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Food allergy in the Netherlands: differences in clinical severity, causative foods, sensitization and DBPCFC between community and outpatients

Food allergy in the Netherlands: differences in clinical severity, causative foods, sensitization... Background: It is unknown whether food allergy (FA) in an unselected population is comparable to those from an outpatient clinic population. Objective: To discover if FA in a random sample from the Dutch community is comparable to that of outpatients. Methods: This study was part of the Europrevall-project. A random sample of 6600 adults received a questionnaire. Those with symptoms to one of 24 defined priority foods were tested for sIgE. Participants with a positive case history and elevated sIgE were evaluated by double-blind placebo-controlled food challenge (DBPCFC). Outpatients with a suspicion of FA were evaluated by questionnaire, sIgE and DBPCFC. Results: In the community, severe symptoms were reported less often than in outpatients (39.3% vs. 54.3%). Participants in the community were less commonly sensitized to any of the foods. When selecting only those with a probable FA (i.e. symptoms of priority food and elevation of sIgE to the respective food), no major differences were observed with respect to severity, causative foods, sensitization and DBPCFC between the groups. Conclusion: In the Netherlands, there are large differences in self-reported FA between community and outpatients. However, Dutch community and outpatients with a probable FA do not differ with respect to severity, causative foods, sensitization and DBPCFC-outcome. Keywords: Adults, Community, DBPCFC, Food allergy, sIgE Background Most studies investigating the clinical aspects of FA A recent meta-analysis showed that self-reported preva- involve patients from a (tertiary) allergy clinic. Since lence of food allergy (FA) ranged from 3% to 35% in only a fraction of food allergic individuals from the gen- adults [1]. However, the prevalence of FA as diagnosed by eral population visit a doctor, [8] it is not clear how rep- double-blind placebo-controlled food challenge (DBPCFC) resentative results from such studies are for the general is estimated to be around 2% to 4% for adults [2-7]. population. However, studies comparing FA between the A study from a regional allergy center in the UK, community and outpatients are lacking. serving a population of 1.6 million, reported a population The aim of this study was to investigate to what extent prevalence of 0.03%, being a factor of 100 less than in FA in a random sample of the Dutch community is com- population-based studies. This suggests that a minority parable to FA in outpatients. of FA patients present to their GP and are subsequently referred [8]. Methods This study was part of the EuroPrevall-project, a multi- * Correspondence: t.t.m.le-2@umcutrecht.nl disciplinary European project investigating several as- Department of Dermatology/Allergology, University Medical Center Utrecht, pects of FA [9]. It consisted, among many different, of PO Box 855003508 GA Utrecht, The Netherlands Full list of author information is available at the end of the article an epidemiological element investigating the prevalence © 2015 Le et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 2 of 8 of FA in the community and an outpatient clinical elem- In vitro diagnosis ent. This study was approved by the local medical ethical sIgE testing for all priority foods were performed in a committee (METC) of the University Medical Center single laboratory using the ImmunoCAP system and re- Utrecht. agents from Phadia (Thermo Fisher Scientific, Uppsala, Sweden). sIgE values of ≥0.35 kU /L were regarded as positive. Community The epidemiological study consisted of three stages and DBPCFC is described in detail elsewhere [10]. In short, the study All participants with symptoms to hen’s egg, cow’s milk, took place from October 2006 until March 2009. The peanut, hazelnut, celery, apple, peach, fish or shrimp 1st stage was a population-based study in which a short were asked to participate in DBPCFC. A detailed proto- questionnaire to screen for FA was sent out to a random col of the EuroPrevall DBFCFC is described elsewhere sample of 6600 adults aged 20–54 years living in the city [11]. Briefly, active and placebo provocations were ran- of Utrecht, The Netherlands. domly performed on two different days with eight in- In the 2nd stage, all those who in the screening ques- creasing doses. The single doses were administered at an tionnaire reported to have experienced adverse reactions interval of at least 20 minutes up to the top dose. The to one of the 24 preselected priority foods (hen’s egg, interval could be extended at the request of the patient, cow’s milk, peanut, soy, hazelnut, walnut, celery, kiwi, according to the case history of the patient, or in case of apple, peach, sesame, mustard, wheat, fish and shrimp, severe persisting subjective symptoms. Challenges were buckwheat, corn, carrot, tomato, melon, banana, lentils, discontinued after the dose leading to the first objective sunflower, poppy seeds) were invited to come to the hos- allergic symptoms or ingestion of the whole meal. Ob- pital for a detailed questionnaire and serum IgE testing . jective symptoms considered for discontinuation of the In the 3rd stage, participants with self-reported symp- provocation were blisters of the oral mucosa, skin symp- toms and sIgE to at least one of the priority foods were toms such as flush, urticaria, angioedema, rhinitis, con- called in for DBPCFC and a full clinical evaluation, iden- junctivitis, drop of blood pressure of at least 20 mmHg, tical to that of the outpatients (see below). drop of FEV1 > 12% or PEF ≥ 20%, laryngeal oedema, diarrhoea, emesis or in case of severe persistent subject- Outpatients ive symptoms lasting for more than 45 minutes such as The outpatient study took place from January 2006 until severe itching of palms, soles, head or severe gastric/ab- June 2009. All adult patients (age 18 years and older) dominal pain. If all DBPCFC doses were negative, pa- who were referred to our tertiary allergy centre with a tients underwent an open food challenge. Patients that suspected FA, were asked to participate in the EuroPrevall had a reaction of any type and any duration on the ac- outpatient clinic study. Inclusion criteria were symptoms tive day and no reaction on the placebo were classified developing within 2 hours after ingestion of a food. as reactors, patients that did not react on the active nor Participating outpatients underwent a clinical evaluation the placebo day were tolerant and patients that reacted comprising a thorough medical history using a standard- on the placebo day were placebo responders. ized questionnaire, sIgE testing and DBPCFC. Statistics Clinical evaluation Chi-square tests and, where appropriate, Fisher’s exact All clinical information was collected following a stan- tests were used to test the differences in several clinical dardized questionnaire which was specifically developed characteristics (i.e. gender, severity of symptoms, causa- for the Europrevall-study. Symptoms were classified into tive foods, atopic diseases, sensitization and DBPCFC mild (symptoms of the oral cavity), moderate (gastro-in- outcome) between the community and outpatients. Dif- testinal symptoms and symptoms of the skin and ferences in age and the number of causative foods mucous membranes) and severe (respiratory or cardio- between the two groups were calculated using Student’s vascular symptoms). T-test and, where appropriate, Mann–Whitney U test. A probable FA was defined as symptoms within Statistical analysis was performed using SPSS version 20 2 hours and sIgE ≥0.35 kU /L to a priority food. Al- (SPSS Inc., Chicago, Illinois, USA) for Windows. though DBPCFC is the gold standard for diagnosis of FA, diagnosis of FA in majority of patients in clinical Results practice is based on medical history and sIgE. Therefore, Study population in this study we chose a pragmatical approach using a Of the screening questionnaires that were sent out to a suggestive history (i.e. symptoms <2 hours of ingestion) random sample of 6600 adults, 3864 responded, of together with IgE sensitization to define a probable FA. whom 967 (25.0%) reported adverse food reactions to Le et al. Clinical and Translational Allergy (2015) 5:8 Page 3 of 8 any food and 416 (10.8%) to at least one priority food with swallowing (15.9% vs. 6.3%) and breathlessness (Figure 1). 