Temporal Association of Reduced Serum Vitamin D with COVID-19 Infection: Two Single-Institution Case–Control Studies

(1) Background: Vitamin D supplementation has been proposed for the prevention and treatment of COVID-19, but it is not clear if reduced serum vitamin D predisposes individuals to COVID-19 and/or is a secondary consequence of infection. This study assessed the temporal association between serum vitamin D and COVID-19 with two single-institution case–control studies through the University of California San Diego (UCSD) Health System. (2) Methods: This study included patients who tested positive for COVID-19 from 1 January to 30 September 2020 with serum 25-hydroxy-vitamin D (25(OH)D) measured within 180 days of diagnosis. Patients were separated based on whether 25(OH)D was measured before (n = 107 cases, 214 controls) or after (n = 203 cases, 406 controls) COVID-19 diagnosis. COVID-19 infection status was the outcome variable in the pre-diagnosis study, whereas serum 25(OH)D level was the outcome variable in the post-diagnosis study. (3) Results: Serum 25(OH)D levels were not associated with the odds of subsequent COVID-19 infection (OR 1.0, 95% CI: 1.0 to 1.0, p = 0.98). However, COVID-19-positive individuals had serum 25(OH)D measurements that were 2.7 ng/mL lower than the controls (95% CI: −5.2 to −0.2, p = 0.03). (4) Conclusions: In our study population, serum 25(OH)D levels were not associated with the risk of acquiring COVID-19 infection but were reduced in subjects after COVID-19 infection. These results support the possibility that reduced serum 25(OH)D is a consequence and not a cause of COVID-19 infection.     

Low Serum Vitamin D in COVID-19 Patients Is Not Related to Inflammatory Markers and Patients’ Outcomes—A Single-Center Experience and a Brief Review of the Literature

The aim of the study was to evaluate the vitamin D status in hospitalized COVID-19 patients and the correlation with C reactive protein (CRP), ferritin, fibrinogen, and peripheral blood leukocytes, as well as inflammatory derived indices. A prospective study was performed on 203 COVID-19 hospitalized patients, classified by disease severity. Blood was collected after admission, and inflammatory biomarkers and vitamin D status were assessed using routine laboratory procedures. No significant correlation was found between vitamin D serum levels and disease severity stratified by different age groups. However, the highest vitamin D levels were found in patients with mild disease: median 29.39 (IQR 12.12–44.02) ng/mL, while for moderate and severe forms the serum levels were significantly lower: median 15.10 (IQR 9.56–24.11) ng/mL for moderate, and 18.86 (IQR 12.50–27.88) ng/mL for severe; p = 0.009. Patients with no comorbidities showed a significantly higher level of vitamin D median 24.72 (IQR 16.05–31.52) ng/mL compared to subjects with at least one comorbidity: median 16.02 (IQR 9.81–25.22) ng/mL, p = 0.004. We did not find an association between vitamin D levels and inflammatory biomarkers except for significantly lower vitamin D levels in moderate and severe COVID-19 compared to mild disease forms.     

Low 25(OH)D Level Is Associated with Severe Course and Poor Prognosis in COVID-19

We evaluated associations between serum 25-hydroxyvitamin D [25(OH)D] level and severity of new coronavirus infection (COVID-19) in hospitalized patients. We assessed serum 25(OH)D level in 133 patients aged 21–93 years. Twenty-five (19%) patients had severe disease, 108 patients (81%) had moderate disease, and 18 (14%) patients died. 25(OH)D level ranged from 3.0 to 97.0 ng/mL (median, 13.5 [25%; 75%, 9.6; 23.3] ng/mL). Vitamin D deficiency was diagnosed in 90 patients, including 37 with severe deficiency. In patients with severe course of disease, 25(OH)D level was lower (median, 9.7 [25%; 75%, 6.0; 14.9] ng/mL), and vitamin D deficiency was more common than in patients with moderate course (median, 14.6 [25%; 75%, 10.6; 24.4] ng/mL, p = 0.003). In patients who died, 25(OH)D was 9.6 [25%; 75%, 6.0; 11.5] ng/mL, compared with 14.8 [25%; 75%, 10.1; 24.3] ng/mL in discharged patients (p = 0.001). Severe vitamin D deficiency was associated with increased risk of COVID-19 severity and fatal outcome. The threshold for 25(OH)D level associated with increased risk of severe course was 11.7 ng/mL. Approximately the same 25(OH)D level, 10.9 ng/mL, was associated with increased risk of mortality. Thus, most COVID-19 patients have vitamin D deficiency; severe vitamin D deficiency is associated with increased risk of COVID-19 severity and fatal outcome.     

