Food Allergies: Advances in Diagnosis and ManagementGreg Black, MD

USC SOM Department of Pediatrics Grand Rounds October 16, 2015Carolina Allergy and Asthma Consultants, PA

Roadmap• Food 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• Conclusions

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 Disease

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.

Food Allergy (FA) Diagnosis• NIAID 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.

Fatal Food Allergy• AAAAI 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.

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• TSLP

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 activity

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.

Dual Allergen Hypothesis

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.

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!

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.

Skin Prick Testing (SPT) for FA• Skin 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 mm

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/L

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.

FA Diagnosis: Food Challenge• Gold 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.

Unproven Diagnostic Methods• Serum IgG level to

potential food allergens• Applied Kinesiology• Hair analysis • Cytotoxicity• Electrodermal testing• Rescue dogs

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, 5

Valenta, R et al. Gastroenterology 2015.

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

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)

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.

FIG E2. Characteristic fluorometric results of microarrays. Pictures offluorometric component recognition patterns in subjects with distinctclinical phenotypes. A, Subject not recognizing any components (negativecontrol). B, Subject recognizing all components (with peanut allergy andhay fever). C, Subject recognizing only major peanut components (withpeanut allergy). D, Subject recognizing only grass and cross-reacting components(with hay fever and asymptomatic peanut sensitization). Nicolaou et al JACI 2010.

Ara h 8 = Bet v 1 homologue• Extensive 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).

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 Persons

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)

CRD Advances in Egg Allergy• Alessandri 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.

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.

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

• Lactoferrin

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.

Du Toit et al . JACI. 2008: 122; 984-91.

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.

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

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.

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

LEAP: Learning Early About Peanut Allergy

• Pro’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.

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.

Management of FA• Avoidance!• 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.

Immunotherapy (IT) for FA

• Need 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.”

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.

OIT Schema• Initial Dose

Escalation• Build-up phase• Maintenance Phase• Avoidance Phase• Assessment of

response by food challenge

Peanut OIT• Anagnostou 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.

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 up

Novel Approaches

• Co-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 adjuvant

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.

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

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.

References• Asarnoj, A et al. Peanut component Ara h 8 sensitization and tolerance to peanut. JACI. 2012;

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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

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References• Nowak-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.

Questions?