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The Impact of Vitamin D Supplementation on the IFNγ-IP10 Axis in Women with Hashimoto's Thyroiditis Treated with Levothyroxine: A Double-blind Randomized Placebo-controlled Trial.
Robat-Jazi, B, Mobini, S, Chahardoli, R, Mansouri, F, Nodehi, M, Esfahanian, F, Saboor Yaraghi, AA
Iranian journal of allergy, asthma, and immunology. 2022;21(4):407-417
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Hashimoto’s thyroiditis is an autoimmune disease characterized by the presence of antibodies against thyroid proteins such as thyroperoxidase (TPO) and thyroglobulin (TG), the local accumulation of inflammatory cells and immune-mediated destruction of the thyroid gland. Disease manifestation is due to a genetic disposition but is also influenced by several environmental factors, including stress, smoking, infections, and levels of nutrients like iodine, selenium and vitamin D. Many cells of the immune system have receptors for Vitamin D and thus have the potential to be influenced by Vitamin D. Indeed, numerous findings demonstrated that vitamin D can exert anti-inflammatory effects on the immune system. This double-blind, randomized, placebo-controlled trial investigated 40 Hashimoto's thyroiditis subjects and the effect of Vitamin D supplementation on various markers of the immune system that mediate the inflammatory response as part of the interferon-gamma-induced protein 10 (IFNγ-IP10) axis. 20 of the enrolled candidates received 50000 IU of Vitamin D (cholecalciferol) once a week – an equivalent to about 7140 IU per day - over three months. The other half received a placebo. All candidates had a fixed dose of thyroid hormone replacement levothyroxine for the duration of the trial. Before and after the intervention several blood biomarkers were investigated relating to Vitamin D levels, D-receptors, immune activity and inflammation. Upon completion of the trial, the intervention group who supplemented Vitamin D had significantly higher Vitamin D levels, which had increased from an average of 25.29 ng/ml to 50.65ng/ml. In addition, several inflammatory factors were significantly decreased. These findings affirmed Vitamin D’s ability to favourably regulate the IFNγ-IP10 axis, which could slow disease progression. This effect may also be useful for the management of other autoimmune disorders involving IP10 overproduction, which attracts other inflammatory cells. More studies in larger groups would help to get more information on other variables not considered in this trial.
Abstract
Hashimoto's thyroiditis (HT) results from chemoattraction of inflammatory cells toward the thyroid gland by inducing the production of interferon-gamma (IFNγ)-induced protein 10 (IP10) by T helper (Th) 1 cells. Vitamin D may suppress the IFNγ-IP10 axis, but this new function of vitamin D has not yet been investigated in HT patients. In an intervention and control group, patients received 50000 IU cholecalciferol or placebo every week for three months, respectively. The CD4+ T cells of 40 patients were isolated, and the mRNA expression levels of vitamin D receptor (VDR), peroxisome proliferator-activated receptors (PPAR)-α, and PPAR-γ genes were determined by real-time PCR. ELISA method was used to determine serum levels of vitamin D, tumor necrosis factor-alpha (TNF-α), IFN-γ, and IP10. Vitamin D levels in the intervention group were significantly higher than in the placebo group after supplementation. PPAR-α and PPAR-γ gene expression levels did not differ significantly between the two groups. The serum levels of IP10, IFNγ, and TNF-α decreased significantly in the vitamin D group, as well as in the placebo group. During this study, vitamin D levels significantly increased in the intervention group and inflammatory factors decreased. Based on the similar results obtained in the placebo group, further studies with larger sample sizes and longer intervention times are recommended.
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Effects of vitamin D treatment on thyroid function and autoimmunity markers in patients with Hashimoto's thyroiditis-A meta-analysis of randomized controlled trials.
