Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis

LETTERS TO THE EDITOR 415

J ALLERGY CLIN IMMUNOL VOLUME 122, NUMBER 2

TABLE I. Outcome of oral challenges to baked egg and specific IgEf1 to children allergic to or sensitized to egg Challenge outcome Negative Age No. of (mo) patients

Allergic 24 (9) Sensitized 24 (18)

51 36

IgEf1 (IU/mL)

Positive SPTs (mm) Patients

3 (13.42) 7 (3.5) 4.62 (8.04) 7 (4)

4 3

IgEf1 (IU/mL)

SPTs (mm)

2.28 (3.83) 4 (5) 7.19 (9.9) 8 (2)

Descriptive statistics are presented as medians (interquartile ranges). SPT and IgE values did not significantly differ between groups (negative vs positive challenges and allergic vs sensitized cases; Mann-Whitney U test, P > .250).

egg (with positive skin prick tests [SPTs] to egg white, egg whitespecific IgE [IgEf1]), or both, usually performed in the context of atopy evaluation) without previous hen’s egg ingestion. The majority of children with egg allergy (67%) and 100% of the sensitized group had atopic eczema (AE). A detailed medical history, SPTs, and specific IgE measurements (CAP FEIA) were available for all children. Children were challenged with increasing quantities of a cake baked with 1 egg. A starting dose of 0.1 g of cake (containing 0.63 mg of total egg protein) was gradually increased (tripling the previous dose) up to 10 g. Negative challenge results were followed by instructions of continuing consumption with a slow and gradual increase of the egg content of the cake to a total quantity of 1.5 g of total egg protein contained in a small piece of cake by using a recipe provided by our dietician. An open challenge to egg was performed 6 months later until the time when a piece of cake was administered daily. More than 90% of subjects could tolerate baked egg in a cake (92.7% of children with egg allergy and 92.3% of sensitized children, Table I). Positive challenge results to baked egg presented with urticaria (n 5 4), AE flare-up (n 5 1), and anaphylaxis (n 5 2). There was no significant difference in specific IgE measures (SPT or CAP) between those with positive and negative challenge results in either group. Among children with egg allergy who tolerated baked egg, there were 15 (27.3%) patients with CAP levels of greater than 6 IU/mL, which is the proposed 95% decision point for a positive challenge (median IgEf1, 16.2 IU/mL; range, 7.34-76.5 IU/mL).6 After a period of 6 months, 87 children who were freely receiving baked egg underwent open food challenges to whole egg. Only 4 (4.6%) of them had positive challenges (AE flare-up, n 5 1; urticaria, n 5 3). Specific IgE levels for these patients ranged from 2.29 to 3.94 IU/mL, whereas all patients with IgEf1 levels of greater than 4.62 IU/mL (67 patients) could now tolerate egg. All patients were prospectively followed up to confirm they had outgrown their allergy to egg. Although appropriate controls were not included, it is noteworthy that the observed percentage of persistence of egg allergy is considerably low in comparison with that described in the literature (ie, 40% or 27% of children with convincing or suggestive history, respectively, at similar time points).6 Therefore the possibility that small quantities of processed antigen consumption in the form of baked egg might alter the natural course of the disease cannot be excluded. A controlled study to evaluate this hypothesis is underway. Furthermore, our data suggest that decision points for challenges to egg7 can be affected by consumption of products that

