Letter to Premier Ford (sent ~a week ago)

 

Dear Premier Ford:

re: A Way Out of Pandemic Dilemma

I appreciate the difficult task that you and the Province of Ontario have in managing the COVID-19 pandemic. You have to protect the population, particularly our most vulnerable members, and you have to protect the economy and society at large. May I suggest some steps to deal with the competing interests.

1. Focus on the capacity of our health care system, mainly hospitals, to handle COVID rather than the number of citizens being infected. With what the world has learned since January, we should be able to manage the numbers who become severely ill even if the total number of cases increases sharply. An inspection of the graphs of cases, hospitalizations and deaths suggests that Ontario can handle a substantial rise in cases and still protect the hospitals and the most vulnerable.

2. Ensure that the population is vitamin D sufficient. I have had an interest in this substance for several years and have come to appreciate its importance to the overall health of individuals. Accordingly, it is more than just a vitamin required to prevent rickets. It is now recognized as a pro-hormone that can affect virtually every cell in the human body. In the context of the current pandemic, its most interesting features include an anti-viral effect and the ability of modulate the inflammatory response to viral infections. Going into this pandemic there was substantial circumstantial evidence that led me and others to suggest that vitamin D sufficiency was crucial to our ability to deal with this disease. Since January there has been an abundance of evidence that indicating that vitamin D deficiency promotes COVID-19 and that supplementation with this compound would reduce both the prevalence and severity of the disease. Please take 80 minutes and watch the excellent video on vitamin D and COVID at https://www.youtube.com/watch?v=8UzpvtRqleY&feature=youtu.be. If you don’t have the time, please have a staff member watch it and summarize it for you; alternatively you could take just a few minutes and read my May 19 blog at https://vitamindcovid.blogspot.com/2020/05/vitamin-d-covid-19-and-me.html and the Sep 10 update at https://vitamindcovid.blogspot.com/2020/09/vitamin-d-and-covid-19-update.html.

Of the many recent reports related to COVID treatment the one that impressed me the most was the August 29 publication by Castillo et al in the Journal of Steroid Biochemistry and Molecular Biology. This small prospective trial compared 50 calcifediol-treated subjects with 26 control subjects in Cordoba, Spain. Among those treated with calcifediol only one (2%) required intensive care compared with 13 (50%) of the control group; there were no deaths in the calcifediol group and two in the group that did not receive this form of vitamin D.

If we were to bring the population of Ontario up to vitamin D sufficiency, it seems possible to bring the burden of COVID-19 down to a level that may well be acceptable to the population at large. Optimistically, the Infection Fatality Ratio (deaths divided by infections) could be ~0.02 to 0.06% with vitamin D sufficiency and the judicious use of calcifediol (faster acting form of vitamin D) and dexamethasone in our most seriously ill patients. I believe that the risk of dying due to COVID-19 could be reduced to be that of seasonal influenza. Under such circumstances, our society and economy could be opened up to that during a serious outbreak of seasonal influenza. In saying this, I do not take seasonal influenza lightly as the number of deaths is far from trivial. At the same time, the adverse effects brought on by our response to COVID-19 are very substantial. These include but are not limited to poor mental health, cancer, opioid deaths, economic disaster, poor physical health, etc; I have addressed some of these in my June 7 blog entry at https://vitamindcovid.blogspot.com/2020/06/human-and-economic-cost-of-covid-19.html. Unfortunately you (we) are in the position of having to balance the adverse effects of COVID-19 against the adverse effects of its treatment- a no win situation for sure.

In order to ensure that residents of long-term care homes are protected, the Province should consider acquiring an adequate stock of vitamin D for them prior to recommending it to the public. Patients needing vitamin D on admission to hospitals should be given calcifediol. Vitamin D tablets are very inexpensive; it would cost just pennies a day per person. It is also very safe. The dose at which adverse effects can be observed is far in excess of that required to prevent or mitigate COVID infections. This compares very well with the thousands of dollars/day it costs for a hospitalized patient.

3. Ventilation of indoor facilities. I understand that the major route of COVID transmission is through inhalation of virally laden air as would be the case in poorly ventilated and crowded rooms. In order to address this the Province has chosen to limit the numbers of people permitted the various establishments. May I suggest the alternative of setting standards for ventilation by area- a certain number of air exchanges per hour. This might allow more people in a room if the air flow was sufficient to dilute/take away exhaled virus particles. I could imagine a restaurant with exhaust tubes above each table collecting exhaled air and expelling it from the building; it this were connected to a heat recovery ventilator this would minimize the added heating expense for the restaurant.

4. Alternatives to mechanical ventilation. We are concerned about overwhelming our hospitals with COVID patients because their lung infections render them hypoxic and in respiratory distress. Accordingly, there has been much effort put into ensuring that they have a sufficient supply of mechanical respiratory ventilators and the personnel to operate them. In the May 15 issue of the Journal of Wound Care, the authors describe using hyperbaric oxygen chambers to treat hypoxia due to COVID-19. As there are numerous hyperbaric chambers in our cities, there would be substantial capacity to relieve our hospitals should it become necessary. In the unlikely event that all of these were insufficient, it should be possible to commandeer a few jet aircraft and pressurize them with oxygen enriched air to create makeshift hyperbaric chambers. This is not an original idea as it has been suggested by others.

In closing, I would like to thank you and your colleagues for all your efforts to keep our most vulnerable family members safe. My 98 year- old aunt is in a Toronto long-term care home and has survived a bout of COVID-19.

