Sunday, 29 November 2020

Covid-19 & Vitamin D. Calcifediol – 96% efficacy : Important analysis

MIT 1, NICE 0


Massachusetts Institute of Technology

The results of the randomised controlled trial from Córdoba, Spain, came to attention on September 2nd 2020. It showed a resounding success of the treatment of Covid-19 pneumonia using Calcifediol (25(OH)D), the natural part-activated form of vitamin D.


Córdoba RCT

Controls: 

26 patients, standard high quality treatment only. 

13 (50%) required transfer to ICU, two died.

Calcifediol treated group:

50 patients, standard high quality treatment + immediate Calcifediol.

1 (2%) required transfer to ICU, no deaths.

This means that compared to the control group, we would have expected 25 (50% of 50) patients in the Calcifediol treatment group to require transfer to ICU, but this was reduced to 1. 

24 out of 25 reduction is a 96% reduction, (24/25)x100. This is 96% efficacy.


Response from NICE

I have indicated in a previous post that this study from Córdoba was rubbished by the UK National Institute for Health and Care Excellence(NICE) in a report of September 20th.  The commentary was provided by Professor Neil Gittoes, Consultant, Honorary Professor of Endocrinology and Associate Medical Director, University Hospitals Birmingham NHS Foundation Trust; Chair of NHS England specialised endocrinology Clinical Reference Group. 

The basis of his report was a series conjectures rather than research.

But it was very effective and the instruction issued to medical staff by NICE was:

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

This instruction has been followed. It appears that Calcifediol has not been used in the UK. Since September 2nd, more than 16,000 people have died from Covid-19 in the UK, and ICUs are reported as being overwhelmed. 

In Switzerland, it has been reported that doctors are recommending that vulnerable people over the age of 60 years, with heart disease or diabetes should sign "Do not Resuscitate" orders so that the ICUs can cope with fewer patients (Times, November 23rd). 

Even today the demonstrated benefit of vitamin D as Calcifediol has remained unused.


Analysis by MIT


The world or its medical-scientific advisors appear to going mad, or are seriously negligent. But not the scientists of the Massachusetts Institute of Technology (MIT).

A major analysis of the Córdoba study has been undertaken at the MIT and it came to my attention when I was watching an interview of David Davis MP, one of our very few scientifically trained members of parliament. He has realised the vital importance of vitamin D deficiency in this pandemic and he is struggling to stir the government and the nation into action.

The MIT analysis is one of great detail, and it puts to shame the cursory approach of NICE. It researched the conduct of the study as well as analysing its results.

The conclusion (of MIT analysis) is that there was no fault in the conduct of the Córdoba trial. It acknowledged that the findings (as above) are robust, and that the chance of the results being in error is less than 1 in 60,000. 

The paper from MIT contains a lot of statistical maths but the message is stated clearly for those inclined to read it. 

Has the MIT report been read by NICE? Is NICE going to respond? Is NICE going to allow medical staff to use Calcifediol in patients seriously ill with Covid-19? Are patients with Covid-19 going to continue to transferred to ICUs in overwhelming numbers? Are people still going to die when they need not?


Is there sufficient Calcifediol

The RCT is being continued in Andalusia, Spain, in a total of five hospitals. Results are due soon and I hear unofficially that Calcifediol has resulted in a 50% reduction of deaths. If the result is so positive there will be no defence in not giving Calcifediol at least to hospital patients with Covid-19 pneumonia. Is there any defence now? 

A problem will be the availability of Calcifediol. I hope that the government has the wisdom to obtain large supplies of Calcifediol so as to meet a sudden large demand. 

There are several manufacturers of Calcifediol, in China, Korea, India, Netherlands, USA. Most of it used as animal feed, as though we care more about cattle than about humankind.

I can find from a USA website that the cost of Calcifediol is $200 for a 200mcg dose. The dose regimes from Córdoba is 532mcg on admission, 266mcg on days 3, 7, 14 and perhaps 21,28. This appears to be about $200 x 5 = $1,000. In 2003 the cost of one day in an ICU was $1364, likely to be greater now. In the Córdoba RCT the result was a reduction of need for ICU transfer by 96%, a major saving with the cost of Calcifediol being very good value for money.  


Sao Paulo, Brazil

An RCT in Brazil investigated giving natural rather than activated vitamin D in an attempt to reduce length of stay of 240 hospital patients admitted with Covid-19 pneumonia. 

They were all given standard care but randomly allocated to receive either a single oral dose of vitamin D 200,000 units or a placebo.

The outcome was no difference between the two groups in respect of length of stay, need for ventilation, or death. In those who received the vitamin D supplement the blood level rose, but the the time sequence was not displayed.


What about Vitamin D?

Vitamin D gave no advantage in the Brazil study.