contain small quantities of egg protein in processed form. Taking into account that such products are widely available and not always avoided by patients, either because of lack of compliance or unclear and insufficient labelling,8 it might be of importance to seek such consumption history in detail when reassessing patients with allergy or sensitization to egg. Finally, it should be pointed out that severe reactions can occur even to heat-treated egg in children with AE who are sensitized but have not previously consumed egg, as in the case of egg challenges.9 Therefore caution should be applied in the introduction of egg in any form in such cases. In conclusion, absolute levels of egg-specific serum IgE levels are not able to predict the challenge outcome in children with egg allergy or sensitization consuming small quantities of egg in baked form. The hypothesis that such consumption might affect the natural course of allergy to egg should be evaluated in controlled trials. George N. Konstantinou, MD, MSc Stavroula Giavi, MD Aleksandra Kalobatsou, MD Emilia Vassilopoulou, PhD Nikolaos Douladiris, MD Photini Saxoni-Papageorgiou, MD, PhD Nikolaos G. Papadopoulos, MD, PhD From the Allergy Department, Pediatric Hospital ‘‘P & A Kiriakou,’’ National and Kapodistrian University of Athens, Athens, Greece. E-mail: [email protected]. Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest. REFERENCES 1. Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol 2007;120:1413-7. 2. Buchanan AD, Green TD, Jones SM, Scurlock AM, Christie L, Althage KA, et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J Allergy Clin Immunol 2007;119:199-205. 3. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: efficacy and clinical patterns of reaction. Allergy 2007;62:1261-9. 4. Eigenmann PA. Anaphylactic reactions to raw eggs after negative challenges with cooked eggs. J Allergy Clin Immunol 2000;105:587-8. 5. Hirose J, Kitabatake N, Kimura A, Narita H. Recognition of native and/or thermally induced denatured forms of the major food allergen, ovomucoid, by human IgE and mouse monoclonal IgG antibodies. Biosci Biotechnol Biochem 2004;68:2490-7. 6. Sampson HA. Utility of food-specific IgE concentrations in predicting symptomatic food allergy. J Allergy Clin Immunol 2001;107:891-6. 7. Sampson HA, Ho DG. Relationship between food-specific IgE concentrations and the risk of positive food challenges in children and adolescents. J Allergy Clin Immunol 1997;100:444-51. 8. Cornelisse-Vermaat JR, Voordouw J, Yiakoumaki V, Theodoridis G, Frewer LJ. Food-allergic consumersÕ labelling preferences: a cross-cultural comparison. Eur J Public Health 2008;18:115-20. 9. de Boissieu D, Dupont C. Natural course of sensitization to hen’s egg in children not previously exposed to egg ingestion. Eur Ann Allergy Clin Immunol 2006;38:113-7. Available online July 1, 2008. doi:10.1016/j.jaci.2008.05.032

Serum 25-hydroxyvitamin D levels are lower in urban African American subjects with chronic rhinosinusitis To the Editor: In addition to its traditional role in the endocrine system, vitamin D decreases the risk of many chronic illnesses, including cancer, autoimmunity, infection, and cardiovascular disease.1 This vitamin has also been implicated in the development of

416 LETTERS TO THE EDITOR

J ALLERGY CLIN IMMUNOL AUGUST 2008

TABLE I. Age, race, sex, and serum vitamin D levels

White subjects Female CRS (n 5 19) Control (n 5 16) P value Male CRS (n 5 37) Control (n 5 17) P value African American subjects Female CRS (n 5 23) Control (n 5 28) P value Male CRS (n 5 7) Control (n 5 7) P value

Age (y)

BMI (kg/m2)

Serum 25(OH)D (ng/mL)

53 6 3.4 42.3 6 3.7 .037

28 6 1.3 28 6 1.5 .942

30.1 6 2.4 30.8 6 3.7 .728

49 6 2 54 6 4 .27

28 6 0.74 28 6 1.6 .45

40.2 6 2.3 29.4 6 2.3 .904

50 6 2.9 46 6 3.3 .25

31 6 1.1 31 6 1.0 .77

13.5 6 2.0 20.8 6 2.6 .018

55 6 6.7 60 6 4.6 .56

34 6 4.9 25 6 1.4 .064

15.4 6 2.1 26 6 2.6 .015

BMI, Body mass index. Data are presented as means 6 SEMs.

atopic diseases, such as asthma, allergic rhinitis, and anaphylaxis.2-4 Because these diseases share clinical and biologic features with chronic rhinosinusitis (CRS), we sought to determine whether serum vitamin D levels might be associated with CRS. We measured serum 25(OH)-vitamin D (25[OH]D) levels in our clinical laboratory by using samples from African American and white adults with and without severe CRS (Table I). Subjects were recruited through our institution’s otolaryngology clinic located in an urban, tertiary care, academic hospital in Chicago through an ongoing study of the genetics of CRS. We attempted to enroll all subjects meeting entry criteria (see below). The institutional review board approved this study, and informed consent was obtained. Definition of cases met consensus diagnostic criteria, including clinical symptoms, nasal endoscopy, and stage IV disease on computed tomographic analysis graded by using the Harvard criteria (ie, pansinusitis).5 Control subjects had normal imaging study results. Data were stratified by factors known to affect serum 25(OH)D, including sex, race, season, and body mass index.6 Comparisons of groups were performed by using nonparametric analysis (Kruskal-Wallis test).7 We found that white female control subjects had higher serum 25(OH)D levels than African American female control subjects (P  .018), and a similar nonsignificant trend between white and African American male subjects was seen, which is consistent with reported variation by ethnicity. There were no significant differences in 25(OH)D levels between white subjects with and without CRS in either sex (P > .05 for all). Levels in African American subjects with CRS were significantly lower than those in race- and sex-matched control subjects (male subjects with CRS, 15.4 6 2.1 ng/mL; male control subjects, 26 6 2.6 ng/mL [P  .015]; female subjects with CRS, 13.5 6 2.0 ng/mL; female control subjects, 20.8 6 2.6 ng/mL [P .018; Table I). Of note, the mean values for all African American groups were less than accepted normative values (see below).

Samples obtained in June through September (summer) were compared with those obtained in November through April (winter); we eliminated ‘‘transition’’ months for clarity. There was a trend toward lower 25(OH)D levels in the winter in all groups. African American subjects with CRS had significantly lower 25(OH)D levels in the winter compared with those seen in control subjects (male subjects with CRS, 22.3 6 3.3 ng/mL; male control subjects, 26.8 6 4 ng/mL [P  .05]; female subjects with CRS, 8.5 6 0.96 ng/mL; female control subjects, 17.4 6 2.5 ng/mL [P  .006]; Fig 1); there were similar trends in summer months, although these did not meet statistical significance (Fig 1). However, it should be noted that the numbers in some of the comparisons by season were not robust. There were no differences between white subjects with CRS and control subjects (P > .05 for all). Demographic factors were similar across comparisons (age and body mass index), except white female subjects with CRS were older than control subjects (53 6 3.4 vs 42 6 3.7 years, P  .037; Table I). The pathogenesis of CRS is not understood. However, there is ample evidence that chronic inflammation is a histopathologic finding in these patients, often similar to that seen in allergic rhinitis and asthma, 2 diseases in which recent evidence supports a role for vitamin D. Nutritional studies in pregnancy indicate that increasing maternal consumption of vitamin D decreases the risk of asthma,3 suggesting that in utero exposure might create a protective program for the developing immune system. These and other data support the role of vitamin D in the development of asthma.8 Anaphylaxis, measured in proxy based on prescription of Epipens (Dey Laboratories, Napa, Calif), varies with geographic latitude, with higher levels found in areas with less sun exposure.9 The prevalence of allergic rhinitis was associated with serum 25(OH)D levels in a population database study.4 Because CRS is known to be associated with asthma and atopy and has similar inflammatory cellular profiles, these studies are consistent with a role for vitamin D in chronic sinus disease. Vitamin D is also known to have a number of immunologic effects, including those on T cells, dendritic cells, and macrophages.10,11 CRS is characterized by severe mucosal inflammation, and thus deficiency might lead to an increase in inflammation, as seen in CRS. Indeed, administration of vitamin D to subjects with steroid-resistant asthma has been reported to enhance subsequent steroid responsiveness, a finding with implications for CRS, a disease in which steroids are an important therapy.12 The mechanism might be related to the ability of vitamin D to promote IL-10 production by regulatory T cells, to regulate glucocorticoid receptor expression, or both.12 Deficits in these pathways might partially explain decreased checks on immune responses, allowing for the abundant inflammation seen in CRS. Some have speculated that lower 25(OH)D levels might be associated with increased susceptibility to viral infections, such as influenza. This suggestion is consistent with the clinical observation that rhinosinusitis exacerbations are more prevalent in the winter and are often virally induced. Thus deficiency of vitamin D in the winter months might partially account for the observed clinical worsening of CRS symptoms during this season, and this supports the role of vitamin D in the pathogenesis of this disease. Although there are no carefully controlled studies of the epidemiology of CRS including race, sex, or geographic

LETTERS TO THE EDITOR 417

J ALLERGY CLIN IMMUNOL VOLUME 122, NUMBER 2

FIG 1. Effect of season on mean serum vitamin D levels in urban African Americans with CRS and control subjects. Summer was defined as June through September, and winter was defined as November through April, corresponding to seasons in Chicago. Data are presented as means 6 SEMs.

