Received: 26 July 2020 Revised: 6 August 2020 Accepted: 8 August 2020

DOI: 10.1002/rmv.2159

REVIEW

Vitamin D and Covid-19: From potential therapeutic effects to

unanswered questions

Majid Teymoori-Rad | Sayed Mahdi Marashi

Department of Virology, School of Public

Health, Tehran University of Medical Sciences,
Tehran, Iran
Correspondence
Sayed Mahdi Marashi, Department of
Virology, School of Public Health, Tehran
University of Medical Sciences, Tehran
14155-6446, Iran.
Email: m-marashi@tums.ac.ir
Summary
Evidence suggests that vitamin D supplementation could potentially be effective either
in treatment or prevention of coronavirus disease 2019 (Covid-19). Indeed, several
studies and trials have begun to investigate the impact of vitamin D supplementation
on patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infec-
tion. In this review, we focus on the potential mechanisms of vitamin D in the patho-
genesis of Covid-19. We consider whether deficiency of vitamin D may be one of the
underlying biological factors that could explain the excess mortality seen among non-
Caucasians. We also raise several important questions which need to be addressed to
provide a clear picture of the extent to which vitamin D supplementation may benefit
patients with Covid-19, particularly those with underlying risk factors.

KEYWORDS

COVID-19, immune response, Vitamin D

1 | I N T RO DU CT I O N remain largely elusive. Here, we provide an update about the role of

The current outbreak of severe acute respiratory syndrome coronavi-
rus 2 (SARS-CoV-2) is causing a pandemic of coronavirus disease-19
(Covid-19). While the majority of Covid-19 cases are asymptomatic
or have mild symptoms, the number of patients with severe symp-
toms is increasing sharply worldwide.1 Once a pandemic was
declared by the World Health Organization (WHO), massive efforts
got underway to investigate different aspects of SARS-CoV-2 infec-
tion (~32 000 papers at the time of publication). Intensive research
has already allowed remdesivir and dexamethasone to be licensed
based on the results of randomized controlled trials while another
randomized controlled trial of inhaled interferon-beta reports clinical
benefit.2
There are growing data indicating that vitamin D supplementation
could potentially be effective in treatment and prevention of Covid-
19.3-6 Indeed, studies7,8 and even trials (summarized in the Table 1)
have already been implemented to investigate the impact of vitamin
D supplementation in Covid-19 patients. While the results of these
studies will be accessible in near future and provide valuable informa-
tion in which to what extent vitamin D supplementation benefit these
patients, the mechanisms by which vitamin D exerts its potential
vitamin D deficiency in different Covid-19 outcomes focused on pos-
sible mechanisms of action. However, there are yet unanswered ques-
tions, which need to be addressed in order to provide a better picture
about the potential therapeutic impact of vitamin D in Covid-19 giving
the considerable discrepancies reported in literature.
2 | EVIDENCE FOR THE IMPORTANCE OF
V I TA M I N D I N CO V I D - 19
2.1 | Epidemiological evidence
Vitamin D deficiency is considered as a growing global public health
problem and the impact of poor vitamin D status in some clinical set-
tings including respiratory viral diseases has been well documented.
Indeed, several studies have highlighted the inverse association
between vitamin D levels with severity and mortality of respiratory
viral infections in both children and adults.9-12 These epidemiological
findings have prompted several randomized controlled trials aimed to
investigate the clinical significance of vitamin D in respiratory infec-
tions. Except for one study that showed no effect,13 other studies

Rev Med Virol. 2020;e2159. wileyonlinelibrary.com/journal/rmv © 2020 John Wiley & Sons, Ltd 1 of 16
https://doi.org/10.1002/rmv.2159
2 of 16 TEYMOORI-RAD AND MARASHI

T A B L E 1 The list of clinical trials registry of the National Institutes of Health (NIH) (clinicaltrials.gov) for evaluation of vitamin D
supplementation

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
Title: Vitamin D and COVID-19 Management
NCT04385940 64 Patients with COVID-19: Patients with dementia, learning - Interventional/ Phase 3
≥ 17 years old/Both sexes disability, mental health needs Treatment
and alcohol or drug
dependency, pregnant
women/Patients with
sarcoidosis, hypercalcemia,
known vitamin D intolerance
Title: Investigating the Role of Vitamin D in the Morbidity of COVID-19 Patients
NCT04386044 1000 In-patient admitted to Final clinical diagnosis NOT United Observational Not yet recruiting
Tameside General COVID-19 Kingdom
Hospital. Clinical diagnosis
of COVID-19 – not
necessary for SARS-CoV-2
swab to be positive/
Patients on vitamin D
treatment to be included,
but this will be adjusted
for in analysis
Title: Vitamin D Supplementation in the Prevention and Mitigation of COVID-19 Infection (VitD-COVID19)
NCT04482673 140 Adults aged 50 years of age Hospitalization at the time of United state Interventional Recruiting
or older who presents to study recruitment/Any
MUSC or its affiliate individual less than 50 years of
hospitals (or associated age
testing centers) for
COVID-19 testing during
the recruitment period is
eligible for participation.
Title: Covid-19 and Vitamin D in Nursing-home (COVIT-EHPAD)
NCT04435119 96 Being suspected or Opposition of the resident France Observational Completed
diagnosed with COVID-19 and/or relatives to the use of
(RT-PCR, chest CT scan) anonymized clinical-biological
data
Title: Vitamin D Supplementation in Patients With COVID-19
NCT04449718 200 Diagnosis of flu syndrome Patient admitted already under Brazil Interventional Not Applicable
with hospitalization invasive mechanical
criteria/Respiratory ventilation/Patient admitted
rate ≥ 24irpm and/or with severe acute respiratory
saturation < 93% in room syndrome and diagnosed with
air, or belonging to the risk an etiologic agent other than
group for complications: SARS-CoV-2/Prior vitamin D
(a) Chronic diseases: heart supplementation (above
disease, diabetes mellitus, 1000 IU/day)/Renal failure
systemic arterial requiring dialysis or creatinine
hypertension and ≥2.0 mg/dL/Admitted patients
neoplasms,(b) with expected hospital
Immunosuppression, (c) discharge in less than
Pulmonary tuberculosis; (d) 24 hoursours/Patient unable
Obesity; Tomographic to sign the consent form.
findings compatible with
coronavirus disease.
Title: Vitamin D Testing and Treatment for COVID 19
NCT04407286 100 Part 1: Adult age 18 or Part 1: None United Interventional Phase 1
older/Previous positive Part 2: Liver impairment/Clinical States Treatment
test result for COVID 19 opinion of study physician that
vitamin D supplementation
TEYMOORI-RAD AND MARASHI 3 of 16

