key: cord-0870177-bjhx7wa0
authors: Vassiliou, Alice G.; Jahaj, Edison; Orfanos, Stylianos E.; Dimopoulou, Ioanna; Kotanidou, Anastasia
title: Vitamin D in infectious complications in critically ill patients with or without COVID-19
date: 2021-07-07
journal: Metabol Open
DOI: 10.1016/j.metop.2021.100106
sha: cb1da30f95c7f08fd5cddd30e08a02863e44faad
doc_id: 870177
cord_uid: bjhx7wa0

25-hydroxyvitamin D [25(OH)D] is an important immunomodulator, whose deficiency may aggravate the incidence and outcome of infectious complications in patients admitted to the intensive care unit. The most recognized extra-skeletal action of vitamin D is the regulation of immune function. Host defense against intracellular pathogens depends upon both innate and adaptive immunity. It has been suggested that vitamin D regulates the pro-inflammatory endothelial response to lipopolysaccharide, rendering it a role in the sepsis cascade. Recent studies have indicated that vitamin D deficiency may be associated with worse outcomes in patients with coronavirus disease 2019 (COVID-19), such as more severe disease and higher mortality rates. To this end, clinical trials with vitamin D supplementation are being carried out in an effort to improve COVID-19 outcomes. In this review, we will discuss the role of vitamin D in the immune response, and more specifically its effect on immune cells. Subsequently, we will provide an overview of the studies that have investigated the predictive value of vitamin D in critical illness outcomes, and its therapeutic value as a supplement in critically ill patients. Finally, the emerging role of vitamin D deficiency in COVID-19 infection risk, and worse outcomes will be discussed.

Vitamin D was primarily recognized for its role in calcium homeostasis, whose deficiency caused rickets [1] . In the recent years, vitamin D has been found to play an important role in modulating immune cells, and inhibiting the inflammatory response [2] . Vitamin D is implicated in the regulation of over 2000 genes, is known to respond to infection, plays a role in antimicrobial peptide production, and triggers innate immunity. The overall result of vitamin D deficiency is the alteration of key immune response biological processes, such as gene expression, cytokine production, metabolism and cell function [3, 4] .

Studies have revealed a high prevalence of vitamin D deficiency in critically-ill patients, and that vitamin D deficiency might be associated with worse outcomes in patients with coronavirus disease 2019 (COVID- 19) , such as more severe disease and higher mortality rates.

Many risk factors have been recognized for decreased vitamin D levels, including age, latitude, the use of sunscreen, limited sun exposure, non-White ethnicity, obesity, low dietary intake of vitamin D, and malabsorption syndromes. However, the low vitamin D levels seen in critically-ill patients may be a result of many factors, including drug interactions, irregular gastrointestinal function and the result of fluid resuscitation [5] .

This review will discuss the findings associated with vitamin D and the risk and severity of complications from infections in the intensive care unit (ICU), including COVID-19.

It should be noted, however, that all of the studies mentioned measured the circulating form of vitamin D, 25(OH)D. Data from studies suggest that its active form, 1,25(OH)2D, is responsible for almost every biological function, including the antimicrobial and immunomodulatory actions of vitamin D discussed [6] . Emerging evidence suggests that other related molecules may contribute to the individual's vitamin D status (e.g., vitamin D binding protein, bioavailable and free 25(OH)D, and 1,25(OH)2D). However, the measurement of these molecules is complex, and it still has not been decided whether their measurement is merited in new research studies. 25 (OH)D is currently the best marker for overall vitamin D status, and hence remains the most commonly measured biomarker in clinical medicine. Herein, we will use the term vitamin D.

Vitamin D3 (cholecalciferol) is made in the skin from 7-dehydrocholesterol when exposed to UVB light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25-hydroxyvitamin D (25(OH)D), then to the active metabolite 1,25-J o u r n a l P r e -p r o o f dihydroxyvitamin D (1,25(OH)2D). The liver has been established as the major source of 25(OH)D production from vitamin D, while the kidney is the major source of circulating levels of 1,25(OH)2D [7] . All genomic actions of 1,25(OH)2D are mediated by the vitamin D receptor (VDR). VDR is a transcription factor that exists in nearly every tissue, and member of the steroid hormone nuclear receptor family. VDR binds to DNA sites termed vitamin D response elements (VDREs). There are thousands of these binding sites throughout the genome regulating hundreds of genes in a cell-specific fashion. Figure 1 illustrates vitamin D metabolism and signaling. Serum total 25(OH)D, the sum of 25(OH)D2 and 25(OH)D3, is the best reflection of vitamin D status.