Your sincerely,

Kanji Nakatsu

Vitamin D and COVID-19 Update

It's been months since my initial entry on COVID-19 and vitamin D.  In that period there have been a number of further publications related to the value of vitamin D in the prevention or mitigation of this viral disease.  The findings of four reports are summarized below; all are consistent with the notion that vitamin D status affects the COVID-19 response.  

One study entitled "Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results" by Meltzer et al can be found at https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157 and was released on 2020 Sep 03.  They looked at the records of 4314 patients at a Chicago medical facility and identified 489 who had their vitamin D status measured before the arrival of COVID-19.  Then they tested those with some COVID symptoms and found 71 who tested positive.  Among patients who were determined to have COVID, those who were considered to have low vitamin D levels had a 77% higher chance of getting the disease, i.e relative risk of 1.77.  Moreover, non-White (mostly Black) people were 154% more likely to contract COVID, relative risk 2.54. 

In a similar study conducted by Merzon et al in Israel, 7807 patients whose vitamin D status had been determined were followed for the development of COVID between Feb 1 and Apr 30.  When tested 782 were positive and 7085 were negative. The authors concluded that those who were deemed to have low plasma vitamin D were 45% more likely to contract the virus, and also more likely to be hospitalized. https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/febs.15495 

In another Israeli study each of 52,405 COVID-infected patients were compared with 10 well matched control individuals, thus, a total of 524,050 controls, https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1.full.pdf.  They found a significant association between low vitamin D levels and COVID occurrence, and the risk of developing the disease was higher for those with severe deficiency (<20 nmol/L) than for those with milder deficiency (<50 nmol/L).

The study entitled "Effect of Calcifediol Treatment and best Available Therapy versus best Available Therapy on Intensive Care Unit Admission and Mortality Among Patients Hospitalized for COVID-19: A Pilot Randomized Clinical study" by Castillo et al was released on August 29 in the Journal of Steroid Biochemistry and Molecular Biology.  This study involved 76 consecutive patients hospitalized with COVID-19 infection in Cordoba, Spain.  Of these 50 were randomly treated with high dose calcifediol and 26 were maintained as controls; both groups were given the best available treatment at the time.  Calcifediol is the molecule that vitamin D is converted to by the liver, and would act faster than vitamin D.  In the treated group, one patient out of 50 had to be placed in ICU, while in the control group 13 out of 26 went to ICU.  No deaths occurred in the treated group but two died in the control group. https://www-sciencedirect-com.proxy.queensu.ca/science/article/pii/S0960076020302764

This latter study is the closest that I have seen to the gold standard large-scale, prospective double-blind study.  Nevertheless, I think that all four recent reports strongly support the widespread use of vitamin D to reduce the burden on our health care system.  

Canada's Policy on COVID-19.  Now that there is considerable evidence that is consistent with idea that vitamin D status matters with respect to the possibility of individuals contracting COVID-19 and the severity of the disease after contracting it, Health Canada should advocate the widespread taking of vitamin D for our population.  If Health Canada takes the position that they require information from a large-scale, prospective, double-blind trial before making such recommendations, then my question becomes "why haven't you done these experiments?"

This leads me to suggest that Canada should have a serious discussion about our approach to this disease.  The national objective to this point appears to be suppression of COVID-19 followed by widespread vaccination of the populace once an acceptable vaccine becomes available. This assumes that a vaccine will become available in a timely manner.   Now that the world knows more about this disease, its treatment and current damage to society inflicted by its indirect effects, we should discuss other possible approaches. One potential approach could be to encourage vitamin D sufficiency in our population and institute appropriate preventive measures for vulnerable populations, and then open up the economy significantly faster.

Let's start by examining the indirect damage being done by this disease; to date I have not observed a federal or provincial analysis of the these adverse effects.  We know the economy has suffered and continues to suffer; how is this affecting the health and quality of life for Canadians?  Workers and business owners in the hospitality industries are hurting.  The travel industry is still a mere shadow of its former self.  How are our isolation policies affecting students and instructors right from kindergarten to post-secondary education?  How has the mental health of our population been affected?  Various reports indicate that mental health problems have resulted in increased domestic violent.  How has physical health been affected?  Many people have reported developments ranging from the trivial (weight gain) to the serious (lack of health services including cancer diagnosis and treatment).  Personally, I have a minor example of delayed treatment; it is about a year since I was diagnosed with a full thickness tear of my left supraspinatus tendon.  COVID has resulted in me not even been interviewed by a surgeon yet.  Many others have serious conditions that have gone untreated.

Let's also consider other ways in which we might try to resume close-to-normal activities.  How badly would COVID-19 affect our collective health if we made the population vitamin D sufficient, used anti-inflammatory steroids, and protected identified populations?  Early in the current pandemic the case fatality ratio (number of deaths divided by the number of confirmed cases, CFR) was estimated to be in the order 5%- i.e. 5 people died for every 100 who tested positive for the disease.  As testing has become more available, and information about vulnerable individuals has accrued, the estimates of the CFR have fallen substantially.  By June, it had decreased to less than 2% in Canada.  By late summer, we began to appreciate that the number of COVID-infected people was substantially greater than the number who had tested positive for the disease; this was due to the use of tests for COVID-19 antibodies.  This had the effect of giving us an Infection Fatality Ratio (number of deaths divided by the number of infections, IFR)  somewhere in the range of 0.2 - 0.6%.  If we consider that these statistics were gathered in the absence of knowledge about the beneficial effects of anti-inflammatory steroids and vitamin D, it may be possible to reduce the IFR estimate by a further order of magnitude to the range of 0.02 to 0.06%.  These numbers put the risk of dying due to COVID-19 close to that of seasonal influenza, and we have not imposed lockdowns for the flu.  What I've not taken into consideration is the relative contagiousness of COVID-19 compared with influenza.  Even if the IFR is considered low, the number of vulnerable people contracting the disease could be sufficient to overwhelm our hospitals. The operative words herein are "number" and "vulnerable", and the former is substantially under our control.  For the most vulnerable, such as those in long-term care homes, the necessary precautions are quite well known now, and these people can be protected.  Control of the numbers of people contracting COVID is largely behavioural.  Perhaps the key question, is how careful or draconian (the word used depends on your point of view) we should be in our efforts to control the overall rate of infection.  The studies cited above and others suggest that we have the tools that can be used to open our society and economy more quickly.

