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https://doi.org/10.69639/arandu.v11i2.381
Propiedades terapéuticas, beneficios para la salud y usos de la
vitamina D como coadyuvante en el tratamiento contra la
COVID-19
Therapeutic properties, health benefits and uses of vitamin D as an adjuvant in the
treatment against COVID-19
María Luisa Muñoz Almaguer
maria.malmaguer@academicos.udg.mx
https://orcid.org/0000-0002-8133-7638
Universidad de Guadalajara
México – Guadalajara
Ana Montserrat Corona España
ana.corona@academicos.udg.mx
https://orcid.org/0009-0003-4604-3604
Universidad de Guadalajara
México – Guadalajara
Carlos Bancalari Organista
carlos.bancalari@academicos.udg.mx
https://orcid.org/0000-0002-2852-0273
Universidad de Guadalajara
México – Guadalajara
Claudia Elena González-Sandoval
claudia.gsandoval@academicos.udg.mx
https://orcid.org/0000-0001-8479-0828
Universidad de Guadalajara
México – Guadalajara
Claudia Verónica Mederos Torres
claudia.mederos@academicos.udg.mx
https://orcid.org/0000-0002-6259-8904
Universidad de Guadalajara
México – Guadalajara
Rosario Lizette Uvalle Navarro
rosario.uvalle@academicos.udg.mx
https://orcid.org/0000-0002-3566-2579
Universidad de Guadalajara
México – Guadalajara
Juan Salvador Rojas Cortés
juan.rcortes@alumnos.udg.mx
Universidad de Guadalajara
México – Guadalajara
Artículo recibido: 20 septiembre 2024 - Aceptado para publicación: 26 octubre 2024
Conflictos de intereses: Ninguno que
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RESUMEN
El uso de dosis de vitamina D, especialmente 2000 UI diarias, ha mostrado una mejora
significativa en pacientes infectados por SARS-CoV-2, incluyendo aquellos con síndrome
respiratorio agudo severo (SARS). Esta terapia ha incrementado la tasa de supervivencia en
pacientes críticos y ha disminuido la progresión de complicaciones relacionadas con la COVID-
19. Este estudio se fundamenta en investigaciones científicas y académicas recientes de bases de
datos como Medline, Pubmed, Hinari y SciELO, además de informes de la Organización Mundial
de la Salud y los Centros para el Control y Prevención de Enfermedades. Los hallazgos respaldan
el uso de la vitamina D como un agente adyuvante en el tratamiento de la COVID-19, destacando
sus propiedades terapéuticas y beneficios para la salud. La vitamina D ejerce su efecto a través de
mecanismos inmunomoduladores, incluyendo la promoción de la autofagia, crucial en la
respuesta viral, y la mejora de las respuestas inmunitarias innatas y adaptativas en diversas
enfermedades. Esto sugiere que la vitamina D no solo podría ayudar en la recuperación de
COVID-19, sino también en la prevención de complicaciones severas, reafirmando su papel como
un complemento importante en la terapia para pacientes afectados por esta enfermedad.
Palabras clave: vitamina D, SARS-CoV-2, COVID – 19
ABSTRACT
The use of different doses of vitamin D, especially 2000 IU daily, has shown a significant
improvement in patients infected by the SARS-CoV-2 virus, including those with severe acute
respiratory syndrome (SARS). This therapy has shown an increase in the survival rate in critically
ill patients and reduced the progression of medical complications related to COVID-19. The
present study was based on recent scientific and academic research, obtained from various
databases and sources such as Medline, Pubmed, Hinari, SciELO, as well as reports from the
World Health Organization, Ministry of Health and Centers for Control and Prevention of
Diseases. The reported results support the use of vitamin D as an adjuvant agent in the treatment
of COVID-19, providing therapeutic properties and health benefits. Vitamin D acts through
immunomodulatory mechanisms, such as promoting autophagy, which is essential in the fight
against viruses, and enhancing innate and adaptive responses in various pathological conditions.
Keywords: vitamin D, SARS-CoV-2 virus, COVID-19
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INTRODUCTION
The objective of this work was to compile the available information on the use of vitamin
D as an adjuvant in the treatment of patients with COVID-19, as a palpable need to develop
therapeutic alternatives due to the collapse of global health systems followed with the arrival of
the virus SARS-CoV-2.
The effectiveness of vitamin D in decreasing the mortality risk in infected patients is
highlighted, which has prompted academic studies and clinical trials to verify its safety and
effectivity as an additional treatment against COVID-19.
This paper addresses topics such as the physicochemical properties of vitamin D,
production and metabolism, therapeutic benefits, and the role it has as an adjuvant in the treatment
of the disease, as well as the specific immunological mechanism of action against the virus, that
it presents.
The topic and chronology were meticulously selected to provide a comprehensive and informed
understanding of the research.
