Thursday, 7 April 2022

Covid-19 & Vitamin D – why is there no herd immunity?


The Covid-19 pandemic has been in progress for a little more than two years, but daily Covid-19 records are still being broken, as in this report from England, similar from Scotland. Why has it not settled? For how much longer will case numbers increase and records be broken?

When the pandemic of Covid-19 emerged in early 2020, the plan of governments collectively (following directives from the WHO) was that the answer must be "vaccinations" (strictly m-RNA injections), which were to be manufatcured as a matter of urgency for the world, and with a great deal of financial support from governments. The introduction of vaccines was anticipated to be at the end of 2020 (at least in the wealthy nations that could afford the vaccines) with the pandemic coming to an end during 2021. 

Herd immunity

It was confidently expected that vaccinations would lead to herd immunity more rapidly than would be the case with nature. 

Herd immunity means that the great majority of the population has immunity, either as a result of infection and recovery, or by vaccination. Historically natural infection followed by survival and immunity has been by far more important, and it has stood the test of time. However the WHO has recently given vaccination a priority in the definition of herd immunity.

In the winter of 1968–69 there was a pandemic of what we called "Hong Kong Flu". It affected a large proportion of the population and it caused an estimated 50,000 deaths in the UK. At the time I was the resident medical officer (RMO) at the Manchester Royal Infirmary, and I can remember how this and other hospitals were overwhelmed by emergency admissions and many deaths. Flu vaccinations were given, but they were of very doubtful effectiveness. Tests for viral antigens and antibodies were not possible at that time.

There was a minor peak in late 1969 but the pandemic settled without any of the multiple peaks that we have seen recently. Herd immunity appears to have been reached after about a year.  The important thing about herd immunity is that it is permanent, locked into the immunity "memory" cells. It also becomes hereditable and is passed on to future generations. Hong Kong Flu has not returned.

At present there is no indication of herd immunity being reached with case numbers still increasing.


Covid-19: no treatment given

While waiting for the vaccines to become available, people diagnosed with Covid-19 were given no treatment and clinical doctors were not allowed to give treatments which could have helped, including VItamin D (especially in its activated form Calcifediol), Hydroxychloroquine, Ivermectin, Beclomethasone aerosol, Vitamin C, and Zinc. People diagnosed with Covid-19 were told to go home, and then to go to hospital if they had difficulty in breathing. It was a disgrace.

It was  promised that vaccinations would end the pandemic, but this did not happen. Something went wrong. In all countries we find similar patterns of the pandemic not settling, and on the contrary case numbers are increasing in multiple peaks, by a factor of up to one thousand.

There are more cases in 2022 

Covid-19 cases per day were higher in the first quarter of 2022 than in the same month in 2021 (Figure 1, below). During March 2021 case numbers were decreasing, but this is not happening in 2022.

We have seen during the previous two years that case numbers fell during the Vitamin D production season of May to August. This should happen again in 2022 but we cannot make any clear predictions.

Many governments have abandoned policies such as mask-wearing, social distancing, and lockdown. Schools and work are now back to normal. For a change in policy at a time of the highest case-rates compared to previous years indicates that governments have abandoned such policies because they have been of no obvious benefit – but of course they have been very damaging to education and the economy, and to many individuals. There will of course be no apology for failure and further vaccinations are being encouraged.

The pattern of Covid-19 is obvious not just in the UK but in many other countries. There have been several peaks that were not predicted and which are not readily explained, but we can recognise that each peak is higher than the one before.

UK

We can look for example at the past three years in the UK, remembering that it was only in March 2020 that the pandemic emerged. At that time there was major concern, and we were subjected to almost total lockdown. But we can compare cases per day in 2020 (blue) with what happened subsequently in 2021 (green) and 2022 (grey). In retrospect the experience of 2020 appears to be quite trivial.


Figure 1. UK Covid-19 cases per day in 2020, 2021, 2022 

It is strange and certainly unexpected that the number of Covid-19 cases per day is so much higher in 2022 than in 2021. It was anticipated that the vaccination programmes during 2021 would have brought the pandemic to an end. But it has not happened, and the pandemic has become worse.

The pattern of Covid-19 is obvious not just in the UK but in many other countries. There has been a series of peaks that were not predicted and which are not readily explained. But we can recognise that succeeding peaks have been progressively higher. 

My previous reports have displayed bar-charts (such as Figure 1) that I have constructed from data displayed daily on "worldometer". However several countries, including the UK, have stopped reporting numbers regularly, and some cases altogether. Even with the UK our Covid-19 case numbers and death numbers are no longer displayed each day, and to find the numbers involves searches from a variety of sites.

However "ourworldindata" continues to supply daily Covid-19 data from around the world, but usually after a few days delay. I will show graphs from this source.

Israel

To understand (or try to understand) what is happening in the Covid-19 pandemic, let us look at Israel as another example. This is about the earliest and most completely vaccinated nation.

First we can see in Figure 2 the first four peaks that occured during 2020 and 2021, and these caused great concern. The head of Pfizer, as a child a survivor of the Holocaust, had promised Israel to be the recipient of the first Pfizer vaccines (and unknowingly the subjects of post-marketing surveillance). The failure of vaccinations to stop the pandemic was not encouraging, but successive vaccination programmes continued.

The first four waves are obvious, two in 2020 and two in 2021.

Figure 2. Israel Covid-19 cases 2020 and 2021

But the pandemic waves in 2020 (maximum 6,000 cases per day) and in 2021 (maximum 10,000 cases per day) 
became less significant when we moved into 2022. The case number hit a maximum of 100,000 per day, ten times the experience of 2021. What has been going wrong? What will happen next?