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
Part 2: Participation in Part could be harmful to the
1/Vitamin D level below participant./Pregnancy/No
30 ng/mL/No symptoms for 2 weeks after
abnormalities on the positive COVID 19 test/
comprehensive metabolic Recovered from symptoms
panel that are clinically
significant to increasing
the risk of an adverse
reaction to vitamin D
supplementation
Title: VITACOV: Vitamin D Polymorphisms and Severity of COVID-19 Infection (VITACOV)
NCT04370808 500 Adults of 18 years and Patients diagnosed with COVID- Portugal Polymorphisms -
above/COVID-19 patients 19 not admitted to hospital.
admitted with mild to
severe disease (admission
to isolation room) or
critical patients (admission
to ICU)
Title: Vitamin D on Prevention and Treatment of COVID-19 (COVITD-19)
NCT04334005 200 Non-severe symptomatic Patients presenting severe Spain Interventional -
patients who present respiratory and or multi- Treatment
cough, fever, nasal systemic symptoms
congestion, compatible with advanced
gastrointestinal symptoms, COVID-19 and inter-current
fatigue, anosmia, or acute or severe chronic
alternative signs of diseases (ie, active cancer).
respiratory infections.
Title: Increased Risk of Severe Coronavirus Disease 2019 in Patients With Vitamin D Deficiency (COVIT-D)
NCT04403932 500 >18 years old/symptoms Bacterial community acquired Spain Observational -
suggestive of COVID-19 pneumonia
positive reverse-
transcriptase polymerase
chain reaction or
antibodies for SARS-CoV-
2
Title: Randomized Proof-of-Concept Trial to Evaluate the Safety and Explore the Effectiveness of Resveratrol for COVID-19
NCT04400890 200 Outpatients presenting to a Asymptomatic patients (eg, United Interventional Phase 2
Mount Carmel Health patients who were screened States Treatment
System (MCHS) without symptoms but tested
Emergency Department positive)/Patients on warfarin,
(ED) or drive-through Novel Oral/Anticoagulants,
COVID-19 testing station, HIV Protease Inhibitors,
the Enhanced Urgent Care immunosuppressants,
center in Hilliard (EUC), or hydroxychloroquine,
other ambulatory MCHS chloroquine/Comorbidities
facility who test positive with a high likelihood of
for infection with SARS- hospitalization within 30 days
CoV-2/Age ≥ 45 years/ (eg, current cancer treatment,
Symptom duration ≤7 days severe COPD or CHF) End
stage liver disease or
Hepatitis/Allergy to grapes or
rice/pregnant
Title: International ALLIANCE Study of Therapies to Prevent Progression of COVID-19
NCT04395768 200 Age ≥ 18 years/Provision of Known G6PD deficiency/ Australia Interventional Phase 2
informed consent in Contra-indication to Treatment
writing, can be electronic/ hydroxychloroquine,
azithromycin or vitamin C:

(Continues)
4 of 16 TEYMOORI-RAD AND MARASHI

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
Diagnosis of active allergy to study interventions,
COVID-19 epilepsy, serious hearing, or
visual problems, history of
severe depression, calcium
oxalate stones, advanced liver
disease, pregnancy or
lactating/History of fever (eg,
night sweats, chills) and/or
acute respiratory infection (eg,
cough, shortness of breath,
sore throat) of more than
7 days' duration. Note, if study
numbers not quickly reached,
the investigators may decide
to include those with
symptoms of longer than
7 days/Calculated creatinine
clearance of <30 mL/receiving
chloroquine, azithromycin,
>3 g vitamin C daily or an
experimental antivirals/
Receipt of a drug known to
increase QTc: quetiapine,
amiodarone/Baseline ECG
showing: QTc ≥470 for males,
QTc ≥480 for females
Title: Impact of Zinc and Vitamin D3 Supplementation on the Survival of Aged Patients Infected With COVID-19 (ZnD3-CoVici)
NCT04351490 3140 Institutionalized Life expectancy <1 month France Interventional/ Not Applicable
independently of Covid-19 Treatment
infection (overall subjects)/
Known hypercalcemia/History
of renal lithalsas
Title: Do Vitamin D Levels Really Correlated With Disease Severity in COVID-19 Patients? (COVIDVIT)
NCT04394390 100 To find out vitamin D levels _Intensive care unit patients Turkey Observational -
and it's relation with the
disease severity serum
25-hydroxy-vitamin D
levels will be measured in
nearly 100 confirmed
COV_ID-19 patients.
Title: Evaluation of the Relationship Between Zinc Vitamin D and b12 Levels in the Covid-19 Positive Pregnant Women
NCT04407572 45 Covid-19 positive pregnant vitamin D, Vitamin B12 or Zinc Turkey Observational Completed
women/under 18 or more supplement use/Multivitamine
than 45 years old use/use of medicines for
vitamin deficiency/having
metabolic disease covid-19
negative pregnant women
Title: A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection (HELPCOVID-19)
NCT04335084 600 Informed consent, provided Refusal to provide informed United State Interventional/ Phase 2
electronically via the EDC, consent/Any previous positive Prevention
demonstrating the subject test for COVID-19 by RT-
understands the PCR/Symptomatic for COVID-
procedures required for 19/Diarrhea prior to the start
the study and the purpose of treatment/Type I or II
of the study/Male or diabetes/Atherosclerotic
female patients 18 years Coronary Artery Disease/Any
of age or older that are contraindication for treatment
considered to be high-risk with hydroxychloroquine
TEYMOORI-RAD AND MARASHI 5 of 16

