Vitamin D, Immune System and Infections

**59**

**Chapter 4**

**Abstract**

System

*Vikram Singh Chauhan*

balancing the immune system.

**1. Introduction**

**Keywords:** Vitamin D, Immunity, Vitamin D receptor

Vitamin D and the Immune

In the past few decades, various novel actions of vitamin D have been discovered. The mechanism of action of calcitriol or vitamin D is mediated by the Vitamin D receptor (VDR), a subfamily of nuclear receptors, which acts as a transcription factor in the target cells after formation of a heterodimer with the retinoid X receptor (RXR). As the VDR has been found in virtually all cell types, vitamin D exerts multiple actions on different tissues. Vitamin D has important immunomodulatory actions, which includes enhancement of the innate immune system and inhibition of the adaptative immune responses. These actions are associated with an increase in production of interleukin (IL)-4 by T helper (Th)-2 lymphocytes and the up-regulation of regulatory T lymphocytes. Vitamin D can regulate the immune responses in secondary lymphoid organs as well as in target organs through a number of mechanisms. Vitamin D inhibits the expression of APC cytokines, such as interleukin-1 (IL-1), IL-6, IL-12, and tissue necrosis factor- α (TNF-α) and decreases the expression of a set of major histocompatibility complex (MCH) class II cell surface proteins in macrophages. Vitamin D also inhibits B cell differentiation and antibody production. These actions reflect an important role of Vitamin D in

Vitamin D is now recognized as a vitamin as well as a pro hormone. It exists in two major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D3 is formed in the human skin and is obtained in the diet through the intake of animal-based foods such as fish oils, whereas vitamin D2 is present in plant sources [1]. Vitamin D is traditionally known to be involved in the regulation of calcium and phosphate metabolism. Apart from its role in maintaining bone mineralization, vitamin D also has a well described function as an immunomodulatory hormone [2]. The Vitamin D receptor (VDR) and metabolizing enzymes are expressed by numerous types of immune cells such as lymphocytes, macrophages, monocytes and dendritic cells [3, 4]. Preliminary studies have revealed that vitamin D has noteworthy biologic activities on the innate and adaptive immune systems. Some preclinical studies have demonstrated that administration of vitamin D leads to changes in the occurrence and progression of many immune-related diseases [2, 5]. This is supported by clinical data that explains the possible association of vitamin D with the incidence of many disorders such as type 1 diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis and infectious diseases. The purpose of the present chapter is to provide a summary

#### **Chapter 4**

## Vitamin D and the Immune System

*Vikram Singh Chauhan*

#### **Abstract**

In the past few decades, various novel actions of vitamin D have been discovered. The mechanism of action of calcitriol or vitamin D is mediated by the Vitamin D receptor (VDR), a subfamily of nuclear receptors, which acts as a transcription factor in the target cells after formation of a heterodimer with the retinoid X receptor (RXR). As the VDR has been found in virtually all cell types, vitamin D exerts multiple actions on different tissues. Vitamin D has important immunomodulatory actions, which includes enhancement of the innate immune system and inhibition of the adaptative immune responses. These actions are associated with an increase in production of interleukin (IL)-4 by T helper (Th)-2 lymphocytes and the up-regulation of regulatory T lymphocytes. Vitamin D can regulate the immune responses in secondary lymphoid organs as well as in target organs through a number of mechanisms. Vitamin D inhibits the expression of APC cytokines, such as interleukin-1 (IL-1), IL-6, IL-12, and tissue necrosis factor- α (TNF-α) and decreases the expression of a set of major histocompatibility complex (MCH) class II cell surface proteins in macrophages. Vitamin D also inhibits B cell differentiation and antibody production. These actions reflect an important role of Vitamin D in balancing the immune system.

**Keywords:** Vitamin D, Immunity, Vitamin D receptor

#### **1. Introduction**

Vitamin D is now recognized as a vitamin as well as a pro hormone. It exists in two major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D3 is formed in the human skin and is obtained in the diet through the intake of animal-based foods such as fish oils, whereas vitamin D2 is present in plant sources [1]. Vitamin D is traditionally known to be involved in the regulation of calcium and phosphate metabolism. Apart from its role in maintaining bone mineralization, vitamin D also has a well described function as an immunomodulatory hormone [2]. The Vitamin D receptor (VDR) and metabolizing enzymes are expressed by numerous types of immune cells such as lymphocytes, macrophages, monocytes and dendritic cells [3, 4]. Preliminary studies have revealed that vitamin D has noteworthy biologic activities on the innate and adaptive immune systems. Some preclinical studies have demonstrated that administration of vitamin D leads to changes in the occurrence and progression of many immune-related diseases [2, 5]. This is supported by clinical data that explains the possible association of vitamin D with the incidence of many disorders such as type 1 diabetes, psoriasis, rheumatoid arthritis, multiple sclerosis and infectious diseases. The purpose of the present chapter is to provide a summary

of the effects of vitamin D on the immune system and the link between vitamin D and numerous types of immune-related diseases and conditions.

#### **2. Vitamin D and the immune system**

A significant role of vitamin D in the regulation of the immune system has been discovered in the last few decades. In 1983, the contribution of macrophages in producing vitamin D was documented by separation of VDR in activated human inflammatory cells [6, 7]. The role of vitamin D in the inhibition of T cell proliferation was discovered by Rigby, *et al* in 1984 [8]. Further evidences were found for elaborating the role of vitamin D in the regulation of the immune system [8].

T cells and B cells respond to 1, 25(OH)2D in a paracrine or autocrine manner in an immune environment. The action of 1,25(OH)2D on the inhibition of T helper cells was documented in preclinical studies. These effects include directly lowering the dendritic cell capability to activate T helper 17, inhibition of T helper 17-related IL-17 and hampering the ability to support T helper 17 polarization of naïve CD4+ T cells production [9]. In an autoimmune uveitis preclinical model, oral administration of 1,25(OH)2D prevented and inhibited immunological responses, as shown by reduction of both ROR-gamma-t (Retinoic acid Receptor-related Orphan Receptor gamma t) and IL-17 in CD4+ T cells, which are two indicators of T helper 17 cell function. Moreover, 1, 25(OH)2D inhibited bone marrow-derived dendritic cell ability to influence T helper 17 polarization of naive CD4+ T cells [9].

1, 25(OH)2D has also been involved in the inhibition of immunoglobulin production and B cell proliferation and differentiation [10]. Low 1, 25(OH) [2] D level had been found in patients with systemic lupus erythematosus (SLE), suggesting that vitamin D could be involved in the regulation of autoantibody expression. Chen, *et al* showed that 1, 25(OH)2D has a direct effect on B cells, including inhibition of proliferation, on generation of class-switched memory B cells and on immunoglobulin production in patients with SLE [10].

Vitamin D is also involved macrophage regulation and affects their cytokine expression. It increases prostaglandin E2 production from macrophages, which has a role in the inflammatory process and inhibits the expression of granulocyte-macrophage colony-stimulating factor. Moreover, 1, 25(OH)2D induces macrophages and epithelial cells to produce cathelicidin, a peptide involved in antimicrobial action [11, 12]. Cathelicidin is responsible for activating the innate immune response by binding to its transmembrane receptor and is correlated to higher levels of the enzyme 1-alpha-hydroxylase in macrophages and keratinocytes [13]. The enzyme 1-alpha-hydroxylase further increases the production of cathelicidin through the production of 1,25(OH)2D.

Vitamin D is also involved in the activation of dendritic cells which enhance expression of CD4+/CD25+ regulatory T cells (T reg). In preclinical study by Gregori *et al*, 1, 25(OH)2D activated dendritic cells with a tolerogenic phenotype and caused an increased percentage of CD4+/CD25+ T reg in the spleen and lymph nodes. These regulatory T cells have a role in the transfer of transplantation tolerance [14].

#### **3. Vitamin D and the innate immune system**

Innate antigen presenting cells (APC), specifically dendritic cells (DC) are principal targets for the immune modulatory effects of vitamin D. APCs have a crucial role in the initiation of the adaptive immune response as they present antigens to B cells and T cells and are able to modulate them by immunogenic signals such as the

**61**

*Vitamin D and the Immune System*

function [15]:

by calcitriol.

synthesis of cytokines [15].

after the seventh month [17].

**5. Vitamin D and autoimmune diseases**

**6. Vitamin D and Type 1 Diabetes Mellitus**

*DOI: http://dx.doi.org/10.5772/intechopen.97300*

**4. Vitamin D and the adaptive immune system**

expression of cytokines. Vitamin D and its analogs modify the function of DCs to induce a more tolerogenic and immature state. Immature DCs result in decreased levels of MHC class II and co-stimulatory molecule expression (CD40, CD80, CD86), which negatively affects antigen presentation accompanied by a lower IL-12 secretion, but an increased production of the tolerogenic interleukin IL-10. Highdose vitamin D supplementation in healthy humans (1 μg twice daily for 7 days) results in significant reduction in the proinflammatory cytokine IL-6 produced by peripheral mononuclear cells. A combination of all these effects results in the induction of potential regulatory T cells which are crucial for controlling immune responses and the development of autoreactivity [15]. A clinical study in 95 patients treated with adjunctive vitamin D therapy, added on to standard tuberculosis therapy demonstrated augmented resolution of inflammatory responses [16].

The expression of the nuclear VDR and vitamin D-activating enzymes in both T- and B types of human adaptive immune cells have been reported in studies. The activation and proliferation of T and B cells results in up-regulation of VDR expression, which ultimately regulates more than 500 vitamin D responsive genes [15]. Following are the proposed mechanisms for influence of vitamin D on T cell

1.Direct, endocrine effects on T cells mediated via systemic vitamin D.

3.Direct, paracrine effects of calcitriol on T cells following monocytes or

4.Indirect effects on antigen presentation to T cells mediated via localized APCs

All these effects of vitamin D result in shifting from a proinflammatory status to a more tolerogenic immune status, including very diverse effects on T cell subtypes: Vitamin D suppresses T helper cell proliferation, differentiation and modulates

Clinical studies investigated the association of vitamin D levels with the risk of developing autoimmunity and effect of vitamin D administration on autoimmune diseases. A systematic review of 219 studies demonstrated that vitamin D levels of<30 ng/mL are significantly associated with autoimmune disease. In patients with type-1 diabetes, the risks are significantly reduced in infants treated with vitamin D

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease with T cell mediated destruction of pancreatic β-cells. It is hypothesized that Vitamin D supplementation

2.Direct, intracrine conversion of 25(OH) D to calcitriol by T cells.

dendritic cells induced conversion of 25(OH) D to calcitriol.

*Vitamin D and the Immune System DOI: http://dx.doi.org/10.5772/intechopen.97300*

expression of cytokines. Vitamin D and its analogs modify the function of DCs to induce a more tolerogenic and immature state. Immature DCs result in decreased levels of MHC class II and co-stimulatory molecule expression (CD40, CD80, CD86), which negatively affects antigen presentation accompanied by a lower IL-12 secretion, but an increased production of the tolerogenic interleukin IL-10. Highdose vitamin D supplementation in healthy humans (1 μg twice daily for 7 days) results in significant reduction in the proinflammatory cytokine IL-6 produced by peripheral mononuclear cells. A combination of all these effects results in the induction of potential regulatory T cells which are crucial for controlling immune responses and the development of autoreactivity [15]. A clinical study in 95 patients treated with adjunctive vitamin D therapy, added on to standard tuberculosis therapy demonstrated augmented resolution of inflammatory responses [16].

#### **4. Vitamin D and the adaptive immune system**

The expression of the nuclear VDR and vitamin D-activating enzymes in both T- and B types of human adaptive immune cells have been reported in studies. The activation and proliferation of T and B cells results in up-regulation of VDR expression, which ultimately regulates more than 500 vitamin D responsive genes [15].

Following are the proposed mechanisms for influence of vitamin D on T cell function [15]:


All these effects of vitamin D result in shifting from a proinflammatory status to a more tolerogenic immune status, including very diverse effects on T cell subtypes: Vitamin D suppresses T helper cell proliferation, differentiation and modulates synthesis of cytokines [15].

#### **5. Vitamin D and autoimmune diseases**

Clinical studies investigated the association of vitamin D levels with the risk of developing autoimmunity and effect of vitamin D administration on autoimmune diseases. A systematic review of 219 studies demonstrated that vitamin D levels of<30 ng/mL are significantly associated with autoimmune disease. In patients with type-1 diabetes, the risks are significantly reduced in infants treated with vitamin D after the seventh month [17].

#### **6. Vitamin D and Type 1 Diabetes Mellitus**

Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease with T cell mediated destruction of pancreatic β-cells. It is hypothesized that Vitamin D supplementation

early in life could be protective therapy against the development of T1DM [18]. Vitamin D supplementation in the first year of life in children produced a 33% risk reduction of developing T1D in a subgroup analysis of the EURODIAB study [19]. A meta-analysis of four clinical studies also revealed a significantly reduced risk of development of T1D among infants receiving vitamin D supplementation [20]. Many trials on vitamin D and T1D are currently ongoing which will hopefully expand our understanding of this topic.

#### **7. Vitamin D and multiple sclerosis**

Hypovitaminosis D is one of the important risk factors for the increased risk of development of multiple sclerosis (MS). In a cohort of the Nurses' Health Study (92953 women) and Nurses' Health Study II (95310 women), the intake of Vitamin D ≥ 400 IU/day was associated with the reduced risk of developing MS. [21] In a study by Merja et al., vitamin D3 add on treatment to interferon β-1b reduces MRI disease activity in MS [22]. Currently ongoing studies such as *SOLAR* and the *EVIDIMS* study will explore many aspects of the role of vitamin D in the management of MS in the coming years.

#### **8. Vitamin D and psoriasis**

Vitamin D is involved in the proliferation and maturation of keratinocytes. This action of vitamin D created interest as a topical therapeutic option in the treatment of psoriasis. A significant association between low vitamin D levels and psoriasis has been reported. Although the exact role of vitamin D in the pathogenesis of psoriasis is unclear, possible mechanisms include the regulation of the cutaneous immune system (inhibition of T cell proliferation, T reg induction) and downregulation of pro-inflammatory cytokines. However robust clinical data regarding a role of vitamin D in psoriasis is still awaited [23].

#### **9. Vitamin D and rheumatoid arthritis**

In addition to inhibiting inflammatory cytokines such as IL-6, TNFα, IL-17 in synovial fluid, vitamin D also reduces fibroblast erosion [24]. Vitamin D supplementation was found to be associated with lower risk of RA in a prospective cohort of 29,368 women over a follow up period of 11 years [25]. A randomized controlled trial (RCT) by Buondonno et al. [26] evaluated the effect of administration of cholecalciferol on T helper cell sub-types and osteoclast precursors. Single dose of cholecalciferol (300,000 IU) along with standard treatment showed improvements in inflammatory cytokines in this study [26]. Further studies are required to estimate the dose of Vitamin D in the treatment of RA.

#### **10. Conclusion and future perspectives**

The role of Vitamin D in autoimmune disease is a major area of research. Addressing questions as to whether vitamin D levels are related to the risk of developing autoimmunity and whether vitamin D supplementation can modify the course of autoimmune diseases, several studies performed over the last four decades support the role of vitamin D in the prevention of autoimmune diseases. However there is still

**63**

**Author details**

Vikram Singh Chauhan

provided the original work is properly cited.

Dr. Chauhan's Clinic and Jabalpur Hospital and Research Center, Jabalpur, India

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: vikramsinghchauhan@gmail.com

*Vitamin D and the Immune System*

*DOI: http://dx.doi.org/10.5772/intechopen.97300*

a need of randomized controlled clinical trials in this field. Upcoming clinical trials will find out the optimal mode and dosage of supplementation of vitamin D. However, with available data, vitamin D emerges as a promising nutrient in the prevention and

adjunctive treatment of diseases caused by impaired immune-homeostasis.

*Vitamin D and the Immune System DOI: http://dx.doi.org/10.5772/intechopen.97300*

a need of randomized controlled clinical trials in this field. Upcoming clinical trials will find out the optimal mode and dosage of supplementation of vitamin D. However, with available data, vitamin D emerges as a promising nutrient in the prevention and adjunctive treatment of diseases caused by impaired immune-homeostasis.

#### **Author details**

Vikram Singh Chauhan Dr. Chauhan's Clinic and Jabalpur Hospital and Research Center, Jabalpur, India

\*Address all correspondence to: vikramsinghchauhan@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Valero-Zanuya M, Hawkins-Carranza F: Metabolism, endogenous and exogenous sources of vitamin D. Rev Esp Enferm Metab Oseas. 2007; 16: 63-70.

[2] Prietl, B.; Treiber, G.; Pieber, T.R.; Amrein, K. Vitamin D and immune function. Nutrients 2013, 5, 2502-2521.

[3] Battault, S.; Whiting, S.J.; Peltier, S.L.; Sadrin, S.; Gerber, G.; Maixent, J.M. Vitamin D metabolism, functions and needs: From science to health claims. Eur. J. Nutr. 2013, 52, 429-441

[4] Adams, J.S.; Rafison, B.; Witzel, S.; Reyes, R.E.; Shieh, A.; Chun, R.; Zavala, K.; Hewison, M.; Liu, P.T. Regulation of the extrarenal CYP27B1-hydroxylase. J. Steroid Biochem. Mol. Biol. 2014, 144, 22-27

[5] Aranow, C. Vitamin D and the immune system. J. Investig. Med. 2011, 59, 881-886

[6] Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest 1983; 72:1856-60.

[7] Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983; 221: 1181-3.

[8] Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1, 25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 1984; 74:1451-5.

[9] Tang J, Zhou R, Luger D, Zhu W, Silver PB, Grajewski RS, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol 2009;182:4624-32.

[10] Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1, 25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179:1634-47.

[11] Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med 2004; 229:1136-42.

[12] Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, et al. Cutting edge: 1, 25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004; 173:2909-12.

[13] Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311:1770-3.

[14] Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha, 25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 2001; 167:1945-53.

[15] Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients. 2013 Jul;5(7):2502-21.

[16] Coussens, A.K.; Wilkinson, R.J.; Hanifa, Y.; Nikolayevskyy, V.; Elkington, P.T.; Islam, K.; Timms, P.M.; Venton, T.R.; Bothamley, G.H.; Packe, G.E.; *et al.* Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. *Proc. Natl. Acad. Sci. USA* 2012, *109*, 15449-15454.

[17] Antico, A.; Tampoia, M.; Tozzoli, R.; Bizzaro, N. Can supplementation with vitamin D reduce the risk or

**65**

*83*, 565-571

*Vitamin D and the Immune System*

*Child.* 2008, *93*, 512-517.

Diabetologia 1999, 42, 51-54

*Child.* 2008, *93*, 512-517

*Neurology* 2004, *62*, 60-65].

[22] Soilu-Hänninen, M.; Aivo, J.; Lindström, B.-M.; Elovaara, I.;

[23] Barrea L, Savanelli MC, Di Somma C, Napolitano M, Megna M, Colao A, Savastano S. Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist. Reviews in Endocrine and Metabolic Disorders.

[24] Bellan M, Sainaghi PP, Pirisi M. Role of vitamin D in rheumatoid arthritis. Ultraviolet Light in Human Health, Diseases and Environment. 2017:155-68.

2017 Jun;18(2):195-205.

Sumelahti, M.-L.; Färkkilä, M.; Tienari, P.; Atula, S.; Sarasoja, T.; Herrala, L.; *et al.* A randomised, double blind, placebo controlled trial with vitamin D3 as add on treatment to interferon β-1b in patients with multiple sclerosis. *J. Neurol. Neurosurg. Psychiatr.* 2012,

127-136.

modify the course of autoimmune diseases? A systematic review of the literature. *Autoimmun. Rev.* 2012, *12*,

*DOI: http://dx.doi.org/10.5772/intechopen.97300*

[25] Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2004 Jan;50(1):72-7.

[26] Buondonno I, Rovera G, Sassi F, Rigoni MM, Lomater C, Parisi S, Pellerito R, Isaia GC, D'Amelio P. Vitamin D and immunomodulation in

early rheumatoid arthritis: A randomized double-blind placebocontrolled study. PLoS One. 2017 Jun

5;12(6):e0178463.

[18] Zipitis, C.S.; Akobeng, A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. *Arch. Dis.* 

[19] Vitamin D supplement in early childhood and risk for Type I (insulindependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group.

[20] Zipitis, C.S.; Akobeng, A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. *Arch. Dis.* 

[21] Munger, K.L.; Zhang, S.M.; O'Reilly, E.; Hernán, M.A.; Olek, M.J.; Willett, W.C.; Ascherio, A. Vitamin D intake and incidence of multiple sclerosis.

*Vitamin D and the Immune System DOI: http://dx.doi.org/10.5772/intechopen.97300*

modify the course of autoimmune diseases? A systematic review of the literature. *Autoimmun. Rev.* 2012, *12*, 127-136.

[18] Zipitis, C.S.; Akobeng, A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. *Arch. Dis. Child.* 2008, *93*, 512-517.

[19] Vitamin D supplement in early childhood and risk for Type I (insulindependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 1999, 42, 51-54

[20] Zipitis, C.S.; Akobeng, A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: A systematic review and meta-analysis. *Arch. Dis. Child.* 2008, *93*, 512-517

[21] Munger, K.L.; Zhang, S.M.; O'Reilly, E.; Hernán, M.A.; Olek, M.J.; Willett, W.C.; Ascherio, A. Vitamin D intake and incidence of multiple sclerosis. *Neurology* 2004, *62*, 60-65].

[22] Soilu-Hänninen, M.; Aivo, J.; Lindström, B.-M.; Elovaara, I.; Sumelahti, M.-L.; Färkkilä, M.; Tienari, P.; Atula, S.; Sarasoja, T.; Herrala, L.; *et al.* A randomised, double blind, placebo controlled trial with vitamin D3 as add on treatment to interferon β-1b in patients with multiple sclerosis. *J. Neurol. Neurosurg. Psychiatr.* 2012, *83*, 565-571

[23] Barrea L, Savanelli MC, Di Somma C, Napolitano M, Megna M, Colao A, Savastano S. Vitamin D and its role in psoriasis: An overview of the dermatologist and nutritionist. Reviews in Endocrine and Metabolic Disorders. 2017 Jun;18(2):195-205.

[24] Bellan M, Sainaghi PP, Pirisi M. Role of vitamin D in rheumatoid arthritis. Ultraviolet Light in Human Health, Diseases and Environment. 2017:155-68.

[25] Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2004 Jan;50(1):72-7.

[26] Buondonno I, Rovera G, Sassi F, Rigoni MM, Lomater C, Parisi S, Pellerito R, Isaia GC, D'Amelio P. Vitamin D and immunomodulation in early rheumatoid arthritis: A randomized double-blind placebocontrolled study. PLoS One. 2017 Jun 5;12(6):e0178463.

**67**

diet [3].

**Chapter 5**

*Srđana Čulić*

**1. Introduction**

**Abstract**

A Mini-Review

virus, and human immunodeficiency virus.

**Keywords:** viral infections, vitamin D, hypovitaminosis, influence

The non-skeletal effect of vitamin D (VD) has been a hot topic of research for almost 20 years, and benefits have been found for many health conditions, including cancer, diabetes, autoimmune diseases, cardiovascular diseases [1, 2]. The increase in global VD deficiency is most likely due to poor sun exposure and poor

The dietary sources of VD cannot fulfill the body's requirements [4]. Sun exposure accounts for >90% of VD production in humans. Most people are now spending more time indoors, therefore, their exposure to sunlight is often limited. In the summer, due to fear of malignant skin diseases, use of creams with high ultraviolet (UV) protection is common, which further contributes to VD deficiency [5]. Air pollution in large urban industrial agglomerations with insufficient insolation also predisposes

Viral Infections, Including

Influenza and Corona Virus

Disease 2019, and Vitamin D:

Recent research about the influence of vitamin D (VD) deficiency on the occurrence of viral infections suggests that children with VD deficiency have attenuated immune response. This, in turn, increases the severity of viral infections, especially those of the respiratory tract, that show a typical seasonality pattern during the winter months. Despite the immunization of children at the global level, outbreaks of influenza do frequently occur. Over the past months, we have witnessed that the explosive pandemic of the corona virus disease 2019 (COVID-19) has caused significant mortality in some countries. Numerous studies have shown that VD deficiency is increasingly prevalent worldwide, and that it is potentially associated with the onset of viral infections. Persons with hypovitaminosis D and subsequent secondary immunodeficiencies ought to be identified and treated, while preventive supplementation of VD should be recommended to the general population to avoid VD deficiency during the winter. In this way, the burden of viral infections on population health and economy could be reduced. This paper also reviews the influence of VD on infections caused by hepatitis B and C viruses, human papillomavirus, Epstein–Barr virus, Human herpes virus 6, herpes simplex

#### **Chapter 5**

## Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D: A Mini-Review

*Srđana Čulić*

### **Abstract**

Recent research about the influence of vitamin D (VD) deficiency on the occurrence of viral infections suggests that children with VD deficiency have attenuated immune response. This, in turn, increases the severity of viral infections, especially those of the respiratory tract, that show a typical seasonality pattern during the winter months. Despite the immunization of children at the global level, outbreaks of influenza do frequently occur. Over the past months, we have witnessed that the explosive pandemic of the corona virus disease 2019 (COVID-19) has caused significant mortality in some countries. Numerous studies have shown that VD deficiency is increasingly prevalent worldwide, and that it is potentially associated with the onset of viral infections. Persons with hypovitaminosis D and subsequent secondary immunodeficiencies ought to be identified and treated, while preventive supplementation of VD should be recommended to the general population to avoid VD deficiency during the winter. In this way, the burden of viral infections on population health and economy could be reduced. This paper also reviews the influence of VD on infections caused by hepatitis B and C viruses, human papillomavirus, Epstein–Barr virus, Human herpes virus 6, herpes simplex virus, and human immunodeficiency virus.

**Keywords:** viral infections, vitamin D, hypovitaminosis, influence

#### **1. Introduction**

The non-skeletal effect of vitamin D (VD) has been a hot topic of research for almost 20 years, and benefits have been found for many health conditions, including cancer, diabetes, autoimmune diseases, cardiovascular diseases [1, 2]. The increase in global VD deficiency is most likely due to poor sun exposure and poor diet [3].

The dietary sources of VD cannot fulfill the body's requirements [4]. Sun exposure accounts for >90% of VD production in humans. Most people are now spending more time indoors, therefore, their exposure to sunlight is often limited. In the summer, due to fear of malignant skin diseases, use of creams with high ultraviolet (UV) protection is common, which further contributes to VD deficiency [5]. Air pollution in large urban industrial agglomerations with insufficient insolation also predisposes to VD deficiency [6, 7]. Taken together, hypovitaminosis D has become a pandemic in itself, identified across ethnicities and age groups worldwide [8–10]. Diekmann investigated the VD status of residents in a German nursing home in Nurnberg, and found VD deficiency (<50 nmol/L) in 93.9% of the residents [11]. Hypovitaminosis D is common in elderly people [12].

VD was classified as a vitamin for historical reasons, although it is actually a hormone in the group of secosteroids (steroids with an open B ring). Until recently, scientists focused on how VD affects the maintenance of plasma calcium and phosphate regulation, particularly in children who have rickets, and in adults, and older people with osteopenia and osteoporosis [13]. New research indicates that this vitamin/hormone plays a significant role in the functioning of the immune system, in fact, it is essential for its optimal functioning [14].

Why is VD so important? Firstly, VD functions as a natural steroid. It is the secosteroid vitamin/hormone, which regulates the immune system function as an immunomodulator. This means that their end-targets are lymphocyte activation and proliferation, and differentiation of promyelocytes and monocytes. Secondly, the VD receptor (VDR) has been identified in most tissues. VD influences the innate and adaptive immune responses. This immunomodulator also targets dendritic cells (DCs), as well as B-lymphocytes, modulating both innate and adaptive immune responses [15].

Thirdly, VD influences the cytokine network through inhibition of secretion of several cytokines by T cells. This immunomodulatory effect may be very important in treatment of viral infections and autoimmune diseases. Different reports have demonstrated the ability of VD to reduce the synthesis of interferon-γ (IFN-γ) and interleukin-2 (IL-2) in peripheral blood lymphocytes (PBL) and T-cell lines [16–18]. VD inhibits IFN-γ production and increased IL-10 production by peripheral blood mononuclear cells (PBMCs) [19]. Initial plasma IFN-γ and IL-10 are higher in COVID-19 Intensive Care Unit (ICU) patients and cytokine storm can occur [20–22].

