Ivermectin and COVID-19

Introduction: You can skip the first three paragraphs of background if you wish. As soon as SARS Corona Virus-2 made its impression on scientists around the world, investigators with a wide range of expertise began to apply their talents to this international problem. The speed with which so many groups have developed various versions of a COVID-19 vaccine has been impressive and welcome. As of the end of December 2020 Canada had already approved the Pfizer-BioNTech and Moderna vaccines with others close behind. Based on the history of vaccine development and projections from various experts, I expected vaccine availability a full year later than it has occurred. Earlier in the year, March 14, we were locked down and being educated on concepts such as social distancing, wearing masks, hand hygiene, avoiding unnecessary social interactions, viral testing and contact tracing.

Beyond this the other big question was what kind of pharmacotherapy might be useful in the treatment or prevention of COVID-19. As a result of my earlier interest in vitamin D, its potential application in prevention and treatment of this disease got my attention and resulted in the writing of my blog on vitamin D and COVID-19 starting in May. There have been a number of drugs that have been considered for the treatment of COVID-19. These have included remdesivir, chloroquine, hydroxychloroquine, calcifediol, doxycycline, atorvastatin, zinc and steroids such as methylprednisoline. The one that has caught my attention recently has been ivermectin.

Ivermectin is the product of a systematic screening program for novel antimicrobials conducted by Professor Satoshi Omura of the Kitasato Institute in Tokyo working with Merck in the USA. The parasitology department at Merck revealed that a group of macrocyclic lactones, collectively called avermectins, had anti-parasitic activity. This is discussed well in the context of novel anti-parasitic drug development by WC Campbell (Lessons from the History of Ivermectin and Other Antiparasitic Agents, Annual Review of Animal Biosciences Volume 4, 2016 pp 1-14). Ivermectin made its commercial debut 1981 as an antiparasitic agent for veterinary applications. Ivermectin was introduced for human use in the treatment of Onchocerciasis in 1987 , and one might be tempted to say “the rest is history” because it has been such a success in the treatment of a number of human parasites. Omura and Campbell were awarded the 2015 Nobel Prize in Physiology or Medicine.

My Bias

I think that we should be using ivermectin for COVID-19 prophylaxis. Given its apparent effectiveness in this capacity along with its relatively low risk of toxicity, its potential benefits far outweigh its negative effects. If we were to acquire enough to treat the entire Canadian population, we could save a tremendous amount of illness and prevent untold deaths. Moreover the costs of using ivermectin would be minuscule compared to the current expenses for COVID treatment not to mention the indirect costs to other aspects on our health and society at large; the latter would include both social and financial costs. Below I have described just some of the evidence regarding ivermectin in COVID-19, but it should provide you with a flavour of its potential for seeing us through this pandemic.  Moreover ivermectin has substantial benefits once COVID-19 has been contracted but my focus today is prophylaxis.

Ivermectin as an anti-viral drug in laboratory experiments. There are two papers that made an impression in this respect. In the first in vitro Australian study, they showed that ivermectin inhibited  replication of SARS-CoV-2 in monkey kidney fibroblasts and had an IC50 of ~2 μM. The second but earlier (2014) in vivo study was done by a former postdoctoral fellow, Robert Kinobe (currently a faculty member at James Cook University in Townsville, QLD, Australia) and his colleagues. Working in a veterinary environment, they worked on a non-human species, crayfish, and showed that ivermectin at a dose of 7 μg/kg blocked paroviruses therein (https://doi.org/10.1016/j.aquaculture.2013.11.022). Experiments such as these indicated that invermectin had the potential to be effective in COVID-19.

Ivermectin effectiveness against COVID-19 in humans in observational reports and clinical trials.

Observations:

The incidence of COVID-19 is much lower in sub-Saharan Africa than was anticipated, and ivermectin has been used for many years in this region for prophylaxis against parasitic infections. Accordingly ivermectin may have reduced COVID-19 infectivity. See data on COVID-19 in Africa in Worldometer. Also Hellwig and Maia (www.ncbi.nlm.nih.gov/pmc/articles/PMC7698683/) analyzed the relationship between ivermectin usage and COVID-19 and concluded that countries with routine mass drug administration of prophylactic chemotherapy including ivermectin have a significantly lower incidence of COVID-19. In another observational study in France, 69 nursing home residents and 52 staff were treated with ivermectin during a scabies outbreak. Seven of the 69 residents fell ill with COVID-19 (10.1%);only one resident required oxygen and none died. In a matched control group of residents from surrounding facilities, 22.6% of residents fell ill and 4.9% died.

Human trials:

The Front Line COVID-19 Critical Care Alliance (FLCCC) is an international team of experts who have reviewed as much information as possible in order to develop prophylactic and curative treatments for COVID-19. They have provided an excellent summary as guide for the prevention and treatment of COVID-19 based information garnered up to December 2020. Please see https://covid19criticalcare.com/wp-content/uploads/2020/11/FLCCC-Ivermectin-in-the-prophylaxis-and-treatment-of-COVID-19.pdf. In their summary of the protective effect of ivermectin, they showed that this drug reduced and sometimes eliminated the chances of contracting COVID-19.

Benha University (Egypt) study. In a comparison of ivermectin with hydroxychloroquine in patients with mild/moderate COVID-19 infection, the ivermectin patients did significantly better with respect to symptoms, and none died in comparison with the four who died in the hydroxychloroquine group. In patients with severe COVID-19 infection, there were 2 deaths in the ivermectin group versus 20 deaths in the hydroxychloroquine group. They also examined the ability of ivermectin to protect against COVID-19 infection in health care workers and household contacts of patients with confirmed COVID-19. In these subjects ivermectin treatment resulted in an infection rate of 2% compared with 10% amongst those who did not receive ivermectin.

Egyptian registered clinical trial (https://clinicaltrials.gov/ct2/show/results/NCT04422561) of ivermectin as COVID-19 prophylactic agent. The study groups were close family contacts of confirmed COVID-19 patients. In those who received ivermectin (203 subjects) only 15 (7.4%) developed symptoms of infection compared with 59 (58.4%) of 101 control subjects who did not receive ivermectin.

In Argentina, health personnel from the Dr. Alberto Eurnekian Interzonal University Hospital were recruited to test the ability of carrageenen plus ivermectin to protect against laboratory confirmed SARSCoV-2 infection. Of the 131 subjects in the carrageenen/ivermectin group none tested positive while in the 98 controls subjects, 11 became positive. See https://clinicaltrials.gov/ct2/show/results/NCT04425850.

Other references. 

www.researchsquare.com/article/rs-100956/v1 Ivermectin reduced the incidence of infection in health care and household contacts to 2% compared with 10% in non-ivermectin group.

 www.ejmed.org/index.php/ejmed/article/view/599  73.3% (44 out of 60) subjects in control group were positive for COVID-19, ivermectin reduced this to 6.9% (4 out of 58)

doi.org/10.1101/2020.10.29.20222661 Two-dose ivermectin prophylaxis, 300 μg/kg, was associated 73% reduction of COVID-19 infection among healthcare workers in the subsequent month. 

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.