Do vitamin D levels or supplementation play A role in COVID-19 outcomes?—a narrative review

Introduction

Background

The outbreak of the novel coronavirus disease 2019 (COVID-19) at the dawn of 2020 was soon followed by its rapid spread worldwide (1). Hitherto, COVID-19 has claimed more than 6.9 million lives worldwide and has left a significant proportion of the population with post-COVID sequelae (2,3). The disease has been more severe in the elderly and those with pre-existing comorbidities (4,5).

Rationale and knowledge gap

Hypovitaminosis D has been proposed as a risk factor for increased susceptibility to COVID-19 (6,7). Ample clinical evidence derived from observational and ecological studies suggest that vitamin D deficiency increases the risk for severe disease and mortality with COVID-19 (8-10). Likewise, vitamin D supplementation has been proposed as an effective means for reducing the risk of COVID-19 infection and severity and thereby improve clinical outcomes (11-16). Nevertheless, available data are inconsistent and most of the randomized controlled trials (RCTs) suggest that vitamin D supplementation does not improve COVID-19-related health outcomes (17-22). Besides, available systematic reviews and meta-analyses also reveal conflicting results (23-29).

Objective

Considering the heterogeneity in the available clinical evidence, we planned to undertake a narrative review and provide a precise summary of the role of vitamin D in COVID-19. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-23-113/rc).

Methods

PubMed/MEDLINE database was searched by one of the authors (R.P.) from inception till September 30, 2023 using the following search strategy: “Vitamin D”[Mesh] AND “COVID-19”[Mesh]. The search was restricted to the English language only. The initial search revealed 900 results. Thereafter, titles and abstracts were scanned, and commentaries, letters, and editorials were excluded. Relevant observational studies and clinical trials/RCTs were full-text assessed, and pertinent data were extracted for this narrative review.

The search strategy has been summarized in Table 1.

Narrative review

25-hydroxyvitamin D [25(OH)D] levels and incidence of COVID-19

Ever since the inception of the pandemic, it had been hypothesized that higher latitude, nutritional risk of vitamin D deficiency and lack of fortification of food with vitamin D could increase the risk of COVID-19 infection and disease severity (30,31). Subsequently, multiple studies have been published to investigate the link between vitamin D levels and the risk of COVID-19. Notably, most of the studies are observational in nature.

In a retrospective cohort study conducted at an urban academic medical center in Chicago, the chances of testing positive for COVID-19 was associated with likely deficient vitamin D status [relative risk =1.77, 95% confidence interval (CI): 1.12–2.81, P=0.02] compared with likely sufficient vitamin D status (6). Similarly, in another retrospective observational analysis that included 191,779 subjects from 50 states of the United States of America, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity rate was 9.3%. The SARS-CoV-2 positivity rate was higher in the 39,190 patients with “deficient” vitamin D status [25(OH)D <20 ng/mL] (12.5%) than in the 27,870 patients with “adequate” vitamin D status (30–34 ng/mL) (8.1%) and the 12,321 patients with values ≥55 ng/mL (5.9%). The association between lower SARS-CoV-2 positivity rates and higher circulating 25(OH)D levels remained significant in a multivariable logistic regression model even after adjusting for multiple demographic factors [adjusted odds ratio (OR) 0.984 per ng/mL increment in 25(OH)D, 95% CI: 0.983–0.986, P<0.001] (32). In another observational study conducted by our group, the prevalence of vitamin D deficiency in non-severe COVID-19 patients admitted to a tertiary care hospital was 97% (7); it is noteworthy that a cross-sectional survey conducted in the same region and the same ethnic population from December 2016 to May 2018 had revealed a prevalence of hypovitaminosis D of 65.4% (33).

Data from systematic reviews and meta-analyses also suggest an inverse association between vitamin D levels and the risk of acquiring COVID-19 (34-36). Notably, in a meta-analysis that included 76 studies pooling data from 1,976,099 patients, vitamin D deficiency/insufficiency was associated with an increased risk of developing COVID-19 with an odds ratio (OR) of 1.46 (95% CI: 1.28–1.65, P<0.0001). No significant publication bias was observed in the meta-analysis (36).

Although available data favors an association between low vitamin D levels and risk of acquiring COVID-19, prophylactic vitamin D supplementation has not been consistently shown to reduce the risk of contracting the disease. In a double-blinded parallel RCT, the SARS-CoV-2 infection risk was lower in the vitamin D-treated group than in the control group (37). However, in the phase 3 CORONAVIT RCT, 6,200 participants from the United Kingdom (UK) were recruited to evaluate the effectiveness of a test-and-treat approach to identify and treat vitamin D deficiency to prevent COVID-19 and other acute respiratory tract infections. The results suggested that vitamin D replacement did not reduce the risk of all-cause acute respiratory infections or COVID-19; nevertheless, the enrolled cohorts had a high baseline prevalence of vitamin D insufficiency (38). Likewise, in a quadruple blinded, randomized placebo-controlled trial conducted in Norway, 34,601 adults were randomized to receive 5 mL/day of cod liver oil (equivalent to 10 µg) or placebo for 6 months. Supplementation with cod liver oil did not reduce the incidence of SARS-CoV-2 infection, serious COVID-19, or other acute respiratory infections compared with placebo (39). Similarly, healthcare workers in the USA receiving 5,000 IU daily of cholecalciferol for nine months did not have a statistically significant difference in the incidence of COVID-19 influenza-like illness than those who did not receive the same (40). A meta-analysis of RCTs failed to demonstrate the role of vitamin D supplementation in preventing COVID-19 (28).

Thus, to summarize, based on the aforementioned evidence, it appears that hypovitaminosis D might be associated with a higher risk of acquiring COVID-19. On the contrary, data with regard to the efficacy of vitamin D supplementation on the reduction of risk of COVID-19 is conflicting.

25(OH)D levels and COVID-19-related health outcomes

Apart from increasing the risk of contracting COVID-19, low vitamin D levels have been linked to an increased risk of severe COVID-19, hospitalization and/or mortality. In a retrospective case-control study from North West England that included 80,670 individuals with test results for serum 25(OH)D between April 1, 2020 and January 29, 2021, 1,808 were admitted to the hospital with COVID-19. Although hypovitaminosis D was not associated with an increased risk of mortality, patients with a serum 25(OH)D <20 ng/mL were at a 2.3–2.4 times higher risk of requiring hospital admission for COVID-19 (41). Likewise, another retrospective observational study from Madrid, Spain found no correlation between vitamin D levels and COVID-19 mortality; nevertheless, vitamin D deficiency [25(OH)D <20 ng/mL] was correlated with an increased risk of hospital admission and the need for critical care (42). In another study that included 105 patients aged ≥65 years presenting with symptoms consistent with COVID-19, vitamin D deficiency (≤12 ng/mL) was associated with higher peak D-dimer levels and higher incidence of non-invasive ventilation support and high dependency unit admission. It is noteworthy that vitamin D status did not predict mortality (8).