Furthermore, VD can suppress cytokine storm by reducing the severity of influenza A. It significantly decreases the levels of tumor necrosis factor-alpha (TNF-α), interferon-beta (IFN-β), and IFN-stimulated gene-15 [23]. This is very important in case of severe clinical presentations of viral infection, especially those of the respiratory system [6]. VD also influences the acquired immunity and regenerate endothelial function and lining [24]. This effect is also important in order to minimize the alveolar damage in acute respiratory distress syndrome (ARDS) which can appear after viral acute respiratory infections (ARI) [25].

The condition of the average person's immune system worsens in winter. To explain this, one hypothesis has focused on VD levels, which depend in part on UV light exposure (higher in summer) that positively modulates the immune system. The best evidence is that VD supplementation reduces the incidence of ARI, according to a meta-analysis of randomized trials. VD supplementation is safe protecting against ARI and very deficient patients experience the most benefit [26]. This effect can explain the variation in influenza incidence in summer and in winter. Epidemiologic evidence links poor VD status to high susceptibility to viral infections and autoimmune diseases. Generally, hypovitaminosis D has been linked to the increased susceptibility to viral infections. It is an area of growing interest in scientific community [27–30].

The latest research indicates an interesting interaction between VD and the viruses, focusing on its antiviral and immunoregulatory activity such as the induction of autophagy and apoptosis [31]. This mini review is focused on the influence of VD on morbidity from viral infections including influenza and corona virus disease 2019 (COVID-19), which have been of special interest in the recent months.

**69**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

The optimal level of VD in serum is recommended at >75 nmol/L [32, 33]. The reference ranges of VD are inconsistent according to different recommendation [34]. The simplest and most acceptable differentiation is that VD insufficiency is considered when VD levels are between 50 and 75 nmol/L, while levels ≤50 nmol/L are considered inadequate and suggest VD deficiency [8]. Deficiency can be strong (30 – 49.9 nmol/L), significant (20 – 29.9 nmol/L) or extreme (<

Alvarez-Lafuente revealed that low levels of VD have been described as one of the possible factors involved in the etiopathogenesis of multiple sclerosis (MS) [35]. Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6) infections have also been proposed as MS triggers [36, 37]. Possible effect of VD levels on viral load have been suggested [35]. VD levels could be involved in the regulation of the replication/reactivation of EBV in peripheral blood cells of MS patients; moreover, viral load seems to be higher when VD levels in serum are low [35]. Maghzi revealed that levels of VD in patients with infectious mononucleosis were significantly lower at the time of infection than in the control group and concluded that it could be a risk

Hypovitaminosis D, Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6) infections have been described as possible MS triggers, but the pathogenesis of MS associated with HHV-6 infection remains unknown [39]. The presence of EBV in the CNS and demonstration of the underlying mechanism (s) linking EBV to the pathogenesis of MS remain to be elucidated. Astrocytes and microglia, in addition to B-cells can also be infected [40]. EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS

Pérez-Pérez analyzes the association between VD and viruses EBV and HHV-6 in 482 patients with multiple sclerosis [41]. The VD levels were significantly higher in the first school semester of the year than in the second and EBV viral load was significantly higher when VD levels were low [41]. Elevated EBV antibody levels and hypovitaminosis D may have impact on the relapsing–remitting form of MS [42]. High-dose oral VD supplementation can help the humoral immune responses against the latent EBV antigen, Ebstein-Barr nuclear antigen (EBNA)1 by decreas-

There are a few clinical studies about the influence of VD deficiency on occurrence of human papillomavirus (HPV) infection, but two authors are particularly worth mentioning because they revealed that VD deficiency enhance severity of HPV cervical infection. Özgü E et al. investigated whether VD deficiency could be a reason for the HPV infection persistence in cervical premalignant lesions [43]. They concluded that, the deficiency of VD and its metabolites could be a possible reason for HPV DNA persistence and related cervical intraepithelial neoplasia [43].

Another group of authors headed by Shim studied the association of sufficient level of VD with cervical-vaginal HPV infection due to high-risk HPV (cancercausing) or vaccine-type HPV and revealed that infections were increased in

These studies are a good guide to some new research into finding evidence of the benefits of VD in the fight against HPV. It is particularly important that supplementation of VD could possibly be considered in therapy of infections caused by HPV.

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

**1.1 Epstein–Barr virus, human herpes virus-6**

factor for the onset of autoimmune disease in general [38].

ing the antibody levels from baseline to week 48 [42].

women with VD levels that were severely deficient [44].

20 nmol/L) [32].

pathogenesis [40].

**1.2 Human papillomavirus**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

The optimal level of VD in serum is recommended at >75 nmol/L [32, 33]. The reference ranges of VD are inconsistent according to different recommendation [34]. The simplest and most acceptable differentiation is that VD insufficiency is considered when VD levels are between 50 and 75 nmol/L, while levels ≤50 nmol/L are considered inadequate and suggest VD deficiency [8]. Deficiency can be strong (30 – 49.9 nmol/L), significant (20 – 29.9 nmol/L) or extreme (< 20 nmol/L) [32].

#### **1.1 Epstein–Barr virus, human herpes virus-6**

*Vitamin D*

D is common in elderly people [12].

immune responses [15].

storm can occur [20–22].

scientific community [27–30].

in fact, it is essential for its optimal functioning [14].

to VD deficiency [6, 7]. Taken together, hypovitaminosis D has become a pandemic in itself, identified across ethnicities and age groups worldwide [8–10]. Diekmann investigated the VD status of residents in a German nursing home in Nurnberg, and found VD deficiency (<50 nmol/L) in 93.9% of the residents [11]. Hypovitaminosis

VD was classified as a vitamin for historical reasons, although it is actually a hormone in the group of secosteroids (steroids with an open B ring). Until recently, scientists focused on how VD affects the maintenance of plasma calcium and phosphate regulation, particularly in children who have rickets, and in adults, and older people with osteopenia and osteoporosis [13]. New research indicates that this vitamin/hormone plays a significant role in the functioning of the immune system,

Why is VD so important? Firstly, VD functions as a natural steroid. It is the secosteroid vitamin/hormone, which regulates the immune system function as an immunomodulator. This means that their end-targets are lymphocyte activation and proliferation, and differentiation of promyelocytes and monocytes. Secondly, the VD receptor (VDR) has been identified in most tissues. VD influences the innate and adaptive immune responses. This immunomodulator also targets dendritic cells (DCs), as well as B-lymphocytes, modulating both innate and adaptive

Thirdly, VD influences the cytokine network through inhibition of secretion of several cytokines by T cells. This immunomodulatory effect may be very important in treatment of viral infections and autoimmune diseases. Different reports have demonstrated the ability of VD to reduce the synthesis of interferon-γ (IFN-γ) and interleukin-2 (IL-2) in peripheral blood lymphocytes (PBL) and T-cell lines [16–18]. VD inhibits IFN-γ production and increased IL-10 production by peripheral blood mononuclear cells (PBMCs) [19]. Initial plasma IFN-γ and IL-10 are higher in COVID-19 Intensive Care Unit (ICU) patients and cytokine

Furthermore, VD can suppress cytokine storm by reducing the severity of influenza A. It significantly decreases the levels of tumor necrosis factor-alpha (TNF-α), interferon-beta (IFN-β), and IFN-stimulated gene-15 [23]. This is very important in case of severe clinical presentations of viral infection, especially those of the respiratory system [6]. VD also influences the acquired immunity and regenerate endothelial function and lining [24]. This effect is also important in order to minimize the alveolar damage in acute respiratory distress syndrome (ARDS) which

The condition of the average person's immune system worsens in winter. To explain this, one hypothesis has focused on VD levels, which depend in part on UV light exposure (higher in summer) that positively modulates the immune system. The best evidence is that VD supplementation reduces the incidence of ARI, according to a meta-analysis of randomized trials. VD supplementation is safe protecting against ARI and very deficient patients experience the most benefit [26]. This effect can explain the variation in influenza incidence in summer and in winter. Epidemiologic evidence links poor VD status to high susceptibility to viral infections and autoimmune diseases. Generally, hypovitaminosis D has been linked to the increased susceptibility to viral infections. It is an area of growing interest in

The latest research indicates an interesting interaction between VD and the viruses, focusing on its antiviral and immunoregulatory activity such as the induction of autophagy and apoptosis [31]. This mini review is focused on the influence of VD on morbidity from viral infections including influenza and corona virus disease 2019 (COVID-19), which have been of special interest in the recent months.

can appear after viral acute respiratory infections (ARI) [25].

**68**

Alvarez-Lafuente revealed that low levels of VD have been described as one of the possible factors involved in the etiopathogenesis of multiple sclerosis (MS) [35]. Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6) infections have also been proposed as MS triggers [36, 37]. Possible effect of VD levels on viral load have been suggested [35]. VD levels could be involved in the regulation of the replication/reactivation of EBV in peripheral blood cells of MS patients; moreover, viral load seems to be higher when VD levels in serum are low [35]. Maghzi revealed that levels of VD in patients with infectious mononucleosis were significantly lower at the time of infection than in the control group and concluded that it could be a risk factor for the onset of autoimmune disease in general [38].

Hypovitaminosis D, Epstein–Barr virus (EBV) and human herpes virus 6 (HHV-6) infections have been described as possible MS triggers, but the pathogenesis of MS associated with HHV-6 infection remains unknown [39]. The presence of EBV in the CNS and demonstration of the underlying mechanism (s) linking EBV to the pathogenesis of MS remain to be elucidated. Astrocytes and microglia, in addition to B-cells can also be infected [40]. EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis [40].

Pérez-Pérez analyzes the association between VD and viruses EBV and HHV-6 in 482 patients with multiple sclerosis [41]. The VD levels were significantly higher in the first school semester of the year than in the second and EBV viral load was significantly higher when VD levels were low [41]. Elevated EBV antibody levels and hypovitaminosis D may have impact on the relapsing–remitting form of MS [42]. High-dose oral VD supplementation can help the humoral immune responses against the latent EBV antigen, Ebstein-Barr nuclear antigen (EBNA)1 by decreasing the antibody levels from baseline to week 48 [42].

#### **1.2 Human papillomavirus**

There are a few clinical studies about the influence of VD deficiency on occurrence of human papillomavirus (HPV) infection, but two authors are particularly worth mentioning because they revealed that VD deficiency enhance severity of HPV cervical infection. Özgü E et al. investigated whether VD deficiency could be a reason for the HPV infection persistence in cervical premalignant lesions [43]. They concluded that, the deficiency of VD and its metabolites could be a possible reason for HPV DNA persistence and related cervical intraepithelial neoplasia [43].

Another group of authors headed by Shim studied the association of sufficient level of VD with cervical-vaginal HPV infection due to high-risk HPV (cancercausing) or vaccine-type HPV and revealed that infections were increased in women with VD levels that were severely deficient [44].

These studies are a good guide to some new research into finding evidence of the benefits of VD in the fight against HPV. It is particularly important that supplementation of VD could possibly be considered in therapy of infections caused by HPV.

#### **1.3 Herpes simplex virus**

Investigations of VD potential to prevent herpes virus infection or reactivation are limited. Kumar has investigated the herpes labialis cells supplementation with VD before herpes simplex virus (HSV)-1 infection and studied the effect after 6, 12, and 24h post-infections [45]. The supplementation of VD downregulate the viral load and Toll-like receptors (TLR) 2 mRNA during the initial phase of the infection [45]. The influence of VD was examined by Choi in vivo mouse model and observed that VD improved herpes simplex virus-induced Behçet's disease-like inflammation by down-regulating the expression of TLR and pro-inflammatory cytokines [46].

Öztekin A and authors have studied the association between VD and recurrent herpes labialis (RHL) in a population with RHL. They compared VD levels in healthy volunteers with and without RHL [47]. The individuals with RHL had significant VD deficiency, with VD levels below the recommended levels in more than 96% of the population. Most importantly, the study established a significant association between low serum VD levels and presence of RHL [47].

#### **1.4 Human immunodeficiency virus**

VD deficiency is also prevalent among patients with human immunodeficiency virus (HIV) infection. High levels of VD and VDR expression are also associated with natural resistance to HIV-1 infection [48]. VD deficiency is linked to a stronger inflammatory response and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients [48]. VD supplementation and restoration of VD level to the recommended serum values in HIV-infected patients may improve immunologic recovery in combination with the antiretroviral therapy by reducing the level of inflammation and immune activation, and by increasing the immune response to viral pathogens [48]. Jiménez-Sousa suggests that VD deficiency may contribute to the pathogenesis of HIV infection and VD supplementation can reverse alterations of the immune system. Author supports VD supplementation as prophylaxis, especially in individuals with more severe VD deficiency [48].

People diagnosed with HIV are vulnerable to VD insufficiency and deficiency. The supplementation acts against HIV disease progression by boosting the immune response [49]. In vitro findings suggest that the VD treatment may reduce HIV-1 transmission modulating levels and function of T cells, and the production of antiviral factors [50].

#### **1.5 Hepatitis B and C virus**

VD deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B (HBV), and C viruses (HCV). High prevalence of VD deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infections has been reported. Current literature was reviewed in order to understand the effects of VD supplementation in combination with IFN-based therapy on the virologic response in HBV and HCV infected patients. Hoan revealed that is important to know the significance of VD hypovitaminosis in the outcome of HBV- and HCV-related chronic liver diseases [51].

VD signaling is involved in infectious and non-infectious liver diseases. It is very important to understand the risk factors for the development of HBV. Probably there is relationship between VDR polymorphisms and the risk of HBV infection. Another group of authors headed by He Q in meta-analysis indicates that VDR

**71**

cells [61].

**2.1 Influenza virus**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

polymorphisms FokI genotype FF, Ff and allele F increase the risk of HBV infection

Low serum levels of VD are associated with increased HBV replication. HBVtransfected cells, inhibit VD impact [53]. The analysis of the immunological response of VD supplementation in chronic HCV patients by Kondo revealed that VD could improve the sensitivity of Peg-IFN/RBV therapy on HCV-infected hepatocytes by reducing the cytokine IP-10 production from PBMCs and expression of IFN-stimulated genes expression in the liver. Th1 responses in subjects treated with VD3/Peg-IFN/RBV were significantly higher than in those treated with Peg-IFN/

A recent study shows that supplementation of VD significantly improves sustained viral response via IFN-based therapy. VD reduces the extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. This finding confirmed the improved efficacy of anti-HCV treatment via the combination of VD and IFN [55]. Calcitriol and VD3, both remarkably inhibit HCV production in a VDR-independent mechanism [56]. A group of authors led by Murayama using an HCV cell culture system identified several compounds with anti-HCV activity by screening VD derivatives, which reduce HCV production by suppressing the

Acute respiratory viral infections (ARVI) remain the leading cause of morbidity and mortality worldwide, and a major global health problem because the availability of the effective antiviral drugs is limited. Such epidemics have significant negative economic consequences worldwide because of the increased absence from work and school resulting in long lasting economic crises. This can also lead to an overall collapse of the health care system. A number of observational studies revealed that VD deficiency is associated with increased risk of ARVI. Metaanalysis of trials revealed that there is protective effect of VD supplementations on the prevention on ARVI [58]. VD and its metabolites have immunomodulatory effect on respiratory epithelial cells surface markers infected with respiratory viruses (RV) modulating secretion of interferon 1, TNF and IL-6 [58]. VD mediates viral entry in epithelial cells and stimulates the expression of potent antimicrobial peptides in the respiratory tract epithelial cells protecting the lung from

Esposito and colleagues reviewed all of the studies published in PubMed over 15 years concerning VD deficiency and supplementations in children with respiratory tract infections. They concluded that VD seems to be very important because of its part of immune system. However, further studies are needed to evaluate the impact of VD deficiency in terms of the epidemiology and the outcome of pediatric

Brockman-Schneider and colleagues hypothesized that VD could directly reduce rhinovirus (RV) replication in airway epithelium but they found that VD does not directly affect RV replication in airway epithelial cells, but can instead influence chemokine synthesis and alters the growth and differentiation of airway epithelial

Influenza appears in a seasonal cycles [62, 63]. Seasonality to influenza correlates with a seasonal drop in VD serum levels and is associated with solar radiation,

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

and possibly has a role in the HBV susceptibility [52].

RBV at 12 weeks after Peg-IFN/RBV therapy (p < 0.05) [54].

expression of apolipoprotein in host cells [57].

**2. Respiratory viruses**

infection [58, 59].

respiratory tract infections [25, 60].

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

polymorphisms FokI genotype FF, Ff and allele F increase the risk of HBV infection and possibly has a role in the HBV susceptibility [52].

Low serum levels of VD are associated with increased HBV replication. HBVtransfected cells, inhibit VD impact [53]. The analysis of the immunological response of VD supplementation in chronic HCV patients by Kondo revealed that VD could improve the sensitivity of Peg-IFN/RBV therapy on HCV-infected hepatocytes by reducing the cytokine IP-10 production from PBMCs and expression of IFN-stimulated genes expression in the liver. Th1 responses in subjects treated with VD3/Peg-IFN/RBV were significantly higher than in those treated with Peg-IFN/ RBV at 12 weeks after Peg-IFN/RBV therapy (p < 0.05) [54].

A recent study shows that supplementation of VD significantly improves sustained viral response via IFN-based therapy. VD reduces the extra- and intracellular levels of HCV core antigen in a concentration-dependent manner. This finding confirmed the improved efficacy of anti-HCV treatment via the combination of VD and IFN [55]. Calcitriol and VD3, both remarkably inhibit HCV production in a VDR-independent mechanism [56]. A group of authors led by Murayama using an HCV cell culture system identified several compounds with anti-HCV activity by screening VD derivatives, which reduce HCV production by suppressing the expression of apolipoprotein in host cells [57].

#### **2. Respiratory viruses**

*Vitamin D*

cytokines [46].

**1.4 Human immunodeficiency virus**

viduals with more severe VD deficiency [48].

antiviral factors [50].

**1.5 Hepatitis B and C virus**

chronic liver diseases [51].

**1.3 Herpes simplex virus**

Investigations of VD potential to prevent herpes virus infection or reactivation are limited. Kumar has investigated the herpes labialis cells supplementation with VD before herpes simplex virus (HSV)-1 infection and studied the effect after 6, 12, and 24h post-infections [45]. The supplementation of VD downregulate the viral load and Toll-like receptors (TLR) 2 mRNA during the initial phase of the infection [45]. The influence of VD was examined by Choi in vivo mouse model and observed that VD improved herpes simplex virus-induced Behçet's disease-like inflammation by down-regulating the expression of TLR and pro-inflammatory

Öztekin A and authors have studied the association between VD and recurrent herpes labialis (RHL) in a population with RHL. They compared VD levels in healthy volunteers with and without RHL [47]. The individuals with RHL had significant VD deficiency, with VD levels below the recommended levels in more than 96% of the population. Most importantly, the study established a significant

VD deficiency is also prevalent among patients with human immunodeficiency virus (HIV) infection. High levels of VD and VDR expression are also associated with natural resistance to HIV-1 infection [48]. VD deficiency is linked to a stronger inflammatory response and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients [48]. VD supplementation and restoration of VD level to the recommended serum values in HIV-infected patients may improve immunologic recovery in combination with the antiretroviral therapy by reducing the level of inflammation and immune activation, and by increasing the immune response to viral pathogens [48]. Jiménez-Sousa suggests that VD deficiency may contribute to the pathogenesis of HIV infection and VD supplementation can reverse alterations of the immune system. Author supports VD supplementation as prophylaxis, especially in indi-

People diagnosed with HIV are vulnerable to VD insufficiency and deficiency. The supplementation acts against HIV disease progression by boosting the immune response [49]. In vitro findings suggest that the VD treatment may reduce HIV-1 transmission modulating levels and function of T cells, and the production of

VD deficiency is involved in the pathogenesis of chronic liver diseases caused by hepatitis B (HBV), and C viruses (HCV). High prevalence of VD deficiency with serum levels below 20 mg/mL in patients with HBV and HCV infections has been reported. Current literature was reviewed in order to understand the effects of VD supplementation in combination with IFN-based therapy on the virologic response in HBV and HCV infected patients. Hoan revealed that is important to know the significance of VD hypovitaminosis in the outcome of HBV- and HCV-related

VD signaling is involved in infectious and non-infectious liver diseases. It is very

important to understand the risk factors for the development of HBV. Probably there is relationship between VDR polymorphisms and the risk of HBV infection. Another group of authors headed by He Q in meta-analysis indicates that VDR

association between low serum VD levels and presence of RHL [47].

**70**

Acute respiratory viral infections (ARVI) remain the leading cause of morbidity and mortality worldwide, and a major global health problem because the availability of the effective antiviral drugs is limited. Such epidemics have significant negative economic consequences worldwide because of the increased absence from work and school resulting in long lasting economic crises. This can also lead to an overall collapse of the health care system. A number of observational studies revealed that VD deficiency is associated with increased risk of ARVI. Metaanalysis of trials revealed that there is protective effect of VD supplementations on the prevention on ARVI [58]. VD and its metabolites have immunomodulatory effect on respiratory epithelial cells surface markers infected with respiratory viruses (RV) modulating secretion of interferon 1, TNF and IL-6 [58]. VD mediates viral entry in epithelial cells and stimulates the expression of potent antimicrobial peptides in the respiratory tract epithelial cells protecting the lung from infection [58, 59].

Esposito and colleagues reviewed all of the studies published in PubMed over 15 years concerning VD deficiency and supplementations in children with respiratory tract infections. They concluded that VD seems to be very important because of its part of immune system. However, further studies are needed to evaluate the impact of VD deficiency in terms of the epidemiology and the outcome of pediatric respiratory tract infections [25, 60].

Brockman-Schneider and colleagues hypothesized that VD could directly reduce rhinovirus (RV) replication in airway epithelium but they found that VD does not directly affect RV replication in airway epithelial cells, but can instead influence chemokine synthesis and alters the growth and differentiation of airway epithelial cells [61].

#### **2.1 Influenza virus**

Influenza appears in a seasonal cycles [62, 63]. Seasonality to influenza correlates with a seasonal drop in VD serum levels and is associated with solar radiation, which triggers seasonal VD skin production. Common winter VD deficiency has negative effects on innate and acquired immunity. UV radiation from artificial sources or from sunlight reduces the incidence of viral respiratory infections [64].

VD supplementation is associated with reduced incidence and severity during influenza A virus (IAV) infection restoring the autophagic flux inhibited by IAV by upregulating the expression of Syntax in-17 (STX17) and V-type proton ATPase subunit (ATP6V0A2). It causes a concomitant decrease in cellular apoptosis via a VDR. VD is useful for limiting IAV-induced cellular injury via its pro-autophagic action [65].

Zhou and colleagues studied the clinical efficacy of VD for preventing influenza A in 400 infants. They revealed that a high-dose VD (1200 IU) is suitable and safe for the prevention of seasonal influenza because of rapid relief from symptoms, rapid decrease in viral loads and quick recovery [66]. This study suggests that VD supplementation during the winter may reduce the incidence of influenza A in infants [66]. Urashima investigated the effect of VD supplementation (1200 IU/d) during the winter on the incidence of seasonal influenza A in schoolchildren and proved that it can reduce it [67].

Very cheap prophylaxis with use of VD as a prophylactic therapy for influenza starting at the end of October till the end of April is very useful; Would be crucial to prove it from a potential easy and cheap prophylaxis or therapy support perspective as far as influenza infections are concerned. Gruber-Bzura **e**xplore the preventive effect of VD supplementation on viral influenza infections also [68].

In people diagnosed with hypovitaminosis D at the beginning of the autumn **s**upplementation with 2000 IU of VD helps to bring levels to normal, but if extremely low serum VD values are proven, the reimbursement doses may be even higher.

#### **2.2 Novel beta-coronavirus SARS-CoV-2**

Coronaviruses are seasonal, with little transmission in the summer. Coronavirus disease (COVID-19) is caused by a novel beta-corona virus, renamed by the WHO to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to destigmatize the association of the virus with any geographic location or nationality. COVID-19 is a potentially fatal disease and has been declared as a global pandemic nowadays.

A number of additional preprints and publications regarding VD on COVID-19 have appeared. Some reviews tried to explain the involvement of micronutrient VD in COVID19 treatment and prophylaxis. Vitamin D supplementation could possibly improve clinical outcomes of patients infected with COVID-19 [69].

Lau revealed that VD insufficiency prevalence in ICU patients was 84.6%, vs. 57.1% in floor patients and concluded that may be an underlying driver of COVID-19 severity [70]. Rharusun in his retrospective Indonesian cohort study revealed that majority of the death cases were older male with pre-existing condition and hypovitaminosis D. Majority of the COVID-19 cases with insufficient and deficient VD status died [71]. Bloukh conclude that adequate serum vitamin D levels are needed for the prevention of severe cases of COVID-19 [72, 73]. The elderly have lower levels of vitamin D due to a variety of biological and behavioral factors [74, 75].

VD deficiency has been found to contribute to ARDS and case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with hypovitaminosis D. This supports the view that VD deficiency may also favor the emergence of more severe forms of the disease. It is also well known that older people, especially those housed in homes, have a high percentage of VD deficiency. Unfortunately, today we are witnessing an explosive rate of infections

**73**

COVID-19 [82].

COVID-19 forms [84].

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

in nursing homes with poor outcomes. VD prevention and treatment for deficiency worldwide would greatly help to overcome this pandemic. VD is known to regenerate endothelial lining, which may be beneficial in minimizing the alveolar damage caused in ARDS. In animal model VD reduce lung permeability by modulation of renin-angiotensin system activity and ACE2 expression [76]. Grant recommends that raising serum VD concentrations to 100 – 150 nmol/l should be able to reduce

McCullough recommends reaching those concentrations rapidly by taking large doses of VD for a few weeks, followed by several thousand IU/d VD for the duration of the COVID-19 pandemic. Such doses have been found not to have adverse health effects. Randomized controlled trials and large population studies should be

There have been a few investigations of VD effect on interstitial pneumonia. Tsujino and his colleagues used human pulmonary fibroblast cell lines (HPFCs) and a mouse model of Bleomycin-induced pulmonary fibrosis. They evaluated whether VD was activated in the lungs and had a preventive effect against interstitial pneumonia [79]. Expression of the VDR gene and genes for enzymes metabolizing VD were evaluated in two HPFCs, as well as the suppressive effect of VD on induction of inflammatory cytokines [79]. Symptoms of Bleomycin-induced pulmonary fibrosis were improved and expression of fibrosis markers/fibrosis inducers was decreased by a high VD diet, so they concluded that VD is activated locally in lung tissues and high dietary intake may have a preventive effect against interstitial pneumonia [79]. Martineau concluded that VD supplementation is safe and protects against acute respiratory tract infection overall. Patients who were very VD

Daneshkhah investigates if there is a link between severe cases of COVID-19 expressing cytokine storm and VD deficiency [81]. Age-specific case fatality (CFR) was investigated for the elderly (age ≥ 70 yr), Italy and Spain present the highest CFR (>1.7 times that of other countries). A more severe deficiency of VD lower than 25 nmol/L is reported in Italy and Spain compared to other countries. His investigation suggests that elimination of severe VD deficiency reduces the risk of high CRP levels, which may be used as a surrogate marker of cytokine storm

Kakodkar in his review points out that VD regenerates endothelial lining and is beneficial in lowering the alveolar damage and ARDS [82]. This protective effect is 19% better on those on a daily bolus compared to those on a monthly one while in those with deficiency protective effect is 70% better. The author and his colleagues consider this vitamin very important in the prevention and treatment of

Recent study of COVID-19 and VD indicate that the severity of the clinical picture of COVID-19 depends of VD deficiency that is more prevalent in patients with severe COVID-19 disease. The inflammatory response is higher with increased chances of mortality [83]. Antiviral and anti-inflammatory action of VD is high and supplementation can have preventive effect on the development of severe

A clinical trial on the severity of COVID-19 clinical imaging and VD deficiency should be performed and useful. Caccialanza R. and other authors propose a pragmatic protocol for early nutritional supplementation of non-critically ill patients hospitalized for COVID-19, explaining that most patients present at admission have severe inflammation and anorexia leading to a drastic reduction of food intake [85]. Many published data revealed that VD has immunomodulatory effect. Prevention by supplementation is recommended [86]. There is a link between immunodeficiency in individuals with obesity and greater viral pathogenicity because of VD

expected to reduce in severe COVID-19 cases of up to 15% [81].

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

the risk of COVID-19 infection and death [77].

conducted to evaluate these recommendations [78].

deficient experienced the most benefit [80].

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

in nursing homes with poor outcomes. VD prevention and treatment for deficiency worldwide would greatly help to overcome this pandemic. VD is known to regenerate endothelial lining, which may be beneficial in minimizing the alveolar damage caused in ARDS. In animal model VD reduce lung permeability by modulation of renin-angiotensin system activity and ACE2 expression [76]. Grant recommends that raising serum VD concentrations to 100 – 150 nmol/l should be able to reduce the risk of COVID-19 infection and death [77].