154 of these 416 (37.0%) were willing to come (11.3% vs. 6.8%). In the group with symptoms other than to our clinic for the second stage consisting of a detailed priority food gastro-intestinal symptoms dominated and questionnaire and sIgE testing. In 37.7% (58/154) sIgE was significantly higher than in the priority food group was positive for the respective food. Of these 58 cases, (47.7% vs. 38.6%). Furthermore, the group without symptoms 46 entered the 3rd stage for a full clinical evaluation. of priority food significantly more often reported that In the outpatient clinical part of the study, all outpa- the symptoms to the culprit food took place once only tients that met the inclusion criteria agreed to partici- (26.8%). pate in the study. In total, 133 outpatients that were referred to our allergy center were included during the Reported adverse reactions to priority foods in study period. Symptoms to at least one priority food community and outpatients were reported by 127 outpatients, in 102 of which sIgE Of the participants reporting adverse reactions to any to the same food(s) was detected. food (n = 967), 43.0% reported symptoms to at least one of the priority foods. Walnut, apple, cow’s milk, hazelnut Reported adverse food reactions to any food in the and kiwi were the most commonly reported priority community foods in the community (Table 1, 2nd stage). The fre- Adverse reactions to any food were reported by 25.0% quency of severe symptoms rose from 21.4% in the 1st of the responders in the community. Cow’s milk (10.7%), stage to 39.3% in the 2nd stage in participants from the nuts (9.5%), apple (9.4%) and fish (6.3%) were the most community. Remarkably, only a small percentage of par- commonly reported causative foods. Mild symptoms ticipants from the community who reported symptoms (consisting of only oral allergy symptoms) were reported to priority foods also had a positive sIgE for the respect- by 10.1%, moderate symptoms by 58.4% and severe ive food (Figure 2). symptoms by 21.4% of participants. In the group with When comparing the community to outpatients, using moderate symptoms, gastro-intestinal symptoms dominated reported symptoms to priority food as selection in both (60.2%). groups, it appeared that severe symptoms were signifi- Of the 967 participants reporting adverse reactions cantly more common in outpatients (54.3% vs. 39.3%, to any food, 416 reported symptoms to priority food p = 0.008). The frequency in which the different priority and 551 reported symptoms to other foods. These two foods were reported, differed significantly for some groups were compared and showed that the group with foods: in the community the frequency of allergy to symptoms to priority food significantly more often re- cow’s milk, fish and shrimp was significantly higher, ported oral allergy symptoms (51.5% vs. 24%), difficulty whereas outpatients reported symptoms to peanut, st 1 stage: 6600 questionnaires sent out Screening questionnaire 3864 responded 967/3864 reported symptoms to any food (25%) 416/3864 reported symptoms to priority food (10.8%) nd 2 stage: 154/416 willing to participate Case-control study 58 positive history and positive serum IgE for priority food (38%) rd 3 stage: 46/58 detailed questionnaire DBPCFC: 18 participated in DBPCFC (39%) Figure 1 Flow-diagram of the epidemiological part of the study in the community. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 4 of 8 Table 1 Patient characteristics of the three different stages 1st stage (possible FA 2nd stage (possible FA to priority 3rd stage: (probable FA to priority || ‡ § to any food) food) food) Community Community Outpatients p-value Community Outpatients p-value (n = 967) % (n = 154) % (n = 127) % (n = 46) % (n = 102) % Male gender 32.0 31.2 35.4 0.52 30.4 38.2 0.36 Age (mean ± SD) 34.7 (±9.3) 34.1 (±9.2) 32.2 (±12.3) 0.16 35.3 30.4 0.01* Number of foods causing 4 (1-17) 5 (1-18) 0.40 6 (1-14) 6 (1-18) 0.96 symptoms (median (range)) Symptom : -mild 10.1 14.0 26.0 0.01* 26.1 21.0 0.50 -moderate 58.4 46.7 19.7 <0.001* 28.3 19.0 0.21 -severe 21.4 39.3 54.3 0.008* 45.7 60.0 0.11 Atopy: -pollen allergy 70.8 94.5 <0.001* 97.8 94.1 0.44 -dermatitis 36.4 33.3 0.61 25.6 37.8 0.18 Symptoms of plant food -Hazelnut 2.4 31.2 32.3 0.84 71.7 37.3 <0.001* -Peanut 2.7 16.2 32.3 0.002* 18.6 34.3 0.04* -Walnut 2.5 36.4 36.2 0.98 52.2 41.2 0.21 -Apple 9.4 33.1 53.5 0.001* 82.6 57.8 0.003* -Peach 1.0 18.8 29.1 0.04* 50.0 34.3 0.07 -Kiwi 4.8 29.2 43.3 0.01* 34.8 40.2 0.53 -Melon 1.2 14.9 15.0 1.00 21.7 16.7 0.46 -Banana 1.4 11.0 17.3 0.17 17.4 18.6 0.86 -Tomato 2.8 13.0 17.3 0.31 13.0 18.6 0.40 -Carrot 1.8 8.4 11.8 0.42 19.6 14.7 0.46 Symptoms of animal food -Cow’s milk 10.7 31.8 8.7 <0.001* 4.3 6.9 0.72 -Hen’s egg 2.4 7.8 8.7 0.79 2.2 8.8 0.17 -Fish 6.3 18.2 5.5 0.001* 6.5 5.9 1.00 -Shrimp 3.7 20.8 10.2 0.02* 8.7 10.8 0.78 FA = food allergy. mild = oral allergy symptoms, moderate = gastro-intestinal symptoms or symptoms of the skin and mucous membranes, severe = respiratory or cardiovascular symptoms. || reported adverse food reaction to any food. positive history for priority food. positive history and serum IgE for priority food. *p-value < 0.05. apple, peach and kiwi at a significantly higher frequency positive sIgE for that food. These participants were (Table 1, 2nd stage). Outpatients had significantly more considered to have a probable FA. When comparing the clinically relevant sIgE sensitisation compared to the com- community participants and outpatients, using symp- munity for all foods, except for hazelnut and apple, where toms and sIgE to priority food as selection in both no difference was seen between both groups (Figure 2). groups (i.e. probable FA), the differences in causative In summary, causative foods, severity and relevant foods as seen in the 2nd stage disappeared largely. Only food sensitization differed between the community and hazelnut and apple were significantly more frequently outpatients when only selecting on self-reported symp- reported as a causative food in the community, whereas toms to priority foods. peanut was more commonly reported in outpatients (Table 1). In contrast to the 2nd stage, no differences Probable FA in community and outpatients were seen in the severity of symptoms between the com- Of the participants from the community that reported munity and outpatients (Table 1). Whereas in the 2nd symptoms to a priority food, 58/154 (37.7%) also had a stage major differences were observed between the two Le et al. Clinical and Translational Allergy (2015) 5:8 Page 5 of 8 sIgE in 2nd stage sIgE in 3rd stage Hazelnut (n=89) Hazelnut (n=71) 87.8 94.7 8 37.5 Peanut* (n=66) 65.9 Peanut* (n=43) 77.1 7.1 8.3 Walnut* (n=102) Walnut* (n=66) 32.6 35.7 68.6 86.8 Apple (n=119) 73.5 Apple (n=97) 84.7 75.9 Peach* (n=n=66) 95.7 Peach (n=58) 94.6 22.2 37.5 Kiwi* (n=100) 47.3 Kiwi (n=57) 63.4 Community Community 8.7 Melon (n=42) 20 Melon (n=27) 36.8 41.2 Outpatients Outpatients 11.8 37.5 Banana* (n=39) 63.6 Banana (n=27) 73.7 Tomato* (n=42) 33.3 Tomato (n=25) 68.2 78.9 Cow’s milk* (n=60) Cow’s milk (n=9) 27.3 42.9 Hen’s egg* (n=23) 0 36.4 Hen’s egg (n=10) 44.4 6.3 Shrimp* (n=45) Shrimp (n=15) 84.6 10.7 66.7 Fish* (n=35) 57.1 Fish (n=9) 66.7 0 10 203040 50607080 90 100 0 1020 3040 5060 7080 90 100 % patients with sIgE ≥0.35 kUA/L % patients with sIgE ≥0.35 kUA/L Figure 2 Percentage of positive sIgE in the community and outpatients with symptoms to the food in the 2nd stage (reported symptoms) and 3rd stage (reported symptoms and positive sIgE for at least 1 food) of the study. The number (n = ..) between brackets indicates the total number of the community and outpatients that reported symptoms to that respective priority food. *p-value <0.05. groups in sensitization to most priority foods, these dif- results are applicable to food allergic persons in the ferences disappeared largely when selecting on FA community. (Figure 2). Table 2 shows the clinical characteristics in To our knowledge this is the first study to compare more detail for the main foods. The majority with a FA in the community and outpatients. In this study we probable food allergy were birch pollen sensitized, had found that, when focusing on self-reported symptoms to symptoms within a few minutes after ingestion of the priority foods, there are large differences in causative culprit food and oral allergy symptoms was the most