Figure 3. Israel Covid-19 cases 2020, 2021 and 2022

Japan

We can see the same in Japan, five waves in 2020 and 2021, with a maximum 25,000 cases per day.

Figure 4. Japan Covid-19 cases 2020 and 2021


And then an enoromous sixth wave in 2022, maximum 94,000 cases per day. What will happen in the near future is impossible to predict.
Figure 5. Japan Covid-19 cases 2020, 2021 and 2022


Germany

The same pattern occured in Germany, five waves during 2020 and 2021, with a maximum of 60,000 cases per day.

Figure 6. Germany Covid-19 cases 2020 and 2021

But then in 2022 a sixth wave with more than 200,000 cases per day. This peak is stubbornly persistent and in early April it is still increasing.

Figure 7. Germany Covid-19 cases 2020, 2021 and 2022


New Zealand 

New Zealand appeared to be protecting itself very well during 2020 and 2021, and was applauded as showing great success from is lockdown enforcement. Case numbers were low with the late 2021 peak reaching only about 200 cases per day, and that was after the vaccination programme was well-established. Cases per day were strangely higher following the vaccination initiative.

Figure 8. New Zealand Covid-19 cases 2020, 2021

But these peaks and numbers are of little significance when we see the current peak in March 2022. New Zealand is now experiencing 20,000 new cases each day. Something has gone seriously wrong, and a one hundred-fold increase in cases per day was completely unexpected. Despite this the end of lockdown enforcement is under way. 

Figure 9. New Zealand Covid-19 cases 2020, 2021 and 2022

Hong Kong

Hong Kong shows a similar peak in March 2022, with more than 60,000 cases per day. The previous numbers of daily deaths can now be regared as insignificant. The present increase is about one thousand times the previous numbers 
Figure 10. Hong Kong Covid-19 cases 2020, 2021 and 2022

South Korea

During 2020 South Korea was applauded for its military style  tight lockdown and there were very few Covid-19 cases, fewer than 1,000 per day. In late 2021 the number increased to 7,000 per day. 

Figure 11. South Korea Covid-19 cases 2020, 2021 and 2022

But in the early Spring of 2022 the numbers increased dramatically, to an astonishing maximum of 400,000 cases per day. Why did this happen following an extensive vaccination programme?

Figure 12. South Korea Covid-19 cases 2020, 2021 and 2022


I could go on to show many other countries, with a graph displaying 2020 and 2021, and then one to include 2022. But the point is obvious that case numbers in 2022 in many countries have overwhelmed by a factor of ten or more the case numbers in 2020 and 2021. We were told that with vaccinations the pandemic would rapidly come to an end, but the reality is that it has become much worse.


Covid-19 death rates are lower in 2022.

As shown in the example of the UK (Figure 13) Covid-19 deaths per day are much lower during the first quarter of 2022 than the same quarter in 2021. However at present in early April 2022 Covid-19 deaths per day are more than in 2021, with a tendency to increase.

Figure 13. UK Covid-19 deaths per day 2020, 2021 and 2022


It is stated that vaccinations have prevented thousands of deaths, but we cannot be certain of this as there has been no appropriate randomised controlled trial. The lower numbers of Covid-19 deaths per day during the pandemic can be seen in the example of the UK. 

You live every day, but you die only once.

There is an obvious explanation for fewer deaths in 2022 than previously in the pandemic.

You will remember that at the beginning of the pandemic, deaths were almost exclusively in the very highly vulnerable. Covid-19 deaths per day reduced during the Summer of 2020 and the Spring of 2021, but there were high numbers in the winter months of no vitamin D production.

The very highly vulnerable died early in the pandemic, and they could only die once. 

It is inevitable that it will be some time before a new cohort of very highly vulnerable will develop from the remaining just vulnerable members of the population. It is always the case that a peak of deaths in the first year of a pandemic is followed by lower than average death rate in the next one or two years.

The vaccinations 

Although vaccinations might have reduced the severity of Covid-19, it would appear that the vaccinations have failed to deliver the anticipated success.

Something has gone wrong with the vaccinations. I have suggested in a previous Blog post that vaccinations, in stimulating the immune response would inevitably have consumed Vitamin D, as a molecule of Vitamin D as 1,25(OH)D can only be used once. Immunity would inevitably suffer.

Are vaccines failing because Vitamin D supplements have not been given with the vaccinations? – especially as we are only just approaching the Vitamin D production season.

The effect of vaccines on immune mechanisms needs further evaluation in a future Blog post.

Note:
Replies and comments that I try to publish are longer accepted, and I cannot understand this. I will need to post my replies in this main text.

This is my reply to Comment 1:

From the beginning of the pandemic, reports of Covid-19 "deaths" have been deaths of people who have tested positive for Covid-19 during the previous 28 days. This definition has not changed, but overall it could have overstated Covid-19 deaths.
Observation of increased Covid-19 cases leads to an suggestion of greater transmissablity of successive variants, but it could equally be the result of a progressive reduction in the immune response of the population.
It now appears that the triple vaccinated have a higher incidence of cases and deaths then double vaccinated and unvaccinated. It also appears that this data will no longer be published in Scotland.

Reply to comment 3: (my reply could not be published)
"The large print giveth and the small print taketh away". That is, our hope for Vitamin D enlightenment. 
The government asks for "advice" concerning vitamin D, but in the text is that this advice is in repect of muscle-skeletal health only. No mention of immunity. But I will try to win the battle for vitamin D.




















