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Eosinophilic colitis in infants

Abstracts

OBJECTIVE:

To review the literature for clinical data on infants with allergic or eosinophilic colitis.

DATA SOURCE:

MEDLINE search of all indexes was performed using the words ''colitis or procto-colitis and eosinophilic'' or ''colitis or proctocolitis and allergic'' between 1966 and February of 2013. All articles that described patients' characteristics were selected.

DATA SYNTHESIS:

A total of 770 articles were identified, of which 32 met the inclusion criteria. The 32 articles included a total of 314 infants. According to the available information, 61.6% of infants were male and 78.6% were younger than 6 months. Of the 314 patients, 49.0% were fed exclusively breast milk, 44.2% received cow's milk protein, and 6.8% received soy protein. Diarrheal stools were described in 28.3% of patients. Eosinophilia was found in 43.8% (115/263) of infants. Colonic or rectal biopsy showed infiltration by eosinophils (between 5 and 25 perhigh-power field) in 89.3% (236/264) of patients. Most patients showed improvement with theremoval of the protein in cow's milk from their diet or the mother's diet. Allergy challenge tests with cow's milk protein were cited by 12 of the 32 articles (66 patients).

CONCLUSIONS:

Eosinophilic colitis occurs predominantly in the first six months of life and in males. Allergy to cow's milk was considered the main cause of eosinophilic colitis. Exclusion of cow'smilk from the diet of the lactating mother or from the infant's diet is generally an effective therapeutic measure.

Colitis; Milk hypersensitivity; Eosinophils; Infant


OBJETIVO:

Revisão da literatura sobre dados clínicos de lactentes com colite eosinofílica oualérgica.

FONTE DOS DADOS:

Pesquisa no Medline de todas as indexações com as palavras ''colitis or proc-tocolitis and eosinophilic'' ou ''colitis or proctocolitis and allergic'' entre 1966 e fevereiro de 2013. Foram selecionados todos os artigos que descreviam as características dos pacientes.

SÍNTESE DOS DADOS:

Foram identificados 770 artigos dos quais 32 preenchiam os critérios de inclusão. Os 32 artigos incluíram o total de 314 lactentes. Conforme as informações disponíveis, 61,6% dos lactentes eram do sexo masculino e 78,6% apresentavam idade inferior a 6 meses. Dos 314 pacientes, 49,0% encontrava-se em aleitamento natural exclusivo, 44,2% recebiam proteína do leite de vaca e 6,8% proteína da soja. Fezes diarreicas foram descritas em 28,3% dos pacientes. Eosinofilia foi encontrada em 43,8% (115/263) dos lactentes. Biópsia retal ou colônica mostrou infiltração por eosinófilos (entre 5 e 25 por campo de grande aumento) em 89,3% (236/264) dos pacientes. A maioria dos pacientes apresentou melhora com a retirada da proteína do leite de vaca da sua dieta ou das suas mães. Teste de desencadeamento com proteína do leite de vaca foi citado em 12 dos 32 artigos (66 pacientes).

CONCLUSÕES:

Colite eosinofílica ocorre predominantemente nos primeiros seis meses de vida e no sexo masculino. Alergia ao leite de vaca foi considerada a principal causa de colite eosinofílica. Dieta de exclusão do leite de vaca da mãe lactante ou da dieta do lactente é uma medidate rapêutica geralmente eficaz.

Colite; Alergia a leite; Eosinófilos; Lactente


Introduction

The prevalence of food allergy has increased in recent decades, especially in the pediatric population.11. Toporovski MS. Pediatricians and nutritionists knowledge about treatment of cow milk allergy in infants. Rev Paul Ped. 2007;25:104-5. , 22. Meyer R. New guidelines for managing cow's milk allergy in infants. J Fam Health Care. 2008;18:27-30. Foods most often related to food allergy are cow's milk, eggs, soy, peanuts, nuts, seafood, and kiwifruit.22. Meyer R. New guidelines for managing cow's milk allergy in infants. J Fam Health Care. 2008;18:27-30. In infants, cow's milk protein allergy (CMA) is the most common, and usually starts in the first six months of life.

