Dr. Lee Frick Lecture

Non-IgE-Mediated Food Allergy Anna Nowak-Węgrzyn, MD

Associate Professor of Pediatrics

Icahn School of Medicine at Mount Sinai

Jaffe Food Allergy Institute

New York, NY

Faculty Disclosure for

Anna Nowak-Wegrzyn

For the 12 months preceding this CME activity, I disclose the following types of financial relationships:

Honoraria received from: Nestle, Thermo Fisher Scientific

Consulted for: Nutricia, Stallergenes

Held common stock in: None

Research, clinical trial, or drug study funds received from: NIH, Nutricia

I will be discussing products that are investigational or not labeled for the use under discussion.

Objectives

Describe manifestations, diagnosis and

management of non-IgE mediated food

allergic disorders

Describe natural history of FPIES and

proctocolitis

Food allergy: immune system-

mediated adverse food reaction

Non-IgE-Mediated

Anaphylaxis; FDEIA

Urticaria / Angioedema

Immediate GI symptoms

Pollen food allergy syndrome

Bronchospasm

Mixed

Atopic dermatitis

Eosinophilic esophagitis /

gastroenteritis

Asthma

IgE-Mediated

Dermatitis herpetiformis

Celiac disease; Enteropathy

FPIES

Allergic proctocolitis

Heiner’s syndrome

•FT, female, breast-fed

•4 weeks of age: a CMF x 2-weeks: intermittent emesis, poor weight

gain, and small specks of blood in her stools [chronic]

•Back to exclusive BF-doing well

•12 weeks old: 1 feeding with a CM-based formula 90 minutes after the

feeding: repetitive, projectile emesis and lethargy [acute]

•In the ED full sepsis workup, toxicology, and metabolic screening

•IVF and antibiotics in hospital x 3 days. Bloody diarrhea only the first

hospital day; tolerated eHCF; cultures negative.

•She avoided CM; tolerated solid foods introduced from 5 to 7 months of

age without symptoms until a jar infant food with cheese was given.

•90 minutes after ingestion: repetitive emesis and lethargy, IVF

resuscitation. [acute]

•CM excluded from the diet

Case 1

Case 2

• FT, male, breast-fed

• Mild GE reflux, and at age 5 months, an H-2 blocker prescribed, rice added to thicken the feedings

• 6 months of age: repetitive emesis, lethargy, dehydration and hospitalization [acute]

• In the hospital: several mucousy, bloody stools. Sepsis work up done; IVF- improvement; all cultures negative. He resumed breast-feeding, diagnosis-viral gastroenteritis.

• One week later: similar symptoms and hospitalization. At that time, his mother indicated that both episodes developed approximately 2 hours after oat cereal was given (mixed with expressed breast milk).

• Serum oat-specific IgE: negative

• The mother refused to add oat to the diet at home.

• OFC in the pediatric office: 90 min after the feeding with oat cereal- recurrent emesis, lethargy, treated with IVF

7

FPIES manifestations

• Chronic • Young infants fed

continuously with milk or soy formulas

• Watery diarrhea

• Mucous, blood in stools

• Intermittent emesis

• Low albumin and t. protein

• Failure to thrive

• Onset: first 1-3 months of life

• Acute • Ingestion following a period

of avoidance (at least several days)

• Onset of emesis: 2- 4 hours

• Lethargy, limpness

(“septic appearance”) • 20% go into shock

• 15% with methemoglobulinemia

• 6-8 hours later: diarrhea

• Onset: usually under 12 months

Acute FPIES: clinical features

Clinical

features

Mehr S

AU

N=66

Hwang J

Korea

N=16

Sopo SM

Italy

N=66

Caubet JC

US/Mt Sinai

N=76

Design Retro,

report

Prospective

milk OFC

Retro, report Prospective,

OFC

Age [median] 5.5 mo 0.5-1.5 mo 5.7 mo 2.8 yrs [1-30]

Vomiting

(1-3 hr)

100% 88% 98% 95%

Lethargy 85% 63% - 5%

Pallor 67% 80% -

Hypotension - - 17%

Diarrhea

(6-10hr)

24% 44% 54% 7%

Temperature

<36°C

6 (24) - - -

Acute FPIES- misdiagnosis common

• Lack of “classic” allergic skin and

respiratory symptoms

• Multiple episodes for baby cereals rice

and oatmeal (“hypoallergenic”)

• Shock

• Sepsis-like appearance-full sepsis work

up and antibiotic treatment

• Ileus-like – laparotomy

FPIES: 16 year experience Mehr et al, Pediatrics 2009

Investigations performed, (N = 64)

Abdominal imaging, n (%)a 22 (34)

