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Proposal to Provide USAP Participants with Vitamin D to Prevent Respiratory Tract Infections

Version 1

May 2015

United States Antarctic Program (USAP)
Support Contract #NSFDACS1219442

This document applies to the following locations:
McM 1
SP 1

Table of Contents 
Introduction    1
Proposal    1
Return on Investment (ROI)    2
RTIs and Vitamin D    3
Additional Benefits    3
Influenza Vaccine and Vitamin D    4
How Vitamin D Works    4
How Much is Needed?    5
Risks of Toxicity    6
Conclusion    7
Literature Cited    7

For many USAP participants, the excitement of deploying to an Antarctic station or vessel is often marred by several days of illness due to a serious respiratory tract infection (RTI) or upper respiratory tract infection (URTI). The illness may be caused by a rhinovirus, influenza, respiratory syncytial virus, or some other infectious agent, and it varies in severity depending on the individual. In some cases it can progress to more serious or long-lasting syndromes, such as bronchitis or pneumonia. Either can require antibiotics and, in some cases, even hospitalization. In McMurdo, all URTI manifestations are generally and popularly referred to as “the crud.” 
Each person affected can lose two or more days of work and suffer from reduced work capacity for several additional days. When a large percentage of the population is affected, as is often the case, this results in a significant seasonal cost to the USAP.
Recent research demonstrates both a clear association between low levels of vitamin D3 and RTIs and a strong connection between vitamin D3 supplementation and reduced RTI incidence. We suggest that this provides the USAP with an opportunity to reduce RTI incidence significantly, improve the overall public health, increase seasonal productivity, and save money. 
Unless deploying USAP participants spend a great deal of time outdoors before deployment, with significant skin exposure to the sun, it is very likely that they are deficient in vitamin D at the outset. Because of the low angle of the sun, even at the height of summer, and because most people work indoors, UVB exposure in Antarctica is insufficient to maintain normalized levels of vitamin D in the blood, exacerbating any initial deficiency. In addition, the food normally consumed by people contains little or no vitamin D (Vieth 1999). The only way for these people to maintain a sufficient level of vitamin D is through oral supplementation.
To make people more aware of their vitamin D levels, and to have a baseline from which to measure success, we suggest the USAP make the vitamin D test a standard for the pre-deployment physical. The test is inexpensive and is rapidly becoming a standard part of a complete blood count (CBC). Participants found to have serum levels of vitamin D <20 ng/ml should be encouraged seek to normalize these levels to 40-50 ng/ml under medical guidance. 
Second, we propose that the USAP provide 4000 IU of vitamin D3 per day for deployed participants, to be taken voluntarily. Available research shows this level of supplementation to be both safe and effective.
There are several ways to do this. Vitamin D could be made available in the store, or it could be dispensed by the clinics. However, simply making vitamin D available for purchase or available by request from the clinic would almost certainly result in low participation, particularly at the outset. Over time, as people observe the effectiveness of supplementation, participation would probably increase. But for the several years this might take, RTIs would continue to exact a significant toll on general health and overall productivity. 
We believe the most efficient method would be to have a vitamin D station in the dining facility, where a dispenser would deliver 2000 IU gel caps. People could then take the supplement as a normal part of their daily meals. It may be possible to have a vendor produce individually wrapped, 4000 IU packs.
We also propose that ASC develop a campaign to encourage participation similar to the one the previous contractor used to encourage hand washing before entering the dining facility. That campaign was very successful, and there is almost universal acceptance of the need to wash one’s hands before eating. We believe that with an adequate level of supplementation, along with education and widespread participation, annual RTI incidence at McMurdo and South Pole Station could be reduced by 50% or more.
Finally, since we believe that RTIs currently exert a significant health and financial toll on the program, we suggest that ASC maintain year-over-year data on RTI incidence to track the effectiveness of this and other interventions.
Return on Investment (ROI)
The cost to the USAP in providing 4000 IU/day of vitamin D to each participant is minimal. 2000 IU gel caps retail for as little as five cents apiece. Wholesale prices may be cheaper. The USAP would require about 300 caps per person per season (at 2 caps/day). If we assume five cents per gel cap, that amounts to $15 per person per season. And if we assume 1250 participants at both McMurdo and South Pole stations, that translates to less than $19,000 per season.
