Vitamin D reduces viral respiratory infections – editorial April 18, 2020

Editorial - Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections

European Review for Medical and Pharmacological Sciences2020; 24: 4048-4052 DOI: 10.26355/eurrev_202004_20876

A. FABBRI1, M. INFANTE1-2, AND C. RICORDI2
1Endocrine Unit, CTO Hospital - ASL Roma 2, Department of Systems Medicine, University of Rome “Tor Vergata”，Rome, Italy andrea.fabbri@uniroma2.it
2Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
Key Words: Vitamin D, Vitamin D deficiency, Innate immunity, Viral respiratory infections, Covid-19.

Innate immune responses represent the initial host defense against invading pathogens. Unlike the adaptive immune responses, innate immune responses are not specific to a specific pathogen and depend upon a group of phagocytic cells and proteins that recognize conserved features of microbes to quickly promote clearance of infectious agents, including viruses, bacteria, fungi and parasites. Innate immune system includes physical (i.e., epithelium) and chemical barriers (i.e., saliva, gastric acid), complement cascade, antimicrobial peptides and antigen-presenting cells1. Antigen-presenting cells (i.e., dendritic cells and macrophages) play a pivotal role in innate immune responses by sensing pathogen-associated molecular patterns (PAMPs) of a large variety of microbes via pattern recognition receptors (PRRs) - such as Toll-like receptors (TLRs) - and subsequently facilitate the full activation of adaptive immune responses1.

Vitamin D deficiency represents a global pandemic afflicting more than one billion individuals across all age groups worldwide2. Over the last decade, several studies supported vitamin D deficiency as a potential risk factor for various diseases, including systemic infections and autoimmune diseases3-7. Apart from its well-known role in the regulation of bone homeostasis, vitamin D has been shown to exert several extraskeletal actions4,8, including the regulation of innate and adaptive immune responses9-11. In particular, vitamin D has been recognized as an important mediator of innate immune responses12, participating in several processes of the innate immunity. Functional VDR has been identified in almost all immune cells, including neutrophils and antigen-presenting cells (macrophages and dendritic cells)10,13-15, as well as in human airway epithelial cells16. Also, in vitro studies have shown that vitamin D decreases the expression of pro-inflammatory cytokines and increases the production of antiviral proteins, suggesting an important role in antiviral innate immunity4,10,16. Of note, calcitriol (the active metabolite of vitamin D, which is also referred to as 1,25-dihydroxyvitamin D3) has been found to induce the transcription of antimicrobial peptides - such as cathelicidin and defensin b2 - in various human cell lines (keratino- cytes, myeloid cells, monocytes/macrophages and neutrophils)17-19. Accordingly, it has been shown that TLR activation of human macrophages leads to increased expression of VDR and vitamin D-activating enzyme 1a-hydroxylase, resulting in the induction of cathelicidin20. In addition, calcitriol promotes differentiation of monocytes/macrophages and enhances their chemotactic and phagocytic capacit y21,22.

Besides being vitamin D targets, immune cells are also local producers of vitamin D12. Therefore, vitamin D can act in an autocrine fashion within a local immunological milieu. In fact, several immune cells (macrophages, dendritic cells, T- and B-lymphocytes) have been found to express the vitamin D-activating enzymes 25- and 1a-hydroxylase23-27, allowing for local conversion of inactive vitamin D precursors into the biologically active form calcitriol24,28 under specific immune signals (i.e., IFN-g)29. Finally, several in vitro studies suggest that vitamin D plays an important role in local “respiratory homeostasis” either by promoting the expression of antimicrobial peptides or by directly affecting the replication of respiratory viruses16.

In humans, cross-sectional clinical studies showed that lower serum vitamin D levels are significantly associated with respiratory tract infections30"32, including epidemic influenza33. A British cohort study revealed that the prevalence of respiratory infections displayed a strong seasonal pattern in the opposite direction to the pattern for serum 25-hydroxyvitamin D concentrations34. Notably, each 10 nmol/L (4 ng/mL) increase in serum 25-hydroxyvitamin D levels was associated with a 7% lower risk of infection after adjustment for lifestyle, socio-economic factors and adiposity34. Interestingly, in a recent Editorial published in The British Medical Journal raising debate on Covid-19 pandemic, different researchers proposed vitamin D deficiency as a putative risk factor, among others, for novel coronavirus infection35.