Septic evaluation, n (%)b 18 (28)

Surgical consultation, n (%) 14 (22)

Electrocardiography, n (%) 5 (8)

Other, n (%)c 5 (8)

Electroencephalography, n (%) 4 (6)

a Abdominal imaging included abdominal radiography (18), barium swallow

testing (12), and abdominal ultrasonography (5)

Some children underwent multiple types of abdominal imaging after a reaction

b Septic evaluation included complete blood cell count and blood culture, chest

radiograph, and/or lumbar puncture

c Other investigations included a Meckel scan (1), echocardiography (1), brain

MRI (1), Holter monitor testing (1), and a urine metabolic screen (1)

FPIES: differential diagnosis

Infectious Non-infectious Surgical

Necrotizing

enterocolitis

Sepsis

Hirschprung’s

disease

Gastrointestinal

infection

(Salmonella,

Shigella,

Campylobacter,

Yersinia sp,

parasites )

Anaphylaxis

Coagulation

disorders

Metabolic

disorders

Vitamin K

deficiency

Food protein-

induced

proctocolitis

Intussusception

Volvulus

Ileus

Epidemiology of milk-FPIES

in Israel

• 13,019 infants in Israeli birth cohort

• 0.5% IgE-mediated milk allergy

• 0.34% milk FPIES in 1st yr of life

– Total of 44 infants

– None with soy sensitivity

– All presented within 6 months

Katz Y et al, JACI 2011

Food allergens in FPIES

Children Adults

Milk

Soybean

Rice

Oat

Fish

Poultry (chicken, turkey)

Egg

Peanut

Wheat

Fish

Shellfish (molluscs)

Ruffner MA, et al. JACI in Practice, 2013

Food Allergens in FPIES:

Mt Sinai 10-year experience

Caubet JM, manuscript in preparation

Single

food

Multiple

N=161, diagnosis confirmed by

OFC in 30%, median age 45 mo

66% 34%

9% reacted to median 3 foods (3-10)

Risk of multiple food FPIES:

Mt Sinai 10-year experience

Caubet JM, manuscript in preparation

Milk-FPIES Soy-FPIES Solid-

FPIES

Soy

37%

Solid

16%

Milk

40%

Solid

16%

Milk

26%

Solid

44%

Soy

26%

Caubet JC, et al. manuscript in preparation

FPIES food-sIgE

0

10

20

30

40

50

60

AD AR IgE-FA Asthma

FPIES & atopy:

Mt Sinai 10-year experience

Positive

in 26%

33%

35% progressed to

immediate allergic

symptoms with milk

Early introduction of formula:

risk factor for milk / soy-FPIES Food involved M/S* Solid food(s)

only* M/S and

solid food(s) P

value*

Age at formula

introduction

Median, months 0.03 1.5 0.2 0.00 IQR+ (0.03-1.5) (0.05-9.5) (0.03-1.3) Age at solid foods

introduction

Median, months 5.3 6.0 5 0.10 (IQR+) (4-6) (5-6) (3.3-6) Duration of exclusive

breast feeding

Median, months 0.03 3.8 0.4 0.00 (IQR+) (0.0-2.1) (0.1-6) (0-4.3)

Caubet JC, et al. manuscript in preparation

Milk-IgE: risk factor

for persistent milk-FPIES Resolved

by age 3

years

Persistent

after age

3 years

No follow-up

after 3 years

of age

P

value*

Number of patients (%) 11 (16) 37 (53) 22 (31)

Age, months (at

resolution)

Median 26 80 19 0.01

(IQR+) (23-32) (56-119) (13-26)

Sex, n (%)

Female 5 (45) 19 (51) 13 (59) 0.75

Male 6 (55) 18 (49) 9 (41)

Diagnosis, n (%) Confirmed by an

OFC 1 (9) 26 (70) 6 (27) 0.00

Based on history 10 (91) 11 (30) 16 (73)

Detectable milk-specific

IgE, n (%)

(positive serum IgE or

skin prick tests)

0 (0)

15 (41)

7 (32)

