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.
“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.
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.
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.
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.
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:
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
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.