Peanut allergy: Clinical and immunologic differences among patients from 3 different geographic regions

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1 Original articles Peanut allergy: Clinical and immunologic differences among patients from 3 different geographic regions Andrea Vereda, MD, PhD, a,b,c * Marianne van Hage, MD, PhD, d,e * Staffan Ahlstedt, PhD, e,f Maria Dolores Iba~nez, MD, PhD, c Javier Cuesta-Herranz, MD, PhD, b Jenny van Odijk, PhD, g Magnus Wickman, MD, PhD, e,f,h and Hugh A. Sampson, MD a New York, NY, Stockholm and Gothenburg, Sweden, and Madrid, Spain Background: Peanut allergy affects persons from various geographic regions where populations are exposed to different dietary habits and environmental pollens. Objective: We sought to describe the clinical and immunologic characteristics of patients with peanut allergy from 3 countries (Spain, the United States, and Sweden) using a molecular component diagnostic approach. Methods: Patients with peanut allergy from Madrid (Spain, n 5 50), New York (United States, n 5 30), Gothenburg, and Stockholm (both Sweden, n 5 35) were enrolled. Clinical data were obtained either from a specific questionnaire or gathered from chart reviews. IgE antibodies to peanut extract and the peanut allergens rara h 1, 2, 3, 8 and 9, as well as to cross-reactive birch (rbet v 1) and grass (rphl p 1, 5, 7, and 12) pollen allergens, were analyzed. Results: American patients frequently had IgE antibodies to rara h 1 to 3 (56.7% to 90.0%) and often presented with severe symptoms. Spanish patients recognized these 3 recombinant peanut allergens less frequently (16.0% to 42.0%), were more From a the Department of Pediatric Allergy, Mount Sinai School of Medicine, New York; b Servicio de Alergia, Fundacion Jimenez Dıaz, Madrid; c Allergy Service, Hospital Infantil Universitario Ni~no Jesus, Madrid; d the Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet and University Hospital, Stockholm; e the Center for Allergy Research, Karolinska Institutet, Stockholm; f the Institute of Environmental Medicine, Karolinska Institutet, Stockholm; g the Department of Respiratory Medicine and Allergy, Sahlgrenska University Hospital, Gothenburg; and h the Department of Paediatrics, Sachs Children s Hospital, Stockholm. *These authors contributed equally to this work. Supported by a Long-term Fellowship from World Allergy Organization, the Swedish Research Council, the Stockholm County Council, the Swedish Asthma and Allergy Association s Research Foundation, the King Gustaf V 80th Birthday Foundation, the Swedish Heart-Lung Foundation, the Hesselman s Foundation and the Centre for Allergy Research at Karolinska Institute, and the Food Allergy Initiative. Disclosure of potential conflict of interest: A. Vereda receives a fellowship from the World Allergy Organization. M. van Hage receives research support from the Swedish Research Council, the Stockholm County Council, and the Swedish Asthma and Allergy Association s Research Foundation. M. Wickman serves as a lecturer for Phadia. H. A. Sampson is a consultant for and 4% shareholder of Allertein Pharmaceuticals, LLC; receives research support from the Food Allergy Initiative and the National Institute of Allergy and Infectious Diseases/National Institutes of Health; serves as a consultant/scientific advisor for the Food Allergy Initiative; has served as president of the American Academy of Allergy, Asthma & Immunology; and is 45% owner of Herbal Springs, LLC. The rest of the authors have declared that they have no conflict of interest. Received for publication February 12, 2010; revised August 26, 2010; accepted for publication September 9, Available online November 18, Reprint requests: Marianne van Hage, MD, PhD, Department of Medicine, Clinical Immunology and Allergy Unit, L2:04, Karolinska University, Hospital Solna, SE Stockholm, Sweden. marianne.van.hage@ki.se /$36.00 Ó 2010 American Academy of Allergy, Asthma & Immunology doi: /j.jaci often sensitized to the lipid transfer protein rara h 9 (60.0%), and typically had peanut allergy after becoming allergic to other plant-derived foods. Swedish patients detected rara h 1 to 3 more frequently than Spanish patients (37.1% to 74.3%) and had the highest sensitization rate to the Bet v 1 homologue rara h 8 (65.7%), as well as to rbet v 1 (82.9%). Spanish and Swedish