- Email: [email protected]
Prevalence of blueberry allergy in a Turkish population
Letters / Ann Allergy Asthma Immunol 114 (2015) 250e260
basophils, 3 control individuals were included. The cells were gated initially based on the histogram defined by the forward and side scatters, and then a second gate of high fluorescein isothiocyanate CD123þ cells and low allophycocyanin HLA-DR was defined to select the basophil population, for an analysis of at least 500 basophils. The percentage of CD63eCD203c expression was defined as the percentage of basophils expressing more CD63eCD203c than the critical point located at 103 < < 104 on the histogram. This was determined by defining region M1 at histographic analysis. After incubation with the C wilfordii extract, the patient’s basophils showed upregulation from 3.1% (spontaneous CD63 expression) to 27.7% for 2 mg/mL of C wilfordii extract (Fig 1A), whereas the CD63 expression in basophils from the 3 healthy controls remained unchanged (<10%). For CD203c expression, a similar dose-dependent upregulation was seen (2.9%e10.5%; Fig 1B). The histographic data also are shown in Figure 1C and D. She had no gastrointestinal symptoms after she stopped taking C wilfordii, and visual findings at follow-up esophagogastroscopy were completely normal. In addition, repeated biopsy findings showed improved eosinophilic infiltrations (20e30/high-power field). This is the first reported case of EoE caused by C wilfordii usage and verified by BAT. We were able to diagnose EoE caused by C wilfordii using various lines of evidence. First, discontinuation followed by the rechallenge from her history suggested C wilfordii as the causative agent, which was the most important clue. Second, EoE was identified by typical findings at endoscopy and histology with improvement after discontinuation. Third, positive results from the intradermal test and BAT using C wilfordii extract showed the strongest evidence of immediate-type hypersensitivity caused by C wilfordii. The prevalence of EoE is increasing, but the cause and pathogenesis of EoE have not been identified clearly, and the cause has been difficult to detect.2 Recently, thymic stromal lymphopoietin and basophils have been considered involved mainly in the pathogenesis of EoE, distinct from an IgE-dependent mechanism.5,6 Currently, BAT has proved sensitive and specific for the diagnosis of immediate allergic reactions, including inhalant allergens, food allergens, hymenoptera venom, and natural rubber latex allergy.7,8
259
However, there are few reports on cases of EoE using BAT. This case is meaningful because it was verified by BAT using C wilfordii extract. We propose that BAT could be a useful additional cellular test, particularly for the diagnosis and identification of causative agents in EoE. In conclusion, we report a case of eosinophilic esophagitis caused by repeated use of C wilfordii, which was confirmed by history, endoscopic findings, histology, and BAT. Jee Youn Oh, MD* Kyung Hoon Min, MD, PhD* Hae-Sim Park, MD, PhDy Gyu-Young Hur, MD, PhD* *Department of Internal Medicine College of Medicine, Korea University y Department of Allergy and Clinical Immunology Ajou University School of Medicine Seoul, Korea [email protected]
References [1] Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3e20. [2] Carr S, Watson W. Eosinophilic esophagitis. Allergy Asthma Clin Immunol. 2011;7:S8. [3] Chang A, Kwak BY, Yi K, et al. The effect of herbal extract (EstroG-100) on pre-, peri- and post-menopausal women: a randomized double-blind, placebocontrolled study. Phytother Res. 2012;26:510e516. [4] Hur GY, Park HJ, Kim HA, et al. Identification of Dioscorea batatas (sanyak) allergen as an inhalant and oral allergen. J Korean Med Sci. 2008;23:72e76. [5] Ray K. Oesophagus: TSLPebasophil axis important in eosinophilic oesophagitis. Nat Rev Gastroenterol Hepatol. 2013;10:502. [6] Siracusa MC, Kim BS, Spergel JM, et al. Basophils and allergic inflammation. J Allergy Clin Immunol. 2013;132:789e801. [7] Boumiza R, Debard AL, Monneret G. The basophil activation test by flow cytometry: recent developments in clinical studies, standardization and emerging perspectives. Clin Mol Allergy. 2005;3:9. [8] Sturm GJ, Kranzelbinder B, Sturm EM, et al. The basophil activation test in the diagnosis of allergy: technical issues and critical factors. Allergy. 2009;64: 1319e1326.
