Vitamin D3 and K2 and their potential contribution to reducing the COVID-19 mortality rate

Abstract

The world is desperately seeking for a sustainable solution to combat the coronavirus strain SARS-CoV-2 (COVID-19). Recent research from Asian scholars indicated that optimizing Vitamin D blood levels could offer a solution approach that promises a heavily reduced fatality rate as well as solving the public health problem of counteracting the general vitamin D deficiency. This paper dived into the immunoregulatory effects of supplementing Vitamin D3 by elaborating a causal loop diagram. Together with D3, vitamin K2 and magnesium should be supplemented to prevent long-term health risks. Follow up clinical randomized trials are required to verify the current circumstantial evidence.

Full text

Short
Communication
Vitamin
D3
and
K2
and
their
potential
contribution
to
reducing
the
COVID-19
mortality
rate
Simon
Goddek
Mathematical
and
Statistical
Methods
(Biometris),
Wageningen
University,
P.O.
Box
16,
6700
AA
Wageningen,
The
Netherlands
A
R
T
I
C
L
E
I
N
F
O
Article
history:
Received
23
June
2020
Received
in
revised
form
2
July
2020
Accepted
26
July
2020
Keywords:
Vitamin
D
COVID-19
Coronavirus
Mortality
rate
Immunology
A
B
S
T
R
A
C
T
The
world
is
desperately
seeking
for
a
sustainable
solution
to
combat
the
coronavirus
strain
SARS-CoV-2
(COVID-19).
Recent
research
indicated
that
optimizing
Vitamin
D
blood
levels
could
offer
a
solution
approach
that
promises
a
heavily
reduced
fatality
rate
as
well
as
solving
the
public
health
problem
of
counteracting
the
general
vitamin
D
deficiency.
This
paper
dived
into
the
immunoregulatory
effects
of
supplementing
Vitamin
D
3
by
elaborating
a
causal
loop
diagram.
Together
with
D
3
,
vitamin
K
2
and
magnesium
should
be
supplemented
to
prevent
long-term
health
risks.
Follow
up
clinical
randomized
trials
are
required
to
verify
the
current
circumstantial
evidence.
©
2020
The
Author(s).
Published
by
Elsevier
Ltd
on
behalf
of
International
Society
for
Infectious
Diseases.
This
is
an
open
access
article
under
the
CC
BY
license
(http://creativecommons.org/licenses/by/4.0/).
Introduction
The
COVID-19
pandemic
is
a
current
pandemic
of
high
international
interest,
caused
by
the
coronavirus
strain
SAR-
S‑CoV‑2.
Up
to
date,
there
is
no
treatment
to
decrease
the
virus-
caused
infection
and
mortality
rates
(Cortegiani
et
al.,
2020).
More
and
more
voices
are
being
raised
supporting
the
supplementation
of
Vitamin
D
3
to
counter
the
pandemic
outbreak
with
the
correlated
mortality
rates
as
well
as
economic
and
social
consequences
(Grant
et
al.,
2020).
In
a
recently
published
review
article,
Sharma
et
al.
(2020)
have
critically
discussed
the
association
of
vitamin
D
with
viral
infections.
A
recent
clinical
study
from
Iran
(n
=
611)
stated
that
there
were
no
COVID-19
deaths
in
a
hospital
if
serum
25(OH)D
concentrations
were
higher
than
41
ng/mL
and
patients
were
younger
than
80
(Maghbooli
et
al.,
2020).
Russian
hospitals
observed
that
the
likelihood
to
have
severe
COVID-19
increases
by
the
factor
of
5
if
vitamin
D
is
deficient
(Karonova
et
al.,
2020).
Similar
observations
have
been
made
by
Panagiotou
et
al.
(2020).
Tan
et
al.
(2020)
observed
a
significant
reduction
in
oxygen
support
for
older
clients
when
providing
them
with
a
relatively
low
daily
dose
of
1000
IU
D
3
OD,
150
mg
magnesium
OD,
and
500
mg
B12
OD
upon
admission.
On
the
other
hand,
one
retrospective
cohort
study
that
investigated
the
correlation
between
the
mean
D3
serum
levels
of
different
European
countries
and
the
COVID-19
mortality
rate
was
not
considered
significant
(Ali,
2020).
An
explanation
for
this
could
be
that
testing
conditions
differ
in
each
European
country,
making
it
difficult
to
reach
a
conclusion
in
such
a
retrospective
study.
Also,
the
mean
D
3
serum
levels
do
not
necessarily
apply
to
people
who
are
especially
vulnerable
to
that
virus
(e.g.
aged
and
bedridden
people).
This
assumption
is
supported
by
De
Smet
et
al.
(2020)
who
documented
a
significantly
lower
median
D
3
value
in
patients
with
COVID-19
compared
to
control
subjects.
The
obviously
correlating
vitamin
D
deficiency
is
linked
to
increasing
the
risk
of
many
common
and
serious
diseases
(Holick,
2004).
In
a
study
conducted
by
Forrest
and
Stuhldreher
(2011),
vitamin
D
deficiency
was
defined
as
a
serum
25(OH)D
concen-
trations
20
ng/mL.
41.6%
of
the
test
subjects
have
been
considered
vitamin
D
deficient.
Of
the
tested
people
of
color
(PoC)
and
Hispanics,
the
deficiency
rate
was
even
69.2%
and
82.1%,
respectively.
Similar
observations
with
respect
to
patients’
ethnicity
have
been
made
by
Holick
(2002)
and
Darling
et
al.
(2020).
The
latter
also
states
that
serum
25(OH)D
concentrations
were
lower
in
obese
people
that
were
tested
COVID-positive,
which
is
most
likely
due
to
increased
relative
body
volume.
Haq
et
al.
(2016)
even
report
that
82.5%
of
studied
patients
in
the
sun-
intensive
Middle
East
were
vitamin
D
deficient.
These
observations
with
respect
to
common
vitamin
D
deficiency,
together
with
evidence
of
several
experimental
studies
(Bendix-Struve
et
al.,
2010;
Casteels
et
al.,
1998;
Holick,
2005;
Seibert
et
al.,
2013),
indicates
that
vitamin
D
is
essential
in
the
modulation
of
immune
function
(Aranow,
2011;
Sassi
et
al.,
2018).
The
threshold
of
Vitamin
D
deficiency
is
a
continuous
subject
of
discussion.
Whereas
the
European
Food
Safety
Authority
recom-
mends
a
minimum
serum
level
of
25(OH)D
of
25
nmol/L
(i.e.
10
ng/
mL)
(EFSA,
2016),
many
scholars
consider
this
value
way
too
conservative.
A
study
that
was
conducted
in
Kenya
on
healthy
black
E-mail
address:
simon.goddek@wur.nl
(S.
Goddek).
https://doi.org/10.1016/j.ijid.2020.07.080
1201-9712/©
2020
The
Author(s).
Published
by
Elsevier
Ltd
on
behalf
of
International
Society
for
Infectious
Diseases.
This
is
an
open
access
article
under
the
CC
BY
license
(http://creativecommons.org/licenses/by/4.0/).
International
Journal
of
Infectious
Diseases
99
(2020)
286–290
Contents
lists
available
at
ScienceDirect
International
Journal
of
Infectious
Diseases
journal
homepage:
www.elsevier.com/locate/ijid