foods, severity and relevant food sensitization between common symptom. A probable cow’s milk en hen’s egg community and outpatients. However, when selecting allergy was rare in our adult population. In those with a those with a probable FA, as defined by reported symp- cow’s milk and hen’s egg allergy anaphylaxis was rela- toms to priority food together with a positive sIgE to the tively frequent (25%). respective food, it became evident that the differences in In total 18 participants from the community and 30 the community and outpatients disappeared. This indi- outpatients underwent DBPCFC. There were no signifi- cates that patients with a probable FA seen in a tertiary cant differences in the severity of symptoms for the indi- outpatient allergy center are not different from those vidual foods between those who agreed to participate in with a probable FA in the community. DBPCFC and those who declined (p > 0.05, data not Previous population based studies showed that the shown). The percentage of positive DPBCFC did not dif- prevalence of self-reported FA to any food varied from fer between community and outpatients (77.8% vs. 3% to as high as 35%, whereas the prevalence of true FA 63.3%, p = 0.47). Of the patients with a positive is estimated to be 2-4% [1-7,12-14]. In our study we DBPCFC, 35.7% of the community and 31.6% of outpa- confirmed for the Dutch population the discrepancy be- tients (p = 0.80) had objective signs. In both groups, the tween the prevalence of self-reported adverse food reac- percentage of placebo reactors was high: 16.7% in the tions (10.8%), a FA as defined by a suggestive history community and 20% in the outpatients. All placebo reac- and supported by sIgE (4.1%) and a FA confirmed by tors reported subjective symptoms and not objective DBPCFC (3.2%). signs on placebo day. The outcome of the challenges per Since non-response bias could play a role in the com- food are shown in Table 3. munity survey, we performed a non-response analysis. In conclusion, when focusing on a probable FA, no The response rate in the 1st stage of the community sur- difference could be demonstrated between the commu- vey was 61%. We calculated the cumulative prevalence nity participants and the outpatients with regard to se- of adverse food reaction at the time of response to ex- verity, causative foods, relevant food sensitization and trapolate the prevalence to non-responders [15]. This DBPCFC-outcome. showed that the cumulative prevalence of adverse food reaction stabilized after a response rate of 40%, indicat- ing that non-response bias does not play a major role in Discussion the 1st stage of the study. For the 2nd stage, we com- Since most studies investigating FA use outpatients as a pared age, gender, doctor-diagnosed FA and the symp- study population, the question arises whether such study toms between responders and non-responders. Only the Le et al. Clinical and Translational Allergy (2015) 5:8 Page 6 of 8 Table 2 Clinical characteristerics per food in patients with a probable food allergy (i.e. symptoms and specific IgE) Community Outpatients Symptoms Time interval sIgE Birch Symptoms Time interval sIgE Birch food IgE* food IgE* NOAS(%) skin GI Resp Cardio Anaph <5 5- 30- > Median (%) N OAS skin GI Resp Cardio Anaph <5 5- 30- > Median (%) (%) (%) (%) (%) (%) min 30 120 2 (Range) (%) (%) (%) (%) (%) (%) min 30 120 2 (range) min min hrs min min hrs Hazelnut 33 90.9 27.3 6.1 42.4 0 0 84.8 9.4 6.3 0 12.5 72.7 36 97.2 27.8 27.8 47.2 2.8 5.6 86.1 13.9 0 0 23.37 97.2 (0.47- (0.65- 74.99) 196.54) Peanut 3 66.7 33.3 33.3 33.3 0 0 50 50 0 0 2.63 100 27 88.9 59.3 29.6 48.1 0 0 77.8 22.2 0 0 2.21 85.2 (0.60- (0.35- 5.58) 321.78) Walnut 2 100 50 50 50 0 0 100 0 0 0 1.04 100 15 93.3 60 20 26.7 6.7 6.7 93.3 0 6.7 0 5.53 93.3 (0.51- (0.36- 1.58) 27.56) Apple 33 97 24.2 21.2 24.2 0 0 75.8 21.2 3 0 1.49 69.7 51 100 28 16 30 0 0 77.6 22.4 0 0 2.03 100 (0.37- (0.42- 21.18) 31.19) Peach 22 95.5 31.8 13.6 27.3 0 0 77.3 18.2 4.5 0 2.00 72.7 36 97.1 31.4 17.1 37.1 0 0 77.1 22.9 0 0 3.79 100 (0.53- (0.59- 12.91) 44.56) Kiwi 6 100 33.3 16.7 16.7 0 0 100 0 0 0 1.07 83.3 26 96.2 19.2 19.2 26.9 0 0 80 20 0 0 1.67 88.5 (0.40- (0.35- 11.21) 152.57) Cow’s milk 0 - - - - - - - - - - - - 4 50 50 50 25 25 25 50 25 0 0 10.05 50 (0.43- 34.12) Hen’s egg 0 - - - - - - - - - - - - 4 75 50 50 25 0 25 25 50 25 0 1.68 75 (0.40- 3.04) OAS = oral allergy symptoms, GI = gastro-intestinal, Resp = respiratory, cardio = cardiovascular, anaph = anaphylaxis. *Birch sIgE = sIgE birch ≥0.35. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 7 of 8 Table 3 Double-blind placebo-controlled food challenge (DBPCFC) in community and outpatients Community Outpatients N Positive Negative Placebo Objective Subjective N Positive Negative Placebo Objective Subjective DBPCFC DBPCFC reactor signs* (%) symptoms* DBPCFC DBPCFC reactor signs* (%) symptoms* (%) (%) (%) (%) (%) (%) (%) (%) Hazelnut 9 77.8 11.1 11.1 42.9 100 10 60 20 20 50 100 Peanut 1 100 0 0 0 100 9 66.7 22.2 11.1 50 100 Apple 5 60 0 40 33.3 66.7 8 50 12.5 37.5 0 100 Peach 2 100 0 0 0 100 1 100 0 0 0 100 Celery 1 100 0 0 100 100 0 - - - - - Cow’s 0 - - - - - 1 100 0 0 0 100 milk Hen’s 0 - - - - - 1 100 0 0 0 100 egg * This is calculated as a percentage from those with a positive DBPCFC. frequency of oral allergy symptoms differed, being higher DBPCFC is also reported in other studies [5,7]. The in the responders (61% vs 49%, p = 0.02), which could in- main reason for refusal to participate in DBPCFC in our dicate that responders from the 2nd stage of the study patients was the lack of time. were more likely to have a probable food allergy com- In general, it might be expected that the frequency of pared to non-responders. This would mean that the dif- severe FA in outpatients referred to a tertiary allergy ferences found between community and outpatients in center is higher compared to the community. In this the 2nd stage would even be larger. For the 3rd stage, study we observed no significant difference in the fre- no differences were seen between responders and non- quency of severe symptoms between both groups. Of the responders with regard to age, sex and symptoms (data participants with a probable FA in the community, not shown). 40.4% had never sought medical care for their symptoms Although the response rate was low, the profile of re- to food and of these, 46.4% had severe symptoms upon sponders and non-responders were largely similar, and ingestion of the causative food (data not shown). Thus, therefore it is thought that a possible non-response bias severe symptoms are not always a trigger for FA-patients would not play a major role. Low response rates are not to seek medical care. unusual in population based studies investigating the prevalence of food allergy [3,5]. Conclusions The gold standard for the diagnosis of FA is DBPCFC In the Netherlands, there are large differences in self- [16]. However, DBPCFC is time-consuming, expensive, reported FA between community and outpatients. How- subjects patients to potential severe allergic reactions, ever, Dutch community and outpatients with a probable requires the need for well equipped facilities and may FA do not differ with respect to severity, causative foods, not be able to reproduce the conditions that occurred sensitization and DBPCFC-outcome. when the reported allergic reaction took place [17,18]. Abbreviations Due to these practical problems, in normal clinical set- DBPCFC: Double-blind placebo-controlled food challenge; FA: Food allergy; tings FA is often diagnosed by a thorough medical his- OR: Odds ratio. tory and a test for sensitization [17,19]. In our study, medical history and sIgE was used to define a probable Competing interests Prof. Dr. S. Vieths reports personal fees from Food Allergy Resource and FA since this could be performed in all participants Research Program, Lincoln, NE USA, personal fees from Medical University of and outpatients. Certain participants in the community Vienna, Austria, grants from Monsanto Company, personal fees from and outpatient studies agreed to undergo DBPCFC and, American Academy of Asthma, Allergy and Immunology, personal fees from Deutsche Dermatologische Gesellschaft, personal fees from Spanish Society whilst a relatively small sample, no differences were seen of Allergy and Clinical Immunology, personal fees from Westdeutsche in the rates of either positive DBPCFC (78% and 64%, Arbeitsgemeinschaft für pädiatrische Pneumologie und