Food Protein Induced Enterocolitis Sydrome (FPIES)

1. Vomiting Bloody diarrhea Failure to thrive Hypotension Shock Soy Cow’s Milk Food Protein Induced Enterocolitis Sydrome (FPIES)

2. FPIES - Overview • Enterocolitis after ingestion of a specific food protein. • Main symptoms • Diarrhea – blood (+) • Vomiting • Hypotension/shock • Failure to thrive FPIES stools (Kabuki, AllergolInt 2007) • Symptoms resolve with removal of allergen from diet. • Usually presents in neonates and infants, “outgrown” by 3 years. Sicherer, J Pediatr1998

3. A trip back in time….

4. 1940 Case Series Am J Med Sci 1940

6. 1966 Case Report • 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”

7. 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

8. 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.”

9. 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)

10. The Challenge • 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 Fed 100 ml of milk or soy formula …. • 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

11. 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)

12. Average change in ANC after oral challenge positive challenges negative challenges

13. Powell’s diagnostic criteria for milk- and soy-induced enterocolitis of infancy: Sx onset <2 months of age, <9 months at time of work-up When receiving formula with the offending protein, infant has watery stools with blood and leukocytes that resolves when that protein is eliminated Challenge causes diarrhea with blood and leukocytes within 24 hours ANC at 6-8h after challenge is increased by >3500/mm3 over baseline

14. 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.

15. Pathophysiology Sicherer, Sampson, JACI Primer 2010

16. Pathophysiology To quote every article: “Not well understood”

17. Pathophysiology

18. 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

19. Pathophysiology • Case 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

20. Pathophysiology • Duodenal biopsy of 28 infants (mean 49 days) with active cow’s milk FPIES (Chung, JACI 02) • Dx confirmed by challenge; compared to 10 controls

21. Pathophysiology • 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% • Elevation of Fecal Eosinophil-Derived Neurotoxin in FPIES (Nomura, JACI Abstract 2010) • Included 38 controls vs.6FPIES (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

22. Pathophysiology

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

24. Differential diagnosis • Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus • Anatomic:volvulus, Meckel’s, AVM, intussusception, anal fissure • Hematologic:coagulopathy, HDN • Allergic:eosinophilicgastroenteropathies, 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) 71% 142 Infection 11% FPIES (cow’s milk) consecutive infants 15-45 days old admitted for vomiting/diarrhea 17% Other

25. Differential diagnosis • Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus • Anatomic:volvulus, Meckel’s, AVM, intussusception, anal fissure • Hematologic:coagulopathy, HDN • Allergic:eosinophilicgastroenteropathies, 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 Metabolic acidosis Albumin Eosinophilcount (serum) Platelets Fecal blood or leukocytes WBC count (serum) Methemoglobinemia

26. Differential diagnosis • Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus • Anatomic:volvulus, Meckel’s, AVM, intussusception, anal fissure • Hematologic:coagulopathy, HDN • Allergic:eosinophilicgastroenteropathies, 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

27. Differential diagnosis • Infection: NEC, bacterial enterocolitis (SSYCE), rotavirus • Anatomic:volvulus, Meckel’s, AVM, intussusception, anal fissure • Hematologic:coagulopathy, HDN • Allergic:eosinophilicgastroenteropathies, food protein-induced proctocolitis, GI anaphylaxis • Misc: swallowed maternal blood • Do not laparotomize FPIES (Jayasooriya, PedEmerCare 2007) • “A case of food protein-induced enterocolitis syndrome, leading to unnecessary surgery, is presented.”

28. Differential diagnosis 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 Discharge diagnoses 2 FPIES 19 5 “food allergy” Initial episodes presenting to ED 4 sepsis 4 gastroenteritis 4 intussusception 2 no dx

29. Differential diagnosis Clinical differentiation of allergic GI disorders of infancy from FPIES Sicherer, JACI 2005

30. 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-mediatedso skin prick testing and specific IgE is typically negative.

31. 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.

32. Spergel, AAAAI 2010

33. Diagnosis Atopy patch test for the diagnosis of FPIES (Fogg/Spergel et al, Ped All Imm2006)

34. 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%

35. Management • Note: these recommendations are based on expert opinion. STOPCOWMILK

36. Acute Management • 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) • 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, epinephrine Sicherer, JACI 2005

37. Chronic Management • FPIES rarely presents vs. new foods after 1 year old • During 1styear: • 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. 80% vs. >1 food Solid FPIES 65% vs. milk/soy 50% vs. soy Milk FPIES 50% vs. another grain 33% vs. solids • After 1st year – inpatient challenges with culprit food 12-18 months after last reaction; observed challenges with untried foods. Sicherer, JACI 2005

38. For the IM trained A/I fellows: Extensively hydrolyzed (casein) formulas: Alimentum Nutramigen Pregestemil* Elemental (amino acid) formulas: Neocate Elecare Nutramigen AA *Contains short/medium chain fatty acids for special cases: short bowel, liver disease, etc

39. 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)

41. Incidence • 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. • Index of suspicion of typical cow’s milk protein-induced enterocolitis (Hwang, J Korean Med Sci 2007) • 142consecutive infants 15-45 days (not exclusively breast fed)admitted for vomiting and/or diarrhea over 3 years. • 11.3% (n=16) withFPIES (all confirmed by OFC)

42. Incidence • 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.”

43. The End