Vitamin D deficiency has been shown to be associated with worse outcomes of infectious complications, especially in patients admitted to the ICU [8] . The most recognized extra-skeletal action of vitamin D is the regulation of immune function [9] . Vitamin D is an important link between toll-like receptor (TLR) activation, leukocyte accumulation, local inflammation, and antibacterial responses in innate immunity [10] [11] [12] . TLRs are essential in innate and adaptive immune responses. Macrophages recognize lipopolysaccharide through TLRs, leading to a series of events, which result in the production of peptides with potent bactericidal activity, namely cathelicidin and β-defensin. These peptides co-localize with ingested microbes, within phagosomes, disrupting their cell membranes [13] . Besides antimicrobial activity, these peptides have antiviral activity, and can also inactivate the influenza virus [14] . Vitamin D deficiency has been shown to be associated with reduced TLR expression levels; therefore 25(OH)D ultimately modulates the expression of cathelicidin and β-defensin, which may enhance endothelial barrier function [15] .

Experimental studies have shown that vitamin D affects numerous immune cells. It inhibits B cell proliferation and differentiation, blocks immunoglobulin secretion [16] , and suppresses T cell proliferation [17] . In response to microbial pathogens, CD4 + T cells differentiate into T-helper (Th)1 or Th2 cells; vitamin D causes a shift from a Th1 to a Th2 phenotype [18, 19] . The Th1 subset produces interferon-gamma and lymphotoxin, and plays an important part in the protection against intracellular bacteria and protozoa; additionally, it has been associated with autoimmune pathologies. Th2 helper cells lead to a humoral immune response, by producing interleukin (IL)-4, IL-5, and IL-13, usually against extracellular parasites. Hence, differentiation of CD 4+ T cells into either Th1 or Th2 cells will determine the outcome of an immune response. Differentiation is J o u r n a l P r e -p r o o f primarily directed by cytokines; IL-12 induces the development of Th1 cells, whereas Th2 cells develop in response to IL-4 [18] . Furthermore, vitamin D affects T cell maturation, inhibits the proliferation of Th17 cells, and facilitates the induction of regulatory T cells [20] [21] [22] [23] . All these vitamin D effects have been proposed to result in decreased production of inflammatory cytokines, such as IL-1, IL-6, IL-8, IL-12, IL-17, IL-21 and tumor necrosis factor alpha (TNF-α) [24] , and increased production of anti-inflammatory cytokines, such as IL-10 [25, 26] .

Vitamin D also has effects on macrophages, monocytes, and dendritic cells (DCs). It modulates the phagocytic activity of macrophages, and inhibits the production of the inflammatory cytokines IL-1, IL-6, IL-8, IL-12, and TNF-α from monocytes [27, 28] . It additionally inhibits differentiation and maturation of the antigen-presenting DCs, resulting in decreased expression of major histocompatibility complex class II molecules, and stimulation of IL-12 [29] . With the regards to the effect of vitamin D on natural killer (NK) cell functions, contradictory results have been reported from in vitro studies [30] [31] [32] ; whether vitamin D induces or inhibits NK cell function in vivo is still unclear [33] . Low circulating NK cell counts have been associated with more severe phenotypes of common variable immunodeficiency, implying a protective role of NK cells against severe bacterial infections, when the adaptive immune response is not the most appropriate [34] .

In vitro data have shown that, in addition to modulating innate immune cells, vitamin D also induces immune tolerance. Data from animal and human studies with vitamin D supplementation, have demonstrated the beneficial effects of vitamin D on immune function in vivo, especially on autoimmunity [35] [36] [37] .