Prevalence of blueberry allergy in a Turkish population Food allergies continue to be one of the health problems that are noticeably increasing throughout the world. In addition to an increased prevalence of allergies, the range of allergens is continually increasing.1 Allergic reactions to ingested food range from minor symptoms to life-threatening anaphylaxis. Blueberry is eaten more in the form of fresh fruit, jam, and marmalade in Turkey and throughout the world. It has been the subject of studies owing to its antioxidant properties.2 There has only been 1 reported case of blueberry allergy in the literature, which was a case reported from Germany.3 We evaluated blueberry allergy status in children in a community-based study of a region of Turkey where blueberries are most produced and consumed. In this cross-sectional study, 20,800 randomly selected 6- to 18-year-old urban schoolchildren were enrolled from the center and 4 districts of Rize, a city in the eastern Black Sea region of Turkey. The study was carried out in 4 phases. In phase 1, questionnaires were distributed to the children and collected after approximately 1 week. Of the children who reported an adverse reaction to blueberry, the following were Disclosure: The authors have declared that there is no conflict of interest.
invited for skin prick tests (SPTs) and prick-to-prick tests (PTPs): those who had any reaction after the consumption of blueberry and those who consented to participate in further evaluation. In phase 2, the children who agreed to participate and whose parents provided consent underwent SPTs and PTPs. In phase 3, all children with a positive PTP reaction to blueberry were invited for a doubleblinded placebo-controlled food challenge (DBPCFC). In phase 4, all children with a negative DBPCFC reaction were invited for an oral food challenge (OFC). All children with suspected IgE-mediated blueberry allergy who consented to participate were invited for SPTs and PTPs (PTP with fresh blueberry fruit) to blueberry and a predefined panel of allergens. The DBPCFC and OFC reactions were considered positive if a single or a combination of clinical reactions were noted, including cutaneous, nasal, ocular, bronchial, gastrointestinal, laryngeal, cardiovascular, and other symptoms. Children received a challenge with placebo or blueberry on 2 different days in a randomized order. The challenge meals were prepared in the form of pudding prepared with 20 g of flour and 20 g of fresh blueberry squash in 100 mL of cherry juice. Blueberry was masked with cherry juice. The placebo closely mimicked the food challenge portion in the form of pudding prepared without blueberry squash.
260
Letters / Ann Allergy Asthma Immunol 114 (2015) 250e260
Randomly selected n:20.800 Collected questionnaires n:15.783 Positive allergic history n:8 PTP (+) n:3 DBPCFC (+) n:1
Blueberry allergy n:1
DBPCFC (-) n:2 OFC (-) n:2
related to blueberry allergy. Only 1 case had consulted a physician for shortness of breath after the ingestion of some food with blueberry. However, the physician did not believe that it was related to the blueberry allergy. Almost all children were judged to have food allergy, but blueberry allergy was not considered in any of these cases. However, we suspected blueberry allergy from the detailed medical history of those 8 children. Then, we performed this study and confirmed the blueberry allergy in 1 case. The strengths of this study include a wide population, the inclusion of children with other allergies that were tested with SPTs, using PTPs for fresh fruit, and using the DBPCFC, which is the accepted gold standard. In conclusion, we emphasize that IgE-mediated allergy to blueberry, although rare, does exist. Therefore, when food allergy is suspected, blueberry allergy should be considered, especially in regions where it is consumed.
Acknowledgments Figure 1. Flowchart of the study.
