers reporting basic science that I would regard as important are:

1. Vitamin D and Evolution: Pharmacologic Implications. Hanel A, Carlberg C.  https://pubmed.ncbi.nlm.nih.gov/31377232/

This paper describes very clearly the development of evolution during the past 500 million years. It emphasises the evolution of the gene-modulator VDR, that requires vitamin D to  activate it.

2. Vitamin D and the immune system: new perspectives on an old theme. Hewison M. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879394/

A review of vitamin D and its effects on immunity and several aspects of human health, including response to respiratory infection.

3. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Chun RF et al.  https://pubmed.ncbi.nlm.nih.gov/24795646/

This is a further review of the importance of vitamin D and VDR, especially in activating and controlling T-lymphocytes

4. Vitamin D deficiency accelerates ageing and age-related diseases. Berridge MJ.   https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP274887

This paper is written by a very highly regarded UK researcher and includes the vital role of vitamin D in down-regulating TNFα in controlling the cytokine storm and reducing inflammation.

Early clinical studies

It was not possible to produce clinical studies of vitamin D and Covid-19 before the pandemic emerged at the beginning of the year. The virus “escaped” from China and appeared in Thailand on January 13th 2020. By January 31st it was in 14 countries, and it appeared in the UK in March. As it started in the east it was possible for enthusiastic and enlightened physicians there to undertake clinical studies and send the results to the west to help physicians and nations who would shortly be experiencing the pandemic. Such studies were inevitably impromptu and there was insufficient time for the slow sophisticated and bureaucratic methods necessary for an RCT.There was however time for western physicians and scientists to plan similar studies.

We have reviewed these studies at some length in previous Blog posts, but I will list them here.

The Philippines. An observational study demonstrated that of patients with mild disease 85% had blood vitamin D levels greater than 30ng/ml (75nmol/L). Those with moderate, severe or critical disease had much lower levels.

Indonesia. Again a short observational study. Of 388 patients with blood levels greater than 30ng.ml (75nmol/L) only 16 died. Of the 179 with blood levels less that 20 (50) 177 died.

There has been a single much-disputed suggestion that these studies were not real. A great deal of investigation of this claim has been undertaken by Lorenz Borsche, and the conclusion is that the authors are real and the work is genuine.

However it is vital to appreciate Sir Austin Bradford Hill’s criterion of “reproducibility” in assessing “proof”. The UK was given adequate time to repeat the studies form the east. If studies have been undertaken, the results are not yet available. If the studies have not been undertaken it is a serious failing of UK medical science.

Singapore. Patients admitted to hospital on account of Covid-19 were given either standard care or standard care plus Vitamin D, Magnesium, and Vitamin B12 (DMB). Those receiving DMB had much milder illness with reduced need for oxygen and ventilation, and death. 

These studies were not even mentioned in the NICE Report. They were observational and not randomised controlled trials. They were far from conclusive but added evidence. If NICE, SACN, PHE (Public Heath England) were not happy with these studies from the east, they should have commissioned as a priority similar studies in the UK. Failure to do so can only be judged as medical-scientific negligence.

The importance of reserves of vitamin D

It has been suggested that there is “reverse causality” in respect of the association between serious or fatal Covid-19 and very low blood levels vitamin D. This means that rather than vitamin D deficiency leading to serious disease, it is the serious disease that leads to the low vitamin D level. There is some truth in this. During escalation of the immune process to serious infection, vitamin D as its active metabolite 1,25(OH)D is “consumed”. So as to avoid too high a concentration of 1,25(OH)D, once it has been used it is irreversibly inactivated to 1,24,25(OH)D. 

The purpose of intracellular 1,25(OH)D is to activate VDR which in turn activates appropriate genes. The cells (mainly T-lymphocytes) can re-use or synthesise unlimited molecules of VDR, but cannot synthesise 1,25(OH)D: they can only produce it from vitamin D as its inactive form 25(OH)D, the store the blood. At a time of escalating defensive immunity, if there is initially a low blood level of vitamin D, the supply will quickly be exhausted. The blood level will fall further to a very low level and the immune reaction will grind to a halt, with uncontrolled TNFα and damaging inflammation, the “cytokine storm”. 

Prepare for the next pandemic

The message is that in advance of a serious infection a good reserve of vitamin D is necessary, greater than 30ng/ml (75nmol/L)  and ideally about 40ng/ml (100nmol/L). NICE and SACN state that a blood level of 10ng/ml (25nmol/L) is adequate, but this is only in the “resting state”, and not when confronted with a serious and life-threatening infection.

The preparations for the present pandemic were completely inadequate. There will inevitably be another epidemic in the future, but no-one knows when. As mentioned, a vaccine cannot be manufacture and tested in a advance of the emergence of the virus. Relying on SACN, NICE, and PHE does not inspire confidence, nor does the prospect of more mathematical modelling. The best plan would be to improve the immunity of the population, and despite the ignorance of the advisory bodies, science has given us the answer: vitamin D.

The cost of vitamin D in a dose of 3,000 units per day is about £10 for a years supply. The cost of the antiviral agent Remdesivir (being tested now for the treatment of the seriously ill) is about £2,000 for a five day course. Is the cheapness of vitamin D a good thing? Or is it a bad thing?

There is a problem. From the present pandemic we have learned that advance warning is very short as in the era of travel by air, the virus travels very quickly. There is little time for preparation and so we should start now. People should have a blood vitamin D level of 40ng/ml (100nmol/L) in advance and when the pandemic arrives. We now have evidence that no matter what dose is given, it will take three weeks for someone without previous supplement to reach this level. For those who do not take vitamin D, the time to start is now.


The graph below shows the increase in blood levels of vitamin D with different dose regimes. The highest dose of 10,000 units daily leads to a target blood level of 40ng/ml (100nmol/L) in just over two weeks, the lower dose taking four weeks to reach target. 50,000 units per week is not very different, but it looks as though a daily dose is better than a weekly dose. After two weeks of 10,000 units per day, a reduction to 40,000 units each week might be ideal.


NICE states that it will not approve the use of vitamin D unless it is supported by a positive randomised controlled trial (RCT). This might cause some discomfort to NICE in forthcoming  months. The development of vaccines by a number of pharmaceutical companies in many countries is well under way. The UK government has invested £84 million and would like some return. When the vaccines become available, will NICE block their use until RCTs have shown positive benefit? To do so would cause long delays and be very costly. Ideally there should be a three-armed RCT between vaccine (which one?), vitamin D, and placebo, but this will never happen. Too costly, too complicated, and too many vested interests. 

But how many RCTs of vaccines will be necessary? One for each? Watch this space and wait for NICE to approve vaccines without RCTs. Big Money talks, and there is no big money in vitamin D.