January 31, 2021

COVID-19

Does vitamin D deficiency raise COVID-19 risk?

Expectations for vitamin D and COVID-19

Read Time 3 minutes

If you’re still confused about how vitamin D deficiency impacts your COVID-19 risk, that is understandable. Especially with infographics like this one from a preprint study floating around, plotting COVID-19 case severity and vitamin D level. As I have mentioned before, observational studies cannot be used to make causal conclusions about associated risk factors and disease. This JAMA article likewise gets to that point. It consolidates mostly retrospective studies that report on the relationship between vitamin D status and COVID-19 risk of infection or disease severity. It concludes that adequate vitamin D levels are important for bone health and immune function but there is insufficient evidence to claim that vitamin D protects against COVID-19 infection. 

So what can we say about supplemented vitamin D and the (extent of) benefit? Let’s be clear—it’s hard, or nearly impossible, to answer the extent that vitamin D may help with disease severity given the data we have. I will discuss how I think about vitamin D and COVID-19 disease and the factors I take into consideration.

I likewise wouldn’t claim that vitamin D is a magic pill against infection, given the evidence we have. But if we are extremely careful, we can learn something by looking at good observational studies. These studies can make observations, with the help of statistics, and draw associations that can inform us. While it is easy to fool ourselves, quasi-experimental studies like this one, for example, shouldn’t be overlooked completely. The study reported the 14 day mortality of 77 elderly (mean age 88 years) hospitalized patients comparing those that regularly supplemented vitamin D in the preceding 12 months and those that started supplementing after COVID-19 diagnosis. Both groups were compared to a third group that didn’t supplement with vitamin D at all. Long-time supplementers had a 93.1% survival rate compared to 81.7% survival rate in the more recent supplementers, and there was a 68.7% survival rate in the group that didn’t take vitamin D. Given the hazard ratio 0.07 in the first group, the study reported a 93% reduced associated risk for those that regularly supplemented vitamin D. In other words, the no supplementation group was associated with 14.3 times the risk of death compared to those who regularly supplemented with vitamin D. 

Randomized controlled trials (RCTs) do, nonetheless, continue to be the gold standard. There is one pilot RCT that looked at the rate of ICU admission and death for 76 people with and without in-hospital vitamin D supplementation. It reported that 98% of the treatment group did not get admitted to the ICU compared to 50% admission in the untreated group, of which 15% (2 people) later died. After adjusting for confounding variables, patients treated with vitamin D had 0.03 times the risk for ICU admission compared to non-treatment. Put another way, patients not treated with vitamin D had 33.3 times the risk of ICU admission compared to patients treated with vitamin D.  And if you want further commentary on the importance of RCTs to distinguish signal from noise on issues like this, my conversation with Vinay Prasad gets to the heart of the matter.

So there is some compelling evidence that associates vitamin D status and disease severity. This makes sense. We know that vitamin D is an important modulator of immune function and that a deficiency can have additional health implications. Deficiency is defined as having a serum vitamin D level less than 20 ng/ml or a vitamin D insufficiency, a milder form, as a level between 20 ng/ml and 30 ng/ml. In youth, deficiency can appear as rickets—the softening or weakening of bones—or osteoporosis and bone disease like osteomalacia in adults. There is little risk with supplementation. Too much vitamin D results in hypercalcemia, most commonly due to an overproduction of calcium that can result in kidney stones. However, vitamin D toxicity is not easy to come by: a review article noted that all published cases involved an intake of at least 40,000 IU/day. Even though the Food and Nutrition Board established a conservative dose threshold of 2,000 IU/day, some studies suggest that doses of up to 10,000 IU/day is safe for most adults. Note, however, that supplemental vitamin D and naturally-derived vitamin D from the sun are not the same thing. Humans are designed to receive their vitamin D from cutaneous synthesis and it may be the preferred method of obtaining vitamin D. So supplementing doesn’t mean giving up on grabbing a few rays of sunshine if you can.

The risk of infection depending on vitamin D levels is hard to determine. It may not prevent you from getting disease. The risk of COVID-19 severity and vitamin D levels is also not so clear cut. The published literature suggests that sufficient vitamin D status is either really beneficial, beneficial, or inconsequential. It is likely beneficial for decreased risk of severity, given what we know about immune system health and function. More concretely, there is virtually no risk to supplementing, say, 5,000 IU/day. But I would add, assume and act as if vitamin D doesn’t significantly reduce the incidence or severity of COVID-19 (but cross your fingers and hope it does). 

Disclaimer: This blog is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this blog or materials linked from this blog is at the user's own risk. The content of this blog is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard, or delay in obtaining, medical advice for any medical condition they may have, and should seek the assistance of their health care professionals for any such conditions.

