Food protein induced enterocolitis syndrome (FPIES) Presented by Athipat Athipongarporn, MD. August25, 2017

1. Food Protein Induced
Enterocolitis Syndrome
(FPIES)
ATHIPAT ATHIPONGARPORN, MD

2. Outlines
 Introduction
 Epidemiology
 Definition and clinical manifestations
 Pathophysiology
 Diagnosis and differential diagnosis
 Management of Acute FPIES
 FPIES in special conditions

3. Update FPIES in 2017

4. Introduction
 Food protein induced enterocolitis syndrome (FPIES) is a non IgE-mediated food
hypersensitivity featured by gastrointestinal symptoms
 Median age of onset 5.5 months after the first or second ingestion of the offensive food
 Most common food are cow’s milk and soy in children, shellfish in adult
 Variable and atypical clinical presentation and the lack of specific diagnostic testing
S. Manti et al. Ann Allergy Asthma Immunol 118 (2017) 411-418

5. Prevalence of Allergy to Specific Foods
Middleton. Ed 8

6. Middleton. Ed 8

7. Middleton. Ed 8

8. Epidemiology of FPIES

9. Epidemiology of Food Allergy
 Children
 Most common in the 1st few years of life
 > 90% of food allergies
 Cow’s milk
 Hen’s egg
 Soybean
 Wheat
 Peanut, tree nuts
 Fish, shellfish
 less common
 Seafood
 Pollen-associated foods (e.g., fruits,
vegetables)
Middleton. Ed 8

10. Epidemiology
 Recognize that onset of FPIES to CM and soy can occur at younger ages compared with
FPIESto solid foods. Patients can have a single trigger or multiple triggers.
[Strength of recommendation: Strong; Evidence strength: IIb-III; Evidence grade: C]
 Consider specific IgE testing of children with FPIES to their trigger food because comorbid
IgEmediated sensitization to triggers, such as CM, can infer a greater chance of persistent
disease.
[Strength of recommendation: Moderate; Evidence strength: IIb-III; Evidence grade: C
 Do not recommend any specific prenatal or postnatal food introduction/avoidance or
health behaviors or advise patients regarding any specific genetic factors known to
moderate the risk of a patient with FPIES.
[Strength of recommendation: Weak; Evidence strength: IIb-III; Evidence grade: C]

11. Definition of FPIES

12. Definition
 Age onset
 Severity
 Duration of Action
 IgE positive or negative

13. J Allergy Clin Immunol 2017;139:1111-26.

14. Clinical Manifestation of FPIES

15. Clinical Manifestations
 Recognize FPIES as a potential medical emergency, which presents as delayed onset
of protracted emesis and/or watery/bloody diarrhea, culminatingin hemodynamic
instability and hypotension in at least 15% of reactions.
[Strength of recommendation: Strong; Evidencestrength: IIa/IIb; Evidence grade: B]
 Recognize that the symptom phenotype in patients with FPIES is determined by the
frequency of food ingestion.
[Strength of recommendation: Strong; Evidence strength: IIa; Evidence grade: B]
J Allergy Clin Immunol 2017;139:1111-26.

16. Clinical Manifestations
 No pathognomonic symptoms makes the diagnosis of FPIES difficult
 Most commonly: infants between 1 week and 3 months
 Protracted vomiting occurs 1 to 4 hours after feeding and diarrhea and dehydration
 Bloody diarrhea, anemia, abdominal distention, and failure to thrive
 Symptoms are most commonly provoked by
 Cow’s milk
 Soy protein–based formulas
 Food proteins passed in maternal breast milk
 Older infants
 Egg, wheat, rice, oat, peanut, nuts,chicken, turkey, and fish sensitivity

17. Clinical Manifestations
 Hypotension (15%) of cases after allergen ingestion
 10% - 30% of patients present with methemoglobinemia
 In adults
 Shellfish hvpersensitivity may provoke symptoms of severe nausea, abdominal cramps, and protracted
vomiting
 Laboratory findings
 increase in the number of peripheral blood neutrophils, peaking at 4 to 6 hours
 Stools often contain occult blood, neutrophils, eosinophils, and Charcot-Leyden crystals
J Allergy Clin Immunol 2017;139:1111-26.

