Role of vitamin D in COVID-19 and other viral infections

Table 1 Effects of vitamin D supplementation on the immune system and other different conditions[25]

Immune system component	Effect
T cells	↓ Th 1/Th 17 and ↑ Th 2
	↓ IL-8, IFN-γ, IL-12, IL-6, TNF-α, IL-17
	↑ IL-4, IL-5, IL-10
	Recognition of viral dsRNA by TLR - 3
B cells	↑ Apoptosis
Plasma cells	↓ Proliferation and immunoglobulin secretion
Neutrophils, monocyte-macrophages and dendritic cells	Reception to infectious areas, ↑ TLR
	↑ Intracellular killing of Mycobacterium tuberculosis (macrophages)
Infected cells	↑ Autophagy and apoptosis
Antimicrobial peptides (human cathelicidin peptide LL - 37 and β-defensin)	Augmented
Respiratory tract infections	Effect
Acute respiratory infections	↓ Proinflammatory cytokines in the lung through modulation of the activity of both macrophages and T lymphocytes
	↓ Risk of getting sick
VAP	↓ IL-6
	↓ Mortality rate
Autoimmune disease	Effect on disease
Type 1 diabetes	Prevention of onset, ↓ serum antibody levels, delayed β cell destruction in early stages of disease
Multiple sclerosis	Prevention of the onset
Rheumatic joint inflammation	Prevention of onset, reduced disease activity
Systemic lupus erythematosus	Prevention of onset, reduced disease activity
Crohn's disease	Prevention of the onset
Thyroiditis	Prevention of the onset
Psoriasis	Prevention of the onset
Polymyalgia rheumatica	Prevention of the onset
Autoimmune gastritis	Prevention of the onset
Systemic sclerosis	Downregulation of TGF-β/Smad signaling (putative antifibrotic effect in early stages of disease)
Pulmonary fibrosis	Effect
IL-1β	Decreased antagonism of pulmonary fibroblast cell activity in a murine model of bleomycin-induced lung fibrosis
Hydroxyproline, col1a1, col3a1, and α-smooth muscle actin mRNAs	Prevention of bleomycin-induced lung fibrosis in a mouse model

Th: T helper; IL: Interleukin; IFN: Interferon; TNF: Tumor necrosis factor; TLR: Toll-like receptor; VAP: Ventilator associated pneumonia.

Table 2 Correlation of vitamin D concentrations with severe acute respiratory syndrome coronavirus 2 infections and outcomes

Ref.	n	Population type	Study type	Vitamin D dosages	Results
Lau et al[111], 2020	20	Adults, average age 65.2 yr	Retrospective observational study	NA	Higher levels of vitamin D deficiency were observed in ICU patients (84.6%) compared to baseline patients (57.1%) (P = 0.29)
Hastie et al[115], 2020	449	Adults, age 37–73 yr	Cross-sectional study	NA	Vitamin D levels showed a significant association with SARS-CoV-2 infection in univariate analysis (P = 0.013)
IIie et al[116], 2020	Cases and deaths/1 M population	Adults	Retrospective	NA	Negative correlation was observed between mean levels of vitamin D and COVID-19 cases (P = 0.050) and deaths (P = 0.053) per million population
Glicio et al[117], 2020	176	Adults, age ≥ 60 yr	Retrospective	NA	Severe patients are more likely than mild patients had a lower level of vitamin D
Tan et al[69], 2020	43	Adults, age ≥ 50 yr	Cohort observational	Vitamin D 1000 IU	Patients treated with vitamin D showed a significant protective effect against clinical deterioration after adjusting for age, sex and comorbidities (P = 0.041)
Darling et al[118], 2020	580 cases and 723 controls	Adults, average age 57.7 yr	Retrospective	NA	No significant difference was observed in vitamin D levels between COVID-19 cases and the control group
Raharusun et al[119], 2020	780 cases	Adults, average age 54.5 yr	Retrospective cohort study	NA	In univariate analysis, older and male cases with pre-existing medical conditions and below normal vitamin D levels were associated with higher mortality rates
Daneshkhah et al[120], 2020	5000 cases	Age ≤ 80 yr	As of March 21, 2020	NA	Approximately 15% reduction in the number of severe COVID-19 cases was observed in a population given a normal vitamin D status

NA: Not available; ICU: Intensive care unit; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019.

