Are Adequate Vitamin D Levels Helpful in Fighting COVID-19? A Look at the Evidence

Abstract

COVID-19 is a global pandemic with high mortality in vulnerable groups. Given the current lack of definitive treatment or vaccine that significantly reduces mortality rate, governments, researchers and healthcare providers are racing to find possible solutions to the crisis. Vitamin D and its analogues have been previously studied for their non-skeletal benefits. In particular, questions regarding their role in the modulation of immunity have re-surfaced, in view of possible epidemiological links observed between COVID-19 and vitamin D levels in selected populations. In this review, we highlight potential mechanisms and summarise the evidence for and against the potential role of vitamin D supplementation in our fight against COVID-19.

Key words

vitamin D - bone/calcium homeostasis - COVID-19 - SARS-CoV-2 - ACE2 - immunity - respiratory tract infections

• References

• 1 Wang Y, Zhu J, DeLuca HF. Where is the vitamin D receptor?. Arch Biochem Biophys 2012; 523: 123-133
• 2 Townsend K, Evans KN, Campbell MJ. et al. Biological actions of extra-renal 25-hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment. J Steroid Biochem Mol Biol 2005; 97: 103-109
• 3 Aranow C. Vitamin D and the Immune System. J Investig Med 2011; 59: 881-886
• 4 Liu PT, Stenger S, Li H. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311 (5768): 1770-1773
• 5 Almerighi C, Sinistro A, Cavazza A. et al. 1Alpha,25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes. Cytokine 2009; 45: 190-197
• 6 Chen S, Sims GP, Chen XX. et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179: 1634-1647
• 7 Daniel C, Sartory NA, Zahn N. et al. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther 2008; 324: 23-33
• 8 Slaats J, ten Oever J, van de Veerdonk FL. et al. IL-1b/IL-6/CRP and IL-18/ferritin: Distinct Inflammatory Programs in Infections. PLoS Pathog 2016; 12: e1005973
• 9 Martineau AR, Jolliffe DA, Hooper RL. et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583
• 10 Bergman P, Lindh AU, Björkhem-Bergman L. et al. Vitamin D and respiratory tract infections: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2013; 8: e65835
• 11 Charan J, Goyal JP, Saxena D. et al. Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis. J Pharmacol Pharmacother 2012; 3: 300-303
• 12 Camargo CA, 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
• 13 Sabetta JR, DePetrillo P, Cipriani RJ. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 2010; 5: e11088
• 14 Bergman P, Norlin A-C, Hansen S. et al. Vitamin D3 supplementation in patients with frequent respiratory tract infections: A randomised and double-blind intervention study. BMJ Open 2012; 2: e001663.
• 15 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
• 16 Martineau AR, James WY, Hooper RL. et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): A multicentre, double-blind, randomised controlled trial. Lancet Respir Med 2015; 3: 120-130
• 17 Kim C, Ko Y, Jung JY. et al. Severe vitamin D deficiency is associated with emphysema progression in male patients with COPD. Respir Med 2020; 163: 105890
• 18 Burkes RM, Ceppe AS, Doerschuk CM. et al. Associations among 25-hydroxyvitamin d levels, lung function, and exacerbation outcomes in COPD: An analysis of the SPIROMICS cohort. Chest 2020; 157: 856-865
• 19 Tachimoto H, Mezawa H, Segawa T. et al. Improved control of childhood asthma with low-dose, short-term vitamin D supplementation: a randomized, double-blind, placebo-controlled trial. Allergy 2016; 71: 1001-1009
• 20 Martineau AR, Cates CJ, Urashima M. et al. Vitamin D for the management of asthma. Cochrane Database Syst Rev 2016; 9: CD011511
• 21 Mao S, Huang S. Vitamin D supplementation and risk of respiratory tract infections: a meta-analysis of randomized controlled trials. Scand J Infect Dis 2013; 45: 696-702