0.01

* Comparison of FPIES resolved by age 3 years and patient with persistent FPIES

after age 3 years

Caubet JC, et al. manuscript in preparation

Katz Y et al, JACI 2011

Kaplan-Meier plot for the

cumulative probability of

recovery from CMP-induced

FPIES in prospective

population-based study

50%

75%

89%

1y 1.5

y

2y

Guidelines for the Diagnosis and

Management of Food Allergy in the United

States: Report of the NIAID-Sponsored

Expert Panel

NIAID-Sponsored Expert Panel

Journal of Allergy and Clinical Immunology

Volume 126 (Supplement); December 2010

DOI: 10.1016/j.jaci.2010.10.007

Copyright © 2010 Terms and Conditions

www.niaid.nih.gov/topics/foodAllergy/

Guideline 14

• The EP recommends using the medical

history and oral food challenge to

establish a diagnosis of FPIES. However,

when history indicates the infants or

children have experienced hypotensive

episodes or multiple reactions to the same

food, a diagnosis may be based on a

convincing history and absence of

symptoms when the causative food is

eliminated from the diet

FPIES: initial diagnosis

History of typical symptoms

Oral food challenge

SPT and sIgE usually negative; however up to 25% may become positive over time (atypical FPIES); IgE positivity may be associated with protracted course

Biopsy in chronic FPIES: eosinophilic inflammation in the colon, villous blunting

Patch test?

Atopy skin testing

A. Prick

B. Patch

C. Patch

Patch testing in FPIES

Study Fogg et al

PAI, 2006

Jarvinen et al

Ann Allergy Asthma

Immunol 2012

N 19 subjects / 33 ofc 25 subjects / 38 ofc

Median (range) age at

OFC

15 mo (5-30 mo) 3.3 years (1.5-16.8 yrs)

Recent rxn prior to OFC 12 mo (4-29 mo) 24.5 months (14.5-79 mo)

Positive ofc 16 of 33 (48%) 16 of 38 (42%)

APT sensitivity 100% 12%

APT specificity 71% 86%

APT PPV 75% 40%

APT NPV 100% 55%

Gradual (over 1 hour) administration of food protein 0.06*- 0.6 g / kg body

weight

If no reaction, discharge after 6 hours

Criteria for a positive challenge

Symptoms

Emesis (typically in 2-4 hours)

Diarrhea (typically in 5-8 hours)

Laboratory findings

Fecal leukocytes

Fecal eosinophils

Increase in peripheral polymorphonuclear leukocyte count > 3,500

cells/mm3 peaking at 6 hours

Interpretation of the challenge outcome

Positive challenge: 3 / 5 criteria positive

Equivocal: 2 / 5 criteria positive

Challenge protocol

26

Increase in neutrophils [ANC]

following FPIES challenge

Pre- Post-

Resolved FPIES

post-resolved rice post-resolved milkpost-resolved soy post-resolved soypost-resolved milk post-resolved soypost-resolved milk post-resolved milkpost-resolved egg

P = 0.24NS

FPIES (n=11) Resolved FPIES (n=9)

Treatment of acute FPIES

Fluid bolus: Normal saline 10-20 mL/kg

Solumedrol 1 mg/kg/dose i.v (single dose)

Potential role of ondansetron [serotonin receptor inhibitor]

Epinephrine generally not helpful in acute reactions without fluid replacement

Extreme cases: vasopressors, life support

Management of

milk / soy-FPIES

Food avoidance M/S: Breast-feeding or hypoallergenic formula (~40%

react to both milk and soy) Solid food introduction at 4-6 months, consider starting

with fruits/vegetables (~20% react to solid food) Re-test every 12 months: 25% may convert to

+sIgE/+SPT (atypical FPIES); of these, 35% will develop immediate allergic sxs

+SPT/sIgE: modify the challenge procedure to more gradual feeding

Re-challenge every 12-18 months (supervised OFC; ~50% reactions require treatment)

A letter for the patient in case of accidents to show in the Emergency Department

Management of

solid food-FPIES

Food avoidance

Breast-feeding or hypoallergenic formula (~40% react to M/S)

Food introduction:

Avoid grains, legumes, and poultry during 1st year of life (~50% reactive to more than 1 food, 40% reactive to another grain)

Tolerance to one food from a food group suggests that other foods will be also tolerated; e.g. soy for legumes, rice/oat for grains, chicken for poultry

Re-test every 12 months: 25% may convert to +sIgE/+SPT (atypical FPIES)

+SPT/sIgE-modify the challenge procedure to more gradual feeding

Re-challenge every 12-18 months post-reaction (supervised OFC)

A letter for the patient in case of accidents to show in the Emergency Department

*FPIES: Case presentations and management lessons.

Sicherer SH, JACI 2005 (January); 115: 149-156

Dear Doctor (To Whom It May Concern),

The patient named above has a food allergy called food protein-induced

enterocolitis syndrome. This is a type of allergy that usually does not result in typical

"allergic" symptoms such as hives or wheezing, but rather with isolated

gastrointestinal symptoms.

