25-Hydroxyvitamin D in Cancer Patients Admitted to Palliative Care: A Post-Hoc Analysis of the Swedish Trial 'Palliative-D'.

The purpose of this study is to explore 25-hydroxyvitamin D (25-OHD) levels in patients with cancer in the palliative phase in relation to season, sex, age, tumor type, colectomy, and survival. To this end, we performed a post-hoc analysis of 'Palliative-D', a randomized placebo-controlled, double-blind trial investigating the effect of daily supplementation with 4000 IU of vitamin D for 12 weeks on pain in patients in palliative cancer care. In the screening cohort (n = 530), 10% of patients had 25-OHD levels < 25 nmol/L, 50% < 50, and 84% < 75 nmol/L. Baseline 25-OHD did not differ between seasons or tumor type and was not correlated with survival time. In vitamin D deficient patients supplemented with vitamin D (n = 67), 86% reached sufficient levels, i.e., >50 nmol/L, after 12 weeks. An increase in 25-OHD was larger in supplemented women than in men (53 vs. 37 nmol/L, p = 0.02) and was not affected by season. In the placebo-group (n = 83), decreased levels of 25-OHD levels were noted during the study period for patients recruited during the last quarter of the year. In conclusion, cancer patients in palliative phase have adequate increase in 25-OHD after vitamin D supplementation regardless of season, age, tumor type, or colectomy.

'Palliative-D'-Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial.

The aim of the 'Palliative-D' study was to test the hypothesis that correction of vitamin D deficiency reduces opioid use in cancer patients admitted to palliative care. A multicenter randomized, placebo-controlled, double-blind trial in three home-based palliative care facilities in Sweden was performed. Patients with advanced cancer and 25-hydroxyvitamin D < 50 nmol/L were randomized to vitamin D3 4000 IU/day or placebo for 12 weeks. The primary endpoint was the difference of long-acting opioid use (fentanyl ug/h) between the groups during 12 weeks, based on four time points. Secondary outcomes included changes in antibiotic use, fatigue and Quality of Life (QoL). A total of 244 patients were randomized, and 150 patients completed the 12 weeks. The major reason for drop-out was death due to cancer. The vitamin D-group had a significantly smaller increase of opioid doses compared to the placebo-group; beta coefficient -0.56 (p = 0.03), i.e., 0.56 µg less fentanyl/h per week with vitamin D treatment. Vitamin D-reduced fatigue assessed with ESAS was -1.1 points after 12 weeks (p < 0.01). Antibiotic use or QoL did not differ significantly between the groups. The treatment was safe and well-tolerated. In conclusion, correction of vitamin D deficiency may have positive effects on opioid use and fatigue in palliative cancer patients, but only in those with a survival time more than 12 weeks.

Vitamin D and Fatigue in Palliative Cancer: A Cross-Sectional Study of Sex Difference in Baseline Data from the Palliative D Cohort.

Background: Fatigue is one of the most distressing symptoms in patients with advanced cancer. Previous studies have shown an association between low vitamin D levels and fatigue. Objectives: The aim of this study was to investigate the association between vitamin D levels and self-assessed fatigue in cancer patients admitted to palliative care, with focus on possible sex differences. Design: This is a cross-sectional study. Subjects: Baseline data from 530 screened patients, 265 women and 265 men, from the randomized placebo-controlled trial "Palliative-D" were analyzed. Measurements: Vitamin D status was measured as 25-hydroxyvitamin D (25-OHD) and fatigue was assessed with EORTC-QLQ-PAL15 and with Edmonton Symptom Assessment System (ESAS). Results: In men, there was a significant correlation between 25-OHD and fatigue measured with the "Tiredness question" (Q11) in EORTC-QLQ-PAL15 (p < 0.05), where higher 25-OHD levels were associated with less fatigue. No correlation between 25-OHD and fatigue was seen for women. Fatigue measured with ESAS did not show any significant association with 25-OHD levels neither in men nor in women. Conclusion: Low vitamin D levels were associated with more fatigue in men but not in women. The study underscores the importance of subgroup analysis of men and women when evaluating the effect of vitamin D in clinical trials since the effect may differ between the sexes. The ongoing "Palliative-D study" will reveal whether vitamin D supplementation may counteract fatigue in both men and women. ClinicalTrial.gov: NCT03038516.

