twere no statistically significant differences between the 2 treat-ment groups regarding any of the study endpoints.When the studyended, we found that during 6 months of treatment, the number ofchildren who experienced asthma exacerbation was significantlylower in the steroid1D3 group than in the steroid group (n [%], 4[17] vs 11 [46]; P 5 .029; Fig 1, B). Despite the lack of any sig-nificant difference between the study groups as far as the absolutechanges of 25(OH)D (Fig 1) were concerned, the number of chil-dren with a decrease of 25(OH)D was significantly lower in thesteroid1 D3 group than the steroid group (Fig 1, B). Logistic re-gression analysis showed that the number of exacerbations, as adependent variable, is associated with 25(OH)D serum level. Inchildren with a decrease of 25(OH)D, the risk of asthma exacer-bation was 8 times higher than in children with a stable or in-creased 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 (TableII). The difference between the groups in ATAQ score was ob-served in only 1 month (Fig 2, A). The improvement in FEV1was the same for both groups. A significant linear correlationbetween baseline 25(OH)D serum level and baseline ATAQ score(R5 .372; P5 .009) was discovered. Children with lower base-line 25(OH)D had more severe clinical manifestations of asthma.All cases of asthma exacerbation were preceded by symptoms ofan acute respiratory infection; short-acting b2-agonists and anti-biotics (if appropriate) were implemented; none of our patients re-munoassay (25-OH-vit.D3-RIA-CT; BioSource Europe SA,Nivelles, Belgium). To determine differences within and betweenthe groups, ANOVA for repeated measurements was used (Statis-

quired hospitalization or intensification of anti-inflammatorytherapy during the study.This is the first prospective study showing that the control ofLetters to

Vitamin D supplementation in children mayprevent asthma exacerbation triggered byacute 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 recentcross-sectional and basic scientific studies in this subject matter,we can speculate that vitamin D supplementation may (1) preventthe development of asthma, (2) reduce the risk of a more severedisease, 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 pop-ulation,2 the results of clinical trials concerning vitamin D supple-mentation seem to be of high clinical importance.1 In the currentstudy, we aimed to assess the effects of vitamin D supplementa-tion on symptom score, lung function, and the number of exacer-bations 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 tohouse dust mites were recruited from our allergy clinic center. Allpatients followed a recommended diet and performed physicalexercises appropriate for school-age children.3 The main exclu-sion criteria were treatment with an oral, inhaled, or intranasalcorticosteroid and supplementation with vitamin D during the6 months preceding the trial, a history of fractures in the last 2years, immunotherapy, obesity (body mass index >30 kg/m2),and other chronic diseases. The study was approved by the ethicscommittee. This was a randomized, double-blind, parallel-group,6-month trial studying the effects of inhaled budesonide with orwithout vitamin D on clinical parameters of asthma control inchildren. There were 2 main study visits and 2 additional inter-view visits. The first visit was scheduled between September2007 and February 2008. The patients were informed about theaim of the study and were instructed on how to use the inhalersand how to complete the Asthma Therapy Assessment Question-naire (ATAQ) for children.4 During the first visit, the patients wererandomized according to a computer-generated allocation sched-ule. The 2 resulting groups received treatment with the following:(1) budesonide 800 mg/d administered as a dry powder and vita-min D placebo (steroid group; n 5 24), and (2) budesonide800 mg/d administered as a dry powder and vitamin D-500 IUcholecalciferol (steroid 1 D3 group; n 5 24). During the mainstudy visits, the 2 following procedures were performed at thesame time of the day, between 9 AM and 12 PM, before the morningdose of ICS: blood sampling (5 mL) for 25-hydroxyvitaminD (25[OH]D) measurement and spirometry (Jaeger Master-ScreenBody; E Jaeger GmbH; Wurzburg, Germany) for the mea-surement of FEV1. During the additional interview visits (2 and4 months after the first visit), ATAQ scores were collected andevaluated for each month separately. Compliance with asthmamedication was checked; the patients were asked to bring allused and unused medication to each follow-up visit. The levelof serum 25(OH)D was determined by using a specific radioim-tica for Windows, release 6.0; StatSoft, Inc, Tulsa, Okla). All

