No longitudinal studies exist on the natural history of food hypersensitivity and IgE sensitisation to food allergens in adults.
To examine the natural history of food hypersensitivity, the natural history of IgE sensitisation to food allergens and to investigate the risk factors for new onset food hypersensitivity.
Food hypersensitivity was questionnaire-assessed in 2307 individuals (aged 20–45 years) from Iceland and Sweden during the European Community Respiratory Health Survey both at baseline and follow-up 9 years later. IgE food and aeroallergen sensitisation were assessed in a subgroup of these individuals (n = 807). Values of 0.35 kU/L and above were regarded as positive sensitisation.
Food hypersensitivity was reported by 21% of the subjects and this proportion remained unchanged at follow-up (p = 0.58). Fruits, nuts and vegetables were the three most common causes of food hypersensitivity, with a similar prevalence at baseline and follow-up. The prevalence IgE sensitisation to food allergens decreased in general by 56% (p<0.001) and IgE sensitisation to peanut decreased in particular by 67% (p = 0.003). The prevalence of timothy grass IgE sensitisation decreased by 15% (p = 0.003) while cat, mite and birch IgE sensitisation did not decrease significantly. Female sex, rhinitis, eczema and presence of IgE sensitisation to aeroallergens were independently associated with new onset food hypersensitivity.
The prevalence of food hypersensitivity remained unchanged while the prevalence of IgE sensitisation to food allergens decreased in adults over a 9-year follow-up period. The decrease in prevalence of IgE sensitisation to food allergens was considerably larger than the change in prevalence of IgE sensitisation to aeroallergens.
Citation: Patelis A, Gunnbjörnsdottir M, Borres MP, Burney P, Gislason T, Torén K, et al. (2014) Natural History of Perceived Food Hypersensitivity and IgE Sensitisation to Food Allergens in a Cohort of Adults. PLoS ONE 9(1): e85333. https://doi.org/10.1371/journal.pone.0085333
Editor: Giuseppe Remuzzi, Mario Negri Institute for Pharmacological Research and Azienda Ospedaliera Ospedali Riuniti di Bergamo, Italy
Received: August 30, 2013; Accepted: December 4, 2013; Published: January 10, 2014
Copyright: © 2014 Patelis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported financially by the Swedish Heart and Lung Foundation, the Vårdal Foundation for Health Care Science and Allergy Research, the Swedish Association against Asthma and Allergy, Agnes and Mac Rudberg's Foundation and the Bror Hjerpstedt Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Kjell Alving is an employee and minority shareholder of Aerocrine AB and has received funds for research from the same company. Magnus Borres is an employee of ThermoFisher Scientific (which manufactures kits to measure IgE antibodies against allergens). This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
Several population surveys in the 1990s have estimated the prevalence of perceived food hypersensitivity, e.g. self-reported adverse reactions after food ingestion, regardless of the underlying mechanism , at 12% to 20% in adults –. The majority of adverse reactions to food are not IgE-mediated  and there is limited information on the prevalence and distribution of IgE food sensitisation. About 15% to 20% of the population has IgE to at least one food allergen over the detection limit ,  e.g. food IgE sensitisation. However, only a small fraction of subjects with IgE antibodies against food allergens have clinical IgE-mediated food allergy. As an example, Liu et al  reported that the prevalence of food IgE sensitisation was 15% whereas the prevalence of IgE-mediated food allergy was only 2%.
Aeroallergen IgE sensitisation, especially against perennial allergens, is linked to asthma and airway inflammation –. The natural history of prevalence of aeroallergen IgE sensitisation has been examined in longitudinal studies in adults –, but the results are contradictory and show the prevalence decreasing , , remaining stable ,  or increasing , , ,  over time.
To the best of our knowledge, no study exists about the natural history of food hypersensitivity and IgE sensitisation to food allergens in adults. Another reason for studying IgE sensitisation to food allergens and IgE-mediated food allergy is that not only aeroallergen sensitisation, but also food IgE sensitisation, is linked to increased exhaled nitric oxide levels and increased risk for asthma , , .