In Brazil, the prevalence of food allergy and the most important types of food allergy are yet to be determined. A study performed in the five geographic regions of Brazil assessed the sensitization of children with atopy, demonstrating that the most sensitizing food allergens were fish, eggs, cow's milk, wheat, peanuts, soybeans, and corn.33. Naspitz CK, Solé D, Jacob CA, Sarinho E, Soares FJ, Dantas V, et al. Sensibilização a alérgicos inalantes e alimentares em crianças brasileiras atópicas, pela determinação in vitro de IgE total e específica. Projeto Alergia (PROAL). J Pediatr (Rio J). 2004;80:203-10. Among infants, the food that most frequently caused sensitization was cow's milk.33. Naspitz CK, Solé D, Jacob CA, Sarinho E, Soares FJ, Dantas V, et al. Sensibilização a alérgicos inalantes e alimentares em crianças brasileiras atópicas, pela determinação in vitro de IgE total e específica. Projeto Alergia (PROAL). J Pediatr (Rio J). 2004;80:203-10. It is noteworthy that the presence of sensitization does not mean that the individual will effectively have food allergy.

Based on information from other countries, CMA is the most common type of food allergy in childhood.44. Høst A. Frequency of cow's milk allergy in childhood. Ann Allergy Asthma Immunol. 2002;89:33-7. It affects approximately 3% of children,55. 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. and its prevalence is higher in the first year of life. An epidemiological study performed in pediatric gastroenterology clinics in several regions of Brazil showed that among 9,478 consultations, 7.3% were prompted by a known or suspected food allergy, and the following were the suspected foods: 77% of cases, cow's milk; 8.7% of cases, soy; 2.7% of cases, egg; and 11.6% of cases, other foods. The analysis of new cases and follow-up allowed for a good estimation of an incidence of 2.2% and prevalence of 5.4% of patients with confirmed or suspected CMA.66. Vieira MC, Morais MB, Spolidoro JV, Toporovski MS, Cardoso AL, Araujo GT, et al. A survey on clinical presentation and nutritional status of infants with suspected cow' milk allergy. BMC Pediatr. 2010;10:25.

CMA should be regarded as an important clinical entity, since that normal infants have high rates of growth and development, and both CMA and the use of inadequate diet substitutes can compromise full growth and development in this important phase of life.66. Vieira MC, Morais MB, Spolidoro JV, Toporovski MS, Cardoso AL, Araujo GT, et al. A survey on clinical presentation and nutritional status of infants with suspected cow' milk allergy. BMC Pediatr. 2010;10:25. , 77. Medeiros LC, Speridião PG, Sdepanian VL, Fagundes-Neto U, Morais MB. Ingestão de nutrientes e estado nutricional de crianças em dieta isenta de leite de vaca e derivados. J Pediatr (Rio J). 2004;80:363-70.

Eosinophilic or allergic colitis has been described as a common entity,55. 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. , 88. Walker-Smith J. An eye witness perspective of the changing patterns of food allergy. Eur J Gastroenterol Hepatol. 2005;17:1313-6. but its exact prevalence is unknown.4 4. Høst A. Frequency of cow's milk allergy in childhood. Ann Allergy Asthma Immunol. 2002;89:33-7. Walker-Smith, one of the pioneers in the study of gastrointestinal food allergy, stated that, since the last decade CMA has been occurring with different manifestations when compared to those observed in the 1970s and 1980s, when there was a predominance of enteropathy induced by the milk in the infants' diet with infections by enteropathogenic Escherichia coli.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. In this context, the epidemiological study performed in Brazil66. Vieira MC, Morais MB, Spolidoro JV, Toporovski MS, Cardoso AL, Araujo GT, et al. A survey on clinical presentation and nutritional status of infants with suspected cow' milk allergy. BMC Pediatr. 2010;10:25. demonstrated that 20.6% of infants with known or suspected CMA had blood in the stool that might be the result of allergic or eosinophilic colitis.