Vitamin D deficiency has been linked to a wide range of metabolic disorders, including malignant, cardiovascular, infectious, neuromuscular, and autoimmune diseases. Local synthesis of vitamin D has been shown to mediate T cell responses, whereas patients with diseases that affect vitamin D metabolism, such as chronic renal failure and rickets, have impaired activity of NK cells [36] . These immunomodulating effects of vitamin D may be responsible for the epidemiological associations between vitamin D status and autoimmune and inflammatory diseases [38] .

The predictive value of vitamin D in the ICU has been the focus of many studies. However, controversial results have been reported on its predictive and therapeutic value. Vitamin D J o u r n a l P r e -p r o o f deficient patients have been shown to have higher infection rates, although not significant [39, 40] , whereas no difference was observed between patients with bacteremia, pneumonia, urinary tract infection, skin-soft tissue infection, or intra-abdominal infection [39] . Vitamin D deficiency has been associated with increased risk of blood culture positivity compared to vitamin D sufficiency [41] . In critically-ill septic patients, extremely low (< 7 ng/mL) vitamin D levels on ICU admission may contribute to poor ICU outcomes, including mortality and higher infection rates [42] . Our group showed that severely low vitamin D levels on ICU admission were associated with a higher rate of respiratory tract infections in initially non-septic patients [43] . The association of vitamin D deficiency with worse outcomes in the critically-ill, including sepsis, mortality, duration of mechanical ventilation, and length of stay, has been demonstrated in a plethora of studies [5, 8, [39] [40] [41] [44] [45] [46] [47] [48] . Very recently, it was shown that vitamin D deficient critically-ill patients had more complications relating to pneumonia severity, such as sepsis and acute respiratory distress syndrome (ARDS), and worse outcomes [49] . A meta-analysis of randomized controlled trials (RCTs) demonstrated that vitamin D supplementation may prevent acute respiratory tract infections, especially in severely vitamin D deficient patients not receiving bolus doses [50] . Other reports, however, have not been able to demonstrate an association between vitamin D deficiency and poor ICU outcomes [51] [52] [53] , or risk of hospital-acquired infections [54] .

It has been proposed that the higher mortality rates, seen in vitamin D deficient and insufficient critically-ill patients, may be a result of glucose and calcium metabolism abnormalities and/or immune and endothelial cell dysfunction [44] . There is still dispute as to whether vitamin D reduces inflammation or whether inflammation decreases vitamin D levels.

Due to the confounding associations and interactions, it is challenging to prove cause and effect on the outcomes of the critically-ill patients. Nonetheless, results from studies showing associations of vitamin D deficiency with worse outcomes, prompted clinical trials to investigate whether vitamin D supplement therapy improves outcomes in critically-ill patients. The largest RCT, VITdAL-ICU, which tested high dose cholecalciferol supplementation in a mixed population of critically-ill patients with vitamin D deficiency, showed that vitamin D3 was not able to reduce ICU or hospital length of stay, in-hospital mortality, or 6-month mortality [55] . In critically-ill patients, although studies have revealed a high prevalence of vitamin D deficiency, vitamin D supplement therapy has yet to be proven beneficial on outcomes.

J o u r n a l P r e -p r o o f COVID-19 usually presents with pneumonia, severe ARDS, myocarditis, microvascular thrombosis and/or cytokine storm, all of which involve underlying inflammation. Reduced levels have been associated with an increase in inflammatory cytokines and an increased risk of developing pneumonia and viral upper respiratory tract infections [56] , including communityacquired pneumonia, the most common medical cause for hospital admissions [57, 58] . Low plasma vitamin D levels have been shown to constitute an independent risk factor for COVID-19 infection and hospitalization [59] , while severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)-positive patients have reduced vitamin D levels compared to negative patients [60, 61] .