The aim of this study was to examine the natural history food hypersensitivity symptoms and IgE sensitisation to food allergens and to investigate the risk factors for new onset food hypersensitivity and sensitisation.
The study was based on the European Community Respiratory Health Survey (ECRHS) I (1991–92) and II (2000–01)  from four participating centres (Reykjavík, Uppsala, Gothenburg and Umeå). Each participant in ECRHS I was sent a brief questionnaire (Stage 1) and among those who responded, both a random and a ‘‘symptomatic’’ sample (consisting of subjects with symptoms of asthma or asthma medication), were invited to undergo a more detailed clinical examination (Stage 2). Subjects from Stage 2 of ECRHS I were invited to participate in the follow-up study, ECRHS II, and answered a standardized questionnaire and underwent a clinical visit . A total of 2,307 individuals answered questions about food hypersensitivity symptoms both at ECRHS I and II. No difference in age, sex, BMI, prevalence of asthma, rhinitis, total IgE, food IgE sensitisation, aeroallergen IgE sensitisation and smoking history were found between subjects with and without follow-up data about food hypersensitivity symptoms (all p>0.05). A subgroup of ECRHS participants in Iceland (Reykjavík) and Sweden (Uppsala, Gothenburg and Umeå) from the random sample (n = 807) was examined against IgE to food allergens at ECRHS I   and ECRHS II (Figure 1).
Diagnosis of asthma
A person was defined as asthmatic if he/she had ever been diagnosed with asthma and had an asthma attack or one of the following symptoms: nocturnal chest tightness, attack of shortness of breath, chest wheezing or whistling during the last 12 months .
Definition of food hypersensitivity
An individual was considered having food hypersensitivity  if he/she answered yes to the following questions “Have you ever had an illness or trouble caused by eating a particular food or foods?” and if so, “Have you nearly always had the same illness or trouble after eating this type of food?” Respondents were then asked to list the food(s) and symptoms .
Measurements of IgE to aeroallergens and food allergens and total IgE
Venous blood samples were drawn from all participants in the clinical visits and frozen at −20°C for measurement of total serum IgE (total IgE) and serum IgE antibodies to cat, D. pteronyssinus, timothy grass, birch, and Cladosporium, as part of the ECRHS I and II protocol . Measurement of IgE antibodies against birch was performed in all centres in the ECRHS I and in the Uppsala centre in ECRHS II. In addition, IgE antibodies to a mix of food allergens (containing egg white, milk, cod fish, wheat, peanut, and soybean) were measured in the subgroup of ECRHS participants in Iceland (Reykjavík) and Sweden (Uppsala, Gothenburg and Umeå) from the random sample by same technique and reagents at ECRHS I and II (Pharmacia CAP System, MultiCap fx5, Thermo Fisher Scientific, Uppsala, Sweden). Serum with a positive reaction to the food panel (fx5) was further analysed for the single allergens in the panel. The results are presented in kU/L, and values of 0.35 kU/L and above were regarded as positive sensitisation . A titre below the detection level (<0.35 kU/L) was arbitrarily given the value 0.17 kU/L). All samples from ECRHS I from Reykjavík, Uppsala, Gothenburg and Umeå were analysed in Uppsala, as previously described  while samples from the random sample of ECRHS II (depending on availability of residual samples) were analysed within the frame of EuroPREVALL in Manchester, as described elsewhere .
