Research

JAMA | Original Investigation

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations

in Children With Asthma and Low Vitamin D Levels
The VDKA Randomized Clinical Trial
Erick Forno, MD, MPH; Leonard B. Bacharier, MD; Wanda Phipatanakul, MD, MS; Theresa W. Guilbert, MD, MS;
Michael D. Cabana, MD, MPH; Kristie Ross, MD, MS; Ronina Covar, MD; James E. Gern, MD;
Franziska J. Rosser, MD, MPH; Joshua Blatter, MD, MPH; Sandy Durrani, MD; Yueh-Ying Han, PhD;
Stephen R. Wisniewski, PhD; Juan C. Celedón, MD, DrPH

Visual Abstract
IMPORTANCE Severe asthma exacerbations cause significant morbidity and costs. Whether Supplemental content
vitamin D3 supplementation reduces severe childhood asthma exacerbations is unclear.
CME Quiz at
OBJECTIVE To determine whether vitamin D3 supplementation improves the time to a severe jamacmelookup.com
exacerbation in children with asthma and low vitamin D levels.

DESIGN, SETTING, AND PARTICIPANTS The Vitamin D to Prevent Severe Asthma Exacerbations
(VDKA) Study was a randomized, double-blind, placebo-controlled clinical trial of vitamin D3
supplementation to improve the time to severe exacerbations in high-risk children with
asthma aged 6 to 16 years taking low-dose inhaled corticosteroids and with serum
25-hydroxyvitamin D levels less than 30 ng/mL. Participants were recruited from 7 US
centers. Enrollment started in February 2016, with a goal of 400 participants; the trial was
terminated early (March 2019) due to futility, and follow-up ended in September 2019.

INTERVENTIONS Participants were randomized to vitamin D3, 4000 IU/d (n = 96), or placebo
(n = 96) for 48 weeks and maintained with fluticasone propionate, 176 μg/d (6-11 years old),
or 220 μg/d (12-16 years old).

MAIN OUTCOMES AND MEASURES The primary outcome was the time to a severe asthma
exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation,
the proportion of participants in whom the dose of inhaled corticosteroid was reduced
halfway through the trial, and the cumulative fluticasone dose during the trial.

RESULTS Among 192 randomized participants (mean age, 9.8 years; 77 girls [40%]), 180
(93.8%) completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33
(34.4%) in the placebo group had 1 or more severe exacerbations. Compared with placebo,
vitamin D3 supplementation did not significantly improve the time to a severe exacerbation:
the mean time to exacerbation was 240 days in the vitamin D3 group vs 253 days in the
placebo group (mean group difference, −13.1 days [95% CI, −42.6 to 16.4]; adjusted hazard
ratio, 1.13 [95% CI, 0.69 to 1.85]; P = .63). Vitamin D3 supplementation, compared with
placebo, likewise did not significantly improve the time to a viral-induced severe
exacerbation, the proportion of participants whose dose of inhaled corticosteroid was
reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were
similar in both groups (vitamin D3 group, n = 11; placebo group, n = 9).

CONCLUSIONS AND RELEVANCE Among children with persistent asthma and low vitamin D
levels, vitamin D3 supplementation, compared with placebo, did not significantly improve the
time to a severe asthma exacerbation. The findings do not support the use of vitamin D3
supplementation to prevent severe asthma exacerbations in this group of patients.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02687815

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Juan C.
Celedón, MD, DrPH, Division of
Pulmonary Medicine, UMPC
Children’s Hospital of Pittsburgh,
JAMA. 2020;324(8):752-760. doi:10.1001/jama.2020.12384 4401 Penn Ave, Pittsburgh, PA 15224
Corrected on June 2, 2021. (juan.celedon@chp.edu).

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 Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels
A
s of 2018, an estimated 5.5 million children in the US
had asthma, a major cause of health care utilization and
costs.1 In 2018, asthma exacerbations led to more than
546 000 emergency department (ED) visits and 80 000
hospitalizations.1
Several observational studies have linked low serum
25-hydroxyvitamin D (henceforth, “vitamin D”) levels to
severe asthma exacerbations, lower lung function, and
reduced response to corticosteroids.2-5 Such findings may be
explained by immune-modulatory and anti-inflammatory
effects of vitamin D, including regulatory T-cell induc-
tion, attenuation of Th2 and Th17 responses, enhance-
ment of IL-10 production, and inhibition of airway smooth
muscle hypertrophy and collagen deposition.6-9 Vitamin D
may attenuate viral-induced asthma attacks by reducing rhi-
novirus replication in bronchial epithelium, promoting
interferon-mediated antiviral pathways and inducing pro-
duction of antimicrobial peptides.10,11
A meta-analysis of clinical trials using participant-level data
showed that vitamin D3 supplementation was associated with
lower risk of asthma exacerbations, but the pooled estimate
was not significant among children younger than 16 years old.12
More recently, a comprehensive review of vitamin D3 for the
prevention of wheeze attacks found insufficient evidence to
recommend vitamin D3 supplementation in children.13 Previ-
ous pediatric randomized clinical trials, however, have not fo-
cused on children with low vitamin D levels or who are at high
risk for severe asthma exacerbations. Moreover, existing trials
did not monitor vitamin D levels or did not show consistently
improved levels after supplementation.
Children with a recent severe asthma exacerbation are at
highest risk for subsequent exacerbations, independent of dis-
ease severity, treatment, or control.14 The primary hypoth-
esis for this trial was that supplementation with vitamin D3
would improve the time to a severe exacerbation in high-risk
children, aged 6 to 16 years, with vitamin D insufficiency and
taking low-dose inhaled corticosteroids for persistent asthma.
The secondary hypotheses were that this protective effect
would result from reduced incidence of viral-induced exac-
erbations or enhanced response to corticosteroids.
Methods
The study protocol was approved by the institutional review
board (IRB) at each participating institution, and an indepen-
dent data and safety monitoring board (DSMB) appointed by
the National Heart, Lung, and Blood Institute monitored the
study. Written parental consent was obtained for participat-
ing children, from whom written assent was also obtained.
Participants
Participants for the Vitamin D to Prevent Severe Asthma
Exacerbations (Vit-D-Kids Asthma [VDKA]) Study were
recruited from 7 sites across the US: Boston Children’s Hospi-
tal, Boston, Massachusetts; Washington University and
St Louis Children’s Hospital, St Louis, Missouri; Cincinnati
Children’s Hospital, Cincinnati, Ohio; Rainbow Babies and
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Original Investigation Research
Key Points
Question In high-risk children with persistent asthma and low
vitamin D levels, does vitamin D3 supplementation prolong the
time to a severe asthma exacerbation?
Findings In this randomized clinical trial that included 192
children, vitamin D3 supplementation, compared with placebo, did
not significantly improve the time to a severe asthma exacerbation
(adjusted hazard ratio, 1.13).
Meaning The findings from this trial do not support the use of
vitamin D3 supplementation to improve the time to a severe
asthma exacerbation in children with asthma and low serum
vitamin D levels.
Children’s Hospital, Cleveland, Ohio; the University of
California at San Francisco Benioff Children’s Hospital;
National Jewish Health, Denver, Colorado; and University of
Pittsburgh Medical Center Children’s Hospital of Pittsburgh,
Pittsburgh, Pennsylvania. The data coordinating center was
based at the University of Pittsburgh Graduate School of Pub-
lic Health. Based on prior observational studies on vitamin D
and asthma outcomes,2,5 eligible participants were high-risk
children with asthma, aged 6 to 16 years, with serum vita-
min D levels less than 30 ng/mL but greater than or equal
to 10 ng/mL (until July 21, 2017) or greater than or equal to
14 ng/mL (after that date, following a protocol amendment).
Entry criteria included (1) physician-diagnosed asthma for
at least 1 year; (2) at least 1 severe asthma exacerbation
(systemic corticosteroids for at least 3 days, or a hospital-
ization or ED visit requiring systemic corticosteroids) in the
previous year; (3) use of asthma medications (daily controller
medications, or inhaled β 2 -agonists at least thrice per
week) for at least 6 months in the previous year; (4) forced
expiratory volume in the first second of expiration (FEV1)
greater than or equal to 70% of predicted; and (5) either
bronchodilator responsiveness (an increment in baseline
FEV1 of 8% or more 15 minutes after inhalation of 180-μg
albuterol) or, in those without bronchodilator response,
increased airway responsiveness (a provocative concentra-
tion of methacholine at which FEV1 decreased by 20% [PC20]
<8 mg/mL if not receiving inhaled corticosteroids, or
<16 mg/mL if receiving inhaled corticosteroids). Exclusion
criteria, listed in the full study protocol (Supplement 1),
included chronic respiratory disorders other than asthma,
chronic oral corticosteroid therapy, severe asthma, and
inability to perform adequate spirometry. Recruitment was
conducted at several locations at each study site, including
EDs, pulmonary and allergy/immunology clinics, and general
pediatric clinics. A study description was also posted in the
study website and at IRB-approved websites (eg, Pitt+Me) to
reach a broader population.
Study Design and Treatment
The study was a randomized, double-blind, parallel, placebo-
controlled clinical trial, with each participant randomly as-
signed to either daily placebo capsules or daily vitamin D3,
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 Research Original Investigation
Figure 1. Selection of Study Participants
595 Participants assessed for eligibility
219 Entered run-in
192 Randomized in permuted
block sizes of 2 and 4
96 Randomized to receive vitamin D3
96 Received vitamin D3 as randomized
4 Lost to follow-up
4 Discontinued intervention
(family decision/moved)
4 Had study medication stopped
4 ≥3 Exacerbations
Included in analyses:
96 With time to severe exacerbation
82 With time to viral exacerbation
14 First exacerbations not tested
91 With reduction in inhaled corticosteroid
4 Withdrew before 24 wk
1 Missed 24-wk visit
96 Cumulative inhaled corticosteroid dose
4000 IU (Pharmavite LLC), plus inhaled fluticasone propio-
nate (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 en-
rolled if they met inclusion criteria. After a 4-week run-in pe-
riod in which participants received placebo capsules plus in-
haled fluticasone and as-needed inhaled albuterol (prior
medications were discontinued), those who met inclusion cri-
teria at entry and during run-in were randomized (Figure 1).
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Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels
376 Excludeda
321 Vitamin D level ≥30 ng/mL
72 No positive bronchodilator response
or airway hyper-responsiveness
43 Vitamin D level <14 ng/mL
28 Recruitment ended
16 FEV1 <70 % of predicted
13 Could not schedule return screening visit
11 Medication change not approved
11 Withdrew
10 Unable to do spirometry
9 Refused procedures
6 Elevated serum calcium
4 Not taking asthma medications
2 No exacerbation in the past year
2 Asthma-related events
1 Reported allergic to albuterol
1 Taking vitamin D supplements
27 Failed run-in (multiple reasons)b
25 Nonadherent
21 Recruitment ended
12 Failed to schedule randomization visit
11 Exacerbation during run-in
10 Withdrew
5 Medication changed during run-in
96 Randomized to receive placebo
96 Received placebo as randomized
1 Lost to follow-up
2 Discontinued intervention
(family decision/moved)
6 Had study medication stopped
2 ≥3 Exacerbations
2 Vitamin D <14 ng/mL at 2 consecutive visits
2 Vitamin D <10 ng/mL FEV1 indicates forced expiratory
volume in the first second of
expiration.
Included in analyses:
a
96 With time to severe exacerbation Sum is greater than 376 because
83 With time to viral exacerbation potential participants could fail
13 First exacerbations not tested screening more than once and could
91 Reduction in inhaled corticosteroid fail for more than 1 reason.
4 Withdrew before 24 wk b
Sum is greater than 27 because
1 Missed 24-wk visit
participants could enter run-in more
96 Cumulative inhaled corticosteroid dose
than once and could fail for more
than 1 reason.
Computer-generated randomization was stratified accord-
ing to study site and race/ethnicity, with treatment assign-
ments made in random permuted block sizes of 2 and 4. The
soft gelatin placebo capsules were matched in appearance to
those containing vitamin D3. At the randomization visit, par-
ticipants and their parents received dietary counseling, in-
cluding a list of foods rich in vitamin D. After randomization,
participants were followed up for 48 weeks, including a total
of 6 in-person visits every 8 weeks and telephone calls
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 Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels
in-between visits. Following randomization, participants con-
tinued taking 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) greater than or equal to 80%
of predicted, were using a rescue inhaler 4 or fewer times per
week, and had asthma symptoms preventing full participa-
tion in daily activities no more than once per month. Asthma
control was assessed using the Asthma Control Test (ACT [score
range, 5-25], for participants aged ≥12 years)15 or the Child-
hood ACT (C-ACT [score range, 0-27], for participants aged <12
years)16; for both tests, higher scores mean better symptom
control, and more than 19 points is considered well-
controlled asthma. Per protocol, study medications were dis-
continued in participants who had 3 or more severe asthma
exacerbations (n = 6); those participants were followed up and
analyzed in the group to which they were randomized.
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 less than 10 ng/mL (n = 2), who were
referred to a pediatric endocrinologist for evaluation and fol-
lowed up in the group to which they were randomized. Par-
ticipants whose vitamin D level was between 10 and 13 ng/mL
(n = 10) received additional dietary counseling along with a ran-
domly selected participant (to prevent unblinding); if their vi-
tamin D level was less than 14 ng/mL at a subsequent visit
(n = 2), study medications were discontinued and the partici-
pant was referred to a pediatric endocrinologist and followed
up 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 moni-
tor (Aardex).
Viral Polymerase Chain Reaction
Nasal blows for polymerase chain reaction (PCR) assessment
of a viral infection were collected within 7 days of a severe
exacerbation. Nasal mucus specimens were tested for com-
mon respiratory viruses (influenza, respiratory syncytial
virus A and B, parainfluenza 1-4, bocavirus, metapneumovi-
rus, rhinoviruses and enteroviruses, and coronavirus [HKU1,
NL63, OC43, and 229E]) using the NxTAG Respiratory Patho-
gen Panel (Luminex). Sensitivity and specificity vary by virus
but on average were approximately 95% and 99%, respec-
tively. Rhinoviruses were typed by partial sequencing as pre-
viously described.17
Outcome Measures
The primary end point was time to a severe asthma exacerba-
tion during the 48-week trial period. A severe asthma exacer-
bation was defined as the occurrence of either (1) use of sys-
temic corticosteroids (tablets, suspension, or injection) for at
least 3 days or (2) a hospitalization or ED visit because of
asthma, requiring systemic corticosteroids.18
There were 3 prespecified secondary outcomes: (1) the time
to a viral-induced severe asthma exacerbation, defined by hav-
ing both a severe exacerbation and a positive PCR result to a
panel of common respiratory viruses, (2) the ability to reduce
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Original Investigation Research
the dose of inhaled steroids by 50% at the 24-week study visit,
and (3) the cumulative dose of inhaled steroids during the study
period. We also evaluated 2 exploratory outcomes: (1) the mean
number of severe asthma exacerbations and (2) the mean num-
ber of viral-induced severe exacerbations.
Prespecified Power Calculations
Based on prior studies, 5 the trial was designed to have a
sample size of 400 participants for 88% power to detect an
absolute reduction in the rate of severe asthma exacerba-
tions of 16% (from 40% in the placebo group19 to 24% in the
intervention group), assuming an overall α of .05, a 2-sided
test, and a withdrawal rate of 15%. Such calculations were
conservative because they did not reflect the primary time-
to-event analysis.
Statistical Analysis
During the trial, all children were followed up in the group to
which they were randomized. In the primary analysis, treat-
ment groups were compared in a Cox proportional hazards re-
gression model that estimated a hazard ratio (HR) for the time
to a severe asthma exacerbation across the 48-week study pe-
riod. The model included dropouts as censored observations
and, per protocol, was stratified by site and race/ethnicity, as
well as by potential confounders that were not balanced by ran-
domization. A similar approach was used for the analysis of
time to a viral-induced severe asthma exacerbation. Both
asthma severity and vitamin D level may vary by race/
ethnicity; information 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). The propor-
tionality assumption was tested visually and by fitting models
with covariates and their interactions with time; none of the
interactions were significant.
Linear regression was used for the analysis of the differ-
ence in mean cumulative dose of inhaled steroids between the
vitamin D3 and placebo groups at the end of the trial with treat-
ment group as the primary explanatory variable, adjusting for
study site, sex, time in study (ie, follow-up time), and race/
ethnicity. Logistic regression was used for the analysis of the
proportion of participants achieving a reduction in inhaled cor-
ticosteroid dose at or after the 24-week visit, adjusting for site,
sex, time in study, and race/ethnicity. Missing data for the pri-
mary and secondary outcomes were minimal (Figure 1) and,
thus, listwise deletion was used in the analyses. Two-sided P
values less than .05 were considered significant. Because of
the potential for type I error due to multiple comparisons, find-
ings for analyses of secondary end points should be inter-
preted as exploratory. All analyses were performed using SAS
version 9.4 (SAS Institute).
Results
Early Termination
After review of the second interim analysis, on March 11,
2019, the DSMB recommended that no new participants be
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 Research Original Investigation Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels

26 events in 90 participants (28.9%) in the placebo group and

Table 1. Baseline Characteristics of Randomized Participants
25 events in 91 participants (27.5%) in the vitamin D3 group.
Participants, No. (%) Conditional power was evaluated under 3 conditions: under
Vitamin D3 Placebo the null (based on no treatment effect); under the alternative
Characteristic (n = 96) (n = 96)
Sex
hypothesis (based on the original assumption of effect); and
under the observed rates. Under all 3, conditional power was
Female 44 (46) 33 (34)
less than 30%. A close-out plan to complete follow-up of ran-
Male 52 (54) 63 (66)
domized participants was reviewed and approved by the Na-
Racea
tional Heart, Lung, and Blood Institute; the DSMB; and the IRBs
White 27 (28) 32 (33)
at all participating institutions in August of 2019. Follow-up
Black 51 (53) 49 (51)
of the last participant was completed in September of 2019.
Other race 18 (19) 15 (16)
Hispanic/Latino ethnicitya 7 (7) 6 (6)
Enrollment and Study Completion
Parental education, No./total No. (%)
After screening, a total of 219 participants entered run-in, and
High school or less 21/94 (22) 20/95 (21) 192 were randomized (96 each to the vitamin D3 and placebo
Some college 22/94 (23) 22/95 (23) groups), of whom 180 (93.8%) completed the trial (92 [51%]
Completed college 37/94 (39) 32/95 (34) in the vitamin D3 group and 88 [49%] in the placebo group)
Postgraduate education 14/94 (16) 21/95 (22) (Figure 1). The median duration of follow-up was 332 days. The
Household smoke exposure, most common reasons for study discontinuation were loss to
No./total No. (%)
follow-up (n = 6), family decision (n = 5), and administrative
Before age 2 y 31/94 (33) 32/94 (34)
decision (n = 1) (Figure 1).
During study 25/93 (27) 22/93 (24)
Season of enrollment
Baseline Characteristics
January-March 30 (31) 25 (26)
The trial enrolled children with a mean (SD) age of 9.8 (2.5)
April-June 26 (27) 26 (27)
years, a mean (SD) ACT or C-ACT score of 21.7 (3.4), and a me-
July-September 22 (23) 22 (23) dian of 1 (interquartile range [IQR], 1-2) severe asthma exac-
October-December 18 (19) 23 (24) erbation in the prior year (Table 1). A total of 77 girls (40%) and
Asthma Control Test score >19b 76 (79) 73 (76) 115 boys (60%) were enrolled, with 44 girls (46%) in the vita-
Age at randomization, mean (SD), y 9.9 (2.5) 9.7 (2.5) min D3 group and 33 girls (34%) in the placebo group. Both
BMI z score, mean (SD)c 0.9 (1.1) [n = 95] 0.9 (1.3) groups were similar in terms of age, race/ethnicity, parental
No. of severe exacerbations 1 (1-2) [n = 88] 1 (1-2) [n = 86] education, household smoke exposure, season of enroll-
in the previous year, median (IQR)
ment, body mass index z score, FEV1, and FEV1/FVC. The mean
Vitamin D, mean (SD), ng/mL 22.5 (4.6) 22.8 (4.6)
(SD) baseline serum vitamin D level was 22.5 (4.6) ng/mL in
FEV1, mean (SD), % predictedd 93.9 (15.8) 90.6 (17.3)
the vitamin D3 group and 22.8 (4.6) ng/mL in the placebo group.
FEV1/FVC, mean (SD), % predictedd 91.5 (9.3) 89.6 (10.1)
Asthma Control Test score, mean (SD)b 22.0 (3.2) 21.3 (3.6)
Serum Vitamin D Levels
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided Compared with participants in the placebo group, those in
by height in meters squared); FEV1, forced expiratory volume in the first second the vitamin D 3 group were significantly more likely to
of expiration; FVC, forced vital capacity; IQR, interquartile range.
a
achieve a vitamin D level of 30 ng/mL or higher (94.4% in the
Race and ethnicity were ascertained per parental report. “Other race” includes
American Indian, Alaskan Native, Asian, mixed, and those reported as “other.” vitamin D3 group vs 40.7% in the placebo group at 16 weeks;
b
Asthma Control Test (ACT)15 was for participants aged 12 years or older, and and 87.2% vs 30.1%, respectively, at 48 weeks; both P < .001)
Childhood Asthma Control Test (C-ACT)16 was for participants aged 6 to and to have a higher vitamin D level at all visits during the
younger than 12 years. The ACT is calculated based on 5 self-administered trial. In the vitamin D3 group, the mean vitamin D levels were
questions and has a score range of 5 to 25. The C-ACT is calculated based on 7
57.2 ng/mL (95% CI, 52.9-61.5) at 16 weeks, 53.8 ng/mL (95%
questions (3 answered by the parent and 4 answered with the child’s input)
and has a score range of 0 to 27. For both, higher scores indicate better CI, 48.9-58.6) at 32 weeks, and 49.4 ng/mL (95% CI, 44.9-
symptom control, and a score greater than 19 indicates well-controlled asthma 53.9) at 48 weeks. In the placebo group, vitamin D serum lev-
symptoms. els were 27.5 ng/mL (95% CI, 25.2-29.9) at 16 weeks,
c
BMI z scores calculated using US Centers for Disease Control and Prevention 25.4 ng/mL (95% CI, 23.6-27.3) at 32 weeks, and 24.6 ng/mL
equations,20 which create z scores and percentiles for the child’s sex and age.
A BMI z score of 0 is equivalent to the 50th percentile.
(95% CI, 22.9-26.3) at 48 weeks (Figure 2), with similar levels
d
All participants performed spirometry following American Thoracic
after excluding participants who received open-label vita-
Society/European Respiratory Society guidelines.21 Calculated using reference min D3 supplementation due to very low levels during the
values from the third National Health and Nutrition Examination Survey.22 trial (eTable in Supplement 2). A total of 23% and 12% of par-
Values 80% of predicted or greater are considered normal.
ticipants had vitamin D levels less than 20 ng/mL at the base-
line visit and study exit visit, respectively. In the vitamin D3
randomized due to futility (lack of efficacy of vitamin D3 group, no participants reported taking (nonstudy) vitamin D3
supplementation), based on the protocol threshold of less than supplements at randomization, and 2 reported such
30% conditional power to detect the prespecified effect (a 16% supplementation at study exit; those numbers were 1 and 6
reduction in severe exacerbations). At that time, there had been participants, respectively, in the placebo group. The median

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 Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels
adherence with study medication was 85% (IQR, 72%-93%)
in the vitamin D3 group and 87% (IQR, 76%-94%) in the pla-
cebo group.
Primary Outcome: Time to Severe Asthma Exacerbation
A total of 36 participants (37.5%) in the vitamin D3 group and
33 participants (34.4%) in the placebo group had at least 1 se-
vere asthma exacerbation during the trial. Vitamin D3 supple-
mentation did not significantly prolong the time to a severe
asthma exacerbation: the mean number of days until a severe
exacerbation was 240 in the vitamin D3 group and 253 in the
placebo group, with a mean group difference of −13.1 days (95%
CI, −42.6 to 16.4) and adjusted HR of 1.13 (95% CI, 0.69-1.85;
P = .63) (Table 2 and Figure 3).
Secondary Outcomes
Vitamin D3 supplementation did not significantly prolong the
time to a first viral-induced severe exacerbation compared with
placebo: the mean number of days was 272 in the vitamin D3
group and 281 in the placebo group, with a mean group dif-
ference of −9.1 days (95% CI, −35.5 to 17.2) and an adjusted HR
of 1.32 (95% CI, 0.63-2.75; P = .46; Table 2; eFigure in Supple-
ment 2). The proportion of participants whose inhaled corti-
costeroid dose could be reduced (halved) at the midpoint of
the trial was not significantly different between the vita-
min D3 (28 participants [31%]) and the placebo (29 partici-
pants [32%]) groups (group difference, −1.1% [95% CI, −14.6%
to 12.4%]; adjusted relative risk ratio, 0.99 [95% CI, 0.66-
1.52]; P = .99) (Table 2). Vitamin D3 supplementation, com-
pared with placebo, did not lead to a significant reduction in
the cumulative dose of fluticasone during the trial (59.6 mg
vs 55.2 mg, respectively; mean group difference, 4.41 mg [95%
CI, −0.99 to 9.80]; adjusted mean difference, 4.40 mg [95%
CI, 0.001 to 8.80]; P = .049) (Table 2).
Exploratory Outcomes
Compared with placebo, vitamin D3 supplementation did not
significantly reduce the number of severe asthma exacerba-
tions (mean number of exacerbations, 0.58 in the vitamin D3
group vs 0.51 in the placebo group; mean group difference, 0.07
[95% CI, −0.14 to 0.28]; P = .50) or viral-induced severe exac-
erbations (mean number of viral-induced exacerbations, 0.26
in the vitamin D3 group vs 0.22 in the placebo group; mean
group difference, 0.03 [95% CI, −0.11 to 0.18]; P = .56) (Table 2).
Adverse Events
Nine participants in the vitamin D3 group and 7 in the placebo
group had a serious adverse event (Table 2). The most com-
mon serious adverse events were hospitalizations for asthma
(8 in the vitamin D3 group and 6 in the placebo group). After
randomization, no participant in the vitamin D3 group and 2
participants in the placebo group had medication stopped due
to vitamin D levels less than 10 ng/mL. Two participants had
a level less than 10 ng/mL and 2 participants had levels be-
tween 10 and 13 ng/mL at 2 visits during the trial; per proto-
col, all instances were referred to a pediatric endocrinologist
for evaluation and management. There were no cases of hy-
percalcemia or vitamin D toxicity in either treatment group.
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Original Investigation Research
Figure 2. Vitamin D Levels During Trial Period by Treatment Group
125
Vitamin D3
100 Placebo
Vitamin D, ng/mL
75
50
25
0
0 16 32 48
Study week
No. of participants
Vitamin D3 95 90 84 68
Placebo 96 92 84 74
Boxes represent median and interquartile ranges with error bars indicating the
highest and lowest values within 1.5 times the interquartile range; dots
represent outlying data.
Discussion
In this randomized clinical trial of vitamin D3 added to low-
dose inhaled corticosteroids in school-aged children with vi-
tamin D insufficiency and persistent asthma at high risk for se-
vere exacerbations, vitamin D3 supplementation did not lead
to a significant improvement in the time to a severe asthma
exacerbation. Moreover, vitamin D3 supplementation had no
significant beneficial effects on any of the trial’s secondary end
points, including time to a viral-induced severe asthma exac-
erbation, the proportion of participants whose inhaled corti-
costeroid dose was reduced, or the mean or cumulative in-
haled corticosteroid dose during the trial. At an observed event
rate of approximately 38% in the control group, such effect
maps to an HR of about 1.93, which is not included in the 95%
CI of the estimate for the primary outcome.
While observational studies have reported associations be-
tween low vitamin D levels and childhood asthma outcomes,2-5
randomized clinical trials have provided less encouraging evi-
dence of a protective effect of vitamin D3 supplementation
against morbidity from asthma.13 Moreover, both the VDAART
(Vitamin D Antenatal Asthma Reduction Trial) and the COPSAC
2010 (Copenhagen Prospective Studies on Asthma in Child-
hood 2010 cohort) trials have recently reported no signifi-
cant effect of vitamin D3 supplementation during pregnancy
on asthma in the offspring by age 6 years, strongly suggesting
that there is no role for such supplementation in the primary
prevention of asthma.23-25
The results from this trial cannot be attributed to failure
to achieve vitamin D sufficiency after vitamin D3 supplemen-
tation because most (>87%) of the participants in the treat-
ment group had vitamin D levels of 30 ng/mL or greater dur-
ing the trial. The placebo group had a relatively low proportion
of participants in the control group achieving and sustaining
vitamin D sufficiency (<40%), and participants in the vita-
min D3 group had consistently higher vitamin D levels than
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 Research Original Investigation Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels

Table 2. VDKA Trial Outcomes and Serious Adverse Events for Vitamin D3 Supplementation vs Placebo

Vitamin D3 Placebo Adjusted analysis

Group difference
Measure No. Mean No. Mean (95% CI) Parameter estimate (95% CI) P value
Primary outcome
Days to a severe exacerbationa 96 240 96 253 −13.1 (−42.6 to 16.4) 1.13 (0.69 to 1.85)b .63
Secondary outcomes
Days to viral-induced severe exacerbationc 82 272 83 281 −9.1 (−35.5 to 17.2) 1.32 (0.63 to 2.75)b .46
Proportion of participants in whom fluticasone dose 91 28 (30.8) 91 29 (31.9) −1.1 (−14.6 to 12.4) 0.99 (0.66 to 1.52)d .99
was halved, No. (%)
Cumulative fluticasone dose, mg 96 59.6 96 55.2 4.41 (−0.99 to 9.80) 4.40 (0.001 to 8.80)e .049
Exploratory outcomes
No. of severe exacerbations 96 0.58f 96 0.51f 0.07 (−0.14 to 0.28) 0.13 (−0.25 to 0.52)e .50
No. of viral-induced severe exacerbations 86 0.26f 85 0.22f 0.03 (−0.11 to 0.18) 0.18 (−0.44 to 0.81)g .56
Serious adverse eventsh
Participants with ≥1 serious adverse events, No. (%) 96 9 (9.4) 96 7 (7.3)
Total No. of serious adverse eventsi 96 11 96 9
Hospitalizations for asthma exacerbation, No. 96 8 96 6
Abbreviation: VDKA, Vitamin D to Prevent Severe Asthma Exacerbations. Poisson regression adjusted for study site, sex, race/ethnicity, and days of
a
Defined as a hospitalization or emergency department visit for asthma follow-up in the study.
f
requiring systemic corticosteroids, or an asthma exacerbation leading to use of Mean number of exacerbations per participant.
systemic corticosteroids (tablets, suspension, or injection) for at least 3 days. g
Parameter estimate (beta coefficient, or adjusted difference in means) from
b
Hazard ratio stratified by site, sex, and race/ethnicity. Poisson regression adjusted for sex, race/ethnicity, and days of follow-up in
c
Defined as a nasal blow, collected within 7 days of the exacerbation, in which the study (model failed to converge when site included as covariate).
h
at least 1 virus was detected by polymerase chain reaction in a panel of Serious adverse events reported as comparative frequencies alone; sample
common respiratory viruses (average, approximately 95% sensitivity and 99% size not sufficient to allow meaningful statistical comparisons.
specificity). i
Serious adverse events included hospitalizations (9 in each group),
d
Relative risk ratio adjusted for sex, race/ethnicity, and days of follow-up in the eosinophilia (1), and severe neutropenia (1). There were no instances of
study (model failed to converge when site included as covariate). hypercalcemia in either group.
e
Parameter estimate (beta coefficient, or adjusted difference in means) from

Daily vitamin D3 supplementation at a dose of 4000 IU/d

Figure 3. Results of the Analysis of Time to a First Severe Asthma
Exacerbation was well tolerated without significant adverse events, as no
study participant developed vitamin D toxicity or hypercalce-
0.5 mia. Moreover, no study participant developed rickets,
Log-rank = 0.54; P =.46
Hazard ratio = 1.13 (95% CI, 0.69-1.85) Vitamin D3
and only a small proportion of participants developed severe
of severe asthma exacerbation

0.4 vitamin D deficiency (a vitamin D level <10 ng/mL) or had a

Cumulative probability

vitamin D level between 10 and 13 ng/mL at 2 visits during

Placebo
0.3
|
the trial, supporting the appropriateness of the monitoring
measures used in the trial. Although vitamin D3 supplemen-
0.2 tation at 4000 IU/d appears effective in achieving vitamin D
sufficiency in most children aged 6 to 16 years with vitamin D
0.1 levels between 14 and 29 ng/mL, study findings cannot be
generalized to settings with no or limited monitoring of vita-
0 min D levels.
0 16 32 48
Study week
No. at risk Limitations
Vitamin D3 96 78 56 16
Placebo 96 85 62 17
This study has several limitations. First, the rate of severe
asthma exacerbations in both the vitamin D3 (37.5%) and
Vertical bars represent single censored events. The adjusted hazard ratio for placebo (34.4%) groups were lower than expected, and the
time from randomization to a first severe exacerbation was 1.13 (95% CI, study was not adequately powered to assess whether such a
0.69-1.85) for the vitamin D3 vs placebo treatment groups (P = .63). Models
small difference was statistically significant. However, there
were stratified by study site, sex, and race/ethnicity. The median observation
time was 274.5 days (interquartile range [IQR], 163-333) in the vitamin D3 group was no evidence of a protective effect of vitamin D against
and 321 days (IQR, 196.5-334) in the control group. severe asthma exacerbations or viral-induced severe asthma
exacerbations, and vitamin D 3 supplementation did not
those in the placebo group throughout the trial. Thus, there lead to a reduction in the mean or cumulative dose of in-
was a low risk of a false-negative result due to failure of supple- haled corticosteroids.
mentation in producing a difference in vitamin D levels be- Second, there was limited statistical power to determine
tween treatment groups. whether vitamin D3 supplementation reduces severe asthma

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 Effect of Vitamin D3 on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels Original Investigation Research

exacerbations in children with vitamin D levels less than

20 ng/mL because only a modest proportion of participants had
such levels. However, most children with vitamin D levels less
than 30 ng/mL in the US have levels greater than 20 ng/mL,
and thus the findings from this study are applicable to most
children with vitamin D insufficiency in this country.26
Third, the findings cannot be extrapolated to other age
groups, including preschool children, or to settings with lim-
ited ability to monitor vitamin D levels.
Conclusions
Among children with persistent asthma and low vitamin D lev-
els, vitamin D3 supplementation, compared with placebo, did
not significantly improve the time to a severe asthma exacer-
bation. The findings do not support the use of vitamin D3
supplementation to prevent severe asthma exacerbations in
this group of patients.

ARTICLE INFORMATION
Accepted for Publication: June 25, 2020.
Correction: This article was corrected online on
June 2, 2021, to fix the numbers of patients who did
not complete the trial in Figure 1.
Author Affiliations: Division of Pulmonary
Medicine, Department of Pediatrics, University of
Pittsburgh Medical Center Children’s Hospital of
Pittsburgh, University of Pittsburgh, Pittsburgh,
Pennsylvania (Forno, Rosser, Han, Celedón);
Division of Allergy, Immunology, and Pulmonary
Medicine, Department of Pediatrics, St Louis
Children’s Hospital, Washington University at St
Louis, St Louis, Missouri (Bacharier, Blatter);
Division of Allergy and Immunology, Boston
Children’s Hospital, Harvard Medical School,
Boston, Massachusetts (Phipatanakul); Division of
Pulmonary Medicine, Department of Pediatrics,
Cincinnati Children’s Hospital, University of
Cincinnati, Cincinnati, Ohio (Guilbert, Durrani);
Division of General Pediatrics, Department of
Pediatrics, University of California, San Francisco
Benioff Children’s Hospital, University of California,
San Francisco (Cabana); Division of Pediatric
Pulmonology, University Hospitals Rainbow Babies
and Children’s Hospital, Case Western Reserve
University, Cleveland, Ohio (Ross); Division of
Allergy and Immunology, Department of Pediatrics,
National Jewish Health, University of Colorado,
Denver (Covar); Department of Pediatrics,
University of Wisconsin-Madison School of
Medicine and Public Health, Madison (Gern);
Department of Epidemiology, University of
Pittsburgh, Pittsburgh, Pennsylvania (Wisniewski).
Author Contributions: Drs Celedón and
Wisniewski had full access to all of the data in the
study and take responsibility for the integrity of the
data and the accuracy of the data analysis.
Concept and design: Wisniewski, Celedón.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Forno, Bacharier,
Phipatanakul, Durrani, Wisniewski, Celedón.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Blatter, Wisniewski.
Obtained funding: Cabana, Celedón.
Administrative, technical, or material support:
Forno, Phipatanakul, Guilbert, Covar, Gern, Rosser,
Blatter, Durrani, Han, Celedón.
Supervision: Forno, Bacharier, Phipatanakul, Ross,
Covar, Rosser, Wisniewski, Celedón.
Conflict of Interest Disclosures: Dr Bacharier
reported receiving grants from the National Heart,
Lung, and Blood Institute (NHLBI) during the
conduct of the study and personal fees from
AstraZeneca, GlaxoSmithKline, Sanofi, Regeneron,
Novartis, Genentech, Boeringher Ingelheim,
Vectura, DBV Technologies, Circassia, Merck, Teva,
Medscape, and Rockpointe outside the submitted
work, as well as receiving royalties as associate
editor from Elsevier (Journal of Allergy and Clinical
Immunology). Dr Phipatanakul reported serving as a
consultant for GlaxoSmithKline, Genentech,
Novartis, Regeneron, Sanofi, and Teva; receiving
clinical trial support or medications from
Genentech, Novartis, Regeneron, Sanofi, Circassia,
Monaghen, Thermo Fisher, Alk Abello, Lincoln
Diagnostics, GlaxoSmithKline, Kaleo, and Merck;
and funding to the institution by Genentech,
Regeneron, Novartis, and the National Institutes of
Health (NIH)—all for projects unrelated to the
current work. Dr Guilbert reported receiving
personal fees from GlaxoSmithKline, TEVA,
Novartis, and the American Board of Pediatrics
(pediatric pulmonary subboard); grants and
personal fees from Sanofi/Regeneron; grants from
AstraZeneca and Novartis; and royalties from
UpToDate outside the submitted work. Dr Cabana
reported serving as a member of the United States
Preventive Services Task Force (USPSTF); this
manuscript does not necessarily represent the
views of the USPSTF. Dr Ross reported receiving
grants from the NIH during the conduct of the
study and grants and nonfinancial support from
TEVA, nonfinancial support from Merck, and grants
from Flamel, the NHLBI, AstraZeneca, and Novartis
outside the submitted work. Dr Covar reported
receiving grants from GlaxoSmithKline during the
conduct of the study. Dr Gern reported receiving
personal fees from AstraZeneca outside the
submitted work. Dr Rosser reported receiving
grants from the NIH/National Center for Advancing
Translational Sciences during the conduct of the
study. Dr Celedón reported receiving nonfinancial
support from Pharmavite and GlaxoSmithKline
during the conduct of the study and nonfinancial
support (Asmanex) for an NIH-funded study from
Merck outside the submitted work. No other
disclosures were reported.
Funding/Support: This study was funded by grant
HL119952 from the US NIH. The project was also
supported by the Pediatric Clinical and Translational
Research Center (PCTRC) at University of
Pittsburgh Medical Center Children’s Hospital of
Pittsburgh through NIH grant UL1TR001857.
Pharmavite LLC provided the vitamin D and
placebo capsules for the study, and
GlaxoSmithKline provided the Flovent given to
study participants.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: The VDKA group members
include the following: University of Pittsburgh
Medical Center Children’s Hospital of Pittsburgh
and University of Pittsburgh: design of the study:
John M. Brehm, MD, MPH. Collection of the data:
Jonathan D. Finder, MD, Mark E. Dovey, MD,
Jonathan E. Spahr, MD, David M. Orenstein, MD,
Geoffrey Kurland, MD, Daniel J. Weiner, MD,
Gregory Burg, MD, Sandeep Puranik, MD, Allyson
Larkin, MD, Hiren Muzumdar, MD, Deborah
Albright, MD, Hey Chong, MD, PhD, David Nash,
MD, Todd Green, MD, Natalie Baldauff, DO, Robert
W. Hickey, MD, John Broyles, MS, CRNP, Lori Holt,
MSN, CRNP, Rose Lanzo, Jamie Adams, Elizabeth
Hartigan, RN, MPH, Cynthia Granny, and Pamela
Vincent. Data management and data analysis:
Zachary Doyle, Heather Eng, and Jim Luther.
Boston Children’s Hospital: Data collection:
Jonathan Gaffin, MD, MMSc, Perdita Permaul, MD,
Margee Louisias, MD, MPH, Marissa Hauptman, MD,
MPH, Nicole Akar-Ghibril, MD, Elizabeth Burke
Roberts, RN, PNP, Sachin Baxi, MD, Lisa Bartnikas,
MD, William Sheehan, MD, Britanny Esty MD, David
Kantor MD, PhD, Peggy Lai, MD, MPH, Michelle
Maciag, MD, Elena Crestani, MD, Mehtap
Haktanir-Abul, MD, Amparito Cunningham MD,
MPH, Anna Cristina Vasquez-Muniz, BA, Nicole
Adler, BS, Reid Mathews, BS, Brian Volonte, BS,
John Pacheco, BA, Anna Ramsey, BS, Vanessa
Konzelmann, BS, Aiza Zia, BS, Julianne Saia, BS,
Alma Castillo-Hernandez, BS, Benjamin Peterson,
BS, Jennifer Rooney, MS, and Robert Rega, BS.
Cincinnati Children’s Hospital Medical Center: Data
collection: Cassie Shipp, MD, Carolyn Kercsmar, MD,
Karen McDowell, MD, Stephanie (Logsdon) Ward,
MD, Nancy Lin, MD, Alisha George, MD, Will Corwin,
Grant Geigle, Alisha Hartmann, and John Broderick.
Rainbow Babies and Children’s Hospital: Data
collection: Laurie Logan, RN, Laura Veri, Daniel
Craven MD, Ben Gaston MD, Amy DiMarino MD,
Erica Roesch MD, and Ross Myers, MD.
Washington University at St Louis: Data collection:
Wanda Caldwell, Tina Norris, and Roseanne Donato.
Data Sharing Statement: See Supplement 3.
Additional Contributions: We 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 that funded the study (the National
Heart, Lung, and Blood Institute) for monitoring the
study progress.
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