Although this can be regarded as a disappointment to those like me who feel that vitamin D has a great therapeutic potential, perhaps the importance is that of timing.

When we measure the blood level of vitamin D we measure it as its 25-hydroxylated form 25(OH)D, which is Calcifediol. The part-activation process by hydroxylation takes place in the liver, but is rather slow and leisurely. This is fine in general life when are just trying to maintain a steady blood level. 

We can see from Figure 1 that for people who are deficient in vitamin D, less than 10ng/ml (25nmol/L), a range of supplement regimens  take up to two weeks to increase the blood level above 30ng/ml (75nmol/L, the safe range. Two weeks is much too slow to help a patient who is critically ill with Covid-19 pneumonia, but is adequate for correcting deficiency in a well person.



Figure 1. Response to vitamin D by mouth, in black is the average of three regimens.  In red is 100,000 units per day, in black the average of the regimens.

There is a distinct pharmaco-kinetic advantage in giving Calcifediol. It bypasses the liver activation process and when given by mouth it will its increase blood to above 30ng/ml (75nmol/L) within about 2 hours. We can see this in Figure 2.


Figure 2. Response to a single dose of Calcifediol


This means that in a patient admitted to hospital with Covid-19 pneumonia, Calcifediol must be given immediately and natural vitamin D is not an adequate substitute at this stage of emergency. 

However natural vitamin D must be given to the well before any illness, and certainly as soon as there is a positive Covid-19 test.



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

Also available from Amazon
or as eBook from iTunes 
















Sunday, 22 November 2020

Covid-19 & Vitamin D : Deaths of doctors from Covid-19

Excess deaths from Black, Asian, and Minority Ethnic Doctors during the Covid-19 Pandemic


I would like to display some information that I have collected during the course of the pandemic this year, and unfortunately finish on a low note.

Most weeks in the British Medical Journal we can read six obituaries to UK doctors who have died. They will not make up a full list of doctors who have died but they are interesting to read. I have recorded for a few years the ages and causes of death, but 2020 is particularly interesting as we can see the personal effects of Covid-19. In recent years the causes of death have been clearly displayed in the BMJ. During 2020 up to November 7th there have been 245 obituaries displayed with cause of death not stated in only 5.

The obituaries are accompanied by names (obviously) but also photographs. It has therefore been possible to assess the ethnicity of those who have died. I have divided them into two groups, White and BAME (Black African and Asian minority Ethnic groups).

They are displayed in Figure 1, a bar chart in which each column represents each of the 25 doctors who have been reported to have died from Covid-19, and the height of the columns represents the ages at death.The youngest death was at the age of 46 years and the oldest at the age of 107 years.


Figure 1. Doctors in the UK who have died from Covid-19

What is most dramatic and disturbing is the complete lack of overlap between the ages at death of the white and BAME groups.

Age range White:  84 to 107

Age range BAME:  46 to  79

Average mean age White:  91

Average mean age BAME:  62

As with the Cigarette Smoking and Lung Cancer study, published in 1950, we are dealing with only doctors, a homogenous group. We can therefore eliminate confounding factors such as income, housing, or socio-economic status.

The only one thing that the two groups do not have in common is skin pigmentation, but it is the one thing that the members of the BAME group do have in common. They might come from a range of nations within Africa, the Middle East, India and Pakistan, and South-east Asia, with different traditions, religions, and inheritance, but they share a melanin-rich skin.

These findings will be very uncomfortable to many people in government, and rightly so. Their advisors have declared that the high death rate of BAME people is due to socio-economic  factors, but this cannot be the case with doctors. The BAME doctors have died 30 years on average younger than their white counterparts. This is a major cause for concern and it must not be dismissed. I can think of no explanation other than skin colour.

The link between skin colour and Covid-19 deaths in the UK is deficiency of vitamin D. Melanin in the skin is a superb sun-shield that blocks 80% or more of the UV light that is incident upon the skin. Vitamin D is produced from the action of UV on 7-dehydrocholesterol which is synthesised within the skin, and this process is reduced by the presence of melanin. UV is diminished not only by absorption by melanin, but also by distance from the equator, the low elevation of the sun in the winter, extensive skin cover by clothes, indoor work, indoor leisure, and sun-avoiding behaviour including excessive use of sunscreens.

The way to reduce the impact of Covid-19 is to correct the widespread vitamin D deficiency which leads to suboptimal defensive immunity. No doubt the 13 BAME doctors recorded here died without knowing their blood level of vitamin D and without any correction of likely deficiency.

Extensive vitamin D deficiency is being ignored. What I have demonstrated will no doubt be dismissed as mere uncontrolled observation. Medical-scientific explanations are unwelcome. No-one listens to clinical doctors but only to mathematicians and sociologists.

