Influence of vitamin D supplementation on muscle strength and exercise capacity in Mongolian schoolchildren: a randomised controlled trial.

Objective: To determine whether weekly oral vitamin D supplementation influences grip strength, explosive leg power, cardiorespiratory fitness or spirometric lung volumes in Mongolian schoolchildren. Methods: Multicentre, randomised, double-blind, placebo-controlled clinical trial conducted in children aged 6-13 years at baseline attending 18 schools in Ulaanbaatar. The intervention was weekly oral doses of 14,000 IU vitamin D3 (n=4418) or placebo (n=4433) for 3 years. Outcome measures were grip strength, standing long jump distance and serum 25-hydroxyvitamin D (25[OH]D) concentrations (determined in all participants), peak oxygen uptake (VO2peak, determined in a subset of 632 participants using 20-metre multi-stage shuttle run tests) and spirometric outcomes (determined in a subset of 1,343 participants). Results: 99.8% of participants had serum 25(OH)D concentrations <75 nmol/L at baseline, and mean end-study 25(OH)D concentrations in children randomised to vitamin D vs. placebo were 77.4 vs. 26.7 nmol/L (mean difference 50.7 nmol/L, 95% CI, 49.7 to 51.4). However, vitamin D supplementation did not influence mean grip strength, standing long jump distance, VO2peak, spirometric lung volumes or peak expiratory flow rate, either overall or within sub-groups defined by sex, baseline 25(OH)D concentration <25 vs. ≥25 nmol/L or calcium intake <500 vs. ≥500 mg/day. Conclusion: A 3-year course of weekly oral supplementation with 14,000 IU vitamin D3 elevated serum 25(OH)D concentrations in Mongolian schoolchildren with a high baseline prevalence of vitamin D deficiency. However, this intervention did not influence grip strength, explosive leg power, peak oxygen uptake or spirometric lung volumes, either overall or in sub-group analyses.

Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Influence of vitamin D supplementation on growth, body composition, pubertal development and spirometry in South African schoolchildren: a randomised controlled trial (ViDiKids).

OBJECTIVE: To determine whether weekly oral vitamin D supplementation influences growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. DESIGN: Phase 3 double-blind randomised placebo-controlled trial. SETTING: Socioeconomically disadvantaged peri-urban district of Cape Town, South Africa. PARTICIPANTS: 1682 children of black African ancestry attending government primary schools and aged 6-11 years at baseline. INTERVENTIONS: Oral vitamin D3 (10 000 IU/week) versus placebo for 3 years. MAIN OUTCOME MEASURES: Height-for-age and body mass index-for-age, measured in all participants; Tanner scores for pubertal development, spirometric lung volumes and body composition, measured in a subset of 450 children who additionally took part in a nested substudy. RESULTS: Mean serum 25-hydroxyvitamin D3 concentration at 3-year follow-up was higher among children randomised to receive vitamin D versus placebo (104.3 vs 64.7 nmol/L, respectively; mean difference (MD) 39.7 nmol/L, 95% CI 37.6 to 41.9 nmol/L). No statistically significant differences in height-for-age z-score (adjusted MD (aMD) -0.08, 95% CI -0.19 to 0.03) or body mass index-for-age z-score (aMD -0.04, 95% CI -0.16 to 0.07) were seen between vitamin D versus placebo groups at follow-up. Among substudy participants, allocation to vitamin D versus placebo did not influence pubertal development scores, % predicted forced expiratory volume in 1 s (FEV1), % predicted forced vital capacity (FVC), % predicted FEV1/FVC, fat mass or fat-free mass. CONCLUSIONS: Weekly oral administration of 10 000 IU vitamin D3 boosted vitamin D status but did not influence growth, body composition, pubertal development or spirometric outcomes in South African schoolchildren. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT02880982, South African National Clinical Trials Register DOH-27-0916-5527.

Detection of Mycobacterium tuberculosis DNA in CD34+ peripheral blood mononuclear cells of adults with tuberculosis infection and disease.

OBJECTIVES: To investigate whether Mycobacterium tuberculosis (Mtb) DNA is detected in peripheral blood mononuclear cells (PBMC) of subjects with tuberculosis (TB) or TB infection (TBI) living in a low-burden country. METHODS: We prospectively enrolled 57 patients with TB, 41 subjects with TBI, and 39 controls in Rome, Italy. PBMC were isolated, cluster of differentiation (CD)34+ and CD34- cells were immunomagnetic separated, DNA was extracted, and digital polymerase chain reaction for IS6110 and rpoB sequences was used to detect Mtb DNA in PBMC subsets and unfractionated PBMC. RESULTS: We detected Mtb DNA at a low copy number in CD34+ cells in 4o f 30 (13%) patients with TB, 2 of 24 (8%) subjects with TBI, and 1 of 24 (4%) controls. Mtb DNA was detected in unfractionated PBMC in 3 of 51 (6%) patients with TB, 2 of 38 (5%) subjects with TBI, and 2 of 36 (6%) controls. In CD34- cells, only 1 of 31 (3%) subjects with TBI tested positive for Mtb DNA. CONCLUSIONS: Mtb DNA was detected at low frequencies and levels in the PBMC of subjects with TBI and donors with TB living in a low-burden country. In particular, Mtb DNA was detected more frequently in CD34+ cells, supporting the hypothesis that these cells may represent a Mtb niche. This finding informs biological understanding of Mtb pathogenesis and may support the development of a microbial blood biomarker for Mtb infection.

