Food Allergies: Advances in Diagnosis and Management - PowerPoint Presentation

Slide1

Food Allergies: Advances in Diagnosis and ManagementGreg Black, MD

USC SOM Department of Pediatrics

Grand Rounds October 16, 2015

Carolina Allergy and Asthma Consultants, PASlide2

RoadmapFood allergies: The Scope of the Problem

Risk

Factors and Theories on FA Development

Conventional Methods of Diagnosis

Component-Resolved Diagnostics

LEAP Study and

Prevention

Advances in Immunotherapy

ConclusionsSlide3

Exclusions

Food Protein Induced Enterocolitis (acute and chronic FPIES)

Allergic

Proctocolitis

Food Dependent Exercise Induced Anaphylaxis

Red meat allergy (alpha-gal sensitivity)

Oral Pollen Syndrome

Celiac Disease

Atopic Dermatitis

Auriculotemporal

Syndrome

Eosinophilic Esophagitis and Gastrointestinal Disease

Food Poisoning

Irritable Bowel Syndrome/

Mastocytic

Enterocolitis

Inflammatory Bowel DiseaseSlide4

Food Allergy (FA)CDC estimates 8% of children and 4% of adults in US have a FA diagnosis.

CDC estimates 50% increase in pediatric FA 1997-2011.

Gupta et al in 2012 reports economic burden of FA is $25 billion USD.

FA results in 300,000 ambulatory care visits a year, and 200,000 ED visits per year (half of ED visits are diagnosed as food allergen induced anaphylaxis).

FA is the leading cause of anaphylaxis outside of the hospital setting.

Co-diagnosis of asthma is a risk factor for fatal food allergy.Slide5

Food Allergy (FA) DiagnosisNIAID describes food allergy as “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food.”

Ninety percent of immediate hypersensitivity to foods in US due to milk, soy, egg, wheat, peanut, tree nut, fish, and shellfish.

Self reporting of food allergies by patients consistently is higher than true immediate hypersensitivity as documented by Oral Food Challenge (OFC).

Food allergy more common in children, and high co-occurrence of other atopic conditions.

Children with moderate to severe persistent atopic dermatitis at 35% increased risk to develop immediate hypersensitivity. Slide6

Fatal Food AllergyAAAAI Statistics Page: 38.7% of FA children have a history of severe reaction.

Xu et al in 2014 reported on 92 cases of fatal anaphylaxis from the Ontario, Canada Coroner’s office.

Forty (43%) due to food allergens.

Sixteen (17%) due to peanut.

RF for FA fatalities: asthma, peanut allergy, teenagers, delayed epinephrine administration.

Umasunthar

et al reported on 10 studies in 2013 in a meta-analysis concerning reported on 240 cases of fatal food allergy at 1.81 per million person years, assuming a FA prevalence of 3.9%.

Incidence of fatal FA less than that of fatal accidents in Europe.Slide7
Slide8

FA: Risk Factors

Family History

7 fold increase in risk of Peanut allergy if primary relative is peanut allergic

Sex

M:F for peanut allergy in childhood 5:1.

Ratio changes to 1:1 with adulthood.

Ethnicity

Lieu et al documents risk of FA in non

hispanic

blacks increased over whites OR 3.06 (95% CI 2.1-4.3). NHANES 2005-06.

Genes

STAT6

IL10

CD14

TSLPSlide9

Food Allergy Diagnosis

History of Ingestion?

Time to symptoms

Foods ingested

Means of preparation

Location where food consumed

Symptoms?

Urticaria

Angioedema

Nausea, Vomiting

Stridor

Change in sensorium

Resolved/Recurring?

Time to resolution

Factors involved in resolution

Has patient returned to eating the food?

Confounders?

NSAIDS, Antibiotics

Venom

Exercise

Latex

Sexual activitySlide10
Slide11

Theories on increase of FA Diagnoses

Hygiene Hypothesis

Lack of early infectious exposure leads to increased allergic sensitization

C-sections involved?

Early Probiotic administration may protect against eczema onset, but not allergic sensitization.

Dietary guidelines

Former AAP guidelines concerning families at risk (atopic history) was to delay introduction of typical allergenic foods, until recently.

No major role for dietary restrictions in pregnancy or lactation that would affect development of FA. Slide12

Dual Allergen HypothesisSlide13

Insights into FA Inception

Bartnikas

et al in 2013

epicutaneously

sensitized BALB/c mice with ovalbumin (OVA) or orally dosed them with OVA-

choleratoxin

.

