Technical note: The use and misuse of threshold diagnostic criteria in paleopathology.

Weighted threshold diagnostic criteria approaches have emerged for diseases that involve skeletal/bony tissue that are readily diagnosed in the field of paleopathology such as Vitamin C deficiency (scurvy), Vitamin D deficiency (rickets) and treponemal disease. These criteria differ from traditional differential diagnosis in that they involve standardized inclusion criteria based on the lesion's specificity to the disease. Here I discuss the limitations and benefits of threshold criteria. I argue that while these criteria will benefit from further revision such as inclusion of lesion severity, and the incorporation of exclusion criteria, threshold diagnostic approaches have considerable value in the future of diagnosis in the field.

A Scoping Review of Vitamin D for Nonskeletal Health: A Framework for Evidence-based Clinical Practice.

BACKGROUND: Low serum 25-hydroxy-vitamin D [25(OH)D] levels are prevalent worldwide. Although the benefits of vitamin D supplementation have focused on skeletal disorders (eg, rickets, osteomalacia, osteoporosis), emerging evidence for nonskeletal health merits further discussion. PURPOSE: The purpose of this review was to critically examine the vitamin D supplementation literature pertaining to nonskeletal health to help guide clinicians. METHODS: A scoping review that included observational studies and randomized clinical trials (RCTs) was performed. Evidence from meta-analyses and individual RCTs are discussed, and controversies and future directions are considered. FINDINGS: 25(OH)D deficiency is a ubiquitous condition associated with multiple nonskeletal diseases, including cardiometabolic (heart disease, diabetes, and kidney disease), immune (HIV/AIDS and cancer), lung (from traditional chronic disorders to coronavirus disease 2019), and gut diseases. Vitamin D deficiency also affects health across the life span (children, pregnant, and elderly), mental illness, and reproduction in both men and women. In contrast, vitamin D supplementation does not necessarily improve major medical outcomes, even when low 25(OH)D levels are treated. Screening for 25(OH)D status remains an important practice, primarily for high-risk patients (eg, elderly, women with osteoporosis, people with low exposure to sunlight). It is reasonable to supplement with vitamin D to treat 25(OH)D deficiency, such that if beneficial nonskeletal health occurs, this may be considered as a coadjutant instead of the central tenet of the disease. Furthermore, optimizing dosing regimens is an important clinical consideration. IMPLICATIONS: Although 25(OH)D deficiency is prevalent in nonskeletal diseases, there is no uniform evidence that vitamin D supplementation improves major medical outcomes, even when low 25(OH)D levels are corrected. Findings from RCTs warrant caution due to possible selection bias. Overall, vitamin D supplementation must be guided by circulating levels as a reasonable medical practice to correct 25(OH)D deficiency.

[SARS-CoV-2 morbidity depending on vitamin D status].

BACKGROUND: The association between vitamin D deficiency and the severity of COVID-19 is currently being actively discussed around the world. AIM: The aim of this study was to assess the prevalence of vitamin D insufficiency and deficiency and compare it with the incidence rates of SARS-CoV-2 in eight Federal Districts of the Russian Federation. MATERIALS AND METHODS: We included 304,564 patients (234,716 women; 77,1%) with serum 25(OH)D levels results performed September 2019 through October 2020. RESULTS: Only 112,877 people (37.1%) had a normal serum 25(OH)D level, others had a deficiency. Vitamin D insufficiency and deficiency was presented with the same frequency in women and men, and no differences were found depending on the geographical location and age in subjects from 18 to 74 years old. However, subjects over 75 years more often had vitamin D deficiency, while subjects under 18 years had normal levels in over 50% cases. In addition, 21,506 patients were tested for SARS-CoV-2 by PCR with further comparison of results with serum 25(OH)D level. The SARS-CoV-2 positivity rate was detected in 3,193 subjects, negative in 18,313. There were no differences in the morbidity in a vitamin D deficiency and a normal level. Thus, 14.8% subjects had positive PCR rates among vitamin D deficiency patients (4,978 tests), 14.9% when 25(OD)D level was from 20 to 30 ng/ml (7,542 tests), 15.0% among those who had 25(OH)D 30- 50 ng/ml (6,622 tests), and 13.9% when vitamin D was more than 50 ng/ml (4,612 tests). CONCLUSION: There was no association between the COVID-19 incidence and vitamin D status in different regions of Russia. Although the nutrient deficiency persists in all regions and is most often diagnosed in people over 75 years old.

