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Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity

  • Sunlight, Nutrition and Health Research Center

Abstract and Figures

Vitamin D deficiency co-exists in patients with COVID-19. At this time, dark skin color, increased age, the presence of pre-existing illnesses and vitamin D deficiency are features of severe COVID disease. Of these, only vitamin D deficiency is modifiable. Through its interactions with a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations, and maintaining endothelial integrity. Fourteen observational studies offer evidence that serum 25-hydroxyvitamin D concentrations are inversely correlated with the incidence or severity of COVID-19. The evidence to date generally satisfies Hill's criteria for causality in a biological system, namely, strength of association, consistency, temporality, biological gradient, plausibility (e.g., mechanisms), and coherence, although experimental verification is lacking. Thus, the evidence seems strong enough that people and physicians can use or recommend vitamin D supplements to prevent or treat COVID-19 in light of their safety and wide therapeutic window. In view of public health policy, however, results of large-scale vitamin D randomized controlled trials are required and are currently in progress.
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Evidence Regarding Vitamin D and Risk of
COVID-19 and Its Severity
Joseph Mercola 1, *, William B. Grant 2and Carol L. Wagner 3
1Owner, Natural Health Partners, LLC, 125 SW 3rd Place, Cape Coral, FL 33991, USA
2Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA 94164-1603, USA;
3Department of Pediatrics, Shawn Jenkins Children’s Hospital, Medical University of South Carolina,
10 McClennan Banks Drive, MSC 915, Charleston, SC 29425, USA;
*Correspondence:; Tel.: +1-239-599-9529
Received: 4 October 2020; Accepted: 29 October 2020; Published: 31 October 2020
Vitamin D deficiency co-exists in patients with COVID-19. At this time, dark skin color,
increased age, the presence of pre-existing illnesses and vitamin D deficiency are features of severe
COVID disease. Of these, only vitamin D deficiency is modifiable. Through its interactions with
a multitude of cells, vitamin D may have several ways to reduce the risk of acute respiratory
tract infections and COVID-19: reducing the survival and replication of viruses, reducing risk of
inflammatory cytokine production, increasing angiotensin-converting enzyme 2 concentrations,
and maintaining endothelial integrity. Fourteen observational studies oer evidence that serum
25-hydroxyvitamin D concentrations are inversely correlated with the incidence or severity of
COVID-19. The evidence to date generally satisfies Hill’s criteria for causality in a biological
system, namely, strength of association, consistency, temporality, biological gradient, plausibility (e.g.,
mechanisms), and coherence, although experimental verification is lacking. Thus, the evidence seems
strong enough that people and physicians can use or recommend vitamin D supplements to prevent
or treat COVID-19 in light of their safety and wide therapeutic window. In view of public health
policy, however, results of large-scale vitamin D randomized controlled trials are required and are
currently in progress.
cathelicidin; COVID-19; endothelial dysfunction; IL-6; immune system; inflammation;
MMP-9; SARS-CoV-2; vitamin D; 25-hydroxyvitamin D
1. Introduction
Until the 21st century, vitamin D was primarily recognized for its role in regulating calcium and
bone health and preventing rickets [
]. In the last 20 years, however, research has shown that vitamin
D also profoundly influences immune cells and generally lowers inflammation [
]. Vitamin D is
a powerful epigenetic regulator, influencing more than 2500 genes [
] and impacting dozens of our
most serious health challenges, including cancer [
], diabetes mellitus [
], acute respiratory tract
infections [8], and autoimmune diseases such as multiple sclerosis [9].
According to the Worldometer website [
], the world had recorded 40,628,492 cases and
1,122,733 deaths from COVID-19 by 19 October 2020.
There are a number of findings regarding COVID-19 that may be related to vitamin D status.
Seasonal dependence: it began in winter in the northern hemisphere and both case and death rates
were lowest in summer, especially in Europe, and rates began increasing again in July, August, or
September in various European countries [
]; it is thus generally inversely correlated with solar
UVB doses and vitamin D production [11,12].
Nutrients 2020,12, 3361; doi:10.3390/nu12113361
Nutrients 2020,12, 3361 2 of 24
African Americans and Hispanics have higher COVID-19 case and death rates than European
Americans [
], possibly due to darker skin pigmentation and lower 25-hydroxyvitamin D
[25(OH)D] concentrations [15].
Much of the damage from COVID-19 is thought to be related to the “cytokine storm”, which is
manifested as hyperinflammation and tissue damage [16].
The body’s immune system becomes dysregulated in severe COVID-19 [17].
This narrative review examines the evidence indicating that vitamin D could play important roles
in reducing the risk and severity of and death from infections, including COVID-19.
2. Findings Regarding Vitamin D and COVID-19
2.1. Vitamin D Deficiency Increases the Risk and Severity of COVID-19
Mainly owing to the recency and novelty of the SARS-CoV-2 virus, the evidence that vitamin D
status aects the risk of COVID-19 comes primarily from observational and ecological studies. Clinical
trials involving vitamin D supplementation and incidence of COVID-19 have not been reported to date.
Of the 48 clinical trials on vitamin D and COVID-19 listed in the Clinical Trials registry maintained by
the U.S. government [
], only four will investigate prevention, and three of those are enrolling health
care workers, a group that is highly exposed to COVID-19.
Table 1lists the findings from observational studies regarding 25(OH)D concentration and
COVID-19 as of 15 October 2020, listed in ascending order by date first posted online. The table lists
the study parameters and findings as well as the strengths and limitations of the studies. Two of the
studies used 25(OH)D concentrations 10–14 years before the COVID-19 incidence data; the others
generally used 25(OH)D concentrations at the time of hospital admission. Many of the studies have
small numbers of COVID-19 patients. Other than the two studies with long intervals between 25(OH)D
concentrations and COVID-19, and one observational study from Austria, the studies found inverse
correlations between COVID-19 severity and/or risk of death.
Table 1.
Summary of observational study findings regarding COVID-19 and 25(OH)D concentrations
posted at by 27 September 2020.
Location Participants Outcomes vs. 25(OH)D
Limitations Reference
1 UK
449 C19 patients
348,598 controls
from UK Biobank
Incidence for 25(OH)D
<10 vs. >10
Univariable OR =1.37
(1.07–1.76, p=0.01)
Multivariable OR =0.92
(0.71–1.21, p=0.56)
Some confounding
variables should not be
used since they aect
concentrations [19,20]
25(OH)D data were
from blood drawn
from 2006 to 2010
Participant 25(OH)D
concentrations change
over time, reducing
correlations with
disease outcomes [21]
Hastie [22]
2 Switzerland
27 patients PCR+
for SARS-CoV-2;
80 patients PCR–
1377 controls with
25(OH)D measured
in same period in
Patients PCR+had mean
25(OH)D =11 vs. 25 for
patients PCR– (p=0.004)
Controls had 25(OH)D =
25, not significantly
dierent from patients
PCR– (p=0.08)
PCR+is for antibodies;
may not be active
Small number of PCR+
D’Avolio [23]
Nutrients 2020,12, 3361 3 of 24
Table 1. Cont.
Location Participants Outcomes vs. 25(OH)D
Limitations Reference
3UK, Newcastle
upon Tyne
92 C19, non-ITU;
42 C19, ITU
Patients were
supplemented with
vitamin D
at doses
correlated with
baseline 25(OH)D
Non-ITU vs. ITU:
25(OH)D 19 ±15 vs. 13
±7 (p=0.30) 25(OH)D
<20 vs. >20 (p=0.02)
RR for death, 25(OH)D =
0.97 (0.42–2.23, p=0.94)
Lack of correlation of
death with baseline
25(OH)D was likely
due to graded
supplementation with
vitamin D
Panagiotou [
5 Italy
42 C19 hospitalized
patients; mean age
65 ±13 years, 88
with ARDS
!L6 for 25(OH)D >30: 80
±40 pg/L; for 25(OH)D
<10, 240 ±470 pg/L
After 10 days, patients
with 25(OH)D <10 had a
50% mortality vs. 5% for
25(OH)D <10 (p=0.02)
Patients with 25(OH)D
<10 ng/mL had a mean
age of 74 ±11 years vs.
63 ±15 years for
patients with 25(OH)D
10 ng/mL
6 Korea
50 C19 patients
with PCR+, 150
controls; mean age
=52 ±20 years
C19 vs. control:
16 (SD 8) vs. 25 (SD 13)
(p<0.001); 20, 74% vs.
43% (p=0.003);
10, 24%
vs. 7% (p=0.001)
Strengths: measured B
vitamin, folate,
selenium and zinc
concentrations as well
as 25(OH)D
Weaknesses: small
number of patients;
incomplete analysis of
data for C19 outcomes
Im [26]
7 Russia
80 C19 patients
Severe: 25(OH)D =12 ±
6 ng/mL; moderate to
severe: 25(OH)D =19 ±
14 ng/mL
Death: 25(OH)D =11
ng/mL; discharged: 18 ±
6 ng/mL
Obesity rates: 62% for
severe, 15% for
discharged, p<0.001
Strengths: studied the
eect of obesity
Weaknesses: small
Karonova [27]
8 Mexico 172 hospitalized
C19 patients
Mean 25(OH)D =17 ±7
ng/mL for hospitalized
C19 patients
Survivors: mean age =
48 ±13 years; 25(OH)D
=17 ±7 ng/mL
Death: mean age =65 ±
12 years; 25(OH)D =14
±6 ng/mL
(pvalue for dierence in
25(OH)D =0.0008)
Weaknesses: survivors
were much younger
than non-survivors
Comorbid factors not
Tort [28]
9 UK
105 patients with
C19 symptoms;
70 C19 PCR+, 35
PCR–; mean age =
80 ±10 years
PCR+: 25(OH)D =11
PCR–: 25(OH)D =21
Comorbid diseases were
not significantly
correlated with 12 vs.
PCR+is for antibodies;
may not be active
Baktash [29]
Nutrients 2020,12, 3361 4 of 24
Table 1. Cont.
