Food Protein Induced Enterocolitis Sydrome (FPIES)

Bloody diarrhea

Vomiting

Failure to thrive

Cow’s MilkSoy

HypotensionShock

FPIES - Overview

Enterocolitis after ingestion of a specific food protein.

Main symptoms Diarrhea – blood (+) Vomiting Hypotension/shock Failure to thrive

FPIES stools (Kabuki, Allergol Int 2007)

Symptoms resolve with removal of allergen from diet. Usually presents in neonates and infants, “outgrown” by 3 years.

Sicherer, J Pediatr 1998

A trip back in time….

1940 Case Series

Am J Med Sci 1940

Onset Symptoms Intervention Outcome

3 weeks Stools with mucus and frank blood

Cow milk to breast milk

Resolution in 48h, recurrence when milk tried again

4 weeksMucusy bloody stools, sometimes just blood without feces

Cow milk to goat milk Resolution in 48h

5 weeksFrankly bloody stools “sufficient to wet a large part of each diaper”, anemia, colic

Cow milk to breast milk (almost had ex-lap for Meckel’s)

Resolution in 48h

5 weeks Mucusy bloody stools, vomiting (lethargic episodes/aspiration) Cow milk to goat milk

Resolution in 48h, recurrence at 7 wks,switched to soy

Joyce D. Gryboski, MD

Infant with 3 episodes of bloody diarrhea and shock within 1-2h when challenged with milk

Rapid resolution of symptoms off of milk

Diagnosis: “milk induced colitis”

1966 Case Report

1967 Case Series

21 cases characterized by GI sx (vomiting, diarrhea, usually mucusy/bloody stools) and poor weight gain that resolved with elimination of cow’s milk

33% developed signs of shock when challenged

Colon bx (before and after milk elimination) demonstrated rapid reversal of colitis after milk eliminated – proposed that “milk induced colitis” be recognized as a distinct entity

1976 Case Series

2 cases: 32 weeker (1.6 Kg) and a term (2 Kg) infant

Both treated for NEC, thriving on hydrolysate formula, and then had acute onset recurrence of NEC-like sx when given standard formula (hypothermia/shock, increased ANC, vomiting, distension, bloody diarrhea).

Without referencing previous articles, reported that “intolerance to whole milk protein can cause a syndrome similar to NEC.”

1978

Collected 9 more cases and proposed diagnostic criteria for “Milk- and soy-induced enterocolitis of infancy.”

Mean age of symptom onset: 11 days - all with FTT, dehydration, bloody diarrhea

8/9 affected by both milk and soy

Patients rehydrated, some had sepsis workups (all negative); symptoms resolved on EHF, asked to come back for challenges with milk and soy (mean age 5.5 months)

Prior to challenge: Must be gaining weight with normal stools for at least 2 weeks NPO for 8 hours Baseline CBC with diff All stools 12 hours prior to challenge checked for blood, leukocytes,

and reducing substances

The Challenge

After the challenge: Directly observed by physician for 2 hours in case of anaphylaxis, VS

monitored for 8 hours, symptoms monitored for 48h CBC with diff at +2, 4, 6, 8, 10, 24 hours Stools for next 48 hours checked for blood, leukocytes, and reducing

substances

Fed 100 ml of milk or soy formula ….

Positive challenges in 14/18 (new onset diarrhea with blood and leukocytes within 24h)

Vomiting onset 1-2.5h (4/16 challenges with no vomiting)

Diarrhea onset 2-10h (most <6h), some grossly bloody

Duration of diarrhea 8-72h (most <24h)

No infants with angioedema, urticaria, wheezing (i.e., type I IgE-mediated allergic reactions)

Average change in ANC after oral challenge

positive challenges

negative challenges

1. Sx onset <2 months of age, <9 months at time of work-up

2. When receiving formula with the offending protein, infant has watery stools with blood and leukocytes that resolves when that protein is eliminated

3. Challenge causes diarrhea with blood and leukocytes within 24 hours

4. ANC at 6-8h after challenge is increased by >3500/mm3 over baseline

Powell’s diagnostic criteria for milk- and soy-induced enterocolitis of infancy:

Triggers Cow’s milk protein and soy are most common in US studies

50% of patients reactive to milk also react to soy.

