Clinical and immunologic reactivity to aeroallergens in “intrinsic” atopic dermatitis patients

can trigger life-threatening reactions by inhalation. Also noteworthy is the fact that the boy, who is now orally tolerant on DBPCFC with cooked rice, reacted as severely as he did to vapor-borne rice allergens. This might be because digestion and/or processing modify allergenicity9; alternatively, the causative proteins could be different in the 2 ways (inhalant and ingestant). The circumstances of the episode that we report compelled us to test whether the boy could be safely exposed to rice vapor; a cumulative dose of 0.1875 mg was sufficient to provoke a reaction. We cannot compare this dose with the amount inhaled during the severe “natural” reaction, but we can argue that it was higher. To the best of our knowledge, this is the first time that a DBPCFC has been conducted in this way. We propose the term double-blind, placebocontrolled food inhalation challenge for this procedure. Inasmuch as the DBPCFC is a clinical diagnostic instrument to define a causative relationship in food allergy, and inasmuch as the spectrum of food allergy is not always reflected in its entirety in a single case, the benchmark should be adaptive rather than immutable. It was in response to analogous circumstances that the double-blind, placebo-controlled food-exercise challenge was developed10 in order to arrive at a diagnosis. Rice allergy being variously reported in the range of 0.7% to 2% in open Western populations, and there being uncertainty as to the actual prevalence, it is all the more important to have diagnostic instruments to cope with the full spectrum of exposure to rice allergens. Alessandro Fiocchi, MDa Gabriel Robert Bouygue, MSca Patrizia Restani, PhDb Antonella Gaiaschi, PhDb Luigi Terracciano, MDa Alberto Martelli, MDa aThe Melloni Child and Maternal Medicine Hospital University of Milan bLaboratory of Toxicology Department of Pharmacological Sciences University of Milan Italy REFERENCES 1. Wüthrich B, Scheitlin T, Ballmer-Weber B. Isolated allergy to rice. Allergy 2002;57:263-4. 2. Zapletal A, Samanek M, Paul T. Lung function in children and adolescents. Basel: Karger; 1987. 3. Nishio T, Iida S. Mutants having a low content of 16kD allergenic protein in rice (Oryza sativa). Theor Appl Genet 1993;86:317-21. 4. Ikezawa Z, Ikebe T, Ogura H, Odajima H, Kurosaka F, Komatu H, et al. Mass trial of hypoallergenic rice (HRS-1) produced by enzymatic digestion in atopic dermatitis with suspected rice allergy. HRS-1 Research Group. Acta Derm Venereol Suppl Stockh 1992;176:108-12 5. De Jong EC, Van Zijverden M, Spanhaak S, Koppelman SJ, Pellegrom H, Penninks AH. Identification and partial characterization of multiple major allergens in peanut proteins. Clin Exp Allergy 1998;28:743-51. 6. Caffarelli C, Cataldi R, Giordano S, Cavagni G. Anaphylaxis induced by exercise and related to multiple food intake. Allergy Asthma Proc 1997;18:245-8. 7. Sander I, Flagge A, Merget R, Halder TM, Meyer HE, Baur X. Identification of wheat flour allergens by means of 2-dimensional immunoblotting. J Allergy Clin Immunol 2001;107:907-13. 8. Bahna SL. Unusual presentations of food allergy. Ann Allergy Asthma Immunol 2001;86:414-20. 9. Fiocchi A, Restani P, Riva E, Restelli AR, Biasucci G, Galli CL, et al. Meat allergy. II. Effects of food processing and enzymatic digestion on the allergenicity of bovine and ovine meats. J Am Coll Nutr 1995;14:245-50. 10. Fiocchi A, Mirri GP, Santini I, Ottoboni F, Riva E. Exercise-induced anaphylaxis following food-contaminant ingestion at double-blinded, placebo-controlled, food-exercise challenge. J Allergy Clin Immunol 1997;100:424-5. doi:10.1067/mai.2003.12