Randomized controlled trials evaluating the efficacy of vitamin D supplementation in reducing the risk of respiratory tract infections among children and adults have yielded controversial results10,36-39. However, a potential design flaw of the majority of these studies is that the study participants were almost vitamin D-replete at baseline. This could have partly affected the interpretation of the study outcomes, since participants with (severe) vitamin D deficiency at baseline may have represented the subset of subjects receiving the highest beneficial effects from vitamin D supplementation. These remarks are based on the principle of nutrition that individuals who are the most deficient in a given micronutrient - such as vitamin D - are the most likely to respond to its replacement40. Interestingly, a meta-analysis published by Martineau et al41 in The British Medical Journal showed that vitamin D supplementation is safe and effective in preventing acute respiratory infections. More importantly, the authors found that the protective effects of vitamin D were stronger in subjects with a baseline serum 25-hydroxyvitamin D concentration of <25 nmol/L (corresponding to <10 ng/mL, which are serum levels indicative of severe vitamin D deficiency) compared to those with a baseline 25-hydroxyvitamin D concentration of >25 nmol/L (>10 ng/mL)41.
A subgroup analysis of the same study showed that the protective effects of vitamin D against acute respiratory infections were observed in participants receiving daily or weekly vitamin D without additional bolus doses, but not in participants receiving one or more bolus doses41. An explanation for the lack of efficacy of bolus dosing in preventing acute respiratory infections could depend on the fact that this therapeutic approach may lead to wide fluctuations in circulating 25-hydroxyvitamin D levels. In this regard, Vieth42 proposed that high circulating levels of 25-hydroxyvitamin D following bolus dosing may chronically alter the activity of enzymes involved in the synthesis and degradation of the active vitamin D form calcitriol, thus leading to reduced concentrations of this metabolite in extra-renal tissues.
Another important remark regarding the study design is that randomized controlled trials evaluating the impact of vitamin D supplementation on clinical outcomes should employ a design primarily based on serum 25-hydroxyvitamin D concentrations rather than administered vitamin D doses43,44. In fact, serum response to a given dose of vitamin D is highly variable between individuals due to several demographic and biological factors, such as baseline vitamin D status, ethnicity, body fat percentage, use of certain medications, genetics, seasonal variations, time of sun exposure, aging and type of vitamin D supplements45.
In conclusion, several studies support the immunomodulatory properties of vitamin D and its important role in the maintenance of immune homeostasis. However, well-designed, randomized controlled trials are needed in the future to understand the potential role of vitamin D status in sustaining the protective immune responses against respiratory pathogens and in preventing different types of respiratory tract infections (i.e., upper respiratory tract infections versus lower respiratory tract infections). Also, it will be important to clarify which is the subset of individuals that would potentially receive the highest benefits from vitamin D supplementation. According to the current evidence, we outline the importance of initiating or maintaining vitamin D supplementation (under proper medical supervision) in individuals with hypovitaminosis D, especially in those previously diagnosed with a severe vitamin D deficiency in order to attain a target serum value of 25-hydroxyvitamin D of at least >30 ng/mL.
We also believe that maintenance of circulating 25-hydroxyvitamin D levels of 40-60 ng/mL would be optimal, since it has been suggested that concentrations amounting to 40 ng/mL represent the beginning point of the plateau where the synthesis of the active form calcitriol becomes substrate-independent 46,47. Additionally, serum 25-hydroxyvitamin D levels of approximately >40 ng/mL could provide protection against acute viral respiratory infections, as demonstrated in a prospective cohort study published in PLoS One and conducted on 198 healthy adults 48. To reach these concentrations in adults, a dietary and/or supplemental intake of vitamin D up to 6000 IU/day - deemed to be safe - is required 49,50.
However, elderly subjects, overweight/obese and diabetic patients, patients with malabsorption syndromes, and patients on medications affecting vitamin D metabolism may require even higher doses under medical supervision 50. Finally, these remarks align well with the current recommendations for prevention and treatment of vitamin D deficiency in relation to skeletal 50 and extraskeletal health 51.