Solid foods: Peas, lentils, peanuts Chicken, turkey, fish (fish-PIES?) Rice, oat, barley Squash, sweet potatoes Fruits (apple, pear, banana, peach) Most with FPIES triggered by a solid food also have history

of reacting to milk and/or soy.

Pathophysiology

Food allergy – adverse immune response to a foodIgE dependent:

Oral allergy syndrome, GI anaphylaxis

IgE associated/cell- mediated:Eosinophilic esophagitis/

gastritis/enteritis/colitis, AD

Cell-mediated: FPIES (Dietary protein enterocolitis), dietary

protein proctitis

Sicherer, Sampson, JACI Primer 2010

PathophysiologyTo quote every article: “Not well understood”Clinical observation Possible conclusionsResolves with EHF or amino acid formula

Triggered by food protein antigens

Does NOT occur to exclusively breast-fed infants

Quantity of food antigen in human milk not adequate to elicit a clinical response? Human milk contains factors that promote tolerance?

In exclusively breast-fed infants, occurs when solids are added to diet

The quantity of solid food protein overwhelms protective effect of breast milk?

PathophysiologyClinical observation Possible conclusionsMost patients with solid FPIES are already on EHF

Immaturity of gut’s food protein tolerance mechanisms plays major role

Rarely develop FPIES to new foods >1 year old

Almost all outgrow FPIES by 3 years old

SPT/sIgE negative; sx not consistent with type-1 hypersensitivity

Likely not IgE-mediated

Pathophysiology

In infants with “gastrointestinal milk allergy”*…

…their peripheral mononuclear cells secrete higher levels of TNF- which increases intestinal permeability (Heyman, Gastroenterology 1994)

…there is elevated TNF- in stools after challenge (Majaama, Clin Exp All 1996)

*may or may not be FPIES

PathophysiologyCase report: 8 mo male with rice FPIES (Mori, Clin Dev Imm 09)

Measured IL-4, IFN-γ, IL-10 expression by peripheral blood T-cells pre/post a positive challenge (at 8 mo) and negative challenge (at 14 mo)

4 hours after positive challenge: vomiting, diarrhea, lethargy requiring IVF resuscitation.

Pre

Post

+8 mo

Neg14 mo

PathophysiologyDuodenal biopsy of 28 infants (mean 49 days) with active cow’s milk

FPIES (Chung, JACI 02)

Dx confirmed by challenge; compared to 10 controlsSpecimen stained for: Relevance Result

TNF-α Inflammatory cytokine, 5GI permeability

Markedly 5 in FPIES (pos. corr. with villous atrophy); absent in controls

TGF-β1 6T-cell inflammation (via Treg?); 5 with gut maturation, secreted in breast milk

Low in FPIES & control

TGF-β RI High affinity receptors for TGF-β1

Low in most FPIES vs. control (& neg. corr. with villous atrophy)

TGF-β RII No difference between FPIES and control

Eosinophilic Inflammation Is Prominent In FPIES – Multi-center Case-series Study (Nomura, JACI Abstract 2009) Included 114 patients (inclusion criteria did not require challenge) Peripheral blood eosinophils >20% in 50% of patients Stool eos in 69%

Pathophysiology

Elevation of Fecal Eosinophil-Derived Neurotoxin in FPIES (Nomura, JACI Abstract 2010) Included 38 controls vs. 6 FPIES (inclusion criteria did not require

challenge) 1.4% of controls with EDN > 20 ng/g; 83% of FPIES (with clinical

sx present) had EDN > 20 ng/g

Tolerance FPIES

TNF-α

Cytotoxic T-cells, ?Eos

IL-4 (TH2)

Immature gut

TGF-β1 and receptors

IFN-γ (TH1)

Tregs, IL-10

Mature gut

Pathophysiology

Differential diagnosis

Toxic appearing infant with poor perfusion and bloody diarrhea…. Sepsis, NEC Surgical emergency

Differential diagnosis Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus Anatomic: volvulus, Meckel’s, AVM, intussusception, anal fissure Hematologic: coagulopathy, HDN Allergic: eosinophilic gastroenteropathies, food protein-induced

proctocolitis, GI anaphylaxis Misc: swallowed maternal blood

Index of suspicion of typical cow’s milk protein-induced enterocolitis (Hwang, J Korean Med Sci 2007)

