维生素 D 缺乏症是全球儿童和成人中最常见的营养性缺乏症。[1]Hossein-Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88:720-755.http://www.mayoclinicproceedings.org/article/S0025-6196(13)00404-7/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/23790560?tool=bestpractice.com[4]Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911-1930.http://press.endocrine.org/doi/10.1210/jc.2011-0385http://www.ncbi.nlm.nih.gov/pubmed/21646368?tool=bestpractice.com[8]McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med. 1992;93:69-77.http://www.ncbi.nlm.nih.gov/pubmed/1385673?tool=bestpractice.com[9]Pettifor JM. Vitamin D deficiency and nutritional rickets in children. In: Feldman D, Pike JW, Glorieux FH, eds. Vitamin D. 2nd ed. Boston, MA: Elsevier Academic Press; 2005:1065-1084.[10]Bodnar LM, Simhan HN, Powers RW, et al. High prevalence of vitamin D insufficiency in black and white pregnant women residing in the northern United States and their neonates. J Nutr. 2007;137:447-452.http://jn.nutrition.org/content/137/2/447.fullhttp://www.ncbi.nlm.nih.gov/pubmed/17237325?tool=bestpractice.com[11]Lee JM, Smith JR, Philipp BL, et al. Vitamin D deficiency in a healthy group of mothers and newborn infants. Clin Pediatr (Phila). 2007;46:42-44.http://www.ncbi.nlm.nih.gov/pubmed/17164508?tool=bestpractice.com在美国和欧洲,50 岁以上成人超过 40% 患有维生素 D 缺乏症。[1]Hossein-Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88:720-755.http://www.mayoclinicproceedings.org/article/S0025-6196(13)00404-7/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/23790560?tool=bestpractice.com血清 25-羟基维生素 D 水平符合维生素 D 缺乏症的 (<50 nmol/L [<20 ng/mL])比例:青春期前白人女孩48%、青春期西班牙和黑人美国男孩和女孩52%、健康青年人32%。[12]Gordon CM, DePeter KC, Feldman HA, et al. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158:531-537.http://archpedi.jamanetwork.com/article.aspx?articleid=485739http://www.ncbi.nlm.nih.gov/pubmed/15184215?tool=bestpractice.com[13]Sullivan SS, Rosen CJ, Halteman WA, et al. Adolescent girls in Maine at risk for vitamin D insufficiency. J Am Diet Assoc. 2005;105:971-974.http://www.ncbi.nlm.nih.gov/pubmed/15942551?tool=bestpractice.com[14]Nesby-O'Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr. 2002;76:187-192.http://ajcn.nutrition.org/content/76/1/187.fullhttp://www.ncbi.nlm.nih.gov/pubmed/12081833?tool=bestpractice.com[15]Tangpricha V, Pearce EN, Chen TC, et al. Vitamin D insufficiency among free-living healthy young adults. Am J Med. 2002;112:659-662.http://www.ncbi.nlm.nih.gov/pubmed/12034416?tool=bestpractice.com在中国西藏和蒙古国,60% 的婴儿因缺乏维生素 D 而患上佝偻病。[16]Harris NS, Crawford PB, Yangzom Y, et al. Nutritional and health status of Tibetan children living at high altitudes. N Engl J Med. 2001;344:341-347.http://www.nejm.org/doi/full/10.1056/NEJM200102013440504#t=articlehttp://www.ncbi.nlm.nih.gov/pubmed/11172165?tool=bestpractice.com在中东,穆斯林女性及其婴儿患有佝偻病和骨质软化症的比例也很高,可能是因为皮肤过多地被衣服覆盖。[17]Sedrani SH. Are Saudis at risk of developing vitamin D deficiency? Saudi Med J. 1986;7:427-433.在发达国家,维生素 D 强化食品和维生素补充剂的使用大大降低了有临床意义的维生素 D 缺乏症发生率。尽管如此,在食用非强化食品的人群中还是会发生维生素 D 缺乏症,尤其是在日光照射有限的地区。