• 22 Xiao L, Xing C, Yang Z. et al. Vitamin D supplementation for the prevention of childhood acute respiratory infections: A systematic review of randomised controlled trials. Br J Nutr 2015; 114: 1026-1034
• 23 Vuichard Gysin D, Dao D, Gysin CM. et al. Effect of Vitamin D3 supplementation on respiratory tract infections in healthy individuals: A systematic review and meta-analysis of randomized controlled trials. PLoS One 2016; 11: e0162996
• 24 Lehouck A, Mathieu C, Carremans C. et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2012; 156: 105-114
• 25 Zittermann A, Pilz S, Hoffmann H. et al. Vitamin D and airway infections: a European perspective. Eur J Med Res 2016; 21: 14
• 26 Rhodes JM, Subramanian S, Laird E. et al. Editorial: low population mortality from COVID-19 in countries south of latitude 35 degrees North supports vitamin D as a factor determining severity. Aliment Pharmacol Ther 2020; 51: 1434-1437
• 27 Jääskeläinen T, Itkonen ST, Lundqvist A. et al. The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr 2017; 105: 1512-1520
• 28 Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020 May 6: 1-4
• 29 Gold JAW, Wong KK, Szablewski CM. et al. Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb Mortal Wkly Rep 2020; 69: 545-550
• 30 State Testing Data by Race [Internet]. Johns Hopkins Coronavirus Resource Center. [cited 2020 May 25]. Available from https://coronavirus.jhu.edu/data/us-state-data-availability
• 31 Coronavirus (COVID-19) related deaths by ethnic group, England and Wales - Office for National Statistics [Internet] [cited 2020 May 26] Available from https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/articles/coronavirusrelateddeathsbyethnicgroupenglandandwales/2march2020to10april2020
• 32 Martin CA, Gowda U, Renzaho AMN. The prevalence of vitamin D deficiency among dark-skinned populations according to their stage of migration and region of birth: A meta-analysis. Nutrition 2016; 32: 21-32
• 33 Li AY, Hannah TC, Durbin JR. et al. Multivariate Analysis of Black Race and Environmental Temperature on COVID-19 In the US. Am J Med Sci 2020;
• 34 Model estimates of deaths involving the coronavirus (COVID-19) by ethnic group, England and Wales - Office for National Statistics [Internet] [cited 2020 Jun 25] Available from https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/datasets/modelestimatesofdeathsinvolvingthecoronaviruscovid19byethnicgroupenglandandwales
• 35 Hastie CE, Mackay DF, Ho F. et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020; 14: 561-565
• 36 Crowe FL, Jolly K, MacArthur C. et al. Trends in the incidence of testing for vitamin D deficiency in primary care in the UK: A retrospective analysis of The Health Improvement Network (THIN), 2005-2015. BMJ Open 2019; 9: e028355
• 37 Cases and Deaths from COVID-19 Virus Pandemic - Worldometer [Internet] [cited 2020 May 23] Available from https://www.worldometers.info/coronavirus/
• 38 Zhou F, Yu T, Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020; 28 395 (10229) 1054-1062
• 39 Li X, Xu S, Yu M. et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol 2020; Apr 12 S0091-6749: 30495-4
• 40 Peng YD, Meng K, Guan HQ. et al. Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV. Zhonghua Xin Xue Guan Bing Za Zhi 2020; 48: E004
• 41 Vanlint S. Vitamin D and Obesity. Nutrients 2013; 5: 949-956
• 42 Scragg R, Sowers M, Bell C. et al. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 2004; 27: 2813-2818
• 43 Kunutsor SK, Apekey TA, Steur M. Vitamin D and risk of future hypertension: Meta-analysis of 283,537 participants. Eur J Epidemiol 2013; 28: 205-221
• 44 Brøndum-Jacobsen P, Benn M, Jensen GB. et al. 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol 2012; 32: 2794-2802