References

1. Turvey SB, Broide DH. Innate immunity. J Allergy Clin Immunol 2010; 125: S24-32.
2. Holick MF. The vitamin D deficiency pandemic: approaches for diagnosis, treatment and prevention. Rev En- docr Metab Disord 2017; 18: 153-165.
3. Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazareth-Castro M, Giustina A, Bilezikian J. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev 2019; 40: 1109-1151.
4. Caprio M, Infante M, Calanchini M, Mammi C, Fabbri A. Vitamin D: not just the bone. Evidence for beneficial pleio- tropic extraskeletal effects. Eat Weight Disord 2017; 22: 27-41.
5. Infante M, Ricordi C, Sanchez J, Clare-Salzler MJ, Padilla N, Fuenmayor V, Chavez C, Alvarez A, Baidal D, Alejandro R, Caprio M, Fabbri A. Influence of vitamin D on islet autoimmunity and beta-cell function in type 1 diabetes. Nutrients 2019; 11. pii: E2185.
6. Ricordi C, Clare-Salzler M, Infante M, Baggerly C, Aliano J, McDonnell S, Chritton S. Vitamin D and Omega 3 field study on progression of type 1 diabetes. CellR4 Repair Replace Regen Reprogram 2019; 7; pii: e2737.
7. Dankers W, Colin EM, van Hamburg JP, Lubberts E. Vitamin D in autoimmunity: molecular mechanisms and therapeutic potential. Front Immunol 2016; 7: 697.
8. Caprio M, Mammi C, Rosano GM. Vitamin D: a novel player in endothelial function and dysfunction. Arch Med Sci 2012; 8: 4-5.
9. Aranow C. Vitamin D and the immune system. J Investig Med 2011; 59: 881-886.
10. Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients 2013; 5: 2502-2521.
11. Infante M, Ricordi C, Padilla N, Alvarez A, Linetsky E, Lanzoni G, Mattina A, Bertuzzi F, Fabbri A, Baidal D, Alejan
12. dro R. The role of vitamin D and Omega-3 PUFAs in islet transplantation. Nutrients 2019; 11. pii: E2937.
13. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol 2010; 10: 482-496.
14. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983; 221: 1181-1183.
15. Takahashi K, Nakayama Y, Horiuchi H, Ohta T, Komoriya K, Ohmori H, Kamimura T. Human neutrophils express messenger RNA of vitamin D receptor and respond to 1alpha,25-dihydroxyvitamin D3. Immunopharmacol Immu- notoxicol 2002; 24: 335-347.
16. White JH. Vitamin D metabolism and signaling in the immune system. Rev Endocr Metab Disord 2012; 13: 21-29.
17. Zdrenghea MT, Makrinioti H, Bagacean C, Bush A, Johnston SL, Stanciu LA. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol 2017; 27. doi: 10.1002/rmv.1909.
18. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White
19. JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173: 2909-2912.
20. 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. FASEBJ 2005; 19: 1067-1077.
21. Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 2009; 4: 1151-1165.
22. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, Ochoa MT, Schauber J, Wu K, M日nken C, Kamen DL, Wagner M, Bals R, St日nmeyer A, ZOgel U, Gallo RL, Eisenberg D, Hewison M, Hollis BW, Adams JS, Bloom BR, Modlin RL Tolllike receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311: 1770-1773.
23. Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr 2003; 23: 117-145.
24. Xu H, Soruri A, Gieseler RK, Peters JH. 1,25-Dihydroxyvitamin D3 exerts opposing effects to IL-4 on MHC class- II antigen expression, accessory activity, and phagocytosis of human monocytes. Scand J Immunol 1993; 38: 535-540.
25. Monkawa T, Yoshida T, Hayashi M, Saruta T. Identification of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression in macrophages. Kidney Int 2000; 58: 559-568.
26. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, Butcher EC. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007; 8: 285-293.
27. Overbergh L, Decallonne B, Valckx D, Verstuyf A, Depovere J, Laureys J, Rutgeerts O, Saint-Arnaud R, Bouillon R, Mathieu C. Identification and immune regulation of 25-hydroxyvitamin D-1-alpha-hydroxylase in murine macrophages. Clin Exp Immunol 2000; 120: 139-146.
28. Stoffels K, Overbergh L, Giulietti A, Verlinden L, Bouillon R, Mathieu C. Immune regulation of 25-hydroxyvita- min-D3-1alpha-hydroxylase in human monocytes. J Bone Miner Res 2006; 21: 37-47.