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Clinical and immunologic reactivity to aeroallergens in “intrinsic” atopic dermatitis patients To the Editor: Atopic eczema (AE) is frequently associated with specific IgE (sIgE) responses against inhalative and nutritional allergens. An intrinsic form of AE has been differentiated from the more common extrinsic AE by normal serum IgE levels, negative skin prick and sIgE test reactions to exogeneous allergens, and the absence of hay fever or allergic asthma.1,2 Because in intrinsic AE a sensitization against these allergens cannot be determined by standard skin prick tests or sIgE determination, other test procedures are needed. We report 3 key patients in whom the epicutaneous application of aeroallergens (atopy patch tests [APTs])3 was used to study the clinically suspected role of aeroallergens in intrinsic AE. A 24-year-old optician (patient 1) and a 59-year-old masseur (patient 2) with clinically characteristic AE lesions had negative personal and family histories for atopy. Each of these patients (both of whom were female) reported an itch sensation after house dust exposure that was followed by a flareup of AE lesions. Results of skin prick tests and sIgE tests (CAP-FEIA, Pharmacia, Freiburg, Germany) were negative; total serum IgE values were 23 and 55 kU/L, respectively. Patient 3, a 48-year-old female shop assistant with clinically characteristic seasonal flexural AE lesions (total serum IgE, 10 kU/L) also fulfilled the criteria (described above) for intrinsic AE, which was diagnosed in all 3 patients. An APT was performed through use of a standard technique that yields positive results in patients with AE but not in patients with hay fever or asthma.3 Briefly, the patch-tested aeroallergens (house dust mite [Dermatophagoides pteronyssinus], birch pollen, cat dander, and grass pollen [Phleum pratense]—all at 200 IR in petrolatum [Stallergenes, Antony, France]), food allergens (egg white, celery, and wheat flour—all at 1/3 w/v in petrolatum [Stallergenes]), and negative vehicle control (petrolatum) were applied on the patients’ backs in large Finn chambers (diameter, 11 mm). After 48 hours, the allergens were removed and the tested areas marked. The test was read after 48 hours and 72 hours. Positive reactions were classified according to the European Task Force on Atopic Dermatitis key, which reflects the appearance of papules, erythema, and infiltration in the tested area.4 Patients had no acute phases of eczema during the test, and none had previously been treated with topical steroids or UV light on the test site. Patients 1 and 2 developed strongly positive (+++) APT reactions for the house dust mite allergen. Patient 3 showed a markedly positive (++) APT reaction to birch pollen. Results for vehicle controls and other allergens remained negative in all 3 patients, as expected from published data pertaining to this technique.3 The overall strength of our intrinsic APT reactions was identical to that of 23 APT reactions in extrinsic control subjects with AE. An immunoblot with aeroallergens was performed through use of a published standard technique.5 House dust mite and birch pollen allergens were separated on 7.5%-to-20% SDS-PAGE. Specific IgE, IgG, and IgG4 were detected by alkaline phosphatase–linked second antibody. Despite the absence of IgE reactivity in patients 1 and 2, an sIgG response—mainly IgG4—to house dust mite allergen was detected. The sera of patients 1 (Fig 1, B) and 2 (not shown) demonstrated major sIgG4 reactivity to a 28-kd allergen (corresponding to Der p 3). In patient 1, we observed minor sIgG4 reactivities to a 14kd allergen (corresponding to Der p 2/5) and a 50-kd allergen (Fig 1, A). Patient 3 had neither sIgE nor sIgG4 reactivities to birch pollen (not shown) and house dust mite (Fig 1, A) allergens. Epidermal dendritic cell phenotyping, a recently standardized diagnostic procedure based on quantitative evaluation of Langerhans cells and inflammatory dendritic epidermal cells (IDECs) of inflamed

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A

B

FIG 1. A, Epidermal dendritic cell phenotyping of house dust mite induced APT lesions from an intrinsic AE patient (patient 1) (IAEAPT; left) and an extrinsic AE patient (EAE-APT; right). Although both lesions show Langerhans cells (LC) and IDECs, the FcεRI expression is much higher in extrinsic AE. B, Lack of specific IgE and detection of specific IgG and IgG4 reactivity to D pteronyssinus allergens by immunoblot in a patient with intrinsic AE and positive APT to house dust mite allergen (patient 1). The serum of a patient not reactive to house dust mite allergen in APT was used as control (patient 3, who was clinically reactive to birch pollen). Molecular weights are given in kd.

Letters to the Editor

skin,6 was performed in all 3 patients. On day 3, shave biopsies were obtained from APT lesions after administration of local anesthesia, and epidermal cell suspensions were prepared by trypsinization of the skin specimens. The resulting cell suspensions were immunolabeled according to a triple-staining protocol and analyzed by flow cytometry to determine the immunophenotype and proportion of epidermal dendritic cells. Mean fluorescence intensities were determined for selected surface molecules, and relative fluorescence indices were

calculated as described.6 Epidermal dendritic cell phenotyping results obtained from our patients’ APT reactions (Fig 1, A) showed a high number of IDECs but low FcεRI expression—a reaction pattern previously seen in chronic lesions of intrinsic AE.2 We conclude from our observations that aeroallergens might be a relevant pathogen for intrinsic AE, even in the absence of detectable aeroallergen-specific serum IgE and negative skin prick test results. APT might become an important diagnostic tool, especially in patients with intrinsic AE in whom standard prick and sIgE tests do not identify allergens relevant to the clinical course of disease, as previously shown in challenge-positive food-allergic children with AE.7 Some patients showed sIgG4 to the APT allergen extract in the context of low FcεRI expression on their lesional DCs. This might be of pathophysiologic relevance to an sIgG-mediated facilitated antigen presentation. In the novel nomenclature for allergy recently proposed by the European Academy of Allergy and Clinical Immunology, AE has been renamed atopic eczema/dermatitis syndrome (AEDS) and divided into nonallergic and allergic AEDS, the latter being subdivided into “IgE-associated AEDS” and “non-IgE associated allergic AEDS.”8 According to this scheme, “[the term] nonallergic AEDS should replace the term intrinsic/cryptogenic variants.”8 How should our patients’ aeroallergens be properly named if we classified their disease as “nonallergic AEDS”? The alternative option— “T-cell–associated AEDS”—seems valid for every AE.8 In view of the demonstration of allergy in our 3 patients, neither “intrinsic AE” nor “nonallergic AEDS” seems to be an optimal descriptor for this apparently non–IgE-associated but allergic and clinically meaningful subtype of AE. In terms of nomenclature, we feel most comfortable diagnosing our patients as having non–IgE-associated AE(DS). Karin Kerschenlohr, MDa Sandra Decarda Ulf Darsow, MDb Markus Ollert, MDb Andreas Wollenberg, MDa aDepartment of Dermatology and Allergy Ludwig-Maximilian-University bDepartment of Dermatology and Allergy Biederstein Technical University Munich Germany

REFERENCES 1. Schmid-Grendelmeier P, Simon D, Simon HU, Akdis CA, Wüthrich B. Epidemiology, clinical features, and immunology of the “intrinsic” (nonIgE-mediated) type of atopic dermatitis (constitutional dermatitis). Allergy 2001;56:841-9.

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A TH2 cytokine inhibitor for airway inflammation in mild asthma To the Editor: TH2 cytokines stimulate IgE production, airway mucosal mastocytosis, and eosinophilic airway inflammation, thereby playing an important role in the pathogenesis of asthma.1 We have recently shown that suplatast tosilate (( ± )-[2-[4-(3-ethoxy-2-hydroxypropoxy) phenylcarbamoyl] ethyl] dimethylsulfonium p-toluenesulfonate), a novel selective TH2 cytokine inhibitor that suppresses the release of IL-4 and IL-5,2 has a steroid-sparing effect in patients with severe asthma.3 In the present placebo-controlled, parallelgroup, multicenter study, we compared the benefits of suplatast tosilate with those of inhaled beclomethasone dipropionate (BDP) in mild persistent asthma. We recruited 43 asthma patients, aged 21 years or older, whose FEV1 values were at least 70% of predicted normal. All patients had been treated with as-needed short-acting inhaled β2-agonist alone for at least 8 weeks before the study. After a 2-week run-in period, each patient was assigned to receive for 8 weeks oral suplatast tosilate (200 µg twice daily), inhaled BDP (200 mg twice daily), or placebo in tablets identical to those used for suplatast. Distribution of age, sex, FEV1, peak expiratory flow rates, or β2-agonist use did not differ significantly between the 3 treatment groups. At the end of the run-in period (baseline) and at week 4 and week 8 of the treatment period, airway inflammation was assessed by differential cell counts in the sputum obtained by inhaled 5% hypertonic saline.4 Concentrations of eosinophil cationic protein and mast cell tryptase in the sputum supernatants were also measured by double-antibody radioimmunoassay and immunofluoroassay, respectively.5 Written informed consent was obtained from each patient, and the study was approved by the Tokyo Women’s Medical University Medical Board and the local ethics committees. During the trial, 5 patients were withdrawn because of missed clinic visits or rejection of sputum induction. Data were available from 13 patients taking suplatast, 13 patients taking BDP, and 12 patients taking placebo. Suplatast tosilate and BDP similarly decreased sputum eosinophil and mast cell counts and concentrations of eosinophil cationic protein and mast cell tryptase at week 8 (Fig 1). Over the 8-week treatment period, the average percentage change from baseline in FEV1 was 11.2% (95% CI, 8.9% to 13.5%) with suplatast, 10.4% (8.0% to 12.8%) with BDP, and 1.8% (0.6% to 3.0%) with placebo (P < .01 for each active treatment compared with placebo; no significant difference between suplatast and BDP).

