- Email: [email protected]
Hypersensitivity to proton pump inhibitors: Diagnostic accuracy of skin tests compared to oral provocation test
LETTERS TO THE EDITOR 547
J ALLERGY CLIN IMMUNOL VOLUME 130, NUMBER 2
For comparison, lung tissue expressed relatively low levels of gap junction and desmosomes and some are fully not detectable (Fig 2, C). Normal human bronchial epithelial cells cultured in ALI expressed claudin-17 (P 5 .03) (Fig 2, A). In contrast, primary keratinocyte in ALI cultures expressed uniquely desmocollin-1 (P 5 .02) (Fig 2, D). Keratinocyte ALIs did not express any TJ proteins in addition to the common junctional proteins observed in skin biopsies and monolayer cultures (Fig 2, B). Detailed statistical analysis is shown in Table E1 (in the Online Repository available at www.jacionline.org). Our data demonstrate that monolayer cell cultures express a similar profile of junction molecules compared with ALI cultures, however, with relatively low levels. After apicobasal differentiation in ALIs, more junctional molecules are expressed (Fig 2). Interestingly, whole tissues expressed a much broader profile of junctional molecules. The main reason behind having additional junctional mRNAs appearing in the whole tissue of lung and skin can be that other cell types, such as endothelial cells, fibroblasts in both, and smooth muscle cells in the lung, are also expressing junctional molecules. ALIs represent here a more cell-type–specific junctional molecule expression pattern. After performing the detailed expression analyses of interepithelial barrier molecules, we realized that it is essential to study the TJs in a broader way. Although some are dominantly expressed, the determination of one or two junctional molecules, especially TJs, may not represent the whole picture. There are distinct and overlapping patterns of TJs and other cell-cell adhesion molecules expressed in the skin and lung epithelia, which implicate a highly regulated and complex pattern. Each cell type shows its own, unique expression profile reflecting its specialization related to its function within the organism. In addition, we have to take into account that TJs are not uniquely expressed in epithelial cells but are also found and regulated in other cells, especially in endothelium. Furthermore, other mesenchymal tissues also express them as recently observed in smooth muscle cells in asthma.9 The number of different junctional proteins, which are expressed, interact in multiple ways in every cell type to form appropriate cell-cell contacts and tissue integrity. Our data demonstrated here suggest that the picture of the junctional apparatus in each cell type and tissue is distinct, and the regulation of epithelial integrity might be more complex than being considered so far. Jeannette I. Kast, BSca Kerstin Wanke, MSca Michael B. Soyka, MDa,b Paulina Wawrzyniak, MSca Deniz Akdis, BSca K€ ulli Kingo, MD, PhDc,d Ana Rebane, PhDa,e Cezmi A. Akdis, MDa From athe Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; bthe Department of Otolaryngology Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland; cthe Department of Dermatology, Tartu University Hospital, Tartu, Estonia; dthe Department of Physiology, Centre of
=
Molecular and Clinical Medicine, and eMolecular Pathology, Faculty of Medicine, University of Tartu, Tartu, Estonia. E-mail: [email protected]. The lab of C.A.A. was supported by the Christine K€uhne Center for Allergy Research and Education (CK-CARE), the Swiss National Science Foundation (grant no. 32132899), the Estonian Science Foundation (grant no. ESF8350), and SCIEX Programme NMS-CH. Disclosure of potential conflict of interest: M. B. Soyka receives research support from the Muller-Gieork Foundation and is employed by University Hospital & ENT Zurich. C. A. Akdis has received research support from Novartis, PREDICTA: European Commission’s Seventh Framework Programme No. 260895, the Swiss National Science Foundation, MeDALL: European Commission’s Seventh Framework Programme No. 261357, the Global Allergy and Asthma European Network, and the Christine K€uhne Center for Allergy Research and Education; has consulted for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member of the American Academy of Asthma, Allergy & Immunology; is a former committee member of the Global Allergy and Asthma European Network; and is director of the Christine K€uhne Center for Allergy Research and Education. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature 2008;454:445-54. 2. Akdis CA. Therapies for allergic inflammation: refining strategies to induce tolerance. Nature Med 2012;18:736-49. 3. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 2011;127:773-86, e1-7. 4. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128: 549-56, e1-12. 5. Furuse M. Molecular basis of the core structure of tight junctions. Cold Spring Harb Perspect Biol 2010;2:a002907. 6. Lal-Nag M, Morin PJ. The claudins. Genome Biol 2009;10:235. 7. Lin H, Li H, Cho HJ, Bian S, Roh HJ, Lee MK, et al. Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies. J Pharm Sci 2007;96:341-50. 8. Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, et al. Predicted expansion of the claudin multigene family. FEBS Lett 2011;585:606-12. 9. Fujita H, Chalubinski M, Rhyner C, Indermitte P, Meyer N, Ferstl R, et al. Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects. J Allergy Clin Immunol 2011;127:1612-21.e18. Available online June 15, 2012. http://dx.doi.org/10.1016/j.jaci.2012.04.044
Hypersensitivity to proton pump inhibitors: Diagnostic accuracy of skin tests compared to oral provocation test To the Editor: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related gastrointestinal diseases because they reduce the gastric acid secretion by blocking the H1/K1-ATPase. PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. PPIs are generally well tolerated, and side effects occur in about 1% of the patients.1 Hypersensitvity reactions are also rare, but several reports have described anaphylaxis, urticaria, or asthma.2-5 The diagnosis of hypersensitivity to PPIs is difficult since PPIs are often used in combination with other drugs. The oral provocation test (OPT) remains a reasonable
junctions (C and D), and of junctional adaptor proteins (E and F). Lung tissue, n 5 5; skin tissue, n 5 4; NHBE ALI, n 5 4; KC ALI, n 5 4; NHBE monolayer, n 5 4; and KC monolayer, n 5 4, were investigated. Mean 6 SEM is displayed. CMLP, CXADR-like membrane protein (ASAM); JAM, junctional adhesion molecules; KC, keratinocyte; MAGI, membrane-associated guanylate kinase inverted; MUPP1, multi-PDZ domain containing protein 1; NHBE, normal human bronchial epithelial; PATJ, inaD-like protein (INADL); ZO, zonula occludens.