Ilie et al. showed an inverse relationship between the mean levels of vitamin D in various European countries and the mortality caused by COVID-19 (43). Similarly, Marik et al. compared fatality rate for COVID-19 in Northern (>40° N latitude) vs. Southern states (6.0% vs. 3.5%, P<0.001) in the US and found a higher mortality rate (44). In a retrospective study from Germany, low serum 25(OH)D levels among COVID-19 patients were associated with invasive mechanical ventilation and/or death (10). In yet another study, vitamin D deficiency was associated with more severe lung involvement, longer disease duration and risk of death, in elderly COVID-19 patients (45). Similarly, another study published from the United Arab Emirates (UAE) that had included 464 patients with COVID-19, serum 25(OH)D levels <12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and mortality (46). Other studies have also shown an inverse association between vitamin D levels and COVID-19 disease severity (47-53).

However, not all studies have yielded consistent results; on the contrary, some studies have shown a lack of association between vitamin D levels and COVID-19 levels (54-57). A mendelian randomization study that had included 443,734 individuals, involving 401,460 participants from the UK Biobank, suggested no association between serum 25(OH)D levels and COVID-19 severity; unfortunately, the 25(OH)D levels were measured on samples obtained many years earlier (57).

Data from systematic reviews and meta-analysis are also conflicting. Few recently published meta-analyses have reported a significant association between low serum 25(OH)D level and an increased risk of mortality, intensive care unit (ICU) admission, and need for invasive or non-invasive ventilation (26,36,58). However, a systematic review and meta-analysis that included 31 peer-reviewed observational studies failed to show any statistically significant difference between serum 25(OH)D level <20 ng/mL and COVID-19-related health outcomes, notably, mortality, ICU admission, invasive mechanical or non-invasive ventilation requirement or SARS-CoV-2 positivity status (59).

Considering the heterogeneity in the results of the available meta-analyses, it is prudent to mention that many studies included in these meta-analyses suffer from certain limitations, notably, inappropriate selection of controls, presence of confounding covariates, marked variability of assays used to measure 25(OH)D levels, as well as cutoffs considered to define low vitamin D levels. Besides, severe hypoalbuminemia and the direct effect of acute illness could imply reverse causality resulting in low levels of 25(OH)D in COVID-19 patients with severe outcomes requiring hospital admission (60). The role of confounding factors in modifying the association between vitamin D status and COVID-19-related health outcomes has been eloquently depicted in the recently published systematic review and meta-analysis by Bignardi et al. The authors included 21 observational studies and observed that the overall mortality was significantly higher in patients who were vitamin D deficient as compared to those who were vitamin D sufficient [risk ratio (RR) =1.49, 95% CI: 1.15–1.83, P<0.001]. Subsequently, they performed a subgroup analysis including only studies adjusted for age and at least one more confounding factor (obesity, hypertension, diabetes, chronic kidney disease, or cardiovascular disease) that revealed no association between low vitamin D levels and death (RR =1.82, 95% CI: 0.61–3.04 for cutoff levels of <10 or <12 ng/mL and RR =1.56, 95% CI: 0.80–2.31 for cutoff levels of <20 or <25 ng/mL). In contrast, the analysis including studies not mentioning adjustment for confounders, showed an increased risk of death for low vitamin D levels (RR =1.72, 95% CI: 1.09–2.36 for cutoff levels of <10 or <12 ng/mL and RR =1.48, 95% CI: 1.23–1.72 for cutoff levels of <20 or <25 ng/mL) (61).

Thus, to conclude, the majority of the available literature, based only on observational studies, hints towards a negative association between 25(OH)D levels and COVID-19 severity, nevertheless, the data is conflicting and causality remains to be established.

Vitamin D supplementation and COVID-19-related health outcomes

With the inception of the pandemic, numerous retrospective, quasi-experimental and non-randomized interventional studies have been conducted exploring the effect of vitamin D supplementation on COVID-19-related health outcomes (11,12,14,15,54,62-71). However, hitherto, only 20 randomized clinical trials have been published looking into the effect of COVID-19 supplementation and hardcore clinical outcomes in COVID-19 patients, notably, disease severity, the requirement of hospital/ICU admission, oxygen requirement, need for non-invasive/invasive ventilation, and/or mortality (13,16-22,72-84). In addition, two randomized clinical trials have looked into the effect of vitamin D supplementation solely on the rate of SARS-CoV-2 RNA negativity (85,86).

The study designs and outcomes of all the relevant clinical trials have been summarized in Table 2. Of note, the majority of the clinical trials does not show any significant difference in clinical outcomes between the intervention (vitamin D supplementation) and control/placebo group (17-22,76,78-84). Only three randomized trials showed improvement in clinical outcomes in the intervention arm as compared to the control/placebo group (13,73,74). Another open-label randomized controlled single-blind clinical trial conducted in the pediatric population (patient age being 1 month to 17 years) showed that vitamin D supplementation may decrease the risk of COVID-19 progression and death, however, the results failed to reach statistical significance (87). On the other hand, clinical trials comparing high-dose vs. low-dose vitamin D supplementation have consistently shown improved outcomes in the high-dose group (16,72,75,77); nevertheless, all these studies did not have a third placebo arm for comparison.

The observed differences in the outcomes of RCTs of vitamin D supplementation in COVID-19 may be attributed to variable study designs in terms of mode of administration, baseline vitamin D status, type and doses of vitamin D used and clinical outcomes observed. Of note, studies have been conducted with cholecalciferol, calcifediol or calcitriol and varying doses ranging from standard supplementation to mega doses (60). In addition, the interaction of vitamin D and corticosteroids has been implicated as a potential explanation for the divergent results reported in the literature with regard to the effects of vitamin D supplementation on COVID-19-related clinical outcomes (88). In this regard, dexamethasone treatment was observed to mitigate the adverse effects of hypovitaminosis D in hospitalized COVID-19 patients (89). Furthermore, the few available aforementioned clinical trials designed to examine the effect of vitamin D supplementation on COVID-19 outcomes are likely insufficiently powered to assure a balance of corticosteroid use between study arms (88).

The majority of the data from meta-analyses suggest significant benefits of vitamin D supplementation in terms of COVID-19 severity and mortality, however, hitherto, most of the meta-analyses have included both RCTs and observational studies. A meta-analysis conducted by our group in the early days of the pandemic that had pooled 13 studies (10 observational studies, 3 RCTs) showed that vitamin D use in COVID-19 was significantly associated with reduced ICU admission/mortality (OR =0.41, 95% CI: 0.20–0.81, P=0.01). On subgroup analysis, only vitamin D supplementation post-COVID-19 diagnosis was found to be associated with improved clinical outcomes and not in those who had received vitamin D before COVID-19 diagnosis (27). Another meta-analysis that had included 13 studies (6 RCTs, 7 non-randomized intervention studies) also showed that vitamin D supplementation was significantly associated with a reduced risk of ICU admission (RR =0.35, 95% CI: 0.20–0.62) and mortality (RR =0.46, 95% CI: 0.30–0.70) (90). In yet another meta-analysis that included only six RCTs, vitamin D supplementation was shown to reduce COVID-19 severity but had no effect on disease mortality (91). Shah et al. conducted a meta-analysis of seven systematic reviews, the majority of whom had included both RCTs and observational/non-randomized interventional studies. Pooled analysis showed that vitamin D supplementation reduces the risk of mortality, need for intensive care and mechanical ventilation (92).