The ROI would be significant. Grant et al (2009) calculated that increasing the mean serum blood level of Europeans to 40 ng/ml, which would require 2000-3000 IU/day per person along with the requisite education and testing, would cost approximately €10,000 million/year. However, the savings in reducing the direct and indirect burden of disease would be about €187,000 million/year, a ROI of nearly 1800%.
The McMurdo Clinic reported 215 cases of RTI last season, with 39 receiving restricted duty. South Pole reported eight cases, with one receiving restricted duty. According to clinic personnel, these can be considered yearly averages. The actual number of RTIs is almost certainly higher, since not everyone who becomes ill reports to the clinic. However, for the purpose of calculating ROI we will restrict ourselves to the 223 reported cases.
We will assume that the 40 restricted duty cases resulted in three lost work days each and the other 183 cases resulted in one lost day each. (Again, the actual number of lost work days was almost certainly far higher.) The total number of lost work days is thus 303 per season. At an average salary of $270 per day per person, the lost days cost the USAP nearly $82,000 per season at McMurdo and South Pole. Even if the USAP were to see only a 50% reduction in days lost because of RTIs (a reasonable estimate with sufficient community participation), the ROI for supplying vitamin D would be more than 100%.
However, these calculations do not take into account partial work days, and reduced productivity days for people working but still not feeling well. They also do not account for work delayed, work postponed, and the domino effect of these factors on the productivity of others. We believe the actual seasonal cost of RTIs to be much higher than $82K and the ROI of prevention correspondingly greater.
Unfortunately, the lack of data on overall RTI incidence (including unreported RTIs) and the lack of data for more than one season prevent a more accurate business case. In addition, there are confounding factors, such as the mandated flu shot.
The remainder of this document lists the clinical and epidemiological research that supports the proposal. 
RTIs and Vitamin D
Evidence associating low levels of vitamin D with increased susceptibility to RTIs have been steadily accumulating. Valencia et al (2009) found that recent epidemiological studies clearly demonstrated a link between vitamin D deficiency and an increased incidence of respiratory infections. Moan et al (2009) concluded that the high numbers of winter influenza and pneumonia deaths in Norway were related to low vitamin D levels at that time of year.
Cannell (2008) noted that RTIs are more frequent in people with low levels of vitamin D. Ginde (2009) also found that low serum levels of vitamin D were associated with a significantly higher RTI rate. Laaksi et al (2007) who found that soldiers with serum D levels of less than 16 ng/mL had a 63% increased risk of absence from duty due to RTI than did soldiers with serum levels 16 ng/mL or more. Aloia et al (2007), conducting a randomized controlled trial to see whether vitamin D could prevent osteoporosis, noted that the people receiving vitamin D supplementation reported cold and flu symptoms three times less often than the people in the placebo group.
Urashima et al (2010) found that vitamin D supplementation in schoolchildren “…significantly reduced the incidence of influenza A within 60 days.” Gigineishvili et al (1990) provided a group of teenage athletes non-burning treatments of UV radiation twice a year for three years. A control group of non-irradiated athletes had “…50% more respiratory viral infections, 300% more days of absences and 30% longer duration of illness than did the UVR subjects.” In earlier studies, people given cod liver oil (which contains vitamin D) reported a 50% reduction in colds (Holmes et al 1932) and industrial absenteeism because of RTIs was reduced by 30% (Holmes et al 1936).
Aloia and Li-Ng (2007) found in their study of 208 post-menopausal African American women that those women given 800 IU per day of vitamin D suffered less than one third the RTIs over the course of three years as a control group receiving a placebo. When the dose was raised to 2000 IU per day during the last year of the trial, only one woman in the vitamin D group reported an RTI. In other words, RTI incidence was virtually eradicated.
Many other clinical and epidemiological studies also show a positive relationship between vitamin D and a reduced incidence of RTIs, including Tsujimoto et al (2011), Sabetta et al (2010), Bergman et al (2012), and Goodall et al (2014). 
