Vitamin D and immunity
- Supports transcription of antimicrobial peptides (Vyas et al., 2021) that have activities against various bacteria, viruses, and fungi (Bae & Kim, 2020; Mitchell, 2020).
- Induces autophagy (cleaning out of damaged or unnecessary cellular components) thereby enhancing clearance of viruses and viral constituents (Malaguarnera, 2020).
- Modulates innate and adaptive immune activity (Radujkovic et al., 2020).
- Regulates growth and differentiation of several types of immune cells (Sulli et al., 2021).
- Suppresses over-expression of pro-inflammatory cytokines (Sulli et al., 2021).
- Supports gut integrity and gut microbial balance (Charoenngam & Holick, 2020).
- Helps maintain the integrity of epithelial tight junctions which decreases risk of infection and pulmonary edema (Shakoor et al., 2021).
- Helps maintain TH1:TH2 immune balance (Malaguarnera, 2020) by reducing TH1 and inducing TH2 immune responses (Bae & Kim, 2020).
Vitamin D deficiency is common:
- Vitamin D deficiency is common in the winter months in countries north of the 42nd parallel (Biesalski, 2020).
- In Germany, France, and Italy more than 25% of the population is vitamin D deficient, especially the elderly (Biesalski, 2020).
- In Scandinavia only around 5% of the population is low in vitamin D – likely due to regular consumption of cod liver oil (sources of vitamin D and A) (Biesalski, 2020).
- Almost 50% of the world’s population is deficient in vitamin D (Getachew & Tizabi, 2021; DiNicolantonio & O’Keefe, 2021).
- COVID-19 patients have been found to have lower levels of 25(OH)D compared to healthy people without COVID-19.
- The rate of vitamin D deficiency was highest in severe or critical cases of COVID-19 (Ye et al., 2021).
› Vitamin D Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic? Nutrients (Brenner et al., 2020)
- The majority of those 50–75 years of age at baseline had insufficient or deficient vitamin D levels.
- Low levels were associated with increased mortality – especially from respiratory diseases.
- Some key risk factors for vitamin D deficiency are age, obesity, diabetes, hypertension, and smoking (Bae & Kim, 2020).
Vitamin D deficiency is common in COVID-19
› The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis. International Journal of Clinical Practice (Ghasemian et al., 2021)
- This meta-analysis of 11 studies that included 360,972 COVID-19 patients.
- 37.7% had vitamin D deficiency
- 32.2 had vitamin D insufficiency
- Most confirmed COVID-19 patients had deficient or insufficient vitamin D levels.
- They were nearly three times more likely to become infected and about five times more likely to progress to severe COVID-19 symptoms.
› 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients (D’Avolio et al., 2020)
- Adults who were vitamin D-deficient were at increased risk of being infected with the COVID-19 virus.
- Those with COVID-19 had lower 25(OH)D levels than those without COVID-19.
Vitamin D deficiency and COVID-19 susceptibility and severity
Vitamin D deficiency:
- has been shown to be associated with increased susceptibility to COVID-19 (Mukherjee et al., 2022).
- was correlated with increased hospitalization and ICU admission due to COVID-19 (Bae & Kim, 2020).
- was inversely correlated to COVID-19 virus positivity (SARS-CoV-2 RNA Nucleic Acid Amplification Test) (Herrera-Quintana et al., 2021).
- is associated with increased inflammation and decreased immune function, which increases risk of severe infection (Vyas et al., 2021).
› Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients (Radujkovic et al., 2020)
Vitamin D-deficient patients:
- had a higher hospitalization rate
- required more oxygen therapy
- needed more invasive mechanical ventilation
Vitamin D deficiency was associated with:
- 6-times greater risk of a severe course of COVID-19
- approximately 15-times greater risk of death
Vitamin D deficiency was shown to be:
- significantly higher in COVID-19 patients and associated with increased COVID-19 severity (Mukherjee et al., 2022)
- correlated with increased severe lung involvement, longer duration of illness, and increased risk of death in elderly patients (Sulli et al., 2021)
› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020)
- People who were deficient in vitamin D were more likely to experience severe COVID-19 disease.
