World Journal of Medical Images, Videos and Cases
ORIGINAL ARTICLE
Vitamin D analogues - a possible therapeutic option in COVID-19?
Grzegorz Piotr Waliszczak 1
Introduction
SARS-CoV-2 (severe acute respiratory
syndrome coronavirus 2) is a novel virus
belonging to the family of coronaviruses
alongside SARS-CoV and MERS-CoV. Its
first occurrence in humans dates back to
December 2019 (Wuhan, People's Republic of
China) and it has subsequently quickly spread
over the world (cumulated, 45,968,799 proven
infections and 1,192,911 deaths as of 1
November 2020, 10 am CEST [2]), causing
severe burden to the general healthcare,
economy, paralysis of state affairs and daily
life of citizens. Its symptoms include fever,
dry cough, shortness of breath, fatigue, nausea,
vomiting or diarrhoea, myalgia, anosmia
and/or ageusia [1]. Although the disease
(named COVID-19 - coronavirus disease
2019) is mild or even asymptomatic in the
majority of the population, more severe
manifestations and poor outcomes are reported
in older people (>50 years-old and the elderly),
in patients with comorbidites (e.g. chronic
kidney disease, cardiovascular diseases,
cerebrovascular diseases, chronic obstructive
pulmonary disease, hypertension, malignancy,
diabetes mellitus, immunodeficiency [1,3] and
obesity [4]) and in Black, Asian and Ethnic
Minorities (BAME) [5]. Higher COVID-19
mortality rate has been reported in minority
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groups in Great Britain and was linked to
lower serum vitamin D levels in these groups,
caused by various factors, including diet and
genetic/geographic interplay [14], although
other studies dispute this correlation [5].
Despite the overall mortality rate of
hospitalised patients suffering from COVID-19
equalling 15-20%, in different age groups it
ranges from less than 5% (<40 years old) to
35-60% (70-89 years old) and is noticeably
higher in patients admitted to the ICU (40%).
Caution needs to be taken regarding mortality
data, as cases of death without confirmation of
SARS-CoV-2 infection are not included in the
statistics. The perceived danger of the virus
lies in the fact that persons unaware of their
ongoing infection, with symptoms that can be
neglected, may involuntarily spread the
pathogen to vulnerable groups. Approximately
48-62% of transmissions occur via
presymptomatic carriers [1]. It deserves a
mention that the mentioned more susceptible
populations (African-Americans, the obese,
and the elderly) require higher
supplementation of vitamin D [13]. Men with
COVID-19 exhibited lower vitamin D levels
than women [33].
The analogues of vitamin D encompass a
group of molecules, most of them exert their
pharmacological action by imitating 1,25-
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 World Journal of Medical Images, Videos and Cases
dihydroxyvitamin D3 and VDR (vitamin D
receptor) binding [6] (Figure 1). They were
introduced in indications where active D3 form
(1,25-dihydroxyvitamin D3) led to
hypercalcaemia [6] and hyperphosphataemia
[7] and exhibited potentiated activities
unrelated to calcium-phosphate balance,
including antiproliferative, prodifferentiative,
immunomodulatory, anti-inflammatory and
proapoptotic effects. Several of them were
approved for treatment of secondary
hyperparathyroidism (19-nor-1,25-(OH)2D2,
paricalcitol, doxercalciferol, falecalcitriol [7],
maxacalcitol [6]), psoriasis (tacalcitol,
calcipotriol, maxacalcitol [6]) and osteoporosis
(alfacalcidol, eldecalcitol [6]) and are currently
studied as purported new agents of cancer
chemotherapy (e.g. TX527, seocalcitol), either
in tumours or leukaemias [6,7]. Calcipotriol is
known to reduce fibrosis in liver by inhibition
of TGFβ1 [6] - antifibrotic drug use is studied
in COVID-19 [1], as intra-alveolar fibrin
deposition with hyaline membranes in the
affected lungs, heart fibrosis due to hypoxia
and fibrosis of pulmonary vessels was reported
[17].
In my hypothesis I postulate that the use of
vitamin D analogues in COVID-19, especially
in the pulmonary manifestations of the disease,
might lead to positive outcomes and mortality
reduction.
The terms 'vitamin D', 'D3', 'calcitriol', etc. in
this article will be used as synonyms of 1,25-
dihydroxyvitamin D3, as the actions of 'vitamin
D' sensu lato are due to the action and
receptoral interaction of its active form, 1,25-
dihydroxyvitamin D3 [6,7]. The articles quoted
usually measure the level of 25-
hydroxyvitamin D3 as the 'vitamin D level'
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(e.g. [5], [13], [19]). The literature cited
supports this terminology and approach and in
general uses the term 'vitamin D' loosely (e.g.
[13],[16],[19]).
Mechanisms of SARS-CoV-2 infection
pathophysiology and their relation to
vitamin D: inflammation and cytokine
storm
SARS-CoV-2 elicits damage to the patients by
its intense inflammatory response induction
[1]. Its activity in severe cases affects mainly
the lung, as the virus prompts the release of
inflammatory cytokines (IL1-β, IL-6, IL-15,
IL-17, IFN-γ, TNF (all belonging to the Th17
family), IP-10, MCP-1 [17, 30]) therein,
causing thrombosis of large and small vessels,
syncytia formation, destruction of normal lung
architecture, interstitial hyalinisation and
pneumocyte deformation. Consequently,
systematic inflammation appears, causing
extensive thrombosis and hypoxemia that
results in multi-organ failure [17].
Vitamin D is suspected to play a role in
COVID-19 susceptibility and mortality [12], a
similar mechanism was proven for influenza
and other viral respiratory infections. This
effect is related to its immunomodulatory
function, as vitamin D is known to reduce
cytokine synthesis and block immune
overreaction towards pathogens, known as the
'cytokine storm'[13], which leads to rapid lung
damage in COVID-19 [1,12]. D3 can block
cytokine excretion by macrophages, causes
their maturation and oxidative burst, stimulates
neutrophils, dendritic cells, monocytes,
epithelial cells and several other lines to
secrete antimicrobial peptides, some with
antiviral activity [12], induces autophagy [15],
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modulates lymphocyte action [16]. That D reduces the number of pro-inflammatory T