548 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2012
TABLE I. Characteristics of the studied population and results of the diagnostic tests
No. Sex (female/male) Age (y), range (mean) Suspected drug
Severity of reaction*
Skin prick (1/tested)
ID test (1/tested)
OPT (1/performed)
Whole population
Grade I and II patients
Grade III patients
53 42/11 19-81 (54) Esomeprazole n 5 16 Lansoprazole n 5 14 Omeprazole n 5 10 Pantoprazole n 5 11 Rabeprazole n 5 2 Grade I: 38 Grade II: 6 Grade III: 9 Esomeprazole: 1/53 Omeprazole: 1/53 Pantoprazole: 1/53 Lansoprazole: 4/23 Rabeprazole: 1/5 Esomeprazole: 4/53 Omeprazole: 5/53 Pantoprazole: 5/53
44 34/10 19-81 (53.8) Esomeprazole n 5 15 Lansoprazole n 5 11 Omeprazole n 5 10 Pantoprazole n 5 7 Rabeprazole n 5 1 Grade I 1 II: 38 1 6
9 8/1 40-74 (55.3) Esomeprazole n 5 1 Lansoprazole n 5 3 Omeprazole n 5 0 Pantoprazole n 5 4 Rabeprazole n 5 1 Grade III: 9
Esomeprazole: 0/44 Omeprazole: 0/44 Pantoprazole: 0/44 Lansoprazole: 2/20 Rabeprazole: 0/2 Esomeprazole: 2/44 Omeprazole: 1/44 Pantoprazole: 0/44
Esomeprazole: 1/9 Omeprazole: 1/9 Pantoprazole: 1/9 Lansoprazole: 2/3 Rabeprazole: 1/3 Esomeprazole: 2/9 Omeprazole: 4/9 Pantoprazole: 5/9
Esomeprazole: 3/13 Omeprazole: 0/9 Pantoprazole: 0/7 Lansoprazole: 3/11
Rabeprazole: 1/1
Esomeprazole: 3/13 Omeprazole: 0/9 Pantoprazole: 0/7 Lansoprazole: 3/11 Rabeprazole: 1/1
*Grade I: only pruritus or flush or urticaria/angioedema; grade II: nausea/cramping or rhinitis or dyspnea or cough or hypotension or arrhythmia (with/without grade I signs). Grade III: vomiting or defecation or cyanosis or bronchospasm or laryngeal edema or shock (with/without grade I signs) (see Ring and Messmer8).