On oral challenge with OVA the

epicutaneously

sensitized mice had anaphylaxis, increased serum IL-4, and an expanded mast cell population in jejunum compared to orally dosed ova-CT mice that tolerated oral challenge.

Hough et al in 2013 determined that household peanut consumption was the most important variable in detecting peanut protein in the house dust of an infant’s crib and play area.

Peanut protein in house dust deemed biologically active as it stimulated basophils of peanut allergic patients in vitro. Slide14

Insights into FA Inception

Noti

et al in 2014 sensitized mice via atopic dermatitis skin lesions to OVA and peanut allergen followed by

intragastric

allergen challenge, with immunologic changes measured thereafter.

Sensitization via this method was associated with expansion of TSLP-elicited basophils in the skin that promote allergen specific Th2 cytokine responses, increased allergen specific serum

IgE

levels, and mast cell accumulation in the intestine, promoting the development of food allergy.

Basophil depletion or disruption of TSLP response decreased susceptibility of food allergic response.

Cell transfer of TSLP-elicited basophils into intact skin promoted disease!

Slide15

Methods of FA Screening

Skin prick testing

Inexpensive

Outpatient setting

Immediate results (15-20 minutes)

May use extract or “prick to prick” method with fresh allergen.

Intradermal testing to food allergens prone to false positivity and anaphylaxis. Slide16
Slide17

Skin Prick Testing (SPT) for FASkin prick testing for FA has a sensitivity of 85% and a specificity of 74% (Sampson H et al JACI 1984).

Judicious and limited skin prick testing should be done within the context of a given anaphylactic or allergic event.

Proves sensitization, not clinical allergy.

Based on wheal diameter of positive prick tests, threshold values to determine if OFC’s are necessary have been set:

Milk 8 mm

Egg 7 mm

Peanut 8 mm

Sesame 8 mmSlide18

Serology (sIgE) Testing for FA

Fluoroscence

-labeled antibody assays to detect the presence of circulating

IgE

to a suspected food allergen.

Also only proves sensitizations, not clinical allergy.

RAST,

Immunocap

,

Immulite

2000, etc.

Non specific testing to multiple allergens should be avoided.

Can be useful if history is suggestive of anaphylaxis and

spt

is negative or if patient cannot do without antihistamine, severe skin disease, dermatographism, etc. Published cutoff values used to avoid OFC: Egg 7 kUA/L

Peanut 14

kUA

/L

Milk 15

kUA

/L

Sesame 7

kUA

/LSlide19

Limitations

Skin Prick Test

PPV based on population and food

NPV relatively high but negative result does not rule out allergy

Food allergy extract not standardized

Wheal size to establish OFC reactivity not determined for most allergens

Cannot skin test patients with active dermatitis

sIgE

Test

Often leads to unnecessary elimination diet

Total

IgE

level and non-specific cross reactive binding

Fleischer et al in 2011 shows large majority of pediatric patients successfully reintroduced foods avoided based on

sIgE values only. Slide20
Slide21

FA Diagnosis: Food ChallengeGold standard of FA diagnosis is Double Blind Placebo Controlled Food Challenge (DBPCFC).

Cumbersome, lengthy, and usually only performed in academic centers.

OFC simple and easier to administer in outpatient setting.

Lieberman et al in 2011 evaluated 701 OFC’s for 521 patients.

18.8% elicited reaction, 1.7% required epinephrine.

OFC’s should start with 0.1% - 1 % of total challenge food.

OFC’s goal challenge dose should be 8-10 gm dry food, 16-20 gm meat or fish, 100 ml wet food; dosing interval should be every 15 minutes. Slide22

Unproven Diagnostic MethodsSerum IgG level to potential food allergens

Applied Kinesiology

Hair analysis

Cytotoxicity

Electrodermal

testing

Rescue dogsSlide23

Component Resolved Diagnostics (CRD)Diagnosis of immediate hypersensitivity to FA historically based on skin testing and

sIgE

, but this approach has disadvantages that may affect the patient’s management.

CRD uses purified allergen proteins from natural sources or recombinant expression of complementary DNA.

Food

Components

Peanut

Ara h

1,2, 3, 6, 8, 9

Milk

Bos

d 4,

5, 6, 8, 12

Egg

Gal d 1, 2, 3, 4, 5Slide24

Valenta

, R et al. Gastroenterology 2015. Slide25

Trimeric Ara h 1 core - an allergenic, heat digestion stable peanut epitope. Slide26

CRD Advances in Peanut Allergy

Ara h 1, 2, 3 – seed storage proteins and HEAT STABLE.