counteracts the SARS-CoV-2 activity that in lymphocytes that synthesise IFN-γ, IL-17, IL-
general causes the reverse [1]. TX527 and 22, IL-9 and TNF [16]. Like influenza virus,
other vitamin D analogues are known to the novel coronavirus can target and kill T
increase T lymphocyte migration [6], vitamin lymphocytes, causing lymphopaenia [1].

Figure 1. The chemical structure of a) 1,25-dihydroxyvitamin D3, b) maxacalcitol, c) calcipotriol.

Figure 2. Actions of vitamin D, important in the context of COVID-19 (direct or indirect).

Red - downregulated, green - upregulated.

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Additionally, vitamin D deficiency is known to
increase inflammation (by induction of TNF-α
and IL-1β), leading to the cytokine storm. The
action of IL-6, a potent factor thereof, can be
mitigated by D3 (promoting anti-inflammatory
cytokines like IL-10, and blocking
proinflammatory ones like IL-17) [13]. This
activity resembles that of tocilizumab, a
monoclonal antibody targeting IL-6R and
already being tested in COVID-19, as IL-6
depends on TNFα and IL-1β and induces
production of ICAM-1, MCP-1 and IL-8 that
cause infiltrates and tissue damage [1,42].
Insufficient levels of D3 correlate with
occurrence of ARDS, an important element of
COVID-19 [20]. Vitamin D elicits a
tolerogenic response on monocytes and
dendritic cells, similar to that of
glucocorticoids, inhibits expression of Th1
cytokines (IL-2, IFNγ, TNF-α) and promotes
expression of Th2 cytokines (IL-3, IL-4, IL-5,
IL-10) [38]. Patients with COVID-19 in
general exhibit Th1 and Th17
immunophenotype with elevated levels of
respective cytokines [30] (Figure 2).
Pirfenidone, a drug currently assessed in
pulmonary (FDA approval), cardiac and renal
fibrosis and discussed as a potential COVID-
19 drug [39, 40], exhibits similar action to
vitamin D, regarding the cytokines, by
blocking Th1 and Th2 response (inhibition of
TGFβ1, TNFα, IFN-γ, IL-1β, IL-4, IL-5, IL-
13, IL-17, IP-10, MIP-1, Mig [39], IL-18 [41],
it is of note that [41] describes Th1 inhibition
and Th2 stimulation instead) [39], reducing
tissue infiltration (downregulation of ICAM),
fibrosis (hinders production of COL1A1 and
fibronectin) and increasing expression of anti-
inflammatory cytokines (IL-10) [40, 41].
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COVID-19, thrombosis and vitamin D
Another type of COVID-19 pathomechanism
involves disseminated thrombi in vital organs,
caused by excess inflammation (notably in
lungs), endothelial disruption and tissue
hypoxia [1, 17]. Vitamin D level is inversely
correlated with incidence of deep vein
thrombosis (which was also reported in
COVID-19) [1, 16]. The so-called
immunothrombosis occurs due to
inflammatory signals, mediated notably by TF,
TLRs and several cytokines (endothelial
activators, described further [34]) [16].
Calcitriol exhibits antithrombotic activity by,
among others, promoting antithrombin,
thrombomodulin and TFPI synthesis, reducing
mean platelet volume, promoting endothelial
protection, vasodilator synthesis (e.g. NO by
eNOS) and NF-κB inhibition, thus reducing
further inflammatory marker production [16,
38]. However, vitamin D suppresses iNOS,
like pirfenidone [38, 41] Active vitamin D3
form downregulated expression of TLR2 and
TLR4 in monocytes, limiting their
inflammatory response [38]. Calcitriol reduces
endothelial adhesion marker production
(VCAM-1, ICAM-1, E-selectin; by
downregulation of the mentioned NF-κB),
thereby leading to reduction of leukocyte
infiltrates [16], that are reported in COVID-19-
affected lungs [1, 17]. Vitamin D and
paricalcitol hindered prothrombotic activity of
TNF-α [16], that is also reported in COVID-19
[13]. Vitamin D serum level was inversely
correlated with D-dimers, a marker of