Thursday, 10 March 2022

Covid-19 and Vitamin D – study from Liverpool

 

Covid-19 and Vitamin D – a study from Liverpool

Liverpool water-front

We have just seen the publication of another paper concerning the outcome of Covid-19 in relation to the blood level of Vitamin D. This study was undertaken in Liverpool, UK.

The results are not entirely straightforward as the study also investigated several parameters of Vitamin D. I will try to extract what I regard as the most important points and integrate them with other studies.

The study was of 992 patients with Covid-19 admitted to hospital in Liverpool between March 18th and November 2nd 2020, early in the pandemic. Of these, 472 were studied in detail because following initial blood testing, there was sufficient surplus blood serum to allow retrospective blood testing for Vitamin D.

Vitamin D levels

From the recent study from Israel, I find it compelling  that Vitamin D deficiency should be defined as less than 30ng/ml, 75 nmol/L. Less than this blood level indicates a high risk of severe or critical Covid-19, whereas above this level can be regarded as a safe range. In the study from Israel about 50% were deficient by this definition, and in a study from Heidelberg, Germany, in 2020 the proportion deficient of Vitamin D in was much higher at about 80%, in Figure 1.

Figure 1. Vitamin D in patients with Covid-19, 2020

In my personal research in Blackburn, UK, 20 years ago the proportion with Vitamin D deficiency as defined above using the Israel data, was 682 in the ethnic white sample of 818 (83%), and a very disturbing 1514 in the ethnic South Asian group of 1574 (96%). 

I have shown this data previously, but as it was two years ago I will display the bar-charts below. Each vertical bar represents the blood vitamin D level of one person. As the distribution is not "normal" or symmetrical, the median is shown. This is the halfway point, 50% of the subjects below or above this level, the vertical orange line. The horizontal yellow line indicates the blood level of the median. The horizontal red line indicates blood vitamin D level of 30ng/ml, 75nmol/L and we can immediately see how few of the subjects were above this safe line.

Figure 2. Distribution of blood level of Vitamin D in 818 ethnic white people


Figure 3. Distribution of blood level of Vitamin D in 1574 ethnic South Asian people

In the ethnic white group the median blood level of Vitamin D is 18ng/ml, 45nmol/L.
In the ethnic South Asian group he median blood level of Vitamin D is 9ng/ml, 22.5nmol/L.

Liverpool experience

Once again we have the problem of two units of measurement of Vitamin D in current use. The paper from Liverpool uses the unit "nmol/L". I will express both even though this might appear cumbersome. 1ng/ml = 2.5nmol/L

The Liverpool study regarded 20ng/ml, 50nmol/L as being the lower limit of the ideal range, and therefore below this to be VItamin D deficiency. However the study from Israel indicated that 30ng/ml, 75 nmol/L would better be regarded as the lower limit of the safe range, based on biological advantage.

Of the 472 Covid-19 patients studied in Liverpool, we can see in Figure 4 the numbers with various blood vitamin D levels.

Figure 4. Distribution of Vitamin D in 472 Covid-19 patients


83% were deficient of Vitamin D with blood levels less than 30ng/ml, 75nmol/L. 
96% had sub-optimal blood levels of less than 40ng/ml, 100ng/L. 
These results indicate a serious but reversible public health problem.

We can see that in these 472 Covid-19 patients, there is an asymmetrical distribution, and so once again an arithmetic mean is not of particular value. The distribution is skewed to the lower range of blood levels of Vitamin D and the median, the middle of the range, was expressed in the study report. 

The proportion with suboptimal levels (as defined by high illness incidence) is the most useful way of expressing Vitamin D status of a population.

The pattern is similar to but not quite as dramatic as the Heidelberg study ahown in Figure 1. In this, there are more sub-divisions of Vitamin D level than in Figure 4.
 

Deaths

Of the 472 Covid-19 patients, 112 died within 28 days, 23.7% overall, 28% in men, 23.5% in women. This proportion of deaths was the general experience during 2020, when the highly vulnerable members of the population died.

Of those who died:

Average (median) blood level of vitamin D was 15.8ng/ml, 39.5nmol/L.

Of those who survived:

Average (median) blood level of vitamin D was 17.3ng/ml, 43nmol/L.

Those who survived had on average a slightly higher blood vitamin D level than those who died, in keeping with other studies, but the difference was not dramatic. The difference did not achieve "statistical significance", meaning that it could have been a chance finding. Whether or not there is clinical significance is a matter of judgement, a balance of potential benefits and risks of using or not using Vitamin D in clinical practice.

Statistical significance is influenced to a major extent in sample size. In investigating the effect of Vitamin D in Covid-19, it is operationally difficult to use a large sample size, unlike a pharmaceutical trial in a sample of normal people in the community.

More detail is shown in Figure 5. Look at it carefully to see which green columns (died) were higher than the blue (survived).

Figure 5. Covid-19 survival or death and Vitamin D

We can see that the chance of death is greatest in those with the lowest blood levels of VItamin D, but also in those with the highest. 

Severe disease

The infuence of Vitamin D on severe Covid-19 was expressed as Odds Ratio, the relative chance of developing severe Covid-19 based on blood level of Vitamin D. The reference was a blood level of 20–30ng/ml, 50–74 nmol/L, as considered to be middle of the range found in the general population.

The odds ratio for severe disease:

for Vitamin D 20–30ng/ml, 50–74 nmol/L OR=1 (reference)

for Vitamin D <10ng/ml, <25nmol/L OR=2.37

There is no surprise here: severe disease is much more likely in those with the the very low blood levels of VItamin D, less than 10ng/ml, 25nmol/L.