› Vitamin D insufficiency as a potential culprit in critical COVID-19 patients. Journal of Medical Virology (Munshi et al., 2021)
- Low vitamin D status significantly correlated to worse prognosis in a meta-analysis of 1368 COVID-19 patients.
Vitamin D deficiency and COVID-19 mortality
- Fatality rates from COVID-19 parallel vitamin D deficiency rates (Herrera-Quintana et al., 2021).
- Below-average vitamin D levels are associated with increased susceptibility to COVID-19 mortality (Vyas et al., 2021; Annweiler et al., 2020).
- Vitamin D levels were significantly lower in people who died during hospitalization compared to survivors (Sulli et al., 2021).
› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020)
› Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. Journal of Endocrinological Investigation (Carpagnano et al., 2021)
- Mortality and morbidity were shown to be higher in patients with vitamin D deficiency.
› Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. American Journal of Clinical Pathology (De Smet et al., 2021)
› Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study. The FEBS Journal (Merzon et al., 2020)
- Vitamin D deficiency is considered to be an independent risk factor for COVID-19 infection, hospitalization, and death.
Vitamin D deficiency has been associated with increased mortality compared with vitamin D-sufficient patients in many studies. Some are listed here:
› Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgraduate Medical Journal (Baktash et al., 2021).
› Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. Journal of Endocrinological Investigation (Carpagnano et al., 2021).
› Vitamin D 25OH deficiency in COVID-19 patients admitted to a tertiary referral hospital. Clinical Nutrition (Edinburgh, Scotland) (Cereda et al., 2021).
› Sex-specific association between vitamin D deficiency and COVID-19 mortality in older patients. Osteoporosis International: A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA (Hars et al., 2020).
› Interaction between age and vitamin D deficiency in severe COVID-19 infection. Nutricion Hospitalaria (Macaya et al., 2020).
› Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients (Radujkovic et al., 2020).
› Vitamin D and Lung Outcomes in Elderly COVID-19 Patients. Nutrients (Sulli et al., 2021).
“…results imply that 87% of COVID-19 deaths may be statistically attributed to vitamin D insufficiency and could potentially be avoided by eliminating vitamin D insufficiency” (Brenner & Schöttker, 2020).
› Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection. PloS One (Maghbooli et al., 2020).
- Mortality rate dropped to almost to 0% when the serum 25(OH) D concentrations were higher than 34 ng/mL (retrospective study).
Vitamin D and COVID-19 symptoms and illness
Vitamin D and viral infection
Low vitamin D levels:
- are significantly associated with an increased likelihood of COVID-19 infection (Pizzini et al., 2020).
- increase the likelihood of COVID-19 infection by 3.3 times, and the risk of severe COVID-19 by around five times (Ghasemian et al., 2021).
A study of 191,779 COVID-19 patients from all 50 US states showed (Gröber & Holick, 2022):
- circulating 25(OH)D levels were inversely associated with the rate of COVID-19 infection. This relationship persisted across latitudes, races and ethnicities, sexes, and ages.
Vitamin D protects from COVID-19 infection by (Bae & Kim, 2020):
- enhancing physical barriers in the body
- increasing production of antimicrobial peptides
Vitamin D has antiviral properties (Vyas et al., 2021) and has been shown to promote viral clearance in COVID-19 patients who were asymptomatic or mildly symptomatic (Gröber & Holick, 2022).
Vitamin D and ACE2 receptors
- The COVID-19 virus uses ACE2 to access cells, which results in decreased ACE2 function.
- ACE2 helps convert ANG II to the protective ANG 1-7.
- ANG II causes problems when not in balance with ANG 1-7.
- Decreased ACE2 function results in less ANG 1-7 which promotes COVID-19 pathology.
- In the context of COVID-19, decreased ACE2 promotes runaway inflammation and progression to cytokine storm (Annweiler et al., 2020).
- High amounts of ANG II can promote ARDS or cardiopulmonary damage (Mercola et al., 2020).
Vitamin D, ACE2 and renin
- upregulates expression of ACE 2 receptors, increasing the conversion of ANG II to ANG 1-7 (Brenner et al., 2020; Mitchell, 2020).
- lowers ANG II levels (Grant et al., 2020).
- suppresses renin, which in turn reduces ANG expression, resulting in decreased ANG II expression (Sulli et al., 2021).