现在已经认识维生素 D 缺乏症还会增加许多慢性疾病的风险,包括癌症、自身免疫性疾病、2 型糖尿病、心脏病和高血压和传染病(包括上呼吸道感染和结核病),以及骨关节炎。[1]Hossein-Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88:720-755.http://www.mayoclinicproceedings.org/article/S0025-6196(13)00404-7/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/23790560?tool=bestpractice.com[4]Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911-1930.http://press.endocrine.org/doi/10.1210/jc.2011-0385http://www.ncbi.nlm.nih.gov/pubmed/21646368?tool=bestpractice.com[18]Sabetta JR, DePetrillo P, Cipriani RJ, et al. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011088http://www.ncbi.nlm.nih.gov/pubmed/20559424?tool=bestpractice.com
据报道,维生素 D 缺乏症与前列腺癌、结肠癌、乳腺癌、卵巢癌和胰腺癌等癌症风险增加呈强相关。[19]Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002;94:1867-1875.http://onlinelibrary.wiley.com/doi/10.1002/cncr.10427/fullhttp://www.ncbi.nlm.nih.gov/pubmed/11920550?tool=bestpractice.com[20]Toriola AT, Surcel HM, Calypse A, et al. Independent and joint effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: a prospective nested case-control study. Eur J Cancer. 2010;46:2799-2805.http://www.ncbi.nlm.nih.gov/pubmed/20601305?tool=bestpractice.com 估计维生素 D 摄入量增加到 1000 IU/天,会降低 50% 的结直肠癌风险。[21]Gorham ED, Garland CF, Garland FC, et al. Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol. 2005;97:179-194.http://www.ncbi.nlm.nih.gov/pubmed/16236494?tool=bestpractice.com另外,一项研究指出较高水平血清 25-羟基维生素 D (平均120 nmol/L [48 ng/mL])的女性发生乳腺癌的风险降低 50%。[22]Bertone-Johnson ER, Chen WY, Holick MF, et al. Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1991-1997.http://cebp.aacrjournals.org/content/14/8/1991.fullhttp://www.ncbi.nlm.nih.gov/pubmed/16103450?tool=bestpractice.com另一项研究发现,加拿大照射阳光的青少年女性乳腺癌发病风险降低超过 60% (阳光促进皮肤中维生素 D 合成)。[23]Knight JA, Lesosky M, Barnett H, et al. Vitamin D and reduced risk of breast cancer: a population-based case-control study. Cancer Epidemiol Biomarkers Prev. 2007;16:422-429.http://cebp.aacrjournals.org/content/16/3/422.fullhttp://www.ncbi.nlm.nih.gov/pubmed/17372236?tool=bestpractice.com
一项在芬兰的研究发现,婴儿在一岁内每天服用 2000 IU 维生素 D,31 年后1 型糖尿病风险降低 78% 的。[24]Hypponen E, Laara E, Jarvelin MR, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500-1503.http://www.ncbi.nlm.nih.gov/pubmed/11705562?tool=bestpractice.com此外,该研究还显示维生素 D 摄入量较高的女性多发性硬化症和类风湿性关节炎风险的降低超过 40%。[25]Munger KL, Levin LI, Hollis BW, et al. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA. 2006;296:2832-2838.http://jama.jamanetwork.com/article.aspx?articleid=204651http://www.ncbi.nlm.nih.gov/pubmed/17179460?tool=bestpractice.com[26]Merlino LA, Curtis J, Mikuls TR, et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum. 2004;50:72-77.http://onlinelibrary.wiley.com/doi/10.1002/art.11434/fullhttp://www.ncbi.nlm.nih.gov/pubmed/14730601?tool=bestpractice.com对青少年发病的 SLE 患者的一项研究表明,维生素 D3 补充 24 周可有效减少疾病活动和改善疲劳。[27]Lima GL, Paupitz J, Aikawa NE, et al. Vitamin D supplementation in adolescents and young adults with juvenile systemic lupus erythematosus for improvement in disease activity and fatigue scores: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 2016;68:91-98.http://onlinelibrary.wiley.com/doi/10.1002/acr.22621/fullhttp://www.ncbi.nlm.nih.gov/pubmed/25988278?tool=bestpractice.com
