Nutrition to reduce COVID-19 serious harm and death

For the Stagi et al. 2015 article on Kawasaki disease and vitamin D: #2015-Stagi.

Different observations show the same relationship between low vitamin D and severe COVID-19, although here the vitamin D blood level is on the vertical axis:

While I share the authors' serious concern about these low levels, I am opposed to fortifying food with vitamin D because it cannot achieve the ~50ng/ml 125nmol/L 25OHD levels we need, because it may give a false sense of security and because all government efforts which might to into food fortification would be better directed at encouraging and supporting everyone to robustly supplement with vitamin D3, all year round, with perhaps less in summer - while avoiding excessive (sunburn creating) UV-B exposure: https://vitamindstopscovid.info/01-supp/

Quick intro

Vitamin D supplementation guide - especially concerning COVID-19

Mother Nature's crossover trial of summer and winter vitamin D levels

The case for worldwide vitamin D supplementation

For links to the latest research into vitamin D, immunity and COVID-19, please see the next section AND the new website https://VitaminDStopsCOVID.info .

See also the section #vaccines below where I argue that a COVID-19 vaccine is absolutely the wrong approach. It doesn't even solve the right problem. This virus is not the problem. The problem is people's weakened and dysregulated immune systems - and this already causes far more trouble than COVID-19 would cause even if everyone in the world contracted the disease with their currently generally weak and dysregulated immune responses.

The most concise, well-referenced, business and moral case for an urgently implemented worldwide program of vitamin D supplementation is Karl Pfleger's frequently updated essay. This was written and is maintained entirely independently of this aminotheory.com material - so the vision of supplementation it presents is not the same as what I am proposing.

Low Vitamin D Worsens COVID-19
http://agingbiotech.info/vitamindcovid19/

While high vitamin D levels may protect somewhat against infection, this is insignificant in the face of the highly contagious SARS-CoV-2 virus.

The first critical point is that vitamin D deficiency is the most important, easily correctable, cause of the immune system weakness and dysregulation which drives COVID-19 harm and death.

The second critical point is that vitamin D deficiency is the most important, easily correctable, cause of high rates of viral shedding and so of rapid spread of SARS-CoV-2 infection.

A worldwide program of vitamin D repletion can reasonably be expected to play a decisive and essential role in improving everyone's immune system health, so as to render COVID-19 at most a nuisance, and (except perhaps for a some people with lung injuries or other severe health conditions) no longer the serious, disastrous, cause of suffering, hospitalisation, harm and death which it is today.

Population-scale vitamin D supplementation can and should be implemented sooner than any safe, effective, well-tested vaccine could be widely deployed, with much greater safety , greater health benefits, and lower cost.

You are reading a very long web page which has grown since late March. Here is my attempt at summarising the urgent need for worldwide vitamin D supplementation, aiming for all babies, children, adolescents and adults to have 40 to 60ng/ml vitamin D levels, with no great concerns that some people's levels will be twice these.

There is a growing body of epidemiological, clinical and cellular evidence which shows that low vitamin D levels are a major cause of the weakened and dysregulated (overly-aggressive, hyper-inflammatory, self-destructive) immune responses which, in some people, cause the severe symptoms of COVID-19, including the endothelial cell (blood vessel lining) damage which causes the body to make the blood thick and hyper-coagulative. This hypercoagulative state drives most of the resulting damage, with microembolisms (tiny blood clots) forming in the lungs, brain, heart, liver kidneys etc. along with heightened risk of large blood clots in the brain (stroke) or the coronary arteries (heart attack). Lasting harm and organ damage typically results from this hypercoagulative state, which sometimes begins even in the presence of relatively mild symptoms.

For decades, a growing body of research has documented the global vitamin D deficiency pandemic. Since 2008 vitamin D specialist researchers and MDs have recommended that everyone should try to attain vitamin D blood levels (25 hydroxy vitamin D, produced in the liver from ingested or UVB produced D3) of 40 to 60ng/ml (100 to 150nmol/L) all year round. 100ng/ml is considered the the high end of normal, but some people are perfectly healthy - indeed with healthier regarding reductions in asthma and other diseases - with higher levels. Toxicity - hypercalcemia which damages bone and blood vessels - bone is possible above 150ng/ml but is most likely to begin at higher levels still.   Such levels cannot be attained through sun or artificial UVB light exposure.

Without supplements most people's year-round average 25OHD levels are in the 10 to 25ng/ml range and are lower still in winter. The best estimate we have of the 25OHD levels of our ancestors is 46ng/ml - the average levels of traditionally living East African Maasai herders and Hadzabe hunter gatherers: https://www.ncbi.nlm.nih.gov/pubmed/22264449 . The internal (autocrine) signaling systems of many of our cells evolved to work with this supply of 25OHD.

As you can read below, some groups of people have 25OHD levels disastrously below 10ng/ml. Yet UK government standards state that 10ng/ml is an adequate level and many other countries, including the USA define vitamin D repletion as 20ng/ml 25OHD. The UK and US recommended supplemental D3 intake for adults is 0.01mg (400IU) and 0.015mg (600IU), which are about a 10th of what normal weight adults, on average, need to attain 40ng/ml.
The Endocrine Society's standard for repletion is 30ng/ml.

Food - including fortified foods and drinks - and multivitamins contain only small amounts of vitamin D. Pharmaceutical grade vitamin D3 (cholecalciferol) is produced industrially mainly in China and India. The ex-factory 1kg lot price is around USD$2.50 a gram. 0.125mg (5000IU) a day is sufficient to raise most normal weight adults' 25OHD levels to at least 40ng/ml. At this rate, a gram lasts for 22 years. So raw cost of this healthy level of supplementation is USD$0.12 a year. D3 need only be taken every week or two, so it would suffice to supply it as 52 capsules a year, each containing 0.875mg (35,000IU). Babies and children need less, according to body weight. Overweight and obese people need significantly more due to their greater body weight and because D3 is absorbed by their greater proportion of adipose tissue.

Ideally, all people would have ready and affordable access to their own personal doctor who advises them according to the best research, and who is able to order blood tests to monitor their 25OHD levels every year or two. However, this is impossible for all 7.8 billion humans, and the costs would vastly exceed those of the D3 supplements. Many doctors are either unaware of the best vitamin D research and/or are constrained by government, professional association, hospital and insurance rules and guidelines regarding 25OHD testing and the ideal blood levels and supplementation intakes they can advise for their patients.

Dozens of chronic and acute diseases are caused by weak and dysregulated (over-inflammatory) immune systems, as listed below.

One primary cause of immune system dysregulation is - with considerable genetic variation between individuals - that our immune systems evolved to be more aggressively inflammatory than is desirable, because our ancestors were all infected with helminths (intestinal worms), which produce a variety of compounds which downmodulate many immune responses. Now, with most humans being free of helminthic infection, some of our immune responses are self-destructive. For instance, patients with Crohn's disease (auto-immune destruction of the intestines) go into remission when infected with the relatively benign pig whipworm. #helminthsgone . Some people, such as those with life-threatening asthma, infect themselves (helminthic therapy) to obtain relief. There is ongoing research into pharmaceutical approaches to mimicking at least some of the helminths' downmodulatory effects, but commercially available products for this are a long way off.

The other primary cause of weakened and dysregulated immune systems is nutritional deficiencies - and, arguably, an excess of salt. Vitamin D deficiency is the best researched, most important and easiest to correct of these. Inadequate omega 3 fatty acids (as found in fish and algae oils) is probably the second most important, and can easily be corrected - though the quantities needed and the annual cost is much greater than for vitamin D.

Inadequate boron #08-boron is also known to drive overly inflammatory immune system dysregulation. Boron supplementation is widely used to treat arthritis, and boron, as borax, is appearing in some mass market multivitamins. However, despite decades of research showing its importance to humans, and its routine use in preventing bone and joint problems in pigs and other agricultural animals, according to conventional (textbook and nutritional guideline) understanding, boron has no role in the nutrition of animals.

Boron, as borax, is readily available, inexpensive and very safe to use in the 6 to 12mg per day range which would probably lead to repletion (there are no standards for this, yet) and significant health benefits over the typical 1mg daily intake of most adults.

Boron's half-life is ~22 hours, so small quantities need to be taken each day. 12mg a day would require 36 grams of borax per year, and it costs less than USD$0.01 per gram. Borax is a sodium oxygen salt of boron. Large deposits of this mineral are mined in Turkey and California, with relatively simple crystallisation purification at the mine site,

Despite the vast amount of vitamin D research, many doctors remain unaware of the benefits of repletion to at least 40ng/ml, or wary about such levels because of outdated and overly cautious concerns about toxicity. The pharmaceutical industry has no interest in promoting vitamin D, since worldwide repletion would greatly reduce the global burden of disease which drives most of its sales of high-profit, patented, drugs. Boron research is generally unknown to doctors and even to most vitamin D researchers.

Even in diseases where research has clearly established very low vitamin D levels to be a distinctive - and no-doubt largely causative - factor, including the childhood immune dysregulation disorder Kawasaki disease #2015-Stagi (now being triggered with much greater frequency by COVID-19), many doctors remain unaware #kdarticles that vitamin D deficiency is involved, so they fail to test or replete their patients' vitamin D levels.

Potassium deficiency, especially in the context of excessive salt, is a global problem which research shows beyond any doubt is the primary avoidable cause of hypertension and stroke kna/ .   Potassium supplementation is challenging because of the quantities involved - such as 2.5 grams potassium a day to approximately double the normal intake.   This is possible, at the cost of around USD$100 a year, with potassium gluconate solution, which has a very mild taste.   However I have never encountered a doctor who is aware of this. So many or most people my age (I am a 1955 model) take expensive hypertension drugs, all of which have significant ill-effects - and sometimes additional drugs to counter those ill effects. Potassium supplementation and modest avoidance of salt solves the problem of K / Na ionic balance in all cells of the body, removes the primary causes of hypertension and stroke, and provides numerous other benefits - no-doubt including immune system strength and regulation.

Iron is a well known nutritional deficiency, and many people are deficient in vitamin C, magnesium and zinc.   Here is a table of the five nutrients whose common deficiency most contribute to immune system dysfunction and general ill-health. A future website, to be known as Five Neglected Nutrients, will cover these in greater detail than is possible here.

Ideally we would replete all five, for all people on Earth, as a matter of urgency - and that was the situation before COVID-19. Since COVID-19 harm and death results only from a subset of the population having weakened and dysregulated immune systems (in combination wit genetic variation, obesity, advanced age and several comorbid conditions) it is absolutely imperative that governments and doctors work together to replete vitamin D and ideally some of the others, with an urgency which only occurs in times of war.

Nutrient	Medical profession knowledge of mechanisms of the nutrient's benefits, and so of the problems caused by deficiency. (Most doctors receive inadequate training in nutrition.)	Medical profession consensus on supplementation.	Practicality for global repletion in the coming months to render COVID-19 no longer a threat.
Vitamin D	Vast amount of research, yet not very well known except to a subset of doctors who are well aware.	General disinterest and some controversy - with a small, growing, number of doctors adamantly promoting vitamin D repletion for general health and protection from COVID-19 harm and death.	Practical, safe, inexpensive and absolutely vital for general health and for reducing COVID-19 severe symptoms and the rate at which the disease spreads. New D3 factories are urgently required.
Omega 3 oils	Good research on immune system benefits, though not very widely known.	General disinterest and some controversy - again with some doctors in favor. No controversy about safety - so should be used by all who have it available. Would surely help with COVID-19, but there is no research to quantify this.	Impossible to quickly scale up fish or algae oil production to meet needs of grams a day per 7.8 billion persons. 2g/day 6 billion adults = 4.4 million tonnes / year.
Boron	Good research, but precise cellular mechanisms not yet well understood. Not recognised as a nutrient. Most doctors have never heard of it, although it is used to reduce or prevent arthritis. See #08-boron .	Only a handful of doctors are aware of it. Would surely help with COVID-19, but there is no research to quantify this.	Readily available as borax, very inexpensive, safe and easy to ingest in water solution. However, doctor's general ignorance of this and widespread misconceptions about its toxicity make boron supplementation challenging in the short time frame we have to render COVID-19 no longer a threat.
Vitamin C	Very well researched and recognised.	Controversy about dosage, with some high dose protocols probably unnecessary for most people, while providing benefits for some. Dr Paul Marik's 10g/day IV vitamin C MATH+ protocol for ICU patients, including especially those with COVID-19, remains controversial despite obvious benefits.	Production could be increased somewhat, but I suspect it would be best to keep limited vitamin C in reserve for people who are COVID-19 positive so they can use multi-gram quantities a day and hopefully stop the virus from infecting their lungs.
Potassium	Excellent research on hypertension and stroke, but not widely known. Fundamental importance to ionic balance of all cells is well established, but not widely recognised by doctors. See kna/ .	Virtually all doctors and, as far as I know, most researchers assume that potassium supplementation is impossible due to the strong taste of the salts. They do not know about potassium gluconate's mild taste. Doctors are coached heavily in the dangers of excessive intravenous potassium supplementation since the body can only handle limited quantities at any one time. Overdoing it, including by drinking excessive potassium gluconate at any one time, will raise blood potassium too much before the cells absorb it and so cause potentially deadly heart problems.	No prospect of ramping up potassium gluconate for global needs except over many years. There are safety concerns with such supplementation being taken too quickly, so it needs to be spread throughout the day. These problems - and many doctors being alarmed at the prospect of patients drinking a potassium solution - mean that progress towards global potassium repletion needs to be made cautiously and not at all in the current crisis.

See also this article on vitamin B: https://www.maturitas.org/article/S0378-5122(20)30348-0/ .

The best, post-COVID-19, review article on vitamin D recommends 40 to 60ng/ml 250HD levels. It is co-written by Michael Holick MD, who has been researching vitamin D since 1971, and is the foremost vitamin D researcher, with Google Scholar reporting 129,193 citations of his articles:

Immunologic Effects of Vitamin D on Human Health and Disease
Nipith Charoenngam, Michael F. Holick 2020-07-15
Nutrients 2020, 12(7), 2097
https://doi.org/10.3390/nu12072097

From a 2019 article (24 citations):

Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience
Patrick J.McCullough, Douglas S.Lehrer, Jeffrey Amend
Journal of Steroid Biochemistry and Molecular Biology V189, May 2019
https://www.sciencedirect.com/science/article/abs/pii/S0960076018306228 (Paywalled.)
https://sci-hub.se/10.1016/j.jsbmb.2018.12.010

Vitamin D is essential for internal (autocrine) signaling in may cell types, including especially those of the immune system which both attack pathogens and regulate such actions:

The exact number of gene products controlled by vitamin D3 is unknown, but the active hormone form of vitamin D3 was recently found to bind via its receptor to 2776 distinct binding sites in a human cell line, many of which were located near autoimmune and cancer associated genes.

Both these articles list diseases for which vitamin D is a significant contributing cause (or at least of severe symptoms, as with COVID-19). The two lists combined result in:

Alzheimer’s disease.

Asthma.

Atopic dermatitis.

Autoimmune diseases such as Cohn’s disease, inflammatory bowel disease, multiple sclerosis, psoriasis, posoriatic arthritis, rheumatoid arthritis and ulcerative colitis.

Cancers including breast, colon, prostate, sarcomas and skin cancer.

Chronic pain.

COVID-19 - hyperinflammatory response.

Dementia = neurodegeneration.

Depression.

Diabetes types 1 and 2.

Epilepsy.

Falls, fractures and muscle weakness.

Fibromyalgia.

Hypertension.

Muscle pain and proximal muscle weakness.

Osteoarthritis.

Parkinson’s disease.

Pregnancy complications including premature birth and death.

Respiratory infection.

Rickets (Failure to develop strong bones in childhood.)
Osteomalacia (Softening of bones, mainly in children and young adults.)
Osteoporosis (Low bone density, mainly in old age.)

Schizophrenia.

Seasonal affective disorder.

Sepsis.

Tuberculosis.

Urticaria.

Vitiligo.

Wheezing disorders.

So there has long been an urgent need for global vitamin D repletion. COVID-19 makes it the most urgent and important step humanity can take to combat the disastrous severe complications which COVID-19 elicits in a substantial subset of the population whose immune systems are weak and dysregulated.

Latest research concerning COVID-19, immune system regulation, vitamin D and other nutrients

News and updates

Vitamin D basics:

Vitamin D in autocrine and paracrine signaling

Vitamin D and COVID-19 in 4.6 million Israelis:

Other pages here

Contents of this long page

Introduction

For an introduction written in late August, please see the 5th comment at: https://quillette.com/2020/08/27/covid-19-returns-to-new-zealand/ .

In general, people infected with COVID-19 only suffer serious harm, or are killed, due to their immune system being weak and/or being dysregulated - their immune response is overly-aggressive, proinflammatory, generally ineffective against the virus and most importantly, damaging to the self.

The same is true of influenza, but COVID-19 is much worse because it is highly infectious and - when the dysregulated immune system allows the virus to infect the lungs - the loss of ACE2 receptors there raises angiotensin II, which causes vasoconstriction of the pulmonary capillaries and a highly coagulative state, which leads to micro-embolisms and larger blood clots there and in other parts of the body. Both the vasoconstriction and the clots reduce the ability of the lungs to exchange oxygen and carbon dioxide. Without hospital care, including oxygen (though ideally not mechanical ventilation, which tends to make things worse), the patient will be seriously injured or killed through lack of oxygen.

Direct viral and/or dysregulated immune responses damage endothelial cells in the lung - and presumably elsewhere - and the body responds to this blood vessel damage by making the blood hypercoagulative. This hypercoagulative state drives most of the harm which results, with micro-embolisms and/or larger blood clots anywhere in the body, including the lungs, brain, spinal cord, heart, kidney and liver. This can lead to death via stroke, heart attack and kidney failure.

There are evolutionary reasons why our immune systems are dysregulated - as explained below, we (in developed countries) lack the helminths (intestinal worms) our ancestors had. Our immune system evolved to counter helminthic downmodulation of many immune responses. Without helminths, many of our immune responses are overly-inflammatory and self destructive.

There is also considerable genetic variation between individuals.