A Cochrane living systematic review that had included three RCTs concluded that the evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 was very uncertain (93). A systematic review and meta-analysis that had included only randomized clinical trials (n=9) reported no significant difference in length of hospital stay (mean difference =−1.05 days, 95% CI: −2.63 to 0.54, P=0.19) or mortality (RR =0.93, 95% CI: 0.57–1.52, P=0.78) compared to control. Based solely on systematic review, the authors concluded that high-dose vitamin D supplementation might have potential benefits in reducing hospital stays and ICU admission in COVID-19 patients compared to low-dose vitamin D, however, a formal meta-analysis was not conducted considering the limitation in the number of the studies (94). Likewise, another systematic review and meta-analysis including only RCTs showed that vitamin D supplementation significantly reduced ICU admission (RR =0.59, 95% CI: 0.41–0.84, P=0.003) compared to control; however, vitamin D supplementation had no significant effects on the need for ventilation, oxygen therapy or length of hospital stay or mortality. Besides, compared to control, vitamin D supplementation did not result in any significant change in biochemical parameters, notably, interleukin-6 (IL-6), C-reactive protein, lactate dehydrogenase, calcium, creatinine, d-dimer, neutrophil count, lymphocyte count, platelet count, or leucocytes (29). Finally, a recently published meta-analysis of only RCTs showed that vitamin D supplementation could significantly reduce the rates of ICU admission (RR =0.63, 95% CI: 0.44–0.89) and mechanical ventilation (RR =0.58, 95% CI: 0.39–0.84), but had no statistically significant effect on mortality (28).

To summarize, most of the available evidence from clinical trials suggest that vitamin D supplementation does not improve clinical outcomes in patients with COVID-19 as compared to no supplementation. However, the available data, as narrated, is heterogeneous and further research is required in this field. Accordingly, the American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinologists (AACE), Endocrine Society, European Calcified Tissue Society (ECTS), National Osteoporosis Foundation (NOF), and International Osteoporosis Foundation (IOF) in their joint guidance recommend that most adults 19 years and older obtain between 400–1,000 IU of vitamin D daily from food and/or with supplements as recommended by Institute of Medicine (IOM) guidelines (95,96). The joint guidance clearly states that the current data do not provide any evidence that vitamin D supplementation help prevent or treat COVID-19 infection (96).

Effects of vitamin D supplementation in patients with severe COVID-19

Most of the aforementioned RCTs that have evaluated the effects of vitamin D supplementation on COVID-19-related health outcomes have included hospitalized patients; in some of these studies, the severity of COVID-19 has not been clearly mentioned. Few studies have specifically included COVID-19 patients with moderate-to-severe or severe disease (17,18,20,21,72,77,79). Most of these studies did not show any beneficial effect of vitamin D supplementation on COVID-19-related health outcomes (17,18,20,21,79). Only two studies that have compared high-dose vitamin D vs. low-dose/moderate-dose vitamin D have shown improved clinical outcomes in the high-dose group (72,77); however, as mentioned above, these two studies did not include a placebo arm.

Vitamin D supplementation and COVID-19 vaccine efficacy

Vitamin D deficiency has been reported to be associated with the impaired development of antigen-specific responses following vaccination. In this context, few recent studies have shown that adequate vitamin D status may improve the immune response to SARS-CoV-2 messenger RNA vaccines (97,98). In a retrospective study, 119 consecutive healthcare-workers without a previous history of acute COVID-19 or presence of anti-SARS-CoV-2 immunoglobulins were immunized with two doses of Comirnaty-vaccine from January to February 2021. Serum 25(OH)D levels were measured at time of first-immunization. Immune response was evaluated at time 0 (T0), before the first-dose; T1, time of second-dose (21 days after T0); T2, T3, T4 at 1, 5 and 9 months after T1, respectively. Vitamin D deficiency, defined as 25(OH)D <20 ng/mL was observed in 29 subjects (24.8%). In those with vitamin D deficiency, the authors reported a non-significant trend towards lower antibody-titers at T3, and significantly lower titers at T4 as compared to those without hypovitaminosis D. A positive correlation between 25(OH)D levels and antibody-titers at T4 (P=0.043) was found. In multiple linear-regression analysis, 25(OH)D deficiency and older-age emerged as negative independent factors associated with antibody titer at T4 (P=0.026, P=0.004; respectively) (99). On the contrary, a recently published study found no significant association between 25(OH)D status and SARS-CoV-2 antibody response after COVID-19 vaccination in nursing home residents and staffs (100).

Three sub-studies nested within the CORONAVIT RCT investigated the effects of offering vitamin D supplements at a dose of 800 or 3,200 IU/day vs. no offer on the risk of acute respiratory infections in UK adults with circulating 25(OH)D concentrations <75 nmol/L. It was observed that vitamin D supplementation did not influence the risk of breakthrough SARS-CoV-2 infection in vaccinated participants. Neither did it influence IgGAM anti-spike titers, neutralizing antibody titers, or interferon-gamma (IFN-γ) concentrations in the supernatants of S-peptide-stimulated whole blood (101). In another recently published study, volunteers being vaccinated with either Pfizer-BioNTech or Sinovac vaccines were randomized to receive either cholecalciferol (3,200 IU per day for 2 months) or no treatment. They were followed up twice at an interval of 28 days. There was no significant difference in immunoglobulin M levels between the two groups. However, the serum immunoglobulin G values were significantly higher in the vitamin D group as compared to control group at the 2^nd and 3^rd follow-up visits. Besides, in the vitamin D group, a positive and moderately strong correlation between serum immunoglobulin G and 25(OH)D levels was observed at the final visit (102).

Pathophysiological mechanisms implicated in the association between vitamin D and COVID-19

Multiple mechanisms have been hypothesized to explain the possible association between vitamin D and COVID-19 outcomes (27). First, vitamin D promotes the induction of cathelicidin (LL-37) and defensins. Cathelicidin (LL-37) impedes viral infection at multiple steps and is effective against both enveloped and non-enveloped viruses (103). In addition, higher levels of LL-37 in serum correspond to lower expression of interleukin-17 (IL-17). In turn, IL-17 is involved in the pathophysiology of COVID-19, including the risk of thrombosis and acute respiratory distress syndrome (ARDS). Thus, COVID-19 severity and acute complications could partly be explained by the up regulation of IL-17 in the setting of hypovitaminosis D (27).

Second, vitamin D promotes up regulation of anti-inflammatory cytokines such as IL-10, and down regulation of proinflammatory cytokines such as IL-1, IL-6 and tumor-necrosis factor-alpha. Thus, a shift from a proinflammatory to an anti-inflammatory milieu can reduce risk of the cytokine storm in COVID-19 (104).

Third, modulation of the renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme 2 (ACE2) has been proposed. Vitamin D induces the physiological ACE2/Ang [1–7] axis activity, thereby increasing the expression and concentration of ACE2 and Ang [1–7]. ACE2/Ang [1–7] system plays an important anti-inflammatory and antioxidant role in protecting the lung against ARDS; indeed, ACE2 has been protective against lethal avian influenza A H5N1 infection (105-107). Thus, up regulation of the ACE2/Ang [1–7] system could potentially protect against acute lung injury and ARDS (27,108).