Though there are a few conflicting studies (Li-Ng et al 2009, Murdoch et al 2012, Rees et al 2013), the majority of studies and the preponderance of data suggest that vitamin D supplementation is effective at reducing the incidence of RTIs, particularly in people with low initial serum D levels. 
Additional Benefits
Although peripheral to this proposal, it should also be noted that insufficient levels of vitamin D are associated with a host of other serious health problems. According to Valencia et al (2009), “Below “normal” vitamin D concentrations in adults have been strongly associated with tuberculosis, influenza, autoimmune diseases, cancer (prostate, colon and breast) and myocardial infarction. Expanded studies in infants and children are also exploring a connection between vitamin D insufficiency and type 1 diabetes mellitus, as well as the risk of developing allergies and atopic diseases. The prototypical example of a connection between vitamin D insufficiency and susceptibility to infectious disease is TB (tuberculosis). Published studies over the past twenty years have strongly connected the association of decreased serum D concentrations and increased severity and/or susceptibility to TB infection.” 
Influenza Vaccine and Vitamin D
In an attempt to reduce the incidence of influenza at Antarctic stations, in 2008-2009 the NSF began mandating an annual flu shot for all deploying participants. Unfortunately, no data currently exists to determine whether or not this approach has been successful, and the “crud” persists. Though many cases are likely caused by viral pathogens unaffected by the vaccine, several recent epidemiological studies also call the effectiveness of the flu vaccine into question. Cannell (2008) notes that “…influenza mortality and hospitalization rates for older Americans significantly increased in the 80's and 90's, 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.”
In a study of elderly Italians, Rizzo et al (2006) “…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%".”
Khurana et al (2013) may have found a reason for this apparent paradox. Using pigs as a model (since porcine physiology and response to influenza infection closely match those of humans), they found that when the active influenza strain did not match the antigens in the vaccine, the flu shot actually enhanced influenza infection.
Charan et al (2012) note that “vaccines are designed to enhance adaptive immunity, but their effectiveness depends on matching vaccine antigens to the predominant active strain, which is not always possible.” In a systematic review and meta-analysis, they found that vitamin D significantly reduced RTIs compared to placebo, and they concluded that “…enhancing innate immunity, in this case by Vitamin D3 supplementation, is more effective than vaccines at reducing the incidence of influenza, as well as other URTIs.”
We note this not to suggest discontinuing the shot, but only to point out that since research shows vitamin D may be more effective  in preventing influenza infection, it may be possible to dispense with the shot at some point (if its efficacy is indeed found to be low), resulting in additional savings. Currently, the lack of data makes it impossible to ascertain whether the shot has been effective in reducing RTIs in the USAP.
How Vitamin D Works
Vitamin D3 (cholecalciferol) is actually a seco-steroid hormone produced by ultraviolet-B (UVB) radiation when it interacts with 7-dehydrocholesterol in the skin. Most people are deficient in vitamin D, especially those in northern climes and those who work indoors most of the time. Most USAP participants are almost certainly deficient before they deploy, and the near total lack of sun exposure in Antarctica exacerbates that condition. A vitamin D study conducted during the Antarctic winter (Smith et al 2009) found that serum D levels dropped in a control group but rose significantly in groups receiving oral supplementation.
There is no known difference in physiological effect between the oral and UVB forms of supplementation (Vieth 1999). Cholecalciferol is converted to 25-hydroxyvitamin D (25(OH)D) by the liver, which is then converted in the kidneys to the active form 1-25dihydroxyvitamin D (1,25(OH)2D). However, the level of 25(OH)D in the blood is the best indicator of vitamin D status, since a powerful physiological mechanism strives to maintain homeostatic levels of 1,25(OH)2D, even in the face of declining levels of 25(OH)D.
Recently, one mechanism by which vitamin D works to enhance immune function has been uncovered. The active form of vitamin D stimulates genetic expression of antimicrobial peptides in certain human white blood cells (Wang et al 2004, Gombart et al 2005, Liu et al 2006). These natural antibiotics directly destroy invading microorganisms (Ganz 2003) and have been shown to inactivate the flu virus (Hiemstra et al 2004, Daher et al 1986). Epithelial cells lining the upper and lower respiratory tract also secrete these antimicrobial peptides (Schutte and McCray 2002, Beisswenger and Bals 2005). Wang et al (2009) also found that vitamin D increased the production of antimicrobial peptides in human monocytic and epithelial cells. Thus, by increasing production of broad-spectrum antimicrobial peptides that destroy the influenza virus, vitamin D plays a major role in in pulmonary defense.