Fluctuations in hematological athlete biological passport biomarkers in relation to the menstrual cycle.

The interpretation of athlete biological passport (ABP) is strengthened by understanding the natural fluctuations in its biological parameters. Here we have assessed the influence of the menstrual cycle on the hematological module of the ABP. Seventeen women with regular menses were included. Blood samples were collected once a week for two consecutive cycles and analyzed for hematological parameters. Menstrual phases were hormonally determined. The intra-individual variation in the hematological parameters was similar between the two cycles. Reticulocyte percentage was significantly lower in the follicle phase (median 0.95%) than in the ovulatory (median 1.10%) and luteal phases (median 1.16%), P = 0.006, whereas no differences were found in hemoglobin concentration, hematocrit, red blood cell count, or red blood cell indices. When the values were entered into the ABP model, findings outside the program-calculated individual thresholds were identified in two participants. One woman showed an atypical low OFF-score in the last sample collected, mainly because of increased reticulocyte percentage. This was likely a response to treated insufficient iron stores. One woman displayed an atypical hemoglobin value at the lower limit 2 weeks after ovulation, which was likely due to fluctuations in plasma volume. In conclusion, the ABP parameters in general are stable throughout the menstrual cycle. Significant differences between the menstrual phases were found in reticulocytes; however, the variation was not related to findings outside the individual thresholds, except in one individual. Moreover, our results highlight the importance of having information about iron supplementation available when evaluating hematological passports.

Are Vitamin D3 Tablets and Oil Drops Equally Effective in Raising S-25-Hydroxyvitamin D Concentrations? A Post-Hoc Analysis of an Observational Study on Immunodeficient Patients.

BACKGROUND: Vitamin D3 supplements are available as tablets or oil drops, but there is no consensus as to whether either of these preparations is more effective than the other. METHODS: We compared the effectiveness of tablets versus oil in raising S-25-hydroxyvitamin D (S-25-OHD) in plasma by re-analyzing data from a previously performed observational study in which immunodeficient patients with S-25-OHD concentrations <75 nmol/L were randomly prescribed vitamin D3 tablets (1600 IU/day) or vitamin D3 oil-drops (1500 IU/day) for twelve months. Tablets and oil were compared for the effect on S-25-OHD concentrations after 3-5 months and antibiotic use. RESULTS: Data on S-25-OHD after ≥ 3 months was available for 137 patients treated with tablets and 69 with oil drops. Both groups exhibited a significant increase in S-25-OHD-oil-drops from 55 to 86 nmol/L and tablets from 52 to 87 nmol/L-with no difference between groups (p = 0.77). In a subgroup of patients without immunoglobulin replacement, vitamin D3 supplementation with oil drops (n = 34) but not with tablets (n = 60) resulted in significantly lower antibiotic administration (p < 0.001 and p = 0.58). CONCLUSION: Vitamin D3 supplementation with tablets and oil drops were equally efficient in raising S-25-OHD concentrations. Only oil drops caused a reduction in antibiotic consumption in immuno-deficient patients who did not receive immunoglobulin replacement.

Vitamin D binding protein is not affected by high-dose vitamin D supplementation: a post hoc analysis of a randomised, placebo-controlled study.

OBJECTIVES: Vitamin D binding protein (VDBP) is the main transporter of 25-hydroxyvitamin D3 (25-OHD) in the circulation. The aim of this study was to investigate if VDBP is affected by high dose vitamin D supplementation and if VDBP-levels correlate with free 25-OHD. Correlation between free 25-OHD measured with ELISA and total 25-OHD in the circulation was also analysed. Plasma samples from a randomized, controlled trial in which persistent MRSA-carriers were randomized to treatment with vitamin D, 4000 IE/day, (n = 27) or placebo (n = 32) for 12 months were used. Plasma from baseline and after 6 months of treatment were analysed for VDBP, 25-OHD and free 25-OHD. RESULTS: VDBP levels were not affected by vitamin D treatment, although the 25-OHD levels increased significantly in the vitamin D treated subjects. There was a strong correlation between 25-OHD and free 25-OHD (r2 = 0.68, p < 0.0001), while there was no correlation between VDBP and free 25-OHD. Thus, our data shows that VDBP are not affected by vitamin D supplementation and the levels of VDBP are not associated with the free fraction of 25-OHD. Since there was a strong correlation between free 25-OHD and total 25-OHD it appears to be sufficient to measure only total 25-OHD. Trial registration http://www.clinicaltrials.gov ; NCT02178488. Date of registration: June 30, 2014; Date of enrolment of the first participant: Dec 1, 2014.