Influence of vitamin D supplementation on bone mineral content, bone turnover markers, and fracture risk in South African schoolchildren: multicenter double-blind randomized placebo-controlled trial (ViDiKids).

Randomized controlled trials (RCTs) to determine the influence of vitamin D on BMC and fracture risk in children of Black African ancestry are lacking. We conducted a sub-study (n = 450) nested within a phase 3 RCT of weekly oral supplementation with 10 000 IU vitamin D3 vs placebo for 3 yr in HIV-uninfected Cape Town schoolchildren aged 6-11 yr. Outcomes were BMC at the whole body less head (WBLH) and LS and serum 25-hydroxyvitamin D3 (25(OH)D3), PTH, alkaline phosphatase, C-terminal telopeptide, and PINP. Incidence of fractures was a secondary outcome of the main trial (n = 1682). At baseline, mean serum 25(OH)D3 concentration was 70.0 nmol/L (SD 13.5), and 5.8% of participants had serum 25(OH)D3 concentrations <50 nmol/L. Among sub-study participants, end-trial serum 25(OH)D3 concentrations were higher for participants allocated to vitamin D vs placebo (adjusted mean difference [aMD] 39.9 nmol/L, 95% CI, 36.1 to 43.6) and serum PTH concentrations were lower (aMD -0.55 pmol/L, 95% CI, -0.94 to -0.17). However, no interarm differences were seen for WBLH BMC (aMD -8.0 g, 95% CI, -30.7 to 14.7) or LS BMC (aMD -0.3 g, 95% CI, -1.3 to 0.8) or serum concentrations of bone turnover markers. Fractures were rare among participants in the main trial randomized to vitamin D vs placebo (7/755 vs 10/758 attending at least 1 follow-up; adjusted odds ratio 0.70, 95% CI, 0.27 to 1.85). In conclusion, a 3-yr course of weekly oral vitamin D supplementation elevated serum 25(OH)D3 concentrations and suppressed serum PTH concentrations in HIV-uninfected South African schoolchildren of Black African ancestry but did not influence BMC or serum concentrations of bone turnover markers. Fracture incidence was low, limiting power to detect an effect of vitamin D on this outcome.

Vitamin D­the "sunshine vitamin"­is essential for helping the body to absorb calcium from the diet, which is laid down in bone to improve its strength. There is a lack of clinical trials testing whether vitamin D supplements can improve bone content of calcium and other minerals, or reduce risk of bone fractures (broken bones) in children of Black African ancestry. We therefore conducted such a study, recruiting 1682 schoolchildren aged 6­11 yr living in Cape Town, South Africa. We found that a weekly dose of 10 000 international units (250 micrograms) of vitamin D3, given by mouth for 3 yr, was effective in boosting vitamin D levels in trial participants who received it. However, this did not have any effect on bone content of calcium and other minerals. Relatively few children experienced a broken bone during the study, so we were unable to say with confidence whether or not vitamin D supplements might affect this outcome.

Long-term air pollution exposure and risk of SARS-CoV-2 infection: A UK-wide cohort study.

BACKGROUND: The association between air quality and risk of SARS-CoV-2 infection is poorly understood. We investigated this association using serological individual-level data adjusting for a wide range of confounders, in a large population-based cohort (COVIDENCE UK). METHODS: We assessed the associations between long-term (2015-19) nitrogen dioxide (NO2) and fine particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5), exposures with SARS-CoV-2 infection, level of antibody response among those infected, and COVID-19 disease severity. We used serological data from 10,489 participants in the COVIDENCE UK cohort, and estimated annual average air pollution exposure at each participant's home postcode. RESULTS: After controlling for potential confounders, we found a positive association between 5-year NO2 and PM2.5 exposures and the risk of seropositivity: 10 unit increase in NO2 (µg/m3) was associated with an increasing risk of seropositivity by 1.092 (95% CI 1.02 to 1.17; p-for-trend 0.012). For PM2.5, 10 unit increase (µg/m3) was associated with an increasing risk of seropositivity by 1.65 (95% CI 1.015-2.68; p-for-trend 0·049). In addition, we found that NO2 was positively associated with higher antibody titres (p-for-trend 0·013) among seropositive participants, with no evidence of an association for PM2.5. CONCLUSION: Our findings suggest that the long-term burden of air pollution increased the risks of SARS-CoV-2 infection and has important implications for future pandemic preparedness. This evidence strengthens the case for reducing long-term air pollution exposures to reduce the vulnerability of individuals to respiratory viruses.