28 Comments

  1. Thanks for the article Peter.
    You distinguish between Vitamin D from supplementation as opposed to the sun.
    Any difference between supplementation with pressed-pills vs. softgels ?

    • I dont no if vititmas D works or not against the virus I am going to take it I ben taken it for about a year now i am 72 years old.

    • I contend that it is the internal concentration of serum vitamin D that is the therapeutic agent and this can be elevated using supplements, sunshine exposure(proper time of day and year) or a tanning bed with proper bulbs. However when it comes to influencing mood, sunshine and tanning beds induce endorphins which is not the case for supplements.

      Probably no difference on the format of the supplements but to be certain have your serum vitamin D levels checked using both formats to know if their is a difference.

  2. Great summary. My opinion on the closing sentence is that it could have stated “But I would add, act as if vitamin D does reduce the severity of COVID-19

  3. Dear Peter,
    one of the biggest problems with observational studies is that they look at
    one variable and make no effort to control for others. In the case of covid 19 and vitamin D, more detailed comparison between Vit D supplementers and non supplementers would very likely uncover the social determinants of health that have become so stark in this pandemic. Those who do poorly are not only deficient in Vitamin D, but also those who have experienced a lifetime of inequity in access to good quality nutrition, housing, economic opportunity and health care.

    • Possibly Margot but most of those observational and intervention studies correct for such determinants. However probably the best example of vitamin D reducing symptom severity is the deaths of BAME doctors in England during the first wave. Of 29 doctors who died after contracting C-19 after treating patients, 27 were Black, Asian, Minority Ethnicity. In other words their skin pigmentation would contribute to low vitamin D levels, especially in a northern climate. They were nonetheless educated medical professionals of reasonable affluence. Notably the Indian doctors association finally recommended their members supplement with vitamin D and to my knowledge, no further deaths of doctors occurred that are attributable to C-19. Listen to Radiolab podcast, episode Invisible Allies from July 30, 2020

  4. Nice article reviewing vitamin D. While I agree with everything presented, my opinion and personal use of vit D is to recommend it’s use. No, it did not prevent me from contracting Covid from my patient but I feel strongly that the cytokines storm was suppressed in tissue with ACE2 expression. Therefore, I strongly support its use, especially in dark skinned patients unless otherwise contraindicated. Thanks.

    • Nicely said Geoffrey. It’s not a coincidence that well documented immune regulation in autoimmune diseases (cytokine storm, Tcell and macrophage activity) also occurs in Covid-19. Historically after the discovery in the 1920’s that vitamin D prevents Rickets, the 1930’s and 40’s were characterised by rampant vitamin D fortification . No pandemics in those decades however after an erroneous conclusion of hypercalcemia in the 1950’s, fortification stopped. Ever since there seems to have been at least one pandemic per decade.

      Interestingly the Finns mandated vitamin D (in effective, but not optimal amounts) be added to their dairy products in 2003. Soon thereafter the incidence of Type 1 diabetes plateaued as the childhood population serum contents escalated from 65 to 80 nmol/L ((Makinen et al 2014,Harjutsalo et al 2013). Me thinks the T1D incidence would have plummeted to near zero had their population achieved serum levels of 120 nmol/l.

      Notably Finland has not been too badly affected by Covid-19 despite their northern latitude.
      Regards

  5. I’ve taken 4,000 IU a day for years. I’m 61 with a 17 year history of Gleason 8 (4+4) prostate cancer. Is there an advantage to increasing to 6-8,000 IU/day?

  6. This was a good read. Any chance you can comment on vitamin D2 vs D3? Its been suggested that whilst D2 needs to be prescribed, D3 is actually safer and more effective. One other point it would be good to hear discussed is some suggestions that your better off taking one larger dose every ~3-5 days instead of a smaller dose daily.

  7. I have read that high-dose vitamin D supplementation can deplete magnesium. Are you aware of this and what would the mechanism be?

  8. That pilot study from Cordoba, Spain that you referenced really struck a chord with me. Although the treatment group was smallish at 50, the reduction of ICU admission to 2% from 50% in the control group was astounding, especially given the fact that the treatment was started only on the day of admission for COVID-19 to hospital. Deterioration to the point of admission to ICU usually takes place over a duration of 2-4 days, so that was a very short window for the (oral) Vit D to do its magic.

    Admittedly, it was high dose and it was given as the active hydroxylated form, but still, that is a huge percentage change.

    I’m 73 this year, and would have a theoretical significant mortality risk if I get COVID-19. Living in freezing old Calgary, I have no skin based Vit D generation, so, since the article came out in August I have been taking Vit D3 4,000 iu a day (actually more like 5,600 iu, including the Vit D in the 2g of Cod Liver Oil I take daily). There is no evidence for increased resistance to infection (it may be there, though), but I’ll take the huge apparent protection of complications from infection if it’s easily and cheaply done, which it is.