The study therefore identified something expected. But there is more to consider.

High blood VItamin D

There were 18 patients with Vitamin D greater than 40ng/ml, 100nmol/L. For these the odds ratio of severe Covid-19 was high, with OR=4.65. This was an unexpected finding.

We know about Vitamin D "intoxication", hypervitaminosis D, in which excess Vitamin D causes an increase in the amount of calcium in the blood and in the urine. This can occur only with very high blood levels of Vitamin D, greater than about 200ng/ml, 500nmol/L.

But in this study there was no hypervitaminosis D, as judged by high calcium level in the blood, but we do see a disadvantage of a blood Vitamin D level just greater than 40ng/ml, 100nmol/L.

The report is of quadruple (OR=4.65) the risk of severe Covid-19 in this group with Vitamin D level >40ng/ml, 100nmol/L compared to the reference range of 20–30ng/ml, 50–74 nmol/L.

An explanation

This finding came as a surprise to me as this result has not appeared in other studies. Is it just a chance finding, a sort of mistake? All findings need to be replicated before they are generally accepted, or there must be a plausible mechanism, some connection that makes sense. But initial findings such as this must not be dismissed.

The paper from the study looked into a plausible explanation. 

We must remember that Vitamin D produced in the skin or taken by mouth must be converted in the liver into 25(OH)D, the form which it circulates in the blood. 

In response to infection and to enable immune response, 25(OH)D is taken up by the immunity cells and is activated into 1,25(OH)D, which then unlocks VDR. A molecule of 1,25(OH)D can be used only once, and then it is converted into the inactive 24,25(OH)D.


 

25(OH)D is converted into the active 1,25(OH)D by the enzyme 1-alpha hydroxylase. Now, it appears that when the blood level of 25(OH)D increases above 40ng/ml, 100nmol/L, "Fibroblast Growth Factor 23" (FGF23) is induced, and this leads to the suppression of the enzyme 1-alpha hydroxylase. Activation of 25(OH)D to 1,25(OH)D will thereby be suppressed, and as a result there will be a diminished immune response.

This is a perfect example of the interaction of enzyme systems,  feedback control mechanisms, that became essential in evolution. The inactivation of 1,25(OH)D to 24,25(OH)D is an excellent example of an essential control system, and the suppression of the enzyme 1-alpha hydroxylase would be another.

Free and bio-available Vitamin D

Other Vitamin D parameters were investigated in the Liverpool study. When we assess blood levels of Vitamin D we measure it in its form that has been processed in the liver, 25(OH)D (also known as calcidiol or calcifediol). This is carried in the blood as a reserve, ready for use as and when necessary. In the blood it is bound to a specific Vitamin D Binding Protein (DBP), the amount of which can vary from person to person. This is because DBP is genetically determined, and the gene penetration is variable, determined by genetic polymorphisms, differences. The vast majority of 25(OH)D is bound to DBP and only 0.03% of it "free", unbound. Did this make a difference? 

This was investigated  and it was found that there was no relationship between DBP, and free D with mortality. Measuring 25(OH)D seems to be a satisfactory way to assess Vitamin D status.

Conclusion


The pandemic of Covid-19 has given huge research opportunity to investigate the optimisation of natural defensive immunity, with the role of Vitamin D based on extensive research during the previous forty years. 


Taking together the Israel and Liverpool studies, we can conclude that to minimise severe or fatal Covid-19 it is necessary for the blood level of Vitamin D to be between 30ng/ml, 75nmol/L and 40ng/ml, 100nmol/L.


It is clear that it is necessary to monitor regularly the blood level of Vitamin D so as to determine the optimal dose. 


We must monitor the blood parameters when correcting Vitamin D deficiency just as we monitor blood parameters when we treat diabetes and thyroid disorders.



I have noted many Comments. I have attempted to reply to them, but unfortunately, and for reasons that I do not understand, my replies do not attach. Sorry about this.



Friday, 4 February 2022

Covid-19 : How much Vitamin D do we need ?

How much Vitamin D should we take?



It is as well to go back to the beginning. 

Emergence of rickets

Rickest was perhaps the first disease of industrial civilisation.

During the 19th century it was clear that the childhood bone disease rickets was very rare, probably unknown, in the coastal communities of Scotland and the mountain communities of Austria, but it became increasingly common in the industrial cities. It was realised that the heavily polluted atmosphere was the cause, but what could be the treatment? Going to live in the mountains of Austria was not a realistic proposition for those living in cities. Similarly the population of Glasgow could not relocate to the coast.

So it was important to identify the factors of living on the coast, or in the mountains, that could somehow be brought to the populations of the cities. In Austria, children affected with rickets and tuberculosis (they often co-existed) had go to mountain fresh air, and as it turned out, the Sun shining out of clear air.

In the coastal communities of Scotland, cod liver oil was the answer. The fact that its active ingredient was unknown was not important: empiricalism was fine. It was obvious from observation and experience that cod liver oil could heal rickets and improve health. No more information was required. There had been no 'Randomised Controlled Trials', but large numbers of informal observations. The dose was ill-defined, just a spoonful a day.

The important thing is that in both Scotland and Austria it was agreed that the cause of rickets was atmospheric pollurion and indoor work, with little exposure to the sun..

Identification of Vitamin D

It was in the early 20th century that chemistry advanced to allow an analysis of cod liver oil, extracting the active ingredient. It was tested using laboratory mice. The amount of Vitamin D was so tiny that it could not be weighed and so it had to be measured by its biological effect. This was not easy and there had to be an international standard that would be equivalent to defined weights. It was decided and accepted that one unit of Vitamin D was the amount that was necessary for the optimal growth and apparent health of a ten gram immature mouse. Because it was accepted by all, it was called an International Unit, iu. 