The challenge and placebo portions were similar in appearance, smell, mouth feel, and taste. Of the 20,800 children, 15,783 (75.9%) returned a completed questionnaire. There were no significant differences among children in age and sex. History of blueberry allergy was positive in 8 children (6 female, 2 male). The prevalence of self-reported IgEmediated blueberry allergy was 0.00051% (95% confidence interval 0.00016e0.00086). These children with suspected blueberry allergy were recruited for the second phase of the study. Of the evaluations made, 3 of 8 subjects had a positive PTP reaction. Of the 3 subjects with a positive PTP reaction, 1 was found to have a positive DBPCFC reaction. The OFC was performed in 2 subjects with a negative DBPCFC reaction. The OFC reaction was negative in these cases (Fig 1). Blueberry allergy was found in only 1 case. Thus, the prevalence of DBPCFC-proven blueberry allergy was 0.0000634% (95% confidence interval 0e0.001877). The subject whose DBPCFC reaction was positive was a 14-year-old girl who had complaints of shortness of breath and itching on the back, which started 15 to 30 minutes after eating blueberries. Also, her medical history included bronchial asthma, allergic rhinitis, and atopic dermatitis. There was a family history of atopy, the mother and father had asthma, and 1 of the siblings had atopic dermatitis. Estimates of the prevalence of food intolerance vary widely, from 2% to more than 20% of the population.4 Food allergies affect more than 1% or 2% but fewer than 10% of the US population.5 However, there are very few study results that have been confirmed with the use of OFCs. Rates of confirmed food allergy have been reported as 1.0% to 5%.6,7 In multicenter studies in Turkey using DBPCFCs, the prevalence of food allergy has been reported as 0.16 0.11% by Mustafayev et al8 and 0.15% by Kaya et al.9 In studies of worldwide prevalence, different prevalences have been reported, such as 1% by Pereira et al6 and 5% by Roehr et al.7 The difference in the frequency of food allergy can be explained by cultural and traditional nutrition habits, environmental factors, and possibly genetics.10 To the best of our knowledge, this is the first study to investigate blueberry allergy on an extensive community basis. The DBPCFC-proven prevalence of blueberry allergy was found to be 0.0000634% in our study. It is noteworthy that this prevalence is much lower than that of other food allergies. Of the 8 children reported by their parents to have blueberry allergy, none had been admitted to any emergency department because of symptoms
The authors thank Hikmet Orhan for statistical analysis and Caroline J. Walker for English-language editing. Selim Dereci, MD* Fazil Orhan, MDy Tugba Koca, MD* Mustafa Akcam, MD* *Division of Pediatric Gastroenterology, Hepatology and Nutrition Department of Pediatrics Faculty of Medicine Suleyman Demirel University Isparta, Turkey y Division of Pediatric Allergy Department of Pediatrics Faculty of Medicine Karadeniz Technical University Trabzon, Turkey [email protected]
References [1] Prescott SL, Pawankar R, Allen KJ, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6:21. [2] Huang WY, Zhang HC, Liu WX, Li CY. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. 2012;13:94e102. [3] Gebhardt C, Vieths S, Gubesch M, Averbeck M, Simon JC, Treudler R. 10 kDa lipid transfer protein: the main allergenic structure in a German patient with anaphylaxis to blueberry. Allergy. 2009;64:498e499. [4] Nelson M, Ogden J. An exploration of food intolerance in the primary care setting: the general practitioner’s experience. Soc Sci Med. 2008;67: 1038e1045. [5] Chafen JJ, Newberry SJ, Riedl MA, et al. Diagnosing and managing common food allergies: a systematic review. JAMA. 2010;303:1848e1856. [6] Pereira B, Venter C, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of sensitization to food allergens, reported adverse reaction to food. Food avoidance and food hypersensitivity among teenagers. J Allergy Clin Immunol. 2005;116:884e892. [7] Roehr CC, Edenharter G, Reimann S, et al. Food allergy and non-allergic food hypersensitivity in children and adolescents. Clin Exp Allergy. 2004;34: 1534e1541. [8] Mustafayev R, Civelek E, Orhan F, Yuksel H, Boz AB, Sekerel BE. Similar prevalence, different spectrum: IgE-mediated food allergy among Turkish adolescents. Allergol Immunopathol (Madr). 2013;41:387e396. lu M, Civelek E, Cakır B, Kocabas CN. Prevalence of confirmed [9] Kaya A, Erkocog IgE-mediated food allergy among adolescents in Turkey. Pediatr Allergy Immunol. 2013;24:456e462. [10] Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol. 2008;121: 1331e1336.
