Thesis (M.S.P.H.)--University of Michigan, 1941.

Thesis (M.S.P.H.)--University of Michigan, 1941.

Background: This thesis focuses on the incidence and remission of reported food hypersensitivity in schoolchildren followed from 8 to 12 -years of age and the prevalence of hypersensitivity to milk, egg, cod and wheat among 12-year olds investigated by reported data, clinical investigation and double-blind placebo-controlled food challenges and biomarkers. Methods: The studies are mainly based on a population based cohort recruited in 2006 from three municipalities in Northern Sweden. All children in first and second grade, aged 7-8 years, were invited to a parental questionnaire study and 2585 (96% of invited) participated. The children in two of the municipalities were also invited to a skin prick test with airborne allergens. At age 11-12 years, there was a follow-up of the cohort using the same methods, with the addition of a child interview and assessment of body mass index (BMI). At the follow-up, children who reported milk hypersensitivity were invited to structured interviews and children reporting complete elimination of milk, egg, cod or wheat due to perceived hypersensitivity were invited to a clinical examination and blood sampling. According to test results, the children were categorized into different food hypersensitivity phenotypes according to preset criteria. Children categorized as current food allergy were then invited to further evaluation with a double-blind placebo-controlled food-challenge using newly developed recipes. Before their use, the recipes were successfully validated regarding detectable sensorial differences between the active and placebo substances in a separate cohort of healthy schoolchildren (n=275). Before and after the challenge series blood samples were collected for analyses of cytokine mRNA expression in peripheral blood mononuclear cells including hallmark cytokines for the humoral allergy-promoting T helper (Th) 2 response, cellular cytotoxicity-promoting Th1 response, inflammatory-, and T regulatory responses. Fecal inflammatory biomarkers were also analyzed before and after the challenge series. Results: Reported food hypersensitivity increased from 21% at age 7-8 years to 26% at 11-12 years. There was a high incidence (15%) as well as a high remission (33%) of reported food hypersensitivity. Risk factors associated with incidence and remission were different for milk hypersensitivity and hypersensitivity to foods other than milk. The agreement between reported symptoms to milk, egg, cod, wheat, soy and peanut and sensitization to the culprit food was poor. At 11 to 12-years of age the prevalence of reported allergy to milk, egg, cod or wheat was 4.8% while the allergy prevalence according to clinical evaluation was 1.4%. This figure was further halved when evaluated with double-blind placebo-controlled food challenges. The majority of children with reported allergy to milk, egg, cod and wheat were categorized as other food hypersensitivity phenotypes, the most common being probable lactose intolerance (40%) and outgrown food allergy (19%). Even though reported milk hypersensitivity among the 11-12 year olds was 14.5%, only 3% were categorized as current milk allergy. Current and outgrown milk allergy was associated with other atopic disorders and a lower BMI (OR 0.8, 95% CI 0.80-0.98). Before the challenge series, the mRNA expression of the cytokines IL-13 and IL-10 were higher among children with a positive compared to a negative challenge outcome. Conclusion: Reported food hypersensitivity was common among school children in Northern Sweden and increased from 7-8 years to 11-12 years of age, and both the incidence and remission of reported hypersensitivity was high. There was an 8-fold difference in the prevalence of allergy to milk, egg, cod or wheat when reported data was assessed by clinical examinations and double-blind placebo-controlled food challenges. Allergy to milk, egg, cod and wheat was an uncommon cause of complete avoidance of these foods due to perceived hypersensitivity. Some of the analyzed biomarkers might serve as prognostic markers for symptomatic, IgE-mediated food allergy but need further validation. / Bakgrund: Födoämnesöverkänslighet håller på att bli ett stort och kostsamt hälsoproblem i västvärlden. Prevalensen av rapporterad födoämnes-överkänslighet bland barn ökar, men det är fortfarande oklart om detta avspeglar en sann ökning i populationen. Det finns en stor spridning mellan uppmätta prevalenstal i olika studier och i de få studier där man följt upp rapporterade data med objektiva metoder ses en hög överrapportering. Data saknas om reell prevalens av födoämnesöverkänslighet bland skolbarn i Sverige. Befintliga prevalensdata baseras på rapporterad födoämnes-överkänslighet och studier saknas där angiven födoämnesöverkänslighet i en barnpopulationskohort validerats med objektiva metoder. Även om dubbelblinda provokationer räknas som ”gold standard” används i praktiken endast sjukhistoria, pricktest och analys av specifikt Immunoglubulin E (IgE) samt öppna provokationer för diagnostik. Metoderna har flera felkällor och mer tillförlitlig diagnostisk behövs, särskilt vid sena och svårtolkade symtom. Korrekt diagnos