Location Participants Outcomes vs. 25(OH)D
Limitations Reference
10 UK
656 C19, 203 died
from C19; 340,824
controls from UK
Incidence for 25(OH)D
<10 vs. >10
Univariable OR =1.56
(1.28–1.90, p<0.0001)
Multivariable OR =1.10
(0.88–1.37, p=0.40)
Death for 25(OH)D <10
ng/mL vs. >10 ng/mL
Univariable OR =1.61
(1.14–2.27, p=0.0007)
Multivariable OR =1.21
(0.83–1.76, p=0.31)
Same comments as for
earlier UK Biobank
Hastie [30]
11 Germany 185 C19; median
age =60 years
Multivariable HR for
death for 25(OH)D <12:
IMV/D, 6.1 (2.8–13.4, p<
D, 14.7 (4.2–52.2, p<
Strengths: HR adjusted
for age, gender, and
Weaknesses: Small
number of IMV and
Radujkovic [
12 Austria
109 C19
patients; mean age
=58 ±14 years
Mild: 26 ±12
Moderate: 22 ±8
Severe: 20 ±10
PTH increased
significantly with age (p
The vitamin D finding
may have been limited
owing to the high
mean 25(OH)D
Mild C19 patients had
mean age =46 ±16
years; moderate and
severe patients has
mean age =60 ±13
PTH increases with
age [32]
Pizzini [33]
13 Spain
80 emergency
patients with a
PCR+test within
the past three
retrospective study
49 non-severe C19,
25(OH)D =19 ng/mL; 31
severe C19, 25(OH)D =
13 ng/mL (p=0.15)
For patients under 65
years, 30 non-severe C19,
25(OH)D =22 (11–31)
ng/mL; 10 severe C19,
25(OH)D =11 (9–12)
ng/mL (p=0.009)
Multivariable OR for
severe C19 for 25(OH)D
<20 ng/mL =3.2 (95% CI,
0.9 to 11.4, p=0.07)
Weaknesses: small
prevalence of
advanced chronic
kidney disease was
higher in severe than
non-severe cases (45%
vs. 24%, p=0.054)
Macaya [34]
14 China 62 C19 patients, 80
healthy controls
age, 25(OH)D:
controls: 43 years, 29
(23–33) ng/mL;
mild/moderate C19:
39 (30–49) years, 23
(18–27) ng/mL;
severe/critical C19:
65 (54–69) years, 15
(13–20) ng/mL
Multivariate OR for
severe/critical C19 for
25(OH)D <20 ng/mL =
15 (1.2 to 187, p=0.03)
Strengths: many
factors measured
Weaknesses: the
severe/critical patients
were much older than
patients and controls
Ye [35]
Abbreviations: ARDS, acute respiratory distress syndrome; C19, COVID-19 patients; D, death; HR, hazard ratio;
IMV, invasive mechanical ventilation; ITU, intensive treatment unit; OR, odds ratio; PCR, polymerase chain reaction;
PTH, parathyroid hormone; RR, relative risk; SD, standard deviation.
The study from Newcastle upon Tyne, UK, supplemented patients with vitamin D
depending on
their baseline 25(OH)D concentration [
]. Those with 25(OH)D concentration <5 ng/mL were given
Nutrients 2020,12, 3361 5 of 24
300,000 IU vitamin D
followed by 1600 IU/d. Those with 25(OH)D between 5 and 10 ng/mL were
given 200,000 IU vitamin D followed by 800 IU/d. Those with 25(OH)D between 10 and 16 ng/mL were
given 100,000 IU vitamin D followed by 800 IU/d. Those with 25(OH)D between 16–30 ng/mL were
given 800 IU/d, while those with 25(OH)D >30 ng/mL were not given vitamin D. Probably as a result,
baseline 25(OH)D concentrations were not associated with mortality (p=0.94).
Table 2presents data on SARS-CoV-2 positivity for large populations independent of whether the
participants had symptomatic COVID-19.
Table 2.
Summary of observational study findings regarding SARS-CoV-2 positivity in general
populations and 25(OH)D concentrations by date of first publication up to October 15, 2020.
Location Participants Outcomes vs. 25(OH)D
Limitations Reference
1 Israel
Data from a
hospital in Tel Aviv
involving patients
who had previous
measurements and
were tested for
SARS-CoV-2 using
782 patients PCR+
7025 patients PCR–
Univariate: 20–29 vs.
>30: OR =1.59
(1.24–2.02, p=0.005);
<20 vs. >30, OR =1.58
(1.13–2.09, p=0.0002).
Multivariate: <30 vs.
>30, OR =1.50
(1.13–1.98, p=0.001)
Strengths: large
number of participants.
Weakness: PCR+is not
Merzon [36]
2 US
489 C19 patients,
PCR+; mean age =
49 ±18 years with
were from
preceding 12
124 <20 vs. 287 >20,
RR =1.77 (1.12–2.81,
Strengths: this is a
retrospective study in
which serum 25(OH)D
concentrations and
vitamin D
history were obtained
during the preceding
12 months.
Meltzer [37]
3 US
191,779 patients
tested for 25(OH)D
and SARS-CoV-2
positivity during
the past year
by Quest
SARS-CoV-2 positivity
for 25(OH)D <20 =
12.5% (95% CI,
12.2–12.8%); positivity
for 25(OH)D >55 =5.9%
(95% CI, 5.5–6.4%).
For 25(OH)D <20,
SARS-CoV-2 positivity
rates were: black
non-Hispanic, 19%;
Hispanic, 16%; white
non-Hispanic, 9%
Strengths: large
number of participants
and is a retrospective
study. 25(OH)D
concentrations were
seasonally adjusted.
SARS-CoV-2 positivity
is a precursor to
COVID-19, but many
with positivity do not
develop COVID-19.
There may be bias in
who was tested since
the tests were ordered
by physicians.
The study from Israel reported that 25(OH)D concentration inversely correlated with COVID-19
in both univariate and multivariate regression analyses except for multivariate hospitalization of
patients [
]. For hospitalization of patients, the only significant factor in the multivariate hospitalization
was age 50 years and older, implying that vitamin D status becomes less important with age. Yet, the
study from the UK with patients of mean age 80
10 years reported that 25(OH)D concentration was
significantly lower for COVID-19 PCR+patients than COVID-19 PCR– patients [29].
The observational study from the U.S. based on test data from Quest Diagnostics (Secaucus, NJ,
USA) [
] is the largest observational study to date, with data for 191,779 patients with a mean age of
50 years (interquartile range, 40–65 years) tested for SARS-CoV-2 between 9 March and 19 June with
25(OH)D tests in the preceding 12 months at Quest Diagnostics. The study reported the following
rates of SARS-CoV-2 positivity vs. 25(OH)D concentration: 39,120 patients <20 ng/mL, 12.5% (95% CI,
12.2–12.8%); 27,870 patients, 30–34 ng/mL, 8.1% (7.8–8.4%); 12,321 patients, >55 ng/mL, 5.9% (5.5–6.4%).
Nutrients 2020,12, 3361 6 of 24
The finding that the SARS-CoV-2-positive rate in the U.S. varied from 6.5% for 25(OH)D
concentration between 40 and 50 ng/mL to approximately 11.3% for 25(OH)D =20 ng/mL may
be due to the eect of vitamin D in reducing survival and replication of the virus by induction of
cathelicidin and defensins as well as by increasing concentrations of free ACE2 [
], thereby preventing
SARS-CoV-2 from entering cells via the ACE2 receptor [
]. The regression fit to all the data indicates
that SARS-CoV-2 positivity is 40% lower for 25(OH)D >50 ng/mL than for 20 ng/mL, the value
recommended by the Institute of Medicine [
]. The SARS-CoV-2-adjusted OR (aOR) for northern
) vs. southern (<32
) was 2.66 (95% CI, 2.54–2.79), whereas that for central (32
) vs. southern
was 1.22 (1.16–1.38).
Regarding the higher rates in the northern states, a genetic variation was evident in SARS-CoV-2
from the original spike protein amino acid D614 form in China to the D614G mutated form it took
in Europe [
]. (The Spike D614GF amino acid change is caused by an A-to-G nucleotide mutation
at position 23,403 in the Wuhan reference strain.) The D614G form has greater transmission and
was introduced to New York by people returning from Europe. Thus, that genetic change probably
accounts for some of the higher SARS-CoV-2 positivity rate in the north. However, the shape of the
25(OH)D positivity rate is similar for all three latitude regions.
As for race/ethnic dierences, African Americans have increased rates of social determinants
predisposing them to COVID-19, such as lower income, education, and employment as well as higher
rates of existing conditions such as diabetes, hypertension, cardiovascular disease, obesity, and lung
disease [
]. Those factors may help explain why black people and Hispanic people have 7% and
4% higher SARS-CoV-2 positivity rates, respectively, than white people at 30 ng/mL. Nonetheless,
the SARS-CoV-2 positive rate spread was much higher for black and Hispanic people than for white
people near 20 ng/mL (18%, 16%, and 9%, respectively) than near 60 ng/mL (11%, 9%, and 5%,
respectively), suggesting that vitamin D status plays a role in the increased COVID-19 rate for black
and Hispanic people.
It can be argued that the association of low serum 25(OH)D concentrations with various diseases
is due to “reverse causation”, i.e., that the disease state lowers the concentrations in proportion to
the severity of the disease. That argument was made to explain why randomized controlled trials
(RCTs) with vitamin D supplementation often fail to support observational studies reporting inverse
correlations between 25(OH)D concentration and disease risk [
]. There are several counters to
that argument.
One is that many vitamin D RCTs did not enroll participants with low 25(OH)D concentrations
and did not supplement with sucient vitamin D to produce a significant change in health outcome.
Robert Heaney pointed out that vitamin D RCTs should be guided by serum 25(OH)D concentrations,
not vitamin D dose [
] (see also, [
]). In addition, more recent RCTs have found that vitamin D
supplementation can reduce risk of some of the non-skeletal health disorders considered by Autier in
2017: cancer incidence and death according to secondary analyses [
], cancer mortality rate [
] and
progression from prediabetes to diabetes in the secondary analyses [7].
A second argument is that the 25(OH)D concentrations used in prospective observational studies
are obtained from blood drawn prior to the disease outcomes of interest. Only three observational
studies listed in Table 1were prospective studies with less than one year lag between blood draw and
COVID-19 or SARS-CoV-2 positivity [3638].
A counter argument is that there is evidence that an acute-inflammatory disease state lowers
25(OH)D concentrations. A systematic review summarized results from eight studies reported between
1992 and 2013 regarding changes in 25(OH)D concentrations after acute inflammatory insult [
Four studies involved surgery. One involving 19 patients undergoing cardiopulmonary bypass
reported an 8 ng/mL drop in five minutes with return to near baseline after 24 h [
]. Three involving
knee or knee/hip arthroplasty or orthopedic surgery reported two-day decreases of 7 ng/mL [
4 ng/mL [
] and 1 ng/mL for males, 3 ng/mL for females [
]. There was no significant change for
malarial infection [
] and a one ng/mL decrease for acute pancreatitis [
]. The largest decease was
Nutrients 2020,12, 3361 7 of 24
15 ng/mL after three days for an injection of bisphosphonate [
]. The nearest outcome to COVID-19
was malaria infection, for which no change was found. Thus, from these studies, it is unclear whether
acute inflammation not associated with surgery results in reduction in 25(OH)D.
