Skip to main content

Advertisement

Log in

Non-IgE-mediated Adverse Food Reactions

  • Food Allergy (T Green, Section Editor)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The purpose of this review is to update what is currently known about the major non-IgE-mediated food allergies: food protein-induced enterocolitis syndrome (FPIES), food protein-induced allergic proctocolitis (FPIAP), and food protein-induced enteropathy (FPE). These conditions are similar in that symptoms are regulated to the gastrointestinal tract; therefore understanding their specific features is important for diagnosis and management.

Recent Findings

The most progress has been made in understanding FPIES with several recent large cohorts being described. The first international consensus guidelines for FPIES were published in 2017 and propose specific diagnostic criteria for acute FPIES as well as guidance for diagnosing chronic FPIES. Recent studies in FPIAP have challenged our thinking about the recommended duration of food avoidance and that cow’s milk avoidance is the primary management with reports of self-resolution without dietary management. FPE continues to appear to be on the decline.

Summary

FPIES, FPIAP, and FPE are distinguished from one another by their main clinical features: delayed repetitive vomiting in FPIES, benign blood in stool in FPIAP, and chronic diarrhea in FPE. Due to the risk of nutritional deficiencies with food avoidance in both infant and maternal diets if breastfeeding, confirmation of diagnosis with challenges is encouraged. Additional studies are needed for these conditions to elucidate pathophysiology, search for diagnostic markers, and understand natural history.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sampson HA, Aceves S, Bock SA, James J, Jones S, Lang D, et al. Food allergy: a practice parameter update-2014. J Allergy Clin Immunol. 2014;134:1016–25 e43.

    Article  PubMed  Google Scholar 

  2. •• Nowak-Wegrzyn A, Chehade M, Groetch ME, Spergel JM, Wood RA, Allen K, et al. 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. J Allergy Clin Immunol. 2017;139:1111–26 e4. First international guidelines diagnosis and management of FPIES.

    Article  PubMed  Google Scholar 

  3. Ruffner MA, Ruymann K, Barni S, Cianferoni A, Brown-Whitehorn T, Spergel JM. Food protein-induced enterocolitis syndrome: insights from review of a large referral population. J Allergy Clin Immunol Pract. 2013;1:343–9.

    Article  PubMed  Google Scholar 

  4. Sopo SM, 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;42:1257–65.

    Article  PubMed  Google Scholar 

  5. Ludman S, Harmon M, Whiting D, du Toit G. Clinical presentation and referral characteristics of food protein-induced enterocolitis syndrome in the United Kingdom. Ann Allergy Asthma Immunol: Off Publ Am College Allergy Asthma Immunol. 2014;113:290–4.

    Article  Google Scholar 

  6. Katz Y, Goldberg MR, 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;127:647–53 e1-3.

    Article  CAS  PubMed  Google Scholar 

  7. • Mehr S, Frith K, Barnes EH, Campbell DE, Group FS. Food protein-induced enterocolitis syndrome in Australia: a population-based study, 2012–2014. J Allergy Clin Immunol. 2017;140(5):1323–1330. Recent population-based study providing some data on incidence.

  8. Tan JA, Smith WB. Non-IgE-mediated gastrointestinal food hypersensitivity syndrome in adults. J Allergy Clin Immunol Pract. 2014;2:355–7.e1.

    Article  PubMed  Google Scholar 

  9. Hsu P, Mehr S. Egg: a frequent trigger of food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2013;131:241–2.

    Article  CAS  PubMed  Google Scholar 

  10. Hwang J-B, Sohn SM, Kim AS. Prospective follow-up oral food challenge in food protein-induced enterocolitis syndrome. Arch Dis Child. 2009;94:425–8.

    Article  PubMed  Google Scholar 

  11. Caubet JC, Ford LS, Sickles L, Järvinen KM, Sicherer SH, Sampson HA, et al. Clinical features and resolution of food protein-induced enterocolitis syndrome: 10-year experience. J Allergy Clin Immunol. 2014;134:382–9.

    Article  PubMed  Google Scholar 

  12. Sopo S, Iacono I, Greco M, Monti G. Clinical management of food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol 2014;14(3):240–5.

  13. Konstantinou G, Bencharitiwong R, Grishin A, Caubet JC, Bardina L, Sicherer SH, et al. The role of casein-specific IgA and TGF-β in children with food protein-induced enterocolitis syndrome to milk. Pediatr Allergy Immunol. 2014;25(7):651–6.

  14. Chung H, Hwang J, Park J, Kim S. Expression of transforming growth factor β1, transforming growth factor type I and II receptors, and TNF-α in the mucosa of the small intestine in infants with food protein–induced enterocolitis syndrome. J Allergy Clin Immunol. 2002;109:150–4.

