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<EMAIL_ADDRESS>
*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<EMAIL_ADDRESS>
© 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.

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[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.

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[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

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*83*, 565-571

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*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.

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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<EMAIL_ADDRESS>
© 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<EMAIL_ADDRESS>
© 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.

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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.

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

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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

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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.

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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.

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2018;10(8):2737-2746.

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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/101101/2<IP_ADDRESS>75838v1

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/101101/2<IP_ADDRESS>75838v1

[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.