On September 13, 2020, I made an important update to my position, which is included at the end of the article. You can click through to it directly using this link.
Yesterday, Dr. Rhonda Patrick, PhD, of Found My Fitness released an email to her list with the subject “Vitamin D may reduce susceptibility to COVID-19-associated lung injury,” which linked to an accompanying YouTube video on the same topic.
Here is my point-by-point response.
Generalizing From Colds and Flu to COVID-19
In the email, Dr. Patrick points out that vitamin D reduces the risk of upper respiratory tract infections:
A ton of evidence suggests that vitamin D is protective against respiratory tract infections. Data from 25 randomized controlled trials from around the world demonstrate that vitamin D supplementation reduced the risk of acute respiratory infection by more than 50 percent, especially in people with low baseline vitamin D levels.
The meta-analysis she links to doesn't say anything about which viruses caused the infections or even which illnesses were involved, but as a group, most upper respiratory tract infections are are the common cold or the flu.
I completely agree vitamin D is important to cold and flu prevention, but I strongly oppose generalizing from colds and flu to COVID-19.
As I pointed out in The Food and Supplement Guide for the Coronavirus, there are major differences between colds and flu, on the one hand, and COVID-19, on the other:
Half of colds are caused by rhinoviruses, and 90% of them dock to intercellular adhesion molecule-1 (ICAM-1). Flu viruses dock to sialic acid. Even the coronaviruses that cause 15% of colds do not dock to ACE2. They use aminopeptidase N or sialic acid. Preventing the virus from docking to host cells is a key strategy for preventing infection, but SARS-CoV-2, the cause of COVID-19, shares its docking mechanism not with cold or flu viruses, but with SARS-CoV, the cause of SARS.
This is especially important for something like vitamin D, which increases ACE2. Colds and flu do not share anything in common with SARS-CoV and SARS-CoV-2 about the role of ACE2 in allowing the virus to enter cells. Therefore, it would be very unwise to assume that the effect of vitamin D on colds and flu will generalize to COVID-19.
But this other snippet from my guide warrants even more caution:
Interferon administered to human volunteers reduced the incidence and severity of colds and, as discussed above, interferon protects mice from otherwise lethal doses of influenza A. Nutrients and herbal remedies that increase the antiviral interferon response should, therefore, protect against colds and flu. However, just as interferon leads to lung damage and death in SARS-infected mice, and apparently to a cytokine storm in human SARS patients, these same nutrients and herbal remedies might actually cause harm in SARS, and, by extension, in COVID-19.
The mouse study discussed in that excerpt is particularly disconcerting: deleting the gene for the receptor for type 1 interferon, and thus disabling the interferon response, did two wildly conflicting things to the flu and to SARS:
It caused an otherwise non-lethal dose of influenza to kill the mice.
It allowed mice given an otherwise lethal dose of SARS-CoV to survive.
In other words, interferon rescues flu-infected mice but kills SARS-infected mice.
If that doesn't warrant caution about generalizing from the flu to COVID-19, I don't know what possibly could.
ACE2: Friend or Foe?
Dr. Patrick continues:
Where does ACE2 fit in?
SARS-CoV-2 virus enters human cells via the ACE2 receptor. Viral particles bind to the ACE2 receptor and together they travel into the cell. These viral particles can bind to a large number of ACE2 molecules, sequestering them from the cell surface and decreasing ACE2. This has been shown to happen with the virus that caused the original SARS outbreak, SARS-CoV-1, which also binds to the ACE2 receptor.
The accompanying loss of ACE2 function can cause serious health consequences due to ACE2's participation in key physiological processes.
I completely agree that ACE2 plays an extremely important role in normal physiology, and that SARS causes lung damage in part by causing the loss of this normal function.
However, I believe Dr. Patrick is missing a fundamental point: the normal metabolites of our enzymes do not reproduce themselves, and they therefore do not grow exponentially; likewise, the enzymes themselves do not self-replicate in response to nutrients, so they also do not grow exponentially; viruses, on the other hand, self-replicate, so they grow exponentially.
We don't know how many virions (virus particles) are released from each SARS-CoV-2 infected cell, but murine coronavirus, which infects mice, releases 600-700 per infected cell. One virus entering a cell can generate hundreds. Each of those hundreds can then generate hundreds more, totaling tens of thousands. Each of those tens of thousands can then generate hundreds more, totaling millions. We don't know how long each cycle takes, but preliminary data for SARS-CoV-2 paired with stronger data from SARS-CoV suggests it is between seven and 36 hours. Viral loads have often peaked by day 4 or 5 of symptoms, but in more severe cases, peak viral loads may not occur until days 10 or 11, or even later. The incubation period between infection and onset of symptoms is typically about 4 to 5 days. This means that there are generally 8 to 16 days of replication until viral loads peak, which is somewhere between 5 and 55 replication cycles that each have the opportunity to compound the number of viruses hundreds-fold.
When dealing with exponential growth, small increases in the seeding lead to huge increases on the back end.
Consider something familiar, like compound interest. If you put $100 into a retirement account that earns 8% per year for 50 years, you get $4,690.16 on the back end. If you add an extra $10, you don't get an extra $10 on the back end. You get an extra $469.02.
