Abstract
Background:
Observational studies have yielded inconsistent findings for the relation between vitamin D level and total IgE or allergic sensitization.
Objective:
To determine whether vitamin D supplementation reduces levels of total IgE and IgE to each of two common indoor allergens in children with asthma and low vitamin D levels.
Methods:
Total IgE, IgE to Dermatophagoides pteronyssinus (Der p), and IgE to Blattella germanica (Bla g) were measured at the randomization and exit visits for 174 participants in the Vitamin D Kids Asthma study (VDKA), a multicenter, double-blind, randomized placebo-controlled trial of vitamin D3 supplementation (4,000 IU/day) to prevent severe exacerbations in children with persistent asthma and vitamin D levels <30 ng/ml. Multivariable linear regression was used for the analysis of the effect of vitamin D supplementation on change in each IgE measure.
Results:
Participants were followed for an average of 316 days. At the exit visit, more subjects in the vitamin D arm achieved a vitamin D level ≥30 ng/ml compared to those in the placebo arm (87% vs. 30%, P<0.001). In a multivariable analysis, vitamin D3 supplementation had no significant effect on change in total IgE, IgE to Der p, or IgE to Bla g between the exit and randomization visits (e.g., for log10 total IgE, ß=0.007, 95% confidence interval= −0.061 to 0.074, P=0.85).
Conclusion:
Vitamin D supplementation, compared to placebo, has no significant effect on serum levels of total IgE, IgE to dust mite, or IgE to cockroach in children with asthma and low vitamin D levels.
Trial registration:
clinicaltrials.gov identifier: NCT02687815
Clinical Implications:
Our findings do not support vitamin D supplementation to reduce the degree or severity of atopy in children with asthma and low vitamin D levels.
Keywords: vitamin D, asthma, immunoglobulin E, children
Capsule Summary:
Vitamin D supplementation (4,000 IU/day), compared with placebo, had no significant effects on total IgE, IgE to dust mite, or IgE to cockroach in children with persistent asthma and low vitamin D levels.
INTRODUCTION
Allergen-specific IgE and total IgE are key biomarkers of asthma, allergic rhinitis, and atopic dermatitis in children (1). Moreover, total IgE is an important therapeutic target in children with severe asthma. Omalizumab, a monoclonal antibody that binds to circulating IgE, reduces the risk of severe asthma exacerbations in children (2), including those triggered by viral infections(3).
In experimental studies, vitamin D has been shown to induce regulatory T-cells, decrease Th2 and Th17 immune responses, and increase IL-10 production, all of which could reduce IgE levels (4-7). Consistent with these results, epidemiologic studies have shown an inverse association between vitamin D level or vitamin D insufficiency (defined as a vitamin D level below 30 ng/ml) and total IgE, IgE to dust mite, and allergic sensitization in children with asthma (8, 9) (10). However, whether vitamin D supplementation reduces levels of total or allergen-specific IgE in children with asthma and low vitamin D levels is unknown.
We recently reported that vitamin D supplementation, compared to placebo, had no significant effects on preventing severe asthma exacerbations in children with persistent asthma and low vitamin D levels who participated in the Vitamin D Kids Asthma Study (VDKA), a multicenter randomized clinical trial (11). Based on published literature, we hypothesized that vitamin D supplementation would reduce serum levels of total and allergen-specific IgEs in children with asthma and vitamin D levels below 30 ng/ml. We tested whether vitamin D supplementation reduces serum levels of total IgE and IgE to each of two common indoor allergens (house dust mite and cockroach) in a secondary analysis of data from the VDKA.
RESULTS AND DISCUSSION
After screening, 219 participants entered a four-week run-in phase, of whom 192 were randomized (96 each to the vitamin D and placebo groups). Of the 192 participants, 181 (94.3%) completed the trial (88 [49%] in the vitamin D group and 93 [51%] in the placebo group). Of these 181 subjects, 84 in the vitamin D group and 90 in the placebo group had measurements for total and allergen-specific IgEs at the randomization and exit visits. Mean duration of follow-up was 316 (± 43.5) days. The most common reasons for study discontinuation were loss to follow-up (n=6), family decision (n=5), and administrative decision (n=1).
