In July, we chatted with John J. Cannell, M.D., about the safety of vitamin D. This month, we will review Dr. Cannell’s study showing that vitamin D is protective against the flu. You may wonder why, with so many people enjoying outdoor activities in the long hours of sunlight of August, that we are talking about vitamin D deficiency and the flu. It’s because we don’t want to wait until it’s too late for you to inform others about vitamin D’s protective action against influenza. The midst of an epidemic is a little late.

Dr. Cannell graduated with a degree in zoology from the University of Maryland, where he was a member of Phi Beta Kappa. He received his M.D. from the medical school at the University of North Carolina. After a year-long surgery internship at the University of Utah and four years of practicing itinerant emergency medicine, he began as a general practitioner in the coalfields of Appalachia.

Later, Dr. Cannell left general practice and went back to school to study psychiatry. He moved to Atascadero, CA, in the late 1990s and began working as a psychiatrist at Atascadero State Hospital, the largest hospital in America for the criminally insane. There, his long-held interest in clinical nutrition was re-awakened. The further he studied nutrition, the more and more vitamin D3 (cholecalciferol) caught his attention.

As Dr. Cannell began to study the effects of vitamin D, he immediately realized that the recommendations of the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) were placing many Americans at risk. He found that vitamin D insufficiency was common in older adults, even using conservative cutoff points for vitamin D blood levels. Dr. Cannell was left wondering whom he should believe: Nature or the FNB? In 2003, he recruited professional colleagues, scientists and friends for a board of directors and took the steps necessary to incorporate The Vitamin D Council as a tax-exempt, nonprofit, 501(c)(e) corporation.

In September 2006, Dr. Cannell’s seminal article, “Epidemic Influenza and Vitamin D” was published in the journal, Epidemiology and Infection. The article presented a revolutionary new theory on vitamin D’s link to influenza and was co-written with some of the world’s top vitamin D experts.

Passwater: Dr. Cannell, I believe that your study about vitamin D protecting against the flu was responsible for many researchers becoming interested in also studying vitamin D. This is indeed a very important study. Please give our readers some of the background for your study.

Cannell: In the spring of 2006, an influenza outbreak occurred at the Atascadero State Hospital where I used to work, Now at that time, I had all of my patients on vitamin D, usually 5,000 IU a day. I watched as the influenza outbreak closed one ward after the other at the hospital. We had about 30 wards. They closed the ward to my right, the ward across the hall and the ward to my left; all were quarantined because of influenza. I knew my patients had been exposed because they shared courtyards and other common areas together. Plus, I knew that my nurses had been exposed, and all of my nurses were on vitamin D at the time. They had worked with me and had seen the benefits of it. I watched and my patients didn’t get sick.

I started writing about this. I realized what I needed was to research the literature. In researching, I came across a really interesting man, and I say that somewhat narcissistically because he reminds me a little of myself in some ways. Of course, I am not anywhere as near as brilliant as he was. His name is Dr. Robert Edgar Hope-Simpson.

Passwater: The British Medical Journal called him one of the most brilliant general practitioner researchers of the 20th century (www.ncbi.nlm.nih.gov/pmc/articles/PMC261759). He was most noted for elucidating the relationship between chicken pox and shingles. After his death in 2003, an article in the British Medical Journal remarked, “Only a great intellect could have conceived the possibility that, remarkably, a virus could commonly lie dormant in the human body, for years, indeed decades, and then reappear in another form. Only an unusually determined researcher could have pursued the idea through fieldwork in the natural history tradition.”

Cannell: Yes, he discovered the etiology of shingles just by thinking about it and then doing some tests on patients. It was just remarkable. He dedicated the last 25 years of his life to studying influenza because it is the one infectious disease that has the ability to bring the world to its knees. It has in the past with devastating epidemics like the one that occurred in 1919.