patients became allergic to peanut at 2 years or later, whereas the American children became allergic around 1 year of age. Conclusions: Peanut allergy has different clinical and immunologic patterns in different areas of the world. Allergen component diagnostics might help us to better understand this complex entity. (J Allergy Clin Immunol 2011;127:603-7.) Key words: Peanut allergy, rara h 1, rara h 2, rara h 3, rara h 8, rara h 9, clinical features, molecular diagnosis Food allergy is a worldwide health problem, and peanut is one of the most allergenic vegetable foods. The prevalence of peanut allergy has increased and varies between 0.5% and 1.5%. 1,2 The reactions can present early in life and range from mild oral allergy syndrome to anaphylactic reactions. 3 Many studies have been conducted to better understand the clinical and immunologic reactivity to peanuts. These reports often focus on patients with peanut allergy with severe and even fatal reactions. As clinicians, we often treat patients who do not appear to fit into that subset of patients. We hypothesized that peanut allergy is a heterogeneous disorder and that differences are not only epidemiologic or clinical but also have a molecular basis, probably because of sensitization from different pollen exposures and culinary traditions. The identification and characterization of allergenic components in peanut have broadened our knowledge of peanut allergy. The major peanut allergens are Ara h 1 to 3 and belong to the seed storage proteins of the vicilin, conglutin, and glycinin families, respectively. 4 Ara h 4 is a member of the glycinin family 4 and is considered to be the same allergen as Ara h 3. Ara h 5 belongs to the profilin family. The conglutins Ara h 6 and 7 are very similar to Ara h 2. Ara h 8 is a Bet v 1 homolog and was shown to be a major allergen in patients with combined birch pollen and peanut allergy. 5,6 The lipid transfer protein (LTP) Ara h 9 has been reported to be an important allergen in patients with peanut allergy from the Mediterranean area. 7,8 Other molecules that have been investigated are the oleosins Ara h 10 and 11. The clinical relevance of the latter components is still unclear. Pollen allergy has been associated with plant-derived food allergy (ie, the pollen-food syndrome or oral allergy syndrome). 9,10 The relationship between pollen and vegetable or fruit allergies is due to cross-reactivity between homologous proteins, 603

2 604 VEREDA ET AL J ALLERGY CLIN IMMUNOL MARCH 2011 Abbreviation used LTP: Lipid transfer protein such as the Bet v 1 homologous PR-10 proteins (eg, Bet v 1 from Betula species, birch, Ara h 8 from peanut, and Mal d 1 from apple), profilins (Phl p 12 from Phleum species, Ara h 5 from peanut, and Bet v 2 from Betula species), and LTPs (eg, Ara h 9 from peanut, Cor a 8 from hazelnut, and Pru p 3 from peach). In this study we sought to investigate whether peanut allergy has a different molecular basis in different geographic regions, probably because of different pollen exposures and dietary traditions. Patients with challenge-proved or convincing histories of peanut allergy from 3 different countries (Spain, the United States, and Sweden) with low, intermediate, or high grass or birch pollen exposure were included, and their reactions to peanut, as well as their history of atopic diseases, were investigated. Quantification of peanut-specific IgE levels, both to peanut extract and to 5 recombinant peanut allergens (rara h 1-3, 8, and 9), was performed in all study subjects. To further characterize the IgE antibody responses, in vitro analyses were done with a panel of recombinant birch and grass pollen allergens: the major birch pollen allergen Bet v 1; the major timothy grass pollen allergens Phl p 1 and Phl p 5, as well as Phl p 7, a polcalcine responsible for cross-reactivity with other pollens, and Phl p 12, a profilin responsible for broad cross-reactivity between pollens and plant-derived fruits, covering the most important pollen sources from the 3 different regions. METHODS Study population A total of 115 patients with peanut allergy from 3 different countries with different flora participated in the study: Spain (n 5 50; Fundacion Jimenez Diaz Hospital and Ni~no Jesus Hospital, Madrid), the United States (n 5 30; Mount Sinai Pediatric Allergy Clinic, New York), and Sweden (n 5 35; Sahlgrenska University Hospital, Gothenburg, and selected from BAMSE birth cohort, Stockholm). Patients were determined to have peanut allergy if they had a positive food challenge result to peanut or a convincing history of acute reaction after peanut ingestion and detectable peanut-specific IgE. Double-blind, placebo-controlled peanut challenges were performed in subjects with unclear clinical histories. In Spain (Madrid) 50 patients were recruited from 2 allergy clinics during All patients with a clear diagnosis of peanut allergy were invited to participate in order of appearance. In the United States (New York) 30 serum samples from patients with peanut allergy were randomly selected from a repository of patients with food allergy evaluated and confirmed as having food allergy in the Mount Sinai Pediatric Allergy Clinic during In Sweden the patients were recruited from a patient group attending the Allergy Clinic at the Sahlgrenska University Hospital (Gothenburg) with typical signs of peanut allergy or with strongly suspected peanut allergy during ; these patients are representative of the group of patients seen at the allergy clinic. The other Swedish patients were recruited from the population-based BAMSE birth cohort (Stockholm). These children were selected based on parent-reported symptoms of peanut allergy at the 8-year follow-up ( ) and are representative of the cohort in general. Clinical information was retrospectively gathered either through the administration of a questionnaire or chart review. This information included a detailed clinical history, including age of onset of the peanut allergy, characteristics of the reaction, treatment used for the reaction, visits to the emergency department, other plant-related food allergies, pollen allergy, and any history of personal or family atopic diseases. Allergen-specific IgE Allergen-specific IgE was measured with the ImmunoCAP System FEIA (Phadia AB, Uppsala, Sweden). Venous blood samples were analyzed for IgE to peanut, as well as to rara h1, rara h 2, rara h 3, rara h 8 and rara h 9, rbet v 1, Phleum pratense whole extract, rphl p 1 and 5, and rphl p 7 and 12. The assay had a lower detection limit of 0.35 ku A /L and an upper limit of 100 ku A /L, with higher values reported as greater than 100 ku A /L. Ethical consent The studies were approved by local institutional review boards. Statistical analysis For statistical analysis, patients were grouped based on their country of recruitment. In addition, other variables, such as age, pollen allergy, age of peanut allergy onset, type of reactions with peanut, or allergen sensitization, were also considered. Quantitative variables, such as specific IgE concentrations or age, were compared with the Mann-Whitney U test because they were not normally distributed. The frequencies of asthma, allergic rhinitis, other food allergies, and other qualitative variables were compared by using the x 2 and Fisher exact tests. Quantitative variables were summarized and displayed with their medians and interquartile ranges. The qualitative variables were expressed as a percentage (without taking into account the missing cases). The Spearman rank correlation analysis was performed to determine correlation coefficients. The statistical program SPSS 12.0 for Windows (SPSS, Inc, Chicago, Ill) was used for analysis. RESULTS Participants characteristics Fifty-nine (51.3%) patients were female. The Swedish subjects were the oldest (P <.01) and the Americans were the youngest compared with patients from the other 2 countries (both P <.05; Table I). The frequency of atopic (family and personal) history was similar in the 3 countries. Most of the patients enrolled had personal histories of allergic rhinitis (77.1%), asthma (69.7%), and atopic dermatitis (61.0%). All patients had a clear IgE-mediated allergic reaction after eating peanut, as well as a positive IgE level to peanut (according to the inclusion criteria). The Spanish patients had the lowest peanut-specific IgE levels (P <.05), followed by the Swedish subjects (Table II). Sensitization to peanut allergens The American patients had the highest frequency of sensitization to rara h 1, rara h 2, and rara h 3 and the highest IgE levels to rara h 1 and rara h 2 (Table II). The differences between American and Swedish patients with respect to the IgE