In addition, certain alternative hydroxyderivatives of vitamin D have been proposed to exert anti-SARS-CoV-2 effects. Apart from the classical canonical pathway wherein vitamin D is activated through hydroxylation at C25 to produce 25(OH)D and then to its active moiety 1,25(OH)₂D following hydroxylation at C1 (109), certain alternative non-canonical pathways of vitamin D activation have been newly discovered. Metabolism of vitamin D by cytochrome P450scc (CYP11A1) generates novel D3-hydroxyderivatives, notably, 20-hydroxyvitamin D₃ [20(OH)D₃], 22(OH)D₃, 20,23(OH)₂D₃, 20,22(OH)₂D₃, 1,20(OH)₂D₃,1,20,23(OH)₃D₃, and 17,20,23(OH)₃D3. The predominant metabolite in human serum is 20(OH)D₃ with a relative concentration ~20 times lower than 25(OH)D₃ (110). Besides, isomerization of previtamin D3 by ultraviolet B radiation generates tachysterol₃ (T₃) and lumisterol₃ (L₃). CYP11A1 and CYP27A1 hydroxylate T₃ producing 20S-hydroxytachysterol₃ [20S(OH)T₃] and 25(OH)T₃, respectively (111). In addition, novel hydroxyderivatives of L₃ as a result of action of CYP11A1 have also been described. Like 20(OH)D₃, 20S(OH)T₃, 25(OH)T₃ and hydroxyderivatives of L₃ are biologically active.

In the context of COVID-19, it has been hypothesized that CYP11A1-derived vitamin D and lumisterol hydroxymetabolites exert anti-inflammatory and antioxidant effects, possibly blunting the cytokine storm induced by SARS-CoV-2. In addition, the non-receptor mediated actions of vitamin D and related lumisterol hydroxymetabolites possibly include interactions with the active sites of SARS-CoV-2 transcription machinery enzymes (M^pro; main protease and RdRp; RNA dependent RNA polymerase). Furthermore, these metabolites might interfere with the binding of SARS-CoV-2 receptor binding domain region of the spike protein with ACE2 by interacting with ACE2 and cellular serine protease (TMPRSS2). These interactions might result in the conformational and dynamical motion changes in TMPRSS2 that might affect the priming of the SARS-CoV-2 spike proteins (112,113).

Keeping in mind the potential beneficial role of novel CYP11A1-derived hydroxyderivates of vitamin D, questions have been raised regarding the effectiveness of orally administered cholecalciferol in COVID-19. Cholecalciferol administered orally during the passage through the liver is hydroxylated to 25(OH)D₃, which is not recognized by CYP11A. This likely results in 30 times lower concentration of 20(OH)D₃ in serum in comparison with 25(OH)D₃. CYP11A1, on the other hand is predominantly expressed in the adrenals, gonads and placenta in addition to its noticeable expression in the brain, gastrointestinal tract, immune systems, and skin (114). Thus, it has been hypothesized that vitamin D, administered parenterally (intramuscular) might result in higher concentration of 20(OH)D and possibly exert greater anti-SARS-CoV-2 activity (115). Nevertheless, hitherto, majority of the RCTs with vitamin D in the context of COVID-19 have used oral rather than parenteral vitamin D.

Despite the well-established role of vitamin D as a regulator of the immune system, firm conclusions cannot be drawn about a putative beneficial role of vitamin D in COVID-19. Patients with severe COVID-19 display a deficient vitamin D response and an enrichment of vitamin-D-repressed genes including pro-inflammatory cytokines. A lack of vitamin D-mediated regulation of pro-inflammatory cytokines might augment the cytokine storm observed in certain subgroups of patients with severe COVID-19. These discoveries suggest that hypovitaminosis D is unlikely to be a driving factor for the development of a severe COVID-19 (116).

Role of vitamin D in long COVID

Like post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are ever-increasing reports of persistent and long-term effects on human health after acute COVID-19. Accordingly, the term long COVID has been coined which is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. The common symptoms of long COVID can include fatigue, shortness of breath and cognitive dysfunction (117). Whether vitamin D is associated with long COVID has not been explored in details.

In a case-control study, 120 COVID-19 survivors were compared with an equal number of age- and sex-matched healthy controls at least 3 months after recovery. Although the serum calcium levels did not differ between the 2 groups, healthy controls had significantly higher 25(OH)D levels (40.32±11.76 ng/mL) than COVID-19 survivors (23.22±8.45 ng/mL) (118). In a recently reported retrospective study, the authors compared 50 patients each with and without long COVID-19 matched for age, sex, comorbidities and previous COVID-19 severity. It was observed that subjects with long COVID had significantly lower vitamin D levels than those without (20.1 vs. 23.2 ng/mL, P=0.03). On multiple regression analyses, lower 25(OH)D levels at follow-up were the only variable significantly associated with long COVID in the cohort (OR =1.09, 95% CI: 1.01–1.16, P=0.008) (119).

Risk factors associated with long COVID-19 include elevated including D-dimer, IL-6, C-reactive protein, procalcitonin, and neutrophils count (120,121). A study conducted in western Mexico involving 22 vitamin D supplemented COVID-19 outpatients [mean 25(OH)D =22.4 ng/mL] and 20 non-supplemented patients [mean 25(OH)D =23.4 ng/mL] found that d-dimer concentrations were not significantly different (74). A study from Saudi Arabia also reported no significant effect on d-dimer concentrations with vitamin D supplementation of 69 COVID-19 patients (16). Additionally, a high-dose vitamin D supplementation study conducted in Turkey involving 95 hospitalized COVID-19 patients found that increasing mean 25(OH)D concentration from 23 to 35 ng/mL had no significant effect on ferritin or d-dimer concentrations (68). Thus, the aforementioned studies indirectly suggests that vitamin D supplementation has not been shown to reduce biomarkers that have been linked to the subsequent development of long COVID (121).

The role of vitamin D supplementation in the prevention or management of long COVID is hitherto unknown. A pilot double-blind clinical trial explored the effects of cholecalciferol supplementation at a dose of 2,000 IU/day for 6 weeks vs. placebo on muscle status in old patients recovering from COVID-19 infection. Vitamin D supplementation led to a significant reduction in creatine kinase compared to placebo. Physical status, as assessed by 6-minute walk test and handgrip strength and lung function as assessed by spirometry did not change significantly with vitamin D supplementation (122). In a post hoc exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial, the authors investigated the effects of a single dose of 200,000 IU of cholecalciferol in hospitalized patients with moderate-to-severe COVID-19. Discharged patients were followed for up to 1 year and evaluated by telephone interviews at 6 and 12 months. No significant differences between groups were observed for fever, cough, fatigue, myalgia, joint pain, runny nose, nasal congestion, sore throat, hypertension, diabetes, cardiovascular disease, rheumatic disease, asthma, chronic obstructive pulmonary, chronic kidney disease, quality of life, and new or persistent symptoms up to 1-year of follow-up (123). Thus, vitamin D possibly does not have any palliative role in post-COVID-19 survivors.

