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

Abstract

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. 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. Anna Nowak-Węgrzyn, MD, PhD Associate Professor of Pediatrics Division of Allergy and Immunology Icahn School of Medicine at Mount Sinai New York, NY Mirna Chehade, MD, MPH Associate Professor of Pediatrics and Medicine Director, Eosinophilic Disorders Center Division of Allergy and Immunology Icahn School of Medicine at Mount Sinai New York, NY Marion E. Groetch, MS, RDN Director of Nutrition Service, Jaffe Food Allergy Institute Division of Allergy and Immunology Icahn School of Medicine at Mount Sinai New York, NY Jonathan M. Spergel, MD, PhD Professor of Pediatrics Division of Allergy and Immunology The Children's Hospital of Philadelphia Perelman School of Medicine at University of Pennsylvania Philadelphia, Pa Robert A. Wood, MD Professor of Pediatrics and International Health Director, Division of Pediatric Allergy and Immunology Johns Hopkins University School of Medicine Baltimore, Md Katrina J. Allen, MD, PhD University of Melbourne Department of Paediatrics Murdoch Children's Research Institute Royal Children's Hospital Melbourne, Australia Institute of Inflammation and Repair University of Manchester Manchester, United Kingdom Dan Atkins, MD Chief, Allergy and Immunology Section Co-Director, Gastrointestinal Eosinophilic Diseases Program Children's Hospital Colorado Associate Professor of Pediatrics University of Colorado School of Medicine Aurora, Colo Sami Bahna, MD, DrPH Professor of Pediatrics & Medicine Chief of Allergy & Immunology Section Louisiana State University Health Sciences Center Shreveport, La Ashis Barad, MD Section Chief, Division of Pediatric Gastroenterology, Hepatology and Nutrition Baylor Scott & White McLane Children's Medical Center Assistant Professor of Pediatrics Texas A&M Health Sciences Center College of Medicine Temple, Tex Cecilia Berin, PhD Associate Professor of Pediatrics Division of Allergy and Immunology Icahn School of Medicine at Mount Sinai New York, NY Terri Brown Whitehorn, MD Division of Allergy and Immunology The Children's Hospital of Philadelphia Associate Professor of Clinical Pediatrics Perelman School of Medicine, University of Pennsylvania Philadelphia, Pa A. Wesley Burks, MD Curnen Distinguished Professor of Pediatrics Executive Dean and Chair Pediatrics University of North Carolina Chapel Hill, NC Jean-Christoph Caubet University Hospitals of Geneva Pediatric Allergy Unit, Department of Child and Adolescent Geneva, Switzerland Antonella Cianferoni, MD, PhD Assistant Professor of Pediatrics Allergy and Immunology Division, Children's Hospital of Philadelphia Perelman School of Medicine, University of Pennsylvania Philadelphia, Pa Marisa L. Conte, MLIS Taubman Health Services Library The University of Michigan Medical School Ann Arbor, Mich Carla Davis, MD Associate Professor of Pediatrics Baylor College of Medicine Houston, Tex Alessandro Fiocchi, MD Director, Division of Allergy Pediatric Hospital Bambino Gesu Rome, Vatican City, Italy Matthew Greenhawt, MD, MBA, MSc Assistant Professor of Pediatrics Pediatric Allergy Section Children's Hospital Colorado University of Colorado Denver School of Medicine Denver, Colo Kate Grimshaw, PhD, RD, RNutr Clinical and Experimental Sciences and Human Development in Health Academic Unit University of Southampton Faculty of Medicine Department of Nutrition & Dietetics, Southampton's Children's Hospital Southampton, United Kingdom Ruchi S. Gupta, MD, MPH Northwestern Medicine, Chicago, IL Ann & Robert H. Lurie Children's Hospital of Chicago Chicago, Ill Brittany Hofmeister, RD Medical Advisory Board International FPIES Association (I-FPIES) Point Pleasant Beach, NJ Jin-Bok Hwang, MD Department of Pediatrics Keimyung University Dongsan Medical Center Daegu, Korea Yitzhak Katz, MD Professor of Pediatrics Sackler School of Medicine Tel-Aviv University, Tel-Aviv, Israel Director, Institute of Allergy Asthma and Immunology and Food Allergy Center “Assaf Harofeh” Medical Center Zerifin, Israel George N. Konstantinou, MD, PhD, MSc Department of Allergy and Clinical Immunology 424 General Military Training Hospital Thessaloniki, Greece Division of Allergy and Immunology Jaffe Food Allergy Institute Icahn School of Medicine at Mount Sinai New York, NY Stephanie A. Leonard, MD Division of Pediatric Allergy & Immunology Rady Children's Hospital San Diego University of California San Diego, Calif Jenifer R. Lightdale, MD, MPH, FAAP, AGAF Chief of Pediatric Gastroenterology and Nutrition UMass Memorial Children's Medical Center Professor of Pediatrics University of Massachusetts Medical School Worcester, Mass Sean McGhee, MD Clinical Associate Professor of Pediatrics Division of Immunology and Allergy Stanford University School of Medicine Palo Alto, Calif Sam Mehr, MD, FRACP Department of Allergy and Immunology Children's Hospital at Westmead Sydney, Australia Stefano Miceli Sopo, MD Pediatric Allergy Unit Department of Women and Child Health Catholic University of Sacred Hearth Agostino Gemelli Hospital Rome, Italy Monti Giovanna, MD, PhD Department of Paediatric and Adolescence Science Regina Margherita Children's Hospital A.O.U. Città della Salute e della Scienza Turin, Italy Antonella Muraro, MD, PhD Food Allergy Referral Centre Veneto Region Department of Women and Child Health Padua General University Hospital Padua, Italy Stacey Katherine Noel, MD Assistant Professor, Emergency Medicine University of Michigan School of Medicine Ann Arbor, Mich Ichiro Nomura, MD, PhD Department of Allergy and Clinical Immunology National Center for Child Health and Development Tokyo, Japan Sally A. Noone, RN, MSN Clinical Research Manager Pediatric Allergy and Immunology Jaffe Food Allergy Institute New York, NY Hugh A. Sampson, MD Kurt Hirschhorn Professor of Pediatrics Director, Jaffe Food Allergy Institute Department of Pediatric Icahn School of Medicine at Mount Sinai New York, NY Fallon Schultz, MSW, LCSW, CAM President and Founder International FPIES Association (I-FPIES) Point Pleasant Beach, NJ Scott H. Sicherer, MD Clinical Professor of Pediatrics Division Chief, Pediatric Allergy and Immunology Icahn School of Medicine at Mount Sinai Jaffe Food Allergy Institute New York, NY Cecilia C. Thompson, MD Division of Critical Care Medicine Department of Pediatrics Icahn School of Medicine at Mount Sinai New York, NY Paul J. Turner, MD MRC Clinician Scientist and Clinical Senior Lecturer, Imperial College London Honorary Consultant in Paediatric Allergy & Immunology Imperial College Healthcare NHS Trust London, United Kingdom Clinical Associate Professor in Paediatrics University of Sydney Sydney, Australia Carina Venter, RD, PhD Research Associate/Dietitian, Division of Allergy & Immunology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio Amity Westcott-Chavez, MA, MFA International FPIES Association (I-FPIES) Point Pleasant Beach, NJ Food protein–induced enterocolitis (FPIES) is a non-IgE cell- mediated food allergy that can be severe and lead to shock.1Boyce J.A. Assa'ad A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel Report.J Allergy Clin Immunol. 2010; 126: 1105-1118Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholar Despite the potential seriousness of reactions, awareness of FPIES is low; high-quality studies providing insight into pathophysiology, diagnosis, and management are lacking; and clinical outcomes are poorly established. Unmet needs in the field include identification of noninvasive biomarkers, understanding of the pathophysiology and prevalence, and having uniform approaches to diagnosis and management. This document presents an executive summary of the first international consensus based on available evidence and aims to assist practitioners in their care of patients with FPIES. The full report is available online as open access in this article's Online Repository at www.jacionline.org. An international workgroup was convened through the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology and the International FPIES Association advocacy group. A comprehensive literature review was performed with the assistance of a research librarian, with searches run in PubMed/Medline, Web of Science, and Embase. Excluding abstracts, a total of 879 citations were identified through February 2014; of these, 110 were included. Individual sections were written by using subgroup teams, critiqued, and revised based on feedback from all authors until consensus was achieved. Evidence was graded according to the previously established grading system for clinical practice guidelines used by the Joint Task Force on Allergy Practice Parameters.2Sampson H.A. Aceves S. Bock S.A. James J. Jones S. Lang D. et al.Food allergy: a practice parameter update—2014.J Allergy Clin Immunol. 2014; 134: 1016-1025.e43Abstract Full Text Full Text PDF PubMed Scopus (546) Google Scholar Summary Statement 1: Recognize FPIES as a potential medical emergency, which presents as delayed onset of protracted emesis and/or watery/bloody diarrhea, culminating in hemodynamic instability and hypotension in at least 15% of reactions. [Strength of recommendation: Strong; Evidence strength: IIa/IIb; Evidence grade: B] FPIES is a non–IgE-mediated food allergy that typically presents in infancy, with repetitive protracted vomiting that begins approximately 1 to 4 hours after food ingestion. Vomiting is often accompanied by lethargy and pallor and can be followed by diarrhea. Delayed onset and absence of cutaneous and respiratory symptoms suggest a systemic reaction different from anaphylaxis.1Boyce J.A. Assa'ad A. Burks A.W. Jones S.M. Sampson H.A. Wood R.A. et al.Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-sponsored Expert Panel Report.J Allergy Clin Immunol. 2010; 126: 1105-1118Abstract Full Text Full Text PDF PubMed Scopus (1176) Google Scholar, 3Jarvinen K. Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome: current management strategies.J Allergy Clin Immunol Pract. 2013; 1: 317Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Severe cases can progress to hypothermia, methemoglobinemia, acidemia, and hypotension, mimicking sepsis.3Jarvinen K. Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome: current management strategies.J Allergy Clin Immunol Pract. 2013; 1: 317Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 4Caubet 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: 382-389Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 5Ruffner M.A. Ruymann K. Barni S. Cianferoni A. Brown-Whitehorn T. Spergel J.M. Food protein-induced enterocolitis syndrome: insights from review of a large referral population.J Allergy Clin Immunol Pract. 2013; 1: 343-349Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar The FPIES clinical phenotype is influenced by the age of onset, nationality, timing, and duration of symptoms and associated IgE-mediated food allergy (Table I).Table IProposed defining features for clinical phenotyping of FPIESFPIES subtypesDefining featuresAge of onset EarlyYounger than age 9 mo LateOlder than age 9 moSeverity Mild-to-moderateRepetitive emesis with or without diarrhea, pallor, mild lethargy SevereRepetitive projectile emesis with or without diarrhea, pallor, lethargy, dehydration, hypotension, shock, methemoglobinemia, metabolic acidosisTiming and duration of symptoms AcuteOccurs with intermittent food exposures, emesis starts usually within 1-4 h, accompanied by lethargy and pallor; diarrhea can follow within 24 hours, with usual onset of 5-10 h. Usual resolution of symptoms within 24 h after elimination of the food from the diet. Growth is normal, and child is asymptomatic during food trigger elimination. ChronicOccurs with daily ingestion of the food (eg, feeding with CM- or soy-based formula in an infant); symptoms include intermittent emesis, chronic diarrhea, poor weight gain, or FTT. Infants with chronic FPIES usually return to their usual state of health within 3-10 d of switching to a hypoallergenic formula, although in severe cases temporary bowel rest and intravenous fluids might be necessary. Subsequent feeding of the offending food after a period of avoidance results in acute symptoms.IgE positivity ClassicFood specific, IgE negative AtypicalFood specific, IgE positive Open table in a new tab Summary Statement 2: 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] The manifestations and severity of FPIES depend on the frequency and dose of the trigger food, as well as the phenotype and age of an individual patient.6Powell G.K. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge.J Pediatr. 1978; 93: 553-560Abstract Full Text PDF PubMed Scopus (303) Google Scholar, 7Burks A.W. Casteel H.B. Fiedorek S.C. Willaims L.W. 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: 40-45Crossref PubMed Scopus (110) Google Scholar, 8Sicherer S.H. Eigenmann P.A. Sampson H.A. Clinical features of food-protein-induced entercolitis syndrome.J Pediatr. 1998; 133: 214-219Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 9Mehr S. Kakakios A. Frith K. Kemp A.S. Food protein-induced enterocolitis syndrome: 16-year experience.Pediatrics. 2009; 123: e459-e464Crossref PubMed Scopus (228) Google Scholar The distinct pattern of emesis starting within 1 to 4 hours after food ingestion (acute FPIES) occurs when the food is ingested intermittently or after a period of avoidance (Tables I and II). Watery diarrhea (occasionally with blood and mucous) develops in some cases within 5 to 10 hours of ingestion and can be present for up to 24 hours.4Caubet 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: 382-389Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 9Mehr S. Kakakios A. Frith K. Kemp A.S. Food protein-induced enterocolitis syndrome: 16-year experience.Pediatrics. 2009; 123: e459-e464Crossref PubMed Scopus (228) Google Scholar, 10Hwang J.B. Lee S.H. Kang Y.N. Kim S.P. Suh S.I. Kam S. Indexes of suspicion of typical cow's milk protein-induced enterocolitis.J Korean Med Sci. 2007; 22: 993-997Crossref PubMed Scopus (55) Google Scholar, 11Hwang J.B. Sohn S.M. Kim A.S. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome.Arch Dis Child. 2009; 94: 425-428Crossref PubMed Scopus (104) Google Scholar, 12Katz Y. Goldberg M.R. Rajuan N. Cohen A. Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study.J Allergy Clin Immunol. 2011; 127: 647-653Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 13Nomura I. Morita H. Hosokawa S. Hoshina H. Fukuie T. Watanabe M. et al.Four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms.J Allergy Clin Immunol. 2011; 127: 685-688, e1-8Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Symptoms of acute FPIES usually resolve within 24 hours after food ingestion. In most children with acute FPIES, they are well between episodes with normal growth.Table IIProposed defining features of mild and severe acute FPIESMild-to-moderate acute FPIESSevere acute FPIESClinical featuresRequired•Vomiting (onset usually 1-4 h, can range from 30 min to 6 h): few episodes of intermittent vomiting (1-3), can be bilious•Decreased activity level•Pallor•Self-resolving; the child is able to tolerate oral rehydration at homeOptional•Mild watery diarrhea, onset usually within 24 hours, can be bloody (occasionally)Required•Vomiting (onset usually at 1-4 h, can range from 30 min to 6 h): projectile (forceful), repetitive (≥4), bilious and dry heaving•Altered behavior ranging from decreased activity to lethargy•Pallor•Dehydration•Requires intravenous hydrationOptional•Hypotension•Abdominal distention•Hypothermia•Diarrhea, onset usually within 24 hours, can be bloody•HospitalizationLaboratory features (optional, when available)•Increased white blood cell count with neutrophilia•Thrombocytosis•Stool might be positive for leukocytes, eosinophils, or increased carbohydrate content•Increased white blood cell count with neutrophilia•Thrombocytosis•Metabolic acidosis•Methemoglobinemia•Stool might be positive for leukocytes, eosinophils, or increased carbohydrate content Open table in a new tab Chronic FPIES is less well characterized compared with acute FPIES and only reported in infants younger than 4 months of age fed with cow's milk (CM) or soy infant formula. Chronic FPIES develops on regular/repeated ingestion of the triggering food, presenting as chronic/intermittent emesis, watery diarrhea, and failure to thrive (FTT; Table I) Severe chronic FPIES can lead to dehydration and shock.6Powell G.K. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge.J Pediatr. 1978; 93: 553-560Abstract Full Text PDF PubMed Scopus (303) Google Scholar, 14Powell G.K. Enterocolitis in low-birth-weight infants associated with milk and soy protein intolerance.J Pediatr. 1976; 88: 840-844Abstract Full Text PDF PubMed Scopus (116) Google Scholar Hypoalbuminemia and poor weight gain can predict chronic CM-induced FPIES in young infants with chronic gastrointestinal symptoms.10Hwang J.B. Lee S.H. Kang Y.N. Kim S.P. Suh S.I. Kam S. Indexes of suspicion of typical cow's milk protein-induced enterocolitis.J Korean Med Sci. 2007; 22: 993-997Crossref PubMed Scopus (55) Google Scholar With elimination of the chronic FPIES food trigger or triggers, symptoms resolve, but subsequent feeding (accidental exposure or oral food challenge [OFC]) induces an acute FPIES reaction within 1 to 4 hours of food ingestion (Table I). The acute symptomatology after food avoidance distinguishes chronic FPIES from food protein–induced enteropathy, eosinophilic gastroenteritis, or celiac disease. Chronic FPIES is uncommon but appears to be diagnosed more frequently in Japan and Korea.10Hwang J.B. Lee S.H. Kang Y.N. Kim S.P. Suh S.I. Kam S. Indexes of suspicion of typical cow's milk protein-induced enterocolitis.J Korean Med Sci. 2007; 22: 993-997Crossref PubMed Scopus (55) Google Scholar, 13Nomura I. Morita H. Hosokawa S. Hoshina H. Fukuie T. Watanabe M. et al.Four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms.J Allergy Clin Immunol. 2011; 127: 685-688, e1-8Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 15Nomura I. Morita H. Ohya Y. Saito H. Matsumoto K. Non-IgE-mediated gastrointestinal food allergies: distinct differences in clinical phenotype between Western countries and Japan.Curr Allergy Asthma Rep. 2012; 12: 297-303Crossref PubMed Scopus (46) Google Scholar There is limited, wide-scale epidemiologic information regarding FPIES.16Mehr S. Frith K. Campbell D.E. Epidemiology of food protein-induced enterocolitis syndrome.Curr Opin Allergy Clin Immunol. 2014; 14: 208-216Crossref PubMed Scopus (51) Google Scholar FPIES was recognized and formally defined in the mid-1970s.6Powell G.K. Milk- and soy-induced enterocolitis of infancy. Clinical features and standardization of challenge.J Pediatr. 1978; 93: 553-560Abstract Full Text PDF PubMed Scopus (303) Google Scholar A 10th revision of the International Statistical Classification of Diseases and Related Health Problems code for FPIES (K52.2) was implemented in October 2015. Before this, no uniform International Classification of Diseases code existed. FPIES prevalence estimates vary greatly. Katz et al12Katz Y. Goldberg M.R. Rajuan N. Cohen A. Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study.J Allergy Clin Immunol. 2011; 127: 647-653Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar presented the only published prospective birth cohort noting a cumulative incidence of infants with CM-induced FPIES of 3 per 1000 newborns born at a single hospital over 2 years (0.34%). Summary Statement 3: 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] The most commonly reported FPIES triggers are CM, soy, and grains.11Hwang J.B. Sohn S.M. Kim A.S. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome.Arch Dis Child. 2009; 94: 425-428Crossref PubMed Scopus (104) Google Scholar, 12Katz Y. Goldberg M.R. Rajuan N. Cohen A. Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study.J Allergy Clin Immunol. 2011; 127: 647-653Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 17Nomura I. Morita H. Hosokawa S. Hoshina H. Fukuie T. Watanabe M. et al.Cluster analysis revealed four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms.Allergy. 2011; 66: 395Google Scholar Soy-induced FPIES and combined soy/CM-induced FPIES are common in the United States (approximately 25% to 50% in reported case series) but uncommon in Australia, Italy, and Israel. Most reported solid food–induced FPIES is attributable to rice and oat. Rice is the most commonly reported grain trigger, except in Italy.18Sopo S.M. Giorgio V. Dello Iacono I. Novembre E. Mori F. Onesimo R. A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes.Clin Exp Allergy. 