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
individuals. High-risk including: Hypoglycemia,
individuals are defined as G6PD deficiency, Porphyria,
all health care workers in Anemia, Neutropenia/
hospitals, clinics, and Alcoholism, Myasthenia
emergency rooms, and Gravis, Skeletal muscle
medical facilities/Subjects disorder, Maculopathy,
must agree to practice at Changes in the visual field,
least two highly effective Liver disease, with
methods of birth control ALT/AST > 2.5 upper limit
for the duration of the normal and total bilirubin >2.5
study This includes upper limit normal, Psoriasis/
condoms with spermicide, Any contraindicated
oral birth control pills, medications found in
contraceptive implants, Appendix 2 Any comorbidities
intra-uterine devices, or which, in the opinion of the
diaphragms. At least one investigator, constitute health
of these must be a barrier risk for the subject.
method. Subjects not of
reproductive potential will
be exempt (eg, post-
menopausal, surgically
sterilized)
Title: COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose vs Standard Dose Vitamin D3 in High-
risk COVID-19 Patients (CoVitTrial)
NCT04344041 260 Age ≥ 70 years old/Infection Organ failure requiring admission France Interventional/ Phase 3
with COVID-19 diagnosed to a resuscitation or high Treatment
with RT-PCR SARS-CoV-2 dependency unit/Comorbidity
or with CT-scan of the that is life-threatening in the
chest suggesting viral short-term (life expectancy
pneumonia of peripheral <3 months)/Vitamin D
predominance in a supplementation in the
clinically relevant context/ previous month, with the
Having at least one of the exception of treatment
following two risk factors providing less than 800 IU of
for complications: vitamin D per
Peripheral capillary oxygen day/Participation in another
saturation (SpO2) ≤ 94% simultaneous trial/Peripheral
ambient air, or a partial capillary oxygen saturation
oxygen pressure (PaO2) to (SpO2) ≤92% in spite of an
fraction of inspired oxygen oxygen therapy >5 L/min
(FiO2) ratio ≤ 300 mmHg,
Diagnosed within the
preceding 3 days
age ≥ 75 years
Title: Hydroxychloroquine as Post-Exposure Prophylaxis Against COVID-19 Infection
NCT04372017 1739 Inclusion Criteria Cohort A: Known allergy to United state Interventional/ Phase 3
≥ 18 years old/Employee of hydroxychloroquine or Prevention
healthcare organization in quinine/Known history of long
South Dakota or Sanford QT syndrome/Known history
Health employee in any of arrhythmia or dysrhythmia/
location and with exposure Known current QTc >500 ms/
to a person with COVID- Known G6PD deficiency/
19 within the last 5 days/ Known history of
Criteria according to hypoglycemia/Pregnant or
Center for Disease Control Nursing by patient history/
(CDC) guidelines/ Use of any of the following
Community exposure concomitant medications: See
(within 6 ft for at least Appendix D for Exclusion
15 minutes)/No prior medication list/Concurrent

(Continues)
6 of 16 TEYMOORI-RAD AND MARASHI

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
COVID-19 positive diagnosis of dermatitis,
diagnosis (eligible if porphyria, or psoriasis/History
previous testing is of chronic liver disease,
negative and meets all including cirrhosis and/or
other inclusion and diagnosis of hepatitis
exclusion) (infectious, idiopathic, or
Inclusion Criteria – Cohort B immune)/History of chronic
≥ 18 years old/High-risk kidney disease/Pre-existing
person defined by: Age retinopathy/Already taking
18-44 with 2 or more hydroxychloroquine/Any
comorbidities listed below, condition or medication in the
Age 45-79 with any opinion of the investigator
comorbid condition listed that would prohibit the use of
below/Age 80 and above/ hydroxychloroquine/
Occupational exposure as Enrollment in another clinical
determined by the with investigational drug or
participant's employee device/Inability to swallow
health department (ie, not pills
wearing the proper
Personal Protective
Equipment)/High-risk
person who had close
contact (ie, within 6 ft for
at least 15 minutes) with a
COVID-19 positive person
within the last 5 days and
is a South Dakota resident
or high-risk person with
close household contact of
a COVID-19 positive
Sanford employee/Co-
morbid list: Congestive
Heart Failure (CHF).
Chronic lung disease
(Includes any of the
following: asthma, chronic
obstructive pulmonary
disease, emphysema), Solid
organ transplant or,
Chronic Kidney Disease, or
End Stage Renal Disease,
Diabetes mellitus,
Cardiovascular disease/
Hypertension/Smoking/
Vaping/Obesity (calculated
by height and weight per
participant report)/
Hyperlipidemia/
Title: A Study of Quintuple Therapy to Treat COVID-19 Infection (HAZDpaC)
NCT04334512 600 Male or female subjects Diarrhea prior to infection/Any United state Interventional/ Phase 2
18 years of age and comorbidities which, in the Treatment
up/Subjects must agree to opinion of the investigator,
practice at least two highly constitute health risk for the
effective methods of birth subject/Any contraindications
control for the duration of for treatment with
the study/This includes hydroxychloroquine/
condoms with spermicide, Hypoglycemia, Known G6PD
oral birth control pills, deficiency, Anemia,
contraceptive implants, Alcoholism, Skeletal muscle
intra-uterine devices, or disorders, Changes in visual
TEYMOORI-RAD AND MARASHI 7 of 16