levels to rara h 1, rara h 2, and rara h 3 IgE were not statistically significant. However, there were significant differences between the Spanish patients and the other 2 groups: Spanish patients were less often sensitized to rara h 1, rara h 2, and rara h 3 (all P <.05) than either American or Swedish patients. Moreover, the IgE levels to rara h 2 were lower in Spanish patients than in American or Swedish subjects (both P <.05), and the IgE levels to rara h 3 were lower in Spanish than in Swedish patients (P <.05 and not statistically significant between Spanish and American patients). Nearly two thirds of the Spanish patients were sensitized to rara h 9 in contrast to only 7.7% of American and 14.3% of Swedish patients (P <.001). The Swedish patients had the highest sensitization rate to rara h 8 compared with the American and Spanish patients (both

3 J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 3 VEREDA ET AL 605 TABLE I. Characteristics of the patients with peanut allergy enrolled in the study Female sex (%) Current age (y), median (Q 1 -Q 3 ) 10.0 ( ) 5.5 ( ) 15.0 ( ) 11.0 ( ) Age of peanut allergy onset (y), median (Q 1 -Q 3 ) 4.0 ( ) 1.4 ( ) 4.0 ( ) 3.0 ( ) Patients with peanut allergy onset >4 y old (%) NA Patients with peanut allergy onset >10 y old (%) NA Patients with pollen allergy (%) Patients with exclusively oral symptoms with peanut (%) Patients who became allergic to peanut after being allergic to other plant-derived foods (%) NA NA NA, Not available; Q 1 -Q 3, interquartile range. TABLE II. Proportion of patients with IgE antibody reactivity to different peanut allergens and allergen-specific IgE levels Peanut-specific IgE (ku A /L), median (Q 1 -Q 3 ) 4.2 ( ) 36.8 ( ) 15.0 ( ) 8.0 ( ) rara h 1 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 4.2 ( ) 23.5 ( ) 6.9 ( ) 7.4 ( ) rara h 2 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 2.4 ( ) 23.4 ( ) 17.3 ( ) 13.3 ( ) rara h 3 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 3.6 ( ) 11.4 ( ) 12.0 ( ) 8.3 ( ) rara h 8 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 1.8 ( ) 1.5 ( ) 2.6 ( ) 1.9 ( ) rara h 9 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 7.1 ( ) 4.3 ( ) 0.8 ( ) 2.9 ( ) Q 1 -Q 3, Interquartile range. P <.01), but the IgE levels to rara h 8 were not statistically different between the countries. A comparison of the number of peanut allergens (rara h 1, rara h 2, rara h 3, rara h 8, and Ara h 9) recognized by the study subjects (range, 0-5) is shown in Table III. Here again, differences among the countries were found. Swedish patients were sensitized to 1, 2, 3, or 4 allergens in equal proportions (20.0% to 25.7%) in comparison with the Americans (56.7% recognized 3 allergens) and the Spanish (54.0% recognized only 1 allergen). Of the 38 subjects monosensitized to one of the studied peanut allergens (Table IV), differences could be found between countries. Thus most of the monosensitized patients were found among the Spanish patients (27/38), who were primarily sensitized to rara h 9 (18/27). Of the 7 Swedish monosensitized subjects, 4 had IgE to rara h 8. Symptoms to peanut American patients became allergic to peanut at a younger age than the other 2 groups (both P <.0001, Table I). One fourth of the Spanish patients became allergic to peanut at 10 years of age or older. There were no differences in the median age of onset between Spanish and Swedish patients. The American patients presented the lowest rate of isolated oral symptoms to peanut (10.0% vs 14.3% in Sweden and 19.4% in Spain [not statistically significant], Table I). Although not statistically significant, the American and Spanish patients tended to present with more severe symptoms to peanut than the Swedish patients (18 American and 15 Spanish patients had an anaphylactic reaction in comparison with 1 Swedish patient). Furthermore, in comparison with the Spanish patients, the American patients reported a higher frequency of anaphylaxis caused by peanut (62.1% vs 41.7%, not statistically significant), use of epinephrine (50.0% vs 24.2%, not statistically significant), and visits to the emergency department after peanut ingestion (64.3% vs 48.6%, not statistically significant). Pollen allergy Almost two thirds of all subjects had pollen allergy (Table I) and symptoms of rhinoconjunctivitis; 53.6% of these patients also