What do allergists in practice need to know about non–IgE-mediated food allergies

Abstract

Key Messages•Non-IgE food allergic conditions have the ability to cause significant morbidity and are being increasingly recognized.•Food protein–induced allergic proctocolitis (FPIAP) is a benign self-limited disorder that presents in otherwise healthy infants with bloody stools. Some centers are advocating observation without initial dietary intervention.•Food protein enteropathy (FPE) is now an uncommon disorder that is often caused by a single food and associated with iron deficiency, hypoalbuminemia, and growth failure.•Eosinophilic esophagitis (EoE) is a chronic disorder that can present at any age, and is treatable, but is associated with lower rates of self-resolution.•Acute food protein–induced enterocolitis syndrome (FPIES) is often caused by a single food, usually not accompanied by fever nor by significant elevations in C-reactive protein, and overall has a good prognosis.•Chronic FPIES is rare, has a similar clinical presentation to FPE, but is differentiated by the presence of acute FPIES when the food trigger is reintroduced after a brief period of exclusion.InstructionsCredit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Please note the instructions listed below:•Review the target audience, learning objectives and all disclosures.•Complete the pre-test.•Read the article and reflect on all content as to how it may be applicable to your practice.•Complete the post-test/evaluation and claim credit earned. At this time, physicians will have earned up to 1.0 AMA PRA Category 1 CreditTM. Minimum passing score on the post-test is 70%.•Approximately 4-6 weeks later you will receive an online outcomes assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive MOC Part II credit from the American Board of Allergy and Immunology.Overall PurposeParticipants will be able to demonstrate increased knowledge of the clinical treatment of allergy/asthma/immunology and how new information can be applied to their own practices.Learning ObjectivesAt the conclusion of this activity, participants should be able to:•Recognize differences in clinical presentation and management among FPIAP, FPE and FPIES.•Describe change in diagnostic criteria for eosinophilic esophagitis.Release Date: June 1, 2019Expiration Date: May 31, 2021Target AudiencePhysicians involved in providing patient care in the field of allergy/asthma/immunologyAccreditationThe American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.DesignationThe American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Disclosure PolicyAs required by the Accreditation Council for Continuing Medical Education (ACCME) and in accordance with the American College of Allergy, Asthma and Immunology (ACAAI) policy, all CME planners, presenters, moderators, authors, reviewers, and other individuals in a position to control and/or influence the content of an activity must disclose all relevant financial relationships with any commercial interest that have occurred within the past 12 months. All identified conflicts of interest must be resolved and the educational content thoroughly vetted for fair balance, scientific objectivity, and appropriateness of patient care recommendations. It is required that disclosure be provided to the learners prior to the start of the activity. Individuals with no relevant financial relationships must also inform the learners that no relevant financial relationships exist. Learners must also be informed when off-label, experimental/investigational uses of drugs or devices are discussed in an educational activity or included in related materials. Disclosure in no way implies that the information presented is biased or of lesser quality. It is incumbent upon course participants to be aware of these factors in interpreting the program contents and evaluating recommendations. Moreover, expressed views do not necessarily reflect the opinions of ACAAI.Disclosure of Relevant Financial