Evaluating the Evidence in Clinical Studies of Vitamin D in COVID-19

Laboratory evidence provides a biological rationale for the benefits of vitamin D in COVID-19, and vitamin D supplementation is associated with reduced risk of respiratory infections. Most of the clinical studies of vitamin D in COVID-19 have been observational, and the most serious problem with observational study design is that of confounding. Observational studies typically assess the relationship of 25(OH)D values with COVID-19 outcomes. Many conditions associated with low vitamin D status are also associated with worse COVID-19 outcomes. Randomized controlled trials (RCTs) overcome the problem of confounding, typically comparing outcomes between groups receiving vitamin D supplementation or placebo. However, any benefit of vitamin D in COVID-19 may be related to the dose, duration, daily vs. bolus administration, interaction with other treatments, and timing of administration prior to or during the illness. Serum 25(OH)D values >50 nmol/L have been associated with reduced infection rates, severity of COVID-19, and mortality in observational studies. Few RCTs of vitamin D supplementation have been completed, and they have shown no benefit of vitamin D in hospitalized patients. Vitamin D may benefit those with mild or asymptomatic COVID-19, and those with greater 25(OH)D values may have lower risk of acquiring infection. Because those at greatest risk of COVID-19 are also at greatest risk of vitamin D deficiency, it is reasonable to recommend vitamin D supplementation 15–20 mcg (600–800 IU) daily for the general population during the COVID-19 pandemic. Vitamin D doses greater than 100 mcg (4000 IU) daily should not be used without monitoring serum 25(OH)D and calcium.     

Vitamin D Supplementation and Disease-Free Survival in Stage II Melanoma: A Randomized Placebo Controlled Trial

Patients with newly resected stage II melanoma (n = 104) were randomized to receive adjuvant vitamin D3 (100,000 IU every 50 days) or placebo for 3 years to investigate vitamin D3 protective effects on developing a recurrent disease. Median age at diagnosis was 50 years, and 43% of the patients were female. Median serum 25-hydroxy vitamin D (25OHD) level at baseline was 18 ng/mL, interquartile range (IQ) was 13–24 ng/mL, and 80% of the patients had insufficient vitamin D levels. We observed pronounced increases in 25OHD levels after 4 months in the active arm (median 32.9 ng/mL; IQ range 25.9–38.4) against placebo (median 19.05 ng/mL; IQ range 13.0–25.9), constantly rising during treatment. Remarkably, patients with low Breslow score (<3 mm) had a double increase in 25OHD levels from baseline, whereas patients with Breslow score ≥3 mm had a significantly lower increase over time. After 12 months, subjects with low 25OHD levels and Breslow score ≥3 mm had shorter disease-free survival (p = 0.02) compared to those with Breslow score <3 mm and/or high levels of 25OHD. Adjusting for age and treatment arm, the hazard ratio for relapse was 4.81 (95% CI: 1.44–16.09, p = 0.011). Despite the evidence of a role of 25OHD in melanoma prognosis, larger trials with vitamin D supplementation involving subjects with melanoma are needed.     

COVID-19 Disease Severity and Death in Relation to Vitamin D Status among SARS-CoV-2-Positive UAE Residents

Insufficient blood levels of the neurohormone vitamin D are associated with increased risk of COVID-19 severity and mortality. Despite the global rollout of vaccinations and promising preliminary results, the focus remains on additional preventive measures to manage COVID-19. Results conflict on vitamin D’s plausible role in preventing and treating COVID-19. We examined the relation between vitamin D status and COVID-19 severity and mortality among the multiethnic population of the United Arab Emirates. Our observational study used data for 522 participants who tested positive for SARS-CoV-2 at one of the main hospitals in Abu Dhabi and Dubai. Only 464 of those patients were included for data analysis. Demographic and clinical data were retrospectively analyzed. Serum samples immediately drawn at the first hospital visit were used to measure serum 25-hydroxyvitamin D [25(OH)D] concentrations through automated electrochemiluminescence. Levels < 12 ng/mL were significantly associated with higher risk of severe COVID-19 infection and of death. Age was the only other independent risk factor, whereas comorbidities and smoking did not contribute to the outcomes upon adjustment. Sex of patients was not an important predictor for severity or death. Our study is the first conducted in the UAE to measure 25(OH)D levels in SARS-CoV-2-positive patients and confirm the association of levels < 12 ng/mL with COVID-19 severity and mortality.     