Table 3 Effect of vitamin D levels on viral infections according to age, gender and systemic conditions

Ref.	Age group	Gender	Preexisting conditions	Results
Martineau et al[43], 2017	0–95 yr	Both genders	Asthma, COPD	Vitamin D supplementation is effective in reducing the risk of acute respiratory infections
Ginde et al[9], 2009	≥ 20 yr	Both genders	Chronic diseases (DM, HT)	Vitamin D deficiency is associated with the prevalence of upper respiratory tract infections
Sabetta et al[44], 2010	20–89 yr	Both genders	Chronic diseases	The risk of respiratory tract infection is reduced in individuals with serum 25(OH)D levels above 38 ng/mL
Cannell et al[7], 2006	0–90 yr	Both genders	Various health conditions	Vitamin D deficiency may increase susceptibility to influenza and respiratory infections
Laaksi et al[45], 2007	18–28 yr	Male	Healthy individuals	Vitamin D supplementation may reduce incidence of respiratory infections
Urashima et al[46], 2010	6–15 yr	Both genders	Healthy children	Vitamin D supplementation is effective in reducing the incidence of influenza A
Berry et al[47], 2011	≥ 65 yr	Both genders	Chronic diseases	Vitamin D deficiency is associated with risk of respiratory infections
Murdoch et al[48], 2012	50–84 yr	Both genders	Chronic diseases (COPD)	Vitamin D supplementation has no protective effect on respiratory infections
Jolliffe et al[49], 2020	0–95 yr	Both genders	Asthma, COPD	Vitamin D supplementation is effective in reducing the risk of acute respiratory infections
Camargo et al[50], 2012	3–24 yr	Both genders	Healthy children	Vitamin D deficiency may increase risk of acute lower respiratory tract infections
Hollams et al[51], 2011	0–10 yr	Both genders	Asthma, allergy	Vitamin D deficiency is associated with asthma and respiratory infections
Majak et al[52], 2011	5–18 yr	Both genders	Asthma	Vitamin D supplementation may reduce infection frequency in children with asthma
Esposito et al[53], 2013	0–16 yr	Both genders	Healthy children	Vitamin D deficiency may increase risk of respiratory infections
Thornton et al[54], 2014	18–45 yr	Both genders	HIV positive individuals	Vitamin D deficiency is associated with risk of respiratory infections
Belderbos et al[55], 2011	0–1 yr	Both genders	Healthy babies	Vitamin D deficiency may increase the risk of respiratory syncytial virus bronchiolitis
McNally et al[56], 2009	0–17 yr	Both genders	Chronic diseases	Vitamin D deficiency associated with respiratory tract infection in intensive care
Le Goaziou et al[57], 2011	0–16 yr	Both genders	Healthy children	Vitamin D deficiency is associated with risk of upper respiratory tract infections
Liu et al[58], 2020	0–18 yr	Both genders	Chronic diseases (asthma, COPD)	Vitamin D deficiency associated with risk of viral respiratory infections
Grant et al[59], 2009	0–95 yr	Both genders	Various health conditions	Vitamin D deficiency may increase risk of influenza and pneumonia
Aloia et al[60], 2007	18–45 yr	Both genders	HIV positive individuals	Vitamin D deficiency is associated with risk of respiratory infections

COPD: Chronic obstructive pulmonary disease; DM: Diabetes mellitus; HT: Hypertension.

Table 4 Summary of current studies examining the use of vitamin D in coronavirus disease 2019 and other viral infections conditions

Ref.	n	Vitamin D type	Vitamin D dosage	Application method	Viral infection	Disease status	Results
Entrenas Castillo et al[61], 2020	76	Vitamin D3 (calcifediol)	0.532 mg on day 1, then 0.266 mg on days 3 and 7, and weekly thereafter	Oral	SARS-CoV-2	Mild–moderate	The need for intensive care and the mortality rate were lower in patients receiving vitamin D treatment
Murai et al[62], 2021	240	Vitamin D3 (cholecalciferol)	200000 IU loading dose	Oral	SARS-CoV-2	Mild–moderate	High-dose vitamin D treatment did not improve clinical outcomes of COVID-19 patients
Rastogi et al[63], 2020	40	Vitamin D3 (cholecalciferol)	60000 IU/d for 7 d	Oral	SARS-CoV-2	Light	Vitamin D treatment shortened the time to PCR negativity
Maghbooli et al[64], 2020	235	Vitamin D3 (cholecalciferol)	50000 IU/wk	Oral	SARS-CoV-2	Mild–moderate	Adequate vitamin D levels shortened hospitalizations and reduced rates of serious illness
Annweiler et al[65], 2020	77	Vitamin D3 (cholecalciferol)	80000 IU single dose	Oral	SARS-CoV-2	Moderate–severe	COVID-19-related mortality rates were lower in patients receiving vitamin D therapy
Cangiano et al[66], 2020	90	Vitamin D3 (cholecalciferol)	25000 IU/mo	Oral	SARS-CoV-2	Moderate–severe	Severity of COVID-19 symptoms decreased in older individuals with vitamin D deficiency
Giannini et al[67], 2021	100	Vitamin D3 (cholecalciferol)	100000 IU/mo	Oral	SARS-CoV-2	Mild–moderate	High doses of vitamin D were found to be effective in reducing complications due to COVID-19
Ling et al[68], 2020	50	Vitamin D3 (cholecalciferol)	400 IU/d	Oral	Respiratory tract infections	Mild–moderate	Vitamin D supplementation has been found effective in reducing the incidence of respiratory infections
Tan et al[69], 2020	43	Vitamin D3 (cholecalciferol)	1000 IU/d	Oral	SARS-CoV-2	Moderate–severe	Vitamin D supplementation was found to be effective in reducing hospital stay and complications

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; COVID-19: Coronavirus disease 2019.