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Vitamin D analogues - a possible therapeutic option in COVID-19?Grzegorz Piotr Waliszczak1 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 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-dihydroxyvitamin D3 and VDR (vitamin D receptor) binding [6] (Figure 1).  Figure 1. The chemical structure of a) 1,25-dihydroxyvitamin D3, b) maxacalcitol, c) calcipotriol. [please click on the image to enlarge] 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' (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], modulates lymphocyte action [16]. That counteracts the SARS-CoV-2 activity that in general causes the reverse [1]. TX527 and other vitamin D analogues are known to increase T lymphocyte migration [6], vitamin D reduces the number of pro-inflammatory T lymphocytes that synthesise IFN-γ, IL-17, IL-22, IL-9 and TNF [16]. Like influenza virus, the novel coronavirus can target and kill T lymphocytes, causing lymphopaenia [1]. 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]. 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 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 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 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 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 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]. 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]. |
 Generate PDF/or right-click and save as.../  Figure 2. Actions of vitamin D, important in the context of COVID-19 (direct or indirect). Red - downregulated, green - upregulated. [please click on the image to enlarge] 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]. 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 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. 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 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 conditions described in this authorization, the known and potential benefits of [the drug] outweigh the known and potential risks of such product; and there is no adequate, approved, and available alternative to the emergency use of [the drug] for the treatment of mild to moderate COVID-19' [44]. The risk of adverse effects of vitamin D analogue therapy appears to be low [6,7,32], unlike in case of heavily studied chloroquine [1] and by the time the concrete proofs of their efficacy in SARS-CoV-2 arrive, many human lives will have perished with only meagre opportunities of treatment. The number of people affected by COVID-19 continues to grow dynamically [2] and the virus endangers almost all aspects of humanity, also posing a huge threat to general healthcare [1,2]. References [1] Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020; 324:782-93. DOI:10.1001/jama.2020.12839 [2] WHO, Weekly epidemiological update - 3 November 2020. Access valid on 4.11.2020: https://www.who.int/ docs/default-source/coronaviruse/ situation-reports/weekly-epi-update-12.pdf?sfvrsn=c5d1b6fc_2 [3] Zádori N, Váncsa S, Farkas N et al. The negative impact of comorbidities on the disease course of COVID-19. Intensive Care Med 2020; 46: 1784-6. DOI:10.1007/s00134-020-06161-9 [4] Sattar N, McInnes IB, McMurray JJV. Obesity Is a Risk Factor for Severe COVID-19 Infection: Multiple Potential Mechanisms. Circulation 2020; 142:4-6. DOI: 10.1161/CIRCULATIONAHA.120.047659. [5] Raisi-Estabragh Z, McCracken C, Bethell MS et al. Greater risk of severe COVID-19 in Black, Asian and Minority Ethnic populations is not explained by cardiometabolic, socioeconomic or behavioural factors, or by 25(OH)-vitamin D status: study of 1326 cases from the UK Biobank. Journal of Public Health 2020; 42:451-60. DOI: 10.1093/pubmed/fdaa095 [6] Leyssens C, Verlinden L, Verstuyf A. The future of vitamin D