I kept reading the literature and then I contacted other researchers including Dr. Ed Giovannucci, M.D., Sc.D., professor of nutrition and epidemiology at Harvard. I wrote a draft and sent it to others in the field that would revise it and then I would send the updated draft to others who also became co-authors. Eventually, we published the first article that implied vitamin D might be helpful and that vitamin D was important in explaining the many mysteries surrounding influenza (1).

Passwater: What did Dr. Hope-Simpson write that stimulated your thinking about vitamin D and the flu?

Cannell: What Dr. Hope-Simpson pointed out was that sunlight might be involved in influenza. When he looked at the latitudes and the sun exposures, he concluded that there was a factor in this that had to do with the sun. He called it the solar factor. Dr. Hope-Simpson wrote in 1981, “Outbreaks are globally ubiquitous and epidemic loci move smoothly to and fro across the surface of the earth almost every year in a sinuous curve that runs parallel with the midsummer curve of vertical solar radiation, but lags about six months behind it … Latitude alone broadly determines the timing of the epidemics in the annual cycle, a relationship that suggests a rather direct effect of some component of solar radiation acting positively or negatively upon the virus, the human host, or their interaction” (2).

Passwater: That reminds me of Drs. Cedric and Frank Garland and their work with vitamin D and colon cancer.

Cannell: It seems fairly obvious, but I have been working at this for 10 years with influenza and the message is still not getting through to many physicians. The Drs. Garland have been trying to educate people about vitamin D and colon cancer for 30 years and the wait goes on.

Passwater: Your vitamin D and influenza paper did, however, get the attention of many scientists.

Cannell: It has been cited several hundred times in other scientific publications. We have since updated and expanded on the seminal paper with a review published in Virology Journal (3).

Passwater: In your seminal paper in 2006, you proposed that vitamin D was the “seasonal stimulus” elucidated by Dr. Hope-Simpson. You presented graphical data correlating flu incidence with average 25-hydroxy vitamin D levels in the blood. You also described a paper that directly examined the relationship between vitamin D and respiratory infections. Dr. P. Rehman gave 60,000 IU of vitamin D a week and 650 mg of calcium daily for six weeks to 27 non-rachitic children (aged 3–12 years) who were also suffering from frequent childhood infections, mostly respiratory infections (4). Dr. Rehman found, “no recurrences were reported for a period of six months, in the treated children.”

Please tell our readers about the questions that Dr. Hope-Simpson asked about the nature of influenza.

Cannell: As we pointed out in the Virology Journal publication, perhaps the most universally accepted assumption about influenza is that it is a highly infectious virus spread by the sick. Dr. Hope-Simpson not only questioned that assumption, but he also went much further. Realizing that solar radiation has profound effects on influenza, he added an unidentified “seasonal stimulus” to the core of his epidemiological model. Unfortunately, the mechanism of action of the “seasonal stimulus” eluded him in life and his theory languished. Nevertheless, he parsimoniously used latent asymptomatic infectors and an unidentified “season stimulus” to fully or partially explain seven epidemiological conundrums:

 1. Why is influenza both seasonal and ubiquitous and where is the virus between epidemics?
 2. Why are the epidemics so explosive?
 3. Why do epidemics end so abruptly?
 4. What explains the frequent coincidental timing of epidemics in countries of similar latitudes?
 5. Why is the serial interval obscure?
 6. Why is the secondary attack rate so low?
 7. Why did epidemics in previous ages spread so rapidly, despite the lack of modern transport?

In our 2008 publication, we added an eighth conundrum—one not addressed by Dr. Hope-Simpson: Why is there a surprising percentage of seronegative volunteers who either escape infection or develop only minor illness after being experimentally inoculated with a novel influenza virus?