One conclusion that can be drawn from this study is that a melanin-rich skin and presumed vitamin D deficiency appears to be much more dangerous than the coronavirus. The virus might have caused death in the very elderly but ethnicity and vitamin D deficiency caused death to be 30 years premature.



To part-counter arguments that my numbers are incomplete, I would like to look at the deaths of BAME doctors in another way, as I have done in a previous Blog post on April 3rd. This information has been known for more than six months but still there is no relevant official action.

Although the deaths of 13 BAME doctors are recorded in the obituaries above, I am aware of 25 BAME working doctors who have died from Covid-19. The 25th death was Dr Krishnan Subramanian, consultant anaesthetist at the University Hospitals of Derby and Burton. He died on November 12th 2020.

Dr Krishnan Subramanian

The first BAME working doctors to die from Covid-19 were Dr Adil El Tatar and Dr Habib Zaidi, both of whom died on March 25th, early in the UK pandemic and just two days after lockdown.

To my knowledge, during the following six weeks a further 22 working doctors died from Covid-19. Only one of the 24 was white, Dr Craig Wakeham, from Dorset. The BAME:White ratio at 23:1 is as dramatic as that above in Figure 1,

The dates of the 23 deaths earlier in the year of BAME working doctors are illustrated in Figure 2.

Figure 2. BAME doctors dying from Covid-19

       
The  deaths seemed to come to a sudden end, the last of the series being the death of Dr Saad Al-Dubbaisi, a general practitioner from Ramsbottom, Bury.

It was obvious that these doctors had just one factor in common, a melanin-rich skin. They would not have experienced socio-economic disadvantage nor small overcrowded houses. They would have almost certainly been deficient in vitamin D, but awareness of this was not general. However it was known by Professor Parag Singhal, endocrinologist and the national secretary of the British Association of Physicians of Indian Origin (BAPIO) and Dr David C Anderson former Professor of Endocrinology and Professor of Medicine. 

The black arrow in Figure 2 indicates April 29th. On this day they sent to all BAME doctors working in England and Wales a communication indicating that they would all be very much at risk from serious or fatal Covid-19 because of likely vitamin D deficiency. They were strongly advised to take take a vitamin D supplement in good dose of about 3,000 units per day, ideally after a single loading dose of 100,000 units, and this was supplied as necessary.

This action was unofficial, but it appears to have been very effective. It was the equivalent Dr John Snow removing the handle of the Broad Street water pump in Soho in 1854 and bringing to an end the epidemic of cholera.  

There was no randomised controlled trial preceding the action of Professors Singhal and Anderson, but we can compare the high mortality before April 29th to the absence of death following May 2nd. 

There has been a very disappointing research activity in the UK during this pandemic, just the study from Tameside having been reported so far. There appears to have been no centrally sponsored research. The Bill & Melinda Gates / Wellcome Foundation consortium, The Covid-19 Therapeutics Accelerator, set aside $20 million to fund research, but research related to vitamin D was excluded.

To prevent BAME doctor deaths was an imperative: they are human beings, not just doctors but husbands, one wife, parents. Their successors need not have become experimental subjects or necessary deaths, but thanks to direct action they continued to live. They were particularly at risk not just because of almost certain serious vitamin D deficiency but also because they were front-line workers.

There has been no national or even professional collation of the doctors who have died from Covid-19. I have brought together this information by reading medical journals, and also national and local newspapers. My evidence is incomplete, but it is powerful.

Apart from individual actions of my friends mentioned above, there does not appear to have been any official national or professional interest in or response to the deaths that I have described. The professional bodies have been silent or asleep.

Perhaps the totality of deaths has been noticed by only three people.


Post script:

Professor Kamlesh Khunti FRCGP FRCP MD PhD FMed Sci professor of primary care diabetes and vascular medicine in Leicester is a member of SAGE, the scientific advisory group for emergencies.

On Saturday November 21st 2020 he addressed a meeting of BAPIO, British association of physicians of Indian origin. 

Being an important person and presumed to be fully up-to-date and knowledgeable, a member of SAGE, his words were anticipated to be a revelation, words that would explain the intentions of the government to acknowledge the high number of deaths of BAME doctors in the UK (described above), and  action to be taken. The audience was to be seriously disappointed.

All members of BAPIO packed into the room would have been well-aware of the importance of vitamin D supplements in correcting wide-spread vitamin D deficiency, and how this can bring deaths from Covid-19 to a halt. There was just one person in the room who was not aware of this: the guest speaker, Professor Kamlesh Khunti. His words can be summarised as:

"The official line is that there is no role for vitamin D.

No discussion, no debate, the words are carved in stone.

This level of ignorance at the centre of government advice is frightening. 

We must be thankful for professors Parag Singhal and David Anderson for their direct well-informed action.