MATERIALS AND METHODS
The present research work focused on the collection of information on the use of vitamin
D as a complementary treatment against COVID-19, using a descriptive methodology that, as its
name indicates, is limited to describing the current information available.
Different stages were followed in order to structure the work. In a first stage, a
bibliographic review was carried out using specific descriptors in a wide variety of databases like:
Medline, Pubmed, Hinari, SciELO, as well as academic works and data from organizations such
as the World Health Organization, the Centers for the Disease Control and Prevention and the
Ministry of Health. Updated articles were selected, which in turn were endorsed by health
professionals and supported by different sources, limiting them to studies published in the last 10-
15 years in Spanish, English and Portuguese, including case-control studies, and clinical trials,
observational and descriptive.
In the second stage, the collected data were correlated and analyzed to expand the
information. Finally, in the third stage, the objectives were set and a sequence for the subtitles
was designed, guaranteeing a coherent progression from the description of basic concepts to the
complexity of the topic.
RESULTS
Generalities and physicochemical properties of vitamin D
Vitamin D is a complex prohormone, which has molecular similarities with classic
steroids, such as cortisol, aldosterone and estradiol, thanks to its
cyclopentaneperhydrophenanthrene ring structure (Zuluaga et al., 2011a). It is mainly obtained
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through sun exposure, diet and oral supplements, being synthesized endogenously under the
action of ultraviolet radiation from 7-dehydrocholesterol. It is also acquired through diet, whether
of animal origin (D3 cholecalciferol) or plant origin (D2 ergo calciferol) (Ramírez et al., 2018).
It functions in both an endocrine and autocrine manner, regulating calcium-phosphorus
homeostasis, promoting cell differentiation and apoptosis in cells with vitamin D receptors, which
prevents diseases such as rickets and osteomalacia (García et al., 2013a). It has the appearance of
a white-yellowish crystalline powder, with solubility in ether and chloroform. A relative thermos
sensitivity, being stable to heat in crystallized form, but susceptible to isomerization in oily
solution (Rodríguez Sangrador, 2007a; 2007b).
Figure 1
Chemical structures of the vitamin D family.
Note. Adapted from Influence of sun exposure and diet on vitamin D nutritional status in adolescent and elderly women:
Optiford-European Union study (p. 12), by M. Rodríguez Sangrador, 2007, Complutense University of Madrid
Sources for obtention of vitamin D
Vitamin D belongs to the group of steroids and is obtained both endogenously and
exogenously. Endogenous synthesis occurs from 7-dehydrocholesterol, which is converted to
cholecalciferol in the skin by ultraviolet radiation (Pérez Castrillón, 2020a). Sun exposure
provides a significant amount of vitamin D, even in elderly people with low levels of 7-
dehydrocholesterol, and a good diet also contributes to achieving adequate levels, but in a less
efficient way. The cutaneous synthesis of vitamin D is highly influenced by several factors.
Starting from the concentration of 7-dehydrocholesterol in the epidermis, that decreases with age,
Ergocalciferol Calcifediol
Cholecalciferol Calcitriol
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making it difficult to achieve optimal levels of vitamin D (Valero and Hawkins, 2007b). Another
notable point is the amount of melanin in the skin, this also has an influence, since people with
darker skin tones need longer sun exposure to produce the same amount of cholecalciferol as
those with lighter tones, because melanin absorbs solar photons (Valero and Hawkins, 2007c).
Other factors that can affect the synthesis of vitamin D include the intensity of sunlight, which
varies with time of day, season, and latitude (Valero and Hawkins, 2007d).
Foods from animal origin contain cholecalciferol, while vegetables contain ergo
calciferol; both forms must be metabolized to be activated (Valero and Hawkins, 2007a). Given
the scarcity of foods rich in vitamin D, foods such as milk, juices, bread, margarine, cereals and
flour have been fortified. Being indicative of the need to implement alternatives for those with fat
absorption difficulties (Sevillano Segura, 2016b; U.S. Department of Health & Human Services,
2021). Daily intake recommendations vary, from 600 IU/day for those under 70 years of age to
2000 IU/day for those at highest risk of deficiency (Pérez Castrillón, 2020b; Sevillano Segura,
2016c). To achieve optimal levels of 25(OH) vitamin D, a daily supplementation of 20-25µg is
recommended, with an approximate ratio of 2.5nmol per 100IU (2.5µg) of vitamin (Sevillano
Segura, 2016d).
Endogenous and exogenous metabolism of vitamin D
Vitamin D is obtained mainly from the diet and endogenous production by photochemical
conversion from 7-dehydrocholesterol in the epidermis. This endogenous synthesis is induced by
exposure to ultraviolet B (UVB) rays from sunlight (Zuluaga et al., 2011b). During exposure to
ultraviolet light, photons are absorbed by 7-dehydrocholesterol, forming precholecalciferol,
which is rapidly converted to cholecalciferol (Valero and Hawkins, 2007g). It must be converted
into the active form, that will be transported by vitamin D binding protein (DBP) for activation
in the liver and subsequently in the kidney (Zuluaga et al., 2011d). 25-hydroxyvitamin D3 is the
main circulating form and the best indicator of vitamin D levels (Zuluaga et al., 2011g). 1,25-
dihydroxyvitamin D3 is the hormonally active form responsible for most biological effects, and
its production is also found in other tissues (Zuluaga et al., 2011i).