basophils, 3 control individuals were included. The cells were gated initially based on the histogram defined by the forward and side scatters, and then a second gate of high fluorescein isothiocyanate CD123þ cells and low allophycocyanin HLA-DR was defined to select the basophil population, for an analysis of at least 500 basophils. The percentage of CD63eCD203c expression was defined as the percentage of basophils expressing more CD63eCD203c than the critical point located at 103 < < 104 on the histogram. This was determined by defining region M1 at histographic analysis. After incubation with the C wilfordii extract, the patient’s basophils showed upregulation from 3.1% (spontaneous CD63 expression) to 27.7% for 2 mg/mL of C wilfordii extract (Fig 1A), whereas the CD63 expression in basophils from the 3 healthy controls remained unchanged (<10%). For CD203c expression, a similar dose-dependent upregulation was seen (2.9%e10.5%; Fig 1B). The histographic data also are shown in Figure 1C and D. She had no gastrointestinal symptoms after she stopped taking C wilfordii, and visual findings at follow-up esophagogastroscopy were completely normal. In addition, repeated biopsy findings showed improved eosinophilic infiltrations (20e30/high-power field). This is the first reported case of EoE caused by C wilfordii usage and verified by BAT. We were able to diagnose EoE caused by C wilfordii using various lines of evidence. First, discontinuation followed by the rechallenge from her history suggested C wilfordii as the causative agent, which was the most important clue. Second, EoE was identified by typical findings at endoscopy and histology with improvement after discontinuation. Third, positive results from the intradermal test and BAT using C wilfordii extract showed the strongest evidence of immediate-type hypersensitivity caused by C wilfordii. The prevalence of EoE is increasing, but the cause and pathogenesis of EoE have not been identified clearly, and the cause has been difficult to detect.2 Recently, thymic stromal lymphopoietin and basophils have been considered involved mainly in the pathogenesis of EoE, distinct from an IgE-dependent mechanism.5,6 Currently, BAT has proved sensitive and specific for the diagnosis of immediate allergic reactions, including inhalant allergens, food allergens, hymenoptera venom, and natural rubber latex allergy.7,8
259
However, there are few reports on cases of EoE using BAT. This case is meaningful because it was verified by BAT using C wilfordii extract. We propose that BAT could be a useful additional cellular test, particularly for the diagnosis and identification of causative agents in EoE. In conclusion, we report a case of eosinophilic esophagitis caused by repeated use of C wilfordii, which was confirmed by history, endoscopic findings, histology, and BAT. Jee Youn Oh, MD* Kyung Hoon Min, MD, PhD* Hae-Sim Park, MD, PhDy Gyu-Young Hur, MD, PhD* *Department of Internal Medicine College of Medicine, Korea University y Department of Allergy and Clinical Immunology Ajou University School of Medicine Seoul, Korea [email protected]
References [1] Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis: updated consensus recommendations for children and adults. J Allergy Clin Immunol. 2011;128:3e20. [2] Carr S, Watson W. Eosinophilic esophagitis. Allergy Asthma Clin Immunol. 2011;7:S8. [3] Chang A, Kwak BY, Yi K, et al. The effect of herbal extract (EstroG-100) on pre-, peri- and post-menopausal women: a randomized double-blind, placebocontrolled study. Phytother Res. 2012;26:510e516. [4] Hur GY, Park HJ, Kim HA, et al. Identification of Dioscorea batatas (sanyak) allergen as an inhalant and oral allergen. J Korean Med Sci. 2008;23:72e76. [5] Ray K. Oesophagus: TSLPebasophil axis important in eosinophilic oesophagitis. Nat Rev Gastroenterol Hepatol. 2013;10:502. [6] Siracusa MC, Kim BS, Spergel JM, et al. Basophils and allergic inflammation. J Allergy Clin Immunol. 2013;132:789e801. [7] Boumiza R, Debard AL, Monneret G. The basophil activation test by flow cytometry: recent developments in clinical studies, standardization and emerging perspectives. Clin Mol Allergy. 2005;3:9. [8] Sturm GJ, Kranzelbinder B, Sturm EM, et al. The basophil activation test in the diagnosis of allergy: technical issues and critical factors. Allergy. 2009;64: 1319e1326.