Rapidly Increasing Serum 25(OH)D Boosts the Immune System,against Infections—Sepsis and COVID-19

Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)₂D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)₂D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D₃ and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D₃ and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D₃ increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D₃ and 25(OH)D enter immune cells for generating calcitriol, using the combination of D₃ (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complications and deaths, healthcare workers should advise patients on safe sun exposure, adequate vitamin D supplementation and balanced diets containing zinc, magnesium, and other micronutrients to support the immune system. Meanwhile, governments, the World Health Organisation, the Centers for Disease Control, and governments should consider similar recommendations to physicians and the public, change the outdated vitamin D and other micronutrient recommendations directed to their population, and organise targetted food fortification programs for the vulnerable groups. This article discusses a rational approach to maintaining a sustained serum 25(OH)D concentration above 50 ng/mL, necessary to attain a robust immune system for overcoming infections. Such would cost-effectively improve the population’s health and reduce healthcare costs. It also describes three cost-effective, straightforward protocols for achieving and sustaining therapeutic serum 25(OH)D concentrations above 50 ng/mL (>125 nmol/L) to keep the population healthy, reduce absenteeism, improve productivity, and lower healthcare costs.     

Vitamin D Deficiency in Children With Intestinal Failure Receiving Home Parenteral Nutrition

Background: Vitamin D plays important roles in both skeletal and nonskeletal health. Limited data suggest that patients with intestinal failure (IF) receiving home parenteral nutrition (PN) are at risk for vitamin D deficiency due to inadequate oral intake, poor absorption, and chronic illness. The purpose of this study was to document vitamin D status in pediatric patients with IF receiving home PN. Materials and Methods: We performed a 2‐year retrospective review of children with IF followed at our center who had been on home PN for ≥6 months and had ≥1 serum 25‐hydroxyvitamin D (25‐OHD) level checked as part of routine clinical care. Patients were then categorized as deficient (<20 ng/mL), insufficient (20–29 ng/mL), or normal (≥30 ng/mL) based on their lowest vitamin D level. Demographic data and clinical characteristics were also assessed. Results: Eleven of 27 children (41%) had ≥1 insufficient 25‐OHD level, including one child with vitamin D deficiency. Diagnosis of short bowel syndrome (compared with dysmotility or malabsorption syndromes) was associated with decreased likelihood of suboptimal vitamin D status, with an odds ratio of 0.12 (95% confidence interval, 0.02–0.8, P = .028). Osteopenia was noted in 59% of the cohort. There was a trend toward higher risk for osteopenia in patients with low 25‐OHD levels compared with those with normal 25‐OHD levels (82% vs 44%, P = .109). Conclusion: Suboptimal 25‐OHD levels are common in children with IF on home PN. This emphasizes the critical importance of routine surveillance of serum vitamin D levels and consideration of enteral supplementation when indicated.     

Vitamin D Status and Acute Respiratory Infection: Cross Sectional Results from the United States National Health and Nutrition Examination Survey, 2001–2006

Vitamin D is a promising, though under-explored, potential modifiable risk factor for acute respiratory infections (ARIs). We sought to investigate the association of vitamin D status with ARI in a large, nationally-representative sample of non-institutionalized individuals from the United States. We analyzed 14,108 individuals over 16 years of age in the National Health and Nutrition Survey (NHANES) 2001–2006 in this cross-sectional study. We used locally weighted scatterplot smoothing (LOWESS) to depict the relationship between increasing 25-hydroxyvitamin D (25OHD) levels and ARI. We then performed a multivariable regression analysis to investigate the association of 25OHD levels with ARI, while adjusting for known confounders. The median serum 25OHD level was 21 (IQR 15–27) ng/mL. Overall, 4.8% (95% CI: 4.5–5.2) of participants reported an ARI within 30 days before their participation in the national survey. LOWESS analysis revealed a near-linear relationship between vitamin D status and the cumulative frequency of ARI up to 25OHD levels around 30 ng/mL. After adjusting for season, demographic factors, and clinical data, 25OHD levels <30 ng/mL were associated with 58% higher odds of ARI (OR 1.58; 95% CI: 1.07–2.33) compared to levels ≥30 ng/mL. Among the 14,108 participants in NHANES 2001–2006, 25OHD levels were inversely associated with ARI. Carefully designed, randomized, controlled trials are warranted to determine the effect of optimizing vitamin D status on the risk of ARI.     

Vitamin D and Lung Outcomes in Elderly COVID-19 Patients

Background and aim: Vitamin D deficiency is frequently reported in patients with SARS-CoV-2 infection. The aim of this study was to correlate the 25OH-Vitamin D serum concentrations with clinical parameters of lung involvement, in elderly patients hospitalized for SARS-CoV-2 infection. Methods: Sixty-five consecutive COVID-19 patients (mean age 76 ± 13 years) and sixty-five sex- and age-matched control subjects (CNT) were analyzed. The following clinical parameters, including comorbidities, were collected at admission: type of pulmonary involvement, respiratory parameters (PaO₂, SO₂, PaCO₂, PaO₂/FiO₂), laboratory parameters (including 25OH-vitamin D, D-dimer, C-reactive protein). Results: Significantly lower vitamin D serum levels were found in COVID-19 patients than in CNT (median 7.9 vs. 16.3 ng/mL, p = 0.001). Interestingly, a statistically significant positive correlation was observed between vitamin D serum levels and PaO₂ (p = 0.03), SO₂ (p = 0.05), PaO₂/FiO₂ (p = 0.02), while a statistically significant negative correlation was found between vitamin D serum levels and D-dimer (p = 0.04), C-reactive protein (p = 0.04) and percentage of O₂ in a venturi mask (p = 0.04). A negative correlation was also observed between vitamin D serum levels and severity of radiologic pulmonary involvement, evaluated by computed tomography: in particular, vitamin D was found significantly lower in COVID-19 patients with either multiple lung consolidations (p = 0.0001) or diffuse/severe interstitial lung involvement than in those with mild involvement (p = 0.05). Finally, significantly lower vitamin D serum levels were found in the elderly COVID-19 patients who died during hospitalization, compared to those who survived (median 3.0 vs. 8.4 ng/mL, p = 0.046). Conclusions: This study confirms that 25OH-vitamin D serum deficiency is associated with more severe lung involvement, longer disease duration and risk of death, in elderly COVID-19 patients. The detection of low vitamin D levels also in younger COVID-19 patients with less comorbidities further suggests vitamin D deficiency as crucial risk factor at any age.     

Vitamin D Intake May Reduce SARS-CoV-2 Infection Morbidity in Health Care Workers

In the last 2 years, observational studies have shown that a low 25-hydroxyvitamin D (25(OH)D) level affected the severity of infection with the novel coronavirus (COVID-19). This study aimed to analyze the potential effect of vitamin D supplementation in reducing SARS-CoV-2 infection morbidity and severity in health care workers. Of 128 health care workers, 91 (consisting of 38 medical doctors (42%), 38 nurses (42%), and 15 medical attendants (16%)) were randomized into two groups receiving vitamin D supplementation. Participants of group I (n = 45) received water-soluble cholecalciferol at a dose of 50,000 IU/week for 2 consecutive weeks, followed by 5000 IU/day for the rest of the study. Participants of group II (n = 46) received water-soluble cholecalciferol at a dose of 2000 IU/day. For both groups, treatment lasted 3 months. Baseline serum 25(OH)D level in health care workers varied from 3.0 to 65.1 ng/mL (median, 17.7 (interquartile range, 12.2; 24.7) ng/mL). Vitamin D deficiency, insufficiency, and normal vitamin D status were diagnosed in 60%, 30%, and 10%, respectively. Only 78 subjects completed the study. Vitamin D supplementation was associated with an increase in serum 25(OH)D level, but only intake of 5000 IU/day was accompanied by normalization of serum 25(OH)D level, which occurred in 53% of cases. Neither vitamin D intake nor vitamin D deficiency/insufficiency were associated with a decrease in SARS-CoV-2 morbidity (odds ratio = 2.27; 95% confidence interval, 0.72 to 7.12). However, subjects receiving high-dose vitamin D had only asymptomatic SARS-CoV-2 in 10 (26%) cases; at the same time, participants who received 2000 IU/day showed twice as many SARS-CoV-2 cases, with mild clinical features in half of them.     

Applying Machine Learning to Determine 25(OH)D Threshold Levels Using Data from the AMATERASU Vitamin D Supplementation Trial in Patients with Digestive Tract Cancer

Some controversy remains on thresholds for deficiency or sufficiency of serum 25-hydroxyvitamin D (25(OH)D) levels. Moreover, 25(OH)D levels sufficient for bone health might differ from those required for cancer survival. This study aimed to explore these 25(OH)D threshold levels by applying the machine learning method of multivariable adaptive regression splines (MARS) in post hoc analyses using data from the AMATERASU trial, which randomly assigned Japanese patients with digestive tract cancer to receive vitamin D or placebo supplementation. Using MARS, threshold 25(OH)D levels were estimated as 17 ng/mL for calcium and 29 ng/mL for parathyroid hormone (PTH). Vitamin D supplementation increased calcium levels in patients with baseline 25(OH)D levels ≤17 ng/mL, suggesting deficiency for bone health, but not in those >17 ng/mL. Vitamin D supplementation improved 5-year relapse-free survival (RFS) compared with placebo in patients with intermediate 25(OH)D levels (18–28 ng/mL): vitamin D, 84% vs. placebo, 71%; hazard ratio, 0.49; 95% confidence interval, 0.25–0.96; p = 0.04. In contrast, vitamin D supplementation did not improve 5-year RFS among patients with low (≤17 ng/mL) or with high (≥29 ng/mL) 25(OH)D levels. MARS might be a reliable method with the potential to eliminate guesswork in the estimation of threshold values of biomarkers.     

COVID-19 and Vitamin D– a Systematic Review

IntroductionThe COVID-19 pandemic has strongly affected global healthcare systems. Prior epidemiological studies on different infectious diseases have shown a strong correlation between serum vitamin D levels and the incidence of certain infectious diseases. Vitamin D has an important immunomodulatory effect on innate immunity and exhibits several other mechanisms in the pathogenesis of the cytokine storm, which is one of the main contributing factors to fatality in COVID-19 patients.MethodsA keyword search was conducted in the PubMed and Google Scholar research databases. The abstracts and/or full texts of selected papers were further evaluated. Articles that fulfilled the inclusion criteria were included in the systematic review.ResultsThe 28 studies summarized in this review provide observational findings that vitamin D levels are related to the incidence, severity, and mortality rate of COVID-19 infection. The literature does not suggest that COVID-19 could be eliminated with supplementation of vitamin D, but there are implications that vitamin D deficiency might increase the risk for COVID-19 infection and severity of the disease progression.DiscussionCurrent literature and several guidelines support the supplementation of vitamin D as a reasonable strategy for correcting and preventing vitamin D deficiency. The recommended dose for maintaining normal 25(OH)D levels by consensus is 1000 to 2000 IU vitamin D daily for at-risk teens and adults.ConclusionVitamin D supplementation might play an important role in protecting from acute respiratory infections like the SARS CoV2, and in high-risk individuals with COVID 19 from progressing to critical clinical condition and reducing mortality.     

Serum 25-hydroxyvitamin D Concentration Significantly Decreases in Patients with COVID-19 Pneumonia during the First 48 Hours after Hospital Admission

It is unclear how ongoing inflammation in Coronavirus Disease 2019 (COVID-19) affects 25-hydroxyvitamin D (25[OH]D) concentration. The objective of our study was to examine serum 25(OH)D levels during COVID-19 pneumonia. Patients were admitted between 1 November and 31 December 2021. Blood samples were taken on admission (day 0) and every 24 h for the subsequent four days (day 1–4). On admission, 59% of patients were 25(OH)D sufficient (>30 ng/mL), and 41% had 25(OH)D inadequacy (<30 ng/mL). A significant fall in mean 25(OH)D concentration from admission to day 2 (first 48 h) was observed (30.7 ng/mL vs. 26.4 ng/mL; p < 0.0001). No subsequent significant change in 25(OH)D concentration was observed between day 2 and 3 (26.4 ng/mL vs. 25.9 ng/mL; p = 0.230) and day 3 and day 4 (25.8 ng/mL vs. 25.9 ng/mL; p = 0.703). The absolute 25(OH)D change between hospital admission and day 4 was 16% (4.8 ng/mL; p < 0.0001). On day 4, the number of patients with 25(OH)D inadequacy increased by 18% (p = 0.018). Therefore, serum 25(OH)D concentration after hospital admission in acutely ill COVID-19 patients should be interpreted with caution. Whether low 25(OH)D in COVID-19 reflects tissue level vitamin D deficiency or represents only a laboratory phenomenon remains to be elucidated in further prospective trials of vitamin D supplementation.     

Vitamin D insufficiency in children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation

BACKGROUND: Cystic fibrosis (CF) with pancreatic insufficiency is associated with poor absorption of fat and fat-soluble vitamins, including vitamin D. Pancreatic enzyme supplementation does not completely correct fat malabsorption in CF patients. OBJECTIVE: The objective of the study was to compare the vitamin D status of children, adolescents, and young adults with CF who were treated with routine vitamin D and pancreatic enzyme supplements with the vitamin D status of a healthy reference group from a similar geographic area. DESIGN: Growth, dietary intake, and serum concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and parathyroid hormone (PTH) were measured in 101 white subjects with CF and a reference group of 177 white subjects. RESULTS: The median daily vitamin D supplementation in the CF group was 800 IU. The mean +/- SD serum concentrations of 25(OH)D were 20.7 +/- 6.5 ng/mL in the CF group and 26.2 +/- 8.6 ng/mL in the reference group (P < 0.001). Vitamin D deficiency and insufficiency were defined as 25(OH)D concentrations < 11 ng/mL and < 30 ng/mL, respectively. Seven percent of the CF group and 2% of the healthy reference group were vitamin D deficient (P < 0.03). Ninety percent of the CF group and 74% of the healthy reference group were vitamin D insufficient (P < 0.01). Twenty-five percent of the CF group and 9% of the healthy reference group had elevated PTH (P < 0.006). The odds of vitamin D insufficiency in the CF group, compared with the healthy reference group, were 1.2 (95% CI: 1.1, 1.3) after adjustment for season and age. CONCLUSION: Despite daily vitamin D supplementation, serum 25(OH)D concentrations remain low in children, adolescents, and young adults with CF.     

A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health

Vitamin D₃ has many important health benefits. Unfortunately, these benefits are not widely known among health care personnel and the general public. As a result, most of the world’s population has serum 25-hydroxyvitamin D (25(OH)D) concentrations far below optimal values. This narrative review examines the evidence for the major causes of death including cardiovascular disease, hypertension, cancer, type 2 diabetes mellitus, and COVID-19 with regard to sub-optimal 25(OH)D concentrations. Evidence for the beneficial effects comes from a variety of approaches including ecological and observational studies, studies of mechanisms, and Mendelian randomization studies. Although randomized controlled trials (RCTs) are generally considered the strongest form of evidence for pharmaceutical drugs, the study designs and the conduct of RCTs performed for vitamin D have mostly been flawed for the following reasons: they have been based on vitamin D dose rather than on baseline and achieved 25(OH)D concentrations; they have involved participants with 25(OH)D concentrations above the population mean; they have given low vitamin D doses; and they have permitted other sources of vitamin D. Thus, the strongest evidence generally comes from the other types of studies. The general finding is that optimal 25(OH)D concentrations to support health and wellbeing are above 30 ng/mL (75 nmol/L) for cardiovascular disease and all-cause mortality rate, whereas the thresholds for several other outcomes appear to range up to 40 or 50 ng/mL. The most efficient way to achieve these concentrations is through vitamin D supplementation. Although additional studies are warranted, raising serum 25(OH)D concentrations to optimal concentrations will result in a significant reduction in preventable illness and death.     

Calcifediol (25OH Vitamin D3) Deficiency: A Risk Factor from Early to Old Age

Vitamin D deficiency is the main cause of nutritional rickets in children and osteomalacia in adults. There is consensus that nutritional access to vitamin D can be estimated by measuring serum concentrations of 25OHD and vitamin D deficiency can thus be considered as calcifediol deficiency. However, the threshold for vitamin D/calcifediol sufficiency remains a matter of debate. Vitamin D/calcifediol deficiency has been associated with musculoskeletal effects but also multiple adverse extra-skeletal consequences. If these consequences improve or if they can be treated with vitamin D supplementation is still unclear. Observational studies suggest a higher infection risk in people with low calcifediol levels. There is also a consistent association between serum calcifediol and cardiovascular events and deaths, but large-scale, long-term intervention studies did not show any benefit on cardiovascular outcomes from supplementation, at least not in subjects without clear vitamin D deficiency. Cancer risk also did not change with vitamin D treatment, although there are some data that higher serum calcifediol is associated with longer survival in cancer patients. In pregnant women, vitamin D supplementation decreases the risk of pre-eclampsia, gestational diabetes mellitus, and low birth weight. Although preclinical studies showed that the vitamin D endocrine system plays a role in certain neural cells as well as brain structure and function, there is no evidence to support a beneficial effect of vitamin D in neurodegenerative diseases. Vitamin D supplementation may marginally affect overall mortality risk especially in elderly subjects with low serum calcifediol concentrations.     

Vitamin d and rehabilitation: improving functional outcomes.

Vitamin D inadequacy is pandemic among rehabilitation patients in both inpatient and outpatient settings. Male and female patients of all ages and ethnic backgrounds are affected. Vitamin D deficiency causes osteopenia, precipitates and exacerbates osteoporosis, causes the painful bone disease osteomalacia, and worsens proximal muscle strength and postural sway. Vitamin D inadequacy can be prevented by sensible sun exposure and adequate dietary intake with supplementation. Vitamin D status is determined by measurement of serum 25-hydroxyvitamin D. The recommended healthful serum level is between 30 and 60 ng/mL. 25-Hydroxyvitamin D levels of >30 ng/mL are sufficient to suppress parathyroid hormone production and to maximize the efficiency of dietary calcium absorption from the small intestine. This can be accomplished by ingesting 1000 IU of vitamin D(3) per day, or by taking 50,000 IU of vitamin D(2) every 2 weeks. Vitamin D toxicity is observed when 25-hydroxyvitamin D levels exceed 150 ng/mL. Identification and treatment of vitamin D deficiency reduces the risk of vertebral and nonvertebral fractures by improving bone health and musculoskeletal function. Vitamin D deficiency and osteomalacia should be considered in the differential diagnosis of patients with musculoskeletal pain, fibromyalgia, chronic fatigue syndrome, or myositis. There is a need for better education of health professionals and the general public regarding the optimization of vitamin D status in the care of rehabilitation patients.     

Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action

The COVID-19 pandemic poses an unprecedented threat to human health, health care systems, public life, and economy around the globe. The repertoire of effective therapies for severe courses of the disease has remained limited. A large proportion of the world population suffers from vitamin D insufficiency or deficiency, with prevalence being particularly high among the COVID-19 high-risk populations. Vitamin D supplementation has been suggested as a potential option to prevent COVID-19 infections, severe courses, and deaths from the disease, but is not widely practiced. This article provides an up-to-date summary of recent epidemiological and intervention studies on a possible role of vitamin D supplementation for preventing severe COVID-19 cases and deaths. Despite limitations and remaining uncertainties, accumulating evidence strongly supports widespread vitamin D supplementation, in particular of high-risk populations, as well as high-dose supplementation of those infected. Given the dynamics of the COVID-19 pandemic, the benefit–risk ratio of such supplementation calls for immediate action even before results of ongoing large-scale randomized trials become available.     

Impact of vitamin D3 supplementation on COVID-19 vaccine response and immunoglobulin G antibodies in deficient women: A randomized controlled trial

BackgroundImmune levels were observed by giving vitamin D supplements to vitamin D deficient women who received the COVID-19 vaccine.MethodsIn the research, there were volunteer women who had received two doses of the COVID-19 vaccine who participated for a mean of more than 65 days. Group D (n=14 Pfizer-BioNTech, 2 Sinovac) received 150,000 IU of vitamin D supplementation, but group C (n=14 Pfizer-BioNTech), 3 Sinovac) no support was provided.ResultsWhen the consumption of vitamin D ends (D group), serum 25-Hydroxy Vitamin D levels were found to increase regularly in the (W3) last measurements (p=0.001). There was no significant difference in immunoglobulin M levels between groups D and C (Control group) (p=0.063). It was observed that the immunoglobulin G levels reached the peak level between the W1 and W2 measurements of the D group (P<0.001) and there were significant differences between the three sizes. Also, no correlation was found between the D group's initial serum immunoglobulin G and 25-Hydroxy Vitamin D levels. However, when the final measurements were examined, a significant positive correlation was found between immunoglobulin G and 25-Hydroxy Vitamin D levels (r=0.558, p=0.031).ConclusionIt was determined that serum IgG levels increased significantly depending on the duration between those who used vitamin D and those who did not and it was above the initial level for a long time. A positive and significant relationship was found between the last measured immunoglobulin G and 25(OH) D levels while vitamin D supplementation continued.Trial Registration: This study registered under ClinicalTrials.gov (Identifier no. NCT05447065)