Toward a molecular microbial blood test for tuberculosis infection.

The World Health Organization's aim to end the global tuberculosis (TB) epidemic by 2050 cannot be achieved without taking measures to identify people with asymptomatic Mycobacterium tuberculosis (Mtb) infection and offer them an intervention to reduce the risk of disease progression, such as preventive antimicrobial therapy. Implementation of this strategy is limited by the fact that existing tests for Mtb infection, which use immunosensitization to Mtb-specific antigens as a proxy for infection, have low positive predictive value for progression to TB. A blood test that detects Mtb deoxyribonucleic acid (DNA) could allow preventive therapy to be targeted at individuals with microbiological evidence of persistent infection. In this review, we summarize recent advances in the development of molecular microbial blood tests for Mtb infection and discuss potential explanations for discordance between their results and those of immunodiagnostic tests in adults with recent exposure to an infectious index case. We also present a roadmap for further development of molecular microbial blood tests for Mtb infection, and highlight the potential for research in this area to provide novel insights into the biology of Mtb infection and yield new tools to support efforts to control the global TB epidemic.

Vitamin D supplements for fracture prevention in schoolchildren in Mongolia: analysis of secondary outcomes from a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin D supplementation has been shown to increase total hip areal bone mineral density in healthy children and adolescents. We aimed to investigate whether supplementing schoolchildren living in Mongolia with weekly vitamin D3 for 3 years affected fracture risk. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial across 18 public schools in Ulaanbaatar, Mongolia. Schoolchildren were eligible if they were aged 6-13 years at screening, had a negative QuantiFERON-TB Gold In-tube assay (QFT) result, were not hypersensitive to vitamin D or immunocompromised, did not use vitamin D supplements, did not have clinical signs of rickets, and had no intention of leaving Ulaanbaatar within 3 years. Participants were randomly assigned (1:1) to receive either vitamin D (oral dose of 14 000 international units [IU] vitamin D3, once per week) or placebo for 3 years using permuted block randomisation stratified by school of attendance. Participants, care providers, and all trial staff were masked to group assignment during the intervention. Prespecified secondary outcomes were incidence of fractures and adverse events, ascertained using questionnaires. The fracture and safety analyses included participants who completed at least one follow-up fracture questionnaire. We estimated adjusted risk ratios (RRs) and 95% CIs using generalised linear models with binomial distribution and a log link function with adjustment for school of attendance. The trial is registered with ClinicalTrials.gov, NCT02276755, and the intervention ended in May, 2019. FINDINGS: Between Sept 2, 2015, and March 20, 2017, 11 475 children were invited to participate in the study and 8851 were recruited and randomly assigned to receive either vitamin D (n=4418) or placebo (n=4433). 8348 participants were included in the fracture and safety analyses (4176 [94·5%] in the vitamin D group and 4172 [94·1%] in the placebo group). Of these, 4125 (49·4%) were female, 4223 (50·6%) were male, and 7701 (92·2%) were of Khalkh ancestry. Median age was 9·2 years (IQR 8·0-10·7) and 7975 (95·5%) participants had baseline serum 25-hydroxyvitamin D concentrations less than 50 nmol/L. During a median follow-up of 3·0 years (IQR 2·9-3·1), 268 (6·4%) participants in the vitamin D group and 253 (6·1%) in the placebo group reported one or more fractures (adjusted RR 1·10, 95% CI 0·93-1·29; p=0·27). Incidence of adverse events did not differ between study groups. INTERPRETATION: Oral vitamin D supplementation at a dose of 14 000 IU/week for 3 years was safe, but did not influence fracture risk in schoolchildren living in Mongolia who had a high baseline prevalence of vitamin D deficiency. FUNDING: US National Institutes of Health.

Long-term symptom profiles after COVID-19 vs other acute respiratory infections: an analysis of data from the COVIDENCE UK study.