Eosinophilic colitis is considered one of the presentations of primary gastrointestinal eosinophilic diseases. This group of diseases also includes eosinophilic esophagitis, eosinophilic gastritis, and eosinophilic gastroenteropathy. The differential diagnosis of eosinophilic diseases must include causes that may result in secondary eosinophilic infiltration, such as certain intestinal parasites (Enterobius vermicularis, Strongyloides stercoralis, and Trichuris trichiura) and drugs (carbamazepine, rifampicin, gold, nonsteroidal anti-inflammatory drugs, and tacrolimus).1010. Okpara N, Aswad B, Baffy G. Eosinophilic colitis. World J Gastroenterol. 2009;15:2975-9. , 1111. Gaertner WB, Macdonald JE, Kwaan MR, Shepela C, Madoff R, Jessurun J, et al. Eosinophilic colitis: University of Minnesota experience and literature review. Gastroenterol Res Pract. 2011;2011:857508. It is also noteworthy that the clinical picture depends on the predominance of eosinophilic infiltration in the different layers of the intestine, that is, mucosal, muscularis, and serosa layers. There is a high association with atopy at all ages; however, in infants, the connection with food allergy is more frequently established.

Conversely, in adults, in addition to the adverse reaction to foods, other mechanisms lead the treatment to often include medicines in addition to elimination diet. Thus, the term allergic colitis can be used as a second alternative to denominate eosinophilic colitis, in a more appropriate form for infants.1010. Okpara N, Aswad B, Baffy G. Eosinophilic colitis. World J Gastroenterol. 2009;15:2975-9. , 1111. Gaertner WB, Macdonald JE, Kwaan MR, Shepela C, Madoff R, Jessurun J, et al. Eosinophilic colitis: University of Minnesota experience and literature review. Gastroenterol Res Pract. 2011;2011:857508.

Thus, considering the increase in the number of infants with bleeding in the stool associated with CMA and the lack of articles with large samples, a literature review of articles indexed from 1966 to February of 2013 was performed, focusing on clinical and evolution aspects of infants with eosinophilic or allergic colitis.

Methods

A search was performed in the MEDLINE database for all indexed articles containing the words ''colitis or proctocolitis and eosinophilic'' and ''colitis or proctocolitis and allergic'', between 1966 and February of 2013. Publications were considered in the following languages: English, Portuguese, and Spanish. All types of articles were included, as long as they contained the clinical information of the infants with colitis or eosinophilic or allergic proctocolitis.

The abstracts were independently analyzed by two authors who selected articles that had samples or case reports of infants (younger than 24 months) whether or not they presented with a clinical picture of elimination of blood in diarrheal stool attributed to colitis or allergic or eosinophilic proctocolitis.

Table 1
Demographic and clinical data on allergic or eosinophilic colitis according to the review of published articles.

Articles whose abstracts were insufficient to define inclusion or exclusion were read in full. In case of disagreements among the researchers regarding the inclusion of a certain article, information was reassessed until consensus was achieved.

Regarding the selected articles, the following data were evaluated: age and gender of the infant, clinical picture and diet at diagnosis, tests, prescribed treatment, and allergy challenge test was performed.

Results

A total of 770 articles were identified in the initial search, of which 32 were selected according to the predefined inclusion criteria, evaluating 314 infants.1111. Gaertner WB, Macdonald JE, Kwaan MR, Shepela C, Madoff R, Jessurun J, et al. Eosinophilic colitis: University of Minnesota experience and literature review. Gastroenterol Res Pract. 2011;2011:857508.

12. Lake AM, Whitington PF, Hamilton SR. Dietary proteininduced colitis in breast-fed infants. J Pediatr. 1982;101: 906-10.

13. Sherman MP, Cox KL. Neonatal eosinophilic colitis. J Pediatr. 1982;100:587-9.

14. 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.