It was much later that it became possible to measure Vitamin D by weight. The mass of one unit was found to be 20 billionths of a gram, a very tiny amount.

We can scale up from the mouse. If one unit is the requirement of a ten gram mouse, a sixty kilogram human would require about 6,000 units. 

This is a good starting point. Basing the dose of a Vitamin D supplement on body weight is sensible, 100 units per kilogram per day. 

Recomendations from the UK Standing Committee on Nutrition (SACN) tells us that the recomended dose of vitamin D supplement is 400 units each day. This is based on the need to avoid rickets in children. Bone health is a steady state process, very different from escalation of defensive immunity. SACN only suggests that Vitamin D might have a role in immunity but is hardly convinced of this.  Perhaps in the interests of caution, half the mouse equivalent dose might be adequate, 3,000 units each day for a 60kg person, 5,000 units each day for a 100kg person.

The need for monitoring and adjustment of dose

There is obviously variation in the need for individuals and so follow up assessment is necessary.. 

It is the same with insulin (discovered in 1922). The starting point for the dose is one unit per hour, the amount normally produced by the body. Once again insulin, identified at about the same time as Vitamin D, is measured in bilogical units, still maintained even though insulin can now be measured by mass.

 For convenience and because of the short half-life of insulin, 24 units per day is usually given as 8 units three times a day, or 16 units in the morning and 8 units in the late afternoon. 

Adjustments are made to meet the requirement of the individual as monitored by blood testing of blood glucose or HbA1c. There is no value in monitoring the blood levels of insulin as the effect of insulin is so variable. Type 2 diabetes is mainly due to insulin resistance, something not well-understood but which reduces the effect of insulin. In Type 2 diabetes blood levels of insulin are usually increased in that we are dealing with resistance not deficiency. The body's production of insulin increases in an attempt to overcome resistance, but the maximum production can be reached before this occurs and so diabetes develops.

There is also a variation of effect of Vitamin D, but this is quite rare and results from genetic variations in the structure of the Vitamin D Receptor, VDR polymorphisms. The way to assess routinely the appropriate dose of Vitamin D is to measure the amount of it circulating in the blood. But in doing so we do not measure, cholecalciferol, Vitamin D itself.

Vitamin D within the body

Most of our Vitamin D is produced in the skin by the action of UV from the sun on the oil 7-dehydro-cholesterol (7-DHC) that is synthesised in the skin (exceptin the very elderly.

When Vitamin D is produced in the skin, taken by mouth, or given by injection, it is taken in the blood to the liver. It then undergoes a slow conversion (by the addition of an -OH group) to 25(OH)D, also known as Calcidiol or Calcifediol. This is the important form of Vitamin D which is the reserve circulating in the blood, like petrol or deisel in the fuel tank of a car, or charge in a battery. 




Figure 1, Pathway of Vitamin D activation and action

25(OH)D, a simple and accurate term, is carried in the blood bound to specific protein, called of course D-binding protein (DBP). 

Genetic variations – polymorphisms

LIke all proteins DBP is synthesised in the body from a template that is genetically encoded. It is in our genes, and with all genes mutations (chemical errors) can occur. When mutations are compatible with life they can become a variation within the species. They are then called 'polymorphisms', different forms. But they might still give a disadvantage, and of course mutations are millions of times more likely to give a disadvantage rather than an advantage. In the reasonably well recorded history of humankind during more than two millenia, has there been a single advantageous mutation? There have certainly been millions of mutations that have been incompatible with life or causing serious disadvantage.

If there is a DBP polymorphism, the blood level of Vitamin D measured in its circulating form of 25(OH)D will not be able to give an accurate assment of Vitamin D status, causing the blood level to be inevitably deficient. This is however rare but is likely to encountered by a Vitamin D clinical specialist.

In practice the blood level of VItamin D as 25(OH)D is used as a measure of Vitamin D status, determining whether an individual is or is not deficient. It is also used to determine the appropriate dose of a supplement to correct Vitamin D deficiency.

'Ideal' or 'normal'?

In the treatment of diabetes, or thyroid disorder (over- or under-activity), or hypertension, or body weight, we do not just give a single dose of a tablet or injection, or diet to all, but we define an ideal target. We aim at an ideal blood glucose or HbA1c, or T4 and TSH, or blood pressure, or body weight. And so it is with Vitamin D. With all the ideal is identified by careful clinical observation.

It is better to use the term 'ideal' rather than 'normal'. 'Normal' is based on an average with the population distributed reasonably evenly on both sides of the average. But if most people are obese there will be a skew, and average 'normal' weight will be excessive, not ideal. We must aim for 'ideal', that which gives the greatest health advantage.

The extent of VItamin D deficiency

Most people have blood levels of Vitamin D that puts them at a disadvantage. The has been shown in many studies before and during the Covid-19 pandemic. An example is a population survey in Germany in 2015. 

Figure 2. Vitamin D status in Germany

We can see in Figure 2 the result of a population sample study undertaken in Germany in 2015. There is an obvious 'skew' in the distribution. We can see that only 11.8% of the sample had a blood vitamin D greater than 75nmol/L, which is 30ng/ml. More than half had a blood level less than 50nmol/L, which is only 20ng/ml.

The solid red line represents the threshold: research during the pandemic has shown us that lower vitamin D levels are associated with a increased risk of serious Covid-19m whereas above this threshold the risk of serious illness is very low. 