Background: Long COVID is a well recognised, if heterogeneous, entity. Acute respiratory infections (ARIs) due to other pathogens may cause long-term symptoms, but few studies compare post-acute sequelae between SARS-CoV-2 and other ARIs. We aimed to compare symptom profiles between people with previous SARS-CoV-2 infection, people with previous non-COVID-19 ARIs, and contemporaneous controls, and to identify clusters of long-term symptoms. Methods: COVIDENCE UK is a prospective, population-based UK study of ARIs in adults. We analysed data for 16 potential long COVID symptoms and health-related quality of life (HRQoL), reported between January 21 and February 15, 2021, by participants unvaccinated against SARS-CoV-2. We classified participants as having previous SARS-CoV-2 infection or previous non-COVID-19 ARI (≥4 weeks prior) or no reported ARI. We compared symptoms by infection status using logistic and fractional regression, and identified symptom clusters using latent class analysis (LCA). This study is registered with ClinicalTrials.gov, NCT04330599. Findings: We included 10,171 participants (1311 [12.9%] with SARS-CoV-2 infection, 472 [4.6%] with non-COVID-19 ARI). Both types of infection were associated with increased prevalence/severity of most symptoms and decreased HRQoL compared with no infection. Participants with SARS-CoV-2 infection had increased odds of problems with taste/smell (odds ratio 19.74, 95% CI 10.53-37.00) and lightheadedness or dizziness (1.74, 1.18-2.56) compared with participants with non-COVID-19 ARIs. Separate LCA models identified three symptom severity groups for each infection type. In the most severe groups (representing 22% of participants for both SARS-CoV-2 and non-COVID-19 ARI), SARS-CoV-2 infection presented with a higher probability of problems with taste/smell (probability 0.41 vs 0.04), hair loss (0.25 vs 0.16), unusual sweating (0.38 vs 0.25), unusual racing of the heart (0.43 vs 0.33), and memory problems (0.70 vs 0.55) than non-COVID-19 ARI. Interpretation: Both SARS-CoV-2 and non-COVID-19 ARIs are associated with a wide range of symptoms more than 4 weeks after the acute infection. Research on post-acute sequelae of ARIs should extend from SARS-CoV-2 to include other pathogens. Funding: Barts Charity.

Influence of vitamin D supplementation on fracture risk, bone mineral density and bone biochemistry in Mongolian schoolchildren: multicenter double-blind randomized placebo-controlled trial.

Background: Randomized controlled trials (RCT) of vitamin D supplementation to reduce fracture risk in children are lacking. Methods: We conducted a Phase 3 RCT of weekly oral supplementation with 14,000 IU vitamin D3 for 3 years in Mongolian schoolchildren aged 6-13 years. Serum 25-hydroxyvitamin D (25[OH]D) concentrations and the proportion of participants reporting ≥1 fracture were secondary outcomes for the main trial. Radial bone mineral density (BMD) was assessed in a nested sub-study, with serum concentrations of parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BALP) determined in a subset of participants. Findings: 8851 children were enrolled in the main trial, of whom 1465 also participated in the sub-study. Vitamin D deficiency was prevalent at baseline (25[OH]D <20 ng/mL in 90.1%). The intervention elevated 25(OH)D concentrations (adjusted inter-arm mean difference [aMD] 20.3 ng/mL, 95% CI 19.9 to 20.6) and suppressed PTH concentrations (aMD -13.6 pmol/L, 95% CI -23.5 to -3.7), but it did not influence fracture risk (adjusted risk ratio 1.10, 95% CI 0.93 to 1.29, P=0.27) or radial BMD z-score (aMD -0.06, 95% CI -0.18 to 0.07, P=0.36). Vitamin D suppressed serum BALP concentrations more among participants with baseline 25(OH)D concentrations <10 vs. ≥10 ng/mL (Pinteraction=0.04). However, effects of the intervention on fracture risk and radial BMD were not modified by baseline vitamin D status (Pinteraction≥0.67). Interpretation: Weekly oral vitamin D supplementation elevated serum 25(OH)D concentrations and suppressed PTH concentrations in vitamin D-deficient schoolchildren in Mongolia. However, this was not associated with reduced fracture risk or increased radial BMD. Funding: National Institutes of Health.

Vitamin D supplementation to prevent tuberculosis infection in South African schoolchildren: multicenter phase 3 double-blind randomized placebo-controlled trial (ViDiKids).

OBJECTIVES: To determine whether weekly oral supplementation with 10,000 IU vitamin D3 for 3 years reduces the risk of sensitization to M. tuberculosis in South African schoolchildren aged 6-11 years with negative QuantiFERON-tuberculosis (TB) Gold Plus (QFT-Plus) assay results at baseline. METHODS: We conducted a phase 3 randomized placebo-controlled trial in 1682 children attending 23 primary schools in Cape Town. The primary outcome was a positive end-trial QFT-Plus result, analyzed using a mixed effects logistic regression model with the school of attendance included as a random effect. RESULTS: 829 vs. 853 QFT-Plus-negative children were randomized to receive vitamin D3 vs. placebo, respectively. Mean end-study 25(OH)D concentrations in participants randomized to vitamin D vs. placebo were 104.3 vs 64.7 nmol/l, respectively (95% confidence interval for difference, 37.6 to 41.9 nmol/l). A total of 76/667 (11.4%) participants allocated to vitamin D vs. 89/687 (13.0%) participants allocated to placebo tested QFT-Plus positive at 3-year follow-up (adjusted odds ratio 0.86, 95% confidence interval 0.62-1.19, P = 0.35). CONCLUSION: Weekly oral supplementation with 10,000 IU vitamin D3 for 3 years elevated serum 25(OH)D concentrations among QFT-Plus-negative Cape Town schoolchildren but did not reduce their risk of QFT-Plus conversion.