thrombosis [33]. IL-6, repressed by D3 [13],
facilitates thrombosis by increasing VIIa,
thrombin and TF levels, promoting platelet
production. Its other effects include interstitial
oedema, increased tissue pressure and
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activation of the complement system, induction
of VEGF and histamine release; IL-6 seems to
be responsible for many symptoms and
elements of COVID-19, including playing a
role in the cytokine storm. Moreover, it
exhibits direct myocardial depressing effects in
humans [42].
The links of vitamin D deficiency and
COVID-19
Martineau and Forouhi note 'the striking
overlap between risk factors for severe
COVID-19 and vitamin D deficiency,
including obesity, older age, and Black or
Asian ethnic origin' and acknowledge the fact
that 'there are good reasons to postulate that
vitamin D favourably modulates host
responses to severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2), both in the early
viraemic and later hyperinflammatory phases
of COVID-19' [18].
Several articles have pointed out the positive
correlation of vitamin D deficiency and
COVID-19 severity and mortality. It is known
that D3 can directly suppress viral replication
by, for example, reducing expression of DPP-
4/CD26 in host tissues - it was proven in
related COVID-MERS. SARS-CoV-2 binds
this receptor with its S1 domain of
glycoprotein spike, facilitating its cellular
integration [20]. Actually, 1,25-
dihydroxyvitamin D has been proven effective
in reducing novel coronavirus replication in
human nasal epithelial cells and Vero E6 cells
[15]. ACE-2, the protein associated with viral
entrance [1], is upregulated by vitamin D [27]
but, paradoxically, higher level of ACE-2 leads
to better COVID-19 outcomes [1, 27] and to
fewer cases of acute lung damage in
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respiratory infections [27]. SARS-CoV-2
downregulates ACE-2 and upregulates
angiotensin II, producing a dysregulation of
renin-angiotensin-aldosterone (RAA) system
which also contributes to myocarditis, cytokine
storm and ARDS [33]. Vitamin D suppresses
the RAA system and reverts the effects of
angiotensin II by PPAR-γ [16].
Vitamin D deficiency has been shown as an
independent predictor of COVID-19
seropositivity (OR 2.6, 95%CI 1.41–4.80;
p=0.002) [19]. Average vitamin D levels in
country populations were inversely correlated
with COVID-19 incidences and mortality [20].
One study reported no significant changes in
outcomes but reduced mortality in the group
treated with vitamin D (ORadj 0.48, 95% CI
0.32 – 0.70, p = 1.79×10-4), also if adjusted for
baseline vitamin D levels (ORadj 0.47, 95% CI
0.33 – 0.70, p = 1.27×10-4) [22]. Vitamin D
level was significantly lower in the patients
who died from COVID-19 than in those who
survived (13.83 ± 12.53 ng/ml compared to
38.41 ± 18.51 ng/ml) and vitamin D deficiency
significantly increased both odds and hazard of
death during hospitalization (OR = 7.77,
P = 0.005, ORadj = 6.84, P = 0.01, HR = 4.15,
P = 0.04). With higher levels of vitamin D
there was less lung involvement, either in a
specific lobe or in general. One unit increase of
vitamin D serum level equals 4% odds
reduction for severe lung involvement
(OR = 0.96, 95% CI 0.93–0.98, P = 0.04) [23].
A study conducted in Turkey revealed that
93.1% of the group with severe-critical
COVID-19 had vitamin D insufficiency and
that severity of COVID-19 correlated with
greater vitamin D deficiency. Comparable
results on D3 level in surviving and dead
patients were provided (19.3 ± 11.2 ng/ml
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compared to 10.4 ± 6.4 ng/ml, P<0.001).
Lymphocyte elevation, WBC reduction and
lower vitamin D serum level were found to be
the predictors of death in multivariate analysis