Allergologie e.V., respectively) or the objective signs between the two Köln, Germany, personal fees from Gesellschaft für pädiatrische Allergologie und Umweltmedizin, personal fees from Ärzteverband Deutscher groups. These data indicate that the clinical characteris- Allergologen, personal fees from Schattauer Allergologie Handbuch, personal tics of individuals with a probable FA in this population fees from Elsevier Nahrungsmittelallergien und Intoleranzen, non-financial were similar between the two populations and that the support from German Research Foundation, non-financial support from Federal Institute for Risk Assessment, non-financial support from Austrian Society for estimates of prevalence relying only on clinical history Allergology and Immunology, non-financial support from European Directorate and sIgE will over-estimate rates of confirmed food for the Quality of Medicines and Health Care, non-financial support from European allergy by around 22-37%. A low participation rate in Academy of Allergy and Clinical Immunology , non-financial support from World Le et al. Clinical and Translational Allergy (2015) 5:8 Page 8 of 8 Allergy Organization, non-financial support from Association Monégasque pour le 4. Kanny G, Moneret-Vautrin DA, Flabbee J, Beaudouin E, Morisset M, Thevenin Perfectionnement des Connaissances des Médicins, non-financial support from F. Population study of food allergy in France. J Allergy Clin Immunol. Federal Office of Consumer Protection and Food Safety , non-financial support 2001;108(1):133–40. from German Chemical Society (GDCh), non-financial support from Austrian 5. Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R. A population Society for Dermatology and Venerology, non-financial support from AKM study of food intolerance. Lancet. 1994;343(8906):1127–30. Allergiekongress, non-financial support from Austrian Food Chemical Society, 6. Osterballe M, Hansen TK, Mortz CG, Host A, Bindslev-Jensen C. The outside the submitted work. E. N. Clare Mills has received research support from prevalence of food hypersensitivity in an unselected population of children the European Union, the Biological and Biotechnological Sciences Research and adults. Pediatr Allergy Immunol. 2005;16(7):567–73. Council, the UK Food Standards Agency; is a board member for Novartis, the UK 7. Jansen JJ, Kardinaal AF, Huijbers G, Vlieg-Boerstra BJ, Martens BP, Ockhuizen Food Standards Agency, PepsiCo International, the UK Biological and Biotechnological T. Prevalence of food allergy and intolerance in the adult Dutch population. Sciences Research Council, the European Food Safety Authority, the European J Allergy Clin Immunol. 1994;93(2):446–56. Academy of Allergy and Clinical Immunology; is consultant for Reacta Biotech Ltd; 8. Jones RB, Hewson P, Kaminski ER. Referrals to a regional allergy clinic - an is employed by the University of Manchester and the Institute of Food Research; eleven year audit. BMC Public Health. 2010;10:790. has stock/stock options in Reacta Biotech Lts; received grants/pending grants from 9. Mills EN, Mackie AR, Burney P, Beyer K, Frewer L, Madsen C, et al. The The Biological and Biotechnological Sciences Research Council, the European union, prevalence, cost and basis of food allergy across Europe. Allergy. the UK Food Standards Agency, DBV Technology, Reacta Biotech Ltd, North West 2007;62(7):717–22. Lung Centre Charity, Medical Research Council; has received travel support from 10. Kummeling I, Mills EN, Clausen M, Dubakiene R, Perez CF, Fernandez-Rivas M, ILSI, EAACI, Europa Bio, the British High Commission, the Iceland Allergy Society, et al. The EuroPrevall surveys on the prevalence of food allergies in children Fresenius, EuroFood Tox 2013, Campden BRI, Food Matters Live and the IUNS and adults: background and study methodology. Allergy. 2009;64(10):1493–7. Annual Meeting (Granada, Spain September 2013); and was paid as a lecturer and 11. Cochrane SA, Salt LJ, Wantling E, Rogers A, Coutts J, Ballmer-Weber BK, et al. supervisor of masters students at Imperial College and as an external examiner at Development of a standardized low-dose double-blind placebo-controlled the University of Birmingham. challenge vehicle for the EuroPrevall project. Allergy. 2012;67(1):107–13. The rest of the authors declare that they have no relevant conflicts of 12. Zuidmeer L, Goldhahn K, Rona RJ, Gislason D, Madsen C, Summers C, et al. interest. The prevalence of plant food allergies: a systematic review. J Allergy Clin Immunol. 2008;121(5):1210–8. 13. Emmett SE, Angus FJ, Fry JS, Lee PN. Perceived prevalence of peanut allergy Authors’ contributions in Great Britain and its association with other atopic conditions and with The study was designed by TL, EvH, IK and ACK. Data was collected by AFML peanut allergy in other household members. Allergy. 1999;54(4):380–5. and TL. Analysis of the data and preparing a first draft was performed by TL. 14. Woods RK, Abramson M, Bailey M, Walters EH. International prevalences of Interpretation of data, drafting and revising the manuscript was done by TL, reported food allergies and intolerances. Comparisons arising from the EvH, IK, JP, BKB, CAFMB, JL, AFML, TML, AM, ENCM, RvR, SV, MF, PGB and European Community Respiratory Health Survey (ECRHS) 1991–1994. Eur J ACK. All authors read and approved the final manuscript. Clin Nutr. 2001;55(4):298–304. 15. Lessler JT, Kalsbeek WD. Nonsampling error in surveys. New York: Wiley; 1992. Acknowledgement 16. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. This work was funded by the EU through EuroPrevall (FP6- FOOD-CT-2005- Guidelines for the diagnosis and management of food allergy in the United 514000). States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. We would like to thank Lucía Jimeno and Domingo Barber, f0072om ALK- 2010;126(6 Suppl):S1–58. Abelló, Spain, for providing the skin prick tests materials. 17. Asero R, Fernandez-Rivas M, Knulst AC, Bruijnzeel-Koomen CA. Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a Funding reappraisal of their limitations and real indications. Curr Opin Allergy Clin This work was funded by the EU through EuroPrevall (FP6- FOOD-CT-2005- Immunol. 2009;9(4):379–85. 514000). 18. Sampson HA. Immunologically mediated food allergy: the importance of food challenge procedures. Ann Allergy. 1988;60(3):262–9. Author details 19. Seitz CS, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Food allergy in adults: Department of Dermatology/Allergology, University Medical Center Utrecht, an over- or underrated problem? Dtsch Arztebl Int. 2008;105(42):715–23. PO Box 855003508 GA Utrecht, The Netherlands. Department of Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK. Allergy Unit, Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. 4 5 Thermo Fisher Scientific, Uppsala, Sweden. Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK. Institute of Inflammation and Repair, Manchester Academic Health Sciences Centre, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK. Department of Experimental Immunology and Department of Otorhinolaryngology, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands. Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany. Allergy Department, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. Current affiliation: NIZO food research, Ede, The Netherlands. Submit your next manuscript to BioMed Central and take full advantage of: Received: 17 June 2014 Accepted: 30 January 2015 • Convenient online submission • Thorough peer review References 1. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The • No space constraints or color figure charges prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. • Immediate publication on acceptance 2007;120(3):638–46. • Inclusion in PubMed, CAS, Scopus and Google Scholar 2. Madsen C. Prevalence of food allergy: an overview. Proc Nutr Soc. 2005;64(4):413–7. • Research which is freely available for redistribution 3. Zuberbier T, Edenharter G, Worm M, Ehlers I, Reimann S, Hantke T, et al. Prevalence of adverse reactions to food in Germany - a population study. Submit your manuscript at Allergy. 2004;59(3):338–45. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Translational Allergy Springer Journals

Food allergy in the Netherlands: differences in clinical severity, causative foods, sensitization and DBPCFC between community and outpatients

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Copyright © 2015 by Le et al.; licensee BioMed Central.