Dealing with the Human and Economic Cost of COVID-19

We all know the disastrous direct effects of COVID-19; as of 2020 June 06 worldwide there were 6,844,705 cases and 398,141 deaths according to www.worldometers.info/coronavirus/. Nevertheless these were only the direct effects of the virus. COVID-19 has affected the world negatively in many other ways, and goal of this entry is to raise awareness of some of the major problems and the extent to which they affect us. Briefly, is our response to COVID-19 worse than the disease? I don’t have the expertise and resources to put a human or monetary price tag on the effect of COVID-19. I hope that a body such as the Parliamentary Budget Office will take this on and publish its findings. Nevertheless, I can describe some of the things that should concern all of us.

Economic downturn: The impact on jobs in this country has been disastrous; we lost approximately 3 million jobs in March and April before receiving a small recovery of about 300,000 in May. It has been said that the total number of hours worked by the labour force has decreased by ~30%. Any long term restriction of our economy will negatively impact all aspects of Canadian life including our health care because all such services require money.

Opioid pandemic: Even before COVID-19 arrived in Canada, we were dealing with a crisis in the abuse of opioids. This has had immeasurable social costs and personal impacts on the families affected. The opioid pandemic has been made worse by our response to COVID-19 because many affected individuals have not accessed safe injection sites and other sources of help. Moreover one would suspect that more people are abusing opioids as a result of the viral pandemic.

Cancer: In the UK, the National Health Service estimated that 24,000 cases of cancer have gone undiagnosed. Due to COVID some 12,750 fewer cancer surgeries have been done, 6,000 fewer chemotherapies have been started and 2,800 fewer radiotherapy treatments have occurred. This surely will result in increased numbers of early deaths in the UK. Undoubtedly a similar situation holds for us; unfortunately I have not found similar data for Canada.

Mental health: COVID-19 per se and our response to it have taken a toll on the mental health of Canadians. Certainly it has decreased the quality of life for virtually everyone in Canada. The stresses imposed might have been as little as the loss of a hug to as much as murder. Various levels of government have estimated that family violence is now 20-30% higher due to the corona virus.

Education: Schools and post-secondary have closed. Some of the coursework has been accomplished using on line technology, thanks to the efforts of conscientious instructors. On the other hand there are huge portions of students’ education that have simply not been addressed. The cost to individuals and the country have not been quantified.

Regular Health Care: A lot of normal health care has gone unattended. This ranges from elective surgeries to vaccinations to normal checkups. One of the major international concerns is the effect of COVID-19 on usual vaccinations to measles and other viruses. The World Health Organization has estimated that 117 million children may not receive measles vaccination due to the way in which COVID-19 has interrupted international vaccination programs. This is of particular interest because the widely used measles-mumps-rubella (MMR) vaccine has been identified for potential protection against SARS-CoV2, through a retrospective analysis.

MMR against COVID-19: Young et al have released their retrospective analysis of observations relating MMR vaccination to possible protection against COVID-19 https://www.medrxiv.org/content/10.1101/2020.04.10.20053207v1.full.pdf

This document has not yet been subjected to peer review and must be appreciated as being preliminary. Briefly, they present three arguments to support the idea that MMR could provide protection against COVID-19. Firstly, the basic science information on the structure of SARS-CoV2 shows analogies with the protein structures of the components of MMR. Accordingly antibodies formed against MMR may have the potential to recognize and thus bind to analogous parts of the SARS-CoV2 virus. This gives me a plausible basic mechanism for their proposal. Secondly, they have reconstructed the time lines of relevant vaccination programs for females and males in Germany, Italy and Spain and compared them to the age profiles of deaths due to COVID-19. The associations are consistent with the idea that these vaccinations provided some protection against COVID-19. For example the ages at which the death rates to COVID-19 start to rise coincide quite well with end of projections for rubella protection in females. It should be noted that males did not receive rubella vaccinations per se but later received MMR, and the death rates for males was higher than females in all three countries. Thirdly, COVID-19 appeared to reinvigorate the formation of antibodies formed against the rubella virus, which implies similarity of antigenic sites of the two viruses. Given that the delivery of an effective vaccine for COVID-19 is still many months away, MMR may be useful in reducing the burden of COVID-19 in the meantime.

The MMR situation seems to be the epitome of irony because vaccination programs are being compromised just as such vaccinations are being touted as possible treatments to mitigate COVID-19.

The Way Forward. Given that the our present response to COVID-19 now seems to be somewhat excessive, I suggest that we open up Canadian society much faster so that the adverse effects described above are at least mitigated. This is in no way a criticism of the direction our leaders have taken through the initial months of this pandemic; the steps they took then were perfectly appropriate for the existing knowledge. But now that so much more is known about the COVID-19 pandemic, we should change our practices to reflect this new knowledge.