analogs. Front Physiol 2014; 5:122. DOI: 10.3389/fphys.2014.00122 [7] Slatopolsky E, Finch J, Brown A. New vitamin D analogs. Kidney International 2003; 63:S83-7. [8] Széles L, Póliska S, Nagy G et al. Research Resource: Transcriptome Profiling of Genes Regulated by RXR and Its Permissive and Nonpermissive Partners in Differentiating Monocyte-Derived Dendritic Cells. Molecular Endocrinology 2010; 24: 2218-31. DOI: 10.1210/me.2010-0215 [9] Schräder M, Bendik I, Becker-André M et al. Interaction between retinoic acid and vitamin D signaling pathways. J Biol Chem 1993; 268:17830-6. [10] Nishikawa J, Kitaura M, Matsumoto M et al. Difference and similarity of DNA sequence recognized by VDR homodimer and VDR/RXR heterodimer. Nucleic Acids Research 1994; 22:2902-7. [11] Riva L, Yuan S, Yin X et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature 2020; 586:113-9. DOI: 10.1038/s41586-020-2577-1 [12] Daneshkhah A, Agrawal V, Eshein A et al. Evidence for possible association of vitamin D status with cytokine storm and unregulated inflammation in COVID-19 patients. Aging Clin Exp Res 2020; 32:2141-58. DOI: 10.1007/s40520-020-01677-y [13] Cannell JJ, Vieth R, Umhau JC et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134:1129-40. DOI: 10.1017/S0950268806007175 [14] Public Health England, Beyond the data: Understanding the impact of COVID-19 on BAME groups, June 2020. Access valid on 4.11.2020: https://assets.publishing.service.gov.uk /government/uploads/system/uploads/ attachment_data/file/892376/COVID_stakeholder_ engagement_synthesis_beyond_the_data.pdf [15] Mok CK, Ng YL, Ahidjo BA et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. medRxiv 2020; DOI: 10.1101/2020.06.21.162396 [16] Mohammad S, Mishra A, Ashraf MZ. Emerging Role of Vitamin D and its Associated Molecules in Pathways Related to Pathogenesis of Thrombosis. Biomolecules 2019; 9:649. DOI: 10.3390/biom9110649 [17] Bussani R et al., Persistence of viral RNA, pneumocyte syncytia and thrombosis are hallmarks of advanced COVID-19 pathology. EBioMedicine 2020. DOI: 10.1016/j.ebiom.2020.103104 [18] Martineau AR, Forouhi NG. Vitamin D for COVID-19: a case to answer? The Lancet Diabetes & Endocrinology 2020; 8:735-6. DOI:10.1016/S2213-8587(20)30268-0 [19] Faniyi AA, Lugg ST, Faustini SE et al., Vitamin D status and seroconversion for COVID-19 in UK healthcare workers who isolated for COVID-19 like symptoms during the 2020 pandemic, medRxiv preprint DOI: https://doi.org/10.1101/2020.10.05.20206706 [20] Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. Journal of Infection and Public Health 2020; 13:1373-80. DOI: 10.1016/j.jiph.2020.06.021 [21] Grant WB, Lahore H, McDonnell SL et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020; 12:988. DOI: 10.3390/nu12040988 [22] Ling SF, Broad E, Rebecca M et al. Vitamin D Treatment Is Associated with Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study. Access valid on 4.11.2020: https://ssrn.com/abstract=3690902 or DOI:10.2139/ssrn.3690902 [23] Abrishami A, Dalili N, Mohammadi Torbati P et al. Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study. Eur J Nutr 2020. DOI: 10.1007/s00394-020-02411-0 [24] Tomisti L, Pulizzi N, Pafundi PC et al. Comparison Of The 25oh-vitamin D Levels Between Old Patients Hospitalized For Sars-cov-2 Pneumonia And Patients With Other Acute Illnesses: A Retrospective Case-control Study. 23 October 2020, PREPRINT (Version 1) available at Research Square. DOI: 10.21203/rs.3.rs-96491/v1+ [25] Karahan S, Katkat F. Impact of Serum 25(OH) Vitamin D Level on Mortality in Patients with COVID-19 in Turkey. J Nutr Health Aging 2020. DOI: 10.1007/s12603-020-1479-0 [26] Hastie CE, Mackay DF, Ho F, Celis-Morales CA, Katikireddi SV, Niedzwiedz CL et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020; 14:561-5. [27] Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 2020; 32:1195-8. https://doi.org/10.1007/s40520-020-01570-8 [28] Germán B, Wei R, Hener P et al. Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis, JCI Insight 2019; 4: e123390. [29] Satake K, Amano T & Okamoto T. Calcipotriol and betamethasone dipropionate synergistically enhances the balance between regulatory and proinflammatory T cells in a murine psoriasis model. Sci Rep 2019; 9:16322. DOI: 10.1038/s41598-019-52892-1 [30] Pacha O, Sallman MA, Evans SE. COVID-19: a case for inhibiting IL-17? Nat Rev Immunol 2020; 20, 345-6. DOI: 10.1038/s41577-020-0328-z [31] Toell A, Polly P, Carlberg C; All natural DR3-type vitamin D response elements show a similar functionality in vitro. Biochem J 2000; 352: 301-9. DOI: https://doi.org/10.1042/bj3520301 [32] Wishart DS, Feunang YD, Guo AC et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res 2017. DOI: 10.1093/nar/gkx1037. [33] Hernández JL, Nan D, Fernandez-Ayala M et al. Vitamin D Status in Hospitalized Patients With SARS-CoV-2 Infection, The Journal of Clinical Endocrinology & Metabolism 2020. DOI: 10.1210/clinem/dgaa733. [34] Bouadma L, Wiedemann A, Patrier J et al. Immune Alterations in a Patient with SARS-CoV-2-Related Acute Respiratory Distress Syndrome. J Clin Immunol 2020; 40:1082-92. DOI: 10.1007/s10875-020-00839-x [35] RECOVERY Collaborative Group, Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report, NEJM 2020. DOI: 10.1056/NEJMoa2021436. [36] Tomazini BM, Maia IS, Cavalcanti AB et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA 2020; 324:1307-16. DOI: 10.1001/jama.2020.17021 [37] Grein J, Ohmagari N, Shin D et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM 2020; 382:2327-36. DOI: 10.1056/NEJMoa2007016 [38] Chun RF, Liu PT, Modlin RL et al. Impact of vitamin D on immune function: lessons learned from genome-wide analysis, Front Physiol 2014; 5:151. DOI: 10.3389/fphys.2014.00151 [39] Visner GA, Liu F, Bizargity P et al. Pirfenidone Inhibits T-Cell Activation, Proliferation, Cytokine and Chemokine Production, and Host Alloresponses. Transplantation 2009; 88:330-8 DOI: 10.1097/TP.0b013e3181ae3392 [40] Seifirad S, Pirfenidone: A novel hypothetical treatment for COVID-19. Med Hypotheses 2020; 144:110005. DOI: 10.1016/j.mehy.2020.110005 [41] Lopez-de la Mora DA, Sanchez-Roque C, Montoya-Buelna M et al. Role and New Insights of Pirfenidone in Fibrotic Diseases. Int J Med Sci 2015; 12:840-7. DOI: 10.7150/ijms.11579 [42] Tleyjeh IM et al. Efficacy and safety of tocilizumab in COVID-19 patients: A living systematic review and meta-analysis. Clinical Microbiol Infect 2020. DOI: 10.1016/j.cmi.2020.10.036 [43] de Mendonça Oliveira L, Mouradian Emidio Teixeira F, Notomi Sato M. Impact of Retinoic Acid on Immune Cells and Inflammatory Diseases. Mediators of Inflammation 2018. DOI: 10.1155/2018/3067126 [44] U.S. Food & Drug Administration. Authorization Letter to Eli Lilly and Company. Attention: Christine Phillips, PhD, RAC Advisor Global Regulatory Affairs - US. 10 November 2020. Access valid on 27.11.2020: https://www.fda.gov/ media/143602/download [45] U.S. Food & Drug Administration. Authorization Letter to Regeneron Pharmaceuticals, Inc. Attention: Yunji Kim, PharmD Director, Regulatory Affairs. 21 November 2020. Access valid on 27.11.2020: https://www.fda.gov/ media/143891/download 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. Authors’ affiliations: 1 Jagiellonian University Medical College, Faculty of Medicine, 4th year Medical Student , Cracow, Poland Corresponding author: Grzegorz Piotr Waliszczak 4th year Medical Student Jagiellonian University Medical College Faculty of Medicine ul. Św. Anny 12 31-008 Kraków 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 |
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