2.2. Vitamin D and Treatment of COVID-10
A study by Ohaegbulam and colleagues involved four COVID-19
patients in New York [
Two, a male aged 41 years and a female aged 57 years, were given five daily 50,000 IU vitamin D
doses, whereas another two, males aged 53 and 74 years, were given five daily 1000 IU vitamin D
doses. Baseline 25(OH)D concentration was between 17 and 22 ng/mL, whereas achieved 25(OH)D
was 40 and 51 ng/mL for patients treated with high-dose vitamin D and 19 and 20 ng/mL for those
treated with standard-dose vitamin D.
Biomarkers of inflammation were significantly reduced with high-dose treatment: CRP went
from 31 to 2 mg/dL and from 17 to 8 mg/dL, compared with 13 to 22 mg/dL and 21 to 18 mg/dL for
low-dose treatment; IL-6 went from 14 and 10 pg/mL to <5 pg/mL for high-dose treatment and from
<5 and 6 pg/mL to <5 and 11 pg/mL for low-dose treatment.
The length of stay was 10 days for the high-dose patients and 13 and 14 days for the low-dose
patients. The oxygen requirement went from zero and 15 L to zero for the high-dose patients and from
2 and 3 L to 2 and 7 L for the low-dose patients. The strengths of this study include that high-dose
vitamin D
supplementation was used and that baseline and post-supplementation values for many
parameters were measured. The main limitation was that only two patients were supplemented with
high-dose vitamin D3.
The results of pilot RCT of treatment of COVID-19 patients in Spain with calcifediol were
announced on August 29 [
]. (Calcifediol [25(OH)D] is often used in Spain. It raises serum 25(OH)D
concentration more quickly but does not last as long in the serum as a result of its lower lipophilia [
The mean age of the patients was 53
10 years. None of the prognostic factors evaluated except
previous high blood pressure [15 (58%) without treatment vs. 11 (24%) with treatment] significantly
aected the outcome. In this study, 50 patients were given soft capsules of 0.532 mg of calcifediol on
the day of admission, then 0.266 ng on day 3 and 7, and then weekly until discharge or admission
to the intensive care unit (ICU). Thus, those in the treatment arm received approximately 130,000 IU
of vitamin D during the first week, then approximately 33,000 IU/week thereafter. Serum 25(OH)D
concentrations were not measured, but the calcifediol dose in the treatment arm was high enough to
raise 25(OH)D concentration by approximately 20 ng/mL.
Forty-nine of the calcifediol-treated patients did not require the ICU, whereas 13 of the 26 not
receiving that treatment did require the ICU. In addition, two of the patients admitted to the ICU died.
The odds ratio (OR) for ICU in treated vs. control patients was 0.02 (95% CI, 0.002 to 0.17), which
increased slightly when adjusted for hypertension and type 2 diabetes mellitus [OR =0.03 (95% CI,
0.003 to 0.25)]. A meta-analysis of 34 studies found that hypertension was a significant risk factor
for several or fatal COVID-19 compared to non-severe/non-fatal COVID-19: OR =3.2 (95% CI 2.5 to
4.1) [
]. Thus, prevalence of hypertension should have been considered when dividing patients into
treatment and control groups. The results of this study cannot be used for policy decisions. The main
value of this study is that it is a pilot study for a study involving 1000 COVID-19 patients.
A “quasi-experimental study” of bolus vitamin D supplementation of residents in a French nursing
home was conducted preceding and during a COVID-19 outbreak in the nursing home [
]. Residents
were normally given a bolus dose of 80,000 IU vitamin D
every two to three months. COVID-19
aected many of the residents starting in March 2020.
Fifty seven of the residents, who had received 80,000 IU vitamin D
in the preceding month,
were included in the “intervention group” while nine who had not were included in the “comparator
group”. The mean age of the residents was 87
9 years. The mean follow-up time was 36
7 days.
Forty-seven (83%) of the intervention group survived compared to only four (44%) of the comparator
Nutrients 2020,12, 3361 8 of 24
group (p=0.02). The fully adjusted HR for mortality according to vitamin D supplementation was 0.11
(95% CI, 0.03 to 0.48, p=0.003).
A clinical trial was conducted regarding bolus vitamin D dose (100,000 IU vitamin D
supplementation involving 30 older (71
6 years) and ten younger (38
8 years) subjects and
ten older controls (71
10 years) [
]. Baseline 25(OH)D was 27
8 ng/mL, rising to 42
9 ng/mL
within six days, then falling in a linear fashion to 32 ng/mL after 70 days. Thus, bolus vitamin D
supplementation monthly would be appropriate for nursing-home residents.
2.3. Vitamin D Helps Immune Cells Produce Antimicrobial Peptides
Many studies have shown that vitamin D activates immune cells to produce AMPs, which include
molecules known as cathelicidins and defensins [
]. AMPs have a broad spectrum of activity, not
only antimicrobial but also antiviral, and can inactivate the influenza virus [
]. The antiviral eects of
AMPs are the result of, among other eects, the destruction of envelope proteins by cathelicidin [
See Figure 1.
Nutrients 2020, 12, x FOR PEER REVIEW 9 of 25
0.003 to 0.25)]. A meta-analysis of 34 studies found that hypertension was a significant risk factor for
several or fatal COVID-19 compared to non-severe/non-fatal COVID-19: OR = 3.2 (95% CI 2.5 to 4.1)
[61]. Thus, prevalence of hypertension should have been considered when dividing patients into
treatment and control groups. The results of this study cannot be used for policy decisions. The main
value of this study is that it is a pilot study for a study involving 1000 COVID-19 patients.
A “quasi-experimental study” of bolus vitamin D supplementation of residents in a French
nursing home was conducted preceding and during a COVID-19 outbreak in the nursing home [62].
Residents were normally given a bolus dose of 80,000 IU vitamin D
every two to three months.
COVID-19 affected many of the residents starting in March 2020.
Fifty seven of the residents, who had received 80,000 IU vitamin D
in the preceding month,
were included in the “intervention group” while nine who had not were included in the “comparator
group”. The mean age of the residents was 87 ± 9 years. The mean follow-up time was 36 ± 7 days.
Forty-seven (83%) of the intervention group survived compared to only four (44%) of the comparator
group (p = 0.02). The fully adjusted HR for mortality according to vitamin D supplementation was
0.11 (95% CI, 0.03 to 0.48, p = 0.003).
A clinical trial was conducted regarding bolus vitamin D dose (100,000 IU vitamin D
supplementation involving 30 older (71 ± 6 years) and ten younger (38 ± 8 years) subjects and ten
older controls (71 ± 10 years) [63]. Baseline 25(OH)D was 27 ± 8 ng/mL, rising to 42 ± 9 ng/mL within
six days, then falling in a linear fashion to 32 ng/mL after 70 days. Thus, bolus vitamin D
supplementation monthly would be appropriate for nursing-home residents.
2.3. Vitamin D Helps Immune Cells Produce Antimicrobial Peptides
Many studies have shown that vitamin D activates immune cells to produce AMPs, which
include molecules known as cathelicidins and defensins [64–67]. AMPs have a broad spectrum of
activity, not only antimicrobial but also antiviral, and can inactivate the influenza virus [68]. The
antiviral effects of AMPs are the result of, among other effects, the destruction of envelope proteins
by cathelicidin [69–71]. See Figure 1.
Figure 1.
The cascade of events by the innate immune system in response to viral infections. Among
the functions of AMPs (antimicrobial peptides) is chemotaxis, the movement of cells in response to a
chemical stimulus, here macrophages, mast cells, monocytes, and neutrophils. Other effects include
activation of the innate immune system, effects on angiogenesis, antiendotoxin activity, and
Figure 1.
The cascade of events by the innate immune system in response to viral infections. Among
the functions of AMPs (antimicrobial peptides) is chemotaxis, the movement of cells in response
to a chemical stimulus, here macrophages, mast cells, monocytes, and neutrophils. Other eects
include activation of the innate immune system, eects on angiogenesis, antiendotoxin activity, and
opsonization (the molecular mechanism whereby pathogenic molecules, microbes, or apoptotic cells
(antigenic substances) are connected to antibodies, complement, or other proteins to attach to the cell
surface receptors on phagocytes and NK cells). LMS (lipopolysaccharide)
Cathelicidins are a distinct class of proteins present in innate immunity of mammals. In humans,
the primary form of cathelicidin is known as LL-37 [
]. LL-37 also blocks viral entry into the cell
similarly to what is seen with other antimicrobial peptides [73].
2.4. Vitamin D Reduces Inflammatory Cytokine Production
Elevated inflammation is an important risk factor for COVID-19 [
]. For example, much of
the pathogenesis surrounding COVID-19 infection involves microvascular injury induced by
Nutrients 2020,12, 3361 9 of 24
hypercytokinemia, namely, by an important inflammatory cytokine—interleukin 6 (IL-6) [
Thus, it is useful to examine the role of vitamin D in reducing inflammation.
A number of reviews have suggested that one of the hallmarks of COVID-19 severity is the
presence of a “cytokine storm” [
]. The “cytokine storm” is defined as the state of out-of-control
release of a variety of inflammatory cytokines [
]. Observational studies, however, have found that
cytokine concentrations are elevated in COVID-19 patients compared to controls, but not as high as in
some other diseases.
A study in the Netherlands compared cytokine levels in critically ill patients [
]. The study
involved 46 COVID-19 patients, 51 with septic shock with acute respiratory tract syndrome (ARDS),
15 with septic shock without ARDS, 30 with out-of-hospital cardiac arrest (OHCA), and 62 with trauma.
Levels of (TNF
) for COVID-19 patients were lower than for septic shock patients but higher than for
OHCA or trauma patients. Levels of IL-6 and IL-8 for COVID-19 patients were lower than for septic
shock patients but comparable with those for OHCA and trauma patients.