• 45 Daly RM, Gagnon C, Lu ZX. et al. Prevalence of vitamin D deficiency and its determinants in Australian adults aged 25 years and older: a national, population-based study. Clin Endocrinol (Oxf) 2012; 77: 26-35
• 46 Alipio M. Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19) [Internet]. Rochester, NY: Social Science Research Network; 2020. Apr [cited 2020 May 26]. Report No.: ID 3571484 Available from https://papers.ssrn.com/abstract=3571484
• 47 Raharusun P, Priambada S, Budiarti C. et al. Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study [Internet]. Rochester, NY: Social Science Research Network; 2020. Apr [cited 2020 May 26] Report No.: ID 3585561 Available from https://papers.ssrn.com/abstract=3585561
• 48 D’Avolio A, Avataneo V, Manca A. et al. 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients 2020; 12: 1359
• 49 Tan CW, Ho LP, Kalimuddin S. et al. A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients. medRxiv. 2020 2020.06.01.20112334
• 50 Wu D, Yang XO. TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. J Microbiol Immunol Infect 2020; 53: 368-370
• 51 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223) 497-506
• 52 Tay MZ, Poh CM, Rénia L. et al. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020; 20: 363-374
• 53 Xie Z, Chen J, Zheng C. et al. 1,25-dihydroxyvitamin D3 -induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells. Immunology 2017; 152: 414-424
• 54 Díaz L, Noyola-Martínez N, Barrera D. et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol 2009; 81: 17-24
• 55 Yu Y, Tian L, Xiao Y. et al. Effect of vitamin D supplementation on some inflammatory biomarkers in type 2 diabetes mellitus subjects: A systematic review and meta-analysis of randomized controlled trials. Ann Nutr Metab 2018; 73: 62-73
• 56 Marshall RP. The pulmonary renin-angiotensin system. Curr Pharm Des 2003; 9: 715-722
• 57 Lambert DW, Hooper NM, Turner AJ. Angiotensin-converting enzyme 2 and new insights into the renin-angiotensin system. Biochem Pharmacol 2008; 75: 781-786
• 58 Bernstein KE, Khan Z, Giani JF. et al. Angiotensin-converting enzyme in innate and adaptive immunity. Nat Rev Nephrol 2018; 14: 325-336
• 59 Marshall RP, Gohlke P, Chambers RC. et al. Angiotensin II and the fibroproliferative response to acute lung injury. Am J Physiol Lung Cell Mol Physiol 2004; 286: L156-L164
• 60 Yan R, Zhang Y, Li Y. et al. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367 (6485) 1444-1448
• 61 Sungnak W, Huang N, Bécavin C. et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med 2020; 26: 681-687
• 62 Hamming I, Timens W, Bulthuis MLC. et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203: 631-637
• 63 Koka V, Huang XR, Chung ACK. et al. Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway. Am J Pathol 2008; May 172: 1174-1183
• 64 Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept 2012; 256294
• 65 Imai Y, Kuba K, Rao S. et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436 (7047) 112-116
• 66 Wösten-van Asperen RM, Lutter R, Specht PA. et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol 2011; 225: 618-627
• 67 Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11: 875-879
• 68 Li YC, Kong J, Wei M. et al. 1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002; 110: 229-238
• 69 Yuan W, Pan W, Kong J. et al. 1,25-dihydroxyvitamin D3 suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem 2007; 282: 29821-29830
• 70 Lin M, Gao P, Zhao T. et al. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep 2016; 43: 397-406
• 71 Forman JP, Williams JS, Fisher NDL. Plasma 25-hydroxyvitamin D and regulation of the renin-angiotensin system in humans. Hypertension 2010; 55: 1283-1288
• 72 Dancer RCA, Parekh D, Lax S. et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax 2015; 70: 617-624
• 73 Thickett DR, Moromizato T, Litonjua AA. et al. Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: A retrospective cohort study. BMJ Open Respir Res 2015; 2: e000074
• 74 Amrein K, Schnedl C, Holl A. et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA 2014; 312: 1520-1530
• 75 Leclair TR, Zakai N, Bunn JY. et al. Vitamin D Supplementation in Mechanically Ventilated Patients in the Medical Intensive Care Unit. JPEN J Parenter Enteral Nutr 2019; 43: 1037-1043
• 76 Zheng S, Yang J, Hu X. et al. Vitamin D attenuates lung injury via stimulating epithelial repair, reducing epithelial cell apoptosis and inhibits TGF-β induced epithelial to mesenchymal transition. Biochem Pharmacol 2020; 177: 113955
• 77 Sakurai R, Shin E, Fonseca S. et al. 1alpha,25(OH)2D3 and its 3-epimer promote rat lung alveolar epithelial-mesenchymal interactions and inhibit lipofibroblast apoptosis. Am J Physiol Lung Cell Mol Physiol 2009; 297: L496-L505
• 78 Amrein K, Parekh D, Westphal S. et al. Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: A study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study). BMJ Open 2019; 9: e031083
• 79 Dudenkov DV, Yawn BP, Oberhelman SS. et al. Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/mL: A 10-year population-based study. Mayo Clin Proc 2015; 90: 577-586
• 80 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357: 266-281
• 81 Forrest KYZ, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res 2011; 31: 48-54
• 82 Sarafin K, Durazo-Arvizu R, Tian L. et al. Standardizing 25-hydroxyvitamin D values from the Canadian Health Measures Survey. Am J Clin Nutr 2015; 102: 1044-1050
• 83 Eloi M, Horvath DV, Szejnfeld VL. et al. Vitamin D deficiency and seasonal variation over the years in São Paulo, Brazil. Osteoporos Int 2016; 27: 3449-3456
• 84 Karonova T, Andreeva A, Nikitina I. et al. Prevalence of Vitamin D deficiency in the North-West region of Russia: A cross-sectional study. J Steroid Biochem Mol Biol 2016; 164: 230-234
• 85 Rabenberg M, Scheidt-Nave C, Busch MA. et al. Vitamin D status among adults in Germany--results from the German Health Interview and Examination Survey for Adults (DEGS1). BMC Public Health 2015; 15: 641
• 86 LJM Boonman-deWinter, Albersen A, Mohrmann K. et al. High prevalence of vitamin D deficiency in the south-west Netherlands. Ned Tijdschr Geneeskd 2015; 159: A8167
• 87 Larose TL, Chen Y, Camargo CA. et al. Factors associated with vitamin D deficiency in a Norwegian population: the HUNT Study. J Epidemiol Community Health 2014; 68: 165-170
• 88 Nakamura K, Kitamura K, Takachi R. et al. Impact of demographic, environmental, and lifestyle factors on vitamin D sufficiency in 9084 Japanese adults. Bone 2015; 74: 10-17
• 89 Wat WZM, Leung JYY, Tam S. et al. Prevalence and impact of vitamin D insufficiency in southern Chinese adults. Ann Nutr Metab 2007; 51: 59-64
• 90 Lu H-K, Zhang Z, Ke Y-H. et al. High prevalence of vitamin D insufficiency in China: Relationship with the levels of parathyroid hormone and markers of bone turnover. PLoS One 2012; 7: e47264
• 91 Gill TK, Hill CL, Shanahan EM. et al. Vitamin D levels in an Australian population. BMC Public Health 2014; 14: 1001
• 92 Vitamin D. Status of New Zealand Adults [Internet]. Ministry of Health NZ. [cited 2020 May 26] Available from https://www.health.govt.nz/publication/vitamin-d-status-new-zealand-adults
• 93 Mogire RM, Mutua A, Kimita W. et al. Prevalence of vitamin D deficiency in Africa: A systematic review and meta-analysis. Lancet Glob Health 2020; 8: e134-e142
• 94 Hosseinpanah F, Yarjanli M, Sheikholeslami F. et al. Associations between vitamin D and cardiovascular outcomes; Tehran Lipid and Glucose Study. Atherosclerosis 2011; 218: 238-242
• 95 Solak I, Cihan FG, Mercan S. et al. Evaluation of 25-Hydroxyvitamin D Levels in Central Anatolia, Turkey. Biomed Res Int 2018; 4076548
• 96 Batieha A, Khader Y, Jaddou H. et al. Vitamin D status in Jordan: dress style and gender discrepancies. Ann Nutr Metab 2011; 58: 10-18