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
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]
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.
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)
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
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]
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]
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