Ara h 4 – isoform of Ara h 3.

Ara h 6 – nearly homologous to Ara h 2.

Ara h 5 –

profilin

(plant based pan-allergen), HEAT LABILE.

Ara h 8 Bet v 1 homologue and HEAT LABILE.

Ara h 9 – Lipid Transfer Protein, HEAT STABLE.

Clincal

Trends in Peanut CRD:

Ara h 2 and 6 sensitization most highly associated with immediate hypersensitivity.

The higher the Ara h 2 sensitization, the more likely a patient will have immediate hypersensitivity.

Sensitization to more than one seed storage proteins more likely to result in severe anaphylaxis.

Peanut component sensitization may vary by geography:

Sweden (increased Ara h 8 +’s)

USA (increased Ara h 1-3 +’s)

Spain (increased Ara h 9 +s)Slide27

CRD Advances in Peanut Allergy

Johannsen et al in 2011 in

Clin

Exp

Allergy found that Peanut SPT < 7 mm and

sIgE

< 2

kUa

/L was associated with 95% OFC tolerance.

Nicolaou

et al in 2010 showed that in a birth cohort of 933 children 11.8% were sensitized to peanut at 8 years of age. OFC’s were performed on children with unconvincing reactions and

sIgE

< 15

kUa/L and spt < 8 mm, finding a prevalence of immediate HS of 22.4% among sensitized patients.

Nicolaou

et al in 2010 also found that peanut sensitized children that were tolerant often were concomitantly sensitized to grass pollen and birch pollen.

Dang

et al in 2012 found in 200 Australian children that peanut skin prick test followed by Ara h 2 measurement limited the need for OFC when compared to a combination of other tests. Slide28

FIG E2. Characteristic

fluorometric

results of microarrays. Pictures of

fluorometric

component recognition patterns in subjects with distinct

clinical phenotypes. A, Subject not recognizing any components (negative

control). B, Subject recognizing all components (with peanut allergy and

hay fever). C, Subject recognizing only major peanut components (with

peanut allergy). D, Subject recognizing only grass and cross-reacting components

(with hay fever and asymptomatic peanut sensitization

).

Nicolaou

et al JACI 2010. Slide29

Ara h 8 = Bet v 1 homologueExtensive

IgE

cross-sensitization exists between peanut allergens and botanical allergens such as birch, alder, and grass allergens.

Asarnoj

et al in 2010 described a group of peanut sensitized children that were sensitized to Ara h 8 only on Peanut CRD. Seventeen percent of these patients described mild symptoms only with peanut ingestion.

Asarnoj

et al in 2012 examined 144 children with lone Ara h 8 sensitization:

82 eating peanuts regularly at time of recruitment.

62 underwent OFC to peanut

1 experienced anaphylaxis (DEVELOPED ARA H 6 SENSITIZATION IN INTERIM FROM RECRUITMENT TO CHALLENGE). Slide30

Considerations for Ordering Peanut CRD

LESS Likely

To Be Informative

MORE Likely To

Be Informative

Recent

convincing clinical reaction

Mild reactions or no reaction history

Remote

significant reaction with peanut

sIgE

> 15

kUa

/L

Remote clinical

reaction with birch sensitization occurring over time

Peanut

sIgE

> 25 or < 0.35

kUa

/L

Peanut

sIgE

0.35 –

15

kUa

/L

Lack of birch sensitization

Birch Sensitization

Younger children

Older PersonsSlide31

CRD Advances in Egg Allergy

Egg allergy affects up to 2% of US children.

Previous estimates that egg allergy is outgrown by a majority of patients at 5 years of age is now considered wrong:

Savage et al 2007 in a chart review estimated 32% of patients still allergic at 16 years.

Sicherer

et al 2014 used birth cohort to document that only half of infants diagnosed with egg allergy were tolerant at age 6 years.

Gal d 1 (

ovomucoid

)

HEAT STABLE

Gal d 2 (ovalbumin)

Gal d 3 (

conalbumin

)

Gal d 4 (lysozyme)Gal d 5 (albumin)Slide32

CRD Advances in Egg AllergyAlessandri

et al in 2012 examined 68 Italian children for suspected egg allergy using CRD and egg-OFC.