We know that the hardest impacted locations have been in nursing homes of large congested cities, particularly Montreal. Therefore we have to protect the residents of these homes. We also know that work places such as meat packing plants have also been hot spots because employees work in close proximity for long periods of time. Accordingly we should ensure that employees have adequate protection including good work space and perhaps more importantly ventilation.

It is also well established that COVID-19 is unevenly distributed across our huge country. As of June 7, there were 7800 deaths in Canada with 4978 in Quebec and 2426 in Ontario. Of the Quebec total Montreal had 3067 deaths, and Ontario's Toronto (city) had 928. With this heterogeneity of disease, our focus should be on Montreal and to a lesser extent the greater Toronto area. The reins on the rest of Canada should be relaxed substantially to reduce the adverse effects of our COVID-19 response to a minimum.

A practice that should be adopted is ensuring vitamin D sufficiency in residents of nursing homes, and front line workers. Given that a specific vaccination against SARS-CoV2 is not imminent, MMR vaccinations for most vulnerable should be considered on a case by case basis.

PS  There is a TVO Agenda video addressing this at https://www.youtube.com/watch?v=d9wEYz7jlu4&t=1398s

Vitamin D and ACE2

Stu asked me about the relationship between vitamin D and the ACE2 receptor. At the time I hadn’t given it much thought but the question was so interesting that it got me reading. What follows is my take on the issue based on what I’ve been able to learn.

For SARS-CoV2 to infect humans the virus has enter cells in order to replicate and produce more copies of itself. It has been determined that the viral entry point into cells in COVID-19 is angiotensin converting enzyme2 (ACE2)- the ACE2 receptor. ACE2 is embedded in the cellular membrane of many different cell types including those of the lungs and lining of blood vessels. Apparently the spike protein of the virus binds to ACE2 by interacting with the part of ACE2 that protrudes from cells (extracellular domain). After this binding occurs, the cell membrane changes shape and effectively swallows the virus and ACE2. Once the virus is inside our cells, it can use the cells’ synthetic machinery to make copies of itself, which can be released to infect more cells. In the context of this blog, I would like to address the existence of a relationship between vitamin D and ACE2.

Various observations have implicated vitamin D with control of the renin-angiotensin sytem (RAS), which is involved in the regulation of blood pressure. Briefly renin released by the kidney activates angiotensin, which can increase blood pressure. For this discussion, I ask you to accept that ACE2 is part of the RAS and changes in blood pressure can be related to changes in ACE2. An early observation associated blood pressure increases with the winter season, when vitamin D status in humans is poorest. Higher blood renin levels have been associated with lower vitamin D levels and vice-versa. Vitamin D treatment has been reported to decreased blood pressure in some studies. Thus, the seed has been planted for the notion that vitamin D might be involved in modifying the activity of ACE2.

In laboratory animal and cell experiments, it has been demonstrated that mice lacking vitamin D receptors had increased activity of RAS. The higher blood pressure of these mice was corrected by inhibitors of RAS. In cultured kidney cells, vitamin D decreased the formation of renin. Experimental observations like these are consistent with the idea that there are mechanisms by which vitamin D can regulate components of RAS. But what about ACE2 per se?

There doesn’t seem to be evidence that vitamin D can interact directly with ACE2, but there are reports that vitamin D has indirect effects. Accordingly vitamin D (calcitriol, 1,25 (OH)₂D) can increase the expression of ACE2. Moreover there are many treatments/conditions that can result in an increase in ACE2 protein. This would be expected to make cells more sensitive to infection by SARS-CoV2 by virtue of providing more entry receptors. On the other hand, increased ACE2 could increase the quantity of angiotensin(1-7) which is vasodilatory and anti-inflammatory and decrease the quantity of angiotensin(1-8) which is vasoconstrictor and pro-inflammatory. Conditions such as diabetes and hypertension are associated with decreased ACE2, and seem to increase the severity of COVID-19. This is further complicated by the possibility that the part of ACE2 to which the virus (SARS-CoV2) binds can be released from cells into the extracellular water (see below); this form of ACE2 can also bind the virus and therefore be protective. With multiple competing processes, it becomes difficult to provide a simple description of the interaction between vitamin D, ACE2 and COVID-19 severity. Nevertheless, the beneficial aspects of increased ACE2 appear to be greater than the negative aspects.

ACE2 is a 806 amino acid protein with an intracellular domain, trans-membrane segment and an extracellular domain. Its carboxypeptidase activity lies in the extracellular domain; it can convert angiotensin(1-8) to angiotensin(1-7), and angiotensin(1-10) to angiotensin(1-9). The extracellular enzymatically active domain can be released into the extracellular space by the action of sheddase. Once released it is still enzymatically active and can also bind SARS-CoV2. Various research groups are working on elucidating details of the steps where the virus binds to ACE2 and enters cells. As it is a multistep process, there are numerous opportunities to target individual steps in the search for drugs that will be able to combat SARS-CoV2 infection. It would be nice to have a drug that nullified all the spike protein binding sites and protected our susceptible cells. I look forward to seeing the results of research in this area.

How will we pay for COVID-19? A dedicated tax?

Our governments are spending a lot of money addressing the problems caused by COVID-19, and they must be collecting less in taxes at the same time.  How are they going to pay for this?

HOW ARE WE GOING TO PAY FOR THIS?  We will have to pay; it's just a question of when and how?