presented with pollen-related asthma. The Swedish patients were more frequently sensitized to birch pollen than the Spanish patients (P <.05), whereas this did not reach significance compared with the American patients. The Swedish patients also had the highest sensitization rate to rbet v 1 (82.9%) in comparison with the Spanish patients (only 3 patients had specific IgE to rbet v 1), and their levels were higher (both P <.05. Table V). In total, 29 of 115 patients had IgE to both rbet v 1 and rara h 8, of whom 23 were Swedish, 5 were American, and 1 was Spanish. The correlation coefficient between IgE to rbet v 1 and rara h 8 for the study population as a whole was 0.76 (P <.0001), and

4 606 VEREDA ET AL J ALLERGY CLIN IMMUNOL MARCH 2011 TABLE III. Number of peanut allergen components (0-5) recognized by patients from Spain, the United States, and Sweden Component-positive IgE determinations: rara h 1, rara h 2, rara h 3, rara h 8, and rara h 9 Spain (n 5 50) United States (n 5 30) Sweden (n 5 35) Patients with IgE to 0 components (%) Patients with IgE to 1 component (%) Patients with IgE to 2 components (%) Patients with IgE to 3 components (%) Patients with IgE to 4 components (%) Patients with IgE to 5 components (%) TABLE IV. Number of patients monosensitized to each peanut allergen component No. of patients monosensitized to: Spain (n 5 50) United States (n 5 30) Sweden (n 5 35) rara h rara h rara h rara h rara h Total for the Swedish patients, it was 0.91 (P <.0001). Analyses of correlation could not be calculated for the Spanish and American patients because of the small numbers. American patients had the lowest sensitization rate to grass pollen and the lowest IgE levels to the whole P pratense, rphl p 1 and 5, and rphl p 7 and 12 (Table V). The Swedish patients had the highest rate of sensitization to grass pollen and its specific allergens (rphl p 1 and 5). Interestingly, almost one fourth of the Spanish patients were sensitized to the panallergens polcalcine and profilin (rphl p 7 and 12) compared with the other 2 groups (P <.05 compared with the American group and not statistically significant compared with the Swedish group). Symptoms to other plant-derived foods Most of the Spanish patients (63.2%) presented with allergies to other plant-derived foods before becoming symptomatic to peanuts compared with 6.9% of the American patients (P <.01). The plant-derived foods responsible for the patients symptoms also depended on the patient s country of origin. Spanish patients tended to experience symptoms with peach, tree nuts, legumes, and kiwi. Swedish patients experienced more symptoms to hazelnut, apple, and carrot. Most American patients did not react to fresh fruits or vegetables. DISCUSSION Peanut allergy is known to be a frequent cause of food allergy worldwide and is responsible for severe and near-fatal reactions. 3 No clear allergenic differences have been found between peanuts from different parts of the world. 11 Peanuts consumed in the United States, Spain, and Sweden are typically dry roasted in comparison with peanuts eaten in China, where they are commonly fried or boiled. Dry roasting has been shown to increase the allergenic property of peanut proteins. 12 However, patients around the world do not necessarily react similarly or recognize the same allergens. All patients included in this study had previously reacted to peanut, some of them on multiple occasions. Double-blind, placebo-controlled peanut challenges were performed in patients with unclear clinical histories. Those who had never eaten peanut were not included in this study, even if they had high levels of peanut-specific IgE. We found that the onset of peanut allergy differed among the 3 countries. The Spanish and Swedish patients became allergic to peanut at 2 years or later, whereas the American children became allergic to peanut around 1 year of age, which is in accordance with previously published studies. 3 This difference might be due to other factors, such as different types of peanut exposure. American children eat peanut products (>40% of the American peanut crop is consumed as peanut butter) 13 from very early childhood. Furthermore, Green et al 14 reported that the ages of first peanut exposure and reaction have decreased among American children with peanut allergy. In all 3 countries families are advised not to feed any whole peanut or tree nuts to infants and young children because of the risk of aspiration. 