44/47 Gal d 1 (

ovomucoid

) negative tolerated boiled egg.

20/21 Gal d 1 positive patients reacted to raw egg.

Lemon-Mule et al in 2008 challenged 117 children to heated-egg OFC and measured egg-CRD and skin test data in the reactive and tolerant groups.

64/117 heated egg tolerant and placed on heated egg diet.

Heated egg diet was associated with the following over 1 year:

Decreased skin prick test wheal to egg white

Increased IgG4 levels to ovalbumin and

ovomucoid

No control group for heated egg diet; followed x 12 months only. Slide33

Baked Egg As a Form of Immunotherapy?

Leonard et al in 2012 divided regular egg allergic children based on their reactivity to baked egg or not. Control group avoided egg completely.

Of the Intention to Treat Group (79 children), 53% of these patients achieved REGULAR EGG TOLERANCE, by incorporating daily baked egg ingestion at 37.8 months.

Patients on baked egg diet saw an decrease in size of skin test, and an increase in egg white specific IgG4 levels. Slide34

CRD Advances in Milk Allergy

D’Urbano

et al in 2010 performed skin prick tests,

sIgE

, CRD, and OFC to 58 milk allergic children.

IgE

reactivity to

Bos

d 8 much higher than other milk components.

+ CRD to

Bos

d 8 outperformed

sIgE

when using a clinical decision point of > 0.6 ISU.

PPV 96%NPV 78%Bos d 4 (a-lactalbumin

)

Bos

d 5 (B-

lactoglobulin

)

Bos

d 7 (bovine IgG)

Bos

d 8 (casein)

HEAT STABLE

LactoferrinSlide35

Heated Milk as a Form of Immunotherapy?

Nowak-

Wegrzyn

et al in 2008 found in 68 Milk allergic patients that tolerated heated milk in their diet had a decrease in skin test size and an increase in IgG4 level over 90 days.

Kim JS et al in 2011 examined 88 milk allergic children and created a treatment group of heated milk diet vs avoidance.

60% tolerated unheated milk over a median 37 months (8-75).

22% in control group developed unheated milk tolerance. Slide36

Du

Toit

et al . JACI. 2008: 122; 984-91.Slide37

LEAP: Learning Early About Peanut Allergy

Du

Toit

et al reported this year in the NEJM a randomized trial for infants at risk for the development of peanut allergy.

640 infants (4-11 months) with egg allergy and eczema were skin tested for peanut. Skin test wheal of 1-4 mm was considered positive.

Skin test results stratified patients into skin test negative and skin test positive groups.

These groups were then randomly assigned into a consumption cohort or an avoidance cohort. Both groups followed regularly with visits, skin testing,

sIgE

to peanut, IgG to peanut, IgG4 to peanut, up to 60 months.

Open food challenge or DBPCFC at end of 60 months assessed rates of peanut allergy development. Slide38

Du

Toit

et al. NEJM. 2015: 372 (9); 803-813.Slide39

LEAP: Learning Early About Peanut Allergy

ITT Analysis – 530 Infants

Negative SPT Group

13.7% peanut allergy in avoidance cohort

1.7% peanut tolerance in consumption cohort

P < 0.001

Positive SPT Group

35.3% peanut allergy in avoidance cohort

10.6% peanut tolerance in consumption group

P < 0.004

No deaths.

No significant differences in adverse events between avoidance and consumption groups.

Increase in peanut-IgG4 predominantly in consumption cohorts.

Large peanut-

IgE

and peanut skin test wheals predominantly in avoidance cohorts. Slide40

Du

Toit

et al. NEJM. 2015: 372 (9); 803-813.Slide41

LEAP: Learning Early About Peanut AllergyPro’s: LEAP study documented an intervention that was “safe, tolerated, and highly efficacious.”

92% adherence rate in both intervention cohorts.

Patients with negative SPT at entry who consumed peanut had 86% risk reduction, compared to patients with positive SPT at entry who consumed peanut with a 70% risk reduction.

Con’s:

Lack of a placebo group.

76 infants in the original recruitment, prior to randomization had SPT wheal > 4 mm.

Of 319 children randomly assigned to peanut consumption group, 7 had positive results of entry food challenge and 9 terminated their consumption based on development of allergic symptoms. Slide42

Response to LEAP Study

Consensus Communication on Early Peanut Introduction and the Prevention of Peanut Allergy in High Risk Infants. Pediatrics. August 2015: 136; 600.