This, of course, is chump change compared to viral replication, because it takes a whole year to gain 8%. With this virus, we are dealing with something more like 60,000-70,000% every 7-36 hours over the course of 8 to 16 days.
ACE2 is the entryway for the virus to enter the cell. It's likely role would either be to increase the number of viruses that can enter cells, or to help them find an entryway sooner and enter faster, decreasing the average time it takes to complete a replication cycle. Either way, it's going to enhance the exponential growth.
Putting 10% more ACE2 into the equation to seed a faster replication time or a larger number of viruses that gain entry in each cell is going to lead to enormously more ACE2-hogging viruses on the back end, and they'll be able to do far more damage to ACE2 function than you gained with that 10% increase.
Imagine a situation where some thief decided to steal $100 from you every time your retirement account increased by $1. You aren't going to protect yourself by depositing more money in your retirement account to make up for it. No matter how much money you put into the account, you will lose far more on the back end. The math will never work in your favor.
If ACE2 enables viral replication and viral replication causes loss of ACE2, then trying to increase ACE2 with a nutrient to compensate for the loss of ACE2 that will happen on the other side of the viral infection is a losing game: you are trying to preserve the loss of ACE2 with a linear effect of a nutrient while enabling exponential growth of the ACE2-smashing virus.
This is supported by data from mice infected with the first SARS virus. Mice can only be infected if they are genetically engineered to have the human version of ACE2. When the mice were given doses of SARS-CoV that killed all of the ones expressing human ACE2 within seven days, the ones that had more copies of the human gene died faster. Among mice with four copies, half were dead by day 5, three quarters were dead by day 6, and the rest were dead by day 7. Among mice with 8 or 10 copies, all the mice were dead by day 5.
Even though virus-induced loss of ACE2 function plays an important role in the severity of the disease, more ACE2 still means more virus, and it's the virus doing all the damage.
We Can't Generalize From Models Where ACE2 Doesn't Enable the Cause of Lung Injury
Dr. Patrick continues:
Here's where vitamin D deficiency comes in…
Vitamin D deficiency leads to overexpression of renin (an enzyme produced in the kidneys) and subsequent activation of the renin-angiotensin system, a critical regulator of blood pressure, inflammation, and body fluid homeostasis. Loss of ACE2 function in the setting of SARS-CoV-2 infection upsets the balance of this critical system, promoting neutrophil infiltration, excessive inflammation, and lung injury. If lung injury progresses to hypoxia, the kidneys release renin, setting up a vicious cycle for decreasing ACE2.
In turn, lower levels of ACE2 promote more damage, culminating in acute respiratory distress syndrome, or ARDS. a severe form of acute lung injury that occurs in as many as 17 percent of all COVID-19 cases and can lead to respiratory failure and death.
But vitamin D acts as an endocrine repressor of the renin-angiotensin system by downregulating the expression of renin, the rate-limiting enzyme of the renin-angiotensin cascade, and rescuing lung function.
A preclinical model of acute lung injury showed that administration of vitamin D provided protection against lung injury by increasing ACE2 levels and decreasing renin production.
Here's the kicker: The acute lung injury led to a decrease in ACE2, driving even worse lung injury. Vitamin D supplementation increased ACE2 receptor levels, but only in conditions of acute lung injury where ACE2 levels decreased. When vitamin D was given to control animals, it didn't increase ACE2 levels. This means that vitamin D normalizes ACE2 levels in situations only where it is decreased.
I cited the exact same study in The Food and Supplement Guide for the Coronavirus. Although vitamin D made the lung outcomes better in this case, this was a model where ACE2 did not play a direct role in the cause of the lung injury. In this case, it was caused by lipopolysaccharide (LPS), a substance from the cell walls of certain types of bacteria that causes inflammation. Quite obviously in COVID-19, where ACE2 enables viral entry and the virus itself is the cause of lung damage, and where lost ACE2 function is only one of many parts of how it causes lung damage, the tables could be completely turned.
In this particular study, the effect of vitamin D on ACE2 was shown in pulmonary vascular endothelial cells, the cells lining the blood vessels that feed the lung. In those cells, vitamin D didn't raise ACE2 unless the ACE2 had been suppressed by LPS first.
These are not the main expressers of ACE2 in the lung, however. It is actually goblet cells, which make mucous, and ciliated cells, which have hairlike projections that move mucous and debris along, that account for most of the lung's ACE2.
In another study, vitamin D did nothing to ACE2 expression in the kidneys of control rats, but diabetes raised ACE2, and adding vitamin D to the mix raised ACE2 even further than diabetes did alone. In the brains of rats, vitamin D does increase ACE2 in control animals, as well as in animals with high blood pressure. In fact, it increased ACE2 by 50% in the healthy control animals. So it's not true that “vitamin D normalizes ACE2 levels in situations only where it is decreased,” as Dr. Patrick claimed.
