Atypical Food protein-induced enterocolitis syndrome in children: Is IgE sensitization an issue longitudinally?

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Athina Papadopoulou
Theano Lagousi
Elpiniki Hatzopoulou
Paraskevi Korovessi
Stavroula Kostaridou
Despina -Zoe Mermiri


Atypical Food protein induced enterocolitis syndrome, Food allergy, Immunoglobulin E, Long term outcomes, Asthma


Background: Food Protein-Induced Enterocolitis Syndrome (FPIES) is a clinically well-characterised, non-Immunoglobulin E (IgE)-mediated food allergy syndrome, yet its rare atypical presen-tation remains poorly understood.
Objective: Aim of this study was to present the 10-year experience of a referral centre high-lighting the atypical FPIES cases and their long-term outcome.
Methods: FPIES cases were prospectively evaluated longitudinally in respect of food outgrowth and developing other allergic diseases with or without concomitant IgE sensitisation.
Results: One hundred subjects out of a total of 14,188 referrals (0.7%) were identified. At pre-sentation, 15 patients were found sensitised to the offending food. Fish was the most frequent eliciting food, followed by cow’s milk and egg. Tolerance acquisition was earlier for cow’s milk, followed by egg and fish, while found not to be protracted in atypical cases. Resolution was not achieved in half of the fish subjects during the 10-year follow-up time. Sensitisation to food was not related to infantile eczema or culprit food, but was related to sensitisation to aeroallergens. In the long-term evaluation, persistence of the FPIES or aeroallergen sensitisation was significantly associated with an increased hazard risk of developing early asthma symptoms. Conclusion: Sensitisation to food was related neither to eczema or culprit food nor to tolerance acquisition but rather to the development of allergic asthma through aeroallergen sen-sitisation. In addition to an IgE profile at an early age, FPIES persistence may also trigger mechanisms switching FPIES cases to a T-helper 2 cells immune response later in life, predis-posing to atopic respiratory symptoms; albeit further research is required.

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1. Leonard SA, Pecora V, Fiocchi AG, Nowak-Wegrzyn A. Food-protein-induced enterocolitis syndrome: A review of the new guidelines. World Allergy Organ J. 2018;11:4. doi: 10.1186/ s40413-017-0182-z.
2. Nowak-Węgrzyn 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. doi: 10.1016/j.jaci.2016.12.966.
3. Sicherer SH, Eigenmann PA, Sampson HA. Clinical features of food protein-induced enterocolitis syndrome. J Pediatr. 1998;133(2): 214–9. doi: 10.1016/s0022-3476(98)70222-7. PMID: 9709708.
4. Cherian S, Varshney P. Food protein-induced enterocolitis syndrome (FPIES): Review of recent guidelines. Curr Allergy Asthma Rep. 2018;18:28. doi: 10.1007/s11882-018-0767-9. PMID: 29623454.
5. Mehr S, Campbell DE. Food protein-induced enterocolitis syndrome: Guidelines summary and practice recommendations. Med J Aust. 2019;210:94–9. doi: 10.5694/mja2.12071. PMID: 30656696.
6. Miceli Sopo S, Fantacci C, Bersani G, Romano A, Liotti L, Monaco S. Is food protein-induced enterocolitis syndrome only a non-IgE-mediated food allergy? Allergol Immunopathol (Madr). 2018;46:499–502. doi: 10.1016/j.aller.2017.10.004. PMID: 29472022.
7. Lee E, Campbell DE, Barnes EH, Mehr SS. Resolution of acute food protein-induced enterocolitis syndrome in children. J Allergy Clin Immunol Pract. 2017;5:486–8.e1. doi: 10.1016/j. jaip.2016.09.032.
8. Goswami R, Blazquez AB, Kosoy R, Rahman A, Nowak-Węgrzyn A, Berin MC. Systemic innate immune activation in food protein-induced enterocolitis syndrome. J Allergy Clin Immunol. 2017;139:1885–96.e9. doi: 10.1016/j.jaci.2016.12.971.
9. Konstantinou GN, 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;25:651–6. doi: 10.1111/pai.12288.
10. Caubet JC, Nowak-Węgrzyn A. Current understanding of the immune mechanisms of food protein-induced enterocolitis syn-drome. Expert Rev Clin Immunol. 2011;7:317–27. PMID: 21595598.
11. Caubet JC, Bencharitiwong R, Ross A, Sampson HA, Berin MC, Nowak Węgrzyn A. Humoral and cellular responses to casein in food protein-induced enterocolitis to cow’s milk. J Allergy Clin Immunol. 2017;139:572–83. doi: 10.1016/j.jaci.2016.02.047.
12. Adel-Patient K, Lezmi G, Castelli FA, Blanc S, Bernard H, Soulaines P, et al. Deep analysis of immune response and metabolic signature in children with food protein-induced enterocolitis to cow’s milk. Clin Transl Allergy. 2018;8:38. doi: 10.1186/s13601-018-0224-9.
13. Mori F, Barni S, Cianferoni A, Pucci N, de Martino M, Novembre E. Cytokine expression in CD3+ cells in an infant with food protein-induced enterocolitis syndrome (FPIES): Case report. Clin Dev Immunol. 2009;2009:679381. PMID: 20011655.
14. 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. doi: 10.1016/j.jaci.2010.12.1105.
15. Douros K, Tsabouri S, Feketea G, Grammeniatis V, Koliofoti EG, Papadopoulos M, et al. Retrospective study identified fish and milk as the main culprits in cases of food protein-induced enterocolitis syndrome. Acta Paediatr. 2019;108:1901–04. doi: 10.1111/apa.14779.
16. 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. doi: 10.1016/j. jaci.2014.04.008.
17. Morita H, Nomura I, Orihara K, Yoshida K, Akasawa A, Tachimoto H, et al. Antigen-specific T-cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to T(H)2. J Allergy Clin Immunol. 2013;131:590–2, e1-6. doi: 10.1016/j.jaci.2012.09.005.
18. Ishige T, Yagi H, Tatsuki M, Hatori R, Nishida Y, Takizawa T, et al. Endoscopic findings in the acute phase of food pro-tein-induced enterocolitis syndrome. Pediatr Allergy Immunol. 2015;26:90–1. PMID: 25534006.
19. Meyer R, Fox AT, Chebar Lozinsky A, Michaelis LJ, Shah N. Non-IgE-mediated gastrointestinal allergies – Do they have a place in a new model of the allergic march. Pediatr Allergy Immunol. 2019;30:149–58. doi:10.1111/pai.13000.
20. Ruffner MA, Wang KY, Dudley JW, Cianferoni A, Grundmeier RW, Spergel JM, et al. Elevated atopic comorbidity in patients with food protein-induced enterocolitis. J Allergy Clin Immunol Pract. 2020;8:1039–46. doi: 10.1016/j.jaip.2019.10.047
21. Baker MG, Nowak-Wegrzyn A. Food protein-induced entero-colitis syndrome: Epidemiology and comorbidities. Curr Opin Allergy Clin Immunol. 2020;20:168–74. doi: 10.1097/ACI. 0000000000000615.
22. Vila L, Garcıa V, Rial MJ, 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;3:621–3. doi: 10.1016/j.jaip.2015.03.006.
23. Nowak-Wegrzyn A, Warren CM, Brown-Whitehorn T, Cianferoni A, Schultz-Matney F, Gupta RS. Food protein-induced enterocolitis syndrome in the US population-based study. J Allergy Clin Immunol. 2019;144:1128–30. PMID: 31288044.
24. Papadopoulou A, Hatziagorou E, Matziou VN, Grigoropoulou DD, Panagiotakos DB, Tsanakas JN, et al. Comparison in asthma and allergy prevalence in the two major cities in Greece: The ISAAC phase II survey. Allergol Immunopathol (Madr). 2011;39:347–55. PMID: 21342745.
25. Priftis KN, Mermiri D, Papadopoulou A, Papadopoulos M, Fretzayas A, Lagona E. Asthma symptoms and bronchial reactivity in school children sensitized to food allergens in infancy. J Asthma. 2008;45:590–5. doi: 10.1080/02770900802032941.
26. Hose AJ, Depner M, Illi S, Lau S, Keil T, Wahn U, et al. MAS, PASTURE study groups. Latent class analysis reveals clinically relevant atopy phenotypes in 2 birth cohorts. J Allergy Clin Immunol. 2017;139:1935–45. e12. doi: 10.1016/j. jaci.2016.08.046.
27. Miceli Sopo S, Giorgio V, DelloIacono 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. doi: 10.1111/j.1365-2222. 2012.04027.x.
28. Xepapadaki P, Kitsioulis NA, Manousakis E, Manolaraki I, Douladiris N, Papadopoulos NG. Remission patterns of food protein-induced enterocolitis syndrome in a Greek pediat-ric population. Int Arch Allergy Immunol. 2019;180:113–9. doi: 10.1159/000500860.
29. Karefylaki S, Gustafsson D. Recovery from food protein-induced enterocolitis syndrome caused by fish. Pediatr Allergy Immunol. 2016;27:105–6. doi: 10.1111/pai.12488.
30. Miceli Sopo S, Monaco S, Badina L, Barni S, Longo G, Novembre E, et al. Food protein-induced enterocolitis syndrome caused by fish and/or shellfish in Italy. Pediatr Allergy Immunol. 2015;26:731–6. PMID: 26287446.
31. Gonzalez-Delgado P, Caparros E, Moreno MV, Clemente F, Flores E, Velasquez L, et al. Clinical and immunological char-acteristics of a pediatric population with food protein-induced enterocolitis syndrome (FPIES) to fish. Pediatr Allergy Immunol. 2016;27:269–75. doi: 10.1111/pai.12529.
32. Radonjic-Hoesli S, Hofmeier KS, Micaletto S, Schmid-Grendelmeier P, Bircher A, Simon D. Urticaria and angioedema: An Update on Classification and Pathogenesis. Clin Rev Allergy Immunol. 2018;54:88–101. doi: 10.1007/s12016-017-8628-1.
33. Shimomura M, Tanaka H, Meguro T, Kimura M. Three cases of food protein-induced enterocolitis syndrome caused by egg yolk. Allergol Int. 2019;68:110–1. PMID: 29759658.
34. Dhanapala P, De Silva C, Doran T, Suphioglu C. Cracking the egg: an insight into egg hypersensitivity. Mol Immunol. 2015;66:375–83. PMID: 25965316.
35. De Silva C, Dhanapala P, King S, Doran T, Tang M, Suphioglu C. Immunological comparison of native and recombinant hen’s egg yolk allergen, chicken serum albumin (Gal d 5), pro-duced in Kluveromyceslactis. Nutrients. 2018;10. pii: E757. PMID: 29895783.
36. Ruiz-García M, Díez CE, García SS, del Río PR, Ibáñez MD. Diagnosis and natural history of food-protein induced entero-colitis syndrome in children from a tertiary hospital in cen-tral Spain. J Investig Allergol Clin Immunol. 2014;24:354–6. PMID: 25345307.
37. Papadopoulou A, Panagiotakos DB, Hatziagorou E, Antonogeorgos G, Matziou VN, Tsanakas JN, et al. Antioxidant foods consumption and childhood asthma and other aller-gic diseases: The Greek cohorts of the ISAACII survey. Allergol Immunopathol (Madr). 2015;4:353–60. doi: 10.1016/j.aller.2014.03.002.
38. Poza-Guedes P, Barrios Y, González-Pérez R, Sánchez-MachínI, Franco A, Matheu V. Role of specific IgE to β-lactoglobulin in the gastrointestinal phenotype of cow’s milk allergy. Allergy Asthma Clin Immunol 2016;12:7. PMID: 26909103.
39. Rupa P, Mine Y. Comparison of glycated ovalbumin-monosaccharides in the attenuation of ovalbumin-induced allergic response in a BALB/C mouse model. J Agric Food Chem. 2019;67:8138–48. PMID: 31294563.
40. Miceli Sopo S, Buonsenso D, Monaco S, Crocco S, Longo G, Calvani M. Food protein-induced enterocolitis syndrome (FPIES) and well-cooked foods: A working hypothesis. Allergol Immunopathol (Madr). 2013;41:346–8. doi: 10.1016/j. aller.2012.06.008.