A recent review examined whether IL-6 concentrations might aect the outcome of COVID-19 [
The evidence presented included age-stratified IL-6 concentrations from a healthy Italian population
were highly correlated with age-stratified Italian COVID-19 deaths, which in turn were highly correlated
with age-stratified COVID-19 death rates in the UK. The researchers also cited trials of vitamin D
supplementation and its eect on IL-6 concentrations, of which eight of 11 showed a significant lowering
of IL-6. People for whom a significant lowering was not found were healthy older adults, asthma
patients, and prediabetic adults. That reviewshowed how IL-6 increases the severity of COVID-19
by upregulating angiotensin-converting enzyme 2 (ACE2) receptors and induction of macrophage
cathepsin L. Cathepsin L mediates the cleavage of the S1 subunit of the coronavirus surface spike
glycoprotein. That cleavage is necessary for coronavirus entry into human host cells, virus–host cell
endosome membrane fusion, and viral RNA release for the next round of replication [81].
A study from Ireland investigated cytokine concentrations of healthy controls, stable
COVID-19 patients, ICU COVID-19 patients, and ICU community-acquired pneumonia patients [75].
ICU-COVID-19 patients had the highest concentrations of IL-1
, IL-6, IL-6 to IL-10 ratio, and tumor
necrosis factor receptor superfamily member 1A (TNFR1). Stable COVID-19 patients had concentrations
that were between the levels noted for healthy controls and those of ICU COVID-19 patients for all of the
cytokines. ICU-community-acquired pneumonia patients had inflammatory cytokine concentrations
between stable and ICU COVID-19 patients but higher IL-10 concentrations.
A study of COVID-19 hyperinflammation (COV-HI) was conducted on 269 polymerase
chain reaction (PCR)-confirmed COVID-19 patients admitted to two UK hospitals in March [
Hyperinflammation was defined as CRP concentration greater than 150 mg/L or doubling within 24 h
from greater than 50 mg/L, or a ferritin concentration greater than 1500
g/L. Ninety (33%) of the
patients met the criteria for COV-HI at admission. Forty percent of COV-HI patients died compared to
26% of the non-COV-HI patients. Meeting the COV-HI criteria was significantly associated with risk of
next-day escalation of respiratory support or death (hazard ratio =2.24 (95% CI, 1.62 to 2.87)).
Another study developed a more extensive set of criteria for COV-HI [
]. The criteria included
elevated temperature, macrophage activation (elevated ferritin), haemotological dysfunction related to
neutrophils and lymphocytes, coagulopathy (elevated D-dimer), hepatic injury (elevated lactate
dehydrogenase or aspartate aminotransferase concentration), and cytokinaemia (elevated IL-6,
triglyceride, or CRP concentration). It is not clear whether vitamin D supplementation could aect any
of these factors other than cytokinaemia.
Other papers have noted that concentrations of many cytokines are elevated in COVID-19
patients [75,84,85].
There are several reasons why the cytokine storm is associated with severe COVID-19 and
death [
]. As outlined in the review by Hojyo [
], the hypothesis that the main cause of death of
COVID-19 is ARDS with cytokine storms can be explained by at least two reasons. One is intravascular
coagulation as an important cause of multiorgan injury, which is mainly mediated by inflammatory
Nutrients 2020,12, 3361 10 of 24
cytokines such as IL-6 [
]. The other is that the SARS-CoV-2 virus aects endothelial cells, causing
further cell death, which leads to vascular leakage and induces a cytopathic eect on airway epithelial
cells [89].
2.5. Type II Pneumocytes and Surfactants in the Lungs
The type II pneumocytes in the lung are the primary target for coronaviruses because the ACE2
receptors to which the virus binds are highly expressed on those cells. One problem with COVID-19 is
that it impairs the function of type II pneumocytes, which then decreases the surfactant concentration in
the alveolar–air interface [
]. That is important because surfactant prevents the collapse of the alveoli.
Surfactant allows alveoli to stay open and compliant during both inhalation and exhalation.
During inhalation, alveoli may collapse if they do not contain surfactant. If they collapse, gas exchange
across the alveoli wall cannot occur. Without surfactant, each breath taken is like blowing up a collapsed
balloon and then letting the air out of that balloon (lungs) and then doing it all over again with the
next breath cycle. Simply put, having enough surfactant is necessary for alveoli to stay open and gas
exchange to occur. Another aspect of surfactant is its protein A (SP-A), which binds to influenza A
viruses via its sialic acid residues and thereby neutralizes the virus [
]. Surfactant protein D clears
influenza A from the lungs of mice [
]. There is some evidence that 1
D increases surfactant
production [93]. Such activity can be generalized to other viruses.
2.6. Vitamin D, Angiotensin II, and ACE2 Receptors
Angiotensin-converting enzyme (ACE) is part of the renin–angiotensin system (RAS), which
controls blood pressure by regulating the volume of bodily fluids. Angiotensin-converting enzyme 1
(ACE1) converts the hormone angiotensin I to the active vasoconstrictor angiotensin II [
]. Angiotensin
II is a natural peptide hormone best known for increasing blood pressure through stimulating
aldosterone [
] ACE2 normally consumes angiotensin I, thereby lowering its concentrations. However,
SARS-CoV-2 infection downregulates ACE2, leading to excessive accumulation of angiotensin II.
Cell cultures of human alveolar type II cells with vitamin D have shown that the SARS-CoV-2
virus interacts with the ACE2 receptor expressed on the surface of lung epithelial cells. Once the virus
binds to the ACE2 receptor, it reduces its activity and, in turn, promotes ACE1 activity, forming more
angiotensin II, which increases the severity of COVID-19 [
]. That eect may also be related to the
vitamin D binding protein [98].
The vitamin D metabolite calcitriol increases expression of ACE2 in the lungs of experimental
animals [
]. (Calcitriol has also been found to increase ACE2 protein expression in rat microglia BV2
cells [
].) The additional ACE2 expressed as a consequence of vitamin D supplementation might
reduce lung injury [
] because it can promote binding of the virus to the pulmonary epithelium.
As mentioned, calcitriol also induces
-1-antitrypsin synthesis, which is vital for lung integrity and
repair, by CD4
T cells, which is required for the increased production of anti-inflammatory IL-10.
Calcitriol should not be used to treat COVID-19 given the risk of hypercalcemia; however, vitamin
D supplementation increases calcitriol concentrations [
] through its regulated conversion in the
proximal tubules of the kidney and in extrarenal cells at the nuclear membrane.
High concentrations of angiotensin II may cause ARDS or cardiopulmonary injury. Renin,
by contrast, is a proteolytic enzyme and a positive regulator of angiotensin II. Vitamin D is a potent
inhibitor of renin. Vitamin D supplementation prevents angiotensin II accumulation and decreases
proinflammatory activity of angiotensin II by suppressing the release of renin in patients infected with
COVID, thus reducing the risk of ARDS, myocarditis, or cardiac injury [103].
Although vitamin D increases expression of ACE2, which promotes the binding of the virus,
it prevents the constriction response of the lung blood vessel in COVID-19, as illustrated in Figure 2[
(permission to reuse granted by copyright holder). ARDS is also due to a variety of mechanisms,
including cytokine storm, neutrophil activation, and increased (micro)coagulation, and it is likely
Nutrients 2020,12, 3361 11 of 24
that vitamin D supplementation would counter those mechanisms [
]. ARDS is responsible for
approximately 70% of fatal COVID-19 cases [106].
Nutrients 2020, 12, x FOR PEER REVIEW 12 of 25
High concentrations of angiotensin II may cause ARDS or cardiopulmonary injury. Renin, by
contrast, is a proteolytic enzyme and a positive regulator of angiotensin II. Vitamin D is a potent
inhibitor of renin. Vitamin D supplementation prevents angiotensin II accumulation and decreases
proinflammatory activity of angiotensin II by suppressing the release of renin in patients infected
with COVID, thus reducing the risk of ARDS, myocarditis, or cardiac injury [103].
Although vitamin D increases expression of ACE2, which promotes the binding of the virus, it
prevents the constriction response of the lung blood vessel in COVID-19, as illustrated in Figure 2
[104] (permission to reuse granted by copyright holder). ARDS is also due to a variety of mechanisms,
including cytokine storm, neutrophil activation, and increased (micro)coagulation, and it is likely
that vitamin D supplementation would counter those mechanisms [105]. ARDS is responsible for
approximately 70% of fatal COVID-19 cases [106].
Figure 2. The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-
converting enzyme.
2.7. Reduces Risk of Endothelial Dysfunction
Jun Zhang and colleagues outlined how endothelial dysfunction (ED) contributes to COVID-19-
associated vascular inflammation and coagulopathy, two hallmarks of severe COVID-19 [107]. Four
stages of ED were identified that contribute to inflammation and coagulopathy. Stage 1 is Type I
endothelial cell (EC) activation after infection by SARS-CoV-2 entering through the ACE2 receptor.
Figure 2.
The role of vitamin D regarding ACE in response to SARS-CoV-2. ACE: angiotensin-converting
2.7. Reduces Risk of Endothelial Dysfunction
Jun Zhang and colleagues outlined how endothelial dysfunction (ED) contributes to
COVID-19-associated vascular inflammation and coagulopathy, two hallmarks of severe
COVID-19 [
]. Four stages of ED were identified that contribute to inflammation and coagulopathy.
Stage 1 is Type I endothelial cell (EC) activation after infection by SARS-CoV-2 entering through the
ACE2 receptor. That results in the loss of anticoagulant molecules. Stage 2 is Type II EC activation which
leads to the de novo synthesis of procoagulant molecules. Stage 3 is endothelial apoptosis involving
endothelial detachment and denudation of basement membrane. Stage 4 is endothelial necrosis.
A number of papers have discussed how vitamin D can reduce risk of ED. In a second review,
Zhang and colleagues notes that vitamin D likely protects against ED by reducing oxidative stress and
B activation [
]. A recent review outlined how vitamin D maintains endothelial function by
reducing the production of reactive oxygen species as well as reducing proinflammatory mediators
such as TNF-
and IL-6 and suppressing the NF-
B pathway [
]. A laboratory study involving mice
Nutrients 2020,12, 3361 12 of 24
as well as type II alveolar epithelial cells found that vitamin D attenuated lung injury by stimulating
type II alveolar epithelial cell proliferation and migration, reducing epithelial cell apoptosis and
inhibiting TGF-β-induced epithelial mesenchymal transition [111].
2.8. Matrix Metalloproteinase 9
Matrix metalloproteinase-9 (MMP-9) is a member of the family of proteases that degrade
extracellular matrix remodeling proteins. MMP-9 has been widely studied in acute lung injury
and acute lung disease [
]. A study in Norway investigated correlations between respiratory failure
and MMP-9 in 21 COVID-19 patients with respiratory failure in comparison with seven COVID-19
patients without respiratory failure [113].