Mean morning peak expiratory flow rates increased in the suplatast and BDP groups, and there were no significant differences in changes from baseline levels between the 2 active treatment groups (Fig 2). Findings from physical examinations or laboratory assessments (hematologic, biochemical, and urinalysis studies) performed every 2 weeks did not change significantly from baseline in either group, and no patient withdrew because of adverse side effects. In asthmatic airways, CD4+ cells and, to a lesser extent, CD8+ cells with a type 2 cytokine phenotype are present. These cells produce IL-5 and GM-CSF, which recruit, mobilize, and activate eosinophils, as well as IL-4, an essential cofactor for local and generalized IgE production. This leads to epithelial shedding, mucus hypersecretion, and airway hyperresponsiveness. Thus, inhibitors and/or antagonists directed against TH2 cells might hold promise for the treatment of asthma. According to many guidelines, inhaled corticosteroids are the first-line maintenance therapy for mild to moderate asthma. They can reduce TH2 cell–mediated airway inflammation but might cause local side effects, such as cough, laryngeal irritation, and oral candidiasis; they might also cause systemic side effects.6 In addition, because of the ease in taking medication, asthma patients generally prefer oral drugs to inhaled drugs for longterm maintenance therapy. Our study provides evidence that suplatast tosilate is as effective as BDP in improving pulmonary function and airway inflammation in patients with mild persistent asthma. Therefore, a selective TH2 cytokine inhibitor might be considered for the treatment of this subset of the asthmatic population. Jun Tamaoki, MD, PhDa Kiyoshi Takeyama, MD, PhDb Kazutetsu Aoshiba, MD, PhDa Junko Nakata, MDc Kazuyuki Nishimura, MDd Atsushi Nagai, MD, PhDa aFirst Department of Medicine Tokyo Women’s Medical University School of Medicine 8-1 Kawada-Cho, Shinjuku Tokyo 162-8666 bRespiratory Center Minami-Tohoku General Hospital 7-115 Hachiyamada, Tomihisa-Cho Koriyama 963-8051 cDepartment of Medicine Kureha General Hospital 1-1 Nishiki-Cho Iwaki 974-8232 dDepartment of Pulmonary Medicine Kurihashi Saiseikai Hospital Kurihashi Kitakatsushika-Gun 349-1105 Japan Supported in part by Grant-in-Aid Nos. 06670243 and 09770429 from the Ministry of Education, Science and Culture, Japan. Special thanks to our patient for his/her kind willingness to agree to sputum induction testing. We thank Masayuki Shino and Yoshimi Sugimura for excellent technical support. REFERENCES 1. Kon OM, Kay AB. T cells and chronic asthma. Int Arch Allergy Immunol 1999;118:133-5. 2. Yamaya H, Basaki Y, Togawa M, Kojima M, Kiniwa M, Matsuura N. Down-regulation of Th2 cell-mediated murine peritoneal eosinophilia by antiallergic agents. Life Sci 1995;19:1647-54. 3. Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al.

Letters to the Editor

2. Oppel T, Schuller E, Günther S, Moderer M, Haberstok J, Bieber T, et al. Phenotyping of epidermal dendritic cells allows the differentiation between extrinsic and intrinsic form of atopic dermatitis. Br J Dermatol 2000;143:1193-8. 3. Darsow U, Vieluf D, Ring J. Evaluating the relevance of aeroallergen sensitization in atopic eczema with the atopy patch test: a randomized, double-blind multicenter study. J Am Acad Dermatol 1999;40:187-93. 4. Darsow U, Ring J. Airborne and dietary allergens in atopic eczema: a comprehensive review of diagnostic tests. Clin Exp Dermatol 2000;25:544-51. 5. Jeep S, Paul M, Müller U, Kunkel G. Honeybee venom allergy: immunoblot studies in allergic patients after immunotherapy and before sting challenge. Allergy 1996;51:540-6. 6. Wollenberg A, Wen S, Bieber T. Phenotyping of epidermal dendritic cells—clinical applications of a flow cytometric micromethod. Cytometry 1999;37:147-55. 7. Majamaa H, Moisio P, Holm K, Kautiainen H, Turjanmaa K. Cow’s milk allergy: diagnostic accuracy of skin prick and patch tests and specific IgE. Allergy 1999;54:346-51. 8. Johansson SGO, Hourihane JO, Bousquet J, Bruijnzeel-Koomen C, Dreborg S, Haahtela T, et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy 2001;56:813-24. doi:10.1067/mai.2003.1