    • Howdy Su-Chong

      I too reside in chilly Calgary, however today is actually quite nice. Enjoy it while you can.

      The critical component of the Cordoba study by Castillo et al was indeed the use of calcifediol. This metabolite is, as you noted, the hydroxylated form of vitamin D that is produced by ones liver when they either ingest or are exposed to the proper UVR. This is then processed by ones kidneys as it is hydoxylated once again into the therapeutic hormone.

      By administering calcifediol, the patients were able to convert it in the kidneys in a matter of hours rather than weeks had they been administered just vitamin D. Peter unfortunately did not emphasize this time element in his summary. I don’t think the dose was huge as it was only 0.266 mg (10, 640 IU by my reckoning) given every 3 days. This is less that the 5,600 IU/d you are taking. Bravo BTW. In a hospital setting, it’s more the rapidity of receiving elevated serum vitamin D that is critical for C-19 patients. An optimal serum concentration IMO, is 110 nmol/L which 5 to 6,000 IU/d would achieve and would provide the best immune system regulation.

      Our organisation based in Calgary, Direct-MS, financed a trial over a decade ago that was trying to determine vitamin D toxicity. We stopped at 40,000 IU/d when we were not able induce hypercalcemia.

      Vitamin D amplifies the innate immune system to produce more antimicrobial peptides (AMP’s), a person’s first line of defence against bacteria and viruses. While AMP’s are not a guarantee of immunity, it does reduce the susceptibility to C-19 as Kaufman et al 2020 found a found a 54% overall reduction in the risk of contracting C-19 if serum levels were sufficient.

      Cheers

  9. Thank you for covering this. I have been reading up from multiple sources and most seem to affirm the strong possibility of it being beneficial. PS – I just re-watched the Joe Rogan podcast you were on #1108 and enjoyed every minute of it. Would love to shoot archery with you and Joe one day! Take care.

  10. I am out in the sun mostly and intentionally – yet succumbed to the virus recently

  11. From personal experience in suffering and being diagnosed with a severe case of Vitamin D deficiency. I beg the differ in that as soon as I my Vitamin D levels drop below NOT 30, but below 40, my body and immune system goes haywire. As you know, it becomes a harmone deficiency aka imbalance. Put, another way, my body start stutting down and malfunctioning to the highest degree to the extent that I have become unsure as to if I will wake up the next day, etc., to say the least. So, as far as I am concerned, unless you have lived through it. You or no one else can tell me much of anything because Vitamin D supplements saved my life.

  12. When I create a Fishbone diagram or Ishikawa diagram, which is a diagram that assists managers in determining the root cause of a problem, I make sure that I insert the (low vitamin D level) at the head of the fish to display the root of my ailments. Then, start filling in all of the symptoms, issues, etc., that I have been experiencing. Then, guess what? Through much research, I discovered that all of my ailments were rooted back to a weak immune system which is exacerbated by being Vitamin D deficient.

  13. From the end of daylight saving time to the beginning the next year, I take it D3 5000 twice a day. During the other months when I spend a lot of time in the sun ( live on a lake in NC I take only one . I had Vit D checked in Nov. it was 78. I had to ask my Dr. to check it ( my previous Dr. always included that in bloodwork). The Dr. now said she didn’t order it because some insurers wouldn’t pay, I am 86 years old, have been told most older people don’t make
    Vitamin D and need to supplement. I don’t know when the last time I had a cold or was even sick. I definitely believe in keeping Vitamin D high.

  14. Peter, the JAMA piece by Rita Rubin that you linked does not deserve mention. It misrepresents very consistent evidence as being much more ambiguous than it really is by cherry picking flawed contrary studies and making erroneous claims (like a claim of financial incentive bias against a nonprofit org dedicated to public health). I detailed the many flaws of the piece in a comment on the JAMA website but JAMA chose not to publish my critical comment, so I have put it up here:
    https://docs.google.com/document/d/12e6Nh8nMQ4yRYYvQoPPhHXPWnQD6SP6g6dgCnQ-UGgc/edit?usp=sharing

  15. Peter is absolutely right that people should not assume that vitamin D allows them to slack off on other anti-pandemic measures such as distancing & masks (and vaccines for that matter). But at the same time, it is worth noting that many hundreds of scientists & physicians, including over 200 international scientist & physician signatories of the VitaminDforAll open letter, 73 French authors + 6 French national scientific societies, and 152 Italian professors & physicians, plus notable public health authorities such as former surgeon general Richard Carmona, all see the evidence as clear enough to recommend increased use of vitamin D during the pandemic, and notably at levels on average considerably above the RDA. See https://vitamindforall.org/rollcall.html for a roundup and links to the various different assessments.