Thus, although the role of vitamin D supplementation in the prevention of long COVID remains controversial, vitamin D deficiency and insufficiency has been reported to be very high in post-COVID-19 survivors (124). Thus, in the absence of further available evidence, it is suggested that 25(OH)D levels may be estimated in post-COVID-19 patients, and vitamin D may be supplemented accordingly (3).

Conclusions

Available data, primarily based on observational and retrospective studies, suggest an association between hypovitaminosis D and increased risk of acquiring SARS-CoV-2 infection and poor COVID-19 outcomes. Nevertheless, RCTs have failed to consistently demonstrate that vitamin D supplementation either reduces the incidence of COVID-19 or improves COVID-19-related clinical outcomes, even in subjects with severe vitamin D deficiency. Hence, based on the available evidence, routine vitamin D supplementation to prevent or treat COVID-19 should not be encouraged. Vitamin D supplementation should be continued as per the standard IOM guidelines.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Prateek Lohia and Shweta Kapur) for the series “Latest Research on COVID-19” published in Annals of Palliative Medicine. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-23-113/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-23-113/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-23-113/coif). The series “Latest Research on COVID-19” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Pal R, Yadav U. COVID-19 Pandemic in India: Present Scenario and a Steep Climb Ahead. J Prim Care Community Health 2020;11:2150132720939402. [Crossref] [PubMed]
2. Banerjee M, Pal R, Dutta S. Risk of incident diabetes post-COVID-19: A systematic review and meta-analysis. Prim Care Diabetes 2022;16:591-3. [Crossref] [PubMed]
3. Pal R, Joshi A, Bhadada SK, et al. Endocrine Follow-up During Post-Acute COVID-19: Practical Recommendations Based on Available Clinical Evidence. Endocr Pract 2022;28:425-32. [Crossref] [PubMed]
4. Pal R, Bhadada SK. COVID-19 and non-communicable diseases. Postgrad Med J 2020;96:429-30. [Crossref] [PubMed]
5. Bhadada SK, Pal R. Diabetes Mellitus and COVID-19. In: Bhadada SK, Mittal N, Katare OP, Garg V, editors. COVID-19: Effects in Comorbidities and Special Populations. BENTHAM SCIENCE PUBLISHERS; 2022 [cited 2022 Dec 13]. p. 29–50. Available from: https://www.eurekaselect.com/node/208287
6. Meltzer DO, Best TJ, Zhang H, et al. Association of Vitamin D Status and Other Clinical Characteristics With COVID-19 Test Results. JAMA Netw Open 2020;3:e2019722. [Crossref] [PubMed]
7. Pal R, Ram S, Zohmangaihi D, et al. High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study. Front Med (Lausanne) 2021;7:590805. [Crossref] [PubMed]
8. Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes for hospitalised older patients with COVID-19. Postgrad Med J 2021;97:442-7. [Crossref] [PubMed]
9. Mariani J, Giménez VMM, Bergam I, et al. Association Between Vitamin D Deficiency and COVID-19 Incidence, Complications, and Mortality in 46 Countries: An Ecological Study. Health Secur 2021;19:302-8. [Crossref] [PubMed]
10. Radujkovic A, Hippchen T, Tiwari-Heckler S, et al. Vitamin D Deficiency and Outcome of COVID-19 Patients. Nutrients 2020;12:2757. [Crossref] [PubMed]
11. Annweiler C, Hanotte B, Grandin de l'Eprevier C, et al. Vitamin D and survival in COVID-19 patients: A quasi-experimental study. J Steroid Biochem Mol Biol 2020;204:105771. [Crossref] [PubMed]
12. Annweiler G, Corvaisier M, Gautier J, et al. Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study. Nutrients 2020;12:3377. [Crossref] [PubMed]
13. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, et al. Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study J Steroid Biochem Mol Biol 2020;203:105751. [Crossref] [PubMed]
14. Giannini S, Passeri G, Tripepi G, et al. Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study. Nutrients 2021;13:219. [Crossref] [PubMed]
15. Ling SF, Broad E, Murphy R, et al. High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study. Nutrients 2020;12:3799. [Crossref] [PubMed]
16. Sabico S, Enani MA, Sheshah E, et al. Effects of a 2-Week 5000 IU versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate Covid-19: A Randomized Clinical Trial. Nutrients 2021;13:2170. [Crossref] [PubMed]
17. Murai IH, Fernandes AL, Sales LP, et al. Effect of a Single High Dose of Vitamin D3 on Hospital Length of Stay in Patients With Moderate to Severe COVID-19: A Randomized Clinical Trial. JAMA 2021;325:1053-60. [Crossref] [PubMed]
18. Murai IH, Fernandes AL, Antonangelo L, et al. Effect of a Single High-Dose Vitamin D3 on the Length of Hospital Stay of Severely 25-Hydroxyvitamin D-Deficient Patients with COVID-19. Clinics (Sao Paulo) 2021;76:e3549. [Crossref] [PubMed]
19. Maghbooli Z, Sahraian MA, Jamalimoghadamsiahkali S, et al. Treatment With 25-Hydroxyvitamin D(3) (Calcifediol) Is Associated With a Reduction in the Blood Neutrophil-to-Lymphocyte Ratio Marker of Disease Severity in Hospitalized Patients With COVID-19: A Pilot Multicenter, Randomized, Placebo-Controlled, Double-Blinded Clinical Trial. Endocr Pract 2021;27:1242-51. [Crossref] [PubMed]
20. Bychinin MV, Klypa TV, Mandel IA, et al. Effect of vitamin D3 supplementation on cellular immunity and inflammatory markers in COVID-19 patients admitted to the ICU. Sci Rep 2022;12:18604. [Crossref] [PubMed]
21. Cannata-Andía JB, Díaz-Sottolano A, Fernández P, et al. A single-oral bolus of 100,000 IU of cholecalciferol at hospital admission did not improve outcomes in the COVID-19 disease: the COVID-VIT-D-a randomised multicentre international clinical trial. BMC Med 2022;20:83. [Crossref] [PubMed]
22. Mariani J, Antonietti L, Tajer C, et al. High-dose vitamin D versus placebo to prevent complications in COVID-19 patients: Multicentre randomized controlled clinical trial. PLoS One 2022;17:e0267918. [Crossref] [PubMed]
23. Ben-Eltriki M, Hopefl R, Wright JM, et al. Association between Vitamin D Status and Risk of Developing Severe COVID-19 Infection: A Meta-Analysis of Observational Studies. J Am Nutr Assoc 2022;41:679-89. [Crossref] [PubMed]