Vitamin D supplementation to persistent carriers of MRSA-a randomized and placebo-controlled clinical trial.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to all beta-lactam antibiotics and can cause severe infections that are difficult to treat. Eradication strategies with conventional antibiotics are not always effective and alternative approaches are warranted. Here, we tested the hypothesis that daily supplementation with vitamin D for 12 months would reduce MRSA carriage rates among a group of persistent carriers. This was a double-blind, placebo-controlled randomized trial with n = 65 persistent MRSA carriers with 25-hydroxy vitamin D3 (25OHD) < 75 nmol/L, who were followed up with bacterial cultures at baseline and every 3 months for 1 year. The primary endpoint was the decline in MRSA positivity during the study period. The study was conducted in two MRSA outpatient clinics at the Karolinska University Hospital, Stockholm, Sweden. In total, n = 65 persistent MRSA carriers were randomized and n = 3 were lost to follow-up. Only patients deficient in vitamin D (< 75 nmol/L) were included. Vitamin D (4000 IU) or placebo/day was administered for 12 months. The decline in MRSA positivity was equal in the vitamin D and placebo group during the study period (OR, 1.00; 95% CI, 0.97-1.03; p = 0.928) and approximately 40% in both groups were MRSA-negative after 12 months. The vitamin D group produced 103 positive cultures out of 318 cultures (32.4%) from nose, throat, and perineum over the study period, whereas the placebo group produced 135/393 positive cultures (34.0%) (Fisher's exact test, p = 0.94). Vitamin D supplementation did not influence MRSA carriage. Thus, available data does not support vitamin D supplementation to persistent MRSA carriers.Trial registration: www.clinicaltrials.gov ; NCT02178488.

Tactile massage reduces rescue doses for pain and anxiety: an observational study.

OBJECTIVES: The aim of this study was to evaluate the effect of tactile massage (TM) on palliative care patients. METHOD: An observational study at a hospice ward in Sweden was carried out. Forty-one palliative patients were offered TM, at an average of three treatments per patient. Before and after every treatment, self-assessed pain, well-being and anxiety according to the Edmonton Symptom Assessment Scale (0-10) were recorded. In addition, the number of rescue doses for pain and anxiety was monitored 24 hours before and after the treatment and in two consecutive days before the patients were offered TM (control data). RESULTS: TM resulted in improvement of self-assessed pain by 1.7 points (SD 1.6), anxiety by 2.3 points (SD 2.0) and well-being by 2.6 points (SD 1.4). The number of rescue doses for pain was reduced from 1.6 to 0.84 doses/patient (P<0.001) and for anxiety from 0.52 to 0.24 doses/patient (P<0.01). The number of rescue doses was not changed in the same patients in two consecutive days before the patients were offered TM. The effect was evident already after the first treatment and did not increase further with repeated treatments. No patients reported any harmful effects of the treatment. CONCLUSION: TM reduced the need for administration of rescue doses for pain and anxiety and improved well-being in palliative care patients. Larger randomised studies with parallel control groups are needed to confirm the findings from this observational pilot study.

Vitamin D in Pain Management.

Vitamin D is a hormone synthesized in the skin in the presence of sunlight. Like other hormones, vitamin D plays a role in a wide range of processes in the body. Here we review the possible role of vitamin D in nociceptive and inflammatory pain. In observational studies, low vitamin D levels have been associated with increased pain and higher opioid doses. Recent interventional studies have shown promising effects of vitamin D supplementation on cancer pain and muscular pain-but only in patients with insufficient levels of vitamin D when starting intervention. Possible mechanisms for vitamin D in pain management are the anti-inflammatory effects mediated by reduced cytokine and prostaglandin release and effects on T-cell responses. The recent finding of vitamin D-mediated inhibition of Prostaglandin E2 (PGE2) is especially interesting and exhibits a credible mechanistic explanation. Having reviewed current literature, we suggest that patients with deficient levels defined as 25-hydroxyvitamin D (25-OHD) levels <30 nmol/L are most likely to benefit from supplementation, while individuals with 25-OHD >50 nmol/L probably have little benefit from supplementation. Our conclusion is that vitamin D may constitute a safe, simple and potentially beneficial way to reduce pain among patients with vitamin D deficiency, but that more randomized and placebo-controlled studies are needed before any firm conclusions can be drawn.

