Nutricia Paediatric Food Allergy Expert Meeting

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Baked milk challenge: for whom is it appropriate?

Paediatric Food Allergy Expert Meeting

Royal College of Physicians, London UK

December 6, 2016

Anna Nowak-Węgrzyn, MD PhD Associate Professor of Pediatrics

Icahn School of Medicine at Mount Sinai

New York, NY, USA

“I am extraordinarily patient, provided I get my own way in the end.”

1) Albert Einstein

2) Donald Trump

3) Shakespear

4) Margaret Thatcher

21

53

4

39

1 2 3 4

Effect of cooking & digestion on food

proteins

1

2

Processing

M I

I M

K

L L I

M

K M

I K L

L

K

Majority of children outgrow milk or egg within first 6 years of life

- children who “outgrow” milk / egg allergy have IgE directed

primarily at conformational epitopes

High temperature affects

1) All proteins in milk equally

2) Caseins more than whey proteins

3) Whey protein more than caseins

4) No significant effect on milk proteins

42 43

35

3

1 2 3 4

α-lactalbumin

β-lactoglobulin

Caseins

Lactoferrin

BSA

Immunoglobulins

Boiling

Time (min)0 5 10 15 20 30 45 60 75 90

Amount

(µg)10 10 10 10 10 10 10 10 10 10

Boiling

Time (min)0 5 10 15 20 30 45 60 75 90

Amount

(µg)10 10 10 10 10 10 10 10 10 10

Standard

+ DTT / heating

Modified

- DTT / heating

0 5 10 15 20 30 45 60 75 90

10 10 10 10 10 10 10 10 10 10

0 5 10 15 20 30 45 60 75 90

10 10 10 10 10 10 10 10 10 10

α-lactalbumin

β-lactoglobulin

caseins

Heated Milk-Reactive Heated Milk-Tolerant

Boiling time

(min)

0 5 10 15 20 25 30 60 90Boiling time

(min)

0 5 10 15 20 25 30 60 90

Negative Control

0 5 10 15 20 25 30 60 900 5 10 15 20 25 30 60 90 0 5 10 15 20 25 30 60 900 5 10 15 20 25 30 60 90

SDS-PAGE and immunoblots with boiled milk

Bloom K et al, PAI 2014

Hypothesis: Children who “outgrow” milk/egg allergy will tolerate baked milk/egg products

BM OFC

N=100

BM-Reactive

N=23

UHM-Tolerant

N=9

UHM OFC

N=43

Not challenged to

UHM due to highly

predictive test results;

N=34 BM-Tolerant

N=77

UHM Reactive

N=34

Strict avoidance

for 12 months

Re-challenge

BM Diet*

3 mo 48 mo

“Baked milk-1” study

-Mean age: 6.7 yrs; range: 2.6 – 17.3 yrs; 62% males

-No difference between groups: age, family hx,

exclusive breast feeding, age of 1st rxn

*The subjects in the BM Diet group are followed every 6 months

for up to 48 months or until become cow’s milk-tolerant. Nowak-Wegrzyn, et al, JACI 2008

35% epi tx during ofc

0% epi tx during ofc

Changes in milk-specific PST, IgE &

IgG4 in baked milk –tolerant subjects

Median Skin Prick Test (wheal diameter, mm)

in BM-tolerant Group over Time

0

5

10

15

20

0 months 3 months

P = <0.001

Median Casein-Specific IgG4 (ug/L)

in BM-tolerant Group over Time

0

3

6

9

12

15

0 months 3 months

P = 0.001

Median Milk-Specific IgE (kUA/L)

in BM-tolerant Group over Time

0

5

10

15

20

0 months 3 months

P = 0.183

Median B Lactoglobulin-Specific IgG4 (ug/L)

in Baked Milk Group over Time

0

1

2

3

4

0 months 3 months

P = 0.592

Milk PST ↓; casein-IgG4 ↑

Nowak-Wegrzyn, et al, JACI 2008

Active ITT group, n=88

Failed initial BM challenge, n=23

Passed initial BM challenge, n=65

Passed subsequent BM challenge, n=5

Active PP group, n=70

Comparison group, n=60

59% developed UHM tolerance

22% developed UHM tolerance Natural history

60% developed UHM tolerance

9% developed UHM tolerance

Kim J et al. JACI 2011

Median age 6.6 yrs

[2.1-17.3]

Follow-up median 37 mo (range 8-75 mo)

ITT - ACTIVE VS. COMPARISON SURVIVAL ANALYSIS

Log-rank p-value comparing survival among ITT Active vs. Comparison groups is 0.0056. There is a significant difference in the time to developing UHM tolerance between ITT active patients and comparison patients.

Hazard Ratio (95% CI)

Comparing ITT Active – Comparison P-value

Crude 2.43 [1.29, 4.57] 0.0059

Adjusted for sex, age at initial visit, and IGE 2.92 [1.47, 5.80] 0.0023

Patients in the ITT active group are 2.92 times more likely to develop UHM tolerance than patients in the Comparison group. This increased risk is statistically significant; HR=2.92 [1.47, 5.80] p=0.0023.

TIME TO UNHEATED MILK TOLERANCE: ITT - ACTIVE VS. COMPARISON

TIME TO UNHEATED MILK TOLERANCE:

ITT – INITIAL BM TOLERANCE VS. INITIAL BM REACTION

Log-rank p-value comparing survival among ITT initial HM tolerance vs. Initial HM reaction groups is <0.0001. There is a significant difference in the time to developing UHM tolerance between patients who were initially HM-tolerant and HM-reactive.