Finally, common nutritional deficiencies and excesses both weaken our immune system, and reduce its ability to regulate its potentially excessive actions. The focus of this web page, and others which lead from it, is to correct these nutritional problems - most importantly by way of vitamin D3 supplements. If all humans do this, then our general health will improve in many ways, and COVID-19 will cause us little trouble.

This is the only way we can deal with the threat of harm and death from COVID-19, and likewise with the rising incidence of numerous chronic and acute health problems which result from our generally weakened and dysregulated immune systems.

We can't stop the spread of the SARS-CoV-2 virus which causes COVID-19 illness. Antivirals have never stopped the spread of any virus. The common hope or expectation that a vaccine could stop it, by being proven effective and safe, and administered to most people in the world, is unlikely in any time frame - and impossible to achieve in the next few months or year.

It is likely that drugs will be developed which reduce the ability of the virus to replicate, and so cause serious symptoms. These will be welcome, but are unlikely to be tested and made available en-masse any time soon. It makes no sense to be using drugs like this while it is easier, safer and less expensive to improve our immune system's strength and ability to regulate itself by correcting nutritional deficiencies.

We cannot continue to contain the spread of the virus by lockdowns, social distancing etc. These measures have unsustainable social, economic and health costs. For now, we should certainly try to slow its spread - but only when most people's immune systems are working properly will it be possible to relax these constraints, and so let the virus spread without causing much harm or death.

Giving humans their proper operating conditions - at least regarding nutrition for general health and strong, well-regulated immune systems - is necessary for numerous other reasons (reducing asthma, neurodegeneration, inflammatory bowel disease, diabetes etc.) and is urgently needed so we can cope with COVID-19 without the twin disasters of widespread harm and death (as is occurring now) and of all the so-far uncounted costs, harm and death which results from lockdowns.

Even children can be affected, with the coronavirus causing their dysregulated immune system to attack the self in a pattern similar to that of Kawasaki disease. In pre-COVID research #2015-Stagi, it was shown all children with this disease were severely vitamin D deficient. The children with the lowest vitamin D levels had the worst outcomes - their vitamin D levels averaged about 1/10th of the levels of African herders and hunter gatherers.

So when children are now, tragically, harmed and killed by COVID-19 in ways which resemble Kawasaki disease, it is reasonable to assume that this is only occurring due to their extremely low vitamin D levels (no-doubt combined with genetic and other factors) - and (in the absence of evidence to the contrary) that their parents and treating doctors were unaware of the need to provide them with adequate vitamin D supplementation.

There is no reason to believe that there ever will be a vaccine which is effective against COVID-19. Immunity to coronaviruses after infection - or which might be elicited by a vaccine - may only likely to last a few years.   Vaccines can cause much worse symptoms in some or many people when the antibodies they raise attach to the virus and are recognised by receptors other than ACE2, which enables the virus to infect other types of cells. (Contrary to this gloomy outlook, see the research mentioned in points 1, 2 and 3 of this nymag.com article: people who test positive a second time are not infectious; SARS-CoV antibodies seem to be effective up to 17 years later and a SARS-CoV antibody is effective, in vitro, against SARS-CoV-2.)

SARS-CoV-2 will continue to mutate. We all have to live indefinitely with current and/or future strains. Fortunately, this virus does not cause serious trouble for people with properly functioning immune systems. Other viral diseases do - for instance smallpox, or ebola. We will be in serious trouble - no matter how good our nutrition and strong our immune systems - if a novel virus emerges which is as deadly as these whilst also being highly infectious.

Unfortunately, for various reasons - most of them spurious - most (but not all) doctors are excessively wary of nutritional supplements. This wariness is part of the reason we have such widespread vitamin D deficiencies. The official vitamin D guidelines are recognised by many researchers and some doctors as being woefully inadequate in terms of desired 25OHD levels and regarding maximum safe dosages of vitamin D3.

This global problem of inadequate nutrition will only be solved by people choosing to take supplements regularly. Ideally this would happen as a result of most or all doctors recognising that their guidance, which lead to the current disastrous situation, was wrong and that they need to accept and promote the regular use of nutritional supplements in quantities sufficient to make most people replete - generally without the need for medical supervision and blood tests, which are more expensive than the supplements themselves.

For instance, an adult taking 4000IU a day of vitamin D3 needs a gram every 27 years. The ex-factory, kilogram lot, price of pharmaceutical D3 is USD$2500. At that rate, the annual cost is USD$0.09 per year. All that is needed is a capsule or tablet a week, so 5,200 such capsules, with a total D3 cost of USD$10, and I guess USD$100 manufacturing cost, would be good for one adult for 100 years.

For various reasons - not all of them good - doctors are extremely resistant to changing their thinking.   In order to avoid a catastrophic continuation of the current harm and death, they will need to change their minds fast - since I can't imagine most people, with the support of their governments (to handle the logistics of obtaining and distributing the nutrients), achieving this level of supplementation without the support of most doctors.

Even if COVID-19 disappeared, we still need to give all humans their proper operating conditions as a matter of urgency, since the same nutritional problems, against a background of genetic variation, drive the growing burden of chronic and acute disease, including: diabetes, neurodegeneration (Alzheimer's, Parkinson's diseases etc.), hypertension, stroke, multiple sclerosis, inflammatory bowel disease (Crohn's disease and others), sepsis, osteoporosis and so on.

Here is a chart depicting vitamin D blood levels in relation to body weight and D3 dosage. The Kawasaki disease figures come from research before COVID-19 elicited a similar, deadly, condition in some children, especially in the UK. You can read below #2016-Caprio research which indicates that 40ng/ml is the minimum 25OHD level for proper immune system functioning. Yet some experts #21authors advise the public that they should supplement to attain merely 10ng/ml. This is very close to the 9.2ng/ml average 250HD levels of children with Kawasaki disease #2015-Stagi .

Other sites concerning Vitamin D, the immune system and COVID-19

Sometime in the future - a new website

Recent articles concerning COVID-19 vitamin D and other nutrients

Spanish Cordoba vitamin D (calcifediol = 25OHD) intervention trial provides dramatic reduction in COVID-19 severity and deaths

Iranian MDs in hospital in Dubai: ratio-based vitamin D recommendations, bolus doses and 25OHD levels above 40ng/ml resulting in COVID-19 hospital stays of no more than 3 days, with no need for intensive care and no deaths

Vitamin D3 bolus AKA loading dosing: 1.5mg (60,000 IU) D3 a day for 7 or more days greatly helps people with asymptomatic or mild COVID-19 overcome the viral infection

25plusD3 - my suggestion for a D3 & 25OHD calcifediol combination supplementation treatment for COVID-19, Kawasaki disease, Multisystem Inflammatory Syndrome, severe influenza and sepsis

Below, in this section, is a graph showing how rapidly oral 25OHD calcifediol raises blood 25OHD levels. See the following sections for where to get calcifediol - it is now available in Australia, the USA and Canada, online, without prescription, as 10 microgram tablets.

2021-05-02: DSM has released d.velop - non-prescription calcifediol, with online ordering for customers and the USA (before about September 2021, they also allowed delivery to Canada), in packets of 60 tablets, each of 0.01 mg (not 20 micograms, as I previously wrote - this is the serving size of 2 tablets). Each packet, which costs USD$30 including shipping contains 0.6mg of calcifediol - just over the 0.532mg which saved lives and greatly reduced the need for intensive care in the Cordoba trial (Castillo et al.).

This is excellent news, since there are millions of people suffering from COVID-19, and at serious risk of harm and death, whose illness could be reduced within hours and days by just one milligram or so of this oral calcifediol. No other compound can do what calcifediol does - raise 25OHD levels robustly in a few hours. All the details are at: https://vitamindstopscovid.info/04-calcifediol/ .

Here, and in https://vitamindstopscovid.info/01-supp/#25plusD3 I propose what I call the 25plusD3 protocol 25OHD (calcifediol) and D3 combination therapy approach, to be implemented without delay for all patients with severe, or potentially severe COVID-19 symptoms. I think it would also work better than any treatments I know of for severe influenza and sepsis.

Please note that the following is written by an electronic technician as a suggestion for what a good treatment protocol would be. However, the single dose of 0.014mg calcifediol per kilogram body weight was developed in consultation with Sunil Wimalawansa MD (retired professor of medicine, endocrinology and nutrition, at what is now Rutger's University, New Jersey) who writes about this at LinkedIn .

25plusD3 is simply the combination of the Han et al. D3 bolus protocol #2016-Han or continuing robust (e.g. 5000 IU/day for a 70kg adult) D3 intake, and approximately double the Castillo et al. 0.566mg 25OHD (on admission) Cordoba calcifediol protocol #2020-Castillo.

However, they complement each other and I believe that this 25plusD3 double whammy approach would be better still than either of them.   (The two plus the rest of the MATH+ would be better still - and I suspect the MATH+ use of corticosteroids could be reduced considerably with these two vitamin D dosage arrangements combined.)

From 2020-11-12, the highly regarded MATH+ protocol https://covid19criticalcare.com- the work of Dr Paul Marik and Colleagues also specifies the use of the exact same 25OHD calcifediol dosing as used in the Cordoba trial. This is the initial 0.532mg 25OHD calcifediol and then half this on days 3, 7, 14, 21 etc.

This is the preferred option for ordinary ward COVID-19 patients who need less than 4 litres of oxygen an hour. If the 25OHD calcifideol is not available, then either daily 0.25mg 10,000 IU D3 or a small bolus D3 (1.5mg 60,000IU) arrangement is recommended. However, only calcifediol can raise levels as required in a few hours. The bolus D3 is too small to achieve this for most people, and it takes days or a week or to to achieve its peak 25OHD level.   5000IU/day will take months to raise most people's 25OHD to at least 50ng/ml.

For such patients who need more than this amount of oxygen, or who are admitted to intensive care, the 2020-11-12 version of the MATH+ protocol recommends a substantial 12mg 480,000 IU D3 bolus. This will still take a few days to raise circulating 25OHD levels properly. 1mg calcifediol will do it within a few hours.

The following graphic is adapted from this version of the protocol.

Be sure to check with the https://covid19criticalcare.com site for the latest version, rather than relying on what I have written about it here at aminotheory.com .

After consulting with Dr Sunil Wimalawansa we agreed that a single dose of 0.014mg oral calcifediol per kg bodyweight will be highly effective in all circumstances and carry no risk of toxicity (unless the person was already near toxic levels due to ingesting completely excessive amounts of D3 for weeks or months). Please see Dr Wimalawansa's LinkedIn post about this and https://vitamindstopscovid.info/04-calcifediol/#hm . This is a single, urgent, attempt to replete someones circulating 25OHD - so we should do a proper job of it.

Sidebar: If I were a hospital director:

I would make a nuisance of myself giving both oral 25OHD and bolus D3 (or a set of capsules to take, one a week or so, for the month or two to follow) to every patient who entered the hospital who was had not already substantially supplementing with D3. I would do the same for their relatives and friends, with the intention that those relatives and friends wouldn't be turning up to my hospital as patients for anything like severe COVID-19 or influenza or sepsis (which is hard to recognise at first, always extremely serious and likely to be deadly).

Calcifediol alone does not provide the benefit (the magnitude of which I am not sure about) of D3 protecting endothelial cells [Gibson et al. 2015] which line our blood vessels.

The double-whammy terminology is inspired by the vitamin D hammer protocol of Gerry Schwalfenberg MD of Canada. Gerry is an MD with decades of experience, is one of the world's foremost vitamin D researchers and since 2009 has been an Assistant Clinical Professor at the Department of Family Medicine University of Alberta. We are most fortunate that he has joined the NISH list. He teaches and continues his private practice in Alberta, Canada. His article describing this protocol is:

Vitamin D for Influenza
Gerry Scwalfenberg MD, Canadian Family Physician, Vol 61, page 507, June 2015
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463890/

A colleague of mine and I have introduced vitamin D at doses that have achieved greater than 100 nmol/L [40ng/ml] in most of our patients for the past number of years, and we now see very few patients in our clinics with the flu or influenza like illness. In those patients who do have influenza, we have treated them with the vitamin D hammer, as coined by my colleague. This is a 1-time 50 000 IU dose of vitamin D3 or 10 000 IU 3 times daily for 2 to 3 days. The results are dramatic, with complete resolution of symptoms in 48 to 72 hours.

For an overview of 155 (2020-11-17) vitamin D bolus dosing arrangements, please see this page https://vitamindwiki.com/Overview+Loading+of+vitamin+D from Henry Lahore's nearly boundless VitaminDWiki. (Synonyms for bolus are loading and stoss.)

Here are the three vitamin D3 cholecalciferol bolus dosing arrangements just mentioned, all known to be beneficial and, within the limits of the experience and trials concerned, safe. I know of no reason to believe that any these could lead to toxicity except if someone was already at extremely high 25OHD levels - in which case they would probably not be having much trouble with COVID-19, influenza or sepsis.

Name / author	Per day	Days	Total	Notes
Vitamin D hammer Schwalfenberg 2015	1.25mg 50,000 IU	1	1.25mg 50,000 IU	Influenza.
Rastogi et al. 2020 #2020-Rastogi	1.5mg 60,000 IU	7 or more if required to reach 50ng/ml 25OHD.	10.5mg 420,000 IU	Initially asymptomatic or mild COVID-19.
Han et al. 2016 #2016-Han	2.5mg 100,000 IU	5	12.5mg 500,000 IU	Sepsis etc. ICU patients on mechanical ventilation. Half this amount resulted in a 25% reduction in hospital time. This dose resulted in a 50% reduction.

The second (the first is below), longer acting, and endothelium protecting part of the 25plusD3 protocol is the Han et al. approach, scaled appropriately by bodyweight for children and adolescents:

2.5mg 100,000 IU oral D3 cholecalciferol per day for 5 days = total 12.5mg 500,000 IU.

This provides immediate (hours) D3 benefits of stabilizing endothelial cells.

It also provides a steady and substantial increase in circulating 25OHD over the next days and week or two, as the D3 is converted in the liver to circulating 25OHD.

(Daily D3 supplementation can be continued, but the substantial bolus dose makes this unnecessary for a few weeks.)

Alternatively, for 55 to 85kg adults, a single bolus dose of 5mg 200,000IU D3 will sustain the immediately boosted levels from the 1mg calcifediol for two weeks or so, after which the patient will ideally be largely recovered and can return to daily or weekly D3 averaging 5000IU a day or so.

The first part is immediately active - the same or similar to the Castillo et al. approach in Cordoba, which was so successful:

A single oral dose of 0.014mg calcifediol per kg body weight at the very earliest opportunity after diagnosis. The the exact dose is not particularly critical. For 55 to 85kg adults, 1mg is fine.

This provides rapid and sustained (for days and weeks, even in the absence of the D3 bolus) rises in circulating 25OHD, such as above 70ng/ml in a few hours.

(Until April, 2021, limited) Availability of 25OHD calcifediol for human use in the USA, and probably in many other countries as well - but it is now available, online, without prescription, in Australia and the USA

DSM's ampli-D® - 25OHD calcifediol tablets for human use is now available as FORTARO, online, without prescription, in Australia!

Mid May 2021:

FORTARO can now be shipped to any country, with a limited quantity of three bottles, totaling 3 x 60 tablets of 0.01mg = 1.8mg per overseas shipment.

2021-05-02: DSM has released d.velop - non-prescription calcifediol, with online ordering for customers in the USA, in packets of 60 tablets, each of 10 micograms. Each packet, which costs USD$30 including shipping contains 0.6mg of calcifediol - just over the 0.532mg which saved lives and greatly reduced the need for intensive care in the Cordoba trial (Castillo et al.).

This is excellent news, since there are millions of people suffering from COVID-19, and at serious risk of harm and death, whose illness could be reduced within hours and days by just one milligram or so of this oral calcifediol. No other compound can do what calcifediol does - raise 25OHD levels robustly in a few hours. All the details are at: https://vitamindstopscovid.info/04-calcifediol/ .

This update was added in the early hours of 2021-03-05. To understand the significance of the matters discussed in this section, you need to be up to speed:

Broadly understand the importance of good, around 50ng/ml 125nmol/L blood vitamin D (25OHD) levels to health in general, and the immune system in general. This whole set of web-pages and my other site https://vitamindstopscovid.info is devoted to helping you acquire this knowledge.

See https://vitamindstopscovid.info/02-autocrine/#04-quraishi for what I think is an especially precise way of measuring the 25OHD levels needed for autocrine / paracrine signaling to enable immune cells in general to work properly.
Ideally, understand vitamin D autocrine / paracrine signaling, which the immune system depends on: https://vitamindstopscovid.info/02-autocrine/ . Most MDs do not know this, but they all need to. They tend to think "vitamin D is a hormone", which is not the case regarding the immune system. This includes, ideally, reading about the McGregor et al. article which shows how Th1 regulatory lymphocytes fail to quell the hyper-inflammatory (cell-destroying) immune responses which cause some people to develop severe COVID-19, when these Th1 lymphocytes do not have sufficient supplies of 25OHD, the form of vitamin D which is tested in blood tests, and which supplies their autocrine (inside the cell) and paracrine (to nearby cells) signaling system: icu/#2020-McGregor .
Understand the need for vitamin D supplementation for almost all people (not those who get sufficient UV-B direct skin exposure all year round - but few do, and this involves elevated risk of skin cancer). This includes newborns who are not breast fed or who are breast-fed by mothers who themselves are not replete. The D3 daily (or equivalent, once a week or so) supplemental intake levels are ideally a ratio of bodyweight, with a higher ratio for those who are suffering from obesity: https://vitamindstopscovid.info/01-supp/ .
Absolutely required reading: Read and understand the sections above on the Cordoba 25OHD calcifediol randomised clinical trial (RCT) involving hospitalised COVID-19 patients: #2020-Castillo , my suggestion for 25OHD calcifediol 0.5 to 1.0mg dosing for immediately raising 25OHD blood levels in those people who have low blood levels and are at risk of developing severe COVID-19: #25plusD3 and the above section on calcifediol 25OHD availability prior to this March 2021 development in Australia: #calcifediol-availability .

