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Epidemiology of food hypersensitivity in schoolchildren: Validation with double-blind placebo-controlled food challenges and biomarkers
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Abstract [sv]

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.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2016. , 108 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1763
Series
The Obstructive Lung Disease in Northern Sweden (OLIN) Studies, Thesis XV
Keyword [en]
food hypersensitivity, schoolchildren, epidemiology, food challenges, biomarkers
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-114047ISBN: 978-91-7601-367-0 (print)OAI: oai:DiVA.org:umu-114047DiVA: diva2:892544
Public defence
2016-02-19, Norrlands Universitetssjukhus, Bergasalen, By 27, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2016-01-29 Created: 2016-01-11 Last updated: 2016-01-28Bibliographically approved
List of papers
1. New validated recipes for double-blind placebo-controlled low-dose food challenges
Open this publication in new window or tab >>New validated recipes for double-blind placebo-controlled low-dose food challenges
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2013 (English)In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 24, no 3, 282-287 p.Article in journal (Refereed) Published
Abstract [en]

Double-blind placebo-controlled food challenges are considered the most reliable method to diagnose or rule out food allergy. Despite this, there are few validated challenge recipes available. The present study aimed to validate new recipes for low-dose double-blind placebo-controlled food challenges in school children, by investigating whether there were any sensory differences between the active materials containing cow's milk, hen's egg, soy, wheat or cod, and the placebo materials. The challenge materials contained the same hypoallergenic amino acidbased product, with or without added food allergens. The test panels consisted of 275 school children, aged 810 and 1415yr, respectively, from five Swedish schools. Each participant tested at least one recipe. Standardized blinded triangle tests were performed to investigate whether any sensory differences could be detected between the active and placebo materials. In our final recipes, no significant differences could be detected between the active and placebo materials for any challenge food (p>0.05). These results remained after stratification for age and gender. The taste of challenge materials was acceptable, and no unfavourable side effects related to test materials were observed. In summary, these new validated recipes for low-dose double-blinded food challenges contain common allergenic foods in childhood; cow's milk, hen's egg, soy, wheat and cod. All test materials contain the same liquid vehicle, which facilitates preparation and dosing. Our validated recipes increase the range of available recipes, and as they are easily prepared and dosed, they may facilitate the use of double-blind placebo-controlled food challenges in daily clinical practice.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keyword
double-blind placebo-controlled food challenges, food allergy, food hypersensitivity, triangle test, validated recipes
National Category
Clinical Science Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-71611 (URN)10.1111/pai.12061 (DOI)000317978500012 ()
Available from: 2013-06-05 Created: 2013-06-04 Last updated: 2017-05-10Bibliographically approved
2. High incidence and remission of reported food hypersensitivity in Swedish children followed from 8 to 12 years of age
Open this publication in new window or tab >>High incidence and remission of reported food hypersensitivity in Swedish children followed from 8 to 12 years of age
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2014 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 69, no Supplement: 99, 151-151 p.Article in journal, Meeting abstract (Refereed) Published
Place, publisher, year, edition, pages
Wiley-Blackwell, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-93818 (URN)000341139400354 ()
Conference
European-Academy-of-Allergy-and-Clinical-Immunology Congress, JUN 07-11, 2014, Copenhagen, DENMARK
Available from: 2014-10-08 Created: 2014-10-01 Last updated: 2017-05-09Bibliographically approved
3. Assessment of Allergy to Milk, Egg, Cod, and Wheat in Swedish Schoolchildren: A Population Based Cohort Study
Open this publication in new window or tab >>Assessment of Allergy to Milk, Egg, Cod, and Wheat in Swedish Schoolchildren: A Population Based Cohort Study
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, e0131804Article in journal (Refereed) Published
Abstract [en]

Objectives Knowledge about the prevalence of allergies to foods in childhood and adolescence is incomplete. The purpose of this study was to investigate the prevalence of allergies to milk, egg, cod, and wheat using reported data, clinical examinations, and double-blind placebo-controlled food challenges, and to describe the phenotypes of reported food hypersensitivity in a cohort of Swedish schoolchildren. Methods In a population-based cohort of 12-year-old children, the parents of 2612 (96% of invited) completed a questionnaire. Specific IgE antibodies to foods were analyzed in a random sample (n=695). Children reporting complete avoidance of milk, egg, cod, or wheat due to perceived hypersensitivity and without physician-diagnosed celiac disease were invited to undergo clinical examination that included specific IgE testing, a celiac screening test, and categorization into phenotypes of food hypersensitivity according to preset criteria. Children with possible food allergy were further evaluated with double-blind challenges. Results In this cohort, the prevalence of reported food allergy to milk, egg, cod, or wheat was 4.8%. Food allergy was diagnosed in 1.4% of the children after clinical evaluation and in 0.6% following double-blind placebo-controlled food challenge. After clinical examination, children who completely avoided one or more essential foods due to perceived food hypersensitivity were categorized with the following phenotypes: allergy (29%), outgrown allergy (19%), lactose intolerance (40%), and unclear (12%). Conclusions There was a high discrepancy in the prevalence of allergy to milk, egg, cod and wheat as assessed by reported data, clinical evaluation, and double-blind food challenges. Food hypersensitivity phenotyping according to preset criteria was helpful for identifying children with food allergy.

National Category
Nutrition and Dietetics Pediatrics
Identifiers
urn:nbn:se:umu:diva-107170 (URN)10.1371/journal.pone.0131804 (DOI)000358154400074 ()26134827 (PubMedID)
Available from: 2015-09-02 Created: 2015-08-19 Last updated: 2017-12-04Bibliographically approved
4. Milk allergy is a minor cause of milk avoidance due to perceived hypersensitivity among schoolchildren in Northern Sweden
Open this publication in new window or tab >>Milk allergy is a minor cause of milk avoidance due to perceived hypersensitivity among schoolchildren in Northern Sweden
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2016 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 105, no 2, 206-214 p.Article in journal (Refereed) Published
Abstract [en]

AIM: We investigated phenotypes of milk hypersensitivity among schoolchildren aged 11-12 in Northern Sweden.

METHODS: In a population-based cohort, 1,824 (98%) children aged 11-12 participated in a questionnaire survey, skin prick testing, interviews on food hypersensitivity and assessment of body mass index (BMI). Of the 265 children reporting milk hypersensitivity, milk avoidance and no celiac disease, 236 (89%) participated in a structured interview and blood samples for analyses of milk-specific Immunoglobulin E. The children were then categorised into milk hypersensitivity phenotypes according to preset criteria.

RESULTS: In all, 14.5% reported milk hypersensitivity. Of these, 3% were categorised as current milk allergy, 23% as outgrown milk allergy, 40% as probable lactose intolerance and 11% were non-definable. Furthermore, 23% had discontinued their elimination diet. Milk allergy was associated with other atopic disorders and lower BMI, with an odds Ratio of 0.82 and 95% confidence interval of 0.80-0.98. Only 2% had previously undergone an oral challenge.

CONCLUSION: The most common symptom phenotypes among Swedish children aged 11-12 with self-reported milk hypersensitivity and milk avoidance, were lactose intolerance and outgrown milk allergy while current milk allergy was uncommon. Children with milk allergy had a lower BMI and most lacked a challenge proven diagnosis. 

Keyword
reference equations, reference sample, Z-scores, percentiles, linear regression, spline functions
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-112382 (URN)10.1111/apa.13253 (DOI)000367921500024 ()26518972 (PubMedID)
Note

Publiceras 2016 Feb;105(2):206-214

Available from: 2015-12-07 Created: 2015-12-07 Last updated: 2017-05-09Bibliographically approved
5. Dynamics of cytokine mRNA expression and fecal biomarkers in school-children undergoing a double-blind placebo-controlled food challenge series
Open this publication in new window or tab >>Dynamics of cytokine mRNA expression and fecal biomarkers in school-children undergoing a double-blind placebo-controlled food challenge series
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2016 (English)In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 88, 259-266 p.Article in journal (Refereed) Published
Abstract [en]

Background: There is need for prognostic markers for symptomatic food allergy since current diagnostic methods are insufficient and/or time and labor consuming. Objective: To estimate the cytokine mRNA profiles in peripheral blood mononuclear cells (PBMC) before and after a double-blind placebo-controlled food challenge series in schoolchildren with suspected allergy to milk, egg or cod and in healthy controls. Analyses of fecal inflammatory biomarkers before and after the challenge were included. Methods: Twelve-year-old children from a population-based cohort reporting complete avoidance of milk, egg, cod or wheat due to perceived hypersensitivity were clinically examined and those with suspected food allergy were evaluated with a 3-session double-blind placebo-controlled food challenge (n = 18). Seven healthy controls participated in a double-blind challenge with egg. Before and after the challenge series, the cytokine mRNA expression was quantified for 13 cytokines discriminating between humoral Th2-, cytotoxic Thl-, regulatory Th3/Tr1- and inflammatory responses. Fecal calprotectin and eosinophil-derived neurotoxin (EDN) were also analyzed in children with suspected food allergy before and after the challenge series. Results: Pre challenge, children with suspected food allergy had higher IL-13 and TNF-alpha expression and lower IFN-gamma and IL-15 expression compared to healthy controls (all p < 0.05). Children with challenge proven food allergy had increased IL13 and IL-10 expression compared to the levels seen in negative challenges (p < 0.05). Post challenge, IL-1 beta and IL-6 mRNA levels were elevated in the food allergic children compared to controls (p < 0.05). Fecal calprotectin and EDN levels were higher in challenge-proven food allergy compared to a negative challenge although not statistically significantly. Conclusion & clinical relevance: Increased baseline mRNA levels of the Th2-related cytokine IL-13 and the regulatory cytokine IL-10 predicted a positive food challenge outcome. These cytokines in combination with fecal calprotectin and EDN might serve as future prognostic markers for symptomatic, IgEmediated food allergy but need further validation in a larger patient cohort.

Keyword
cytokines, fecal biomarkers, food allergy, children, IL-10, IL-13, tolerance
National Category
Pediatrics Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-114048 (URN)10.1016/j.cyto.2016.09.014 (DOI)000386862100033 ()27697703 (PubMedID)
Note

Originally published in thesis in manuscript form.

Available from: 2016-01-11 Created: 2016-01-11 Last updated: 2017-12-01Bibliographically approved

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