How Much is Needed?
According to Vieth (1999), “…modern society in general is vitamin D–deprived compared with prehistoric humans. The concentrations of 25(OH)D observed today are arbitrary and based on contemporary cultural norms (clothing, sun avoidance, food choices, and legislation) and the range of vitamin D intakes being compared may not encompass what is natural or optimal for humans as a species.” 
Hollis et al (2007) concluded that few people get enough vitamin D, even if they take several thousand IU per day. They found that 25(OH)D levels had to exceed 40 ng/ml, and often 50 ng/ml, before cholecalciferol (the precursor) could be detected in the blood. Until that point is reached, all available cholecalciferol is used immediately and the production of 25(OH)D is thus artificially limited. “Not a single other steroidal hormone system in the body is limited in this fashion since their starting point is cholesterol. When humans are sun- (or dietary) replete, the vitamin D endocrine system will function in a fashion as do these other steroid synthetic pathways, not limited by substrate availability.”
According to Cannell (2006), this indicates that “…levels above 40 ng/mL appear to represent the lower limit of "normal" 25(OH) D levels,” which means almost everyone has a chronic cholecalciferol deficiency, at least in the winter, and therefore a functional vitamin D deficiency. He calls attention to the fact that one full-body, non-burning exposure (about 30 minutes) to UVB radiation triggers the release of about 20,000 IU of vitamin D into the circulation of light-skinned persons within 48 hours (Adams et al 1982), a mechanism that would not have evolved if the output were not important. He therefore believes ideal levels should be close to those present when humans evolved in sub-equatorial Africa, or about same as those found in people who spend the summer working outside (50 ng/ml).
Valencia et al (2009) notes that at serum 25(OH)D concentrations of less than 20 ng/ ml, the resulting low ionized calcium concentration stimulates parathyroid hormone secretion, which eventually leads to increased 1,25(OH)2D synthesis. “PTH and 25(OH)D concentrations are inversely related until the 25D concentration is greater than 30-40 ng/ml, after which PTH concentrations fall precipitously.” This would seem to indicate that serum levels of greater than 40 ng/ml are required.
Laaksi (2007) states that a serum 25(OH)D concentration of less than 32 ug/ml is insufficient. Heaney (2005) estimated that about 3000 IU/day is needed to ensure 97% of Americans attain a blood level of greater than 35 ng/ml. Cannell (2006) recommends that “…enough vitamin D be taken daily to maintain 25-hydroxy vitamin D levels at levels normally achieved through summertime sun exposure (50 ng/ml).”
According to Vieth (1999), for serum concentrations to exceed 40 ng/ml, people must take 4000 IU per day. Vieth et al (2004) found that administering 4000 IU per day of vitamin D3 for more than six months to middle-aged endocrinology outpatients produced average 25(OH)D levels of 44 ng/ml and no side-effects other than an improved mood.
Cannell (2006) estimates that, “In the absence of significant UVB exposure, input from diet and supplements of approximately 1,000 IU per day for every 15 kg of body weight may be needed.” That translates to about 5500 IU per day for an 82 kg (180 lb) individual and about 3500 IU per day for someone weighing 55 kg (120 lbs). Dark-skinned individuals, the obese (Zwart 2011), the elderly, and people who avoid the sun may need more. 
Heaney et al (2003) determined that healthy men use 3000-5000 IU cholecalciferol per day. Supplementing with 1000 IU/day did not raise blood ng/ml appreciably above the starting level of 28 ng/ml. 5000 IU/day raised it to 60 ng/ml after 120 days. 
In a study by Vieth et al (2001), the beginning serum baseline for participants was 16 + 6 ng/ml. After 3 months, levels plateaued at 27.6 + 6.8 ng/ml for a 1000 IU/day group and 38.4 + 5.8 for a 4000 IU/day group. The researchers monitored blood calcium levels and saw no increase in either group. He considers 4000 IU/day to be a safe dose. 