I suggest that they consider a dedicated COVID-19 tax.  This should be worked on by an all-party committee rather than just the party in power.  We have seen how elected officials can work together in dealing with the pandemic, so let's see more working together going forward.  If governments take this approach, they can provide us with a target of how much has to be paid off.  We will also know exactly how much we are contributing each year, and the remaining balance.  Eventually the balance has to reach zero and the dedicated tax should disappear.

I believe that this approach will lead to better acceptance of our responsibility to pay for this pandemic.  You shouldn't hear the grumbling about another tax grab.  Make this a project that we work on together just as we have worked toward containing this virus.  Let's be transparent about this.  There could even be a web site with daily updates.

Vitamin D: Why I Think it’s Anti-viral

When I wrote my initial blog entry, I realized that there wasn’t direct evidence for its application for prevention or mitigation of COVID-19, and this has been pointed out to me by three people. Nevertheless, I think that vitamin D is likely to be anti-viral because (a) of circumstantial evidence correlating vitamin D deficiency with viral infections, (b) an immunological role of vitamin D and (c) new trials to directly test vitamin D against SARS-CoV2.

(a) Circumstantial evidence. There are many studies that have shown that viral infections are more frequent and severe in the presence of poor vitamin D status. As early as 1979 a strong association between “colds” and rickets (frank vitamin D deficiency) was reported among children. In a survey (published in 2009) of over 18000 individuals in the USA between 1988 and 1994, there was a correlation between serum levels of 25-OH vitamin D3 (25-OHD3, the standard marker for vitamin D status) and upper respiratory tract infections. A more recent review in 2015 (Can J Physiol Pharmacol 93(5):363-8) updated the association between vitamin D deficiency and the increased risk of acquiring various infections.

In the specific case of COVID-19, it started in China in mid-winter when vitamin D status is at its worst. This viral infection has been a lesser problem to date in the southern hemisphere, notably New Zealand and Australia, where it was summer when it started to spread internationally. The evidence associating vitamin D deficiency and increased COVID-19 severity includes a May 2020 publication by Ilie et al who reviewed a number of European studies for which the incidence of the disease and blood levels of 25-OHD3 were available. They found a correlation between vitamin D deficiency and the numbers of both cases and deaths due to COVID-19; there was a statistically significant downward slope showing fewer cases and deaths with higher 25-OHD3 levels. Examples of factors that result in low serum 25-OHD3 concentrations were given as avoidance of sunlight and more skin pigmentation by people in southern Europe. Higher amounts of serum 25-OHD3 in northern countries was attributed to fortification of food with vitamin D and consumption of cod liver oil and vitamin D supplements. (Ilie, P.C., Stefanescu, S. & Smith, L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res (2020). https://doi.org/10.1007/s40520-020-01570-8) Somali immigrants in Sweden are 10-fold over represented as victims of COVID-19. While there are socio-economic explanations for this, their more extensive skin pigmentation puts them at risk for vitamin D deficiency. Similarly in the United States the order of vitamin D deficiency in racial groups is Blacks, Hispanics, Whites, which is the same order as deaths rates due to COVID-19.

(b) Immunological role. It is now widely accepted that vitamin D is essential for proper immunological functions. In a comprehensive discussion of vitamin D and viral infections, Teymoori-Rad et al (2019) describe the vitamin D-induced formation of cathelicidin and βdefensin. They address mechanisms by which these peptides might exert anti-viral activity as well as mechanisms by which vitamin D could interfere with the “cytokine storm” associated with severe viral infections including that of COVID-19. (Majid Teymoori‐Rad, Fazel Shokri,Vahid Salimi, Sayed Mahdi Marashi. The interplay between vitamin D and viral infections. Reviews in Medical Virology March 2019, Volume 29(Issue2) 16 pages.)

The role of vitamin D in immune function is just one of several that have been added to the classical bone calcium effect. Due to these many functions it is referred to as a hormone rather than a vitamin. Nevertheless there is one striking difference between vitamin D and classical hormones such as insulin. Vitamin D release in the body is not regulated by negative feedback. In the case of insulin, lower blood sugar results in decreased insulin release.

Vaccine or herd immunity?

Canada’s response to the COVID-19 pandemic has been well-articulated for the short term in the form of disease suppression to ensure that our health care system is not overwhelmed. Overall our governments have managed to maintain adequate capacity in our hospitals and clinics to handle COVID-19 and the regular health care load. The major black mark on the way we have handled the disease is in relation to our elderly in long-term care facilities. This now appears not to be specific to COVID-19 but the pandemic has exposed the weaknesses in our long-term care homes. With the publicity our long-term care homes have received it seems possible that these problems will now receive the attention they deserve.

On the other hand, Canada’s full strategy to address COVID-19 has not been well communicated to the populace. Is our way forward dependent on a vaccine or herd immunity? This question must be explored and fully communicated to the Canadian public. For the sake of argument, I would like to suggest that our national strategy should be achievement of herd immunity. The rationale for this is that most authorities warn that the earliest that a vaccine will be available is by the summer of 2021 and it could be much longer than that. Most of us cannot wait that long for our way of life to resume some normalcy. In addition, all governments cannot wait that long; to be blunt- we cannot afford the current path. If we accept this position, our goal should be to attain herd immunity. Now that the world has learned more about COVID-19, I think there is a way forward.