Sunday, 15 November 2020

Covid-19 & Vitamin D: Evidence from Tameside, Milan, Wuhan


Ashton – Peak Forest canal junction, Tameside

More evidence is now available to demonstrate the advantages of vitamin D if developing Covid-19. It is all positive in favour of vitamin D, with no evidence to the contrary.

There are now to my knowledge 21 reported studies indicating the dangers of low blood levels of vitamin D and the advantages of supplements. The three most recent are shown here.


Tameside, NW England

"Vitamin D treatment is associated with a reduced risk of mortality in patients with Covid-19".

This is from a pre-print of a paper that will appear in The Lancet.

[This pre-print link is not currently active. The main author tells me that the paper is being rewritten]

A prospective study of 986 subjects was undertaken in England, based in Ashton under Lyne, Tameside (to the east of Manchester), and including hospitals in Preston and Leicester. The study was of patients admitted to hospital on account of proven Covid-19 infection. The blood for vitamin D testing was taken on admission, and so this was a predictive study of vitamin D in the course Covid-19 infection. No intervention was given. However some of the patients had been taking a vitamin D supplement before admission, and they were analysed separately.

The conclusion of the study is in the title: "Vitamin D treatment is associated with a reduced risk of mortality in patients with Covid-19".

And so it was. Those patients previously taking a vitamin D supplement had just half the risk of death.

A wide range of parameters were measured in this study, and the results can be summarised in Figure 1.


Figure 1. Odds ratio of death. Log scale, 1 = average, less than one an advantage, greater than one a disadvantage.


As predictors of death, an advantage was seen in those on vitamin D treatment (supplement), and also those with a history of asthma, an observation without a clear explanation.

Disadvantages were age >74, the need for high-flow oxygen, a history of heart disease, low oxygen levels in the blood, high C-reactive protein (cytokine marker), high creatinine (indicating kidney damage), and female. Generally these are predictable, but not the slight excess risk of females.

There were three groups of vitamin D reported:

 >20ng/ml.   >50 nmol/L

10–20ng/ml. 25–50 nmol/L 

<10ng/ml.  <25 nmol/L 

This is the weakness of the study. It would have been of great advantage to create four groups, so as to identify:

>30ng/ml. >75 nmol/L 

20–30ng/ml. 50–75 nmol/L 

10–20ng/ml. 25–50 nmol/L 

<10ng/ml.  <25 nmol/L 

It would not have been known in the early part of the year when this study was defined, but other studies during the pandemic have demonstrated that a blood level of >30ng/ml. >75 nmol/L marks the transition between high risk and low risk, with a rapid change, a watershed. This is shown in Figure 2. Defining 20ng/ml (30nmol/L) as "normal" (or "replete" as in the Tameside paper) is wrong as it can be seen that it is associated with a relatively high risk of death. It is is far from the ideal of >30ng/ml (75nmol/L), and it is ideal that should be the objective.



Figure 2. Death rate from Covid-19 based on blood levels of vitamin D. 
A dramatic diminution of death risk above 30ng/ml is obvious

It is for this reason that the results of vitamin blood levels in this paper are disappointing.

In Figure 3 we can see the distribution of blood levels of vitamin D in the 953 subjects tested. 75% had blood levels of less than 20ng/ml (50nmol/L), that is they were deficient. Of the remaining 25%, we are not informed of the proportion with an ideal blood level of >30ng/ml (75nmol/L). It might have been less than 10%. This indicates a major public health challenge.


            Figure 3. Distribution of blood levels of 953 subjects

There was an assessment of the blood level of vitamin D related to the need for intubation / ventilation on the ICU. The odds ratio was 1.83 for patients with a low vitamin D blood level of less than 20ng/ml (<50nmol/L). This is an increased risk, almost double the average in the study.

For those with a blood level greater than 20ng/ml (50nmol/L) the risk of ventilation was below average, about half average, with odds ratio 0.55.   

This is shown in Figure 4, again a log scale showing odds ratio. 



Figure 4. Odds ratio of need for ventilation / ICU


The lower, reduced, risk of ventilation / ICU is in those with blood vitamin D levels greater than 20ng/ml (50nmol/L). Once again a low level of vitamin D increases the risk of intensive care ventilation and a high level is much safer,

We also observe that 75% of those investigated were deficient in vitamin D. There is need for public health action.


Milan, Italy

Low vitamin D levels independently associated with severe COVID-19 cases and death.

A study was undertaken of 103 severely ill patients admitted to the San LucHospital, Milan, COVID-19 unibetween March 9 and April 30, 2020. Blood was taken on admission for testing including levels of vitamin D as 25(OH)D and the study was to observe subsequent progress.

This was therefore a predictive study. There was no vitamin D intervention.

They were compared with 52 patients with Covid-19 but with either no symptoms or very mild symptoms, and also with 205 community matched controls who had recently had blood vitamin D testing as routine health assessment.