Prevalence of blueberry allergy in a Turkish population Food allergies continue to be one of the health problems that are noticeably increasing throughout the world. In addition to an increased prevalence of allergies, the range of allergens is continually increasing.1 Allergic reactions to ingested food range from minor symptoms to life-threatening anaphylaxis. Blueberry is eaten more in the form of fresh fruit, jam, and marmalade in Turkey and throughout the world. It has been the subject of studies owing to its antioxidant properties.2 There has only been 1 reported case of blueberry allergy in the literature, which was a case reported from Germany.3 We evaluated blueberry allergy status in children in a community-based study of a region of Turkey where blueberries are most produced and consumed. In this cross-sectional study, 20,800 randomly selected 6- to 18-year-old urban schoolchildren were enrolled from the center and 4 districts of Rize, a city in the eastern Black Sea region of Turkey. The study was carried out in 4 phases. In phase 1, questionnaires were distributed to the children and collected after approximately 1 week. Of the children who reported an adverse reaction to blueberry, the following were Disclosure: The authors have declared that there is no conflict of interest.
invited for skin prick tests (SPTs) and prick-to-prick tests (PTPs): those who had any reaction after the consumption of blueberry and those who consented to participate in further evaluation. In phase 2, the children who agreed to participate and whose parents provided consent underwent SPTs and PTPs. In phase 3, all children with a positive PTP reaction to blueberry were invited for a doubleblinded placebo-controlled food challenge (DBPCFC). In phase 4, all children with a negative DBPCFC reaction were invited for an oral food challenge (OFC). All children with suspected IgE-mediated blueberry allergy who consented to participate were invited for SPTs and PTPs (PTP with fresh blueberry fruit) to blueberry and a predefined panel of allergens. The DBPCFC and OFC reactions were considered positive if a single or a combination of clinical reactions were noted, including cutaneous, nasal, ocular, bronchial, gastrointestinal, laryngeal, cardiovascular, and other symptoms. Children received a challenge with placebo or blueberry on 2 different days in a randomized order. The challenge meals were prepared in the form of pudding prepared with 20 g of flour and 20 g of fresh blueberry squash in 100 mL of cherry juice. Blueberry was masked with cherry juice. The placebo closely mimicked the food challenge portion in the form of pudding prepared without blueberry squash.
260
Letters / Ann Allergy Asthma Immunol 114 (2015) 250e260
Randomly selected n:20.800 Collected questionnaires n:15.783 Positive allergic history n:8 PTP (+) n:3 DBPCFC (+) n:1
Blueberry allergy n:1
DBPCFC (-) n:2 OFC (-) n:2
related to blueberry allergy. Only 1 case had consulted a physician for shortness of breath after the ingestion of some food with blueberry. However, the physician did not believe that it was related to the blueberry allergy. Almost all children were judged to have food allergy, but blueberry allergy was not considered in any of these cases. However, we suspected blueberry allergy from the detailed medical history of those 8 children. Then, we performed this study and confirmed the blueberry allergy in 1 case. The strengths of this study include a wide population, the inclusion of children with other allergies that were tested with SPTs, using PTPs for fresh fruit, and using the DBPCFC, which is the accepted gold standard. In conclusion, we emphasize that IgE-mediated allergy to blueberry, although rare, does exist. Therefore, when food allergy is suspected, blueberry allergy should be considered, especially in regions where it is consumed.
Acknowledgments Figure 1. Flowchart of the study.
