Kurt G. Harris MD

The PāNu approach to nutrition is grounded on clinical medicine and basic sciences disciplined by knowledge of evolutionary biology and paleoanthropology. The best evidence from multiple disciplines supports eating an animal-based diet high in fat, low in cereal grains and relatively low in carbohydrate.

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Monday
Sep282009

H1N1, Vitamin D3 and Innate Immunity

New Evidence

I recently received an email from the Vitamin D Council regarding recent evidence that having adequate serum Vitamin D levels could be very important to avoiding illness from the H1N1 (swine) flu that is making the rounds. That will seem intuitive to those of you who read my earlier post about D, but it’s good to see some real evidence. Some of you may have seen this information already on other blogs, including Richard’s, but I have some new information and some comments to add.

Here is the text of a letter written by Morris Glick, MD to Dr. Cannell of the Vitamin D Council – a non-profit group that does excellent work in promoting the benefits of Vitamin D.

Dr. Cannell:

Your recent newsletters and video about Swine flu (H1N1) prompted me to convey our recent experience with an H1N1 outbreak at Central Wisconsin Center (CWC). Unfortunately, the state epidemiologist was not interested in studying it further so I pass it on to you since I think it is noteworthy.

CWC is a long-term care facility for people with developmental disabilities, home for approx. 275 people with approx. 800 staff. Serum 25-OHD has been monitored in virtually all residents for several years and patients supplemented with vitamin D.

In June, 2009, at the time of the well-publicized Wisconsin spike in H1N1 cases, two residents developed influenza-like illness (ILI) and had positive tests for H1N1: one was a long-term resident; the other, a child, was transferred to us with what was later proven to be H1N1.

On the other hand, 60 staff members developed ILI or were documented to have H1N1: of 17 tested for ILI, eight were positive. An additional 43 staff members called in sick with ILI. (Approx. 11–12 staff developed ILI after working on the unit where the child was given care, several of whom had positive H1N1 tests.)

So, it is rather remarkable that only two residents of 275 developed ILI, one of which did not develop it here, while 103 of 800 staff members had ILI. It appears that the spread of H1N1 was not from staff-to-resident but from resident-to-staff (most obvious in the imported case) and between staff, implying that staff were susceptible and our residents protected.

Sincerely,

 

Norris Glick, MD

Central Wisconsin Center

Madison, WI

 

Here is an excerpt from Dr. Cannell’s comments found here.

This is the first hard data that I am aware of concerning H1N1 and vitamin D. It appears vitamin D is incredibly protective against H1N1. Dr. Carlos Carmago at Mass General ran the numbers in an email to me. Even if one excludes 43 staff members who called in sick with influenza, 0.73% of residents were affected, as compared to 7.5% of staff. This 10-fold difference was statistically significant (P<0.001). That is, the chance that this was a chance occurrence is one less than one in a thousand.

My comments:

The gist of this is that we have an accidental controlled experiment. We cannot say it is randomized as of course the segregation into treated residents and untreated staff is non- random. However, one would have to strain to explain how being indoors and developmentally disabled would confer some immune advantage over being an employed staff member at the facility.

The central Wisconsin center is in my home state of Wisconsin. Curious about the level of supplementation, I called for Dr. Glick but he was out of town at the time. However, I did speak with the assistant medical director, Dr. Jeff Seltz, and he was kind enough to answer a few questions about the protocol at CWC.

The supplements ranged from 400 to 2000 iu/day, and were tailored to each resident’s (25) OH D level.

Supplementation has been ongoing for several years, with each resident tested at least yearly.

The target level for (25) OH D was 50 ng/ml or higher, the same level recommended by Dr. Cannell and that I recommended as a minimum in my earlier post.

There is already good evidence for seasonal variation in Vitamin D levels accounting for the peculiar epidemiology of influenza.

Two excellent review articles are:

On the epidemiology of influenza

and

Epidemic influenza and Vitamin D

These articles also have excellent discussions on Vitamin D and its salutary effects on immune function generally.

I’d like to summarize a bit because these papers are pretty interesting.

Vitamin D is the likely explanation for Influenza Epidemiology.

