Tamiflu: “a nice little earner”

The feature, Tamiflu: “a nice little earner” [1] points out that Tamiflu is very expensive but has not proven to be effective in responding to influenza pandemic such as the H1N1 influenza pandemic of 2009. This comment outlines the case for a very inexpensive, readily available natural compound for use in reducing the risk of influenza and ensuing death from pneumonia.

The ultraviolet-B-vitamin D-influenza hypothesis was proposed by John J. Cannell and colleagues in 2006 to explain the seasonality [2]. This hypothesis was quickly supported by the results of a randomized controlled trial (RCT) involving postmenopausal black women with low baseline 25-hydroxyvitamin D [25(OH)D] levels [3]. A subsequent vitamin D RCT on school children in Japan found that taking 1000 IU/d vitamin D3 reduced the risk of type A influenza by 66% for those not taking vitamin D prior to the trial, but had no effect on type B influenza. Both of the pandemics of 1918-19 and 2009 were type A/H1N1 influenza. A more recent RCT in Mongolia on children with baseline 25(OH)D level of 7 ng/mL found a 50% reduction in acute respiratory infections by taking 300 IU/d vitamin D3 [5]. These three RCTs were conducted in general agreement with the latest guidelines for vitamin D RCTs [6]. Vitamin D RCTs conducted on populations with baseline 25(OH)D levels above 15-20 ng/mL are very unlikely to show any benefit [7].

An ecological study of case-fatality rates in 12 communities in the United States during the 1918-19 influenza pandemic found that half of the variance could be explained by solar ultraviolet-B doses ]8]. As stated in the abstract: “Vitamin D upregulates production of human cathelicidin, LL-37, which has both antimicrobial and antiendotoxin activities. Vitamin D also reduces the production of proinflammatory cytokines, which could also explain some of the benefit of vitamin D since H1N1 infection gives rise to a cytokine storm.”

Vitamin D has been found to have many health benefits in observational studies [9, 10]. The lack of supporting RCTs can be explained by the fact that most vitamin D RCTs to date have enrolled people with 25(OH)D levels above 15-20 ng/mL and given too little vitamin D (400-1000 IU/d) to produce an effect that would be larger than the 95% confidence intervals of the trials [6,7]. Influenza pandemics occur when 25(OH)D levels are low [11]. Supplementing with 2000-4000 IU/d vitamin D during winter and giving high dose vitamin D to those diagnosed with influenza [12] should go a long way towards reducing the risk of the next influenza pandemic from claiming many lives.

References
1. Jack A. Tamiflu: “a nice little earner”. BMJ 2014;348:g2524
2. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect. 2006;134:1129-40.
3. Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect. 2007;135:1095-6; author reply 1097-8.
4. Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91:1255-60.
5. Camargo CA Jr, Ganmaa D, Frazier AL, Kirchberg FF, Stuart JJ, Kleinman K, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130:e561-7.
6. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48-54.
7. Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
8. Grant WB, Giovannucci E. The possible roles of solar ultraviolet-B radiation and vitamin D in reducing case-fatality rates from the 1918–1919 influenza pandemic in the United States. Dermatoendocrinol. 2009;1:215-9.
9. Hossein-Nezhad A, Holick MF. Vitamin D for health: A global perspective. Mayo Clin Proc. 2013;88:720-55.
10. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
11. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr. 2007;85:860-8.
12. Alam U, Chan AW, Buazon A, Van Zeller C, Berry JL, Jugdey RS, et al. Differential effects of different vitamin D replacement strategies in patients with diabetes. J Diabetes Complications. 2014;28:66-70.