18. J Allergy Clin Immunol 2017;139:1111-26.

19. Causative Foods
 Most common in children
 CM, soy, and rice, grains (eg, rice, oats, barley, corn)
 Meat (eg, beef,chicken, turkey), vegetables and legumes (eg, potato, squash, string
bean, peanut, green pea, lentil)
 Fruit (tomato), eggs
 Fish and seafood
 Probiotic (Saccharomyces boulardii)
 35% reacted to multiple triggers (% vary each country)

20. Coallergies in FPIES
J Allergy Clin Immunol 2017;139:1111-26.

21. Pathophysiology

22. Middleton. Ed 8
Gastrointestinal Barrier to Food Ag

23. CMI Responses
 T-cell mediated disorder
 Cytokines
 Increase serum TNF-a ( release by antigen-specific T cells) at intestinal epithelium
 Decrease expression of transformimg growth factor B (TGF-B) receptor
 Increased fecal TNF-a levels in patients with CM-mediated FPIES
 Counterbalance the destructive effect of T-cell cytokines
 Impaired function of epithelial barrier function
S. Manti et al. Ann Allergy Asthma Immunol 118 (2017) 411-418

24. CMI Responses
 Successively, a TH2-mediated immune response
 After ingestion of causative foods,
 Increase in interleukin (IL) 4
 Decrease in IFN-g expression
 Higher serum IL-10 and IFN-g values
 Immune Tolrance
 Outgrowing non IgE mediated hypersensitivity of CM
 Significant increase CD4= CD25+ and Treg
Ann Allergy Asthma Immunol 118 (2017) 411e418

25. Humeral Responses
 Healthy children with high secretory IgA at the mucosal surface
 In children affected by FPIES,
 Jejunal biopsies revealed increased numbers of IgM- and IgA-containing plasma cells.
 Elevated serum IgA and IgG antibodies to food
 Specific IgE antibody responses are generally absent
 Significantly higher serum level of IL-8 in patients with FPIES after a positive
OFC result compared with those with a negative OFC result
Ann Allergy Asthma Immunol 118 (2017) 411e418

26. Diagnosis

27. Diagnosis
 Elimination of the responsible allergen leads to resolution of symptoms within 72 hours
 Oral challenge provokes symptoms
 administering 0.3 to 0.6 g/kg of body weight of the suspected protein allergen.
 Vomiting usually develops within 1 to 4 hours
 Diarrhea or loose stools often develop after 4 to 8 hours

28. J Allergy Clin Immunol 2017;139:1111-26.
Diagnosis ≥ 1 major criteria or 3 minor criteria
Diagnostic OFC: strongly considered to confirm the
diagnosis
Diagnosis : Resolution of symptoms within
days after elimination,
recurrent symptoms when reintroduced

29. Diagnosis
 Diagnose FPIES primarily based on a clinical history of typical characteristic
signs and symptoms with improvement after withdrawal of the suspected
trigger food. Exclude other potential causes and use OFCs to help confirm the
diagnosis if the history is unclear and there is a favorable risk/benefit ratio.
[Strength of recommendation: Strong; Evidence strength: IIb-III; Evidence grade: B]
 Conduct OFCs in patients with suspected FPIES in medically supervised settings
in which access to rapid fluid resuscitation is available and prolonged
observation can be provided, if necessary.
[Strength of recommendation: Strong; Evidence strength: IIb; Evidence grade: B]

30. Laboratory Findings
 CBC
 Increase in the number of peripheral blood neutrophils, peaking at 4 to 6 hours
 Stools exam
 Often contain occult blood, neutrophils, eosinophils, and Charcot-Leyden crystals
 Skin prick test
 Negative
 Jejunal biopsies
 Classically reveal flattened villi, edema, and increased numbers of lymphocytes, eosinophils, and mast
cells.