approach to confirm hypersensitivity, but it is time-consuming and not devoid of risks.6 Thus, a reliable in vivo test to replace OPT would be desirable. Skin tests for PPIs have been described, but their accuracy is not defined.4,5 In this multicenter study, we compared the efficiency of skin tests with that of OPT in patients with immediate hypersensitivity reactions to PPIs. This study was conducted between 2008 and 2010 in 4 allergy units and was approved by local ethics committees. Only patients with a definite history of immediate reactions due to PPIs were enrolled. Patients reporting symptoms attributable to known side effects, or with nonimmediate reactions, or with reactions while taking concomitant drugs were excluded. Clinical data were recorded by using an adapted version of the European Network on Drug Allergy questionnaire.7 The severity of reactions was assessed by using the Ring-Messmer scale.8 Skin prick tests (SPTs) were performed in all patients with the undiluted commercial preparation (40 mg/mL) for omeprazole, esomeprazole, and pantoprazole. Solutions of rabeprazole (40 mg/mL) and lansoprazole (30 mg/mL) were prepared by dissolving the powder in saline. Intradermal tests (IDTs) were performed only with the injectable preparations of omeprazole, esomeprazole, and pantoprazole at 0.4 and 4 mg/mL. SPT results were read after 20 minutes and after 48 hours, and considered positive if a wheal of 3 mm or more _5 was observed at 20 minutes or if an erythematous induration (> mm) was observed on day 2. IDTs involved the injection of 0.03 mL of the solution, and the results were read after 20 minutes and 2 days. They were considered positive if the initial wheal increased by more than 3 mm and was surrounded by erythema after 20 minutes or if an induration appeared at 48 hours.9 Histamine (0.01%) and saline were the positive and negative controls. A single-blind, placebo-controlled OPT with the suspect PPI was performed in patients who gave their informed consent
after skin testing. On day 1, 4 talc capsules were given. On day 2, omeprazole or pantoprazole or esomeprazole or rabeprazole (5 mg, 5 mg, 10 mg, 20 mg), or lansoprazole (5, 10, 15 mg) was given at 30-minute intervals. Before starting, and after each dose, blood pressure, heart rate, oxygen saturation, and FEV1 were recorded. The test result was considered positive when clinical signs (urticaria, angioedema, rash) or 20% change in heart rate or oxygen saturation below 90% or 20% fall in FEV1 was documented. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LRs) were calculated for skin tests in comparison to OPT, considering those patients who completed the procedure. Positive likelihood ratio (LR1) was defined as sensitivity/ (1 2 specificity), and negative likelihood ratio (LR2) was defined as (1 2 sensitivity)/specificity. Difference in latency times was evaluated by using the Mann-Whitney test. Since there were 4 missing data for OPT among grade I and grade II patients, adjusted parameters were also calculated by using Begg-Greenes estimators under missing at random assumption. Fifty-three patients (42 women, 11 men, mean age 54 years, range 19-81 years) were studied, and 41 completed the procedure. Only 1 of 9 grade III patients accepted the OPT; thus, all subjects with grade III reactions were excluded from accuracy analysis, and the 12 patients (3 grade II) who refused OPT were not included in the calculations. The characteristics of patients are detailed in Table I. Skin test results (SPT and/or IDT) were positive in 12 of the 53 patients, and mostly in those with previous grade III reactions (7 of 9). Five of the 9 patients with grade III reactions had positive skin test results to multiple PPIs. The interval between the reaction and the diagnostic procedure was not different between patients with positive and negative skin test results (P 5 .1818).
LETTERS TO THE EDITOR 549
J ALLERGY CLIN IMMUNOL VOLUME 130, NUMBER 2
For esomeprazole, SPT results were positive in 1 of the 53 and IDT results in 4 of the 53 patients; for omeprazole and pantoprazole, 1 of the 53 patients had a positive result to SPTs and 5 of the 53 patients had a positive result to IDTs (Table I). SPT result with lansoprazole was positive in 4 and with rabeprazole in 1. Accuracy analysis was performed in patients with previous grade I and II reactions. Of the 44 patients with reactions of grades I and II, 40 underwent OPT. Of the 40 patients tested, 3 of 3 with skin test positivity and 3 of 37 patients with skin test negativity reacted to OPT. Therefore, among this population, unadjusted sensitivity was 50% and specificity was 100%. Adjusted sensitivity was 61.3% (CI 25.0%-87.5%), and adjusted specificity was 100.0% (CI 97.2%-100.0%). LR1 calculated by using adjusted sensitivity and specificity was 61.3 (assuming a specificity of 99.0%) while LR2 was 0.39. Positive predictive value was 100%, and negative predictive value was 91.9%. The diagnostic use of skin tests in patients with immediate PPI reactions has been sporadically described. For omeprazole, Lobera et al4 reported a skin test positivity in 8 of 9 patients and Sobrevia et al5 in 5 of 5 patients. In this study, we analyzed 53 patients with immediate reactions to PPIs and estimated the diagnostic performance of SPT and IDT versus OPT. In our population, skin test results were positive in 12 of the 53 patients; 4 of these patients underwent OPT with the suspected drug and the results were positive in all cases. In the 41 patients with a negative result, 3 had a positive OPT result with the suspected drug. We obtained good results with skin tests in terms of specificity (100%), positive predictive value (100%), and negative predictive value (91.9%), whereas the sensitivity was lower. These results were confirmed by a high LR1. In addition, we observed a higher frequency of skin test positivity in patients with more severe reactions. Concerning the cross-reactivity, we observed that