The results were as follows

Of the 103 severely ill patients, the mean blood level of vitamin D was 18.2ng/ml (44nmol/L) compared to the control group in whom the mean level was 25.4ng/ml (62nmol/L).

Of those who were severely ill and required admission to ICU the mean blood vitamin D level was 14.4ng/ml (29nmol/L), compared to 22.4ng/ml (56nmol/L) in those who did not require ICU admission.

19 (18.44%) died and their mean blood level of vitamin D was 13.2ng/ml (33nmol/L).

35 survived and they had a mean blood vitamin D level 19.3 ng/ml (48.25nmol/L).

Those with mild disease had a mean blood vitamin D level of 30ng/ml (75nmol/L).

The controls, assumed to represent the national average, had mean blood vitamin level 25.4ng/ml (63nmol/L).


Figure 5. Outcome from COVID-19 based on blood levels of
vitamin D on admission


This study was presented by Professor Luigi Gennari MD of the Universitof Siena in Italyat the American Societfor Bone and Mineral Research virtual meeting, September 11th 2020.


Wuhan, China

The report was published in the Journal of Nutrition on November 13th 2020.

The study involve 335 consecutive patients admitted to Tongji Hospital, Wuhan, in March 2020 on account of Covid-19. Six of the patients died. All had vitamin D blood levels performed on admission to hospital. There was not vitamin D intervention.

The study also involved 560 matched controls from a database of 22,397 from a recent community examination program.

Results

Vitamin D, mean:

Controls 13.0ng/ml, 32.5nmol/L

Patients 10.6ng/ml, 26.5nmol/L

Deficient = <12ng/ml, <30nmol/L

controls 40.7%, patients 65.7%

Risk of severe disease:

Odds ration 2.72 for those deficient compared with non-deficient

Deaths:

Vitamin D mean = 7.48ng/ml, 18.7nmol/L



Figure 6. Vitamin D and outcome, ng/ml



Figure 7. Vitamin D and outcome, nmol/L


We see a lower blood level of vitamin D in Covid-19 hospital patients compared to controls and the lowest levels associated with severe illness, and in particular with death.

The study gives the opinion that vitamin D deficiency is a global public health concern.

The blood levels of vitamin D are remarkably low compared to studies in Europe. This is likely to be the result of the extremely serious atmospheric pollution for which Wuhan is known, the pollution preventing UV from the sun penetrating to ground level, and thereby vitamin D production is inhibited. The other factor is possible sun-avoiding behaviour of the population. Vitamin D deficiency certainly appears to be a serious problem in Wuhan.

In this study, deficiency of vitamin D was defined as less than 12ng/ml (30nmol/L), and "non-deficient" as greater than this level. It is more usual for 20ng/ml (50nmol/L) to be the boundary between deficient and non-deficient. Other studies undertaken during the pandemic demonstrate that a blood vitamin D level greater than 30ng/ml (75nmol/L) can be judged as safe from significant risk of unfavourable or fatal outcome from Covid-19. 


Conclusion

It is clear once again that low blood levels of vitamin D predict critical disease and fatal outcome from Covid-19 infection. 

This has now been demonstrated on many occasions. If there is a desire to reduce ICU admissions and deaths from Covid-19 it would seem to be sensible to correct the widespread low levels, that is deficiency, of vitamin D in the community. It is so obvious and so simple. It is beyond belief that it has not yet been done, despite the UK having now experienced more than 50,000 deaths from Covid-19.






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













Sunday, 8 November 2020

Covid-19 & Vitamin D : demonstration of proof


Covid-19 & Vitamin D : demonstration of proof

The evidence that a low blood level of vitamin D leads to an increased risk of serious or fatal Covid-19 infection, compared to those with higher (ideal) levels, is indisputable. There is widespread deficiency of vitamin D and this is a world-wide phenomenon. 47% of the population pf Spain are deficient in vitamin D, and 80% of those admitted to hospital with Covid-19.

There are several reasons for this widespread deficiency, including extensive skin cover by clothing, many more people working indoors, and in the age of air conditioning many people seeking leisure indoors where it is cooler. The problem is compounded by much of the population living in the temperate zones of the northern hemisphere where the sun produces vitamin D in the skin for only six months of the year. This puts people with melanin-rich skin living in temperate zones at a great disadvantage, as melanin blocks much of the UV light and diminishes vitamin D production. The atmospheric pollution of world cities blocks UV light penetration to ground level and also reduces vitamin D production.

Low blood levels of vitamin D associated with severe or fatal Covid-19 have been demonstrated in India, Singapore, Newcastle upon Tyne, Iran, Turkey, Mexico, France and St Petersburg. Low blood levels of vitamin D predicting Covid-19 have been demonstrated in Bari (severe or fatal), Chicago, Israel, Santander, Heidelberg (severe or fatal), Boston, and Tehran (severe or fatal).

