Vitamin D and influenza

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Vitamin D up-regulates genetic expression of various endogenous antimicrobial peptides (AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses. Reports discussed below indicate that susceptibility to influenza is reduced with higher levels of sun exposure or vitamin D supplementation. Seasonal variation of vitamin D levels in humans can help explain the seasonality of flu epidemics.

Recent studies

Recently, Cannell and colleagues have suggested that vitamin D deficiency is a major risk factor for influenza and that vitamin D may be effective in reducing influenza incidence and severity.[1][2]

In both publications, the authors concluded that physiological doses of vitamin D (5,000 IU/day for adults and 1,000 IU/day for every 25 pounds of body weight in children) might reduce the incidence of influenza, and proposed that pharmacological doses (2,000 IU/kg/day for 3–4 days) may have a treatment effect in influenza. The authors present epidemiological evidence suggesting that the seasonality of vitamin D deficiency may explain the seasonality of influenza epidemics and that the epidemiology of vitamin D deficiency may help explain the confusing epidemiology of influenza. However, the seasonality of influenza may also be explicable by other factors. For example, it has been shown that low absolute humidity favours the survival of the influenza virus. [3]

Links with ultraviolet radiation

In fact, significant evidence exists that suggests Vitamin D, whether from ultraviolet B lamps, the sun, or from supplements, reduces the incidence of respiratory infections. In 1926, Smiley, who first discovered the strong inverse association between sun exposure and upper respiratory tract infections, also first theorized that such seasonality was caused by “disordered vitamine metabolism in the human. . . directly due to a lack of solar radiation during the dark months of winter.”[4] Dutch children with the least sun exposure were twice as likely to develop a cough, and 3 times as likely to have a runny nose, as the children with the most sun exposure.[5]

Furthermore, vitamin D–producing ultraviolet radiation administered twice a week for 3 years to 410 teenage Russian athletes, compared to 446 non-irradiated athletes, resulted in 50% fewer respiratory viral infections and 300% fewer days of absences.[6]

Blood calcidiol levels and respiratory infections

Blood calcidiol [25(OH)D] levels are inversely related to respiratory infections.

Wayse et al compared 80 non-rachitic children with lower respiratory tract infections to healthy controls and found that the children with the lowest 25(OH)D levels were 11 times more likely to become infected.[7]

Sixty thousand international units (IU) of vitamin D per week administered for 6 weeks to 27 children with frequent respiratory infections resulted in a complete disappearance of such infections for the following 6 months.[8]

Aloia and Li-Ng[9], in a post hoc analysis of their original 3-year randomized controlled interventional trial, discovered that 104 African American women given vitamin D were 3 times less likely to report cold and flu symptoms than were 104 placebo control subjects (p < 0.002). A very low dose (800 IU/d) for two years abolished the seasonality of reported colds and flu, and even a sub-physiological dose of 2,000 IU/d (40% of treated women still had serum 25(OH)D levels of less than 32 ng/mL after 1 year) for an additional year virtually eradicated all reports of upper respiratory tract infections. However, when the same authors gave 2,000 IU/day for four months in the winter, they found no preventative effect, hypothesizing that the dose and length of study was inadequate to show an effect.[10]

This implies that starting sub-physiological doses of vitamin D, such as 2,000 IU/day, in the late fall and winter will be too little and too late and very recent evidence from Creighton University indicates 25(OH)D levels of even 30 ng/ml, the levels usually obtained by 2,000 IU/day, often signify chronic substrate starvation[11], thus the full antimicrobial properties of vitamin D require physiological serum 25(OH)D levels (44-70 ng/ml) levels less than 10% of Americans obtain.

More recently, Ginde et al found, using NHANES data, that lower 25(OH)D levels were strongly associated with frequent respiratory tract infections and that, in patients with asthma and COPD, the odds ratio was OR, 5.67 and 2.26, respectively.[12] Finnish military recruits with serum 25(OH)D concentrations < 40 nmol/L had significantly (P = 0.004) more days of absence from duty due to respiratory infection.[13] The same is true of newborns.[14]

Mechanism of action

As far as mechanism, several groups have recently reported that vitamin D dramatically up-regulates genetic expression of various endogenous antimicrobial proteins (AMP), which exhibit broad-spectrum microbicidal activity against bacteria, fungi, and viruses.[15][failed verification] In general, AMP rapidly damage the lipoprotein membranes of microbial targets, including enveloped viruses such as influenza. Both the epithelium, in which they form a protective shield in mucus, and professional phagocytes, in which they provide microbicidal activity within the phagolysosome, produce AMPs. The innate immune system not only provides direct antimicrobial defense for these “front lines,” but it also signals and primes the adaptive immune system to produce antigen-specific T lymphocytes and immunoglobulins. In addition, AMPs — such as the potent antimicrobial cathelicidin — trigger tissue repair through activation of epithelial growth and angiogenesis.