15 Regarding the sensitization profile to peanut allergens, we found that the most commonly recognized peanut allergen in the United States and Sweden was rara h 2, which is in line with previous studies. 16 This allergen has been suggested as the most useful candidate for diagnosing peanut allergy. 6,17,18 However, Ara h 2 might not be a good predictor of peanut allergy in Spain because only 42% of patients with peanut allergy recognized rara h 2. The Swedish patients had the highest sensitization rate to the Bet v 1 homologue rara h 8 (65.7%), as well as to rbet v 1 (82.9%). rara h 8 was actually their second most common allergen recognized. This reflects the high birch pollen exposure in that country. Swedish subjects also reported symptoms to Bet v 1 related plant food allergens (eg, hazelnut, apple, and carrot). Whether rara h 8 is responsible for the clinical reaction to peanut has to be further investigated because the Swedish patients in this study cohort were also sensitized to rara h 1, rara h 2, or rara h 3. On the other hand, 60.0% of the Spanish patients had IgE to rara h 9, and 60.0% of the patients sensitized to rara h 9 were monosensitized to this allergen. Ara h 9 has been recently reported as a new member of the LTP allergen family and to play an important role in peanut allergy among patients from the Mediterranean area. 7,8 Lauer et al 7 used rara h 9 with 62% to 68% amino acid sequence identity with Pru p 3 (peach LTP) and demonstrated IgE antibody reactivity in 29 of 32 Spanish compared with 6 of 41 non-mediterranean patients with peanut allergy. In line with these observations, we found that 60.0% of the Spanish patients were sensitized to rara h 9 compared with only 2.0% and 14.3% among American and Swedish patients, respectively. Patients with peach allergy sensitized to Pru p 3 have been previously described as having systemic allergic reactions to peach 19,20 and reacting at times to peanut. 21 Other tree nut LTPs, such as hazelnut s Cor a 8 22 or the walnut LTP, 23 have also been associated with systemic symptoms. In our study Spanish patients typically had peanut allergy after becoming allergic to other plant-derived foods, such as peach. Interestingly, 16 of the 18 Spanish patients monosensitized to rara h 9 presented with systemic symptoms to peanut (no information about the reaction

5 J ALLERGY CLIN IMMUNOL VOLUME 127, NUMBER 3 VEREDA ET AL 607 TABLE V. Proportion of patients with IgE antibody reactivity to timothy grass and birch pollen allergen components and allergen-specific IgE levels Phleum pratense specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 10.7 ( ) 2.3 ( ) 4.8 ( ) 3.6 ( ) Phl p 1 and 5 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 12.5 ( ) 6.0 ( ) 11.0 ( ) 10.8 ( ) Phl p 7 and 12 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 6.4 ( ) 0.7 ( ) 1.0 ( ) 5.3 ( ) Bet v 1 specific IgE (ku A /L) Positive results (%) Median (Q 1 -Q 3 ) 0.7 ( ) 4.1 ( ) 27.0 ( ) 8.6 ( ) Q 1 -Q 3, Interquartile range. with peach was available because it was not the object of the study). In conclusion, we have shown that peanut allergy has different clinical and immunologic patterns in different areas of the world, possibly because of differing environmental pollen exposures and culinary traditions of the populations. Component-resolved diagnosis with the different peanut allergens might help us better understand the complex entity of peanut allergy. We thank Inger Kull, PhD, and Eva Hallner from the BAMSE study group and Ulf Bengtsson, MD, PhD, for their contribution to the study and Michelle Mishoe at Mount Sinai for performing all the specific IgE determinations. We also thank Phadia AB for providing reagents for IgE analyses. Clinical implications: Not all patients with peanut allergy react to peanuts in the same way, which might reflect the allergenic proteins to which they are sensitized. REFERENCES 1. Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and approaches for an apparent epidemic. J Allergy Clin Immunol 2007;120: Crespo JF, James JM, Fernandez-Rodriguez C, Rodriguez J. Food allergy: nuts and tree nuts. Br J Nutr 2006;96(suppl):S Burks AW. Peanut allergy. Lancet 2008;371: Allergen. 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