(OR 0.927, 95%CI 0.875 – 0.982, p = 0.010)
[25]. Hernández et al. did not find any
correlation of D3 deficiency and severity of
COVID-19 in a given patient, although the
infected patients had lower vitamin D level as
compared to controls (13.8 ± 7.2 ng/ml
compared to 20.9 ± 7.4 ng/ml, p<0.0001, after
multivariate analysis: 11.9 (95%CI, 9.6-14.3)
ng/ml compared to 21.2 (95%CI, 19.7-22.7)
ng/ml (p<0.0001). Patients with higher vitamin
D level had significantly lower serum ferritin
and troponin I levels and stayed shorter at the
hospital. A greater PaO2/FIO2 ratio<300
prevalence, less radiological progression and
less admittance to ICU were noted, but were
not significant [33].
However, the exact relation of D3 and COVID-
19 is still disputed, as there were studies (e.g.
[24], [26]) which report no such coincidence
and results of RCTs and observational trials
frequently provide conflicting results. Grant et
al. attribute this to 'enrolling participants with
relatively high 25(OH)D concentrations and
using low vitamin D doses and not measuring
baseline and achieved 25(OH)D
concentrations' [21]. Many studies encompass
small sample sizes [23, 24, 25]. A study of 656
patients in Great Britain found an association
of severe COVID-19 infection and mortality in
univariate analysis, but it was insignificant
after adjustment to confounders [26]. Some
associated lower vitamin D levels in COVID-
19 with the fact that 25-hydroxyvitamin D is a
negative acute-phase reactant and its levels are
reduced, as a positive reactant, ferritin, is
elevated [33]. Therefore, further analyses and
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studies are needed, though a correlation is
plausible and worth consideration.
Vitamin D analogues, psoriasis and COVID-
19 immunology: a proof of concept
The synthesis of vitamin D analogues was
honed for their non-calcemic activity,
including immunomodulatory. Tacalcitol,
calcipotriol and maxacalcitol are used topically
or orally in the treatment of psoriasis [6,7].
Psoriasis infiltrates include the same cells that
are present in COVID-19 (neutrophils, T
lymphocytes, dendritic cells) and has been
linked to increased risks of cardiovascular
pathologies [28] that COVID-19 features [1].
IL-23/IL-17 axis, notable in psoriasis, begins
with macrophages and dendritic cells
producing IL-23 that leads to stimulation of
Th17 and Tγδ+ lymphocytes, which in turn
secrete IL-17, recruit neutrophils and other
cells [28] (via IL-1β, TNF, IL-6, neutrophil
chemoattractants - IL-8, CCL20, CCL2, all
also involved in COVID-19) [30] and elicit
keratinocyte hypertrophy. IL-36 is the
promoter and enforcer of this pathway,
excreted by keratinocytes prompted by TNF-α,
IFN-γ and IL-17A. Another cytokine axis, IL-
17/IL-22, also comprises IL-36 and features a
positive feedback loop within. In humans and
mice, calcipotriol reduced expression of IL-
23p19, IL-17A, IL-22 and IL-23/IL-12p40.
The described action is related to direct
suppression of IL-36α and IL-36γ in
keratinocytes. The presence of IL-23p19+ cells
(e.g. macrophages, neutrophils) and their
infiltrates in dermis of murine psoriasis model
was diminished after calcipotriol
administration, the same effect seems to occur
due to 1α,25-dihydroxyvitamin D3. The
substance acted in mice via keratinocyte VDR
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and, surprisingly, did not affect the immune
cells directly - contrarily to that, in humans a
direct action of inhibiting IL-17 and IL-23 in
dendritic cells, Langerhans cells and T
lymphocytes was described [28] and other
studies report that calcipotriol does affect T
cells in murine psoriasis model [29].
Calcipotriol displays considerable synergy in
action with betamethasone, complementing
each other's actions [28]. When used together