1294he Editor

patients completed the study. The characteristics of the patientsare presented in Table I. At the starting point of the study, there

TABLE I. Baseline characteristics*

Baseline

characteristics

Steroid group

(n 5 24)

Steroid 1 D3 group

(n 5 24)

Age (y) 11.1 (3.3) 10.8 (3.2)

Male sex, n (%) 18 (75) 14 (58.3)

BMI (kg/m2) 18.8 (3.5) 18.5 (4.7)

FEV1 (% predicted) 98.7 (12) 94.4 (13)

ATAQ score 3.43 (0.88) 3.08 (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

Before treatment After treatment

P levelMean (SD) Mean (SD)

Steroid group

ATAQ score (points) 3.43 (0.88) 0.33 (0.23)

J ALLERGY CLIN IMMUNOL

VOLUME 127, NUMBER 5

LETTERS TO THE EDITOR 1295supplementation. We observed that vitamin D supplementation inthe period from September to July prevented declining serumconcentrations of 25(OH)D and reduced the risk of asthmaexacerbation triggered by acute respiratory tract infection.VitaminD, apart from its role in bone and calciummetabolism, is involvedin the regulation of innate as well as adoptive immune functions,including the response to respiratory infection.5We suspect that vi-tamin D boosts the effectiveness of the antimicrobial response ofthe innate immune system, simultaneously diminishing the naturalconsequences of inflammation, which appear to have an adverseeffect on asthma pathogenesis.6 This may explain our results,which deliver new clinical evidence supporting the role of vitaminD in the prevention of asthma exacerbation in children; such find-ings are in accordance with other studies.7 We did not observesmaller clinical improvement in children with a very high 25

FIG 1. Between-group comparison of changes over time

95% CIs (whiskers) (A). Between-group comparisons ofand changes from baseline in serum level of 25(OH)Dpointed in boxes.(OH)D serum level at baseline. Moreover, the significant increaseof 25(OH)D was not associated with a weaker clinical response toantiasthma treatment. Both findings seem important consideringthe risk of supplementation with vitamin D in children withasthma. On the basis of our results, we can only speculate on theprecise mechanism by which vitamin D interferes with immunefunctions. Therefore, more in-depth studies are needed to explainall aspects of vitamin D activity in asthma. The dose of vitamin Din the current study approximated the dose recommended by theInstitute of Medicine, but it was clearly inadequate to increase25(OH)D serum levels. Interestingly, the childrens response var-ied greatly as well (Fig 1, C), which could be a result of noncom-pliance or genetic susceptibility. Although the dose of vitamin Dwas inadequate, significant benefits were achieved in the currentstudy.

in ATAQ score. Data are presentedwithmeans and

incidence of asthma exacerbation (% of patients; B)(ng/mL; C). Patients with decreased 25(OH)D were

J ALLERGY CLIN IMMUNOL

MAY 2011

1296 LETTERS TO THE EDITORPawe 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. GindeAA, LiuMC,CamargoCA Jr. Demographic differences and trends of vitaminD

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 adoles-

cents. 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 transplantassoci-ated IgE-mediated food allergy in children

To the Editor:New-onset posttransplantation food allergy (FA) is an estab-

lished complication in children who have undergone livertransplantation (LT) that can be life-threatening because ofanaphylaxis.1 Pathogenesis of post-LTrelated FA remains un-clear, but tacrolimus immunosuppressive therapy, as well ashost factors, are likely to play a role.2,3