Jiang, H, Chen, X, Qian, X, Shao, S
Journal of clinical pharmacy and therapeutics. 2022;47(6):767-775
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Hashimoto's thyroiditis (HT), also called chronic lymphocytic thyroiditis, is the most prevalent organ-specific autoimmune disorder as well as the most common cause of thyroid hypofunction. The main purpose of HT treatment is the control of hypothyroidism, including oral administration of a synthetic hormone to achieve normal circulating thyrotropin levels. The aim of this study was to review the association between vitamin D treatment in patients with HT by assessing patients’ serum circulating 25-hydroxyvitamin D - 25(OH)D - level to evaluate whether a change occurs in the course of disease. This study is a systematic review and meta-analysis of seven cohorts of patients from six studies (3 prospective cohort studies and 3 randomised controlled trials). Results show that vitamin D might significantly increase the serum 25(OH)D levels and produce changes in thyroid peroxidase antibodies titres. However, there wasn't a significant association between serum vitamin D supplementation and the levels of thyroid-stimulating hormone, thyroglobulin antibodies, free triiodothyronine and free thyroxine. Authors conclude that their findings suggest that vitamin D is not associated with the function of the thyroid in patients with HT. Thus, further well-designed randomised controlled trials with sufficient sample sizes investigating the effect of vitamin D on thyroid function are still warranted.
Abstract
INTRODUCTION Recent evidence suggested that vitamin D deficiency was associated with Hashimoto's thyroiditis (HT) pathogenesis and thyroid hypofunction. This study aimed to investigate whether vitamin D supplementation would be effective in the prevention and progression of hypothyroidism in patients with HT. METHODS PubMed, Embase and the Cochrane library were searched for randomized controlled trials (RCTs) and prospective cohort studies published from inception to August 2021. RESULTS A total of 7 cohorts of patients from six clinical trials with 258 patients with HT were included. Significant difference was found (WMD = 19.00, 95% CI: 12.43, 25.58, p < 0.001; I2 = 90.0%, pheterogeneity < 0.001) between the vitamin D group and control group in serum 25-hydroxyvitamin D level. And the combined results indicated vitamin D supplementation significantly reduced the level of thyroid peroxidase antibodies (TPO-Ab) compared to the control group (WMD = -158.18, 95% CI: -301.92, -14.45, p = 0.031; I2 = 68.8%, pheterogeneity = 0.007). Whereas no significant differences were found on the levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4) compared to the control group (p > 0.05). WHAT IS NEW AND CONCLUSION Our study demonstrated that vitamin D treatment might significantly increase the serum 25(OH)D levels and produce changes in TPO-Ab titres. No significant association was found between serum vitamin D treatment and the levels of TG-Ab, TSH, FT3 and FT4, suggesting that vitamin D is not associated with the function of the thyroid in patients with HT.
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The Role of Vitamin D in Sleep Disorders of Children and Adolescents: A Systematic Review.
Prono, F, Bernardi, K, Ferri, R, Bruni, O
International journal of molecular sciences. 2022;23(3)
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Vitamin D deficiency or insufficiency is a global epidemic, estimated to affect over one billion people worldwide, including children. The main function of vitamin D is the regulation of bone homeostasis but it is also involved in many other conditions such as cardiovascular disease, cancer, diabetes mellitus and autoimmune disorders. Recent studies show that sufficient levels of vitamin D seem to be necessary to maintain sleep and low vitamin D levels have been associated with shorter sleep duration. This systematic review is the first to assess the association between Vitamin D and sleep disorders in children, 14 articles were included. Vitamin D deficiency in children is associated with decreased sleep duration and poorer sleep efficiency, as well as with delayed bedtimes. Children with reduced vitamin D serum levels have a higher risk of excessive daytime sleepiness (EDS). Since vitamin D levels influence sleep duration, sleep duration can also influence vitamin D serum concentration suggesting a bidirectional relationship. Evidence is scarce and so further high-quality prospective cohort studies and well-designed randomized controlled trials (RCTs) are needed to determine the effect of vitamin D supplementation in children with sleep disorders.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Vitamin D plays an important role in the sleep quality of children. Healthcare practitioners may wish to establish vitamin D status in children presenting with sleep disturbances.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
Vitamin D levels have been associated with improved sleep in adults, but few studies have concentrated on the paediatric population. In order to identify if vitamin D plays a role regulating sleep in children and adolescents the paper reviewed studies, which looked at vitamin D in relation to sleep duration and quality of sleep. This included the following sleep disorders: obstructive sleep apnoea (OSA), restless leg syndrome (RLS) and insomnia.