The benefit of treating with Covid-19 pneumonia with vitamin D patientshave been demonstrated in Singapore and Córdoba, Spain. The latter was a randomised controlled trial, using Calcifediol, the part-activated form of vitamin D.

But the government and its advisors deny that vitamin D should be used as a prevention or treatment of Covid-19. A fact that is hard to believe is that the advisory body NICE (National Institute for Health and Care Excellence) has advised that the very positive study from Córdoba should not influence the way in which patients with Covid-19 pneumonia are to be treated. This is outrageous.

It is claimed that there is an absence of "proof"

When most people use the word "proof" they only rarely understand the meaning of the word. When challenged, they will usually say "Well, you know, er...."  But is essential to understand what it means.

Proof is "The fulfilment of pre-determined criteria". In other words the question of proof must be thrown back at the sceptic. He or she must decide the criteria that would be accepted as proof of a given proposition. Proof would be based on the evidence that would lead to the recognition of truth. The criteria must be testable, real science.

The problem is that there is no absolute truth, and the evidence of proof is always pragmatic. New evidence might bring about a re-evaluation of truth. For example the proposition that the sum of the angles of a triangle is always 180 degrees was accepted until the 20th century when the  triangle was superimposed on the curvature of the Earth. 

The important decision in reaching the truth is based on the legal concept of the weight of evidence, but then there is a problem. Karl Popper used the example of swans, in which a proposition  might be made that all swans are white. Researchers might travel widely counting white swans thereby adding to the "weight of evidence". But then a black swan is discovered. The truth of the proposition does not become determined by the majority. The weight of evidence might be in favour of swans being being white, but the single black swan invalidates the assertion. Popper championed falsification (the null hypothesis) as the true pursuit of experimentation,

We must be careful. The propostion that low levels of vitamin D lead to a increased incidence of critical or fatal Covid-19 is not quite so black and white as swans. 

It might be found that some people with what are considered to be ideal blood levels of vitamin D might become critically ill and die from Covid-19. We know that some people have a genetic inheritance of sub-optimal vitamin D receptors (VDR), called polymorphisms. This is has been recognised in the clinical syndrome of "vitamin D resistant rickets", in which vitamin D does not work. Its target molecule (VDR) is defective and so the key does to fit in the lock. This has been found to be relatively common in people with tuberculosis, leading to sub-optimal immunity. 

But it is rare and we must look at the great majority when seeking proof, accepting exceptions.

QED

An experiment must always have controls, and I first learnt this in science at school. If we want to investigate the proposition that the growth of a seed requires the presence of water, we put two seeds in two pots of compost and apply water to just one. The criterion of proof is that all other things being equal only the seed exposed to water will grow.

As in mathematical solutions, we would then state "QED", quod erat demonstrandum, that has been demonstrated, proved.

Simple experiments in humankind are usually not quite so straightforward, but they can be. Correction of deficiency states are easy to understand once that the deficiency is understood by measurement of a physiological parameter. It became clear that Type 1 Diabetes is due to deficiency of insulin, the failure of  insulin being manufactured in the pancreas. The administration of insulin to someone in a diabetic coma was like a miracle, there having been many unfortunate "historical control" patients who had died before the discovery of insulin (I appreciate that the measurement of insulin in the blood was not possible at the time, but it could be inferred). The clinical experiment of a randomised controlled trial (RCT) was unknown at the time (1922) but it might be enforced today. Similarly deficiency of thyroid hormone and its replacement in treating myxoedema, or cortisone in Addison's disease.

Asleep at the wheel

During the pandemic of Covid-19 there has been a refusal rather than a reluctance to consider vitamin D deficiency as a major risk factor for critical and potentially fatal disease. There has been in the UK no co-ordinated  effort to investigate the extent of vitamin D deficiency, no effort to associate it with the level of severity of Covid-19, and no attempt to provide vitamin D replacement therapy for those deficient. The evidence of 18 published studies has been ignored, and there has been no scientific undertaking to disprove the proposition.

The UK has witnessed almost 50,000 deaths, and yet the government or its advisors have failed to provide a very cheap, very safe, and readily available way to minimise deaths.

Sir Austin Bradford Hill and Sir Richard Doll – the importance of careful observation

If lack of proof, or rather a serious lack of understanding of proof, has been paralysing the government and its advisors, let me bring to attention the very important work of the distinguished British statistician Sir Austin Bradford Hill, who I have mentioned in previous Blog posts. Repetition can be essential.

Sir Austin Bradford Hill and Sir Richard Doll produced in 1950 the important study that brought about the general acceptance that cigarette smoking causes lung cancer, using a sample of doctors who declared their smoking habits. It was a time-related (temporal) observational study and the results can be seen in the figure.



It is obvious that the more cigarettes smoked per day, the greater the chance of dying from lung cancer.