Antimicrobial peptides protect mucosal epithelial surfaces by creating a hostile antimicrobial barricade. The epithelia secrete them constitutively into the thin layer of fluid that lies above the apical surface of the epithelium but below the viscous mucous layer. To effectively access the epithelium, a microbe must first infiltrate the mucous barrier and then survive assault by the AMPs present in this fluid. Should microbes breach this constitutive cordon, their binding to the epithelium rapidly mobilizes the expression of high concentrations of specific inducible AMPs such as human β-defensin 2 and cathelicidin, which provide a “backup” antimicrobial shield.

Role in innate immunity

Various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.

Vitamin D’s pivotal role in innate immunity has become evident only recently.[16] First White’s group at McGill University,[17] then 2 independent groups at the University of California–Los Angeles,[18][19] showed that activated vitamin D [1,25(OH)2D] dramatically up-regulates genetic expression of AMPs in immune cells. (For details of the mechanism of action, see White’s[20] review.) Both epithelial cells and macrophages increase expression of the antimicrobial cathelicidin upon exposure to microbes — an expression that is dependent upon the presence of vitamin D. Pathogenic microbes, much like the commensals that inhabit the upper airway, stimulate the production of a hydroxylase that converts 25(OH)D to 1,25(OH)2D, a seco-steroid hormone. In turn, this rapidly activates a suite of genes involved in pulmonary defense.

In the macrophage, the presence of vitamin D also suppresses the pro-inflammatory cytokines interferon γ, tumor necrosis factor α, and interleukin-12 and down-regulates the cellular expression of several pathogen associated molecular pattern (PAMP) receptors. In the epidermis, vitamin D induces additional PAMP receptors, enabling keratinocytes to recognize and respond to microbes.[21] Thus, vitamin D both enhances the local capacity of the epithelium to rapidly produce endogenous antibiotics and, at the same time, dampens certain arms of adaptive immunity, especially those responsible for the signs and symptoms of acute inflammation.

The work of Liu et al[22] is of particular interest. Plasma levels of vitamin 25(OH)D in African Americans, known to be about one half those of light-skinned individuals, are inadequate to fully stimulate the vitamin D—25(OH)D restores the dependent circuits and the expression of cathelicidin. High concentrations of melanin in dark-skinned individuals shield the keratinocytes from the ultraviolet radiation required to generate vitamin D in skin.

Therefore, relative — but easily correctable — deficiencies in innate immunity probably exist in many children during the dark days of winter, with dark-skinned children at highest risk. Black children continue to have twice the rate of mortality from pneumonia of white children, despite modern antibiotics.[23] Furthermore, during any season, for any skin type, and at any latitude, a percentage of the population is vitamin D–deficient, although the percentage is highest in the winter and in dark-skinned individuals, and increases the further poleward the population.

For example, seasonal variation of vitamin D levels even occurs in equatorial Hong Kong,[24] and widespread vitamin D deficiency occurs at such latitudes,[25] probably because of sun avoidance, rainy seasons,[26] and air pollution.[27] A study of Hong Kong infants showed that about half had 25(OH)D levels of less than 20 ng/mL in the winter.[28] None of the infants had levels higher than 40 ng/ mL, even in the summer. Thus, a substantial percentage of all children will have impaired innate immunity at any given time, although the impairment is greatest during the dark days of the cold and flu season.

Role in prevention

Vitamin D can potentially play a significant role in prevention of influenza, given a well demonstrated link between vitamin D deficiency and the incidence of respiratory infections. The diagnosis and treatment of vitamin D deficiency is straight-forward, cheap and without substantial risk. Thus, physicians should make an effort to diagnose and adequately treat vitamin D deficiency to prevent influenza recurrence. Given what is known about vitamin D and influenza, many contend that the problem of vitamin D deficiency should be considered an important public health issue.

References

  1. ^ Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006;134:1129-40.
  2. ^ Cannell JJ, Zasloff M, Garland CF, Scragg R, Giovannucci E. On the epidemiology of influenza. Virol J 2008;5:29.
  3. ^ Jeffrey Shamana, Melvin Kohn. Absolute humidity modulates influenza survival, transmission, and seasonality. PNAS, published online before print February 9, 2009, doi: 10.1073/pnas.0806852106.
  4. ^ Smiley DF. Seasonal factors in the incidence of the acute respiratory infections. Am J Hyg 1926;6:621-6, p. 626
  5. ^ Termorshuizen F, Wijga A, Gerritsen J, Neijens HJ, van Loveren H. Exposure to solar ultraviolet radiation and respiratory tract symptoms in 1-year-old children. Photodermatol Photoimmunol Photomed 2004;20:270-1.
  6. ^ Gigineĭshvili GR, Il’in NI, Suzdal’nitskiĭ RS, Levando VA. The use of UV irradiation to correct the immune system and decrease morbidity in athletes [in Russian]. Vopr Kurortol Fizioter Lech Fiz Kult 1990 May-Jun:30-3.
  7. ^ Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory infection in Indian children under 5 y. Eur J Clin Nutr 2004;58:563-7.
  8. ^ Rehman PK. Sub-clinical rickets and recurrent infection. J Trop Pediatr 1994;40:58.
  9. ^ Aloia JF, Li-Ng M. Re: epidemic influenza and vitamin D. Epidemiol Infect 2007;135:1095-6; author reply 1097-8.
  10. ^ Li-Ng M, Aloia JF, Pollack S, Cunha BA, Mikhail M, Yeh J, Berbari N. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009 Oct;137(10):1396-404. Epub 2009 Mar 19. PMID 19296870
  11. ^ Heaney RP, Armas LA, Shary JR, Bell NH, Binkley N, Hollis BW. 25-Hydroxylation of vitamin D3: relation to circulating vitamin D3 under various input conditions. Am J Clin Nutr. 2008, 87(6):1738-1742.
  12. ^ Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384-90.
  13. ^ Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamäki H, Ylikomi T. An association of serum vitamin D concentrations < 40 nmol/L with acute respiratory tract infection in young Finnish men. Am J Clin Nutr. 2007 Sep;86(3):714-7.
  14. ^ Karatekin G, Kaya A, Salihoğlu O, Balci H, Nuhoğlu A. Association of subclinical vitamin D deficiency in newborns with acute lower respiratory infection and their mothers. Eur J Clin Nutr. 2009 Apr;63(4):473-7.
  15. ^ Zasloff M. Antimicrobial peptides of multicellular organisms.Nature 2002;415:389-95.
  16. ^ Zasloff M. Fighting infections with vitamin D. Nat Med 2006;12:388-90.
  17. ^ Wang TT, Nestel FP, Bourdeau V, et al. Cutting edge:1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909-12. [Erratum in J Immunol 2004;173:6489.]
  18. ^ Gombart AF, Borregaard N, Koeffler HP. 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 2005;19:1067- 77.
  19. ^ Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D–mediated human antimicrobial response. Science 2006;311:1770-3.
  20. ^ White JH. Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun 2008;76:3837-43.
  21. ^ Schauber J, Dorschner RA, Coda AB, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism. J Clin Invest 2007;117:803-11.
  22. ^ Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D–mediated human antimicrobial response. Science 2006;311:1770-3
  23. ^ Dowell SF, Kupronis BA, Zell ER, Shay DK. Mortality from pneumonia in children in the United States, 1939 through 1996. N Engl J Med 2000;342:1399-407.
  24. ^ MacDonald D, Swaminathan R. Seasonal variation in 25-OH vitamin D in plasma of Hong Kong Chinese. Clin Chem 1988;34:2375.
  25. ^ Levis S, Gomez A, Jimenez C, et al. Vitamin D deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab 2005;90:1557-62.
  26. ^ Shek LP, Lee BW. Epidemiology and seasonality of respiratory tract virus infections in the tropics. Paediatr Respir Rev 2003;4:105-11.
  27. ^ Agarwal KS, Mughal MZ, Upadhyay P, Berry JL, Mawer EB, Puliyel JM. The impact of atmospheric pollution on vitamin D status of infants and toddlers in Delhi, India. Arch Dis Child 2002;87:111-3.
  28. ^ Leung SS, Lui S, Swaminathan R. Vitamin D status of Hong Kong Chinese infants. Acta Paediatr Scand 1989;78:303-6.

See also