Edgar Hope-Simpson proposed in 1981 that an unknown “seasonal stimulus” accounted for the outbreak of influenza in the winter months

I cannot cut and paste the graph, but in the second article is a nice graphic summary of seasonal outbreaks of influenza by latitude. In both the northern and southern hemisphere, the peak of influenza is nearly perfectly coincident with the nadir of solar irradiation, the winter solstice for those of us in the north.

Hope-Simpson's seasonal stimulus is serum levels of (25)-OH D3 dropping gradually along with decreasing sun exposure as summer transitions to winter.

Influenza is unusual in that it is both ubiquitous and seasonal, the epidemics are explosive and end abruptly, epidemics occur simultaneously among populations at similar latitudes but separated by big differences in longitude, the measure of the serial interval is obscure and the secondary attack rate is very low at only about 20%.

It is surprisingly hard to purposefully infect people with influenza. In the months after the 1918 pandemic, cringe-worthy experiments were performed where Navy “volunteers” were directly inoculated in the eyes, throat and lungs with a soup of bronchial mucus, nasal washings and throat swabs obtained from infected subjects within 1-3 days of onset of their illness. This and at least 6 similar experiments failed to demonstrate effective sick-to-well transmission.

All of these epidemiologic observations can be explained by the virus being present in the population when D levels are high, but D both prevents transmission in the uninfected, and modulates the virulence of the infection in the infected. Once D levels start to drop, the rate of cases clinically evident picks up until peaking in the northern hemisphere around the winter solstice, when D stores will have dropped by as much as half.

Let’s see how this works.

Vitamin D affects the Immune system in ways that prevent infection.

Recall that there are two main divisions to our system of immune defenses, the adaptive immune response and the innate immune response. The adaptive immune response is the one involving antibodies and specific recognition and responses to specific agents (viruses, allergens) that we have encountered before. It is also the system that can go haywire by causing damage to innocent tissues of our own body in those who have rheumatoid arthritis, autoimmune thyroid disease or just allergic rhinitis.

The innate immune response is the sum of cellular and structural defenses that are our first line of defense, and what we rely on to defend us from infection by novel agents that we have not encountered before.

Vitamin D, acting through the Vitamin D receptor (VDR), stimulates cells used in the innate response to produce AMPs or anti-microbial peptides. These AMPs are basically endogenously produced antibiotics with names like defensin 2, defensin 3, and cathelicidin . The cells stimulated include the white blood cells known as monocytes, neutrophils and natural killer cells and the epithelial cells that line the respiratory tract (nose, tracheobronchial tree and lungs).

Say a dose of virus particles is inhaled as an aerosol into your bronchus. The particles must first penetrate the physical barrier of mucus lining the respiratory epithelium. Once past that barrier, there is an aqueous film containing AMPs that can immediately attack the virus. In addition, contact with cells by molecules from the invading organism like PAMPs (pathogen associated molecular patterns) stimulate production and release of more AMPs. The AMPs, in an action reminiscent of the lectins plants use as self-defense against animals like us, bind to and damage the lipoprotein cell membrane of bacteria or the viral envelope of the virus. Any damage to epithelial cells induces release of yet more AMP to fend off the invader, and more immune cells are called in to the scene. The net effect of more AMP production is lower penetration by and poorer survival and replication of virus particles.

Vitamin D enables the machinery to produce more AMPs to act as the primary line of defense. In this way, transmission of the virus to the uninfected is discouraged, and those infected who have higher D levels will have a lower viral load to infect others.

Vitamin D affects the Immune system in ways that mitigate the damage if you are infected.

The lower ability of the virus to replicate in those with higher D levels and better innate immunity will diminish the severity of the illness in those affected.

In addition, there are VDRs on macrophages that respond to higher D levels. This is where the adaptive immune response comes in. Certain arms of the adaptive response (including the macrophage response) are actually attenuated by having higher D levels.

Macrophages elaborate proinflammatory cytokines like Interferon g, TNFa and IL-2 in a “destroy the village in order to save it” fashion in an attempt to kill the virus. There can consequently be a lot of local tissue damage that in fact accounts for much of the phenotype (nastiness) of the virus in the infected. Such a cytokine storm as part of the adaptive response is characteristic of avian (bird) flu, where patients “drown in mucus” due to the overwhelming nature of the response and often require ventilator support to avoid death. The cytokine storm is thought to be a key feature of the virulence of the virus in the 1918 pandemic.