    Article  CAS  PubMed  Google Scholar 

  15. • Goswami R, Blazquez AB, Kosoy R, Rahman A, Nowak-Wegrzyn A, Berin MC. Systemic innate immune activation in food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2017;139:1885–96 e9. Mechanistic study providing some evidence of the innate immune system’s role in the pathophysiology of FPIES.

    Article  CAS  PubMed  Google Scholar 

  16. Caubet JC, Bencharitiwong R, Ross A, Sampson HA, Berin MC, Nowak-Wegrzyn A. Humoral and cellular responses to casein in patients with food protein-induced enterocolitis to cow’s milk. J Allergy Clin Immunol. 2017;139:572–83.

    Article  CAS  PubMed  Google Scholar 

  17. Richards DG, Somers S, Issenman RM, Stevenson GW. Cow’s milk protein/soy protein allergy: gastrointestinal imaging. Radiology. 1988;167:721–3.

    Article  CAS  PubMed  Google Scholar 

  18. Pecora V, Prencipe G, Valluzzi R, Dahdah L, Insalaco A, Cianferoni A, et al. Inflammatory events during food protein-induced enterocolitis syndrome reactions. Pediatr Allergy Immunol. 2017;28:464–70.

    Article  PubMed  Google Scholar 

  19. Kimura M, Shimomura M, Morishita H, Meguro T, Seto S. Serum C-reactive protein in food protein-induced enterocolitis syndrome versus food protein-induced proctocolitis in Japan. Pediatr Int. 2016;58:836–41.

    Article  CAS  PubMed  Google Scholar 

  20. Ruiz-García M, Díez CE, García SS, del Río PR, Ibáñez MD. Diagnosis and natural history of food protein-induced enterocolitis syndrome in children from a tertiary hospital in central Spain. J Investig Allergol Clin Immunol. 2014;24:354–6.

    PubMed  Google Scholar 

  21. Nomura 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;127:685–8 e1-8.

    Article  CAS  PubMed  Google Scholar 

  22. Kimura M, Ito Y, Tokunaga F, Meguro T, Shimomura M, Morishita H, et al. Increased C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome. Pediatr Int. 2016;58:826–30.

    Article  CAS  PubMed  Google Scholar 

  23. Mehr S, Kakakios A, Frith K, Kemp AS. Food protein-induced enterocolitis syndrome: 16-year experience. Pediatrics. 2009;123:e459–64.

    Article  PubMed  Google Scholar 

  24. Katz Y, Goldberg MR. Natural history of food protein-induced enterocolitis syndrome. Curr Opin Allergy Clin Immunol. 2014;14(3):229–39.

  25. Järvinen K, Caubet J, Sickles L, Ford L, Sampson HA, Nowak-Węgrzyn A. Poor utility of atopy patch test in predicting tolerance development in food protein-induced enterocolitis syndrome. ANAI. 2012;109:221–2.

    Google Scholar 

  26. Gonzalez-Delgado P, Caparros E, Moreno MV, Clemente F, Flores E, Velasquez L, et al. Clinical and immunological characteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish. Pediatr Allergy Immunol. 2016;27:269–75.

    Article  PubMed  Google Scholar 

  27. Nowak-Wegrzyn A, Sampson HA, Wood RA, Sicherer SH. Food protein-induced enterocolitis syndrome caused by solid food proteins. Pediatrics. 2003;111:829–35.

    Article  PubMed  Google Scholar 

  28. Miceli Sopo S, Bersani G, Monaco S, Cerchiara G, Lee E, Campbell D, et al. Ondansetron in acute food protein-induced enterocolitis syndrome, a retrospective case-control study. Allergy. 2017;72:545–51.

    Article  CAS  PubMed  Google Scholar 

  29. Holbrook T, Keet CA, Frischmeyer-Guerrerio PA, Wood RA. Use of ondansetron for food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2013;132:1219–20.

    Article  PubMed  Google Scholar 

  30. • Elizur A, Cohen M, Goldberg MR, Rajuan N, Cohen A, Leshno M, et al. Cow’s milk associated rectal bleeding: a population based prospective study. Pediatr Allergy Immunol. 2012;23:766–70. A recent population-based study on cow’s milk proctocolitis in infants.

    Article  PubMed  Google Scholar 

  31. Lozinsky AC, Morais MB. Eosinophilic colitis in infants. J Pediatr. 2014;90:16–21.

    Article  Google Scholar 

  32. Erdem SB, Nacaroglu HT, Karaman S, Erdur CB, Karkiner CU, Can D. Tolerance development in food protein-induced allergic proctocolitis: single centre experience. Allergol Immunopathol (Madr). 2017;45:212–9.

    Article  CAS  Google Scholar 

  33. Ravelli A, Villanacci V, Chiappa S, Bolognini S, Manenti S, Fuoti M. Dietary protein-induced proctocolitis in childhood. Am J Gastroenterol. 2008;103:2605–12.

    Article  PubMed  Google Scholar 

  34. Jang HJ, Kim AS, Hwang JB. The etiology of small and fresh rectal bleeding in not-sick neonates: should we initially suspect food protein-induced proctocolitis? Eur J Pediatr. 2012;171:1845–9.

    Article  PubMed  Google Scholar 

  35. Odze RD, Bines J, Leichtner AM, Goldman H, Antonioli DA. Allergic proctocolitis in infants: a prospective clinicopathologic biopsy study. Hum Pathol. 1993;24:668–74.

    Article  CAS  PubMed  Google Scholar 

  36. Arvola T, Ruuska T, Keränen J, Hyöty H, Salminen S, Isolauri E. Rectal bleeding in infancy: clinical, allergological, and microbiological examination. Pediatrics. 2006;117:e760–8.

    Article  PubMed  Google Scholar 

  37. Xanthakos SA, Schwimmer JB, Melin-Aldana H, Rothenberg ME, Witte DP, Cohen MB. Prevalence and outcome of allergic colitis in healthy infants with rectal bleeding: a prospective cohort study. J Pediatr Gastroenterol Nutr. 2005;41:16–22.

    Article  PubMed  Google Scholar 

  38. Jenkins HR, Pincott JR, Soothill JF, Milla PJ, Harries JT. Food allergy: the major cause of infantile colitis. Arch Dis Child. 1984;59:326–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goldman H, Proujansky R. Allergic proctitis and gastroenteritis in children. Clinical and mucosal biopsy features in 53 cases. Am J Surg Pathol. 1986;10:75–86.

    Article  CAS  PubMed  Google Scholar 

  40. Anveden-Hertzberg L, Finkel Y, Sandstedt B, Karpe B. Proctocolitis in exclusively breast-fed infants. Eur J Pediatr. 1996;155:464–7.

    Article  CAS  PubMed  Google Scholar 

  41. Machida HM, Catto Smith AG, Gall DG, Trevenen C, Scott RB. Allergic colitis in infancy: clinical and pathologic aspects. J Pediatr Gastroenterol Nutr. 1994;19:22–6.

    Article  CAS  PubMed  Google Scholar 

  42. Nevoral J, Rada V, Vlkova E, Blahova K, Bronsky J, Bubakova D, et al. Intestinal microbiota in exclusively breast-fed infants with blood-streaked stools. Folia Microbiol (Praha). 2009;54:167–71.

    Article  CAS  Google Scholar 

  43. Kumagai H, Maisawa S, Tanaka M, Takahashi M, Takasago Y, Nishijima A, et al. Intestinal microbiota and secretory immunoglobulin a in feces of exclusively breast-fed infants with blood-streaked stools. Microbiol Immunol. 2012;56:657–63.

    Article  CAS  PubMed  Google Scholar 

  44. Baldassarre ME, Laforgia N, Fanelli M, Laneve A, Grosso R, Lifschitz C. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. J Pediatr. 2010;156:397–401.

    Article  CAS  PubMed  Google Scholar 

  45. Lake AM, Whitington PF, Hamilton SR. Dietary protein-induced colitis in breast-fed infants. J Pediatr. 1982;101:906–10.

    Article  CAS  PubMed  Google Scholar 

  46. Maloney 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;18:360–7.

    Article  PubMed  Google Scholar 

  47. Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome and allergic proctocolitis. Allergy Asthma Proc. 2015;36:172–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pumberger W, Pomberger G, Geissler W. Proctocolitis in breast fed infants: a contribution to differential diagnosis of haematochezia in early childhood. Postgrad Med J. 2001;77:252–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lake AM. Food-induced eosinophilic proctocolitis. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S58–60.

    Article  CAS  PubMed  Google Scholar 

  50. Pittschieler K. Cow’s milk protein-induced colitis in the breast-fed infant. J Pediatr Gastroenterol Nutr. 1990;10:548–9.

    Article  CAS  PubMed  Google Scholar 

  51. Koksal BT, Baris Z, Ozcay F, Yilmaz Ozbek O. Single and multiple food allergies in infants with proctocolitis. Allergol Immunopathol (Madr). 2017. https://doi.org/10.1016/j.aller.2017.02.006

  52. Lucarelli S, Di Nardo G, Lastrucci G, D'Alfonso Y, Marcheggiano A, Federici T, et al. Allergic proctocolitis refractory to maternal hypoallergenic diet in exclusively breast-fed infants: a clinical observation. BMC Gastroenterol. 2011;11:82.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Caubet JC, Szajewska H, Shamir R, Nowak-Wegrzyn A. Non-IgE-mediated gastrointestinal food allergies in children. Pediatr Allergy Immunol. 2017;28:6–17.