McCullough recommends reaching those concentrations rapidly by taking large doses of VD for a few weeks, followed by several thousand IU/d VD for the duration of the COVID-19 pandemic. Such doses have been found not to have adverse health effects. Randomized controlled trials and large population studies should be conducted to evaluate these recommendations [78].

There have been a few investigations of VD effect on interstitial pneumonia. Tsujino and his colleagues used human pulmonary fibroblast cell lines (HPFCs) and a mouse model of Bleomycin-induced pulmonary fibrosis. They evaluated whether VD was activated in the lungs and had a preventive effect against interstitial pneumonia [79]. Expression of the VDR gene and genes for enzymes metabolizing VD were evaluated in two HPFCs, as well as the suppressive effect of VD on induction of inflammatory cytokines [79]. Symptoms of Bleomycin-induced pulmonary fibrosis were improved and expression of fibrosis markers/fibrosis inducers was decreased by a high VD diet, so they concluded that VD is activated locally in lung tissues and high dietary intake may have a preventive effect against interstitial pneumonia [79]. Martineau concluded that VD supplementation is safe and protects against acute respiratory tract infection overall. Patients who were very VD deficient experienced the most benefit [80].

Daneshkhah investigates if there is a link between severe cases of COVID-19 expressing cytokine storm and VD deficiency [81]. Age-specific case fatality (CFR) was investigated for the elderly (age ≥ 70 yr), Italy and Spain present the highest CFR (>1.7 times that of other countries). A more severe deficiency of VD lower than 25 nmol/L is reported in Italy and Spain compared to other countries. His investigation suggests that elimination of severe VD deficiency reduces the risk of high CRP levels, which may be used as a surrogate marker of cytokine storm expected to reduce in severe COVID-19 cases of up to 15% [81].

Kakodkar in his review points out that VD regenerates endothelial lining and is beneficial in lowering the alveolar damage and ARDS [82]. This protective effect is 19% better on those on a daily bolus compared to those on a monthly one while in those with deficiency protective effect is 70% better. The author and his colleagues consider this vitamin very important in the prevention and treatment of COVID-19 [82].

Recent study of COVID-19 and VD indicate that the severity of the clinical picture of COVID-19 depends of VD deficiency that is more prevalent in patients with severe COVID-19 disease. The inflammatory response is higher with increased chances of mortality [83]. Antiviral and anti-inflammatory action of VD is high and supplementation can have preventive effect on the development of severe COVID-19 forms [84].

A clinical trial on the severity of COVID-19 clinical imaging and VD deficiency should be performed and useful. Caccialanza R. and other authors propose a pragmatic protocol for early nutritional supplementation of non-critically ill patients hospitalized for COVID-19, explaining that most patients present at admission have severe inflammation and anorexia leading to a drastic reduction of food intake [85]. Many published data revealed that VD has immunomodulatory effect. Prevention by supplementation is recommended [86]. There is a link between immunodeficiency in individuals with obesity and greater viral pathogenicity because of VD

*Vitamin D*

action [65].

even higher.

proved that it can reduce it [67].

**2.2 Novel beta-coronavirus SARS-CoV-2**

and behavioral factors [74, 75].

which triggers seasonal VD skin production. Common winter VD deficiency has negative effects on innate and acquired immunity. UV radiation from artificial sources or from sunlight reduces the incidence of viral respiratory infections [64]. VD supplementation is associated with reduced incidence and severity during influenza A virus (IAV) infection restoring the autophagic flux inhibited by IAV by upregulating the expression of Syntax in-17 (STX17) and V-type proton ATPase subunit (ATP6V0A2). It causes a concomitant decrease in cellular apoptosis via a VDR. VD is useful for limiting IAV-induced cellular injury via its pro-autophagic

Zhou and colleagues studied the clinical efficacy of VD for preventing influenza A in 400 infants. They revealed that a high-dose VD (1200 IU) is suitable and safe for the prevention of seasonal influenza because of rapid relief from symptoms, rapid decrease in viral loads and quick recovery [66]. This study suggests that VD supplementation during the winter may reduce the incidence of influenza A in infants [66]. Urashima investigated the effect of VD supplementation (1200 IU/d) during the winter on the incidence of seasonal influenza A in schoolchildren and

Very cheap prophylaxis with use of VD as a prophylactic therapy for influenza starting at the end of October till the end of April is very useful; Would be crucial to prove it from a potential easy and cheap prophylaxis or therapy support perspective as far as influenza infections are concerned. Gruber-Bzura **e**xplore the preventive

In people diagnosed with hypovitaminosis D at the beginning of the autumn

Coronaviruses are seasonal, with little transmission in the summer. Coronavirus disease (COVID-19) is caused by a novel beta-corona virus, renamed by the WHO to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to destigmatize the association of the virus with any geographic location or nationality. COVID-19 is a potentially fatal disease and has been declared as a global pandemic nowadays. A number of additional preprints and publications regarding VD on COVID-19 have appeared. Some reviews tried to explain the involvement of micronutrient VD in COVID19 treatment and prophylaxis. Vitamin D supplementation could possibly

Lau revealed that VD insufficiency prevalence in ICU patients was 84.6%, vs. 57.1% in floor patients and concluded that may be an underlying driver of COVID-19 severity [70]. Rharusun in his retrospective Indonesian cohort study revealed that majority of the death cases were older male with pre-existing condition and hypovitaminosis D. Majority of the COVID-19 cases with insufficient and deficient VD status died [71]. Bloukh conclude that adequate serum vitamin D levels are needed for the prevention of severe cases of COVID-19 [72, 73]. The elderly have lower levels of vitamin D due to a variety of biological

VD deficiency has been found to contribute to ARDS and case-fatality rates increase with age and with chronic disease comorbidity, both of which are associated with hypovitaminosis D. This supports the view that VD deficiency may also favor the emergence of more severe forms of the disease. It is also well known that older people, especially those housed in homes, have a high percentage of VD deficiency. Unfortunately, today we are witnessing an explosive rate of infections

**s**upplementation with 2000 IU of VD helps to bring levels to normal, but if extremely low serum VD values are proven, the reimbursement doses may be

effect of VD supplementation on viral influenza infections also [68].

improve clinical outcomes of patients infected with COVID-19 [69].

**72**

deficiency/insufficiency in this population [87]. Among patients with COVID-19 in intensive care units (ICU) the prevalence of obesity was 47.5% (49/103). In a multivariate analysis, severe obesity (BMI ≥35 kg/m2) was associated with ICU admission [88].

The first preliminary data collected by Giancarlo Isaia in Turin indicate that patients hospitalized for COVID-19 have a very high prevalence of hypovitaminosis D. Italy is currently the country with the third highest number of Coronavirus cases after the United States and Spain. If we compare the data of southern and northern Italy, published on-line by Statista Research Department, we can see that in southern Italy, which is also poorer, there are significantly fewer infected with SARS-Cov-2 [89].

Vitamin D levels are severely low in the aging population especially in Spain, Italy, and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19 [90–92]. There is a variation in mortality of COVID-19 between different countries and countries in southern hemisphere have a relatively low mortality. For instance, there is a big difference between Australia's 2 per million in 10th the UK's 68 per million by April 3rd 2020., which may support the hypothesis that VD is a factor that determines the severity of the disease [93].

#### **3. Discussion**

The viruses that have already been circulating among the population earlier are less severe than the new ones, which have an advantage because the population was not previously immunized to them. Many respiratory viruses are winter-seasonal in temperate regions. For influenza, it has been shown in the lab that absolute humidity strongly affects flu transmission, where drier conditions are more favorable.

There is a significant correlation between VD deficiency in children and the incidence and severity of lower respiratory tract infection (LTRI). Children with LRTI have significantly lower mean VD levels as compared to controls and their disease manifestation was severe [94].

The hypothesis that hypovitaminosis D can influence severity of influenza or COVID-19 has to be confirmed by future research.

Analyzing the immune mechanisms might help us to understand why some people show severe complications while others can be asymptomatic. We have to discover the influence of VD on specific targets in immune system immunomodulating the response on virus influenzas and SARS-CoV-2.

This knowledge can be useful for preventive therapeutic purposes when VD can be used as an immune-protector and antiviral factor. Increasingly, there is a growing awareness that this secosteroid hormone/vitamin is a very important factor in the proper functioning of the immune system in response to various viral infections and consequent complications such as autoimmune or malignant diseases.

In recent years, we have witnessed explosive flu epidemics, generally respiratory infections including this year pandemic of COVID-19 that we can associate with the worldwide epidemic of hypovitaminosis D. It would be necessary that organizations, societies, and country government institutional bodies be lobbied to recommend VD in winter time and adopt guidelines for the prevention of hypovitaminosis D, in order to prevent or at least minimize the outcome of this pandemic with is causing grave and tragic consequences on the health of mankind and of course the economy**.**

Interventional and observational epidemiological studies provide evidence that VD deficiency may confer increased risk of influenza and respiratory tract infection. Cell culture experiments support the thesis that VD has direct anti-viral effects particularly against enveloped viruses [95].

**75**

**Table 1.**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

and maintained 1200-1400 IU depending on the severity of the deficit.

reduced risk of symptoms better than just >75 nmol/L.

Children 1. 2000 IU 8 weeks, then VD serum levels control

Adults 1. 4000 IU 8 weeks, then VD serum levels control

Elderly 1. 5000 IU 8 weeks, then VD serum levels control

*Recomandations for daily VD administration.*

2. Maintenance 1200-1400 IU,

2. Maintenance 1200-2000 IU,

2. Maintenance 2000 - 3000 IU

VD serum levels control every two months

VD serum levels control every two months

VD serum levels control every two months

Considering the recommendations presented in **Table 1**, a personalized approach to the treatment and prevention of VD deficiency is extremely important. It is important to identify in the population individuals with secondary immune deficiency caused by hypovitaminosis VD. Such persons have to be treated with

In children and adults, we have to bring serum VD levels to >75 nmol/L and maintain them between 90 and 120 nmol / L especially in epidemic conditions to 150 nmol/L After VD replacement therapy, a rechecking of the serum VD concentration is recommended after two months. In period of maintenance therapy rechecking has to be every two months. As can be seen in the preprints and publications on severity of COVID-19 infections those with concentrations >75 nmol/L still have symptomatic infections. Thus, going to 100 to 150 nmol/L would result in

It is known that VD concentrations decrease with age because the skin is old and has reduced capacity to produce VD and the intestines absorb VD more slowly from food. Elderly Europeans, are thus at risk of hypovitaminosis D during winter [96, 97]. The same is happening worldwide, especially among the older population living in the northern hemisphere. They have to be tested for levels of VD in serum at the beginning of November and at the end of February. The elderly population is the most susceptible to influenza and COVID-19 and has the most frequently fatal complications. It is the same population that is most likely to suffer from hypovitaminosis D, which significantly worsens the condition of the aging immune system [98]. A serum VD lower than 25 nmol/L was found in 2 to 30% of adults, while this percentage may increase to 75% or more in older persons in institutions [90, 91]. The Institute of Medicine (IOM) finds doses <4000 IU/day are safe for old people. Boucher suggest that ≥1000–2000 IU of VD daily is necessary in this

**Therapy for hipovitaminosis D Prevention of hipovitaminosis D**

1. 800 IU – 1200 IU

1. 1200 IU – 2000 IU

two months

months

months

1. 2000 - 3000 IU

VD serum levels control every

VD serum levels control every two

VD serum levels control every two

For optimal functioning of the immune system and protection against infections caused by viruses, serum VD concentration has to be between 75 and 150 nmol/L. Preventive doses for adults in risk of hypovitaminosis D have to be from 1200- 2000 IU and for children at risk for hypovitaminosis D have to be from 800-1200 IU. For proven VD deficiency for adults, 4000 IU have to be prescribed for the first 8 weeks and then maintained at 1200-2000 IU and for children 2000 IU 8 weeks

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

**3.1 Recommendations**

higher doses.

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

#### **3.1 Recommendations**

*Vitamin D*

admission [88].

**3. Discussion**

disease manifestation was severe [94].

COVID-19 has to be confirmed by future research.

effects particularly against enveloped viruses [95].

lating the response on virus influenzas and SARS-CoV-2.

deficiency/insufficiency in this population [87]. Among patients with COVID-19 in intensive care units (ICU) the prevalence of obesity was 47.5% (49/103). In a multivariate analysis, severe obesity (BMI ≥35 kg/m2) was associated with ICU

The first preliminary data collected by Giancarlo Isaia in Turin indicate that patients hospitalized for COVID-19 have a very high prevalence of hypovitaminosis D. Italy is currently the country with the third highest number of Coronavirus cases after the United States and Spain. If we compare the data of southern and northern Italy, published on-line by Statista Research Department, we can see that in southern Italy, which is also poorer, there are significantly fewer infected with SARS-Cov-2 [89]. Vitamin D levels are severely low in the aging population especially in Spain, Italy, and Switzerland. This is also the most vulnerable group of the population in relation to COVID-19 [90–92]. There is a variation in mortality of COVID-19 between different countries and countries in southern hemisphere have a relatively low mortality. For instance, there is a big difference between Australia's 2 per million in 10th the UK's 68 per million by April 3rd 2020., which may support the hypothesis that VD is a factor that determines the severity of the disease [93].

The viruses that have already been circulating among the population earlier are less severe than the new ones, which have an advantage because the population was not previously immunized to them. Many respiratory viruses are winter-seasonal in temperate regions. For influenza, it has been shown in the lab that absolute humidity strongly affects flu transmission, where drier conditions are more favorable. There is a significant correlation between VD deficiency in children and the incidence and severity of lower respiratory tract infection (LTRI). Children with LRTI have significantly lower mean VD levels as compared to controls and their

The hypothesis that hypovitaminosis D can influence severity of influenza or

Analyzing the immune mechanisms might help us to understand why some people show severe complications while others can be asymptomatic. We have to discover the influence of VD on specific targets in immune system immunomodu-

and consequent complications such as autoimmune or malignant diseases.

This knowledge can be useful for preventive therapeutic purposes when VD can be used as an immune-protector and antiviral factor. Increasingly, there is a growing awareness that this secosteroid hormone/vitamin is a very important factor in the proper functioning of the immune system in response to various viral infections

In recent years, we have witnessed explosive flu epidemics, generally respiratory infections including this year pandemic of COVID-19 that we can associate with the worldwide epidemic of hypovitaminosis D. It would be necessary that organizations, societies, and country government institutional bodies be lobbied to recommend VD in winter time and adopt guidelines for the prevention of hypovitaminosis D, in order to prevent or at least minimize the outcome of this pandemic with is causing grave and tragic consequences on the health of mankind and of

Interventional and observational epidemiological studies provide evidence that VD deficiency may confer increased risk of influenza and respiratory tract infection. Cell culture experiments support the thesis that VD has direct anti-viral

**74**

course the economy**.**

For optimal functioning of the immune system and protection against infections caused by viruses, serum VD concentration has to be between 75 and 150 nmol/L. Preventive doses for adults in risk of hypovitaminosis D have to be from 1200- 2000 IU and for children at risk for hypovitaminosis D have to be from 800-1200 IU.

For proven VD deficiency for adults, 4000 IU have to be prescribed for the first 8 weeks and then maintained at 1200-2000 IU and for children 2000 IU 8 weeks and maintained 1200-1400 IU depending on the severity of the deficit.

Considering the recommendations presented in **Table 1**, a personalized approach to the treatment and prevention of VD deficiency is extremely important. It is important to identify in the population individuals with secondary immune deficiency caused by hypovitaminosis VD. Such persons have to be treated with higher doses.

In children and adults, we have to bring serum VD levels to >75 nmol/L and maintain them between 90 and 120 nmol / L especially in epidemic conditions to 150 nmol/L After VD replacement therapy, a rechecking of the serum VD concentration is recommended after two months. In period of maintenance therapy rechecking has to be every two months. As can be seen in the preprints and publications on severity of COVID-19 infections those with concentrations >75 nmol/L still have symptomatic infections. Thus, going to 100 to 150 nmol/L would result in reduced risk of symptoms better than just >75 nmol/L.

It is known that VD concentrations decrease with age because the skin is old and has reduced capacity to produce VD and the intestines absorb VD more slowly from food. Elderly Europeans, are thus at risk of hypovitaminosis D during winter [96, 97].

The same is happening worldwide, especially among the older population living in the northern hemisphere. They have to be tested for levels of VD in serum at the beginning of November and at the end of February. The elderly population is the most susceptible to influenza and COVID-19 and has the most frequently fatal complications. It is the same population that is most likely to suffer from hypovitaminosis D, which significantly worsens the condition of the aging immune system [98].

A serum VD lower than 25 nmol/L was found in 2 to 30% of adults, while this percentage may increase to 75% or more in older persons in institutions [90, 91].

The Institute of Medicine (IOM) finds doses <4000 IU/day are safe for old people. Boucher suggest that ≥1000–2000 IU of VD daily is necessary in this


#### **Table 1.**

*Recomandations for daily VD administration.*

population with numerous clinical problems related to the indicated age, especially when independence is lost, when hypovitaminosis D is also present worsening the patient's clinical condition. Much higher doses than these are needed for the treatment of the established deficiency [99].

A preventative strategy should be established and endorsed by the organizations, societies, and country governments be lobbied to recommend VD in winter, which is extremely important for maintaining the good health of the world's population. Preventive administration of VD or replacement therapy in the early winter months to early spring could reduce the severity of clinical symptoms in patients with COVID-19 infection. It is necessary to optimize VD status to enhance every one's immunity for protection against SARS-CoV-2 infection. Prevention of influenza outbreaks and COVID-19 must begin as early as the first days of November so that the population enters a season of respiratory infections with a prepared and strengthened immune system. Jakovac in his letter to the editor recommends intensive supplementation as possible prophylaxis with VD with even higher doses [100]. Maintenance of adequate VD status may be an effective and inexpensive prophylactic method against viral infections, but the optimal supplementation regimen has to be defined.

The latest literature by Paul Marik and East Virginia Medical School (EVMS) medical group published on line a protocol explaining prevention and treatment COVID-19 with instructions for applying VD 1000-4000 IU (unknown optimal dose) in prevention and therapy in mildly symptomatic patients [101].

#### **4. Conclusion**

Persons with VD deficiency have attenuated immune responses with secondary immunodeficiency. This condition increases the severity of viral infections especially those of respiratory tract that show typical seasonality pattern during the winter months. Children, adults, especially older population have to take supplementation of VD for reason to cure and deficiency prevention. By the general acceptance of the fact that VD supplementation has a positive effect on immunity we can reduce the risk and severity of viral infections with important public health benefits.

#### **Author details**

Srđana Čulić Medical School University of Split, Split, Croatia

\*Address all correspondence to: srdjana.culic.sc@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**77**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

[9] Ritterhouse LL, Lu R, Shah HB, Robertson JM, Fife DA, Maecker HT, et al. Vitamin D deficiency in a multiethnic healthy control cohort and altered immune response in vitamin D deficient European-american healthy controls.

PLoS One 2014;9(4):e94500.

2013;24(11):2775-2787.

2013;46:403-409.

[11] Diekmann R, Winning K, Bauer JM, Uter W, Stehle P, Lesser S, et al. Vitamin D status and physical function in nursing home residents: A 1-year observational study. Zeitschrift für Gerontologie und Geriatrie.

[12] Samefors M, Östgren CJ, Mölstad S, Lannering C, Midlöv P, Tengblad A. Vitamin D deficiency in elderly people in Swedish nursing homes is associated

with increased mortality. Eur J Endocrinol. 2014;170(5):667-75.

Biol. 2019;188:141-146.

2017;453:68-78.

[13] Uday S, Högler W.Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia. J Steroid Biochem Mol

[14] Dimitrov V, White JH. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol Cell Endocrinol.

[15] Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482-496.

[16] Borges MC, Martini LA,

Rogero MM. Current perspectives on

[10] Yoshimura N, Muraki S, Oka H, Morita M, Yamada H, Tanaka S, et al. Profiles of Vitamin D Insufficiency and Deficiency in Japanese Men and Women: Association With Biological, Environmental, and Nutritional Factors and Coexisting Disorders: The ROAD Study. Osteoporos Int.

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

[1] Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC,

Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019;

[2] Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019;380(1):33-44.

[3] Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ. Plasma Concentrations of 25-hydroxyvitamin D in Meat Eaters, Fish Eaters, Vegetarians and Vegans: Results From the EPIC-Oxford Study Public Health Nutr.

[4] Saternus R, Vogt T, Reichrath J. A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population With a Western Diet. Nutrients. 2019;11(11):2682.

[5] Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients.

[6] Hoseinzadeh E, Taha P, Wei C, Godini H, Ashraf GM, Taghavi M, et al. The impact of air pollutants, UV exposure and geographic location on vitamin D deficiency. Food Chem

[7] Mousavi SE, Amini H, Heydarpour P, Amini Chermahini F, Godderis L.Air pollution, environmental chemicals, and smoking may trigger vitamin D deficiency: Evidence and

potential mechanisms. Environ Int.

Ientile R. Health Risks of Hypovitaminosis D: A Review of New Molecular Insights.

[8] Caccamo D, Ricca S, Currò M,

Int J Mol Sci. 2018;19(3):892.

Toxicol. 2018;113:241-254.

2019;122:67-90.

2011;14(2):340-346.

2010;2(5):482-495.

Aroda VR, et al. Vitamin D

381(6):520-530.

**References**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

#### **References**

*Vitamin D*

ment of the established deficiency [99].

regimen has to be defined.

**4. Conclusion**

**76**

**Author details**

Medical School University of Split, Split, Croatia

provided the original work is properly cited.

\*Address all correspondence to: srdjana.culic.sc@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

population with numerous clinical problems related to the indicated age, especially when independence is lost, when hypovitaminosis D is also present worsening the patient's clinical condition. Much higher doses than these are needed for the treat-

A preventative strategy should be established and endorsed by the organizations, societies, and country governments be lobbied to recommend VD in winter, which is extremely important for maintaining the good health of the world's population. Preventive administration of VD or replacement therapy in the early winter months to early spring could reduce the severity of clinical symptoms in patients with COVID-19 infection. It is necessary to optimize VD status to enhance every one's immunity for protection against SARS-CoV-2 infection. Prevention of influenza outbreaks and COVID-19 must begin as early as the first days of November so that the population enters a season of respiratory infections with a prepared and strengthened immune system. Jakovac in his letter to the editor recommends intensive supplementation as possible prophylaxis with VD with even higher doses [100]. Maintenance of adequate VD status may be an effective and inexpensive prophylactic method against viral infections, but the optimal supplementation

The latest literature by Paul Marik and East Virginia Medical School (EVMS) medical group published on line a protocol explaining prevention and treatment COVID-19 with instructions for applying VD 1000-4000 IU (unknown optimal

Persons with VD deficiency have attenuated immune responses with secondary immunodeficiency. This condition increases the severity of viral infections especially those of respiratory tract that show typical seasonality pattern during the winter months. Children, adults, especially older population have to take supplementation of VD for reason to cure and deficiency prevention. By the general acceptance of the fact that VD supplementation has a positive effect on immunity we can reduce the

dose) in prevention and therapy in mildly symptomatic patients [101].

risk and severity of viral infections with important public health benefits.

Srđana Čulić

[1] Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med. 2019; 381(6):520-530.

[2] Manson JE, Cook NR, Lee IM, Christen W, Bassuk SS, Mora S, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med. 2019;380(1):33-44.

[3] Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ. Plasma Concentrations of 25-hydroxyvitamin D in Meat Eaters, Fish Eaters, Vegetarians and Vegans: Results From the EPIC-Oxford Study Public Health Nutr. 2011;14(2):340-346.

[4] Saternus R, Vogt T, Reichrath J. A Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population With a Western Diet. Nutrients. 2019;11(11):2682.

[5] Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients. 2010;2(5):482-495.

[6] Hoseinzadeh E, Taha P, Wei C, Godini H, Ashraf GM, Taghavi M, et al. The impact of air pollutants, UV exposure and geographic location on vitamin D deficiency. Food Chem Toxicol. 2018;113:241-254.

[7] Mousavi SE, Amini H, Heydarpour P, Amini Chermahini F, Godderis L.Air pollution, environmental chemicals, and smoking may trigger vitamin D deficiency: Evidence and potential mechanisms. Environ Int. 2019;122:67-90.

[8] Caccamo D, Ricca S, Currò M, Ientile R. Health Risks of Hypovitaminosis D: A Review of New Molecular Insights. Int J Mol Sci. 2018;19(3):892.

[9] Ritterhouse LL, Lu R, Shah HB, Robertson JM, Fife DA, Maecker HT, et al. Vitamin D deficiency in a multiethnic healthy control cohort and altered immune response in vitamin D deficient European-american healthy controls. PLoS One 2014;9(4):e94500.

[10] Yoshimura N, Muraki S, Oka H, Morita M, Yamada H, Tanaka S, et al. Profiles of Vitamin D Insufficiency and Deficiency in Japanese Men and Women: Association With Biological, Environmental, and Nutritional Factors and Coexisting Disorders: The ROAD Study. Osteoporos Int. 2013;24(11):2775-2787.

[11] Diekmann R, Winning K, Bauer JM, Uter W, Stehle P, Lesser S, et al. Vitamin D status and physical function in nursing home residents: A 1-year observational study. Zeitschrift für Gerontologie und Geriatrie. 2013;46:403-409.

[12] Samefors M, Östgren CJ, Mölstad S, Lannering C, Midlöv P, Tengblad A. Vitamin D deficiency in elderly people in Swedish nursing homes is associated with increased mortality. Eur J Endocrinol. 2014;170(5):667-75.

[13] Uday S, Högler W.Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia. J Steroid Biochem Mol Biol. 2019;188:141-146.

[14] Dimitrov V, White JH. Vitamin D signaling in intestinal innate immunity and homeostasis. Mol Cell Endocrinol. 2017;453:68-78.

[15] Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482-496.

[16] Borges MC, Martini LA, Rogero MM. Current perspectives on vitamin D, immune system, and chronic diseases. Nutrition. 2011;27(4):399-404.

[17] Ikemoto Y, Kuroda K, Nakagawa K, Ochiai A, Ozaki R, Murakami K, et al. Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women. Nutrients. 2018 13;10(7):902.

[18] Zhang Z, Chen F, Li J, Luo F, Hou T, Xu J, et al. 1,25(OH)2D3 suppresses proinflammatory responses by inhibiting Th1 cell differentiation and cytokine production through the JAK/STAT pathway.Am J Transl Res. 2018;10(8):2737-2746.

[19] Ragab D, Soliman D, Samaha D, Yassin A. Vitamin D status and its modulatory effect on interferon gamma and interleukin-10 production by peripheral blood mononuclear cells in culture. Cytokine. 2016;85:5-10.

[20] Sun X, Wang T, Cai D, Hu Z, Chen J, Liao H, et al. Cytokine Storm Intervention in the Early Stages of COVID-19 Pneumonia Cytokine Growth Factor Rev. 2020;S1359-6101(20)30048-4.

[21] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet. 2020;395(10223):497-506.

[22] Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev. 2020: doi: 10.1016/j. cytogfr.2020.05.002

[23] Khare D, Godbole NM, Pawar SD, Mohan V, Pandey G, Gupta S, et al. Calcitriol [1, 25[OH]2 D3] Pre- And Post-Treatment Suppresses Inflammatory Response to Influenza A (H1N1) Infection in Human Lung A549 Epithelial Cells. Eur J Nutr. 2013;52(4):1405-1415.

[24] Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and Endothelial Function. Nutrients. 2020; 12(2): 575.

[25] Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax. 2015;70(7):617-624.

[26] Adrian R Martineau AR, David A Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583

[27] 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(1). doi: 10.1002/rmv.

[28] Cepeda S J, Zenteno A D, Fuentes S C, Bustos B R. Vitamin D and pediatrics respiratory diseases]. Rev Chil Pediatr. 2019;90(1):94-101.

[29] Bryson KJ, Nash AA, Norval M. Does vitamin D protect against respiratory viral infections? Epidemiol Infect. 2014;142(9):1789-801.

[30] Aygun . H. Vitamin D Can Prevent COVID-19 Infection-Induced Multiple Organ Damage. Naunyn Schmiedebergs Arch Pharmacol. 2020;1-4.doi: 10.1007/ s00210-020-01911-4

[31] Teymoori-Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol. 2019;29(2):e2032.

[32] Čulić S, Markić J, Petrović D, Armanda V, Konjevoda P, Pavelić J. Vitamin D Status in Pediatric Patients with Newly Diagnosed Malignant

**79**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

Martínez-Ginés M, García-Domínguez JM, et al. Study of the possible link of 25-hydroxyvitamin D with Epstein-Barr virus and human herpesvirus 6 in patients with multiple sclerosis. Eur J Neurol. 2018;25(12):1446-1453.