RelationshipsAll identified conflicts of interest have been resolved. Any unapproved/investigative uses of therapeutic agents/devices discussed are appropriately noted.Planning Committee•Larry Borish, MD, Consultant, Fees/Contracted Research: AstraZeneca, Novartis, Regeneron, Teva•Mariana C. Castells, MD, PhD, has no relevant financial relationships to disclose•Anne K. Ellis, MD, MSc, Advisory Board/Speaker, Honorarium: Alk-Abello, Aralez, AstraZeneca, Boehringer Ingelheim, Circassia Ltd., GlaxoSmithKline, Meda, Merck, Novartis, Pediapharma, Pfizer, Sanofi, Takeda; Research, Grants: Bayer, Circassia Ltd., Green Cross Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi, Sun Pharma•Mitchell Grayson, MD, Advisory Board, Honorarium: AstraZeneca, Genentech, Novartis•Matthew Greenhawt, MD, Advisory Board/Consultant/Speaker, Fees/Honorarium: Allergenis, Aquestive, DVB Technologies, Genentech, Intrommune, Kaleo, Nutricia, Sanofi/Genzyme•William Johnson, MD, has no relevant financial relationships to disclosure•Donald Leung, MD, Chair, DSMC/ Consultant, Fees: AbbVie, Aimmune, Regeneron, Sanofi-Aventis Pharma; Research, Grants: Incyte Corp, Pfizer•Jay Lieberman, MD, Advisory Board/Author/Speaker, Honorarium/Contracted Research: Aimmune, ALK-Abello, Aquestive Therapeutics, DBV Technologies•Gailen D. Marshall, Jr, MD, PhD, has no relevant financial relationships to disclose•Anna Nowak-Wegrzyn, MD, Chair, Honorarium/Contracted Research: Alk-Abello, Merck; Consultant, Fees: LabCorp; Co-Investigator, Fees: Sanofi Aventis; Private Investigator, Contracted Research/Honorarium: Abbott, Astellas Pharma, Danone Nutricia, DBV Technologies, Nestle•John J. Oppenheimer, MD, Consultant, Fees: DBV Technologies, GlaxoSmithKline, Sanofi, Teva; Adjudication, Fees: MedImmune•Jonathan M. Spergel, MD, PhD, Advisory Board/Consultant/Research, Fees/Contracted Research/Honorarium: Aimmune Therapeutics, DBV Technologies, Regeneron, Pfizer; Speaker, Honorarium: AbbottAuthorThe following individuals have no relevant financial relationships to disclose:•Sam Mehr, MBBS, BMedSci, FRACP, FRCPA•Terri Brown-Whitehorn, MDRecognition of Commercial Support: This activity has not received external commercial support.Copyright Statement: 2015-2019 ACAAI. All rights reserved.CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at [email protected] or 847-427-1200. •Non-IgE food allergic conditions have the ability to cause significant morbidity and are being increasingly recognized.•Food protein–induced allergic proctocolitis (FPIAP) is a benign self-limited disorder that presents in otherwise healthy infants with bloody stools. Some centers are advocating observation without initial dietary intervention.•Food protein enteropathy (FPE) is now an uncommon disorder that is often caused by a single food and associated with iron deficiency, hypoalbuminemia, and growth failure.•Eosinophilic esophagitis (EoE) is a chronic disorder that can present at any age, and is treatable, but is associated with lower rates of self-resolution.•Acute food protein–induced enterocolitis syndrome (FPIES) is often caused by a single food, usually not accompanied by fever nor by significant elevations in C-reactive protein, and overall has a good prognosis.•Chronic FPIES is rare, has a similar clinical presentation to FPE, but is differentiated by the presence of acute FPIES when the food trigger is reintroduced after a brief period of exclusion. Credit can now be obtained, free for a limited time, by reading the review article in this issue and completing all activity components. Please note the instructions listed below:•Review the target audience, learning objectives and all disclosures.•Complete the pre-test.•Read the article and reflect on all content as to how it may be applicable to your practice.•Complete the post-test/evaluation and claim credit earned. At this time, physicians will have earned up to 1.0 AMA PRA Category 1 CreditTM. Minimum passing score on the post-test is 70%.•Approximately 4-6 weeks later you will receive an online outcomes assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive MOC Part II credit from the American Board of Allergy and Immunology. Overall Purpose Participants will be able to demonstrate increased knowledge of the clinical treatment of allergy/asthma/immunology and how new information can be applied to their own practices. Learning Objectives At the conclusion of this activity, participants should be able to:•Recognize differences in clinical presentation and management among FPIAP, FPE and FPIES.•Describe change in diagnostic criteria for eosinophilic esophagitis. Release Date: June 1, 2019 Expiration Date: May 31, 2021 Target Audience Physicians involved in providing patient care in the field of allergy/asthma/immunology Accreditation The American College of Allergy, Asthma & Immunology (ACAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Designation The American College of Allergy, Asthma & Immunology (ACAAI) designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure Policy As required by the Accreditation Council for Continuing Medical Education (ACCME) and in accordance with the American College of Allergy, Asthma and Immunology (ACAAI) policy, all CME planners, presenters, moderators, authors, reviewers, and other individuals in a position to control and/or influence the content of an activity must disclose all relevant financial relationships with any commercial interest that have occurred within the past 12 months. All identified conflicts of interest must be resolved and the educational content thoroughly vetted for fair balance, scientific objectivity, and appropriateness of patient care recommendations. It is required that disclosure be provided to the learners prior to the start of the activity. Individuals with no relevant financial relationships must also inform the learners that no relevant financial relationships exist. Learners must also be informed when off-label, experimental/investigational uses of drugs or devices are discussed in an educational activity or included in related materials. Disclosure in no way implies that the information presented is biased or of lesser quality. It is incumbent upon course participants to be aware of these factors in interpreting the program contents and evaluating recommendations. Moreover, expressed views do not necessarily reflect the opinions of ACAAI. Disclosure of Relevant Financial Relationships All identified conflicts of interest have been resolved. Any unapproved/investigative uses of therapeutic agents/devices discussed are appropriately noted. Planning Committee•Larry Borish, MD, Consultant, Fees/Contracted Research: AstraZeneca, Novartis, Regeneron, Teva•Mariana C. Castells, MD, PhD, has no relevant financial relationships to disclose•Anne K. Ellis, MD, MSc, Advisory Board/Speaker, Honorarium: Alk-Abello, Aralez, AstraZeneca, Boehringer Ingelheim, Circassia Ltd., GlaxoSmithKline, Meda, Merck, Novartis, Pediapharma, Pfizer, Sanofi, Takeda; Research, Grants: Bayer, Circassia Ltd., Green Cross Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, Pfizer, Sanofi, Sun Pharma•Mitchell Grayson, MD, Advisory Board, Honorarium: AstraZeneca, Genentech, Novartis•Matthew Greenhawt, MD, Advisory Board/Consultant/Speaker, Fees/Honorarium: Allergenis, Aquestive, DVB Technologies, Genentech, Intrommune, Kaleo, Nutricia, Sanofi/Genzyme•William Johnson, MD, has no relevant financial relationships to disclosure•Donald Leung, MD, Chair, DSMC/ Consultant, Fees: AbbVie, Aimmune, Regeneron, Sanofi-Aventis Pharma; Research, Grants: Incyte Corp, Pfizer•Jay Lieberman, MD, Advisory Board/Author/Speaker, Honorarium/Contracted Research: Aimmune, ALK-Abello, Aquestive Therapeutics, DBV Technologies•Gailen D. Marshall, Jr, MD, PhD, has no relevant financial relationships to disclose•Anna Nowak-Wegrzyn, MD, Chair, Honorarium/Contracted Research: Alk-Abello, Merck; Consultant, Fees: LabCorp; Co-Investigator, Fees: Sanofi Aventis; Private Investigator, Contracted Research/Honorarium: Abbott, Astellas Pharma, Danone Nutricia, DBV Technologies, Nestle•John J. Oppenheimer, MD, Consultant, Fees: DBV Technologies, GlaxoSmithKline, Sanofi, Teva; Adjudication, Fees: MedImmune•Jonathan M. Spergel, MD, PhD, Advisory Board/Consultant/Research, Fees/Contracted Research/Honorarium: Aimmune Therapeutics, DBV Technologies, Regeneron, Pfizer; Speaker, Honorarium: Abbott Author The following individuals have no relevant financial relationships to disclose:•Sam Mehr, MBBS, BMedSci, FRACP, FRCPA•Terri Brown-Whitehorn, MD Recognition of Commercial Support: This activity has not received external commercial support. Copyright Statement: 2015-2019 ACAAI. All rights reserved. CME Inquiries: Contact the American College of Allergy, Asthma & Immunology at [email protected] or 847-427-1200. Unlike immunoglobulin (Ig) E–mediated food allergy (FA), in which 1 pathophysiological mechanism explains 1 disease process, non-IgE FA encapsulates a number of disease states caused by different mechanisms1Nowak-Wegrzyn A. Katz Y. Mehr S.S. Koletzko S. Non-IgE-mediated gastrointestinal food allergy.J Allergy Clin Immunol. 2015; 135: 1114-1124Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar, 2O’Shea K.M. Aceves S.S. Dellon E.S. et al.Pathophysiology of eosinophilic esophagitis.Gastroenterology. 2018; 154: 333-345Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar but unified in their ability to cause gastrointestinal inflammation. The commonest non–IgE-mediated disorders encountered and managed by allergists include food protein–induced allergic proctocolitis (FPIAP), eosinophilic esophagitis (EoE), food protein–induced enteropathy (FPE), and food protein–induced enterocolitis syndrome (FPIES). Knowledge of celiac disease (CD) is beyond the scope of this review, and is briefly discussed in supplementary section. Non-IgE FA is increasing, particularly in children (the predominant group afflicted by these disorders).3Mullins R.J. Turner P.J. Barnes E.H. Campbell D.E. Allergic gastroenteritis hospital admission time trends in Australia and New Zealand.J Paediatr Child Health. 2018; 54: 398-400Crossref PubMed Scopus (5) Google Scholar, 4Dellon E.S. Epidemiology of eosinophilic esophagitis.Gastroenterol Clin North Am. 2014; 43: 201-218Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar Although it has not been reported to cause fatality, non-IgE FA is capable of causing significant morbidity. Parents of children with FPIES report lower quality of life5Groetch M.E. AZ Nowak-Wegrzyn A. Quality of life and feeding difficulties associated with childhood Fpies and IgE-mediated food allergies.J Allergy Clin Immunol. 2016; 137: AB239Abstract Full Text Full Text PDF Google Scholar and experience greater difficulties in feeding compared with parents of children with IgE-mediated FA.6Squire J.D. SA Food protein-induced enterocolitis syndrome (FPIES) is associated with increased risk of feeding disorders.J Allergy Clin Immunol. 2018; 141: AB132Abstract Full Text Full Text PDF Google Scholar Often non-IgE FA is poorly recognized, particularly in those with EoE and FPIES, leading to delays in diagnosis.7Mehr 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, 8Mehr S. Frith K. Barnes E.H. Campbell D.E. Group F.S. Food protein-induced enterocolitis syndrome in Australia: a population-based study, 2012-2014.J Allergy Clin Immunol. 2017; 140: 1323-1330Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 9Schoepfer A.M. Safroneeva E. Bussmann C. et al.Delay in diagnosis of eosinophilic esophagitis increases risk for stricture formation in a time-dependent manner.Gastroenterology. 2013; 145: 1230-1236Abstract Full Text Full Text PDF PubMed Scopus (473) Google Scholar This can result in unnecessary investigations, repeated hospital admissions, inappropriate therapies, increased risk of stricturing disease in EoE, and substantial health care costs.7Mehr 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, 8Mehr S. Frith K. Barnes E.H. Campbell D.E. Group F.S. Food protein-induced enterocolitis syndrome in Australia: a population-based study, 2012-2014.J Allergy Clin Immunol. 2017; 140: 1323-1330Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10Nowak-Wegrzyn A. ZA Economic impact of childhood Fpies and IgE-mediated food allergies.J Allergy Clin Immunol. 2016; 137: AB240Abstract Full Text Full Text PDF Google Scholar Some children with FPIES and EoE have concomitant IgE food allergies,8Mehr S. Frith K. Barnes E.H. Campbell D.E. Group F.S. Food protein-induced enterocolitis syndrome in Australia: a population-based study, 2012-2014.J Allergy Clin Immunol. 2017; 140: 1323-1330Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar adding to the burden of food elimination, and need for different action plans. Non-IgE FA has the potential to cause growth failure because of the underlying disease itself or from restricted intake; the cause of which can be multifactorial and may include food aversion, parental hesitation in introducing new foods, and implementation of overly restricted diets.11Mukkada V.A. Haas A. Maune N.C. et al.Feeding dysfunction in children with eosinophilic gastrointestinal diseases.Pediatrics. 2010; 126: e672-e677Crossref PubMed Scopus (101) Google Scholar, 12Jose J. Virojanapa A. Lehman E.B. et al.Parental perception of anxiety in children with eosinophilic esophagitis in a tertiary care center.Ann Allergy Asthma Immunol. 2017; 119: 382-383Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Compounding matters further is the multitude of advice from social media platforms and diets downloadable from the Internet. The keys of managing patients with non-IgE FA allergy are to provide an accurate diagnosis, and provide a plan that balances food avoidance with new food introduction. In more complex cases, in which multiple food triggers need to be avoided, regular medical and psychological support is required, preferably through a multidisciplinary clinic staffed by medical and allied health staff. In this review, we discuss what allergists in practice need to know about non-IgE FA, discussing the clinical characteristics that differentiate non-IgE FAs from one another, and management principles. We focus on the 4 common non-IgE FAs: FPIAP, EoE, FPE, and FPIES. The clinical, laboratory, and endoscopic features of these disorders are summarized (Table 1).Table 1Proposed Diagnostic Criteria for Patients Presenting with Acute FPIES in the Community Setting from the International Consensus Guidelines for the Diagnosis and Management of Food Protein-Induced Enterocolitis SyndromeaThe diagnosis of acute FPIES reactions requires the major criterion and 3 or more of the minor criteria. If only a single FPIES reaction has occurred, it is strongly recommended that a diagnostic food challenge is performed. Although not part of the criteria, recovery within a few hours is typical for FPIES but atypical for gastroenteritis/sepsis.,62Caubet J.C. Ford L.S. Sickles L. 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 ScholarMajor criterionMinor criteria (3 or more)Vomiting (1-4 hours after ingestion of the suspect food) and absence of classic IgE-mediated allergic skin or respiratory symptoms•A second (or more) episode of repetitive vomiting after eating the same suspect food•Repetitive vomiting episode 1-4 hours after eating a different food•Extreme lethargy with any suspected reaction•Marked pallor with any suspected reaction•Need for emergency department visit with any suspected reaction•Need for intravenous fluid support with any suspected reaction•Diarrhea in 24 hours (usually 5-10 hours)•Hypotension•HypothermiaAbbreviations: FPIES, food protein–induced enterocolitis syndrome; IgE, immunoglobulin E.a The diagnosis of acute FPIES reactions requires the major criterion and 3 or more of the minor criteria. If only a single FPIES reaction has occurred, it is strongly recommended that a diagnostic food challenge is performed. Although not part of the criteria, recovery within a few hours is typical for FPIES but atypical