    Article  PubMed  Google Scholar 

  54. Nowak-Wegrzyn A, Katz Y, Mehr SS, Koletzko S. Non-IgE-mediated gastrointestinal food allergy. J Allergy Clin Immunol. 2015;135:1114–24.

    Article  CAS  PubMed  Google Scholar 

  55. Gryboski JD. Gastrointestinal milk allergy in infants. Pediatrics. 1967;40:354–62.

    CAS  PubMed  Google Scholar 

  56. Odze RD, Wershil BK, Leichtner AM, Antonioli DA. Allergic colitis in infants. J Pediatr. 1995;126:163–70.

    Article  CAS  PubMed  Google Scholar 

  57. Vanderhoof JA, Murray ND, Kaufman SS, Mack DR, Antonson DL, Corkins MR, et al. Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants. J Pediatr. 1997;131:741–4.

    Article  CAS  PubMed  Google Scholar 

  58. Vitoria JC, Sojo A, Rodriguez-Soriano J. Changing pattern of cow’s milk protein intolerance. Acta Paediatr Scand. 1990;79:566–7.

    Article  CAS  PubMed  Google Scholar 

  59. Verkasalo M, Kuitunen P, Savilahti E, Tiilikainen A. Changing pattern of cow’s milk intolerance. An analysis of the occurrence and clinical course in the 60s and mid-70s. Acta Paediatr Scand. 1981;70:289–95.

    Article  CAS  PubMed  Google Scholar 

  60. Kokkonen J, Holm K, Karttunen TJ, Mäki M. Enhanced local immune response in children with prolonged gastrointestinal symptoms. Acta Paediatr. 2004;93:1601–7.

    Article  CAS  PubMed  Google Scholar 

  61. Paajanen L, Vaarala O, Karttunen R, Tuure T, Korpela R, Kokkonen J. Increased IFN-gamma secretion from duodenal biopsy samples in delayed-type cow’s milk allergy. Pediatr Allergy Immunol. 2005;16:439–44.

    Article  PubMed  Google Scholar 

  62. Kuitunen P, Visakorpi JK, Savilahti E, Pelkonen P. Malabsorption syndrome with cow’s milk intolerance. Clinical findings and course in 54 cases. Arch Dis Child. 1975;50:351–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Walker-Smith JA. Cow milk-sensitive enteropathy: predisposing factors and treatment. J Pediatr. 1992;121:S111–5.

    Article  CAS  PubMed  Google Scholar 

  64. Iyngkaran N, Robinson MJ, Prathap K, Sumithran E, Yadav M. Cows’ milk protein-sensitive enteropathy. Combined clinical and histological criteria for diagnosis. Arch Dis Child. 1978;53:20–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Savilahti E. Food-induced malabsorption syndromes. J Pediatr Gastroenterol Nutr. 2000;30 Suppl:S61–6.

    Article  CAS  PubMed  Google Scholar 

  66. Chung HL, Hwang JB, Kwon YD, Park MH, Shin WJ, Park JB. Deposition of eosinophil-granule major basic protein and expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the mucosa of the small intestine in infants with cow’s milk-sensitive enteropathy. J Allergy Clin Immunol. 1999;103:1195–201.

    Article  CAS  PubMed  Google Scholar 

  67. Kuitunen P, Kosnai I, Savilahti E. Morphometric study of the jejunal mucosa in various childhood enteropathies with special reference to intraepithelial lymphocytes. J Pediatr Gastroenterol Nutr. 1982;1:525–31.

    Article  CAS  PubMed  Google Scholar 

  68. Maluenda C, Phillips AD, Briddon A, Walker-Smith JA. Quantitative analysis of small intestinal mucosa in cow’s milk-sensitive enteropathy. J Pediatr Gastroenterol Nutr. 1984;3:349–56.

    Article  CAS  PubMed  Google Scholar 

  69. Kokkonen J, Haapalahti M, Laurila K, Karttunen TJ, Mäki M. Cow’s milk protein-sensitive enteropathy at school age. J Pediatr. 2001;139:797–803.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephanie A. Leonard.

Ethics declarations

Conflict of Interest

The author declares no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Food Allergy

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leonard, S.A. Non-IgE-mediated Adverse Food Reactions. Curr Allergy Asthma Rep 17, 84 (2017). https://doi.org/10.1007/s11882-017-0744-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-017-0744-8

Keywords

Navigation