Kampman MT, Jørgensen L, et al. Effect of high-dose vitamin D3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis. Mult Scler.

[42] Røsjø E, Lossius A, Abdelmagid N, Lindstrøm JC,

2017;23(3):395-402.

2016;11(3):177-180.

2018;31(8):589-593.

67):S13-S19.

2019;32(6):258-262.

[43] Özgü E, Yılmaz N, Başer E, Güngör T, Erkaya S, Yakut Hİ. Could 25-OH vitamin D deficiency be a reason for HPV infection persistence in cervical premalignant lesions? J Exp Ther Oncol.

[44] Shim J, Pérez A, Symanski E, Nyitray AG. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect

Dis. 2016;213(12):1886-1892.

[45] Kumar A, Singh MP, Kumar RS, Ratho RK. 25-Hydroxyvitamin D3 and 1,25 Dihydroxyvitamin D3 as an Antiviral and Immunomodulator Against Herpes Simplex Virus-1

Infection in HeLa Cells. Viral Immunol.

[46] Choi B, Lee ES, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behçet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol. 2011;29(4 Suppl

[47] Öztekin A, Öztekin C. Vitamin D Levels in Patients with Recurrent Herpes Labialis. Viral Immunol.

[48] Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A,

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

Disease: Preliminary Results. Central Eur J Paed. 2018:14(2):160-166.

[33] Qamar S, Akbani S, Shamim S, Khan G. Vitamin D Levels in Children With Growing Pains. J Coll Physicians

[34] Ghanaati S, Choukroun J, Volz U, Hueber R, Mourão CF, Sader R, et al. One hundred years after Vitamin D discovery: Is there clinical evidence for supplementation doses? Int J Growth Factors Stem Cells Dent. 2020;3:3-11

[35] Alvarez-Lafuente R. Vitamin D serum levels and viral load of human herpesvirus 6 and Epstein-Barr virus in patients with multiple sclerosis after one year of follow-up. ECTRIMS Online Library. Oct 27, 2017; 200662; P1007.

[37] Christensen T.The role of EBV in MS pathogenesis.Int MS J. 2006;13(2):52-57.

Zahednasab H, Keyvani H, Gheiasian M, Jalilian FA. Serum levels of matrix metalloproteinase-2, −9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity. Braz J Infect Dis. 2020.

[40] Hassani A, Corboy JR, Al-Salam S, Khan G. Epstein-Barr Virus Is Present

[41] Pérez-Pérez S, Domínguez-Mozo MI,

Khorvash F, Yaran M, Maghzi AH. Association Between Acute Infectious

[36] Christensen T . Human Herpesviruses in MS. Int MS J.

2007;14(2):41-47.

[38] Maghzi H, Ataei B,

2016;29(7):397-400

Mononucleosis and Vitamin D Deficiency.Viral Immunol.

[39] Amini R, Karampoor S,

pii: S1413-8670(20)30020-9.

in the Brain of Most Cases of Multiple Sclerosis and May Engage More Than Just B Cells. PLoS One.

García-Martínez MÁ, Aladro Y,

2018;13(2):e0192109.

Surg Pak. 2011;21(5):284-287.

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

Disease: Preliminary Results. Central Eur J Paed. 2018:14(2):160-166.

*Vitamin D*

vitamin D, immune system, and chronic diseases. Nutrition. 2011;27(4):399-404.

[24] Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and Endothelial Function. Nutrients. 2020;

[25] Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, et al. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax.

[26] Adrian R Martineau AR, David A Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583

[27] 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(1). doi: 10.1002/rmv.

2019;90(1):94-101.

[30] Aygun .

s00210-020-01911-4

2019;29(2):e2032.

[28] Cepeda S J, Zenteno A D, Fuentes S C, Bustos B R. Vitamin D and pediatrics respiratory diseases]. Rev Chil Pediatr.

[29] Bryson KJ, Nash AA, Norval M. Does vitamin D protect against

Infect. 2014;142(9):1789-801.

[31] Teymoori-Rad M, Shokri F, Salimi V, Marashi SM. The interplay between vitamin D and viral infections. Rev Med Virol.

[32] Čulić S, Markić J, Petrović D, Armanda V, Konjevoda P, Pavelić J. Vitamin D Status in Pediatric Patients with Newly Diagnosed Malignant

respiratory viral infections? Epidemiol

COVID-19 Infection-Induced Multiple Organ Damage. Naunyn Schmiedebergs Arch Pharmacol. 2020;1-4.doi: 10.1007/

H. Vitamin D Can Prevent

12(2): 575.

2015;70(7):617-624.

[17] Ikemoto Y, Kuroda K, Nakagawa K, Ochiai A, Ozaki R, Murakami K, et al. Vitamin D Regulates Maternal T-Helper Cytokine Production in Infertile Women. Nutrients. 2018 13;10(7):902.

[18] Zhang Z, Chen F, Li J, Luo F, Hou T, Xu J, et al. 1,25(OH)2D3 suppresses proinflammatory responses by inhibiting Th1 cell differentiation and cytokine production through the JAK/STAT pathway.Am J Transl Res.

[19] Ragab D, Soliman D, Samaha D, Yassin A. Vitamin D status and its modulatory effect on interferon gamma and interleukin-10 production by peripheral blood mononuclear cells in culture. Cytokine. 2016;85:5-10.

Hu Z, Chen J, Liao H, et al. Cytokine Storm Intervention in the Early Stages of COVID-19 Pneumonia Cytokine Growth Factor Rev. 2020;S1359-6101(20)30048-4.

[21] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China.Lancet.

2018;10(8):2737-2746.

[20] Sun X, Wang T, Cai D,

2020;395(10223):497-506.

cytogfr.2020.05.002

Post-Treatment Suppresses

2013;52(4):1405-1415.

[22] Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev. 2020: doi: 10.1016/j.

[23] Khare D, Godbole NM, Pawar SD, Mohan V, Pandey G, Gupta S, et al. Calcitriol [1, 25[OH]2 D3] Pre- And

Inflammatory Response to Influenza A (H1N1) Infection in Human Lung A549 Epithelial Cells. Eur J Nutr.

**78**

[33] Qamar S, Akbani S, Shamim S, Khan G. Vitamin D Levels in Children With Growing Pains. J Coll Physicians Surg Pak. 2011;21(5):284-287.

[34] Ghanaati S, Choukroun J, Volz U, Hueber R, Mourão CF, Sader R, et al. One hundred years after Vitamin D discovery: Is there clinical evidence for supplementation doses? Int J Growth Factors Stem Cells Dent. 2020;3:3-11

[35] Alvarez-Lafuente R. Vitamin D serum levels and viral load of human herpesvirus 6 and Epstein-Barr virus in patients with multiple sclerosis after one year of follow-up. ECTRIMS Online Library. Oct 27, 2017; 200662; P1007.

[36] Christensen T . Human Herpesviruses in MS. Int MS J. 2007;14(2):41-47.

[37] Christensen T.The role of EBV in MS pathogenesis.Int MS J. 2006;13(2):52-57.

[38] Maghzi H, Ataei B, Khorvash F, Yaran M, Maghzi AH. Association Between Acute Infectious Mononucleosis and Vitamin D Deficiency.Viral Immunol. 2016;29(7):397-400

[39] Amini R, Karampoor S, Zahednasab H, Keyvani H, Gheiasian M, Jalilian FA. Serum levels of matrix metalloproteinase-2, −9, and vitamin D in patients with multiple sclerosis with or without herpesvirus-6 seropositivity. Braz J Infect Dis. 2020. pii: S1413-8670(20)30020-9.

[40] Hassani A, Corboy JR, Al-Salam S, Khan G. Epstein-Barr Virus Is Present in the Brain of Most Cases of Multiple Sclerosis and May Engage More Than Just B Cells. PLoS One. 2018;13(2):e0192109.

[41] Pérez-Pérez S, Domínguez-Mozo MI, García-Martínez MÁ, Aladro Y,

Martínez-Ginés M, García-Domínguez JM, et al. Study of the possible link of 25-hydroxyvitamin D with Epstein-Barr virus and human herpesvirus 6 in patients with multiple sclerosis. Eur J Neurol. 2018;25(12):1446-1453.

[42] Røsjø E, Lossius A, Abdelmagid N, Lindstrøm JC, Kampman MT, Jørgensen L, et al. Effect of high-dose vitamin D3 supplementation on antibody responses against Epstein-Barr virus in relapsing-remitting multiple sclerosis. Mult Scler. 2017;23(3):395-402.

[43] Özgü E, Yılmaz N, Başer E, Güngör T, Erkaya S, Yakut Hİ. Could 25-OH vitamin D deficiency be a reason for HPV infection persistence in cervical premalignant lesions? J Exp Ther Oncol. 2016;11(3):177-180.

[44] Shim J, Pérez A, Symanski E, Nyitray AG. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect Dis. 2016;213(12):1886-1892.

[45] Kumar A, Singh MP, Kumar RS, Ratho RK. 25-Hydroxyvitamin D3 and 1,25 Dihydroxyvitamin D3 as an Antiviral and Immunomodulator Against Herpes Simplex Virus-1 Infection in HeLa Cells. Viral Immunol. 2018;31(8):589-593.

[46] Choi B, Lee ES, Sohn S. Vitamin D3 ameliorates herpes simplex virus-induced Behçet's disease-like inflammation in a mouse model through down-regulation of Toll-like receptors. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S13-S19.

[47] Öztekin A, Öztekin C. Vitamin D Levels in Patients with Recurrent Herpes Labialis. Viral Immunol. 2019;32(6):258-262.

[48] Jiménez-Sousa MÁ, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino S. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol. 2018;9:458.

[49] Akimbekov NS, Ortoski RA, Razzaque MS. Effects of sunlight exposure and vitamin D supplementation on HIV patients. J Steroid Biochem Mol Biol. 2020;200:105664.

[50] González SM, Aguilar-Jiménez W, Trujillo-Gil E, Zapata W, Su RC, Ball TB, et al. Vitamin D treatment of peripheral blood mononuclear cells modulated immune activation and reduced susceptibility to HIV-1 infection of CD4+ T lymphocytes. PLoS One. 2019;14(9):e0222878.

[51] Hoan NX, Tong HV, Song LH, Meyer CG, Velavan TP.Vitamin D deficiency and hepatitis viruses associated liver diseases: A literature review. World J Gastroenterol. 2018;24(4):445-460.

[52] He Q, Huang Y, Zhang L, Yan Y, Liu J, Song X, et al. Association between vitamin D receptor polymorphisms and hepatitis B virus infection susceptibility: A meta-analysis study. Gene. 2018;645:105-112.

[53] Gotlieb N, Tachlytski I, Lapidot Y, Sultan M, Safran M, Ben-Ari Z. Hepatitis B virus downregulates vitamin D receptor levels in hepatoma cell lines, thereby preventing vitamin D-dependent inhibition of viral transcription and production. Mol Med. 2018;24(1):53..

[54] Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, et al. 1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response During Peg-IFN/ RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial. PLoS On. 2013;8(5):e63672.

[55] Matsumura T, Kato T, Sugiyama N, Tasaka-Fujita M, Murayama A, Masaki T, et al. 25-Hydroxyvitamin D3 Suppresses Hepatitis C Virus Production. Hepatology. 2012;56(4):1231-1239.

[56] Ravid A, Rapaport N, Issachar A, Erman A, Bachmetov L, Tur-Kaspa R, et al. 25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism. Int J Mol Sci. 2019;13;20(9):2367.

[57] Murayama A, Saitoh H, Takeuchi A, Yamada N, Matsumura T, Shiina M, et al. Vitamin D derivatives inhibit hepatitis C virus production through the suppression of apolipoprotein. Antiviral Res. 2018;160:55-63

[58] Greiller CL, MartineauAR. Modulation of the Immune Response to Respiratory Viruses by Vitamin D. Nutrients 2015; 7(6): 4240-70.

[59] Jolliffe DA, Greiller CL, Mein CA, Hoti M, Bakhsoliani E, Telcian AG, et al. Vitamin D receptor genotype influences risk of upper respiratory infection. Br J Nutr. 2018;120:891-900.

[60] Esposito S, Baggi E, Bianchini S, Marchisio P, Principi N. Role of vitamin D in children with respiratory tract infection. Int J Immunopathol Pharmacol. 2013;26(1):1-13.

[61] Brockman-Schneider RA, Pickles RJ, Gern JE. Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS One. 2014;9(1):e86755.

[62] Martinez ME. The calendar of epidemics: Seasonal cycles of infectious diseases. PLoS Pathog. 2018;14(11):e1007327.

[63] Cohen J. Sick Time. Science. 2020;367(6484):1294-1297.

**81**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

26, 2020). Available at SSRN: https:// ssrn.com/abstract=3585561 or http:// dx.doi.org/10.2139/ssrn.3585561

[72] Bloukh SH. Shaikh AA, Pathan HM, Edis Z. Prevalence of COVID-19: A Look behind the Scenes from the UAE and India. - 2020 – preprints.org file:///C:/ UsersDownloads/preprints202004.0179.

Honardoost M, Khamsch ME. Role of Vitamin D in Pathogenesis and Severity of COVID-19 Infection. https://www. preprints.org/manuscript/202004.0355/

Church FC. Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson's Disease.

v2%20(2).pdf

v1/download

[73] Ghavideldarestani M,

[74] Hribar CA, Cobbold PH,

Brain Sci. 2020;*10*(5):284.

cfm?abstract\_id=3593258

2017;16:7432-7438.

2019;189:228-239

[76] Xu J, Yang J, Chen J, Luo Q,

[77] Grant WB, Lahore H, Sharon L McDonnell SL, Baggerly CA,

[78] McCullough PJ, Lehrer DS, Amend J. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol

[79] Tsujino I, Ushikoshi-Nakayama R, Yamazaki T, Matsumoto N, Saito I.

French CB, et al. Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020;12(4):E988.

Zhang Q, Zhang H. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system. Mol Med Rep.

[75] Galicio EJ. Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report. https://papers.ssrn.com/sol3/papers.

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

Tiwari S, Pawar SD, Dhole TN. Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated antiapoptotic signaling. Virus Res.

[66] 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(8):749-754.

[68] Gruber-Bzura BM. Vitamin D and Influenza-Prevention or Therapy? Int J

Mol Sci. 2018;19(8):pii: E2419.

[69] Alipio, Mark, Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19) (April 9, 2020). Available at SSRN: https://ssrn.com/ abstract=3571484 or http://dx.doi.

org/10.2139/ssrn.3571484

[70] Lau FH, Majumder R, Torabi R, Saeg F, Hoffman R,

[71] Raharusun, Prabowo and

Cirillo JD, Greiffenstein P, et al. Vitamin D Insufficiency is Prevalent in Severe COVID-1. https://www.medrxiv.org/con tent/101101/2020.04.24.20075838v1

Priambada, Sadiah and Budiarti, Cahni and Agung, Erdie and Budi, Cipta, Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study (April

[67] Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children. Am J Clin Nutr. 2010;91(5):1255-1260.

[64] 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(6):1129-1140.

[65] Godbole NM, Sinha RA,

2020;282:197936.

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

[64] 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(6):1129-1140.

*Vitamin D*

Resino S. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. [55] Matsumura T, Kato T, Sugiyama N, Tasaka-Fujita M, Murayama A, Masaki T, et al. 25-Hydroxyvitamin D3 Suppresses

[56] Ravid A, Rapaport N, Issachar A, Erman A, Bachmetov L, Tur-Kaspa R, et al. 25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-

Independent Mechanism. Int J Mol Sci.

[57] Murayama A, Saitoh H, Takeuchi A, Yamada N, Matsumura T, Shiina M, et al. Vitamin D derivatives inhibit hepatitis C virus production through the suppression of apolipoprotein. Antiviral

2019;13;20(9):2367.

Res. 2018;160:55-63

[58] Greiller CL, MartineauAR. Modulation of the Immune Response to Respiratory Viruses by Vitamin D. Nutrients 2015; 7(6): 4240-70.

Nutr. 2018;120:891-900.

[59] Jolliffe DA, Greiller CL, Mein CA, Hoti M, Bakhsoliani E, Telcian AG, et al. Vitamin D receptor genotype influences risk of upper respiratory infection. Br J

[60] Esposito S, Baggi E, Bianchini S, Marchisio P, Principi N. Role of vitamin D in children with respiratory tract infection. Int J Immunopathol Pharmacol. 2013;26(1):1-13.

[61] Brockman-Schneider RA,

[62] Martinez ME. The calendar of epidemics: Seasonal cycles of infectious diseases. PLoS Pathog.

[63] Cohen J. Sick Time. Science. 2020;367(6484):1294-1297.

2014;9(1):e86755.

2018;14(11):e1007327.

Pickles RJ, Gern JE. Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. PLoS One.

Hepatitis C Virus Production. Hepatology. 2012;56(4):1231-1239.

Front Immunol. 2018;9:458.

Ortoski RA, Razzaque MS. Effects of sunlight exposure and vitamin D supplementation on HIV patients. J Steroid Biochem Mol Biol.

[50] González SM, Aguilar-Jiménez W, Trujillo-Gil E, Zapata W, Su RC, Ball TB, et al. Vitamin D treatment of peripheral blood mononuclear cells modulated immune activation and reduced susceptibility to HIV-1 infection of CD4+ T lymphocytes. PLoS One.

[51] Hoan NX, Tong HV, Song LH, Meyer CG, Velavan TP.Vitamin D deficiency and hepatitis viruses associated liver diseases: A literature review. World J Gastroenterol.

[52] He Q, Huang Y, Zhang L, Yan Y, Liu J, Song X, et al. Association between vitamin D receptor polymorphisms and hepatitis B virus infection susceptibility:

A meta-analysis study. Gene.

[53] Gotlieb N, Tachlytski I, Lapidot Y, Sultan M, Safran M, Ben-Ari Z. Hepatitis B virus downregulates vitamin D receptor levels in hepatoma cell lines, thereby preventing vitamin D-dependent inhibition of viral transcription and production. Mol Med. 2018;24(1):53..

[54] Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, et al. 1(OH) Vitamin D3 Supplementation Improves the Sensitivity of the Immune-Response During Peg-IFN/ RBV Therapy in Chronic Hepatitis C Patients-Case Controlled Trial. PLoS

On. 2013;8(5):e63672.

[49] Akimbekov NS,

2020;200:105664.

2019;14(9):e0222878.

2018;24(4):445-460.

2018;645:105-112.

**80**

[65] Godbole NM, Sinha RA, Tiwari S, Pawar SD, Dhole TN. Analysis of influenza virus-induced perturbation in autophagic flux and its modulation during Vitamin D3 mediated antiapoptotic signaling. Virus Res. 2020;282:197936.

[66] 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(8):749-754.

[67] Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y, Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in school children. Am J Clin Nutr. 2010;91(5):1255-1260.

[68] Gruber-Bzura BM. Vitamin D and Influenza-Prevention or Therapy? Int J Mol Sci. 2018;19(8):pii: E2419.

[69] Alipio, Mark, Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19) (April 9, 2020). Available at SSRN: https://ssrn.com/ abstract=3571484 or http://dx.doi. org/10.2139/ssrn.3571484

[70] Lau FH, Majumder R, Torabi R, Saeg F, Hoffman R, Cirillo JD, Greiffenstein P, et al. Vitamin D Insufficiency is Prevalent in Severe COVID-1. https://www.medrxiv.org/con tent/101101/2020.04.24.20075838v1

[71] Raharusun, Prabowo and Priambada, Sadiah and Budiarti, Cahni and Agung, Erdie and Budi, Cipta, Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study (April

26, 2020). Available at SSRN: https:// ssrn.com/abstract=3585561 or http:// dx.doi.org/10.2139/ssrn.3585561

[72] Bloukh SH. Shaikh AA, Pathan HM, Edis Z. Prevalence of COVID-19: A Look behind the Scenes from the UAE and India. - 2020 – preprints.org file:///C:/ UsersDownloads/preprints202004.0179. v2%20(2).pdf

[73] Ghavideldarestani M, Honardoost M, Khamsch ME. Role of Vitamin D in Pathogenesis and Severity of COVID-19 Infection. https://www. preprints.org/manuscript/202004.0355/ v1/download

[74] Hribar CA, Cobbold PH, Church FC. Potential Role of Vitamin D in the Elderly to Resist COVID-19 and to Slow Progression of Parkinson's Disease. Brain Sci. 2020;*10*(5):284.

[75] Galicio EJ. Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report. https://papers.ssrn.com/sol3/papers. cfm?abstract\_id=3593258

[76] Xu J, Yang J, Chen J, Luo Q, Zhang Q, Zhang H. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the reninangiotensin system. Mol Med Rep. 2017;16:7432-7438.

[77] Grant WB, Lahore H, Sharon L McDonnell SL, Baggerly CA, French CB, et al. Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients. 2020;12(4):E988.

[78] McCullough PJ, Lehrer DS, Amend J. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience. J Steroid Biochem Mol Biol 2019;189:228-239

[79] Tsujino I, Ushikoshi-Nakayama R, Yamazaki T, Matsumoto N, Saito I.

Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia. J Clin Biochem Nutr. 2019;65(3):245-251.

[80] Martineau AR, Jolliffe DA , HooperRL, Greenberg L, Aloia JF, Bergman P. Vitamin D Supplementation to Prevent Acute Respiratory Tract Infections: Systematic Review and Meta-Analysis of Individual Participant Data. BMJ. 2017;356:0.

[81] Daneshkhah A, Eshein A , Subramanian H, Roy HK, Backman V.The Role of Vitamin D in Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality. doi: https://doi.org/10.1101/2020.04. 08.20058578. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

[82] Kakodkar P, Kaka N, Baig MN.A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)Cureus. 2020; 12(4): e7560.

[83] Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis of vitamin D level among asymptomatic and citically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020).

[84] Torehan Aslan M, Aslan IO, Ozdemir O. Is vitamin D One of the Key Elements in COVID-19 Days? J Nutr Health Aging.2020;24(9):1038-1039.

[85] Caccialanza R, Laviano A, Lobascio F, Montagna E, Bruno R, Ludovisi S, et al. Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol. Nutrition. 2020;3:110835.

[86] McCartney DM, Byrne DG. Optimisation of Vitamin D Status for Enhanced Immuno-protection Against Covid-19. Ir Med J. 2020;113(4):58.

[87] Carter SJ, Baranauskas MN, Fly AD. Considerations for obesity, vitamin D, and physical activity amid the COVID-19 pandemic. Obesity (Silver Spring). 2020. doi: 10.1002/oby.22838.

[88] Kalligeros M, Shehadeh F, Mylona EK, Benitez G, Beckwith CG, Chan PA, et al. Association of Obesity with Disease Severity among Patients with COVID-19. Obesity (Silver Spring). 2020 Apr 30. doi: 10.1002/oby.22859.

[89] https://www.statista. com/statistics/1099375/ coronavirus-cases-by-region-in-italy/

[90] Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D, Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporos Int. 2003l;14(7):577-582.

[91] Quesada JM, Jans I, Benito P, J A Jimenez JA, R Bouillon R. Vitamin D status of elderly people in Spain. Age Ageing1989;18(6):392-397.

[92] 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). https://doi.org/10.1007/ s40520-020-01570-8

[93] Rhodes JM, Subramanian S, Laird E, Anne Kenny R.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 Apr 20.

[94] Kana Ram Jat. Vitamin D Deficiency and Lower Respiratory Tract Infections in Children: A Systematic Review and Meta-Analysis of Observational Studies. Trop Doct. 2017; 47(1):77-84.

**83**

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D…*

*DOI: http://dx.doi.org/10.5772/intechopen.96102*

[95] Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin

Virol. 2011;50(3):194-200.

Löwik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, et al. Serum vitamin concentrations among elderly people in Europe.Lancet.

[97] MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest.

[98] Basile M, Ciardi L, Crespi I,

[99] Boucher BJ. The Problems of Vitamin D Insufficiency in Older People. Aging Dis. 2012; 3(4):313-329.

Metab. 2020;318(5):E589.

greenbeltoutdoors.com/

marik-evms-medical-group/

[101] Marik P, (EVMS Medical Group). Coronavirus / Covid-19 Vitamin C, D, Zinc And Immune System Building Protocol –

Saliva E, Bellomo G, Vidali M. Assessing Serum Concentrations of 25-Hydroxy-Vitamin D in North-Western Italy. J Frailty Aging. 2013;2(4):174-178.

[100] Jakovac H. COVID-19 and vitamin D-Is there a link and an opportunity for intervention?Am J Physiol Endocrinol

PREVENTION / TREATMENT.https://

coronavirus-covid-19-vitamin-c-dzinc-and-immune-system-buildingprotocol-prevention-treatment-dr-paul-

[96] van der Wielen RP,

1995;346(8969):207-210.

1985;76(4):1536-1538.

*Viral Infections, Including Influenza and Corona Virus Disease 2019, and Vitamin D… DOI: http://dx.doi.org/10.5772/intechopen.96102*

[95] Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194-200.

*Vitamin D*

2019;65(3):245-251.

BMJ. 2017;356:0.

Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia. J Clin Biochem Nutr.

Enhanced Immuno-protection Against Covid-19. Ir Med J. 2020;113(4):58.

[87] Carter SJ, Baranauskas MN, Fly AD. Considerations for obesity, vitamin D, and physical activity amid the COVID-19 pandemic. Obesity (Silver Spring).

2020. doi: 10.1002/oby.22838.

[88] Kalligeros M, Shehadeh F, Mylona EK, Benitez G, Beckwith CG, Chan PA, et al. Association of Obesity with Disease Severity among Patients with COVID-19. Obesity (Silver Spring). 2020 Apr 30. doi: 10.1002/oby.22859.

[89] https://www.statista. com/statistics/1099375/

[90] Isaia G, Giorgino R,

coronavirus-cases-by-region-in-italy/

Rini GB, Bevilacqua M, Maugeri D, Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporos Int. 2003l;14(7):577-582.

[91] Quesada JM, Jans I, Benito P, J A Jimenez JA, R Bouillon R. Vitamin D status of elderly people in Spain. Age

[92] 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). https://doi.org/10.1007/

Ageing1989;18(6):392-397.

s40520-020-01570-8

[93] Rhodes JM, Subramanian S, Laird E, Anne Kenny R.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 Apr 20.

Trop Doct. 2017; 47(1):77-84.

[94] Kana Ram Jat. Vitamin D Deficiency and Lower Respiratory Tract Infections in Children: A Systematic Review and Meta-Analysis of Observational Studies.

[80] Martineau AR, Jolliffe DA , HooperRL, Greenberg L, Aloia JF, Bergman P. Vitamin D Supplementation to Prevent Acute Respiratory Tract Infections: Systematic Review and Meta-Analysis of Individual Participant Data.

[81] Daneshkhah A, Eshein A , Subramanian H, Roy HK,

Backman V.The Role of Vitamin D in Suppressing Cytokine Storm in COVID-19 Patients and Associated Mortality. doi: https://doi.org/10.1101/2020.04. 08.20058578. COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

[82] Kakodkar P, Kaka N, Baig MN.A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)Cureus. 2020; 12(4): e7560.

[83] Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis of vitamin D level among asymptomatic and citically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020).

[84] Torehan Aslan M, Aslan IO,

[85] Caccialanza R, Laviano A, Lobascio F, Montagna E, Bruno R, Ludovisi S, et al. Early nutritional supplementation in non-critically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): Rationale and feasibility of a shared pragmatic protocol. Nutrition.

[86] McCartney DM, Byrne DG. Optimisation of Vitamin D Status for

Ozdemir O. Is vitamin D One of the Key Elements in COVID-19 Days? J Nutr Health Aging.2020;24(9):1038-1039.

**82**

2020;3:110835.

[96] van der Wielen RP, Löwik MR, van den Berg H, de Groot LC, Haller J, Moreiras O, et al. Serum vitamin concentrations among elderly people in Europe.Lancet. 1995;346(8969):207-210.

[97] MacLaughlin J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest. 1985;76(4):1536-1538.

[98] Basile M, Ciardi L, Crespi I, Saliva E, Bellomo G, Vidali M. Assessing Serum Concentrations of 25-Hydroxy-Vitamin D in North-Western Italy. J Frailty Aging. 2013;2(4):174-178.

[99] Boucher BJ. The Problems of Vitamin D Insufficiency in Older People. Aging Dis. 2012; 3(4):313-329.

[100] Jakovac H. COVID-19 and vitamin D-Is there a link and an opportunity for intervention?Am J Physiol Endocrinol Metab. 2020;318(5):E589.

