validation with double-blind placebo-controlled food
TRANSCRIPT
Epidemiology of food hypersensitivity in schoolchildren
Validation with double-blind placebo-controlled food challenges and biomarkers
THE OBSTRUCTIVE LUNG DISEASE IN NORTHERN SWEDEN (OLIN) STUDIES, THESIS XV
Anna Winberg
Articles included in thesis:
• I Winberg A, Nordström L, Strinnholm Å, Nylander A, Jonsäll A, Rönmark E, West CE. New validated recipes for double-blind placebo-controlled low-dose food challenges. Pediatr Allergy Immunol 2013;24:282-7.
• II Winberg A, Strinnholm Å, Hedman L, West C.E, Perzanowski M.S, Rönmark E. High incidence and remission of reported food hypersensitivity in Swedish children followed from 8 to 12 years of age – a population based cohort study. Clin Transl Allergy 2014;4:32.
• III Winberg A, West CE, Strinnholm Å, Nordström L, Hedman L, Rönmark E. Assessment of Allergy to Milk, Egg, Cod, and Wheat in Swedish Schoolchildren: A Population Based Cohort Study. PLoS One. 2015;10(7):e0131804.
• IV Winberg A, West CE, Strinnholm Å, Nordström L, Hedman L, Rönmark E. Milk allergy is a minor cause of milk avoidance due to perceived hypersensitivity among schoolchildren in Northern Sweden. Acta Paediatr. 2015 Epub ahead of print 2015/11/01.
• V Winberg A, Nagaeva O, Nagaev I, Lundell C, Arencibia I, Mincheva-Nilsson L,Rönmark E, West CE. Dynamics of cytokine mRNA expression and fecal biomarkers in school-children undergoing a double-blind placebo-controlled food challenge series.(In manuscript)
Study population (OLIN-cohort)
7-8 years
2585(96%)
11-12years
2612(96%)
2378(89%
of those whoparticipated
in 2006)
2006 2010
Paper II
• Objectives:
– To investigate the incidence and remission of parentally reported food hypersensitivity in a population based cohort followed from 7-8 to 11-12 years of age
PARTICIPANTS
Questionnaire2585 (96%)
Skin Prick Test1700 (90%)
STUDY START 2006
Age 7-8 years
FOLLOW-UP 2010
Age 11-12 years
PARTICIPANTS(2006+2010)
Questionnaire2378 (89%)
Skin Prick Test1451 (77%)
Serologicaltests
(IgE+ tTGA)
652 (71%)
Paper II
Prevalence of FHS
STUDY START 2006
Age 7-8 years
Any FHS 21.3 %
FHS milk/egg/wheat/cod10.3 %
FHS milk 9.0 %
FOLLOW-UP 2010
Age 11-12 years
Any FHS 25.9 %
FHS milk/egg/wheat/cod14.7%
FHS milk 13.1 %
p<0.001
Winberg et al. Clin Transl Allergy 2014
Cumulative incidence (%) and remission (%) of perceived food hypersensitivity (FHS) to different foods from age 8 to 12 years
FHS Incidence Remission n (%) n (%)
Milk 147 (7.9) 94 (43.9)
Egg 8 (0.4) 15 (44.1)
Fish 4 (0.2) 12 (38.7)
Wheat 8 (0.4) 17 (77.3)
Soy 6 (0.3) 7 (58.3)
Kiwi 85 (4.6) 87 (44.6)
Orange 28 (1.5) 74 (69.2)
Apple 45 (2.4) 25 (26.9)
Raw carrots 9 (0.5) 17 (51.5)
Banana 6 (0.3) 8 (50.0)
Nuts 36 (1.9) 33 (38.8)
Peanuts 25 (1.3) 28 (36.8)
Almonds 16 (0.9) 25 (54.3
Any FHS 274 (14.7) 167 (32.7)
Winberg et al. Clin Transl Allergy 2014
Associated risk factors
• For incidence:
• For remission:
Non-milk FHS
MilkFHS
Female sex OR 1.8 (1.3-2.5)Allergic heredity OR 1.6 (1.1-2.2)Current rhinitis OR 4.0 (2.2-7.3)Any positive SPT OR 2.1 (1.4-3.2)
Female sex OR 1.7 (1.2-2.4)Allergic heredity OR 1.6 (1.1-2.4)
Current asthma OR 0.5 (0.2-0.9)Any positive SPT OR 0.6 (0.5-1.0)
Living in Kiruna OR 0.2 (0.1-0.5)
Winberg et al. Clin Transl Allergy 2014
Paper IIHigh incidence and remission of reported food hypersensitivity in Swedish children
followed from 8 to 12 years of age – a population based cohort studyWinberg A, Strinnholm Å, Hedman L, West C.E, Perzanowski M.S, Rönmark E
Clin Transl Allergy 2014;4:32
Main results:
There was a high incidence as well as a high remission of reported food hypersensitivity from age 8 to 12 years of age
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 IgE-sensitization to the culprit food was poor.
Paper III
• Objectives:
– To assess the prevalence of allergy to cow’s milk, hen’s egg, cod and wheat among 11-12-year old Swedish children using
• reported data
• clinical investigations and
• double-blind placebo-controlled
food challenges
STU
DY O
VERVIE
W
Winberg et al PLOS One, 2015
Distribution of phenotypes of food hypersensitivity (FHS) based on the clinical examinations
Participants
(n=94)
FHS PHENOTYPE n (%)
ALLERGY
IgE-mediated allergy 18 (19)
Non-IgE-mediated allergy 6 (6)
Suspected allergy 3 (3)
Outgrown allergy 18 (19)
LACTOSE INTOLERANCE
Lactose intolerance 27 (29)
Suspected lactose intolerance 11 (12)
CELIAC DISEASE 1 (1)
NON-DEFINABLE CASES
Symptoms not definable 2 (3)
No blood analyses
(specific IgE/tTGA)
7 (7)
NON-AVOIDANCE DIET 1 (1)
Winberg et al PLOS One, 2015
STU
DY O
VERVIE
W
Winberg et al PLOS One, 2015
Main results:
– The majority of children reporting allergy to milk, egg, wheat or cod were categorized as another FHS-phenotype
– Children reacting with an anaphylaxis during DBPCFC werenot equipped with rescue medication
ReportedAny FHS
25.9%
ReportedFHS
milk, egg, wheat, cod
14.7%
Clinical examinationmilk, egg, wheat,
cod
1.4%
ReportedAllergymilk, egg, wheat, cod
4.8%
DBPCFCmilk, egg, wheat, cod
0.6%
Paper IIIAssessment of Allergy to Milk, Egg, Cod, and Wheat in Swedish Schoolchildren:
A Population Based Cohort StudyWinberg A, West CE, Strinnholm Å, Nordström L, Hedman L, Rönmark E
PLoS One. 2015;10(7):e0131804
Paper IV
PARTIALMILK AVOIDANCE
• Objectives:
– To describe the food hypersensitivity phenotypes among Swedish 11-12-year old children reporting hypersensitivity to cow’s milk
– To analyze how the different phenotypes correlated to body mass index (BMI), living conditions, allergic sensitization, allergic heredity and physician diagnosed asthma, rhinitis and eczema
Distribution of different FHS phenotypes among children reporting any milk avoidance, complete milk avoidance and partial milk avoidance
Milk
Avoidance (All)
(n=236)
Complete
milk avoidance
(n=56)
Partial
milk avoidance
(n=180)
p-value
FHS PHENOTYPE n (%) n (%) n (%)
MILK ALLERGY 7 (3%) 7 (12 %) 0 (0%) <0.001
Current IgE-mediated Allergy 2 (1 %) 2 (4 %) 0 (0%)
Current Non-IgE-mediated Allergy 5 (2 %) 5 (9 %) 0 (0%)
Suspected Current Allergy 0 (0%) 0 (0%) 0 (0%)
OUTGROWN MILK ALLERGY 54 (23 %) 16 (28.1%) 38 (21.1%) 0.281
LACTOSE INTOLERANCE 95 (40 %) 30 (53 %) 65 (36 %) 0.030
Lactose intolerance 60 (25 %) 22 (39 %) 38 (21 %)
Suspected Lactose intolerance 35 (15 %) 8 (14 %) 27 (15 %)
CELIAC DISEASE 1 (0.4 %) 0 (0 %) 1 (0.5%) 1.000
NON-DEFINABLE 25 (11 %) 3 (5 %) 22 (12 %) 0.214
Symptoms not definable 8 (3 %) 1 (2 %) 7 (4 %)
No blood analyses (specific IgE/tgA) 17 (7 %) 2 (4 %) 15 (8 %)
DISCONTINUED MILK
AVOIDANCE54 (23 %) 0 (0 %) 54 (30.6%) < 0.001
Winberg et al Acta Paediatr 2016
Prevalence of milk allergy in relation to risk factors and adjusted risk analyzed by multiple logistic regression analysis expressed as odds ratios (OR) with 95% confidence intervals (CI)
MILK ALLERGY
(current or outgrown)
% Adjusted OR (95% CI)
Sex Boys 2.5 1.0
Girls 4.2 1.90 (1.02-3.55)
Physician diagnosed Asthma No 2.9
Yes 6.6 1.24 (0.55-2.76)
Physician diagnosed Rhinitis No 2.9 1.0
Yes 6.8 1.25 (0.54-2.88)
Physician diagnosed Eczema No 2.3 1.0
Yes 9.0 3.53 (1.79-6.98)
FHS heredity No 2.1 1.0
Yes 7.5 4.45 (2.42-8.19)
Any positive SPT No 2.7 1.0
Yes 4.6 1.05 (0.53-2.06)
BMI 0.82 (0.80-0.98)
Winberg et al Acta Paediatr 2016
Paper IVMilk allergy is a minor cause of milk avoidance due to perceived hypersensitivity
among schoolchildren in Northern SwedenWinberg A, West CE, Strinnholm Å, Nordström L, Hedman L, Rönmark E
Acta Paediatr. 2016 Feb;105(2):206-14
Main results:
Even though reported milk hypersensitivity among the 11-12 year olds was as high as 14.5%,
only 3% of them were categorized as current milk allergy
The most common milk hypersensitivity phenotypes were probable lactose intolerance and outgrown milk allergy
Current and outgrown milk allergy was associated with other atopic disorders and lower BMI
Only 9 % of the children currently avoiding milk reported that they had ever been referred to a dietician for nutritional advice and
only 2% had a milk hypersensitivity diagnosis established by an oral challenge.
Paper V
• Objectives:
– Cytokine mRNA expression in peripheral mononuclear cells (PBMC)
• children with suspected food allergy (n=18)
• healthy controls (n=7)
– Fecal inflammatory markers (children with suspected food allergy)
…before and after the DBPCFC-series and in relation to the challenge outcome.
Thank you…The OLIN studiesEva RönmarkLinnea HedmanHelena BackmanBritt-Marie EklundSigrid SundbergMatt PerzanowskiAnders BjergBo Lundbäck
Umeå UniversityPediatricsChristina WestOlle HernellCatarina Lundell
Clinical ImmunologyLucia Mincheva-NilssonOlga NagaevaIvan NagaevIgnacio Arancibia
DieteticsAnnika NylanderAnette Jonsäll
The ”ADIOS” teamÅsa StrinnholmLisbeth Nordström
…and many more…
…to all of the participating familieswho made this study
possible!
The study was mainly funded by:
the Swedish research council; the Swedish Heart and Lung Foundation; VISARE Norr; the Swedish Asthma and Allergy Foundation; by a regional agreement between Umeå University and
Västerbotten and Norrbotten County Council (ALF); the State Government funding for Health Care research (FoU); the Swedish society of Medicine, the Sven Jerring Foundation, Insamlings-
stiftelsen and the Oskar foundation. ThermoFisher Diagnostics, Uppsala, Sweden provided funding for parts of the IgE tests and for the tissue transglutaminase IgA antibody analyses and Nutricia
AB is acknowledged for providing DBPCFC test material.