Methods
- A broad systematic review following the PRISMA guidelines and using PubMed and Cochrane databases
- Search identified 748 papers. After exclusions for non-relevance, incorrect age group, or lack of data on sleep, 14 papers were included
- Due to the shortage of papers on this topic none of these papers were excluded, regardless of quality
- The participants in each study varied from 39 to 5289.
Results
The results highlighted:
- Plasma levels of vitamin D affect sleep duration and quality of sleep in children. Data taken from 5 studies
- Vitamin D cord blood levels were correlated to sleep in preschool children. Partly this was due to the mother’s vitamin D level during pregnancy affecting the level of vitamin D available to the foetus. Venous blood vitamin D level was linked to the sleep wake cycle of children. Data taken from 2 studies
- OSA was more likely to develop in children who had low vitamin D levels with a risk of 14.16% compared to a control group of 5.83% (1 study)
- Vitamin D supplementation was found to reduce neuron damage caused by hypoxia (1 study)
- An association exists between parental vitamin D insufficiency and their child’s vitamin D status (1 study). Data taken from 5 studies
- Vitamin D levels in specific diseases, such as coeliac disease (CD) showed a negative correlation with RLS
- For familial Mediterranean fever (FMF) vitamin D deficiency reduced sleep quality (36.5%). Data taken from 2 studies.
Conclusion
Notwithstanding the small number of studies, the review shows vitamin D deficiency, defined as <20 ng/mL, is associated with an increased risk for sleep disorders in children.
Clinical practice applications:
- Due to the role vitamin D plays in sleep in children, establishing vitamin D status may be useful for children presenting with sleep disturbances
- Adequate vitamin D levels during pregnancy are important to establish a vitamin D pool in the foetus
- Vitamin D supplementation is something to rule out in the case of OSA and associated hypoxia, metabolic dysfunction and systemic inflammation in children
- Due to the negative impact poor sleep has on the body, improving sleep quality at a young age could form an important part of preventative health care.
Considerations for future research:
- Additional studies are required to support the conclusion in this study
- Due to the low number of studies, any additional research should be of a high standard and include prospective cohort studies and randomised control trials.
Abstract
This review investigates the association between vitamin D and sleep disorders. Vitamin D is an essential nutrient known to play an important role in the growth and bone health of the human body, but it also appears to play a role in sleep. The goal of our review is to examine the association between vitamin D and sleep disorders in children and adolescents. We summarize the evidence about the role and the mechanism of action of vitamin D in children and adolescents with sleep disorders such as insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and other sleep disorders. Systematic electronic database searches were conducted using Pubmed and Cochrane Library. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The studies that met the established inclusion criteria were analyzed and compared. Results suggest a strict relationship between vitamin D deficiency in children and sleep disorders. There is evidence that vitamin D is implicated in the different neurochemical mechanisms involved in sleep regulation and mainly in the serotonergic and dopaminergic pathways. This might be responsible for the association of vitamin D deficiency and restless sleep, sleep hyperhidrosis, OSA, and RLS.
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Daily Nutritional Supplementation with Vitamin D₃ and Phenylbutyrate to Treatment-Naïve HIV Patients Tested in a Randomized Placebo-Controlled Trial.