Oral vitamin D supplemental therapy to attain a desired serum 25-hydroxyvitamin D concentration in essential healthcare teams.

BACKGROUND: The study objectives were to ascertain the efficacy of vitamin D supplementation in rapidly increasing serum vitamin D and of implementation of a hybrid (virtual and in-person) trial. METHODS: In a randomized triple-blind controlled trial, healthcare workers were allocated to receive an oral bolus of 100,000 IU with 10,000 IU/week of vitamin D3 or placebo. The co-primary outcomes were the change from baseline in serum 25-hydroxyvitamin D [(Δ) 25(OH)D] and proportion with vitamin D sufficiency (25(OH)D ≥ 75 nmol/L), at endpoint. Adherence to supplements and procedures as well as adverse event rates were documented. RESULTS: Thirty-four (19 intervention, 15 control) subjects were randomized, with 28 (41%) virtual visits. After 44.78 ± 11.00 days from baseline, a significant adjusted group difference of 44.2 (34.7, 53.8) nmol/L was observed in the Δ 25(OH)D (95% CI) in favor of supplementation; 77.8% of intervention, and 13.3% of control, patients were vitamin D sufficient (OR:6.11, 95% CI:1.6, 22.9). The adherence to intervention was 94.7% in the intervention and 100% in the control groups. Irrespective of visit type, high adherence was observed in sampling procedures and completion of fortnightly online questionnaire. No adverse events attributable to vitamin D were reported. CONCLUSION: The vitamin D supplementation rapidly and safely raised 25(OH)D levels to sufficient levels for a biological effect. Similarly high adherence to study procedures was observed with virtual and in-person participation. TRIAL REGISTRATION: This trial was registered at https://clinicaltrials.gov on July 23, 2020 (# NCT04483635 ).

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).

OBJECTIVE: To determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19. DESIGN: Phase 3 open label randomised controlled trial. SETTING: United Kingdom. PARTICIPANTS: 6200 people aged ≥16 years who were not taking vitamin D supplements at baseline. INTERVENTIONS: Offer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months. MAIN OUTCOME MEASURES: The primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat. RESULTS: Of 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63). CONCLUSIONS: Among people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04579640.

Severe Vitamin D Deficiency in Youth with Autism Spectrum Disorder During the COVID-19 Pandemic.

BACKGROUND: Decrease in sunlight exposure during periods of social distancing during the COVID-19 pandemic increased the risk of severe manifestations of vitamin D deficiency (VDD) in a particular "high-risk" population. Our objective was to highlight the importance of vitamin D screening in youth with autism spectrum disorder (ASD) and restrictive eating. CASE PRESENTATION: We describe 3 adolescent male patients with ASD who developed severe manifestations of VDD and hypocalcemia in late 2020 during the COVID-19 pandemic. All spent less time outdoors than in prior years because of isolation at home during the pandemic. Presenting symptoms included seizures and atraumatic fractures. All 3 were found to have hypocalcemia and severe VDD. Limited sun exposure because of isolation indoors during the COVID-19 pandemic was a likely contributing factor to the severity of VDD. All 3 were treated with intravenous calcium acutely, followed by oral calcium and vitamin D. Laboratory tests performed post-treatment showed biochemical resolution of hypocalcemia and VDD. CONCLUSION: These cases highlight the importance of screening "at-risk" youth for VDD. Clinicians should be cognizant that children and adolescents with ASD and restricted eating can have severe manifestations of hypocalcemia and VDD. Decreased sun exposure because of isolating indoors during the COVID-19 pandemic increased their risk for this.

The effect of prescribing vitamin D analogues and serum vitamin D status on both contracting COVID-19 and clinical outcomes in kidney dialysis patients'.