Moreover, vitamin D deficiency increased the risk of developing COVID-19 [62] . In a Northern Italy hospital, however, the averaged vitamin D levels were similar in SARS-CoV2-positive and negative patients [63] . This was also observed in a Brazilian study, where the authors concluded that in their specific population, clinical, environmental, socioeconomic, and cultural factors had a greater influence, rather than vitamin D levels, in determining susceptibility to COVID-19

infection [64] . In an Arab Gulf country, vitamin D deficiency was not associated with SARS-CoV2 infection, but the authors suggested that it may increase the mortality risk in severely deficient cases [65] . A study in hospitalized COVID-19 patients showed that higher vitamin D levels were associated with less extent of lung involvement, and with a significant decrease in the risk of mortality, instigating the authors to suggest that vitamin D might be protective against the development of severe disease, once infected [66] . Vitamin D deficiency has also been associated with the progression and severity of COVID-19, as documented by the need for invasive mechanical ventilation and/or mortality [67] [68] [69] [70] [71] [72] [73] [74] . Thus, it has been proposed that diagnosis of vitamin D deficiency could aid in identifying patients prone to developing severe COVID-19, defined as presence of ARDS and/or need for mechanical ventilation, ICU vs ward admission, and lower survival probability. Vitamin D levels were lower in hospitalized COVID-19 patients compared to healthy controls, however, no relationship could be established between vitamin D concentrations and the severity of the disease or its clinical course [75, 76] . No significant association between vitamin D levels and severity, mortality, mechanical ventilation, ICU admission, and the development of thromboembolism was observed in COVID-19 patients [77, 78] . Lower vitamin D levels were associated with SARS-CoV2 infection and mortality in the Indian population [79] , and among Asian countries [80] . In a Tehran referral hospital, vitamin D levels were not associated with mortality, however the authors concluded that in severe COVID-J o u r n a l P r e -p r o o f 19, vitamin D deficiency seemed to affect the course of the disease and mortality, especially in comorbid and older patients [81] . In a Mendelian randomization study, evidence supporting an association between 25(OH)D levels and COVID-19 susceptibility, severity, or hospitalization was not observed [82] .

In a large meta-analysis, vitamin D deficiency was not associated with a higher chance of infection by SARS-CoV2; nevertheless, severe cases of COVID-19 were more vitamin D deficient compared to mild cases. Moreover, vitamin D insufficiency increased risk of infection, hospitalization and mortality rates, and a positive association was observed between vitamin D deficiency and COVID-19 severity [83] [84] [85] . Two large meta-analyses assessed the association between vitamin D deficiency and COVID-19 incidence, complications, and mortality, in 46 and 43 countries, respectively. The results of the analyses suggested an association between vitamin D deficiency and SARS-CoV2 infection risk, COVID-19 disease severity, and mortality risk [86, 87] . Other systematic reviews and meta-analyses have indicated that low vitamin D levels might be associated with an increased risk of COVID-19 infection [88, 89] , and/or COVID-19 severity, and mortality [90] . With regard to infection, the authors suggested caution in interpreting the results, due to inherent study limitations, while for ICU admission, hospitalization, and pulmonary involvement, they concluded that the evidence is inconsistent and insufficient [90] . A strong correlation between severe vitamin D deficiency prevalence and COVID-19 mortality rate in Europe was established, following the analysis of data sets from 10 countries [91] . In elder patients with low vitamin D levels, cytokine storm markers were elevated, and those patients presented with hypoxia requiring non-invasive ventilatory support [92] . On the contrary, other studies do not support a relationship between pre-hospitalization vitamin D status and COVID-19 clinical outcomes [93] .

In critically-ill COVID-19 patients there are far less studies. One study demonstrated that vitamin D levels were very low, and that the corresponding inflammatory response and fatality rate were higher in critically-ill patients compared to asymptomatic carriers [94] . The lowest vitamin C and D levels were found in critically-ill patients. However, a study showed that it was older age and low vitamin C levels that were co-dependent risk factors for mortality, and not vitamin D levels [95] . In a respiratory intermediate care unit, patients with 25(OH) levels below 10 ng/mL had a 50% mortality probability, following a 10-day hospitalization period [96] . Our group was able to J o u r n a l P r e -p r o o f demonstrate that in a small cohort of critically-ill patients, lower ICU admission vitamin D levels (<15.2 ng/mL) were associated with an increased 28-day ICU mortality risk [97] . In another study, we found that in critically and non-critically-ill COVID-19 patients, vitamin D deficient COVID-19 patients (< 20 ng/mL) had a decreased number of NK cells [98] . In COVID-19 patients, reduced numbers of NK cells and exhaustion have been linked to the progression and severity of COVID-19 [99] [100] [101] . In severe disease, NK cells have been shown reduced but strongly activated; the authors suggested that it was their activation that correlated with the development of severe disease [102] . On the contrary, no difference was observed in the vitamin D levels of those hospitalized and those admitted to the ICU, and furthermore, among the ICU patients, there were no significant differences in ICU clinical outcomes between patients with low and normal vitamin D levels [103] .