Note that this was not a double blind randomised controlled trial. To create an RCT would have been an impossible task. Think about it. It was an observational study, a method discounted by our supposedly betters concerning Covid-19 and vitamin D

The authors of the study had thought about the meaning of proof, and in 1965 Bradford Hill produced  a set of criteria. He considered that if these were met, it would constitute "proof". 


We must apply these to the proposition that:

"Vitamin D deficiency leads to an increased risk of critical or fatal Covid-19"

The studies quoted are reviewed in a previous Blog post

1. Strength of association:

Examples: 

A study from India demonstrated the following association in Covid-19:

Blood vitamin D level >30ng/ml, 62% had severe disease

Blood vitamin D level <30ng/ml, 85% had severe disease


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


I have mentioned a study from Spain (published on October 27th 2020):

Covid-19 hospital patients: 80% deficient in vitamin D.

Community controls: 47% deficient in Vitamin D.

2. Consistency of association:

Similar associations were demonstrated in:

3. Specificity:
The studies that I have listed are specific for the link between low levels of vitamin D and high risk of critical illness or death from Covid-19. However I accept that not everyone with a low blood level of vitamin D will become seriously ill or die from Covid-19 infection. Similarly, not everyone who dies from Covid-19 is deficient in vitamin D. There are other factors at work in a sub-optimal immune system (for example VDR polymorphisms), but it is not possible to measure "immunity" directly.

4. Temporality:
The association between cigarette smoking and lung cancer was criticised on the basis that having lung cancer might cause people to having smoked cigarettes decades earlier. This is called "reverse causality" but one the example illustrated it is not very plausible.

It has been stated with some truth that a serious infection with Covid-19 reduces the blood level of vitamin D. I have indicated previously that this is true in that vitamin D (as the active 1,25(OH)D) is consumed, irreversibly inactivated after use. It is therefore essential for the blood level of 25(OH)D not to be low in advance of the infection. A reservoir of 25(OH)D in the blood is essential if a serious infection occurs so that production of 1,25(OH)D can be escalated.

It is important that observations are time-related, the sequence of events being demonstrated rather than just a "snapshot". Temporality means the ability of a low level of vitamin D to predict critical or fatal Covid-19. This has been demonstrated in the following studies:

Bari. 
Blood level of vitamin D >30ng/ml, 5% died subsequently
Blood level of vitamin D <10ng/ml, 50% died subsequently

5. Biological gradient:
This criterion is met by looking at a range of blood levels of vitamin D and relating them to the development of or the outcome from Covid-19. This information is best illustrated in the study from Israel, but there are limitations as it looked at ethnicity and infection, and did not include deaths. In respect of Covid-19 infection rates, there appeared to be a threshold level at 30ng/ml, above which infection rates drop to half compared to lower blood levels.

A biological gradient was demonstrated in the Heidelberg study, with unfavourable outcome progressively increasing with decreasing blood vitamin D levels. The hazard ratio, the risk of adverse events, for the lowest vitamin D levels was 14.73 compared to the highest, with a gradient between.

Hazard ratios for death:
Vitamin D >30ng  HR = 1.00
Vitamin D <20ng  HR = 11.27 
Vitamin D <12ng  HR = 14.73

The gradient can be seen on the graph. The higher the blood level of vitamin D, the lower the death hazard (>20ng/ml is standardised as 1).



6. Plausibility
Is it biologically plausible that vitamin D might protect against Covid-19 symptomatic infection, the cytokine storm, escalation of illness to a critical, and death? The answer is that it is very plausible, based on a large amount of research that has been undertaken since about 1980. The role of vitamin D is often dismissed on the basis of ignorance of this information.

There is a wealth of published information that demonstrates that vitamin D has a pivotal role in activating VDR (vitamin D receptor), which in turn activates genes that control T- and B-lymphocytes and suppress TNF-alpha. I have described these processes in a previous post in April of this year.

7. Coherence
This involves linking together the information obtained from basic science with information obtained from observations of the population and the Covid-19 pandemic. There is a very coherent story, which includes the serious disadvantage of BAME people (Black and Asian Minority Ethnic) in the UK, US, and Sweden, based on their known low blood levels of vitamin D. This could have been investigated in much more detail during the pandemic, but if that happened ( and I doubt it) the results are not yet released. 

The proposition that low blood levels of vitamin D predispose to critical disease and death from Covid-19 is also supported by the observations of a latitude effect, that there have been few deaths in equatorial Africa, and deaths per million are more than 100 times higher in the UK.

8. Experiment 
There are strict limitations on experiments that can be performed on humankind, especially when these involve the correction of a demonstrated deficiency state. We find both logistic challenges and also ethical constraints.  At a a time of a dangerous pandemic, should people be denied the potential benefits of a known and a safe pre-hormone such as vitamin D, of which they are definitely or likely to be deficient?