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria: Scientific exclusion criteria: Locations Study type Current status
diaphragms/At least one field/Neutropenia/
of these must be a barrier Maculopathy/Psoriasis/
method/Subjects not of Abnormal EKG with QT
reproductive potential will prolongation acquired or from
be exempt (eg, post- birth/Allergies to
menopausal, surgically 4-Aminoquinolines/History of
sterilized)/Diagnosis of jaundice or high fevers prior to
COVID-19 by RT-PCR developing COVID-19/
Treatment with any other drug
not listed that affects the QT
interval/Treatment with any
anti-epileptic drug, whether
prescribed for seizures or
otherwise/Pregnant or
breastfeeding women
Title: Oral 25-hydroxyvitamin D3 and COVID-19
NCT04386850 1500 Older than 18 years old and Ongoing treatment with Iran Interventional/ Phase 2 Phase 3
younger than 75 years old pharmacologic doses of Prevention
for all study groups/Meet vitamin D, vitamin D
the diagnostic criteria of metabolites or analogs/
COVID-19 for different Pregnant or lactating women/
types (including ordinary History of elevated serum
type, heavy type and calcium >10.6 mg/dL; that is
critical type) in infected corrected for albumin
patients/No medications concentration or subjects with
or disorders that would a history of hypercalciuria and
affect vitamin D kidney stones/
metabolism/Ability and Supplementation with over
willingness to give the counter formulations of
informed consent and vitamin D2 or vitamin
comply with protocol D3/Consuming medication
requirements affecting vitamin D
metabolism or absorption
(anticonvulsants, anti-
tuberculosis medication
glucocorticoids, HIV
medications and
cholestyramine), Subjects with
a history of an adverse
reaction to orally administered
vitamin D, vitamin D
metabolites or analogs,
Inability to give informed
consent
Title: The Effects of Standard Protocol With or Without Colchicine in Covid-19 Infection
NCT04360980 80 Patients >18 years old with Patient who is not willing to Iran Interventional/ Phase 2
nasopharyngeal swab enter in study/Known Treatment
confirmed COVID-19 PCR, hypersensitivity to colchicine/
CT involvement Hepatic failureRenal failure
compatible with COVID, with eGFR<20 mL/min
Fever, and Dyspnea
without hypoxemia.
Title: Prevention and Treatment With Calcifediol of COVID-19 Induced Acute Respiratory Syndrome (COVIDIOL)
NCT04366908 1008 Age ≥ 18 and < 90 years/ Being treated with Calcifediol or Spain Interventional/ Phase 2
PCR confirmed diagnosis Cholecalciferol in any of its Treatment
of COVID-19/Radiological presentations and dosages/
image compatible with Intolerance or allergy to
inflammatory Calcifediol or its components/
pleuropulmonary exudate Pregnancy

(Continues)
8 of 16 TEYMOORI-RAD AND MARASHI

TABLE 1 (Continued)

Clinical trials.
gov identifier Enrollment Scientific inclusion criteria:
Title: Use of UC-MSCs for COVID-19 Patients
NCT04355728 Patients > = 18 years old
diagnosed with COVID-19
(as evaluated by PCR test
confirming infection with
SARS-CoV-2/All the
following criteria must be
present within a 24-hour
time period at the time of
enrollment: Acute onset of
a need for positive
pressure ventilation by an
endotracheal or tracheal
tube with a PaO2/FiO2
ratio < 300 mmHg with at
least 5 cm H2O positive
end-expiratory airway
pressure (PEEP), No
clinical evidence of left
atrial hypertension or
significant left heart failure
Title: Proflaxis Using Hydroxychloroquine Plus Vitamins-Zinc During COVID-19 Pandemia
NCT04326725 80 person who are working as
health professional with
contact to known COVID
positive case/Their first
degree relatives (child,
spouse, or parents)
Scientific exclusion criteria: Locations Study type Current status
Greater than 24 h since first United Interventional/ Phase 1 Phase 2
meeting ARDS criteria (Berlin States Treatment
definition) or 72 hours of ICU
admission/PaO2/FiO2 ≥ 300
with PEEP ≤5 cm H2O at the
time of enrollment Anticipated
extubation within 24 hours of
enrollment in the study/Use of
any investigational products
within 4 weeks of
enrollment/A previous MSC
infusion not related to this
trial/Pregnant or lactating
patient/Unstable arrhythmia/
Patients with previous lung
transplant/Patients currently
receiving chronic dialysis for
chronic kidney disease/
Presence of any active
malignancy (other than non-
melanoma skin cancer) that
required treatment within the
last 1 year/Moderate to
severe liver failure (Childs-
Pugh Score > 12)/Severe
chronic respiratory disease
with a PaCO2 > 50 mmHg or
the use of home oxygen/
Moribund patient not
expected to survive >24 hours
Already using plaquenil for other Turkey Observational -
reasons (RA etc)/person with
the diagnosis of COVID
infection/Documented allergic
history to chloroquine/
Documented history of
chronic liver and kidney
diseases/Documented history
of retina or hearing
dysfunction history of
hematological system
diseases; Documented history
of cardiac arrhythmia or
chronic heart diseases;
Documented history of mental
illnesses; 10. Use of digitalis
due to the previous disease.