males
showed
that
25(OH)D
levels
<30
ng/mL
were
associated
with
a
significant
rise
in
physiological
markers
such
as
parathyroid
hormone
(PTH)
(Kagotho
et
al.,
2018).
Thus,
desirable
25(OH)D
levels
are
rather
to
be
found
between
30–48
ng/mL
(Bischoff-
Ferrari,
2008;
Raftery
and
O’Sullivan,
2015;
Vieth,
2011),
i.e.
3–5
times
higher
than
recommended
by
the
European
authorities.
Looking
into
optimal
25(OH)D
serum
levels
from
an
epidemiologi-
cal
and
evolutionary
perspective
could
be
another
approach
to
getting
a
rough
indication
on
these
levels
(Carlberg,
2019;
Luxwolda
et
al.,
2012).
It
has
been
shown
that
traditional
African
hunter-gatherers
had
an
average
serum
level
of
48
ng/mL.
This
publication
set
out
to
show
the
metabolic
pathways
behind
the
immunomodulating
effect
of
vitamin
D
by
following
a
systems
thinking
approach.
The
output
will
also
give
advice
on
which
other
dietary
supplements
one
should
consider.
Methodology
One
of
the
basic
principles
that
is
used
to
combine
valuable
scientific
findings
and
knowledge
from
often
interdisciplinary
domains
is
called
systems
analysis.
Causal
loop
diagrams
(CLDs)
functioned
as
a
tool
to
illustrate
the
principle
of
causality
of
25(OH)
D
serum
levels
on
the
human
metabolism
and
form
the
basis
for
systems
analysis
(Mabin
et
al.,
2006).
Such
causal
loop
diagrams
are
powerful
instruments
for
problem
identification
and
problem
resolving
purposes
by
breaking
down
a
comprehensive
system
into
fragments
in
order
to
enhance
its
comprehensibility
(Haraldsson,
2004).
Visualizing
concepts
makes
it
much
easier
to
understand
complex
correlations
and
casualties
(i.e.
cause
and
effect
mecha-
nisms).
The
problem
(in
this
case
immune
systems
that
have
difficulties
coping
with
COVID-19)
stands
in
the
center
of
the
systems
analysis.
Data
on
the
impact
of
vitamin
D
3
on
the
immune
system
have
been
collected
and
elaborated
in
the
results
and
discussion
section.
Based
on
these
findings,
the
CLDs
have
been
created
and
digitized
using
the
Vensim
software
(Ventana
Systems,
2015).
Results
and
Discussion
Figure
1
illustrates
a
causal
loop
diagram
coping
with
the
effects
of
vitamin
D
3
and
K
2
supplementation.
The
diagram
will
be
elaborated
and
discussed
throughout
this
section.
In
a
simplified
scheme,
the
majority
of
the
previtamin
D
3
is
both
acquired
in
the
human
skin
from
the
conversion
of
7-dehydro-
cholesterol
through
cutaneous
solar
ultraviolet
radiation
(Kheiri
Figure
1.
Causal
loop
diagram
of
the
impact
of
vitamin
D3
on
the
immune
system.
S.
Goddek
/
International
Journal
of
Infectious
Diseases
99
(2020)
286–290
287

