Immunogenicity of COVID-19 vaccines and their effect on HIV reservoir in older people with HIV.

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. Our study on 68 PWH and 23 HIV-negative participants aged 55 and older post-three vaccine doses showed equally strong anti-spike IgG responses in serum and saliva through week 48 from baseline, while PWH salivary IgA responses were low. PWH had diminished live-virus neutralization responses after two vaccine doses, which were 'rescued' post-booster. Spike-specific T cell immunity was enhanced in PWH with normal CD4+ T cell count, suggesting Th1 imprinting. The frequency of detectable HIV viremia increased post-vaccination, but vaccines did not affect the size of the HIV reservoir in most PWH, except those with low-level viremia. Thus, older PWH require three doses of COVID-19 vaccine for maximum protection, while individuals with unsuppressed viremia should be monitored for adverse reactions from HIV reservoirs.

Immunogenicity of COVID-19 vaccines and their effect on the HIV reservoir in older people with HIV.

Older individuals and people with HIV (PWH) were prioritized for COVID-19 vaccination, yet comprehensive studies of the immunogenicity of these vaccines and their effects on HIV reservoirs are not available. We followed 68 PWH aged 55 and older and 23 age-matched HIV-negative individuals for 48 weeks from the first vaccine dose, after the total of three doses. All PWH were on antiretroviral therapy (cART) and had different immune status, including immune responders (IR), immune non-responders (INR), and PWH with low-level viremia (LLV). We measured total and neutralizing Ab responses to SARS-CoV-2 spike and RBD in sera, total anti-spike Abs in saliva, frequency of anti-RBD/NTD B cells, changes in frequency of anti-spike, HIV gag/nef-specific T cells, and HIV reservoirs in peripheral CD4 + T cells. The resulting datasets were used to create a mathematical model for within-host immunization. Various regimens of BNT162b2, mRNA-1273, and ChAdOx1 vaccines elicited equally strong anti-spike IgG responses in PWH and HIV - participants in serum and saliva at all timepoints. These responses had similar kinetics in both cohorts and peaked at 4 weeks post-booster (third dose), while half-lives of plasma IgG also dramatically increased post-booster in both groups. Salivary spike IgA responses were low, especially in INRs. PWH had diminished live virus neutralizing titers after two vaccine doses which were 'rescued' after a booster. Anti-spike T cell immunity was enhanced in IRs even in comparison to HIV - participants, suggesting Th1 imprinting from HIV, while in INRs it was the lowest. Increased frequency of viral 'blips' in PWH were seen post-vaccination, but vaccines did not affect the size of the intact HIV reservoir in CD4 + T cells in most PWH, except in LLVs. Thus, older PWH require three doses of COVID-19 vaccine to maximize neutralizing responses against SARS-CoV-2, although vaccines may increase HIV reservoirs in PWH with persistent viremia.

Nutritional management of people living with cystic fibrosis throughout life and disease continuum: Changing times, new challenges.

Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding for the ion channel cystic fibrosis transmembrane conductance regulator (CFTR). The management of CF disease has evolved in recent decades from treating downstream disease manifestations affecting the airways, the lungs and the gastrointestinal system to addressing the CFTR gene defect. The advent of CFTR modulators, which correct the functionality of the defective CFTR, contributes to reshaping the landscape of CF demographics, prognosis and therapies, including nutritional management. A spectrum of clinical manifestations is emerging within the same patient population where undernutrition and nutritional deficiencies coexist with excessive weight gain and metabolic derangements. Such contrasting presentations challenge current practices, require adjustments to traditional approaches, and involve more individualised interventions. This narrative review examines the current state of knowledge on the nutritional management of people living with cystic fibrosis from early life to adulthood in the era of CFTR modulation.

Third and Fourth Vaccine Doses Broaden and Prolong Immunity to SARS-CoV-2 in Adult Patients with Immune-Mediated Inflammatory Diseases.

Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in patients with immune-mediated inflammatory diseases (IMIDs), particularly those treated with anti-TNF biologics. We previously reported that IMID patients diagnosed with inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, or rheumatoid arthritis exhibited greater waning of Ab and T cell responses than healthy control subjects after SARS-CoV-2 vaccine dose 2. Fewer data are available on the effects of third and fourth doses. This observational cohort study collected plasma and PBMCs from healthy control subjects and untreated or treated patients with IMIDs prevaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2-specific Ab levels, neutralization, and T cell cytokine release were measured against wild-type and Omicron BA.1 and BA.5 variants of concern. Third vaccine doses substantially restored and prolonged Ab and T cell responses in patients with IMIDs and broadened responses against variants of concern. Fourth-dose effects were subtle but also prolonged Ab responses. However, patients with IMIDs treated with anti-TNF, especially patients with inflammatory bowel disease, exhibited lower Ab responses even after the fourth dose. Although T cell IFN-γ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 mo postvaccination. Our study demonstrates that third and fourth doses of the SARS-CoV-2 mRNA vaccines sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in patients with IMIDs.

A glycosylated hemoglobin A1c above 6% (42 mmol/mol) is associated with a high risk of developing Cystic Fibrosis-Related Diabetes and a lower probability of weight gain in both adults and children with Cystic Fibrosis.

OBJECTIVES: The classical glycosylated hemoglobin A1c threshold of 6.5% is an insensitive screening test for cystic fibrosis-related diabetes (CFRD). We sought to identify CF-specific A1C thresholds associated with 1) risk of progression to CFRD and 2) changes in body mass index (BMI) and forced expiratory volume (FEV1). METHODS: We studied the cross sectional and longitudinal associations between A1c, BMI, and FEV1 in 2 cohorts of 223 children (followed for up to 8 years) and 289 adults (followed for a mean of 7.5 ± 4.3 years) with CF but without diabetes at baseline and undergoing regular assessments including Oral Glucose Tolerance Test (OGTT). RESULTS: For the onset of OGTT-defined CFRD optimal A1c threshold was 5.9% in adults (sensitivity: 67% and specificity: 71%) and 5.7% for children (sensitivity: 60% and specificity: 47%). Kaplan-Meier analysis of progression to CFRD according to baseline A1C showed increased the risk of developing CFRD for A1c ≥ 6.0% in adults (P = 0.002) and ≥ 5.5% in children (p = 0.012). Temporal changes in BMI and FEV1 according to baseline A1C in adults were assessed with a linear mixed-effect model, BMI significantly increased over time in subjects with a baseline A1c < 6%, but those with a A1C ≥ 6.0% gained significantly less weight over time (P = 0.05). There was no difference in FEV1 according to baseline A1c category. CONCLUSION: An A1C above 6% may be associated with a high risk of developing CFRD and a lower probability of weight gain in both adults and children with CF.

Nutrition and immunity: perspectives on key issues and next steps.

In January 2022, a group of experts came together to discuss current perspectives and future directions in nutritional immunology as part of a symposium organized by the Canadian Nutrition Society. Objectives included (1) creating an understanding of the complex interplay between diet and the immune system from infants through to older adults, (2) illustrating the role of micronutrients that are vital to the immune system, (3) learning about current research comparing the impact of various dietary patterns and novel approaches to reduce inflammation, autoimmune conditions, allergies, and infections, and (4) discussing select dietary recommendations aimed at improving disease-specific immune function. The aims of this review are to summarize the symposium and to identify key areas of research that require additional exploration to better understand the dynamic relationship between nutrition and immune function.

New-onset Obesity After Lung Transplantation: Incidence, Risk Factors, and Clinical Outcomes.

BACKGROUND: Lung transplant (LTx) recipients who gain weight after transplantation may experience an upward shift in body mass index (BMI) that places them in the obese category. The incidence, risk factors, and impact on metabolic health and mortality of new-onset obesity have not been documented in the LTx setting. METHODS: This single-center retrospective study included 564 LTx recipients. Individuals were stratified according to their BMI trajectories from pretransplant evaluation up to 10 y posttransplant. New-onset obesity was defined as a pretransplant BMI <30 kg/m 2 and posttransplant BMI >30 kg/m 2 . The incidence, risk factors, and posttransplant diabetes mellitus, metabolic syndrome, and mortality of recipients with new-onset obesity were compared with those of nonobese (BMI <30 kg/m 2 , pre/post-LTx), consistently obese (BMI >30 kg/m 2 , pre/post-LTx), and obese recipients with weight loss (BMI >30 kg/m 2 pre-LTx, BMI <30 kg/m 2 post-LTx). RESULTS: We found that 14% of recipients developed obesity after transplantation. Overweight individuals (odds ratio [OR]: 9.01; 95% confidence interval [CI] [4.86-16.69]; P < 0.001) and candidates with chronic obstructive pulmonary disease (OR: 6.93; 95% CI [2.30-20.85]; P = 0.001) and other diagnoses (OR: 4.28; 95% CI [1.22-14.98]; P = 0.023) were at greater risk. Multivariable regression analysis showed that new-onset obesity was associated with a greater risk of metabolic syndrome (hazard ratio: 1.70; 95% CI [1.17-2.46]; P = 0.005), but not of posttransplant diabetes mellitus, than nonobesity. Recipients with new-onset obesity had a survival comparable to that of consistently obese individuals. CONCLUSIONS: A greater understanding of the multifaceted nature of post-LTx obesity may lead to interventions that are better tailored to the characteristics of these individuals.

Long-term bone mineral density changes and fractures in lung transplant recipients with cystic fibrosis.

BACKGROUND: Little is known about long-term bone mineral density (BMD) changes and fractures in lung transplant recipients with cystic fibrosis (CF). We examined femur and lumbar spine (LS) BMD changes in men and women with CF up to 10 years post-transplant and documented post-transplant fracture prevalence. METHODS: Retrospective study of individuals who had undergone a lung transplant (2000-2015) and had a pre-transplant and at least one BMD measurement after transplant. Vertebral fractures were assessed on chest computed tomography scans and other fractures abstracted from medical records. RESULTS: The cohort consisted of 131 individuals; 53% males, median age: 28 years [interquartile range: 24-35] and 31% having pre-transplant low bone mass. Most recipients were given bisphosphonates after transplant with proportion reaching 94% at 10 years. Up to 10 years post-transplant, men experienced positive or little change in LS BMD, indicating minimal loss from pre-transplant values. In contrast, women displayed negative changes in BMD up to 5 years post-transplant before recovering pre-transplant BMD values by 10 years. Similar patterns were observed at the femur BMD where men demonstrated a lower bone loss and faster recovery towards pre-transplant values than women. After transplant, 88% of recipients maintained their pre-transplant bone status, 3% experienced an improvement, mostly progressing from low bone mass to normal status whereas 9% had a deterioration of their pre-transplant bone status. Twenty-seven recipients suffered fractures in the post-transplant period. CONCLUSIONS: These findings underline that lung recipients with CF remain at risk of skeletal fragility despite prompt initiation of post-transplant anti-osteoporosis therapy.

Combined Indeterminate and Impaired Glucose Tolerance Is a Novel Group at High Risk of Cystic Fibrosis-Related Diabetes.

BACKGROUND: Indeterminate glycemia (INDET) and impaired glucose tolerance (IGT) are independently associated with cystic fibrosis-related diabetes (CFRD) risk. We determined whether patients meeting both criteria have increased risk of diabetes in 2 separate adult cohorts. METHODS: The Montreal Cystic Fibrosis Cohort (MCFC; n = 293 baseline and 198 for prospective analysis excluding subjects identified with incident CFRD at baseline) and the Lyon cystic fibrosis cohort [Determination of the Predictive Factors in the Reversibility or the Aggravation in the Disorders of the Glucose Metabolism in Cystic Fibrosis Patients (DIAMUCO); n = 144/105] are prospective observational cohorts. RESULTS: In the MCFC and DIAMUCO cohorts, mean age was 25.5 ±â€…7.7 and 25.0 ±â€…8.6 years; body mass index, 21.7 ±â€…3.0 and 20.2 ±â€…2.2 kg/m2; percentage of forced expiratory volume expired in 1 sec, 73.2 ±â€…22.1 and 62.5 ±â€…21.9; and follow-up, 6.9 ±â€…3.8 and 2.4 ±â€…1.2 years, respectively. In the MCFC cohort, the IGT only and combined INDET and IGT (INDET + IGT) groups had greater risk of CFRD (P = 0.0109). In the DIAMUCO cohort, there was lower diabetes-free survival in the INDET + IGT group (P = 0.0105). In both cohorts, CFRD risk ranged from 17% in normal glucose tolerance patients up to 42% to 56% in patients with INDET + IGT. CONCLUSION: Patients who meet combined criteria have a higher risk of developing diabetes probably justifying closer follow-up.

Glycated Hemoglobin as a First-line Screening Test for Cystic Fibrosis‒Related Diabetes and Impaired Glucose Tolerance in Children With Cystic Fibrosis: A Validation Study.

OBJECTIVES: Our aims in this study were to document the screening rate for cystic fibrosis‒related diabetes (CFRD) in children followed at a cystic fibrosis (CF) clinic in Canada and to evaluate the accuracy of various glycated hemoglobin (A1C) cutoffs to screen for CFRD and impaired glucose tolerance (IGT) in a pediatric CF population. METHODS: The CFRD screening rate was calculated over a follow-up period of up to 8 years among children who attended the CF clinic between 1993 and 2018. Test performance of A1C at various thresholds ranging from 5.5% to 6.2% was compared with the oral glucose tolerance test (OGTT) as the reference method. Children with CF aged ≥10 years with an OGTT performed within 120 days of A1C measurement were included in the analysis. RESULTS: The overall CFRD screening rate was 53.0%. A total of 256 children were included for the A1C performance analysis, of whom 8.6% had an OGTT-confirmed CFRD diagnosis. An A1C threshold of 5.8% demonstrated an optimal balance between sensitivity (90.9%) and specificity (60.7%) for CFRD screening, leading to a potential reduction of 56.3% of the annual required OGTTs. A1C demonstrated poor accuracy for identifying children with IGT. CONCLUSIONS: An A1C threshold ≥5.8% allows for identification of children requiring further CFRD investigations, which may reduce the clinical burden of children with CF without compromising the ability of early CFRD diagnosis.

Abnormal glucose tolerance in a pediatric cystic fibrosis cohort: Trends in clinical outcomes and associated factors in the preceding years.

BACKGROUND AND AIMS: Deterioration of anthropometric and lung function parameters was shown to precede the onset of cystic fibrosis-related diabetes (CFRD) in adults. In children, studies have been conducted in small cohorts with relatively short observation period. Study objectives were to document the longitudinal trends of anthropometric, pulmonary, nutritional and metabolic parameters from cystic fibrosis (CF) diagnosis to the ascertainment of abnormal glucose tolerance and identify parameters associated with the incidence of such abnormalities in a pediatric CF cohort. METHODS AND RESULTS: Retrospective cohort study of 281 children with CF. Longitudinal trends of anthropometric, lung function, nutritional and metabolic data were generated from CF diagnosis to the ascertainment of abnormal glucose tolerance defined as the presence of either impaired glucose tolerance (IGT), unconfirmed CFRD or CFRD. Cox models and Kaplan-Meier curves were used to identify factors associated with developing abnormal glucose tolerance. Forty-five percent of cohort had normal glucose tolerance (NGT), 27% IGT, 10% unconfirmed CFRD and 18% CFRD. Children who developed CFRD displayed lower height z-scores from a very early age. Conversely, HbA1c levels began to rise closer to CFRD ascertainment. Height z-scores (HR: 0.45; CI 95% [0.29-0.69]) and HbA1c (HR: 2.43; CI 95% [1.86-3.18]) in years preceding ascertainment were associated with the risk of developing CFRD. CONCLUSION: Children who developed CFRD display distinctive trends for height z-scores from a very early age, whereas HbA1c appears as a marker of established glucose metabolism derangements.

Comparison of two vitamin D supplementation strategies in children with sickle cell disease: a randomized controlled trial.

Previously, we showed that nearly 70% of children followed in our sickle cell disease (SCD) clinic were vitamin D- deficient and had low vitamin intake with poor use of supplements. We compared the change in serum 25-hydroxyvitamin D [25(OH)D], safety and clinical impact of two vitamin D supplementation regimens in children with SCD. Children (5-17 years, all genotypes) were randomized to a single bolus of vitamin D3 (300 000 IU; n = 18) or placebo (n = 20). All children received a prescription for daily 1 000 IU vitamin D3 . Serum 25(OH)D and calcium, urinary calcium/creatinine ratio, musculoskeletal pain, quality of life, haematology and bone markers were assessed at baseline and three months post intervention. Bolus administration led to a greater rise in 25(OH)D levels from baseline compared to placebo (20 ± 16 nmol/l vs. 2 ± 19 nmol/l; P = 0·003) and correction of vitamin D deficiency. No hypercalcaemia nor hypercalciuria occurred during the study, but more children in the bolus group experienced gastrointestinal symptoms within the first month (P = 0·04). There were no differences between groups for other outcomes. The use of a high-dose vitamin D bolus combined with daily 1 000 IU vitamin D3 was more efficient in raising 25(OH)D levels than daily supplementation alone in children with SCD.

Vitamin D and Immunity in Infants and Children.

The last couple of decades have seen an explosion in our interest and understanding of the role of vitamin D in the regulation of immunity. At the molecular level, the hormonal form of vitamin D signals through the nuclear vitamin D receptor (VDR), a ligand-regulated transcription factor. The VDR and vitamin D metabolic enzymes are expressed throughout the innate and adaptive arms of the immune system. The advent of genome-wide approaches to gene expression profiling have led to the identification of numerous VDR-regulated genes implicated in the regulation of innate and adaptive immunity. The molecular data infer that vitamin D signaling should boost innate immunity against pathogens of bacterial or viral origin. Vitamin D signaling also suppresses inflammatory immune responses that underlie autoimmunity and regulate allergic responses. These findings have been bolstered by clinical studies linking vitamin D deficiency to increased rates of infections, autoimmunity, and allergies. Our goals here are to provide an overview of the molecular basis for immune system regulation and to survey the clinical data from pediatric populations, using randomized placebo-controlled trials and meta-analyses where possible, linking vitamin D deficiency to increased rates of infections, autoimmune conditions, and allergies, and addressing the impact of supplementation on these conditions.

CFTR deletion affects mouse osteoblasts in a gender-specific manner.

Advancements in research and care have contributed to increase life expectancy of individuals with cystic fibrosis (CF). With increasing age comes a greater likelihood of developing CF bone disease, a comorbidity characterized by a low bone mass and impaired bone quality, which displays gender differences in severity. However, pathophysiological mechanisms underlying this gender difference have never been thoroughly investigated. We used bone marrow-derived osteoblasts and osteoclasts from Cftr+/+ and Cftr-/- mice to examine whether the impact of CF transmembrane conductance regulator (CFTR) deletion on cellular differentiation and functions differed between genders. To determine whether in vitro findings translated into in vivo observations, we used imaging techniques and three-point bending testing. In vitro studies revealed no osteoclast-autonomous defect but impairment of osteoblast differentiation and functions and aberrant responses to various stimuli in cells isolated from Cftr-/- females only. Compared with wild-type controls, knockout mice exhibited a trabecular osteopenic phenotype that was more pronounced in Cftr-/- males than Cftr-/- females. Bone strength was reduced to a similar extent in knockout mice of both genders. In conclusion, we find a trabecular bone phenotype in Cftr-/- mice that was slightly more pronounced in males than females, which is reminiscent of the situation found in patients. However, at the osteoblast level, the pathophysiological mechanisms underlying this phenotype differ between males and females, which may underlie gender differences in the way bone marrow-derived osteoblasts behave in absence of CFTR.

Trends, Determinants, and Impact on Survival of Post-Lung Transplant Weight Changes: A Single-center Longitudinal Retrospective Study.

BACKGROUND: Weight gain is commonly seen in lung transplant (LTx) recipients. Although previous studies have focused on weight changes at fixed time periods and relatively early after transplant, trends over time and long-term weight evolution have not been described in this population. The study objectives were to document weight changes up to 15 years post-LTx and assess the predictors of post-LTx weight changes and their associations with mortality. METHODS: Retrospective cohort study of LTx recipients between January 1, 2000, and November 30, 2016 (n = 502). Absolute weight changes from transplant were calculated at fixed time periods (6 mo, 1, 2, 5, 10, and 15 y), and continuous trends over time were generated. Predictors of weight changes and their association with mortality were assessed using linear and Cox regression analysis. RESULTS: LTx recipients experienced a gradual increase in weight, resulting from the combination of multiple weight trajectories. Interstitial lung disease diagnosis negatively predicted post-LTx weight changes at all time points, whereas transplant body mass index categories were significant predictors at earlier time points. Patients with a weight gain of >10% at 5 years had a better survival (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.20-0.66), whereas a 10% weight loss at earlier time points was associated with worse survival (1 y: HR, 2.04; 95% CI, 1.22-3.41 and 2 y: HR, 2.37; 95% CI, 1.22-4.58). CONCLUSIONS: Post-LTx weight changes display various trajectories, are predicted to some extent by individual and LTx-related factors, and have a negative or positive impact on survival depending on the time post-LTx. These results may lead to a better individualization of weight management after transplant.

Association between fat-soluble nutrient status and auditory and visual related potentials in newly diagnosed non-screened infants with cystic fibrosis: A case-control study.

Nutritional deficiencies often precede the diagnosis of cystic fibrosis (CF) in infants, and occur at a stage where the rapidly developing brain is more vulnerable to insult. We aim to compare fat-soluble nutrient status of newly diagnosed non-screened infants with CF to that of healthy infants, and explore the association with neurodevelopment evaluated by electroencephalography (EEG). Our results show that CF infants had lower levels of all fat-soluble vitamins and docosahexaenoic acid (DHA) compared to controls. The auditory evoked potential responses were higher in CF compared to controls whereas the visual components did not differ between groups. DHA levels were correlated with auditory evoked potential responses. Although resting state frequency power was similar between groups, we observed a negative correlation between DHA levels and low frequencies. This study emphasizes the need for long-term neurodevelopmental follow-up of CF infants and pursuing intervention strategies in the future.

Impact of two oral doses of 100,000 IU of vitamin D3 in preschoolers with viral-induced asthma: a pilot randomised controlled trial.

BACKGROUND: New evidence supports the use of supplemental vitamin D in the prevention of exacerbation of asthma; however, the optimal posology to sufficiently raise serum levels while maximising adherence is unclear. The objective was to ascertain the efficacy of high-dose vitamin D3 in increasing serum vitamin D in preschoolers with asthma and provide preliminary data on safety and efficacy outcomes. METHODS: We conducted a 7-month, triple-blind, randomised, placebo-controlled, pilot trial of children aged 1-5 years with viral-induced asthma. Participants were allocated to receive two oral doses of 100,000 IU vitamin D3 (intervention) or identical placebo (control) 3.5 months apart, once in the fall and once in the winter. Serum 25-hydroxyvitamin D (25OHD) was measured by tandem mass spectrometry at baseline, 10 days, 3.5 months, 3.5 months + 10 days, and 7 months. The main outcome was the change in serum 25OHD from baseline (Δ25OHD) over time and at 3.5 and 7 months; other outcomes included the proportion of children with 25OHD ≥ 75 nmol/L, safety, and adverse event rates. RESULTS: Children (N = 47) were randomised (intervention, 23; control, 24) in the fall. There was a significant adjusted group difference in the Δ25OHD (95% confidence interval) of 57.8 (47.3, 68.4) nmol/L, p < 0.0001), with a time (p < 0.0001) and group*time interaction effect (p < 0.0001), in favour of the intervention. A significant group difference in the Δ25OHD was observed 10 days after the first (119.3 [105.8, 132.9] nmol/L) and second (100.1 [85.7, 114.6] nmol/L) bolus; it did not reach statistical significance at 3.5 and 7 months. At 3.5 and 7 months, respectively, 63% and 56% of the intervention group were vitamin D sufficient (≥ 75 nmol/L) compared to 39% and 36% of the control group. Hypercalciuria, all without hypercalcaemia, was observed in 8.7% of intervention and 10.3% of control samples at any time point. Exacerbations requiring rescue oral corticosteroids, which appear as a promising primary outcome, occurred at a rate of 0.87/child. CONCLUSION: Two oral boluses of 100,000 IU vitamin D3,once in the fall and once in the winter, rapidly, safely, and significantly raises overall serum vitamin D metabolites. However, it is sufficient to maintain 25OHD ≥ 75 nmol/L throughout 7 months in only slightly more than half of participants. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02197702 (23 072014). Registered on 23 July 2014.

Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): protocol for a multicentre randomised placebo-controlled triple-blind trial.

INTRODUCTION: Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D3 supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations. METHODS AND ANALYSIS: This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D3 (3.5 months apart) with 400 IU vitamin D3 daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety. ETHICS AND DISSEMINATION: This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines. TRIAL REGISTRATION NUMBER: NCT03365687.