So higher D levels make you less likely to get infected.

With higher D levels, if you do get infected, you are much less likely to get severely ill, and more likely to be able to breathe on your own.

With higher D levels, if you do get infected, you are probably also less likely to spread the virus to others.

How high a level do you need?

From Cannell, Vieth, et al. :

 

Prevent rickets                                             10 ng/ml

Suppress parathyroid hormone                  20 ng/ml

Maximize intestinal calcium absorption         34 ng/ml

Maximize muscle strength                           50 ng/ml

 

We don’t know the minimal number to protect against influenza, but the above levels of benefit are well established.

I continue to recommend, at minimum, supplementation to above 50 ng/ml and preferably above 60 ng/ml. Per my previous article, this will usually take sunlight or at least 4000 iu/day for adults

Finally, I like the following question posed by Cannell from the Cannell and Vieth paper:

Is influenza infection a sign of Vitamin D deficiency as much as Pneumocystis Carinii is a sign of AIDS?

References (1)

References allow you to track sources for this article, as well as articles that were written in response to this article.
  • Response
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Reader Comments (25)

The only possible confounding factor I was thinking about in the nursing home was that all of the patients were older, and thus may have immunity through exposure to one of the earlier outbreaks of a similar flu. It has been suggested that people in their 50s and up are more likely to be immune to this strain. And I'm figuring the workers were younger.

I'm not taking issue with the point in general. And I take 2500-5000 units a day because I do believe in the need for adequate levels of D. I'm really amazed that they have been monitoring their patients for their D levels. I'd be interested in some more information about other benefits they've seen, and why they started doing this in the first place. I had never heard of anyone in similar settings doing that.

September 28, 2009 | Unregistered CommenterCharles

Hi, I discovered your blog a few weeks ago-- love it.

If I could be so bold as to make a suggestion, it might be good for you to list the side effects of too much Vitamin D, so people know in case they try supplementing. I assumed I was deficient (barely ever in the sun) and started taking 4000 mg daily. Turns out I'm not deficient, or at least not that deficient. I experienced many of the symptoms listed here. Fortunately I stumbled upon that page and figured out what was going on (symptoms didn't start for a while and I hadn't connected them with the Vit. D I'd started taking). Everything seems to be much better a few days after ceasing supplementation.

Anyway, thank you again, your blog is very helpful.

September 28, 2009 | Unregistered CommenterDaniel Smith

I am curious to how this plays out as you move closer to the equator. I am 6 degrees north of the equator in Thailand. Obviously, less vitamin D fluctuation. I work in a school. Three students came down with H1N! last week, but probably contracted it while traveling. The nurse says there 100,000 confirmed cases in Thailand. Haven't checked up on that. Taking her word for it. Is there a world map that shows H1N1 infection as a percent of populations by latitudes?

September 28, 2009 | Unregistered CommenterMark

Daniel

I don't doubt that you might have reacted to something in the D formulation you took, but I do very much doubt it was true D toxicity. Some people have adverse reactions to the fish oil vehicle in some gel caps.

What were your precise symptoms? The symptoms listed in the link you gave are entirely non-speciic

What was your serum Vitamin D level? That is the only way to prove toxicity.

Yours would be the first reported case of toxicity in anyone taking less than 10,000 units/day/!

Reference - http://www.ajcn.org/cgi/content/full/69/5/842

Mark

As you might expect, the seasonality is less as one approaches the equator. However, influenza is by no means unknown, and people can still be D deficient when they have darker skin, spend more time indoors, or during the rainy season.

Charles

What you are proposing as a hypothetical is more adaptive immunity in older residents - this goes against what we know about viral susceptibility and influenza in general, and exposure to prior strains is not thought to protect against H1N1. I am not sure about age differences, as this is not an"old folks home" but a home for the developmentally disabled. Finally, the difference is nearly 10-fold. It's good to try to think of these things, though.