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Medicine & Public Health; Allergology; Immunology; Molecular Medicine
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2045-7022
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10.1186/s13601-015-0051-1
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25774288
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Abstract

Background: It is unknown whether food allergy (FA) in an unselected population is comparable to those from an outpatient clinic population. Objective: To discover if FA in a random sample from the Dutch community is comparable to that of outpatients. Methods: This study was part of the Europrevall-project. A random sample of 6600 adults received a questionnaire. Those with symptoms to one of 24 defined priority foods were tested for sIgE. Participants with a positive case history and elevated sIgE were evaluated by double-blind placebo-controlled food challenge (DBPCFC). Outpatients with a suspicion of FA were evaluated by questionnaire, sIgE and DBPCFC. Results: In the community, severe symptoms were reported less often than in outpatients (39.3% vs. 54.3%). Participants in the community were less commonly sensitized to any of the foods. When selecting only those with a probable FA (i.e. symptoms of priority food and elevation of sIgE to the respective food), no major differences were observed with respect to severity, causative foods, sensitization and DBPCFC between the groups. Conclusion: In the Netherlands, there are large differences in self-reported FA between community and outpatients. However, Dutch community and outpatients with a probable FA do not differ with respect to severity, causative foods, sensitization and DBPCFC-outcome. Keywords: Adults, Community, DBPCFC, Food allergy, sIgE Background Most studies investigating the clinical aspects of FA A recent meta-analysis showed that self-reported preva- involve patients from a (tertiary) allergy clinic. Since lence of food allergy (FA) ranged from 3% to 35% in only a fraction of food allergic individuals from the gen- adults [1]. However, the prevalence of FA as diagnosed by eral population visit a doctor, [8] it is not clear how rep- double-blind placebo-controlled food challenge (DBPCFC) resentative results from such studies are for the general is estimated to be around 2% to 4% for adults [2-7]. population. However, studies comparing FA between the A study from a regional allergy center in the UK, community and outpatients are lacking. serving a population of 1.6 million, reported a population The aim of this study was to investigate to what extent prevalence of 0.03%, being a factor of 100 less than in FA in a random sample of the Dutch community is com- population-based studies. This suggests that a minority parable to FA in outpatients. of FA patients present to their GP and are subsequently referred [8]. Methods This study was part of the EuroPrevall-project, a multi- * Correspondence: t.t.m.le-2@umcutrecht.nl disciplinary European project investigating several as- Department of Dermatology/Allergology, University Medical Center Utrecht, pects of FA [9]. It consisted, among many different, of PO Box 855003508 GA Utrecht, The Netherlands Full list of author information is available at the end of the article an epidemiological element investigating the prevalence © 2015 Le et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 2 of 8 of FA in the community and an outpatient clinical elem- In vitro diagnosis ent. This study was approved by the local medical ethical sIgE testing for all priority foods were performed in a committee (METC) of the University Medical Center single laboratory using the ImmunoCAP system and re- Utrecht. agents from Phadia (Thermo Fisher Scientific, Uppsala, Sweden). sIgE values of ≥0.35 kU /L were regarded as positive. Community The epidemiological study consisted of three stages and DBPCFC is described in detail elsewhere [10]. In short, the study All participants with symptoms to hen’s egg, cow’s milk, took place from October 2006 until March 2009. The peanut, hazelnut, celery, apple, peach, fish or shrimp 1st stage was a population-based study in which a short were asked to participate in DBPCFC. A detailed proto- questionnaire to screen for FA was sent out to a random col of the EuroPrevall DBFCFC is described elsewhere sample of 6600 adults aged 20–54 years living in the city [11]. Briefly, active and placebo provocations were ran- of Utrecht, The Netherlands. domly performed on two different days with eight in- In the 2nd stage, all those who in the screening ques- creasing doses. The single doses were administered at an tionnaire reported to have experienced adverse reactions interval of at least 20 minutes up to the top dose. The to one of the 24 preselected priority foods (hen’s egg, interval could be extended at the request of the patient, cow’s milk, peanut, soy, hazelnut, walnut, celery, kiwi, according to the case history of the patient, or in case of apple, peach, sesame, mustard, wheat, fish and shrimp, severe persisting subjective symptoms. Challenges were buckwheat, corn, carrot, tomato, melon, banana, lentils, discontinued after the dose leading to the first objective sunflower, poppy seeds) were invited to come to the hos- allergic symptoms or ingestion of the whole meal. Ob- pital for a detailed questionnaire and serum IgE testing . jective symptoms considered for discontinuation of the In the 3rd stage, participants with self-reported symp- provocation were blisters of the oral mucosa, skin symp- toms and sIgE to at least one of the priority foods were toms such as flush, urticaria, angioedema, rhinitis, con- called in for DBPCFC and a full clinical evaluation, iden- junctivitis, drop of blood pressure of at least 20 mmHg, tical to that of the outpatients (see below). drop of FEV1 > 12% or PEF ≥ 20%, laryngeal oedema, diarrhoea, emesis or in case of severe persistent subject- Outpatients ive symptoms lasting for more than 45 minutes such as The outpatient study took place from January 2006 until severe itching of palms, soles, head or severe gastric/ab- June 2009. All adult patients (age 18 years and older) dominal pain. If all DBPCFC doses were negative, pa- who were referred to our tertiary allergy centre with a tients underwent an open food challenge. Patients that suspected FA, were asked to participate in the EuroPrevall had a reaction of any type and any duration on the ac- outpatient clinic study. Inclusion criteria were symptoms tive day and no reaction on the placebo were classified developing within 2 hours after ingestion of a food. as reactors, patients that did not react on the active nor Participating outpatients underwent a clinical evaluation the placebo day were tolerant and patients that reacted comprising a thorough medical history using a standard- on the placebo day were placebo responders. ized questionnaire, sIgE testing and DBPCFC. Statistics Clinical evaluation Chi-square tests and, where appropriate, Fisher’s exact All clinical information was collected following a stan- tests were used to test the differences in several clinical dardized questionnaire which was specifically developed characteristics (i.e. gender, severity of symptoms, causa- for the Europrevall-study. Symptoms were classified into tive foods, atopic diseases, sensitization and DBPCFC mild (symptoms of the oral cavity), moderate (gastro-in- outcome) between the community and outpatients. Dif- testinal symptoms and symptoms of the skin and ferences in age and the number of causative foods mucous membranes) and severe (respiratory or cardio- between the two groups were calculated using Student’s vascular symptoms). T-test and, where appropriate, Mann–Whitney U test. A probable FA was defined as symptoms within Statistical analysis was performed using SPSS version 20 2 hours and sIgE ≥0.35 kU /L to a priority food. Al- (SPSS Inc., Chicago, Illinois, USA) for Windows. though DBPCFC is the gold standard for diagnosis of FA, diagnosis of FA in majority of patients in clinical Results practice is based on medical history and sIgE. Therefore, Study population in this study we chose a pragmatical approach using a Of the screening questionnaires that were sent out to a suggestive history (i.e. symptoms <2 hours of ingestion) random sample of 6600 adults, 3864 responded, of together with IgE sensitization to define a probable FA. whom 967 (25.0%) reported adverse food reactions to Le et al. Clinical and Translational Allergy (2015) 5:8 Page 3 of 8 any food and 416 (10.8%) to at least one priority food with swallowing (15.9% vs. 6.3%) and breathlessness (Figure 1). 