The dotted red line represents 100nmol/L, which is 40ng/ml. This should be the safe target blood level.

A recent study in Israel observed 1176 people admitted hospital with Covid-19 and of whom 253 in retropect were found to have records of previous blood levels of Vitamin D. 

Figure 3. Blood levels of Vitamin D in Israel

Once again we find that half the group of patients had blood levels of Vitamin D less than 20ng/ml, 50nmol/L.

The serious disadvantage of Vitamin D deficiency

I have reviewed the findings of this study from Israel in a previous Blog post. If we look at the patients who were critically ill with Covid-19 we can see a summary of the findings of the study.

Figure 4. Blood levels of VItamin D predicting severity of Covid-19


It shows what previous studies had shown, that patients with critical or fatal Covid-19 almost entirely had low levels of Vitamin D. We can also judge the blood level of Vitamin D that appears to be 'safe', like a safe blood pressure or glucose. This can only be judged by careful observation, as in Israel. The role of observation has been repeatedly trivialised during the pandemic (apart from in vaccine assessments), but science is based on careful observation.

Observation tells us that a blood Vitamin D level above 30ng/ml, 75nmol/L, is perfectly safe and reduces considerably the risk of critical or fatal Covid-19. To aim at the range of 40 to 60 ng/ml, 100 to 150 nmol/L is wise, to make certain that we have a full reserve. Various studies, including that from Israel, have shown no cases of Vitamin D excess.

We can also see from the study in Israel that very few people have a blood level of Vitamin D greater that 30ng/ml, 75nmol/L, despite living in a very sunny country. Vitamin D deficiency is very common, 50% in this sample, remembering that the blood testing was well in advance of the illness.

The present definition of Vitamin D deficiency

Vitamin D deficiency should be defined as a blood level less than 30ng/ml, 75nmol/L. It has previously been defined as less than 10ng/ml, 25nmol/L but this was based on the prevention of rickets, not on optimisation of immunity and protection against serious infection. As mentioned above SACN, the UK Standing Advisory Committee on Nutrition, does not acknowledge the pivotal role of Vitamin D in defensive immunity, just mentioning that there is a 'suggestion'. I hope that during the pandemic of Covid-19 SACN has learned as much about the importance of Vitamin D as I have learned.

There is sometmes the expression of 'Vitamin D insufficiency', meaning somewhere between deficiency and adequacy or ideal. 'Insufficiency effectively  means little reserve, a situation best avoided if possible, whether Vitamin D, fuel in the car, money in the bank. When setting out on a car journey it would be unwise to have an insufficiency of fuel.

I have used the analogy previously of the motor car and the importance of a full tank of petrol or diesel, or a full battery charge, when setting out on a long and uncertain journey. And so it is with Vitamin D during our uncertain journey through life: we do not want to 'conk out' on the way, before reaching our expected destination.

The need for a constant supply of VItamin D

It is important that we have a fairly constant supply of Vitamin D so as to maintain the reserve of 25(OH)D, calcifediol, in the blood. This is difficult when we live closer to the North Pole than to the Equator, and especially with indoor work. Solar UV has little opportunity to produce Vitamin D in our skin.

We have seen that in temperate zones serious Vitamin D deficiency is common and serious illness can result from it. In the interests of the health of the public it would be sensible to screen for blood levels of Vitamin D and correct with appropriate supplement if deficient. Screening should certainly occur early in pregnancy so that no baby is born with Vitamin D deficiency.

This is the ideal but before we get to that point, a 60kg person living in temperate zones should take a supplement of Vitamin D 3,000 units daily, scaled up or down depending on body weight. Even if you are not deficient, taking this will be of no disadvantage.


Winter sun at 45 degrees north of the equator, but no Vitamin D production

















Sunday, 2 January 2022

Covid-19 & Vitamin D : Malaysia, Indonesia – Protease inhibitors

Can we learn anything from the experience of Malaysia and Indonesia?

Viral protease inhibitors



I have been following the Covid-19 pandemic in Malaysia as I have visited this country on several occasions. It is a good example of a country very close to the Equator, and by contrast the UK is closer to the North Pole than to the Equator.

Quiet in 2020

While the UK and Europe were experiencing large numbers of cases and deaths from Covid-19 during early and late 2020, all was quiet in Malaysia (population 32.7 million, see Figure 3) and neighbouring Indonesia (population 273.5 million), even though they are very close to China, the epicentre of the pandemic. 

In the UK, the high numbers in early 2020 diminished as expected in the Spring and Summer, as a result of the production of vitamin D in our skin with the mid-day Sun being more than 45 degrees above the horizon. This gives the ambient sunlight a sufficiently high energy to break the specific intramolecular bond in the 7-dehydrocholesterol (7-DHC) molecule synthesised in the skin so as to form Vitamin D (see Figure 1). 

Figure 1. Action of UV on the molecule of 7-dehydrocholesterol (7-DHC)


Figure 2, below, shows how the pandemic in the UK settled during mid-2020, under the influence of Vitamin D produced in the skin.

Figure 2. UK: Covid-19 cases each during 2020 


At the Equator, UV from the Sun has high intensity all the year round, giving those who live there the opportunity for adequate vitamin D production with subsequent optimal immunity and health advantages. This was the most obvious and most simple explanation for the low numbers and deaths from Covid-19 during the early part of 2020, despite the close proximity to China. However this did not continue and Covid-19 cases increased rapidly in late 2020. This must be regarded as the arrival of the virus, as there are no solar seasons close to the equator.