Respiratory failure was defined as arterial partial pressure of oxygen to fraction of inspired oxygen
ratio (P/F ratio) <40 kPa (300 mmHg), corresponding to the threshold in ARDS. The researchers found a
significant inverse correlation of the P/F ratio with respect to the log
(MMP-9) as well as significantly
higher MMP-9 concentrations for P/F below the threshold than above it. In a study of 171 healthy
British Bangladeshi adults, vitamin D status was the sole determinant of circulating MMP-9 (inversely)
and an independent determinant of CRP (inversely) [114].
A search of for articles regarding vitamin D, MMP-9 and infections did not
find any related to viral infections, but did find some regarding bacterial infections. A laboratory
study in the UK found that Mycobacterium tuberculosis induced the production of MMP-1, MMP-7,
and MMP-10 [
]. MMP-9 gene expression, secretion and activity were significantly inhibited by
1α,25(OH)2D3irrespective of infection.
2.9. RAS-Mediated Bradykinin Storm
Several recent publications looked at the role of bradykinin (BK) in the progression of COVID-19.
Jacobson used the Summit supercomputer at Oak Ridge National Lab in Tennessee is the second fastest
supercomputer in the world and in the summer of 2020 analyzed data on more than 40,000 genes
from 17,000 samples from COVID-19 patients [
]. The analysis revealed that SARS-CoV-2 actively
upregulates ACE2 receptors in places where they’re typically expressed at low levels, including
the lungs.
Additionally, an imbalance in RAS was also found, represented by decreased ACE in combination
with increases in ACE2, renin, angiotensin, key RAS receptors, kininogen and many kallikrein enzymes
that activate it, and both BK receptors, which produces a BK storm [
]. Since BK dilates blood vessels
and increases permeability, excessive BK leads to fluid to soft tissue fluid accumulation. This leads to
several adverse eects seen in COVID-19 patients, including on the heart, vascular system, pulmonary
system, brain, and muscles [
]. The authors suggested that vitamin D could reduce the risk of the
BK storm through several mechanisms including regulation of RAS.
Renin is the enzyme that catalyzes the first step in the activation pathway of angiotensinogen
by cleaving angiotensinogen to form angiotensin I, which is then converted to angiotensin II by
angiotensin I converting enzyme. In the COVID samples Jacobson analyzed renin levels were increased
380-fold compared to controls. Vitamin D is a negative endocrine RAS modulator and inhibits renin
expression and generation [
] and it appears likely that vitamin D deficiency amelioration would
limit the COVID-19 BK storm. However, further investigation is needed to evaluate the role of vitamin
D in this context
2.10. Summary: How Vitamin D Might Reduce Risk, Severity, and Death from COVID-19
Many reviews consider the ways in which vitamin D reduces the risk of viral
Vitamin D probably reduces the risk of viral respiratory infections because
it influences several immune pathways [126].
Vitamin D appears to decrease the risk of respiratory tract infections, including COVID-19, through
six potential mechanisms:
Nutrients 2020,12, 3361 13 of 24
Inactivates some viruses by stimulating antiviral mechanisms such as antimicrobial peptides,
as discussed in Section 2.3.
Reduces proinflammatory cytokines through modulating the immune system, as discussed in
Section 2.4.
Increases ACE2 concentrations and reduces risk of death from ensuing ARDS, as discussed in
Section 2.5.
Reduces risk of endothelial dysfunction, as discussed in Section 2.7.
Reduces MMP-9 concentrations, as discussed in Section 2.8.
Reduces risk of the bradykinin storm, as discussed in Section 2.9.
However, much further research is required to confirm the mechanisms by which vitamin D
reduces the risk and severity of COVID-19.
2.11. Vitamin D Seasonality and COVID-19
Since epidemic influenza rates are higher in winter than in summer [
], it was expected that
COVID-19 would also exhibit a seasonal dependence. Two recent papers provide evidence on monthly
and seasonal variation of viral infections. One in 2019 performed a systematic analysis of global
patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus and
metapneumovirus [128].
The second one, published in 2020, did the same for the global seasonality of human seasonal
coronaviruses [
]. For nearly all of these viruses, infection rates in northern mid and high latitudes
are highest from November through March. They examined correlations of meteorological conditions
with coronavirus infections, finding the highest correlation with low temperature combined with
high relative humidity. In winter, high relative humidity is associated with low absolute humidity.
Low absolute humidity was found as an important factor for transmission of epidemic influenza [
A recent analysis of influenza seasonality in northern Europe found that low temperature was the
most important factor facilitating transmission, followed by solar UV radiation and low humidity [
That paper also noted that high humidity favors transmission in tropical and subtropical zones,
in accordance with the findings by Li et al. [
]. According to data posted at WorldoMeter [
COVID-19 case rates in Northern Europe peaked in spring, were very low in summer, then started
rising in July (e.g., Spain), August (e.g., Italy) or September (e.g., the UK).
At higher latitudes in the southern hemisphere, COVID-19 rates were very low through April,
then started to rise in June and continued rising into October as in Argentina. On the other hand, in the
tropical South American countries such as Brazil, COVID-19 rates started rising in April, peaking around
early August then declined, in general agreement with other coronavirus infections [
]. Of course,
a number of factors help determine the case rate including the extent to which social distancing and
mask wearing are practiced, when school attendance begins, and solar and meteorological factors.
However, mortality rates were only high in the spring. Most likely the low mortality rates in September
were due to the COVID-19 rates being highest for those aged 20 to 29 years [
]. Yet, with time,
COVID-19 rates will increase among the elderly as well.
2.12. Racial/Ethnic Disparities
As mentioned in the introduction, African American and Hispanic individuals have higher
COVID-19 case and death rates than European Americans [
], possibly due to darker skin
pigmentation and lower 25(OH)D concentrations [
]. Confounding these findings, however, is that
both African Americans and Hispanics are also at greater risk of COVID-19 due to other factors such
as working and living in close proximity to many people and having higher rates of hypertension and
other chronic diseases such as type II diabetes, often associated with COVID-19 [133].
The findings regarding SARS-CoV-2 positivity by race/ethnicity from the Quest Diagnostics data
set are useful regarding racial/ethnic variations in risk of COVID-19 [
]. Mean serum 25(OH)D
Nutrients 2020,12, 3361 14 of 24
concentrations for dierent racial/ethnic groups in the U.S. can be used to estimate the eect of
vitamin D status on the risk of COVID-19. Figure 2shows that Black non-Hispanics with 25(OH)D
20 ng/mL had a 19% SARS-CoV-2 positivity, Hispanics with 25(OH)D concentration =21 ng/mL
had 15% positivity, while white non-Hispanics with 25(OH)D concentrations near 26 ng/mL had a
positivity near 8%. If black non-Hispanics had a mean 25(OH)D concentration near 26 ng/mL, it is
projected that they would have a positivity of approximately 17%.
Thus, the contribution of vitamin D status to positivity higher than for white non-Hispanics
is 2%(19%–8%) ~20%, while that for Hispanics is 2%(15%–8%) to ~30%. Thus, while disparities in
vitamin D status do not explain much of the ethnic/racial dierences in SARS-CoV-2 positivity, if black
non-Hispanics were to raise their mean serum 25(OH)D concentration to 50 ng/mL, they could lower
risk by approximately 40%, Hispanics by ~50%, and white non-Hispanics by ~25%. A recent letter
suggested that African Americans have a high risk of severe disease and mortality by SARS-CoV-2
due to vitamin D deficiency [
]. The mechanism proposed was reduced ACE2 due to vitamin
D deficiency.
An analysis of physician deaths in the UK showed that 18 of 19 doctors and dentists who died
by 22 April 2020, were of black, Asian, and mixed ethnicity [
]. Presumably, they were not of low
socioeconomic status and had similar contact with patients as their white counterparts. They could
have had low vitamin D status due to darker skin and/or vegetarian or vegan diets. In England, a study
involving white residents reported that vegans and vegetarians have 25(OH)D concentrations as much
as 8 ng/mL lower than those of meat eaters [136].
2.13. Vitamin D Reduces Risk of COVID-19 in a Causal Manner
Hill’s criteria for causality oer a scientific approach to determine causal relationships in biological
systems [
]. The important criteria for vitamin D include temporality, strength of association,
dose–response relationship, consistency of findings, plausibility (e.g., mechanisms), accounting for
alternate explanations, experiment (e.g., randomized controlled trial), and coherence with known facts.
Annweiler and colleagues evaluated the evidence that vitamin D reduces the risk and severity of
COVID-19 in a causal manner [
]. An updated summary of the evidence is presented in Table 3.
Most of the criteria are satisfied. A number of mechanisms have been identified or proposed regarding
how vitamin D could reduce risk of COVID-19. Further experimental verification is warranted for
some of them.
Table 3. Hill’s criteria for causality applied to vitamin D and COVID-19.
Criterion Evidence Reference
Strength of association
A retrospective study in Chicago found a 77%
increased risk of COVID-19 for 25(OH)D
<20 ng/mL vs. >20 ng/mL
Thirteen of 16 observational studies of
COVID-19 or SARS-CoV-2 positivity reported
inverse correlations with respect to 25(OH)D
concentration. Two studies that did not find
an inverse association used 25(OH)D values
from more than a decade prior to COVID-19
and in the multivariable analysis used some
confounding factors that aect 25(OH)D
Tables 1and 2
Nutrients 2020,12, 3361 15 of 24
Table 3. Cont.
Criterion Evidence Reference
Four retrospective studies found inverse
correlations between serum 25(OH)D and
incidence of COVID-19 or
SARS-CoV-2 positivity
Biological gradient
The large observational study of SARS-CoV-2
positivity found a large decrease as serum
25(OH)D increased from <20 to 50 ng/mL
Mechanisms have been proposed to explain
how vitamin D reduces risk of SARS-CoV-2
infection and COVID-19
Discussed in this
Coherence with known
Serum 25(OH)D concentrations are inversely
correlated with risk and outcome of many
diseases, also supported by RCTs in
several cases
Two intervention studies provide weak
experimental support.