Similar results were observed in another study, in which 96% of critically ill COVID-19 ARDS patients exhibited vitamin D deficiency; however, the low levels of 25(OH)D were not related to changes in clinical course, whereas the low levels of 1,25(OH)D were associated with prolonged mechanical ventilation [104] . Table 1 summarizes the findings of the vitamin D studies in critically ill COVID-19 patients.

Due to the above, clinical trials with vitamin D supplementation are underway in COVID-19 patients in an effort to improve outcomes. In the frail elderly with less severe COVID-19, a single oral bolus vitamin D3 dose of 50,000 IU per month, or 80,000-100,000 IU every 2-3 months, during, or just before COVID-19 infection, was associated with a better survival rate [105, 106] .

Very recently, a cross-sectional multicenter observational study showed that a high dose cholecalciferol booster therapy (approximately ≥ 280,000 IU in a time period of up to 7 weeks) was associated with a reduced risk of COVID-19 mortality [107] . A retrospective study suggested a potential benefit of cholecalciferol (400,000 IU bolus oral cholecalciferol, 200,000 IU administered in two consecutive days) in comorbid COVID-19 patients [108] . In outpatients, 10,000 IU of vitamin D3, for 14 days resulted in fewer symptoms compared to the control group [109] . On the other hand, administration of 200,000 IU vitamin D3 as a loading dose and 10,000 IU daily thereafter via enteral feeding did not impact the biologically active metabolite 1,25(OH)D, prompting the authors to suggest that both forms should be included in monitoring vitamin D status, and future interventional studies should target the usefulness of calcitriol administration in COVID-19 patients [104] . A systematic review and meta-analysis on vitamin D supplementation J o u r n a l P r e -p r o o f and clinical outcomes in COVID-19, including 10 observational studies and 3 RCTs, concluded that vitamin D supplementation might be associated with improved clinical outcomes, especially when administered after the diagnosis of COVID-19 [110] . The results of the pragmatic trial underway of Wang et al. of parallel testing vitamin D3 supplementation for early treatment and post-exposure prophylaxis of COVID-19 are being eagerly awaited [111] . Issues regarding the appropriate dose, duration, and mode of administration of vitamin D remain unanswered and need further research. Ongoing vitamin D supplementation trials have been extensively reported in [112] .

It becomes evident, that further studies are warranted to evaluate the effect of vitamin D levels on the prognosis of COVID-19 patients, and the impact of vitamin D supplementation on clinical severity.

Vitamin D has important immunomodulatory effects. The high prevalence of vitamin D deficiency in critically ill patients, including those with COVID-19, has been shown to be associated with worse outcomes of infectious complications. The need for more observational studies with COVID-19 patients to assess the role of vitamin D in relation to risk, disease severity, and outcomes is evident. More randomized clinical trials with larger populations are also required to evaluate the efficacy of supplementation, in both a therapeutic and preventive context. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

There is no conflict of interest to disclose.

Vassiliou AG, Jahaj E, Orfanos SE, Dimopoulou I and Kotanidou A drafted the manuscript;

Vassiliou AG, Dimopoulou I and Kotanidou A performed the final editing. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

Vitamin D, calcium or a combination of vitamin D and calcium for the treatment of nutritional rickets in children. The Cochrane database of systematic reviews

Vitamin D and inflammatory diseases

Vitamin D and critical illness outcomes

Vitamin D in sepsis: from basic science to clinical impact

Vitamin D deficiency is associated with mortality in the medical intensive care unit