154 of these 416 (37.0%) were willing to come (11.3% vs. 6.8%). In the group with symptoms other than to our clinic for the second stage consisting of a detailed priority food gastro-intestinal symptoms dominated and questionnaire and sIgE testing. In 37.7% (58/154) sIgE was significantly higher than in the priority food group was positive for the respective food. Of these 58 cases, (47.7% vs. 38.6%). Furthermore, the group without symptoms 46 entered the 3rd stage for a full clinical evaluation. of priority food significantly more often reported that In the outpatient clinical part of the study, all outpa- the symptoms to the culprit food took place once only tients that met the inclusion criteria agreed to partici- (26.8%). pate in the study. In total, 133 outpatients that were referred to our allergy center were included during the Reported adverse reactions to priority foods in study period. Symptoms to at least one priority food community and outpatients were reported by 127 outpatients, in 102 of which sIgE Of the participants reporting adverse reactions to any to the same food(s) was detected. food (n = 967), 43.0% reported symptoms to at least one of the priority foods. Walnut, apple, cow’s milk, hazelnut Reported adverse food reactions to any food in the and kiwi were the most commonly reported priority community foods in the community (Table 1, 2nd stage). The fre- Adverse reactions to any food were reported by 25.0% quency of severe symptoms rose from 21.4% in the 1st of the responders in the community. Cow’s milk (10.7%), stage to 39.3% in the 2nd stage in participants from the nuts (9.5%), apple (9.4%) and fish (6.3%) were the most community. Remarkably, only a small percentage of par- commonly reported causative foods. Mild symptoms ticipants from the community who reported symptoms (consisting of only oral allergy symptoms) were reported to priority foods also had a positive sIgE for the respect- by 10.1%, moderate symptoms by 58.4% and severe ive food (Figure 2). symptoms by 21.4% of participants. In the group with When comparing the community to outpatients, using moderate symptoms, gastro-intestinal symptoms dominated reported symptoms to priority food as selection in both (60.2%). groups, it appeared that severe symptoms were signifi- Of the 967 participants reporting adverse reactions cantly more common in outpatients (54.3% vs. 39.3%, to any food, 416 reported symptoms to priority food p = 0.008). The frequency in which the different priority and 551 reported symptoms to other foods. These two foods were reported, differed significantly for some groups were compared and showed that the group with foods: in the community the frequency of allergy to symptoms to priority food significantly more often re- cow’s milk, fish and shrimp was significantly higher, ported oral allergy symptoms (51.5% vs. 24%), difficulty whereas outpatients reported symptoms to peanut, st 1 stage: 6600 questionnaires sent out Screening questionnaire 3864 responded 967/3864 reported symptoms to any food (25%) 416/3864 reported symptoms to priority food (10.8%) nd 2 stage: 154/416 willing to participate Case-control study 58 positive history and positive serum IgE for priority food (38%) rd 3 stage: 46/58 detailed questionnaire DBPCFC: 18 participated in DBPCFC (39%) Figure 1 Flow-diagram of the epidemiological part of the study in the community. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 4 of 8 Table 1 Patient characteristics of the three different stages 1st stage (possible FA 2nd stage (possible FA to priority 3rd stage: (probable FA to priority || ‡ § to any food) food) food) Community Community Outpatients p-value Community Outpatients p-value (n = 967) % (n = 154) % (n = 127) % (n = 46) % (n = 102) % Male gender 32.0 31.2 35.4 0.52 30.4 38.2 0.36 Age (mean ± SD) 34.7 (±9.3) 34.1 (±9.2) 32.2 (±12.3) 0.16 35.3 30.4 0.01* Number of foods causing 4 (1-17) 5 (1-18) 0.40 6 (1-14) 6 (1-18) 0.96 symptoms (median (range)) Symptom : -mild 10.1 14.0 26.0 0.01* 26.1 21.0 0.50 -moderate 58.4 46.7 19.7 <0.001* 28.3 19.0 0.21 -severe 21.4 39.3 54.3 0.008* 45.7 60.0 0.11 Atopy: -pollen allergy 70.8 94.5 <0.001* 97.8 94.1 0.44 -dermatitis 36.4 33.3 0.61 25.6 37.8 0.18 Symptoms of plant food -Hazelnut 2.4 31.2 32.3 0.84 71.7 37.3 <0.001* -Peanut 2.7 16.2 32.3 0.002* 18.6 34.3 0.04* -Walnut 2.5 36.4 36.2 0.98 52.2 41.2 0.21 -Apple 9.4 33.1 53.5 0.001* 82.6 57.8 0.003* -Peach 1.0 18.8 29.1 0.04* 50.0 34.3 0.07 -Kiwi 4.8 29.2 43.3 0.01* 34.8 40.2 0.53 -Melon 1.2 14.9 15.0 1.00 21.7 16.7 0.46 -Banana 1.4 11.0 17.3 0.17 17.4 18.6 0.86 -Tomato 2.8 13.0 17.3 0.31 13.0 18.6 0.40 -Carrot 1.8 8.4 11.8 0.42 19.6 14.7 0.46 Symptoms of animal food -Cow’s milk 10.7 31.8 8.7 <0.001* 4.3 6.9 0.72 -Hen’s egg 2.4 7.8 8.7 0.79 2.2 8.8 0.17 -Fish 6.3 18.2 5.5 0.001* 6.5 5.9 1.00 -Shrimp 3.7 20.8 10.2 0.02* 8.7 10.8 0.78 FA = food allergy. mild = oral allergy symptoms, moderate = gastro-intestinal symptoms or symptoms of the skin and mucous membranes, severe = respiratory or cardiovascular symptoms. || reported adverse food reaction to any food. positive history for priority food. positive history and serum IgE for priority food. *p-value < 0.05. apple, peach and kiwi at a significantly higher frequency positive sIgE for that food. These participants were (Table 1, 2nd stage). Outpatients had significantly more considered to have a probable FA. When comparing the clinically relevant sIgE sensitisation compared to the com- community participants and outpatients, using symp- munity for all foods, except for hazelnut and apple, where toms and sIgE to priority food as selection in both no difference was seen between both groups (Figure 2). groups (i.e. probable FA), the differences in causative In summary, causative foods, severity and relevant foods as seen in the 2nd stage disappeared largely. Only food sensitization differed between the community and hazelnut and apple were significantly more frequently outpatients when only selecting on self-reported symp- reported as a causative food in the community, whereas toms to priority foods. peanut was more commonly reported in outpatients (Table 1). In contrast to the 2nd stage, no differences Probable FA in community and outpatients were seen in the severity of symptoms between the com- Of the participants from the community that reported munity and outpatients (Table 1). Whereas in the 2nd symptoms to a priority food, 58/154 (37.7%) also had a stage major differences were observed between the two Le et al. Clinical and Translational Allergy (2015) 5:8 Page 5 of 8 sIgE in 2nd stage sIgE in 3rd stage Hazelnut (n=89) Hazelnut (n=71) 87.8 94.7 8 37.5 Peanut* (n=66) 65.9 Peanut* (n=43) 77.1 7.1 8.3 Walnut* (n=102) Walnut* (n=66) 32.6 35.7 68.6 86.8 Apple (n=119) 73.5 Apple (n=97) 84.7 75.9 Peach* (n=n=66) 95.7 Peach (n=58) 94.6 22.2 37.5 Kiwi* (n=100) 47.3 Kiwi (n=57) 63.4 Community Community 8.7 Melon (n=42) 20 Melon (n=27) 36.8 41.2 Outpatients Outpatients 11.8 37.5 Banana* (n=39) 63.6 Banana (n=27) 73.7 Tomato* (n=42) 33.3 Tomato (n=25) 68.2 78.9 Cow’s milk* (n=60) Cow’s milk (n=9) 27.3 42.9 Hen’s egg* (n=23) 0 36.4 Hen’s egg (n=10) 44.4 6.3 Shrimp* (n=45) Shrimp (n=15) 84.6 10.7 66.7 Fish* (n=35) 57.1 Fish (n=9) 66.7 0 10 203040 50607080 90 100 0 1020 3040 5060 7080 90 100 % patients with sIgE ≥0.35 kUA/L % patients with sIgE ≥0.35 kUA/L Figure 2 Percentage of positive sIgE in the community and outpatients with symptoms to the food in the 2nd stage (reported symptoms) and 3rd stage (reported symptoms and positive sIgE for at least 1 food) of the study. The number (n = ..) between brackets indicates the total number of the community and outpatients that reported symptoms to that respective priority food. *p-value <0.05. groups in sensitization to most priority foods, these dif- results are applicable to food allergic persons in the ferences disappeared largely when selecting on FA community. (Figure 2). Table 2 shows the clinical characteristics in To our knowledge this is the first study to compare more detail for the main foods. The majority with a FA in the community and outpatients. In this study we probable food allergy were birch pollen sensitized, had found that, when focusing on self-reported symptoms to symptoms within a few minutes after ingestion of the priority foods, there are large differences in causative culprit food and oral allergy symptoms was the most foods, severity and relevant food sensitization between common symptom. A probable cow’s milk en hen’s egg community and outpatients. However, when selecting allergy was rare in our adult population. In those with a those with a probable FA, as defined by reported symp- cow’s milk and hen’s egg allergy anaphylaxis was rela- toms to priority food together with a positive sIgE to the tively frequent (25%). respective food, it became evident that the differences in In total 18 participants from the community and 30 the community and outpatients disappeared. This indi- outpatients underwent DBPCFC. There were no signifi- cates that patients with a probable FA seen in a tertiary cant differences in the severity of symptoms for the indi- outpatient allergy center are not different from those vidual foods between those who agreed to participate in with a probable FA in the community. DBPCFC and those who declined (p > 0.05, data not Previous population based studies showed that the shown). The percentage of positive DPBCFC did not dif- prevalence of self-reported FA to any food varied from fer between community and outpatients (77.8% vs. 3% to as high as 35%, whereas the prevalence of true FA 63.3%, p = 0.47). Of the patients with a positive is estimated to be 2-4% [1-7,12-14]. In our study we DBPCFC, 35.7% of the community and 31.6% of outpa- confirmed for the Dutch population the discrepancy be- tients (p = 0.80) had objective signs. In both groups, the tween the prevalence of self-reported adverse food reac- percentage of placebo reactors was high: 16.7% in the tions (10.8%), a FA as defined by a suggestive history community and 20% in the outpatients. All placebo reac- and supported by sIgE (4.1%) and a FA confirmed by tors reported subjective symptoms and not objective DBPCFC (3.2%). signs on placebo day. The outcome of the challenges per Since non-response bias could play a role in the com- food are shown in Table 3. munity survey, we performed a non-response analysis. In conclusion, when focusing on a probable FA, no The response rate in the 1st stage of the community sur- difference could be demonstrated between the commu- vey was 61%. We calculated the cumulative prevalence nity participants and the outpatients with regard to se- of adverse food reaction at the time of response to ex- verity, causative foods, relevant food sensitization and trapolate the prevalence to non-responders [15]. This DBPCFC-outcome. showed that the cumulative prevalence of adverse food reaction stabilized after a response rate of 40%, indicat- ing that non-response bias does not play a major role in Discussion the 1st stage of the study. For the 2nd stage, we com- Since most studies investigating FA use outpatients as a pared age, gender, doctor-diagnosed FA and the symp- study population, the question arises whether such study toms between responders and non-responders. Only the Le et al. Clinical and Translational Allergy (2015) 5:8 Page 6 of 8 Table 2 Clinical characteristerics per food in patients with a probable food allergy (i.e. symptoms and specific IgE) Community Outpatients Symptoms Time interval sIgE Birch Symptoms Time interval sIgE Birch food IgE* food IgE* NOAS(%) skin GI Resp Cardio Anaph <5 5- 30- > Median (%) N OAS skin GI Resp Cardio Anaph <5 5- 30- > Median (%) (%) (%) (%) (%) (%) min 30 120 2 (Range) (%) (%) (%) (%) (%) (%) min 30 120 2 (range) min min hrs min min hrs Hazelnut 33 90.9 27.3 6.1 42.4 0 0 84.8 9.4 6.3 0 12.5 72.7 36 97.2 27.8 27.8 47.2 2.8 5.6 86.1 13.9 0 0 23.37 97.2 (0.47- (0.65- 74.99) 196.54) Peanut 3 66.7 33.3 33.3 33.3 0 0 50 50 0 0 2.63 100 27 88.9 59.3 29.6 48.1 0 0 77.8 22.2 0 0 2.21 85.2 (0.60- (0.35- 5.58) 321.78) Walnut 2 100 50 50 50 0 0 100 0 0 0 1.04 100 15 93.3 60 20 26.7 6.7 6.7 93.3 0 6.7 0 5.53 93.3 (0.51- (0.36- 1.58) 27.56) Apple 33 97 24.2 21.2 24.2 0 0 75.8 21.2 3 0 1.49 69.7 51 100 28 16 30 0 0 77.6 22.4 0 0 2.03 100 (0.37- (0.42- 21.18) 31.19) Peach 22 95.5 31.8 13.6 27.3 0 0 77.3 18.2 4.5 0 2.00 72.7 36 97.1 31.4 17.1 37.1 0 0 77.1 22.9 0 0 3.79 100 (0.53- (0.59- 12.91) 44.56) Kiwi 6 100 33.3 16.7 16.7 0 0 100 0 0 0 1.07 83.3 26 96.2 19.2 19.2 26.9 0 0 80 20 0 0 1.67 88.5 (0.40- (0.35- 11.21) 152.57) Cow’s milk 0 - - - - - - - - - - - - 4 50 50 50 25 25 25 50 25 0 0 10.05 50 (0.43- 34.12) Hen’s egg 0 - - - - - - - - - - - - 4 75 50 50 25 0 25 25 50 25 0 1.68 75 (0.40- 3.04) OAS = oral allergy symptoms, GI = gastro-intestinal, Resp = respiratory, cardio = cardiovascular, anaph = anaphylaxis. *Birch sIgE = sIgE birch ≥0.35. Le et al. Clinical and Translational Allergy (2015) 5:8 Page 7 of 8 Table 3 Double-blind placebo-controlled food challenge (DBPCFC) in community and outpatients Community Outpatients N Positive Negative Placebo Objective Subjective N Positive Negative Placebo Objective Subjective DBPCFC DBPCFC reactor signs* (%) symptoms* DBPCFC DBPCFC reactor signs* (%) symptoms* (%) (%) (%) (%) (%) (%) (%) (%) Hazelnut 9 77.8 11.1 11.1 42.9 100 10 60 20 20 50 100 Peanut 1 100 0 0 0 100 9 66.7 22.2 11.1 50 100 Apple 5 60 0 40 33.3 66.7 8 50 12.5 37.5 0 100 Peach 2 100 0 0 0 100 1 100 0 0 0 100 Celery 1 100 0 0 100 100 0 - - - - - Cow’s 0 - - - - - 1 100 0 0 0 100 milk Hen’s 0 - - - - - 1 100 0 0 0 100 egg * This is calculated as a percentage from those with a positive DBPCFC. frequency of oral allergy symptoms differed, being higher DBPCFC is also reported in other studies [5,7]. The in the responders (61% vs 49%, p = 0.02), which could in- main reason for refusal to participate in DBPCFC in our dicate that responders from the 2nd stage of the study patients was the lack of time. were more likely to have a probable food allergy com- In general, it might be expected that the frequency of pared to non-responders. This would mean that the dif- severe FA in outpatients referred to a tertiary allergy ferences found between community and outpatients in center is higher compared to the community. In this the 2nd stage would even be larger. For the 3rd stage, study we observed no significant difference in the fre- no differences were seen between responders and non- quency of severe symptoms between both groups. Of the responders with regard to age, sex and symptoms (data participants with a probable FA in the community, not shown). 40.4% had never sought medical care for their symptoms Although the response rate was low, the profile of re- to food and of these, 46.4% had severe symptoms upon sponders and non-responders were largely similar, and ingestion of the causative food (data not shown). Thus, therefore it is thought that a possible non-response bias severe symptoms are not always a trigger for FA-patients would not play a major role. Low response rates are not to seek medical care. unusual in population based studies investigating the prevalence of food allergy [3,5]. Conclusions The gold standard for the diagnosis of FA is DBPCFC In the Netherlands, there are large differences in self- [16]. However, DBPCFC is time-consuming, expensive, reported FA between community and outpatients. How- subjects patients to potential severe allergic reactions, ever, Dutch community and outpatients with a probable requires the need for well equipped facilities and may FA do not differ with respect to severity, causative foods, not be able to reproduce the conditions that occurred sensitization and DBPCFC-outcome. when the reported allergic reaction took place [17,18]. Abbreviations Due to these practical problems, in normal clinical set- DBPCFC: Double-blind placebo-controlled food challenge; FA: Food allergy; tings FA is often diagnosed by a thorough medical his- OR: Odds ratio. tory and a test for sensitization [17,19]. In our study, medical history and sIgE was used to define a probable Competing interests Prof. Dr. S. Vieths reports personal fees from Food Allergy Resource and FA since this could be performed in all participants Research Program, Lincoln, NE USA, personal fees from Medical University of and outpatients. Certain participants in the community Vienna, Austria, grants from Monsanto Company, personal fees from and outpatient studies agreed to undergo DBPCFC and, American Academy of Asthma, Allergy and Immunology, personal fees from Deutsche Dermatologische Gesellschaft, personal fees from Spanish Society whilst a relatively small sample, no differences were seen of Allergy and Clinical Immunology, personal fees from Westdeutsche in the rates of either positive DBPCFC (78% and 64%, Arbeitsgemeinschaft für pädiatrische Pneumologie und