Vitamin D supplementation to palliative cancer patients: protocol of a double-blind, randomised controlled trial 'Palliative-D'.

BACKGROUND: According to a small pilot study on palliative cancer patients at our ward, vitamin D supplementation had beneficial effects on pain (measured as opioid consumption), infections and quality of life (QoL) without having any significant side effects. OBJECTIVE: The primary objective of the 'Palliative-D' study is to test the hypothesis that vitamin D supplementation for 12 weeks reduces opioid consumption. The secondary objectives are to study if reduction of antibiotic consumption and fatigue as well as improvement in QoL assessments can be observed. Effect on the 25-hydroxy vitamin D (25-OHD) levels in serum after 12 weeks of treatment will be studied, as well as the change in opioid dose in relation to genetic polymorphism in genes involved in the effect and metabolism of vitamin D. METHOD: A randomised, double-blind placebo-controlled multicentre trial has been designed. The trial will include 254 adult palliative cancer patients with 25-OHD levels <50 nmol/L and a life expectancy of more than 3 months recruited from two advanced palliative home care centres in Stockholm. Included patients will be randomly assigned to 12 weeks of treatment with cholecalciferol (vitamin D3) 4000 IU/day or placebo. The study will start in November 2017 and will finish in December 2019. The study is approved by the Regional Ethical Committee, Dnr2017/405-31/1, by the Swedish Medical Products Agency, EudraCT: 2017-000268-14, and is registered at Clinicaltrial.gov: NCT03038516. The study is financed with research grants from the Swedish Cancer Society and the Stockholm County Council.

Vitamin D supplementation to palliative cancer patients shows positive effects on pain and infections-Results from a matched case-control study.

BACKGROUND: We previously showed an association between low vitamin D levels and high opioid doses to alleviate pain in palliative cancer patients. The aim of this case-controlled study was to investigate if vitamin D supplementation could improve pain management, quality of life (QoL) and decrease infections in palliative cancer patients. METHODS: Thirty-nine palliative cancer patients with levels of 25-hydroxyvitamin D < 75 nmol/L were supplemented with vitamin D 4000 IE/day, and were compared to 39 untreated, matched "control"-patients from a previous study at the same ward. Opioid doses, antibiotic consumption and QoL-scores measured with the Edmonton Symptom Assessment Scale (ESAS) were monitored. The primary endpoint was the change from baseline after 1 and 3 months compared between the groups using linear regression with adjustment for a potential cofounding factor. RESULTS: After 1 month the vitamin D treated group had a significantly decreased fentanyl dose compared to the untreated group with a difference of 46 µg/h; 95% CI 24-78, which increased further at 3 months to 91 µg/h; 95% CI 56-140 µg/h. The ESAS QoL-score improved in the Vitamin D group the first month; -1.4; 95% CI -2.6 - (-0.21). The vitamin D-treated group had significantly lower consumption of antibiotics after 3 months compared to the untreated group, the difference was -26%; 95%CI -0.41%-(-0.12%). Vitamin D was well tolerated by all patients and no adverse events were reported. CONCLUSION: Vitamin D supplementation to palliative cancer patients is safe and improvement in pain management is noted as early as 1 month after treatment. Decreased infections are noted 3 months after vitamin D treatment. The results from this pilot-study have been used for the power-calculation of a future randomized, placebo-controlled, double-blind study called "Palliative-D" that will start in Nov 2017 and will include 254 palliative cancer patients.

Vitamin D3 Supplementation and Antibiotic Consumption - Results from a Prospective, Observational Study at an Immune-Deficiency Unit in Sweden.