September 28, 2009 | Registered CommenterKurt G. Harris MD

Popular Science had a recent article about H1N1 and how it seems to be disproportionally affecting younger people. The article was in the print edition of the magazine, and I can't find it online. According to the article people over 50 are less affected by the virus.

The LA Times had a similar article here: http://www.latimes.com/news/nationworld/nation/la-sci-flu-mysteries18-2009sep18,0,2108779.story
They suggest that the healthy, vigorous immune systems in younger people causes a more severe cytokine storm, which can lead to serious complications and even death. Since older people have less vigorous immune systems the cytokine storm is not as severe and life threatening. Of course this is all speculation and none of it has been proven as far as I can determine.

I've been taking 4000IU per day of Carlson Vitamin D drops. They use coconut oil instead of fish oil as the base. I've had reactions to fish oil based Vitamin D supplements, but haven't had any issues with the Carlson Vitamin D drops. Just something for people to consider if they are having issues with fish oil based supplements.

September 28, 2009 | Unregistered CommenterCavePainter

Cavepainter

Whether less likely to have the cytokine storm if young or less likely to acquire it at any age, D status should help in either case.

I will probably switch to the Carlson's drops as well - the gel caplets seem to get stuck in my throat.

September 28, 2009 | Registered CommenterKurt G. Harris MD

I have excellent 25 OHD readings (63-70 ng/dl) from supplementing 6,000 IU's D3 per day normally and 10,000 IU's D3 per day in December, January and February. Over the past three years, I seemed to be immune to colds and flu as I just wasn't sick at all. I did attribute this to my diligent D3 supplementation.

However, all good things come to an end. Over the past twelve months (also the first twelve months months of my first child's post-partum existence, including day care), I have had an influenza-like illness no less than four times, including a particularly brutal week-long bout last month. I did not have tests to resolve the virus behind any of my ili's, though I wish I had for last month's (since my symptoms were less severe versions of those reported by Sanjay Gupta WRT his bout of H1N1).

Though my personal account is only an anecdote (and anecdote is not the singular form of "data"), Vitamin D3, powerful pro-hormone that it is, probably does not represent an unassailable defense against the flu. Unfortunately.

September 28, 2009 | Unregistered CommenterRoss

I think seasonality is important in everything we humans, not living in tropical area's, do. Our 25 OHD 'should' fluctuate : ignoring non-life threatening virus infections in summer (much to much to do, eat and play). When winter is there, it's time to fight of the remaining infections (there is not much else to do in winter, food is scarce, it's too cold to go out).
The same thing with transitioning from a higher intake of Omega3 vs Omega6 in spring (eating lots of green and animals that eat fresh fast growing gras: spring fats) versus higher intake of Omega6 vs Omega3 in autumn (eating more seeds and animals that eat seeds: autumn fats)
The same thing with transitioning from long days/short nights in summer to short days/long nights in winter.

In other words : we are ignoring lots of important biological signals that are telling us to :
- relax, repair, rest, slow down metabolism in winter
and
- be active, grow, ignore infections, high metabolism in summer.

I agree that we get much to little sun exposure these days and adding D3 can help, but keeping the 25 OHD level high all year round : that's asking for trouble after a while. (same thing as keeping the Omega3 intake high and the the length of the days the same all year round)

What do you think ?

September 28, 2009 | Unregistered CommenterAhrand

The major one that got my attention was fatigue, I felt like I was tired but could not really sleep, it was very odd. I also had a bad taste in my mouth, a slight headache, pains in my wrists and finger joints, and my gums started feeling sensitive. Oh, and my heart raced sometimes while I was not doing anything, and occasionally thumped oddly (I'd call it a palpitation, but I'm not 100% sure what that feels like).

I was taking a solid tablet, not a capsule, so I don't think there was fish oil involved.

September 28, 2009 | Unregistered CommenterDaniel Smith

Oh, one more, I was congested, as well.

September 28, 2009 | Unregistered CommenterDaniel Smith

Daniel

Did you have a serum (25) OH D level drawn?

Ross

Not claiming anything makes us unassailable. It's all probabilities. My own anecdotal experience is dramatic reduction in susceptibility to infection and when they occur, recovery in hours versus days. Also, if you have a child in day care, all bets are off.

Who knows how sick you might have been if D deficient or what other factors might be affecting your immunity.

Ahrand

I totally disagree. I think you are falliing for the naturalist fallacy. Certainly if you are not in the tropics, one would expect D levels to show seasonality, but to say that having a lower level in the winter would be healthier or desirable is not biologically plausible.

September 28, 2009 | Registered CommenterKurt G. Harris MD

No, I did not.

September 28, 2009 | Unregistered CommenterDaniel Smith

I've been taking D3 (Carlson's gelcaps) now for nearly two years and getting some strange 25(OH)D results (which I've posted about to Dr Cannell and Dr Vieth who have been most reassuring):

After only four months of 4,000 IU D3 per day during the winter before last (in UK) my 25(OH)D measured 384 nmol/L (154 ng/dl) which was much too high. I stopped taking D3 altogether for a few months and then was instructed by my endocrinologist to resume at 2,000 IU per day which I have carried on doing. My 25(OH)D was measured every few months and measured between 125 nmol/L (50 ng/dl) and 200 nmol (80 ng/dl). Then in July it shot up to 250 nmol/L (100 ng/dl) even though I had avoided what little sun we got. My endo instructed me to continue with the 2,000 IU as he felt the rise was due to the sun (even though I hadn't gone out in it !) and asked me to retest after a holiday in the south of France. I decided to see exactly how much D the sun would give me and got as much sun as I could ! I got out in it everyday and mostly full body. The retest came out at 188 nmol/L (75 ng/dl) ! More sun, stronger sun, same dosage of D3 and a drop of 25 ng/dl !

All along people have been saying that it must be the lab at fault as some labs are not too reliable. I've thought so too, except that every time my 25(OH)D has been too high my level of alkaline phosphatase (bone) has gone above normal and every time the 25(OH)D is more normal the alkaline phosphatase lowers to normal levels, so I have to think that even if the lab is not entirely accurate there is still some truth in my 25(OH)D results.

At all times, whether the 25(OH)D has been high or normal I have felt absolutely fine, no symptoms of toxicity.

Anne

September 28, 2009 | Unregistered CommenterAnne

Anne

You and the other posters have identified good reasons to consider using a UV lamp instead of pills.
I am seriously considering that myself. Cannell's site has links to providers of such.

I have not been supplementing with pills until a few weeks ago - I tried to get an hour a day of midday sun starting in June to see how my D levels would respond - will be testing soon.

September 28, 2009 | Registered CommenterKurt G. Harris MD

I don't think there's that much need to avoid pills (though I do like the LEF drops myself).

I wouldn't put too much credibility into a single test result. The error bars on these tests can be substantial, with much depending on the lab and their repeatability. Since I am an advocate of Vitamin D supplementation controlled by testing, many of my friends have joined me and I have had a chance to see a LOT of 25 OH D test results. All of us have seen an anomalously high test result here and there. A repeat test often shows normal (or otherwise expected) levels.

Don't sweat a single test result, especially if it seems like it puts you at death's door. The test is probably wrong and a second test will often reveal that your 25(OH) D3 levels are right where you left them.

September 28, 2009 | Unregistered CommenterRoss

Kurt,
I'm really looking forward to your 'sunshine" D results so please publish them. Based on your original article, I too started working on getting about 1 hour of late morning sun every day and will have my vit D levels tested at the time I do my next HbA1c test in either late December or early January. I'm not taking any supplements so it will be interesting to see what my levels are in mid winter here in the Los Angeles area. My normal annual lab tests are in July so I'll have an opportunity to see how my summer levels compare with winter.

Lex

September 28, 2009 | Unregistered CommenterLex Rooker

Very informative article. I take 6000iu a day with no adverse effects. Are there any good rules of thumb for the dosing of children? By the way, thanks for your effort with this blog, it is fantastic!

September 29, 2009 | Unregistered CommenterWayne Zenoble

Chris Masterjohn over at "The Daily Lipid" posted an article back on April 7th about a Tuft's University study backing up his hypothosis that Vitamin A works synergistically with Vitamin D (and K2) to prevent Vitamin D toxicity. (Vitamin D also protects against A toxicity).

If you haven't already done so, you might want to check this out, and also click on his links to read his original articles published in the WAPF publication "Wise Traditions".

http://www.cholesterol-and-health.com/cholesterol-blog.html

If you are eating plenty of animal fat (heavy cream etc), as well as lots of eggs and liver, you are probably getting adequate Vit A. If you are not, you might want to consider getting your A & D from HIGH VITAMIN cod liver oil.

I think the theory here, is that to much of one, with not enough of another could potentially be a problem for some people.

September 29, 2009 | Unregistered CommenterJenny Light

Did Carlson's change their clo formula? It used to be very high in vitamin A compared to D. Looking at the label online today, it seems that it is now more like Green Pasture's Blue Ice fermented clo, which is what I take from autumnal to vernal equinox. I do get sun as well here in TX, so I do not supplement daily.

Also, aren't certain fish like herring and salmon good for vitamin D? And can anyone address the apparent issue of vitamin D variability in lard? IOW, is fat from pastured pork raised in sunlight a decent source of vitamin D? TIA.

September 29, 2009 | Unregistered CommenterSatya

Wayne

Thank you

For kids, I think it's reasonable to linearly adjust the adult doses on a weight basis. For example, 4000 iu/day for 70 kg would be roughly 1000 iu/day for 17 kg. Sunshine without burning would work fine, too.

September 29, 2009 | Registered CommenterKurt G. Harris MD

Jenny

You said:

"If you are eating plenty of animal fat (heavy cream etc), as well as lots of eggs and liver, you are probably getting adequate Vit A. If you are not, you might want to consider getting your A & D from HIGH VITAMIN cod liver oil."

I agree with this.

I walk a fine line between making simple and safe general recommendations and confusing and frightening people with too much discussion of rare or obscure possibilities.

It's fair to view all my recommendations in the context of the 12 steps under "get started", which form the whole framework to my approach.
Sunshine and D supplementation follow 4 steps that should already result in very high consumption of animal products -and hence plenty of all the fat-soluble vitamins that work to optimize the effects of D. I am not preaching to the vegan or "healthy whole grain" choir.

Thanks for your comments and the link. Stephan covers the fat soluble vitamin synergy as well.

Satya

I am not a supplement aficionado, so can't answer your question about brands. Animals need D3 like we do, so eating their Vit D storage depot (fat) will give us some for sure. Animals livers, especially fish, more so.

I can't quantitate it for you right away, but I feel we were designed to make our own D with sunlight and animal sources can't come close to the D we make with UVB unless we seek artifically high amounts like that contained in CLO.

September 29, 2009 | Registered CommenterKurt G. Harris MD

IMPORTANT NOTE for all who are considering cod liver oil supplementation:

The ratio of A to D is very important, and should be at least 10 to 1 (unfortunately, in some commercial brands of cod liver oil the ratio is as low as 100 to 1).

Also, as a side note, all CLO sourced from from Norway now contains synthetic vitamins as an additive!

The consensus seems to be that Green Patures Fermented Cod Liver Oil is the best reliable source at this time, as it contains no synthetics, and has adequate vitamin A to D ratios.

September 30, 2009 | Unregistered CommenterJenny Light

Dr. Harris: Excellent post. I would add that labs are quite poor(but improving) in their measurement of D3. Some time ago this was highlighted in the New York Times where Quest D3 results overstated blood levels of D3. To your knowledge has this problem been rectified?

Steve

October 1, 2009 | Unregistered Commentersteve

Hi Steve

See this

/panu-weblog/2009/10/1/vitamin-d-home-testing.html

Don't know if they have fixed the problem yet.

October 1, 2009 | Registered CommenterKurt G. Harris MD

Doctor,

I stumbled upon this study, which reported that a multivitamin supplement, having 400 IU of vitamin D, increased 25(OH)D levels from 77 to 100 nmol/L, while the placebo group's levels didn't change. I know you recommend around 4000 IU. Is there any explanation for the conflicting results from different studies? Could it be that a multivitamin supplement is much more efficient for increasing vitamin D levels?

October 9, 2009 | Unregistered CommenterMike
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