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

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 children’s 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

Paweł Majak, MD, PhD Małgorzata Olszowiec-Chlebna, MD Katarzyna Smejda, MD Iwona Stelmach, MD, PhD From the Department of Pediatrics and Allergy, Medical University of Lodz, Poland. E-mail: [email protected]. 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 response—the 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 post–liver transplant–associated 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-LT–related 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 treatment–matched

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