15. 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.

16. Perisic VN, Filipovic D, Kokai G. Allergic colitis with rectal bleeding in an exclusively breast-fed neonate. Acta Paediatr Scand. 1988;77:163-4.

17. Berezin S, Schwarz SM, Glassman M, Davidian M, Newman LJ. Gastrointestinal milk intolerance of infancy. Am J Dis Child. 1989;143:361-2.

18. Hill SM, Milla PJ. Colitis caused by food allergy in infants. Arch Dis Child. 1990;65:132-3.

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

20. Harrison CJ, Puntis JW, Durbin GM, Gornall P, Booth IW. Atypical allergic colitis in preterm infants. Acta Paediatr Scand. 1991;80:1113-6.

21. 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.

22. 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.

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

24. Bloom DA, Buonomo C, Fishman SJ, Furuta G, Nurko S. Allergic colitis: a mimic of Hirschsprung disease. Pediatr Radiol. 1999;29:37-41.

25. Kumar D, Repucci A, Wyatt-Ashmead J, Chelimsky G. Allergic colitis presenting in the first day of life: report of three cases. J Pediatr Gastroenterol Nutr. 2000;31:195-7.

26. Patenaude Y, Bernard C, Schreiber R, Sinsky AB. Cow's-milkinduced allergic colitis in an exclusively breast-fed infant: diagnosed with ultrasound. Pediatr Radiol. 2000;30:379-82.

27. 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.

28. Diaz NJ, Patricio FS, Fagundes-Neto U. Allergic colitis: clinical and morphological aspects in infants with rectal bleeding. Arq Gastroenterol. 2002;39:260-7.

29. Sorea S, Dabadie A, Bridoux-Henno L, Balançon-Morival M, Jouan H, Le Gall E. Hemorrhagic colitis in exclusively breast-fed infants. Arch Pediatr. 2003;10:772-5.

30. Swart JF, Ultee K. Rectal bleeding in a preterm infant as a symptom of allergic colitis. Eur J Pediatr. 2003;162:55-6.

31. Faber MR, Rieu P, Semmekrot BA, Van Krieken JH, Tolboom JJ, Draaisma JM. Allergic colitis presenting within the first hours of premature life. Acta Paediatr. 2005;94:1514-5.

32. 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.

33. 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.

34. Sierra Salinas C, Blasco Alonso J, Olivares Sánchez L, Barco Gálvez A, del Río Mapelli L. Allergic colitis in exclusively breastfed infants. An Pediatr (Barc). 2006;64:158-61.

35. Ohtsuka Y, Shimizu T, Shoji H, Kudo T, Fujii T, Wada M, et al. Neonatal transient eosinophilic colitis causes lower gastrointestinal bleeding in early infancy. J Pediatr Gastroenterol Nutr. 2007;44:501-5.

36. 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.

37. Cseh A, Molnár K, Pintér P, Szalay B, Szebeni B, Treszl A, et al. Regulatory T cells and T helper subsets in breast-fed infants with hematochezia caused by allergic colitis. J Pediatr Gastroenterol Nutr. 2010;51:675-7.

38. Yamada Y, Nishi A, Ebara Y, Kato M, Yamamoto H, Morita H, et al. Eosinophilic gastrointestinal disorders in infants: a Japanese case series. Int Arch Allergy Immunol. 2011;155:40-5.

39. 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.

40. Fretzayas A, Moustaki M, Priftis KN, Attilakos A, Lapa E, Nicolaidou P. Thrombocytosis as an overt sign of cow's milk allergic proctocolitis. Allergol Immunopathol (Madr). 2011;39: 381-3.

41. Ohtsuka Y, Jimbo K, Inage E, Mori M, Yamakawa Y, Aoyagi Y, et al. Microarray analysis of mucosal biopsy specimens in neonates with rectal bleeding: is it really an allergic disease? J Allergy Clin Immunol. 2012;129:1676-8.
-4242. Baldassarre ME, Cappiello A, Laforgia N, Vanderhoof J. Allergic colitis in monozygotic preterm twins. Immunopharmacol Immunotoxicol. 2013;35:198-201.