differences, analysis of International Classification of Diseases, Ninth Revision, codes in Olmsted County, Minnesota, revealed that 67.7% of patients given diagnoses of CRS were female in 2000.13 Minnesota is located in a northern latitude, and therefore these findings are consistent with other data relating sun exposure and vitamin D levels to atopic disease. Aging has been noted to affect serum vitamin D levels,14 although we found no age differences between groups in our African American subjects that would affect our results. Our results suggest an ethnic difference in CRS disease profile. Two factors that might affect our results include small sample size and location of recruitment (outpatient clinic at an urban academic medical center vs population-based recruitment). It should be noted that a reference range for normal serum 25(OH)D levels is controversial; hypovitaminosis D is generally accepted as less than 30 ng/mL or, alternatively, a level that results in an increased parathyroid hormone level, testing of which was cost prohibitive for this study. All of our African American subjects showed levels markedly less than this threshold, an observation with important implications for a variety of diseases. Because we only examined patients with severe disease, we do not know whether serum 25(OH)D levels correlate with CRS disease severity or clinical symptoms. Further study of this phenomenon might provide novel hypotheses for the development of CRS and, perhaps, ideas for new therapeutic interventions. Jayant M. Pinto, MD John Schneider, MD Rosanne Perez, BS Marcella DeTineo, BSN Fuad M. Baroody, MD Robert M. Naclerio, MD From the Section of Otolaryngology–Head and Neck Surgery, the Department of Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Ill. E-mail: [email protected]. Supported by an American Geriatrics Society/Dennis W. Jahnigen Scholars Award (J.M.P.); the Department of Surgery, the University of Chicago; and the McHugh Otolaryngology Research Fund. Disclosure of potential conflict of interest: J. M. Pinto has received research support from Schering-Plough, the American Geriatric Society, and the American Rhinologic Society. F. M. Baroody is on the speakersÕ bureau for GlaxoSmithKline and Merck, has

received research support from GlaxoSmithKline, and has served as an expert witness in litigation regarding airway foreign bodies in children. R. M. Naclerio has consulting arrangements with Merck, GlaxoSmithKline, Allux, Schering-Plough, and Johnson & Johnson and has received research support from Merck, GlaxoSmithKline, and Schering-Plough. The rest of the authors have declared that they have no conflict of interest. REFERENCES 1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81. 2. Camargo CA Jr, Rifas-Shiman SL, Litonjua AA, Rich-Edwards JW, Weiss ST, Gold DR, et al. Maternal intake of vitamin D during pregnancy and risk of recurrent wheeze in children at 3 y of age. Am J Clin Nutr 2007; 85:788-95. 3. Devereux G, Litonjua AA, Turner SW, Craig LC, McNeill G, Martindale S, et al. Maternal vitamin D intake during pregnancy and early childhood wheezing. Am J Clin Nutr 2007;85:853-9. 4. Wjst M, Hypponen E. Vitamin D serum levels and allergic rhinitis. Allergy 2007; 62:1085-6. 5. Gliklich RE, Metson R. A Comparison of Sinus Computed Tomography (CT) Staging Systems for Outcomes Research. Am J Rhinol 1994;8:291-7. 6. Nesby-O’Dell S, Scanlon KS, Cogswell ME, Gillespie C, Hollis BW, Looker AC, et al. Hypovitaminosis D prevalence and determinants among African American and white women of reproductive age: third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 2002;76:187-92. 7. Glantz SA. Primer of Biostatistics. New York: McGraw Hill; 2002. p. 79. 8. Weiss ST, Litonjua AA. Childhood asthma is a fat-soluble vitamin deficiency disease. Clin Exp Allergy 2008;38:385-7. 9. Camargo CA Jr, Clark S, Kaplan MS, Lieberman P, Wood RA. Regional differences in EpiPen prescriptions in the United States: the potential role of vitamin D. J Allergy Clin Immunol 2007;120:131-6. 10. Wintergerst ES, Maggini S, Hornig DH. Contribution of selected vitamins and trace elements to immune function. Ann Nutr Metab 2007;51:301-23. 11. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, Soler D, et al. DCs metabolize sunlight-induced vitamin D3 to ‘‘program’’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007;8:285-93. 12. Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoidresistant asthma patients. J Clin Invest 2006;116:146-55. 13. Shashy RG, Moore EJ, Weaver A. Prevalence of the chronic sinusitis diagnosis in Olmsted County, Minnesota. Arch Otolaryngol Head Neck Surg 2004;130: 320-3. 14. Maggio D, Cheryubini A, Lauretani F, Russo RC, Bartali B, Pierandrei M, et al. 25(OH)D Serum levels decline with age earlier in women than in men and less efficiently prevent compensatory hyperparathyroidism in older adults. J Gerontol A Biol Sci Med Sci 2005;60:1414-9. Available online July 1, 2008. doi:10.1016/j.jaci.2008.05.038