- has been shown to inhibit renin and ANG II expression, while supporting ACE2 levels in LPS-induced respiratory distress (Vyas et al., 2021).
- has been shown effective against acute lung injury by modulating renin, ACE2, (Ebadi & Montano-Loza, 2020), and ANG 1-7 (Singh & Singh, n.d.).
Vitamin D and the cytokine storm
Vitamin D can inhibit cytokine storm by:
- boosting innate immunity while decreasing over-expression of adaptive immunity, and suppressing excessive immune reactions to pathogens (Vyas et al., 2021)
- decreasing pro-inflammatory cytokines while increasing anti-inflammatory cytokines (Lakkireddy et al., 2021).
- maintaining tight junctions and killing enveloped viruses (Singh & Singh, n.d.)
- increasing serum vitamin D levels to 80 ng/ml has been shown to decrease the severity of cytokine storms (Lakkireddy et al., 2021)
Sufficient levels of vitamin D can help prevent and control cytokine storms (Brenner et al., 2020; Junaid et al., 2020).
Vitamin D and oxidative stress
Roles of vitamin D in managing oxidative stress include:
- activating several antioxidant pathways and inhibiting oxidative stress-activating pathways (Abdrabbo et al., 2021)
- inducing antioxidant defenses including catalase, superoxide dismutase, and glutathione to reduce oxidative stress (Gröber & Holick, 2022)
- inhibition of inflammatory mediator inducible nitric oxide synthase (Malaguarnera, 2020)
Vitamin D and inflammation
Vitamin D can balance inflammation by:
- regulating the inflammatory response by decreasing the production of pro-inflammatory cytokines and increasing the production of anti-inflammatory cytokines (Shakoor et al., 2021; Lakkireddy et al., 2021)
- inhibiting pro-inflammatory Th1 activity and upregulating anti-inflammatory Th2 and T regulatory cells (Abdrabbo et al., 2021)
- suppressing over-expression of inflammatory cytokines (Sulli et al., 2021)
- helping to reduce the inflammatory response to COVID-19 infection (Mitchell, 2020)
Vitamin D deficiency was shown to be correlated to C-reactive protein (CRP):
- CRP, a marker of inflammation and surrogate marker of the cytokine storm, was highly elevated in severe COVID-19 patients and correlated with vitamin D deficiency (Shakoor et al., 2021).
Vitamin D and ARDS
Vitamin D offers protection against ARDS by:
- mediating innate and adaptive immune activity (Brenner et al., 2020)
- decreasing production of pro-inflammatory cytokines (Annweiler et al., 2020)
- increasing production of anti-inflammatory cytokines (Annweiler et al., 2020)
- stabilizing physical barriers (maintaining tight junctions) (Annweiler et al., 2020) and maintaining the integrity of epithelial barriers (Vyas et al., 2021), in conjunction with vitamin A (Biesalski, 2020)
- inactivating some viruses by stimulating antiviral mechanisms such as antimicrobial peptides (Srivastava et al., 2021)
- increasing ACE2 concentrations (Srivastava et al., 2021)
- reducing the risk of bradykinin storm (Srivastava et al., 2021) (Bradykinin is a compound formed in injured tissue that has bronchodilation, vasodilation, and pro-inflammatory properties)
- reducing MMP concentrations (Srivastava et al., 2021) (MMP is involved in the degradation of extracellular matrix during inflammatory episodes (Ben Moftah & Eswayah, 2022)
- increasing proliferation of alveolar type-II cells (lung cells) and stimulating their production of surfactant (Ebadi & Montano-Loza, 2020). Decreased surfactant increases the risk of developing ARDS (Xu et al., 2020)
- reducing apoptosis of pneumocytes preventing severe lung injury (Xu et al., 2020)
- attenuating LPS-induced lung damage (Biesalski, 2020)
Vitamin D deficiency and upper respiratory tract infection:
- Low vitamin D status has been shown to increase susceptibility to acute respiratory infections (Martineau et al., 2017; Mitchell, 2020).
- The US Third National Health and Nutrition Examination Survey of 18,883 adults showed an inverse relationship between vitamin D levels and upper respiratory tract infections (Calder et al., 2020).