Determinants of QuantiFERON Plus-diagnosed tuberculosis infection in adult Ugandan TB contacts: A cross-sectional study.

BACKGROUND: The tuberculin skin test is commonly used to diagnose latent tuberculosis infection (LTBI) in resource-limited settings, but its specificity is limited by factors including cross-reactivity with BCG vaccine and environmental mycobacteria. Interferon-gamma release assays (IGRA) overcome this problem by detecting M. tuberculosis complex-specific responses, but studies to determine risk factors for IGRA-positivity in high TB burden settings are lacking. METHODS: We conducted a cross-sectional study to determine factors associated with a positive IGRA by employing the QuantiFERON-TB® Gold-plus (QFT Plus) assay in a cohort of asymptomatic adult TB contacts in Kampala, Uganda. Multivariate logistic regression analysis with forward stepwise logit function was employed to identify independent correlates of QFT Plus-positivity. RESULTS: Of the 202 participants enrolled, 129/202 (64%) were female, 173/202 (86%) had a BCG scar, and 67/202 (33%) were HIV-infected. Overall, 105/192 (54%, 95% CI 0.48-0.62) participants had a positive QFT Plus result. Increased risk of QFT-Plus positivity was independently associated with casual employment/unemployment vs. non-casual employment (adjusted odds ratio (aOR) 2.18, 95% CI 1.01-4.72), a family vs. non-family relation to the index patient (aOR 2.87, 95% CI 1.33-6.18), living in the same vs. a different house as the index (aOR 3.05, 95% CI 1.28-7.29), a higher body mass index (BMI) (aOR per additional kg/m2 1.09, 95% CI 1.00-1.18) and tobacco smoking vs. not (aOR 2.94, 95% CI 1.00-8.60). HIV infection was not associated with QFT-Plus positivity (aOR 0.91, 95% CI 0.42-1.96). CONCLUSION: Interferon Gamma Release Assay positivity in this study population was lower than previously estimated. Tobacco smoking and BMI were determinants of IGRA positivity that were previously unappreciated.

Vitamin D for the management of asthma.

BACKGROUND: Since the previous Cochrane Review on this topic in 2016, debate has continued surrounding a potential role for vitamin D in reducing risk of asthma exacerbation and improving asthma control. We therefore conducted an updated meta-analysis to include data from new trials completed since this date. OBJECTIVES: To evaluate the effectiveness and safety of administration of vitamin D or its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control. SEARCH METHODS: We searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: 8 September 2022. SELECTION CRITERIA: We included double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control, or both. DATA COLLECTION AND ANALYSIS: Four review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). The primary outcome was the incidence of severe asthma exacerbations requiring treatment with systemic corticosteroids. Secondary outcomes included the incidence of asthma exacerbations precipitating an emergency department visit or requiring hospital admission, or both, end-study childhood Asthma Control Test (cACT) or Asthma Control Test (ACT) scores, and end-study % predicted forced expiratory volume in one second (FEV1). We performed subgroup analyses to determine whether the effect of vitamin D on risk of asthma exacerbation was modified by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, form of vitamin D given, and age of participants. MAIN RESULTS: We included 20 studies in this review; 15 trials involving a total of 1155 children and five trials involving a total of 1070 adults contributed data to analyses. Participant ages ranged from 1 to 84 years, with two trials providing data specific to participants under five years (n = 69) and eight trials providing data specific to participants aged 5 to 16 (n = 766). Across the trials, 1245 participants were male and 1229 were female, with two studies not reporting sex distribution. Fifteen trials contributed to the primary outcome analysis of exacerbations requiring systemic corticosteroids. The duration of trials ranged from three to 40 months; all but two investigated effects of administering cholecalciferol (vitamin D3). As in the previous Cochrane Review, the majority of participants had mild to moderate asthma, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare. Administration of vitamin D or its hydroxylated metabolites did not reduce or increase the proportion of participants experiencing one or more asthma exacerbations treated with systemic corticosteroids (odds ratio (OR) 1.04, 95% CI 0.81 to 1.34; I2 = 0%; 14 studies, 1778 participants; high-quality evidence). This equates to an absolute risk of 226 per 1000 (95% CI 185 to 273) in the pooled vitamin D group, compared to a baseline risk of 219 participants per 1000 in the pooled placebo group. We also found no effect of vitamin D supplementation on the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.86, 95% CI 0.62 to 1.19; I2 = 60%; 10 studies, 1599 participants; high-quality evidence), or the time to first exacerbation (hazard ratio 0.82, 95% CI 0.59 to 1.15; I2 = 22%; 3 studies, 850 participants; high-quality evidence). Subgroup analysis did not reveal any evidence of effect modification by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, or age. A single trial investigating administration of calcidiol reported a benefit of the intervention for the primary outcome of asthma control. Vitamin D supplementation did not influence any secondary efficacy outcome meta-analysed, which were all based on moderate- or high-quality evidence. We observed no effect on the incidence of serious adverse events (OR 0.89, 95% CI 0.56 to 1.41; I2 = 0%; 12 studies, 1556 participants; high-quality evidence). The effect of vitamin D on fatal asthma exacerbations was not estimable, as no such events occurred in any trial. Six studies reported adverse reactions potentially attributable to vitamin D. These occurred across treatment and control arms and included hypercalciuria, hypervitaminosis D, kidney stones, gastrointestinal symptoms and mild itch. In one trial, we could not ascertain the total number of participants with hypercalciuria from the trial report. We assessed three trials as being at high risk of bias in at least one domain; none of these contributed data to the analysis of the outcomes reported above. Sensitivity analyses that excluded these trials from each outcome to which they contributed did not change the null findings. AUTHORS' CONCLUSIONS: In contrast to findings of our previous Cochrane Review on this topic, this updated review does not find evidence to support a role for vitamin D supplementation or its hydroxylated metabolites to reduce risk of asthma exacerbations or improve asthma control. Participants with severe asthma and those with baseline 25(OH)D concentrations < 25 nmol/L were poorly represented, so further research is warranted here. A single study investigating effects of calcidiol yielded positive results, so further studies investigating effects of this metabolite are needed.