24. Hu Y, Kung J, Cave A, et al. Effects of Vitamin D Serum Level on Morbidity and Mortality in Patients with COVID-19: A Systematic Review and Meta-Analysis. J Pharm Pharm Sci 2022;25:84-92. [Crossref] [PubMed]
25. Kümmel LS, Krumbein H, Fragkou PC, et al. Vitamin D supplementation for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. Front Immunol 2022;13:1023903. [Crossref] [PubMed]
26. Wang Z, Joshi A, Leopold K, et al. Association of vitamin D deficiency with COVID-19 infection severity: Systematic review and meta-analysis. Clin Endocrinol (Oxf) 2022;96:281-7. [Crossref] [PubMed]
27. Pal R, Banerjee M, Bhadada SK, et al. Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis. J Endocrinol Invest 2022;45:53-68. [Crossref] [PubMed]
28. Meng J, Li X, Liu W, et al. The role of vitamin D in the prevention and treatment of SARS-CoV-2 infection: A meta-analysis of randomized controlled trials. Clin Nutr 2023;42:2198-206. [Crossref] [PubMed]
29. Zaazouee MS, Eleisawy M, Abdalalaziz AM, et al. Hospital and laboratory outcomes of patients with COVID-19 who received vitamin D supplementation: a systematic review and meta-analysis of randomized controlled trials. Naunyn Schmiedebergs Arch Pharmacol 2023;396:607-20. [Crossref] [PubMed]
30. Tyrovolas S, Tsiampalis T, Morena M, et al. COVID-19 Mortality in Europe, by Latitude and Obesity Status: A Geo-Spatial Analysis in 40 Countries. Nutrients 2022;14:471. [Crossref] [PubMed]
31. Pedrosa LFC, Barros ANAB, Leite-Lais L. Nutritional risk of vitamin D, vitamin C, zinc, and selenium deficiency on risk and clinical outcomes of COVID-19: A narrative review. Clin Nutr ESPEN 2022;47:9-27. [Crossref] [PubMed]
32. Kaufman HW, Niles JK, Kroll MH, et al. SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels. PLoS One 2020;15:e0239252. [Crossref] [PubMed]
33. Aggarwal A, Ram S, Garg A, et al. Metabolic Bone Profile of Healthy Adult North Indian Population from Chandigarh Urban Bone Epidemiological Study (CUBES). Indian J Clin Biochem 2021;36:67-73. [Crossref] [PubMed]
34. Chiodini I, Gatti D, Soranna D, et al. Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes. Front Public Health 2021;9:736665. [Crossref] [PubMed]
35. Liu N, Sun J, Wang X, et al. Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. Int J Infect Dis 2021;104:58-64. [Crossref] [PubMed]
36. Dissanayake HA, de Silva NL, Sumanatilleke M, et al. Prognostic and Therapeutic Role of Vitamin D in COVID-19: Systematic Review and Meta-analysis. J Clin Endocrinol Metab 2022;107:1484-502. [Crossref] [PubMed]
37. Villasis-Keever MA, López-Alarcón MG, Miranda-Novales G, et al. Efficacy and Safety of Vitamin D Supplementation to Prevent COVID-19 in Frontline Healthcare Workers. A Randomized Clinical Trial. Arch Med Res 2022;53:423-30. [Crossref] [PubMed]
38. Jolliffe DA, Holt H, Greenig M, et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT). BMJ 2022;378:e071230. [Crossref] [PubMed]
39. Brunvoll SH, Nygaard AB, Ellingjord-Dale M, et al. Prevention of covid-19 and other acute respiratory infections with cod liver oil supplementation, a low dose vitamin D supplement: quadruple blinded, randomised placebo controlled trial. BMJ 2022;378:e071245. [Crossref] [PubMed]
40. van Helmond N, Brobyn TL, LaRiccia PJ, et al. Vitamin D3 Supplementation at 5000 IU Daily for the Prevention of Influenza-like Illness in Healthcare Workers: A Pragmatic Randomized Clinical Trial. Nutrients 2022;15:180. [Crossref] [PubMed]
41. Jude EB, Ling SF, Allcock R, et al. Vitamin D Deficiency Is Associated With Higher Hospitalization Risk From COVID-19: A Retrospective Case-control Study. J Clin Endocrinol Metab 2021;106:e4708-15. [Crossref] [PubMed]
42. Diaz-Curiel M, Cabello A, Arboiro-Pinel R, et al. The relationship between 25(OH) vitamin D levels and COVID-19 onset and disease course in Spanish patients. J Steroid Biochem Mol Biol 2021;212:105928. [Crossref] [PubMed]
43. 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. [Crossref] [PubMed]
44. Marik PE, Kory P, Varon J. Does vitamin D status impact mortality from SARS-CoV-2 infection? Med Drug Discov 2020;6:100041. [Crossref] [PubMed]
45. Sulli A, Gotelli E, Casabella A, et al. Vitamin D and Lung Outcomes in Elderly COVID-19 Patients. Nutrients 2021;13:717. [Crossref] [PubMed]
46. AlSafar H, Grant WB, Hijazi R, et al. COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents. Nutrients 2021;13:1714. [Crossref] [PubMed]
47. Beheshti M, Neisi N, Parsanahad M, et al. Correlation of vitamin D levels with serum parameters in Covid-19 patients. Clin Nutr ESPEN 2023;55:325-31. [Crossref] [PubMed]
48. Saponaro F, Franzini M, Okoye C, et al. Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19? Front Immunol 2022;12:745713. [Crossref] [PubMed]
49. Manojlovic M, Ilincic B, Naglic DT, et al. Association between vitamin D hypovitaminosis and severe forms of COVID-19. Eur Rev Med Pharmacol Sci 2023;27:5318-26. [PubMed]
50. Topan A, Lupse M, Calin M, et al. 25 Hydroxyvitamin D Serum Concentration and COVID-19 Severity and Outcome-A Retrospective Survey in a Romanian Hospital. Nutrients 2023;15:1227. [Crossref] [PubMed]
51. di Filippo L, Uygur M, Locatelli M, et al. Low vitamin D levels predict outcomes of COVID-19 in patients with both severe and non-severe disease at hospitalization. Endocrine 2023;80:669-83. [Crossref] [PubMed]
52. Rathod BD, Ahirwar AK, Banerjee S, et al. Association of vitamin D with the severity of disease and mortality in COVID-19: Prospective study in central India. Ann Afr Med 2023;22:117-23. [Crossref] [PubMed]
53. Tan MKA, Lim Alba R, Li K. Association of Vitamin D levels on the Clinical Outcomes of Patients Hospitalized for COVID-19 in a Tertiary Hospital. J ASEAN Fed Endocr Soc 2023;38:81-9. [Crossref] [PubMed]
54. Jevalikar G, Mithal A, Singh A, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep 2021;11:6258. [Crossref] [PubMed]
55. Orchard L, Baldry M, Nasim-Mohi M, et al. Vitamin-D levels and intensive care unit outcomes of a cohort of critically ill COVID-19 patients. Clin Chem Lab Med 2021;59:1155-63. [Crossref] [PubMed]
56. Osman W, Al Fahdi F, Al Salmi I, et al. Serum Calcium and Vitamin D levels: Correlation with severity of COVID-19 in hospitalized patients in Royal Hospital, Oman. Int J Infect Dis 2021;107:153-63. [Crossref] [PubMed]
57. Butler-Laporte G, Nakanishi T, Mooser V, et al. Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study. PLoS Med 2021;18:e1003605. [Crossref] [PubMed]