- Vitamin D insufficiency and deficiency resulted in strongly increased respiratory mortality when compared to those with sufficient vitamin D (Brenner et al., 2020).
- Levels lower than 15 ng/mL (37.5 nmol/L) are known to significantly increase risk of acute respiratory infections (Lordan, 2021).
- Serum 25(OH)D levels below 75 nmol/L were shown in a retrospective study of 2000 critically ill patients to increase the risk of severe respiratory tract infection and ARDS (Annweiler et al., 2020).
- Supplementation of vitamin D has been shown to result in decreased risk of respiratory tract infection, especially in those with vitamin D deficiency (Martineau et al., 2017; (Annweiler et al., 2020; Brenner et al., 2020).
› Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ (Clinical Research Ed).(Martineau et al., 2017)
- Vitamin D supplementation was shown to be protective against acute respiratory tract infections in a meta-analysis of 25 randomized controlled trials (RCTs) with 11,321 people.
Vitamin D deficiency was shown to:
- increase the risk of pneumonia in a systematic review and meta-analysis involving 20,966 subjects (Shakoor et al., 2021)
- increase the risk of intensive care admission and mortality in those with severe pneumonia (Dramé et al., 2021)
Vitamin D deficiency and sepsis
- Sepsis, a systematic inflammatory response by the body to a microbial pathogen, is a major cause of death in hospitalized patients (Charoenngam & Holick, 2020).
- In regard to sepsis, vitamin D deficiency has been shown in multiple observational studies to be linked to (Charoenngam & Holick, 2020):
- increased occurrence
- increased morbidity and mortality
- prolonged length of stay in the ICU
Vitamin D protects against sepsis by (Charoenngam & Holick, 2020):
- preventing vascular leakage
- decreasing over-expression of inflammatory cytokines
- promoting anti-bacterial immune responses
Vitamin D and coagulation abnormalities
COVID-19-associated coagulopathy is strongly associated with the rate of survival after COVID-19 (Vyas et al., 2021)
Vitamin D has roles in:
- regulation of blood-clotting pathways (Sulli et al., 2021)
- upregulating anticoagulant activity and downregulating pro-coagulation activity (Lau et al., 2020).
Vitamin D deficiency:
- can worsen COVID-19 severity by increasing blood clotting action leading to both arterial and venous thrombosis (Abou-Ismail et al., 2020)
- has been shown in clinical studies to be correlated with increased thrombosis (Vyas et al., 2021), and is associated with an increased risk of thrombotic events (Sulli et al., 2021)
Causes of vitamin D deficiency
- limited sun exposure
- strict vegan diet (most sources of vitamin D are animal-based)
- darker skin (the pigment melanin reduces the vitamin D production by the skin)
- digestive tract and kidney issues
- obesity (vitamin D is sequestered by fat cells)
Some drugs that affect vitamin D absorption or metabolism include (Vitamin D, 2014):
- mineral oil
- HIV treatment drugs
Measuring vitamin D
The best indicator of vitamin D status is serum 25(OH)D, also known as 25-hydroxyvitamin D. 25(OH)D reflects the amount of vitamin D in the body that is produced by the skin and obtained from food and supplements.
Serum 25(OH)D levels (Ghasemian et al., 2021):
Sufficiency – greater than 30ng/mL (75 nmol/L)
Insufficiency – 20-30 ng/mL (50–75 nmol/L)
Deficiency: – less than 20 ng/mL (50 nmol/L)
Vitamin D food sources and supplementation
Top sources of vitamin D based on serving size (Office of Dietary Supplements – Vitamin D, 2020)
- cod liver oil
- pink salmon
- fortified cereal, milk, and orange juice
- fortified almond, soy, and oat milks
- egg yolk
Comprehensive food list
Table 3: Vitamin D Content of Selected Foods
Referenced Dietary Intakes
RDAs for vitamin D (IU/day)
Adolescents (14-18 years): 600 (M) 600 (F)
Adults (19-50 years): 600 (M) 600 (F)
Adults (51 years and older): 800 (M) 800 (F)
Tolerable Upper Intake: 4000 IU/day
(Office of dietary supplements, 2020)
Vitamin D supplementation
- Amounts of vitamin D used in practice and research range from 400-14 000 IU/day. (Vitamin D, 2014)
Supplementing vitamin D in COVID-19 patients has been shown to :
- positively affect immune response (Xu et al., 2020)
- suppress pathogen activity (Xu et al., 2020).