Doctors “should recommend” peanut introduction in high risk infants in countries where peanut allergy is prevalent.

Infants with eczema and egg allergy under 6 months of age should have allergy referral to determine peanut status and whether they should be challenged using LEAP Protocol.

More formal NIAID/EAACI food introduction guidelines to follow.

Editorial Response JACI: In Practice. 2015: 3(5); 649-51.

Protocol suggested in Consensus non-specific and open ended.

Leaves up to primary care doctors to define “high risk.”

Did not discuss implications of adherence with target dose.

Did not address implications of widespread testing and financial burden of this practice. Slide43

Management of FAAvoidance!

There is no cure.

Education of patient, family, friends, school, social contacts etc.

Training of patient and caregivers on correct Epi Pen or

Auvi

Q technique.

Re-assessment of immunologic reactivity.

Tolerated an accidental ingestion after years of consisted avoidance?

Twenty percent likelihood of outgrowing peanut allergy. Slide44

Immunotherapy (IT) for FANeed is clear as prevalence of FA worldwide is growing.

Avoidance is a imperfect management.

Accidental ingestion is common (20%).

Gupta et al in 2011 reports 38.7% of children diagnosed with FA have experienced anaphylaxis that includes hypotension and/or dyspnea.

Terms for defining goals of Immunotherapy FA Trials.

Desensitization: tolerating escalating doses of food allergen during a trial.

Sustained unresponsiveness: tolerated a controlled food challenge 2-6 weeks after desensitization was halted and food allergen was avoided.

Immunological Tolerance: “Growing Out of It.”Slide45

Forms of IT for FA OIT: Oral Immuno-therapy

SLIT: Sublingual immunotherapy

Recombinant Protein Therapy

Epicutaneous

Immunotherapy

OIT trials are most numerous and better characterized compared to other forms.

More patients reach active desensitization but with a higher rate of adverse events. Slide46

OIT SchemaInitial Dose Escalation

Build-up phase

Maintenance Phase

Avoidance Phase

Assessment of response by food challengeSlide47

Peanut OITAnagnostou

et al in 2014 released results of STOP II trial for peanut allergic children undergoing OIT. 39/49 patients in the treatment completed 6 months of maintenance 800 mg peanut dosing; 24/39 passed a 1400 mg oral challenge.

Study did not assess for sustained unresponsiveness.

Syed et al in 2014 compared antigen induced

Treg

characteristics of 23 patients on peanut OIT vs peanut allergic controls.

After 2 years of maintenance peanut OIT, therapy was stopped and 35% were peanut tolerant at 3 months, and 13% at 6 months.

Vickery et al in 2014 documented 24/39 patients that completed 4 years of peanut OIT

50% passed peanut OFC at 1 month after peanut abstinence. Slide48

OIT for Other Food Allergens

Escudero

et al in 2015 completed a RCT for egg allergic children to examine effectiveness of egg OIT over 90 days.

11/30 of egg-OIT (37%) tolerated egg OFC 1 month after discontinuing egg OIT; for this group, they were still consuming all forms of egg ad lib with 36 months of documented follow up.

Burks et al in 2012 randomized 40/55 children into an Egg OIT group with 22 month treatment phase.

11/40 (28%) passed egg OFC two months after egg OIT discontinuation; these children had documented sustained unresponsiveness at 30 and 36 months of follow up.

Meglio

et al published follow up study of 21 milk allergic children 4 years after they were desensitized.

15/21 (71%) achieved desensitization over 6 months in 2004

14/21 (66%) had sustained unresponsiveness at 4 year follow upSlide49

Novel ApproachesCo-administer Peanut OIT with probiotic

OIT for multiple foods (Stanford Program)

Omalizumab

usage for rush oral desensitization

DARPins

Epicutaneous

patch therapy

Rectal delivered peanut vaccine of Ara h 1/2/3 with E.coli as adjuvantSlide50

Take Home Points

sIgE

testing for random foods indicates sensitization only and may lead to unnecessary anxiety and elimination.

CRD can improve FA diagnosis and management.

Ara h 1,2,3,9 + for peanut associated with immediate HS

Gal d 1 or

Ovomucoid

+ associated with immediate HS

Bos

d 8 or Casein + associated with immediate HS

Children with confirmed unheated milk and/or regular egg allergy are likely to gain tolerance more quickly if they tolerate heated milk and/or baked egg, and eat foods containing these regularly.

Early peanut introduction for selected high risk patients likely can protect against development of peanut allergy.

OIT for FA is NOT READY FOR CLINICAL USE.Slide51

It’s a Long Way to the Top if You Want to Rock ‘N’ Roll!!!Slide52

References

Sicherer

et al. Advances in diagnosing peanut allergy. JACI In Practice. 2013: 1 (1); 1-13.

O’Keefe et al. Diagnosis and management of food allergies: new and emerging options: a systematic review. Journal of Asthma and Allergy. 2014: 7; 141-164.

Lack, G. Update on risk factors for food allergy. JACI. 2012: 129 (5); 1187-97.

Kattan

, JD et al. Allergen component testing for food allergy: ready for prime time?

Curr

Allergy asthma Rep. 2013: 13; 58-63.

Chhiba

, KD et al. New development in immunotherapies for food allergy. Immunotherapy. 2015: 7(8); 913-22.

Fleischer et al. Consensus communication on early peanut introduction and the prevention of peanut allergy in high risk infants. Pediatrics. 2015: 136; 600-04.

Bartnikas

, LM et al.

Epicutaneous sensitization result in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis. JACI. 2013; 131 (2); 451-60.

Noti

et al. Exposure to food allergens through inflamed skin promotes intestinal food allergy through the

thymic

stromal

lymphopoietin

-basophil axis. JACI. 2014: 133 (5); 1390-99.

Du

Toit

, G et al. Randomized Trial of Peanut Consumption in Infants

arisk

for peanut allergy. NEJM. 2015: 372 (9); 803-13.

Valenta

, R et al. Food allergies: the basics. Gastroenterology. 2015: 148; 1120-1131.Slide53

References

Asarnoj

, A et al. Peanut component Ara h 8 sensitization and tolerance to peanut. JACI. 2012; 130(2): 468-472.

Nicolaou

, N et al. Allergy or tolerance in children sensitized to peanut: Prevalence and differentiation using component resolved diagnostics. JACI. 2010; 125(1); 191-7.

Caubet

, J et al. Significance of

ovomucoid

and

ovalumin

specific

IgE

/IgG4 ratios in egg allergy. JACI. 2012; 129(3): 739-747.

Umasunthar

, T et al. Incidence of fatal food anaphylaxis in people with food allergy. Clin Exp Allergy. 2013; 43: 1333-41.Xu et al. Anaphylaxis related deaths in Ontario: a retrospective review of cases from 1986-2011. Allergy, Asthma, and Clin

Imm

. 2014; 10(38): 1-8.

Leonard, SA et al. Dietary baked egg accelerates resolution of egg allergy in children. JACI. 2012; 130(2): 473-480.

Lemon-Mule, H et al. Immunologic changes in children with egg allergy ingesting extensively heated egg. JACI. 2008; 122 (5):977-83.

D’Urbano

LE et al. Performance of component based micro-array in the diagnosis of cow’s milk and hen’s egg allergy.

Clin

Exp

Allergy. 2010; 40: 1561-1570.

Escudero

C et al. Early Sustained Unresponsiveness after short course egg OIT: a RCT study in egg allergic children.

Clin

Exp

Allergy. Ahead of publication.

Alessandri

C et al.

Ovomucoid

specific

IgE

detected by microarray predicted tolerability to boiled hen’s egg and an increased risk to progress to multiple environmental allergen

sensitisation

.

Clin

Exp

Allergy. 2011; 42: 441-450.Slide54

ReferencesNowak-

Wegrzyn

, A et al. Tolerance to extensively heated milk in children with cow’s milk allergy. JACI. 2008; 122 (2): 342-7.

Anagnostou

, K et al. Study of induction of tolerance to oral peanut: STOP II TRIAL. Efficacy and Mechanism Evaluation. 2014; 1(4).

Ott

, H et al. Clinical usefulness of micro-array based

IgE

detection in children with suspected food allergy. Allergy. 2008; 63: 1521-28.

Brough

, HA et al. Peanut protein in household dust is related to household peanut consumption and is biologically active. JACI. 2013. 132(3): 630-8.

Johannsen, H et al. Skin prick testing and specific

IgE

can predict peanut challenge outcomes in preschool children with peanut sensitization.

Clin Exp Allergy. 2011; 41 (7):994-1000.Kim JS et al. Dietary baked milk accelerates of cow’s milk allergy in children. JACI.

2011; 128(1): 125-131.Slide55

Questions?