Statistical analyses were performed using STATA 12.1 software (Stata Corp., 2011, Texas, USA). IgE titres (both total and specific) were log transformed before analysis. Mc Nemar's test was used to compare prevalence of food hypersensitivity, various food related symptoms and IgE sensitisation in ECRHS I and II. Chi-squared test (for categorical variables) and unpaired t-test (for numerical variables) were used to compare individuals with new onset and no food hypersensitivity and prevalence of IgE sensitisation to food, cat/mite and timothy grass allergens. Chi-squared test was also used to compare prevalence of IgE sensitisation to food in subjects according to age (< or > median age). Paired t-test was used to compare levels of IgE to specific allergens between ECRHS I and II in subjects sensitised to each respective allergen at either ECRHS I or II and unpaired t-test was used to compare levels of IgE against food allergens at ECRHS I in subjects with persistence and remission of IgE sensitisation to food allergens. Multiple logistic regression models were used when examining predictors for new onset food hypersensitivity, and persistent food sensitisation. These models always included age, gender, body mass index, rhinitis, current asthma, total IgE, IgE against food allergens, sample and IgE against aeroallergens. A p–value of <0.05 was considered statistically significant.
The study population comprised of 2,307 individuals who answered questions about food hypersensitivity symptoms in both ECRHS I and II. Of these, 53% were women. The group characteristics of the participants are presented in Table 1.
Natural history of food hypersensitivity symptoms
Around 21% of the interviewed subjects reported food hypersensitivity symptoms in both ECRHS I and II (Table 2). The most common foods related to these symptoms were fruits followed by nuts and then vegetables. The prevalence of food hypersensitivity in relation to ingestion of fish (including seafood and shellfish) increased significantly from ECRHS I to II and become, together with vegetables, the fourth most common cause of food hypersensitivity. Food hypersensitivity symptoms due to dairy products, wheat products (gluten, cereal and wheat) and spices (herbs, chili, and garlic) also increased significantly from ECRHS I to II (Table 2).
Skin reactions were the most common reported symptoms both at baseline and follow-up (Table 3). No significant change in the prevalence of the different symptoms was found during the 9-year period between ECRHS I and II.
Natural history of prevalence of IgE sensitisation to food and aeroallergens
Prevalence of IgE sensitisation to at least one food allergen decreased by 56% during the study (Figure 2A). Prevalence of peanut IgE-sensitisation was the highest among food allergens and decreased by 67%. The prevalence of soy IgE sensitisation decreased significantly between ECRHS I and II, whereas similar prevalence of IgE sensitisation to wheat, milk, egg and fish was found at both time points (Figure 2B). No significant change of prevalence of cat, birch and mite IgE sensitisation was found, whereas prevalence of timothy grass IgE sensitisation decreased by 15% (from 17% to 15%) (Figure 2A).
Birch pollen was measured only in Uppsala (n = 138).
The prevalence of IgE sensitisation to food allergens decreased from ECRHS I to ECRHS II by 63% (from 6% to 2%) (p<0.001) in subjects younger than 31 years and by 44% (from 4% to 2%) (p<0.001) in subjects older than 31 years (median age of cohort in ECRHS I).
Changes over time of levels of IgE against food- and aeroallergens and total IgE
Significant decreases of IgE antibodies against peanut (p<0.001, Figure 3a) and soy (p<0.001 Figure 3b), but not against wheat (p = 0.12, Figure 3c), milk (p = 0.9), egg (p = 0.4) were found between ECRHS I and II among individuals who were IgE-sensitised to the respective allergen either at baseline or follow-up.
(The dotted line corresponds to the detection limit of 0.35 kU/L and the red lines correspond to the geometrical mean of levels of specific IgE against each respective allergen).
Similarly, among the aeroallergens, the levels of IgE antibodies against timothy grass decreased (p<0.001) whereas levels of IgE against cat (p = 0.18), birch (p = 0.43) and mite (p = 0.12) remained stable between ECRHS I and II among individuals who were IgE-sensitised to the respective allergen either at baseline or follow-up.
Total IgE increased between ECHRS I and II (17.7 (16.0, 19.7) vs. 25.7 (23.4, 28.2) kU/L (geometric mean) (p<0.001)).
Incidence of food hypersensitivity
The incidence of food hypersensitivity was 11.7% during this 9-year study. The incidence in the symptomatic sample was higher than the random sample (20.6% vs. 9.9%, p<0.001). Female sex, rhinitis, eczema, asthma and presence of IgE sensitisation to aeroallergens were associated with new onset food hypersensitivity (Table 4) and these associations were consistent in a multiple logistic regression model (Figure 4).
Odds ratios are adjusted for the variables in the figure and age, body mass index, current smoking, sample and total IgE.
Incidence and persistence of IgE sensitisation to food allergens
New onset IgE food sensitisation (n = 8) was not associated with age, gender, BMI, current rhinitis, current asthma, current smoking and IgE sensitisation to aeroallergens (data not shown). Persistent IgE food sensitisation was associated with higher total IgE levels at baseline (Table 5) and this association remained significant also after adjusting for age, gender, BMI, current rhinitis, current asthma, current smoking and IgE sensitisation to aeroallergens (OR (95% CI) = 9.8 (1.6, 60.5) per unit of natural logarithm-transformed total IgE). No relation between persistence of IgE sensitisation to food allergens and specific IgE levels to food allergens or aeroallergens or prevalence of IgE sensitisation to aeroallergens at baseline was found (Table 5).
The main findings in the present investigation are that one in five adults reported food hypersensitivity symptoms after food intake and this proportion remained unchanged during this 9-year longitudinal study. The prevalence of IgE-sensitisation to food allergens decreased during that 9-year period whereas the prevalence of sensitisation to aeroallergens remained relatively unchanged.
To our knowledge this is the first study that analysed longitudinal changes of perceived self-reported food hypersensitivity in adults. The prevalence of food hypersensitivity reported here is in line with reports from previous cross-sectional studies –, . Our results showing an unchanged prevalence of food hypersensitivity over time are opposite to what is known about the natural history of food hypersensitivity in children, where major remission of symptoms has been reported –.
The two most common reported symptoms of food hypersensitivity were skin reactions and gastrointestinal reactions. Reactions occurring at the skin or mucosa were also the most prevalent in a previous study . Fruits, nuts and vegetables were the three most common causes of food hypersensitivity in our population, with a similar prevalence at baseline and follow-up. A previous study  showed the same major causes of adverse reactions to foods.
The risk factors for new onset food hypersensitivity in the present study were female sex, rhinitis, eczema, asthma and presence of IgE sensitisation to aeroallergens. Thus, incidence of food hypersensitivity seems to be related to the atopic trait of an individual. We are not aware of any published longitudinal study to compare our results with. However, there are cross-sectional studies showing that food hypersensitivity in adults is often associated with concomitant sensitisation to aeroallergens , IgE sensitisation to food allergens  and other manifestations of atopy, especially rhinitis .
A novel finding of the study was the marked reduction of prevalence of IgE sensitisation to food allergens over time in adults. The natural history of prevalence of IgE sensitisation to food allergens has previously been studied only in children  where sensitisation rates to food allergens remained stable during the first 6 years of life (10%). The majority of children outgrow their allergies to milk, soy, egg, and wheat, and some to peanut also . The decrease in the prevalence of IgE sensitisation to food allergens does not appear to be related to the initial age of the subjects, which tends to preclude the possibility that the effect is related to a specific birth cohort. Reductions of similar size could be observed in both younger and older subjects. This probably signals that the decreasing prevalence is somehow related to aging. Previous longitudinal studies , , ,  on the prevalence of IgE sensitisation to aeroallergens in relation to age report inconsistent results.
In the present study the prevalence of sensitisation to aeroallergens decreased to a much lesser extent than sensitisation to food allergens. However, the levels of IgE antibodies decreased during the 9-year follow-up period for both food and aeroallergens, whereas the levels of total IgE increased. Most of the longitudinal studies have analysed changes in the prevalence of IgE sensitisation without reporting changes in the degree of IgE sensitisation. A decrease of IgE titres to mite in a long-term follow-up of subjects with house-dust allergic asthma has been reported . Karakaya and Kalyoncu  reported that the wheal diameter in response to skin prick test decreased under a two-year period for two of the studied allergens, timothy grass and mite. The reason why specific IgE decreased and total IgE increased in the present study is unclear. However our finding of increase total IgE is consistent with an increase of total IgE in all ECRHS centres  even if other longitudinal studies reported stable levels over time , . The total IgE levels reflect more than the sum of specific IgE towards a broad panel of allergens . Moreover the fraction of total IgE not-related to specific sensitisations was not related to the specific IgE fraction of total IgE . The factors that control the fraction of total IgE that are not related to specific IgE sensitisation are not fully understood.
Subjects with higher total IgE levels at baseline were more likely to have persistent sensitisation to food allergens in our study. Increased levels of total IgE have been reported to predict the development of IgE sensitisation to aeroallergens and asthma symptoms in children . As far as we know, no study has analysed the relation between baseline total IgE levels and persistence of IgE sensitisation to food allergens, whereas increased total IgE at baseline related  to persistence of aeroallergen IgE sensitisation in previous longitudinal studies.
The strength of this study is the population setting and the long follow-up period. This is the first study to our knowledge assessing food hypersensitivity and IgE levels against food allergens in a longitudinal setting. A weakness of the present study is that we were not able to assess the persistence/remission of food hypersensitivity as the questions refer to ever having food hypersensitivity. A limitation is the fairly limited number of participants for whom we had data from repeated measurements of IgE against food allergens. Another limitation is that several of the most common food allergens in adulthood, such as hazelnut, shrimp, peach and apple , were not analysed at both time points. The different freezing times before analysis of IgE for samples from ECRHS I and II and that measurements were performed in different laboratories (Uppsala for ECRHS I and Manchester for ECRHS II) does not appear to influence the measured IgE levels , . Cross reactivity with IgE antibodies against birch or timothy grass can influence the measured IgE sensitisation to food allergens, and the lower prevalence of IgE sensitisation to food allergens at follow-up could have been due to a reduced prevalence of IgE sensitisation to birch at the follow-up. However, the prevalence of IgE sensitisation to birch did not decrease in the present study while the prevalence of IgE sensitisation to timothy grass decreased to a much lesser degree than IgE sensitisation to food allergens.
In conclusion, the prevalence of food hypersensitivity remained unchanged while IgE sensitisation to food allergens decreased in this 9 year follow up study performed in adults. The prevalence of IgE sensitisation towards food allergens decreased to a larger extent than the prevalence and persistence of IgE sensitisation to aeroallergens. The biological explanation for the high prevalence of food hypersensitivity should be further investigated.
Conceived and designed the experiments: AP CJ AM. Performed the experiments: CJ PB TG KT BF MG. Analyzed the data: AP CJ AM. Contributed reagents/materials/analysis tools: CJ MB KA. Wrote the paper: AP AM CJ. Revised critically: AP MG MB PB TG KT BF KA AM CJ. Final approval: AP MG MB PB TG KT BF KA AM CJ.
- 1. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, et al. (2004) Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol 113: 832–836.
- 2. Woods RK, Abramson M, Bailey M, Walters EH (2001) International prevalences of reported food allergies and intolerances. Comparisons arising from the European Community Respiratory Health Survey (ECRHS) 1991–1994. Eur J Clin Nutr 55: 298–304.
- 3. Altman DR, Chiaramonte LT (1996) Public perception of food allergy. Journal of Allergy and Clinical Immunology 97: 1247–1251.
- 4. Schafer T, Bohler E, Ruhdorfer S, Weigl L, Wessner D, et al. (2001) Epidemiology of food allergy/food intolerance in adults: associations with other manifestations of atopy. Allergy 56: 1172–1179.
- 5. Taylor SL (1986) Food allergies and sensitivities. J Am Diet Assoc 86: 599–600.