31. Other Tests
 sIgE and SPT
 Often negative
 24-37% of the patients had positive specific IgE levels
 Positive due to TH2 skewing of the T-cell cytokine profile and with gastrointestinal
inflammation and enhancing the mucosal permeability to food proteins
 prudent for purposes of follow-up and to adapt the OFC protocol

32. Other Tests
 Atopic Patch Testing
 2006
 19 patients aged 5 to 30 months who had suspected FPIES on the basis of clinical
history
 In all 16 cases of FPIES, the APT result was positive to the suspected food
 APT seems to be a promising diagnostic tool for the diagnosis of FPIES

33. Other Tests
 Atopic Patch Testing
 Based on the potential involvement of allergen-specific T lymphocytes
 25 pt FPIES, median age 3.3 y
 Only 2 subjects had a positive APT
 Sensitivity of 11.8%, specificity 85.7%, positive predictive value 40%, and negative
predictive value 54.5%
 The median age in the study by Fogg et al3 was younger, and the median time since
the most recent reaction was shorter (12 months, range 4–29 months), which could
represent a group of children with more “active” disease
APTs to common food allergens have poor utility in the follow-up
prediction of outgrowing FPIES in children

34. Other Tests
 OFC
 Gold standard for FPIES diagnosis, follow-up OFCs are needed
 Follow-up OFCs
 Recommended after 12 months of age for CM and between 6 and 8 months of age for soy
 OFC with a mixture of foods that are considered at risk (Avoid in less than 1 Y)
 Dose 0.15 to 0.6 g/kg, in 3 equal doses every 15 minute (0.06 g/kg if reaction severe)
 Not exceed 3 to 6 g or 10 to 20 g of total food weight or 100 mL of total liquid

35. Other Tests
 Antigen-Specific Lymphocyte Stimulation Test
 Investigating antigen-specific T-cell response with non–IgE-mediated gastrointestinal
food allergy are predominantly skewed to TH2
 Usefulness for diagnosis of FPIES is considered controversial

36. Other Tests
 Radiologic finding
 Air-fluid levels,
 Nonspecific narrowing and thumbprinting of the rectum and sigmoid
 Thickening of the plicae circulares in the duodenum and jejunum with excess luminal fluid
 Resolution of radiologic abnormalities after dietary restriction has been assessed.

37. Other Tests
 Gastric Juice Analysis
 2008, N = 16 (aged 14 to 44 days)
 gastric juice analysis (GJA) as a diagnostic criterion of a
positive challenge in a standard oral cow’s milk challenge
(OCC) to confirm typical cow’s milk protein-induced
enterocolitis (CMPIE).
 Three symptoms (vomiting, lethargy, and bloody or pus-
like stool), and four laboratory findings (GJA [3 hr],
We suggest advanced diagnostic criteria in combination
with a single open standard OCC protocol When vomiting or lethargy
after OCC is not apparent or vague

38. Other Tests
 To investigate humoral and cellular responses to casein in children with milk-FPIES, including the
role of casein-specific (cs) IgA and T-cell mediated TGF-β responses.
 N = 31 pt of milk FPIES
 Casein-specific IgE, IgG, IgG4 and IgA were measured in serum and TGF-β levels
 All of them had significantly lower levels of csIgG, csIgG4 and csIgA than control children (p-
value<0.001).
 There were no TGF-β responses in supernatants of active milk-FPIES children.
 Children with milk-FPIES have low levels of csIgG, csIgG4 and csIgA.
 Children with active FPIES to cow’s milk have deficient T-cell mediated TGF-β responses to
casein, rendering TGF-β a promising biomarker in identifying children who are likely to
experience FPIES reactions to this allergen.

39. Other Tests
csIgA between milk FPIES and negative control
(0.01≤p≤0.001), other FPIES (p≤0.001)
TGF-B between milk FPIES and resolve ( p = 0.041)

40. Diagnosis
 Do not routinely perform testing for food sIgE to identify food triggers of FPIES because
FPIES is not an IgE-mediated process. However, because some patients with FPIES can
exhibit coexisting IgE-mediated allergies testing can be considered in patients with certain
comorbid conditions. Assessment of chemistry or blood counts can help rule out other
causes of symptoms if obtained in the acute setting.
[Strength of recommendation: Moderate; Evidence strength: III; Evidence grade: C]
 Do not obtain radiographic testing in the routine diagnostic work-up of suspected FPIES.
[Strength of recommendation: Strong; Evidence strength: III; Evidence grade: C]