Accordingly, we should relax our procedures so that a sufficient portion of the population is exposed to the SARS-Cov2 virus to allow 50 to 70% of the population to develop immunity. This is where we should use the knowledge that the world has learned about COVID-19 to make the cost of herd immunity acceptable to Canadians. There is a lot of information indicating that a deficiency of vitamin D in the Canadian (and world) population has made COVID-19 about 10 times worse than it should be in terms of morbidity and mortality. https://vitamindcovid.blogspot.com/2020/05/vitamin-d-covid-19-and-me.html I would argue that if we make the Canadian population vitamin D sufficient, the effects of COVID-19 can be mitigated enough to be acceptable to the public. Thus we require a program that creates vitamin D sufficiency in our population by sunlight exposure and/or oral supplementation immediately with step-wise opening of the economy during the summer. The aim should be herd immunity before the onset of seasonal influenza. My concern is that COVID-19 combined with seasonal influenza will be far more deleterious to the health of our population than sequential COVID-19 followed by seasonal influenza. At the same time, we know that the most vulnerable Canadians are those in our nursing homes; we will require special consideration for this population.

This will not be a popular suggestion or solution to the problem facing us as a nation but we need to have this discussion now. I do not think that we should continue without a clear goals.

Vitamin D Absorption and Excretion

Vitamin D comes in two forms, Vit D₂ and Vit D₃ . Most of the information being published now refers to Vit D₃ , which is the form made in the skin of humans; Vit D₂ is obtained from plant sources. Vit D₃ is converted to 25-hydroxy Vit D₃ in the liver, and then to 1,25-dihydroxy Vit D₃ (active form) in the kidney and other tissues. Before I go into perhaps too much detail, I should say that vitamin D activity stays in the body for a long time, and that daily dosing with fatty food is probably best.

Vit D₃ is fat soluble and appears to be absorbed best when it is taken with food containing some fat; I take it with peanut butter at breakfast time. Once it has been absorbed it distributes into fat with a half-life of about 1.5 days, and then is removed by metabolism with a half-life reported be three days to almost a month. There is likely to be considerable variability in the both phases in part because of the varying amounts of fat in the bodies of different people. The original study I read was done on a small number of people in 1969 when obesity was less prevalent. The half-life of 25-hydroxy Vit D₃ and 1,25-dihydroxy Vit D₃ appear to be 15 days and 15 hours, respectively. In practical terms, this means that the blood levels take quite a long time to stabilize fully; some authorities suggest 6-8 weeks (see below). For most of us, taking a consistent dose will get us to a steady state level after 4-5 times the half-life of the longest lived molecule in question (Goodman & Gilman, the Pharmacological Basis of Therapeutics, Chap 1). I think (guess?) that we get some vitamin D benefit almost immediately and then continue to get it full benefits over a period of many days. Using the principles of pharmacokinetics, one might predict that a loading dose followed by a maintenance dose would be best, but the observations seem to support just daily dosing. Maybe the modelling, multiple variables and unknown properties of vitamin D₃ and its metabolites are just complex for me to understand.

Another variable that complicates predictions about body content of vitamin D is exposure to sunlight. The rate at which a person’s skin makes vitamin D depends on-

(a) duration of exposure- longer exposure results in more synthesis

(b) skin colour- darker skin contains more melanin and decreases synthesis; tanning reduces synthesis

(c) area of skin exposed- more area results in more synthesis

(d) time of year- summer months produce the most and winter months the least

(e) latitude- closer to the equator is best, all of Canada is in a low synthesis zone

(f) time of day- maximum vitamin D synthesis coincides with the time of maximum sunburn risk

(g) altitude- there is less atmosphere to block UV radiation at higher altitudes

(h) age- older people tend to make less vitamin D

To put this into context, a light skinned person with full body exposure to sunlight at mid-day may start to turn pink in 15-20 minutes and make 10000 IU of vitamin D.

The American Association of Clinical Endocrinologists has a nice set of slides on vitamin D requirements and dosing at https://www.aace.com/sites/default/files/2019-02/Vitamin_D_Deficiency_formatted.pdf

Slide 3 shows how the definitions of deficiency vary in comparison with other academic parties; nevertheless there is a trend toward recommending higher intakes of vitamin D. Slide 10 describes using a loading strategy to address frank vitamin D deficiency; this would be done under medical supervision for individuals whose blood level of 25-hydroxy Vit D₃ has been determined.

I think that the now known properties of vitamin D, where we live and how we live are consistent with a number of health issues facing contemporary Canadian society. For example, we know that the “flu” season occurs in winter; this would be about the time that our bodies become quite depleted in vitamin D. Before the advent of effective drugs, tuberculosis used to be treated by putting patients in the sun. We have seen an unexplained increase in the prevalence of asthma, since about 1970 and this coincides with kids spending less time outdoors, partially because of computer toys and partially because of overprotective parents who are hesitant to chase their kids out to play. Obesity is a stated risk factor for death in COVID-19; is this due to the larger vitamin D sink or the generation of inflammatory cytokines by adipocytes? Too many questions, not enough answers.

Walking Paths in Kingston

Exercise during COVID isolation.

Susie and I have isolated ourselves since the middle of March so we are a few days over two months since we had to change our social habits.  I don't know about anyone else but the first month seemed like three months, and the days seem to go by faster now.  I suppose that it has been accepting the social restrictions that has made the last few weeks less onerous than the initial weeks.  Here is how my life has changed.  There are just the two of us in our household, and that has meant that we are each other's company for the duration.  Isolating ourselves from others has not meant staying indoors all day, every day. In normal circumstances, we got our exercise in social settings- Susie in YMCA exercise classes and me playing hockey or ball hockey.  With imposed isolation our exercise had to be solitary or preferably something that we could do together. While the weather was still cold, our daily exercise was walking and with the onset of warmer weather, we have been able to ride our bicycles as an alternative. 