ANTECEDENTES: Desde la revisión Cochrane anterior sobre este tema en 2016, ha continuado el debate en torno a una posible función de la vitamina D en la reducción del riesgo de exacerbación del asma y la mejora de su control. Por lo tanto, se realizó un metanálisis actualizado para incluir los datos de los nuevos ensayos completados desde esta fecha. OBJETIVOS: Evaluar la eficacia y seguridad de la administración de vitamina D o sus metabolitos hidroxilados para reducir el riesgo de exacerbaciones graves del asma (definidas como aquellas que requieren tratamiento con corticosteroides sistémicos) y mejorar el control de sus síntomas. MÉTODOS DE BÚSQUEDA: Se buscó en el registro de ensayos del Grupo Cochrane de Vías respiratorias (Cochrane Airways Group) y en las listas de referencias de los artículos. Se estableció contacto con los autores de los estudios para identificar ensayos adicionales. Fecha de la última búsqueda: 8 de septiembre de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron los ensayos doble ciego, aleatorizados, controlados con placebo de vitamina D en niños y adultos con asma que evaluaron el riesgo de exacerbación o el control de los síntomas del asma, o ambos. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Cuatro autores de la revisión aplicaron de forma independiente los criterios de inclusión de los estudios, extrajeron los datos y evaluaron el riesgo de sesgo. Cuando fue posible, se obtuvieron los datos faltantes a través de los autores de los estudios. Los resultados se informaron con intervalos de confianza (IC) del 95%. El desenlace principal fue la incidencia de exacerbaciones graves del asma que requirieron tratamiento con corticosteroides sistémicos. Los desenlaces secundarios incluyeron la incidencia de exacerbaciones del asma que precipitaron acudir al servicio de urgencias o requirieron ingreso hospitalario, o ambas, las puntuaciones de la childhood Asthma Control Test (cACT) o la Asthma Control Test (ACT) al final del estudio, y el % previsto de volumen espiratorio forzado en un segundo (VEF1) al final del estudio. Se realizaron análisis de subgrupos para determinar si el efecto de la vitamina D sobre el riesgo de exacerbación del asma se veía modificado por el estado inicial de vitamina D, la dosis de vitamina D, la frecuencia de la posología, la formulación de la vitamina D administrada y la edad de los participantes. RESULTADOS PRINCIPALES: En esta revisión se incluyeron 20 estudios; 15 ensayos con un total de 1155 niños y cinco ensayos con un total de 1070 adultos aportaron datos para los análisis. Las edades de los participantes variaron entre 1 y 84 años, con dos ensayos que proporcionaron datos específicos de participantes menores de 5 años (n = 69) y ocho ensayos que proporcionaron datos específicos de participantes de 5 a 16 años (n = 766). En todos los ensayos, 1245 participantes eran hombres y 1229 mujeres, y dos estudios no informaron acerca de la distribución por sexos. Quince ensayos contribuyeron al análisis del desenlace principal: exacerbaciones que requirieron corticosteroides sistémicos. La duración de los ensayos fue de entre 3 y 40 meses; todos menos dos investigaron los efectos de la administración de colecalciferol (vitamina D3). Al igual que en la revisión Cochrane anterior, la mayoría de los participantes presentaban asma de leve a moderada y la deficiencia importante de vitamina D (25­hidroxivitamina D [25(OH)D] < 25 nmol/l) al inicio del estudio fue poco frecuente. La administración de vitamina D o sus metabolitos hidroxilados no redujo ni aumentó la proporción de participantes que presentaron una o más exacerbaciones del asma tratada con corticosteroides sistémicos (odds ratio [OR] 1,04; IC del 95%: 0,81 a 1,34; I2 = 0%; 14 estudios, 1778 participantes; evidencia de calidad alta). Esto equivale a un riesgo absoluto de 226 por cada 1000 (IC del 95%: 185 a 273) en el grupo de vitamina D agrupado, en comparación con un riesgo inicial de 219 participantes por cada 1000 en el grupo placebo agrupado. Tampoco se encontraron efectos de la administración de suplementos de vitamina D sobre la tasa de exacerbaciones que requirieron corticosteroides sistémicos (cociente de tasas 0,86; IC del 95%: 0,62 a 1,19; I2 = 60%; 10 estudios, 1599 participantes; evidencia de calidad alta) ni sobre el tiempo transcurrido hasta la primera exacerbación (cociente de riesgos instantáneos 0,82; IC del 95%: 0,59 a 1,15; I2 = 22%; tres estudios, 850 participantes; evidencia de calidad alta). El análisis de subgrupos no reveló una evidencia de modificación del efecto en función del estado inicial de vitamina D, la dosis de vitamina D, la frecuencia de la posología ni la edad. Un único ensayo que investigó la administración de calcidiol informó sobre un efecto beneficioso de la intervención en el desenlace principal de control del asma. La administración de suplementos de vitamina D no influyó en ninguno de los desenlaces secundarios de eficacia metanalizados, todos ellos basados en evidencia de calidad moderada o alta. No se observaron efectos sobre la incidencia de eventos adversos graves (OR 0,89; IC del 95%: 0,56 a 1,41; I2 = 0%; 12 estudios, 1556 participantes; evidencia de calidad alta). No fue posible determinar el efecto de la vitamina D sobre las exacerbaciones mortales del asma ya que no se produjeron tales eventos en ningún ensayo. Seis estudios informaron sobre la presencia de reacciones adversas potencialmente atribuibles a la vitamina D. Estas se dieron en los grupos de tratamiento y control e incluyeron hipercalciuria, hipervitaminosis D, cálculos renales, síntomas gastrointestinales y prurito leve. En un ensayo, no fue posible determinar el número total de participantes con hipercalciuria a partir del informe del ensayo. Tres ensayos se consideraron con alto riesgo de sesgo en al menos un dominio; ninguno de ellos aportó datos al análisis de los desenlaces informados anteriormente. Los análisis de sensibilidad que excluyeron estos ensayos de cada desenlace al que contribuyeron no cambiaron los hallazgos nulos. CONCLUSIONES DE LOS AUTORES: En contraposición con los hallazgos de la revisión Cochrane anterior sobre este tema, esta revisión actualizada no encuentra evidencia que respalde una función de los suplementos de vitamina D o sus metabolitos hidroxilados en la reducción del riesgo de exacerbaciones del asma o la mejoría del control del asma. Los participantes con asma grave y aquellos con concentraciones iniciales de 25(OH)D < 25 nmol/l estuvieron escasamente representados, por lo que se justifica la realización de más estudios de investigación. Un único estudio que investigó los efectos del calcidiol proporcionó resultados positivos, por lo que se necesitan más estudios que investiguen los efectos de este metabolito.