29. Chen S, Sims GP, Chen XX, Gu YY, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179: 1634-1647.
30. Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD, Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003; 170: 5382-5390.
31. Overbergh L, Stoffels K, Waer M, Verstuyf A, Bouillon R, Mathieu C. Immune regulation of 25-hydroxyvitamin D-1alpha-hydroxylase in human monocytic THP1 cells: mechanisms of interferon-gamma-mediated induction. J Clin Endocrinol Metab 2006; 91: 3566-3574.
32. Laaksi I, Ruohola JP, Tuohimaa P, Auvinen A, Haataja R, Pihlajamaki 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; 86: 714-717.
33. Ginde AA, Mansbach JM, Camargo CA. 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.
34. Cannell JJ, Vieth R, Willett W, Zasloff M, Hathcock JN, White JH, Tanumihardjo SA, Larson-Meyer DE, Bischoff-Fer- rari HA, Lamberg-Allardt CJ, Lappe JM, Norman AW, Zittermann A, Whiting SJ, Grant WB, Hollis BW, Giovannucci
35. E. Cod liver oil, vitamin A toxicity, frequent respiratory infections, and the vitamin D deficiency epidemic. Ann Otol Rhinol Laryngol 2008; 117: 864-870.
36. Cannell JJ, Vieth R, Umhau JC, Holick MF, Grant WB, Madronich S, Garland CF, Giovannucci E. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134: 1129-1140.
37. Berry DJ, Hesketh K, Power C, Hypponen E. Vitamin D status has a linear association with seasonal infections and lung function in British adults. BrJ Nutr 2011; 106: 1433-1440.
38. Watkins J. Preventinga Covid-19 pandemic. BMJ 2020; 368: m810. https://www.bmj.com/content/368/bmj. m810/rapid-responses.
39. Urashima M, Segawa T, Okazaki M, Kurihara M, WadaY, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr 2010; 91: 1255-1260.
40. Zhou J, Du J, Huang L, Wang Y, Shi Y, Lin H. Preventive effects of vitamin D on seasonal influenza a in infants: a multicenter, randomized, open, controlled clinical trial. Pediatr Infect Dis J 2018; 37: 749-754.
41. Murdoch DR, Slow S, Chambers ST, Jennings LC, Stewart AW, Priest PC, Florkowski CM, Livesey JH, Camargo CA, Scragg R. Effect of vitamin D3 supplementation on upper respiratory tract infections in healthy adults: the VIDARIS randomized controlled trial. JAMA 2012; 308: 1333-1339.
42. 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; 137: 1396-1404.
43. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011; 305: 1348-1349.
44. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, Dubnov-Raz G, Esposito S, Ganmaa D, Ginde AA, Goodall EC, Grant CC, Griffiths CJ, Janssens W, Laaksi I, Manasek卜Holland S, Mauger D, Murdoch DR, Neale R, Rees JR, Simpson S Jr, Stelmach I, Kumar GT, Urashima M, Camargo CA Jr. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017; 356: i6583.
45. Vieth R. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase enzymology. Anticancer Res 2009; 29: 3675-3684.
46. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on 25-hydroxyvi- tamin D concentrations. J Steroid Biochem Mol Biol 2018; 177: 266-269.
47. Infante M, Ricordi C, Baidal DA, Alejandro R, Lanzoni G, Sears B, Caprio M, Fabbri 八 VITAL study: an incomplete picture? Eur Rev Med Pharmacol Sci 2019; 23: 3142-3147.
48. Mazahery H, von Hurst PR. Factors Affecting 25-Hydroxyvitamin D concentration in response to Vitamin D supplementation. Nutrients 2015; 7: 5111-5142.
49. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res 2011; 26: 2341-2357.
50. Wagner CL, Hollis BW. The implications of vitamin D status during pregnancy on mother and her developing child. Front Endocrinol (Lausanne) 2018; 9: 500.
51. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin d and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One 2010; 5: e11088.
52. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003; 77: 204-210.
53. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911-1930.
54. Holick MF. Vitamin D: extraskeletal health. Rheum Dis Clin North Am 2012; 38: 141-160.

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