The foods that this child is avoiding include: MILK

The symptoms of this type of allergic reaction include repetitive vomiting that

may not start for a few hours (e.g., 2 hrs) following ingestion of the food to which the

child is allergic. Even very small amounts can trigger a reaction. There is sometimes

diarrhea that starts later (after 6 hours). In some cases (~20%), the reaction includes

hypotension and lethargy. The treatment is symptomatic and can include

intravenous fluids (e.g., normal saline bolus, hydration) and steroids (e.g.,

Solumedrol 1-2 mg/kg) for significant symptoms. The latter is given because the

pathophysiology is that of a T cell response.

This information is being given so that this could be considered in the differential

diagnosis for this patient in the event of symptoms. Of course, this illness does not

preclude the possibility of other illnesses (e.g., infection) or even other types of

allergic reactions leading to symptoms, so it is up to the evaluating physician to

consider all possibilities. Similarly, the treating physician is encouraged to pursue

any other treatments deemed necessary (e.g., symptomatic such as epinephrine for

shock, antibiotics for presumed infection, etc).

Please feel free to contact us for any further assistance.

Sincerely,

*http://iaffpe.org/docs/Emergency_Plan.pdf

Case

2 month-old exclusively breast-fed baby develops visible blood and mucous in the stool

No irritability, discomfort, normal appetite

On exam: no rectal fissure

Infectious work up: negative for bacteria and parasites

Colonoscopy: eosinophilic inflammation in rectum

Case-continued

Mother avoids milk and soy in her diet with disappearance of gross blood and mucous within 3 days

Occult blood persists despite further maternal dietary restrictions

Baby continues to be breast-fed and becomes mildly anemic despite iron supplementation

His allergy tests are negative at 12 months

He is introduced to milk and soy in his diet after 12 months and tolerates these foods well

Frequency (%)

Initial presentation

Blood-tinged stools 100

Pain during defecation 22

Diarrhea / loose stools 4

Failure to thrive 0

Endoscopic findings

Focal rectal erythema or erosions 100

Lymphoid nodular hyperplasia 48

Positive response to dietary protein elimination

Cow’s milk 65

Egg 19

Corn 6

Soy 3

Two of the above 5

Not identified 12

Response to L – amino acid formula only 4

Clinical features of allergic proctocolitis

in 95 exclusively breast-fed infants

Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr 2000;

30:S58-S60.

Sigmoidoscopy findings

A. Nodular hyperplasia with

circumscribed erosions

B. Nodular hyperplasia with

central pit-like erosions

C. Nodular hyperplasia in

endoscopically deflated state

Hwang JB et al, J Korean Med Sci. 2007

35

(A) Overview of rectal biopsy:

lymphoid aggregate, (2)

eosinophilic infiltration,

(3) crypts, (4) lumen, (5) muscularis

mucosae;

Faber et al, 2005 Acta Pediatrica

Allergic proctocolitis-

eosinophilic inflammation

(B) Detail: eosinophilic infiltration also

in between epithelial cells.

Apoptotic cells (6).

Xanthakos S et al, Journal of Pediatric Gastroenterology & Nutrition. July 2005.

Prospective cohort study of

22 healthy infants <6 mo

with rectal bleeding

7 initially CMF fed eHF

rectal bleeding resolved

within 2 wks (1-5 wks)

5 initially BF with avg

resolution at 6 wks (2-8

wks) after maternal milk

elimination

1 in each group required AA

formula for resolution

>6 eos/hpf

mucosa

and/or eos

in crypts or

muscularis

+1 lost to

follow up

A Serum eosinophil counts

(103/mm3) in infants with

allergic colitis and normal

biopsies

B Natural log of serum IgE

counts in infants with

allergic colitis and infants

with normal histology

Xanthakos S et al, Journal of Pediatric Gastroenterology & Nutrition. July 2005.

Severe Mild / Moderate

Necrotizing enterocolitis

Sepsis

Hirschprung’s disease

Intussusception

Volvulus

FPIES

Anal fissure

Perianal dermatitis /

excoriations

Gastrointestinal infection

(Salmonella, Shigella,

Campylobacter,Yersinia

sp, parasites )

Coagulation disorders

Vitamin K deficiency

Allergic proctocolitis

Differential diagnosis

of rectal bleeding in infancy

Management of allergic proctocolitis

Dietary elimination in maternal diet or hypoallergenic formula (casein hydrolysate)

Introduce solids at 4-6 months

SPT/sIgE at 12 months

Home introduction of foods after 12 months of age if SPT/sIgE negative

Usually gradual introduction starting from baked goods

Summary 40

▶ FPIES and allergic proctocolitis: non-IgE-mediated food allergy of the gut with poorly-defined pathophysiology

▶ Early introduction of milk/soy: risk factor for milk/soy FPIES; breast-feeding protective

▶ Milk-IgE: risk factor for persistence of milk-FPIES

▶ Favorable prognosis