BACKGROUND: Vitamin D supplementation has been proposed to improve clinical symptoms during respiratory tract infections (RTIs), but results from randomized, placebo-controlled trials (RCT) are inconclusive. Previously, we performed an RCT in patients with various immune-disorders and observed that supplementation with 4000 IU vitamin D/day during 12 months significantly reduced antibiotic consumption and RTIs. This formed the basis for new guidelines at our unit; i.e. patients with insufficient levels of 25-hydroxyvitamin D (≤75 nmol/L) are now offered vitamin D supplementation. The aim of this prospective follow-up study was to evaluate the outcome of these new recommendations with regard to antibiotic consumption in our unit. METHOD: 277 patients with insufficiency were supplemented with vitamin D3, 1500-1600 IU/day for 12 months. Each patient was its own control and data on antibiotic consumption was monitored 12 months before and 12 months after initiation of vitamin D3 supplementation. RESULTS: Vitamin D3 supplementation resulted in a significantly reduced antibiotic consumption, from 20 to 15 days/patient (p<0.05). The number of antibiotic-free patients increased from 52 to 81 after vitamin D3 supplementation; OR 1.79; 95% CI 1.20-2.66 (p<0.01). The number of antibiotic-prescriptions decreased significantly, a finding that mainly was attributed to a reduction of respiratory tract antibiotics (p<0.05). Subgroup analysis showed that only patients without immunoglobulin substitution (n = 135) had a significant effect of vitamin D supplementation. CONCLUSION: Vitamin D3 supplementation of 1600 IE /day is safe to use in immunodeficient patients with 25-OHD levels less than 75 nmol/L and significantly reduced the antibiotic consumption in patients without immunoglobulin substitution.

Vitamin D and patients with palliative cancer.

Vitamin D is a hormone that is synthesised in the skin in the presence of sunlight. Sufficient vitamin D levels are important-not only for a healthy skeleton-but also for a healthy immune system. Many patients with cancer have insufficient vitamin D levels, and low vitamin D levels are associated with increased 'all-cause mortality' and especially mortality due to cancer. Low vitamin D levels have also been associated with increased risk of infections, increased pain, depressive disorders and impaired quality of life. We review the role of vitamin D in the immune system, in relation to cancer disease, pain and depression. We have recently performed an observational study in 100 patients with palliative cancer in Sweden. The main result was that low vitamin D levels were associated with higher opioid dose, that is, more pain. We also describe a case report where vitamin D supplementation resulted in radically decreased opioid dose, less pain and better well-being. Vitamin D supplementation is not connected with any adverse side effects and is easy to administrate. Thus, we hypothesise that vitamin D-supplementation to patients with palliative cancer might be beneficial and could improve their well-being, decrease pain and reduce susceptibility to infections. However, more clinical studies in this field are needed before firm conclusions can be drawn.

Effect of Statin Treatment on Plasma 4ß-Hydroxycholesterol Concentrations.

The endogenous oxysterol 4ß-hydroxycholesterol may be used as a marker for the drug-metabolizing enzymes cytochrome P450 3A (CYP3A). The primary aim of this study was to investigate the effect of statin treatment on plasma 4ß-hydroxycholesterol concentrations. Plasma samples from a previously performed clinical study where gallstone patients had been treated with placebo (n = 6), 20 mg fluvastatin (n = 9) or 80 mg atorvastatin (n = 9) daily for 4 weeks were analysed. Hepatic CYP3A mRNA levels had previously been shown to be unchanged in all three treatment groups. Plasma 4ß-hydroxycholesterol did not change significantly (p = 0.92) in the placebo group, but treatment with low-dose fluvastatin or high-dose atorvastatin resulted in reductions in plasma concentration of 10.7% (p < 0.05) and 36.5% (p < 0.01), respectively. However, the 4ß-hydroxycholesterol/cholesterol ratio did not change significantly for the patients receiving placebo or patients receiving low-dose fluvastatin. The ratio for patients receiving high-dose atorvastatin increased by 12% (p < 0.05). In conclusion, the total plasma cholesterol level is an important determinant for the plasma 4ß-hydroxycholesterol level.

Vitamin D supplementation improves well-being in patients with frequent respiratory tract infections: a post hoc analysis of a randomized, placebo-controlled trial.