  16. Can we just step back for a minute from the academic head swirl and look at this from the ground level of science and common sense?

    Let me ask this question: do you think a healthier immune system will help to protect you from Covid? If you haven’t been so brainwashed by the “a vaccine is the only thing that can save us” rhetoric and know anything at all about health and the human body then you know that this is clearly true.

    Moving on: all you need to do is some basic (not oversimplified, not wrong, just basic) research into what we have KNOWN for many years about vitamin D, as well as A, C, Zinc, and other nutrients to understand that they are ESSENTIAL for optimal immune system functioning.

    Now let’s put these two things together, shall we? If you are deficient in vitamin D, or any other nutrient that we know is NECESSARY for optimal immune function, then you ARE going to be more at risk for infectious diseases, including Covid-19! That’s just basic logic. We don’t need to spend billions of dollars on years of double blind placebo controlled studies to know that! The studies that have come out, for example the ones showing that (surprise!) folks with vitamin D deficiency are more at risk for Covid complications only reaffirm the science that we already know.

    I’m not necessarily saying to not take a vaccine — that’s for you to research and decide for yourself. What I am saying is let’s get back to common sense: the best thing that we can do to protect ourselves and others from Covid-19 and other infectious diseases is to strengthen our immune system. And that is not done with vaccines; it is done through proper nutrition (including supplementation when needed) and other factors like stress management, exercise, etc.

  17. My daughter tested positive for corona the same night I woke up with deep dry cough I felt a burning in my chest I took vitamin D went back to sleep the chest burning stopped but I still got sick with corona from caring for my daughter. I truly believe Vitamin D helped me not get it really bad in my chest area 👍

  18. Peter

    I believe you vastly undersell the use of the vitamin D metabolite calcifediol in reducing Covid-19 symptom severity. The therapeutic hormone, calcitriol , that ingestion of vitamin D ultimately ends up as takes weeks to occur within the human body as it goes through digestion, into the blood, then to the liver and finally into the kidneys. So if a sufferer of Covid-19 is administered conventional vitamin D for therapy, it’s essentially a race against time.

    Specifically when the final therapeutic hormone will be produced versus the progression of the disease. In some intervention trials conventional vitamin D was administered to seriously ill patients , which will understandably yield modest, poor or no results as the disease will progress unabated while the body produces the final hormone calcitriol .

    However the use of the metabolite calciferiol expedites the creation of the final vitamin D hormone. Calciferiol is the prehormone that the liver emits in the vitamin D process within the body. Fortunately calciferiol can be manufactured artificially outside of the body and its ingestion affords the vitamin D conversion process to be significantly expedited. Instead of weeks or even a month for the final hormone, calcitriol, to be be produced, the shortened process only takes hours.

    Thus the use of calcifediol is akin to using a pharmaceutical in terms of immediacy.

    Of the vitamin D intervention trials conducted for Covid-19 only one used calciferiol. That was Castillo et al 2020 and it’s the RCT trial you referred to. Bloody outstanding results I figure. Super inexpensive, safe and readily available too.

    Well done for promoting the daily consumption of sufficient vitamin D when healthy but for the medical community, and that includes you, to not be widely promoting for the application of calcifediol for treating Covid-19 symptoms is unconscionable.

    Sincerely

  19. Interesting and a good summary – although in my opinion the safety profile dictates that we should perhaps be less cautious with D and more with the vaccines. They seem to have different standards applied to them. My D was very high from sun exposure only. I did get covid, but after 4 or 5 days of fever it was pretty much over, and I believe having a decent amount help me with a measured response. I was taking zinc and lactoferrin and with so many other factors it of course it proves very little.

    But I think one of the strongest cases for D is the effect on the co-morbid conditions – and of course that’s why sun may be superior. In that context, D may be more of a marker rather than causative of good metabolic health – or a least causative along with other factors – which questions supplementation only. Insulin resistance is I think huge in this situation due to the potential ACE2 expression changes and rises in PAI-1. A paper by Matsuyama suggested the virus may dysregulate STAT1, hyperactivating STAT3 through increased PAI-1 – which increases cytokine production by binding to macrophage TLR4s. I believe this is key to the predisposition of hypertension, diabetes, obesity etc together with the existing RAAS problems these people have – and lower NO production may also play a part.

    If you look at Japan, with the oldest population on the planet, two things that set them a part are better metabolic health and better D levels in their aged…they may well have some cross immunity, but it’s around a 50x drop in mortality between them and the UK. They’re doing something right.

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