J Steroid Biochem Mol Biol. 2015 Jan 24. pii: S0960-0760(15)00029-1. doi: 10.1016/j.jsbmb.2015.01.017. [Epub ahead of print]
Yawn J1, Lawrence LA1, Carroll WW1, Mulligan JK2.
A large number of human, animal and in vitro studies have suggested that vitamin D3 (VD3) plays a critical role in inflammatory airway diseases such as asthma, chronic rhinosinusitis, and allergic rhinitis. VD3 acts upon a broad range of immune cells involved in the pathogenesis of these diseases including T-cells, dendritic cells (DCs), macrophages, and B-cells. In addition, VD3 can also regulate the functions of a number of non-immune cells including epithelial cells, fibroblasts, and smooth muscle cells. Given that VD3 has known effects on the immune system, it seems logical that supplementation with VD3 would prove efficacious in the treatment of these three diseases. While many studies, most of which are observational, have suggested that VD3 deficiency is associated with more severe disease, VD3 supplementation trials in humans have resulted in varied outcomes in terms of efficacy. In this review article we will discuss the role of VD3 in these three commonly associated respiratory diseases. We will explore the literature describing associations of VD3 deficiency with patient outcomes, cells in the respiratory microenvironment susceptible to VD3 regulation, conflicting results of VD3 supplementation trials, and potential gaps in our knowledge that may be limiting the widespread use of VD3 for the treatment of respiratory diseases such asthma, chronic rhinosinusitis and allergic rhinitis. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
Copyright © 2015. Published by Elsevier Ltd.
Vitamin D does reduce risk of upper respiratory infections!
Disclosure I receive funding from Bio Tech Pharmacal (Fayetteville, AR), MediSun Technology (Highland Park, IL), and the Vitamin D Council (San Luis Obispo, CA).
The paper by Yawn and colleagues reported that the evidence for vitamin D for the treatment of respiratory diseases was weak since random controlled trials (RCTs) have not supported the observational studies finding inverse correlations between 25-hydroxyvitamin D [25(OH)D] concentrations and incidence of respiratory diseases . However, the analysis of the RCTs and the literature search were not conducted well.
There have been two vitamin D RCTs that demonstrated a beneficial effect in reducing risk of influenza. The first was conducted on black post-menopausal women living on Long Island. Those taking 800 or 2000 IU/d vitamin D3 had significantly lower incidence of colds and influenza than those taking the placebo .
However, the same research group conducted a second vitamin D RCT on a similar group without finding a beneficial effect as noted in Ref. 1 . The primary difference between the two trials was the baseline 25(OH)D concentration. As reported in Ref. 3, in the first one, it was 46.9±20.6 nmol/l (95% CI 43.9–50.39) while in the second one it was 64.3±25.4 nmol/L.
The second was a vitamin D RCT conducted on school children in Japan. For those not taking vitamin D prior to entering the trial, there was a 64% reduction in incidence of type A influenza for those taking 1200 IU/d vitamin D3 compared to the placebo .
Another vitamin D RCT overlooked was conducted in Mongolia. In this study, school children with mean baseline 25(OH)D concentration of 7.0 (5.0–9.9) ng/mL (to convert ng/mL to nmol/L, divide by 2.5). were given 300 IU/d vitamin D3 which raised 25(OH)D concentration to 18.9 (15.5–22.9) ng/mL . A significant reduction in acute respiratory infections was found.
Two negative studies were reviewed in Ref. 1. A study from New Zealand started with a baseline 25(OH)D concentration of 29 (SD, 9) ng/mL, achieved a 25(OH)D concentration of 48 ng/mL, and found no beneficial effect . Another vitamin D RCT followed two groups, each with mean baseline 25(OH)D concentration near 25 ng/mL and achieved 25(OH)D concentration near 32 ng/mL . Again, no significant effect of vitamin D supplementation was found.
Summarizing the findings from vitamin D trials, those trials that had baseline 25(OH)D concentrations below 50 nmol/L (20 ng/mL) found reduced risk of respiratory tract infections from taking vitamin D3 while those with higher baseline concentrations did not.
Robert Heaney recently outlined guidelines for optimizing designs of nutrients such as vitamin D . The important points for vitamin D are to start with an understanding of the 25(OH)D concentration-health outcome relation, measure 25(OH)D concentrations, enroll only those with low 25(OH)D concentrations, supplement with enough vitamin D3 to raise concentrations high enough to see an effect, and remeasure 25(OH)D concentrations. Very few vitamin D trials satisfied these steps. Many 25(OH)D concentration-health outcome relations show rapid changes below 15 ng/mL with very little change after 30 ng/mL [9, 10]. Thus, vitamin D RCTs should seek to enroll people with baseline 25(OH)D concentrations below 20 ng/mL.
Additional evidence that vitamin D reduces risk of respiratory tract infections comes from an ecological study of influenza case-fatality rates in 12 communities in the United States from the 1918–1919 influenza pandemic. Case fatalities were generally due to pneumonia and occurred about 10 days after the influenza infection. In a comparison with solar UVB doses for summer or winter, rates were significantly lower in communities with higher solar UVB doses . The mechanisms proposed were that vitamin D induces cathelicidin, which can kill bacteria, and reduction in the cytokine storm that often accompanies influenza. The cytokine storm can damage the lining of the lungs, thereby permitting the ever present bacteria to give rise to pneumonia. The influenza in that pandemic was type A H1N1.
Thus, there is plenty of evidence that vitamin D can prevent and treat upper respiratory tract infections.
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- 3. Li-Ng M, Aloia JF, Pollack S, et al. A randomized controlled trial of vitamin D3 supplementation for the prevention of symptomatic upper respiratory tract infections. Epidemiol Infect. 2009;137(10):1396-404.
- 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(5):1255-60.
- 5. Camargo CA Jr, Ganmaa D, Frazier AL, et al. Randomized trial of vitamin D supplementation and risk of acute respiratory infection in Mongolia. Pediatrics. 2012;130(3):e561-7.
- 6. Murdoch DR, Slow S, Chambers ST, et al. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA. 2012;308(13):1333-9.
- 7. Rees JR, Hendricks K, Barry EL, et al. Vitamin d3 supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis. 2013;57(10):1384-92.
- 8. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54.
- 9. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010;101(2):130–6.
- 10. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104(8):e43-50.
- 11. 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(4): 215-9.
- Respiratory infections reduced by 63 percent with 4000 IU vitamin D daily - RCT Dec 2012
- Vitamin D and Respiratory Tract Infections – meta-analysis with charts June 2013
- Vitamin D reduces respiratory tract infections by 40 percent– meta-analysis Dec 2012
- Respiratory Tract visits 2.5 less likely with vitamin D: Pregnancy 2000 IU, Infant 800 IU – RCT Oct 2014
- Acute respiratory infection treated by vitamin D in 6 of 12 clinical trials – review Nov 2012
- 100 % of Acute Respiratory Failure patients had low vitamin D - April 2012
- All items in Breathing and Vitamin D
- Just 300 IU daily of vitamin D reduced respiratory infections by 50% – RCT Aug 2012
- Acute lower respiratory infection 5X more frequent with low vitamin D intake – June 2012
- Hypothesis: Respiratory problems will decrease with increased vitamin D – Jan 2012
- Vitamin D and the Lung – professional book 2012
- Lung and Vitamin D – Special Issue Dec 2011
- Common cold (Acute Rhinosinusitis) 12 percent more likely for every 10 nanogram lower Vitamin D – Oct 2015
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