Many RCTs are either planned or in progress
to evaluate the role of vitamin D
supplementation on COVID-19 risk and
outcomes [18]
Analogy Vitamin D supplementation reduces risk of
some acute respiratory tract infections [8]
Account for confounding
Univariate or multivariate regression
analyses with confounding factors [29,31,36,37]
The pilot calcifediol treatment RCT conducted in Spain was of low quality due to the low number
of participants and failure to measure 25(OH)D concentrations [
]. While the meta-analysis of acute
respiratory tract infections found a significant reduction with respect to vitamin D supplementation
in RCTs [
], vitamin D supplementation does not reduce risk of all respiratory tract infections, e.g.,
pneumonia in infancy and early childhood [140].
Hill stated: “None of my nine viewpoints can bring indisputable evidence for or against the
cause-and-eect hypothesis and none can be required as a sine qua non. What they can do, with greater
or less strength, is to help us to make up our minds on the fundamental question—is there any other
way of explaining the set of facts before us, is there any other answer equally, or more, likely than
cause and eect?” p. 36 in [137].
Evidence-based medicine (EBM) has generally come to mean a heavy reliance on RCTs. Yet, that
was only one type of evidence proposed by Sackett, the father of EBM. The practice of evidence-based
medicine means integrating individual clinical expertise with the best available external clinical
evidence from systematic research. By best available external clinical evidence, we mean clinically
relevant research, often from the basic sciences of medicine, but especially from patient-centered clinical
research into the accuracy and precision of diagnostic tests (including the clinical examination), the
power of prognostic markers, and the ecacy and safety of therapeutic, rehabilitative, and preventive
regimens [141].
Indeed, several reviews of EBM have discussed the relative roles of RCTs and observational
studies. A review from 2004 compared results from RCTs and observational studies for four health
outcomes, reporting that if a reasonable number of each type of study was available, the results were
very similar [
]. A review from 2010 proposed a hierarchy with meta-analysis on top, followed by
systematic review, RCT, and so on [143].
A review tabulated the ways both RCTs and their meta-analyses could have biased results, either
in domains or in design [
]. One design bias is the wrong dose, often a problem with vitamin D
Nutrients 2020,12, 3361 16 of 24
RCTs in that vitamin D doses have generally been 1000 IU/d or less until recently. Another problem
is enrolling participants with relatively high 25(OH)D concentrations and giving doses too low to
be eective [
]. Finally, a review published in 2017 compared RCTs with “real-world studies”
(observational studies) [
]. Among other strengths, observational studies generally include more
diverse and larger populations than RCTs.
Regarding the comparison of findings for vitamin D from observational studies and RCTs, they are
in general agreement—though with some caveats. RCTs support the role of vitamin D supplementation
in reducing the risk of acute respiratory tract infections (ARTIs) [
]. However, an RCT reporting that
vitamin D supplementation reduced risk of influenza type A for schoolchildren showed no reduction
for influenza type B [
]. Vitamin D
supplementation (14,000 IU/wk) did not result in a lower
risk of tuberculosis infection, tuberculosis disease, or ARTIs than placebo among vitamin D-deficient
schoolchildren in Mongolia [
]. Thus, vitamin D supplementation does not reduce risk of all types
of respiratory tract infections in all places.
2.14. Other Nutrients That May Augment the Eectiveness of Vitamin D Supplementation
Magnesium supplementation is recommended when taking vitamin D supplements. Magnesium
facilitates vitamin D-related processes. All the enzymes that metabolize vitamin D seem to require
magnesium, which acts as a cofactor in the enzymatic reactions in the liver and kidneys [
]. The dose
of magnesium should be in the range of 250–500 mg/d. Magnesium activates more than 600 enzymes and
influences extracellular calcium concentrations [
]. It is essential for the stability of cell function, RNA
and DNA synthesis, and cell repair, as well as maintaining the cell’s antioxidant status. Magnesium
is an important cofactor for activating a wide range of transporters and enzymes [
], many of
which involve vitamin D metabolism.
Although vitamin D is likely to be the most important nutrient to optimize COVID-19 prevention,
other nutrients, such as magnesium, vitamin K
and other micronutrients, are also known to impact
the immune system and infection risk [152154].
3. Conclusions
As discussed here, there is emerging evidence that higher serum 25(OH)D concentrations are
associated with the reduced risk and severity of COVID-19. It might do so through a variety of
mechanisms, such as maintaining intact epithelial layers, reducing the survival and replication of
viruses, reducing the production of pro-inflammatory cytokines, and increasing ACE2 concentrations.
More research is required to evaluate the mechanisms whereby vitamin D might reduce the risk
of COVID-19.
The strongest evidence to date comes from 14 observational studies that report inverse correlations
between serum 25(OH)D concentrations and SARS-CoV-2 positivity and/or COVID-19 incidence,
severity and/or death. Hill’s criteria for causality in a biological system are largely satisfied for vitamin
D in reducing risk of COVID-19, with the exception of successful large-scale vitamin D supplementation
RCTs demonstrating significantly reduced risk of or improved outcome for COVID-19. Such RCTs are
now under way [
]. Until then, individuals and physicians can use vitamin D supplementation
as they wish, but public health policies likely will not include vitamin D to reduce risk or death from
COVID-19 until large-scale RCTs are reported demonstrating significant reductions in COVID-19
incidence, severity, and/or death from vitamin D supplementation.
Author Contributions:
Conceptualization, J.M.; methodology, J.M. and W.B.G.; writing—original draft
preparation, J.M.; writing—review and editing, J.M., W.B.G., and C.L.W.; visualization, J.M. All authors have read
and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Conflicts of Interest:
J.M. sells vitamin D and other supplements; W.B.G. receives funding from Bio-Tech
Pharmacal, Inc. (Fayetteville, AR, USA). C.L.W. has no conflicts of interest to declare.
Nutrients 2020,12, 3361 17 of 24
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... It is also associated with several chronic and immune disorders, including obesity, diabetes, asthma, and atopic dermatitis [18][19][20][21][22][23]. Moreover, several studies have demonstrated its protective role against infection and exacerbation of COVID-19 [24,25]. Research findings showing that supplementation with vitamin D prevents Nutrients 2022, 14, 4863 2 of 10 respiratory infections [26] has sparked further interest in people's vitamin D status after the COVID-19 pandemic. ...
... As COVID-19 spread rapidly around the world, people became more interested in health promotion. The results of numerous studies on the benefits of the intake of vitamin D and other nutritional supplements, particularly as related to respiratory infection prevention, have been cited and reported [25,26,[32][33][34][35]. Although the results of these studies are inconsistent, many people have taken vitamin D supplements to prevent COVID-19 infection and stop it from worsening into more serious conditions. ...
Full-text available
The aim of this study was to investigate changes in 25(OH)D (25-hydroxyvitamin D) levels and in the vitamin D status of Korean adults before and during the coronavirus disease (COVID-19) pandemic. This study compared serum 25(OH)D levels before and after the pandemic in 1483 adults aged 19 years and older who were screened at a university hospital. Subjects were selected only from participants tested in the same season before and after the pandemic. The pre-COVID-19 testing period was from 1 March 2018 to 31 November 2019; the testing period in the COVID-19 era was from 1 June 2020 to 31 November 2021. The mean 25(OH)D level for all participants was 21.4 ± 10.2 ng/mL prior to the outbreak of COVID-19, which increased to 23.6 ± 11.8 ng/mL during the COVID-19 lockdown period (p < 0.001). The increase was particularly dramatic in elderly females (28.8 ± 12.3 ng/mL to 37.7 ± 18.6 ng/mL, p = 0.008). The prevalence of vitamin D deficiency decreased in both males (48.4% to 44.5%, p = 0.005) and females (57.0% to 46.0%, p < 0.001). In conclusion, 25(OH)D levels in Korean adults increased during the COVID-19 era, and the prevalence of vitamin D deficiency decreased accordingly.
... The situation may become more complicated in COVID-19 subjects with special baseline conditions, including renal failure and pregnancy, leading to considerable physiological alterations [5]. COVID-19 is associated with many abnormalities in vitamins, electrolytes, trace elements, and acid-base homeostasis [6][7][8][9]. Electrolyte abnormalities are a common complication observed in COVID-19 infection due to renal, gastrointestinal, metabolic, and adrenal disturbances [6,[10][11][12][13]. Among different electrolyte abnormalities, hypophosphatemia is a less considered phenomenon in which several organs might be affected and easily overlooked by the symptoms of the disease [14]. ...
... On the other hand, the effect of COVID-19 on vitamin D, calcium, and phosphorus homeostasis is suggested to be associated with phosphate metabolism disturbances. Vitamin D depletion is common in severely ill COVID-19 patients [7]. The connection between abnormal kidney function, abnormal vitamin D metabolism, and hypophosphatemia has been demonstrated in a recent study done by Povaliaeva et al. [35]. ...
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Coronavirus disease 2019 (COVID-19) has various manifestations on different body organs, including the lungs, heart, kidneys, and central nervous system. However, the frequency of electrolyte abnormalities, especially hypophosphatemia, is still debated in this pandemic. Our main aim in this review is to evaluate the frequency and complications of hypophosphatemia in COVID-19-infected individuals. A systematic literature review was performed in Web of Science, Scopus, PubMed, EMBASE, and Cochrane electronic databases with the combination of different keywords till October 2021. We recruited all relevant published records (including cross-sectional and case-control studies as well as editorials and brief reports) assessing hypophosphatemia among patients with COVID-19 infection. After assessing all 928 recruited records and discarding duplicates, 4 records met the inclusion criteria. Three articles were further included during a manual search of the literature. Overall, the included studies reported 1757 subjects (males: 51.3%), with the mean age ranging from 37.2 ± 13.6 years to 65.9 ± 13.9 years. Hypophosphatemia prevalence has been reported from 7.6% to 19.5%. Patients with the severe status of COVID-19 had a higher prevalence of low serum phosphate levels than those with moderate infection. This review indicates that hypophosphatemia might be categorized as a complication in clinical settings during the COVID-19 pandemic, requiring a high clinical suspicion to implement appropriate diagnostic and therapeutic interventions to prevent life-threatening outcomes. However, it needs to be more elucidated by further studies whether hypophosphatemia in severe COVID-19 is directly related to COVID-19 or is just a complication of severe illness.
... Сорок пациентов (93%) перенесли COVID-19 в легкой форме, либо не переносили данное заболевание при среднем уровне витамина D 38,56±1,28 нг/мл. Три пациента (7%) перенесли COVID-19 В ряде исследований было доказано, что более высокие концентрации витамина D в сыворотке крови связаны со сниженным риском и тяжестью течения COVID-19 инфекции [12]. Многие исследования подтвердили, что витамин D активирует иммунные клетки для производства иммунных пептидов и белков, например, таких как кателицидины и дефензины, обладающие широким противомикробным и противовирусным спектром действия [13]. ...