Once you have done this you will know that supplementing with 25OHD calcifediol is of no importance for people who already have good (such as 50ng/ml 125nmol/L) vitamin D (25OHD calcifediol) blood levels, which (except for people with a lot of recent UV-B skin exposure, and ideally unpigmented skin) means that they must have been robustly supplementing vitamin D3 for several months.

See also a further section below #calcifediol-lab-agri on obtaining potentially (likely, in the case of severe COVID-19) lifesaving calcifediol as lab-grade ~99.9% pure powder or in a diluted powder form intended for supplementing agricultural animals.

Some people need higher 25OHD levels, such as to deal with multiple sclerosis and other autoimmune disorders: https://www.grassrootshealth.net/blog/dr-coimbras-protocol-multiple-sclerosis/ . To quickly attain such higher levels (which should be monitored in the long term by a Coimbra-protocol-aware MD to ensure there are no problems) it is reasonable to consider calcifediol 25OHD, as discussed here and above, as a faster way of attaining such higher 25OHD levels, despite this involving more than the one tablet a day recommendation.

Thanks to Robert Andrew Brown of the UK-based McCarrison Society https://mccarrison.com for alerting me and other vitamin D researchers and advocates to this most welcome development.

Disclaimer:

Please remember that you are reading the best efforts of an electronic technician and computer programmer. I probably know more about vitamin D than 99.9% of doctors and nurses, but they know far, far, more about health and medicine than I ever will. Medical advice is what you get from a qualified medical professional after they have examined you. The following is for everyone's interest and edification. If you make your own decisions about health and medical care, read on. If you don't, read by all means - but please encourage your healthcare professional to read and research very widely, including this material, so they can be as up-to-date as possible with the latest research.

Dutch (human and animal) nutritional supplement company DSM is selling calcifediol tablets, without any need for a prescription, via an online site, based at their Australian headquarters in Wagga Wagga, a major regional city in southern inland New South Wales, Australia. Deliveries were initially to Australia only, but to all countries in early May 2021, with an overseas limit of 3 bottles per order.

https://shop.fortaro.com/products/fortaro

DSM ampli-D FORTARO calcifediol 15OHD 25-hydroxyvitamin D tablets 10ug 10 micrograms Cordobal RCT Castillo et al. COVID-19 rapidly raise blood vitamin D levels

FORTARO provides 0.6mg calcifediol per bottle for USD$20 = USD$33.33 per milligram.

This is somewhat more expensive than Hidroferol (mentioned above) which is 2.66mg a box of 10 capsules for about USD$14 = USD$5.26 per milligram in theory - I do not know where to obtain Hidroferol, and is price was from pharmacies in Georgia, the country, not the US state.

FORTARO is a lot less expensive than Rayaldee, at USD$1,340.98 per milligram. FORTARO does not require a prescription in Australia.

2021-03-09: at the end of this section #2021-03-09 are details of the small tablets themselves, and a link to an article about neurological harm in children and adolescents suffering from COVID-19.

There doesn't seem to be a limit on how many can be ordered for delivery to customers in Australia. In March clicked the quantity up to 500 and the shopping cart software did not complain.

It is probably possible to order more than three of these bottles for indirect delivery to countries outside Australia via a mail/parcel/package forwarding company such as: https://fromaustralia.parcl.com or https://www.sosmail.com.au/pages/international-shopping/shop-in-australia . Please let me know of any success or otherwise with such companies.

Presumably the same 10ug calcifediol tablets are also sold as a practitioner-only supplement (sold only to naturopaths and I guess pharmacies, since medical doctors in Australia do not usually directly provide supplements or drugs to patients) by Bioclinic Naturals / Factors Group, as Opti Active D in bottles of 60 or 120 tablets:

https://bioclinicnaturals.com.au/product/optiactived

There's no pricing there and it is not available to the public, so the rest of this section refers specifically to the FORTARO tablets direct from DSM Australia.

My interest in the easy availability of calcifediol tablets is based on using it in ways quite different to what they are intended for, according to the FORTARO product brochure and the TGA approval document(s) linked to at the end of this section.

The manufacturer (DSM) makes no mention of SARS-CoV-2 / COVID-19, sepsis, Kawasaki Disease (KD, see #2015-Stagi) of the similarly extreme immune dysregulation disorder Multisystem Inflammatory Syndrome (MIS, see my comments on a RebelEM article). The brochure does however cite research on higher vitamin D blood levels being protective against respiratory infections.

I am interested in how these tablets could be used to treat severe COVID-19 (or the risk of it developing) and likewise sepsis, KD and MIS. My interest is solely due to the way calcifediol 25OHD goes straight into the circulation, without needing the days to week or so of processing in the liver D3 needs to be transformed into circulating 25OHD. There is also a concern with D3 bolus doses, such as 100,000 IU to 400,000 IU, that this (apparently, I have not researched the details) upregulates 24-hydroxylase enzyme activity to unusually high levels, which degrades D3, 25OHD and 1,25OHD.

For longer term protection, as far as I know, D3 supplementation is perfectly adequate. Calcifediol supplements would work too, but I know of no long-term advantage, and D3 is less expensive and much more readily available.

For this use - emergency 25OHD repletion, within hours - the 10 micrograms a day intended dosage of these products would be of almost no use. I am interested in the use of oral calcifediol in quantities such as 0.5 to 1mg (500 to 1000 micrograms) or more for obese adults, all at once, or over a few hours, As Soon As Possible, with these sick people. (I don't call them patients, since I am not a doctor, and nor would many readers who want this to protect their loved ones and friends in a crisis, especially when MDs can't or won't provide calcifediol.)

These people are either in intensive care, or are at significant risk of needing it. As I mention above in #25plusD3, I think the only need for calcifediol is for this ASAP initial dose, and that D3 every day or few days thereafter should be fine to maintain 25OHD levels (though D3 on its own is known to protect epithelial cells).

So my interest is the use of the whole bottle of 60 tablets, over a few hours or whatever is required, to raise an adult's 25OHD levels as in the Cordoba RCT. See #25plusD3 for the graph depicting the rapid rise of 25OHD levels in young, healthy, presumably non-obese, subjects.

Before discussing how I think this product could be used in emergency (hospital, or risk of hospitalisation) settings with COVID-19, sepsis etc. I want to discuss how the claims made by DSM et al. for the speed of action of these 10ug calcifediol tablets are:

Unrelated to the benefit of D3 not needing to be converted in the liver to circulating 25OHD.
Arguably inaccurate. While I am very glad this product is available, and that DSM has invested in its manufacture, marketing, retail sales business and in particular getting TGA approval for it, I think their claims about it being faster than D3 at raising 25OHD levels, on the timescale of months, which is what they cite, are a poor account of what is actually happening.

Only about 1/4 of ingested or cutaneously produced vitamin D3 cholecaldiferol is converted into circulating 25-hydroxyvitamin D

#vitD3conversion

It is widely recognised that over time periods of weeks to months, 25OHD calcifediol will contribute to circulating 25OHD levels about the same amount as 2 to 3 times the same mass of vitamin D3 cholecalciferol. (The article cited below states this. However, I think the factor is more likely to be 4 or perhaps higher.) This shows that only about 1/2 to 1/3 of the D3 molecules we ingest, or produce in our skin when exposed to UV-B light, are actually converted to circulating 25OHD. The other 2/3 - as D3 or recently produced 25OHD - must be broken down in some way, most likely by the 24-hydroxylase enzyme.

This well-known efficiency factor, which I assume here is around 3 - fully explains the earlier attainment of specific 25OHD levels mentioned in the DSM brochure (linked to at the end of this section), since the graph in the brochure, here squished and rearranged a little, involves timescales substantially longer than the 3, 4, 7 or whatever day delay for converting most D3 into 25OHD.

Contrary to the text next to the diagram in the brochure, which refers to a "Graeff-Armas" article I can't find, this graph seems to be adapted from this article, which is cited on the last page of the brochure, with an incorrect 2018 date:

Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults
Laura A Graeff-Armas, Igor Bendik, Iris Kunz, Rotraut Schoop, Sarah Hull, and Mareike Beck
Journal of Nutrition 2019-09-13
https://academic.oup.com/jn/article/150/1/73/5569650

This brochure graph concerns 20ug/day calcifediol raising levels to 30ng/ml supposedly in about 8 days (the intercept is actually 7 days) while 20ug D3 supposedly takes about 50 days. This is twice the amount of calcifediol as the recommended dose of these tablets. The speed ratio, when looking closely at the brochure graph, 6 or 7 to 1, not 3 to 1.

In the article's graph, the baselines are well aligned and the intercepts to 30ng/ml are about 3 and 46 days, for a circa 15 to 1 speed ratio for 20ug/day calcifediol / D3. However, the text of the article states that these times are 7 and 40 days respectively, which I don't understand, and which leads to a 5.7 to 1 speed ratio.

Cholecalciferol certainly does work faster than D3, and in the original article, the timescales are short enough that the lack of liver processing is significant.

Regarding D3 being processed in the liver, the brochure states "This is a slow process, thus it can take months to reach optimal vitamin D levels.". It is more accurate to state that it is an inefficient process, by a factor of about 3 (below I mention 4 or perhaps more), and that it entails some delay such as up to a week or so to process most of the D3. As far as I know, the levels take two months or so to stabilise since there is considerable storage of 25OHD in adipose tissue - so I guess it would take longer for obese people. (Also, I am not sure that the adipose tissue gives all the 25OHD back to the circulation when blood levels drop.)

The article reports that steady state levels were achieved in the same times for the three calcifediol dosages and for the D3. Both the lack of liver delay and the greater efficiency explains a shorter time for calcifediol to raise 25OHD levels above some low threshold, such as 30ng/ml.

#2021-03-07

NOTE 2021-03-07: The following attempt to calculate the ratio by which calcifediol raises 25OHD levels with respect to the same mass of D3 is flawed.

I hope to revise it soon. The assumption below is that we can take, for instance in the graph above, the 25OHD level rising 3 times as much with 20ug calcifediol per day as with the same mass of D3 per day and call this a 3:1 ratio. This ignores the fact that it gets progressively more difficult to raise 25OHD levels due to the self-limiting activation of 24-hydroxylase enzyme, degrading the 25OHD, and how this is upregulated by at least the 25OHD level itself, and perhaps the D3 level as well (I don't recall). See the Ekwaru et al. 2014 graph at: https://vitamindstopscovid.info/01-supp/a-ratios/ . However, I suspect the way those curves roll off so strongly towards the horizontal is more extreme than the real situation.

The only way to determine this ratio is to choose a desired target level - such as 50ng/ml - well above a known baseline, and find how much calcifediol and how much D3 is required to attain this target level in two similar populations of people, ideally with the same ingestion arrangements and with the calcifediol and D3 similarly available as powders, tablets or ideally with oil. None of these three articles provide such data. My guess is the real ratio is around 4:1 - but that is just a guess.

The full article graph supports the hypothesis that 20ug/day 25OHD calcifediol raises 25OHD levels in the long term about 3 times as much as 20ug/day vitamin D3 - and this 3:1 ratio is mentioned in the article's conclusion.

But please remember that this 20ug D3 per day is only 800 IU a day, and research such as Ekwaru et al. 2014, the graph from which is at: https://vitamindstopscovid.info/01-supp/a-ratios/ indicates that average weight adults need (on average) 125ug 5000 IU / day D3 to reach, in the long-term, a healthy 25OHD level of 50ng/ml. This Graeff-Armas et al. graph shows just 20ug / day calcifediol achieving this goal after 8 weeks, which is great. I am not suggesting that calcifediol is any less effective than DMS claim it is, just that their claims do not fit well with the observations, and that they fail to distinguish between the 0.5 to 1 week delay inherent in liver processing and the overall greater efficiency, in the long term of calcifediol. Also, their description of the 25OHD needing to be processed in the kidneys to produce 1,25OHD only applies to hormonal 1,25OHD. It is irrelevant to almost all the other functions of vitamin D, which rely on autocrine and paracrine signaling.

As far as I know, there is no advantage to taking 10ug/day calcifediol over 125ug 5000 IU / day D3 - both take two months or so to attain, on average, a healthy 50ng/ml 25OHD level - or probably longer and a lower level in obese adults.

(Update 2021-03-06.)

The Graeff-Armas research reports that 20ug/day calcifediol attaining long-term ~57ng/ml, from a baseline ~18ng/ml. If this really does represent the general situation for average weight adults (I assume ~70kg for Caucasians, with Asians being significantly lighter [WP]) then rather than the 3:1 ratio DSM claim in their FORTARO brochure, the real ratio would be in the order of 6:1 to 7:1 in favour of calcifediol. This is based on my analysis of Ekwaru et al. 2014 where, approximately, and on average, for their average weight, North American fitness-seeking survey adult subjects, 0.125mg 5000 IU D3 a day raised long-term 25OHD levels to around 50ng/ml. https://vitamindstopscovid.info/01-supp/a-ratios/ .

Opinions vary on the relative abilities of calcifediol (25OHD) and D3 to raise circulating 25OHD. Here are two pertinent articles, kindly suggested by Owen Parry. The exact ratio would depend on the formulation of the two supplements (dry powder, tablet or oil capsule) and the way in which they were ingested: empty stomach with water vs. start of meal (pushed through fast) vs. near end of meal with fats (as I aim to do: good fat absorption and a longer time to be absorbed).

Effects of Cholecalciferol vs Calcifediol on Total and Free 25-Hydroxyvitamin D and Parathyroid Hormone
Albert Shieh, Christina Ma, Rene F. Chun, Sten Witzel, Brandon Rafison, Hannah T. M. Contreras, Jonas Wittwer-Schegg, Leon Swinkels [DSM], Tonnie Huijs, Martin Hewison, John S. Adams
The Journal of Clinical Endocrinology & Metabolism, Volume 102, Issue 4, 2017-04-01
https://academic.oup.com/jcem/article/102/4/1133/2982842

20ug calcifediol per day was compared with 60ug 2400 IU D3 for 16 weeks. Both were DSM powder in capsules. Baseline average 25OHD levels were 16.2 and 17.0 ng/ml in the calcifediol and D3 groups respectively. Total 25OHD rose 25.5 vs 13.8 ng/ml, which is a factor of 1.847. Free 25OHD rose 6.6 vs. 3.5 pg/ml, which is a factor of 1.886.

Since the comparison was with 3 times the mass of D3, I calculate an overall 25OHD raising factor of (3 * 1.847) = 5.54:1 in favour of calcifediol.

The graphs show no significant earlier response to calcifediol, which is not surprising given the low quantities of both supplements and the first measurement taking place at 28 days, which is much longer than the 0.5 to 1.0 week time it apparently takes the liver to process most of the newly circulating D3.

Superior efficacy of calcifediol soft gelatin capsules vs cholecalciferol independently of bmi, for the management of vitamin d deficiency in postmenopausal women: a treatment to be considered in therapeutic guidelines
Esteban Jódar, José Luis Pérez-Castrillón, Antonio Dueñas-Laita, Gonzalo Hernández*, Nieves Fernández-Hernando* and Paula Arranz-Gutiérrez*. * Faes Farma R&D Department.
Endocrine Abstracts, 22nd European Congress of Endocrinology 2020-09-05 (No PDF.)
https://www.endocrine-abstracts.org/ea/0070/ea0070oc2.6

RCT in which one Faes Farma (so, Hidroferol) 0.266mg oil-filled calcifediol capsule per month were compared with 0.625mg D3 per month (form unknown, but I don't recall any oil filled capsules above 5000 or perhaps 10,000 IU, so I guess it was powder in capsule. Per day, this is 8.74ug calcifediol and 20.5ug D3, a 1:2.35 ratio.

I think that vitamin D supplements are best taken daily to weekly or perhaps every 2 weeks. Every month (4.35 weeks) is surely better than having none, but a supplemental intake every 7 days or less is surely a better match for the week or so liver processing and few weeks half-life (less at higher levels, more at lower) of circulating 25OHD.

41.3% of these postmenopausal women were obese, 32.6% overweight and 25.1% normal weight - with the remaining 1% underweight not included in the analysis. I don't understand the 4 or 12 month "test regime" time frames. I assume the results were for 12 months, which represents steady state and which would also automatically null out seasonal variations. Baseline 25OHD levels were all below 20ng/ml, so I guess the mean was 13 to 18ng/ml. Here are the changes in ng/ml 25OHD, with the ratios I calculated to represent effectiveness of equal masses of calcifediol / D3, considering the 1:2.35 dose ratio:

Morphology Calcifediol   D3       Ratio

Normal       16.6         12.6      3.1
Overweight   15.6          9.8      3.7
Obese        13.4          8.9      3.5

I am inclined to think of calcifediol being 3 to 6 times more effective at raising 25OHD levels than D3, but there will be considerable variation due to the form it is taken in, whether it is taken with a meal or not, the nature of the meal and any liquids, whether taken at the start, middle or end of the meal etc. (End of 2021-03-06 update.)

This article from 2012 to some extent avoids the abovementioned problem of assuming that 25OHD levels rise linearly in proportion to supplied 25OHD or D3:

Relative effectiveness of oral 25-hydroxyvitamin D3 and vitamin D3 in raising wintertime serum 25-hydroxyvitamin D in older adults
Kevin D Cashman, Kelly M Seamans, Alice J Lucey, Elisabeth Stöcklin, Peter Weber, Mairead Kiely and Tom R Hill.
American Journal of Clinical Nutrition 2012-05-01
https://academic.oup.com/ajcn/article/95/6/1350/4568381

>= 50 year old apparently healthy adults not in hospital or care homes were given 20ug (800IU) D3, 7ug calcifediol and 20ug calcifediol. This was in late winter at 51° N, over a treatment period of 10 weeks. This is not very long, but is probably long enough to render the ~~1 week liver delay unimportant.

Both capsules used spray dried #spray-dry D3 or calcifediol, both manufactured by DSM.

The most interesting comparison is between the 7.7ng/ml increase in 25OHD for the 20ug D3 group (19.9 to 27.6) and the 11.3ng/ml increase for the 7ug calcifediol group (17.0 to 28.3), though the latter was from a somewhat lower baseline, and so easier to achieve. The effectiveness ratio calculated from the masses of the supplements and the increases is 4.2:1 calcifediol : D3. However, with the lower baseline, I would adjust this down a little. So my guess is that for these modest intakes, and modest 25OHD level rises

This makes me more confident of my 4:1 ratio guesstimate of the relative effectiveness of calcifediol and cholecalciferol D3.