är särskilt viktig när baslivsmedel har eliminerats eftersom kostrestriktionerna riskerar att leda till negativa konsekvenser för livskvalitet och intag av viktiga näringsämnen. Syfte: Studierna i denna avhandling fokuserade på incidens och remission av födoämnesöverkänslighet bland skolbarn i Norrbotten, som följdes från 7-8 år till 11-12 års ålder, och på prevalens av överkänslighet mot mjölk, ägg, fisk och vete bland 12-åringar, undersökt med rapporterade data, klinisk undersökning samt dubbelblinda placebokontrollerade födoämnes-provokationer och biomarkörer. Metod: Den huvudsakliga delen av det här projektet är baserat på en populations-baserad kohort som rekryterades 2006 från 3 kommuner i norra Sverige. Föräldrar till alla barn i klass 1 och 2 (7-8 år) bjöds in till ett frågeformulär, som besvarades av 96% (n=2585) av de inbjudna. Barnen från två av kommunerna, Luleå och Kiruna, bjöds också in till ett pricktest med 10 vanliga luftburna allergen och 90% (n=1700) av de inbjudna deltog. År 2010, när barnen var 11-12 år, gjordes en studieuppföljning med samma metoder och med ytterligare tillägg av en intervju med barnet och bestämning av body mass index (BMI). Studiedeltagandet i enkäter och pricktest var lika högt vid uppföljningen som vid studiestart. Vid studieuppföljningen bjöds barn med rapporterad mjölköverkänslighet in till en strukturerad intervju och barn som helt undvek mjölk, ägg, fisk eller vete på grund av upplevd överkänslighet, bjöds in till klinisk undersökning och provtagning. Baserat på testresultaten kategoriserades barnen i olika fenotyper av födoämnesöverkänslighet utifrån förutbestämda kriterier. Barn som bedömdes ha en aktuell födoämnesallergi bjöds därefter in till vidare utredning med dubbelblind placebokontrollerad födoämnes-provokation. De recept som användes vid de dubbelblinda provokationerna hade dessförinnan validerats avseende detekterbara smak- och konsistens-skillnader mellan aktiv- och placebosubstans i en separat kohort av friska skolbarn (n=275). Före och efter den dubbelblinda provokationen samlades blodprover in för analys av cytokin mRNA-uttryck i mononukleära celler. Analyserna inkluderade cytokiner kännetecknande för humoralt allergidrivande T-hjälpar 2 (Th2) svar, cellulärt cytotoxiskt drivande Th1 svar samt inflammatoriskt- och T-reglerande svar. Vidare insamlades avföringsprover för analys av inflammatoriska biomarkörer före och efter genomgången provokationsserie. Resultat: Prevalensen av föräldrarapporterad födoämnesöverkänslighet ökade från 21% vid 7-8 år till nästan 26% vid 11-12 års ålder. Incidensen av rapporterad födoämnesöverkänslighet var hög (15%), liksom remissionen (33%). Riskfaktorer associerade med incidens och remission var olika för mjölk-överkänslighet och överkänslighet mot andra födoämnen. Vi såg också en bristande samstämmighet mellan föräldrarapporterad överkänslighet mot mjölk, ägg, fisk, vete, soja och jordnöt och IgE-sensibilisering mot det aktuella födoämnet. Vid 11-12 års ålder var prevalensen av rapporterad allergi mot mjölk, ägg, fisk eller vete 4.8%, medan prevalensen baserad på klinisk undersökning och provtagning var 1.4%. Prevalenssiffran halverades ytterligare när kliniskt bedömd födoämnesallergi validerades med dubbelblinda placebo-kontrollerade födoämnesprovokationer. Majoriteten av barnen med rapporterad allergi mot mjölk, ägg, fisk eller vete klassificerades som andra fenotyper av födoämnesöverkänslighet, varav de vanligast förekommande var möjlig laktosintolerans (40%) och utläkt födoämnesallergi (19%). Även om förekomsten av rapporterad mjölköverkänslighet bland 11-12 åringarna var så hög som 14.5%, kategoriserades bara 3% av dessa som en aktuell mjölkallergi. Mjölkallergi, aktuell eller utläkt, var associerat med andra atopirelaterade tillstånd och ett lägre BMI (OR 0.82, 95% CI 0.80-0.98) jämfört med barn som inte undvek mjölkprodukter. Före den dubbelblinda provokationsserien var mRNA-uttrycket av den Th2-relaterade cytokinen IL-13 och den regulatoriska cytokinen IL-10 högre bland barn med provokationspåvisad födoämnesallergi jämfört med barn med en negativ födoämnesprovokation. Såväl före som efter provokationsserien kunde högre nivåer av inflammationsmarkörerna eosinofil-deriverat neurotoxin (EDN) och kalprotektin uppmätas i avföringsprover från barn med positivt provokationsutfall jämfört med barn med negativ födoämnesprovokation. Skillnaderna i uppmätta nivåer av biomarkörer i faeces uppnådde dock inte statistisk signifikans. Slutsats: Rapporterad födoämnesöverkänslighet var vanligt förekommande bland skolbarn i Norrbotten och ökade från 7-8 år till 11-12 års ålder. Incidensen av rapporterad födoämnesöverkänslighet var hög, liksom remissionen. Prevalensen av rapporterad allergi mot mjölk, ägg, fisk eller vete var 8 gånger högre än den prevalens som kunde påvisas med dubbelblind placebokontrollerad födoämnesprovokation. Allergi mot mjölk, ägg, fisk och vete var en ovanlig orsak till att barn helt undvek dessa födoämnen på grund av upplevd överkänslighet. Några av de biomarkörer som analyserades innan provokationsserierna visade lovande resultat som möjliga, framtida prognostiska markörer för symptomatisk, IgE-medierad födoämnesallergi. Dessa resultat behöver dock valideras med ytterligare studier.

Lic. -avh. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 2 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.

While food hypersensitivity can be a life-threatening problem, its scope is yet to be fully developed. More work is needed to further define its parameters but basic food hypersensitivity has been significantly clarified in the decade of the 80's to become standard practice for most updated allergists. Studies related to inhalation of food antigens remains within the purview of research centers as does other immunologic processes. The diagnosis of food hypersensitivity remains dependent on the medical history with test like elimination diets, skin testing, and RAST. Double-blind, placebo-controlled, food challenges (DBPCFC) provide the most definitive support for the association between certain symptoms and a specific food.

Lui, Kit Yee. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 150-157). / Abstracts and questionnaire in English and Chinese. / Title --- p.1 / Abstract --- p.2 / Acknowledgement --- p.7 / Table of contents --- p.8 / List of tables --- p.11 / List of figures --- p.12 / Glossary of terms and abbreviations --- p.13 / Chapter Section I: --- Overview --- p.14 / Chapter Chapter 1: --- Introduction --- p.15 / Chapter 1.1 --- Prevalence of food allergy in children --- p.15 / Chapter 1.1.1 --- Methodologies for studying food allergy --- p.18 / Chapter 1.1.2 --- Skin Prick Test and its mechanism --- p.19 / Chapter 1.1.3 --- Measurement of serum specific IgE levels --- p.21 / Chapter 1.1.4 --- Gold standard for diagnosis of food allergy --- p.22 / Chapter 1.2 --- Aim of Study --- p.25 / Chapter Chapter 2: --- Plan of Study --- p.26 / Chapter Section II: --- Literature Review --- p.28 / Chapter Chapter 3: --- Epidemiology of food allergy --- p.30 / Chapter 3.1 --- Prevalence of food allergy in children in western countries --- p.30 / Chapter 3.2 --- Prevalence of atopic allergies in children in rural areas --- p.34 / Chapter 3.3 --- Euro Prevail - A standardized methodology in studying food allergies --- p.38 / Chapter 3.4 --- Epidemiology of adverse food reaction in Hong Kong pre-school children --- p.40 / Chapter Chapter 4: --- Diagnosis of food allergies --- p.44 / Chapter 4.1 --- History --- p.44 / Chapter 4.2 --- Use of Skin Prick Test for diagnosis --- p.45 / Chapter 4.3 --- Use of serum specific IgE level for diagnosis --- p.47 / Chapter 4.4 --- Use of double-blind placebo-controlled food challenge for diagnosis --- p.49 / Chapter 4.5 --- Factors affecting precise diagnosis of food allergies --- p.51 / Chapter 4.5.1 --- Procedure-related Factors --- p.51 / Chapter 4.5.1.1 --- Performance of skin prick test --- p.51 / Chapter 4.5.1.2 --- Cross-reactivity of serum specific IgE --- p.52 / Chapter 4.5.1.3 --- Different diagnostic decision points in different populations --- p.53 / Chapter 4.5.1.4 --- Sensitization and allergy --- p.54 / Chapter 4.5.1.5 --- False negative oral food challenges --- p.55 / Chapter 4.5.2 --- Patient Factors --- p.56 / Chapter 4.5.2.1 --- Age of subjects --- p.56 / Chapter 4.5.2.2 --- Diet before tests --- p.57 / Chapter 4.5.2.3 --- Anti-histamine medications --- p.57 / Chapter 4.5.2.4 --- Skin sensitivity of subjects --- p.58 / Chapter Chapter 5: --- Risk factors for development of food allergies --- p.59 / Chapter 5.1 --- Factors associated with development of food allergies --- p.59 / Chapter 5.2 --- Food allergy and asthma --- p.62 / Chapter 5.3 --- Food allergy and eczema --- p.63 / Chapter Section III: --- Original Study --- p.64 / Chapter Chapter 6: --- Methodology --- p.65 / Chapter 6.1 --- Study Population --- p.65 / Chapter 6.1.1 --- Sample size calculation --- p.66 / Chapter 6.2 --- The EuroPrevall Study --- p.67 / Chapter 6.3 --- EuroPrevall Questionnaires --- p.68 / Chapter 6.4 --- Standardized Approach for Answering Questions in the Field --- p.69 / Chapter 6.5 --- Anthropometric Measurements and Ethics Approval --- p.70 / Chapter 6.6 --- Skin Prick Testing --- p.71 / Chapter 6.7 --- Measurement of serum specific IgE level --- p.72 / Chapter 6.8 --- Classification of Subjects --- p.74 / Chapter 6.9 --- Statistical Analysis --- p.75 / Chapter Chapter 7: --- Results --- p.76 / Chapter 7.1 --- Subjects and Demography --- p.76 / Chapter 7.2 --- Reported Symptoms in Chinese Children --- p.80 / Chapter 7.3 --- Food allergen sensitization in Chinese Children --- p.81 / Chapter 7.4 --- Association between food sensitization and allergic symptoms --- p.89 / Chapter 7.5 --- Prevalence of Food Allergy in Chinese Schoolchildren --- p.93 / Chapter Chapter 8: --- Discussion --- p.96 / Chapter Chapter 9: --- Conclusion and Further Studies --- p.102 / Appendix 1 Screening questionnaire (Chinese Version) --- p.106 / Appendix 2 Screening questionnaire (English Version) --- p.109 / Appendix 3 Case-control questionnaire (Chinese Version) --- p.111 / Appendix 4 Case-control questionnaire (English Version) --- p.132 / References --- p.150

Introdução: A doença do refluxo gastroesofágico (DRGE) refratária pode estar relacionada à maior sensibilização a alimentos pelo dano ácido-péptico às junções intercelulares e/ou pelo aumento do pH gástrico pelos inibidores de bomba de prótons (IBPs). A falha na resposta ao tratamento da DRGE tem sido atribuída, entre outras causas, à esofagite eosinofílica (EE). Objetivo: O objetivo principal do estudo foi avaliar a sensibilização a alimentos nos pacientes com DRGE refratária. Como objetivos secundários, comparamos as características dos pacientes sensibilizados com os não sensibilizados e verificamos a resposta clínica da DRGE à dieta de restrição aos alimentos aos quais o paciente estava sensibilizado. Métodos: Os pacientes com DRGE refratária realizaram dieta de restrição baseada no resultado de teste cutâneo de leitura imediata (TCLI) e teste cutâneo de contato (TCC) com alimentos. As características dos pacientes sensibilizados foram comparadas com os não sensibilizados com relação à atopia e número de eosinófilos na mucosa esofágica. Resultados: A prevalência de sensibilização a alimentos nos pacientes com DRGE refratária foi de 27,7%, sendo 15,3% pelo TCLI e 12,3% pelo TCC. Os asmáticos apresentaram maior sensibilização a alimentos (p=0,008). Foi identificada a presença de eosinófilos na mucosa esofágica em 15,8% dos pacientes e esta correlacionou-se com maior sensibilização a alimentos (p=0,011). Foi confirmado um caso de EE. A dieta de exclusão aos alimentos identificados promoveu melhora clínica dos sintomas da DRGE (p=0,004). Conclusão: A presença de eosinófilos na mucosa esofágica associada à maior sensibilização a alimentos e a resposta à dieta de exclusão em pacientes com testes positivos sugere que a DRGE refratária pode representar um estágio inicial da EE. / Abstract: Refractory gastroesophageal reflux disease (GERD) can be related to greater sensitization to foods due to peptic acid damage to intercellular junctions and/or due to the increase in gastric pH by proton pump inhibitors (PPIs). The lack of response to treatment of GERD has been attributed to, among other causes, eosinophilic esophagitis (EE). Objective: The principal objective of the study was to evaluate the sensitization to foods in patients with refractory GERD. As secondary objectives, we compared the characteristics of sensitized patients with those non-sensitized and found a clinical response of GERD to a diet restricting foods to which the patient was sensitized. Methods: Patients with refractory GERD were put on a restriction diet based on the results of skin prick test (SPT) and atopy patch test (APT) with foods. The characteristics of the sensitized patients were compared to those non-sensitized in relation to atopia and number of eosinophils in the esophageal mucosa. Results: The prevalence of sensitization to foods in patients with refractory GERD was 27.7%, where 15.3% were determined by SPT and 12.3% by APT. Asthmatics showed higher sensitization to foods (p=0.008). The presence of eosinophils in the esophageal mucosa was determined in 15.8% of patients, and this correlated with greater sensitization to foods (p=0.011). One case of EE was confirmed. A diet excluding identified sensitizing foods led to clinical improvement with regard to GERD symptoms (p=0,004). Conclusion: The presence of eosinophils in esophageal mucosa associated with greater sensitization to foods and the response to restriction diet in patients with positive tests suggest that refractory GERD can represent an initial stage of EE.

O Teste de Provocação Oral Duplo Cego Placebo Controlado (TPODCPC) é considerado um método diagnóstico de extrema importância na alergia alimentar, entretanto não existe, em nosso meio, uma padronização em relação aos materiais e métodos para a sua execução, especialmente na faixa etária pediátrica. O objetivo deste estudo foi adaptar TPODCPC para o diagnóstico de alergia às proteínas do leite de vaca (APLV) mediada por IgE, em crianças e adolescentes. O objetivo secundário foi descrever a relação entre os antecedentes de atopia associados a dados laboratoriais e os resultados dos TPODCPC. Foram incluídos 58 pacientes que se dividiram em dois grupos. O grupo 1 foi composto por 39 pacientes (mediana de idade: 5,3 anos; 1,6M:1F) com história sugestiva de APLV IgE mediada, sem relato de história de anafilaxia recente e com pesquisa positiva de IgE específica para leite de vaca (LV) e/ou frações. No grupo 2 foram incluídos 19 pacientes (mediana de idade: 8,3 anos; 1,4 M:1F) sem história sugestiva de APLV. Os itens avaliados na adaptação deste método diagnóstico incluíram: escolha do local, materiais a serem utilizados e operacionalização do teste. O hospital dia mostrou-se, por suas características, adequado à realização do exame. Em relação aos materiais escolhidos para a oferta do veículo, os recipientes opacos e vedados revelaram-se mais adaptados às necessidades do teste, os veículos de maior aceitação foram sopa de legumes e bebida à base de soja e o LV a ser oferecido de maneira mais apropriada foi na forma líquida e com baixo teor de lactose. As dificuldades observadas na realização do TPODCPC não comprometeram a sua execução, entretanto houve dificuldade na interpretação dos resultados especialmente nos pacientes com sintomas como pápulas periorais ou achados clínicos inespecíficos. Observou-se concordância entre os critérios clínico-laboratoriais adotados para a definição dos grupos 1 e 2 com os resultados do TPODCPC. Em conclusão, o teste mostrou-se exeqüível e seguro e a adaptação deste para o diagnóstico de APLV IgE mediada nesta faixa etária pediátrica foi possível, sendo necessária a avaliação da sua reprodutibilidade em outras populações. / The Double Blind Placebo Controlled Food Challenge (DBPCFC) is considered an important method for food allergy diagnosis, nevertheless it is not standardized among us. The aim of this study was to adapt DBPCFC for cows milk allergy (CMA) diagnosis in children and adolescents. A secondary aim was to describe the relation between history of atopy and laboratorial findings with DBPCFC results. It was included 58 patients that were distributed in two groups. Group 1 was composed of 39 patients (median age: 5,3 years; 1,6M:1F) with suggestive history of CMA without recent anaphylaxis, and specific IgE to cow´s milk (CM) and/or its fractions. In group 2 was included 19 patients (median age 8,3 years; 1,4 M:1F) where the CMA diagnosis was excluded based on clinical findings. The items evaluated in the adaptation of this method were: setting choice, kind of milk processing and vehicles, besides material and test performance. Day hospital was considered adequate for this test. Regarding to elected materials to offer the vehicle, opaque and sealed recipients showed more suitable to test demands. Vehicles more accepted were legumes soup and soy beverage and the most adequate CM to be offered was liquid and with low lactose concentration. The difficult observed in performance of DBPCFC do not compromise its execution, however the interpretation of the results was very difficult specially in patients with perioral wheals and unspecific clinical findings. There is an agreement Comparing adopted clinical and laboratorial criterion for definition of group 1 and 2 with DBPCFC results. In conclusion, the test proved to be feasible and safe and its adaptation is possible for IgE mediated CMA diagnosis, being necessary to evaluate its reproducibility in other populations.