have shown that vitamin D supplementation reduced the risk of acute
respiratory tract infection.14-16 These findings highlight that vitamin D
could potentially be considered as an alternative approach (either pre-
ventive or therapeutic) in respiratory tract infections after additional
17
studies and trials recommended by WHO. It has also been
suggested that vitamin D deficiency might lead to an increased sus-
ceptibility to some respiratory viruses such as respiratory syncytial
virus (RSV) and influenza infection, particularly at the peak of these
viral infections when vitamin D level appears to be the lowest in
winter.12,18
Although seasonal Covid-19 patterns are not yet clear, short term
studies with regard to vitamin D status in Covid-19 patients have
been published. D'Avolio et al, reported a lower level of 25-OHD
(25-hydroxyvitamin D) in SARS-CoV-2 patients with positive PCR
TEYMOORI-RAD AND MARASHI
compared to patients with negative PCR (median = 11.1 ng/mL vs
24.6 ng/mL).7 Furthermore, serum level of 25-OHD was lowest in
critical cases, but highest in mild cases.8 Currently, there are several
clinical trials evaluating vitamin D in Covid-19 patients (Table 1), there
is no doubt that their results will be key to the validation of this
adjunctive treatment for Covid-19 patients.19
2.2 | Underlying risk factors
It is well documented that several host risk factors including aging,
male sex, diabetes mellitus, coronary artery disease, hypertension,
COPD, chronic renal disease, and obesity are involved in worsening
the outcome of Covid-19 or even death.20-22 Interestingly, vitamin D
deficiency is not only considered as a potential risk factor in Covid-19
patients8 but also commonly reported in these underlying
conditions.23-25
Vitamin D deficiency might be considered as one of the reasons
behind many of these underlying complications including Covid-19.
There are several reports highlighting that vitamin D deficiency could
potentially lead to hypertension, diabetes, cancers, cardiovascular par-
ticularly in elderly.24 Vitamin D deficiency might also play an impor-
26
tant role in older men and in sex-related different susceptibility to
27
SARS-CoV-2. It would be naïve to think that less vitamin D uptake
is the sole reason for vitamin D deficiency in these clinical set-
tings.28,29 Reduced outdoor activity, seasonal variance, long-term glu-
cocorticoid usage, age, thyroid dysfunction, pregnancy, and obesity
30-32
can also influence circulating vitamin D levels. It is also important
to differentiate between immune effects of UV exposure independent
of vitamin D and immune effects by vitamin D per se. Although less
data are available, it is yet unclear to what extend sociocultural factors
such as ethnic origin play a role in this scenario. Furthermore, there
are studies reporting an association between vitamin D-related gene
polymorphisms and the risk of these diseases.33-35 While vitamin D
deficiency is generally considered as a potential risk factor in different
clinical settings including patients with Covid-19, vitamin D deficiency
in these patients may, in part, result from the underlying risk factors
per se. Indeed, disruption of vitamin D metabolism has been reported
36,37
in chronic renal disease as the tissue responsible for vitamin D
anabolism. Although a lower bioavailability of vitamin D in the obese
state is thought to be the main reason for vitamin D deficiency in
obesity,38,39 other mechanisms have been hypothesized, including
lower dietary intake of vitamin D, lesser skin exposure to sunlight,
decreased intestinal absorption, and impaired hydroxylation in adipose
tissue. Although there is evidence that obesity could lead to vitamin D
deficiency, it speculated that vitamin D deficiency itself could cause
obesity or prevent weight loss.25 Regardless of which scenario could
be true, vitamin D deficiency appears to exert potential role in differ-
ent clinical settings including Covid-19. Underlying diseases in Covid-
19 patients could augment some features of vitamin D deficiency
40,41
such as immunomodulatory effect, which might make these
patients more susceptible to the effects of vitamin D deficiency than
other patients.
9 of 16
2.3 | Race and genetic evidence
The relationship between ethnicity and Covid-19 has been identified
as an urgent public health research priority. There are recent reports
that mortality rate for black patients is higher than the rate for white
Covid-19 patients.42-47 Indeed, a provisional analysis in the UK has
shown that the risk of death among some ethnic groups is significantly
higher than that of those of White ethnicity. When taking into
account age in the analysis, Black males are 4.2 times more likely to
die from a Covid-19-related death and Black females are 4.3 times
more likely than White males and females.48 Ethnic groups such as
black communities are disproportionately affected by poverty, mass
incarceration, infant mortality, limited health care access, and health-
related conditions.42 While low socioeconomic status alone is consid-
ered as a risk factor for total mortality independent of any other risk
factors, social determinants of health and other risk factors must be
considered in a complex equation to better justify the reasons behind
high mortality rate among some ethnic groups.46
Although yet to be proved, vitamin D deficiency might contribute
to the black-white disparities in adverse Covid-19 outcomes given the
highlighted role of vitamin D in patients with Covid-19 and the fact
that the skin is the main source of vitamin D, contains the vitamin D-
metabolizing enzymes, and expresses the vitamin D receptor (VDR).49
Several studies have reported vitamin D deficiency among black pop-
ulation50-54 and serum 25-OHD concentrations are generally lower
among blacks than whites in the course of 1 year.55 Given the impor-
tant role of vitamin D in the evolution of human skin color,56,57 vita-
min D deficiency could impair health and increase mortality rates.
Black women have higher circulating concentrations of 1,25(OH)2D,
which suggests that they may have gut resistance to the actions of
1,25(OH)2D.58 In response to oral administration of 1,25(OH)2D, the
increase in fractional calcium absorption was reduced among blacks
compared to whites.59
A strong correlation between skin color and effect of UV radia-
tion levels supports the notion that dark skin might be less efficient
in terms of vitamin D metabolism.56,60 While blacks, and whites
might have similar capacities to absorb and synthesize vitamin D in
the skin, at usual levels of sun exposure, vitamin D synthesis is less
efficient among blacks because of their greater skin pigmenta-
tion.61-64 Differences in underlying vitamin D levels between fair
skinned and darker-skinned individuals may reflect differences in
sun exposure behavior and it remains to be defined to what extent
these differences relate to different outcomes in patients with
Covid-19.
Given the fact that genetic susceptibility may also play a role in
different Covid-19 outcomes,65 it is unclear to what extent genetic
factors influence highly affecting groups although several genetic pre-
disposition models and host genetic factors have been suggested.65,66
Higher expressions of angiotensin-coverting enzyme-2 (ACE2) recep-
tor that serves as an entry point for SARS-CoV-267 increased the sus-
ceptibility of several cells such as HEK293T and lymphatic cell lines to
SARS-CoV.68,69 East Asian populations were reported to exert higher
allele frequencies of expression quantitative trait loci (eQTL) variants
10 of 16
and found to be associated with higher expression of ACE2 levels
compared to Caucasians.70 Although less data are available, such an
association between ACE2 genetic variants and disease outcome has
71
not been confirmed for SARS-CoV.
Given the high prevalence of glucose-6-phosphate dehydroge-
nase (G6PD) deficiency in persons of African, Asian, and Mediterra-
72
nean descent, a potential association between G6PD deficiency and
Covid-19 has been suggested.73 Due to its cellular redox state, G6PD
deficiency increases viral replication and susceptibility to viral infec-
tions. Indeed, it has been found that G6PD deficiency can facilitate
74
human coronavirus 229E infection. These findings may provide a
rationale for future studies with Covid-19. Although less data is avail-
able, vitamin D enhanced expression of the gene G6PD encoding
glucose-6-phosphate dehydrogenase. Vitamin D could enhance anti-
oxidant pathways to protect various other types of epithelial cell from
oxidative stress. This action of vitamin D likely contributes to its
capacity to suppress IL-6 production by particulate matter-stimu-
lated.75 Oxidative stress also contributes to corticosteroid resistance,
76
a major feature of severe asthma, and vitamin D exerts a steroid-
sensitizing action in severe asthma, restoring dexamethasone-induced
77
IL-10 production by T cells.
Furthermore, vitamin D-related gene polymorphisms might also
be responsible for variable disease severity among Covid-19 patients
given the fact that mutations in VDR, DBP, CYP27B1, and CYP24A1
can cause profound disturbances49 in vitamin D efficacy in viral infec-
tions.12 Indeed, VDR gene polymorphisms downregulate VDR activity
and increase susceptibility to acute lower respiratory infections in
children.78-81 Ethnic affiliation is likely a factor in the observed differ-
ences of vitamin D-related genes polymorphism.82 In-depth investiga-
tions of vitamin D-related genes polymorphisms and other genetic
factors in affected subjects may explain the unusual behavior of
SARS-CoV-2 and various outcomes of Covi-19.83
3 | VITAMIN D AND COVID-19:
POTENTIAL MECHANISMS
Recognition of the mechanisms by which vitamin D exerts its poten-
tial in Covid-19 patients is essential given the complex interplay
12
between vitamin D and viral infections.
3.1 | The immunomodulatory effects of vitamin D
Acute respiratory disease syndrome and inflammatory-related disor-
ders are considered as the main reason behind Covid-19 morbidity
84
and mortality. Innate dysregulated immune cells including neutro-
phils, monocytes/macrophages,21,85 and mast cells86 and cytokine
storm (IL-6, IL-2, IL-7, G-CSF, IP-10, MCP-1, MIP-1A, and TNFα),21,87
lymphopenia and reduced functional state of T cells are also reported
87-90
to play a key role in disease pathogenesis.
Given its potential beneficial effects, vitamin D appears to mini-
mize the pro-inflammatory responses in these patients through
TEYMOORI-RAD AND MARASHI
different mechanisms including selective suppression of inflammatory
cytokines, reducing leukocyte infiltration into the inflammatory sites,12
interaction with immune cells such as neutrophils,91 monocytes/
macrophages,92 and mast cells.93 Vitamin D could also increase mem-
ory and regulatory T cells (Treg),90,94 decrease neutrophil/lymphocyte
ratio,95 and influence the functional state of T lymphocytes.96,97 It has
been recently found that activation of complement component C3
could exacerbate disease in SARS-CoV-associated Acute respiratory
disease syndrome (ARDS). Indeed, C3-deficient mice infected with
SARS-CoV exhibited less respiratory dysfunction despite equivalent
viral loads in the lungs, and this was associated with decreased lung
infiltration of neutrophils and inflammatory monocytes and lower
levels of cytokines and chemokines in both the lungs and sera.98 These
findings suggest C3 inhibition may also alleviate the inflammatory lung
complications of SARS-CoV-2 infection.99
Vitamin D can induce various innate antimicrobial responses and
its antimicrobial activity is mainly dependent on the induction of the
cationic host defense peptides (CHDPs).12 The anti-viral activities of
vitamin D in respiratory viral infections were highlighted in several
studies.100,101 Vitamin D in RSV not only decreases the inflammation
in airway epithelium but also maintains the antiviral state.102 Although
the exact mechanism by which vitamin D exerts its potential to keep
the balance between minimizing inflammation and improving antiviral
state is not fully understood, vitamin D may target essential inflamma-
tory pathways that are dispensable for active viral infections, as
suggested for other immune modulating agents.90
While our knowledge about the impact of vitamin D on acquired
immune response against viruses is still at an early stage, there is evi-
dence in cancers and viral infections, 96,97,103
which indicate vitamin
D status can influence influenza by improving serological response to
influenza vaccine as well as the function of CD8+ T lymphocytes.
Since lymphopenia and dysfunction of T lymphocytes are related to
the severity of Covid-19,87-89,104 vitamin D may improve the function
of CD8+ T cell response to better control SARS-COV-2 although fur-
ther studies are warranted to confirm these findings.
Given the fact that autophagy and apoptosis can impact several
aspects of innate and adaptive immunity through a distinct set of
adaptors that lead to an enhanced host resistance against microbial
insults,105 the induction of autophagy and apoptosis can be another
mechanism by which vitamin D may exert its potential effects. Given
the potential cross-talk between coronavirus infection with autophagy
and apoptotic signaling,100,106 the role vitamin D in this aspect can be
an interesting area for future studies.
3.2 | Interaction with key cellular and viral factors
in SARS-CoV-2 life cycle or pathogenesis
The importance of ACE2 in SARS-COV-2 entry was primarily
highlighted in animal models and cell culture.107 It was subsequently
realized that binding of SARS-CoV-2 to ACE2 downregulates its
expression and function,107 which appears to increase the risk of local
pulmonary angioedema via kinin-kallikrein system108 and severe acute
TEYMOORI-RAD AND MARASHI 11 of 16