AIMS: Vitamin D plays a role in innate immune system activation, and deficiency increases susceptibility to respiratory infections and disease severity including COVID-19. We determined whether vitamin D levels and medications were associated with contracting COVID-19, and disease severity defined by hospitalisation and dialysis patient mortality. METHODS: We reviewed serum vitamin D levels, and prescription of cholecalciferol and alfacalcidol along with corresponding medical records of adult dialysis patients from a United Kingdom tertiary centre between March 2020 and May 2021. COVID-19 infection was determined by polymerase chain reaction (PCR) results. RESULTS: 362 (35%) of 1035 dialysis patients tested PCR positive for COVID-19. COVID-19 positive patients had lower native median vitamin D (65 (39-95) versus 74 (40.5-101) nmol/L (p = .009) despite greater prescription of cholecalciferol (median 20 000 (20000-20 000) versus 20 000 (0-20 000) IU/week), p < .001, but lower prescription of alfacalcidol 0 (0-3.0) versus 2.0 (0.-5.0) ug/week, p < .001. On multivariate logistic regression COVID-19 infection was associated with haemodialysis versus peritoneal dialysis (p < .001), cholecalciferol dose (p < .001) and negatively with alfacalcidol (p < .001). However, serum vitamin D levels and alfacalcidol dosages were not significantly different for those requiring hospitalisation compared to those managed at home, although those who died were prescribed lower alfacalcidol dosages. CONCLUSION: Dialysis patients who contracted COVID-19 had lower levels of native vitamin D prior to COVID-19 and were prescribed lower dosages of alfacalcidol. However, there was no association between vitamin D status and disease severity. This retrospective observational analysis supports a potential role for vitamin D and susceptibility to COVID-19 infection in dialysis patients.

Deficiency of Vitamin D, a Major Risk Factor for SARS-CoV-2 Severity.

BACKGROUND: The SARS-CoV-2 outbreak started in March 2020 with more than 120,552,261 cases at present and having caused over 2,667,248 deaths worldwide at the time this paper was written. The clinical signs of SARS-CoV-2 infection are especially evident in the respiratory and cardiovascular systems. Patients can be asymptomatic or present mild respiratory symptoms to severe acute lung injury leading to multiorgan failure and death. The study aims to assess the levels of serum 25-hydroxyvitamin D (25-(OH)-D) in 20 hospitalized patients infected with SARS-CoV-2 and 20 deceased people and to analyze the influence of vitamin D status on the severity of their disease. METHODS: The present study was conducted on 40 patients who tested positive for SARS-CoV-2 infection. They were divided into two groups: 20 patients admitted to the "Victor Babes" Hospital of Infectious Diseases and 20 postmortem cases autopsied at the Institute of Legal Medicine Timisoara, Romania. During the autopsy, blood and bronchial fluid samples were collected for the laboratory. Automate Viral RNA extraction was performed on the Maxwell 48 RSC Extraction System (Promega, USA) using the Maxwell RSC Viral Total Nucleic Acid Purification kit (Promega, USA). After RNA extraction, the samples were amplified on a 7500 real-time PCR (Applied Biosystems, USA) using the genesig® Real-Time PCR Assay 2G (Primer Design, UK). RESULTS: The living and deceased patients selected for the research presented decreased vitamin D levels, which are associated with increased levels of D-dimers, C reactive protein (CRP), and interleukin-6 (IL-6). These patients had a severe form of the SARS-CoV-2 disease, which led to death. CONCLUSIONS: We conclude that deficiency of vitamin D in patients infected with SARS-CoV-2 presents a major risk factor related to the evolution and severity of the disease.

High-dose vitamin D substitution in patients with COVID-19: study protocol for a randomized, double-blind, placebo-controlled, multi-center study-VitCov Trial.

BACKGROUND: The coronavirus disease 19 (COVID-19) pandemic has caused millions of deaths, and new treatments are urgently needed. Factors associated with a worse COVID-19 prognosis include old age (> 65 years), ethnicity, male sex, obesity, and people with comorbidities. Furthermore, vitamin D deficiency was reported as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. According to a recent clinical case series, vitamin D deficiency is a modifiable risk factor, which has the prospect of reducing hospital stay, intensive care, and fatal outcomes. Vitamin D has potent immunomodulatory properties, and its supplementation might improve important outcomes in critically ill and vitamin D-deficient COVID-19 patients. Despite the evidence that supports an association between vitamin D deficiency and COVID-19 severity, there is uncertainty about the direct link. Therefore, the aim of the trial is to assess if high-dose vitamin D supplementation has a therapeutic effect in vitamin D-deficient patients with COVID-19. METHODS: As the trial design, a randomized, placebo-controlled, double-blind, multi-center approach was chosen to compare a high single dose of vitamin D (140,000 IU) followed by treatment as usual (TAU) (VitD + TAU) with treatment as usual only (placebo + TAU) in patients with COVID-19 and vitamin D deficiency. DISCUSSION: Vitamin D substitution in patients with COVID-19 and vitamin D deficiency should be investigated for efficacy and safety. The study aim is to test the hypothesis that patients with vitamin D deficiency suffering from COVID-19 treated under standardized conditions in hospital will recover faster when additionally treated with high-dose vitamin D supplementation. Latest studies suggest that vitamin D supplementation in patients with COVID-19 is highly recommended to positively influence the course of the disease. With this randomized controlled trial, a contribution to new treatment guidelines shall be made. TRIAL REGISTRATION: ClinicalTrials.gov NCT04525820 and SNCTP 2020-01401.

25 (OH) Vitamin D Levels of Patients with COVID-19 are not Associated with the Length of Hospital Stay.

BACKGROUND: Vitamin D is known to suppress the release of proinflammatory cytokines, increase the release of anti-inflammatory cytokines, and present an immunomodulatory effect. In light of the foregoing, it is suggested that vitamin D may play an important role in the course of COVID-19 infection. This study, therefore, aimed to examine the relationship between vitamin D levels and length of hospital stay of COVID-19 patients. METHODS: This retrospective study was conducted between March 15th and October 15th, 2020, among 768 patients who were hospitalized due to the diagnosis of COVID-19 infection confirmed with PCR tests taken at the Health Sciences University, Antalya Training and Research Hospital. The study included 39 patients aged 18 - 65 years, whose 25 (OH) vitamin D levels were examined within 3 months prior to the diagnosis with PCR, and whose results were found ≥ 30 ng/mL, and those patients whose 25 (OH) vitamin D levels were examined within 3 months after the diagnosis with PCR, and whose results were found < 30 ng/mL. The patients were grouped according to 25 (OH) vitamin D levels and evaluated in terms of length of hospital stay. RESULTS: Of all the 39 patients in this study, 61.5% were female, 38.5% were male, with a mean age of 48.64 ± 11.79 years. The average of 25 (OH) vitamin D levels of the patients was 21.44 ± 11.17 ng/mL, the average length of hospital stay was 9.41 ± 8.90 days. The length of stay was found to increase significantly in participants who were 45 years and older, who were male, those with chronic diseases, and those with lung involvement detected on thoracic CT imaging at the time of admission. No statistically significant difference appeared with respect to the length of hospital stay when the patients were evaluated according to their 25 (OH) vitamin D levels. CONCLUSIONS: No statistically significant relationship was found between the patients' length of hospital stay due to the COVID-19 infection and their 25 (OH) vitamin D levels in patients aged 18 - 65 years. Further prospective clinical studies still need to be conducted with large numbers of patients excluding independent risk factors such as the presence of a chronic disease.

Golden opportunity for intervention? Identifying vitamin D deficiency in patients with substance use disorders in hospital.

SETTING: Based at a busy city hospital, the alcohol care team is a drug and alcohol specialist service, taking referrals for a wide range of patients with substance use disorders (SUD). OBJECTIVES: Patients with SUD are at high risk of vitamin D deficiency; this relates to frequent fractures and proximal myopathy. The coronavirus pandemic brought vitamin D into focus. Local guidelines advise that patients at high risk of vitamin D deficiency are offered replacement. There were no local data on vitamin D deficiency prevalence or any mention of patients with SUD in local vitamin D guidelines. The main aim of this project was to offer vitamin D checks and replacement to all appropriate patients. RESULTS: We collected data on 207 patients, [pilot study (n=50) and two subsequent samples (n=95 and n=62)]. Our pilot study showed that no patients were offered vitamin D testing or replacement. We then offered vitamin D checks to 95 patients. Most had low vitamin D (30 patients were vitamin D deficient and 26 were vitamin D insufficient). We provided vitamin D replacement and follow-up advice. Quality improvement was demonstrated 6 months later. We collected data on a further 62 patients who were all on our current or recent caseload. Following exclusions, nearly half (48%) of patients had had a vitamin D check. Almost all of these (95%) had low vitamin D (60% being classified as deficient). CONCLUSIONS: Patients had not been offered vitamin D replacement despite often having multiple risk factors for vitamin D deficiency. Vitamin D checks (and subsequent replacement) rose in frequency since the outset of this project. Local guidelines should add SUD as a risk factor for vitamin D deficiency. Hospital admission provides a rich opportunity to offer this simple intervention to patients who are often poorly engaged with community services.

Prevalence of vitamin D deficiency among psychiatric inpatients: a systematic review.