According to data shown in Table 1, of the 314 infants, most were male and younger than 6 months. Diarrheal stools were described in 28.3% of patients.

Regarding diet at diagnosis, 153 infants (49%) were exclusively breastfed, and the remaining received cow's milk protein (44.2%), except for 21 infants (6.8%) who received soy-based formula.

Regarding complementary tests, eosinophilia was found in 43.8% (115/263) of infants (Table 2). Sensitization to cow's milk was assessed by skin prick test in 98 patients, and was positive in 10 (10.2%) infants. Specific IgE against cow's milk protein was tested in 91 patients, and was positive in 13 (14.3%).

Of the 314 patients, 225 (71.6%) underwent colonoscopy or rectosigmoidoscopy, which showed areas of friability and erosive lesions of the mucosa. In addition to these patients, 39 underwent rectal biopsy without endoscopic procedure. Thus, biopsies were performed in 264 patients showing eosinophil infiltration (between 5 and 25 per highpower field) in 236 (89.3%) patients. Other histopathological findings were foci of erythema, chronic inflammatory infiltrate with areas of activity (lymphocytes, plasma cells, eosinophils), and signs of degeneration and regeneration of epithelial cells.

Cow's milk protein was removed from the diet of the mother and/or of the infant in most cases, with disappearance of intestinal bleeding.

Allergy challenge tests with cow's milk protein were mentioned in 12 of 32 articles, and were performed in 66 patients. Of these, 47 tests were performed two to three months after diagnosis and start of the elimination diet, and were positive in 34 (72.4%) patients, while 47 other tests were performed after one year of age, and were positive in only 10 (21.2%) patients.

Discussion

Eosinophilic or allergic colitis is a frequent manifestation of CMA in infants, occurring predominantly in males and usually starting in the first six months of life. According to the literature, approximately half of the cases occur during exclusive breastfeeding. Treatment consists of the exclusion of cow's milk proteins from the diet of the lactating mother and/or infant.

The first description of eosinophilic colitis was made by Kaijser in 1937.4343. Behjati S, Zilbauer M, Heuschkel R, Phillips A, Salvestrini C, Torrente F, et al. Defining eosinophilic colitis in children: insights from a retrospective case series. J Pediatr Gastroenterol Nutr. 2009;49:208-15. Allergic proctocolitis was described by Rubin in 1940 and subsequently by Grybosky in the 1960s. They manifest as inflammatory changes of the colon and rectum, secondary to immune reactions triggered by ingestion of food proteins.4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42.

Its exact prevalence is unknown. Arvola et al., in 2006, evaluated the cause of rectal bleeding in 40 infants and found an association with CMA through allergy challenge test in 18% of cases.3333. 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. This result differs from the data retrieved by the present literature search, which demonstrated that most patients experienced recovery when submitted to elimination diet excluding cow's milk and dairy products (Table 2). However, it is important to observe that only a small percentage of the articles analyzed mentioned the use of the allergy challenge test to confirm the diagnosis of CMA. According to the data compiled in this article, 72.4% of allergy challenge tests were positive when performed up to two to three months of the elimination diet onset.

Eosinophilic colitis can occur since the neonatal period. In the present review, six reports of eosinophilic colitis in the first week of life were retrieved.1313. Sherman MP, Cox KL. Neonatal eosinophilic colitis. J Pediatr. 1982;100:587-9. , 2525. Kumar D, Repucci A, Wyatt-Ashmead J, Chelimsky G. Allergic colitis presenting in the first day of life: report of three cases. J Pediatr Gastroenterol Nutr. 2000;31:195-7. , 3131. Faber MR, Rieu P, Semmekrot BA, Van Krieken JH, Tolboom JJ, Draaisma JM. Allergic colitis presenting within the first hours of premature life. Acta Paediatr. 2005;94:1514-5. , 3535. Ohtsuka Y, Shimizu T, Shoji H, Kudo T, Fujii T, Wada M, et al. Neonatal transient eosinophilic colitis causes lower gastrointestinal bleeding in early infancy. J Pediatr Gastroenterol Nutr. 2007;44:501-5. , 3939. 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. , 4141. Ohtsuka Y, Jimbo K, Inage E, Mori M, Yamakawa Y, Aoyagi Y, et al. Microarray analysis of mucosal biopsy specimens in neonates with rectal bleeding: is it really an allergic disease? J Allergy Clin Immunol. 2012;129:1676-8.

The main clinical manifestation of the disease is the presence of blood in stool, whether or not associated with diarrheal stools.4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82. In general, the infant presents no weight loss, impairment of general health status, or changes at abdominal palpation.55. 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. , 4343. Behjati S, Zilbauer M, Heuschkel R, Phillips A, Salvestrini C, Torrente F, et al. Defining eosinophilic colitis in children: insights from a retrospective case series. J Pediatr Gastroenterol Nutr. 2009;49:208-15. In all descriptions compiled in this article, the clinical manifestation of blood in the stool was reported in all patients, while diarrhea was reported in only 28.3% of cases.

Table 2
Additional tests used for the diagnosis of eosinophilic or allergic colitis according to the literature review.

Several foods have been associated with the development of eosinophilic colitis, but most cases are associated with cow's milk protein.44 44. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42. About 50% of cases occur in children on exclusive breastfeeding.55. 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. , 4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42. , 45 45. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82. Kilshaw and Cant demonstrated that the presence of β-lactoglobulin can be detected in most samples of breast milk from mothers who consume cow's milk.46 46. Kilshaw PJ, Cant AJ. The passage of maternal dietary proteins into human breast milk. Int Arch Allergy Appl Immunol. 1984;75:8-15. In the present review, 49% of the described patients were exclusively breastfed. Most articles mention that the process is controlled when the proteins in cow's milk are excluded from the lactating mother's diet. Especially in recent years, studies have identified a subgroup of infants with eosinophilic colitis in the presence of exclusive breastfeeding that did not improve with the exclusion of cow's milk proteins from their mothers' diet.3737. Cseh A, Molnár K, Pintér P, Szalay B, Szebeni B, Treszl A, et al. Regulatory T cells and T helper subsets in breast-fed infants with hematochezia caused by allergic colitis. J Pediatr Gastroenterol Nutr. 2010;51:675-7. , 3939. 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. , 4747. Academy of Breastfeeding Medicine. ABM Clinical Protocol #24: allergic proctocolitis in the exclusively breastfed infant. Breastfeed Med. 2011;6:435-40.

Patients with this characteristic have been attended to at this service; however, no data are available on the proportion of infants with eosinophilic colitis during exclusive breastfeeding who do not improve after the exclusion of cow's milk from their mothers' diet.4747. Academy of Breastfeeding Medicine. ABM Clinical Protocol #24: allergic proctocolitis in the exclusively breastfed infant. Breastfeed Med. 2011;6:435-40. A conducted in Hungary evaluated 34 infants on exclusive breastfeeding with blood in stool caused by eosinophilic colitis. Of the 34 patients, ten had persistent hematochezia when their mothers eliminated cow's milk and egg proteins from their diet. After confirming the diagnosis by colonoscopy and biopsy, breast milk was discontinued and replaced by an amino acid formula. All ten patients improved and showed no recurrence during the 13-month minimum follow-up.3737. Cseh A, Molnár K, Pintér P, Szalay B, Szebeni B, Treszl A, et al. Regulatory T cells and T helper subsets in breast-fed infants with hematochezia caused by allergic colitis. J Pediatr Gastroenterol Nutr. 2010;51:675-7.

In this circumstance, two hypotheses can be raised: (1) persistence of small amounts of cow's milk proteins in the maternal diet despite the recommendation of elimination diet, considering that it is very difficult for the lactating mother to effectively remove cow's milk proteins from their diet; (2) Allergy to other foods present in the mother's diet that are transported through breast milk, thus raising the suspicion of eosinophilic colitis by multiple food allergies. In this context, a preliminary study performed in Italy3939. 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. evaluated 14 infants with allergic colitis that did not improve after their mothers started having a hypoallergenic diet (free of cow's milk, soy, and egg). The authors performed a skin prick test, specific IgE measurement, and patch test.

All foods tested by the skin prick test and IgE were negative. Conversely, the patch test was positive with their own mother's milk in all cases, with cow's milk in 50% of cases, with soy in 28%, with egg in 21%, with rice in 14%, and with wheat in 7%. Thus, it can be deduced that other foods that were not investigated and that are transported through breast milk could also be responsible for the process of eosinophilic colitis. The results of this article should be interpreted with caution, given the small number of patients and the lack of comparison groups consisting of children with eosinophilic colitis responsive to elimination diet carried out by the mother and another group with normal infants. The main objective of the Academy of Breastfeeding Medicine is to develop protocols for the treatment of diseases that may compromise the success of breastfeeding. Allergic proctocolitis was the subject of one of these protocols.

For cases that did not improve with the exclusion of cow's milk from the mother's diet, the exclusion of other foods (soy, citrus, eggs, peanuts, wheat, corn, strawberries and chocolate) is recommended. They emphasize that such a diet can only be carried out with the supervision of a dietician experienced in the area, to ensure the mother's diet meets her basic nutritional and lactation needs. It recognizes that an infant with more severe eosinophilic colitis that does not respond to an elimination diet conducted by the mother should be fed exclusively on formula adequate for the treatment of CMA.4747. Academy of Breastfeeding Medicine. ABM Clinical Protocol #24: allergic proctocolitis in the exclusively breastfed infant. Breastfeed Med. 2011;6:435-40. In general, when the allergen is excluded from the mother's diet, the bleeding disappears within 72 to 96 hours, with a maximum waiting period of two weeks.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4747. Academy of Breastfeeding Medicine. ABM Clinical Protocol #24: allergic proctocolitis in the exclusively breastfed infant. Breastfeed Med. 2011;6:435-40.

The diagnosis of eosinophilic colitis caused by CMA should be established based on history and thorough physical examination.55. 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. , 45 45. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82. It is important to exclude the differential diagnosis of rectal bleeding, such as infections, necrotizing enterocolitis, intestinal intussusception, and anal fissure.55. 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. , 4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42.

To date, there are no non-invasive tests to confirm the diagnosis. Eosinophilia can be found in approximately 50% of patients with allergic colitis. The skin prick test and measurement of specific IgE against cow's milk can show negative results in infants, as identified in the present review. In turn, the patch test was evaluated in a few studies and, due to the lack of result standardization, it is not recommended to date.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82.

The diagnostic confirmation is based on the favorable clinical response by the patient after the start of the allergen elimination diet (cow's milk) and recurrence of bleeding with the reintroduction (allergy challenge test) of cow's milk protein in the diet.55. 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. , 4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82. The allergy challenge test is considered the most reliable method for the diagnosis of food allergy.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. It can be performed in three different ways: non-blind (open), single-blind, and double-blind placebocontrolled test.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. The two blinded modalities should be used when the clinical manifestations are subjective. In the case of infants, the non-blind allergy challenge test is traditionally recommended.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82.

It is noteworthy that only 12 of the 32 articles analyzed in this review sought to confirm the diagnosis with an allergy challenge test. 78.8% of the patients who were submitted to the allergy challenge test after 12 months of age showed negative result, indicating the development of tolerance. Conversely, when the allergy challenge test was performed two to three months after the start of the elimination diet, the diagnosis was confirmed in 72.4% of patients. Thus, when tested, the diagnosis of CMA is confirmed early in most patients, whereas after 12 months, the development of tolerance to cow's milk proteins is usually observed.