Returning to my interest in calcifediol in emergency settings, with COVID-19, sepsis, KD and MIS etc. the advantage is that we know from the Cordoba clinical results and the Faes Farma patent graph mentioned above, that 0.532mg calcifediol in oil - specifically in the particular oil and capsule formulation of Faes Farma's Hidroferol gel caps - works wonders with the 25OHD level, taking it up to 60ng/ml or so in 4 hours or so, at least with the patent trial's healthy and presumably non-obese subjects.

The three calcifediol preparations discussed here are all quite different:

The Faes Farma Hidroferol capsules have the calcifediol dissolved in 80% or more by mass oil and 0.3 to 6% by mass solvents. According to the patent:

- an oily component selected from the group consisting of a medium chain triglyceride, isopropyl myristate, C₁₄-C₁₈ alkyl alcohol, a C₁₄-C₁₈ alkenyl alcohol, lanolin alcohol and mixtures thereof, and

- a pharmaceutically acceptable organic solvent selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, benzyl alcohol and mixtures thereof;

The capsules used in the Graeff-Armas et al. trial used a "spray dried" form of calcifediol, dry in a capsule, made by DSM. More spray drying below.
FORTARO is a solid tablet. I assume it uses the spray dried powder, pressed together with the various excipients.

We known nothing about how the Hidroferol capsules were ingested in the patent trial or in the Cordoba trial. In the latter hospital setting I guess it would have been with water, not with a meal - since they were keen to treat the patients ASAP. The oil in the capsule and perhaps the solvents would have helped with absorption of the calcifediol.

Calcifediol with two hydroxyl groups is apparently more easily absorbed into the bloodstream than D3, with one, but my experience reading the absorption literature is confusing.

#spray-dry

As far as I know, from reading about industrial production of both pharma and feed grade vitamin D, the waxy solid semi-crystalline (at least for pharma grade, the feed grade is not so well refined) D3 is dissolved in hot cottonseed oil. I guess it is actually hydrolyzed cottonseed oil so that its melting point is well above room temperature. This is sprayed under pressure into cool air together with a dusting of powders which coat the small solid particles, which form in mid-air, so they do not stick together. This is only a few percent, or a fraction of a percent, D3, but the powder is relatively stable and easy to handle and mix with other substances. I assume the same process is used for calcifediol.

I would expect the Faes Farma calcifediol to be more readily absorbed than the dry powder capsule and compacted tablet forms from DSM.

My interest is in how these DSM FORTARO capsules might be used in emergency (in or pre-hospital, immediate danger for the sick person) situations. Here are some thoughts about practical matters.

The Faes Farma 0.266mg capsules are obviously the superior product. They use oil and are known to work well in the Cordoba trial and in raising 25OHD levels. Two capsules does the trick. I am just an electronic technician, but I would probably use 3 capsules for Justin - Justin Case - unless the person was 60kg or less. Obese adults need all the help they can get. I would give 4 capsules for morbidly obese people. (See the #2021-03-09 update for more thoughts on calcifediol dosage by bodyweight.) Unless they already had very high 25OHD levels, this couldn't do any harm - and if they had such levels they probably would not be in danger with COVID-19 and would not have sepsis, KD or MIS.
However, hardly anyone can obtain these Hidroferol capsules. They are prescription only, not sold in the USA and are not available in any reputable site I am aware of. (Please let me know any such sites.)
FORTARO is easy to get in Australia. See the #2021-03-09 update for details of the tablets themselves.    I ordered some in Case I know anyone who needs urgent 25OHD boosts this Australian winter, when the new variants of SARS-CoV-2 will surely be causing harm and death, probably worse than last winter.

Probably most people in most countries could order it if they go through a package forwarding company in Australia. These companies may be good at flying things under the Customs radar, so in practical terms, the US ban on importing prescription items (which they would be under US law, I assume) may not matter.

Since everyone already has D3, the only reason for wanting calcifediol is for these COVID-19 emergencies.   Even in Australia it can take a week or more for mail deliveries, so it is no good waiting for the emergency and ordering some. The sick person needs their 25OHD boosted now - this hour or the next - since their health and life hangs in the balance.

So any form of calcifediol needs to be pre-ordered so it is ready for these emergencies. Doctors and nurses can and should do this, since it can be a lifesaver.   No matter where I lived, I would order some to be ready for emergencies with friends and family, or neighbours, who haven't been robustly supplementing with D3 for months.
To be useful in such emergencies, these FORTARO tablets need to be taken in large quantities, such as the whole 60 capsules in a bottle, ASAP (hours or a day) to be useful. If the 60 x 0.01 = 0.600mg intake needed is stretched out over a week, then this is likely to be little or no better than giving the person two or three 50,000 IU D3 capsules.

So I would assume at least one 60 tablet bottle per emergency for adults At a 3:1 effectiveness ratio, the 0.6mg total calcifediol in the bottle would be roughly equivalent to 1.8mg = 72,000 IU D3. At a 6:1 effectiveness ratio, it would be equivalent to 3.6mg 144,000 IU D3. Neither of these D3 quantities are particularly big for a bolus dose, for a 70kg adult. So except for very light adults or adolescents and children, I would be inclined to think the person would generally do better with all 60 tablets, or more, as soon as they could safely be ingested, than with fewer.

Morbidly obese adults' lives are in peril anyway with their extreme adiposity - and surely low vitamin D levels, unless they have been supplementing very robustly for a few months at least. They face grave risks with COVID-19. So I would think two bottles per emergency. (Please remember you are reading the ramblings of an electronic technician, for the interest of MDs, nurses and autodidacts such as myself. If you want medical advice, you need a qualified health professional to examine you - and hopefully all the material at this site will be of interest to them, as part of them keeping up with the latest research.)

UK doctors (many of whom seem to think D3 is akin to LSD, strychnine, ultra-prednisolone or whatever) should probably take some alprazolam before even thinking about this step beyond the UK government's 4000 IU/day upper limit - but I am an electronic technician and I know of no reason to fear any adverse outcomes of this 25OHD boost for such people. See also #2016-Han for 500,000 IU D3 over 5 days halving ICU patients' time in hospital while half this reduced hospitalisation times by a quarter.
The tablets are small and should be easy to ingest - see below for details.
I am not sure to what degree it might be practical to add some oil, or take them with a meal, to (ideally) enhance absorption. I assume that the excipients would pose no danger in these quantities, but that is just an assumption. Can anyone advise? From the TGA approvals:

calcium hydrogen phosphate \
dihydratecroscarmellose
sodium crospovidone
dl-alpha-tocopherol
magnesium stearate
medium chain triglycerides
microcrystalline cellulose
silicon dioxide
sodium ascorbate
starch
sodium octenyl succinate
sucrose

The world is currently going to hell in a handbasket due to the direct effects of COVID-19 and the lockdowns, travel, social and business restrictions - and the likely ongoing nature of these as countries enforce "vaccine passports" or "immunity passports" and other such privacy horrors to facilitate limited travel.

COVID-19 would be far less of a problem - probably not requiring most of these terrible measures - if everyone was vitamin D replete. They won't be for years, because there is entrenched opposition from many MDs and administrators, who should know better than to fear this nutrient. The drug companies would loose countless billions of dollars if everyone was vitamin D replete. Likewise hospitals.

Calcifediol is not important for long-term repletion, but nothing else compares with its ability to protect health and lives through raising 25OHD levels robustly in a few hours.

I was not expecting calcifediol to be available without a prescription anywhere - but now it is! These tablets are not as convenient, and may not be as effective, as the excellent Faes Farma capsules, but they are available and affordable.

Some background to DSM's recent human calcifediol initiatives:

DSM's 2021-03-03 ampli-D® press release has a very long URL . The statement about 25OHD needing to be processed in the kidneys to form the 1,25OHD calcitriol, which activates vitamin D receptors, is only true regarding the circulating (hormonal) 1,25OHD which regulates calcium-bone metabolism. This very low level of hormonal 1,25OHD does not affect immune cells, which convert 25OHD to 1,25OHD inside themselves, with vitamin D based autocrine signaling: https://vitamindstopscovid.info/02-autocrine/#02-nothorm . (What is the Get to market faster graphic meant to represent? A salt or sand timer?) A write-up of the press release is at another long URL: https://www.pharmiweb.com/press-release/2021-03-03/...

DSM's ampli-D® product page is:

https://www.dsm.com/markets/human-nutrition/en-ap/products/vitamins/ampli-d.html

This links (or did in early March - in late March I can't find a link or the brochure itself) to an attractive ampli-D® product brochure: Where others see VITAMIN D we see the opportunity to deliver it FASTER (PDF creation date 2021-02-12) with images of two cheerful-looking women and a thoughtful-looking outdoorsy fellow who looks like he would really appreciate some cheering up. The brochure cites articles including two written by long time vitamin D researcher and advocate Bill Grant http://www.sunarc.org/biography.html and colleagues.

Documents from the Australian Government Health Department's Therapeutic Goods Administration:

https://www.tga.gov.au/book-page/14-calcifediol-monohydrate

2020-05-07 or 2020-06-01 decision to allow 10ug/day calcifediol. I haven't read it all, but it contains potentially interesting historical material from various countries concerning vitamin D regulations.

Three PDFs with very long URLs which are the public summary for ARTG entries for these three products:

2020-11-30-FORTARO--DSM

2020-12-18-Opti-Active-D--Factors-Group-Australia

2021-01-25-Ampli-D-Generic-Bulk-Tablets--DSM

All three have the same product description (0.01mg calcifediol monohydrate plus the same hopefully benign excipients in an uncoated tablet) and warnings:

Calcifediol may have similar effects to Vitamin D. Consult your health care professional before taking in combination with other medicines.

The medicine should not be taken in combination with supplements containing Vitamin D without medical advice (or words to that effect).

Use in children under 9 years is not recommended.

The Indication Requirements of the DMS products are, with * indicating those which also apply to Opti-Active-D:

Product presentation must not imply or refer to mental illnesses, disorders or conditions.

* If product is indicated for supplementation, Label statement: [Vitamins/minerals/nutrients/dietary supplements] can only be of assistance if dietary intake is
inadequate OR [Vitamins/minerals/nutrients/dietary supplements] should not replace a balanced diet (or words to that effect).

Product presentation must not imply or refer to serious immunological diseases.

* Product presentation must not imply or refer to bone disease or disorders e.g. rheumatoid arthritis, juvenile arthritis, debilitating osteoarthritis, osteoporosis. Note: this requirement is not intended to apply where the indications referring to osteoporosis specified in column 2 of Table 2 of this instrument are also used.

* Label statement: [Vitamins/minerals/nutrients/dietary supplements] can only be of assistance if dietary intake is inadequate OR [Vitamins/minerals/nutrients/dietary supplements] should not replace a balanced diet (or words to that effect).

Product presentation must not imply or refer to serious cardiovascular conditions.

One additional Indication Requirement applies to Opti-Active-D:

Label statement: Advise your doctor of any medicine you take during pregnancy, particularly in your first trimester.

The Permitted Indications for the DSM products are, with bold indicating those which also apply to Opti-Active-D:

Maintain/support general health and wellbeing
Maintain/support healthy teeth
Maintain/support bone health
Aids/assists healthy bone development/growth/building
Help maintain/support bone mineralisation
Maintain/support heart health
Maintain/support immune system health
Maintain/support healthy immune system function
Maintain/support muscle health
Maintain/support muscle function
Maintain/support absorption of dietary (state vitamin/mineral/nutrient)
Maintain/support (state vitamin/mineral/nutrient) levels in the body
Helps prevent dietary (state vitamin/mineral/nutrient) deficiency
Maintain/support neuromuscular function
Maintain/support nervous system health

The additional Permitted Indications for Opti-Active-D are:

Maintain/support bone health in post-menopausal women
Maintain/support bone mass/density/integrity in post-menopausal women
Maintain/support bone mass/density/integrity
Maintain/support bone strength in post-menopausal women
Maintain/support bone strength
Vitamin D helps calcium absorption (or words of like intent) and a diet deficient in calcium can lead to osteoporosis in later life
Enhance/improve/promote immune defence/immunity
Maintain/support immune system to fight illness
Enhance/improve/promote/increase (state vitamin/mineral/nutrient) levels in the body
Helps prevent dietary (state vitamin/mineral/nutrient) deficiency
Maintains/support healthy foetal development
Maintain/support healthy pregnancy

2021-03-09 update:

The tablets arrived 5 days after the day of my 2AM order.

They are 0.15 grams, 6.5mm in diameter and 4.5mm top to bottom. With 10ug calcifediol, these tablets are 0.0000667 = 0.0067% calcifediol. To get 1 milligram of calcifediol, we need 100 tablets, which weigh 15 grams.

Here are 60 of them on 2mm graph paper.

A tablet disintegrated in my mouth after about 15 seconds and had no taste or smell. In a glass of warm water, each tablet disintegrates in a few seconds.

I can't imagine anyone having difficulty ingesting 2 a minute, or even 10 a minute. So I expect it would be safe to take a bunch of them - such as all 60 for a calcifediol quantity of 0.6mg, very similar to the Cordoba RCT's 0.532mg - in half an hour or less. However, I think it would be best not to use too much water for this, so the tablets don't get washed though the intestines too quickly. The upper part of the small intestine is best for absorbing oils, and calcifediol is more oily than watery. (People who have had Roux en Y gastric bypass weight loss surgery have had this part removed, specifically to reduce fat absorption, so they may need higher than usual D3 supplements - and so perhaps calcifediol supplements - to counter this impaired absorption.)

Perhaps the oil-filled Hidroferol capsules used in Cordoba might be more bioavailable than these tablets. Calcifediol 25OHD is more readily absorbed into circulation than D3, because it has two hydroxyl groups rather than D3's one - making D3 less soluble in water and more in oil. Maybe taking these tablets towards the end of a fatty meal would aid absorption. However, this suggested use is for emergency treatment of people who are, or may soon become, very ill - so there's no time for fussing around with theoretically (perhaps) ideal meals.

Everything you read here, apart from direct quotes from other sources, is the ramblings of an electronic technician. It is intended for MDs, nurses, other health practitioners, nutritionists and autodidacts such as myself - primarily as a guide to the latest research. My opinions should carry no weight whatsoever, but I hope my discussion is of interest and helps with understanding the research If you make your own decisions about health - go right ahead, they are your decisions. If you don't, you should seek medical advice and, ideally, encourage your healthcare provider to read this material and other sources as part of keeping up with the latest research.

Please remember that my interest in these tablets is for a totally different use from what the manufacturer intends: 60 or more - or over hundred at a time - for morbidly obese people, as a one-off emergency 25OHD vitamin D repletion measure for people at risk of, or already suffering from, severe COVID-19 & influenza, sepsis, Kawasaki disease, Multisystem Inflammatory Syndrome or any other acute illness which is driven primarily by dysregulated, overly-inflammatory immune responses.

This differs from the use the manufacturers intend the product for, and what they are allowed to claim it might be useful for. Firstly, my suggested use is one off, for emergencies - rather than long term supplementation. Secondly I am contemplating large numbers of tablets in an hour or so, or less, while this product is intended to be used one a day for adults.

Assuming the person needing vitamin D repletion has not been supplementing substantially with D3 for the last month or two, and has not been getting a lot of unprotected UV exposure (or they have been, but their skin is brown or black), then it is reasonable to assume their 25OHD level is between 3 and 20 or maybe 25ng/ml (7 and 50 or maybe 62nmol/L). We need to get it up to at least 50ng/ml ASAP. There's no time for tests, and no way of knowing how responsive they will be. I would aim higher, since there is no downside in attaining 100ng/ml, and there is a serious downside in attaining only a level which is not as high as the person really needs.

Children as well as adults can suffer serious harm from COVID-19 and the other conditions just mentioned:

Kids Hospitalized With COVID-19 Frequently Have Neuro Symptoms - Most are transient, but some develop into life-threatening disorders, by Judy George

https://www.medpagetoday.com/infectiousdisease/covid19/91509

Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome
Kerri L. LaRovere et al.
Jama Neurology 2021-03-05
https://jamanetwork.com/journals/jamaneurology/fullarticle/2777392
(The word "vitamin" does not appear. 47 of the 48 authors are MDs. They should all read #2015-Stagi.)

I would err on the high side to do everything possible with vitamin D to reduce this dysregulation ASAP. Vitamin C, perhaps IV, and other measures according to the FLCCC's MATH+ protocol should also be considered: https://covid19criticalcare.com/math-hospital-treatment/ .

I guess that 14 micrograms calcifediol per kilogram bodyweight would do the trick, even for children and adults suffering from obesity. So that is 1.4 tablets per kilogram, or 0.7 tablets per pound bodyweight. Probably half this would be fine for most people, but there's no way of knowing who needs more.

The Cordoba trial was very successful with 532 micrograms. If we guess the patients body weights were about 70kg (they could easily have been more) than this was 7.6 micrograms per kg bodyweight. Maybe their obese adult patients would have done even better with twice or three times this amount: 110kg is far from the extremes of obesity (photo #54 here). The Cordoba dose would have been 5 micrograms per kg bodyweight for a 110kg person.

Alternative sources of calcifediol, including lab grade pure powder and DSM Hy-D diluted powder intended for agricultural animal feed

Vitamin D3 itself, without conversion to 25OHD, protects endothelial cells, which form the inner lining of blood vessels

Vitamin D 25OHD levels of Iranian patients without COVID-19, with COVID-19 who survived and of those who died due to COVID-19

Indian hospital observational study of initially asymptomatic patients and those who were admitted, at first, to intensive care

Milan study: Vitamin D levels correlate inversely with COVID-19 severity

Newcastle upon Tyne (UK) COVID-19 patients are vitamin D deficient - and the ICU patients are more deficient

Israeli COVID-19 positive patients who require hospital treatment have lower vitamin D levels than those who don't

Iranian COVID-19 patients' symptom severity, inflammatory biomarkers and death rate correlate with low vitamin D levels

Contemplating a COVID-19 suffering, harm and death hazard curve according to vitamin D levels

Baktash et al. in Southern England: Elderly COVID-19 patients have low vitamin D levels

Shakoor et al. Be well: A potential role for vitamin B in COVID-19

The majority of Italian COVID-19 patients are vitamin D deficient

Latitude and COVID-19 severity - solar UV exposure and vitamin D

Arizona State University trial of vitamin D to reduce COVID-19 severity

Reports of research from Indonesia and the Philippines which I previously accepted and quoted are, in my opinion now, completely fictitious

Singapore trial of 1000IU vitamin D3, B12 and magnesium

Research from Belgium, Louisiana, a homeless shelter in Boston . . .

. . . . France (nicotine?), Ireland . . .

A large survey of Irish males 40 to 60 yo revealed they had a median 25OHD level of 18.8ng/ml. 25% of them had 16.4ng/ml or less! 25% of them had 26ng/ml or more. So, assuming for the moment that the Indonesian and Philippino reports above are relevant to Irish men (and ignoring any nicotine use) most of these Irish men are at much higher risk of serious harm and death from COVID-19 than if they supplemented with vitamin D3 to bring their 25OHD levels well above 30ng/ml - say to the 40 to 50 range.

The report concerns 33 males 40yo and above with COVID-19 pneumonia and respiratory failure. None of them suffered from cancer, diabetes, CVD or had received chronic immunosuppressive therapy. 12 were placed on mechanical ventilators and four of these men died. The 21 who did not need mechanical ventilation had mean 25OHD 16.4ng/ml, while the 12 who needed this had mean 25OHD 10.8ng/ml. All these levels are very low. indeed.

2015: Severe vitamin D deficiency in Italian children with Kawasaki disease

By mid-May 2020 it has become clear that some children are suffering severe symptoms from COVID-19 - and some of them are suffering serious harm or are dying. The inflammatory symptoms are similar to Kawasaki disease and it is reasonable to regard such cases as instances of Kawasaki disease [W].

However, due to some specific disease features - presumably due to particular characteristics of the SARS-CoV-2 infection - and its sudden wide prevalence, a new diagnostic category has been created for this condition when triggered by COVID-19:
Paediatric multisystem inflammatory syndrome [W]. Here I will use "KD" and "Kawasaki disease" to include both diagnostic categories.

Here is a 2015 article of crucial importance from Italy:

Ending the global vitamin D deficiency pandemic

Inadequate vitamin D levels - such as 25OHD levels below 40ng/ml (100nmol/L) - are a slippery slope leading to multiple forms of ill-health, disease and sometimes death.   This is a global pandemic. See the Google search results for vitamin D deficiency pandemic .

We are now living in what I hope will be the last months or year or so of the Vitamin D Dark Ages.

Future generations will look back in bewilderment that we had such sophisticated technology, hospital care and social and scientific achievements - yet still expected most people to live with inadequate nutrition, including especially vitamin D. This will be clumped together with other health-horrors-now-thankfully-and-firmly-in-the-past: The days before sewerage systems; hand-washing and basic sanitation; antibiotics; vaccines; anesthetics; chemical analysis of blood and tissue samples; X-ray and MRI machines; Internet access to health information and lively discussions like this one . . . .   The days when many people, including many doctors, smoked. (They still do in China.)

It is not practical to repeatedly test the 25OHD levels of every person on Earth. This would be far more trouble and expense than the vitamin D supplements themselves. There are some concerns about vitamin D toxicity (link) among a small fraction of the population, which I want to analyse and write more about later - but in general everyone needs to get their 25OHD to 40ng/ml or more in order that their immune system works correctly.   This goal is at odds with the advice given by some, such as #21authors, that we should aim for 25OHD levels merely above 10ng/ml (25nmol/L).

Here are some arguments for robust vitamin D supplementation to ensure 25OHD levels above 40ng/ml which will ensure, in most people, strong initial immune responses to infections and well-regulated later responses with good resolution mechanisms - not the overly-aggressive, pro-inflammatory, self-destructive responses which cause the harm in Kawasaki disease, COVID-19 and many other conditions.

I am using Kawasaki disease (see the article linked to in the previous section) in children as an example, but the principles apply to people of all ages, and for all sorts of conditions - of which COVID-19 is the one which most urgently demands our attention.

The estimated vitamin D intakes of the KD children did not differ significantly from those of the control group. The numbers in brackets are the standard deviation [W].   Significance [W] values show the probability that this difference would occur by chance due to random differences even if there was no actual relationship between the two variables. NS means the difference is not statistically significant - in this article, below 0.05. NS means that there is a greater than 1 in 20 chance the difference in these observations could occur due to random variation rather than due to a real cause.

	Control	KD	Significance
Vitamin D from diet IU/day micrograms	209(43) 5.2	220(49) 5.5	NS
Vit D supplementation in prior 6 months	10.7%	11.4%	NS
25OHD vit D ng/ml KD children with heart damage	23.3(10.6)	9.17(4.9) 4.92(1.4)	< 0.0001

Only about 11% of the children had received vitamin D supplements in the past 6 months. We don't know how much they were given, or how these children's 25OHD levels differed from those who were not supplemented. The control group's 23OHD level of 23.3ng/ml is (I guess) about the same as for many adolescents and adults. However, older people, and those with darker skins would have generally lower levels.

A simplistic analysis of this might be that the KD children had the same (or slightly more) vitamin D intake as the controls (their sunlight exposure and sunscreen use was about the same too) and that a viral or bacterial infection trigger caused their 25OHD levels to plummet in the course of their illness. In this basis, there might be no argument for greater vitamin D supplementation to prevent illness.

There are, of course, strong arguments for supplementing these children with vitamin D once they are ill. However I have not found any reports of doctors doing this. It seems that most doctors are unaware of these low vitamin D levels, or consider them insignificant or at least not amenable to change once in hospital. I am not a doctor, but it seems obvious to me that these children should get oral, intravenous or intramuscular 25OHD (25 dihyhdroxy vitamin D = calcifediol = Rayaldee) supplements as a matter of urgency, since this will directly raise the blood 25OHD their immune system relies upon. Failing this, they should at least get oral vitamin D3, which will take some days to be converted by their livers into the circulating 25OHD.

It is possible that the viral infection (and the direct, helpful - even if weakened - immune response to it) and/or the KD disease process itself (which is a self-destructive dysregulated immune response) depletes 25OHD levels. I am still researching this, but I think there is limited evidence for substantial declines like this in any illness.

The half-life of 25OHD in adults is weeks, but I guess it might be shorter in children. Being ill, they may have been out of the sun for a month or so by the time they were admitted to hospital, and they may have not been eating well, absorbing vitamin D3 or converting it in their livers to 25OHD in the bloodstream. So even without direct effects of the viral or KD illnesses, we might expect these children's 25OHD levels to drop a few percent to 30% (my guess) over this month or so of ill-health.

(Whatever small amount of boron they might have had from their normal food - fruits, vegetables and nuts mainly - would be rapidly depleted if they stopped eating this due to illness. The half life in adults is less than a day. Hospital food probably has little or no boron, since it is not recognised as a nutrient.)

Accepting that some non-trivial fraction of the difference between 25OHD levels of the control and KD children is caused by the viral illness and the immune system's subsequent attack (all the KD literature indicates that KD occurs weeks after the peak of viral replication), here is my attempt to explain the causative role of vitamin D deficiency in Kawasaki disease in general, KD or anything like it in children due to COVID-19 and more generally severe symptoms from COVID-19 in adults.

For completeness, this explanation also attempts to cover severe outcomes for adolescents whose disease progression differs significantly from that of KD and of adult COVID-19. Adult COVID-19 severe symptoms result from viral replication in the lungs driving endothelial damage and a resulting hypercoagulative state. icu/ KD does not seem to involve the lungs so much, and most of the harm is observed in mid-sized arteries - especially those supplying the heart muscles - though I think stroke is also a cause of harm and death.

We start with a population of children of suitable age for KD, before any disease trigger. We assume that the dietary vitamin D estimates and those for sunlight are valid and that the 23.3ng/ml average 25OHD levels of the control group apply to this whole group.

The first thing to note is that although the Endocrine Society regards levels of 30ng/ml or as being replete, 23.3ng/ml is too low by a factor of about 2. It is half the average level of 25OHD in African herders and hunter gatherers. See #2020-Baker-a and #2016-Caprio below for why we should aim for 40 to 60ng/ml.

Assuming (for simplicity in this example) a Gaussian distribution [K] the 10.6 standard deviation indicates that 16% of these children have 25OHD levels below 12.7ng/ml, which is very low. Let's take these children and call them subset AA. The reasons for these low levels include some mixture of:

These children, on average, had lower than average (for the entire initial set of children) vitamin D3 intake from food and supplements.
Darker skin pigments. (Dark skinned people also have more melanin and another uncoloured protein in their skin which absorbs the UVB light before it can reach the lower parts of the skin where vitamin D3 can be made.)
Less skin exposure to sunlight with UVB, due to latitude, clothing, sunscreen, air pollution, lifestyle, living in dense urban environments etc.
Poor absorption of D3 in food and supplements due to genetic differences, nutritional differences (not yet known, but they likely exist), whether or not the D3 was taken with a fatty meal - which is best for absorbing this fat-soluble vitamin - and potentially other unknown reasons.
Genetic or other reasons why the D3 is not converted to circulating 25OHD so well in the liver.
Body size variations and fat storage diluting the D3 in the whole body so there is a lower concentration in the blood.
Genetic, nutritional and other currently unknown variations affecting the quantity of vitamin D transporter protein in the blood. This affects the availability of 25OHD to the immune system cells.
Likewise other variations in the genes which determine the structure of this transporter protein, and in the proclivity of 25OHD to bind to any other proteins there (I recall albumin is one of them).

Now, by some magical means, we sort these children AA according to their genetic proclivity to mount an overly-aggressive pro-inflammatory immune response to infection even if they were replete in all nutrients including vitamin D and any we currently know little about (such as boron) which affect immune functioning. This proclivity is due to numerous types of genetic variation concerning their immune system cells, on top of the general human tendency for our inflammatory immune response to be overly-aggressive due to the fact that we have no intestinal worms. (See #helminthsgone below.) Let's pick the 20% of these AA children with the most destructively dysregulated immune responses, and call them group BB.

BB are 3.2% of the initial group of children whose age made them possibly at risk of KD.

Now I will assume that 5% of these BB children - group CC - are infected with SARS-CoV-2. This is 0.16% of the initial set of children.

Ignoring, for simplicity, genetic variations in the virus, some children will get a mild initial dose and others will get a large initial viral load, which is inherently more difficult to fight. There could be 100 to 1 variations in the viral load these children get.

Some of these SARS-CoV-2 infected children will develop a fever. Of these, a fraction will be given drugs to lower that fever. As far as I know, from all the research fever/ I found regarding viral infection fevers in general - not specific to COVID-19 - this is a bad idea, and is likely to cause a weakened innate and adaptive antiviral response, and so a greater chance that the infection will worsen and so increase the likelihood of triggering KD.

Assuming the lack of helminths and genetic variations in overly-aggressive pro-inflammatory responses are not important in the initial stages of the infection (in the throat, or perhaps the eyes), there will be some inherent genetic variation in how strongly the children can fight the virus, even if they were replete in all nutrients.

However, all of group AA, BB and CC are very low in vitamin D (less than or equal to 12.7ng/ml in this example), and this greatly reduces the ability of their innate (at first [K]) and later adaptive [K] immune systems to fight the virus directly. So we expect some fraction of the CC children not to stop the viral infection in the first few days.

I will assume this is 20%. For these children, group DD, the virus replicates in large numbers in their lungs, blood vessels or wherever else it is active in a way which tends to stimulate a self-destructive immune response we later diagnose as Kawasaki disease. This is group DD - now 0.16 * 0.5 * 0.05 * 0.20 = 0.08% of the whole initial group of children - one in 1,250.

These children are in trouble - and these are the ones who, in general, get Kawasaki disease or whatever else their condition might be called - severe symptoms with possible lasting damage the heart and other organs, triggered by COVID-19.

The short version of this story is that a SARS-CoV-2 viral infection has triggered KD in a relatively small subset of all children, according to the combined effects of various circumstances as just described. I have assumed a sharp cutoff of 25OHD 12.7ng/ml to denote the children at risk of KD. In fact, there is no sharp cutoff. Some children with higher levels will get KD - presumably due to some bad combination of all the variables just mentioned. Still, for discussion, this 12.7ng/ml sharp threshold is good enough.

Now lets re-run the situation with one major change. This change is easier to make than changing lifestyle, urban shadowing, culturally driven patterns of clothing and sunscreen use, or food choices. This change is also a hell of a lot easier than coping with the situation described above, in which some children - thousands to hundreds of thousands in any one country as COVID-19 affects almost the entire population - suffer illness, lasting harm and perhaps death, with all the efforts at treatment etc.

The change is that with the support of most doctors and the government, the great majority of parents recognise the need to get their children's 25OHD levels safely at or above 40ng/ml. This means lifelong robust vitamin D supplementation (except perhaps if, as adults, they spend a lot of time all-year round in UVB rich sunlight without clothing or sunscreen protection). It also requires robust vitamin D supplementation for women in general and especially women of childbearing age, since their baby's 25OHD levels depend entirely on their own before birth, and frequently after when they rely on breast feeding.

(This will also significantly reduce the incidence of autism and probably numerous other health conditions. Low vitamin D in-utero and/or early life seems to be a significant cause of autism: https://www.scientificamerican.com/article/vitamin-d-and-autism/ .)

The whole set of children now average 46ng/ml 25OHD. The proportion of them with dangerously low 25OHD levels is now reduced. So the incidence of KD in general, and in response to COVID-19, will be correspondingly lower. Likewise adolescents and adults regarding severe symptoms from COVID-19 and numerous other chronic conditions and acute diseases.

If doubling the average level also doubled the standard deviation, then:

Ave.    SD       Proportion below
25OHD              12.7ng/ml

23.3    10.6      15.9%   calc

46.6    21.2       5.5% calc

in theory, 65% (1 - (5.5 / 15.9))of the children at risk of KD in the first scenario due to low vitamin D levels would no longer be at risk. Likewise any other diseases which strongly depend on low 25OHD levels.

If everyone supplemented about the same amount, to double the average levels, the standard deviation would probably increase by less than a factor of 2, as I have assumed here. The bell curve would be narrower and the proportion of children with less than 12.7ng/ml 25OHD would be even less than this. If the SD was 16, only 1.7% of the children would have 25OHD levels below 12.7ng/ml - a reduction of 89% from 15.9%.

In this future era of ubiquitous vitamin D awareness, any children diagnosed with KD or similar conditions would be quickly treated with extra vitamin D, ideally 25OHD, and any other nutrients which would improve their immune system dysregulation. At present, this does not occur, and hospital treatment relies on transfusions of donated plasma with antibodies, anti-inflammatory drugs, aspirin and (as far as I know - and though the doctors may not recognise this) probably a low level of vitamin D3 which may be in the food or IV drips the children receive once in hospital.

The same reductions in severe disease should apply for adolescents and adults with COVID-19, sepsis, severe symptoms from influenza etc.

Come the revolution we will all have generally good levels of vitamin D supplementation, generally good (40ng/ml) 25OHD levels and so a great reduction in the incidence of severe disease states, with prompt repletion as soon as such states are diagnosed.

COVID-19 induced Kawasaki disease in children and babies

UK discussion about BAME community susceptibility to severe COVID-19 symptoms generally ignores vitamin D

Pep-talk for doctors regarding the need for robust vitamin D supplementation to protect against severe COVID-19 symptoms

Articles concerning vitamin D supplementation to protect against harm and death from COVID-19

2400IU (0.06mg) a day D3 raises the 25OHD levels of most, but not all, white women in the USA above 30ng/ml - but few have their levels raised to the 40 to 60ng/ml range required for optimum health

Doctors advising vitamin D supplementation in sufficient quantities to raise 25OHD to 40 to 60ng/ml, which they regard as being vitamin D replete

Indian Police receive substantial vitamin D supplementation

Other articles not yet mentioned

Irish doctors debate whether to use low or ridiculously low doses of vitamin D3

21 authors advise very low levels of D3 supplementation, aiming for a minimum 25OHD level of only 10ng/ml

COVID-19 pathology - weak and dysregulated immune systems

Weak and dysregulated, over-inflammatory, immune responses are caused by lack of helminths, individual genetic variation, dietary excesses and several common nutritional deficiencies

COVID-19 vaccines and immunity - robust vitamin D supplementation will be far superior to even the most perfect vaccine

Epidemiological studies investigating ADE in individuals with multiple SARS-CoV-2 infections or cross-reactivity to common-cold-causing CoVs will likely take several years.

In my opinion, the best way for black people to get adequate levels of vitamin D is by supplementation. And the research shows that adults should be getting no less than 10,000 IUs a day.

Read more at: https://www.vanguardngr.com/2020/07/vitamin-d-crucial-in-management-of-covid-19-sickle-cell-disorders-dr-david-ajibade/

Most members of the public, and of governments - and probably quite a few doctors - have a vision of a vaccine being a safe, well-tested, highly effective means of creating lasting immunity - akin to a magic bullet.   However, the safety of any vaccine cannot be known until it has been used in hundreds of thousands of people, since even rare incidences of ACE making subsequent SARS-CoV-2 infection much worse are a serious matter. For more on this, click the aforementioned search link and see Out of the frying pan and into the fire? Due diligence warranted for ADE in COVID-19 (2020-06-240 https://www.sciencedirect.com/science/article/pii/S1286457920301246 .

I don't have time to read these articles and I doubt of you do either.   However, if you think that a safe, effective, vaccine for SARS-CoV-2 can be developed and tested without years of work, then you should at least cast your eyes over the Lessons and frying pan articles.

Also, some of these COVID-19 vaccines - including the Oxford one the Australian government is so keen to get - work by injecting an artificial virus which can infect cells but not reproduce.   The infected cells produce parts of the virus's spike protein, which together with adjuvants, causes the immune system to recognise these as other and mount an immune response, just like in a real infection.