Objectives: Vitamin D deficiency is associated with worse physical and mental health outcomes. Low vitamin D levels are more common among people who experience mental health issues. This is particularly vital due to the outdoor restrictions which arose from the COVID-19 pandemic. This systematic review assessed vitamin D deficiency and insufficiency among psychiatric inpatients.Methods: A literature search was performed using the key words 'vitamin D', 'mental health', 'mental illness' and 'inpatient' and articles were selected by two independent reviewers. Eighteen studies were identified as eligible according to inclusion and exclusion criteria.Results: Vitamin D deficiency (29 - 96%) and insufficiency (20 - 63%) were common among psychiatric inpatients. Over half of the studies recommended or advised consideration of vitamin D level screening among psychiatric inpatients, while nine recommended consideration of vitamin D supplementation.Conclusions: Screening for vitamin D deficiency during psychiatric admission may be clinically indicated and improve patient wellbeing and outcomes.Key pointsLow vitamin D levels are very common among people admitted to inpatient mental health services.Vitamin D level screening upon inpatient psychiatric admission is warranted to optimise general health outcomes.Vitamin D supplementation should be considered among inpatients with vitamin D deficiency or insufficiency.

Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity.

CONTEXT: A high prevalence of vitamin D (VD) deficiency in COVID-19 patients has been reported and hypothesized to increase COVID-19 severity likely because of its negative impact on immune and inflammatory responses. Furthermore, clear associations between hypovitaminosis D and fat body mass excess and diabetes, factors associated with COVID-19 severity, have been widely recognized. OBJECTIVE: The aim of this study was to evaluate in COVID-19 patients the relationship between VD levels and inflammatory response, body mass index (BMI), blood glucose (GLU), and disease severity. METHODS: Patients admitted to San Raffaele-Hospital for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing VD metabolism. 25-Hydroxyvitamin D levels, plasma GLU levels, BMI, and inflammatory parameters were evaluated at admission. RESULTS: A total of 88 patients were included. Median VD level was 16.3 ng/mL and VD deficiency was found in 68.2% of patients. VD deficiency was found more frequently in male patients and in those affected by severe COVID-19. Regression analyses showed a positive correlation between VD and PaO2/FiO2 ratio, and negative correlations between VD and plasma GLU, BMI, neutrophil/lymphocyte ratio, C-reactive protein, and interleukin 6. Patients with both hypovitaminosis D and diabetes mellitus, as well those with hypovitaminosis D and overweight, were more frequently affected by a severe disease with worse inflammatory response and respiratory parameters, compared to those without or just one of these conditions. CONCLUSION: We showed, for the first-time, a strict association of VD levels with blood GLU and BMI in COVID-19 patients. VD deficiency might be a novel common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.

Seroprevalence of Toxoplasma gondii, Rubella, Group A Streptococcus, CMV and HSV-1 in COVID-19 Patients with Vitamin D Deficiency.

<b>Background and Objective:</b> In recent years, respiratory tract viral infections have caused many pandemics that impact the whole world. To investigate the seropositivity of <i>Toxoplasma gondii</i>, rubella, CMV, HSV-1 and group A <i>Streptococcus</i> in recovered COVID-19 patients and correlate these findings with vitamin D levels. <b>Materials and Methods:</b> A total of 417 COVID-19 patients with diarrhoea were enrolled in this study. Vitamin D and seroprevalence for <i>Toxoplasma gondii</i>, rubella, CMV, HSV-1 and group A <i>Streptococcus</i> were evaluated and correlated. <b>Results:</b> It was found that recent infection in COVID-19 patients with HSV-1, rubella, <i>Toxoplasma</i> and CMV, respectively. IgG was detected indicating the development of adaptive immunity with all microbes. <b>Conclusion:</b> Current study detected a correlation between vitamin D levels and HSV-1 and no correlation between this infection and vitamin D deficiency with the other microbes.

A Narrative Review of Recent Studies on the Role of Vitamin D in the Prevention of Cardiac and Renal Risk and Additional Considerations for COVID-19 Vulnerability.

