Ellen M. Smith

Vitamin D Deficiency in Critically Ill Children

OBJECTIVE: Vitamin D influences cardiovascular and immune function. We aimed to establish the prevalence of vitamin D deficiency in critically ill children and identify factors influencing admission 25-hydroxy vitamin D (25(OH)D) levels. We hypothesized that levels would be lower with increased illness severity and in children with serious infections. METHODS: Participants were 511 severely or critically ill children admitted to the PICU from November 2009 to November 2010. Blood was collected near PICU admission and analyzed for 25(OH)D concentration by using Diasorin radioimmunoassay. RESULTS: We enrolled 511 of 818 (62.5%) eligible children. The median 25(OH)D level was 22.5 ng/mL; 40.1% were 25(OH)D deficient (level <20 ng/mL). In multivariate analysis, age and race were associated with 25(OH)D deficiency; summer season, vitamin D supplementation, and formula intake were protective; 25(OH)D levels were not lower in the 238 children (46.6%) admitted with a life-threatening infection, unless they had septic shock (n = 51, 10.0%) (median 25(OH)D level 19.2 ng/mL; P = .0008). After adjusting for factors associated with deficiency, lower levels were associated with higher admission day illness severity (odds ratio 1.19 for a 1-quartile increase in Pediatric Risk of Mortality III score per 5 ng/mL decrease in 25(OH)D, 95% confidence interval 1.10–1.28; P < .0001). CONCLUSIONS: We found a high rate of vitamin D deficiency in critically ill children. Given the roles of vitamin D in bone development and immunity, we recommend screening of those critically ill children with risk factors for vitamin D deficiency and implementation of effective repletion strategies.

Vitamin D deficiency is associated with anaemia among African Americans in a US cohort.

Vitamin D deficiency is highly prevalent in the US population and is associated with numerous diseases, including those characterised by inflammatory processes. We aimed to investigate the link between vitamin D status and anaemia, hypothesising that lower vitamin D status would be associated with increased odds of anaemia, particularly anaemia with inflammation. A secondary aim was to examine the effects of race in the association between vitamin D status and anaemia. We conducted a cross-sectional analysis in a cohort of generally healthy adults in Atlanta, GA (n 638). Logistic regression was used to evaluate the association between vitamin D status and anaemia. Serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/l (compared to 25(OH)D ≥ 50 nmol/l) was associated with anaemia in bivariate analysis (OR 2·64, 95% CI 1·43, 4·86). There was significant effect modification by race (P= 0·003), such that blacks with 25(OH)D < 50 nmol/l had increased odds of anaemia (OR 6·42, 95% CI 1·88, 21·99), v. blacks with 25(OH)D ≥ 50 nmol/l, controlling for potential confounders; this association was not apparent in whites. When categorised by subtype of anaemia, blacks with 25(OH)D < 50 nmol/l had significantly increased odds of anaemia with inflammation than blacks with serum 25(OH)D ≥ 50 nmol/l (OR 8·42, 95% CI 1·96, 36·23); there was no association with anaemia without inflammation. In conclusion, serum 25(OH)D < 50 nmol/l was significantly associated with anaemia, particularly anaemia with inflammation, among blacks in a generally healthy adult US cohort.

Critically Ill Children Have Low Vitamin D-Binding Protein, Influencing Bioavailability of Vitamin D.

RATIONALE Vitamin D deficiency, often defined by total serum 25-hydroxyvitamin D (25[OH]D) <20 ng/ml, is common in critically ill patients, with associations with increased mortality and morbidity in the intensive care unit. Correction of vitamin D deficiency in critical illness has been recommended, and ongoing clinical trials are investigating the effect of repletion on patient outcome. The biologically active amount of 25(OH)D depends on the concentration and protein isoform of vitamin D-binding protein (VDBP), which is also an acute-phase reactant affected by inflammation and injury. OBJECTIVES We performed a secondary analysis of a cohort of critically ill children in which we reported a high rate of vitamin D deficiency, to examine how VDBP level and genotype would impact vitamin D status. METHODS We prospectively enrolled 511 children admitted to the pediatric intensive care unit over a 12-month period. MEASUREMENTS AND MAIN RESULTS We measured serum VDBP in 479 children. We genotyped single nucleotide polymorphisms rs7041 and rs4588 in the VDBP gene (GC) to determine haplotypes GC1F, GC1S, and GC2 in 178 subjects who consented, then calculated bioavailable 25(OH)D from serum 25(OH)D, VDBP, albumin, and GC haplotype. The median serum VDBP level was 159 μg/ml (interquartile range, 108-221), lower than has been reported in healthy children. Factors predicting lower levels in multivariate analysis included age <1 year, nonwhite race, being previously healthy, 25(OH)D <20 ng/ml and greater illness severity. In the subgroup that was genotyped, GC haplotype had the strongest association with VDBP level; carriage of one additional copy of GC1S was associated with a 37.5% higher level (95% confidence interval, 31.9-44.8; P < 0.001). Bioavailable 25(OH)D was also inversely associated with illness severity (r = -0.24, P < 0.001), and ratio to measured total 25(OH)D was variable and related to haplotype. CONCLUSIONS Physiologic deficiency of 25(OH)D in critical illness may be more difficult to diagnose, given that lower VDBP levels increase bioavailability. Treatment studies conducted on the basis of total 25(OH)D level, without consideration of VDBP concentration and genotype, may increase the risk of falsely negative results.

Free 25-Hydroxyvitamin D Concentrations in Cystic Fibrosis

Background:Vitamin D deficiency is common in cystic fibrosis (CF), but there is no previous data on free 25-hydroxyvitamin D (25[OH]D) in CF or in relation to healthy individuals. Methods:We assessed total serum 25(OH)D concentration by chemiluminescence and serum free 25(OH)D concentration by both direct measurement (ELISA) and calculation, using serum albumin and vitamin D binding protein (VDBP) levels in 80 subjects (28 healthy adults, 25 clinically stable adults and children with CF and 27 adults experiencing a CF exacerbation). Results:Serum albumin and VDBP concentrations were lower in CF compared with healthy controls. Total serum 25(OH)D concentrations were positively correlated with both calculated and measured free 25(OH)D (P < 0.001 for both). Calculated and directly measured serum free 25(OH)D levels were positively correlated (P < 0.001). Conclusions:Serum levels of directly measured free 25(OH)D positively correlated with total 25(OH)D, suggesting that achieving sufficient total serum 25(OH)D may result in adequate free 25(OH)D levels in CF.

High-Dose Vitamin D3 Administration Is Associated With Increases in Hemoglobin Concentrations in Mechanically Ventilated Critically Ill Adults A Pilot Double-Blind, Randomized, Placebo-Controlled Trial

BACKGROUND Anemia and vitamin D deficiency are highly prevalent in critical illness, and vitamin D status has been associated with hemoglobin concentrations in epidemiologic studies. We examined the effect of high-dose vitamin D therapy on hemoglobin and hepcidin concentrations in critically ill adults. MATERIALS AND METHODS Mechanically ventilated critically ill adults (N = 30) enrolled in a pilot double-blind, randomized, placebo-controlled trial of high-dose vitamin D3 (D3 ) were included in this analysis. Participants were randomized to receive placebo, 50,000 IU D3 , or 100,000 IU D3 daily for 5 days (totaling 250,000 IU D3 and 500,000 IU D3 , respectively). Blood was drawn weekly throughout hospitalization for up to 4 weeks. Linear mixed-effects models were used to assess change in hemoglobin and hepcidin concentrations by treatment group over time. RESULTS At enrollment, >75% of participants in all groups had plasma 25-hydroxyvitamin D (25(OH)D) concentrations <30 ng/mL, and >85% of participants across groups were anemic. In the 500,000-IU D3 group, hemoglobin concentrations increased significantly over time (Pgroup × time = .01) compared with placebo but did not change in the 250,000-IU D3 group (Pgroup × time = 0.59). Hepcidin concentrations decreased acutely in the 500,000-IU D3 group relative to placebo after 1 week (P = .007). Hepcidin did not change significantly in the 250,000-IU D3 group. CONCLUSION In these critically ill adults, treatment with 500,000 IU D3 was associated with increased hemoglobin concentrations over time and acutely reduced serum hepcidin concentrations. These findings suggest that high-dose vitamin D may improve iron metabolism in critical illness and should be confirmed in larger studies.

Changes in Mineral Micronutrient Status During and After Pulmonary Exacerbation in Adults With Cystic Fibrosis

BACKGROUND Patients with cystic fibrosis (CF) may be at risk for micronutrient depletion, particularly during periods of illness and infection. The purpose of this study was to investigate serum micronutrient status over time in adults with CF initially hospitalized with a pulmonary exacerbation. MATERIALS AND METHODS This was an ancillary study of a multicenter trial investigating the role of high-dose vitamin D supplementation in 24 adults with CF (mean age, 29.6 ± 7.3 years). We measured serum concentrations of copper (Cu), iron (Fe), calcium (Ca), magnesium (Mg), potassium (K), and sulfur (S) in subjects at the beginning of a pulmonary exacerbation and again at 3 months. RESULTS Serum concentrations of Cu, Fe, and Ca were significantly lower at baseline compared with 3 months following the pulmonary exacerbation (Cu: baseline, 1.5 ± 0.6 vs 3 months, 1.6 ± 0.6 µg/mL, P = .027; Fe: 0.8 ± 0.3 vs 1.3 ± 1.1 µg/mL, P = .026; Ca: 9.7 ± 0.8 vs 10.8 ± 2.0 mg/dL, P = .024). Serum concentrations of K, Mg, and S did not change over time (K: baseline, 4.9 ± 0.3 vs 3 months, 5.1 ± 0.5 mEq/L; Mg: 1.8 ± 0.2 vs 2.0 ± 0.3 mg/dL; S: 1288.6 ± 343 vs 1309.9 ± 290 µg/mL; P > .05 for all). CONCLUSION Serum concentrations of Cu, Fe, and Ca increased significantly several months following recovery from acute pulmonary exacerbation in adults with CF. This may reflect decreased inflammation, improved food intake, and/or increased absorption following recovery.

DRIVING UP THE DOSE: IMPLICATIONS FOR HIGH-DOSE VITAMIN D THERAPY

Vitamin D is a unique nutrient and secosteroid hormone, in that it can be given either as a daily, weekly, or monthly supplement to correct vitamin D status owing to the long circulating half-life (approximately 2 to 3 weeks) of its major metabolite, 25-hydroxyvitamin D (25[OH]D) (1,2). There has been a great deal of interest in prescribing high-dose vitamin D for rapid correction of vitamin D status and/or as an adjunctive treatment for other diseases which may be modified by vitamin D therapy (3); however, there is no universally accepted regimen (4). In the United States, high-dose bolus vitamin D is typically given as a capsule of 50,000 IU of vitamin D2 or vitamin D3. Both forms of vitamin D are available over the counter or by prescription, though only vitamin D2 is U.S. Food and Drug Administration (FDA) approved (despite evidence that high-dose vitamin D3 may be more effective in raising serum 25[OH]D concentrations) (5). However, intramuscular high-dose vitamin D has not been widely available due to variability in the potency of different vitamin D preparations and is not currently FDA approved (6). In this issue of Endocrine Practice, Masood et al (7) report the evaluation of high-dose oral or intramuscular vitamin D3 therapy in patients with vitamin D deficiency (serum 25[OH]D 30 ng/mL at those time points; however, this did not improve the rate of vitamin D sufficiency. The investigators reported no differences in adverse events in response to the high-dose bolus of vitamin D. High-dose vitamin D therapy, termed Stoss therapy, originated in Germany in the late 1930s for the rapid repletion of vitamin D status in the treatment or prevention of rickets. Since that time, high-dose vitamin D therapy has evolved as a strategy not only for rapid repletion in rickets but as a treatment and maintenance regimen in conditions potentially modifiable by vitamin D, including cystic fibrosis, chronic kidney disease, and infections (8,9). Though clinical trials of high-dose vitamin D in various disease states have been mixed (3), as the role of vitamin D in health continues to be defined, other conditions in which rapid repletion of vitamin D status may be beneficialhave emerged, including infection, inflammation, and anemia (10). With the widespread distribution of CYP27B1 (the enzyme that converts 25[OH]D to 1,25-dihydroxyvitamin D [1,25(OH)2D]) throughout the body, including in immune cells, there has been much attention given to extraskeletal functions of vitamin D. One such function is the role of vitamin D in enhancing immunity, with increasing evidence for anti-inflammatory properties of vitamin D (11). It has been demonstrated that vitamin D can upregulate expression of the antimicrobial peptide cathelicidin through intracrine/paracrine activation of 25(OH)D to the active, hormonal 1,25(OH)2D in macrophages in response to a pathogenic stimulus. Given the intracrine/paracrine activation of 25(OH)D, it follows that adequate serum concentrations are needed to support the local activation of vitamin D. Therefore, high-dose vitamin D therapy, as a useful tool to rapidly replete vitamin D status, may support immune function in the context of an acute or chronic infection (12). Recent evidence also suggests that vitamin D may favorably influence anemia, particularly in the context of inflammation, by decreasing pro-inflammatory cytokines and the antimicrobial peptide hepcidin (the hormonal regulator of systemic iron concentrations). Under pro-inflammatory conditions, hepcidin is elevated, resulting in decreased iron absorption and sequestration of iron in macrophages, which may leave insufficient iron available to support hemoglobin synthesis and erythropoiesis. Vitamin D has been found to directly suppress hepcidin expression and downregulate hepcidin-stimulatory pro-inflammatory cytokines, which may help to improve anemia (13,14). Therefore, in the context of inflammation and conditions where anemia is prevalent, including chronic kidney disease, cardiovascular disease, and critical illness, high-dose vitamin D supplementation may be beneficialin rapidly repleting and maintaining 25(OH)D concentrations and may serve as a complement to other treatment regimens to improve anemia. However, trials evaluating the dosing and frequency of administration are needed to determine the optimal efficacy of high-dose vitamin D therapy in improving anemia and supporting immunity. While high-dose vitamin D may be a promising therapy in certain conditions, there are other circumstances in which bolus high-dose vitamin D may have limited efficacy, including in lactating mothers, where daily vitamin D is necessary to provide adequate daily amounts of vitamin D in breast milk for the infant (15). In addition, patients with hypercalcemic disorders such as hyperparathyroidism and those with chronic granulomatous disease prone to elevated extrarenal production of 1,25(OH)2D may have increased risk of hypercalcemia when given high-dose vitamin D for a prolonged period of time. Caution should be exercised, and pre-existing conditions that could be exacerbated by high-dose vitamin D therapy should be evaluated when considering high-dose vitamin D therapy. Patients should be screened for hypercalcemia and hyper-calciuria prior to high-dose vitamin D therapy, and urinary and serum calcium levels should be monitored during vitamin D treatment so as to avoid toxicity. There are some data that very high-dose vitamin D therapy may increase the risk of fractures; however, the cause of this is not known (3). High-dose vitamin D therapy is effective in rapidly raising 25(OH)D concentrations and has historically been used to treat rickets. Implications in other disease states are continuing to be elucidated, though actions in immunity and anemia appear promising. Further research is needed to establish the optimal dosing regimens in various groups. This paper by Masood et al (7) demonstrates the efficacy and safety of both oral and intramuscular administration of high-dose cholecalciferol in correcting vitamin D deficiency in the large majority of patients by 2 months. The results presented in this paper indicate that intramuscular administration of vitamin D3 may provide a more sustained increase in 25(OH)D concentrations compared to oral administration. However, intramuscular injections have the limitation of potential discomfort of administration, and the bioavailability of the vitamin D may be affected by the vehicle of the preparation. Despite these limitations, intramuscular formulations, though not commonly used in the United States, may offer an effective alternative route of administration where nonadherence is a concern or in populations at risk for vitamin D malabsorption or in those intolerant of oral medications. Future research on long-term maintenance strategies post–bolus dosing will be helpful in determining optimal dosing regimens to support the actions of vitamin D in various health conditions.

The Vitamin D for Enhancing the Immune System in Cystic Fibrosis (DISC) trial: Rationale and design of a multi-center, double-blind, placebo-controlled trial of high dose bolus administration of vitamin D3 during acute pulmonary exacerbation of cystic fibrosis

Vitamin D deficiency is highly prevalent in children and adults with cystic fibrosis (CF). Recent studies have found an association between vitamin D status and risk of pulmonary exacerbations in children and adults with CF. The ongoing Vitamin D for enhancing the Immune System in Cystic fibrosis (DISC) study, a multi-center, double-blind, randomized, placebo-controlled trial, will test the hypothesis of whether high dose vitamin D given as a single oral bolus of 250,000 IU to adults with CF during a pulmonary exacerbation followed by a maintenance dose of vitamin D will improve time to next pulmonary exacerbation and re-hospitalization, improve survival and lung function compared to placebo and reduce the rates of pulmonary exacerbation. Subjects will be randomized 1:1 at each clinical site to vitamin D or placebo within 72 h of hospital admission for pulmonary exacerbation. Clinical follow-up visits will occur at 1, 2, 3, and 7 days, and 1, 3, 6 and 12 months after randomization. Blood and sputum will be collected and determination of clinical outcomes will be assessed at each visit. The primary endpoint will be the time to next pulmonary exacerbation requiring antibiotics, re-hospitalization or death. The secondary endpoints will include lung function assessed by forced expiratory volume in 1 s (FEV1), blood markers of inflammatory cytokines, anti-microbial peptide expression by peripheral blood mononuclear cells and circulating concentrations in blood. Other exploratory endpoints will examine the phenotype of neutrophils and monocyte/macrophages in sputum. Nutritional status will be assessed by 3 day food records and food frequency questionnaire.