How do the virus creators know which cells are going to produce these fragments? What happens if the vaccine is given to someone who has already been infected with COVID-19? They may not know it, and we can't give everyone an antibody test before vaccination to prevent this. Let's imagine this person having an overly twitchy immune response - strong immunity from antibodies and/or memory cells AND genetic differences making them prone to dysregulation AND lousy vitamin D, boron, omega 3 fatty acid etc. intakes. Why wouldn't their immune system go bananas with this sudden explosion of spike proteins and adjuvant and so cause extreme hyper-inflammatory reactions, including cytokine storm damage to endothelial cells? This would lead to the same deadly coagulopathy which harms and kills most or all of the people who are killed by their immune system's response to a real COVID-19 infection.

Most doctors, ordinary people and governments are operating according to the following "conventional wisdom":

Infection with SARS-CoV-2 is potentially very harmful or deadly.
Without a vaccine it can only be stopped with extreme and unsustainable lockdowns, social distancing etc. or by herd immunity. (There are numerous arguments that the early, low-dose use of hydroxychloroquine and some other drugs are safe, highly protective and inexpensive - and that some government bodies are unreasonably restricting their use to the advantage of companies which make vaccines and more expensive drugs. I tend to agree with this view. I mention it because there is a growing body of opinion that the early and ICU care of COVID-19 patients could be much better than it is, so rendering the threat posed by the virus significantly lower than many people believe it is. I think there is merit in this, but that vitamin D repletion is a much more powerful, safer and more generally useful approach than band-aid approaches involving drugs once people are infected.)
Herd immunity (something like 70 to 90% or more people being immune) will stop, or dramatically slow, the spread of the virus, so even those with no immunity are completely or largely protected.
Few, if any, governments aim for herd immunity to be achieved via most of their population being infected, so they have their populations living in fear, isolation, locked down etc. waiting for a population-scale vaccination program to achieve herd immunity with minimal direct infections. This is personally, socially, economically and politically extremely destructive.

Consequently governments and populations alike, are, in general, doing their civil duty by enforcing and complying with lockdowns etc. while eagerly awaiting the boffins to develop, test and mass-produce their magic bullet vaccines, ready for a bevy of hypodermic equipped nurses to administer to the great majority of the population. This is reckless and at odds with all we know about vaccine development and testing, which normally takes many years.

A growing number of people are becoming alarmed and bitterly frustrated with this mainstream government approach, as supported by most doctors. There are numerous websites devoted to this. Tucker Carlson's 2020-08-24 video When do we get America back? encapsulates quite a bit of this frustration which I think is well founded and doesn't depend at all on avoidant themes such as the virus being a hoax. I would really like to bring him and numerous other influential people up to speed on nutrition for immune system health!

Let's imagine the best case outcome for COVID-19 vaccination:

A vaccine is available next week, in sufficient quantities to supply the country's entire population.
The government has convinced (or perhaps will force) most or all of the people to accept vaccination.
The doctors and nurses are ready to go, including to all corners of the country - bearing in mind that some of these vaccines involve two separate injections spaced two weeks apart.
Although it is impossible to establish, beyond reasonable doubt, that the vaccine is safe (zero or exceedingly low incidence of serious ill effects, including especially ADE), for the purposes of this discussion let's assume that it actually is 100% safe AND highly, perhaps, 100% effective AND produces very low levels of normal effects, such as headache, GI problems, being unable to work for a few days etc.
The financial cost of the vaccine is zero. So to, by some magical means, is the cost of deploying all these medical personnel, and the administrative and logistical support for them.

Even with these ideal conditions, vaccination against COVID-19 is absolutely the wrong approach.

It is an attempt to solve the wrong problem.

The problem is not the virus.

The problem is that many people's immune systems are weak and dysregulated.

There are three sets of reasons for this, considering a whole population of individuals:

Humans now, with rare exception, are no longer infested with helminths (intestinal worms), which in our ancestors downmodulated several immune responses. Our immune systems evolved with helminths and so some aspects of our systems' operation are dysregulated: overly aggressive, hyper-inflammatory and so (without helminths downmodulating these responses) cause the cytokine storm which is a crucial step in the development of severe COVID-19. See #helminthsgone . (Lack of helminths lead to dysregulation, not immune system weakness.)

We can't easily fix this, since helminths are at least somewhat pernicious and many are extremely harmful.
Individual genetic variations on the average human genetic pattern which cause some people to have weaker and/or more dysregulated immune responses than average.

Again, we can't fix this.
Nutritional deficiencies and some excesses (such as salt, high-fructose corn syrup, excessive omega 6 and trans fatty acids). We can and must fix these since the health benefits vastly exceed the costs of doing so.

The most important and best researched deficient nutrient is vitamin D. Only tiny quantities, at very low cost, are required to bring everyone's 25OHD levels safely into the 40 to 60ng/ml range. See #kp above and #plan below for details of the other deficient nutrients.

A country-wide, ideally global, program of vitamin D repletion will be much easier, less expensive and safer than any vaccine program. Although it will take some months to build new vitamin D3 factories to produce the quantities we need, these quantities and costs are very small compared to vaccines. An average weight person needs 1/22 of a gram D3 per year - and it costs about USD$2.50 a gram.

The same principle applies to influenza vaccines: influenza only causes serious harm to people with weakened and dysregulated immune systems. This weakness and dysregulation has several contributing causes, but in most people it can be largely or completely overcome with vitamin D supplementation to achieve 25OHD levels of 40 to 60ng/ml.

#cannell

There is well-known seasonality driving influenza and common cold respiratory infections:

This is from:

The seasonality of the spread of influenza - and no-doubt COVID-19 - can be explained in terms of two potentially variable items, assuming the population mixes and behaves reasonably consistently throughout the year. (For simplicity I am ignoring other factors like dry air leading to exhaled droplets drying into 0.12 micrometre virus particles which stay airborne for longer than the droplets would in humid air. I am also ignoring sickness keeping people at home, and so spreading the virus less - which is probably not much affected by the season.)

I For a given viral insult, the average chance that a person becomes infected.

S The total number of viruses an infected person sheds, at least when in the company of others who have not yet been infected.

The product of these two variables (I x S) has an enormous effect on the spread of the infection. The number of viruses shed is likely to scale with the severity of the infection. So even if I did not alter throughout the year, we could explain the wide seasonal variation in spread rate in terms of seasonal changes to the second variable alone: S.

The first chart above - seasonality of influenza by latitude - does not enable us to distinguish the degree to which I or S varies, but we know the product of them varies a lot with summer / winter in locations about 30° or more from the equator, and not much for locations closer to the equator. (There is, of course, no summer or winter at the equator.)

The two most obvious mechanisms by which I and S vary at locations 30° or more from the equator (and each could be affected completely differently by these two mechanisms) are:

W - Summer warmth and comparative dryness vs. winter coldness and wetness, with rain and perhaps snow.

D - Variations in vitamin D synthesis in the skin due to the Sun shining more directly downwards in summer, compared to at a shallow angle from the horizon in winter. (Also, people exposing more skin in the warmer months.) This directly affects the average vitamin D level of most of the population. (Even those who get no sun exposure are caught up in winter waves of infection, due to that year's somewhat novel flu strain being passed around in most of the population during winter.)

The second chart is evidence for the hypothesis that the dominant mechanism for changing (I x S) is D, because the women were still subject to strong W summer / winter temperature changes in New York State (40.6° north) and those who took the relatively small 0.02mg (800IU) D3 had hardly any more episodes of flu or common cold in winter than in any other season.

This second graph also enables us to distinguish whether it I or S which changed most, going high in winter and low in summer. Since all the women in the trial were a tiny proportion of the population, their viral exposure was essentially unaffected by being part of the trial, including when half of them were taking vitamin D.   So, on average, the intervention group suffered the same number of viral insults, with the same seasonality, as the control group.   This trial's outcomes are unaffected by the viral shedding of its subjects. So this data supports the hypothesis that, at least for these women, the variation in their vitamin D alone, and its effect on their susceptibility to infection alone, was sufficient for them to escape infection during the winter when they are most subject to the viral shedding of everyone else.

This doesn't tell us that viral shedding is unaffected by vitamin D, or by any other seasonal variable. Maybe they are - and it is obvious that a person who is very sick for a long time will shed more viruses than someone who has few, if any, symptoms, for a shorter time.

Since these infections were self-reported - not detected by any medical examination or blood tests - we don't know to what degree the women were infected with too few symptoms for them to notice as the flu or a common cold.

What is clear from this data (and there are various other research studies on vitamin D levels and respiratory diseases, with a range of outcomes) is that even low levels of vitamin D supplementation greatly reduced the subjective experience of illness in whatever infections the women actually had.   It is also worth noting that African American women living in New York state are likely to be generally very low in vitamin D, especially in winter, in the absence of supplementation.   So even small supplemental quantities could make a significant difference to the 25OHD levels and to to improving the strength and regulation of their immune systems.

We also see that 0.05mg (2000IU) vitamin D provided much greater protection from noticeable infection than 0.02mg (800IU).   This is not surprising.

With SARS-CoV-2, being so infectious and with most people (as far as we know, and research is continuing on levels of pre-existing immunity), I doubt if the proclivity to be infected due to a given viral insult varies a lot between people with low and high 25OHD levels.

The enormous drop in reported flu / cold infections in this trial, due to 0.05mg (2000IU) D3 a day may not be representative of all people, but there are numerous research studies indicating that influenza and viral respiratory tract infections in general (and COVID-19 starts off, and ideally ends, in the respiratory tract) are made much less likely and/or severe, for any given viral insult, by higher levels of vitamin D. For more such research:

https://vitamindwiki.com/tiki-index.php?page_id=1304

I believe that the severity of symptoms and so the degree of viral shedding will vary enormously between a person with very low 25OHD levels, such as of these women in New York State in winter without supplements (perhaps 10ng/ml or less) and such a person having taken 0.05mg (2000IU) D3 a day for a year. We would expect 0.125mg (5000IU) a day to be still more effective at reducing the chance of infection and/or the severity of infection and so the amount of viral shedding.

I am advocating all people - or as many as choose do so with good information, access their choice of quality supplements at suitably low cost, and without coercion or unreasonable cajoling or pressure - take enough vitamin D3 to get their 25OHD levels to the 40 to 60ng/ml range. This is what we aim for - but there's no time or money, and not enough labs or doctors, to do 25OHD tests for most of these people.

The solution needs to scale globally, since I don't know of a single country where average 25OHD levels are in this range. As you can read above, this is the range of our ancestors, the range our immune systems evolved to work from, the level needed for proper autocrine signaling within immune system cells, and the range recommended by the best researchers.

By scaling the intake with bodyweight - and probably at a higher multiplier for weights much beyond average, which indicate overweight or obesity - we can aim to get people's average 25OHD levels into this safe and healthy range, without prior knowledge or subsequent testing of their levels. Some will arrive at levels below 40ng/ml and some will get to levels well above 60ng/ml, which is OK. See the d3/ page. This is the best we can do without global testing, which is vastly more expensive than the actual D3 supplements. The 150ng/ml threshold above which toxicity might be a problem can only be reached with much higher intakes than are needed when aiming for 40 to 60ng/ml.

It is no good advocating a scheme which works for middle-class people in developed countries, but not for their poor, remote and/or indigenous people, or not for developing countries with limited health infrastructure. The plan has to work for all people.

It need not be expensive - its just a few cents a year per person of D3, packaged into weekly or fortnightly capsules. Average weight (say 55 to 75kg): get a pack of 52 capsules each with 0.125mg (5000IU) and take one a week. Other sizes would be made for children and young adolescents, and for overweight and obese people. Morbidly obese people need medical care urgently, so their doctor can sort out their vitamin D and numerous other nutritional and medical needs. Sick people need medical care too. The mainstream program would be to make such capsules, independently tested, available from multiple manufacturers with good advice about how to use them. In these quantities, they need not cost much. However, new pharma grade D3 factories will need to be built.

As you can read in https://sci-hub.se/10.1016/B978-0-12-381978-9.10006-X , in 2010 about 90 tonnes of vitamin D3 (cholecalciferol) was manufactured. About 20 tonnes of this was refined for human pharmaceutical use and the rest was for agricultural animals. This 20 tonnes is about 0.009 milligrams (360IU) a day per person, though of course most of it went to only a few people.   Pharmaceutical grade vitamin D costs about USD$2.50 a gram ex-factory in 1kg lots. So 0.125mg (5000IU) a day, would cost USD$0.12 a year.

Assume 0.125mg/day (1/8000th of a gram) for 7 billion adults (more for the overweight, less for children, and some people will choose not to take it) = 875kg/day = 320 tonnes a year.   So we need new D3 factories. There's no reason to expect the major factories in China and India to export to other countries once everyone realises how their current production meets only part of the needs of their own people.

Even a fraction of this would make a big difference, since (as far as I can tell, based on limited research to date) the people most at risk have very low vitamin D levels, and even small daily doses would raise these levels significantly and so reduce the chance they would suffer serious harm or be killed by their body's own weakened and dysregulated immune response to what is, for most people, the relatively benign SARS-CoV-2 virus.

The difficulty, disruption (to medical care, with so many doctors and nurses vaccinating rather than working in their regular roles), expense etc. of a global vaccination program can be imagined.   It is far, far, beyond the cost and difficulty of the D3 repletion plan I propose.

For the sake of the argument, lets assume that global scale vaccination was about as easy as D3 repletion. Let's assume it is a single injection and that there is usually no need for medical supervision or care to deal with serious side-effects.

Here are the arguments which show that even then, vaccination is vastly inferior to D3 repletion - and why D3 repletion makes vaccination for both COVID-19 and influenza unnecessary.   This is not a generalised argument against vaccination.   There are good reasons for vaccinating against other diseases which are still deadly or exceedingly harmful with perfectly good immune responses and all the best nutrition.   Its just that COVID-19 and influenza are generally benign viruses (or at least not seriously harmful, in the case of influenza) and that the whole reason people want to vaccinate against them is because a small subset of people can be harmed or killed by the disease AND because that subset is harmed due to inadequate vitamin D (most importantly, of several nutrients) causing their immune systems be weakened and dysregulated.

So here we contemplate a vaccination scheme as lightweight as giving most people about 1/22 of a gram of D3 a year, in weekly capsules, without need for direct medical supervision.

	Vaccination	D3 repletion aiming for 40 to 60ng/ml 25OHD
COVID-19 current and very similar strains	Assumed to be effective at stopping infection, or greatly reducing its severity, to the point where there would be almost no serious symptoms if people were infected AND there would be very few people infected anyway, due to herd immunity. In reality, there are dangers of adverse reactions, inadequate immunity, variations in how many years immunity lasts and potentially serious outcomes if the vaccine causes Antibody-Dependent Enhancement in some people.	In the case of infection, will generally lead to no or mild symptoms, and will make serious symptoms, harm, and death unlikely except in rare cases where people have multiple serious comorbidities and immune dysregulation which remains a problem even with adequate vitamin D. The generally low levels of viral shedding by most people, if they are infected, means that the disease cannot spread very far except in the most extreme situations of close personal contact.
A new strain of COVID-19 which evades the immunity elicited by the vaccine	The current strains will be under strong selection pressure to evolve a spike protein which still attaches to ACE2 but which is not recognised by the antibodies which vaccinated people produce. Given the global scale of the disease, this cannot be ruled out. On the other hand, coronaviruses mutate less than flu viruses and there is at least some cross reactivity between antibodies raised by SARS-CoV and the SARS-C0V-2 spike protein, which is functionally different and superior in how it attaches to ACE2.	People will handle all new strains of COVID-19 as they do the current ones, unless the new strain has evolved to cause far more symptoms with increased viral shedding. The virus is already highly infectious for a given viral insult, so there's not a lot of scope for it improving its performance in this respect. There should be no problems unless the virus develops an entirely new mode of operation, evading healthy, strong, well-regulated innate defenses so it causes lots of shedding, presumably stronger symptoms and so it gets to the lungs and causes damage there even with well regulated, strong responses, The virus already attaches strongly to ACE2. Even if it attaches more strongly, it will be basically the same disease and D3 replete people will be infected briefly, with the infection being halted in the upper respiratory tract, at it is for most people today.
Influenza	No protection against infection or serious symptoms and death.	All the above applies to influenza as well.
Common cold and other respiratory diseases	No protection.	All the above applies.
Sepsis and ARDS	No protection.	All the above replies. Hardly anyone - except those with profoundly damaging pre-existing conditions - will get sepsis or ARDS. (Still, those who smoke and abuse their bodies may harm their lungs.)
Numerous other chronic and acute diseases	No protection.	Partial or very substantial protection against dozens of diseases and chronic conditions. See the list above at the end of the #kp section. See also the long list of diseases on the left of the Vitamin D Wiki main page.
Need for medical personnel, syringes, hypodermic needles, refrigerated transport, privacy invasive record keeping etc. to fan out over whole cities and sparsely populated areas?	Yes.	No, but there needs to be good, well-labeled, inexpensive (or zero cost through government subsidy) supplement capsules and drops for babies, with a really good, multi-lingual, education campaign funded by the government and either approved by or paralleled by similar educational campaigns by internationally and locally trusted NGOs. This must not be seen as a purely government initiative, and there must be no coercion, or any other crap such as only allowing people to travel or work if they do a 25OHD blood test to prove they are replete. The same education and supply programs could also support increased intake of omega 3 fatty acids, boron, vitamin C, B vitamins, zinc, iron etc.
Longer term maintenance	Ongoing program for children and any new arrivals from overseas if not already vaccinated. At present we have no idea of how long vaccine elicited immunity would last for. Since it will be impractical to test people individually, research will show, for particularly sub-groups of the population, how often vaccination needs to be repeated. Maybe it will last a lifetime - but this seems unlikely.	D3 supplementation needs to be maintained from birth (except for babies breastfed by replete mothers).
Other opportunities	If medical teams comb the countryside and reach most settlements, there would be opportunities for medical checkups and other healthcare services.	No such medical contact, except perhaps to reach particularly vulnerable people in remote areas.
Overall health benefits for people, and so reduced health costs for governments and better national productivity	No improvement on the pre-COVID-19 situation, which is very poor compared with the levels of health which can and should be achieved with proper nutrition.	There will be profound, long-term, improvement in health in numerous respects, so boosting happiness, productivity, reducing health care expenditure, taxation, poverty and crime.
Dependence upon or government?	As currently conceived, most national vaccination plans seem to be the work of government, though middle-class and wealthy people might have the opportunity to choose between multiple vaccines if such vaccines exist, are sold in their country and have made it through government approval mechanisms. Otherwise, this is likely to be a highly government -centric operation, with all the privacy problems this entails, and profound resistance by many people (myself included) against getting injected with some concoction because the government says it is good.	I envisage government support, but multiple sources of D3, all independently tested and available at low or perhaps government subsidised zero cost. There's no need for privacy invasive record keeping or medical involvement for the vast majority of people. In chaotic third-world countries, it is possible that NGOs might do a lot of the work even if the government is not supportive. There is technically no need for government support, other than to allow the sale of this nutrient in the quantities required. For instance, in Australia, the maximum D3 content of any one capsule is 0.025mg (1000IU) which would make proper supplementation awkward and expensive.