- 6. Patelis A, Gunnbjornsdottir M, Malinovschi A, Matsson P, Onell A, et al. (2012) Population-based study of multiplexed IgE sensitization in relation to asthma, exhaled nitric oxide, and bronchial responsiveness. J Allergy Clin Immunol 130: : 397–402 e392.
- 7. Liu AH, Jaramillo R, Sicherer SH, Wood RA, Bock SA, et al. (2010) National prevalence and risk factors for food allergy and relationship to asthma: results from the National Health and Nutrition Examination Survey 2005–2006. J Allergy Clin Immunol 126: : 798–806 e713.
- 8. Sears MR, Herbison GP, Holdaway MD, Hewitt CJ, Flannery EM, et al. (1989) The relative risks of sensitivity to grass pollen, house dust mite and cat dander in the development of childhood asthma. Clin Exp Allergy 19: 419–424.
- 9. Malinovschi A, Janson C, Holmkvist T, Norback D, Merilainen P, et al. (2006) IgE sensitisation in relation to flow-independent nitric oxide exchange parameters. Respir Res 7: 92.
- 10. Sporik R, Ingram J, Price W, Sussman J, Honsinger R, et al. (1995) Association of asthma with serum IgE and skin test reactivity to allergens among children living at high altitude. Tickling the dragon's breath. Am J Respir Crit Care Med 151: 1388–1392.
- 11. Peat JK, Tovey E, Toelle BG, Haby MM, Gray EJ, et al. (1996) House dust mite allergens. A major risk factor for childhood asthma in Australia. Am J Respir Crit Care Med 153: 141–146.
- 12. Jarvis D, Luczynska C, Chinn S, Potts J, Sunyer J, et al. (2005) Change in prevalence of IgE sensitization and mean total IgE with age and cohort. J Allergy Clin Immunol 116: 675–682.
- 13. Barbee RA, Kaltenborn W, Lebowitz MD, Burrows B (1987) Longitudinal changes in allergen skin test reactivity in a community population sample. J Allergy Clin Immunol 79: 16–24.
- 14. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, et al. (2002) Is the increase in allergic respiratory disease caused by a cohort effect? Clin Exp Allergy 32: 1702–1705.
- 15. Warm K, Backman H, Lindberg A, Lundback B, Ronmark E (2012) Low incidence and high remission of allergic sensitization among adults. J Allergy Clin Immunol 129: 136–142.
- 16. Broadfield E, McKeever TM, Scrivener S, Venn A, Lewis SA, et al. (2002) Increase in the prevalence of allergen skin sensitization in successive birth cohorts. J Allergy Clin Immunol 109: 969–974.
- 17. Oryszczyn MP, Annesi I, Neukirch F, Dore MF, Kauffmann F (1995) Longitudinal observations of serum IgE and skin prick test response. Am J Respir Crit Care Med 151: 663–668.
- 18. Karakaya G, Kalyoncu AF (2006) The natural course of atopy determined by skin prick tests in patients with bronchial asthma and/or rhinitis. Allergol Immunopathol (Madr) 34: 257–262.
- 19. Linneberg A, Friedrich N, Husemoen LL, Thuesen B, Gonzalez-Quintela A, et al. (2010) Incidence and remission of specific IgE aeroallergen sensitization from age of 40 to 60 years, and association with alcohol consumption. Int Arch Allergy Immunol 151: 142–148.
- 20. Hughes JL, Brown T, Edgar JD, Shields MD (2010) Peanut allergy and allergic airways inflammation. Pediatr Allergy Immunol 21: 1107–1113.
- 21. Burney PG, Luczynska C, Chinn S, Jarvis D (1994) The European Community Respiratory Health Survey. Eur Respir J 7: 954–960.
- 22. Bjornsson E, Janson C, Plaschke P, Norrman E, Sjoberg O (1996) Prevalence of sensitization to food allergens in adult Swedes. Ann Allergy Asthma Immunol 77: 327–332.
- 23. Gislason D, Bjornsson E, Gislason T, Janson C, Sjoberg O, et al. (1999) Sensitization to airborne and food allergens in Reykjavik (Iceland) and Uppsala (Sweden) - a comparative study. Allergy 54: 1160–1167.
- 24. The European Community Respiratory Health Survey II. Eur Respir J 20: 1071–1079.
- 25. Olafsdottir IS, Gislason T, Thjodleifsson B, Olafsson I, Gislason D, et al. (2005) C reactive protein levels are increased in non-allergic but not allergic asthma: a multicentre epidemiological study. Thorax 60: 451–454.
- 26. Bousquet J, Chanez P, Chanal I, Michel FB (1990) Comparison between RAST and Pharmacia CAP system: a new automated specific IgE assay. J Allergy Clin Immunol 85: 1039–1043.
- 27. Burney P, Summers C, Chinn S, Hooper R, van Ree R, et al. (2010) Prevalence and distribution of sensitization to foods in the European Community Respiratory Health Survey: a EuroPrevall analysis. Allergy 65: 1182–1188.
- 28. Young E, Stoneham MD, Petruckevitch A, Barton J, Rona R (1994) A population study of food intolerance. The Lancet 343: 1127–1130.
- 29. Sampson HA (1996) Epidemiology of food allergy. Pediatr Allergy Immunol 7: 42–50.
- 30. Eggesbo M, Halvorsen R, Tambs K, Botten G (1999) Prevalence of parentally perceived adverse reactions to food in young children. Pediatr Allergy Immunol 10: 122–132.
- 31. Sicherer SH, Leung DY (2013) Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2012. J Allergy Clin Immunol 131: 55–66.
- 32. Skypala I (2011) Adverse food reactions–an emerging issue for adults. J Am Diet Assoc 111: 1877–1891.
- 33. Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U, et al. (1999) Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol 103: 1173–1179.
- 34. Ramesh S (2008) Food allergy overview in children. Clin Rev Allergy Immunol 34: 217–230.
- 35. Rawle FC, Burr ML, Platts-Mills TA (1983) Long-term falls in antibodies to dust mite and pollen allergens in patients with asthma or hay fever. Clin Allergy 13: 409–417.
- 36. Carsin AE, Zock JP, Jarvis D, Basagana X, Heinrich J, et al. (2013) Serum total immunoglobulin E is a surrogate of atopy in adult-onset asthma: a longitudinal study. Int Arch Allergy Immunol 160: 387–392.
- 37. Barbee RA, Halonen M, Kaltenborn W, Lebowitz M, Burrows B (1987) A longitudinal study of serum IgE in a community cohort: correlations with age, sex, smoking, and atopic status. J Allergy Clin Immunol 79: 919–927.
- 38. Jackola DR, Blumenthal MN, Rosenberg A (2004) Evidence for two independent distributions of serum immunoglobulin E in atopic families: cognate and non-cognate IgE. Hum Immunol 65: 20–30.
- 39. Sherrill DL, Stein R, Halonen M, Holberg CJ, Wright A, et al. (1999) Total serum IgE and its association with asthma symptoms and allergic sensitization among children. J Allergy Clin Immunol 104: 28–36.
- 40. Linneberg A, Nielsen NH, Madsen F, Frolund L, Dirksen A, et al. (2000) Increasing prevalence of specific IgE to aeroallergens in an adult population: two cross-sectional surveys 8 years apart: the Copenhagen Allergy Study. J Allergy Clin Immunol 106: 247–252.
- 41. Paganelli R, Ansotegui IJ, Sastre J, Lange CE, Roovers MH, et al. (1998) Specific IgE antibodies in the diagnosis of atopic disease. Clinical evaluation of a new in vitro test system, UniCAP, in six European allergy clinics. Allergy 53: 763–768.