Our initial walking routes were those that we used frequently over the past several years.  A favourite has been to leave our house and walk through Polson Park and the St Lawrence College area into Lake Ontario Park, then to follow the shore of Lake Ontario past Providence Hospital and Portsmouth Olympic Harbour.  From there we returned through Queen's West Campus, then up by Calvin Park Public Library and then home via the walk-throughs of Calvin Park.  This loop is about 8 km.  While this walk is really pleasant, it got a bit boring so we explored every interesting walk within a reasonable distance of home.  If you look at a map and place our home at 10 Holland Crescent in the middle of a clock face and Portsmouth Olympic Harbour at 5 o'clock you can follow the routes that we have discovered. 

At ~7 o'clock is King Street West, which we have used to access LeMoines Point Conservation Area to the west and then the start of the Rideau Trail at the west end of Lake Ontario Park.  We have walked Rideau Trail per se up to Bath Road, but have also found a number of side paths toward the wetlands to the west that are interesting alternatives.  From ~10 o'clock on Bath Road we have gone westward as well as northward.  To the west is Arbour Ridge Park.  You can take it from Tanner Drive all along the creek and under Centennial Drive and into the wetlands north of Meadowbrook Park.  It is also possible to cross the train tracks over to Taylor-Kidd Boulevard.  From there it's a sidewalk stroll to the Via Rail Station, which is ~11 o'clock from our house.  From the Via Station there are numerous ways to get back home.  The one we never use is the Princess Street Overpass because of all the traffic noise.  Just beside Princess Street to the northeast is a section of the Rideau Trail along an abandoned road that takes you back to Princess at Parkway.  From that intersection the Rideau Trail runs south to Bath Road.  This is an interesting path because there are many side trails into the the wetland to the west, and toward Balsam Grove and Grenville Park to the east.  There is even a connection in Balsam Grove toward Grenville Park via the south end of Hawthorne Avenue.  Another way to get from the Via Station to Princess Street is to cross the railway on John Counter Blvd then go across Little Cataraqui Creek.  As soon as you come to William Hackett Park there is a paved path along the creek and through a wooded area to Princess Street and Parkway.

From the Via station, we have followed Old Mill Road until it ends and then taken unmarked paths northward through the trees up to the K & P Trail.  There is also an unmarked trail north of the K & P where mountain bikers have created some interesting routes. We have taken the K & P Trail westward under the 401 and then as far as the parking area at the corner of Cordukes Road and Burr Brook Road.  Along the K & P just south of the 401 underpass you can access paths that take you through the woods to Venture Drive.  We have also used the K & P Trail east ward as it goes to the industrial park to the parking lot at the west end of Dalton Avenue.  It follows streets to the intersection of Dalton and St Remy Place where it picks up the abandoned railbed again to the north of the CN line to Division St.  From there you have to follow Division and John Counter Blvd to Elliott Avenue where it again follows the old rail line to Railway and Montreal and then runs parallel to Rideau St to River St. At the east end of River St it runs southward along the Cataraqui River to the south end of Doug Fluhrer Park.  From there it becomes part of the Waterfront Trail and takes you to Confederation Park in front of Kingston City Hall.  Waterfront Trail takes you along Lake Ontario in front of Queen's University to Portsmouth Olympic Harbour at the 5 o'clock position from home.  This spring there has been a real visual treat by the yacht club where a family of foxes has taken up residence under a storage building.  They seem to like posing for pictures.  Bruce Payne says that he has seen mink and weasels in the area as well.

At the intersection of Montreal St and Rideau St you can walk eastward on multiple trails to Belle Island as well as northward to the end of John Counter Blvd where they are building the third crossing over to Gore St. At the 2 o'clock position from home we have accessed the new path starting at the north end of MacDonnell St in Third Avenue Park.  It runs northward through a grassy area up to John Counter Blvd.  We have also picked up the CN spur line at the 9 o'clock position and followed it northwestward to point just north of the CN main line behind the Riocan Centre. There is a short path behind the Riocan Centre that runs northeastward into the residential area west of Centennial Dr.  Unfortunately, we can't walk the tracks any more because we were stopped by the railway police, who warned us about a law that were breaking.  Since they now have our names, we are marked.  We have also walked from our house to the Little Cataraqui Conservation Area north of the 401 at the end of Sir John A MacDonald Blvd.  There are several walking paths there that go north to near Burr Brook Rd.  These are really nice as they are entirely in the woods and away from traffic.

Most of the paths that we walked are essentially flat so we have identified three areas that give us some vertical work for our legs.  There is a good set of stairs in Lake Ontario Park and another one on the the bleachers on the north side of the Memorial Centre. In O'Connor Park straight north of us, there is a hill that we use for vertical exercise. Starting about May 20th I started including some pushups on alternate days.  I hadn't been able to do any since before Christmas because of a torn tendon in my left rotator cuff- specifically "a full-thickness tear of the anterodistal supraspinatus tendon". I struggled to do a set of 10; it's going to be a slow grind back to normal.  Theoretically I am supposed to have an appointment with a surgeon to consider a procedure to repair the tendon.  Who knows when that will happen?  I've had physiotherapy until isolation started.

Two more paths.  At the 10 o'clock position from home, we have found a short but pleasant path in Meadowbrook Park off Kingsdale Avenue behind Frontenac Mall.  Then northwest of that is Trillium Ridge Park just off Edgar Street.  You can walk the marked paths through to Waterloo Drive.  There is a green space further east and just north of Grandtrunk Avenue with rough paths though to Grandtrunk where it turns northwest.