Both cyclosporine and tacrolimus block T-cell cytokine pro-duction. Tacrolimus, a more powerful immunosuppressive drugthan cyclosporine, is now used as first-line therapy in post-LTsettings.4 A specific tacrolimus-associated side effect is its effecton intestinal barrier function.2 Tacrolimus increases intestinalpermeability, which might favor transport of antigens from the in-testinal lumen and exposure to the immature intestinal mucosalsystem of children, increasing the risk of sensitization and FA de-velopment. In children with post-LT FA undergoing a tacrolimusregimen, a switch to a cyclosporine regimen has been recommen-ded, but the management and evolution of FA after an immuno-suppressive regimen switch have not been reported.1,5,6 Herewe report on the therapeutic management of 7 children withpost-LT FA in whom a switch from tacrolimus to cyclosporineand an elimination diet induced serum specific IgE level decreaseand negativization of prick skin test responses, allowing success-ful incriminated food reintroduction.Seven children who underwent LT for biliary atresia at age

156 5 months (mean6 SD) and had FA after LTwere compared

with a control group of 7 age- and tacrolimus treatmentmatchedchildren with a comparable atopic familial background whounderwent LT for biliary atresia and did not have FA symptoms.These were consecutive patients within our cohort undergoing LTwho had FA during a tacrolimus regimen, who were treatedaccording to the approach reported below, and in whom follow-upafter normal diet reintroduction was 6 months or longer.After transplantation, all patients received immunosuppresion

based on a tacrolimus regimen (with prednisone [patients 1-2] orbasiliximab [anti-CD25/IL-2 receptor a; patients 3-7]). A familyhistory of atopy (allergic rhinitis, eczema, asthma, and urticaria)was noted in 4 of the 7 patients. A complete clinical history wasobtained in all cases. The presence of immediate symptoms of FAwas validated by a senior pediatrician/allergologist (J.-L. D. or J.C.). Allergic manifestations occurred 33 6 19 months after LTand 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 werehazelnut (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 allergensby means of ImmunoCAP (Phadia, Uppsala, Sweden) testing(Fig 1). Initial serum IgE levels (mean6 SD) were as follows: ha-zelnut, 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 16.3kUA/L; almond, 25.4 6 15.6 kUA/L; soybean, 14.8 6 11.1kUA/L; lentil, 48.36 10.8 kUA/L; pistachio, 16 kUA/L; mustard,9.6 kUA/L; wheat, 30 kUA/L; and sesame seed, 7 kUA/L. The con-trol group was tested for the same panel (16 allergens) of serumspecific and total IgE at a delay after LT similar to that at whichFA occurred in the 7 patients. All control children had negativespecific IgE levels. In addition, the median value of total IgElevels was significantly increased in patients compared withthat seen in control subjects (285 [interquartile range, 194-978]vs 23 [interquartile range, 16-100]; P 5 .01, Mann-WhitneyU test), with only 1 child from the control group having anincreased total IgE level (459 kU/L).In each patient there was a concordance between incriminated

food allergen species and biological data (positive specific IgElevels and skin prick test responses). In patients 6 and 7 morespecific IgE species than food allergens were found. After a severeclinical manifestation of FA (angioedema or Quincke edema), aswitch from tacrolimus to cyclosporine and an elimination diet ofincriminated food allergens were performed systematically in allcases. Thereafter, no recurrence of symptoms of allergy and adecrease in serum specific IgE levels were observed in all patients.When serum specific IgE levels and skin prick test responsesnormalized, an oral challenge with each incriminated food wasperformed (Fig 1). In patient 7 an oral challenge was performedwhile the level of specific IgE was still slightly increased. Theincriminated food was successfully reintroduced in all children37 6 27 months after immunosuppressive switch and eliminationdiet introduction. Importantly, during the cyclosporine regimen,no FA recurrence was observed after oral challenge and diet liber-alization, with a follow-up of 27 6 21 months. During the overallfollow-up period during the cyclosporine regimen, serum liver testresults remained normal, indicating the absence of liver rejection.Pediatric IgE-dependent FA after LT is a well-known compli-cation. Yet there are no internationally accepted guidelines

Vitamin D supplementation in children may prevent asthma exacerbation triggered by acute respiratory infectionReferences