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Primary problems concerning immunity, health in general and COVID-19 in particular

Problems and Solutions:

P1: COVID-19 spreads quickly unless unsustainable - and ultimately harmful and deadly - lockdown measures are enforced. If the disease only caused a week or two of suffering and inability to function properly, this would not be such a serious matter.

I have broken P2 into three sub-types. All these are strongly associated with very low levels of vitamin D and of other nutrients. However, there is much more to the interrelated set of health problems we are trying to solve than lack of vitamin D.

P2c: Coagulation. With current (generally inadequate) approaches to nutrition and hospital care, a significant number of people who contract COVID-19 die (0.5 to 5%) or suffer serious harm (5 to 20%). (2020-06-15: The UK death rate is 14% of the confirmed cases! While the latter is surely an underestimate, the death rate will rise even if new infections stopped today.) Most of these are elderly people with known health problems, but there are lots of people in middle age, in their 20s and 30s - and some children - who are suffering lasting harm and death.

The main reason for all this harm is the SARS-CoV-2 virus' ability, once it is replicating in the lungs (which would not occur if the immune system successfully fought it in the throat), to elicit a dysregulated immune response which damages the epithelium (inner lining of blood vessels and capillaries) in the lung. The fragments of epithelial cells cause the blood to become hypercoagulative - the natural, evolved, response to these signs of broken blood vessels.

This hypercoagulopathy causes blood clots (including thousands or millions of micro-embolisms) to form in the lungs. These, plus the viral and immune system damage, reduces oxygen and CO₂ exchange progressively over a week or so. Beyond a certain point, unless their breathing is assisted in hospital (with oxygen via nasal canula, trying as much as possible to avoid mechanical ventilation, with its sedation, invasive plumbing and lung damage) the person will die.

Even without significant breathing difficulties, the hypercoagulative state causes blood clots all over the body, resulting in permanent harm or death.

P2i: Inflammation. Many people, particularly as we age, suffer serious harm or are killed by a long list of chronic and acute illnesses caused by excessive inflammation. These include diabetes (type 2 and type 1 which strikes in childhood), asthma, inflammatory bowel disease, neurodegeneration (dementia), some forms of cancer and the mechanisms by which it metastasizes, multiple sclerosis, coeliac disease etc.

P2s: Sepsis. Many bacterial and viral diseases - and some injuries such as near-drowning and burns - if severe enough, can prompt the immune system to respond in an overly-aggressive, pro-inflammatory way known as sepsis. This develops rapidly and even with ICU hospital care, often leads to permanent disability and death. (Though see the Marik Protocol in icu/ for techniques which achieve better outcomes, in part by fixing the extreme vitamin C deficiency which afflicts sepsis and most other patients who need critical care.)

Most deaths caused by influenza are due to sepsis, in the form of Acute Respiratory Distress Syndrome (ARDS), in which the lungs are flooded (pneumonia) due to over-inflammation. This fluid reduces the ability to breathe, potentially killing the person. Even if this inflammation does not kill, it may lead to later bacterial infection - bacterial pneumonia - which again can flood the lungs, damage other organs and kill.

(Initially, it was assumed that COVID-19 produced a similar form of sepsis and ARDS. We now know that the virus's direct harm to the epithelium of the lung, together with the overly-inflammatory response there, drives an extremely destructive hypercoagulative state, which is not found in traditional sepsis or ARDS.)

P2c and P2s are caused to some extent by existing illness and injuries, such as to the lungs, but are primarily caused by P3w and P3d:

P3w: The immune system has one or more of its many antiviral, antibacterial, antifungal or antiparasite mechanisms weakened. This causes no direct harm to the self.

P3d: The immune system has one or more of these mechanisms dysregulated. Overly aggressive, overly inflammatory, immune responses ensue, often taking place at the wrong time or the wrong place. These responses are typically ineffective at combating the pathogen, but the most important result of this immune system dysregulation is inappropriate inflammation, including destruction of cells of the body which do not really need to be destroyed in order to stop viral or bacterial replication.

P2i is caused primarily by:

P3d on its own.
P4 (wheat, below).
By P3d exacerbating the problems caused by P4:

P4 The noxious properties of gluten proteins in wheat and related grains. Rice and oats are fine.

These grains evolved sulphur cross-links in the protein of the wheat grain to make them difficult to digest by birds, animals and insects which would otherwise eat the grain. These links give rise to wheat's dough's unique stretchy nature which is essential to bread-making. The linked sections of protein cannot be broken into separate amino acids by our digestive enzymes. The resulting protein fragments (the most notorious one is called 33-mer, with 33 amino acids) disturb the lining of the intestine and trigger an immune response there. The whole intestinal lining is in a constant state of inflamed preparedness, to accept food and defend against pathogens. This opens gaps in the tight junctions between the brush-border cells [W], allowing lumen (digestive juices, food fragments and bacteria) to enter the bloodstream, so causing inflammation and other problems throughout the body. For instance, in some people, wheat causes neurological problems, such as gluten ataxia [W] even though the problems in their digestive tract to not result in any noticeable symptoms.

While the sourdough processes used for all bread until the early 20th century reduces this disturbance by breaking down the noxious protein fragments, our taste for wheat condemns many of us to a lifelong struggle against the ill-effects of these indigestible fragments.

Other plants we eat contain noxious substances too. Wheat gluten would still cause us some harm even if our immune system was working perfectly. Today, due to human genetic variation and unknown triggers, some people suffer intense harm with coeliac disease, while most of us other wheat-eaters suffer more subtle forms of harm over a lifetime of eating non-sourdough wheat products.

There are several contributing causes to P3w (weak immune responses) and P3d (dysregulated, overly-aggressive, proinflammatory responses):

P5: P3w - Generally poor nutrition (including the separately listed problems of inadequate intake of macronutrients omega-3 fatty acids P15 and potassium P16 and of multiple micronutrients, such as vitamin D and boron P14), lack of exercise and lack of other essentials for health and happiness including clean air and water, sunshine, close friends and loving relationships, social contact, good medical support when needed etc.

P6: P3w - Prior injuries and illnesses.

P7: P3w & P3d - Nutritional excesses, such as salt, omega-6, saturated and trans fatty acids.

P8: P3w - Use of recreational drugs which harm health in general and immunity in particular, including alcohol and no-doubt tobacco, cannabis, cocaine etc. (Though there are suggestions that nicotine has anti-inflammatory effects which protect against severe problems with COVID-19: #nicotine .)

P9: P3w - The use of prescription drugs which weaken immune responses (immunosuppresants are helpful in some medical conditions, often due to our lack of helminths) or which cause particular problems with COVID-19. There has been discussion about particular hypertension drugs making things worse for COVID-19 patients. Some drugs such as hyroxychloroquine (for lupus) or others which dampen down excessive immune responses, such as for asthma or Crohn's disease, may be protective against severe COVID-19 symptoms. (Mehra et al. 2020-05-22 report (hydroxy)chloroquine apparently causing heart arrhythmia and being associated with higher death rates and an earlier RCT showed no antiviral or other benefits.) Prescription drugs should be continued unless advised by your doctor.

P10: P3w - Some people seriously curtail their body's initial attempts to fight the virus by lowering their temperature when they have a fever. See the fever/ page.

P11: P3w and P3d - Individual immune responses differing from from the norm due to genetic variations. These variations are primarily in the codons of our DNA, but there is also an epigenetic [W] component, in which long lasting (and impossible to change, as far as we know) methylation and other additions to the DNA occur due to life experience - including especially in-utero - affect how our bodies interpret the genes we inherited from our parents.

P12: P3d - Assuming that the person does not have any helminth infections (intestinal worms, as described in the previous section), some aspects of their immune system, due to evolution, being set up for overly-aggressive actions which are not being downmodulated by the helminths our ancestors had. See above: #helminthsgone . This is the condition of essentially all people in developed countries - our immune systems, in general, are primed to respond in damaging, overly-aggressive, proinflammatory ways to many stimuli, including especially SARS-CoV-2 infection of the lungs.

P13: P3w and P3d - People with helminth infections face P12 in general, but to some extent these P3d excesses will be moderated by the chemicals their helminths exude. These people may have weak responses to the virus due to helminthic downmodulation of normally effective immune responses. Their (without helminths) overly-aggressive responses may persist, may be downmodulated to being about optimal, with a good balance between fighting infection and harming the self. These responses may also be downregulated below the point of optimality - being ineffective against the virus, and hopefully being still less harmful to the self.

P14: P3w and P3d - Deficiencies in nutrients which cause significant weakening and/or dysregulation of the immune system. Of course all nutrition affects general health and so the immune system, but there are a number of micronutrients which are important here: vitamin D, boron, vitamin C, zinc, magnesium and probably quite a few others.

There are also two macronutrients of interest in this regard - macro because we need grams of them per day, not milligrams or micrograms: omega-3 fatty acids and potassium.

Most of what follows on this page, and in the forthcoming 5 Neglected Nutrients website, concerns vitamin D, boron, vitamin C, omega-3 fatty acids and potassium. These are all of widely neglected, but are vital to immune system functioning and to avoiding hypertension and stroke.

This article is highly relevant, but I haven't read it yet. It mentions vitamins A, D, C, E, B6, and B12, folate, zinc, iron, copper, and selenium.

A Review of Micronutrients and the Immune System–Working in Harmony to Reduce the Risk of Infection
Adrian F. Gombart, Adeline Pierre and Silvia Maggini Nutrients 2020, 12(1), 236 2020-01-16
https://www.mdpi.com/2072-6643/12/1/236

We can't stop the virus spreading, or change the genes which evolved in our ancestors

Nor can we coexist with COVID-19 by using vaccines, antivirals or lockdowns

We can - and must - improve nutrition to correct many of the failings which cause people's immune systems to be weak and/or dysregulated

Problems and Solutions:

S1: The public should be advised, in general (with whatever exclusions properly apply) that they should not lower their fever, with drugs or other means. This is potentially a complete solution to P10.

However, since it is impossible and generally undesirable to advise people to do this against the wishes of most doctors in general, and their doctor in particular, and since many doctors (I don't know the proportion - I guess 20% to 80%) still support the use of anti-pyretic drugs in general, and so I guess with COVID-19, this could only be fully achieved if we somehow solve another problem:

P20: How to convince the great majority of doctors of the need for this advice, in the next few weeks, so their united position will cause health authorities to promptly issue the required advice to the public, with the backing of almost all doctors. There is an urgent need for this, since the next wave of COVID-19 infections are coming, with lockdowns impossible to extend. (At least in the northern hemisphere, I hope people will get some sunlight on their skin over their summer and so boost their vitamin D levels a little.)

In principle this could be done by having them all read the research, such as that which I found and link to at the fever/ page. However, there are challenges regarding doctors changing their minds, rapidly, about a matter on which they have long held a contrary position. Arguments against lowering fever with antipyretics have been controversial for decades, and some doctors recognise the essential role fever plays in fighting infections. There is a long way to go, and here we run into numerous reasons - not all of them good - for the great resistance to change and new information which for many or most members of the medical profession constitutes a profound herd mentality.

Ideally there wouldn't be any urgency, and the doctors who still advocate lowering fever could be gently cajoled and convinced of the need to (generally) let fever do its work, over decades. This would be the polite thing to do, and would respect doctors' dignity and professionalism.

The trouble is, that with COVID-19 inducing protective fever in a large fraction of the population in the months to come, waiting and hoping for doctors to change their mind would vastly increase suffering, harm and death.

I think P20 is insoluble. Therefore, any improvement on the currently parlous situation - (P10) of people lowering their fever and so frequently suffering a more prolonged illness with more harmful and deadly hypercoagulation - will result from partial or full solutions to P21 and/or P22:

P21: How to convince health authorities to issue good advice against lowering fever for COVID-19 and perhaps other diseases, with suitable exceptions) despite a lack of consensus on this among doctors.

I regard P21 this as insoluble, since authorities generally would only advise according to broad consensus among doctors, and since many people would not accept such advice even if it was contrary to their understanding of doctors' consensus views.

P22: How to convince most people to ignore the opinion of many doctors, including perhaps their own AND the absence of suitable guidance by health authorities, with them placing more trust in the advice of particular doctors they know to be respected, and who advise (with suitable exceptions) against lowering fever for COVID-19 and/or in general.

This can probably be achieved to some limited extent, with Internet communications. It would be a pretty dodgy for this to be done by people like me who lack medical training, so I hope that the solution will be along the lines of:

S2: Directly to P22, indirectly to P21 and P20 and so towards fully achieving S1: Well-respected doctors and nurses communicate their advice on letting fever (in general, with suitable exceptions) do its work - primarily to the public, and secondarily to other doctors and nurses.

You know who you are. Blog! Write opinion pieces for news websites! Turn on your cellphone camera and talk to the public via YouTube and the like! Your place in history: one day wayward, impressionable, tragically optimistic doctors gone astray; the next day (or year or decade): celebrated, righteous rebel who gave the best advice contrary to cranky old paradigms now consigned to history's dustbin.

This article by Josh Farkas is pertinent:

https://emcrit.org/pulmcrit/pulmcrit-american-research-infrastructure-is-killing-us-
the-misbegotten-battle-between-the-ivory-tower-academics-and-the-rogue-cowboys/

On paper, the Ivory Tower Academics [who want RCTs before introducing any new treatment] will always look better. Their arguments are technically impeccable. It’s easy for them to paint themselves as the paragon of scientific virtue, while shaming others as irresponsible dilettantes. However, the closer one gets to the bedside struggle against COVID-19, the less compelling these intellectual arguments become. Thus, I daresay that among frontline providers actually caring for patients with COVID-19, the rogue cowboy mentality [who use RCT-unproven therapies which seem safe and effective] often has greater appeal.

I think emcrit.org articles and discussions I have read are the very heights of erudition, thoughtfulness and pertinence.

However, see Dr Roger Seheult's Update 74 in which he cites a CNN interview with YouTube CEO Susan Wojcicki, who states that videos which contradict the WHO's COVID-19 advice contravene YouTube's Terms of Service - so raising the spectre of academic censorship in the middle of a crisis.

S3: Directly to P7 and P8, and so in part to P3w & P3d - Everyone should be advised not to drink alcohol (or at least not to drink it regularly or to the point of intoxication) or use excessive salt - and of course not to harm their immune systems with other recreational drugs.

This is basic, uncontroversial, medical advise which can safely be given to everyone. So there should be no problems with changing doctor's thinking, or any controversy.

Again, it is unseemly for non-medicos such as me to be leading the charge here. So doctors and nurses should communicate directly and urgently with the public, and with their patients, as well as advocating health authorities to issue suitable directives.

Only a subset of people will take any notice, but it will help.

(There is a suggestion that some cannabis compounds might reduce COVID-19 severity. Maybe so, but this is of no interest to me since there's no way of deploying such compounds or any other drugs to the population in general in any time frame, let alone the months we have to cope with the second wave of COVID-19 infections.)

S4: We can and should urgently reduce the toll of harm and death for hospitalised patients, even within the currently poor nutritional arrangements by which most people live. See the Marik Protocol icu/ .

However, this would only relevant for the general population if all the people who start to develop the hypercoagulative state are able to be treated in hospital very promptly. People at home with symptoms continuing beyond a week or so, beyond the throat infection stage, with the virus replicating in their lungs, develop this hypercoagulative state and so are at high and ever-increasing risk of serious harm or death from blood clots forming in their lungs, brain, spinal cord, heart, liver, kidneys etc. People at home are suffering permanent neurological damage, stroke, heart attack etc. Children and babies are suffering and dying from a form of Kawasaki disease.

Generally (New Zealand potentially excepted) national governments can't slow the spread of the disease sufficiently to ensure that the 20% or so of their people who do get lung infections can all go immediately to hospital. If they could, then in principle it would be possible to fully achieving S4, which would have huge benefits and largely solve P2c.

In order to achieve S4 (ignoring for the moment that we can't generally slow the infection rate as just mentioned) we face problems regarding conservatism, herd mentality and getting changes made to departmental guidelines in a hurry similar to those mentioned above regarding fever (S2). As with S2 and S3 it would be unseemly for non-medicos like me to be advocating change, so it is vital that doctors and nurses work within their professions, and by communicating to the public in general, about the need for hospital treatment protocols such as those pioneered by Dr Marik, which result in far less harm and death than is the norm in most hospitals so far (to May 2020 at least).

However, even if S4 was fully achieved, this is only relevant for the general population to the extent that all the people who start to develop the hypercoagulative state are able to be treated in hospital very promptly.

People at home with symptoms continuing beyond a week or so, beyond the throat infection stage, with the virus replicating in their lungs, develop hypercoagulopathy and so are at high and ever-increasing risk of serious harm or death from blood clots forming in their lungs, brain, spinal cord, heart, liver, kidneys etc. People at home are suffering permanent neurological damage, stroke, heart attack etc. Children and babies are suffering and dying from a form of Kawasaki disease.

The Marik protocol works, in part, by solving a severe nutritional deficiency, of vitamin C, by way of intravenous vitamin C (ascorbic acid) around 10 grams per day.

I believe these techniques could be improved by repleting patients' deficiencies of vitamin D, boron and other nutrients as well.