The percentage of subjects sickened by iatrogenic aerosol inoculation of influenza virus is less than 50%, although such experiments depend on the dose of virus used. Only three of eight subjects without pre-existing antibodies developed illness after aerosol inhalation of a flu virus. Intranasal administration of various wild viruses to seronegative volunteers only resulted in constitutional symptoms 60% of the time; inoculation with Fort Dix Swine virus (H1N1)—a virus thought to be similar to the 1918 virus—in six seronegative volunteers failed to produce any serious illness, with one volunteer suffering moderate illness, three mild, one very mild and one no illness at all. Similar studies on other H1N1 viruses found 46 of 55 directly inoculated volunteers failed to develop constitutional symptoms. If influenza is highly infectious, why doesn’t direct inoculation of a novel virus cause universal illness in seronegative volunteers?

We also added a ninth conundrum in the 2008 publication. Epidemiological studies question vaccine effectiveness, contrary to randomized controlled trials, which show vaccines to be effective. For example, influenza mortality and hospitalization rates for older Americans significantly increased in the 80s and 90s, during the same time that influenza vaccination rates for elderly Americans dramatically increased. Even when aging of the population is accounted for, death rates of the most immunized age group did not decline. Rizzo and colleagues studying Italian elderly, concluded, “We found no evidence of reduction in influenza-related mortality in the last 15 years, despite the concomitant increase of influenza vaccination coverage from ~10% to ~60%” (5). Given that influenza vaccinations increase adaptive immunity, why don’t epidemiological studies show increasing vaccination rates are translating into decreasing illness?

Passwater: What were the explanations presented in your articles?

Cannell: As we published in our 2006 paper, the compelling epidemiological evidence indicates vitamin D deficiency is the “seasonal stimulus” suggested by Dr. Hope-Simpson. Furthermore, recent evidence confirms that lower respiratory tract infections are more frequent, sometimes dramatically so, in those with low 25(OH)D levels (6–8).

In 1992, Dr. Hope-Simpson predicted, “Understanding the mechanism (of the seasonal stimulus) may be of critical value in designing prophylaxis against the disease.” Twenty-five years later, Drs. Aloia and Li-Ng found 2,000 IU of vitamin D per day abolished the seasonality of influenza and dramatically reduced its self-reported incidence (9).

Passwater: What biochemical mechanism is involved in vitamin D’s protection against the flu?

Cannell: It’s really neat. Several vitamin D response elements (see Part 2) are sitting on genes that regulate the production of antimicrobial peptides. Recently it has been shown that 1,25(OH)2D dramatically stimulates genetic expression of antimicrobial peptides (10–12). Antimicrobial peptides are the very simple, very potent naturally occurring antibiotics that our bodies make. They are made by our immune system cells as well as by our epithelial cells that line our throats, respiratory tracts and intestines. They exist in immune system cells including neutrophils, monocytes and natural killer cells. In the epithelial cells lining the respiratory tract, they play a major role in protecting the lung from infection. They are part of what is called the innate immune system. They’re rapid action. They’re ready to go in milliseconds of a virus penetrating the mucus of the respiratory tract. They don’t need to be primed with an antibody like the acquired immune system does. The antimicrobial peptides are useful not only in killing the bacteria, but also in regulating the immune response.

One of the reasons that so many young people died in the 1919 epidemic was once the 1919 virus infected you, it made you sick, but your immune system would make you even sicker because it would mount this inappropriate all-out attack that killed not just the virus, but also many of the respiratory cells in your respiratory tract. The victims had their respiratory tracts denuded of epithelial cells. Doctors had never seen this before.

Vitamin D works in many ways in the immune system. Antimicrobial peptide production is just one of them. What vitamin D does is make your immune system smarter, not stronger. If your immune system becomes too strong, you can get autoimmune diseases. What is important about vitamin D is that it makes your immune system smarter.

What I used to do with the Vitamin D Council back in the days when there was just one article being published in the scientific literature every week or so—now there are hundreds every month—I would write a newsletter about each new study. Now, I can’t do that because there are too many new studies.

One of the highlights of my scientific career is that within days of my first influenza paper on vitamin D and influenza being published in England in the journal Epidemiology and Infection—which is the same journal that Dr. Hope-Simpson published in—the editor received a letter from Dr. John Aloia’s research group in New York. The group had been doing a vitamin D study in bone and by chance, one of the questions they happened to ask the patients in their study was, “Had you had any symptoms of a cold or flu within the last month?” Dr. John Aloia read my paper, and then looked at his data. Lo and behold, the women he had on vitamin D were much less likely to get a cold or flu. He wrote that as a letter to the editor announcing his findings (13). It is very unusual for a theory to get supportive evidence so quickly. Now, the theory basically has been accepted as true by many. Of course, nothing can be proven to be true.

Passwater: And, we can all put that knowledge to practical use immediately as there are other health benefits from 5,000 IU of vitamin D daily in addition to reducing the incidence of influenza.

That certainly is an important contribution to our health, but you have other contributions from your research that our readers will be interested in. Let’s discuss your research linking vitamin D deficiency with autism in next month’s column. WF

References
1. J.J. Cannell, “Epidemic Influenza and Vitamin D,” Epidemiol. Infect. 134 (6), 1129–1140 (2006).
2. R.E. Hope-Simpson, “The Role of Season in the Epidemiology of Influenza,” J. Hyg. 86 (1), 35–47 (1981).
3. J.J. Cannell et al., “On the Epidemiology of Influenza,” Virol. J. 25 (5), 29 (2008).
4. P.K. Mujeeb Rehman, “Sub-clinical Rickets and Recurrent Infection,” J. Trop. Pediatr. 40 (1), 58 (1994).
5. C. Rizzo et al., “Influenza-Related Mortality in the Italian Elderly: No Decline Associated with Increasing Vaccination Coverage,” Vaccine, 24, 6468–6475 (2006).
6. V. Wayse et al., “Association of Subclinical Vitamin D Deficiency with Severe Acute Lower Respiratory Infection in Indian Children under 5 y,” Eur. J. Clin. Nutr. 58 (4), 563–567 (2004).
7. I. Laaksi et al., “An Association of Serum Vitamin D Concentrations <40 nmol/L with Acute Respiratory Tract Infection in Young Finnish Men,” Am. J. Clin. Nutr. 86 (3), 714–717 (2007).
8. G. Karatekin, “Association of Subclinical Vitamin D Deficiency in Newborns with Acute Lower Respiratory Infection and their Mothers,” Eur. J. Clin. Nutr. 63 (4), 473–477 (2009).
9. J. Aloia and M. Li-Ng, “Re: Epidemic Influenza and Vitamin D,” Epidemiol. Infect. 135 (7), 1095–1096 (2007).
10. T.T. Wang et al., “Cutting Edge: 1,25-dihydroxyvitamin D3 is a Direct Inducer of Antimicrobial Peptide Gene Expression,” J. Immunol. 173 (5), 2909–2912 (2004).
11. A.F. Gombart, N. Borregaard and H.P. Koeffler, “Human Cathelicidin Antimicrobial Peptide (CAMP) Gene Is a Direct Target of the Vitamin D Receptor and Is Strongly Up-Regulated in Myeloid Cells by 1,25-dihydroxyvitamin D3,” FASEB J. 19, 1067–1077 (2005).
12. P.T. Liu et al., “Toll-Like Receptor Triggering of a Vitamin D-Mediated Human Antimicrobial Response,” Science 311 (5768), 1770–1773 (2006).
13. J.F. Aloia and M. Li-Ng, “Re: Epidemic Influenza and Vitamin D,” Epidemiol. Infect. 135 (7), 1095–1096 (2007), author reply 1097–1098.

Dr. Richard Passwater is the author of more than 40 books and 500 articles on nutrition. He is the vice president of research and development for Solgar Vitamin and Herb. Dr. Passwater has been WholeFoods Magazine’s science editor and author of this column since 1984. More information is available on his Web site, www.drpasswater.com.

Published in WholeFoods Magazine, August 2011