Food protein induced enterocolitis syndrome (FPIES)

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

Outlines

Introduction

Epidemiology

Definition and clinical manifestations

Pathophysiology

Diagnosis and differential diagnosis

Management of Acute FPIES

FPIES in special conditions

Update FPIES in 2017

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

Prevalence of Allergy to Specific Foods

Middleton. Ed 8

Middleton. Ed 8

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Epidemiology of FPIES

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

Epidemiology

Recognize that onset of FPIES to CM and soy can occur at younger ages compared with FPIES to 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 IgE mediated 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]

Definition of FPIES

Definition

Age onset

Severity

Duration of Action

IgE positive or negative

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

Clinical Manifestation of FPIES

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


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



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)

Coallergies in FPIES



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]


Pathophysiology

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Gastrointestinal Barrier to Food Ag

CMI Responses

T-cell mediated disorder

Cytokines

Increase serum TNF-a ( release by antigen-specific T cells) at intestinal epithelium

Decrease expression of transforming 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

CMI Responses

Expert Rev. Clin. Immunol. 7;317–327.2011

CMI Responses

Successively, a TH2-mediated immune response

After ingestion of causative foods,

Increase in interleukin (IL) 4

Decrease in IFN-g expression

Immune Tolrance

On Acquired immune tolerance : Higher serum IL-10 and IFN-g values

Outgrowing non IgE mediated hypersensitivity of CM

Significant increase CD4= CD25+ and Treg

Ann Allergy Asthma Immunol 118 (2017) 411e418

CMI Responses

F. Mori et al. Clinical and Developmental Immunology. 2009

Clinical FPIES FPIES Outgrown

CMI Responses

J. Exp. Med. Volume 199, Number 12, 2004 1679–1688

Increase of circulatingCD4,CD25,T cells 1 wk after in vivo exposure to cow’s milk normalized in relation to the prechallenge levels

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

Diagnosis

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


Diagnosis ≥ 1 major criteria or 3 minor criteriaDiagnostic OFC: strongly considered to confirm the

diagnosis

Diagnosis : Resolution of symptoms within days after elimination,

recurrent symptoms when reintroduced

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]

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

Jejunal biopsies

Classically reveal flattened villi, edema, and increased numbers of lymphocytes, eosinophils, and mast cells.

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

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

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 al 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

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 30-45 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

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

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.

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 combinationwith a single open standard OCC protocol When vomiting or lethargy

after OCC is not apparent or vague

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). .

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.

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)

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]

Differential diagnosis


Differential diagnosis


Management

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


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

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

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

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

Management summary

Treat acute FPIES as a medical emergency and be prepared to provide aggressive fluid resuscitationbecause 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]

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]

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]]

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

Natural History of FPIES

13,019 infants with probable adverse reactions to cow’s milk protein (CMP) were clinically examined, skin prick tested, and challenged orally

CMP induced FPIES included age less than 9 months,

The cumulative incidence for FPIES was 0.34% (44/13,019 patients).

By the age of 3 years,90%of the patients had recovered.

Eight patients with FPIES had IgE-mediated cow’s milk allergy (IgE-CMA)

Conclusions:

Most patients with FPIES recover, although

A proportion might convert to IgE-CMA. The likelihood for a

Cross-reactivity to soy in this population was less than previously estimate

Katz et al. J ALLERGY CLIN IMMUNOL.2011

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]

FPIES in Special Conditions

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.

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

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

Ruffner et al. found egg to be relevant in 11% of their 462 patients

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



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

Take Home Messages

FPIES is emergency condition and no absolute criteria and laboratory investigations

Confirm diagnosis of FPIES is Elimination and OFC

Emergency management are fluid resuscitation and supportive medication (Ondansetron)

Prognosis: Outgrown in children

Adult FPIES should be recognition in patient with recurrent vomiting while ingest some food.

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Food protein induced enterocolitis syndrome (FPIES)