Ashenafi, S, Amogne, W, Kassa, E, Gebreselassie, N, Bekele, A, Aseffa, G, Getachew, M, Aseffa, A, Worku, A, Hammar, U, et al
Nutrients. 2019;11(1)
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Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD3) deficiency. VitD3 together with phenylbutyrate (PBA) can induce an antimicrobial peptide called cathelicidin which has anti-viral properties. VitD3 and PBA can also enhance autophagy, a physiological process known to enhance destruction of intracellular viruses. The aim of this double-blind, placebo-controlled trial was to evaluate whether vitD3 + PBA could reduce viral replication and restore immune and nutritional status in HIV infection. 173 previously untreated HIV patients were randomised to receive either 5000 IU vitD3 and 500 mg PBA or placebos for 16 weeks with follow-up of a further 8 weeks. Most subjects had low plasma vitD3 levels at baseline which increased significantly in the vitD3 + PBA group compared with placebo at weeks 4, 8 and 16, indicating good compliance and response to the treatment. There were no statistical differences in any of the measured outcomes, including viral load, CD4 cells, CD8 cells and body mass index, between treatment and placebo group at any point during the study and follow-up.
Abstract
Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD₃) deficiency. We conducted a double-blinded, randomized, and placebo-controlled trial in Addis Ababa, Ethiopia, to investigate if daily nutritional supplementation with vitD₃ (5000 IU) and phenylbutyrate (PBA, 2 × 500 mg) could mediate beneficial effects in treatment-naïve HIV patients. Primary endpoint: the change in plasma HIV-1 comparing week 0 to 16 using modified intention-to-treat (mITT, n = 197) and per-protocol (n = 173) analyses. Secondary endpoints: longitudinal HIV viral load, T cell counts, body mass index (BMI), middle-upper-arm circumference (MUAC), and 25(OH)D₃ levels in plasma. Baseline characteristics were detectable viral loads (median 7897 copies/mL), low CD4⁺ (median 410 cells/µL), and elevated CD8⁺ (median 930 cells/µL) T cell counts. Most subjects were vitD₃ deficient at enrolment, but a gradual and significant improvement of vitD₃ status was demonstrated in the vitD₃ + PBA group compared with placebo (p < 0.0001) from week 0 to 16 (median 37.5 versus 115.5 nmol/L). No significant changes in HIV viral load, CD4⁺ or CD8⁺ T cell counts, BMI or MUAC could be detected. Clinical adverse events were similar in both groups. Daily vitD₃ + PBA for 16 weeks was well-tolerated and effectively improved vitD₃ status but did not reduce viral load, restore peripheral T cell counts or improve BMI or MUAC in HIV patients with slow progressive disease. Clinicaltrials.gov NCT01702974.
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The effects of two vitamin D regimens on ulcerative colitis activity index, quality of life and oxidant/anti-oxidant status.
Karimi, S, Tabataba-Vakili, S, Yari, Z, Alborzi, F, Hedayati, M, Ebrahimi-Daryani, N, Hekmatdoost, A
Nutrition journal. 2019;18(1):16
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Ulcerative colitis (UC) is a type of Inflammatory bowel disease (IBD), which involves the immune system attacking healthy bowel tissue. Vitamin D has an effect on the immune response, possibly by reducing inflammation, promoting immune system tolerance and improving the health of the bowel lining. Several studies have found a link between vitamin D deficiency and IBD, but the optimum dosage for vitamin D supplementation is not yet known. The aim of this study was to look at the effects of two dosages of vitamin D supplementation on serum vitamin D, total antioxidant capacity (TAC), total oxidant status (TOS), quality of life, and disease activity index in patients with UC. In this double blind randomised clinical trial, 50 patients with mild to moderate UC received either 1,000 (‘low dose’) or 2,000 (‘high dose’) IU/day of vitamin D for 12 weeks. At the end of study, serum 25-OHD levels had significantly increased in the high dose group and the increase was significantly more (6.7 ± 3.8 ng/mL) than the low dose (0.2 ± 0.5 ng/mL) group. Serum TOS concentration decreased significantly (- 0.37 ± 0.26) only in the high dose group. There was no significant change in serum TAC between two groups during the study. The quality of life score significantly improved in the high dose group compared to the low dose group and disease activity index score reduce in both groups but was significant only in the high dose group. The authors concluded that 2,000 IU a day of vitamin D can increase serum 25-OHD concentration and quality of life, and reduce disease activity in UC patients with vitamin D deficiency. They recommend that all patients with UC should have their vitamin D status assessed because they may benefit from vitamin D therapy.