... 18 Reviews and studies have linked vitamin D deficiency with COVID-19 disease (SARS-COV-19). 19,20 They supported vitamin D activity in reducing the risk of covid-19 infection and deaths documented. The benefit of vitamin D in covid-19 patients is due to its suggested mechanisms of action, such as maintaining cell junctions and enhancing cell immunity by reducing cytokine storms with affected interferon-Ƴ and tumor necrotic factor α. Hypovitaminosis C stimulates the renin-angiotensin system (RAS); activation leads to chronic cardiovascular disease, reduces lung function, and increases the comorbidity risk of covid-19. ...
Full-text available
Background: Vitamin D deficiency (VDD) is a global health concern. This study aimed to determine the prevalence of vitamin D deficiency and its associated comorbidities in Palestine, such as diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular and autoimmune diseases. Methods: A retrospective, descriptive study retrieved medical data from the Nat Health insurance processor database from 2014 to 2020. Patient information included age, sex, vitamin D laboratory order, symptoms, and comorbidities. This study included patients prescribed vitamin D at a dose of 50000IU for vitamin D deficiency confirmed by a serum vitamin D laboratory test. The collected data were analyzed using IBM SPSS. In addition, a chi-square test was conducted to assess the association between vitamin D deficiency, symptoms, and comorbidities. Results: Data of 3011 patients were collected; 639 patients were diagnosed with osteoporosis, and 39 patients prescribed vitamin D without a laboratory test were excluded. Approximately, 1837 (78%) participants had vitamin D deficiency. A total of 1330 women (81.3%) were significantly more likely to have vitamin D deficiency than males, 507 (72.7%; P < 0.001). Joint pain, back pain, and cervicalgia were significantly associated with vitamin D deficiency (P < 0.001). Asymptomatic participants (2.1%) were significantly less likely to have vitamin D deficiency than symptomatic participants (9.5%, p < 0.001). Hypothyroidism is significantly associated with vitamin D deficiency (p = 0.048). Conclusion: In this retrospective study, the prevalence of vitamin D was high and alarming. There was a significant association between VDD, patients who presented with back pain, arthritis, and cervicalgia symptoms, and patients diagnosed with hypothyroidism. Therefore, health initiative programs are warranted to increase awareness regarding screening, prevention, and treatment. Further studies are needed to confirm the relationship between vitamin D supplementation and the reduced risk of comorbid diseases.
... Thus, these criteria appear to be sufficient for patients and physicians to use or recommend vitamins or supplements to prevent or treat COVID-19 in view of its safety and wide therapeutic window. New results from large-scale randomized clinical trials with vitamins are in progress [42]. ...
Full-text available
The COVID-19 has challenged the professions and Implantology also has its challenges in the pandemic. Several factors can interfere with the osseointegration process and more associated factors, greater the interference risks. Risk assessment in the therapy indication is the main decision to define the best technique, the best biomaterial, the best surgical access and the best moment to intervene. The purpose of this review was to investigate and synthesize the scientific evidence on the factors that may interfere with dental implant therapy in the midst of pandemic. The literature was reviewed in databases such as PubMed, Web of Science, Sciello and Google Scholar using the keywords “COVID-19”, “pandemic”, “risk factors”, “impact factor”, “dental implants”, “dentistry”, “oral health”, “osseointegration”, “bone metabolism”, “drug risk factors”, “chronic stress”, “antidepressants”, “zinc”, “hydroxychloroquine”, “ivermectin”, “vitamins”, “corticosteroids”, “surgical risks” and “disinfection”. The present review showed that chronic stress and depression caused by the pandemic, the consequent use of antidepressants, the use of prophylactic and therapeutic drugs such zinc, vitamin D, hydroxychloroquine and corticosteroids, can interfere with bone metabolism and consequently in osseointegration establishment and/or maintenance. Any osseointegrable biomaterial can be influenced by systemic factors and drugs’ actions that can affect the homeostasis of the inflammatory process, cell proliferation and bone remodeling. These factors’ influence on dental implant therapy should be investigated through new reviews, observational studies and randomized clinical trial. Indexing terms COVID-19; Dental implants; Risks factors
... Overall, data from reported clinical studies have satisfied Hill's criteria for causality [183] in a biological system [184]. Despite the vast published information described earlier, policymakers and regulators with conflicts of interest or unfamiliar with the emerging data disregard the health benefits of vitamin D, especially for COVID-19 continue to ignore scientific data. ...
Full-text available
With the advent of COVID19, the attitude of health authorities around the world, led mainly by the West, demanded a level of proof as evidence for cheap, non-patented remedies while promoting expensive, patented, and untested remedies by using emergency use authorization and special provisions afforded to the status of a pandemic emergency. Western science has neither a tested nor a valid historical basis of a logical system that informs to authenticate scientific practices. Here we use a logical heuristic derived from ancient Buddhist logic, which is consistent with the conduct of modern science. We applied the heuristic to show that enough evidence was available for using cost-effective early therapies such as vitamin D supplementation as a public health measure during the first half of 2020. Strong supporting evidence has since accumulated. Apart from political and financial decisions incompatible with science and other conflicts of interest, a critical barrier to evaluating and approving early therapies appears to be the fallacy that the randomized controlled trial (RCT) is the superior proof method in medical hypotheses, including those for nutrients. Logically, no reason exists why properly designed retrospective, ecological, and naturalistic studies with adequate sample sizes and applied appropriate statistical methods would not be as valid as RCTs, especially when elucidating a causative factor instead of treatment. That assertion is particularly true for nutrient deficiencies, interventions, and other cost-effective therapies. Leading health authorities’ failure or refusal to consider other study types (because of either poor logic or vested interest) probably contributed to the spread of misinformation, symptomatic disease, complications, and deaths from COVID19. Partial immunity derived from vaccines and the later development of more contagious variants—and thus a sense of acceptance that SARS-CoV-2 had progressed from a pandemic to an endemic—shows the hollowness of the initial promotions and mandates of vaccines as a cure. Adequate knowledge was available in 2020 to advise that SARS-CoV-2 will continue to mutate, with variants emerging a few times per year, making the vaccine less effective. Emerging evidence confirms that natural immunity better protects against new variants than vaccination against the spike protein. Had vitamin D been adopted as part of the public health measure through a broader supplementation program in 2020 or even today (through sun exposure or as a prophylactic or adjunct therapy early on), the viral spread and symptomatic disease may have been suppressed, with minimal lockdowns and quarantine, and economic harm. The pandemic could have been halted with a significantly reduced need for hospitalization, complications, and deaths, potentially saving millions of lives.
... Не менее важным является сбалансированное питание, обеспечиваю щее поступление достаточного количества питательных веществ, необходимых не только для восполнения всех энергетических и пластических потребностей организма, но и для формирования адекватного иммунного ответа. При этом немаловажную роль в функционировании иммунной системы играет баланс микронутриентов -витаминов и минеральных веществ [8], наиболее значимыми являются витамин D [9] и С [10], а также кальций, хром, медь, магний, марганец, железо и цинк [11]. Показано, что селен, железо, калий, натрий, кальций, магний, фолиевая кислота, медь и цинк улучшают иммунитет и способствуют уменьшению продолжительности заболевания и госпитализации среди пациентов с COVID-19 [12]. ...
Despite the development and implementation of vaccines in various countries of the world, COVID-19 remains a significant medical and social problem. This is directly related to the characteristic feature of SARS-CoV-2 to form new strains, which reduces the effectiveness of vaccination. In connection with the foregoing, the priority in the prevention of COVID-19 is to improve and maintain the normal functioning of the human immune system. Recently, more and more scientists have noted the significant role of micronutrients in ensuring immune function. However, most research focuses on micronutrients such as zinc, selenium, iron and copper, while it is known that the balance of micronutrients depends on all its constituents. Consequently, any change in the content of one mineral substance can affect the level of others, leading to an imbalance of trace elements in the body. The aim of this work was to analyze literature data on less studied microelements in the context of the COVID-19 pandemic, both essential and toxic, that can affect the state of the immune system and, as a result, the incidence and risk of complications and adverse outcomes in COVID-19. An analysis of the literature on the effect of manganese, chromium, iodine, cadmium, mercury, lead, arsenic and lithium on human antiviral protection, including in the case of a disease caused by SARS-CoV-2, showed that the determination of the microelement status, taking into account the above microelements and, with necessary, the appointment of preparations containing minerals is promising for the purpose of prevention and as an additional therapy for COVID-19.
... According to Whittemore, direct skin exposure to sunlight promotes vitamin D production, a vital component that regulates the immune system [72]. Vitamin D can lower the risk of respiratory tract infections such as COVID-19 through a multitude of cellular interactions that involve the maintenance of endothelium integrity, a reduction in the production of inflammatory cytokines and elevation of angiotensin-converting enzyme 2 (ACE2) [73]. ...
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Since the year 2020, coronavirus disease 2019 (COVID-19) has emerged as the dominant topic of discussion in the public and research domains. Intensive research has been carried out on several aspects of COVID-19, including vaccines, its transmission mechanism, detection of COVID-19 infection, and its infection rate and factors. The awareness of the public related to the COVID-19 infection factors enables the public to adhere to the standard operating procedures, while a full elucidation on the correlation of different factors to the infection rate facilitates effective measures to minimize the risk of COVID-19 infection by policy makers and enforcers. Hence, this paper aims to provide a comprehensive and analytical review of different factors affecting the COVID-19 infection rate. Furthermore, this review analyses factors which directly and indirectly affect the COVID-19 infection risk, such as physical distance, ventilation, face masks, meteorological factor, socioeconomic factor, vaccination, host factor, SARS-CoV-2 variants, and the availability of COVID-19 testing. Critical analysis was performed for the different factors by providing quantitative and qualitative studies. Lastly, the challenges of correlating each infection risk factor to the predicted risk of COVID-19 infection are discussed, and recommendations for further research works and interventions are outlined.
... The ingestion of H 2 S may be an effective treatment for COVID-19. Other antioxidants, including CoQ10 with NADH, curcumin, vitamins C, D, and E, selenium, melatonin with pentoxifylline, ebselen, and disulfiram, can target redox imbalance in COVID-19 [72][73][74][75][76][77][78][79]. For example, the use of antioxidants such as vitamin C, E, and NAC with pentoxifylline decreased the lipid peroxidation and total antioxidant capacity in COVID-19 patients at the end of the hospital stay, while pentoxifylline alone did not decrease the oxidative stress markers [80], suggesting the use of antioxidants as a possible adjuvant therapy for improving survival prognosis in COVID-19 patients. ...