However, the earlier all these nutritional deficiencies are fixed, the better - so that the people don't get seriously ill and never need to go near a hospital.

Other solutions having been highlighted, we now focus on nutrition to improve the function of the immune system, general health and to reduce hypertension and the risk of stroke

Updated version of the message I wrote to clinicians and researchers in late March

Poor survival rate once people need breathing assistance

Most people's battle against the virus will be lost or won at home, not in hospitals or doctors' clinics. Zhou et al. (below) report that of 34 patients receiving invasive mechanical ventilation or ECMO [WP], only 1 survived. The survival rate for non-invasive ventilation was 2/26 and for nasal breathing support, 8/41. Antivirals and antibiotics help, but we will soon run out of these.

Coronavirus home remedies as suggested here - nutritional supplements to enhance immune system function, especially by reducing the overly-aggressive pro-inflammatory responses which cause sepsis - can make a substantial contribution to public health in this disastrous situation, given doubling times of half a week, and the impossibility of retaining sufficient social distancing for 6 months or more.

Clear guidance regarding paracetamol, ibuprofen, aspirin and NSAIDs in general

Reducing the cytokine storm of sepsis

The cytokine storm, lead by IL-6, TNF-alpha and other pro-inflammatory cytokines is the primary or sole cause of death - and probably of pneumonia and so most hospital admissions. The graphs in Fei Zhou et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

show that those who survived usually did so without radically elevated IL-6 levels, and that those whose IL-6 levels kept on rising died. Thrombosis (D-dimer) increased progressively in those who died, but not in survivors. These averages are extremely divergent. Serum ferritin kept rising in those who died, indicating not iron overload, but (www.bmj.com/content/351/bmj.h3692.full) excessive inflammation.

The real enemy with COVID-19 is not the virus itself, but the excessive and inappropriate inflammatory response to it - the same thing which drives sepsis, neurodegeneration (Alzheimers, Parkinsons), osteoporosis, diabetes etc. One probable cause of this is that some aspects of our immune system are far more aggressive than they should be, due to them evolving in the presence of ubiquitous infection with intestinal parasites and/or H. pylori, both which attenuate these mechanisms. However, now is not the time for helminthic therapy. (Google search for helminthic therapy.)

Another set of causes, which can be fixed - and must be fixed in the next few weeks in order to prevent millions of deaths - are nutritional deficiencies, particularly in vitamin D, boron, omega 3 PUFAs and probably other nutrients such as vitamin C. For brevity I state the following arguments as if they were facts.

Starting in March 2020 and peaking in May, June and beyond, billions of people will contract COVID-19 and a substantial fraction of them will be pushed into sepsis-induced pneumonia, respiratory distress and organ failure - with a high risk of lasting disability and death.

Doctors, nurses and health organisations have an urgent responsibility to read the research and make the connections so they can advise everyone on readily available nutritional supplements which will reduce the incidence of sepsis in the months to come. These levels of nutrition are known to be safe. There is no need, or time, for RCTs.

Vitamin D3

Vitamin D deficiency is a major causative factor for Acute Respiratory Distress Syndrome, which is what kills most people with COVID-19.

Dancer RCA, Parekh D, Lax S, et al.
Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS)
Thorax 2015;70:617-624.
thorax.bmj.com/content/70/7/617

With the knowledge from this trial, how is it ethical to admit people to hospital like this and not give them 500,000IU (12.5mg) vitamin D3 in the first 5 days?

The cost is USD$30 for 100 capsules. The cost of giving ICU patients 500,000 IU vitamin D (12.5mg) is USD$3.00. To save:

So the cost of avoiding one day in hospital, with vitamin D supplementation = USD$0.17.

A 2014 article PMC4220998 relates blood levels to vitamin D3 supplement quantities for underweight, normal, overweight and obese people. For normal weight people, 4000 IU/d provides 117 nmol/L, which is 47 ng/ml. Toxicity (PMC6158375) occurs with blood levels more than three times this.

If all adults (who wisely have little UVB exposure) took 4000IU vitamin D3 a day (a gram every 27 years) then they would avoid most of the diseases caused by vitamin D deficiency. This chart from Garland et al. 2014 PMC4103214 shows the importance of achieving at least 40ng/ml.

Numerous peer-reviewed journal articles showing adequate vitamin D reduces inflammation AKA sepsis can be found at:

COVID-19 Vitamin D dose recommendations from doctors

Omega 3 PUFAs

The same is true of omega 3 fatty acids. I believe that if the WHO et al. recommended adults take 2 grams of fish oil a day and 4000IU vitamin D3, that this - to the extent that people were willing and able to comply - would significantly reduce disease severity and death for hundreds of millions of people, especially those with a Western, indoor, lifestyle.

Zinc

It may be best to recommend zinc supplements, since Zn++ in the cytoplasm inhibits viral RNA synthesis - including zinc lozenges to slow the initial infection in the throat, before it gets into the lungs. Zinc is needed for hundreds of enzymes. Please see what Google scholar returns for zinc inflammation immune.

Vitamin C

Vitamin B1 thiamine

Boron

2020-06-15: I have a box of boron research papers and am keen to write them up as an annotated bibliography. I don't know when I will have the time for this. I will do it on the new website.

For now, please start by reading this excellent review article from 2018, which has a lot of links to research on boron's role in the immune system, especially regarding inflammation.

the work of long-time US Department of Agriculture boron researcher, Forrest Nielsen, such as:

One advantage of boron over the other micronutrients mentioned here is that while supplies of the others could easily be snapped up if everyone wanted them, there is plenty of boron for the whole population sitting on supermarket shelves, in the form of laundry borax.

It is a scandal that boron is not officially recognised as an essential nutrient. Most people turn their noses up at the thought. The word sounds like "boring" and rhymes with "moron". They know borax is used in laundry, as a welding flux, as an ant and cockroach poison and in children's slime. Many people recoil at the idea of ingesting boron, because they see borax is the active ingredient of Ant Rid (8.5% borax). But boron is in many foods, and vitamin D3 is a widely used rat and mouse poison. (See my second comment at quillette.com/2020/03/22/covid-19-statistical-and-science-update-for-march-22/ .)

The naturally pure mineral borax - sodium tetraborate - is mined at large scale in Turkey and California, and then refined into the bright crystals sold in supermarkets. USP boron is used in nutritional supplements and medication, but it is difficult to obtain at a retail level.

If a drug company found a patentable compound with boron's health benefits and safety profile - including especially its ability to restrain the body's overactive, sepsis-causing, inflammatory response - then we would all be singing its praises and paying top dollar for it.

Borax, 100mg a day, in water solution, provides 11.36mg boron a day, and I believe this will significantly reduce the inflammation which is killing COVID-19 patients. (I have a box of journal articles on boron, and no time now to write up an annotated bibliography of boron nutrition.)

3mg boron capsules are readily available, but an alternatiive is to get a heaped teaspoon of borax (about 8 grams), divide it by 4, and dissolve each quarter in 2 litres of water. Two 50ml drinks a day provides 11.36 mg boron.

500 grams of borax is enough for 5,000 days at this rate, so a single borax purchase would help a dozen or so households through the current crisis. Beware that in the European Union the sale of borax is apparently banned - and what is sold as "borax" for laundry use is something else entirely.

Two later articles, also from Iraq, mention boron and other mineral levels in RA patients: 2015-05 and 2015-07 . In both cases the RA patients' boron levels were also about half of those of the control subjects. These two are in a well-known predatory journal: the Pakistan-based, so-called: American Journal of Internal Medicine. I regard these articles as probably being based on real research, but not really citable due to the journal they appear in.

Boron supplement capsules and tablets are available from numerous companies, usually with 3mg boron. This is suitable for taking two a day, since this gives 6mg a day, and the half-life of boron in the bloodstream is a little less than a day. An eBay search for boron and 3mg showed products from obscure companies and major ones such as Now, Solgar, Life Extension and Solaray. The best deal I found was 250 3mg capsules for USD$6 or less: swansonvitamins.com .

I have noticed small amounts of boron, such in some Australian supplement tablets containing other compounds for arthritis:

I was pleasantly surprised to see boron in some mass-market (larger supermarkets all over Australia) multivitamin capsules, from Cenovis: https://cenovis.com.au/?s=boron :

Salt

Exercise

Potassium supplementation with potassium gluconate solution is superior to blood pressure medication

Overcoming Western Medicine's blind spots in the next week or two

Conventional Western medicine excels at surgery and other acute interventions, but has blind-spots regarding nutrition and chronic diseases.

Since there is no money to be made from the nutrients mentioned above, their full benefits are known only to some clinicians and researchers. In the developed world, most people are deficient in potassium, vitamin D and especially boron. This leads to illness with aging, diabetes, stroke, CVD, sepsis etc.

As best we know, SARS-CoV-2 will induce debilitating and potentially deadly sepsis in 5 to 20% of the population in April, May and June. The terrible toll which is likely to come from this is due, in large part, to easily corrected nutritional inadequacies. These they can be solved, since the necessary nutrients are widely available.

icu/	Doctors! Be sure to see the sections on this page on the Marik Protocol and the closely related MATH+ Protocol for ICU treatment of COVID-19 patients. It results in higher survival rates than the techniques used in most hospitals today. This page also has more detailed discussion of COVID-19 endothelial pathology in the lungs and the importance of good vitamin D levels to ensure our immune responses are both strong and well regulated.
obesity/	Fat cells (adipocytes) in obesity are known to increase inflammatory responses and so worsen the cytokine storm which characterises COVID-19 with severe symptoms. This is true of visceral adipocytes around the heart and other organs in the abdomen. Ectopic (growing where they shouldn't) adipocytes in the lungs are also a problem. Furthermore, adipocytes may express the ACE2 receptor and so be subject to infection by SARS-CoV-2. Obesity is perhaps the biggest single risk factor for severe COVID-19 symptoms, and so for death or lasting harm from microembolisms and resulting organ damage for those who survive. On one hand, it could be argued that repleting all relevant nutrients to ensure good immune function - including vitamin D to achieve at least 40ng/ml 25OHD - will help immune system function in general, but that these excess adipocyte problems will remain. On the other hand, as far as I know, the problematic behaviour of these adipocytes is generally only observed in patients whose vitamin D levels have been low for years, and remain low. So there's a chance that with nutrient repletion, their potentially destructive role in the immune response will be significantly less than is normally the case.
d3/	Links to the best research articles on desired vitamin D blood levels and what amounts of supplemental vitamin D3 are needed to achieve this, on average, for underweight, normal, overweight and obese body types. Links to (and in the future discussion of) the most pertinent research on the vexed question of vitamin D toxicity - in general and for individuals with particular genetic makeups, particular tumors or granulatomous diseases such as sarcoidosis.
3-reasons/	Three reasons I want everyone in the world to have good nutrition for immune system health, to greatly reduce the chances of their immune responses being weak and/or dysregulated.
crisis-diy/	(I haven't written this yet.) If demand for pharmaceutical vitamin D greatly exceeds supply (as I expect it will once most people recognise they need substantial supplements to stop their immune system causing harm and death when responding to the SARS-CoV-2 virus), what are we going to do for people who cannot get the supplemental D3 they need or good, high-elevation sun exposure most days? Firstly, access some of the vitamin D3 used for agricultural feed, which is where about 75% of D3 production goes. Secondly, use boron - which is worth using anyway for its anti-inflammatory and other immune-system benefits. Thirdly, find UV light sources which can drive D3 synthesis in our skin - this is tricky. Finally, build vitamin D3 factories in our own countries - skunkworks-style as in war-time, since our lives depend upon it. Regarding this, for now please refer to this excellent description of industrial production of vitamin D3 cholecalciferol by Arnold L. Hirsch in 2010 : https://sci-hub.se/10.1016/B978-0-12-381978-9.10006-X .
prisons/	About 10 million people are confined in prisons and jails. They and the prison staff are at high risk of COVID-19 infection. While (in the USA, so far, 2020-06-22) rates of prison harm and death per confirmed case from COVID-19 are generally lower than in the outside world, this is primarily due to few prisoners being over the age of 60. The number of confirmed cases is generally higher - which may be partly due to better testing in prisons. The rate of harm and death for younger prisoners may be higher than in the outside world - in part because prisoners in general have even lower vitamin D levels than free living people. There is an urgent need to give all these people substantial vitamin D supplements - and more generally the full range of vitamins, minerals and omega-3 fatty acids. The health and other benefits have already been shown to far exceed the small cost of providing these - and COVID-19 infection is close to inevitable in the months to come.
kna/	Decreasing sodium (salt) consumption and boosting potassium intake - including with supplements in the form of potassium gluconate solution drinks - reduces the incidence of high blood pressure and stroke.
fever/	Links to research articles indicating that in general, with certain exceptions, fever (at least in the initial stages) should not be lowered because it is an important part of the body's defense against viral and bacterial infection. Also links to some research which may indicate there is little harm and perhaps some benefit of lowering fever with COVID-19 with particular drugs.

#intro	Introduction.
#othersites	Some other sites of interest.
#cv19vitd	Recent articles concerning COVID-19 and vitamin D.
#2015-Stagi	Severe vitamin D deficiency in Italian children with Kawasaki disease.
#pandend	Ending the global vitamin D deficiency pandemic by aiming for at least 40ng/ml 25OHD. This is the only way we can ensure that COVID-19 causes far less harm and fewer deaths.
#cvkd	COVID-19 induced Kawasaki disease in children and babies AKA Paediatric multisystem inflammatory syndrome.
#uk-bame	Discussion of the high rate of harm and death to black, Asian and minority ethnic people in the UK has generally not mentioned their very high rates of vitamin D deficiency.
#pep-talk	Pep-talk for doctors regarding the need for robust vitamin D supplementation to protect against severe COVID-19 symptoms. Written specifically for BAME doctors, but really to all doctors - and not just because of COVID-19.
#2020-Baker-a	Articles concerning vitamin D supplementation to protect against harm and death from COVID-19, including research which shows that 40ng/ml or more 25OHD is required for proper immune system functioning. Also a list of other articles of interest I have not read or written about yet.
#low-verylow	Irish doctors debate whether to use low or ridiculously low doses of vitamin D3.
#21authors	21 authors advise very low levels of D3 supplementation, aiming for a minimum 25OHD level of only 10ng/ml.
#weak-sys	COVID-19 pathology - weak and dysregulated immune systems. The icu/ page has all the details.
#helminthsgone	Weak and dysregulated, over-inflammatory, immune responses are caused by lack of helminths, individual genetic variation, dietary excesses and several common nutritional deficiencies.
#vaccines	A safe, effective, reasonably long-lasting vaccine to protect against COVID-19 may never be devised. Even if it is, it will take a long time and be much more expensive and risky than vitamin D and other nutritional supplements which will actually, to a substantial degree, solve, the immune system weakness and dysregulation which drives COVID-19 severe symptoms.
#disclaimer	I am not a doctor etc. About these pages. Contact and copying information.
#plan	Global plan for better nutrition for immune system health, and for better guidance regarding fever. Written for people who are fusspots for detail.
#msg	This section is older, and not so recently updated. It is based on the email I sent out to doctors, researchers etc. starting on 22 March 2020. This has a section on boron: #08-boron .

	Patients	Did not need intensive care Number Percentage	ICU	Died in ICU
Control	26	13 50%	13 50%	2 8%
Vitamin D	50	49 98%	1 2%

	Not COVID-19	COVID-19 positive total	COVID-19 positive who died
Patients	60	63	4
25OHD ng/ml	30.2	18.5	8.2

	Group A Asymptomatic	Group B ICU	Notes
Patients	91	63
Mean 25OHD ng/ml	27.8	14.4	P = 0.0001.
25OHD > 20ng/ml	62 (68%)	2 (3%)
25OHD < 20ng/ml	29 (32%)	62 (97%)
Highest tertile 25OHD: 27.8 to 49.1ng/ml	52 (57%)	1 (1.6%)
Middle tertile 25OHD: 9.2 to 27.7ng/ml	27 (30%)	23 (37%)
Lowest tertile 25OHD: 3.2 to 9.1ng/ml	12 (13%)	39 (62%)

	Ferritin ng/ml	IL-6 pg/ml	Tumor necrosis factor alpha pg/ml
Highest tertile 25OHD: 27.8 to 49.1ng/ml	170	10.4	10.4
Middle tertile 25OHD: 9.2 to 27.7ng/ml	231	17.4	12.6
Lowest tertile 25OHD: 3.2 to 9.1ng/ml	384	21.2	14.3

	Vitamin D 25OHD levels below 20ng/ml (50nmol/L)	Vitamin D 25OHD levels 20ng/ml (50nmol/L) and above
Patients	90	64
Died	19 = 21%	2 = 3%
Ferritin ng/ml	19.3	12.2
IL-6 pg/ml	13.6	11.9
Tumor necrosis factor alpha pg/ml	319	186

Clinical outcomes	< 30ng/ml N = 158	>= 30ng/ml N = 77	P value
Deaths	20.0% (26)	9.0% (7)	0.04
Unconsciousness	8.3% (13)	1.3% (1)	0.03
Hypoxia	39.2% (62)	19.4% (15)	0.004
CFP > 40ng/L	77·2% (122)	61.0% (47)	0.01
Lymphocytes < 20%	60·1% (95)	45·5% (35)	0.03
Severe - critical	77·2% (122)	63·6% (49)	0.02

#00-survival	Poor survival rate once people need breathing assistance
#01-fever	Clear guidance regarding paracetamol, ibuprofen, aspirin and NSAIDs in general
#02-sepsis	Reducing the cytokine storm of sepsis
#03-vit-d #03-vit-d-dose	Vitamin D3 Doctor's recommended vitamin D3 doses for COVID-19
#04-omega-3	Omega 3 PUFAs
#05-zinc	Zinc
#06-vit-c	Vitamin C
#07-vit-b1	Vitamin B1
#08-boron	Boron
#09-salt	Salt
#10-exercise	Exercise
#11 -ht-drugs	Potassium gluconate solution is superior to blood pressure medication
#12-blind-spots	Overcoming Western Medicine's blind spots in the next week or two

Vitamin D & other nutritional supplements to protect against severe COVID-19 symptoms

I have a second website, and some infographics there and below: