Dietary Mangement of Food protein–induced enterocolitis (FPIES)
Food protein–induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock. Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into the pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. This consensus document is the result of work done by an international workgroup convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. These are the first international evidence-based guidelines to improve the diagnosis and management of patients with FPIES. Research on prevalence, pathophysiology, diagnostic markers, and future treatments is necessary to improve the care of patients with FPIES. These guidelines will be updated periodically as more evidence becomes available.
Dietary Management of Food protein–induced enterocolitis (FPIES)
- 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]
- 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]
Acute FPIES can result readily in hypovolemic shock and should be managed appropriately whether from a positive OFC result or accidental exposure. The priority in management of severe FPIES is restoration of stable hemodynamics through aggressive isotonic fluid resuscitation (eg, 10-20 mL/kg boluses of normal saline) repeated as needed and dextrose saline as a continuous intravenous maintenance infusion . A single dose of intravenous methylprednisolone (1 mg/kg; maximum, 60-80 mg), can decrease presumed cell-mediated inflammation, although no studies support this recommendation.33 In severe reactions patients might require supplemental oxygen, mechanical ventilation, or noninvasive positive pressure ventilation for respiratory insufficiency or failure, vasopressors for hypotension, bicarbonate for acidemia, and methylene blue for methemoglobulinemia. Epinephrine autoinjectors are not routinely recommended/prescribed for FPIES, although those with concomitant IgE-mediated allergy should be prescribed epinephrine autoinjector at the physician’s discretion if the patient is deemed at risk for food-induced anaphylaxis. Mild-to-moderate acute FPIES can resolve with oral rehydration, including breast-feeding, at home
Management of acute FPIES episode at the medical facility
| 1-2 Episodes of emesis
|>3 Episodes of emesis and mild lethargy||>3 Episodes of emesis, with severe lethargy, hypotonia, ashen or cyanotic appearance|
Strong consideration should be lent to performing food challenges in children with a history of severe FPIES in the hospital or other monitored setting with immediate availability of intravenous resuscitation. Oral challenges in the physician’s office can be considered in patients with no history of a severe FPIES reaction, although caution should be urged because there are no data that can predict the future severity of FPIES reactions.
Management of acute FPIES episode at home
|Symptoms||1-2 Episodes of emesis
No or mild lethargy
|>3 Episodes of emesis and moderate-to-severe lethargy|
|Management||Attempt oral rehydration at home (eg, breast-feeding or clear fluids)||Call 911 or go to the emergency department|
- A. Child with history of severe FPIES reaction: call 911 or go to the emergency department if the triggering food was definitely ingested, even in the absence of symptoms or with any symptoms regardless of severity.
- B. Child with no history of severe FPIES reaction.
Consider ondansetron as an adjunctive management of emesis in patients with acute FPIES. [Strength of recommendation: Weak; Evidence strength: IV; Evidence grade: D]
- Ondansetron is a 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 Two small case series reported that use of intravenous ondansetron was helpful in stopping emesis during FPIES-related OFCs. This intervention is promising, but its use is poorly studied at present. Rigorous trials are needed to determine the role and efficacy of ondansetron in the management of acute FPIES.
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]
- Long-term FPIES management involves elimination of the trigger food or foods, plans for dietary advancement, treatment of symptoms at presentation or on re-exposure (including emergency treatment planning), and monitoring for FPIES resolution. Nutritional consultation should be strongly considered for any patient, irrespective of the number of food avoidances recommended, to ensure adherence to dietary avoidance and adequate nutrition.
- Infants with suspected CM- or soy-induced FPIES are generally advised to avoid all forms of these foods, including baked and processed foods, unless they are already included in the diet. There are no conclusive studies to date evaluating tolerance to CM and egg proteins in baked products in children with FPIES, although a small case series reported tolerance of baked CM and egg in some children. Introduction of baked CM and egg should be done under physician supervision because there are unclear long-term outcomes associated with this practice.