58. Pereira M, Dantas Damascena A, Galvão Azevedo LM, et al. Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Crit Rev Food Sci Nutr 2022;62:1308-16. [Crossref] [PubMed]
59. Bassatne A, Basbous M, Chakhtoura M, et al. The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism 2021;119:154753. [Crossref] [PubMed]
60. Bilezikian JP, Binkley N, De Luca HF, et al. Consensus and Controversial Aspects of Vitamin D and COVID-19. J Clin Endocrinol Metab 2023;108:1034-42. [Crossref] [PubMed]
61. Bignardi PR, de Andrade Castello P, de Matos Aquino B, et al. Is the vitamin D status of patients with COVID-19 associated with reduced mortality? A systematic review and meta-analysis. Arch Endocrinol Metab 2023;67:276-88. [Crossref] [PubMed]
62. Hernández JL, Nan D, Fernandez-Ayala M, et al. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. J Clin Endocrinol Metab 2021;106:e1343-53. [Crossref]
63. Cereda E, Bogliolo L, Lobascio F, et al. Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy, Italy. Nutrition 2021;82:111055. [Crossref] [PubMed]
64. Mingiano C, Picchioni T, Cavati G, et al. Vitamin D Deficiency in COVID-19 Patients and Role of Calcifediol Supplementation. Nutrients 2023;15:3392. [Crossref] [PubMed]
65. Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, et al. Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients 2021;13:1760. [Crossref] [PubMed]
66. Lohia P, Nguyen P, Patel N, et al. Exploring the link between vitamin D and clinical outcomes in COVID-19. Am J Physiol Endocrinol Metab 2021;320:E520-6. [Crossref] [PubMed]
67. Cangiano B, Fatti LM, Danesi L, et al. Mortality in an Italian nursing home during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests. Aging (Albany NY) 2020;12:24522-34. [Crossref] [PubMed]
68. Gönen MS, Alaylıoğlu M, Durcan E, et al. Rapid and Effective Vitamin D Supplementation May Present Better Clinical Outcomes in COVID-19 (SARS-CoV-2) Patients by Altering Serum INOS1, IL1B, IFNg, Cathelicidin-LL37, and ICAM1. Nutrients 2021;13:4047. [Crossref] [PubMed]
69. Ogasawara T, Tajima Y, Nakamura N, et al. The effect of 1-hydroxy-vitamin D treatment in hospitalized patients with COVID-19: A retrospective study. Clin Nutr 2023;42:2045-50. [Crossref] [PubMed]
70. Gibbons JB, Norton EC, McCullough JS, et al. Association between vitamin D supplementation and COVID-19 infection and mortality. Sci Rep 2022;12:19397. [Crossref] [PubMed]
71. Oristrell J, Oliva JC, Casado E, et al. Vitamin D supplementation and COVID-19 risk: a population-based, cohort study. J Endocrinol Invest 2022;45:167-79. [Crossref] [PubMed]
72. Sarhan N, Abou Warda AE, Sarhan RM, et al. Evidence for the Efficacy of a High Dose of Vitamin D on the Hyperinflammation State in Moderate-to-Severe COVID-19 Patients: A Randomized Clinical Trial. Medicina (Kaunas) 2022;58:1358. [Crossref] [PubMed]
73. De Niet S, Trémège M, Coffiner M, et al. Positive Effects of Vitamin D Supplementation in Patients Hospitalized for COVID-19: A Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients 2022;14:3048. [Crossref] [PubMed]
74. Sánchez-Zuno GA, González-Estevez G, Matuz-Flores MG, et al. Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation. J Clin Med 2021;10:2378. [Crossref] [PubMed]
75. Annweiler C, Beaudenon M, Gautier J, et al. High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial. PLoS Med 2022;19:e1003999. [Crossref] [PubMed]
76. Elamir YM, Amir H, Lim S, et al. A randomized pilot study using calcitriol in hospitalized COVID-19 patients. Bone 2022;154:116175. [Crossref] [PubMed]
77. Torres M, Casado G, Vigón L, et al. Changes in the immune response against SARS-CoV-2 in individuals with severe COVID-19 treated with high dose of vitamin D. Biomed Pharmacother 2022;150:112965. [Crossref] [PubMed]
78. Karonova TL, Golovatyuk KA, Kudryavtsev IV, et al. Effect of Cholecalciferol Supplementation on the Clinical Features and Inflammatory Markers in Hospitalized COVID-19 Patients: A Randomized, Open-Label, Single-Center Study. Nutrients 2022;14:2602. [Crossref] [PubMed]
79. Domazet Bugarin J, Dosenovic S, Ilic D, et al. Vitamin D Supplementation and Clinical Outcomes in Severe COVID-19 Patients-Randomized Controlled Trial. Nutrients 2023;15:1234. [Crossref] [PubMed]
80. Bishop CW, Ashfaq A, Melnick JZ, et al. REsCue trial: Randomized controlled clinical trial with extended-release calcifediol in symptomatic COVID-19 outpatients. Nutrition 2023;107:111899. [Crossref] [PubMed]
81. Seely D, Legacy M, Conte E, et al. Dietary supplements to reduce symptom severity and duration in people with SARS-CoV-2: a double-blind randomised controlled trial. BMJ Open 2023;13:e073761. [Crossref] [PubMed]
82. Jaun F, Boesing M, Luethi-Corridori G, et al. Effect of Single High Dose Vitamin D Substitution in Hospitalized COVID-19 Patients with Vitamin D Deficiency on Length of Hospital Stay. Biomedicines 2023;11:1277. [Crossref] [PubMed]
83. Partap U, Sharma KK, Marathe Y, et al. Vitamin D and Zinc Supplementation to Improve Treatment Outcomes among COVID-19 Patients in India: Results from a Double-Blind Randomized Placebo-Controlled Trial. Curr Dev Nutr 2023;7:101971. [Crossref] [PubMed]
84. Soliman AR, Abdelaziz TS, Fathy A. Impact of Vitamin D Therapy on the Progress COVID-19: Six Weeks Follow-Up Study of Vitamin D Deficient Elderly Diabetes Patients. Proc Singap Healthc 2022;31: [Crossref]
85. Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study). Postgrad Med J 2022;98:87-90. [Crossref] [PubMed]
86. Abroug H, Maatouk A, Bennasrallah C, et al. Effect of vitamin D supplementation versus placebo on recovery delay among COVID-19 Tunisian patients: a randomized-controlled clinical trial. Trials 2023;24:123. [Crossref] [PubMed]
87. Zurita-Cruz J, Fonseca-Tenorio J, Villasís-Keever M, et al. Efficacy and safety of vitamin D supplementation in hospitalized COVID-19 pediatric patients: A randomized controlled trial. Front Pediatr 2022;10:943529. [Crossref] [PubMed]
88. Efird JT, Anderson EJ, Jindal C, et al. Interaction of Vitamin D and Corticosteroid Use in Hospitalized COVID-19 Patients: A Potential Explanation for Inconsistent Findings in the Literature. Curr Pharm Des 2022;28:1695-702. [Crossref] [PubMed]