lung failure109 in Covid-19 patients. Vitamin D increased ACE2
expression,110 which may potentially disrupt the impact of SARS-
111 112
CoV-2. Given the fact that both vitamin D and ACE2 act as neg-
ative regulators of the renin-angiotensin system, it is not clear to what
extent this phenomenon can benefit SARS-CoV-2, as enhanced ACE2
expression might also increase the risk of severe Covid-19 develop-
ment.113 If this is the case, it is tempting to speculate that ACE2 may
have a double sword activity that might further challenge the efficacy
of antiviral drugs targeting ACE2 in these patients. Considering SARS-
CoV-2 infection as two or three stages,114 it further highlights the
necessity of determining the optimal time and dosage of vitamin D for
therapeutic approaches.
SARS coronaviruses can also regulate cell stress response and
apoptosis as shown by deletion of the E gene (encoding envelope pro-
tein) from SARS-CoV can increase the expression of host genes
involved in stress response and immunoregulation.106 Interestingly,
vitamin D and its metabolites/analogs could also inhibit endoplasmic
reticulum (ER) stress and inhibition of ER stress and oxidative stress
by vitamin D has been previously reported in endothelial cells.115
Moreover, it has been shown that 25-OHD could suppress macro-
phage adhesion and migration by downregulation of ER stress and
scavenger receptor A1 in type 2 diabetes.116 These findings may also
have application in Covid-19 patients with underlying diseases.
3.3 | Local conversion of 25-OHD to 1,25(OH)D
Kidneys are considered the main site of producing the active form of
vitamin D, 1,25 dihydroxyvitamin D [1,25(OH)2D] via cytochrome
P450 family 27 subfamily B member 1 (CYP27B1) action, but other
cells including respiratory epithelial cells and some immune cells also
express CYP27B1.49 High level expression of activating CYP27B1 in
primary lung epithelial cells can increase the expression of vitamin D-
regulated genes particularly those with important immunomodulatory
functions.115 This process appears to have a beneficial impact on lung
function as well as in response to viral infections particularly

F I G U R E 1 The proposed mechanisms of vitamin D in Covid-19. Along with its highlighted role in underlying risk factors in Covid-19 such as
smoking, genetic background, obesity, and underlying diseases (1), vitamin D could also potentially impact SARS-CoV-2 infection outcomes
through several pathways: induce anti-inflammatory effect and/or reduce neutrophil/lymphocyte ratio (2), induce innate and acquired antiviral
responses (3), interact with cellular factors such as ACE2 (4), interact with viral factors and/or disrupt virus life cycle (5), local conversion of
25-OHD to active form by immune cells and airway epithelial cells (6), and vitamin D-related genes polymorphism. 1,25(OH)2D, 1,25 di-hydroxy-
vitamin D; 25-OHD, 25 hydroxyvitamin D; ACE2, angiotensin-converting enzyme 2; ARDS, Acute respiratory disease syndrome; ER, endoplasmic
reticulum; HBDs, Human β-defensins, Neut/lymph, neutrophils/lymphocytes ratio; Tregs, Regulatory T cells; VDR, Vitamin D receptor; VDRE,
Vitamin D responsive elements
12 of 16 TEYMOORI-RAD AND MARASHI

respiratory viruses. Exposing airway epithelium to vitamin D induces
NF-kB-linked chemokines and cytokines with a potential beneficial
effect on host defense against RSV without jeopardizing viral clear-
ance.102 Moreover, RSV infection can induce in vivo expression of
VDR and 1-α-hydroxylase.116 These findings indicate that vitamin D
can influence acute lower respiratory tract infections through reduc-
ing inflammation. Although yet to be defined, an insufficient local pro-
duction of vitamin D together with SARS-CoV-2 infection may
worsen the ongoing inflammation associated with infection (Figure 1).
4 | F R O M T HE R A P E U T I C P O T E N T I A L T O
UNANSWERED QUESTIONS
It is not yet clear how vitamin D strikes a balance between the
functional state of immune responses and antiviral state in these
patients. Given the fact that both vitamin D and ACE2 act as nega-
tive regulators of renin-angiotensin system, it is not clear how
these mechanisms benefit the pathogenesis of SARS-CoV-2. Con-
sidering the general distribution of ACE2 in many tissues particu-
larly kidneys and liver, it is unclear to what extent the interaction
of SARS-CoV-2 with its receptor disrupts vitamin D metabolism.
Given the wide variation in baseline 25-OHD levels in general pop-
ulation and reports about low levels of 1,25(OH)2D in some
patients with rickets despite normal levels of 25-OHD,49 it is diffi-
cult to justify vitamin D status in clinical settings without determi-
nation of serum 1,25(OH)2D, circulating levels of DBP, and
genotyping vitamin D-related genes. Moreover, it is not clear to
what extend insufficient local production of vitamin D in lung
together with SARS-CoV-2 infection plays a role in Covid-19
patients. Given the highlighted role of vitamin D-related genes
polymorphism in vitamin D efficacy in several viral infections,12 it