Table 1 displays the baseline characteristics of the 174 participants in the current analysis, by treatment arm. At the randomization visit, participants in the vitamin D supplementation arm were more likely to be female and to have a higher IgE to Der p than those in the placebo arm. There were no significant differences in age, race/ethnicity, current exposure to second-hand smoke, federal poverty level, season of enrollment, BMI z-score, asthma control test score, serum vitamin D level, serum level of total IgE or IgE to Bla g, or time in the study between the treatment and placebo arms.
Table 1.
Baseline characteristics of the participants in the Vitamin D Kids Asthma Study who were included in this analysis, by treatment arm
| Measure | Vitamin D arm (n =84) |
Placebo arm (n = 90) |
P value |
|---|---|---|---|
| Age, years | 9.8 ± 2.5 | 9.7 ± 2.5 | 0.73 |
| Sex, female | 40 (47.6) | 29 (32.2) | 0.04 |
| Race | 0.79 | ||
| Black | 43 (51.2) | 44 (48.9) | |
| White | 25 (29.8) | 31 (34.4) | |
| Other | 16 (19.0) | 15 (16.7) | |
| Hispanic/Latino | 6 (7.1) | 5 (5.6) | 0.67 |
| Current exposure to second-hand tobacco smoke | 26 (31.3) | 31 (34.8) | 0.63 |
| Federal poverty level | 0.45 | ||
| < 100% | 18 (23.1) | 23 (27.4) | |
| < 200% | 30 (38.5) | 29 (34.5) | |
| < 400% | 28 (35.9) | 32 (38.1) | |
| ≥ 400% | 2 (2.6) | 0 (0.0) | |
| Season at enrollment | 0.82 | ||
| Spring | 22 (26.2) | 23 (25.6) | |
| Summer | 22 (26.2) | 19 (21.1) | |
| Autumn | 20 (23.8) | 22 (24.4) | |
| Winter | 20 (23.8) | 26 (28.9) | |
| Time in the study, days | 317 ± 41.3 | 314 ± 45.7 | 0.76 |
| Body mass index (BMI) z-score | 0.92 ± 1.07 | 0.92 ± 1.26 | 0.96 |
| Serum vitamin D (ng/ml)* | 22.6 ± 4.6 | 23.0 ± 4.6 | 0.60 |
| Asthma control test score | 22.4 ± 3.5 | 21.6 ± 3.8 | 0.18 |
| FEV1, %predicted | 94.3 ± 16.2 | 92.3 ± 17.7 | 0.19 |
| FEV1/FVC, %predicted | 90.9 ± 8.9 | 90.4 ± 9.1 | 0.92 |
| Bronchodilator response (%) | 7.6 ± 12.2 | 7.4 ± 13.4 | 0.82 |
| Peripheral blood eosinophils (%) | 6.9 ± 4.6 | 6.3 ± 4.4 | 0.29 |
| Log10 total IgE (IU/ml) | 2.4 ± 0.6 | 2.3 ± 0.8 | 0.50 |
| IgE to Der p (IU/ml) | 18.1 ± 29.9 | 13.2 ± 28.1 | 0.03 |
| IgE to Bla g (IU/ml) | 3.7 ± 13.0 | 2.4 ± 7.7 | 0.80 |
| Atopy | 72 (85.7) | 66 (77.3) | 0.74 |
Values presented as mean ± standard deviation or N (%). P values from X2, Student t test (age, BMI z-score, tmain D level), or Mann-Whitney U test. Federal poverty level calculated using U.S. Department of Health and Human Services (HHS) Poverty Guidelines, calculated per year of enrollment. FEV1, forced expiratory volume in the first second; FVC, forced vital capacity IgE= Immunoglobulin E; Der p=Dermatophagoides pteronyssinus; Bla g=Blattella germanica. The Childhood Asthma Control Test (C-ACT) was used in children younger than 12 years. Atopy was defined as a total IgE ≥ 100 IU/mL or an IgE to Der p ≥ 0.35 IU/ml or an IgE to Bla g ≥ 0.35 IU/ml.