Abstract
BACKGROUND The optimum dosage for vitamin D supplementation has not yet been elucidated in patients with Ulcerative colitis (UC). The aim of this study was to investigate the effects of two vitamin D regimens in UC patients with vitamin D deficiency. METHODS In this double blind randomized clinical trial, 50 patients with mild to moderate UC, who met inclusion criteria, received either 1000 or 2000 IU/day of vitamin D (as low dose or high dose group, respectively) for 12 weeks. Serum 25-hydroxy vitamin D (25-OHD) level, total antioxidant capacity (TAC), and Total Oxidant Status (TOS), the inflammatory bowel disease questionnaire - 9 (IBDQ-9) score and the Simple Clinical Colitis Activity Index Questionnaire (SCCAI) score were assessed before and after intervention. RESULTS At the end of study, serum 25-OHD levels significantly increased in the high dose group (P < 0.001) and the increase was significantly more than low dose group (6.7 ± 3.8 ng/mL in the high dose group versus 0.2 ± 0.5 ng/mL in the low dose group) (P < 0.001). Serum TOS concentration decreased significantly (- 0.37 ± 0.26) only in the high dose group (P value = 0.023). There was no statistically significant change in serum TAC between two groups during the study. IBDQ-9 mean score significantly increased in high dose group compared to the low dose group (P value = 0.001) and SCCAI score in both groups reduced (- 2.58 ± 2.16 and - 0.9 ± 0.3 in high dose and low dose respectively), while this reduction was significant only in the high dose group (P value ≥0.001). CONCLUSION Our results indicate that 2000 IU daily dose of vitamin D can increase serum 25-OHD concentration, and quality of life, while it reduces disease activity in UC patients with vitamin D deficiency. We recommend assessment of the vitamin D status in all patients with UC because they may benefit from vitamin D therapy.
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The Effect of Serum 25-Hydroxyvitamin D on Serum Ferritin Concentrations: A Longitudinal Study of Participants of a Preventive Health Program.
Munasinghe, LL, Ekwaru, JP, Mastroeni, SSBS, Mastroeni, MF, Veugelers, PJ
Nutrients. 2019;11(3)
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Serum ferritin (SF) is the storage form of iron in the body. SF has been shown to increase as part of the body’s response to inflammation, and is therefore recognised as a marker of inflammation. Vitamin D has a key function in bone metabolism and is increasingly recognised for its anti-inflammatory effect. This longitudinal study looked at the association of serum 25-hydroxyvitamin D (25(OH)D) with levels of SF concentrations, and examined whether changes in serum 25(OH)D concentrations over time were accompanied by a change in SF concentrations. The study analysed data from 6812 Canadian adults who participated in a preventative health program. Just under half the participants were taking vitamin D supplements at a dose of 2000-5000iU per day. Measurements were taken at the start of the study, and at follow-up, which was an average of 12 months later. 25(OH)D levels at baseline were grouped into categories: <50nmol/L, 50 to <75nmol/L, 75 to <100nmol/L, 100 to <125nmol/L and >125nmol/L. During the follow-up, 25(OH)D concentrations increased from 80.7 to 115.0 nmol/L whereas SF concentrations decreased from 122.0 to 92.0 µg/L. Compared to participants with very low 25(OH)D concentrations of <50 nmol/L, those with concentrations of 75 to <100, 100 to <125, and ≥125 nmol/L had SF levels that were 13.00, 23.15, and 27.59 µg/L lower respectively (p < 0.001). Participants who improved their 25(OH)D levels by ≥50 nmol/L over the study period, decreased their SF concentrations by an average of 5.71 µg/L. The authors concluded that interventions aiming to lower SF concentrations through sun-exposure and vitamin D supplementation should aim for increases in 25(OH)D concentrations of at least 50nmol/L. Intervention studies are needed to further establish the beneficial effects of vitamin D on inflammation and cardiovascular health.
Abstract
Various studies have suggested a role of vitamin D in inflammation. However, its effect on ferritin, a biomarker of inflammation, has received relatively little attention. Therefore, we aimed to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with serum ferritin (SF) concentrations, and to examine whether temporal increases in serum 25(OH)D concentrations are paralleled by a reduction in SF concentrations. Data from a community sample of Canadian adults who participated in a preventive health program (n = 6812) were analyzed. During the follow-up, serum 25(OH)D concentrations increased from 80.7 to 115.0 nmol/L whereas SF concentrations decreased from 122.0 to 92.0 µg/L (median follow-up time was 11.67 months). Cross-sectional analyses revealed that compared to participants with 25(OH)D concentrations of <50 nmol/L, those with 25(OH)D concentrations of 75 to <100, 100 to <125, and ≥125 nmol/L had SF concentrations that were 13.00, 23.15, and 27.59 µg/L lower respectively (p < 0.001). Compared to those without temporal improvements in 25(OH)D concentrations between baseline and follow-up, participants who improved their 25(OH)D concentrations with ≥50 nmol/L decreased their SF concentrations with 5.71 µg/L. For participants for whom the increase in 25(OH)D concentrations was less than 50 nmol/L, decreases in SF concentrations were less pronounced and not statistically significant. These observations suggest that despite strong associations between 25(OH)D and SF concentrations, interventions aiming to lower SF concentrations through sun-exposure and vitamin D supplementation should target substantial increases in 25(OH)D concentrations.
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Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data.
Martineau, AR, Jolliffe, DA, Hooper, RL, Greenberg, L, Aloia, JF, Bergman, P, Dubnov-Raz, G, Esposito, S, Ganmaa, D, Ginde, AA, et al
BMJ (Clinical research ed.). 2017;356:i6583
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Acute respiratory tract infections are responsible for more than 2.5 million deaths worldwide. Previous studies report consistent associations between low vitamin D levels and an increased risk of acute respiratory tract infection. Vitamin D may protect against respiratory pathogens of viral and bacterial origin, due to antimicrobial and other mechanisms. This paper is a systematic review and meta-analysis of 25 randomised double-blind placebo controlled trials of vitamin D supplementation for the prevention of acute respiratory tract infection. The trials were conducted in 14 countries in 4 continents and included a total of 11,321 participants of both sexes, aged 0-95 years. The follow-up durations ranged from seven weeks to 1.5 years. All studies administered vitamin D3 orally, using either daily or weekly doses or bolus doses 1-3 months apart, or combined daily and bolus doses. Individual participant data were obtained from 96.6% of participants. The majority of studies that were included in the analyses were considered to be of a high quality, with a low risk of bias. The analyses showed that vitamin D supplementation reduced the risk of acute respiratory tract infections among all participants. The strongest positive effects were seen in those with baseline vitamin D levels less than 25 nmol/l, when compared to those with levels higher than 25 nmol/l, although benefits were also seen in the latter. Furthermore, daily or weekly vitamin D supplementation, without additional bolus doses were shown to protect against acute respiratory tract infections, while regimens with large bolus doses did not. The authors concluded that people who are very deficient in vitamin D are most likely to benefit from daily or weekly vitamin D supplementation, without additional bolus doses, in the prevention of acute respiratory tract infections. They call for the introduction of public health measures, such as food fortification, to improve vitamin D status, particularly in settings where vitamin D deficiency is common.
Abstract
Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.