第三次全国健康和营养调查 (NHANES 3) 显示,血清 25-羟基维生素 D 水平最高的成人,其发生 2 型糖尿病的相对风险度下降 33%。[28]Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006:29:650-656.http://care.diabetesjournals.org/content/29/3/650.longhttp://www.ncbi.nlm.nih.gov/pubmed/16505521?tool=bestpractice.com[29]Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87:1080S-1086S.http://ajcn.nutrition.org/content/87/4/1080S.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18400738?tool=bestpractice.com 对于已经每天服用 2000 IU 维生素 D 达 1 年的绝经后妇女,上呼吸道感染的风险降低 90%。这与 NHANES 3 的结果一致,NHANES 3显示,血清 25-羟基维生素 D 水平最高的儿童和成人全年发生呼吸道感染的可能性更低。[18]Sabetta JR, DePetrillo P, Cipriani RJ, et al. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010;5:e11088.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0011088http://www.ncbi.nlm.nih.gov/pubmed/20559424?tool=bestpractice.com[29]Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr. 2008;87:1080S-1086S.http://ajcn.nutrition.org/content/87/4/1080S.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18400738?tool=bestpractice.com[30]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;169:384-390.http://www.ncbi.nlm.nih.gov/pubmed/19237723?tool=bestpractice.com 在蒙古服用 300 IU 维生素 D3 强化牛奶的学龄儿童,患急性呼吸道感染的风险下降约 50%。[31]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:e561-e567.http://www.ncbi.nlm.nih.gov/pubmed/22908115?tool=bestpractice.com此外,一项研究显示在日本从 12 月到 3 月底,服用 1200 IU 维生素 D3 的儿童流感风险下降近乎 50%。[32]Urashima M, Segawa T, Okazaki M, et al. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91:1255-1260.http://www.ncbi.nlm.nih.gov/pubmed/20219962?tool=bestpractice.com
维生素 D 缺乏会增加高血压和心脏病风险。[33]Lee JH, O'Keefe JH, Bell D, et al. Vitamin D deficiency: an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol. 2008;52:1949-1956.http://www.ncbi.nlm.nih.gov/pubmed/19055985?tool=bestpractice.com[34]Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503-511.http://circ.ahajournals.org/content/117/4/503.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18180395?tool=bestpractice.com针对既往无心血管疾病(CVD)的 Framingham 后代研究的受试者进行研究,调查其维生素 D营养 状态,结果显示如果患者维生素 D 缺乏,发生心肌梗死的风险增加 50%。该研究也提示维生素 D 缺乏的 CVD 患者死亡风险更高。[35]Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340-1349.http://archinte.jamanetwork.com/article.aspx?articleid=414333http://www.ncbi.nlm.nih.gov/pubmed/18574092?tool=bestpractice.comCVD死亡率:有中等质量证据显示维生素 D 缺乏的 CVD 患者与没有维生素 D 缺乏的患者相比,死亡风险增加大于 100%。[35]Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch Intern Med. 2008;168:1340-1349.http://archinte.jamanetwork.com/article.aspx?articleid=414333http://www.ncbi.nlm.nih.gov/pubmed/18574092?tool=bestpractice.com受试者<200名的随机对照临床试验(RCT)、受试者>200名且方法学存在缺陷的随机对照临床试验(RCT)、方法学存在缺陷的系统评价或者高质量的观察性(队列)研究。 另外,该研究也显示,血清 25-羟基维生素 D 水平>72 nmol/L(>29 ng/mL)的成人发生外周血管疾病的风险降低 80%。[36]Melamed ML, Muntner P, Michos ED, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol. 2008;28:1179-1185.http://atvb.ahajournals.org/content/28/6/1179.