All participants had a serum vitamin D level below 30 ng/ml.
Table 2 shows selected measures at the exit visit, by treatment arm. A comparison of treatment groups showed that there were no significant differences in the levels of total or cockroach-specific IgE between treatment arms, but that subjects in the vitamin D arm had a significantly higher IgE to Der p than those in the placebo arm. At the exit visit, a much higher proportion of subjects in the vitamin D arm had achieved a vitamin D level ≥30 ng/ml than those in the placebo arm (87% vs. 30%, P<0.01).
Table 2.
Selected characteristics of study participants at the exit study visit, by treatment arm
| Measure | Vitamin D arm (n =84) |
Placebo arm (n = 90) |
P value |
|---|---|---|---|
| Log10 total IgE (IU/ml) | 2.4 ± 0.6 | 2.3 ± 0.8 | 0.35 |
| IgE to Der p (IU/ml) | 18.1 ± 29.1 | 12.7 ± 26.2 | 0.04 |
| IgE to Bla g (IU/ml) | 4.0 ± 14.5 | 2.1 ± 6.3 | 0.79 |
| BMI z-score | 1.00 ± 1.09 | 0.96 ± 1.26 | 0.80 |
| Vitamin D ≥30 ng/ml | 73 (87%) | 27 (30%) | <0.001 |
Values presented as mean ± standard deviation or N (%). P values from X2 or Mann-Whitney U test, as appropriate. IgE= Immunoglobulin E; Der p=Dermatophagoides pteronyssinus; Bla g=Blattella germanica.
Table 3 shows the results of the multivariable linear regression analysis of the relation between vitamin D supplementation, compared with placebo, and change in total or allergen-specific IgE level between the exit and randomization visits. In this analysis, there was no effect of vitamin D supplementation on change in the levels of total IgE or allergen-specific IgEs between the exit and randomization visits. Moreover, there was no modification of the estimated effect of vitamin D supplementation on total or allergen-specific IgE levels by having achieved a vitamin D level ≥30 ng/ml at the exit visit (P for interaction=0.23). In a secondary analysis restricted to 138 subjects who had evidence of atopy at baseline (defined as a total IgE >100 IU/ml and/or an IgE to Der p ≥0.35 IU/ml and/or an IgE to Bla g ≥0.35 IU/ml), we obtained similar results.
Table 3.
Analysis of Vitamin D supplementation, compared with placebo, and change in total or allergen-specific IgE level between the exit and randomization visits.
|
Unadjusted
|
Adjusted
|
|||||
|---|---|---|---|---|---|---|
| Parameter | β | 95% CI | P | β | 95% CI | P |
| Treatment | ||||||
| Change in: | ||||||
| Log10 total IgE (IU/mL) | 0.011 | −0.056 – 0.077 | 0.75 | 0.007 | −0.061 – 0.074 | 0.85 |
| IgE to Der p (IU/ml) | 1.467 | −0.901 – 3.835 | 0.22 | 1.239 | −1.170 – 3.648 | 0.31 |
| IgE to Bla g (IU/ml) | 0.592 | –0.341 – 1.525 | 0.21 | 0.501 | −0.422 – 1.424 | 0.29 |
| Treatment (in atopic subjects only [n=138]) | ||||||
| Change in: | ||||||
| Log10 total IgE (IU/mL) | 0.015 | −0.051 – 0.081 | 0.65 | 0.012 | −0.055 – 0.080 | 0.72 |
| IgE to Der p (IU/ml) | 1.810 | −1.188 – 4.808 | 0.23 | 1.297 | −1.757 – 4.352 | 0.40 |
| IgE to Bla g (IU/ml) | 0.755 | −0.427 – 1.936 | 0.21 | 0.640 | −0.520 – 1.801 | 0.28 |
Models adjusted for sex, race, study site, and time in the study.
Der p= Dermatophagoides pteronyssinus, Bla g= Blattella germanica
Atopy was defined as a total IgE ≥100 IU/ml or an IgE to Der p ≥0.35 IU/ml or an IgE to Bla g ≥0.35 IU/ml
After imputing total and allergen-specific IgE levels in 18 subjects with missing values (Figure E1), we conducted a sensitivity analysis following intention-to-treat principles in all 192 randomized subjects in the VDKA, obtaining similar results (data not shown). In another sensitivity analysis, we included the baseline total or allergen-specific IgE level in the multivariable models, obtaining similar results (data not shown).
Figure 1 displays the change in the levels of total IgE, IgE to Der p, and IgE to Bla g between the exit and randomization visits, per participant by treatment arm (vitamin D supplementation vs. placebo).
Figure 1: Immunoglobulin E (IgE) levels at the baseline and exit visits of the Vitamin D Kids Asthma Study, by treatment arm.
The figure shows exit vs. baseline values by VDKA participant, per treatment group, for (A) log10 total serum IgE, (B) IgE to Dermatophagoides pteronyssinus (Der p), and (C) IgE to Blattella germanica (Bla g). Because of clustering for low levels of IgE to Der p and IgE to Bla g, panel B and C have more overlapping data points in the lower left corner than Panel A.
We found that most participants (≥89% for each allergen-specific IgE and treatment group) did not change sensitization status (e.g., from an IgE to Der p ≥0.35 IU/ml to one <0.35 IU/ml , or vice versa) between visits (Table 4).
Table 4.
Change in having a positive or negative IgE to dust mite or cockroach between the randomization and exit visits of the VDKA Study, by treatment group
| Treatment Group | ||
|---|---|---|
| Vitamin D arm | Placebo arm | |
| N | 83 | 90 |
| No change in status | ||
| Positive IgE, Der p | 46 (55%) | 37 (41%) |
| Negative IgE, Der p | 28 (34%) | 44 (49%) |
| Positive IgE, Bla g | 20 (24%) | 23 (22%) |
| Negative IgE, Bla g | 58 (70%) | 64 (71%) |
| Change from a positive to a negative IgE to: | ||
| Der p | 5 (6%) | 6 (7%) |
| Bla g | 4 (5%) | 3 (3%) |
| Change from a negative to a positive IgE to: | ||
| Der p | 4 (5%) | 3 (3%) |
| Bla g | 1 (1%) | 0 (0%) |
Results displayed as N (%).
Der p= Dermatophagoides pteronyssinus. Bla g= Blattella germanica.
A positive IgE was defined as ≥0.35 IU/ml
In this secondary analysis of data from a multicenter, double-blind, placebo-controlled randomized clinical trial of vitamin D supplementation to prevent severe asthma exacerbations in children with persistent asthma and vitamin D levels <30 ng/ml, vitamin D supplementation had no significant effect on change in total IgE, IgE to Der p, or IgE to Bla g over an average of 316 days of follow-up.
Our findings in school-aged children with asthma are consistent with those from a birth cohort study in the U.S., which found no significant association between estimated vitamin D intake (via supplementation or diet) during the first and second trimester of pregnancy on total IgE or allergic sensitization in school-aged offspring (12). Similar negative findings for serum vitamin D and total IgE or allergic sensitization were reported among adults in a cross-sectional nationwide study in the U.S., though that study reported an association between vitamin D levels <15 ng/ml and sensitization to several allergens in children and adolescents (10). In contrast to our findings in children with asthma, calcitriol (1,25-(OH)2 D3) supplementation led to reduced mean total IgE in Mexican adults with allergic asthma after six months of treatment (mean (SD) total IgE= 108.8 ±33.2 IU/ml vs. 209.8 ±95.6 IU/mL in the treatment and placebo arms, respectively)(13). However, that study found no difference in sensitization to common allergens between the treatment and placebo arms, and was limited by lack of data on vitamin D levels at the baseline and exit visits. Because subjects included in that prior study had allergic asthma (IgE >90 IU/ml and eosinophil count >300/μl), we conducted a sensitivity analysis restricted to sensitized subjects, again finding no association. Our findings further support conclusions from a Mendelian randomization study in predominately European adults, which reported no significant association between 25-hydroxyvitamin D and total IgE (14).
Similar to prior studies (15), 55% and 29% of participants in this study had a positive IgE to dust mite and cockroach at the baseline visit, respectively. Consistent with our negative findings for change in dust mite or cockroach IgE, a U.S. nationwide observational study found that vitamin D level was not significantly associated with dust mite sensitization after adjusting for confounders, though dust mite IgE level was higher in children with very low vitamin D levels than in others (10). In that prior study, a vitamin D level <15 ng/ml was significantly associated with 2.2 increased odds of cockroach sensitization, compared with a normal vitamin D level (95% confidence interval for odds ratio= 1.05 – 4.62) (10). In contrast to that observational study, we had very few participants with levels below 15 ng/ml.
As expected for children with asthma (16), most participants in our study were atopic at the baseline visit. Only 8 participants (5%) were found to have de novo sensitization to either dust mite or cockroach during the trial. Thus, while we found no effect of vitamin D supplementation on levels of IgE to Der p or IgE to Bla g in school-aged children with asthma, we cannot determine if vitamin D supplementation prevents the development of dust mite or cockroach sensitization. Such question has been previously examined in studies of young children, which have yielded inconsistent results(17) (18).
Our results cannot be explained by failure to achieve vitamin D sufficiency after vitamin D3 supplementation, as most participants in the treatment group had vitamin D levels ≥30 ng/ml during the trial, while a relatively low proportion of participants in the placebo group achieved levels ≥30 ng/ml. Moreover, subjects in the vitamin D group had consistently higher vitamin D levels than those in the placebo group throughout the trial (11).
We recognize additional study limitations. First, we lacked data on sensitization to seasonal and pet allergens and are thus unable to determine the effects of vitamin D supplementation on sensitization to allergens other than dust mite or cockroach in children with asthma. However, we found no effect of vitamin D on total IgE, and exposure to dust mite and cockroach allergens may be more important than seasonal allergens in children with asthma (19) (who spend most of their time indoors (20)). Moreover, sensitization to dust mite and cockroach allergens are associated with severe asthma exacerbations among U.S. children with asthma(10)(21). Second, our results are not generalizable to children with asthma and very low vitamin D levels (i.e., <10 ng/ml) or to children living in rural areas.
In summary, vitamin D supplementation, compared to placebo, had no significant effect on levels of total IgE or IgE to each of two common allergens (dust mite and cockroach) in children with asthma and low vitamin D levels. Our results do not support recommending vitamin D supplementation to attenuate the degree of atopy in this population.
METHODS
Study population
Subject recruitment and the design of the Vitamin D Kids Asthma Study (VDKA) were recently described in detail(1). In brief, children were recruited from 7 sites across the US: Boston Children’s Hospital (Boston, MA), Washington University and St. Louis Children’s Hospital (St. Louis, MO), Cincinnati Children’s Hospital (Cincinnati, OH), Rainbow Babies and Children’s Hospital (Cleveland, OH), the University of California at San Francisco Benioff Children’s Hospital (San Francisco, CA), National Jewish Health (Denver, CO), and the University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh (Pittsburgh, PA). The data coordinating center was based at the University of Pittsburgh Graduate School of Public Health. The study protocol was approved by the institutional review board (IRB) at each participating institution, and an independent data and safety monitoring board (DSMB) appointed by the National Heart, Lung, and Blood Institute monitored the study. Written parental consent was obtained for participating children, from whom written assent was also obtained.
Eligible participants were children with asthma, aged 6 to 16 years, with serum vitamin D levels <30 ng/mL but ≥ 10 ng/mL (until July 21, 2017) or ≥14 ng/mL (after that date, following a protocol amendment). Entry criteria included i. physician-diagnosed asthma for at least 1 year; ii. at least 1 severe asthma exacerbation (defined as use of systemic corticosteroids for at least 3 days, or a hospitalization or ED visit requiring systemic corticosteroids) in the previous year (2); iii. use of asthma medications (daily controller medications, or inhaled β2-agonists at least thrice per week) for at least 6 months in the previous year; iv. forced expiratory volume in one second (FEV1) ≥70% of predicted; and v. either bronchodilator responsiveness or, in those without bronchodilator responsiveness, increased airway responsiveness to methacholine. Exclusion criteria included chronic respiratory disorders other than asthma, chronic oral corticosteroid therapy, severe asthma, and inability to perform adequate spirometry.
Study design
The VDKA Study was a randomized, double-blind, parallel, placebo-controlled clinical trial of vitamin D supplementation to prevent severe asthma exacerbations in children with persistent asthma and low vitamin D levels, with each participant randomly assigned to either daily placebo capsules or daily vitamin D3, 4,000 IU (Pharmavite LLC), plus inhaled fluticasone propionate (88 μg twice per day in children aged 6-11 years and 110 μg twice per day in children ≥12 years). Eligible participants were screened between February of 2016 and March of 2019 and enrolled if they met inclusion criteria. After a four-week run-in period in which participants received placebo capsules plus inhaled fluticasone and as-needed inhaled albuterol (prior medications were discontinued), those who met inclusion criteria at entry and during run-in were randomized.
Computer-generated randomization was stratified according to study site and race/ethnicity, with treatment assignments made in random permuted block sizes of 2 and 4. At the randomization visit, participants and their parents received dietary counseling, including a list of foods rich in vitamin D. After randomization, participants were followed for 48 weeks, including a total of six in-person visits every 8 weeks and phone calls in-between visits. Following randomization, participants continued on the same dose of fluticasone until the 24-week visit, when their fluticasone dose was reduced by 50% if their asthma was well controlled and if they had FEV1 and FEV1 to forced vital capacity (FEV1/FVC) ≥80% of predicted, were using a rescue inhaler ≤4 times per week, and had asthma symptoms preventing full participation in daily activities no more than once per month.
During the trial, vitamin D levels were measured during in-person study visits at 0 (randomization), 16, 32, and 48 weeks. Study medications were discontinued in participants with a vitamin D level <10 ng/ml (n=2), who were referred to a pediatric endocrinologist for evaluation and followed in the group to which they were randomized. Participants whose level was between 10 and 13 ng/ml at any visit during the trial (n=10) received additional dietary counseling along with a randomly selected participant (to prevent unblinding); if their vitamin D level was <14 ng/ml at a subsequent visit (n=2), study medications were discontinued and the participant was referred to a pediatric endocrinologist and followed in the group to which they were randomized. Adherence to placebo or vitamin D capsules was assessed both through returned pill counts and electronically, using the MEMS monitor (Aardex).
Spirometry was conducted with an EasyOne (NDD Medical Technologies, Andover, Mass) spirometer, following ATS/ERS recommendations(3) . Percent predicted lung function measures (FEV1, and FEV1/FVC) were calculated at the baseline and exit visits, based on the Global Lung Function Initiative [GLI] data(4). Bronchodilator response (BDR) was defined as ([postbronchodilator FEV1- prebronchodilator FEV1]/prebronchodilator FEV1)×100. Asthma control was assessed using the Asthma Control Test (ACT, score=5-25) for participants aged ≥12 years, and the Childhood ACT (C-ACT, score=0-27) for participants aged <12 years. A change of 2-3 points in the ACT or C-ACT has been suggested as clinically meaningful(5). Body mass index (BMI) z scores were calculated on the basis of 2000 US Centers for Disease Control and Prevention growth charts.
Serum total IgE, IgE to Dermatophagoides pteronyssinus (Der p 1) and Blattella germanica (Bla g 2) were measured at the randomization and exit study visits using a solid phase, two-step, chemiluminescent immunoassay (the Immunlite 2000 CLEIA, Siemens Healthcare Diagnostics, Tarrytown, NY). Using this assay, the detection range for total IgE is 1-2000 IU/mL and that for specific IgE is ≥0.10 to 100 IU/ml. For data analysis, a constant equal to half the lower limit of detection (LLOD) was assigned to undetectable values. Total IgE levels were transformed to a log10 scale for data analysis. Atopy was defined as a total IgE >100 IU/mL or a positive IgE (≥ 0.35 IU/ml) to either of the two allergens tested.
For this secondary analysis, our key outcomes were changes in the serum levels of total IgE, IgE to Der p, and IgE to Bla g between the randomization (baseline) and exit study visits. In addition, we examined change in sensitization status to either allergen (e.g., going from positive IgE to Der p to having a negative IgE to Der p, or vice versa).
Statistical Analysis
During the trial, all children were followed up in the group to which they were randomized. Race/ethnicity was ascertained by parental report using fixed categories for race and a separate question for Hispanic/Latino ethnicity, and analyzed using a combined variable (non-Hispanic White, non-Hispanic Black, and other). Multivariable linear regression was used for the analysis of treatment group (vitamin D3 vs. placebo) and the change in total or each allergen-specific IgE between the randomization and exit visits, adjusting for study site, sex, time in the study (i.e. follow-up time), and race/ethnicity. Because 18 (9%) of the 192 randomized participants were excluded from the analysis due to not completing the study or missing data for IgE levels (Figure E1), a multiple imputation procedure (10 imputations) was used to include these participants in a sensitivity analysis using the intention to treat principle. Expectation maximization (EM) algorithm with general iterative method of maximum likelihood estimation for incomplete data was used for multiple imputation. Two-sided P values less than .05 were considered significant. All analyses were performed using SAS version 9.4 (SAS Institute).
Supplementary Material
ACKNOWLEDGEMENTS
We would like to thank all study participants and their families, the research coordinators and research teams at each of the study sites and the data coordinating center; the Data and Safety Monitoring Board; and the Clinical Trials Specialist (Julie Bamdad, MSE) and Program Officer (Patricia Noel, PhD) for the project at the federal agency who funded the study (the National Heart, Lung, and Blood Institute), for monitoring the study progress.
Sources of funding:
This study was funded by grant HL119952 from the U.S. National Institutes of Health (NIH). The project was also supported by the Pediatric Clinical and Translational Research Center (PCTRC) at the University of Pittsburgh Medical Center Children’s Hospital of Pittsburgh through NIH grant UL1TR001857. Dr. Rosser’s contribution was supported by grant KL2 TR001856 from the NIH. Pharmavite LLC provided the vitamin D and placebo capsules for the study, and Glaxo Smith Kline (GSK) provided the Flovent® given to study participants.
ABBREVIATIONS
- VDKA
Vitamin D Kids Asthma Study
- IgE
Immunoglobulin E
- Der p
Dermatophagoides pteronyssinus
- Bla g
Blattella germanica
Footnotes
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Conflicts of interest: Dr. Celedón has received Asmanex® from Merck for another NIH-funded study, unrelated to the current work. Dr. Guilbert reports personal fees from the American Board of Pediatrics (Pediatric Pulmonary Sub-board), GSK, and TEVA; grants from Astra-Zeneca and Novartis, grants and personal fees from Sanofi/Regeneron, and other support from UpToDate; all unrelated to the current work. Dr. Phipatanakul has served as consultant for GSK, Genentech, Novartis, Regeneron, Sanofi, and Teva; has received clinical trial support or medications from Genentech, Novartis, Regeneron, Sanofia, Circassia, Monaghen, Thermo Fisher, Alk Abello, Lincoln Diagnostics, GSK, Kaleo, and Merck; and reports funding to the institution by Genentech, Regeneron, Novartis, and the US NIH; all for projects unrelated to the current work. Dr. Cabana is a member of the United States Preventive Services Task Force (USPSTF). The contents of this manuscript do not necessarily represent the views of the USPSTF. The other authors report no conflicts of interest.
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