in murine psoriatic model, Th17γδ level
reduction was higher than in each drug used
separately [29]. It is known that vitamin D in
general suppresses Tγδ+ lymphocytes [38].
Calcipotriol had a more potent effect on
reducing their level in draining lymph nodes
than betamethasone and lowered IL-23A, IL-
22 and TNF-α levels while betamethasone did
not show such effect while administered alone
[29]. As lymphocyte population abnormalities
are reported in COVID-19 [34], there might be
a possibility that some of the changes reflect
those known in psoriasis (regarding regulatory
T and B cells). Calcipotriol decreased the
levels of CD4+ Treg cells (CD4+CD25+
Foxp3+), increased the levels of CD8+ Treg
cells (CD8+CD122+PD-) and restored the
balance of CD4+ Treg/Th17γδ ratio (with
betamethasone, also the CD8+ Treg/Th17 γδ
ratio) [29, 38].
Vitamin D and dexamethasone
Dexamethasone, already utilised in COVID-19
treatment [1], inhibits IL-23 expression in
dendritic cells and macrophages, IL-17/IL-22
expression in T lymphocytes and hinders IL-
36α and IL-36γ production, albeit to a lesser
extent than calcipotriol [28].
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Th17 lymphocytes, IL-1, IL-17 and TNF were
shown to participate in excess inflammation
and contribute to the severity of COVID-19.
IL-17 takes a major part in ARDS and ALI,
destroying lung parenchyma, recruiting
neutrophils and blocking their apoptosis and
unleashing other proinflammatory cytokines,
contributing to a vicious cycle of uncontrolled
tissue destruction. IL-17 level positively
correlated with greater lung injury and disease
severity in COVID-19 patients. The Th17
immunophenotype was also associated with
SARS-CoV2 myocarditis [30]. Tγδ+
lymphocytes, producing IL-17, were markedly
elevated in COVID-19 and the patient
presented with a huge array of inflammatory
cytokines (IFN-γ, MIP-1α, MIP-1β, TGFα,
MCP-1, TNF-α, IL-1α, β-NGF, basic FGF,
IFN-α2, IL-5, G-CSF), a burst of Th1
cytokines (IL-2, IL-3, IL-12 (p70)) and Th2
cytokines (IL-4, IL-5, IL-6), then supported
with a group responsible for lymphocyte T
exhaustion and apoptosis (4-
1BB/TNFRSF9/CD137, GM-CSF, Midkine,
IL-21, Flt-3 Ligand, CCL28, Fas
Ligand/TNFSF6, IL-17E/IL-25, IL-23, CD40
Ligand/TNFSF5, CXCL14/BRAK, IL-
31,Granzyme A, PD-L1/B7-H1), followed by
markers of neutrophil chemotaxis and
endothelial activation (MIG, VEGF, IL-7,
Granzyme B, GRO-a, PDGF-BB, RANTES,
IL-8, IL-9, EGF). Near death, another wave of
inflammation and T cell activation, with
elevation of IL-2, IP-10, TRAIL, IL-17, IL-
12(p70), CD163, IL-12 (p40), IL-15, TNF-β,
SDF-1a, LIF, IL-1β was noted. The results
might be obscured by the fact that the patient
received remdesivir during hospitalization and
was given 10 μg of IFNβ-1a a day before death
[34].
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Vitamin D and the immunology of retinoids
Although active D3 can cause VDR/RXR
heterodimerisation in a physiological state [7],
vitamin D analogues are known to especially
stimulate heterodimerisation of VDR with
RXR, recruit VDR/RXR cofactors more
readily and at lower concentrations. This
affinity was proven for 20-epi-1,25(OH)2D3,
maxacalcitol, CD578, inecalcitol, TX527 and
seocalcitol [6].
Actually, VDR forms heterodimers with any
isoform of RXR and is the 'dominant' partner
of the dimer, as its ligand is required for action
and the latter's exerts meagre response,
although the RXR receptor can still be
stimulated by its own ligands in specific
circumstances [8]. Other configurations
include VDR/RAR [9] and RAR/RXR (all
isoforms thereof) [8]. All three combinations
share some target binding sites [8, 9] and the
VDR/RXR heterodimer displays more DNA
binding sites than VDR/VDR homodimer [10],
however, the exact relation of VDR dimers has