89. Wenban C, Heer RS, Baktash V, et al. Dexamethasone treatment may mitigate adverse effects of vitamin D deficiency in hospitalized Covid-19 patients. J Med Virol 2021;93:6605-10. [Crossref] [PubMed]
90. Hosseini B, El Abd A, Ducharme FM. Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis. Nutrients 2022;14:2134. [Crossref] [PubMed]
91. Varikasuvu SR, Thangappazham B, Vykunta A, et al. COVID-19 and vitamin D (Co-VIVID study): a systematic review and meta-analysis of randomized controlled trials. Expert Rev Anti Infect Ther 2022;20:907-13. [Crossref] [PubMed]
92. Shah K, Varna VP, Sharma U, et al. Does vitamin D supplementation reduce COVID-19 severity?: a systematic review. QJM 2022;115:665-72. [Crossref] [PubMed]
93. Stroehlein JK, Wallqvist J, Iannizzi C, et al. Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev 2021;5:CD015043. [PubMed]
94. Sîrbu AC, Sabin O, Bocșan IC, et al. The Effect of Vitamin D Supplementation on the Length of Hospitalisation, Intensive Care Unit Admission, and Mortality in COVID-19-A Systematic Review and Meta-Analysis. Nutrients 2023;15:3470. [Crossref] [PubMed]
95. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academies Press; 2011 [cited 2023 Oct 17]. Available online: http://www.nap.edu/catalog/13050
96. Joint Guidance on Vitamin D in the Era of COVID-19 from the ASBMR, AACE, Endocrine Society, ECTS, NOF, and IOF. [cited 2023 Oct 15]. Available online: https://www.asbmr.org/about/statement-detail/joint-guidance-on-vitamin-d-in-the-era-of-covid-19
97. Piec I, Cook L, Dervisevic S, et al. Age and vitamin D affect the magnitude of the antibody response to the first dose of the SARS-CoV-2 BNT162b2 vaccine. Curr Res Transl Med 2022;70:103344. [Crossref] [PubMed]
98. Zelini P, d'Angelo P, Cereda E, et al. Association between Vitamin D Serum Levels and Immune Response to the BNT162b2 Vaccine for SARS-CoV-2. Biomedicines 2022;10:1993. [Crossref] [PubMed]
99. di Filippo L, Frara S, Terenzi U, et al. Lack of vitamin D predicts impaired long-term immune response to COVID-19 vaccination. Endocrine 2023;82:536-41. [Crossref] [PubMed]
100. Meyers E, De Smet E, Vercruysse H, et al. No Significant Association between 25-OH Vitamin D Status and SARS-CoV-2 Antibody Response after COVID-19 Vaccination in Nursing Home Residents and Staff. Vaccines (Basel) 2023;11:1343. [Crossref] [PubMed]
101. Jolliffe DA, Vivaldi G, Chambers ES, et al. Vitamin D Supplementation Does Not Influence SARS-CoV-2 Vaccine Efficacy or Immunogenicity: Sub-Studies Nested within the CORONAVIT Randomised Controlled Trial. Nutrients 2022;14:3821. [Crossref] [PubMed]
102. Cesur F, Atasever Z, Özoran Y. Impact of vitamin D3 supplementation on COVID-19 vaccine response and immunoglobulin G antibodies in deficient women: A randomized controlled trial. Vaccine 2023;41:2860-7. [Crossref] [PubMed]
103. Brice DC, Diamond G. Antiviral Activities of Human Host Defense Peptides. Curr Med Chem 2020;27:1420-43. [Crossref] [PubMed]
104. Bilezikian JP, Bikle D, Hewison M, et al. MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19. Eur J Endocrinol 2020;183:R133-47. [Crossref] [PubMed]
105. Pal R, Bhansali A. COVID-19, diabetes mellitus and ACE2: The conundrum. Diabetes Res Clin Pract 2020;162:108132. [Crossref] [PubMed]
106. Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun 2014;5:3594. [Crossref] [PubMed]
107. Pal R, Bhadada SK. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab Syndr 2020;14:513-7. [Crossref] [PubMed]
108. Grant WB, Lahore H, Rockwell MS. The Benefits of Vitamin D Supplementation for Athletes: Better Performance and Reduced Risk of COVID-19. Nutrients 2020;12:3741. [Crossref] [PubMed]
109. Bikle DD. Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 2014;21:319-29. [Crossref] [PubMed]
110. Slominski AT, Kim TK, Shehabi HZ, et al. In vivo evidence for a novel pathway of vitamin D₃ metabolism initiated by P450scc and modified by CYP27B1. FASEB J 2012;26:3901-15. [Crossref] [PubMed]
111. Slominski AT, Kim TK, Slominski RM, et al. Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors. FASEB J 2022;36:e22451. [Crossref] [PubMed]
112. Qayyum S, Mohammad T, Slominski RM, et al. Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes. Am J Physiol Endocrinol Metab 2021;321:E246-51. [Crossref] [PubMed]
113. Qayyum S, Slominski RM, Raman C, et al. Novel CYP11A1-Derived Vitamin D and Lumisterol Biometabolites for the Management of COVID-19. Nutrients 2022;14:4779. [Crossref] [PubMed]
114. Slominski RM, Raman C, Elmets C, et al. The significance of CYP11A1 expression in skin physiology and pathology. Mol Cell Endocrinol 2021;530:111238. [Crossref] [PubMed]
115. Slominski RM, Stefan J, Athar M, et al. COVID-19 and Vitamin D: A lesson from the skin. Exp Dermatol 2020;29:885-90. [Crossref] [PubMed]
116. Feentved Ødum SL, Kongsbak-Wismann M. Vitamin D and SARS-CoV-2. Basic Clin Pharmacol Toxicol 2023;133:6-15. [Crossref] [PubMed]
117. Post COVID-19 condition (Long COVID). [cited 2023 Oct 15]. Available online: https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-condition
118. Gameil MA, Marzouk RE, Elsebaie AH, et al. Long-term clinical and biochemical residue after COVID-19 recovery. Egypt Liver J 2021;11:74. [Crossref] [PubMed]
119. di Filippo L, Frara S, Nannipieri F, et al. Low Vitamin D Levels Are Associated With Long COVID Syndrome in COVID-19 Survivors. J Clin Endocrinol Metab 2023;108:e1106-16. [Crossref] [PubMed]
120. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond) 2021;53:737-754. [Crossref] [PubMed]
121. Barrea L, Verde L, Grant WB, et al. Vitamin D: A Role Also in Long COVID-19? Nutrients 2022;14:1625. [Crossref] [PubMed]
122. Caballero-García A, Pérez-Valdecantos D, Guallar P, et al. Effect of Vitamin D Supplementation on Muscle Status in Old Patients Recovering from COVID-19 Infection. Medicina (Kaunas) 2021;57:1079. [Crossref] [PubMed]
123. Fernandes AL, Sales LP, Santos MD, et al. Persistent or new symptoms 1 year after a single high dose of vitamin D(3) in patients with moderate to severe COVID-19. Front Nutr 2022;9:979667. [Crossref] [PubMed]
124. Mohamed Hussein AAR, Galal I, Amin MT, et al. Prevalence of vitamin D deficiency among patients attending Post COVID-19 follow-up clinic: a cross-sectional study. Eur Rev Med Pharmacol Sci 2022;26:3038-45. [PubMed]