Based on the foregoing, it seems reasonable to conclude that the serum level of 25(OH)D should be maintained between 40 and 50 ng/ml, and that 4000 IU/day is a safe and appropriate dose for attaining that level.
Risks of Toxicity
Toxic levels of vitamin D are actually quite difficult to achieve. Vieth (1999) found that serum 25(OH)D concentration is maintained within a narrow range (<30-88 ng/ml) across vitamin D supplies from 800 IU/day to 20,000 IU/day. “The most reasonable explanation for this kind of relation is that there are homeostatic control systems to regulate serum 25(OH)D and to buffer against variability in vitamin D supply.” He notes a classic rise in the dose-response curve after 10,000 IU/day and postulates that this “…reflects the introduction of vitamin D and 25(OH)D at rates that exceed the capabilities of the various mechanisms to regulate 25(OH)D.”
He goes on to note that, in the absence of sunshine, reaching the “no observed adverse effect level” (NOAEL) of 56 ng/ml would require prolonged intake of about 10,000 IU per day. “All of the reports of vitamin D toxicity showing the convincing evidence of hypercalcemia involve serum 25(OH)D concentrations well above 200 nmol/L [80 ng/ml], which requires a daily intake of  >1000 ug (40,000 IU), and which could thus be conservatively considered the lowest observed adverse effect level (LOAEL).”
Valencia et al (2009) note that “Hypervitaminosis D is arbitrarily defined as 25D concentrations > 100 ng/mL (250 nmol/L). However, people living and/or working in sun-enriched environments, such as lifeguards and sunbathers, reached 25D concentrations exceeding this value without evidence of deleterious consequences beyond the well characterized solar damage from UVR (ultra violet radiation). Symptoms of vitamin D intoxication typically do not manifest until circulating 25D concentrations rise above 150 ng/ml.”
Barger-Lux et al (1998) found no evidence of toxicity in young men taking 50,000 IU per day for six weeks. However, Cannell (2006) notes that “…such a dose would be toxic if taken over a longer period.”
In a study by Heaney et al (2003) “…20 weeks of supplementation at 5500 and 11,000 IU/d, starting from a status of relative vitamin D repletion, produced no elevation of serum calcium above the upper limits of normal in any subject.” 
Based on the absence of adverse effects in clinical trials using doses up to 50,000 IU of vitamin D and the absence of toxicity in trials conducted in healthy adults using 10,000 IU per day, Hathcock et al (2007) express a high level of confidence that 10,000 IU represents a safe upper level for a daily dose.  They also found that “a serum 25(OH)D concentration of  >700 nmol/L [280 ng/ml] may be needed to evoke hypercalcemia in normal adults.” 
In Vitamin and Mineral Safety, 3rd Edition (2013), Hathcock states “The amount of daily vitamin D ingestion needed to produce adverse effects varies widely. In most adults, daily intake in excess of 50,000 IU (1.25 mg) is needed to produce toxicity (Miller and Hayes 1982). Clinical trials in the last decade or so have found no hypercalcemia in subjects in subject taking 10,000 IU (250 μg) in long-term clinical trials.”
The Institute of Medicine (IOM) has established an upper level 4,000 IU/day. Hathcock et al (2007) note that “The data by Heaney and coworkers (2003) indicate that the NOAEL for vitamin D is at least 250 μg (10,000 IU). Thus, from the available data, the [Lowest Observed Adverse Effect Level] LOAEL is greater than 250 μg per day in relation to its hypercalcemic effects.”
Finally, “It is noteworthy that hypercalcemia has never been observed in a causal relationship to vitamin D in a randomized clinical trial. All the evidence for vitamin D causing hypercalcemia comes from anecdotal reports of accidental or misinformed consumption of much higher amounts” (Hathcock 2013).
If 10,000 IU/day is a safe upper limit for vitamin D intake, as the many foregoing studies suggest, 4000 IU/day once again appears to be an appropriate supplementation level for normalizing serum D levels.
The available evidence strongly suggests that vitamin D supplementation of 4000 IU/day for USAP participants may significantly reduce the incidence of RTIs, significantly reduce RTI-caused lost work days, improve overall public health, and result in increased productivity and significant cost savings for the Program.
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