Incidence determinants and serological correlates of reactive symptoms following SARS-CoV-2 vaccination.

Prospective population-based studies investigating associations between reactive symptoms following SARS-CoV-2 vaccination and serologic responses to vaccination are lacking. We therefore conducted a study in 9003 adults from the UK general population receiving SARS-CoV-2 vaccines as part of the national vaccination programme. Titres of combined IgG/IgA/IgM responses to SARS-CoV-2 spike (S) glycoprotein were determined in eluates of dried blood spots collected from all participants before and after vaccination. 4262 (47.3%) participants experienced systemic reactive symptoms after a first vaccine dose. Factors associating with lower risk of such symptoms included older age (aOR per additional 10 years of age 0.85, 95% CI: 0.81-0.90), male vs. female sex (0.59, 0.53-0.65) and receipt of an mRNA vaccine vs. ChAdOx1 nCoV-19 (0.29, 0.26-0.32 for BNT162b2; 0.06, 0.01-0.26 for mRNA-1273). Higher risk of such symptoms was associated with SARS-CoV-2 seropositivity and COVID-19 symptoms prior to vaccination (2.23, 1.78-2.81), but not with SARS-CoV-2 seropositivity in the absence of COVID-19 symptoms (0.94, 0.81-1.09). Presence vs. absence of self-reported anxiety or depression at enrolment associated with higher risk of such symptoms (1.24, 1.12-1.39). Post-vaccination anti-S titres were higher among participants who experienced reactive symptoms after vaccination vs. those who did not (P < 0.001). We conclude that factors influencing risk of systemic symptoms after SARS-CoV-2 vaccination include demographic characteristics, pre-vaccination SARS-CoV-2 serostatus and vaccine type. Participants experiencing reactive symptoms following SARS-CoV-2 vaccination had higher post-vaccination titres of IgG/A/M anti-S antibodies. Improved public understanding of the frequency of reactogenic symptoms and their positive association with vaccine immunogenicity could potentially increase vaccine uptake.

Rebound in asthma exacerbations following relaxation of COVID-19 restrictions: a longitudinal population-based study (COVIDENCE UK).

BACKGROUND: The imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. METHODS: We conducted a population-based longitudinal study in 2312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and severe asthma exacerbations were collected via monthly online questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. RESULTS: Relaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted OR 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). CONCLUSIONS: Relaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. STUDY REGISTRATION NUMBER: NCT04330599.

Influence of Vitamin D Supplementation on Growth, Body Composition, and Pubertal Development Among School-aged Children in an Area With a High Prevalence of Vitamin D Deficiency: A Randomized Clinical Trial.

Importance: Vitamin D deficiency (defined as 25-hydroxyvitamin D [25(OH)D] <20 ng/mL) is prevalent among children living in temperate climates and has been reported to associate independently with stunting, obesity, and early activation of the hypothalamic-pituitary-gonadal axis. Phase 3 randomized clinical trials to investigate the influence of long-term vitamin D replacement on growth, body composition, and pubertal development of school-aged children with vitamin D deficiency are lacking. Objective: To determine whether weekly oral vitamin D supplementation influences linear growth, body composition, or pubertal development in school-aged children living in a setting where vitamin D deficiency is highly prevalent. Design, Setting, and Participants: This secondary analysis of a double-blind, placebo-controlled randomized clinical trial was conducted from June 2016 to June 2019 at 18 grade schools in Ulaanbaatar, Mongolia. School-aged children (6 to 13 years at baseline) attending participating schools were included. Exclusion criteria included a positive QuantiFERON-TB Gold in-tube assay result, conditions or medications associated with altered vitamin D metabolism, use of vitamin D supplements, signs of rickets, or intention to move from Ulaanbaatar within 4 years. Of 11 475 children invited to participate in the study, 9814 underwent QFT testing, and 8851 with negative results were included in the study. All but 1 participant in the placebo group completed follow-up and were included in the present analysis. Data were analyzed from November 2021 to February 2022. Interventions: Weekly oral doses of vitamin D3, 14 000 IU, (n = 4418), or placebo (n = 4433) for 3 years. Main Outcomes and Measures: Mean z scores for height for age, body mass index for age, and waist-to-height ratio; mean percentage body fat, fat mass, and fat-free mass; and mean Tanner scores for pubertal development. Results: Of 8851 participants, 4366 (49.3%) were female, and 8165 (92.2%) were of Khalkh ethnicity; the mean (SD) age was 9.4 (1.6) years. A total of 8453 participants (95.5%) were vitamin D deficient at baseline, and mean end-of-study 25(OH)D concentrations among participants randomized to vitamin D vs placebo were 31.0 vs 10.7 ng/mL (mean difference, 20.3; 95% CI; 19.9-20.6). However, vitamin D supplementation did not influence mean height for age, body mass index for age, waist-to-height ratio, percentage body fat, fat mass, fat-free mass, or Tanner scores, either overall or within subgroups defined by baseline 25(OH)D concentration less than 10 ng/mL vs 10 ng/mL or greater, estimated calcium intake less than 500 mg/d vs 500 mg/d or greater, or male vs female sex. Conclusions and Relevance: In school-aged children in this study with low baseline vitamin D status, oral vitamin D3 supplementation at a dose of 14 000 IU per week for 3 years was effective in elevating 25(OH)D concentrations but did not influence growth, body composition, or pubertal development. Trial Registration: ClinicalTrials.gov Identifier: NCT02276755.