BACKGROUND: The aim of this study was to test the hypothesis that vitamin D supplementation improves well-being in patients with frequent respiratory tract infections (RTIs). We performed a post hoc analysis of a randomized, placebo-controlled and double-blind study in which patients with frequent RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124). At the last visit of the study, patients were asked to perform a general assessment of their well-being during the study. RESULTS: The majority of patients, both placebo- and vitamin D treated, stated that they had felt 'better' during the study; 52% in the placebo group and 70% in the vitamin D group, relative risk 1.3 (95% CI 1.0-1.8; p = 0.06, Fisher's exact test). Statement of better well-being was associated with an increase in 25-hydroxyvitamin D (25-OHD) levels (p < 0.001). In contrast, worse well-being was associated with unchanged 25-OHD levels. Notably, a 25-OHD level above 100 nmol/L at the study end was associated with a higher chance of having a better well-being (p < 0.01). Four patients on anti-depressive treatment could terminate their antidepressant medication during the study. These patients had a significant increase in 25-OHD levels from low levels at study-start. CONCLUSION: Vitamin D supplementation to patients with frequent RTIs might be beneficial, not only for infections, but also for their general well-being. However, given the post hoc design of this study, these findings need to be confirmed in additional clinical trials before firm conclusions can be drawn. TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT01131858), registered March 22, 2010.

Vitamin D supplementation to patients with frequent respiratory tract infections: a post hoc analysis of a randomized and placebo-controlled trial.

BACKGROUND: Vitamin D is considered to be important for a healthy immune system. The aim of this study was to test the hypothesis that vitamin D supplementation reduces number of respiratory tract infections (RTIs) and prolong the time to the first RTI in adult patients with frequent RTIs. METHODS: We performed a post hoc analysis of a randomized, placebo-controlled and double-blinded study, where adult patients with a high burden of RTIs were randomized to placebo or vitamin D (4000 IE/day for 1 year, n = 124 in the per protocol cohort presented here). RESULTS: Vitamin D supplementation increased the probability to stay free of RTI during the study year (RR 0.64, 95% CI 0.43-0.94). Further, the total number of RTIs was also reduced in the vitamin D-group (86 RTIs) versus placebo (120 RTIs; p = 0.05). Finally, the time to the first RTI was significantly extended in the vitamin D-group (HR 1.68, 95% CI 1.03-2.68, p = 0.0376). CONCLUSION: Vitamin D supplementation was found to significantly increase the probability of staying infection free during the study period. This finding further supports the notion that vitamin D-status should be monitored in adult patients with frequent RTIs and suggests that selected patients with vitamin D deficiency are supplemented. This could be a safe and cheap way to reduce RTIs and improve health in this vulnerable patient population. The original trial was registered at http://www.clinicaltrials.gov (NCT01131858).

Low vitamin D levels are associated with higher opioid dose in palliative cancer patients--results from an observational study in Sweden.

BACKGROUND: Vitamin D deficiency is common among palliative cancer patients and has been connected to an increased risk for pain, depressions and infections. Therefore we wanted to test the hypothesis that low 25-hydroxyvitamin D (25OHD) levels are associated with higher opioid dose, higher infectious burden and impaired quality of life in palliative cancer patients. The secondary aim was to investigate the association between 25OHD-levels and survival time. METHOD: In this prospective, observational study in palliative cancer-patients (n = 100) we performed univariate and multiple linear regression analysis to assess the association of 25OHD levels with opioid dose, infectious burden (antibiotic consumption), quality of life (Edmonton Symptom Assessment Scale, ESAS) and survival time, controlling for potential confounding factors. RESULTS: The median 25OHD level was 40 nmol/L (range 8-154 nmol/L). There was a significant association between 25OHD levels and opioid dose, beta coefficient -0.67; p=0.02; i.e. a low 25OHD level was associated with a higher opioid dose. This association remained significant after adjustment for stage of the cancer disease in a multivariate analysis, beta coefficient -0.66; p = 0.04. There was no association between 25OHD levels and antibiotic use or quality of life. Univariate cox regression analysis showed a weak correlation between survival time and 25OHD levels (p<0.05). However, decreased albumin levels and increased CRP levels were superior markers to predict survival time; p<0.001 for both analyses. CONCLUSION: Low 25OHD-levels are associated with increased opioid consumption in palliative cancer patients. Future interventional studies are needed to investigate if pain can be reduced by vitamin D supplementation in these patients. In addition, this study confirms previous findings that low albumin and increased CRP levels are useful markers for survival time in palliative cancer patients.