Vitamin D is inactivated in the liver and is eliminated mainly through the bile (Valero
and Hawkins, 2007h). The skin production of this vitamin decreases with age and is influenced
by factors such as the amount of melanin in the skin, geographical latitude, and the season of the
year (Busturia Jimeno, 2012). The absorption of vitamin D from the diet occurs at the duodenum
and jejunum through a passive diffusion mechanism (Rodríguez Sangrador, 2007c). Once
absorbed, it binds to DBP and enters the blood circulation (Rodríguez Sangrador, 2007d).
Additionally, certain medications and adipose tissue can affect the metabolism and bioavailability
of the vitamin (Flores, Macías Morales & Rivera Pasquel, 2012a).
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Therapeutic properties and health benefits
The action of vitamin D is mediated by the vitamin D receptor (VDR), which binds to
specific DNA sequences and regulates gene transcription. It is estimated that RVD can regulate
between 100 to 1,250 genes (Higdon and Delage 2017a). The 1,25-dihydroxyvitamin D Receptor
(VDR) regulates the expression of genes related to the biological activity of vitamin D, as part of
the family of nuclear hormone receptors (Zanchetta & Fradinger, 2009a). The actions of vitamin
D, including non-genomic ones, are carried out through the VDR located in the plasma membrane,
which is widely distributed in 36 different tissues (Zanchetta & Fradinger, 2009b).
Multiple physiological functions are attribute to vitamin D and the deficiency of it is
associated with several diseases, for example bone disorders (Vásquez Awad et al., 2017a). The
causes of deficiency can be extrinsic (inadequate intake or low sun exposure) or intrinsic (diseases
that affect the absorption or metabolism of the vitamin) (Varsavsky et al., 2017a, 2017b). Despite
discrepancies between standardization of optimal levels, vitamin D insufficiency is considered to
be between 50 and 75 nmol/L, while levels below 50 nmol/L indicate definetely a deficiency.
Although more research is needed, higher levels of vitamin D are associated with greater
protection against respiratory viral infections (Flores, Macias Morales & Rivera Pasquel, 2012d).
Figure 2
Metabolic pathways to produce Vitamin D.
Note. Adapted from Effects of vitamin D on health, immune response, and neurodevelopment in children (1st ed., pp.
13-43) by F. Macías Morales & Rivera Pasquel, 2012, Mexico: National Institute of Public Health.
(Skin)
(1α-hydroxylase)
Cholesterol
7-Dehydrocholesterol
Vitamin D
3
25-hydroxyvitamin D3
24(R),25-(OH)
2
D
3
Calcitriol
1α,25(OH)
2
D
Calcitroic acid
Δ
7
250
Δ7
Δ7
7-Dehydrocholesterol Δ
7
-reductasa
UVB
(290-320 nm)
(Diet Intake: 20%)
Intestinal absorption
Vitamin D
2
(Plant Sources)
Blood Circulation
LIVER
P450
(25-hydroxylases)
KIDNEY
CYP2R1 (Microsomal)
CYP27A1 (Mitochondrial)
(Billiary excretion)
(Active Form)
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Musculoskeletal and Cardiovascular system
Vitamin D continues to be widely used in the preservation of bone mass and as an
adjuvant in the treatment of osteoporosis (Vásquez Awad, 2013b). It improves bone quality
through several mechanisms, such as decreasing bone resorption and increasing cortical bone
formation (Vásquez Awad, 2013c). Low levels of vitamin D are associated with chronic diseases
like metabolic syndrome, type 2 diabetes and cardiovascular disease. Vitamin D can influence
endothelial function, lipid metabolism and the regulation of the immune response, which may
have implications in the prevention of cardiovascular diseases (Vásquez Awad, 2013e, 2013f,
2013g).
Cancer
It has been suggested that vitamin D may influence the reduction of cancer risk, regulating
cellular processes related to apoptosis, proliferation, and differentiation (Vásquez Awad, 2013h).
However, the evidence is still limited, and the mechanism is not fully described or understood
(Vásquez Awad et al., 2017c).
Multiple sclerosis
Vitamin D may play a role in the prevention of multiple sclerosis by inhibiting the activity
of CD4 T lymphocytes and modulating the immune response (Vásquez Awad, 2013i).
Renal system
Calcitriol, the active form of vitamin D, plays a crucial role in renal calcium handling,
regulating the reabsorption and homeostasis (Zanchetta & Fradinger, 2009d, 2009e).
Immune system
Vitamin D can induce the expression of antibacterial proteins and regulate the immune
response, influencing the cells of both the innate and adaptive immune system (Vásquez Awad et
al., 2017e; Vásquez Awad, 2013j). Another piece which plays an important role in the inmune
response and genetic polymorphisms, es the vitamin D receptor, that can influence susceptibility
to viral infections (Bilezikian et al., 2020h, 2020i).
Other functions of vitamin D
Calcitriol has effects on cell proliferation and differentiation, regulation of immune
function and fetal development, with vitamin D receptors being identified in various organs and
tissues (Rodríguez Sangrador, 2007f, 2007g, 2007h).
Benefits of the use of vitamin D, as an adjuvant in the treatment against COVID-19
To understand how the action mechanism of vitamin D works as an adjuvant in the
treatment against Covid-19, it is necessary to know the mechanisms that the virus uses to damage
the human body. Infection with the SARS-CoV-2 virus causes a pathophysiological phenomenon
known as "pulmonary cytokine storm", which is the causal agent of most cases of mortality and
morbidity, as it is the result of an imbalance in the immune system. innate causing a large release
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of proinflammatory cytokines and chemokines, leading to an abnormal activation of adaptive
immunity resulting in acute respiratory distress syndrome (ARDS). (Bilezekian, J. et al, 2020k).
The SARS-CoV-2 virus enters cells to bind to the ACE2 receptor, which is found in type
II alveolar cells. This binding causes a systemic inflammatory response to be generated, beginning
with a storm of proinflammatory cytokines (IFN-a, IFN -g, IL-1b, IL-6, IL-12, IL-18, IL - 33,
TNF ‐ α, TGFb, etc.) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10).
Causing a cascade of inflammation in the lower respiratory tract, bringing with it acute respiratory
distress syndrome (Oliva Marín, 2020a). Another effect of the virus binding to the ACE2 receptor
is the negative regulation of cellular expression, causing it to stop exercising its protective
functions. Leading to the accumulation of angiotensin II, since one of the functions of the receptor
is to catalyze the cleavage of angiotensin II into angiotensin. This accumulation and uncontrolled
activity of angiotensin II is believed to be responsible for acute lung injury in COVID-19 disease,
unfavorable myocardial remodeling, increased vascular permeability, peripheral
vasoconstriction, inflammation, oxidative stress, and pulmonary fibrosis, which are the causes of
severe respiratory symptoms due to COVID-19 (Oliva Marín, 2020b; Seijo and Oliveri 2020a).
At least 3 mechanisms have been proposed for how vitamin D can fight infection and
reduce the risk of developing serious complications caused by COVID-19. These 3 mechanisms
are based on acting on physical barriers, innate immunity and adaptive immunity. On the other
hand, vitamin D helps maintain integrity after binding to its receptor by stimulating the genes that
encode proteins responsible for maintaining cellular junctions, such as occludins (tight junctions),
connexins 43 (gap junctions) and E -cadherin (adherent junctions) (Mansur, 2020a). Epithelial
and endothelial cell junctions guarantee the permeability and integrity of the alveolar wall.
The SARS-CoV-2 virus, as a virus with destructive action, causes tissue alteration, on
cell junctions needed to reduce cell progression and superinfection with other microorganisms
such as bacteria and to avoid pneumonia (Seijo and Oliveri 2020b).
Vitamin D induces the differentiation of monocytes and macrophages, improving both
phagocytic and chemotactic capacity. Additionally, when toll-like receptors are present, innate
immune response cells, such as macrophages; bind to pathogen-associated molecular patterns
(PAMPs), generating a response that causes greater expression of VDR and CYP27B1, increasing
the capacity of macrophages and monocytes to transform 25(OH)D into 1,25(OH)D. Which are
responsible, together with the VDR, for interacting with vitamin D response elements (VDRE) of
cellular DNA, positively regulating the expression of genes such as nucleotide-binding
oligomerization domain containing protein 2 (NOD2), which is an important receptor that
recognizes intracellular PAMPs and enhances the expression of β-defensin, hepcidin
antimicrobial protein (HAMP), cathelicidin (CAMP), and β-defensin 4 (DEFB4) (Seijo and
Oliveri 2020c; Bilezekian, J. et al, 2020l).
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All these molecules participate in the destruction of infectious agents, altering their
capsids, blocking viral invasion of cells, reducing the amount of intracellular iron, which is vital
for the survival of viruses, preventing cell death of the epithelium of the respiratory tract.
respiratory and neutralizing the activity of endotoxins. In this way, the VD regulates the
production of antimicrobial peptides that allow the immune response to be modulated by
reinforcing the function of lung epithelial cells (Seijo and Oliveri 2020d; Bilezekian, J. et al,
2020m).
Stimulating innate immunity, Vitamin D also manages to promote the homeostasis of
cellular oxidation and reduction, that is, it manages to stimulate the production of reactive oxygen
species nitric oxide and superoxide. Vitamin D is important to produce these reactive oxygen
species, which maintains normal mitochondrial function and inhibits oxidative stress pathways
(Seijo and Oliveri 2020f). Which brings us to autophagy, a mechanism that cells use to maintain
their homeostasis since through this process they manage to degrade and eliminate all damaged
proteins and organelles. This process is also a defense mechanism against viral infections since
with autophagy; Viral particles can be encapsulated and, through lysosomal degradation,
destroyed to subsequently carry out antigen presentation and activate the adaptive immune
response (Bilezekian, J. et al, 2020n).
Through studies it has been proven that 1,25(OH)D can induce autophagy in monocytes,
the mechanism by which it does so is through the inhibition of the protein kinase 2 associated
with the S phase Skp2, this protein It has been seen that it is synthesized by the SARS-CoV-2
virus, which manages to block the autophagy process and thereby promote its accelerated
replication (Seijo and Oliveri 2020g). Vitamin D stimulates the promotion of enzymes autophagy
stimulants such as Beclin 1 and PI3KC3, which produce the elongation of the autophagosome and
its fusion with the lysosome. In addition, vitamin D stimulates the formation of autophagosomes
that facilitate viral elimination indirectly. Through the induction of cathelicidin expression, which
will subsequently stimulate Beclin 1 (Bilezekian, J. et al, 2020ñ; Rodríguez et al. 2020a). The
vitamin can influence the activation of adaptive immunity, due to its inhibitory and anti-
inflammatory action. By having the ability for dendritic cells to present antigens, decreasing the
activation of T lymphocytes (Bilezekian, J. et al, 2020o).
Secondly, Vitamin D influences the different populations of T lymphocytes, favoring the
proliferation of Th2 lymphocytes and Treg lymphocytes, which in turn stimulates the production
of anti-inflammatory cytokines. In addition, Vitamin D inhibits the proliferation of Th1 and Th17
lymphocytes, causing a decrease in the production of pro-inflammatory cytokines. This activation
and inhibition of T lymphocytes helps prevent the cytokine storm, mainly responsible for the
complications caused by the SARS-CoV-2 virus (Seijo and Oliveri 2020h). In addition to the 3
mechanisms mentioned above, vitamin D is capable of exerting effects on the renin-angiotensin-
aldosterone system. These effects are of utmost importance since large amounts of angiotensin II
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contribute to the appearance of acute lung injury (ALI) and acute respiratory distress syndrome
(ARDS) (Rivera, Medina, Vargas, Gómez & González, 2020). VD increases ACE2 levels,
decreasing the levels of Ang I and Ang II and causing greater synthesis of Ang 1.9 and Ang 1.7,
which counteracts the harmful effects at the lung level (Seijo and Oliveri 2020i).
Although vitamin D is known to participate in the maintenance of bone health and
calcium-phosphorus metabolism. However, various functions of this hormone have recently been
discovered, especially as an immunomodulator, promoting antiviral immunity, which is important
due to its role in COVID-19 infection (Bilezikian et al., 2020p; Panfili et al., 2020a). In addition
to the immunomodulatory role of vitamin D, it is known that VDR activation can regulate the
expression of more than 900 genes, many of which are involved in innate and adaptive immunity
(Panfili et al., 2020b). On the other hand, VDR is expressed on almost all immune cells, including
activated CD4+ and CD8+ T cells, B cells, and antigen-presenting cells such as macrophages and
dendritic cells. The receptor acts as a modulator of innate and adaptive immunity. In turn, it is
known that vitamin D improves the expression of two antimicrobial peptides called cathelicidin
and β-defensin, and that they play a key role in innate immunity. These peptides are involved in
direct microbicidal effects in addition to pleiotropic effects in the induction of immunomodulatory
responses to pathogenic stimuli (Panfili et al., 2020c).
In particular, the human cathelicidin peptide LL37 exhibits a variety of effects by
interacting with formyl peptide receptor type 1 (FPRL1), recruiting neutrophils, monocytes, and
T cells to infectious sites. Promoting apoptosis of infected cells by showing potent antiviral effects
on a variety of viruses, including HIV-1, influenza viruses, HSV1-2, rhinovirus and HCV. Several
studies reported a high prevalence of vitamin D deficiency among HIV-infected people. More
specifically, faster HIV progression and severity, lower CD4+ counts, increased risk of mortality,
and increased vulnerability (Panfili et al., 2020d).
Another property of vitamin D relevant to antibacterial and antiviral mechanisms is the
promotion of autophagy. Autophagy is a fundamental biological process that maintains cellular
homeostasis through the encapsulation of damaged organelles and misfolded proteins in the
intracellular membrane (Bilezikian et al., 2020q). Autophagy is also an essential mechanism
through the which cells cope with viruses. Autophagic encapsulation of viral particles packages
them for lysosomal degradation and subsequent antigen presentation and adaptive antiviral
immune responses. Therefore, autophagy facilitates, but does not guarantee, a hostile cellular
antiviral environment (Bilezikian et al., 2020r). Beyond the immediate regulation of pathways
associated with the induction of autophagy, vitamin D may also stimulate the formation of
autophagosomes to facilitate viral clearance indirectly through the induction of cathelicidin
expression, which in turn stimulates factors key to autophagy such as Beclin 1 (Bilezikian et al.,
2020).
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Vitamin D may play a crucial role in maintaining an appropriate balance between
autophagy and apoptosis to maximize antiviral responses to infection (Bilezikian et al., 2020t). It
promotes self-tolerance by changing cytokine patterns from a Th-1 to a Th-2 environment,
resulting in a reduction of Th1 and Th17-stimulating cytokines with a depletion of the Th-17 cells
themselves that are related to tissue damage, inflammation and a positive regulation of type 2
regulatory cells (T reg) (Panfili et al., 2020e). Finally, 25‐hydroxyvitamin D and 1,25(OH)2D
modulate T cell immunity, reducing type 1 proinflammatory cytokines (IL‐8, IFN‐γ, IL‐12, IL‐6,
TNF ‐α and IL‐17) and the increase in type 2 anti‐inflammatory cytokines (such as IL‐4, IL‐5 and
IL‐10). Specifically, 1,25(OH)2D inhibits plasma cell proliferation and immunoglobulin secretion
and induces B cell apoptosis.
A devastating pathophysiological aspect of SARS-CoV-2 infection is the so-called
“pulmonary cytokine storm”, one of the main causes of morbidity and mortality. Cytokine storm
is the result of a dysviosis of the innate immune system with an avalanche of proinflammatory
cytokines and chemokines, leading to abnormal activation of the adaptive immune pathway
(Bilezikian et al., 2020u). The serious damage caused by coronaviruses such as SARS-COV-2 is
due to their infection of the upper and lower respiratory tract with rapid virus replication, massive
infiltration of inflammatory cells producing an increase in proinflammatory cytokines and
chemokines that lead to acute illnesses and respiratory distress syndrome (Bilezikian et al.,
2020v). Approximately 5 percent of patients infected with Covid-19 will develop ARDS, due to
a dysfunctional immune response, resulting in a "cytokine storm" and subsequently multi-organ
failure (Slominski et al., 2020a).
The main proinflammatory elements in a cytokine storm are IL-1β, IL-6, TNF-α, INFγ
and IL-17. The important master regulation of proinflammatory responses is NF-κΒ, while Th17
responses are related to the retinoic acid receptor (RORγ). Oxidative stress may be another
etiological factor in the development of ARDS. It can be triggered by a virus and can activate
toll-like receptors (TLRs) with subsequent release of cytokines (Slominski et al., 2020b).
Oxidative stress induced by a viral infection or cytokine storm can amplify the damage
inflicted on target organs. Breaking this vicious and self-amplifying cycle without toxic side
effects and an impairment of the host antiviral response would represent a logical management of
COVID-19 (Slominski et al., 2020c). That said, it is known that active forms of vitamin D,
including classical calcitriol [1,25(OH)2D3] and hydroxyderivatives of CYP11A1, can inhibit the
production of proinflammatory cytokines from a cytokine storm with a mechanism of action
involving negative regulation of NF-κΒ and inverse agonism at RORγ. Counteracting oxidative
stress by activating TNF α and p53-dependent pathways. Therefore, it is possible that hydroxide
derivatives of vitamin D3 are candidates for the treatment of COVID-19, because if they target
both the cytokine storm and oxidative stress, they could have antiviral effects (Slominski et al.,
2020d).
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COVID-19 has been associated with cardiovascular sequelae, including myocardial
injury, type 1 myocardial infarction, acute coronary syndromes, cardiomyopathy, arrhythmias,
thrombotic complications, and cardiogenic shock. Myocardial injury, with elevation of cardiac
biomarkers, as well as electrocardiographic or echocardiographic changes, are common and
reported in between 20 and 30 percent of hospitalized patients with COVID-19 (Bilezikian et al.,
2020w). It has been associated with cardiovascular sequelae, including myocardial injury, type 1
myocardial infarction, acute coronary syndromes, cardiomyopathy, arrhythmias, thrombotic
complications, and cardiogenic shock. Myocardial injury, with elevation of cardiac biomarkers
as well as electrocardiographic or echocardiographic changes, is common, reported in 20-30
percent of hospitalized patients with COVID-19 (Bilezikian et al., 2020w).
Cardiomyopathy has been reported in 7-33 percent of critically ill COVID-19 patients.
Cardiac arrhythmias, including new-onset atrial fibrillation and atrial flutter, heart block, and
ventricular arrhythmias have been reported in 17 percent of hospitalized patients and 44 percent
of ICU patients (Bilezikian et al., 2020x). On the other hand, the various cardiovascular risk
factors that have been correlated with increased mortality from COVID-19 are also more evident
in experimental and clinical studies of Vitamin D deficiency (Bilezikian et al., 2020y).
Vitamin D deficiency may predispose to hypertension and other types of conditions by
upregulating the RAAS and increasing vascular resistance and vasoconstriction. While direct
causal evidence for a role of vitamin D deficiency in SARS-CoV-2-related heart disease is not
available, extrapolation of evidence from previous animal and human studies allows speculation
about several plausible mechanisms (Bilezikian et al., 2020z).
Academic studies and research regarding the use of Vitamin D in the treatment of
COVID-19
The relationship between low levels of Vitamin D and the severity of COVID-19 has
generated a series of investigations, in order to validate this hypothesis. When analyzing the
epidemiological data, a correlation was observed between COVID-19 mortality and latitude,
suggesting a relationship with sun exposure and the endogenous synthesis of Vitamin D, as
exposed before (Cortina-Gutiérrez et al., 2020a). Age is another factor that correlates with the
decreased of vitamin D levels, which mathces with severity and mortality in older patients
(Cortina-Gutiérrez et al., 2020b).
Studies done in the Philippines, have shown a significant inverse correlation between
clinical severity and Vitamin D levels. Lower levels were associated with severe cases (Mansur,
2020d). Similarly, in Indonesia and Iran, higher mortality was observed among patients with
lower Vitamin D levels (Mansur, 2020d). In studies carried out in Mexico, although no
statistically significant differences were found, it was observed that most deceased patients had
vitamin D deficiencies. At the same time, it was determined that most hospitalized patients had
lower levels of vitamin D, revealing that the majority of deaths corresponded to subjects with low
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levels or deficiencies of vitamin D3, as well as the majority of those hospitalized (Rodríguez et
al., 2020f).
A six-week prospective observational study conducted in India found that patients with
lower levels of vitamin D showed greater disease severity and therefore higher mortality rates
(Jain et al., 2020a). Jain et al., in their studies, demonstrated that patients with low concentrations
of vitamin D3 had higher levels of pro-inflammatory interleukins such as IL-6 and serum ferritin
(Jain et al., 2020e).
A meta-analysis showed a beneficial effect of Vitamin D in reducing respiratory
infectious diseases, especially in those who had a severe deficiency and to whom the vitamin was
administered daily or weekly (Pérez Castrillón et al., 2021a). Although various clinical trials have
been proposed to investigate this hypothesis, more studies are still required to confirm the
beneficial effects and determine the appropriate doses of supplementation (Pérez Castrillón et al.,
2021b).
Table 1
Vitamin D studies in patients infected with COVID-19. This table has been adapted from COVID-
19 and Vitamin D. Position paper of the Spanish Society for Bone Research and Mineral
Metabolism (SEIOMM) by Pérez Castrillón et al., 2021, Revista de Osteoporosis y Metabolismo
Mineral, 12(4) , (pp. 155-159)
A study carried out in France, on the other hand, evaluated whether the constant
administration of Vitamin D could influence the survival of elderly patients hospitalized with
COVID-19. Dividing them into three groups: those who received supplements regularly one year
in advance (Group 1), those who received supplements after diagnosis (Group 2) and those who
did not receive supplementation (Group 3) (Annweiler et al., 2020a).
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The results showed that the mortality proportion of patients with severe COVID-19 was
lower in Group 1 compared to Group 3. However, Group 2 did not show significant improvements
compared to the group without supplementation (Annweiler et al. , 2020c). It was concluded that
supplementation after diagnosis did not show significant benefits, while a regular Vitamin D
supplementation could be associated with a decrease in the severity of COVID-19 and a better
survival rate, during hospital stay (Annweiler et al., 2020e).
A study done in Spain, showed that the administration of calcifediol helped to improve
the progression of the disease and reduced the number of admissions to the Intensive Care Unit
(ICU), reducing mortality (Entrenas Castillo et al., 2020c). Despite certain comorbidities such as
high blood pressure and diabetes mellitus, calcifediol was shown to significantly reduce the need
for ICU admission in patients with COVID-19 (Entrenas Castillo et al., 2020f).
DISCUSSION
During the execution of this research work, different clinical studies were analyzed,
where hundreds of patients were subjected to treatments with Vitamin D. It is worth mentioning
that these trials were carried out around the world in people infected with SARS-CoV-2, with
different doses and schedules of Vitamin D, to evaluate the evolution of each of them.
The most relevant studies were those where patients infected with SARS-CoV-2 who
presented hypovitaminosis or plasma concentrations of vitamin D ≤ 20 ng/mL, had worse disease
progression and a higher mortality rate than those with desirable concentrations, that is, greater
than 30 ng/mL. This is because, adding the hypovitaminosis of Vitamin D, with latitude, a worse
evolution of the COVID-19 disease can be observed. For example, in countries further away from
the Equator, that is, to the north, the intensity of UV rays is lower and therefore the endogenous
production of the vitamin decreases considerably. Another important factor for the decrease in
serum Vitamin D is age. It was observed that elderly patients developed greater complications
caused by this disease.
Mansur J., in 2020, found in publications from countries such as: Switzerland, Ireland,
Belgium, the United Kingdom, Philippines, Israel and the United States, significant differences
were found between patient groups and control groups.
Studies carried out in the Philippines present an inversely significant relationship between
the severity of the evolution, the clinical picture and plasma concentrations of vitamin D in 212
patients. Where the serum average was 31.2 ng/mL in mild patients, 25.4 ng/mL in moderate
patients, 20.2 ng/mL in severe patients and 17.1 ng/mL in critical patients. Of these, 47 cases were
mild (representing 85.5 percent) and only 2 were critical (3.6 percent), within the deficient group
(less than 20 ng/mL) only 1 of the cases (1, 4 percent) were mild and 25 of them (32.5 percent)
were critical. On the other hand, in Indonesia, in 780 confirmed cases, 46.7 percent of those
deficient in Vitamin D died, 49.1 percent of those deficient in Vitamin D (between 20 and 30
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ng/mL) and only 4.2 percent of those had a plasma level greater than 30 ng/mL. Finally, in Iran
it was reported that 20 percent of those hospitalized died with less than 30 ng/mL and 9.7 percent
with a higher value.
At the same time, Rodríguez et al., in 2020, carried out a study at the Central Military
Hospital of Mexico of a retrospective observational, case-control, analytical and cross-sectional
type that included hospitalized patients with a diagnosis of SARS-CoV-2 infection or with
suspicion of COVID-19 in whom the serum concentration of Vitamin D was determined before
hospital admission. This was with the objective of investigating whether there was any direct
relationship between serum vitamin D levels before hospital admission and the mortality rate of
the patients. To standardize Vitamin D levels as: optimal, insufficient and deficient, the group of
researchers in charge was based on the levels presented by the Endocrinology Society of the
United States (SEO). Among the results observed, the SEO obtained that 20.3 percent of patients
with COVID-19 had levels lower than 8 ng/mL (that is, they presented Vitamin D
hypovitaminosis).
Consequently, the mortality rate presented was 20.5 percent, and although there was no
statistically significant difference between the mortality of the patients and the categorization of
Vitamin D levels. It could be observed that patients with optimal levels (≥ 30 ng/mL) none died,
while the majority of patients who died (77.1 percent) had deficient levels (<20 ng/mL). Within
the group of patients who died, they had lower levels of vitamin D (13.60 ± 6.36 ng/mL) compared
to patients who survived (17.30 ± 7.44 ng/mL). Additionally, patients who had plasma levels less
than 8 ng/ml had a 3.69 times greater risk of dying compared to those who had levels above 8
ng/ml. In relation to the above, it was observed that infected patients who required hospitalization
for COVID-19 presented, on average, deficient levels of Vitamin D (16.54± 7.37 ng/mL), among
which only 4.1 percent of hospitalized patients, presented optimal levels.
During the research, the role of Vitamin D in the cytokine storm in people with COVID-
19 was also evaluated. Likewise, in 2020 Daneshkhah et al. observed that patients with a marked
Vitamin D deficiency (≤15 ng/mL) had higher levels of proinflammatory markers and/or
cytokines than control groups with desirable concentrations.
Furthermore, patients with low plasma concentrations had a significant increase in “C-
reactive protein” which, in turn, also increased the probability of triggering cytokine storm and
this, consequently, drastically increased the probability of developing a severe course due to
COVID-19.
The use of Vitamin D as an adjuvant in the treatment and medical management of patients
infected by SARS-CoV-2 has shown, in the majority of studies carried out around the world, a
beneficial and immunomodulatory effect for the improvement and evolution of the patients with
COVID-19, especially when given daily in small doses, rather than in boluses or occasionally in
higher concentrations.
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CONCLUSIONS
According to current literature, the role of Vitamin D in the evolution of COVID-19 has
led to considering its use as a complementary treatment, with studies showing a correlation
between vitamin D deficiency and a severe evolution of the disease.
Although some studies have been limited by the size of the sample, a significant
difference is observed between patients with normal levels of vitamin D and those with
deficiency; they were more resistant and had greater survival, requiring less oxygen supply or
admission to intensive care.
Regarding the administration of Vitamin D supplements, there are divergences in the
results: while some studies show improvements with post-diagnosis administration, others do not
find significant benefits. Some authors report not having found any benefit, which suggests that
more studies should be carried out with larger samples and more risk factors should be considered.
In summary, although vitamin D supplementation after COVID-19 diagnosis may not
represent a significant improvement, maintaining adequate vitamin D levels before infection
appears to reduce complications and risks of severe illness from COVID-19, according to the
results of clinical trials.
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