et
al.,
2018),
and
to
a
lesser
extent
through
dietary
supplementa-
tion
(D
2
and
D
3
).
The
metabolic
pathway
continues
in
the
liver
where
D
2
and
D
3
are
hydroxylated
to
25(OH)D.
25(OH)D
is
eventually
transformed
into
1,25(OH)
2
Vitamin
D
3
(the
physiologi-
cally
active
form
of
vitamin
D)
in
the
kidneys
(Keane
et
al.,
2018).
The
high
degree
of
vitamin
D
deficiency
may
not
be
due
solely
to
the
modern
office-lifestyle
(i.e.
home
-
car
-
office
-
car
-
home;
repeat)
but
also
depend
on
factors
such
as
higher
latitude,
degree
of
skin
pigmentation,
seasons
(i.e.
winter)
and
dietary
intake
(i.e.
fatty
fish,
liver,
fermented
foods,
etc.)
(Mithal
et
al.,
2009).
Oral
supplementation
of
D
3
is
the
easiest
means
to
prevent
deficiencies.
A
frequent
argument
against
supplementation
of
vitamin
D
3
is
that
an
increased
intake
could
lead
to
a
vitamin
D
toxicity,
also
called
hypervitaminosis
D
(Orme
et
al.,
2016).
This
again
can
cause
hypercalcemia,
which
is
the
buildup
of
calcium
in
the
blood
leading
to
vascular
calcification,
osteoporosis,
and
kidney
stones.
However,
it
has
been
reported
that
the
reason
for
hypercalcemia
rather
lays
in
a
vitamin
K
2
deficiency
(Flore
et
al.,
2013;
Vermeer
and
Theuwissen,
2011),
as
K
2
activates
the
bone
gamma-carboxyglutamic
acid-containing
protein
(osteocalcin)
through
carboxylation.
Activated
osteocalcin
deposits
calcium
in
the
bones,
whereas
non-activated
osteocalcin
inhibits
calcium
absorption
by
the
bones.
As
the
osteocalcin
synthesis
rate
is
increased
by
higher
25(OH)D
serum
levels,
K
2
is
required
as
a
natural
antagonist
(Yasui
et
al.,
2006;
Dofferhoff
et
al.,
2020).
It
has
also
been
observed
that
D
3
supplementation
led
to
an
increase
in
anti-inflammatory
and
immunoregulating
interleukin
10
(IL-10)
cytokines
and
reduced
frequency
in
Th17
cells
(Allen
et
al.,
2012),
which
in
turn
leads
to
a
decrease
in
IL-17
and
the
proinflammatory
cytokine
TNFα
production,
decreasing
inflam-
matory
effects
in
the
host
(Ferreira
et
al.,
2020;
Latella
and
Viscido,
2020).
Also,
Zheng
et
al.
(2014)
reported
that
TNFα
promotes
pathogenic
Th17
cell
differentiation.
On
the
other
hand,
IL-10
reduces
the
activity
of
the
TNF-α-converting
enzyme
(TACE)
(Brennan
et
al.,
2008).
Brennan
et
al.
(2008)
also
observed
that
lipopolysaccharides
(LPS)
in
the
bloodstream
enhanced
TNFα
values.
Whereas
Th1
and
Th17
cells
are
proinflammatory,
regulatory
T-
cells
(Tregs)
have
anti-inflammatory
effects.
Prietl
et
al.
(2013,
2010)
proclaim
that
vitamin
D
3
supplementation
showed
an
increase
in
regulatory
Tregs
and
a
more
tolerogenic
immunological
status
in
general.
As
illustrated
in
Figure
1,
a
chronic
D
3
deficit
would
shift
the
T-cell
ratio
towards
the
inflammatory
pathway.
Given
the
fact
that
an
abundance
of
Th17
cells
are
highly
associated
with
autoimmune
diseases
(Waite
and
Skokos,
2011;
Yasuda
et
al.,
2019),
it
is
therefore
unsurprising
that
many
fatal
cases
showed
comorbidities.
There
are
many
follow-up
studies
required
to
substantiate