Vitamin D status: measurement, interpretation, and clinical application

Vitamin D: Production, Metabolism, and Mechanisms of Action

Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill

Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity

Differential roles of Tolllike receptors in the elicitation of proinflammatory responses by macrophages

Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response

Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin

The vitamin D-antimicrobial peptide pathway and its role in protection against infection

Epidemic influenza and vitamin D

Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression

Vitamin D and the immune system

25-Dihydroxyvitamin D3 inhibits antigeninduced T cell activation

25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells

Inhibition of Th1 development and treatment of chronic-relapsing experimental allergic encephalomyelitis by a nonhypercalcemic analogue of 1,25-dihydroxyvitamin D(3)

In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)-and Th2-inducing cytokines

Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes

Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance

Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3

25-dihydroxyvitamin D3 inhibits CD40L-induced pro-inflammatory and immunomodulatory activity in human monocytes

Dendritic cell modulation by 1alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo

1,25-dihydroxyvitamin D3 is an autonomous regulator of the transcriptional changes leading to a tolerogenic dendritic cell phenotype

Vitamin D3: a helpful immunomodulator

Vitamin D3 as Potential Treatment Adjuncts for COVID-19

Regulation of Dendritic Cell Function by Vitamin D

Vitamin D, invariant natural killer T-cells and experimental autoimmune disease. The Proceedings of the Nutrition Society

1,25-Dihydroxyvitamin D3 regulates NK-cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses

The effects of 1,25-dihydroxyvitamin D3 on in vitro human NK cell development from hematopoietic stem cells

Differential effect of dietary vitamin D supplementation on natural killer cell activity in lean and obese mice

Low Circulating Natural Killer Cell Counts are Associated With Severe Disease in Patients With Common Variable Immunodeficiency

MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19

Vitamin D and immune regulation: antibacterial, antiviral, anti-inflammatory. JBMR plus

Vitamin D and immune function

Vitamin D and inflammation

Effects of vitamin D deficiency in critically ill surgical patients

Relationship of vitamin D deficiency to clinical outcomes in critically ill patients

Low serum 25-hydroxyvitamin D at critical care initiation is associated with increased mortality

Clinical and microbiological outcome in septic patients with extremely low 25-hydroxyvitamin D levels at initiation of critical care. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases

Serum Admission 25-Hydroxyvitamin D Levels and Outcomes in Initially Non-Septic Critically Ill Patients

Vitamin D deficiency is associated with poor outcomes and increased mortality in severely ill patients

Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill

Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients

Relationship between vitamin D status and ICU outcomes in veterans

Deficiency in 25-hydroxyvitamin D and 30-day mortality in patients with severe sepsis and septic shock

Serum level of vitamin D as a predictor for severity and outcome of pneumonia

Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Is vitamin d insufficiency associated with mortality of critically ill patients?

Vitamin D deficiency in septic patients at ICU admission is not a mortality predictor

Incidence and risk factors of vitamin D deficiency in critically ill patients: results from a prospective observational study

Vitamin d status and the risk for hospital-acquired infections in critically ill adults: a prospective cohort study

Effect of High-Dose Vitamin D3 on Hospital Length of Stay in Critically Ill Patients With Vitamin D Deficiency: The VITdAL-ICU Randomized Clinical Trial

Does vitamin D deficiency increase the severity of COVID-19? Clinical medicine

Association between serum concentration of 25-hydroxyvitamin D and community-acquired pneumonia: a case-control study

Addition of vitamin D status to prognostic scores improves the prediction of outcome in community-acquired pneumonia

Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. The FEBS journal

The association between the level of serum 25(OH) vitamin D, obesity, and underlying diseases with the risk of developing COVID-19 infection: A case-control study of hospitalized patients in Tehran

25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2

Increased risk for COVID-19 in patients with vitamin D deficiency

No significant association between vitamin D and COVID-19. A retrospective study from a northern Italian hospital. International journal for vitamin and nutrition research Internationale Zeitschrift fur Vitamin-und Ernahrungsforschung Journal international de vitaminologie et de nutrition

No association between vitamin D status and COVID-19 infection in São Paulo, Brazil. Archives of endocrinology and metabolism