41. Differential diagnosis
J Allergy Clin Immunol 2017;139:1111-26.

42. Differential diagnosis
J Allergy Clin Immunol 2017;139:1111-26.

43. Management

44. Mild FPIES
1-2 Episodes of emesis, No lethargy
 Attempt oral rehydration (eg, breastfeeding or clear fluids)
 If age 6 mo and older: consider ondansetron
 intramuscular, 0.15 mg/kg/dose; maximum, 16 mg/dose
 Monitor for resolution about 4-6 h from the onset of a reaction
J Allergy Clin Immunol 2017;139:1111-26.

45. Moderate FPIES
>3 Episodes of emesis and mild lethargy
 If age greater than 6 mo:
 Administer ondansetron intramuscular 0.15 mg/kg/dose; maximum, 16 mg/dose
 Consider placing a peripheral intravenous line
 Normal saline bolus 20 mL/kg, repeat as needed
 Transfer the patient to the emergency department or intensive care unit in case of persistent or
severe hypotension, shock, extreme lethargy, or respiratory distress
 Monitor vital signs
 Monitor for resolution at least 4-6 h from the onset of a reaction
 Discharge home if patient is able to tolerate clear liquids

46. Severe FPIES
>3 Episodes of emesis, with severe lethargy, hypotonia, ashen or cyanotic appearance
 Place a IV line and administer normal saline bolus, and fluid resusucitation
 If age 6 mo and older: ondansetron, 0.15 mg/kg/dose; maximum, 16 mg/dose IV or IM
 Consider administering IV methylprednisolone, 1 mg/kg; maximum, 60-80 mg/dose
 Monitor and correct acid base and electrolyte and methemoglobinemia
 Discharge after 4-6 h from the onset of a reaction when the tolerating oral fluids
 Transfer the patient to intensive care unit for further management in case of persistent or
severe hypotension, shock, extreme lethargy, respiratory distress

47. Management of FPIES
 IV Fluid resuscitation
 recommend 20 ml/kg/dose and repeated dose if poor perfusion
 In severe reactions
 Supplemental oxygen, mechanical ventilation, or noninvasive positive
pressureventilation for respiratory insufficiency or failure, vasopressors for
hypotension
 Single dose of intravenous methylprednisolone
 1 mg/kg; maximum, 60-80 mg
 Can decrease presumed cell-mediated inflammation, although no studies support
this recommendation

48. Management of FPIES
 Epinephrine autoinjectors
 Not routinely recommended/prescribed for FPIES, although those with concomitant
IgEmediated allergy should be prescribed epinephrine
 Ondansetron
 serotonin 5-HT3 receptor antagonist
 used to treat nausea and vomiting, often after chemotherapy, but is used also in
patients with viral gastroenteritis.
 Special caution might be warranted in children with heart disease because of the
potential to prolong the QT interval

49. Management summary
 Treat acute FPIES as a medical emergency and be prepared to provide aggressive fluid
resuscitation because approximately 15% of patients can have hypovolemic shock.
[Strength of recommendation: Strong; Evidence strength: IIa; Evidence grade: B]
 Use dietary elimination of the trigger food or foods for the primary management of FPIES and
educate caregivers and other care providers regarding avoidance strategies.
[Strength of recommendation: Strong Evidence strength: IIb/IIIIV; Evidence grade: C]
 Manage acute FPIES individually according to severity and review treatment strategies with the
caregivers of each patient.
[Strength of recommendation Moderate; Evidence strength: IIb/III; Evidence grade: C]

50. Management summary
 Do not recommend routine maternal dietary elimination of offending triggers while breast-
feeding if the infant is thriving and remains asymptomatic.
[Strength of recommendation: Moderate; Evidence strength: III-IV; Evidence grade: C]
 Recognize that infants with CM or soy-induced FPIES might be at increased risk of having FPIES
to other foods.
[Strength of recommendation: Strong; Evidence strength: III; Evidence grade: C]
 Reintroduce the foods triggering FPIES under a physician’s supervision.
[Strength of recommendation: Strong; Evidence strength: Ia/IIb; Evidence grade: B]