Figure 3. Malaysia  – Covid-19 cases per day 2020


Adjacent Indonesia (Figure 4) showed a similar pattern during 2020. In relationship to populations size, the cases in Malaysia were much higher than in Indonesia. The reason for this is not obvious.

 

Figure 4. Indonesia  – Covid-19 cases per day 2020


Note in Figure 3 that in late 2020 there was a maximum of 2,250 cases per day in Malaysia. We can regard this as "quiet", especially if we display it in the same scale (Figure 5) that will be used for 2021 (Figure 6).

Figure 5. Malaysia  – Covid-19 cases per day 2020
(same data as Figure 3, but different scale)


2021 was very different 

The early months on 2021 continued to be "quiet" in Malysia, Covid-19 case numbers reaching a maximum of about 5,000 per day. However during the latter part of the 2021 there was a considerable increase in cases to 22,500 per day (Figure 6).

Figure 6. Malaysia – Covid-19 cases each day in 2021



Covid-19 deaths had been very few in Malaysia during 2020 and early 2021, but there was a very rapid increase during the middle of the year (Figure 7). 


Figure 7. Malaysia – Covid-19 deaths each day in 2021

The reason for this was not obvious. With Covid-19 cases being so low for more than year, why was there was such a dramatic increase in June 2021? What happened immediately before the increase that might have caused it?

The answer is a major vaccination programme, starting at the beginning of June 2021 (Figure 8).


Figure 8. Malaysia – vaccination initiative starting in early June 2021


The vaccination initiative was similar in Indonesia (Figure 9), but more gradual as the country is much larger and widespread than Malaysia.

Figure 9. Indonesia – vaccination initiative starting in early June 2021


We are seeing what also occurred in many if not most countries of the world, a large increase of Covid-19 immediately following the onset of a large vaccination initiative.

Reason for Covid-19 increase following vaccination initiative

Why might a vaccination programme cause such a surge in Covid-19 cases? Some people might regard it as a direct "poisoning" effect of the vaccines, with damage to immune mechanisms, but I suggest an alternative explanation which would be readily reversible. It all depends on the vitally important role of VItamin D, which appears to be understood by very few people, including our officials.

To recap: most of our Vitamin D is produced in the skin from synthesised 7-DHC. Otherwise it is taken by mouth, or it can be given by injection. However it all passes in the blood stream to the liver. Here it undergoes slow hydroxylation to form 25(OH)D, which is the important reserve circulating in the blood. It is also known as calcidiol or calcifediol. When required for immune escalation, this is taken into the immunity cells and further hydroxylated to its active form 1,25(OH)D, calcitriol.


Figure 19. Vitamin D and its essential role in defensive immunity

I have discussed this in a recent Blog post. The vaccination induces an intense inflammatory immune reaction, which involves activation of T-cells and other cells of immunity. It requires the appropriate nuclear genes to be switched on, and for this the intracellular heterodimer VDR–RXR must be activated. And what is essential for the activation of VDR specifically? Vitamin D in its own fully activated form 1,25(OH)D, calcitriol. 

We need a full tank

We never know when we are going to encounter a serious infection, such as Covid-19, but when we do it is essential to have a good reserve of vitamin D as 25(OH)D in the blood. This will be required to activate the defensive immune response. 

It is like a car journey. If we are setting out on a long and uncertain car journey it is both sensible and indeed essential to have a full fuel tank. If not there is a danger of "conking out", coming to a halt in the middle of nowhere, or possible on a busy motorway.


And so it is with Vitamin D. If we encounter a serious infection and we have a low reserve of Vitamin D in the blood, there is a danger of critical illness or death. We can "conk out" in just the same way as the car with an empty tank. Unlike a car, we do not have Vitamin D level indicator, but these days it is simple to have the blood level of Vitamin D tested.

We know the critical blood levels of Vitamin D. Experience from Israel has confirmed previous experience that a blood level greater than 40ng/ml (100nmol/L) is safe, a full reserve. On the other hand a level of 20ng/ml (50nmol/L) is very low, and there is a risk of danger ahead.

Fuel, power, and Vitamin D comsumption

There is another analogy. When driving a car on a long journey it is essential to have a full tank because fuel can only be used once. When it has been used (combustion) all that remains is exhaust gases. There is a limit to the number of miles or kilometers to the gallon or litre, or to a full battery charge. When diesel, petrol or battery charge are consumed, the tank must be refuelled or the battery recharged. 

Fuel/power consumption is low at steady state "Green" speeds, but it increases when the car is driven faster (fuel consumption is high at low speeds as inefficient low gears are used). In a similar way, Vitamin D comsumption is low when we are in steady state good health, but when we are ill, when disease is actve, Vitamin D consumption increases to enable defensive immunity. 

Figure 20. Fuel consumption related to car speed


A constant amount of Vitamin D as the circulating 25(OH)D is essential to supply its intracellular activated form 1,25(OH)D, which links to and activates VDR (Vitamin D Receptor). The VDR–RXR dimer switches on appropriate genes, but it also automatically stimulates the enzyme 24-hydroxylase. This is safety mechanism that converts 1,25(OH)D into 24,25(OH)D. This is an irreversible process and 24,25(OH)D is inactive. a molecule of vitamin D can only be used once. 


Figure 21. Vitamin D molecule can only be used once

This a success of evolution. If 1,25(OH)D were to remain active, then during an immune escalation the level of 1,25(OH)D would build up to toxic levels. The enzyme 24-hydroxylase ensures that this does not happen. However it necessitates a constant supply of vitamin from the skin or by mouth, and a large reserve of 25(OH)D in the blood to iron out as much a possible natural fluctuations of Vitamin D production during the year.

Vitamin D deficiency in Malaysia and Indonesia

It might be thought that people living in Malaysia and Indonesia, both on the equator, have good reserves of Vitamin D with all year round production of it. But not so. 90% of babies born in Indonesia are deficient of Vitamin D, and this represents the Vitamin D status of their mothers. During childhood Vitamin D levels increase as a consequence of exposure to the Sun. but this is constrained in adult life.

Generally people in hot tropical countries avoid the Sun as much as possible. . But it is important to remember that Malaysia and in particular Indonesia have very large Muslim populations, and skin cover by clothing  is carried to extremes. UV from the Sun does not penetrate most clothing, and so Vitamin D deficiency is inevitable. 

Vitamin D deficiency and Covid-19 vaccination

How many of the populations of Malaysia and Indonesia develop mild or subclinical Covid-19 during 2020 is unknown, but they must have encountered the vaccination programme when generally deficient of Vitamin D. The intense immune response following vaccination (and it definitely is intense as judged by the high frequency of mild and transient symptoms) will have consumed a great deal of Vitamin D, but the quantity involved is unknown. As far as I am aware there has been no research so far on the effect of vaccination of blood levels of Vitamin D. 

Figure 22 illustrates what will be happening. Vitamin D will be sunsumed by vaccinations, and at this time of the year without natural replenishment. The blood level of Vitamin D will inevitably go down and might reach critically low levels – unless a Vitamin D supplement is taken (dose about 4,000 units daily).

Figure 22. Illustration of the effect of vacc=inations on VItamin D

The mass vaccinations must have resulted in mass serious and critical Vitamin D deficiency. The immune process cannot happen without consuming Vitamin D. In fact without adequate Vitamin D the vaccinations could not have given the expected level of protection against Covid-19 – the level and duration of protection has been much less than anticipated, hence so many cases among the vaccinated.

Viral protease inhibitors

The peaks obviously settled, as they always do. But here we see a difference between Malaysia and Indonesia.

In Malaysia the decline of cases and deaths dropped but not completely. There is a continuing steady state of 3,000 to 4,000 cases per day, and 20 to 40 deaths per day.

On the other hand in Indonesia there are many fewer at 100 to 200 new cases each day and only about 10 deaths each day.

Figure 23. Malaysia & Indonesia Covid-19 cases per day –
 the endings of the peaks


This difference is interesting. I can think of only one plausible answer and that is the additional therapeutic intervention in Indonesia. I am not aware of Vitamin D supplements being given to the population, but apparently Ivermectin therapy was adopted in Indonesia on September 1st 2021. This went against the advice of the WHO, but it was based on the experience of several countries in the east which had good results from Ivermectin, together with much published evidence. 

Ivermectin

I have not followed the Ivermectin story in detail and I am by no means an expert on it. It appears that Ivermectin is "controversial" and it seems to be clear that there has been a successful and co-ordinated mis-information campaign against it. A meta-analysis of 74 papers evaluating Ivermectin showed benefit in 71 of them. I suspect that most informed people accept the value and safety of Ivermectin within its recommended dose, but very few people are informed. This has been the problem during the Covid-19 pandemic: we have not been supplied with much information, just sound-bites. 

The most absurd and desperate reason to be vaccinated against Covid-19 came from the UK Prime Minister Boris Johnson as reported in the national press on Christmas Eve:


Among other properties, Ivermectin is a viral protease inhibitor, which makes it effective against a number of mammalian parasites, including viruses.

Pfizer has developed its own viral protease inhibitor, during development known as PF-07321332, and unofficially as "Pfizermectin". On December 23rd 2021 it received an Emergency Use Authorisation (EUA) from the US FDA. It is now called Paxlovid.

Now we see why Ivermectin has been ridiculed and buried. Patients with Covid-19 have been told officially that there is no treatment available. They have been denied treatment with Ivermectin 12mg per day for five days from the onset of symptoms. 30 years experience has shown an excellent safety profile of Ivermectin in the correct dose. 

The EUA for Paxlovid was given on the "understanding" that there were no other treatments available for Covid-19, hence the essential denial and burial of Ivermectin. 

Exactly the same thing happened with Vitamin D, official denial that it might be of any benefit so that EUAs could be granted for the vaccines.

The main problem with both Vitamin D and Ivermectin is that they are too cheap. There is no big money to be made, unlike with vaccines and Paxlovid, which will be sold at several hundred times the price of Vitamin D and Ivermectin.

Perhaps it is true to say that the Covid-19 pandemic has been an exercise in transfering money from the poor (the great majority of us) to the very rich. In the process there have been many avoidable deaths and undue pressure being put on the hospitals.

Vitamin D consumption

But the most important thing at present is the rapid escalation of cases, especially on North America and Europe. My interpretation is that the undoubted intense inflammatory immune response to the vaccinations is inevitably consuming Vitamin D (Figure 22). The resulting immune deficiency is driving the increase in cases, which although usually mild will consume even more Vitamin D, and so we can expect infections of all sorts to become more frequent. This is particularly important during the winter months as it will be a few months before we start to produce Vitamin D.

New York has experienced a cluster of tuberculosis. This infection is well-established as developing when immunity is suppressed, as in AIDS, but also resulting from Vitamin D deficiency.

There is every medical reason why Vitamin D should be used extensively at the present time, especially if vaccinations are being given increasingly and at shorter intervals.

Vitamin D is needed now.



Figure 24: Covid-19 cases per day UK & USA at the end of 2021