not been thoroughly elucidated as of now.
It is worth mentioning that retinoid receptor
agonists (acitretin, AGN-190521, AGN-
191659, AM 580, arotinoic acid, EC-23
(AGN-190205), LGD-1550, MDI-101, MDI-
403, RO-13-7410, tamibarotene, tazarotene,
tretinoin) are theoretically capable of stopping
novel coronavirus replication [11]. VDR/RXR
binds preferentially to the DR3 response
element, which explains vitamin D analogue
use in secondary hyperparathyroidism (PTH
gene hosts a DR3 element) [31]. The same
element was found for IL-36γ and its binding
induces transrepression, which in turn reduces
inflammatory response in psoriasis [30].
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Actually, retinoid receptor agonists show a
similar activity to vitamin D: they induce
tolerogenic response in macrophages and
dendritic cells, support the differentiation of
Foxp3+ Treg cells and hinder that of Th17
cells (blockade of IL-23 and IL-6 signalling),
induce IL-10, suppress TNF and IL-12
production (by inhibition of NF-κB) and NO
synthesis in macrophages, suppress IFNγ in
NK cells (by the same mechanism) and cause
differentiation to Th2 by IL-4 expression and
IL-12 repression. In lungs, however, their
action is more controversial, as they either
increase numbers of Treg cells while
diminishing levels of Th2 and Th17
lymphocytes (suppression of IL-5 and IL-13)
or promote Th2 response in local ILC2 (Innate
Lymphoid Cells) [43]. In psoriasis, retinoids
are used alongside steroids and vitamin D
analogues [28, 29, 43] due to similar effects -
counteracting the IL-1 family cytokines (IL-17
and TNF-α) and IL-33. As compared to
vitamin D, retinoids are a double-edged sword;
apart from lessening the inflammation, they
present more proinflammatory activities, for
example may induce IL-22 and IFNγ
production in certain tissues or promote Th17
differentiation in certain circumstances.
Altogether, their action is very tissue-
dependent and varied [43].
As retinoid use is discussed in COVID-19 [11],
the analogues of vitamin D might have a
similar activity, based on their molecular
action and cause a curative response in
COVID-19.
Financial benefits of vitamin D analogues
The side effects of antipsoriatic vitamin D
analogues are perceived as mild and include
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elevation of seral calcium [28, 32]. Many of
these drugs are already approved for use in
several countries [6,7, 32]. Their price is
relatively low (calcipotriol - from 0.81 USD
per 50 µg/1g ointment), as at least one patent
for calcipotriol hydrate synthesis expired and
generic products are readily available [32].
This allows for their use in developing
countries, with great needs [2] and insufficient
funds [36]. Of course, in this case the
aforementioned drugs could be administered
orally, intravenously or by inhalation, as
opposed to most-known formulations in the
form of ointments or creams. A combination
with steroids, as proven in the psoriasis
studies, will supposedly produce more potent
effects due to their synergy and similar targets
[29, 30].
Dexamethasone, a steroid already included in
COVID-19 treatment scheme [1] and
administered orally or intravenously [35, 36],
reduced the incidence of death in patients
under invasive mechanical ventilation (29.3%
compared to 41.4%; rate ratio 0.64; 95% CI,
0.51-0.81) and in patients receiving oxygen
without invasive mechanical ventilation
(23.3% compared to 26.2%; rate ratio 0.82;
95% CI, 0.72 -0.94). Its administration reduced
the mortality at 28 days (22.9% compared to
25.7%, rate ratio 0.83, 95%CI 0.75-0.93;
P<0.001). The greatest absolute and
proportional benefit was shown for patients
receiving invasive mechanical ventilation (11.5
by chi-square test for trend) and for patients
with longer duration of symptoms (more than 7
days, 12.3 by chi-square test for trend). No
effect was reported for patients without any
respiratory support.
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Additionally, dexamethasone administration
shortened hospital stay by 1 day and facilitated
live discharge within 28 days, especially in
patients with invasive mechanical ventilation.
The steroid reduced progression of the
therapeutic measures from oxygen
administration to invasive techniques [35].
Another study reported more mean days alive
and free from mechanical ventilation (6.6,
95%CI 5.0-8.2 days compared to 4.0, 95% CI
2.9-5.4 days, P = 0.04) and less organ
dysfunction in 7 days as measured by the
SOFA score (6.1, 95%CI 5.5-6.7 for
dexamethasone as compared to 7.5, 95%CI
6.9-8.1 for standard care, p = 0.004) [36].
Conclusions
Off-label and compassionate use of various
FDA-approved drugs already occurs in
COVID-19 [30], including anticoagulants,
antivirals, immunosuppressants, antifibrotics
[1], sometimes based only on theoretical
predictions of efficacy, undisputed curative
value in similar diseases, good clinical safety
profile and the absence of any directed and
proven therapy apart from supportive care
[37].
As it was described, vitamin D and its
analogues fulfil many of these roles. Other
therapeutic interactions with human tissues
than the mentioned cannot be excluded (due to
different array of immune cells, additional
metabolic pathways present, other cofactors of
VDR or VDR-related transcription factors,
capable of novel activity, etc.). Vitamin D
analogues seem to be promising new
candidates for COVID-19 treatment and offer a
complete array of beneficial effects worth
consideration in this disease. Remdesivir, a
 2020 WJOMI
 World Journal of Medical Images, Videos and Cases
drug termed 'the most promising' [1], was also
introduced on basis of compassionate use [37].
Similarly, anti-spike protein monoclonal
antibodies in single dose regimens
(bamlanivimab [44], casirivimab + imdevimab
[45]), which were 'investigational drug[s] (...)
not currently approved for any indication',
were allowed for emergency use by FDA after
proving their efficacy in either phase 2 interim
analysis [44] or analysis of phase 1/2 data [45].
Quoting the argumentation for their
introduction, 'based on the totality of scientific
evidence available to FDA, it is reasonable to
believe that [the drug] may be effective in
treating mild to moderate COVID-19 in adults
and paediatric patients (...) who are at high risk
for progressing to severe COVID-19 and/or
hospitalization, and that, when used under the
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Conflict of interest: none declared
Acknowledgements
I would like to thank Dr. Piotr Kochan for support in writing this
article and the possibility to publish it in WJOMI.
Author's affiliations:
1
Jagiellonian University Medical College, Faculty of Medicine,
4th year Medical Student , Cracow, Poland
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 World Journal of Medical Images, Videos and Cases

Corresponding author:
Grzegorz Piotr Waliszczak
4th year Medical Student
Jagiellonian University Medical College
Faculty of Medicine
ul. Św. Anny 12
31-008 Krak w
Poland
Tel. +48 609 542 424
e-mail: grzegorz.waliszczak@gmail.com

To cite this article: Waliszczak GP. Vitamin D analogues - a

possible therapeutic option in COVID-19? World J Med Images
Videos Cases 2020; 6:e44-55.

Submitted for publication: 10 November 2020

Accepted for publication: 24 November 2020
Published on: 30 November 2020

ISSN: 2450-5773
© World Journal of Medical Images, Videos and Cases

November 2020, Volume 6, World J Med Images Videos Cases  2020 WJOMI

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