Vitamin D, COVID-19 and Me

2020 May 19

    I have decided to start a blog regarding my experiences imposed by the arrival of COVID-19 in Canada. This first entry is a document that I sent to various federal and provincial political leaders and is based on what I have learned over the past several years. While I wound down my career in Pharmacology at Queen's University, I developed an interest in a variety of topics- vitamin D just happens to be one of them. Accordingly, I do not have any special expertise in vitamin D.  I plan to make regular entries in this blog until we return to our normal lives.

COVID-19: the Case for Making the Canadian Population Vitamin D Sufficient and Relaxing Restrictions

1. Vitamin D deficiency/insufficiency is prevalent in the Canadian population.

G.K. Schwalfenberg*, S.J. Genuis, M.N. Hiltz Addressing vitamin D deficiency in Canada: A public health innovation whose time has come public health 124 (2010) 350–359

These authors reviewed 16 studies and found that 70-97% of Canadians were vitamin D insufficient, and 14-60 % were clearly deficient. Herein insufficiency is defined as less than 72-80 nM and deficiency was less than 25-40 nM.

2. Vitamin D effects go well beyond bone health.

In their 2013 review, Uwe Gröber, ^{1 ,*} Jörg Spitz, ² Jörg Reichrath, ³ Klaus Kisters, ^{1 , 4} and Michael F Holick ⁵ ( Vitamin D: Update 2013: From rickets prophylaxis to general preventive healthcare. Dermatoendocrinol. 5(3): 331–347, 2013) summarized the role of vitamin D in a number of functions beyond bone health. Accordingly, diseases associated with vitamin D deficiency include autoimmune diseases (multiple sclerosis, type 1 diabetes) inflammatory bowel disease (Crohn disease), infections (such as infections of the upper respiratory tract), immune deficiency, cardiovascular diseases (hypertension, heart failure, sudden cardiac death), cancer (colon cancer, breast cancer, non-Hodgkin’s lymphoma) and neurocognitive disorders (Alzheimer disease).

3. Vitamin D is anti-viral.

In the context of COVID-19, the germaine property of vitamin D is its anti-viral action. Vitamin D promotes the activity of both the adaptive immune response and the innate immune response. One mechanism by which the innate anti-viral effect is enhanced is through up regulation of cathelicidin and defensin, which are anti-viral and anti-microbial peptides.

John Campbell a retired academic nurse in the United Kingdom has prepared daily video lessons on COVID-19, and clearly explains the potential of Vitamin D in his video on You Tube. https://www.youtube.com/watch?v=1fxw3nTZYlA. Harvard Medicine’s JoAnn Manson has recently taken a supportive position as well.

https://www.medscape.com/viewarticle/930152 These are just two of a growing number of researchers, physicians and concerned citizens who have marshalled respectable arguments in support of vitamin supplementation to face COVID-19.

4. Vitamin D is effective against COVID-19.

Prabowo Raharusuna*, Sadiah Priambada, Cahni Budiarti, Erdie Agung, and Cipta Budi have released a preprint of their retrospective cohort study of 780 (active and expired) cases with laboratory-confirmed infection of SARS-CoV-2. Cases were divided on the basis of serum 25(OH) vitamin D levels with normal being > 30 ng/ml (75 nM), insufficient being 21-29 ng/ml, and (3) deficient being < 20 ng/ml (45 nM) Individuals whose vitamin D levels were insufficient were ~13 times more likely to die while those who were vitamin D deficient were 19 times more likely to die. There are many more published studies that have implicated vitamin D insufficiency and deficiency with greater risk for viral infections.

5. Current status of vitamin D and COVID-19.

There are abundant data showing an inverse relationship between vitamin D status of individuals and their susceptibility to COVID-19. While it would be desirable to have a randomized, double-blind clinical trial showing that vitamin D supplementation is prophylactic, it can be argued that it is unethical to wait for this. People are getting sick and dying as we wait. It is time to promote supplementary vitamin D (≥2000 IU/day) for the Canadian population.

Effect of supplementary vitamin D.

On the basis of current data from Europe, Asia and USA, it can be estimated that the case fatality rate for COVID-19 exposure is ~0.5% (John Campbell, Friday May 15). Germany’s Hendrik Streeck (Director of the Institute for Virology at the University Hospital Bonn) calculated lower estimates of between 0.24 and 0.37% (https://medicalxpress.com/news/2020-05-team-covid-infection-fatality.html) These values for case fatality rate are based on populations following conventional recommendations for vitamin D intake, which would be based on anti-Rickets dosages. Results of recently released study information suggest that making a population genuinely vitamin D sufficient could reduce this by 10-fold or more- bringing the rate down to the range of 0.05%. This would be similar to influenza, which we have learned to live with.

Economic and social effect.

Undoubtedly, COVID-19 restrictions have had a tremendous economic, mental and social cost. I cannot calculate the economic effect on Canada at large but just one company, Air Canada has stated that it lost over $1 billion in the last quarter. Governments are spending huge sums of money addressing the direct effects of COVID-19, and their tax revenues have diminished. Eventually we will have to pay for this in cash. Another incalculable cost is the future effect on our population health due to reductions in tax revenues. In comparison, the cost of every Canadian taking supplementary vitamin D would be negligible- less than five cents/day.

A recommendation.

In closing, may I suggest that we immediately encourage our citizens to supplement themselves with vitamin D3 (2000 IU/day or more but less than 10,000 IU/day, Michael Holick Boston Univ Sch of Med) or get moderate exposure to sunlight, and then proceed with relaxing our social restrictions and opening our economy as soon as the population can be made vitamin D sufficient.