[101] Marik P, (EVMS Medical Group). Coronavirus / Covid-19 Vitamin C, D, Zinc And Immune System Building Protocol – PREVENTION / TREATMENT.https:// greenbeltoutdoors.com/ coronavirus-covid-19-vitamin-c-dzinc-and-immune-system-buildingprotocol-prevention-treatment-dr-paulmarik-evms-medical-group/

**85**

**Chapter 6**

**Abstract**

metabolites.

immune response

**1. Introduction**

Vitamin D and Its Relationship

Thrombosis and Various Diseases

Vitamin D known for its vital role in diverse biological function such as calcium and phosphorus homeostasis, also exert an anticoagulant effect emphasizing its essential role in the thrombosis pathogenesis. Thrombosis is the formation and propagation of a blood clot or thrombus either in the arterial or the venous system resulting in several severe complications. Various studies have also reported the association of vitamin D deficiency with the increased incidences of thromboembolism. This may be in part due to its anticoagulant effects through upregulation of thrombomodulin, an anticoagulant glycoprotein, and downregulation of Tissue Factor, a critical coagulation factor. The protective effects of vitamin D and its receptor in endothelial cells may further explain some of the reported beneficial effects of vitamin D in the prevention or treatment of cardiovascular diseases. Additionally, the immunomodulatory role of vitamin D has been observed through its ability to alter the secretion of inflammatory cytokines that can induce a procoagulant milieu by multiple pathways. Therefore, it becomes pertinent to discuss the close link between vitamin D and human health and to improve our knowledge of the molecular pathways regulated or influenced by vitamin D and its associated

with the Pathways Related to

**Keywords:** vitamin D, vitamin D receptor, thrombosis, coagulation,

Vitamin D is a lipophilic, steroid hormone, obtained from various food sources as well as majorly synthesized by the body in the skin through exposure to ultraviolet irradiation [1, 2]. In nature, vitamin D exists in two forms, vitamin D2, and vitamin D3. 25-hydroxyvitamin D (25(OH)D) is the major circulatory form and 1,25-dihydroxyvitamin D (1,25(OH)2D) is the active form of vitamin D that exerts its activity by binding to and activating the nuclear vitamin D receptor (VDR), which is a ligand-inducible transcription factor [3]. Upon activation, VDR forms a heterodimer with the retinoid-X receptor (RXR) that interacts with particular DNA sequences in the promoter region of target genes called vitamin response elements (VDREs) [4]. Vitamin D exerts a diverse biological function such as cell

*Syed Mohd, Swati Sharma, Aastha Mishra* 

*and Mohammad Zahid Ashraf*

#### **Chapter 6**

## Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases

*Syed Mohd, Swati Sharma, Aastha Mishra and Mohammad Zahid Ashraf*

#### **Abstract**

Vitamin D known for its vital role in diverse biological function such as calcium and phosphorus homeostasis, also exert an anticoagulant effect emphasizing its essential role in the thrombosis pathogenesis. Thrombosis is the formation and propagation of a blood clot or thrombus either in the arterial or the venous system resulting in several severe complications. Various studies have also reported the association of vitamin D deficiency with the increased incidences of thromboembolism. This may be in part due to its anticoagulant effects through upregulation of thrombomodulin, an anticoagulant glycoprotein, and downregulation of Tissue Factor, a critical coagulation factor. The protective effects of vitamin D and its receptor in endothelial cells may further explain some of the reported beneficial effects of vitamin D in the prevention or treatment of cardiovascular diseases. Additionally, the immunomodulatory role of vitamin D has been observed through its ability to alter the secretion of inflammatory cytokines that can induce a procoagulant milieu by multiple pathways. Therefore, it becomes pertinent to discuss the close link between vitamin D and human health and to improve our knowledge of the molecular pathways regulated or influenced by vitamin D and its associated metabolites.

**Keywords:** vitamin D, vitamin D receptor, thrombosis, coagulation, immune response

#### **1. Introduction**

Vitamin D is a lipophilic, steroid hormone, obtained from various food sources as well as majorly synthesized by the body in the skin through exposure to ultraviolet irradiation [1, 2]. In nature, vitamin D exists in two forms, vitamin D2, and vitamin D3. 25-hydroxyvitamin D (25(OH)D) is the major circulatory form and 1,25-dihydroxyvitamin D (1,25(OH)2D) is the active form of vitamin D that exerts its activity by binding to and activating the nuclear vitamin D receptor (VDR), which is a ligand-inducible transcription factor [3]. Upon activation, VDR forms a heterodimer with the retinoid-X receptor (RXR) that interacts with particular DNA sequences in the promoter region of target genes called vitamin response elements (VDREs) [4]. Vitamin D exerts a diverse biological function such as cell

proliferation, calcium and phosphorus homeostasis, and cell differentiation. Most of these actions are carried out by regulating the expression of target genes through VDR activation [3].

Vitamin D deficiency is a widespread condition, reportedly occurring in 30 to 60% of the general population worldwide [5–7]. Vitamin D is commonly known for its vital role in calcium homeostasis and bone mineralization. It is also crucial in the prevention of rickets during early age and osteomalacia during adult age [8, 9]. Increasing evidence from clinical reports, cross-sectional studies, and cell culture studies further indicate that vitamin D may exert an anticoagulant effect emphasizing an essential role of vitamin D metabolites in the pathogenesis of thrombosis [10–12]. VDR is expressed throughout the body including various immune cells such as macrophages, dendritic cells, and lymphocytes [13–17]. They are also expressed in the vascular endothelial cells [18], which are relevant to hemostasis.

Thrombosis is the formation of a blood clot within the intact vascular system. It can occur in both arterial and venous systems [19]. Rudolf Virchow, a German scientist, and physician proposed the three main factors that may predispose an individual to the development of thrombosis: stasis, endothelial dysfunction, and hypercoagulability. Apart from these three factors, the innate inflammatory system also has an intrinsic link with coagulation, whereby activation of the inflammatory system promotes thrombosis and vice versa [20, 21]. Interventional studies have shown vitamin D treatment enhances endothelial functions and reduces the production of pro-inflammatory cytokines [22–24]. Apart from this, the anti-thrombotic effect of vitamin D on the pro-thrombotic and anti-thrombotic components of the coagulation system has also been well defined [25–27]. In this chapter, we are defining the effect of vitamin D deficiency in the three most important parameters viz. coagulation, endothelial activation, and immune responses affecting the occurrence of thrombosis. This chapter will also discuss the clinical impact of Vitamin D in various diseases including COVID-19.

#### **2. Vitamin D in coagulation**

Vitamin D deficiency is defined based on the plasma levels of 25(OH)D. Individuals with plasma levels under 20 ng/mL are considered vitamin D deficient. Vitamin D deficiency is highly prevalent worldwide with approximately 30–50% incidences [28–30]. Several reports have established the significant association of vitamin D deficiency with the increased risk of various cardiovascular diseases (CVDs) and mortality [31–33]. Various studies have also reported the association of vitamin D deficiency with the increased incidences of thromboembolism [34–36]. As suggested by the studies, the underlying molecular mechanism for the antithrombotic potential of vitamin D includes up-regulation of thrombomodulin and downregulation of tissue factor (TF) [25, 36, 37]. Additionally, vitamin D upregulates and increases the level of anti-inflammatory cytokines like IL-10 [24, 38]. The expression profile of more than 200 genes involved in the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis is directly or indirectly regulated by vitamin D [39]. The experimental shreds of evidence obtained from cell culture studies depicted that biologically active form of vitamin D3 i.e., 1,25(OH)2D, and its synthetic analogs exerted the anticoagulant effects [40]. Koyama et al. have demonstrated in their experiments on human peripheral monocytes that 1,25(OH)2D exerted the anticoagulant effects by upregulating the expression of thrombomodulin, an anticoagulant glycoprotein, and downregulating the expression of TF, a critical coagulation factor [13]. 1,25 (OH)2D directly suppresses renin gene expression via a vitamin D-response (VDR) element that is

**87**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

present in the renin gene [41]. Different studies on mouse embryonic fibroblasts from VDR Knockout (VDRKO) mice asserted an increase in pro-fibrotic factors including nuclear factor kappa B, interleukin (IL)- 6, and TNF-α suggesting that 1,25 (OH)2D may have antifibrotic effect and hence modulates multiple signaling pathways, like the transforming growth factor-β/Smad signaling [42]. Experiments with VDRKO mice showed enhanced ADP-induced platelet aggregation, downregulation of thrombomodulin and anti-thrombin, and upregulation of TF at mRNA level [43]. The VDR system has a physiological role in the maintenance of anti-thrombotic homeostasis as exacerbated multiorgan thrombus formation has been observed in VDRKO mice after lipopolysaccharide injection [43]. Recently, it has been documented that human platelets and megakaryocyte lineage also express VDR [44]. Hyppönen et al. documented that serum 25(OH)D level inversely associated with tPA antigen, fibrinogen, and D-dimer, suggesting a possible role for vitamin D3 status in determining thrombolytic profile [45]. It is well studied that inflammation can cause coagulation with high sensitivity C-reactive protein (hs-CRP) [46, 47]. A study comprising of 206 individuals reported significant inverse associations between 25(OH)D and PAI-1 and tPA antigen levels and between

However, because of the small number of clinical trials and heterogeneity, more studies need to be conducted to further define the haemostatic abnormalities seen in individuals with vitamin D3-deficiency, and to precisely define the potential benefits of vitamin D3 supplementation as a preventive measure for various CVDs.

The pathogenesis of cardiovascular diseases is governed by endothelium homeostasis. The vascular endothelium is of mesodermal origin and is located at the confluence between blood and the underlying vascular tissues. It not only works as a barrier function but also exerts several vasoprotective roles, and is considered as the main regulator of blood vessel homeostasis. Due to its inherent capability to perceive humoral and hemodynamic stimuli [49], the endothelium is instrumental in local regulation of vascular tone and structure, regulation of migration and growth of VSMCs, and controlling the adhesion and extravasation of leukocytes [50, 51]. Destabilization and activation of the endothelium take place as a result of injury, hemodynamic alteration, response to inflammatory cytokines, as well as genetic disorders [52, 53]. Endothelial dysfunction is found in various conditions that adversely affect the cardiovascular system, including hypertension, diabetes mellitus, atherosclerosis, chronic renal failure, and Deep venous thrombosis (DVT) [54]. Endothelial cells (ECs) in a quiescent form exhibit an anti-coagulant, vasodilatory, and anti-adhesive property [55]. However, when activated they express pro-coagulant, vasoconstricting, and pro-adhesive properties [56]. Hemostasis is facilitated by an equilibrium of anticoagulant and procoagulant factors [56]. On one side of the hemostatic equilibrium, the ECs express anticoagulant factors such as thrombomodulin TM, tissue factor pathway inhibitor (TFPI), and tissue-type plasminogen activator (t-PA). On the other side, they express thrombin receptors,

TF, plasminogen activator, and von Willebrand factor (vWF) [56].

The VDR has been identified in endothelium cells, and hydroxylation of 25(OH) D to 1,25(OH)2D also takes place in the endothelium [18, 57]. The expression of VDR and 1-alfa hydroxylase in the endothelium was found to be decreased with 25(OH)D deficiency [58]. In the vascular system, it has been recognized that vitamin D controls the proliferation of endothelial cells and vascular smooth muscle cells [59, 60]. Vitamin D up-regulates the production of nitric oxide (NO) in ECs [31],

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

1,25(OH)2D and tPA and hs-CRP levels [48].

**3. Vitamin D in endothelium homeostasis**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

present in the renin gene [41]. Different studies on mouse embryonic fibroblasts from VDR Knockout (VDRKO) mice asserted an increase in pro-fibrotic factors including nuclear factor kappa B, interleukin (IL)- 6, and TNF-α suggesting that 1,25 (OH)2D may have antifibrotic effect and hence modulates multiple signaling pathways, like the transforming growth factor-β/Smad signaling [42]. Experiments with VDRKO mice showed enhanced ADP-induced platelet aggregation, downregulation of thrombomodulin and anti-thrombin, and upregulation of TF at mRNA level [43]. The VDR system has a physiological role in the maintenance of anti-thrombotic homeostasis as exacerbated multiorgan thrombus formation has been observed in VDRKO mice after lipopolysaccharide injection [43]. Recently, it has been documented that human platelets and megakaryocyte lineage also express VDR [44]. Hyppönen et al. documented that serum 25(OH)D level inversely associated with tPA antigen, fibrinogen, and D-dimer, suggesting a possible role for vitamin D3 status in determining thrombolytic profile [45]. It is well studied that inflammation can cause coagulation with high sensitivity C-reactive protein (hs-CRP) [46, 47]. A study comprising of 206 individuals reported significant inverse associations between 25(OH)D and PAI-1 and tPA antigen levels and between 1,25(OH)2D and tPA and hs-CRP levels [48].

However, because of the small number of clinical trials and heterogeneity, more studies need to be conducted to further define the haemostatic abnormalities seen in individuals with vitamin D3-deficiency, and to precisely define the potential benefits of vitamin D3 supplementation as a preventive measure for various CVDs.

#### **3. Vitamin D in endothelium homeostasis**

The pathogenesis of cardiovascular diseases is governed by endothelium homeostasis. The vascular endothelium is of mesodermal origin and is located at the confluence between blood and the underlying vascular tissues. It not only works as a barrier function but also exerts several vasoprotective roles, and is considered as the main regulator of blood vessel homeostasis. Due to its inherent capability to perceive humoral and hemodynamic stimuli [49], the endothelium is instrumental in local regulation of vascular tone and structure, regulation of migration and growth of VSMCs, and controlling the adhesion and extravasation of leukocytes [50, 51]. Destabilization and activation of the endothelium take place as a result of injury, hemodynamic alteration, response to inflammatory cytokines, as well as genetic disorders [52, 53]. Endothelial dysfunction is found in various conditions that adversely affect the cardiovascular system, including hypertension, diabetes mellitus, atherosclerosis, chronic renal failure, and Deep venous thrombosis (DVT) [54]. Endothelial cells (ECs) in a quiescent form exhibit an anti-coagulant, vasodilatory, and anti-adhesive property [55]. However, when activated they express pro-coagulant, vasoconstricting, and pro-adhesive properties [56]. Hemostasis is facilitated by an equilibrium of anticoagulant and procoagulant factors [56]. On one side of the hemostatic equilibrium, the ECs express anticoagulant factors such as thrombomodulin TM, tissue factor pathway inhibitor (TFPI), and tissue-type plasminogen activator (t-PA). On the other side, they express thrombin receptors, TF, plasminogen activator, and von Willebrand factor (vWF) [56].

The VDR has been identified in endothelium cells, and hydroxylation of 25(OH) D to 1,25(OH)2D also takes place in the endothelium [18, 57]. The expression of VDR and 1-alfa hydroxylase in the endothelium was found to be decreased with 25(OH)D deficiency [58]. In the vascular system, it has been recognized that vitamin D controls the proliferation of endothelial cells and vascular smooth muscle cells [59, 60]. Vitamin D up-regulates the production of nitric oxide (NO) in ECs [31],

*Vitamin D*

VDR activation [3].

in various diseases including COVID-19.

**2. Vitamin D in coagulation**

proliferation, calcium and phosphorus homeostasis, and cell differentiation. Most of these actions are carried out by regulating the expression of target genes through

Vitamin D deficiency is a widespread condition, reportedly occurring in 30 to 60% of the general population worldwide [5–7]. Vitamin D is commonly known for its vital role in calcium homeostasis and bone mineralization. It is also crucial in the prevention of rickets during early age and osteomalacia during adult age [8, 9]. Increasing evidence from clinical reports, cross-sectional studies, and cell culture studies further indicate that vitamin D may exert an anticoagulant effect emphasizing an essential role of vitamin D metabolites in the pathogenesis of thrombosis [10–12]. VDR is expressed throughout the body including various immune cells such as macrophages, dendritic cells, and lymphocytes [13–17]. They are also expressed in the vascular endothelial cells [18], which are relevant to hemostasis. Thrombosis is the formation of a blood clot within the intact vascular system. It can occur in both arterial and venous systems [19]. Rudolf Virchow, a German scientist, and physician proposed the three main factors that may predispose an individual to the development of thrombosis: stasis, endothelial dysfunction, and hypercoagulability. Apart from these three factors, the innate inflammatory system also has an intrinsic link with coagulation, whereby activation of the inflammatory system promotes thrombosis and vice versa [20, 21]. Interventional studies have shown vitamin D treatment enhances endothelial functions and reduces the production of pro-inflammatory cytokines [22–24]. Apart from this, the anti-thrombotic effect of vitamin D on the pro-thrombotic and anti-thrombotic components of the coagulation system has also been well defined [25–27]. In this chapter, we are defining the effect of vitamin D deficiency in the three most important parameters viz. coagulation, endothelial activation, and immune responses affecting the occurrence of thrombosis. This chapter will also discuss the clinical impact of Vitamin D

Vitamin D deficiency is defined based on the plasma levels of 25(OH)D. Individuals with plasma levels under 20 ng/mL are considered vitamin D deficient. Vitamin D deficiency is highly prevalent worldwide with approximately 30–50% incidences [28–30]. Several reports have established the significant association of vitamin D deficiency with the increased risk of various cardiovascular diseases (CVDs) and mortality [31–33]. Various studies have also reported the association of vitamin D deficiency with the increased incidences of thromboembolism [34–36]. As suggested by the studies, the underlying molecular mechanism for the antithrombotic potential of vitamin D includes up-regulation of thrombomodulin and downregulation of tissue factor (TF) [25, 36, 37]. Additionally, vitamin D upregulates and increases the level of anti-inflammatory cytokines like IL-10 [24, 38]. The expression profile of more than 200 genes involved in the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis is directly or indirectly regulated by vitamin D [39]. The experimental shreds of evidence obtained from cell culture studies depicted that biologically active form of vitamin D3 i.e., 1,25(OH)2D, and its synthetic analogs exerted the anticoagulant effects [40]. Koyama et al. have demonstrated in their experiments on human peripheral monocytes that 1,25(OH)2D exerted the anticoagulant effects by upregulating the expression of thrombomodulin, an anticoagulant glycoprotein, and downregulating the expression of TF, a critical coagulation factor [13]. 1,25 (OH)2D directly suppresses renin gene expression via a vitamin D-response (VDR) element that is

**86**

by increasing eNOS expression [61], which helps in reducing arterial stiffness [62]. Various randomized control trials (RCTs) have demonstrated an improvement in endothelial dysfunction in healthy individuals [23, 63, 64], as well as in patients [65, 66] and improvement of arterial stiffness with improved flow-mediated dilation (FMD) after vitamin D supplementation [67]. A study by Davide Carrara et al. showed restoration of normal vitamin D levels after prolonged supplementation with a high dose of cholecalciferol (50,000 IU/week orally for 8 weeks) is associated with inhibition of peripheral renin-angiotensin system and with an improvement of FMD in essential hypertensive patients with hypovitaminosis [68]. The 25(OH)D presumed to be an inactive sterol is also found to be a potent mediator of endothelial stability in a non-genomic manner at physiologically relevant levels [69].

1,25(OH)2D3 supplementation reduces oxidation stress, NF-kappa B activation, Intercellular Adhesion Molecule 1 (ICAM-1), and Monocyte chemoattractant protein-1 levels in the endothelium cells [70]. Vitamin D also downregulates platelet-activating factor (PAF) induced ICAM-1 expression in the ECs [71]. Another study observed a greater level of p65 subunit of NF-kB, and IL-6 in vitamin D deficient groups as compared to the vitamin D sufficient group [72]. Vitamin D has also been shown to inhibit activation of proinflammatory TF, NF-kB, and its downstream target, IL-6 [73], which is a pro-inflammatory cytokine in cultured vascular ECs [74] In addition, Vitamin D has been demonstrated to reverse Angiotensin II (Ang II) induced oxidative stress, a key mediator of endothelial dysfunction [75]. Ang II not only induces the production of ROS but also activates TF NF-kB, which further upregulates several cytokines such as TNF-alfa, IL-6, and adhesion molecules ICAM-1, Vascular cell adhesion molecule 1 (VCAM-1), and E-selectin prompting vascular injury [76]. In vivo, VDR knockdown leads to an increase in leukocytes-endothelial interaction associated with endothelial cell activation markers VCAM-1 and ICAM-1 in endothelial cells [77].

Given the recognized significance of endothelial function in the homeostasis of the cardiovascular system, the protective effects of VDR in endothelial cells may explain by some of the reported beneficial effects of vitamin D attributed to the prevention or curing of cardiovascular disease [78, 79]. Vitamin D therapy has been observed to be associated with improvement in endothelial function in ischemic heart disease (IHD) patients with vitamin D deficiency or insufficiency [80]. Further, *in vitro* supplementation of vitamin D improved endothelial progenitor cell ability in the formation of colonies in type 2 diabetes mellitus patients [81]. Cuenca *et al.* demonstrated that paricalcitol, a vitamin D substitute attenuates the endothelium damage induced by the chronic kidney disease in the thoracic aorta and directly mediates stability of endothelium in vitro by enhancing cell–cell interactions resembling a protective mechanism [82].

#### **4. Inflammation and thrombosis**

Thrombosis and inflammation are the two intrinsically interlinked processes. Inflammation can induce a procoagulant milieu by multiple pathways such as by causing an imbalance between procoagulant and anticoagulant characteristics of the endothelium that can lead to local stimulation of coagulation cascade. TNF-α, a pro-inflammatory cytokine that is a potent inducer of the immune defense mechanism and the first to be released at the site of infection promotes a pro-coagulant state by eliciting the production of TF on the endothelium [83] and suppressing the synthesis of the anticoagulant protein C [84], thereby stimulating fibrin formation. Inflammatory stimuli change the cellular program of the endothelium by expressing adhesion molecules such as p-selectin and E-selectin facilitating a transition toward a more procoagulant phenotype [85].

**89**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

Other cells of the circulation are also customized by inflammatory molecules toward a pro-thrombotic state such as neutrophils and monocytes expression of TF [86, 87], which is upregulated upon inflammation. The role of sterile inflammation has also been demonstrated in the thrombosis by a direct association between nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome complex, and hypoxia-inducible factor-1 alpha in hypoxia-induced thrombosis associated with an increase in the relative expression of caspase-1, interleukin-1beta and IL-18 transcripts in the individuals with venous thrombosis [20]. In recent years, the role of vitamin D as a regulator of both innate and adaptive immune responses has become very clear [88]. Local synthesis of 1,25- (OH)2D at the site of inflammation can modulate the immune response in a paracrine manner [89]. 1,25(OH)2D binds to the nuclear VDR which has been found to be expressed in various cells of the immune system such as macrophages, activated

The immunomodulatory role of vitamin D has been observed through its ability to alter the secretion of inflammatory cytokines [92, 93]. Additionally, multiple studies are suggesting an inverse association between vitamin D level and inflammatory cytokines such as TNF-α, IL-6, and CRP [16–20], which are correctable by vitamin D supplementation [94–96]. Furthermore, lower vitamin D levels have also been associated with an increase in the levels of cellular adhesion molecules such as

Moreover, an increased incidence of auto-immune disorders in higher latitudes has been reported, which could be attributed to low UV-radiation that reduces the ability to synthesize vitamin D [98, 99]. Elderly peoples usually tend to have Hypovitaminosis D [26], which has been associated with an increased risk for chronic diseases where inflammation plays an integral component [100, 101]. A study by EM Akbas *et al*. revealed an inverse association between Vitamin D levels and inflammation through Neutrophil-to-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio (PLR) which are novel and inexpensive markers of inflammation. They found a significantly higher NLR and PLR in patients with lower 25(OH)D

Further, several cross-sectional studies have associated vitamin D levels and inflammation. Amer and Qayyam Studied 15,167 men and women aged 18 years and older [103]. They observed a negative association between vitamin D and inflammatory markers such as CRP and IL-6 in the vitamin D deficient groups (<25 nmol/L). This association was not observed in groups with insufficient and sufficient vitamin D status [104]. Bellia et al. examined the association of vitamin D and inflammatory markers in 137 morbidly obese individuals including both men and women. They also observed a significant inverse association between serum 25(OH)D levels and inflammatory markers like CRP, IL-6, and TNF-α [105]. A clinical trial by SS Bidar et al. observed a significant decrease in the systemic inflammatory markers including hsCRP, serum amyloid A, TNF-α, and IL-6 with the increase in circulating vitamin D after a daily intake of vitamin D fortified yogurt drink in the subjects with type 2 diabetes (T2D) [96]. However, in another clinical trial, Jorde et al. [106] observed no significant effects on hsCRP levels in the subjects randomly assigned to the therapy for 1 year with vitamin D3 40,000 IU per

There is a close link between vitamin D and human health, vitamin D deficiency is widely associated with several diseased conditions by physicians and patients.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

T-cells, B-cells, Dendritic cells, and monocytes [90, 91].

VCAM and ICAM [97].

status [102].

week, 20,000 IU per week, or placebo.

**5. Clinical impact of vitamin D in various diseases**

#### *Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

Other cells of the circulation are also customized by inflammatory molecules toward a pro-thrombotic state such as neutrophils and monocytes expression of TF [86, 87], which is upregulated upon inflammation. The role of sterile inflammation has also been demonstrated in the thrombosis by a direct association between nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome complex, and hypoxia-inducible factor-1 alpha in hypoxia-induced thrombosis associated with an increase in the relative expression of caspase-1, interleukin-1beta and IL-18 transcripts in the individuals with venous thrombosis [20]. In recent years, the role of vitamin D as a regulator of both innate and adaptive immune responses has become very clear [88]. Local synthesis of 1,25- (OH)2D at the site of inflammation can modulate the immune response in a paracrine manner [89]. 1,25(OH)2D binds to the nuclear VDR which has been found to be expressed in various cells of the immune system such as macrophages, activated T-cells, B-cells, Dendritic cells, and monocytes [90, 91].

The immunomodulatory role of vitamin D has been observed through its ability to alter the secretion of inflammatory cytokines [92, 93]. Additionally, multiple studies are suggesting an inverse association between vitamin D level and inflammatory cytokines such as TNF-α, IL-6, and CRP [16–20], which are correctable by vitamin D supplementation [94–96]. Furthermore, lower vitamin D levels have also been associated with an increase in the levels of cellular adhesion molecules such as VCAM and ICAM [97].

Moreover, an increased incidence of auto-immune disorders in higher latitudes has been reported, which could be attributed to low UV-radiation that reduces the ability to synthesize vitamin D [98, 99]. Elderly peoples usually tend to have Hypovitaminosis D [26], which has been associated with an increased risk for chronic diseases where inflammation plays an integral component [100, 101]. A study by EM Akbas *et al*. revealed an inverse association between Vitamin D levels and inflammation through Neutrophil-to-lymphocyte ratio (NLR) and platelet-tolymphocyte ratio (PLR) which are novel and inexpensive markers of inflammation. They found a significantly higher NLR and PLR in patients with lower 25(OH)D status [102].

Further, several cross-sectional studies have associated vitamin D levels and inflammation. Amer and Qayyam Studied 15,167 men and women aged 18 years and older [103]. They observed a negative association between vitamin D and inflammatory markers such as CRP and IL-6 in the vitamin D deficient groups (<25 nmol/L). This association was not observed in groups with insufficient and sufficient vitamin D status [104]. Bellia et al. examined the association of vitamin D and inflammatory markers in 137 morbidly obese individuals including both men and women. They also observed a significant inverse association between serum 25(OH)D levels and inflammatory markers like CRP, IL-6, and TNF-α [105]. A clinical trial by SS Bidar et al. observed a significant decrease in the systemic inflammatory markers including hsCRP, serum amyloid A, TNF-α, and IL-6 with the increase in circulating vitamin D after a daily intake of vitamin D fortified yogurt drink in the subjects with type 2 diabetes (T2D) [96]. However, in another clinical trial, Jorde et al. [106] observed no significant effects on hsCRP levels in the subjects randomly assigned to the therapy for 1 year with vitamin D3 40,000 IU per week, 20,000 IU per week, or placebo.

#### **5. Clinical impact of vitamin D in various diseases**

There is a close link between vitamin D and human health, vitamin D deficiency is widely associated with several diseased conditions by physicians and patients.

*Vitamin D*

by increasing eNOS expression [61], which helps in reducing arterial stiffness [62]. Various randomized control trials (RCTs) have demonstrated an improvement in endothelial dysfunction in healthy individuals [23, 63, 64], as well as in patients [65, 66] and improvement of arterial stiffness with improved flow-mediated dilation (FMD) after vitamin D supplementation [67]. A study by Davide Carrara et al. showed restoration of normal vitamin D levels after prolonged supplementation with a high dose of cholecalciferol (50,000 IU/week orally for 8 weeks) is associated with inhibition of peripheral renin-angiotensin system and with an improvement of FMD in essential hypertensive patients with hypovitaminosis [68]. The 25(OH)D presumed to be an inactive sterol is also found to be a potent mediator of endothelial

stability in a non-genomic manner at physiologically relevant levels [69].

cell activation markers VCAM-1 and ICAM-1 in endothelial cells [77].

tions resembling a protective mechanism [82].