Hazard Ratio (95% CI) Comparing ITT HM Tolerant – HM

Reactive

P-value

Crude 10.95 [2.63, 45.53] 0.0010

Adjusted for sex, age at initial visit, and IGE 7.62 [1.75, 33.14] 0.0068

Reactions to baked milk:

1) Are always mild

2) Are never treated with epinephrine

3) May be severe

4) Usually occur within more than 4 hours of eating

8 4

104

10

1 2 3 4

Subjects

Total (n=88)

Initially baked-

milk tolerant

(n=65)

Initially baked-

milk reactive

(n=23)

P value

# Challenges

performed

172 154 (90%) 18 (10%) <0.001

# Failed (%) 58 (34%) 47 (31%) 11 (61%) 0.009

# Treated with

epinephrine

(%)

8 (4.7%) 5 (3.2%) 3 (17%) 0.04

Severity of reactions

during OFC to baked milk

Long-term follow up of baked milk

Active group,

n=85 median f/u 83 months

range 63-106

Failed initial BM challenge, n=23

Passed initial BM challenge, n=52

1 (14%) 60% mIlk-FDEIA and avoided all milk

Nowak-Wegrzyn & Sampson, 2013

13% became BM tolerant

78% remained BM reactive

9% became UHM tolerant

Passed initial UHM challenge, n=7

86% continued unrestricted milk

19% remained BM tolerant

9% avoided all milk

72% became UHM tolerant

2 (5%) EoE 2 (5%) milk-FDEIA

8 (20%) disliked UHM 5 with intermittent mild oral sxs

Outcomes of 114 consecutive challenges to baked milk in the allergy office

• Jan 2008-Dec 2015

• Excluded from analysis b/c did not ingest the full dose: muffin-15, pizza-2

• 72% tolerated muffin OFC (50/69)

• 82% (22/28) tolerated pizza OFC

• Muffin reactors:

• n=10

• Median cumulative dose=1/4 muffin=325 mg of milk protein=0.33 oz milk

• Pizza reactors:

• n=5

Agyemang A, et al, manuscript submitted

Outcomes of 114 consecutive challenges to baked milk in the allergy office

Agyemang A, et al, manuscript submitted G) H)

3.3 3.3 3.1

p = 0.99

B)

3.5 2.8 5.2

p = 0.003*

A)

E) F)

4.1 4.1 2.4

p = 0.61

D)

2.6 1.4

9.5

p = 0.03* C)

9 9 9

p = 0.44

9 8.5 8

p = 0.73

Outcomes of 114 consecutive challenges to baked milk in the allergy office

Agyemang A, et al, manuscript submitted

Severity of reactions to baked milk:

1. Can be predicted by large skin prick test wheal

2. Cannot be reliably predicted

3. Can be predicted by higher level of serum sIgE

to cow’s milk

4. Can be predicted by prior history

5

60

3127

1 2 3 4

Severe vs. mild reactions to baked milk

Agyemang A, et al, manuscript submitted

Clinical Characteristics

Required epi Did not require epi

P value OR

Age, years 10.6 (3.03-14.8)

7.1 ( 3.17-9.84 )

0.37 -

CM IgE (kIU/L) 4.3 (3.1-11.7) 6.17 (3.4-10) 0.88 -

SPT (mm) 7.5 (3.6- 13.6) 9 (8-13) 0.37

Anaphylaxis to milk in the past

10.5% 15.8% * >0.99 1.67 (0.22-10.7)

+Asthma 21.1% 36.8% * >0.99 1.7 (0.23-11)

+Atopic Dermatitis

10.5% 57.9% *** 0.046 0.09 ( 0.01-0.9)

+Allergic Rhinitis 21.1% 47.4% * >0.99 0.89 (0.1-6.3)

Clinical phenotypes of milk allergy

• Baked-milk reactivity ~20%

• Less likely to “outgrow” milk allergy

• More severe reactions

• Most in need of effective therapy

• Majority of those with CM-IgE>35 kIU/L react to baked milk

• Baked milk tolerance ~80%

• Excellent chances of outgrowing milk allergy

• Mild reactions

• Introduction of baked-milk products into the diet changes similar to immunotherapy; PST, IgE & IgG4 [“natural OIT”?]

• Strict avoidance may account for delay in tolerance in children who have mild / transient milk allergy

Persistent / Severe Mild / Transient

Practical tips for introducing baked milk: the US approach

• Non-IgE mediated CMA, non-FPIES: introduce baked milk and regular milk at home gradually

• FPIES: physician-supervised challenge

• IgE-CMA:

-CM-IgE>35 kIU/L: defer challenge

-CM-IgE <35 kIU/L: consider physician-supervised challenge

-CM-IgE and casein-IgE < 1 kIU/L more than 95% likely to tolerate

Conclusions-1 • Heating reduces allergenicity of milk proteins

• Majority of milk and egg allergic children do not react to baked milk

• Baked milk diets are well tolerated

• Introduction of baked milk into diet is associated with increasing sIgG4 and

decreasing basophil reactivity and skin prick test wheal size suggesting an

immunomodulatory effect

• Children who incorporate baked milk to their diet appear to progress to tolerating

unheated milk at an accelerated pace compared to the children who maintain strict

avoidance

Conclusions-2 • Reactivity to baked milk is a marker of a more severe and more persistent milk

allergy

• Children with higher cow milk and casein-sIgE are more likely to react to baked milk

• sIgE and SPT do not discriminate between severe and mild baked milk-reactors (Epi

vs. no Epi)

• We need a biomarker to identify those at risk for more severe reactions and those

who are not at risk to recommend home introduction of baked milk

THANK YOU