142 71%

17%

11% consecutive infants 15-45 days old

admitted for vomiting/diarrhea

Infection

FPIES (cow’s milk)

Other

Differential diagnosis Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus Anatomic: volvulus, Meckel’s, AVM, intussusception, anal fissure Hematologic: coagulopathy, HDN Allergic: eosinophilic gastroenteropathies, food protein-induced

proctocolitis, GI anaphylaxis Misc: swallowed maternal blood

Index of suspicion of typical cow’s milk protein-induced enterocolitis (Hwang, J Korean Med Sci 2007)

Failure to thrive Albumin

WBC count (serum)

Metabolic acidosis

Eosinophil count (serum) Platelets Fecal blood or leukocytes

Methemoglobinemia

Differential diagnosis Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus Anatomic: volvulus, Meckel’s, AVM, intussusception, anal fissure Hematologic: coagulopathy, HDN Allergic: eosinophilic gastroenteropathies, food protein-induced

proctocolitis, GI anaphylaxis Misc: swallowed maternal blood

Index of suspicion of typical cow’s milk protein-induced enterocolitis (Hwang et al, J Korean Med Sci 2007)

Failure to thrive Albumin

Differential diagnosis

Do not laparotomize FPIES (Jayasooriya, Ped Emer Care 2007) “A case of food protein-induced enterocolitis syndrome,

leading to unnecessary surgery, is presented.”

Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus Anatomic: volvulus, Meckel’s, AVM, intussusception, anal fissure Hematologic: coagulopathy, HDN Allergic: eosinophilic gastroenteropathies, food protein-induced

proctocolitis, GI anaphylaxis Misc: swallowed maternal blood

FPIES: 16-Year Experience (Mehr, Pediatrics 2009) Australian retrospective case series of 35 children with FPIES (66 total

episodes); age at presentation 5.5 ± 2.4 months 71% of children with ≥2 episodes before diagnosis (20% with 4 episodes) 1 child with laparotomy

192

4

5Initial episodes

presenting to ED

FPIES

“food allergy”

sepsis

4 gastroenteritis

4 intussusception

2 no dx

Discharge diagnoses

Differential diagnosis

Differential diagnosisClinical differentiation of allergic GI disorders of infancy from FPIES

Sicherer, JACI 2005

Disorder Key features Distinction from FPIESGI anaphylaxis (Type-1 immediate hypersensitivity)

Acute vomiting, diarrhea, angioedema, urticaria, wheezing, hypotension

Cutaneous/respiratory involvement, SPT/specific IgE positive

Eosinophilic Gastroenteropathies

Depends on site of eosinophilic inflammation in GI tract: vomiting, obstruction, gastric or colonic bleeding, diarrhea, FTT

Gradual onset of sx after ingestion, gradual improvement after elimination (weeks); many with positive SPT/specific IgE

Food protein-induced proctocolitis

Blood streaked stools, eosinophilia in colon bx

No vomiting or systemic sx, usually breast-fed, thriving

Diagnosis

Thorough history! Infant with 5 ICU admissions, each after ingestion of cereal added to

formula (Wegrzyn, Pediatrics 2003) FTT, low albumin, plt >500k, temp <36 °C identified as most unique

presenting features in case series (Mehr, Hwang)

Powell’s criteria - inpatient oral food challenge with IV access, physician supervision. Dose for challenge is arbitrary; 0.15 to 0.6 g protein per Kg reported

Not IgE-mediated so skin prick testing and specific IgE is typically negative.

Diagnosis Gastric Juice Analysis in Cow’s Milk Protein-

Induced Enterocolitis (Hwang, J Korean Med Sci 2008)

Challenged 17 consecutive patients to confirm diagnosis of FPIES to cow’s milk; 16 with positive challenge (needed IVF)

Gastric juice analyzed at 3 hours post challenge: >10 WBC per HPF in 15/16 patients with FPIES.

Spergel, AAAAI 2010

DiagnosisAtopy patch test for the diagnosis of FPIES

(Fogg/Spergel et al, Ped All Imm 2006)

19 infants with suspected FPIES(some with reactions to multiple foods)

Patch tested with suspected foods (off at 48h, read at 72h)

Within 2 weeks orally challenged with suspected foods

APT predicted results of OFC in 27/32 cases(Sens 100%, Spec 71%, PPV 75%, NPV 100%)

Will APT revert to negative when they outgrow FPIES?