**4. Inflammation and thrombosis**

a more procoagulant phenotype [85].

1,25(OH)2D3 supplementation reduces oxidation stress, NF-kappa B activation, Intercellular Adhesion Molecule 1 (ICAM-1), and Monocyte chemoattractant protein-1 levels in the endothelium cells [70]. Vitamin D also downregulates platelet-activating factor (PAF) induced ICAM-1 expression in the ECs [71]. Another study observed a greater level of p65 subunit of NF-kB, and IL-6 in vitamin D deficient groups as compared to the vitamin D sufficient group [72]. Vitamin D has also been shown to inhibit activation of proinflammatory TF, NF-kB, and its downstream target, IL-6 [73], which is a pro-inflammatory cytokine in cultured vascular ECs [74] In addition, Vitamin D has been demonstrated to reverse Angiotensin II (Ang II) induced oxidative stress, a key mediator of endothelial dysfunction [75]. Ang II not only induces the production of ROS but also activates TF NF-kB, which further upregulates several cytokines such as TNF-alfa, IL-6, and adhesion molecules ICAM-1, Vascular cell adhesion molecule 1 (VCAM-1), and E-selectin prompting vascular injury [76]. In vivo, VDR knockdown leads to an increase in leukocytes-endothelial interaction associated with endothelial

Given the recognized significance of endothelial function in the homeostasis of the cardiovascular system, the protective effects of VDR in endothelial cells may explain by some of the reported beneficial effects of vitamin D attributed to the prevention or curing of cardiovascular disease [78, 79]. Vitamin D therapy has been observed to be associated with improvement in endothelial function in ischemic heart disease (IHD) patients with vitamin D deficiency or insufficiency [80]. Further, *in vitro* supplementation of vitamin D improved endothelial progenitor cell ability in the formation of colonies in type 2 diabetes mellitus patients [81]. Cuenca *et al.* demonstrated that paricalcitol, a vitamin D substitute attenuates the endothelium damage induced by the chronic kidney disease in the thoracic aorta and directly mediates stability of endothelium in vitro by enhancing cell–cell interac-

Thrombosis and inflammation are the two intrinsically interlinked processes. Inflammation can induce a procoagulant milieu by multiple pathways such as by causing an imbalance between procoagulant and anticoagulant characteristics of the endothelium that can lead to local stimulation of coagulation cascade. TNF-α, a pro-inflammatory cytokine that is a potent inducer of the immune defense mechanism and the first to be released at the site of infection promotes a pro-coagulant state by eliciting the production of TF on the endothelium [83] and suppressing the synthesis of the anticoagulant protein C [84], thereby stimulating fibrin formation. Inflammatory stimuli change the cellular program of the endothelium by expressing adhesion molecules such as p-selectin and E-selectin facilitating a transition toward

**88**

The various diseases affected by vitamin D deficiency can be categorized as cardiovascular disease (hypertension, thrombosis), various cancers, autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and metabolic syndromes like osteomalacia, diabetes, and muscle weakness (**Figure 1**).

Osteomalacia is a classical human manifestation associated with vitamin D deficiency. It is a clinical condition in which bone mineralization is hampered due to low concentrations of phosphorus and calcium in the extracellular fluid [107]. Vitamin D plays a crucial role in maintaining an adequate level of serum phosphorus and calcium. In the absence of vitamin D or its deficiency, only 10 to 15% of dietary calcium and 60% of phosphorus are absorbed in the human body [108–110]. With the advent of technologies, molecular biology has permitted a more detailed characterization of the effects of vitamin D deficiency, via working on the animals lacking the VDR and studying their phenotype. Subtle abnormalities in the immune and cardiovascular system have been defined in the global VDRKO mouse, but their relevance to human disease is still obscure [111]. Greater awareness of the high prevalence of vitamin D inadequacy and its associated abnormalities is required among researchers, clinicians, and patients. There has been a large number of trials concerning the effects of vitamin D on the management and prevention in the last two decades. The most studied diseases in this aspect have been discussed below:

#### **5.1 Osteoporosis**

The association between osteoporosis and vitamin D deficiency is well established especially in the elderly. Vitamin D deficiency has been linked with the significant suppression in intestinal Calcium absorption and the impairment of its balance, which causes low bone mineral content and density. Decreased bone mineral density (BMD) raises the risk of bone fractures, which contributes significantly to the hospitalization, morbidity, and mortality of elderlies [112, 113]. Several studies have demonstrated the efficacy of vitamin D as a preventive measure for fractures. Clinical trials recommending the use of 700 to 800 IU/d oral vitamin D with or without Ca supplementation reported a significant 26% decrease in the risk of sustaining a hip fracture and a significant 23% decrease in the risk of sustaining any non-vertebral fracture vs. placebo or Calcium alone [114].

**91**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

One of the prominent features of vitamin D deficiency is muscle weakness. Several clinical data of patients with nonspecific muscle weakness, muscle aches, and pains have shown vitamin D inadequacy [115, 116]. It has been reported that skeletal muscle tissue contains VDR and needs vitamin D to attain maximum function [117]. Recent studies have associated the increased vitamin D levels with improved muscle performance, and thereby reduced incidences of fall and fracture. A 5-month randomized controlled trial study has exhibited a 72% reduction in the risk of falls as compared with the placebo group in elderly people in a nursing home

Hypertension affects the population globally. Increasing evidence in recent times suggests that vitamin D has a crucial role in regulating blood pressure. Animal studies indicate that 1,25-dihydroxy vitamin D inhibits renin expression in the juxtaglomerular apparatus and blocks the proliferation of vascular smooth muscle cells, which affects systemic blood pressure [119]. People taking oral supplementation of vitamin D were found to have reduced blood pressure. The exposure of skin to UVB rays, a major source of vitamin D formation, has been associated with lower

Multiple sclerosis (MS) is an auto-immune disease characterized by the attack of self- immune system on the myelin sheath which works as a nerve insulator. The transmission of nerve signals gets affected leading to disrupted communication between the body and brain.. There have been several reports claiming the increased frequency of MS in temperate climates than in the tropics [123, 124]. Furthermore, studies also suggest that there is a strong negative correlation between the short annual, winter hours and frequency of occurrence of MS [125, 126]. Hence, these studies could hypothesized that vitamin D synthesized during sun exposure exerted a protective effect [127–129]. In addition, There are few studies that indicated low or insufficient levels of vitamin D in MS patients [130–132].

The re-arrival of worldwide vitamin D deficiency has led to the re-emergence of rickets. Low levels of vitamin D in breastfeeding mothers can, often, lead to deficiencies in their children. The recommended levels of vitamin D supplements

Garland and Garland for the first time reported that vitamin D deficiency could

be associated with a higher risk of colon cancer mortality. Recent studies have reported an increased risk of several cancers with vitamin D deficiency, suggesting that vitamin D deficiency may account for premature mortality from colon, breast, ovarian, and prostate cancer [133–135]. Vitamin D is a potent hormone and regulates cell growth. VDRs are expressed by various cells and get activated by 1,25(OH)2 D, inducing differentiation into normally functioning cells, and inhibiting proliferation, angiogenesis, invasiveness, and metastatic potential.

are 400 IU/d for infants to avoid diseases such as rickets [8].

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

receiving 800 IU of vitamin D2 plus calcium daily [118].

**5.2 Muscle weakness**

**5.3 Hypertension**

blood pressure [120–122].

**5.4 Multiple sclerosis**

**5.5 Rickets**

**5.6 Cancer**

#### **Figure 1.**

*Reported Association of Vitamin D deficiency with various human disease.*

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

#### **5.2 Muscle weakness**

*Vitamin D*

The various diseases affected by vitamin D deficiency can be categorized as cardiovascular disease (hypertension, thrombosis), various cancers, autoimmune diseases like multiple sclerosis, rheumatoid arthritis, and metabolic syndromes like osteo-

Osteomalacia is a classical human manifestation associated with vitamin D deficiency. It is a clinical condition in which bone mineralization is hampered due to low concentrations of phosphorus and calcium in the extracellular fluid [107]. Vitamin D plays a crucial role in maintaining an adequate level of serum phosphorus and calcium. In the absence of vitamin D or its deficiency, only 10 to 15% of dietary calcium and 60% of phosphorus are absorbed in the human body [108–110]. With the advent of technologies, molecular biology has permitted a more detailed characterization of the effects of vitamin D deficiency, via working on the animals lacking the VDR and studying their phenotype. Subtle abnormalities in the immune and cardiovascular system have been defined in the global VDRKO mouse, but their relevance to human disease is still obscure [111]. Greater awareness of the high prevalence of vitamin D inadequacy and its associated abnormalities is required among researchers, clinicians, and patients. There has been a large number of trials concerning the effects of vitamin D on the management and prevention in the last two decades. The most studied diseases in this

The association between osteoporosis and vitamin D deficiency is well established especially in the elderly. Vitamin D deficiency has been linked with the significant suppression in intestinal Calcium absorption and the impairment of its balance, which causes low bone mineral content and density. Decreased bone mineral density (BMD) raises the risk of bone fractures, which contributes significantly to the hospitalization, morbidity, and mortality of elderlies [112, 113]. Several studies have demonstrated the efficacy of vitamin D as a preventive measure for fractures. Clinical trials recommending the use of 700 to 800 IU/d oral vitamin D with or without Ca supplementation reported a significant 26% decrease in the risk of sustaining a hip fracture and a significant 23% decrease in the risk of sustaining any non-vertebral fracture vs. placebo or

malacia, diabetes, and muscle weakness (**Figure 1**).

aspect have been discussed below:

**5.1 Osteoporosis**

Calcium alone [114].

**90**

**Figure 1.**

*Reported Association of Vitamin D deficiency with various human disease.*

One of the prominent features of vitamin D deficiency is muscle weakness. Several clinical data of patients with nonspecific muscle weakness, muscle aches, and pains have shown vitamin D inadequacy [115, 116]. It has been reported that skeletal muscle tissue contains VDR and needs vitamin D to attain maximum function [117]. Recent studies have associated the increased vitamin D levels with improved muscle performance, and thereby reduced incidences of fall and fracture. A 5-month randomized controlled trial study has exhibited a 72% reduction in the risk of falls as compared with the placebo group in elderly people in a nursing home receiving 800 IU of vitamin D2 plus calcium daily [118].

#### **5.3 Hypertension**

Hypertension affects the population globally. Increasing evidence in recent times suggests that vitamin D has a crucial role in regulating blood pressure. Animal studies indicate that 1,25-dihydroxy vitamin D inhibits renin expression in the juxtaglomerular apparatus and blocks the proliferation of vascular smooth muscle cells, which affects systemic blood pressure [119]. People taking oral supplementation of vitamin D were found to have reduced blood pressure. The exposure of skin to UVB rays, a major source of vitamin D formation, has been associated with lower blood pressure [120–122].

#### **5.4 Multiple sclerosis**

Multiple sclerosis (MS) is an auto-immune disease characterized by the attack of self- immune system on the myelin sheath which works as a nerve insulator. The transmission of nerve signals gets affected leading to disrupted communication between the body and brain.. There have been several reports claiming the increased frequency of MS in temperate climates than in the tropics [123, 124]. Furthermore, studies also suggest that there is a strong negative correlation between the short annual, winter hours and frequency of occurrence of MS [125, 126]. Hence, these studies could hypothesized that vitamin D synthesized during sun exposure exerted a protective effect [127–129]. In addition, There are few studies that indicated low or insufficient levels of vitamin D in MS patients [130–132].

#### **5.5 Rickets**

The re-arrival of worldwide vitamin D deficiency has led to the re-emergence of rickets. Low levels of vitamin D in breastfeeding mothers can, often, lead to deficiencies in their children. The recommended levels of vitamin D supplements are 400 IU/d for infants to avoid diseases such as rickets [8].

#### **5.6 Cancer**

Garland and Garland for the first time reported that vitamin D deficiency could be associated with a higher risk of colon cancer mortality. Recent studies have reported an increased risk of several cancers with vitamin D deficiency, suggesting that vitamin D deficiency may account for premature mortality from colon, breast, ovarian, and prostate cancer [133–135]. Vitamin D is a potent hormone and regulates cell growth. VDRs are expressed by various cells and get activated by 1,25(OH)2 D, inducing differentiation into normally functioning cells, and inhibiting proliferation, angiogenesis, invasiveness, and metastatic potential.

Studies reveal that tumor models of lung, colon, kidney, breast, and prostate cancer, vitamin D showed activity against metastasis [136–141]. These studies have also shown the immunomodulatory effect of Vitamin D. It has been reported that when elicited by an inappropriate and overly exuberant immune response, vitamin D acts in a paracrine manner and decreases T cell responsiveness via inhibition of cellular proliferation and reduced lymphokine production. Thus, vitamin D shows a beneficial effect as an immunosuppressant.

#### **5.7 Diabetes**

Vitamin D deficiency is known to inhibit pancreatic secretion and turnover of insulin, causing impaired glucose tolerance. An association was found between a low level of vitamin D and a high incidence of type 1 diabetes [142].

#### **5.8 Tuberculosis**

Tuberculosis **(**TB) is one of the global health problems causing 2 million deaths a year. It is estimated that approximately one-third of the global population carries latent TB infection, which poses potential health risks of reactivation in the future. Before the use of antibiotics to treat TB, high doses of vitamin D were widely used [143]. Cross-sectional studies indicated that patients with TB possess a decrease 25(OH)D levels in comparison with the control population.

#### **5.9 Thrombosis**

As discussed in previous sections, vitamin D can tackle thrombosis by influencing inflammatory pathways, coagulation factors, and endothelium homeostasis in a pleiotropic manner. **Figure 2** illustrates a possible mechanism through which vitamin D might impart its protective role against the occurrence of thrombosis. Several clinical trials have also highlighted the anti-thrombotic actions of vitamin D. A study by TM Beer *et al.* involving 250 cancer patients for high dose calcitriol supplementation, a total of 13 thrombotic events were observed of which 11 occur placebo-treated and only 2 occur in high dose calcitriol-treated cancer patients [35]. Vitamin D has been found to inhibits *in-vitro* anti beta2GPI antibodies (purified from patients with antiphospholipid syndrome (APS)) induced TF expression indicating the association of vitamin D deficiency and decreased inhibition of TF expression and increased coagulation in APS [34]. M Blondon *et al.* investigated the role of oral supplementation of vitamin D3 in the placebo-controlled RCT in 36,282 postmenopausal women. Subjects were randomized to receive 1000 mg of calcium carbonate and 400 IU of vitamin D3 per day for an average period of 7 years and observed a reduced risk of idiopathic VTE in women randomized to calcium and vitamin D [144]. A 60% lower rate of VTE was observed in 769 renal transplant recipients after combined therapy with calcitriol 0.5ug/day, angiotensin-converting enzyme inhibitor (ACEi), and angiotensin receptor blocker (ARB) [145]. Another prospective study which included a cohort comprising of 40,000 women followed for a mean period of 11 years concluded a 30% lower risk of VTE in women with a habit of more active sun exposure [146]. Moreover, another study determined a 50% increased risk of VTE in winter, during which vitamin D status has been established to be the lowest as compared to another season [147].

#### **5.10 COVID-19**

The COVID-19 pandemic has affected all of us globally. The lack of understanding of the mechanism of action of SARS-CoV2 virus has generated an overall

**93**

**Figure 2.**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

interest in understanding the potential risk factors that may explain the mechanistic basis for disease propagation and control. The role of vitamin D has emerged in COVID-19 as well. The innate immune system forms the first line of defense against invading pathogens including viruses. 1,25(OH)2D enhances innate defense by inducing antimicrobial peptides like cathelicidin that result in the destruction and clearance of viral particles via several molecular mechanisms. It also helps in the recruitment of neutrophils, monocytes/macrophages, and dendritic cells for killing and clearance of viral particles, and initiation of the immune response. Further, the chronic activation of the innate immune system in COVID-19 infection results in a cytokine storm. It has been hypothesized that 1,25(OH)2D helps in curtailing this chronic innate immune response through various biological mechanisms such as downregulation of TLRs and direct inhibition of TNF/NFκB and IFNγ signaling pathways. 1,25(OH)2D, regulates adaptive immune response by limiting maturation of dendritic cells along with their ability to present antigen to T cells, thus limiting shifting of the T cell profile from proinflammatory Th1 and Th17 subsets to Th2 and Treg subsets. Thus, inhibits the pro-inflammatory processes. Although all these findings come from different studies with a variety of pathogens (virus/bacteria)

*Possible mechanism of the protective role of vitamin D in the occurrence of thrombosis.*

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

#### **Figure 2.**

*Vitamin D*

**5.7 Diabetes**

**5.8 Tuberculosis**

**5.9 Thrombosis**

Studies reveal that tumor models of lung, colon, kidney, breast, and prostate cancer, vitamin D showed activity against metastasis [136–141]. These studies have also shown the immunomodulatory effect of Vitamin D. It has been reported that when elicited by an inappropriate and overly exuberant immune response, vitamin D acts in a paracrine manner and decreases T cell responsiveness via inhibition of cellular proliferation and reduced lymphokine production. Thus, vitamin D shows a

Vitamin D deficiency is known to inhibit pancreatic secretion and turnover of insulin, causing impaired glucose tolerance. An association was found between a

Tuberculosis **(**TB) is one of the global health problems causing 2 million deaths a year. It is estimated that approximately one-third of the global population carries latent TB infection, which poses potential health risks of reactivation in the future. Before the use of antibiotics to treat TB, high doses of vitamin D were widely used [143]. Cross-sectional studies indicated that patients with TB possess a decrease

As discussed in previous sections, vitamin D can tackle thrombosis by influencing inflammatory pathways, coagulation factors, and endothelium homeostasis in a pleiotropic manner. **Figure 2** illustrates a possible mechanism through which vitamin D might impart its protective role against the occurrence of thrombosis. Several clinical trials have also highlighted the anti-thrombotic actions of vitamin D. A study by TM Beer *et al.* involving 250 cancer patients for high dose calcitriol supplementation, a total of 13 thrombotic events were observed of which 11 occur placebo-treated and only 2 occur in high dose calcitriol-treated cancer patients [35]. Vitamin D has been found to inhibits *in-vitro* anti beta2GPI antibodies (purified from patients with antiphospholipid syndrome (APS)) induced TF expression indicating the association of vitamin D deficiency and decreased inhibition of TF expression and increased coagulation in APS [34]. M Blondon *et al.* investigated the role of oral supplementation of vitamin D3 in the placebo-controlled RCT in 36,282 postmenopausal women. Subjects were randomized to receive 1000 mg of calcium carbonate and 400 IU of vitamin D3 per day for an average period of 7 years and observed a reduced risk of idiopathic VTE in women randomized to calcium and vitamin D [144]. A 60% lower rate of VTE was observed in 769 renal transplant recipients after combined therapy with calcitriol 0.5ug/day, angiotensin-converting enzyme inhibitor (ACEi), and angiotensin receptor blocker (ARB) [145]. Another prospective study which included a cohort comprising of 40,000 women followed for a mean period of 11 years concluded a 30% lower risk of VTE in women with a habit of more active sun exposure [146]. Moreover, another study determined a 50% increased risk of VTE in winter, during which vitamin D status has been established to be the lowest as compared to another season [147].

The COVID-19 pandemic has affected all of us globally. The lack of understand-

ing of the mechanism of action of SARS-CoV2 virus has generated an overall

low level of vitamin D and a high incidence of type 1 diabetes [142].

25(OH)D levels in comparison with the control population.

beneficial effect as an immunosuppressant.

**92**

**5.10 COVID-19**

*Possible mechanism of the protective role of vitamin D in the occurrence of thrombosis.*

interest in understanding the potential risk factors that may explain the mechanistic basis for disease propagation and control. The role of vitamin D has emerged in COVID-19 as well. The innate immune system forms the first line of defense against invading pathogens including viruses. 1,25(OH)2D enhances innate defense by inducing antimicrobial peptides like cathelicidin that result in the destruction and clearance of viral particles via several molecular mechanisms. It also helps in the recruitment of neutrophils, monocytes/macrophages, and dendritic cells for killing and clearance of viral particles, and initiation of the immune response. Further, the chronic activation of the innate immune system in COVID-19 infection results in a cytokine storm. It has been hypothesized that 1,25(OH)2D helps in curtailing this chronic innate immune response through various biological mechanisms such as downregulation of TLRs and direct inhibition of TNF/NFκB and IFNγ signaling pathways. 1,25(OH)2D, regulates adaptive immune response by limiting maturation of dendritic cells along with their ability to present antigen to T cells, thus limiting shifting of the T cell profile from proinflammatory Th1 and Th17 subsets to Th2 and Treg subsets. Thus, inhibits the pro-inflammatory processes. Although all these findings come from different studies with a variety of pathogens (virus/bacteria)

the relevance of these protective actions of vitamin D on SARS-CoV-2 can merit further investigation [148]. In a recent study of hospitalized COVID-19 patients, vitamin D deficiency was reported in 75% of the overall cohort and in 85% of those who required ICU admission [149]. Also, a European study analysis of SARS-CoV-2 severity based on vitamin D status suggested that countries with the highest rate of vitamin D deficiency are associated with the highest rates of COVID-19 infection and mortality [150]. Therefore, vitamin D supplements as a part of standard nutrition in COVID-19 may provide certain clinical benefits though more research related to this subject is solicited [151].

### **6. Conclusion**

Inadequacy or deficiency of vitamin D is a global problem. Though recent studies have established vitamin D as a key regulatory molecule in various physiological processes and have proposed it as a promising predictive/therapeutic tool still the close association of vitamin D with human health, and its deficiency in the body is not widely recognized as a health concern by both common man and physicians. The relation between vitamin D deficiency and the associated risk of various chronic and acute diseases is still obscure and requires intensive research efforts. In recent years, various studies have explored several non-calcemic consequences of vitamin D. There are reports that corelates lower doses of vitamin D with thrombosis and various cardiovascular diseases. Still, there is an impelling need to enhance our knowledge of the molecular pathways regulated/influenced via vitamin D and their effect on various organ systems including the cardiovascular system. This would require conducting large-scale intervention clinical trials to firmly establish the association of vitamin D status to cardiovascular health. Additionally, it is important to state that although deficiency of vitamin D is common and widespread, it can be safely corrected with a variety of supplement types and regimens available and thus should be identified and addressed in the clinical practice of treating diseases associated with it.

**95**

**Author details**

Syed Mohd1†, Swati Sharma1†, Aastha Mishra2

\*Address all correspondence to: zashraf@jmi.ac.in

provided the original work is properly cited.

† These authors have contributed equally to this work.

1 Department of Biotechnology, Jamia Millia Islamia, Delhi, India

2 CSIR-Institute of Genomics and Integrative Biology, Delhi, India

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Mohammad Zahid Ashraf1

\*

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

#### **Conflict of interest**

The authors declare no conflict of interest.

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

#### **Author details**

*Vitamin D*

**6. Conclusion**

related to this subject is solicited [151].

treating diseases associated with it.

The authors declare no conflict of interest.

**Conflict of interest**

the relevance of these protective actions of vitamin D on SARS-CoV-2 can merit further investigation [148]. In a recent study of hospitalized COVID-19 patients, vitamin D deficiency was reported in 75% of the overall cohort and in 85% of those who required ICU admission [149]. Also, a European study analysis of SARS-CoV-2 severity based on vitamin D status suggested that countries with the highest rate of vitamin D deficiency are associated with the highest rates of COVID-19 infection and mortality [150]. Therefore, vitamin D supplements as a part of standard nutrition in COVID-19 may provide certain clinical benefits though more research

Inadequacy or deficiency of vitamin D is a global problem. Though recent studies have established vitamin D as a key regulatory molecule in various physiological processes and have proposed it as a promising predictive/therapeutic tool still the close association of vitamin D with human health, and its deficiency in the body is not widely recognized as a health concern by both common man and physicians. The relation between vitamin D deficiency and the associated risk of various chronic and acute diseases is still obscure and requires intensive research efforts. In recent years, various studies have explored several non-calcemic consequences of vitamin D. There are reports that corelates lower doses of vitamin D with thrombosis and various cardiovascular diseases. Still, there is an impelling need to enhance our knowledge of the molecular pathways regulated/influenced via vitamin D and their effect on various organ systems including the cardiovascular system. This would require conducting large-scale intervention clinical trials to firmly establish the association of vitamin D status to cardiovascular health. Additionally, it is important to state that although deficiency of vitamin D is common and widespread, it can be safely corrected with a variety of supplement types and regimens available and thus should be identified and addressed in the clinical practice of

**94**

Syed Mohd1†, Swati Sharma1†, Aastha Mishra2 and Mohammad Zahid Ashraf1 \*

1 Department of Biotechnology, Jamia Millia Islamia, Delhi, India

2 CSIR-Institute of Genomics and Integrative Biology, Delhi, India

\*Address all correspondence to: zashraf@jmi.ac.in

† These authors have contributed equally to this work.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Black LJ, Seamans KM, Cashman KD, Kiely M. An updated systematic review and meta-analysis of the efficacy of vitamin D food fortification. The Journal of nutrition. 2012 Jun 1;142(6):1102-8.

[2] Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. The Journal of Clinical Endocrinology & Metabolism. 2003 Dec 1;88(12):5766-72.

[3] Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec 15;83(6):835.

[4] Poon AH, Gong L, Brasch-Andersen C, Litonjua AA, Raby BA, Hamid Q, Laprise C, Weiss ST, Altman RB, Klein TE. Very important pharmacogene summary for VDR. Pharmacogenetics and genomics. 2012 Oct;22(10):758.

[5] Takeyama KI, Masuhiro Y, Fuse H, Endoh H, Murayama A, Kitanaka S, Suzawa M, Yanagisawa J, Kato S. Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. Molecular and Cellular Biology. 1999 Feb 1;19(2):1049-55.

[6] Targher G, Pichiri I, Lippi G. Vitamin D, thrombosis, and hemostasis: more than skin deep. InSeminars in thrombosis and hemostasis 2012 Feb (Vol. 38, No. 01, pp. 114-124). Thieme Medical Publishers.

[7] Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC,

Gallo RL, Jones G, Kovacs CS. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism. 2011 Jan 1;96(1):53-8.

[8] Holick MF. Resurrection of vitamin D deficiency and rickets. The Journal of clinical investigation. 2006 Aug 1;116(8):2062-72.

[9] Aaron JE, Stasiak L, Gallagher JC, Longton EB, Nicholson M, Anderson J, Nordin BE. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. The Lancet. 1974 Feb 16;303(7851):229-33.

[10] Khademvatani K, Seyyed-Mohammadzad MH, Akbari M, Rezaei Y, Eskandari R, Rostamzadeh A. The relationship between vitamin D status and idiopathic lower-extremity deep vein thrombosis. International journal of general medicine. 2014;7:303.

[11] Wu WX, He DR. Low vitamin D levels are associated with the development of deep venous thromboembolic events in patients with ischemic stroke. Clinical and applied thrombosis/hemostasis. 2018 Dec;24(9\_suppl):69S–75S.

[12] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. In Seminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03, pp. 217-226). Copyright© 1998 by Thieme Medical Publishers, Inc..

[13] Koyama T, Shibakura M, Ohsawa M, Kamiyama R, Hirosawa S. Anticoagulant effects of 1α, 25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes. Blood, The Journal of the American Society of Hematology. 1998 Jul 1;92(1):160-7.

**97**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

of innate immunity. Nature Reviews Immunology. 2013 Jan;13(1):34-45.

Erdoğan G. 25-Hydroxy vitamin D levels and endothelial vasodilator function in normotensive women. Archives of medical science: AMS. 2012 Feb

[22] Ertek S, Akgül E, Cicero AF, Kütük U, Demirtaş S, Çehreli S,

[23] Harris RA, Pedersen-White J, Guo DH, Stallmann-Jorgensen IS, Keeton D, Huang Y, Shah Y, Zhu H, Dong Y. Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. American journal of hypertension. 2011 May 1;24(5):557-62.

[24] Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a doubleblind, randomized, placebo-controlled trial. The American journal of clinical nutrition. 2006 Apr;83(4):754-9.

[25] Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R. 1α, 25-dihydroxyvitamin D3 and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin

[26] Martinez-Moreno JM, Herencia C, Oca AM, Muñoz-Castañeda JR,

Rodríguez-Ortiz ME, Díaz-Tocados JM, Peralbo-Santaella E, Camargo A, Canalejo A, Rodriguez M,

Velasco-Gimena F. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. The FASEB Journal. 2016 Mar;30(3):1367-76.

[27] Toderici M, de la Morena-Barrio ME, Padilla J, Miñano A,

expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL.

Circulation. 2000 Dec 5;102(23):2867-72.