F I G U R E 2 Potential advantages and disadvantages of vitamin D supplementation in Covid-19. Potential advantages and disadvantages
of vitamin D supplementation in four stages of Covid-19. Stage 1- Before virus exposure and virus entry – Advantages: Inducing non-
specific response, local production of active vitamin D. Disadvantages: Increasing ACE2 expression. Stage 2- Virus replication –
Advantages: Direct interaction with virus life cycle, inhibit ER stress. Disadvantages: undefined. Stage 3- Immune response against viral
infection – Advantages: Inducing non-specific and specific anti-viral response. Disadvantages: undefined. Stage 4- Uncontrolled immune
response – Advantages: Inhibition of inflammatory responses, increasing ACE2 expression, and decrease neutrophil to lymphocyte ratio,
inhibition of complement. Disadvantages: Risk of secondary infections, inducing innate response. ACE2, Angiotensin-converting enzyme 2;
ARDS, Acute respiratory disease syndrome; ER, endoplasmic reticulum; Neut/lymph, neutrophils/lymphocytes ratio
TEYMOORI-RAD AND MARASHI 13 of 16

remains to be defined to what extent genetic background could inflammatory responses, increasing ACE2 expression, decreasing the
alter vitamin D metabolism in these patients. neutrophil to lymphocyte ratio, and inhibition of complement.
Given the fact that socioeconomic status and genetic background Although there are concerns about risk of secondary infections, fur-
cannot fully explain the reason behind higher morbidity and mortality ther studies are needed to evaluate the specific actions of vitamin D
reported in non-Caucasian patients with Covid-19, the potential role in this stage.
environmental factors particularly vitamin D, should be taken into
account. Moreover, many intrinsic and extrinsic factors including
genetic polymorphisms, skin type (pigmentation), age, health, sun 6 | CONC LU SION
exposure behavior, season, latitude, clothing and nutrition can modu-
late vitamin D status,117 as such, strict inclusion, or exclusion criteria The complex interplay between SARS-CoV-2 infection and vitamin D
in research studies and clinical trials should not be underestimated. status remains an intriguing concept. Given the wide variation in base-
While the beneficial effects of vitamin D supplementation are well line levels of vitamin D in general population and the fact that benefi-
document in different clinical settings, optimal dosage of vitamin D cial effects are mainly based on serum 25-OHD concentrations,
appears to be critical,118-120 given reduced efficacy following treat- measuring serum 1,25(OH)2D and circulating levels of vitamin D bind-
14
ment with large amount of vitamin D and even increased risk of ing protein along with genotyping vitamin D-related genes would pro-
adverse outcomes.121 vide a better picture in Covid-19. Moreover, a detailed understanding
of the biological actions of vitamin D and underlying risk factors can
further provide insights into disease pathogenesis in patients with
5 | PROPOSED HYPOTHESIS Covid-19. Given the fact that vitamin D status is modulated by many
intrinsic and extrinsic factors including genetic polymorphisms, skin
Given the fact that Covid-19 exert different stages of disease, vitamin type (pigmentation), age, sun exposure behavior, season, latitude, obe-
D supplementation as an effective, safe, low-cost, and easily available sity and nutrition,117 carefully designed studies with inclusion or
agent could have potential advantages and disadvantages in each exclusion criteria will be crucial to improve our understanding about
stage of Covid-19 as summarized in Figure 2. However, vitamin D the exact role of vitamin D supplementation in Covid-19.
supplementation might have its own disadvantages and further stud-
ies are warranted not only to clarify but also to evaluate the clinical CONFLIC T OF INT ER E ST
significance of vitamin D supplementation in each stage of Covid-19. The authors declare no conflicts of interest.
Stage 1: Vitamin D induces non-specific responses that could act
as a general inhibitor of viral infection. Optimal local production of DATA AVAILABILITY STAT EMEN T
active vitamin D could strengthen respiratory airway against SARS- Data sharing not applicable to this article as no datasets were gener-
CoV-2 infection. However, it could also increase ACE2 expression to ated or analysed during the current study.
increase the chance of virus binding to host cells. However, more data
are needed to evaluate both advantages and disadvantages of the
optimal vitamin D supplementation at this stage, either as preventive, NOME NCLATURE
or therapeutic approach.
Stage 2: After infection is initiated, vitamin D could potentially 1,25(OH)2D 1,25 di-hydroxy-vitamin D
modulate infection via interaction with both cell and virus factors. 25-OHD 25-hydroxyvitamin D
While our knowledge about SARS-CoV-2 is in its infancy, vitamin D ARDS Acute respiratory disease syndrome
could regulate some key elements in infected cells such as ER stress ACE2 angiotensin-converting enzyme 2
that may inhibit virus infection. However, further information could CHDPs cationic host defense peptides
reveal novel roles of vitamin D in this stage of infection. Covid-19 coronavirus disease-19
Stage 3: Host immune responses act against infection to keep CYP27B1 cytochrome P450 family 27 subfamily B member 1
the virus in check and this stage could determine the fate of infection ER endoplasmic reticulum
from mild to severe disease. Given the fact that vitamin D could eQTL expression quantitative trait loci
impact both innate and adaptive immune responses, vitamin D sup- G6PD glucose-6-phosphate dehydrogenase
plementation appears to improve the efficacy of immune response in HBDs Human β-defensins
the battle between host and virus. Although its disadvantage is Neut/lymph neutrophils/lymphocytes
undefined at this stage, further comprehensive studies are needed to Tregs Regulatory T cells
reveal the global imprint of vitamin D supplementation on immune RSV respiratory syncytial virus
responses. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
Stage 4: Uncontrolled immune response is one of the main rea- VDR Vitamin D receptor
sons behind severity and fatality of Covid-19. As such, vitamin D sup- VDRE Vitamin D responsive elements
plementation may play a key role in this stage through inhibition of WHO World Health Organization
14 of 16
ORCID
Majid Teymoori-Rad https://orcid.org/0000-0002-7004-6392
Sayed Mahdi Marashi https://orcid.org/0000-0001-7754-2674
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How to cite this article: Teymoori-Rad M, Marashi SM.
Vitamin D and Covid-19: From potential therapeutic effects to
unanswered questions. Rev Med Virol. 2020;e2159. https://
doi.org/10.1002/rmv.2159
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