2012; 42: 1257-1265Crossref PubMed Scopus (159) Google Scholar Combined rice/oat-induced FPIES has been reported in almost a third of cases of rice-induced FPIES in both the United States and Australia.4Caubet 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: 382-389Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 5Ruffner M.A. Ruymann K. Barni S. Cianferoni A. Brown-Whitehorn T. Spergel J.M. Food protein-induced enterocolitis syndrome: insights from review of a large referral population.J Allergy Clin Immunol Pract. 2013; 1: 343-349Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 9Mehr S. Kakakios A. Frith K. Kemp A.S. Food protein-induced enterocolitis syndrome: 16-year experience.Pediatrics. 2009; 123: e459-e464Crossref PubMed Scopus (228) Google Scholar In contrast, fish-induced FPIES is common in Italy and Spain but less common elsewhere.18Sopo S.M. Giorgio V. Dello Iacono I. Novembre E. Mori F. Onesimo R. A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes.Clin Exp Allergy. 2012; 42: 1257-1265Crossref PubMed Scopus (159) Google Scholar, 19Vila L. Garcia V. Rial M.J. Novoa E. Cacharron T. Fish is a major trigger of solid food protein-induced enterocolitis syndrome in Spanish children.J Allergy Clin Immunol Pract. 2015; 3: 621-623Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar Multiple factors can be involved to explain this geographic variation, including differences in the populations studied in the case series, presence of atopic disease, breast-feeding and dietary practices, and yet-to-be-discovered genetic factors.11Hwang J.B. Sohn S.M. Kim A.S. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome.Arch Dis Child. 2009; 94: 425-428Crossref PubMed Scopus (104) Google Scholar, 12Katz Y. Goldberg M.R. Rajuan N. Cohen A. Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study.J Allergy Clin Immunol. 2011; 127: 647-653Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 17Nomura I. Morita H. Hosokawa S. Hoshina H. Fukuie T. Watanabe M. et al.Cluster analysis revealed four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms.Allergy. 2011; 66: 395Google Scholar, 20Levy Y. Danon Y.L. Food protein-induced enterocolitis syndrome—not only due to cow's milk and soy.Pediatr Allergy Immunol. 2003; 14: 325-329Crossref PubMed Scopus (63) Google Scholar FPIES occurs once CM or soy-based formulas, solid foods, or both are introduced into the infant's diet, usually between 2 and 7 months of age.4Caubet 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: 382-389Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 8Sicherer S.H. Eigenmann P.A. Sampson H.A. Clinical features of food-protein-induced entercolitis syndrome.J Pediatr. 1998; 133: 214-219Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar, 9Mehr S. Kakakios A. Frith K. Kemp A.S. Food protein-induced enterocolitis syndrome: 16-year experience.Pediatrics. 2009; 123: e459-e464Crossref PubMed Scopus (228) Google Scholar, 12Katz Y. Goldberg M.R. Rajuan N. Cohen A. Leshno M. The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk: a large-scale, prospective population-based study.J Allergy Clin Immunol. 2011; 127: 647-653Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar, 16Mehr S. Frith K. Campbell D.E. Epidemiology of food protein-induced enterocolitis syndrome.Curr Opin Allergy Clin Immunol. 2014; 14: 208-216Crossref PubMed Scopus (51) Google Scholar, 18Sopo S.M. Giorgio V. Dello Iacono I. Novembre E. Mori F. Onesimo R. A multicentre retrospective study of 66 Italian children with food protein-induced enterocolitis syndrome: different management for different phenotypes.Clin Exp Allergy. 2012; 42: 1257-1265Crossref PubMed Scopus (159) Google Scholar, 21Leonard S.A. Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome: an update on natural history and review of management.Ann Allergy Asthma Immunol. 2011; 107: 95-101Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Infants with CM- and soy-induced FPIES typically present at a younger age (<6 months) compared with those with solid food–induced FPIES (6-12 months) reflecting earlier introduction of CM and soy. The median age of solid food–induced FPIES onset is similar between most series (5-7 months), with grain-induced FPIES presenting before FPIES to fish, egg, and poultry (see Table E1 in this article's Online Repository at www.jacionline.org).4Caubet 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: 382-389Abstract Full Text Ful