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H1N1, Vitamin D3 and Innate Immunity

Posted Oct 16 2009 10:03pm

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/dl 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/dl

Suppress parathyroid hormone                  20 ng/dl

Maximize intestinal calcium absorption         34 ng/dl

Maximize muscle strength                           50 ng/dl

 

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/dl and preferably above 60 ng/dl. 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?

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