patients with hypersensitivity to pantoprazole, confirmed by skin tests, also had positive skin test results to omeprazole (4 of 5 patients) and, more rarely, to esomeprazole. This result confirms previous reports10,11 and is probably due to the similar chemical structure of these PPIs. On the contrary, patients monosensitized to lansoprazole and rabeprazole, which have a different side chain, had negative test results with omeprazole, pantoprazole, and esomeprazole. This observation may have important clinical implications, as patients monosensitized to lansoprazole or rabeprazole would more likely tolerate other PPIs. Indeed, the small number of patients does not allow us to make final conclusions about cross-reactive patterns and requires further studies. In conclusion, this multicenter study suggests the usefulness of skin tests in patients with immediate hypersensitivity reactions to PPIs, because a positive skin test result allows one to avoid an oral provocation. Patrizia Bonadonna, MDa* Carla Lombardo, MDa* Oscar Bortolami, PhDb Andreas Bircher, MDc Kathrin Scherer, MDc Annick Barbaud, MDd Giovanni Passalacqua, MDe Mauro Pagani, MDf From athe Allergy Unit and bthe Research Support Unit and Biostatistics, Verona University Hospital, Verona, Italy; cthe Allergy Unit, Department of Dermatology, University Hospital, Basel, Switzerland; dthe Dermatology Department, Fournier Hospital, University Hospital of Nancy, Nancy, France; eAllergy and Respiratory Diseases, DIMI, University of Genoa, Genoa, Italy; and fthe Medical Department, Asola
Hospital, Azienda Ospedaliera C. Poma, Mantua, Italy. E-mail: patrizia.bonadonna@ ospedaleuniverona.it. *These authors contributed equally to this work. Disclosure of potential conflict of interest: A. Bircher serves on a board for Basilea, has consultant arrangements with ALK, and has received research support from Novartis. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010;16:2323-30. 2. Ottervanger JP, Phaff RA, Vermeulen EG, Stricker BH. Anaphylaxis to omeprazole. J Allergy Clin Immunol 1996;97:1413-4. 3. Confino-Cohen R, Goldberg A. Anaphylaxis to omeprazole: diagnosis and desensitization protocol. Ann Allergy Asthma Immunol 2006;96:33-6. 4. Lobera T, Navarro B, Del Pozo MD, Gonzalez I, Blasco A, Escudero R, et al. Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors. J Invest Allergol Clin Immunol 2009;19:57-60. 5. Sobrevia Elfau MT, Garces Sotillos M, Ferrer Claverıa L, Segura Arazuri N, Monzon Ballarin S, Colas Sanz C. Study of cross-reactivity between proton pump inhibitors. J Invest Allergol Clin Immunol 2010;20:157-61. 6. Rerkattanapipat T, Chiriac AM, Demoly P. Drug provocation tests in hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol 2011;11:299-304. 7. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. J Allergy 1999;54:999-1003. 8. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977;1:466-9. 9. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002;57:45-51. 10. Garrido Fernandez S, Cumplido JA, Rabano A, Martınez D, Blanco C, Carrillo A. Allergy to proton pump inhibitors: diagnosis and assessment of cross-reactivity. J Invest Allergol Clin Immunol 2008;18:140-1. 11. Perez Pimiento AJ, Prieto Lastra L, Rodrıguez Cabreros MI, Gonzalez Sanchez LA, Mosquera MR, Cubero AG. Hypersensitivity to lansoprazole and rabeprazole with tolerance to other proton pump inhibitors. J Allergy Clin Immunol 2006;117: 707-8. Available online June 22, 2012. http://dx.doi.org/10.1016/j.jaci.2012.04.048
Organ-specific symptoms during oral food challenge in children with food allergy To the Editor: Food-allergic patients have been known to develop a heterogeneous pattern of clinical symptoms on food intake. Symptoms might be expressed via the skin, the gastrointestinal (GI) tract, the respiratory system, and/or the cardiovascular system.1 However, why and in which constellation these different organ systems are affected is not clear. Cow’s milk, hen’s egg, peanut, tree nuts, wheat, and soy are responsible for the majority of food-induced allergic reactions in young children2 with a rate of 2% to 6% in children in the first year of life.3 Oral food challenges (OFCs) are the gold standard in the diagnostic workup in patients with suspected food allergy.4 Based on this, our study aimed to analyze the distribution of clinical signs and symptoms on OFCs and to test whether this distribution is dependent on the tested food allergen. Here we report on a retrospective analysis of 1843 consecutive OFCs, which were performed for clinical purposes on children with 1 or more suspected food allergies based on their clinical history (Table I). For 880 OFCs a positive test outcome occurred. Clinical reactivity to pasteurized, whisked hen’s egg, pasteurized cow’s milk (3.5% fat content), wheat (gluten powder), soy milk, roasted peanut, and/or raw hazelnut was investigated by OFCs as described in detail previously.4 In brief, patients received allergen or placebo on 2 different days. A dietician performed randomization and preparation of the challenges. By plan, the
J ALLERGY CLIN IMMUNOL VOLUME 130, NUMBER 2