However a clinical experiment (RCT, randomised controlled trial) was undertaken at the Reina Sofía University Hospital, Córdoba, Spain. Of 50 patients with Covid-19 pneumonia receiving standard high quality care plus vitamin D in its part-activated form Calcifediol, just one required transfer to the ICU and there were no deaths. In the randomly selected 26 in the control group, who received standard high quality care only, 13 required transfer to the ICU and two died.

This was an experiment with a very positive result, despite it being rubbished by NICE. Unfortunately two deaths occurred. Had this been a trial of a vaccine or a new anti-viral agent, the results would have made headlines in all newspapers. But with vitamin D this was not to be.

More similar experiments might follow. The problem is that natural vitamin D might be used, but it takes one or two weeks to achieve good blood levels of the liver-activated form 25(OH)D. The Córdoba study used by mouth 25(OH)D which is Calcifediol. This bypasses the slow liver hydroxylation process and achieves good blood levels within just two hours. My concern is that future RCTs will use natural vitamin D and will fail to produce a positive result. It would be the rial structure at fault, not vitamin D. 
 
9. Analogy
Are there any studies that are similar to the identification of the deficiency of a natural hormone being associated with a health disadvantage? Of course there are. We have the recognition of Type 1 Diabetes resulting from insulin deficiency and being corrected by insulin replacement therapy. We have the recognition of the clinical syndrome of myxoedema being the result of under-activity of the thyroid gland, and corrected by thyroid hormone. We have Addison's disease being identified as being the result of failure of the adrenal glands and being corrected by cortisone. 

There is the rare VDR polymorphism in which vitamin D fails to activate its target, similar to insulin resistance in which physiological amounts of insulin are not effective (Type 2 Diabetes).

The analogies of the proposition that low blood levels of vitamin D lead to immune deficiency are many and are obvious. Similarly, vitamin C deficiency results in dangerously weak soft tissue

10. Reversibility
If low blood levels of vitamin D are associated with a high risk critical illness or death from Covid-19, does correction of this with vitamin D supplement reverse this risk? Here we have incomplete information.

Unfortunately the study from Córdoba did not measure blood levels of vitamin D. The studies from Bari, Israel, Heidelberg, Boston, Tehran, Santander identified low blood levels being associated with a later unfavourable outcome, but they did not intervene and they did not reverse the low blood levels that they had or could have observed. In Heidelberg and Santander the blood was taken from the patients on admission to hospital but not tested for vitamin D until the end of the trial. This kept the investigators and clinical staff "blind" to the vitamin D status of the patients, and it also avoided any ethical conflict in withholding replacement therapy.

An approach could be to identify on admission to hospital the blood vitamin D levels of patients with Covid-19. The results would be available within one or two hours, and then those with low levels could be randomised to receive vitamin D or just standard care. It is important that vitamin D is given to very ill patients in the form of  Calcifediol as explained above. It would be superfluous to randomise between vitamin D and Calcifediol as the different pharmaco-dynamics of them are known. Such an approach of sick patients identified as having vitamin D being denied correction of the deficiency (and informed of this) is most unlikely to receive ethical approval  

It is possible that other studies addressing reversibility are awaiting publication, but there is the increasing ethical factor that now all patients (or well people) known to have low blood levels of vitamin D will expect to have this corrected. The effect will be obvious if hospital and ICU admission rates and death rates fall rapidly. 

Proof

All the criteria of Sir Austin Bradford Hill have been met, with the possible exception of reversibility, which cannot  be assessed ethically.

This means that "Proof" can be accepted.

Need more be said? Is there any reason not to protect people who have a low blood level of vitamin D by correcting it? Is there a reason not to treat with Calcifediol patients sick with Covid-19 pneumonia? If there is it must be demonstrated clearly to the public, ideally in the form of a debate.Since September 3rd when the result of the Córdoba became available, 7344 citizens of the UK have died as the result of Covid-19 (November 8th). When will "proof" be accepted? How many more deaths must occur before the population and the sick are protected using vitamin D?

There is, however, one logistic problem. The nation is not prepared to test the blood levels of vitamin D in the population. It could be achieved but it would take time. However vitamin D in a dose of 4,000 units per day given to all the population without knowing blood levels would be perfectly safe, as identified by SACN, the Scientific Advisory Committee on Nutrition. 

Is there sufficient vitamin D to meet the needs of all the population? People such as the BAME, the elderly, the obese, and those with diabetes are known to have a high prevalence of low blood levels of vitamin D and so must have priority. Blood levels of vitamin D could be measured later to check on the appropriateness of dose.

Is there sufficient Calcifediol to meet the needs of of all patients admitted to hospital with Covid-19 pneumonia?

Are preparations being made?




 

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


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