The challenge and placebo portions were similar in appearance, smell, mouth feel, and taste. Of the 20,800 children, 15,783 (75.9%) returned a completed questionnaire. There were no significant differences among children in age and sex. History of blueberry allergy was positive in 8 children (6 female, 2 male). The prevalence of self-reported IgEmediated blueberry allergy was 0.00051% (95% confidence interval 0.00016e0.00086). These children with suspected blueberry allergy were recruited for the second phase of the study. Of the evaluations made, 3 of 8 subjects had a positive PTP reaction. Of the 3 subjects with a positive PTP reaction, 1 was found to have a positive DBPCFC reaction. The OFC was performed in 2 subjects with a negative DBPCFC reaction. The OFC reaction was negative in these cases (Fig 1). Blueberry allergy was found in only 1 case. Thus, the prevalence of DBPCFC-proven blueberry allergy was 0.0000634% (95% confidence interval 0e0.001877). The subject whose DBPCFC reaction was positive was a 14-year-old girl who had complaints of shortness of breath and itching on the back, which started 15 to 30 minutes after eating blueberries. Also, her medical history included bronchial asthma, allergic rhinitis, and atopic dermatitis. There was a family history of atopy, the mother and father had asthma, and 1 of the siblings had atopic dermatitis. Estimates of the prevalence of food intolerance vary widely, from 2% to more than 20% of the population.4 Food allergies affect more than 1% or 2% but fewer than 10% of the US population.5 However, there are very few study results that have been confirmed with the use of OFCs. Rates of confirmed food allergy have been reported as 1.0% to 5%.6,7 In multicenter studies in Turkey using DBPCFCs, the prevalence of food allergy has been reported as 0.16 0.11% by Mustafayev et al8 and 0.15% by Kaya et al.9 In studies of worldwide prevalence, different prevalences have been reported, such as 1% by Pereira et al6 and 5% by Roehr et al.7 The difference in the frequency of food allergy can be explained by cultural and traditional nutrition habits, environmental factors, and possibly genetics.10 To the best of our knowledge, this is the first study to investigate blueberry allergy on an extensive community basis. The DBPCFC-proven prevalence of blueberry allergy was found to be 0.0000634% in our study. It is noteworthy that this prevalence is much lower than that of other food allergies. Of the 8 children reported by their parents to have blueberry allergy, none had been admitted to any emergency department because of symptoms
The authors thank Hikmet Orhan for statistical analysis and Caroline J. Walker for English-language editing. Selim Dereci, MD* Fazil Orhan, MDy Tugba Koca, MD* Mustafa Akcam, MD* *Division of Pediatric Gastroenterology, Hepatology and Nutrition Department of Pediatrics Faculty of Medicine Suleyman Demirel University Isparta, Turkey y Division of Pediatric Allergy Department of Pediatrics Faculty of Medicine Karadeniz Technical University Trabzon, Turkey [email protected]
References [1] Prescott SL, Pawankar R, Allen KJ, et al. A global survey of changing patterns of food allergy burden in children. World Allergy Organ J. 2013;6:21. [2] Huang WY, Zhang HC, Liu WX, Li CY. Survey of antioxidant capacity and phenolic composition of blueberry, blackberry, and strawberry in Nanjing. J Zhejiang Univ Sci B. 2012;13:94e102. [3] Gebhardt C, Vieths S, Gubesch M, Averbeck M, Simon JC, Treudler R. 10 kDa lipid transfer protein: the main allergenic structure in a German patient with anaphylaxis to blueberry. Allergy. 2009;64:498e499. [4] Nelson M, Ogden J. An exploration of food intolerance in the primary care setting: the general practitioner’s experience. Soc Sci Med. 2008;67: 1038e1045. [5] Chafen JJ, Newberry SJ, Riedl MA, et al. Diagnosing and managing common food allergies: a systematic review. JAMA. 2010;303:1848e1856. [6] Pereira B, Venter C, Grundy J, Clayton CB, Arshad SH, Dean T. Prevalence of sensitization to food allergens, reported adverse reaction to food. Food avoidance and food hypersensitivity among teenagers. J Allergy Clin Immunol. 2005;116:884e892. [7] Roehr CC, Edenharter G, Reimann S, et al. Food allergy and non-allergic food hypersensitivity in children and adolescents. Clin Exp Allergy. 2004;34: 1534e1541. [8] Mustafayev R, Civelek E, Orhan F, Yuksel H, Boz AB, Sekerel BE. Similar prevalence, different spectrum: IgE-mediated food allergy among Turkish adolescents. Allergol Immunopathol (Madr). 2013;41:387e396. lu M, Civelek E, Cakır B, Kocabas CN. Prevalence of confirmed [9] Kaya A, Erkocog IgE-mediated food allergy among adolescents in Turkey. Pediatr Allergy Immunol. 2013;24:456e462. [10] Lack G. Epidemiologic risks for food allergy. J Allergy Clin Immunol. 2008;121: 1331e1336.