For comparison, lung tissue expressed relatively low levels of gap junction and desmosomes and some are fully not detectable (Fig 2, C). Normal human bronchial epithelial cells cultured in ALI expressed claudin-17 (P 5 .03) (Fig 2, A). In contrast, primary keratinocyte in ALI cultures expressed uniquely desmocollin-1 (P 5 .02) (Fig 2, D). Keratinocyte ALIs did not express any TJ proteins in addition to the common junctional proteins observed in skin biopsies and monolayer cultures (Fig 2, B). Detailed statistical analysis is shown in Table E1 (in the Online Repository available at www.jacionline.org). Our data demonstrate that monolayer cell cultures express a similar profile of junction molecules compared with ALI cultures, however, with relatively low levels. After apicobasal differentiation in ALIs, more junctional molecules are expressed (Fig 2). Interestingly, whole tissues expressed a much broader profile of junctional molecules. The main reason behind having additional junctional mRNAs appearing in the whole tissue of lung and skin can be that other cell types, such as endothelial cells, fibroblasts in both, and smooth muscle cells in the lung, are also expressing junctional molecules. ALIs represent here a more cell-type–specific junctional molecule expression pattern. After performing the detailed expression analyses of interepithelial barrier molecules, we realized that it is essential to study the TJs in a broader way. Although some are dominantly expressed, the determination of one or two junctional molecules, especially TJs, may not represent the whole picture. There are distinct and overlapping patterns of TJs and other cell-cell adhesion molecules expressed in the skin and lung epithelia, which implicate a highly regulated and complex pattern. Each cell type shows its own, unique expression profile reflecting its specialization related to its function within the organism. In addition, we have to take into account that TJs are not uniquely expressed in epithelial cells but are also found and regulated in other cells, especially in endothelium. Furthermore, other mesenchymal tissues also express them as recently observed in smooth muscle cells in asthma.9 The number of different junctional proteins, which are expressed, interact in multiple ways in every cell type to form appropriate cell-cell contacts and tissue integrity. Our data demonstrated here suggest that the picture of the junctional apparatus in each cell type and tissue is distinct, and the regulation of epithelial integrity might be more complex than being considered so far. Jeannette I. Kast, BSca Kerstin Wanke, MSca Michael B. Soyka, MDa,b Paulina Wawrzyniak, MSca Deniz Akdis, BSca K€ ulli Kingo, MD, PhDc,d Ana Rebane, PhDa,e Cezmi A. Akdis, MDa From athe Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland; bthe Department of Otolaryngology Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland; cthe Department of Dermatology, Tartu University Hospital, Tartu, Estonia; dthe Department of Physiology, Centre of
=
Molecular and Clinical Medicine, and eMolecular Pathology, Faculty of Medicine, University of Tartu, Tartu, Estonia. E-mail: [email protected]. The lab of C.A.A. was supported by the Christine K€uhne Center for Allergy Research and Education (CK-CARE), the Swiss National Science Foundation (grant no. 32132899), the Estonian Science Foundation (grant no. ESF8350), and SCIEX Programme NMS-CH. Disclosure of potential conflict of interest: M. B. Soyka receives research support from the Muller-Gieork Foundation and is employed by University Hospital & ENT Zurich. C. A. Akdis has received research support from Novartis, PREDICTA: European Commission’s Seventh Framework Programme No. 260895, the Swiss National Science Foundation, MeDALL: European Commission’s Seventh Framework Programme No. 261357, the Global Allergy and Asthma European Network, and the Christine K€uhne Center for Allergy Research and Education; has consulted for Actellion, Aventis, Stallergenes, and Allergopharma; is president of the European Academy of Allergy and Clinical Immunology; is a fellow and interest group member of the American Academy of Asthma, Allergy & Immunology; is a former committee member of the Global Allergy and Asthma European Network; and is director of the Christine K€uhne Center for Allergy Research and Education. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature 2008;454:445-54. 2. Akdis CA. Therapies for allergic inflammation: refining strategies to induce tolerance. Nature Med 2012;18:736-49. 3. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 2011;127:773-86, e1-7. 4. Xiao C, Puddicombe SM, Field S, Haywood J, Broughton-Head V, Puxeddu I, et al. Defective epithelial barrier function in asthma. J Allergy Clin Immunol 2011;128: 549-56, e1-12. 5. Furuse M. Molecular basis of the core structure of tight junctions. Cold Spring Harb Perspect Biol 2010;2:a002907. 6. Lal-Nag M, Morin PJ. The claudins. Genome Biol 2009;10:235. 7. Lin H, Li H, Cho HJ, Bian S, Roh HJ, Lee MK, et al. Air-liquid interface (ALI) culture of human bronchial epithelial cell monolayers as an in vitro model for airway drug transport studies. J Pharm Sci 2007;96:341-50. 8. Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, et al. Predicted expansion of the claudin multigene family. FEBS Lett 2011;585:606-12. 9. Fujita H, Chalubinski M, Rhyner C, Indermitte P, Meyer N, Ferstl R, et al. Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects. J Allergy Clin Immunol 2011;127:1612-21.e18. Available online June 15, 2012. http://dx.doi.org/10.1016/j.jaci.2012.04.044
Hypersensitivity to proton pump inhibitors: Diagnostic accuracy of skin tests compared to oral provocation test To the Editor: Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related gastrointestinal diseases because they reduce the gastric acid secretion by blocking the H1/K1-ATPase. PPIs include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. PPIs are generally well tolerated, and side effects occur in about 1% of the patients.1 Hypersensitvity reactions are also rare, but several reports have described anaphylaxis, urticaria, or asthma.2-5 The diagnosis of hypersensitivity to PPIs is difficult since PPIs are often used in combination with other drugs. The oral provocation test (OPT) remains a reasonable
junctions (C and D), and of junctional adaptor proteins (E and F). Lung tissue, n 5 5; skin tissue, n 5 4; NHBE ALI, n 5 4; KC ALI, n 5 4; NHBE monolayer, n 5 4; and KC monolayer, n 5 4, were investigated. Mean 6 SEM is displayed. CMLP, CXADR-like membrane protein (ASAM); JAM, junctional adhesion molecules; KC, keratinocyte; MAGI, membrane-associated guanylate kinase inverted; MUPP1, multi-PDZ domain containing protein 1; NHBE, normal human bronchial epithelial; PATJ, inaD-like protein (INADL); ZO, zonula occludens.