Many authors do not use the allergy challenge test to diagnose food allergy, which is the reason for the large discrepancy in reported prevalence and incidence of food allergy. A cohort study that followed 480 children from birth to 3 years of age showed that 28% of parents thought that their children's symptoms could be due to food allergy, especially in the first year of life. Conversely, when the allergy challenge test was performed, the diagnosis was confirmed in only 8% of cases. This result shows the importance of completing the allergy challenge test in the diagnosis of food allergy, avoiding unnecessary costs and maintenance of an elimination diet.4848. Bock SA. Prospective appraisal of complaints of adverse reactions to foods in children during the first 3 years of life. Pediatrics. 1987;79:683-8.

Additionally, the possibility of tolerance development during the interval between the diagnosis and the allergy challenge test cannot be ruled out. In this context, it should be noted that, since the 1990s, the European Society of Pediatric Gastroenterology and Nutrition has considered the non-blind allergy challenge test appropriate for infants, in view of the fact that at this age range the suggestion component induced by the test is virtually nonexistent.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4949. Diagnostic criteria for food allergy with predominantly intestinal symptoms. The European Society for Paediatric Gastroenterology and Nutrition Working Group for the Diagnostic Criteria for Food Allergy. J Pediatr Gastroenterol Nutr. 1992;14:108-12. It should be noted that allergy challenge tests should not be performed if there is risk of anaphylaxis. It is currently recommended to start the test in a hospital environment.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82.

The diagnostic workup can be performed by invasive procedures such as sigmoidoscopy and colonoscopy, always associated with local biopsies.

The most common findings are extensive involvement of the rectum and colon mucosa with areas of erosion interspersed with those of normal mucosa. Lymphoid nodular hyperplasia can also be observed. The characteristic histological analysis of food allergy discloses signs of inflammation and eosinophil infiltration in the intestinal mucosa and lamina propria. Although there are controversies, the presence of more than 20 eosinophils per high-power field is generally considered indicative of eosinophilic infiltration. The indication of these procedures should be made considering the clinical characteristics of each particular case.4444. Boné J, Claver A, Guallar I, Plaza AM. Allergic proctocolitis, food-induced enterocolitis: immune mechanisms, diagnosis and treatment. Allergol Immunopathol (Madr). 2009;37: 36-42. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82.

The treatment of eosinophilic colitis consists in the exclusion of the allergen from the diet (cow's milk protein), constituting the ''elimination diet''. In the case of infant formula, which uses cow's milk as basis, its substitution by a formula containing extensively hydrolyzed protein should be recommended.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. Patients who have not responded well to these should receive free amino acid formula.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. In cases of exclusive breastfeeding, the mother's diet should exclude cow's milk and dairy foods, and breastfeeding should be maintained.99. Koletzko S, Niggemann B, Arato A, Dias JA, Heuschkel R, Husby S, et al. Diagnostic approach and management of cow'smilk protein allergy in infants and children: ESPGHAN GI Committee practical guidelines. J Pediatr Gastroenterol Nutr. 2012;55:221-9. , 4545. Morais MB, Speridião PG, Sillos MD, Ribeiro CC. Allergy to cow milk protein. Pediatr Mod. 2010;46:165-82.

In conclusion, CMA should be considered the main cause of eosinophilic colitis. Tests to assess sensitization to cow's milk do not contribute to establish the diagnosis. Despite the heterogeneity in diagnostic criteria, the infiltration of the rectal mucosa with eosinophils is reported in most biopsies. Exclusion of cow's milk and dairy products from the diet of the mother or infant is an effective therapeutic measure. Allergy challenge test confirmed the diagnosis of CMA in most patients when performed a few weeks after recovery attained through the elimination diet, while tolerance to cow's milk was characterized in most cases with eosinophilic colitis after 12 months of age.

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Publication Dates

  • Publication in this collection
    jan-feb 2014

History

  • Received
    10 Jan 2013
  • Accepted
    04 Mar 2013
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