- Infants with CM/soy-induced FPIES can be breast-fed or use a hypoallergenic formula, such as casein-based extensively hydrolyzed formula. When possible, breast-feeding should be continued, which is consistent with official recommendations for infant feeding. Ten percent to 20% might require an amino acid–based formula (AAF). In infants with CM-induced FPIES, introduction of soy formula should be considered under a physician’s supervision and vice versa.
- The risk of coreactivity to CM and soy is reported in approximately 20% to 40% of US patients but is noticeably absent in similar reports from Australia, Israel, and Italy.9, 12, 18 Based on high homology of the protein sequences in these animal milks, goat and sheep milk are not recommended in patients with CM-induced FPIES.61 It is possible that milks from donkeys, camels, or both might be tolerated in patients with CM-induced FPIES because they are usually well tolerated in those with IgE-mediated CM allergy. Infants with chronic FPIES usually return to their usual state of health within 3 to 10 days of switching to a hypoallergenic formula, although in severe cases temporary bowel rest and intravenous fluids might be necessary.
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]
- The majority of infants do not react to food allergens present in maternal breast milk. In the case of symptomatic FPIES occurring in an exclusively breast-fed infant, the mother should eliminate the suspected trigger food or foods from her diet if reactions occur after breast-feeding or the infant has FTT; the mother should seek immediate consultation with an allergy specialist.15, 69 Nutritional consultation should be considered to assist the elimination diet. If resolution of symptoms is not accomplished with a maternal dietary elimination diet, discontinuation of breast-feeding and introduction of a hypoallergenic formula should be considered
Reintroduce the foods triggering FPIES under a physician’s supervision. [Strength of recommendation: Strong; Evidence strength: Ia/IIb; Evidence grade: B]
- Foods that triggered FPIES reactions in the past should generally be reintroduced under a physician’s supervision during a formal OFC or supervised feeding. The timing of such reintroduction is variable. Placement of secure peripheral intravenous access before the OFC might be warranted in patients with past severe reactions requiring an emergency department visit or hospitalization, as well as in infants and patients with anticipated difficult intravenous access. Between 45% and 95% of the challenge reactions were treated with intravenous fluids, steroids, or both. In patients with milder reactions, oral rehydration might be sufficienh. Although some providers might elect to allow families to try certain foods at home, this should be a shared decision between medical care providers and caregivers, accounting for access and distance to local emergency departments, caregiver comfort, the nature of the trigger food, and the severity of past FPIES reactions.
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]
- The majority of children (65% to 80%) have FPIES to a single food, most commonly CM. In a large US case series at a tertiary care center, about 5% to 10% of children reacted to more than 3 foods, some to as many as 6 or more foods. Children with either CM- or soy-induced FPIES can also react to both foods, with this likelihood being higher among those who had symptoms of FPIES in the first month of life, although the risk or odds of this occurring are not known. In these infants with early onset of FPIES, it might be prudent to breast-feed or introduce a hypoallergenic formula in the first 6 to 12 months of life, although data pertaining to primary/secondary FPIES prevention do not exist. In such potentially dually reactive children, it is recommended to perform supervised OFCs to introduce the uncertain FPIES trigger.
Common food coallergies in children with FPIES
|FPIES to:||Clinical cross-reactivity/coallergy||Observed occurrence∗|
|CM||Soy||<30% to 40%|
|Any solid food||<16%|
|Soy||CM||<30% to 40%|
|Any solid food||<16%|
|Solid food (any)||Another solid food||<44%|
|CM or soy||<25%|
|Grains: rice, oats, etc∗||Other grains (including rice)||About 50%|
- Note: where a child already tolerates a food type in a particular group (eg, beans), clinical reactions to other members of the same group (eg, other legumes) are unlikely. Caution is warranted in interpreting these data because they were derived from single centers and from patient populations skewed toward the more severe phenotype of FPIES and might overestimate the actual risk of coallergy.
- Children with CM- or soy-induced FPIES can also have an increased likelihood of reacting to a solid food, most commonly rice or oat. Current early feeding guidelines do not recommend delay in introducing complementary foods past 6 months of life because of FPIES. A practical ordering for introducing solids at about 6 months of age at home could start with fruits and vegetables, followed by other complementary foods, such as red meats and cereals . If an infant tolerates a variety of early food proteins, subsequent introduction might be more liberal. Tolerance to one food from the food group is considered a favorable prognostic indicator for tolerance to other foods from the same group.
Empiric guidelines for selecting weaning foods in infants with FPIES
|Ages and stages||Lower-risk foods||Moderate-risk foods∗||Higher-risk foods∗|
|4-6 mo (as per AAP, CoN)||Vegetables|
|If developmentally appropriate and safe and nutritious foods are available:
||Broccoli, cauliflower, parsnip, turnip, pumpkin||Squash, carrot, white potato, green bean (legume)||Sweet potato, green pea (legume)|
|6 mo (as per WHO)||Fruits|
|Complementary feeding should begin no later than 6 mo of age:
||Blueberries, strawberries, plum, watermelon, peach, avocado||Apple, pear, orange||Banana|
|8 mo of age or when developmentally appropriate:||High-iron foods|
||Lamb, fortified quinoa cereal, millet||Beef, fortified grits and corn cereal, wheat (whole wheat and fortified), fortified barley cereal||Higher-iron foods: fortified, infant rice and oat cereals|
|12 mo of age or when developmentally appropriate:||Other|
||Tree nuts and seed butters∗ (sesame, sunflower, etc.)||Peanut, other legumes (other than green pea)||Milk, soy, poultry, egg, fish|
This table should be considered in the context of the following notes:
- A. Exclusive breast-feeding until 4 to 6 months of age and continuing breast-feeding through the first year of life or longer as long as mutually desired by both mother and child (Baker RD, Greer FR, Committee on Nutrition American Academy of Pediatrics. Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age). Pediatrics 2010;126:1040-50).
- B. If an infant tolerates a variety of early foods, subsequent introduction can be more liberal. Additionally, tolerance to one food in a food group (green pea) is considered a favorable prognostic indicator for tolerance of other foods from the same group (legumes; Sicherer SH. Food protein-induced enterocolitis syndrome: case presentations and management lessons. J Allergy Clin Immunol 2005;115:149-56).
- AAP, CoN, American Academy of Pediatrics, Committee on Nutrition; WHO, World Health Organization.
Nutritional management for FPIES
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]
- Children with food allergy have been noted to have deficiencies in energy, protein, vitamin A, vitamin D, calcium, iron, and zinc.73, 74, 75, 76 Infantile FPIES is a risk for deficiencies caused by dietary restrictions and delayed introduction of new foods. Limited food experiences can adversely affect food intake for many years to come.77 It is commonly recommended that caregivers introduce a new food as a single ingredient and, in the case of high-risk foods, to wait at least 4 days before introducing another food to observe for the development of a reaction. Providers should recognize that even single-food elimination can be associated with significant nutritional deficiency Consultation with a dietitian is highly recommended to facilitate weaning. in this article’s Online Repository at www.jacionline.org details the nutrients typically provided by the foods most commonly triggering FPIES.
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]
- No studies have identified a reliable threshold dose (TD) in patients with FPIES. Among 28 children undergoing OFC to CM, 53.6% tolerated 121 mL of CM and 82% tolerated 50 mL of CM before having a reaction. High TDs have been reported. However, further studies have reported a TD of only 0.15 g of protein/kg body weight in 15 (93.7%) of 16 cases of confirmed FPIES caused by CM, soy, egg, rice, and oat.36 Therefore strict avoidance of trigger foods is recommended.
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]
- The official guidelines1 recommend a hypoallergenic formula for the treatment of FPIES based on several studies demonstrating that most children tolerated extensively hydrolyzed formula, although there are selected children who exclusively tolerate AAFs. AAFs are the only completely nonallergenic formulas and can be effective in patients not responding to extensively hydrolyzed formulas and those with FTT. Soy formula might be an acceptable alternative, especially in infants older than 6 months; however, cautious introduction is warranted because of the potential for coreactivity between patients with soy-induced FPIES and those with CM-induced FPIES.