548 LETTERS TO THE EDITOR
J ALLERGY CLIN IMMUNOL AUGUST 2012
TABLE I. Characteristics of the studied population and results of the diagnostic tests
No. Sex (female/male) Age (y), range (mean) Suspected drug
Severity of reaction*
Skin prick (1/tested)
ID test (1/tested)
OPT (1/performed)
Whole population
Grade I and II patients
Grade III patients
53 42/11 19-81 (54) Esomeprazole n 5 16 Lansoprazole n 5 14 Omeprazole n 5 10 Pantoprazole n 5 11 Rabeprazole n 5 2 Grade I: 38 Grade II: 6 Grade III: 9 Esomeprazole: 1/53 Omeprazole: 1/53 Pantoprazole: 1/53 Lansoprazole: 4/23 Rabeprazole: 1/5 Esomeprazole: 4/53 Omeprazole: 5/53 Pantoprazole: 5/53
44 34/10 19-81 (53.8) Esomeprazole n 5 15 Lansoprazole n 5 11 Omeprazole n 5 10 Pantoprazole n 5 7 Rabeprazole n 5 1 Grade I 1 II: 38 1 6
9 8/1 40-74 (55.3) Esomeprazole n 5 1 Lansoprazole n 5 3 Omeprazole n 5 0 Pantoprazole n 5 4 Rabeprazole n 5 1 Grade III: 9
Esomeprazole: 0/44 Omeprazole: 0/44 Pantoprazole: 0/44 Lansoprazole: 2/20 Rabeprazole: 0/2 Esomeprazole: 2/44 Omeprazole: 1/44 Pantoprazole: 0/44
Esomeprazole: 1/9 Omeprazole: 1/9 Pantoprazole: 1/9 Lansoprazole: 2/3 Rabeprazole: 1/3 Esomeprazole: 2/9 Omeprazole: 4/9 Pantoprazole: 5/9
Esomeprazole: 3/13 Omeprazole: 0/9 Pantoprazole: 0/7 Lansoprazole: 3/11
Rabeprazole: 1/1
Esomeprazole: 3/13 Omeprazole: 0/9 Pantoprazole: 0/7 Lansoprazole: 3/11 Rabeprazole: 1/1
*Grade I: only pruritus or flush or urticaria/angioedema; grade II: nausea/cramping or rhinitis or dyspnea or cough or hypotension or arrhythmia (with/without grade I signs). Grade III: vomiting or defecation or cyanosis or bronchospasm or laryngeal edema or shock (with/without grade I signs) (see Ring and Messmer8).