- induce apoptosis of infected epithelial cells to promote clearance of respiratory pathogens (Xu et al., 2020).
- decrease oxygen requirements (Sulli et al., 2021).
- decrease severity of COVID-19 symptoms (Annweiler et al., 2020).
- decrease length of hospitalization (Sulli et al., 2021).
- increase survival rate in hospitalized frail elderly patients (Annweiler et al., 2020).
› Vitamin D Supplementation in COVID-19 Patients: A Clinical Case Series. American Journal of Therapeutics. (Ohaegbulam et al., 2020)
- 50,000 IU/day for 5 days in COVID-19 patients resulted in decreased inflammation and decreased recovery time compared to those receiving 1000 IU/day.
› Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study. The Journal of Steroid Biochemistry and Molecular Biology (Entrenas Castillo et al., 2020)
- In combination with standard of care treatment, early high-dose vitamin D treatment prevented COVID-19-patient need for ICU admission.
Vitamin D dosing
“The aim of a therapy with vitamin D should be a normalization of the vitamin D status, preferably > 75 nmol/L” (Biesalski, 2020).
It is important to consider that vitamin D works synergistically with vitamin A in the body (Biesalski, 2020), and this is especially relevant in the context of respiratory tract health and COVID-19. Therefore it is recommended that vitamins A and D be supplemented together.
Vitamin D dosing to PREVENT deficiency
- 1500–2000 IU/day of vitamin D3 for adults of any age who are at high risk for vitamin D deficiency (Brenner et al., 2020).
- At least 400 IU/day of vitamin D for infants and children (Wong et al., 2021).
Vitamin D dosing to ADDRESS deficiency
With the goal of achieving sufficiency (25(OH)D level above 30 ng/ml) (Holick et al., 2011):
Institute of Medicine:
- Adults 19 years and older –10,000 IU/day
- 50,000 IU once a week for 8 weeks
- Followed by maintenance therapy of 1500–2000 IU/day
In obese patients, patients with malabsorption syndromes, and patients on medications affecting vitamin D metabolism
- 6000–10,000 IU/day to maintain above 30 ng/ml
- Followed by maintenance therapy of 3000–6000 IU/day
Vitamin D dosing in research
- 10,000 IU for a few weeks to increase levels above 40–60 ng/mL, followed by 5000 IU/day to decrease COVID-19 risk (Vyas et al., 2021).
- 200,000–300,000 IU/week to decrease the risk and severity of COVID-19 (Vyas et al., 2021).
- In the context of minimal sunlight exposure, 4000–6000 IU/day would be required to maintain serum 25(OH)D levels in the range of 40–60 ng/mL (50–100 nmol/L) (Charoenngam & Holick, 2020).
Vitamin D dosing in COVID-19 research
- 800 to 1000 IU daily is recommended for all SARS-CoV-2-positive patients upon diagnosis (Lordan, 2021).
- Up to 2,000 IU/day of oral vitamin D was safe and protective against acute respiratory tract infection and COVID-19 (Getachew & Tizabi, 2021).
- At least one single dose of 50,000 IU of vitamin D to all COVID-19 patients as soon as possible after being hospitalized (Charoenngam & Holick, 2020).
- 50,000 IU twice in the first week following diagnosis for patients with vitamin D below 50 nmol/L (Ebadi & Montano-Loza, 2020)
- 60,000 IU for 7 days resulted in a larger proportion of vitamin D-deficient COVID-19 patients becoming SARS-CoV-2 RNA negative (Lordan, 2021).
“Vitamin D supplementation could be especially important for older people as they are at high risk of poor outcome from COVID-19 and of vitamin D deficiency” (Mitchell, 2020).
SAFETY, SIDE EFFECTS (Vitamin D, 2014)
- “Research suggests that vitamin D toxicity is very unlikely in healthy people at intake levels lower than 10,000 IU/day”
- Vitamin D can increase the risk of hypercalcemia with calcium-related medical conditions – including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma
- Certain medical conditions can increase the risk of hypercalcemia in response to vitamin D, including primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma
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