We do not at this time know how vitamin D impacts the expression of ACE2 in the goblet and ciliated cells of the lung. The balance of data indicates that it increases ACE2 across multiple cell and tissue types, and that this sometimes, but not always, leads to substantially greater than normal expression of ACE2, not just rescuing the loss of ACE2. There is no basis for assuming this would protect lung health in the context of COVID-19, where the cause of the lung injury is the virus whose infection is enabled by ACE2.
Other Circumstantial Evidence
In the YouTube video, Dr. Patrick makes some additional points:
ACE2 decreases with age, and is lower in males than females, and it is older males who are at the greatest risk of severe cases.
COVID-19 hospitalization rates are higher in obese, African Americans, Somali immigrants in Sweden, and older people, all of whom have lower vitamin D status.
She cites a paper showing that ACE2 declines with age, and does so more in males than females, in the lungs of rats. However, ACE2 expression was recently measured in the lungs of humans, and it did not differ by age or sex.
While I think it is plausible that the second set of associations is explained by poor vitamin D status (and, if so, that it is for completely other reasons than the effect of vitamin D on ACE2), there could easily be other explanations. For example, hypertension is more prevalent among obese people, African Americans, males, and older people. Hypertension doubles the risk of needing ventilation in COVID-19, and is more strongly associated with ventilation requirement than age, breathing rate, diabetes, heart disease, and chronic obstructive lung disease. My suspicion is that this is because hypertension is associated with poor function of the lining of the blood vessel, called “endothelial dysfunction.” When humans are subject to acute hypoxia, those with hypertension are less able to adapt by supplying a larger amount of blood to the tissues that are starving for oxygen. I suspect poor endothelial function also prevents COVID-19 patients with low oxygen levels in their blood from compensating in the same way.
These explanations are not mutually exclusive. Vitamin D status below a certain threshold might, despite the ACE2 issue, compromise immunity or worsen the risk of inflammation, and yet hypertension could be a major explanation for all these associations as well.
These explanations are also not the only ones available to us.
I believe we will have to be patient and analyze the data as it continues to emerge for quite some time before we can confidently explain all of the associations between demographics and disease risk.
The Bottom Line
I maintain my position that we should take a conservative stance toward vitamin D supplementation at this time:
I would not attempt to induce a vitamin D deficiency under any circumstances.
I would not stop using vitamin D if it is providing a clearly identifiable benefit. However, I would attempt to find the lowest dose that provides this benefit.
I would take a conservative approach toward supplementing on a theoretical basis. Arguments for maintaining 25(OH)D levels above 30 ng/mL (75 nmol/L) in the general population are weak. All-cause mortality is lowest at about 28 ng/mL according to one meta-analysis of eight European studies, seven conducted in the general population, pooling data from just under 27,000 people. Another widely circulated meta-analysis showing a bottoming-out in the 40-60 ng/mL range derived it's data in that range entirely from a conference abstract. If that one outlier is removed, as can clearly be seen in Figure 4 of the paper, the bottoming out of all-cause mortality is below 40 ng/mL and probably close to 30 ng/mL. This is consistent with the amount needed to maximally suppress parathyroid hormone (PTH) in most people, which is the body's own sign of inadequacy in the vitamin D and calcium economy.
Personally, I believe until we understand the relationship between vitamin D and COVID-19 risk much more clearly, it is best to continue to eat vitamin D-containing foods (e.g. fatty fish and pastured egg yolks), get normal outdoor sun exposure, and leave it at that.
The upper bound of what I would consider reasonable, based on what is likely needed to maintain 30 ng/mL (75 nmol/L) for most people, would be 1700 IU per day.
Important Updates to My Position
Updated September 13, 2020
Since I wrote this post, numerous vitamin D and COVID-19 studies have been published, including most recently the first randomized controlled trial.
You can see the evolution of my view as the research emerged by reading these posts:
Update on Vitamin D and COVID-19 Using the First Observational Study Released
The First Vitamin D Study With Pre-Infection Levels Weakens the Association
Vitamin D Does Not Explain the Race/Ethnicity-COVID-19 Relationship
Finally Confirmed! Vitamin D Nearly Abolishes ICU Risk in COVID-19
Here is my current position:
The treatment effect of vitamin D has been established, and the size of it appears huge. I find it unlikely future studies will overturn the existence of a treatment effect, but they may change how big the effect seems, and place limitations on how far it can be generalized across populations, contexts, and stages of COVID-19 disease, and from treatment to prevention.
Rhonda Patrick was right in her expectation that vitamin D would have a treatment effect, and I was wrong in my expectation that it would increase risk, but I believe I was justified in being concerned about that risk and in avoiding hasty generalization from colds and flu.
I also have seen nothing to overturn the concern that increased ACE2 on the cell surface, all other things held equal, increases COVID-19 risk, and vitamin D status does not appear to explain much of the correlation between race and COVID-19 risk.
I believe the best thing to do is maintain 25(OH)D in the 30-40 ng/mL range, and if you don't know what dose or lifestyle measure best keeps you there, supplement with 1700 IU vitamin D3 per day. Upon illness, temporarily using 7,600 IU per day from symptom onset would best mimic the treatment used in the first RCT for someone in this context. I wrote this out in more detail here.
Stay safe and healthy,
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