Letters to the Editor

Vitamin D supplementation in children may

prevent asthma exacerbation triggered by
acute respiratory infection
To the Editor:
Previous studies suggest that vitamin D may play a role in the
pathogenesis of asthma.1 On the basis of the results of recent
cross-sectional and basic scientific studies in this subject matter,
we can speculate that vitamin D supplementation may (1) prevent
the development of asthma, (2) reduce the risk of a more severe
disease, and (3) enhance clinical response to glucocorticosteroids.
However, none of these hypotheses have been verified so far.
Taking into account deficiency of vitamin D in the asthmatic population,2 the results of clinical trials concerning vitamin D supplementation seem to be of high clinical importance.1 In the current
study, we aimed to assess the effects of vitamin D supplementation on symptom score, lung function, and the number of exacerbations in children with newly diagnosed asthma.
Forty-eight children from 5 to 18 years of age (mean [SD], 11.5
[3.3] years) with newly diagnosed asthma and sensitive only to
house dust mites were recruited from our allergy clinic center. All
patients followed a recommended diet and performed physical
exercises appropriate for school-age children.3 The main exclusion criteria were treatment with an oral, inhaled, or intranasal
corticosteroid and supplementation with vitamin D during the
6 months preceding the trial, a history of fractures in the last 2
years, immunotherapy, obesity (body mass index >30 kg/m2),
and other chronic diseases. The study was approved by the ethics
committee. This was a randomized, double-blind, parallel-group,
6-month trial studying the effects of inhaled budesonide with or
without vitamin D on clinical parameters of asthma control in
children. There were 2 main study visits and 2 additional interview visits. The first visit was scheduled between September
2007 and February 2008. The patients were informed about the
aim of the study and were instructed on how to use the inhalers
and how to complete the Asthma Therapy Assessment Questionnaire (ATAQ) for children.4 During the first visit, the patients were
randomized according to a computer-generated allocation schedule. The 2 resulting groups received treatment with the following:
(1) budesonide 800 mg/d administered as a dry powder and vitamin D placebo (steroid group; n 5 24), and (2) budesonide
800 mg/d administered as a dry powder and vitamin D-500 IU
cholecalciferol (steroid 1 D3 group; n 5 24). During the main
study visits, the 2 following procedures were performed at the
same time of the day, between 9 AM and 12 PM, before the morning
dose of ICS: blood sampling (5 mL) for 25-hydroxyvitamin
D (25[OH]D) measurement and spirometry (Jaeger MasterScreenBody; E Jaeger GmbH; Wurzburg, Germany) for the measurement of FEV1. During the additional interview visits (2 and
4 months after the first visit), ATAQ scores were collected and
evaluated for each month separately. Compliance with asthma
medication was checked; the patients were asked to bring all
used and unused medication to each follow-up visit. The level
of serum 25(OH)D was determined by using a specific radioimmunoassay (25-OH-vit.D3-RIA-CT; BioSource Europe SA,
Nivelles, Belgium). To determine differences within and between
the groups, ANOVA for repeated measurements was used (Statistica for Windows, release 6.0; StatSoft, Inc, Tulsa, Okla). All
1294

TABLE I. Baseline characteristics*

Baseline
characteristics

Age (y)
Male sex, n (%)
BMI (kg/m2)
FEV1 (% predicted)
ATAQ score

Steroid group
(n 5 24)

11.1
18
18.8
98.7
3.43

Steroid 1 D3 group
(n 5 24)

(3.3)
(75)
(3.5)
(12)
(0.88)

10.8
14
18.5
94.4
3.08

(3.2)
(58.3)
(4.7)
(13)
(0.88)

BMI, Body mass index.

*Unless otherwise indicated, data are presented as mean (SD).

TABLE II. Within-group comparisons of study endpoint

Study outcome

Steroid group
ATAQ score (points)
FEV1 (% predicted)
25(OH)D (ng/mL)
Steroid 1 D3 group
ATAQ score (points)
FEV1 (% predicted)
25(OH)D (ng/mL)

Before treatment
Mean (SD)

After treatment
Mean (SD)

P level

3.43 (0.88)
98.7 (12)
35.1 (16.9)

0.33 (0.23)
103.1 (12.1)
31.9 (12.1)

<.001
.003
.25

3.08 (0.88)
94.4 (13.0)
36.1 (13.9)

0.63 (0.23)
99.0 (11.1)
37.6 (13.1)

<.001
.002
.26

patients completed the study. The characteristics of the patients

are presented in Table I. At the starting point of the study, there
were no statistically significant differences between the 2 treatment groups regarding any of the study endpoints. When the study
ended, we found that during 6 months of treatment, the number of
children who experienced asthma exacerbation was significantly
lower in the steroid 1 D3 group than in the steroid group (n [%], 4
[17] vs 11 [46]; P 5 .029; Fig 1, B). Despite the lack of any significant difference between the study groups as far as the absolute
changes of 25(OH)D (Fig 1) were concerned, the number of children with a decrease of 25(OH)D was significantly lower in the
steroid 1 D3 group than the steroid group (Fig 1, B). Logistic regression analysis showed that the number of exacerbations, as a
dependent variable, is associated with 25(OH)D serum level. In
children with a decrease of 25(OH)D, the risk of asthma exacerbation was 8 times higher than in children with a stable or increased 25(OH)D serum level (odds ratio, 8.6; 95% CI, 2.1-34.6).
After 6 months of treatment, a significant improvement in
ATAQ score and FEV1 was observed in both study groups (Table
II). The difference between the groups in ATAQ score was observed in only 1 month (Fig 2, A). The improvement in FEV1
was the same for both groups. A significant linear correlation
between baseline 25(OH)D serum level and baseline ATAQ score
(R 5 .372; P 5 .009) was discovered. Children with lower baseline 25(OH)D had more severe clinical manifestations of asthma.
All cases of asthma exacerbation were preceded by symptoms of
an acute respiratory infection; short-acting b2-agonists and antibiotics (if appropriate) were implemented; none of our patients required hospitalization or intensification of anti-inflammatory
therapy during the study.
This is the first prospective study showing that the control of
newly diagnosed asthma in children can be facilitated by vitamin D

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 5

LETTERS TO THE EDITOR 1295

FIG 1. Between-group comparison of changes over time in ATAQ score. Data are presented with means and
95% CIs (whiskers) (A). Between-group comparisons of incidence of asthma exacerbation (% of patients; B)
and changes from baseline in serum level of 25(OH)D (ng/mL; C). Patients with decreased 25(OH)D were
pointed in boxes.

supplementation. We observed that vitamin D supplementation in

the period from September to July prevented declining serum
concentrations of 25(OH)D and reduced the risk of asthma
exacerbation triggered by acute respiratory tract infection. Vitamin
D, apart from its role in bone and calcium metabolism, is involved
in the regulation of innate as well as adoptive immune functions,
including the response to respiratory infection.5 We suspect that vitamin D boosts the effectiveness of the antimicrobial response of
the innate immune system, simultaneously diminishing the natural
consequences of inflammation, which appear to have an adverse
effect on asthma pathogenesis.6 This may explain our results,
which deliver new clinical evidence supporting the role of vitamin
D in the prevention of asthma exacerbation in children; such findings are in accordance with other studies.7 We did not observe
smaller clinical improvement in children with a very high 25

(OH)D serum level at baseline. Moreover, the significant increase

of 25(OH)D was not associated with a weaker clinical response to
antiasthma treatment. Both findings seem important considering
the risk of supplementation with vitamin D in children with
asthma. On the basis of our results, we can only speculate on the
precise mechanism by which vitamin D interferes with immune
functions. Therefore, more in-depth studies are needed to explain
all aspects of vitamin D activity in asthma. The dose of vitamin D
in the current study approximated the dose recommended by the
Institute of Medicine, but it was clearly inadequate to increase
25(OH)D serum levels. Interestingly, the childrens response varied greatly as well (Fig 1, C), which could be a result of noncompliance or genetic susceptibility. Although the dose of vitamin D
was inadequate, significant benefits were achieved in the current
study.

1296 LETTERS TO THE EDITOR

J ALLERGY CLIN IMMUNOL

MAY 2011

Pawe Majak, MD, PhD

Magorzata Olszowiec-Chlebna, MD
Katarzyna Smejda, MD
Iwona Stelmach, MD, PhD
From the Department of Pediatrics and Allergy, Medical University of Lodz, Poland.
E-mail: alergol@kopernik.lodz.pl.
Supported by grant nos. 502-12-760 and 503-2056-1 from the Medical University of
Lodz, Poland.
Disclosure of potential conflict of interest: The authors have declared that they have no
conflict of interest.
REFERENCES
1. Gined AA, Sutherland ER. Vitamin D in asthma: panacea or true promise? J Allergy
Clin Immunol 2010;126:59-60.
2. Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D
insufficiency in the US population, 1988-2004. Arch Intern Med 2009;169:626-32.
3. Kleinman RE. Pediatric nutrition handbook, 4th ed. Elk Grove Village (IL):
American Academy of Pediatrics; 1998.
4. Skinner EA, Diette GB, Algatt-Bergstrom PJ, Nguyen TT, Clark RD, Markson LE.
The Asthma Therapy Assessment Questionnaire (ATAQ) for children and adolescents. Dis Manag 2004;7:305-13.
5. Dimeloe S, Nanzer A, Ryanna K, Hawrylowicz C. Regulatory T cells, inflammation
and the allergic responsethe role of glucocorticoids and vitamin D. J Steroid
Biochem Mol Biol 2010;31:86-95.
6. Brightling C, Berry M, Amrani Y. Targeting TNF-alpha: a novel therapeutic
approach for asthma. J Allergy Clin Immunol 2008;121:5-10.
7. Brehm JM, Schuemann B, Fuhlbrigge AL, Hollis BW, Strunk RC, Zeiger RS, et al.
Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma
Management Program study. J Allergy Clin Immunol 2010;126:52-8.
Available online February 18, 2011.
doi:10.1016/j.jaci.2010.12.016

Management of postliver transplantassociated IgE-mediated food allergy in children

To the Editor:
New-onset posttransplantation food allergy (FA) is an established complication in children who have undergone liver
transplantation (LT) that can be life-threatening because of
anaphylaxis.1 Pathogenesis of post-LTrelated FA remains unclear, but tacrolimus immunosuppressive therapy, as well as
host factors, are likely to play a role.2,3
Both cyclosporine and tacrolimus block T-cell cytokine production. Tacrolimus, a more powerful immunosuppressive drug
than cyclosporine, is now used as first-line therapy in post-LT
settings.4 A specific tacrolimus-associated side effect is its effect
on intestinal barrier function.2 Tacrolimus increases intestinal
permeability, which might favor transport of antigens from the intestinal lumen and exposure to the immature intestinal mucosal
system of children, increasing the risk of sensitization and FA development. In children with post-LT FA undergoing a tacrolimus
regimen, a switch to a cyclosporine regimen has been recommended, but the management and evolution of FA after an immunosuppressive regimen switch have not been reported.1,5,6 Here
we report on the therapeutic management of 7 children with
post-LT FA in whom a switch from tacrolimus to cyclosporine
and an elimination diet induced serum specific IgE level decrease
and negativization of prick skin test responses, allowing successful incriminated food reintroduction.
Seven children who underwent LT for biliary atresia at age
15 6 5 months (mean 6 SD) and had FA after LT were compared
with a control group of 7 age- and tacrolimus treatmentmatched

children with a comparable atopic familial background who

underwent LT for biliary atresia and did not have FA symptoms.
These were consecutive patients within our cohort undergoing LT
who had FA during a tacrolimus regimen, who were treated
according to the approach reported below, and in whom follow-up
after normal diet reintroduction was 6 months or longer.
After transplantation, all patients received immunosuppresion
based on a tacrolimus regimen (with prednisone [patients 1-2] or
basiliximab [anti-CD25/IL-2 receptor a; patients 3-7]). A family
history of atopy (allergic rhinitis, eczema, asthma, and urticaria)
was noted in 4 of the 7 patients. A complete clinical history was
obtained in all cases. The presence of immediate symptoms of FA
was validated by a senior pediatrician/allergologist (J.-L. D. or J.
C.). Allergic manifestations occurred 33 6 19 months after LT
and were as follows: intense angioedema (5/7), Quincke edema
(2/7), and generalized urticaria or gastrointestinal symptoms
(diarrhea). Two allergens were identified in patients 1, 2, 3, and 5,
and 3 allergens were identified in patients 4, 6, and 7 and were
hazelnut (3/7), peanut (3/7), egg white (2/7) and yolk (3/7), lentil
(2/7), fish (1/7), almond (1/7), pistachio (1/7), and mustard (1/7).
Positive skin prick test responses for food allergens were
present in all cases. All patients were found to have a positive
(>0.3 kUA/L) serum specific IgE level to multiple food allergens
by means of ImmunoCAP (Phadia, Uppsala, Sweden) testing
(Fig 1). Initial serum IgE levels (mean 6 SD) were as follows: hazelnut, 12.3 6 13.4 kUA/L; peanut, 9.2 6 7.7 kUA/L; egg white,
3.8 6 1.1 kUA/L; egg yolk, 17.8 6 18 kUA/L; fish, 15.6 6 16.3
kUA/L; almond, 25.4 6 15.6 kUA/L; soybean, 14.8 6 11.1
kUA/L; lentil, 48.3 6 10.8 kUA/L; pistachio, 16 kUA/L; mustard,
9.6 kUA/L; wheat, 30 kUA/L; and sesame seed, 7 kUA/L. The control group was tested for the same panel (16 allergens) of serum
specific and total IgE at a delay after LT similar to that at which
FA occurred in the 7 patients. All control children had negative
specific IgE levels. In addition, the median value of total IgE
levels was significantly increased in patients compared with
that seen in control subjects (285 [interquartile range, 194-978]
vs 23 [interquartile range, 16-100]; P 5 .01, Mann-Whitney
U test), with only 1 child from the control group having an
increased total IgE level (459 kU/L).
In each patient there was a concordance between incriminated
food allergen species and biological data (positive specific IgE
levels and skin prick test responses). In patients 6 and 7 more
specific IgE species than food allergens were found. After a severe
clinical manifestation of FA (angioedema or Quincke edema), a
switch from tacrolimus to cyclosporine and an elimination diet of
incriminated food allergens were performed systematically in all
cases. Thereafter, no recurrence of symptoms of allergy and a
decrease in serum specific IgE levels were observed in all patients.
When serum specific IgE levels and skin prick test responses
normalized, an oral challenge with each incriminated food was
performed (Fig 1). In patient 7 an oral challenge was performed
while the level of specific IgE was still slightly increased. The
incriminated food was successfully reintroduced in all children
37 6 27 months after immunosuppressive switch and elimination
diet introduction. Importantly, during the cyclosporine regimen,
no FA recurrence was observed after oral challenge and diet liberalization, with a follow-up of 27 6 21 months. During the overall
follow-up period during the cyclosporine regimen, serum liver test
results remained normal, indicating the absence of liver rejection.
Pediatric IgE-dependent FA after LT is a well-known complication. Yet there are no internationally accepted guidelines