for gastroenteritis/sepsis. Open table in a new tab Abbreviations: FPIES, food protein–induced enterocolitis syndrome; IgE, immunoglobulin E. Food protein–induced allergic proctocolitis (FPIAP) is a benign self-limited disorder that affects young infants within the first few months of life.13Lake A.M. Food-induced eosinophilic proctocolitis.J Pediatr Gastroenterol Nutr. 2000; 30: S58-S60Crossref PubMed Scopus (199) Google Scholar, 14Kaya A. Toyran M. Civelek E. Misirlioglu E. Kirsaclioglu C. Kocabas C.N. Characteristics and prognosis of allergic proctocolitis in infants.J Pediatr Gastroenterol Nutr. 2015; 61: 69-73Crossref PubMed Scopus (31) Google Scholar, 15Odze R.D. Wershil B.K. Leichtner A.M. Antonioli D.A. Allergic colitis in infants.J Pediatr. 1995; 126: 163-170Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 16Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome and allergic proctocolitis.Allergy Asthma Proc. 2015; 36: 172-184Crossref PubMed Scopus (80) Google Scholar, 17Machida H.M. Catto Smith A.G. Gall D.G. Trevenen C. Scott R.B. Allergic colitis in infancy: clinical and pathologic aspects.J Pediatr Gastroenterol Nutr. 1994; 19: 22-26Crossref PubMed Scopus (163) Google Scholar, 18Lake A.M. Whitington P.F. Hamilton S.R. Dietary protein-induced colitis in breast-fed infants.J Pediatr. 1982; 101: 906-910Abstract Full Text PDF PubMed Scopus (174) Google Scholar, 19Sicherer S.H. Clinical aspects of gastrointestinal food allergy in childhood.Pediatrics. 2003; 111: 1609-1616Crossref PubMed Google Scholar, 20Arvola T. Ruuska T. Keranen J. Hyoty H. Salminen S. Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination.Pediatrics. 2006; 117: e760-e768Crossref PubMed Scopus (169) Google Scholar, 21Elizur A. Cohen M. Goldberg M.R. et al.Cow's milk associated rectal bleeding: a population based prospective study.Pediatr Allergy Immunol. 2012; 23: 766-770Crossref PubMed Scopus (56) Google Scholar, 22Bone J. Claver A. Guallar I. Plaza A.M. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment.Allergol Immunopathol (Madr). 2009; 37: 36-42Crossref PubMed Scopus (44) Google Scholar, 23Maloney J. Nowak-Wegrzyn A. Educational clinical case series for pediatric allergy and immunology: allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow's milk allergy.Pediatr Allergy Immunol. 2007; 18: 360-367Crossref PubMed Scopus (115) Google Scholar, 24Boyle J.T. Gastrointestinal bleeding in infants and children.Pediatr Rev. 2008; 29: 39-52Crossref PubMed Scopus (67) Google Scholar The prevalence of FPIAP is unknown. In a population-based prospective Israeli study, 0.16% of infants had rectal bleeding caused by cow’s milk ingestion.21Elizur A. Cohen M. Goldberg M.R. et al.Cow's milk associated rectal bleeding: a population based prospective study.Pediatr Allergy Immunol. 2012; 23: 766-770Crossref PubMed Scopus (56) Google Scholar In addition, in otherwise healthy infants who present with rectal bleeding, FPIAP is the cause in 60% of cases.23 The diagnosis of FPIAP is made based on the history and presentation of a well-appearing, robust infant with streaks of blood and possibly mucus in stool.13Lake A.M. Food-induced eosinophilic proctocolitis.J Pediatr Gastroenterol Nutr. 2000; 30: S58-S60Crossref PubMed Scopus (199) Google Scholar, 14Kaya A. Toyran M. Civelek E. Misirlioglu E. Kirsaclioglu C. Kocabas C.N. Characteristics and prognosis of allergic proctocolitis in infants.J Pediatr Gastroenterol Nutr. 2015; 61: 69-73Crossref PubMed Scopus (31) Google Scholar, 15Odze R.D. Wershil B.K. Leichtner A.M. Antonioli D.A. Allergic colitis in infants.J Pediatr. 1995; 126: 163-170Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar, 16Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome and allergic proctocolitis.Allergy Asthma Proc. 2015; 36: 172-184Crossref PubMed Scopus (80) Google Scholar, 17Machida H.M. Catto Smith A.G. Gall D.G. Trevenen C. Scott R.B. Allergic colitis in infancy: clinical and pathologic aspects.J Pediatr Gastroenterol Nutr. 1994; 19: 22-26Crossref PubMed Scopus (163) Google Scholar, 18Lake A.M. Whitington P.F. Hamilton S.R. Dietary protein-induced colitis in breast-fed infants.J Pediatr. 1982; 101: 906-910Abstract Full Text PDF PubMed Scopus (174) Google Scholar, 19Sicherer S.H. Clinical aspects of gastrointestinal food allergy in childhood.Pediatrics. 2003; 111: 1609-1616Crossref PubMed Google Scholar, 20Arvola T. Ruuska T. Keranen J. Hyoty H. Salminen S. Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination.Pediatrics. 2006; 117: e760-e768Crossref PubMed Scopus (169) Google Scholar, 21Elizur A. Cohen M. Goldberg M.R. et al.Cow's milk associated rectal bleeding: a population based prospective study.Pediatr Allergy Immunol. 2012; 23: 766-770Crossref PubMed Scopus (56) Google Scholar, 22Bone J. Claver A. Guallar I. Plaza A.M. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment.Allergol Immunopathol (Madr). 2009; 37: 36-42Crossref PubMed Scopus (44) Google Scholar, 23Maloney J. Nowak-Wegrzyn A. Educational clinical case series for pediatric allergy and immunology: allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow's milk allergy.Pediatr Allergy Immunol. 2007; 18: 360-367Crossref PubMed Scopus (115) Google Scholar This is in contrast to an ill-appearing infant who appears in pain and has growth concerns (not FPIAP).24Boyle J.T. Gastrointestinal bleeding in infants and children.Pediatr Rev. 2008; 29: 39-52Crossref PubMed Scopus (67) Google Scholar Thriving infants also are seen in between, with bouts of abdominal pain and times with more or less mucus or blood in stool. Most parents describe a gradual onset of symptoms that persist unless the offending food is removed. In a cohort of 95 children with food protein colitis, 25% had abdominal pain and 5% had diarrhea at presentation.13Lake A.M. Food-induced eosinophilic proctocolitis.J Pediatr Gastroenterol Nutr. 2000; 30: S58-S60Crossref PubMed Scopus (199) Google Scholar In a Finnish cohort, 70% of infants had bloody diarrhea, 25% blood in stool only, 5% diarrhea only, 18% vomiting, and 10% growth concerns.20Arvola T. Ruuska T. Keranen J. Hyoty H. Salminen S. Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination.Pediatrics. 2006; 117: e760-e768Crossref PubMed Scopus (169) Google Scholar In summary, most babies with FPIAP have normal growth. If over time the child develops growth or other gastrointestinal concerns, an alternative diagnosis should be explored. Results of a physical examination are often normal, although one should pay close attention to the growth chart (monitoring percentiles) and the presence or absence of an anal fissure. A history of either constipation or recent acute diarrhea in an otherwise well infant should increase suspicion for a fissure.24Boyle J.T. Gastrointestinal bleeding in infants and children.Pediatr Rev. 2008; 29: 39-52Crossref PubMed Scopus (67) Google Scholar In addition, routine testing for occult blood in fussy infants is not recommended. No laboratory studies (blood or stool) confirm the diagnosis of FPIAP. Stool cultures or polymerase chain reaction studies may be performed to assess for underlying infection if clinically indicated.24Boyle J.T. Gastrointestinal bleeding in infants and children.Pediatr Rev. 2008; 29: 39-52Crossref PubMed Scopus (67) Google Scholar Results of a complete blood count, if obtained, often are normal, although a few may develop mild iron-deficiency anemia.13Lake A.M. Food-induced eosinophilic proctocolitis.J Pediatr Gastroenterol Nutr. 2000; 30: S58-S60Crossref PubMed Scopus (199) Google Scholar, 16Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome and allergic proctocolitis.Allergy Asthma Proc. 2015; 36: 172-184Crossref PubMed Scopus (80) Google Scholar, 23Maloney J. Nowak-Wegrzyn A. Educational clinical case series for pediatric allergy and immunology: allergic proctocolitis, food protein-induced enterocolitis syndrome and allergic eosinophilic gastroenteritis with protein-losing gastroenteropathy as manifestations of non-IgE-mediated cow'