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.