Allergologie e.V., respectively) or the objective signs between the two Köln, Germany, personal fees from Gesellschaft für pädiatrische Allergologie und Umweltmedizin, personal fees from Ärzteverband Deutscher groups. These data indicate that the clinical characteris- Allergologen, personal fees from Schattauer Allergologie Handbuch, personal tics of individuals with a probable FA in this population fees from Elsevier Nahrungsmittelallergien und Intoleranzen, non-financial were similar between the two populations and that the support from German Research Foundation, non-financial support from Federal Institute for Risk Assessment, non-financial support from Austrian Society for estimates of prevalence relying only on clinical history Allergology and Immunology, non-financial support from European Directorate and sIgE will over-estimate rates of confirmed food for the Quality of Medicines and Health Care, non-financial support from European allergy by around 22-37%. A low participation rate in Academy of Allergy and Clinical Immunology , non-financial support from World Le et al. Clinical and Translational Allergy (2015) 5:8 Page 8 of 8 Allergy Organization, non-financial support from Association Monégasque pour le 4. Kanny G, Moneret-Vautrin DA, Flabbee J, Beaudouin E, Morisset M, Thevenin Perfectionnement des Connaissances des Médicins, non-financial support from F. Population study of food allergy in France. J Allergy Clin Immunol. Federal Office of Consumer Protection and Food Safety , non-financial support 2001;108(1):133–40. from German Chemical Society (GDCh), non-financial support from Austrian 5. Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R. A population Society for Dermatology and Venerology, non-financial support from AKM study of food intolerance. Lancet. 1994;343(8906):1127–30. Allergiekongress, non-financial support from Austrian Food Chemical Society, 6. Osterballe M, Hansen TK, Mortz CG, Host A, Bindslev-Jensen C. The outside the submitted work. E. N. Clare Mills has received research support from prevalence of food hypersensitivity in an unselected population of children the European Union, the Biological and Biotechnological Sciences Research and adults. Pediatr Allergy Immunol. 2005;16(7):567–73. Council, the UK Food Standards Agency; is a board member for Novartis, the UK 7. Jansen JJ, Kardinaal AF, Huijbers G, Vlieg-Boerstra BJ, Martens BP, Ockhuizen Food Standards Agency, PepsiCo International, the UK Biological and Biotechnological T. Prevalence of food allergy and intolerance in the adult Dutch population. Sciences Research Council, the European Food Safety Authority, the European J Allergy Clin Immunol. 1994;93(2):446–56. Academy of Allergy and Clinical Immunology; is consultant for Reacta Biotech Ltd; 8. Jones RB, Hewson P, Kaminski ER. Referrals to a regional allergy clinic - an is employed by the University of Manchester and the Institute of Food Research; eleven year audit. BMC Public Health. 2010;10:790. has stock/stock options in Reacta Biotech Lts; received grants/pending grants from 9. Mills EN, Mackie AR, Burney P, Beyer K, Frewer L, Madsen C, et al. The The Biological and Biotechnological Sciences Research Council, the European union, prevalence, cost and basis of food allergy across Europe. Allergy. the UK Food Standards Agency, DBV Technology, Reacta Biotech Ltd, North West 2007;62(7):717–22. Lung Centre Charity, Medical Research Council; has received travel support from 10. Kummeling I, Mills EN, Clausen M, Dubakiene R, Perez CF, Fernandez-Rivas M, ILSI, EAACI, Europa Bio, the British High Commission, the Iceland Allergy Society, et al. The EuroPrevall surveys on the prevalence of food allergies in children Fresenius, EuroFood Tox 2013, Campden BRI, Food Matters Live and the IUNS and adults: background and study methodology. Allergy. 2009;64(10):1493–7. Annual Meeting (Granada, Spain September 2013); and was paid as a lecturer and 11. Cochrane SA, Salt LJ, Wantling E, Rogers A, Coutts J, Ballmer-Weber BK, et al. supervisor of masters students at Imperial College and as an external examiner at Development of a standardized low-dose double-blind placebo-controlled the University of Birmingham. challenge vehicle for the EuroPrevall project. Allergy. 2012;67(1):107–13. The rest of the authors declare that they have no relevant conflicts of 12. Zuidmeer L, Goldhahn K, Rona RJ, Gislason D, Madsen C, Summers C, et al. interest. The prevalence of plant food allergies: a systematic review. J Allergy Clin Immunol. 2008;121(5):1210–8. 13. Emmett SE, Angus FJ, Fry JS, Lee PN. Perceived prevalence of peanut allergy Authors’ contributions in Great Britain and its association with other atopic conditions and with The study was designed by TL, EvH, IK and ACK. Data was collected by AFML peanut allergy in other household members. Allergy. 1999;54(4):380–5. and TL. Analysis of the data and preparing a first draft was performed by TL. 14. Woods RK, Abramson M, Bailey M, Walters EH. International prevalences of Interpretation of data, drafting and revising the manuscript was done by TL, reported food allergies and intolerances. Comparisons arising from the EvH, IK, JP, BKB, CAFMB, JL, AFML, TML, AM, ENCM, RvR, SV, MF, PGB and European Community Respiratory Health Survey (ECRHS) 1991–1994. Eur J ACK. All authors read and approved the final manuscript. Clin Nutr. 2001;55(4):298–304. 15. Lessler JT, Kalsbeek WD. Nonsampling error in surveys. New York: Wiley; 1992. Acknowledgement 16. Boyce JA, Assa’ad A, Burks AW, Jones SM, Sampson HA, Wood RA, et al. This work was funded by the EU through EuroPrevall (FP6- FOOD-CT-2005- Guidelines for the diagnosis and management of food allergy in the United 514000). States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. We would like to thank Lucía Jimeno and Domingo Barber, f0072om ALK- 2010;126(6 Suppl):S1–58. Abelló, Spain, for providing the skin prick tests materials. 17. Asero R, Fernandez-Rivas M, Knulst AC, Bruijnzeel-Koomen CA. Double-blind, placebo-controlled food challenge in adults in everyday clinical practice: a Funding reappraisal of their limitations and real indications. Curr Opin Allergy Clin This work was funded by the EU through EuroPrevall (FP6- FOOD-CT-2005- Immunol. 2009;9(4):379–85. 514000). 18. Sampson HA. Immunologically mediated food allergy: the importance of food challenge procedures. Ann Allergy. 1988;60(3):262–9. Author details 19. Seitz CS, Pfeuffer P, Raith P, Brocker EB, Trautmann A. Food allergy in adults: Department of Dermatology/Allergology, University Medical Center Utrecht, an over- or underrated problem? Dtsch Arztebl Int. 2008;105(42):715–23. PO Box 855003508 GA Utrecht, The Netherlands. Department of Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, UK. Allergy Unit, Department of Dermatology, University Hospital Zürich, Zürich, Switzerland. 4 5 Thermo Fisher Scientific, Uppsala, Sweden. Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK. Institute of Inflammation and Repair, Manchester Academic Health Sciences Centre, Manchester Institute of Biotechnology, The University of Manchester, Manchester, UK. Department of Experimental Immunology and Department of Otorhinolaryngology, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands. Division of Allergology, Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany. Allergy Department, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. Current affiliation: NIZO food research, Ede, The Netherlands. Submit your next manuscript to BioMed Central and take full advantage of: Received: 17 June 2014 Accepted: 30 January 2015 • Convenient online submission • Thorough peer review References 1. Rona RJ, Keil T, Summers C, Gislason D, Zuidmeer L, Sodergren E, et al. The • No space constraints or color figure charges prevalence of food allergy: a meta-analysis. J Allergy Clin Immunol. • Immediate publication on acceptance 2007;120(3):638–46. • Inclusion in PubMed, CAS, Scopus and Google Scholar 2. Madsen C. Prevalence of food allergy: an overview. Proc Nutr Soc. 2005;64(4):413–7. • Research which is freely available for redistribution 3. Zuberbier T, Edenharter G, Worm M, Ehlers I, Reimann S, Hantke T, et al. Prevalence of adverse reactions to food in Germany - a population study. Submit your manuscript at Allergy. 2004;59(3):338–45. www.biomedcentral.com/submit

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Clinical and Translational Allergy – Springer Journals

Published: Feb 25, 2015

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