and
consolidate
the
hypothesis
that
there
is
a
strong
correlation
between
low
25(OH)D
serum
concentrations
and
mortality
rates.
But
what
we
know
is
that
people
with
“sufficient”
vitamin
D
blood
serum
levels
tend
to
have
considerably
less
severe
symptoms
caused
by
COVID-19
(Pugach
&
Pugach,
2020).
Dietary
considerations
Given
that
vitamin
D
3
is
an
immunoregulating
hormone
and
can
be
considered
safe
when
supplementing
it
together
with
K
2
,
Table
1
provides
a
rough
guideline
on
how
to
raise
vitamin
D
levels
to
desired
values.
Supplementation
of
magnesium
(200–250
mg/
day)
should
also
be
considered,
as
all
enzymes
that
metabolize
vitamin
D
seem
to
require
magnesium
(Uwitonze
and
Razzaque,
2018).
Other
dietary
supplementations
to
consider
are:
(1)
lipoic
acid
has
been
shown
to
inhibit
pro-inflammatory
IL-6
and
IL-17
production
(Salinthone
et
al.,
2010);
(2)
omega-3
fatty
acids
that
are
anti-inflammatory
and
reduce
kinase
excretion.
Consume
as
a
supplement
or
in
form
of
cod
liver
oil
or
fatty
fish
(such
as
salmon)
once
or
twice
per
week
(Vasquez,
2016);
(3)
Cannabidiol
(CBD)
that
promotes
anti-inflammatory
IL-10
secretion
(Joffre
et
al.,
2020)
while
preventing
LPS-induced
microglial
inflammation
(dos-
Santos-Pereira
et
al.,
2020);
and
(4)
Green
Tea,
since
epigalloca-
techin-3-gallate
is
the
most
biologically
active
catechin
in
green
tea.
It
reduces
Th17
cells
and
increases
regulatory
T-cells
(Byun
et
al.,
2014).
Conclusions
Recent
COVID-19-related
data
evaluation
showed
indica-
tions
that
a
high
25(OH)D
blood
serum
level
might
have
an
impact
on
the
mortality
rate
of
coronavirus
patients.
Even
though
ethical
issues
might
arise
(Muthuswamy,
2013),
the
paper’s
hypothesis
requires
clinical
randomized
trials
to
verify
the
circumstantial
evidence.
This
publication
illustrated
the
metabolic
mechanisms
behind
that
observed
phenomenon.
It
is
highly
suggested
to
also
consider
K
2
and
magnesium
intake
to
avoid
unintended
long-term
side-effects
such
as
arteriosclero-
sis
and
osteoporosis.
Conflict
of
interests
The
author
declares
that
they
have
no
competing
interests
in
this
section.
Ethics
approval
and
consent
to
participate
Not
applicable.
Consent
of
publication
Not
applicable.
Availability
of
data
and
materials
Data
sharing
not
applicable
to
this
article
as
no
datasets
were
generated
or
analysed
during
the
current
study.
Table
1
Tabular
indicator
for
raising
the
25(OH)D
blood
serum
levels
from
20
ng/mL
to
40
ng/mL
and
maintaining
them
after
consultation
with
the
physician
(von
Helden,
2011).
Body
weight
10
days
fill
up
Daily
D3
supplementation
(IU)
Daily
K2
(MK7)
supplementation
(
m
g)
50
14.000
2.200
100
60
16.800
2.600
120
70
19.600
3.000
140
80
22.400
3.500
160
90
25.200
3.950
180
100
28.000
4.380
200
110
30.800
4.820
220
288
S.
Goddek
/
International
Journal
of
Infectious
Diseases
99
(2020)
286–290

Funding
Not
applicable.
Author’s
contributions
One
author
only.
I
wrote
everything.
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