29;8(1):47.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

autoimmunity: the potential of vitamin

immunology. 2005 Feb 1;233(2):115-24.

[15] Bhalla AK, Amento EP, Serog B, Glimcher LH. 1, 25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. The Journal of Immunology.

[14] Adorini L. Intervention in

D receptor agonists. Cellular

1984 Oct 1;133(4):1748-54.

16;221(4616):1181-3.

Jun 1;83(6):1903-15.

2;114(18):4763-8.

[21] Engelmann B, Massberg S.

Thrombosis as an intravascular effector

[16] Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1,

25-dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983 Sep

[17] Brennan A, Katz DR, Nunn JD, Barker S, Hewison M, Fraher LJ, O'Riordan JL. Dendritic cells from human tissues express receptors for the

immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology. 1987 Aug;61(4):457.

[18] Merke J, Milde P, Lewicka S, Hügel U, Klaus G, Mangelsdorf DJ, Haussler MR, Rauterberg EW, Ritz E. Identification and regulation of 1, 25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1, 25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. The Journal of clinical investigation. 1989

[19] Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood reviews. 2009 Sep 1;23(5):225-9.

[20] Gupta N, Sahu A, Prabhakar A, Chatterjee T, Tyagi T, Kumari B, Khan N, Nair V, Bajaj N, Sharma M, Ashraf MZ. Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia. Proceedings of the National Academy of Sciences. 2017 May

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

[14] Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cellular immunology. 2005 Feb 1;233(2):115-24.

[15] Bhalla AK, Amento EP, Serog B, Glimcher LH. 1, 25-Dihydroxyvitamin D3 inhibits antigen-induced T cell activation. The Journal of Immunology. 1984 Oct 1;133(4):1748-54.

[16] Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC. 1, 25-dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983 Sep 16;221(4616):1181-3.

[17] Brennan A, Katz DR, Nunn JD, Barker S, Hewison M, Fraher LJ, O'Riordan JL. Dendritic cells from human tissues express receptors for the immunoregulatory vitamin D3 metabolite, dihydroxycholecalciferol. Immunology. 1987 Aug;61(4):457.

[18] Merke J, Milde P, Lewicka S, Hügel U, Klaus G, Mangelsdorf DJ, Haussler MR, Rauterberg EW, Ritz E. Identification and regulation of 1, 25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1, 25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. The Journal of clinical investigation. 1989 Jun 1;83(6):1903-15.

[19] Esmon CT. Basic mechanisms and pathogenesis of venous thrombosis. Blood reviews. 2009 Sep 1;23(5):225-9.

[20] Gupta N, Sahu A, Prabhakar A, Chatterjee T, Tyagi T, Kumari B, Khan N, Nair V, Bajaj N, Sharma M, Ashraf MZ. Activation of NLRP3 inflammasome complex potentiates venous thrombosis in response to hypoxia. Proceedings of the National Academy of Sciences. 2017 May 2;114(18):4763-8.

[21] Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nature Reviews Immunology. 2013 Jan;13(1):34-45.

[22] Ertek S, Akgül E, Cicero AF, Kütük U, Demirtaş S, Çehreli S, Erdoğan G. 25-Hydroxy vitamin D levels and endothelial vasodilator function in normotensive women. Archives of medical science: AMS. 2012 Feb 29;8(1):47.

[23] Harris RA, Pedersen-White J, Guo DH, Stallmann-Jorgensen IS, Keeton D, Huang Y, Shah Y, Zhu H, Dong Y. Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. American journal of hypertension. 2011 May 1;24(5):557-62.

[24] Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a doubleblind, randomized, placebo-controlled trial. The American journal of clinical nutrition. 2006 Apr;83(4):754-9.

[25] Ohsawa M, Koyama T, Yamamoto K, Hirosawa S, Kamei S, Kamiyama R. 1α, 25-dihydroxyvitamin D3 and its potent synthetic analogs downregulate tissue factor and upregulate thrombomodulin expression in monocytic cells, counteracting the effects of tumor necrosis factor and oxidized LDL. Circulation. 2000 Dec 5;102(23):2867-72.

[26] Martinez-Moreno JM, Herencia C, Oca AM, Muñoz-Castañeda JR, Rodríguez-Ortiz ME, Díaz-Tocados JM, Peralbo-Santaella E, Camargo A, Canalejo A, Rodriguez M, Velasco-Gimena F. Vitamin D modulates tissue factor and protease-activated receptor 2 expression in vascular smooth muscle cells. The FASEB Journal. 2016 Mar;30(3):1367-76.

[27] Toderici M, de la Morena-Barrio ME, Padilla J, Miñano A,

**96**

*Vitamin D*

**References**

1;142(6):1102-8.

15;83(6):835.

Oct;22(10):758.

Feb 1;19(2):1049-55.

Medical Publishers.

[6] Targher G, Pichiri I, Lippi G.

Vitamin D, thrombosis, and hemostasis: more than skin deep. InSeminars in thrombosis and hemostasis 2012 Feb (Vol. 38, No. 01, pp. 114-124). Thieme

[7] Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC,

[1] Black LJ, Seamans KM, Cashman KD, Kiely M. An updated systematic review and meta-analysis of the efficacy of vitamin D food fortification. The Journal of nutrition. 2012 Jun

Gallo RL, Jones G, Kovacs CS. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism. 2011 Jan

[8] Holick MF. Resurrection of vitamin D deficiency and rickets. The Journal of

[9] Aaron JE, Stasiak L, Gallagher JC, Longton EB, Nicholson M, Anderson J, Nordin BE. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. The Lancet. 1974 Feb

clinical investigation. 2006 Aug

1;96(1):53-8.

1;116(8):2062-72.

16;303(7851):229-33.

[10] Khademvatani K, Seyyed-Mohammadzad MH, Akbari M,

Rezaei Y, Eskandari R, Rostamzadeh A. The relationship between vitamin D status and idiopathic lower-extremity deep vein thrombosis. International journal of general medicine. 2014;7:303.

[11] Wu WX, He DR. Low vitamin D levels are associated with the development of deep venous

thrombosis/hemostasis. 2018 Dec;24(9\_suppl):69S–75S.

[12] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. In Seminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03, pp. 217-226). Copyright© 1998 by Thieme Medical

Publishers, Inc..

1998 Jul 1;92(1):160-7.

thromboembolic events in patients with ischemic stroke. Clinical and applied

[13] Koyama T, Shibakura M, Ohsawa M, Kamiyama R, Hirosawa S. Anticoagulant effects of 1α, 25-dihydroxyvitamin D3 on human myelogenous leukemia cells and monocytes. Blood, The Journal of the American Society of Hematology.

[2] Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. The Journal of Clinical Endocrinology & Metabolism.

2003 Dec 1;88(12):5766-72.

[3] Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM. The nuclear receptor superfamily: the second decade. Cell. 1995 Dec

[4] Poon AH, Gong L, Brasch-Andersen C, Litonjua AA, Raby BA, Hamid Q, Laprise C, Weiss ST, Altman RB, Klein TE. Very important pharmacogene summary for VDR. Pharmacogenetics and genomics. 2012

[5] Takeyama KI, Masuhiro Y, Fuse H, Endoh H, Murayama A, Kitanaka S, Suzawa M, Yanagisawa J, Kato S. Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. Molecular and Cellular Biology. 1999

Antón AI, Iniesta JA, Herranz MT, Fernández N, Vicente V, Corral J. Identification of regulatory mutations in SERPINC1 affecting vitamin D response elements associated with antithrombin deficiency. Plos one. 2016 Mar 22;11(3):e0152159.

[28] Holick MF. Vitamin D deficiency. New England Journal of Medicine. 2007 Jul 19;357(3):266-81.

[29] Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein JB, Group IH. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. The American journal of cardiology. 2010 Oct 1;106(7):963-8.

[30] Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA. Vitamin D deficiency and supplementation and relation to cardiovascular health. The American journal of cardiology. 2012 Feb 1;109(3):359-63.

[31] Kheiri B, Abdalla A, Osman M, Ahmed S, Hassan M, Bachuwa G. Vitamin D deficiency and risk of cardiovascular diseases: a narrative review. Clinical hypertension. 2018 Dec;24(1):1-9.

[32] Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency: an important, common, and easily treatable cardiovascular risk factor?. Journal of the American College of Cardiology. 2008 Dec 9;52(24):1949-56.

[33] Pilz S, Tomaschitz A, März W, Drechsler C, Ritz E, Zittermann A, Cavalier E, Pieber TR, Lappe JM, Grant WB, Holick MF. Vitamin D, cardiovascular disease and mortality. Clinical endocrinology. 2011 Nov;75(5):575-84.

[34] Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, Doria A, Cervera R, Miesbach W, Stojanovich L, Barak V. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Annals of the Rheumatic Diseases. 2011 Jan 1;70(1):145-50.

[35] Beer TM, Venner PM, Ryan CW, Petrylak DP, Chatta G, Dean Ruether J, Chi KN, Curd JG, DeLoughery TG. High dose calcitriol may reduce thrombosis in cancer patients. British journal of haematology. 2006 Nov;135(3):392-4.

[36] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. InSeminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03, pp. 217-226). Copyright© 1998 by Thieme Medical Publishers, Inc.

[37] Maillard CH, Berruyer MI, Serre CM, Amiral JE, Dechavanne MA, Delmas PD. Thrombomodulin is synthesized by osteoblasts, stimulated by 1, 25-(OH) 2D3 and activates protein C at their cell membrane. Endocrinology. 1993 Aug 1;133(2):668-74.

[38] Michel G, Gailis A, Jarzebska-Deussen B, Muüschen A, Mirmohammadsadegh A, Ruzicka T. 1, 25-(OH) 2-vitamin D 3 and calcipotriol induce IL-10 receptor gene expression in human epidermal cells. Inflammation Research. 1997 Jan;46(1):32-4.

[39] Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocrine reviews. 2005 Aug 1;26(5):662-87.

[40] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. InSeminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03,

**99**

1;29(3):332-6.

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

[48] Jorde R, Haug E, Figenschau Y, Hansen JB. Serum levels of vitamin D and haemostatic factors in healthy subjects: the Tromsø study. Acta haematologica. 2007;117(2):91-7.

[49] Vanhoutte PM. Endothelial dysfunction and atherosclerosis. European heart journal. 1997 Nov

[50] Davignon J, Ganz P. Role of endothelial dysfunction in

15;109(23\_suppl\_1):III-27.

[51] Schuett H, Luchtefeld M,

signalling in atherosclerosis. Thrombosis and haemostasis.

[52] Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology. 2007 Oct;7(10):803-15.

[53] Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Developmental cell. 2009

[54] Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vascular health and risk management.

[55] Bombeli T, Mueller M, Haeberli A. Anticoagulant properties of the vascular

[56] Nawroth PP, Handley D, Stern DM. The multiple levels of endothelial cell-coagulation factor interactions. Clinics in haematology. 1986 May

endothelium. Thrombosis and haemostasis. 1997;77(03):408-23.

2009;102(08):215-22.

Feb 17;16(2):209-21.

2005 Sep;1(3):183.

1;15(2):293-321.

atherosclerosis. Circulation. 2004 Jun

Grothusen C, Grote K, Schieffer B. How much is too much? Interleukin-6 and its

1;18(suppl\_E):19-29.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

pp. 217-226). Copyright© 1998 by Thieme Medical Publishers, Inc..

[41] Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1, 25-Dihydroxyvitamin D 3 is a negative endocrine regulator of the renin-angiotensin system. The Journal of clinical investigation. 2002 Jul

[42] Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC. Increased NF-κB activity in fibroblasts lacking the vitamin D receptor. American Journal of Physiology-Endocrinology

[43] Aihara KI, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T, Hayashi H, Yamada Y, Endoh F, Fujimura M, Yoshida T. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. Journal of Biological Chemistry. 2004

[44] Silvagno F, De Vivo E, Attanasio A, Gallo V, Mazzucco G, Pescarmona G. Mitochondrial localization of vitamin D

25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort. PloS one. 2010 May 24;5(5):e10801.

[46] Stewart GJ. Neutrophils and deep venous thrombosis. Pathophysiology of

[47] Pabinger I, Ay C. Biomarkers and

Haemostasis and Thrombosis. 1993;23(Suppl. 1):127-40.

venous thromboembolism. Arteriosclerosis, thrombosis, and vascular biology. 2009 Mar

15;110(2):229-38.

and Metabolism. 2006 Aug;291(2):E315-22.

Aug 20;279(34):35798-802.

receptor in human platelets and differentiated megakaryocytes. PLoS

One. 2010 Jan 13;5(1):e8670.

[45] Hyppönen E, Berry D, Cortina-Borja M, Power C. *Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

pp. 217-226). Copyright© 1998 by Thieme Medical Publishers, Inc..

*Vitamin D*

Antón AI, Iniesta JA, Herranz MT, Fernández N, Vicente V, Corral J.

deficiency. Plos one. 2016 Mar

22;11(3):e0152159.

Jul 19;357(3):266-81.

1;106(7):963-8.

1;109(3):359-63.

Dec;24(1):1-9.

Identification of regulatory mutations in SERPINC1 affecting vitamin D response elements associated with antithrombin

[34] Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, Doria A, Cervera R, Miesbach W, Stojanovich L, Barak V. Vitamin D: an instrumental factor in the anti-phospholipid

syndrome by inhibition of tissue factor expression. Annals of the Rheumatic Diseases. 2011 Jan 1;70(1):145-50.

[35] Beer TM, Venner PM, Ryan CW, Petrylak DP, Chatta G, Dean Ruether J, Chi KN, Curd JG, DeLoughery TG. High dose calcitriol may reduce thrombosis in cancer patients. British journal of haematology. 2006 Nov;135(3):392-4.

[36] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. InSeminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03, pp. 217-226). Copyright© 1998 by Thieme Medical Publishers, Inc.

[37] Maillard CH, Berruyer MI,

C at their cell membrane. Endocrinology. 1993 Aug

Deussen B, Muüschen A,

[38] Michel G, Gailis A, Jarzebska-

Research. 1997 Jan;46(1):32-4.

2005 Aug 1;26(5):662-87.

[40] Koyama T, Hirosawa S. Anticoagulant effects of synthetic retinoids and activated vitamin D3. InSeminars in thrombosis and hemostasis 1998 Jun (Vol. 24, No. 03,

Mirmohammadsadegh A, Ruzicka T. 1, 25-(OH) 2-vitamin D 3 and calcipotriol induce IL-10 receptor gene expression in human epidermal cells. Inflammation

[39] Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocrine reviews.

1;133(2):668-74.

Serre CM, Amiral JE, Dechavanne MA, Delmas PD. Thrombomodulin is synthesized by osteoblasts, stimulated by 1, 25-(OH) 2D3 and activates protein

[28] Holick MF. Vitamin D deficiency. New England Journal of Medicine. 2007

[29] Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein JB, Group IH. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. The American journal of cardiology. 2010 Oct

[30] Vacek JL, Vanga SR, Good M, Lai SM, Lakkireddy D, Howard PA.

[31] Kheiri B, Abdalla A, Osman M, Ahmed S, Hassan M, Bachuwa G. Vitamin D deficiency and risk of cardiovascular diseases: a narrative review. Clinical hypertension. 2018

[32] Lee JH, O'Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency: an important, common, and easily treatable cardiovascular risk factor?. Journal of the American College

[33] Pilz S, Tomaschitz A, März W, Drechsler C, Ritz E, Zittermann A, Cavalier E, Pieber TR, Lappe JM, Grant WB, Holick MF. Vitamin D, cardiovascular disease and mortality.

Clinical endocrinology. 2011

Nov;75(5):575-84.

of Cardiology. 2008 Dec 9;52(24):1949-56.

Vitamin D deficiency and supplementation and relation to cardiovascular health. The American journal of cardiology. 2012 Feb

**98**

[41] Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1, 25-Dihydroxyvitamin D 3 is a negative endocrine regulator of the renin-angiotensin system. The Journal of clinical investigation. 2002 Jul 15;110(2):229-38.

[42] Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC. Increased NF-κB activity in fibroblasts lacking the vitamin D receptor. American Journal of Physiology-Endocrinology and Metabolism. 2006 Aug;291(2):E315-22.

[43] Aihara KI, Azuma H, Akaike M, Ikeda Y, Yamashita M, Sudo T, Hayashi H, Yamada Y, Endoh F, Fujimura M, Yoshida T. Disruption of nuclear vitamin D receptor gene causes enhanced thrombogenicity in mice. Journal of Biological Chemistry. 2004 Aug 20;279(34):35798-802.

[44] Silvagno F, De Vivo E, Attanasio A, Gallo V, Mazzucco G, Pescarmona G. Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes. PLoS One. 2010 Jan 13;5(1):e8670.

[45] Hyppönen E, Berry D, Cortina-Borja M, Power C. 25-Hydroxyvitamin D and pre-clinical alterations in inflammatory and hemostatic markers: a cross sectional analysis in the 1958 British Birth Cohort. PloS one. 2010 May 24;5(5):e10801.

[46] Stewart GJ. Neutrophils and deep venous thrombosis. Pathophysiology of Haemostasis and Thrombosis. 1993;23(Suppl. 1):127-40.

[47] Pabinger I, Ay C. Biomarkers and venous thromboembolism. Arteriosclerosis, thrombosis, and vascular biology. 2009 Mar 1;29(3):332-6.

[48] Jorde R, Haug E, Figenschau Y, Hansen JB. Serum levels of vitamin D and haemostatic factors in healthy subjects: the Tromsø study. Acta haematologica. 2007;117(2):91-7.

[49] Vanhoutte PM. Endothelial dysfunction and atherosclerosis. European heart journal. 1997 Nov 1;18(suppl\_E):19-29.

[50] Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004 Jun 15;109(23\_suppl\_1):III-27.

[51] Schuett H, Luchtefeld M, Grothusen C, Grote K, Schieffer B. How much is too much? Interleukin-6 and its signalling in atherosclerosis. Thrombosis and haemostasis. 2009;102(08):215-22.

[52] Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nature Reviews Immunology. 2007 Oct;7(10):803-15.

[53] Dejana E, Tournier-Lasserve E, Weinstein BM. The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Developmental cell. 2009 Feb 17;16(2):209-21.

[54] Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vascular health and risk management. 2005 Sep;1(3):183.

[55] Bombeli T, Mueller M, Haeberli A. Anticoagulant properties of the vascular endothelium. Thrombosis and haemostasis. 1997;77(03):408-23.

[56] Nawroth PP, Handley D, Stern DM. The multiple levels of endothelial cell-coagulation factor interactions. Clinics in haematology. 1986 May 1;15(2):293-321.

[57] Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M. Synthesis of 1, 25-dihydroxyvitamin D3 by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. Journal of the American Society of Nephrology. 2002 Mar 1;13(3):621-9.

[58] Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension. 2011 Jan;57(1):63-9.

[59] Mitsuhashi T, Morris RC, Ives HE. 1, 25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. The Journal of clinical investigation. 1991 Jun 1;87(6):1889-95.

[60] Mantell DJ, Owens PE, Bundred NJ, Mawer EB, Canfield AE. 1α, 25-dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. Circulation research. 2000 Aug 4;87(3):214-20.

[61] Molinari C, Uberti F, Grossini E, Vacca G, Carda S, Invernizzi M, Cisari C. 1α, 25-dihydroxy cholecalciferol induces nitric oxide production in cultured endothelial cells. Cellular Physiology and Biochemistry. 2011;27(6):661-8.

[62] Andrukhova O, Slavic S, Zeitz U, Riesen SC, Heppelmann MS, Ambrisko TD, Markovic M, Kuebler WM, Erben RG. Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Molecular Endocrinology. 2014 Jan 1;28(1):53-64.

[63] Tarcin O, Yavuz DG, Ozben B, Telli A, Ogunc AV, Yuksel M, Toprak A, Yazici D, Sancak S, Deyneli O, Akalin S. Effect of vitamin D deficiency and

replacement on endothelial function in asymptomatic subjects. The Journal of Clinical endocrinology & metabolism. 2009 Oct 1;94(10):4023-30.

[64] Kamen DL, Oates J. A pilot randomized, controlled trial of vitamin D repletion to determine if endothelial function improves in patients with systemic lupus erythematosus. The American journal of the medical sciences. 2015 Oct;350(4):302.

[65] Carrara D, Bernini M, Bacca A, Rugani I, Duranti E, Virdis A, Ghiadoni L, Taddei S, Bernini G. Cholecalciferol administration blunts the systemic renin–angiotensin system in essential hypertensives with hypovitaminosis D. Journal of the Renin-Angiotensin-Aldosterone System. 2014 Mar;15(1):82-7.

[66] Chitalia N, Ismail T, Tooth L, Boa F, Hampson G, Goldsmith D, Kaski JC, Banerjee D. Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PloS one. 2014 Mar 19;9(3):e91363.

[67] Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, Li K, Bassali R, Guo DH, Thomas J, Pierce GL. A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness. The Journal of Clinical Endocrinology & Metabolism. 2010 Oct 1;95(10):4584-91.

[68] Carrara D, Bruno RM, Bacca A, Taddei S, Duranti E, Ghiadoni L, Bernini G. Cholecalciferol treatment downregulates renin–angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D. Journal of hypertension. 2016 Nov 1;34(11):2199-205.

**101**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

injury via the PPAR-γ/HO-1 pathway.

[76] Liang B, Wang X, Zhang N, Yang H, Bai R, Liu M, Bian Y, Xiao C, Yang Z.

angiotensin II-induced ICAM-1, VCAM-1, and MCP-1 expression via the MAS receptor through suppression of P38 and NF-κB pathways in HUVECs. Cellular Physiology and Biochemistry.

[77] Bozic M, Álvarez Á, de Pablo C, Sanchez-Niño MD, Ortiz A, Dolcet X, Encinas M, Fernandez E, Valdivielso JM.

Impaired vitamin D signaling in endothelial cell leads to an enhanced leukocyte-endothelium interplay: implications for atherosclerosis development. PLoS One. 2015 Aug

[78] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Archives of internal medicine.

2007 Sep 10;167(16):1730-7.

[79] Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D

and calcium supplementation in prevention of cardiovascular events. Annals of internal medicine. 2010 Mar

[80] Hashemi SM, Mokhtari SM,

[81] Hammer Y, Soudry A, Levi A, Talmor-Barkan Y, Leshem-Lev D, Singer J, Kornowski R, Lev EI. Effect of vitamin D on endothelial progenitor cells function. PloS one. 2017 May

Sadeghi M, Foroozan R, Safari M. Effect of vitamin D therapy on endothelial function in ischemic heart disease female patients with vitamin D deficiency or insufficiency: A primary report. ARYA atherosclerosis. 2015

Journal of vascular research.

Angiotensin-(1-7) attenuates

2019;56(1):17-27.

2015;35(6):2472-82.

31;10(8):e0136863.

2;152(5):315-23.

Jan;11(1):54.

17;12(5):e0178057.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

[69] Gibson CC, Davis CT, Zhu W, Bowman-Kirigin JA, Walker AE, Tai Z, Thomas KR, Donato AJ, Lesniewski LA,

Li DY. Dietary vitamin D and its metabolites non-genomically stabilize the endothelium. PloS one. 2015 Oct

[70] Kanikarla-Marie P, Jain SK. 1, 25 (OH) 2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with

acetoacetate (ketosis). The Journal of steroid biochemistry and molecular biology. 2016 May 1;159:94-101.

25-Dihydroxyvitamin D3 decreased ICAM-1 and ELAM-1 expressions on pulmonary microvascular endothelial cells and neutrophil motivation. The Journal of steroid biochemistry and

[72] Rahman A, Fazal F. Blocking NF-κB: an inflammatory issue. Proceedings of the American Thoracic Society. 2011

[73] Equils O, Naiki Y, Shapiro AM, Michelsen K, Lu D, Adams J, Jordan S. 1, 25-Dihydroxyvitamin D3 inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clinical & Experimental Immunology.

[74] Suzuki Y, Ichiyama T, Ohsaki A, Hasegawa S, Shiraishi M, Furukawa S. Anti-inflammatory effect of 1α, 25-dihydroxyvitamin D3 in human coronary arterial endothelial cells: Implication for the treatment of

Kawasaki disease. The Journal of steroid biochemistry and molecular biology.

[75] Xu W, Hu X, Qi X, Zhu R, Li C, Zhu Y, Yin S, Cheng L, Zhu R. Vitamin D ameliorates angiotensin II-induced human endothelial progenitor cell

15;10(10):e0140370.

[71] Chen SF. 1 alpha,

molecular biology. 1995 Jan

1;52(1):67-70.

Nov 1;8(6):497-503.

2006 Jan;143(1):58-64.

2009 Jan 1;113(1-2):134-8.

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

[69] Gibson CC, Davis CT, Zhu W, Bowman-Kirigin JA, Walker AE, Tai Z, Thomas KR, Donato AJ, Lesniewski LA, Li DY. Dietary vitamin D and its metabolites non-genomically stabilize the endothelium. PloS one. 2015 Oct 15;10(10):e0140370.

[70] Kanikarla-Marie P, Jain SK. 1, 25 (OH) 2D3 inhibits oxidative stress and monocyte adhesion by mediating the upregulation of GCLC and GSH in endothelial cells treated with acetoacetate (ketosis). The Journal of steroid biochemistry and molecular biology. 2016 May 1;159:94-101.

[71] Chen SF. 1 alpha,

*Vitamin D*

1;13(3):621-9.

[57] Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM, Hewison M. Synthesis of 1, 25-dihydroxyvitamin D3 by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. Journal of the American Society of Nephrology. 2002 Mar

replacement on endothelial function in asymptomatic subjects. The Journal of Clinical endocrinology & metabolism.

randomized, controlled trial of vitamin D repletion to determine if endothelial function improves in patients with systemic lupus erythematosus. The American journal of the medical sciences. 2015 Oct;350(4):302.

[65] Carrara D, Bernini M, Bacca A, Rugani I, Duranti E, Virdis A, Ghiadoni L, Taddei S, Bernini G. Cholecalciferol administration blunts the systemic renin–angiotensin system

in essential hypertensives with hypovitaminosis D. Journal of the Renin-Angiotensin-Aldosterone System.

[66] Chitalia N, Ismail T, Tooth L, Boa F, Hampson G, Goldsmith D, Kaski JC, Banerjee D. Impact of vitamin D supplementation on arterial

vasomotion, stiffness and endothelial biomarkers in chronic kidney disease

[67] Dong Y, Stallmann-Jorgensen IS, Pollock NK, Harris RA, Keeton D, Huang Y, Li K, Bassali R, Guo DH, Thomas J, Pierce GL. A 16-week randomized clinical trial of 2000 international units daily vitamin D3 supplementation in black youth: 25-hydroxyvitamin D, adiposity, and arterial stiffness. The Journal of Clinical Endocrinology & Metabolism. 2010 Oct

[68] Carrara D, Bruno RM, Bacca A, Taddei S, Duranti E, Ghiadoni L, Bernini G. Cholecalciferol treatment downregulates renin–angiotensin system and improves endothelial function in essential hypertensive patients with hypovitaminosid D. Journal of hypertension. 2016 Nov

patients. PloS one. 2014 Mar

19;9(3):e91363.

1;95(10):4584-91.

1;34(11):2199-205.

2014 Mar;15(1):82-7.

2009 Oct 1;94(10):4023-30.

[64] Kamen DL, Oates J. A pilot

[58] Jablonski KL, Chonchol M, Pierce GL, Walker AE, Seals DR. 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension. 2011 Jan;57(1):63-9.

1991 Jun 1;87(6):1889-95.

Mawer EB, Canfield AE. 1α, 25-dihydroxyvitamin D3 inhibits angiogenesis in vitro and in vivo. Circulation research. 2000 Aug

4;87(3):214-20.

2011;27(6):661-8.

1;28(1):53-64.

[59] Mitsuhashi T, Morris RC, Ives HE. 1, 25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells. The Journal of clinical investigation.

[60] Mantell DJ, Owens PE, Bundred NJ,

[61] Molinari C, Uberti F, Grossini E, Vacca G, Carda S, Invernizzi M, Cisari C. 1α, 25-dihydroxy

cholecalciferol induces nitric oxide production in cultured endothelial cells. Cellular Physiology and Biochemistry.

[62] Andrukhova O, Slavic S, Zeitz U,

Kuebler WM, Erben RG. Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Molecular Endocrinology. 2014 Jan

[63] Tarcin O, Yavuz DG, Ozben B, Telli A, Ogunc AV, Yuksel M, Toprak A, Yazici D, Sancak S, Deyneli O, Akalin S. Effect of vitamin D deficiency and

Riesen SC, Heppelmann MS, Ambrisko TD, Markovic M,

**100**

25-Dihydroxyvitamin D3 decreased ICAM-1 and ELAM-1 expressions on pulmonary microvascular endothelial cells and neutrophil motivation. The Journal of steroid biochemistry and molecular biology. 1995 Jan 1;52(1):67-70.