Vitamin D and Respiratory Tract Infections: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Low levels of 25-OH vitamin D are associated with respiratory tract infection (RTI). However, results from randomized controlled trials are inconclusive. Therefore, we performed a systematic review and meta-analysis to assess the preventive effect of vitamin D supplementation on RTI. METHODS: Randomized, controlled trials of vitamin D for prevention of RTI were used for the analysis. The risks of within-trial and publication bias were assessed. Odds ratios of RTI were pooled using a random-effects model. Heterogeneity was assessed using Cochran's Q and I(2). Meta-regressions and subgroup analyses were used to assess the influence of various factors on trial outcome. The pre-defined review protocol was registered at the PROSPERO international prospective register of systematic reviews, registration number CRD42013003530. FINDINGS: Of 1137 citations retrieved, 11 placebo-controlled studies of 5660 patients were included in the meta-analysis. Overall, vitamin D showed a protective effect against RTI (OR, 0.64; 95% CI, 0.49 to 0.84). There was significant heterogeneity among studies (Cohran's Q p<0.0001, I(2) = 72%). The protective effect was larger in studies using once-daily dosing compared to bolus doses (OR = 0.51 vs OR = 0.86, p = 0.01). There was some evidence that results may have been influenced by publication bias. INTERPRETATION: Results indicate that vitamin D has a protective effect against RTI, and dosing once-daily seems most effective. Due to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution.

Serum levels of 25-hydroxyvitamin D and the CYP3A biomarker 4ß-hydroxycholesterol in a high-dose vitamin D supplementation study.

The primary aim was to study the relationship between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol, which is an endogenous biomarker of the drug-metabolizing CYP3A enzymes. In addition, the relationship between this biomarker and inflammation, measured as C-reactive protein (CRP), was investigated. Serum samples were used from a recently performed clinical trial in patients with antibody deficiency or increased susceptibility to respiratory tract infections that were randomized to either placebo or high-dose (4000 IU/day) vitamin D for 12 months. One hundred sixteen patients were included in the final analyses, and serum samples collected 6 months after study start were analyzed. At this time point, 25-hydroxyvitamin D levels were found to range between 10 and 284 nM. Individual levels of 25-hydroxyvitamin D as well as CRP were compared with 4ß-hydroxycholesterol levels. In addition, all participants were genotyped for two polymorphisms (Taq1 and Foq1) in the vitamin D receptor gene. There was no significant correlation between individual serum levels of 25-hydroxyvitamin D and 4ß-hydroxycholesterol. However, a moderate, but statistically significant, negative correlation between CRP and 4ß-hydroxycholesterol levels was observed. This study in patients with highly variable serum levels of 25-hydroxyvitamin D could not reveal any relationship between vitamin D and 4ß-hydroxycholesterol, an endogenous biomarker of CYP3A activity. However, the negative correlation between CRP and 4ß-hydroxycholesterol supports earlier experimental results that inflammation may suppress hepatic CYP3A activity, a finding of potentially high clinical relevance that warrants further exploration.

Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D(3) are associated with an increased risk of respiratory tract infections (RTIs). Clinical trials with vitamin D(3) against various infections have been carried out but data are so far not conclusive. Thus, there is a need for additional randomised controlled trials of effects of vitamin D(3) on infections. OBJECTIVE: To investigate if supplementation with vitamin D(3) could reduce infectious symptoms and antibiotic consumption among patients with antibody deficiency or frequent RTIs. DESIGN: A double-blind randomised controlled trial. SETTING: Karolinska University Hospital, Huddinge. PARTICIPANTS: 140 patients with antibody deficiency (selective IgA subclass deficiency, IgG subclass deficiency, common variable immune disorder) and patients with increased susceptibility to RTIs (>4 bacterial RTIs/year) but without immunological diagnosis. INTERVENTION: Vitamin D(3) (4000 IU) or placebo was given daily for 1 year. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was an infectious score based on five parameters: symptoms from respiratory tract, ears and sinuses, malaise and antibiotic consumption. Secondary endpoints were serum levels of 25-hydroxyvitamin D(3), microbiological findings and levels of antimicrobial peptides (LL-37, HNP1-3) in nasal fluid. RESULTS: The overall infectious score was significantly reduced for patients allocated to the vitamin D group (202 points) compared with the placebo group (249 points; adjusted relative score 0.771, 95% CI 0.604 to 0.985, p=0.04). LIMITATIONS: A single study centre, small sample size and a selected group of patients. The sample size calculation was performed using p=0.02 as the significance level whereas the primary and secondary endpoints were analysed using the conventional p=0.05 as the significance level. CONCLUSIONS: Supplementation with vitamin D(3) may reduce disease burden in patients with frequent RTIs.