Severe vitamin D deficiency is not related to SARS-CoV-2 infection but may increase mortality risk in hospitalized adults: a retrospective case-control study in an Arab Gulf country

Possible association of vitamin D status with lung involvement and outcome in patients with COVID-19: a retrospective study

A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency. Frontiers in public health

Serum 25(OH)D Level on Hospital Admission Associated With COVID-19 Stage and Mortality. American journal of clinical pathology

Vitamin D sufficiency, a serum 25-hydroxyvitamin D at least 30 ng/mL reduced risk for adverse clinical outcomes in patients with COVID-19 infection

Association of vitamin D with the modulation of the disease severity in COVID-19

Vitamin D insufficiency as a potential culprit in critical COVID-19 patients

Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalized with COVID-19 are associated with greater disease severity

Vitamin D Deficiency and Outcome of COVID-19 Patients

Vitamin D and disease severity in coronavirus disease 19 (COVID-19)

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection

Vitamin D Levels Are Reduced at the Time of Hospital Admission in Sicilian SARS-CoV-2-Positive Patients

Exploring the link between vitamin D and clinical outcomes in COVID-19

Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19

Lower levels of vitamin D are associated with SARS-CoV-2 infection and mortality in the Indian population: An observational study

Impact of the vitamin D deficiency on COVID-19 infection and mortality in Asian countries

Evaluation of vitamin D levels in COVID-19 patients referred to Labafinejad hospital in Tehran and its relationship with disease severity and mortality

Vitamin D and COVID-19 susceptibility and severity in the COVID-19 Host Genetics Initiative: A Mendelian randomization study

Vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis. Critical reviews in food science and nutrition

Low Serum 25-hydroxyvitamin D (Vitamin D) Level Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-Analysis. Frontiers in nutrition

Effects of Vitamin D on COVID-19 Infection and Prognosis: A Systematic Review. Risk management and healthcare policy

Association Between Vitamin D Deficiency and COVID-19 Incidence, Complications, and Mortality in 46 Countries: An Ecological Study. Health security

Therapeutic and prognostic role of vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies

Low vitamin D status is associated with coronavirus disease 2019 outcomes: a systematic review and meta-analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases

The Impact of Vitamin D Level on COVID-19 Infection: Systematic Review and Meta-Analysis. Frontiers in public health

Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis

Strong correlation between prevalence of severe vitamin D deficiency and population mortality rate from COVID-19 in Europe

Prognostic implications of vitamin D in patients with COVID-19

Vitamin D Status and COVID-19 Clinical Outcomes in Hospitalized Patients

Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers

Serum levels of vitamin C and vitamin D in a cohort of critically ill COVID-19 patients of a north American community hospital intensive care unit in may 2020. A pilot study

Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19

Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit

Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort

Vitamin D deficiency correlates with a reduced number of natural killer cells in intensive care unit (ICU) and non-ICU patients with COVID-19 pneumonia. Hellenic journal of cardiology : HJC = Hellenike kardiologike epitheorese

Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure

COVID-19: Unanswered questions on immune response and pathogenesis

Flattening the COVID-19 Curve With Natural Killer Cell Based Immunotherapies

Natural killer cell immunotypes related to COVID-19 disease severity

Vitamin-D levels and intensive care unit outcomes of a cohort of critically ill COVID-19 patients

Vitamin D deficiency in critically ill COVID-19 ARDS patients

Vitamin D and survival in COVID-19 patients: A quasi-experimental study

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

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

Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study

Vitamin D Levels in COVID-19 Outpatients from Western Mexico: Clinical Correlation and Effect of Its Supplementation

Vitamin D supplementation and clinical outcomes in COVID-19: a systematic review and meta-analysis

The vitamin D for COVID-19 (VIVID) trial: A pragmatic cluster-randomized design

Vitamin D Insufficiency May Account for Almost Nine of Ten COVID-19 Deaths: Time to Act. Comment on: "Vitamin D Deficiency and Outcome of COVID-19 Patients

Artwork was created with the use of the Smart Servier Medical Art website (https://smart.servier.com/) and free artwork from all-free-download.com.

J o u r n a l P r e -p r o o f