Diagnosis

Food Allergy Testing: Atopy Patch Test (Spergel, AAAAI meeting 2010)

Discussed 20 patients with FPIES (all with negative SPT), patch tested prior to OFC 5/5 with negative APT had negative OFC 12/15 with positive APT had positive OFC Sens 80%, Spec 100%, PPV 100%, NPV 62.5%

Note: these recommendations are based on expert opinion.

Management

STOPCOWMILK

Acute Management

If accidental ingestion occurs in a child with FPIES, take child to ED for observation, have a letter with instructions from the allergist to the ED physician.

15-40% may be hypotensive and require IV fluid resuscitation, ±corticosteroids (to suppress cell-mediated inflammation)

No known role for antihistamines, anti-IgE, epinephrineSicherer, JACI 2005

If presenting for the first time with signs of shock – thou shalt perform an extensive evaluation to rule out other causes (e.g. r/o sepsis)

Chronic Management FPIES rarely presents vs. new foods after 1 year old During 1st year:

Milk FPIES

50% vs. soy

33% vs. solids

SolidFPIES 65% vs. milk/soy

50% vs. another grain

80% vs. >1 food

After 1st year – inpatient challenges with culprit food 12-18 months after last reaction; observed challenges with untried foods.

If cow’s milk FPIES – switch to EHF, then AA formula if still symptomatic (skip soy formula), delay introduction of solids.

If solid FPIES – switch to EHF/AA formula, eliminate grains, legumes, poultry, ?fish.

Sicherer, JACI 2005

For the IM trained A/I fellows:

Extensively hydrolyzed (casein) formulas:AlimentumNutramigenPregestemil*

Elemental (amino acid) formulas:NeocateElecareNutramigen AA

*Contains short/medium chain fatty acids for special cases: short bowel, liver disease, etc

Prognosis

Prospective follow-up of oral food challenge in FPIES (Hwang, Arch Dis Child 2009) 23 infants with cow’s milk FPIES, diagnosed via OFC at mean age of 36

days, randomized into 2 groups:

Cow’s milk challenge:

Soy milk challenge:

Based on these findings, authors recommend soy OFC at 6-8 months and cow’s milk OFC at 12 months (when most will have negative challenge)

11 8 (6 mo)

4 (10 mo)

3 (14-16

mo)

0(18-20

mo)

12 3 (6 mo)

1 (10 mo)

0 (14-16

mo)

Food Resolution Rate StudyMilk 60% by 3 yo Sicherer 1998

64% by 10 mo(100% by 20 mo)

Hwang 2009

55% by 32 mo Seppo 2010Soy 83% by 3 yo Mehr 2009

20% by 3 yo Sicherer 199827% by 3 yo Nowak-Wegrzyn 200367% by 3 yo Fogg 200692% by 10 mo(100% by 14 mo)

Hwang 2009

28% by 34 mo Seppo 2010Rice 80% by 3 yo Mehr 2009

40% by 3 yo Nowak-Wegrzyn 200350% by 42 mo Seppo 2010

Oat 58% by 45 mo Seppo 2010

The Incidence, Manifestations And Natural Course Of (Cow’s Milk) FPIES (Katz, JACI abstract 2010) Medical center in Israel: 98.4% of all newborns born over 2 years

successfully contacted (n=13,019) 2.9% with suspicion of cow’s milk intolerance 0.33% determined to have FPIES (25/44 confirmed by OFC). 95%

tolerated CM by age 3.

Incidence

Index of suspicion of typical cow’s milk protein-induced enterocolitis (Hwang, J Korean Med Sci 2007) 142 consecutive infants 15-45 days (not exclusively breast

fed)admitted for vomiting and/or diarrhea over 3 years. 11.3% (n=16) with FPIES (all confirmed by OFC)

Clinical Characteristics of Children with Food Protein-Induced Enterocolitis (Seppo, JACI abstract 2010) Mt. Sinai Medical Center, NYC “We analyzed records of children with FPIES evaluated in

the Allergy Clinics between 2001 and 2009. 76 children with FPIES were identified.”

Incidence

The End