The role of vitamin D in maintaining a healthy cardiovascular (CV) and the renal system has received increasing attention. Low vitamin D levels are associated with the incidence of hypertension, cardiac remodeling, and chronic congestive heart failure. Low vitamin D levels also influence renal disease progression and albuminuria deterioration. Moreover, recent research indicates that vitamin D deficiency can be a potential risk factor for coronavirus disease-19 (COVID-19) infection and poorer outcomes. Data are inconclusive as to whether supplementation with vitamin D agents reduces CV disease risk or COVID-19 severity. Conversely, in patients with kidney disease, vitamin D supplementation is associated with an improvement in kidney function and albuminuria. This narrative review considers recent data on the effects of vitamin D on the CV and renal system, as well as its possible role regarding COVID-19 complications.

Vitamin D Serum Levels in Subjects Tested for SARS-CoV-2: What Are the Differences among Acute, Healed, and Negative COVID-19 Patients? A Multicenter Real-Practice Study.

Vitamin D might play a role in counteracting COVID-19, albeit strong evidence is still lacking in the literature. The present multicenter real-practice study aimed to evaluate the differences of 25(OH)D3 serum levels in adults tested for SARS-CoV-2 (acute COVID-19 patients, subjects healed from COVID-19, and non-infected ones) recruited over a 6-month period (March-September 2021). In a sample of 117 subjects, a statistically significant difference was found, with acute COVID-19 patients demonstrating the lowest levels of serum 25(OH)D3 (9.63 ± 8.70 ng/mL), significantly lower than values reported by no-COVID-19 patients (15.96 ± 5.99 ng/mL, p = 0.0091) and healed COVID-19 patients (11.52 ± 4.90 ng/mL, p > 0.05). Male gender across the three groups displayed unfluctuating 25(OH)D3 levels, hinting at an inability to ensure adequate levels of the active vitamin D3 form (1α,25(OH)2D3). As a secondary endpoint, we assessed the correlation between serum 25(OH)D3 levels and pro-inflammatory cytokine interleukin-6 (IL-6) in patients with extremely low serum 25(OH)D3 levels (<1 ng/mL) and in a subset supplemented with 1α,25(OH)2D3. Although patients with severe hypovitaminosis-D showed no significant increase in IL-6 levels, acute COVID-19 patients manifested high circulating IL-6 at admission (females = 127.64 ± 22.24 pg/mL, males = 139.28 ± 48.95 ng/mL) which dropped drastically after the administration of 1α,25(OH)2D3 (1.84 ± 0.77 pg/mL and 2.65 ± 0.92 ng/mL, respectively). Taken together, these findings suggest that an administration of 1α,25(OH)2D3 might be helpful for treating male patients with an acute COVID-19 infection. Further studies on rapid correction of vitamin D deficiency with fast acting metabolites are warranted in COVID-19 patients.

The prognostic significance of vitamin D deficiency in patients with COVID-19 pneumonia.

BACKGROUND: Vitamin D has anti-inflammatory and immunomodulatory effects via the downregulation of pro-inflammatory cytokines. We aimed to demonstrate the effect of vitamin D levels on survival in COVID-19 patients. MATERIALS AND METHODS: 207 COVID-19 patients were included in the study. Serum vitamin D levels were measured, and patients with levels <20 ng/ml or 21 to 30 ng received a single 300.000 IU dose of vitamin D. RESULTS: Of 207 patients, 37 received vitamin D, while 170 did not. Demographic, radiologic and mean laboratory values were similar between the groups. The mean plasma vitamin D level without vitamin D support (n=170) was 50.82±16.12 ng/ml (30.28-81.35) vs. 16.98±6.2 ng/ml (4.20-28.30) in vitamin D group. The most remarkable finding were the mortality rates; while only 1 patient (2.7 %) died in the vitamin D group, 24 patients (14.1 %) died in no vitamin D supplementation group (p=0.038). CONCLUSION: Although a few retrospective studies put forth a relation between vitamin D deficiency and COVID-19 course severity there is still paucity of data about the efficacy of vitamin supplementations in COVID-19 patients. A single 300.000 IU dose of vitamin D seems to represent a useful, practical, and safe adjunctive approach for the treatment or prevention of COVID-19 (Tab. 1, Fig. 1, Ref. 30).

Screening for Vitamin D Deficiency in Adults: US Preventive Services Task Force Recommendation Statement.

Importance: Vitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency. Objective: To update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment. Population: Community-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended. Evidence Assessment: The USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined. Recommendation: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).

Vitamin D supplementation for the treatment of COVID-19: a living systematic review.

BACKGROUND: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required. OBJECTIVES: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events. MAIN RESULTS: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7,  whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically.