1. Bloody diarrhea Vomiting Failure to thrive Cow’s Milk Soy Hypotension Shock

2.  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

4. Am J Med Sci 1940

6.  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.  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.  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.  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. 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 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 ….

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. 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/mm 3 over baseline Powell’s diagnostic criteria for milk- and soy-induced enterocolitis of infancy:

14.  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. Food allergy – adverse immune response to a food IgE 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

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

18.  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. 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 Neg 14 mo

20. 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.  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. 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

22. ToleranceFPIES TNF-α Cytotoxic T-cells, ?Eos IL-4 (TH2)Immature gut TGF-β1 and receptors IFN-γ (TH1)Tregs, IL-10Mature gut

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

24.  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

25.  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

26.  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

27. 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

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

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

30.  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.

31.  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. Atopy 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?

34. 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.  Note: these recommendations are based on expert opinion. STOP COW MILK

36.  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 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)

37.  FPIES rarely presents vs. new foods after 1 year old  During 1 st year: Milk FPIES 50% vs. soy 33% vs. solids Solid FPIES Solid FPIES 65% vs. milk/soy 50% vs. another grain 80% vs. >1 food  After 1 st 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

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.  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)

41.  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)  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)

42.  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.”