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Over hundreds of years, humans have faced multiple pandemics and have overcome many of them with scientific advancements. However, the recent coronavirus disease (COVID-19) has challenged the physical, mental, and socioeconomic aspects of human life, which has introduced a general sense of uncertainty among everyone. Although several risk profiles, such as the severity of the disease, infection rate, and treatment strategy, have been investigated, new variants from different parts of the world put humans at risk and require multiple strategies simultaneously to control the spread. Understanding the entire system with respect to the commonly involved or essential mechanisms may be an effective strategy for successful treatment, particularly for COVID-19. Any treatment for COVID-19 may alter the redox profile, which can be an effective complementary method for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and further replication. Indeed, redox profiles are one of the main barriers that suddenly shift the immune response in favor of COVID-19. Fortunately, several redox components exhibit antiviral and anti-inflammatory activities. However, access to these components as support elements against COVID-19 is limited. Therefore, understanding redox-derived species and their nodes as a common interactome in the system will facilitate the treatment of COVID-19. This review discusses the redox-based perspectives of the entire system during COVID-19 infection, including how redox-based molecules impact the accessibility of SARS-CoV-2 to the host and further replication. Additionally, to demonstrate its feasibility as a viable approach, we discuss the current challenges in redox-based treatment options for COVID-19.
Conference Paper
In a case-control study, fifty two subjects with COVID-19 were included in the study and 30 gender and age matched apparently healthy individuals were included as control. Vitamin D serum level determined by Mini Vidus, WBC, Lymphocytes and PCV by Swelab. CRP determined manually. SPSS package used for statistical analysis. Vitamin D mean serum level in COVID-19 subjects was significantly lower [P=0.007] than that in control group. Vitamin D mean serum value was lower than normal recommended value in patients with COVID-19. Additionally, the frequency of < 10 ng/ml was 30% in controls, while it was 42% in patients group. When the results stratified on < 20 ng/ml strata, controls show 70%, while patients corresponding value was 81%. The mean serum levels of vitamin D were higher in male compared to female, in smoker as compared to non-smoker and in patients with age of ≥ 50 years. However, the differences not reach significant values. There was inverse correlation between Vitamin D low serum levels and CRP levels indicating a significant association between disease severity and vitamin D serum levels. Serum vitamin D was higher in patients with chronic diseases than that in patients without chronic diseases history, however, the difference not reach significant level.
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Background As effective medication to treat COVID-19 is currently unavailable, preventive remedies may be particularly important. Objective To examine the relationship between serum 25-hydroxy vitamin D (25(OH)D) level and COVID-19 infection, its severity, and its clinical case characteristics. Methods This case-control study compared serum 25(OH)D levels and rates of vitamin D deficiency (VDD) between 80 healthy controls and 62 patients diagnosed with COVID-19 and admitted to Guangxi People’s Hospital, China, 2/16/2020–3/16/2020. Cases were categorized into asymptomatic, mild/moderate, and severe/critical disease. Logistic regression analysis was conducted to examine the associations between 25(OH)D level, or VDD, and case status/severity of COVID-19 while controlling for demographics and comorbidities. A threshold level of vitamin D for conveying COVID-19 risk was estimated. Results Severe/critical COVID-19 cases were significantly older and had higher percentages of comorbidity (renal failure) compared to mild cases. The serum 25(OH)D concentration in COVID-19 patient was much lower than that in healthy control. And 25(OH)D level was the lowest in severe/critical cases, compared with mild cases. In further, significantly higher rates of VDD were found in COVID-19 cases (41.9%) compared to healthy controls (11.1%). And VDD was the greatest in severe/critical cases (80%), compared with mild cases (36%). These statistically significant associations remained even after controlling for demographics and comorbidities. A potential threshold of 25(OH)D (41.19 nmol/L) to protect against COVID-19 was identified. Conclusion Elderly and people with comorbidities were susceptible to severe COVID-19 infection. VDD was a risk factor for COVID-19, especially for severe/critical cases. While further confirmation is needed, vitamin D supplementation may have prevention or treatment potential for COVID-19 disease.
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The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional "receptor" and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the "cytokine storm." Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.
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The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.
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This is an open access article under the CC BY 4.0 license ( There is emerging evidence to suggest that vitamin D deficiency is associated with adverse outcomes in COVID-19 patients. Conversely, vitamin D supplementation protects against an initial alveolar diffuse damage of COVID-19 becoming progressively worse. The mechanisms by which vitamin D deficiency exacerbates COVID-19 pneumonia remain poorly understood. In this review we describe the rationale of the putative role of endothelial dysfunction in this event. Herein, we will briefly review (1) antiinflammatory and anti-thrombotic effects of vitamin D, (2) vitamin D receptor and vitamin D receptor ligand, (3) protective role of vitamin D against endothelial dysfunction, (4) risk of vitamin D deficiency, (5) vitamin D deficiency in association with endothelial dysfunction, (6) the characteristics of vitamin D relevant to COVID-19, (7) the role of vitamin D on innate and adaptive response, (8) biomarkers of endothelial cell activation contributing to cytokine storm, and (9) the bidirectional relationship between inflammation and homeostasis. Finally, we hypothesize that endothelial dysfunction relevant to vitamin D deficiency results from decreased binding of the vitamin D receptor with its ligand on the vascular endothelium and that it may be immune-mediated via increased interferon 1 α. A possible sequence of events may be described as (1) angiotensin II converting enzyme-related initial endothelial injury followed by vitamin D receptor-related endothelial dysfunction, (2) endothelial lesions deteriorating to endothelialitis, coagulopathy and thrombosis, and (3) vascular damage exacerbating pulmonary pathology and making patients with vitamin D deficiency vulnerable to death.
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Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.
Vitamin D may be a central biological determinant of COVID-19 outcomes. The objective of this quasi-experimental study was to determine whether bolus vitamin D3 supplementation taken during or just before COVID-19 was effective in improving survival among frail elderly nursing-home residents with COVID-19. Sixty-six residents with COVID-19 from a French nursing-home were included in this quasi-experimental study. The “Intervention group” was defined as those having received bolus vitamin D3 supplementation during COVID-19 or in the preceding month, and the “Comparator group” corresponded to all other participants. The primary and secondary outcomes were COVID-19 mortality and Ordinal Scale for Clinical Improvement (OSCI) score in acute phase, respectively. Age, gender, number of drugs daily taken, functional abilities, albuminemia, use of corticosteroids and/or hydroxychloroquine and/or antibiotics (i.e., azithromycin or rovamycin), and hospitalization for COVID-19 were used as potential confounders. The Intervention (n = 57; mean ± SD, 87.7 ± 9.3years; 79 %women) and Comparator (n = 9; mean, 87.4 ± 7.2years; 67 %women) groups were comparable at baseline, as were the COVID-19 severity and the use of dedicated COVID-19 drugs. The mean follow-up time was 36 ± 17 days. 82.5 % of participants in the Intervention group survived COVID-19, compared to only 44.4 % in the Comparator group (P = 0.023). The full-adjusted hazard ratio for mortality according to vitamin D3 supplementation was HR = 0.11 [95 %CI:0.03;0.48], P = 0.003. Kaplan-Meier distributions showed that Intervention group had longer survival time than Comparator group (log-rank P = 0.002). Finally, vitamin D3 supplementation was inversely associated with OSCI score for COVID-19 (β=-3.84 [95 %CI:-6.07;-1.62], P = 0.001). In conclusion, bolus vitamin D3 supplementation during or just before COVID-19 was associated in frail elderly with less severe COVID-19 and better survival rate.
Background: A subset of patients with COVID-19 develops a hyperinflammatory syndrome that has similarities with other hyperinflammatory disorders. However, clinical criteria specifically to define COVID-19-associated hyperinflammatory syndrome (cHIS) have not been established. We aimed to develop and validate diagnostic criteria for cHIS in a cohort of inpatients with COVID-19. Methods: We searched for clinical research articles published between Jan 1, 1990, and Aug 20, 2020, on features and diagnostic criteria for secondary haemophagocytic lymphohistiocytosis, macrophage activation syndrome, macrophage activation-like syndrome of sepsis, cytokine release syndrome, and COVID-19. We compared published clinical data for COVID-19 with clinical features of other hyperinflammatory or cytokine storm syndromes. Based on a framework of conserved clinical characteristics, we developed a six-criterion additive scale for cHIS: fever, macrophage activation (hyperferritinaemia), haematological dysfunction (neutrophil to lymphocyte ratio), hepatic injury (lactate dehydrogenase or asparate aminotransferase), coagulopathy (D-dimer), and cytokinaemia (C-reactive protein, interleukin-6, or triglycerides). We then validated the association of the cHIS scale with in-hospital mortality and need for mechanical ventilation in consecutive patients in the Intermountain Prospective Observational COVID-19 (IPOC) registry who were admitted to hospital with PCR-confirmed COVID-19. We used a multistate model to estimate the temporal implications of cHIS. Findings: We included 299 patients admitted to hospital with COVID-19 between March 13 and May 5, 2020, in analyses. Unadjusted discrimination of the maximum daily cHIS score was 0·81 (95% CI 0·74-0·88) for in-hospital mortality and 0·92 (0·88-0·96) for mechanical ventilation; these results remained significant in multivariable analysis (odds ratio 1·6 [95% CI 1·2-2·1], p=0·0020, for mortality and 4·3 [3·0-6·0], p<0·0001, for mechanical ventilation). 161 (54%) of 299 patients met two or more cHIS criteria during their hospital admission; these patients had higher risk of mortality than patients with a score of less than 2 (24 [15%] of 138 vs one [1%] of 161) and for mechanical ventilation (73 [45%] vs three [2%]). In the multistate model, using daily cHIS score as a time-dependent variable, the cHIS hazard ratio for worsening from low to moderate oxygen requirement was 1·4 (95% CI 1·2-1·6), from moderate oxygen to high-flow oxygen 2·2 (1·1-4·4), and to mechanical ventilation 4·0 (1·9-8·2). Interpretation: We proposed and validated criteria for hyperinflammation in COVID-19. This hyperinflammatory state, cHIS, is commonly associated with progression to mechanical ventilation and death. External validation is needed. The cHIS scale might be helpful in defining target populations for trials and immunomodulatory therapies. Funding: Intermountain Research and Medical Foundation.