Monitor growth (weight and height/length) regularly in children with FPIES. [Strength of recommendation: Moderate; Evidence strength: III; Evidence grade: C]
- Nowak and others reported that infants with CM- or soy-induced FPIES exposed to these proteins on a daily basis typically manifest poor weight gain, weight loss, or FTT that resolves with elimination of the implicated food. Poor growth in children with FPIES who have successfully eliminated the implicated food and remain asymptomatic has not been reported. Children with FPIES and multiple food avoidances or difficulty advancing the diet might be at increased risk. Growth (weight, length/height, and head circumference) should be assessed at regular intervals based on national standards.
Recommend foods that enhance developmental skills in infants in the complementary feeding period to prevent aversive feeding behaviors and delay in the development of food acceptance and feeding skills. [Strength of recommendation: Weak; Evidence strength: IV; Evidence grade: D]
- Timely introduction of various tastes and textures affects flavor acceptance, feeding skills, and eating behaviors. Finding appropriate flavors and textures for infants and children with FPIES requires creativity when multiple solid foods are restricted.93 Many textures can be provided, even if only 1 food is tolerated, because a single fruit or vegetable can be prepared into a thin or thick puree, pureed with lumps, soft cooked for finger foods, or freeze-dried or fried/oven baked in refined oil for a crispy crunchy texture
International consensus guidelines for the diagnosis and management of food protein–induced enterocolitis syndrome: Executive summary—Workgroup Report of the Adverse Reactions to Foods Committee, American Academy of Allergy, Asthma & Immunology. http://www.jacionline.org/article/S0091-6749(17)30153-7/fulltext#cebib0010
- Jarvinen, K. and Nowak-Wegrzyn, A. Food protein-induced enterocolitis syndrome: current management strategies. J Allergy Clin Immunol Pract. 2013; 1: 317
- Caubet, J.C., Ford, L.S., Sickles, L., Järvinen, K.M., Sicherer, S.H., Sampson, H.A. et al. Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol. 2014; 134: 382–389
- Ruffner, M.A., Ruymann, K., Barni, S., Cianferoni, A., Brown-Whitehorn, T., and Spergel, J.M. Food protein-induced enterocolitis syndrome: insights from review of a large referral population. J Allergy Clin Immunol Pract. 2013; 1: 343–349
- Powell, G.K. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge. J Pediatr. 1978; 93: 553–560
- Burks, A.W., Casteel, H.B., Fiedorek, S.C., Willaims, L.W., and Pumphrey, C.L. Prospective oral food challenge study of two soybean protein isolates in patients with possible milk or soy protein enterocolitis. Pediatr Allergy Immunol. 1994; 5: 40–45
- Burks, A.W., Tang, M., Sicherer, S., Muraro, A., Eigenmann, P.A., Ebisawa, M. et al. ICON: food allergy. J Allergy Clin Immunol. 2012; 129: 906–920
- Miceli Sopo, S., Greco, M., Monaco, S., Tripodi, S., and Calvani, M. Food protein-induced enterocolitis syndrome, from practice to theory. Exp Rev Clin Immunol. 2013; 9: 707–715
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- Nowak-Wegrzyn, A., Bloom, K.A., Sicherer, S.H., Shreffler, W.G., Noone, S., Wanich, N. et al. Tolerance to extensively heated milk in children with cow’s milk allergy. J Allergy Clin Immunol. 2008; 122: 342–347
- Ford, L.S., Bloom, K.A., Nowak-Wegrzyn, A.H., Shreffler, W.G., Masilamani, M., and Sampson, H.A. Basophil reactivity, wheal size, and immunoglobulin levels distinguish degrees of cow’s milk tolerance. J Allergy Clin Immunol. 2013; 131: 180–186, e1-3
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