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18417640?tool=bestpractice.com两个研究显示维生素 D 缺乏症是心源性猝死和致死性卒中的危险因素。[37]Pilz S, Dobnig H, Fischer JE, et al. Low vitamin D levels predict stroke in patients referred to coronary angiography. Stroke. 2008;39:2611-2613.http://stroke.ahajournals.org/content/39/9/2611.fullhttp://www.ncbi.nlm.nih.gov/pubmed/18635847?tool=bestpractice.com[38]Pilz S, März W, Wellnitz B, et al. Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography. J Clin Endocrinol Metab. 2008;93:3927-3935.http://press.endocrine.org/doi/full/10.1210/jc.2008-0784http://www.ncbi.nlm.nih.gov/pubmed/18682515?tool=bestpractice.com 大规模流行病学研究一致发现,维生素 D 缺乏会增加死亡、心血管疾病和癌症(特别是结直肠癌)的风险。[39]Bischoff-Ferrari HA. "Vitamin D - why does it matter?" - defining vitamin D deficiency and its prevalence. Scand J Clin Lab Invest Suppl. 2012;243:3-6.http://www.ncbi.nlm.nih.gov/pubmed/22536756?tool=bestpractice.com[40]LeBlanc ES, Zakher B, Daeges M, et al. Screening for vitamin D deficiency: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:109-122.http://annals.org/article.aspx?articleid=1938934http://www.ncbi.nlm.nih.gov/pubmed/25419719?tool=bestpractice.comFramingham 心脏研究受试者中,维生素 D 缺乏的患者发生骨关节炎的风险增加。[41]McAlindon TE, Felson DT, Zhang Y, et al. Relation of dietary intake and serum levels of vitamin D to progression of osteoarthritis of the knee among participants in the Framingham Study. Ann Intern Med. 1996;125:353-359.http://www.ncbi.nlm.nih.gov/pubmed/8702085?tool=bestpractice.com但是,一些研究也对补充维生素对预防癌症、心血管事件和认知下降的价值和效果提出了质疑[42]Fortmann SP, Burda BU, Senger CA, et al. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: An updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159:824-834.http://annals.org/article.aspx?articleid=1767855http://www.ncbi.nlm.nih.gov/pubmed/24217421?tool=bestpractice.com[43]Chowdhury R, Kunutsor S, Vitezova A, 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.http://www.bmj.com/content/348/bmj.g1903.longhttp://www.ncbi.nlm.nih.gov/pubmed/24690623?tool=bestpractice.com[44]Theodoratou E, Tzoulaki I, Zgaga L, et al. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.http://www.bmj.com/content/348/bmj.g2035.longhttp://www.ncbi.nlm.nih.gov/pubmed/24690624?tool=bestpractice.com及治疗高血压。[45]Beveridge LA, Struthers AD, Khan F, et al; D-PRESSURE Collaboration. Effect of vitamin D supplementation on blood pressure: a systematic review and meta-analysis incorporating individual patient data. JAMA Intern Med. 2015;175:745-754.http://www.ncbi.nlm.nih.gov/pubmed/25775274?tool=bestpractice.com