51. Management: Nutrition
 Provide guidance during the introduction of complementary foods to ensure nutritional
adequacy during this time and beyond.
[Strength of Recommendation: Strong; Evidence Strength: III; Grade C]
 Do not routinely recommend avoidance of products with precautionary allergen labeling in
patients with FPIES.
[Strength of recommendation: Weak; Evidence strength: IV; Evidence grade: D]
 Use hypoallergenic formula in formula-fed infants or infants who can no longer breast-feed and
are given a diagnosis of FPIES caused by CM.
[Strength of recommendation: Strong; Evidence strength: IIa/IIb; Evidence grade: B

52. Natural History of FPIES
 Recognize that the age of development of tolerance in patients with FPIES
varies by type of food trigger and country of origin.
[Strength of recommendation: Strong; Evidence strength: IIa/IIb; Evidence grade: B]
 Evaluate patients with FPIES at regular intervals according to the patient’s age
and food allergen to determine whether she or he is still allergic.
[Strength of recommendation: Strong; Evidence strength: IIb/III; Evidence grade: C]

53. FPIES in Special Conditions

54. FPIES in Adult
 In adults, mollusks (scallop), crustacean shellfish, and fish hypersensitivity may
provoke a similar syndrome
 Symptoms
 severe nausea, abdominal cramps, protracted vomiting, and diarrhea.

55. FPIES in Adult
 A 53-year-old man was referred to our center following 2 episodes of diarrhea and
vomiting (in 2008 and 2011), which occurred approximately 4 hours after eating scallops
(Mollusca: Bivalvia: Pectinidae)
 The differential diagnosis of gastrointestinal symptoms following seafood ingestion usually
includes gastroenteritis, scombroid poisoning, and allergy to Anisakis simplex
 SPT seafood negative, sIgE negative
 graded open food challenge test with poached scallop, using 2.5 g, 5.5 g, 12 g, and 34 g
(total;12.5 g protein) positive 1 hr from final dose
J Allergy Clin Immunol 2012

56. FPIES in Adult
 A 43-year-old female with two-year history of recurrent episodes of vomiting and diarrhea with
abdominal pain
 Skin prick testing revealed negative responses to egg white and yolk
 Serum-specific immunoglobulin E (IgE) to both egg white and yolk were similarly negative
 OFC egg positive
 Caubet reported 160 cases of FPIES,
 predominantly in children, with only
 13 of the patients having a diagnosis after the age of 5 years,
 few of which were adults
 Egg is far from the most common food associated with FPIES in published series [1, 14], although
 Ruffner et al. found egg to be relevant in 11% of their 462 patients and Ludman et al. in 13% of their
54

57. Breast milk : 2011-2012
 Case1 (2011)
 An exclusively breast-fed girl, whose mother’s diet had been unrestricted since the girl’s birth,
 presented at 1 month of age to the local hospital emergency department for persistent diarrhea,
weight loss, and anorexia without fever
 The clinical history and laboratory findings were indicative of an episode of FPIES, although in this
case it was presumed to be caused by CMP passed through the breast milk
 Case2
 At age 5 months, the infant received his first bottle of soy formula, second episode begin when he
had breastmilk that mother had soy icecream
J Allergy Clin Immunol 2012
J Allergy Clin Immunol 2011

58. Breast milk : 2014
 Case3
 exclusively breast-fed infant suffering from atopic dermatitis
 3 months, persistent hypotonia, pallor and bloody diarrhea
 mother eat pasta, daily product and CM
 SPT negative all, positive OFC CM
 Case4
 exclusively breast-fed infant suffering from mild atopic dermatitis
 8–9 episodes of abundant regurgitations, colic and diarrhea
 Associated large volume CM that mother ingest
 No OFC, his mother still followed a strict CM-free diet and the baby had not experienced any further
FPIES episodes
- This is probably due to early, daily consumption of CM proteins passed through maternal milk.
- We hypothesize that the daily and early contact with the culprit food are necessary for the
development of chronic FPIES
- Guidelines suggest that a 2-week food elimination, followed by a supervised OFC

59. THANK YOU