[72] Rahman A, Fazal F. Blocking NF-κB: an inflammatory issue. Proceedings of the American Thoracic Society. 2011 Nov 1;8(6):497-503.

[73] Equils O, Naiki Y, Shapiro AM, Michelsen K, Lu D, Adams J, Jordan S. 1, 25-Dihydroxyvitamin D3 inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clinical & Experimental Immunology. 2006 Jan;143(1):58-64.

[74] Suzuki Y, Ichiyama T, Ohsaki A, Hasegawa S, Shiraishi M, Furukawa S. Anti-inflammatory effect of 1α, 25-dihydroxyvitamin D3 in human coronary arterial endothelial cells: Implication for the treatment of Kawasaki disease. The Journal of steroid biochemistry and molecular biology. 2009 Jan 1;113(1-2):134-8.

[75] Xu W, Hu X, Qi X, Zhu R, Li C, Zhu Y, Yin S, Cheng L, Zhu R. Vitamin D ameliorates angiotensin II-induced human endothelial progenitor cell

injury via the PPAR-γ/HO-1 pathway. Journal of vascular research. 2019;56(1):17-27.

[76] Liang B, Wang X, Zhang N, Yang H, Bai R, Liu M, Bian Y, Xiao C, Yang Z. Angiotensin-(1-7) attenuates angiotensin II-induced ICAM-1, VCAM-1, and MCP-1 expression via the MAS receptor through suppression of P38 and NF-κB pathways in HUVECs. Cellular Physiology and Biochemistry. 2015;35(6):2472-82.

[77] Bozic M, Álvarez Á, de Pablo C, Sanchez-Niño MD, Ortiz A, Dolcet X, Encinas M, Fernandez E, Valdivielso JM. Impaired vitamin D signaling in endothelial cell leads to an enhanced leukocyte-endothelium interplay: implications for atherosclerosis development. PLoS One. 2015 Aug 31;10(8):e0136863.

[78] Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Archives of internal medicine. 2007 Sep 10;167(16):1730-7.

[79] Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Annals of internal medicine. 2010 Mar 2;152(5):315-23.

[80] Hashemi SM, Mokhtari SM, Sadeghi M, Foroozan R, Safari M. Effect of vitamin D therapy on endothelial function in ischemic heart disease female patients with vitamin D deficiency or insufficiency: A primary report. ARYA atherosclerosis. 2015 Jan;11(1):54.

[81] Hammer Y, Soudry A, Levi A, Talmor-Barkan Y, Leshem-Lev D, Singer J, Kornowski R, Lev EI. Effect of vitamin D on endothelial progenitor cells function. PloS one. 2017 May 17;12(5):e0178057.

[82] Vila Cuenca M, Ferrantelli E, Meinster E, Pouw SM, Kovačević I, de Menezes RX, Niessen HW, Beelen RH, Hordijk PL, Vervloet MG. Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability. Journal of the American Heart Association. 2018 Sep 4;7(17):e008776.

[83] Kirchhofer D, Tschopp TB, Hadvary P, Baumgartner HR. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogenous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors. The Journal of clinical investigation. 1994 May 1;93(5):2073-83.

[84] Yamamoto K, Shimokawa T, Kojima T, Loskutoff DJ, Saito H. Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor-α, interleukin-1, and transforming growth factor-β. Thrombosis and haemostasis. 1999;82(10):1297-301.

[85] van Hinsbergh VW. Endothelium role in regulation of coagulation and inflammation. InSeminars in immunopathology 2012 Jan (Vol. 34, No. 1, pp. 93-106). Springer-Verlag.

[86] Eilertsen KE, Østerud B. Tissue factor:(patho) physiology and cellular biology. Blood coagulation & fibrinolysis. 2004 Oct 1;15(7):521-38.

[87] Darbousset R, Thomas GM, Mezouar S, Frere C, Bonier R, Mackman N, Renné T, Dignat-George F, Dubois C, Panicot-Dubois L. Tissue factor–positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood, The Journal of the American Society of Hematology. 2012 Sep 6;120(10):2133-43.

[88] Hewison M. An update on vitamin D and human immunity. Clinical endocrinology. 2012 Mar;76(3):315-25.

[89] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition. 2008 Apr 1;87(4):1080S–6S.

[90] Veldman CM, Cantorna MT, DeLuca HF. Expression of 1, 25-dihydroxyvitamin D3 receptor in the immune system. Archives of biochemistry and biophysics. 2000 Feb 15;374(2):334-8.

[91] Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. Journal of cellular biochemistry. 2003 Aug 1;89(5):922-32.

[92] van Etten E, Mathieu C. Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts. The Journal of steroid biochemistry and molecular biology. 2005 Oct 1;97(1-2):93-101.

[93] Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nature clinical practice Endocrinology & metabolism. 2008 Feb;4(2):80-90.

[94] Dutta D, Mondal SA, Choudhuri S, Maisnam I, Reza AH, Bhattacharya B, Chowdhury S, Mukhopadhyay S. Vitamin-D supplementation in prediabetes reduced progression to type 2 diabetes and was associated with decreased insulin resistance and systemic inflammation: an open label randomized prospective study from Eastern India. Diabetes research and clinical practice. 2014 Mar 1;103(3):e18-23.

[95] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype:

**103**

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

1;12(4):721.

15;109(2):226-30.

and inflammation: evaluation with neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. Archives of medical science: AMS. 2016 Aug

[103] Amer M, Qayyum R. Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006). The American journal of cardiology. 2012 Jan

[104] Laird E, McNulty H, Ward M, Hoey L, McSorley E, Wallace JM, Carson E, Molloy AM, Healy M, Casey MC, Cunningham C. Vitamin D

inflammation in older Irish adults. The Journal of Clinical Endocrinology & Metabolism. 2014 May 1;99(5):1807-15.

[105] Bellia A, Garcovich C, D'Adamo M, Lombardo M, Tesauro M, Donadel G, Gentileschi P, Lauro D, Federici M,

[106] Jorde R, Sneve M, Torjesen PA, Figenschau Y, Gøransson LG, Omdal R. No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects. Cytokine. 2010 May

[107] Ward KA, Das G, Roberts SA, Berry JL, Adams JE, Rawer R,

Mughal MZ. A randomized, controlled trial of vitamin D supplementation upon musculoskeletal health in

postmenarchal females. The Journal of Clinical Endocrinology & Metabolism.

photobiology, metabolism of action,

2010 Oct 1;95(10):4643-51.

[108] Holick MF. Vitamin D:

deficiency is associated with

Lauro R, Sbraccia P. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Internal and emergency medicine. 2013

Feb;8(1):33-40.

1;50(2):175-80.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

mechanisms for inflammatory damage in chronic disorders?. Qjm. 2002 Dec

Shariatzadeh N, Khalaji N, Gharavi AA. Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects

metabolism research and reviews. 2012

[97] Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent association of low serum 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Archives of internal medicine. 2008 Jun

[98] Ponsonby AL, McMichael A, Van Der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology.

[99] Staples JA, Ponsonby AL, Lim LL, McMichael AJ. Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environmental

[96] Shab-Bidar S, Neyestani TR, Djazayery A, Eshraghian MR, Houshiarrad A, Kalayi A,

with type 2 diabetes. Diabetes/

1;95(12):787-96.

Jul;28(5):424-30.

23;168(12):1340-9.

2002 Dec 27;181:71-8.

Health Perspectives. 2003

Research. 2011 Jul;1(2):71.

[100] Boucher BJ. The problems of vitamin d insufficiency in older people. Aging and disease. 2012 Aug;3(4):313.

[101] Dudani SJ, Kalhan S, Sharma SP. Vitamin D and multiple sclerosis: Potential pathophysiological role and clinical implications. International Journal of Applied and Basic Medical

[102] Akbas EM, Gungor A, Ozcicek A, Akbas N, Askin S, Polat M. Vitamin D

Apr;111(4):518-23.

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

mechanisms for inflammatory damage in chronic disorders?. Qjm. 2002 Dec 1;95(12):787-96.

*Vitamin D*

4;7(17):e008776.

[82] Vila Cuenca M, Ferrantelli E, Meinster E, Pouw SM, Kovačević I, de Menezes RX, Niessen HW, Beelen RH, Hordijk PL, Vervloet MG. Vitamin D attenuates endothelial dysfunction in uremic rats and maintains human endothelial stability. Journal of the American Heart Association. 2018 Sep [89] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. The American journal of clinical nutrition. 2008 Apr

[90] Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,

immune system. Archives of

25-dihydroxyvitamin D3 receptor in the

biochemistry and biophysics. 2000 Feb

[91] Mahon BD, Wittke A, Weaver V, Cantorna MT. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. Journal of cellular biochemistry. 2003

1;87(4):1080S–6S.

15;374(2):334-8.

Aug 1;89(5):922-32.

[92] van Etten E, Mathieu C. Immunoregulation by 1, 25-dihydroxyvitamin D3: basic concepts. The Journal of steroid biochemistry and molecular biology.

2005 Oct 1;97(1-2):93-101.

Feb;4(2):80-90.

[93] Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nature clinical practice Endocrinology & metabolism. 2008

[94] Dutta D, Mondal SA, Choudhuri S, Maisnam I, Reza AH, Bhattacharya B, Chowdhury S, Mukhopadhyay S. Vitamin-D supplementation in

prediabetes reduced progression to type 2 diabetes and was associated with decreased insulin resistance and systemic inflammation: an open label randomized prospective study from Eastern India. Diabetes research and

clinical practice. 2014 Mar

[95] Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, Aganna E, Price CP, Boucher BJ. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype:

1;103(3):e18-23.

[83] Kirchhofer D, Tschopp TB,

1994 May 1;93(5):2073-83.

1999;82(10):1297-301.

inflammation. InSeminars in

biology. Blood coagulation & fibrinolysis. 2004 Oct 1;15(7):521-38.

[87] Darbousset R, Thomas GM, Mezouar S, Frere C, Bonier R,

2012 Sep 6;120(10):2133-43.

Mackman N, Renné T, Dignat-George F, Dubois C, Panicot-Dubois L. Tissue factor–positive neutrophils bind to injured endothelial wall and initiate thrombus formation. Blood, The Journal of the American Society of Hematology.

[88] Hewison M. An update on vitamin D and human immunity. Clinical endocrinology. 2012 Mar;76(3):315-25.

[84] Yamamoto K, Shimokawa T, Kojima T, Loskutoff DJ, Saito H. Regulation of murine protein C gene expression in vivo: effects of tumor necrosis factor-α, interleukin-1, and transforming growth factor-β. Thrombosis and haemostasis.

[85] van Hinsbergh VW. Endothelium role in regulation of coagulation and

immunopathology 2012 Jan (Vol. 34, No. 1, pp. 93-106). Springer-Verlag.

[86] Eilertsen KE, Østerud B. Tissue factor:(patho) physiology and cellular

Hadvary P, Baumgartner HR. Endothelial cells stimulated with tumor necrosis factor-alpha express varying amounts of tissue factor resulting in inhomogenous fibrin deposition in a native blood flow system. Effects of thrombin inhibitors. The Journal of clinical investigation.

**102**

[96] Shab-Bidar S, Neyestani TR, Djazayery A, Eshraghian MR, Houshiarrad A, Kalayi A, Shariatzadeh N, Khalaji N, Gharavi AA. Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects with type 2 diabetes. Diabetes/ metabolism research and reviews. 2012 Jul;28(5):424-30.

[97] Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent association of low serum 25-hydroxyvitamin D and 1, 25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Archives of internal medicine. 2008 Jun 23;168(12):1340-9.

[98] Ponsonby AL, McMichael A, Van Der Mei I. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology. 2002 Dec 27;181:71-8.

[99] Staples JA, Ponsonby AL, Lim LL, McMichael AJ. Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environmental Health Perspectives. 2003 Apr;111(4):518-23.

[100] Boucher BJ. The problems of vitamin d insufficiency in older people. Aging and disease. 2012 Aug;3(4):313.

[101] Dudani SJ, Kalhan S, Sharma SP. Vitamin D and multiple sclerosis: Potential pathophysiological role and clinical implications. International Journal of Applied and Basic Medical Research. 2011 Jul;1(2):71.

[102] Akbas EM, Gungor A, Ozcicek A, Akbas N, Askin S, Polat M. Vitamin D

and inflammation: evaluation with neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio. Archives of medical science: AMS. 2016 Aug 1;12(4):721.

[103] Amer M, Qayyum R. Relation between serum 25-hydroxyvitamin D and C-reactive protein in asymptomatic adults (from the continuous National Health and Nutrition Examination Survey 2001 to 2006). The American journal of cardiology. 2012 Jan 15;109(2):226-30.

[104] Laird E, McNulty H, Ward M, Hoey L, McSorley E, Wallace JM, Carson E, Molloy AM, Healy M, Casey MC, Cunningham C. Vitamin D deficiency is associated with inflammation in older Irish adults. The Journal of Clinical Endocrinology & Metabolism. 2014 May 1;99(5):1807-15.

[105] Bellia A, Garcovich C, D'Adamo M, Lombardo M, Tesauro M, Donadel G, Gentileschi P, Lauro D, Federici M, Lauro R, Sbraccia P. Serum 25-hydroxyvitamin D levels are inversely associated with systemic inflammation in severe obese subjects. Internal and emergency medicine. 2013 Feb;8(1):33-40.

[106] Jorde R, Sneve M, Torjesen PA, Figenschau Y, Gøransson LG, Omdal R. No effect of supplementation with cholecalciferol on cytokines and markers of inflammation in overweight and obese subjects. Cytokine. 2010 May 1;50(2):175-80.

[107] Ward KA, Das G, Roberts SA, Berry JL, Adams JE, Rawer R, Mughal MZ. A randomized, controlled trial of vitamin D supplementation upon musculoskeletal health in postmenarchal females. The Journal of Clinical Endocrinology & Metabolism. 2010 Oct 1;95(10):4643-51.

[108] Holick MF. Vitamin D: photobiology, metabolism of action, and clinical applications. Primer on the Metabolic Bone Diseases. 1999.

[109] Feldman D, Malloy PJ, Gross C. Vitamin D: biology, action, and clinical implications. InOsteoporosis 2001 Jan 1 (pp. 257-303). Academic Press.

[110] DeLuca HF. Overview of general physiologic features and functions of vitamin D. The American journal of clinical nutrition. 2004 Dec 1;80(6):1689S–96S.

[111] Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocrine reviews. 2008 Oct 1;29(6):726-76.

[112] Mussolino ME, Gillum RF. Low bone mineral density and mortality in men and women: the Third National Health and Nutrition Examination Survey linked mortality file. Annals of epidemiology. 2008 Nov 1;18(11):847-50.

[113] Suzuki T, Yoshida H. Low bone mineral density at femoral neck is a predictor of increased mortality in elderly Japanese women. Osteoporosis international. 2010 Jan;21(1):71-9.

[114] Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. Jama. 2005 May 11;293(18):2257-64.

[115] Nieves J, Cosman F, Herbert J, Shen V, Lindsay R. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology. 1994 Sep 1;44(9):1687-.

[116] Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific

musculoskeletal pain. InMayo clinic proceedings 2003 Dec 1 (Vol. 78, No. 12, pp. 1463-1470). Elsevier.

[117] Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. The American journal of clinical nutrition. 2006 Jun 1;84(1):18-28.

[118] Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin D reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. Journal of the American Geriatrics Society. 2007 Feb;55(2):234-9.

[119] Carthy EP, Yamashita W, Hsu A, Ooi BS. 1, 25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth. Hypertension. 1989 Jun;13(6\_pt\_2):954-9.

[120] Michos ED, Melamed ML. Vitamin D and cardiovascular disease risk. Current Opinion in Clinical Nutrition & Metabolic Care. 2008 Jan 1;11(1):7-12.

[121] Kuneš J, Tremblay J, Bellavance F, Hamet P. Influence of environmental temperature on the blood pressure of hypertensive patients in Montreal. American journal of hypertension. 1991 May 1;4(5\_Pt\_1):422-6.

[122] Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet (British edition). 1998;352(9129):709-10.

[123] McAlpine D, Compston A. McAlpine's multiple sclerosis. Elsevier Health Sciences; 2005.

[124] Gale CR, Martyn CN. Migrant studies in multiple sclerosis. Progress in

**105**

1;14:35-45.

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases*

Lancet Neurology. 2010 Jun

1980 Sep 1;9(3):227-31.

[134] Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Preventive medicine. 1990 Nov 1;19(6):614-22.

[135] LEFKOWITZ ES, Garland CF. Sunlight, vitamin D, and ovarian cancer

International journal of epidemiology.

[136] Young MR, Halpin J, Hussain R, Lozano Y, Djordjevic A, Devata S, Matthews JP, Wright MA. Inhibition of tumor production of granulocytemacrophage colony-stimulating factor by 1 alpha, 25-dihydroxyvitamin D3 reduces tumor motility and metastasis. Invasion & metastasis. 1993 Jan

mortality rates in US women.

[137] Evans SR, Shchepotin EI,

D3 synthetic analogs inhibit spontaneous metastases in a 1, 2-dimethylhydrazine-induced colon carcinogenesis model. International journal of oncology. 2000 Jun

Young HE, Rochon JA, Uskokovic MI, Shchepotin IB. 1, 25-dihydroxyvitamin

[138] FUJIOKA T, HASEGAWA M, ISHIKURA K, MATSUSHITA Y, SATO M, TANJI S. Inhibition of tumor growth and angiogenesis by vitamin D3 agents in murine renal cell carcinoma. The Journal of urology. 1998 Jul;160(1):247- 51. Sundaram S, Sea A, Feldman S,

Strawbridge R, Hoopes PJ,

Demidenko E, Binderup L, Gewirtz DA. The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation

1994 Dec 1;23(6):1133-6.

1;13(4):169-77.

1;16(6):1249-303.

[133] Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer?.

International journal of epidemiology.

1;9(6):599-612.

*DOI: http://dx.doi.org/10.5772/intechopen.97299*

neurobiology. 1995 Nov 1;47(4-5):425-48.

Nov;35(S147):132-47.

1983 Jan 1;36(8):551-9.

vitamin D and calcium as environmental determinants of prevalence: (A viewpoint) part 2. biochemical and genetic factors. International Journal of Environmental

[125] Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatrica Scandinavica. 1960

[126] Norman Jr JE, Kurtzke JF, Beebe GW. Epidemiology of multiple sclerosis in US veterans: 2. Latitude, climate and the risk of multiple sclerosis. Journal of chronic diseases.

[127] Goldberg P. Multiple sclerosis:

Studies. 1974 Jan 1;6(2-3):121-9.

[128] Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatrica Scandinavica. 1960

[129] Sutherland JM, Tyrer JH, Eadie MJ. The prevalence of multiple sclerosis in

[130] VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. European journal of clinical nutrition. 2004

Souberbielle JC. Vitamin D and multiple sclerosis: an update. Multiple sclerosis and related disorders. 2017 May

[132] Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. The

Nov;35(S147):132-47.

1;85(1):149-64.

Aug;58(8):1095-109.

[131] Pierrot-Deseilligny C,

Australia. Brain. 1962 Mar

*Vitamin D and Its Relationship with the Pathways Related to Thrombosis and Various Diseases DOI: http://dx.doi.org/10.5772/intechopen.97299*

neurobiology. 1995 Nov 1;47(4-5):425-48.

*Vitamin D*

and clinical applications. Primer on the

musculoskeletal pain. InMayo clinic proceedings 2003 Dec 1 (Vol. 78, No. 12,

Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. The American journal

pp. 1463-1470). Elsevier.

[117] Bischoff-Ferrari HA,

of clinical nutrition. 2006 Jun

study. Journal of the American Geriatrics Society. 2007

[119] Carthy EP, Yamashita W, Hsu A, Ooi BS. 1, 25-Dihydroxyvitamin D3 and rat vascular smooth muscle cell growth.

[120] Michos ED, Melamed ML. Vitamin D and cardiovascular disease risk. Current Opinion in Clinical Nutrition

[121] Kuneš J, Tremblay J, Bellavance F, Hamet P. Influence of environmental temperature on the blood pressure of hypertensive patients in Montreal. American journal of hypertension. 1991

Sharma AM. Ultraviolet B and blood pressure. Lancet (British edition).

[123] McAlpine D, Compston A. McAlpine's multiple sclerosis. Elsevier

[124] Gale CR, Martyn CN. Migrant studies in multiple sclerosis. Progress in

[118] Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin D reduces the risk of falls in nursing home residents: a randomized, multiple-dose

1;84(1):18-28.

Feb;55(2):234-9.

Hypertension. 1989 Jun;13(6\_pt\_2):954-9.

1;11(1):7-12.

& Metabolic Care. 2008 Jan

May 1;4(5\_Pt\_1):422-6.

1998;352(9129):709-10.

Health Sciences; 2005.

[122] Krause R, Bühring M, Hopfenmüller W, Holick MF,

[109] Feldman D, Malloy PJ, Gross C. Vitamin D: biology, action, and clinical implications. InOsteoporosis 2001 Jan 1

[110] DeLuca HF. Overview of general physiologic features and functions of vitamin D. The American journal of

Verlinden L, van Etten E, Verstuyf A, Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocrine reviews. 2008 Oct

[112] Mussolino ME, Gillum RF. Low bone mineral density and mortality in men and women: the Third National Health and Nutrition Examination Survey linked mortality file. Annals of

[113] Suzuki T, Yoshida H. Low bone mineral density at femoral neck is a predictor of increased mortality in elderly Japanese women. Osteoporosis international. 2010 Jan;21(1):71-9.

[114] Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled

[115] Nieves J, Cosman F, Herbert J, Shen V, Lindsay R. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology.

[116] Plotnikoff GA, Quigley JM.

Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific

epidemiology. 2008 Nov

trials. Jama. 2005 May 11;293(18):2257-64.

1994 Sep 1;44(9):1687-.

1;18(11):847-50.

Metabolic Bone Diseases. 1999.

(pp. 257-303). Academic Press.

clinical nutrition. 2004 Dec

[111] Bouillon R, Carmeliet G,

1;80(6):1689S–96S.

1;29(6):726-76.

**104**

[125] Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatrica Scandinavica. 1960 Nov;35(S147):132-47.

[126] Norman Jr JE, Kurtzke JF, Beebe GW. Epidemiology of multiple sclerosis in US veterans: 2. Latitude, climate and the risk of multiple sclerosis. Journal of chronic diseases. 1983 Jan 1;36(8):551-9.

[127] Goldberg P. Multiple sclerosis: vitamin D and calcium as environmental determinants of prevalence: (A viewpoint) part 2. biochemical and genetic factors. International Journal of Environmental Studies. 1974 Jan 1;6(2-3):121-9.

[128] Acheson ED, Bachrach CA, Wright FM. Some comments on the relationship of the distribution of multiple sclerosis to latitude, solar radiation, and other variables. Acta Psychiatrica Scandinavica. 1960 Nov;35(S147):132-47.

[129] Sutherland JM, Tyrer JH, Eadie MJ. The prevalence of multiple sclerosis in Australia. Brain. 1962 Mar 1;85(1):149-64.

[130] VanAmerongen BM, Dijkstra CD, Lips P, Polman CH. Multiple sclerosis and vitamin D: an update. European journal of clinical nutrition. 2004 Aug;58(8):1095-109.

[131] Pierrot-Deseilligny C, Souberbielle JC. Vitamin D and multiple sclerosis: an update. Multiple sclerosis and related disorders. 2017 May 1;14:35-45.

[132] Ascherio A, Munger KL, Simon KC. Vitamin D and multiple sclerosis. The

Lancet Neurology. 2010 Jun 1;9(6):599-612.

[133] Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer?. International journal of epidemiology. 1980 Sep 1;9(3):227-31.

[134] Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Preventive medicine. 1990 Nov 1;19(6):614-22.

[135] LEFKOWITZ ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in US women. International journal of epidemiology. 1994 Dec 1;23(6):1133-6.

[136] Young MR, Halpin J, Hussain R, Lozano Y, Djordjevic A, Devata S, Matthews JP, Wright MA. Inhibition of tumor production of granulocytemacrophage colony-stimulating factor by 1 alpha, 25-dihydroxyvitamin D3 reduces tumor motility and metastasis. Invasion & metastasis. 1993 Jan 1;13(4):169-77.

[137] Evans SR, Shchepotin EI, Young HE, Rochon JA, Uskokovic MI, Shchepotin IB. 1, 25-dihydroxyvitamin D3 synthetic analogs inhibit spontaneous metastases in a 1, 2-dimethylhydrazine-induced colon carcinogenesis model. International journal of oncology. 2000 Jun 1;16(6):1249-303.

[138] FUJIOKA T, HASEGAWA M, ISHIKURA K, MATSUSHITA Y, SATO M, TANJI S. Inhibition of tumor growth and angiogenesis by vitamin D3 agents in murine renal cell carcinoma. The Journal of urology. 1998 Jul;160(1):247- 51. Sundaram S, Sea A, Feldman S, Strawbridge R, Hoopes PJ, Demidenko E, Binderup L, Gewirtz DA. The combination of a potent vitamin D3 analog, EB 1089, with ionizing radiation reduces tumor growth and induces apoptosis of MCF-7 breast tumor xenografts in nude mice. Clinical Cancer Research. 2003 Jun 1;9(6):2350-6.

[139] Holick MF. Vitamin D: its role in cancer prevention and treatment. Progress in biophysics and molecular biology. 2006 Sep 1;92(1):49-59.

[140] Feskanich D, Ma J, Fuchs CS, Kirkner GJ, Hankinson SE, Hollis BW, Giovannucci EL. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiology and Prevention Biomarkers. 2004 Sep 1;13(9):1502-8.

[141] John EM, Schwartz GG, Dreon DM, Koo J. Vitamin D and breast cancer risk: the NHANES I epidemiologic follow-up study, 1971-1975 to 1992. Cancer Epidemiology and Prevention Biomarkers. 1999 May 1;8(5):399-406.

[142] Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes care. 2004 May 1;27(5):1047-53.

[143] Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ. Vitamin D in the treatment of pulmonary tuberculosis. The Journal of steroid biochemistry and molecular biology. 2007 Mar 1;103(3-5):793-8.

[144] Blondon M, Rodabough RJ, Budrys N, Johnson KC, Berger JS, Shikany JM, Raiesdana A, Heckbert SR, Manson JE, LaCroix AZ, Siscovick D. The Effect of Calcium plus vitamin D supplementation on the risk of venous thromboembolism in the Women's Health Initiative Randomized Controlled Trial. Thrombosis and haemostasis. 2015 May;113(5):999.

[145] Moscarelli L, Zanazzi M, Bertoni E, Caroti L, Rosso G, Farsetti S, Annunziata F, Paudice N, Salvadori M. Renin angiotensin system blockade and

activated vitamin D as a means of preventing deep vein thrombosis in renal transplant recipients. Clinical nephrology. 2011 May 1;75(5):440-50.

[146] Lindqvist PG, Epstein E, Olsson H. Does an active sun exposure habit lower the risk of venous thrombotic events? AD-lightful hypothesis. Journal of Thrombosis and Haemostasis. 2009 Apr;7(4):605-10.

[147] Brot C, Vestergaard P, Kolthoff N, Gram J, Hermann AP, Sørensen OH. Vitamin D status and its adequacy in healthy Danish perimenopausal women: relationships to dietary intake, sun exposure and serum parathyroid hormone. British Journal of Nutrition. 2001 Aug;86(S1):S97-103.

[148] Bilezikian JP, Bikle D, Hewison M, Lazaretti-Castro M, Formenti AM, Gupta A, Madhavan MV, Nair N, Babalyan V, Hutchings N, Napoli N. Mechanisms in endocrinology: vitamin D and COVID-19. European journal of endocrinology. 2020 Nov 1;183(5):R133-47.

[149] Lau FH, Majumder R, Torabi R, Saeg F, Hoffman R, Cirillo JD, Greiffenstein P. Vitamin D insufficiency is prevalent in severe COVID-19. MedRxiv. 2020 Jan 1.

[150] Lanham-New SA, Webb AR, Cashman KD, Buttriss JL, Fallowfield JL, Masud T, Hewison M, Mathers JC, Kiely M, Welch AA, Ward KA. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutrition, Prevention & Health. 2020;3(1):106.

[151] Aslan MT, Aslan İÖ, Özdemir Ö. Letter to the Editor: Is Vitamin D One of the Key Elements in COVID-19 Days? J Nutr Health Aging. 2020;24(9):1038- 1039. doi: 10.1007/s12603-020-1413-5. PMID: 33155635; PMCID: PMC7597430.

**107**

Section 3

Vitamin D and Dental

Medicine

### Section 3