也已经观察到维生素 D 缺乏症与妊娠期先兆子痫、低出生体重和早产以及剖腹产的风险增加有关。[46]Bodnar LM, Catov JM, Simhan HN, et al. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92:3517-3522.http://press.endocrine.org/doi/full/10.1210/jc.2007-0718http://www.ncbi.nlm.nih.gov/pubmed/17535985?tool=bestpractice.com[47]Merewood, A, Mehta SD, Chen TC, et al. Association between vitamin D deficiency and primary caesarean section. J Clin Endocrinol Metab. 2009;94:940-945.http://www.ncbi.nlm.nih.gov/pubmed/19106272?tool=bestpractice.com[48]Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012;26(suppl 1):75-90.http://onlinelibrary.wiley.com/doi/10.1111/j.1365-3016.2012.01283.x/fullhttp://www.ncbi.nlm.nih.gov/pubmed/22742603?tool=bestpractice.com[49]De-Regil LM, Palacios C, Lombardo LK, et al. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2016;(1):CD008873.http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008873.pub3/fullhttp://www.ncbi.nlm.nih.gov/pubmed/26765344?tool=bestpractice.com在妊娠晚期补充维生素 D3 可增加出生后线性生长。[50]Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010;170:1135-1141.http://www.ncbi.nlm.nih.gov/pubmed/20625021?tool=bestpractice.com根据现有证据进行的荟萃分析显示,儿童的一些健康指标,包括出生体重和龋齿,都与维生素 D 营养状态有关。[51]Knekt P, Kilkkinen A, Rissanen H, et al. Serum vitamin D and the risk of Parkinson disease. Arch Neurol. 2010;67:808-811.http://www.ncbi.nlm.nih.gov/pubmed/20625085?tool=bestpractice.com
另外,该分析提示美国黑人中许多健康差距都源自维生素 D 缺乏。[52]Giovannucci E, Liu Y, Willett WC. Cancer incidence and mortality and vitamin D in black and white male health professionals. Cancer Epidemiol Biomarkers Prev. 2006;15:2467-2472.http://cebp.aacrjournals.org/content/15/12/2467.longhttp://www.ncbi.nlm.nih.gov/pubmed/17132768?tool=bestpractice.com美国黑人发生高血压和 2 型糖尿病的风险高于美国白人。他们的前列腺癌、结肠癌和乳腺癌发病率也较高,且其发病趋势越来越凶猛。另外,美国黑人感染结核病,特别是更具侵袭性的形式的风险也较高,其部分原因是维生素 D 缺乏。[53]Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770-1773.http://www.ncbi.nlm.nih.gov/pubmed/16497887?tool=bestpractice.com
维生素 D 缺乏症也与精神分裂症、帕金森病、认知功能障碍、阿尔茨海默病、痴呆和抑郁症有关,但在这些方面仍需进一步研究。[50]Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010;170:1135-1141.http://www.ncbi.nlm.nih.gov/pubmed/20625021?tool=bestpractice.com[51]Knekt P, Kilkkinen A, Rissanen H, et al. Serum vitamin D and the risk of Parkinson disease. Arch Neurol. 2010;67:808-811.http://www.ncbi.nlm.nih.gov/pubmed/20625085?tool=bestpractice.com[54]Shen L, Ji HF. Vitamin D deficiency is associated with increased risk of Alzheimer's disease and dementia: evidence from meta-analysis. Nutr J. 2015;14:76.http://nutritionj.biomedcentral.com/articles/10.1186/s12937-015-0063-7http://www.ncbi.nlm.nih.gov/pubmed/26231781?tool=bestpractice.com另外,已经显示维生素 D 摄入量高时,可降低急性呼吸道感染、哮喘和喘息病的发病率。[1]Hossein-Nezhad A, Holick MF. Vitamin D for health: a global perspective. Mayo Clin Proc. 2013;88:720-755.http://www.mayoclinicproceedings.org/article/S0025-6196(13)00404-7/fulltexthttp://www.ncbi.nlm.nih.gov/pubmed/23790560?tool=bestpractice.com[55]Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr. 2007;85:788-795.http://ajcn.nutrition.org/content/85/3/788.fullhttp://www.ncbi.nlm.nih.gov/pubmed/17344501?tool=bestpractice.com[56]Monlezun DJ, Bittner EA, Christopher KB, et al. Vitamin D status and acute respiratory infection: cross sectional results from the United States National Health and Nutrition Examination Survey, 2001-2006. Nutrients. 2015;7:1933-1944.http://www.mdpi.com/2072-6643/7/3/1933/htmhttp://www.ncbi.nlm.nih.gov/pubmed/25781219?tool=bestpractice.com