approach to confirm hypersensitivity, but it is time-consuming and not devoid of risks.6 Thus, a reliable in vivo test to replace OPT would be desirable. Skin tests for PPIs have been described, but their accuracy is not defined.4,5 In this multicenter study, we compared the efficiency of skin tests with that of OPT in patients with immediate hypersensitivity reactions to PPIs. This study was conducted between 2008 and 2010 in 4 allergy units and was approved by local ethics committees. Only patients with a definite history of immediate reactions due to PPIs were enrolled. Patients reporting symptoms attributable to known side effects, or with nonimmediate reactions, or with reactions while taking concomitant drugs were excluded. Clinical data were recorded by using an adapted version of the European Network on Drug Allergy questionnaire.7 The severity of reactions was assessed by using the Ring-Messmer scale.8 Skin prick tests (SPTs) were performed in all patients with the undiluted commercial preparation (40 mg/mL) for omeprazole, esomeprazole, and pantoprazole. Solutions of rabeprazole (40 mg/mL) and lansoprazole (30 mg/mL) were prepared by dissolving the powder in saline. Intradermal tests (IDTs) were performed only with the injectable preparations of omeprazole, esomeprazole, and pantoprazole at 0.4 and 4 mg/mL. SPT results were read after 20 minutes and after 48 hours, and considered positive if a wheal of 3 mm or more _5 was observed at 20 minutes or if an erythematous induration (> mm) was observed on day 2. IDTs involved the injection of 0.03 mL of the solution, and the results were read after 20 minutes and 2 days. They were considered positive if the initial wheal increased by more than 3 mm and was surrounded by erythema after 20 minutes or if an induration appeared at 48 hours.9 Histamine (0.01%) and saline were the positive and negative controls. A single-blind, placebo-controlled OPT with the suspect PPI was performed in patients who gave their informed consent
after skin testing. On day 1, 4 talc capsules were given. On day 2, omeprazole or pantoprazole or esomeprazole or rabeprazole (5 mg, 5 mg, 10 mg, 20 mg), or lansoprazole (5, 10, 15 mg) was given at 30-minute intervals. Before starting, and after each dose, blood pressure, heart rate, oxygen saturation, and FEV1 were recorded. The test result was considered positive when clinical signs (urticaria, angioedema, rash) or 20% change in heart rate or oxygen saturation below 90% or 20% fall in FEV1 was documented. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios (LRs) were calculated for skin tests in comparison to OPT, considering those patients who completed the procedure. Positive likelihood ratio (LR1) was defined as sensitivity/ (1 2 specificity), and negative likelihood ratio (LR2) was defined as (1 2 sensitivity)/specificity. Difference in latency times was evaluated by using the Mann-Whitney test. Since there were 4 missing data for OPT among grade I and grade II patients, adjusted parameters were also calculated by using Begg-Greenes estimators under missing at random assumption. Fifty-three patients (42 women, 11 men, mean age 54 years, range 19-81 years) were studied, and 41 completed the procedure. Only 1 of 9 grade III patients accepted the OPT; thus, all subjects with grade III reactions were excluded from accuracy analysis, and the 12 patients (3 grade II) who refused OPT were not included in the calculations. The characteristics of patients are detailed in Table I. Skin test results (SPT and/or IDT) were positive in 12 of the 53 patients, and mostly in those with previous grade III reactions (7 of 9). Five of the 9 patients with grade III reactions had positive skin test results to multiple PPIs. The interval between the reaction and the diagnostic procedure was not different between patients with positive and negative skin test results (P 5 .1818).
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For esomeprazole, SPT results were positive in 1 of the 53 and IDT results in 4 of the 53 patients; for omeprazole and pantoprazole, 1 of the 53 patients had a positive result to SPTs and 5 of the 53 patients had a positive result to IDTs (Table I). SPT result with lansoprazole was positive in 4 and with rabeprazole in 1. Accuracy analysis was performed in patients with previous grade I and II reactions. Of the 44 patients with reactions of grades I and II, 40 underwent OPT. Of the 40 patients tested, 3 of 3 with skin test positivity and 3 of 37 patients with skin test negativity reacted to OPT. Therefore, among this population, unadjusted sensitivity was 50% and specificity was 100%. Adjusted sensitivity was 61.3% (CI 25.0%-87.5%), and adjusted specificity was 100.0% (CI 97.2%-100.0%). LR1 calculated by using adjusted sensitivity and specificity was 61.3 (assuming a specificity of 99.0%) while LR2 was 0.39. Positive predictive value was 100%, and negative predictive value was 91.9%. The diagnostic use of skin tests in patients with immediate PPI reactions has been sporadically described. For omeprazole, Lobera et al4 reported a skin test positivity in 8 of 9 patients and Sobrevia et al5 in 5 of 5 patients. In this study, we analyzed 53 patients with immediate reactions to PPIs and estimated the diagnostic performance of SPT and IDT versus OPT. In our population, skin test results were positive in 12 of the 53 patients; 4 of these patients underwent OPT with the suspected drug and the results were positive in all cases. In the 41 patients with a negative result, 3 had a positive OPT result with the suspected drug. We obtained good results with skin tests in terms of specificity (100%), positive predictive value (100%), and negative predictive value (91.9%), whereas the sensitivity was lower. These results were confirmed by a high LR1. In addition, we observed a higher frequency of skin test positivity in patients with more severe reactions. Concerning the cross-reactivity, we observed that patients with hypersensitivity to pantoprazole, confirmed by skin tests, also had positive skin test results to omeprazole (4 of 5 patients) and, more rarely, to esomeprazole. This result confirms previous reports10,11 and is probably due to the similar chemical structure of these PPIs. On the contrary, patients monosensitized to lansoprazole and rabeprazole, which have a different side chain, had negative test results with omeprazole, pantoprazole, and esomeprazole. This observation may have important clinical implications, as patients monosensitized to lansoprazole or rabeprazole would more likely tolerate other PPIs. Indeed, the small number of patients does not allow us to make final conclusions about cross-reactive patterns and requires further studies. In conclusion, this multicenter study suggests the usefulness of skin tests in patients with immediate hypersensitivity reactions to PPIs, because a positive skin test result allows one to avoid an oral provocation. Patrizia Bonadonna, MDa* Carla Lombardo, MDa* Oscar Bortolami, PhDb Andreas Bircher, MDc Kathrin Scherer, MDc Annick Barbaud, MDd Giovanni Passalacqua, MDe Mauro Pagani, MDf From athe Allergy Unit and bthe Research Support Unit and Biostatistics, Verona University Hospital, Verona, Italy; cthe Allergy Unit, Department of Dermatology, University Hospital, Basel, Switzerland; dthe Dermatology Department, Fournier Hospital, University Hospital of Nancy, Nancy, France; eAllergy and Respiratory Diseases, DIMI, University of Genoa, Genoa, Italy; and fthe Medical Department, Asola
Hospital, Azienda Ospedaliera C. Poma, Mantua, Italy. E-mail: patrizia.bonadonna@ ospedaleuniverona.it. *These authors contributed equally to this work. Disclosure of potential conflict of interest: A. Bircher serves on a board for Basilea, has consultant arrangements with ALK, and has received research support from Novartis. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol 2010;16:2323-30. 2. Ottervanger JP, Phaff RA, Vermeulen EG, Stricker BH. Anaphylaxis to omeprazole. J Allergy Clin Immunol 1996;97:1413-4. 3. Confino-Cohen R, Goldberg A. Anaphylaxis to omeprazole: diagnosis and desensitization protocol. Ann Allergy Asthma Immunol 2006;96:33-6. 4. Lobera T, Navarro B, Del Pozo MD, Gonzalez I, Blasco A, Escudero R, et al. Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors. J Invest Allergol Clin Immunol 2009;19:57-60. 5. Sobrevia Elfau MT, Garces Sotillos M, Ferrer Claverıa L, Segura Arazuri N, Monzon Ballarin S, Colas Sanz C. Study of cross-reactivity between proton pump inhibitors. J Invest Allergol Clin Immunol 2010;20:157-61. 6. Rerkattanapipat T, Chiriac AM, Demoly P. Drug provocation tests in hypersensitivity drug reactions. Curr Opin Allergy Clin Immunol 2011;11:299-304. 7. Demoly P, Kropf R, Bircher A, Pichler WJ. Drug hypersensitivity: questionnaire. EAACI interest group on drug hypersensitivity. J Allergy 1999;54:999-1003. 8. Ring J, Messmer K. Incidence and severity of anaphylactoid reactions to colloid volume substitutes. Lancet 1977;1:466-9. 9. Brockow K, Romano A, Blanca M, Ring J, Pichler W, Demoly P. General considerations for skin test procedures in the diagnosis of drug hypersensitivity. Allergy 2002;57:45-51. 10. Garrido Fernandez S, Cumplido JA, Rabano A, Martınez D, Blanco C, Carrillo A. Allergy to proton pump inhibitors: diagnosis and assessment of cross-reactivity. J Invest Allergol Clin Immunol 2008;18:140-1. 11. Perez Pimiento AJ, Prieto Lastra L, Rodrıguez Cabreros MI, Gonzalez Sanchez LA, Mosquera MR, Cubero AG. Hypersensitivity to lansoprazole and rabeprazole with tolerance to other proton pump inhibitors. J Allergy Clin Immunol 2006;117: 707-8. Available online June 22, 2012. http://dx.doi.org/10.1016/j.jaci.2012.04.048
Organ-specific symptoms during oral food challenge in children with food allergy To the Editor: Food-allergic patients have been known to develop a heterogeneous pattern of clinical symptoms on food intake. Symptoms might be expressed via the skin, the gastrointestinal (GI) tract, the respiratory system, and/or the cardiovascular system.1 However, why and in which constellation these different organ systems are affected is not clear. Cow’s milk, hen’s egg, peanut, tree nuts, wheat, and soy are responsible for the majority of food-induced allergic reactions in young children2 with a rate of 2% to 6% in children in the first year of life.3 Oral food challenges (OFCs) are the gold standard in the diagnostic workup in patients with suspected food allergy.4 Based on this, our study aimed to analyze the distribution of clinical signs and symptoms on OFCs and to test whether this distribution is dependent on the tested food allergen. Here we report on a retrospective analysis of 1843 consecutive OFCs, which were performed for clinical purposes on children with 1 or more suspected food allergies based on their clinical history (Table I). For 880 OFCs a positive test outcome occurred. Clinical reactivity to pasteurized, whisked hen’s egg, pasteurized cow’s milk (3.5% fat content), wheat (gluten powder), soy milk, roasted peanut, and/or raw hazelnut was investigated by OFCs as described in detail previously.4 In brief, patients received allergen or placebo on 2 different days. A dietician performed randomization and preparation of the challenges. By plan, the