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Failure to thrive and two weeks of persistent vomiting in an 11-month-old infant
Clinical allergy–immunology rounds Supported by an unrestricted grant from Aventis Pharmaceuticals
Failure to thrive and two weeks of persistent vomiting in an 11-month-old infant Kumaravel Rajakumar, MD*; Mary Beth Hogan, MD†; and Nevin W Wilson, MD†
CHIEF COMPLAINT An 11-month-old male infant of Asian origin with failure to thrive was evaluated by his pediatrician for persistent vomiting of 2 weeks duration. HISTORY OF PRESENT ILLNESS This infant presented with a 2-week history of vomiting. Initially, the episodes of vomiting were infrequent and appeared to the parents to be possibly self-induced. They were often associated with tantrums. After 1 week, the episodes of emesis gradually became more frequent and copious. At the time of the initial evaluation, the vomiting was occurring about 4 to 5 times a day. There was no particular time of day or activity in which the vomiting occurred more frequently. There was no relationship with meals. The parents noted a gradual failure to gain weight over the previous 5 months. There was no associated history of fever, diarrhea, or constipation. His activity level was unchanged and he was developmentally appropriate for his age. There was no history of travel or exposure to any pets. He was on no medications. PAST MEDICAL HISTORY He was a 3.2 kg. term infant born after a non-complicated pregnancy, labor, Department of Pediatrics, Sections of General Pediatrics* and Pediatric Allergy and Immunology† West Virginia University, School of Medicine Morgantown, West Virginia. Received for publication December 6, 1999. Accepted for publication in revised form May 8, 2000.
VOLUME 85, NOVEMBER, 2000
and delivery. At 5 months of age he developed scaly, erythematous macular, papular rash on his face and arms which was consistent with atopic dermatitis. This was successfully treated with topical emollients and steroids. FAMILY HISTORY There were no siblings. The parents were non-consanguineous. There was a family history of allergy. There was no family history of inherited metabolic disorders or immunologic problems. DIETARY HISTORY He was initially breastfed and no dietary restrictions were practiced by the mother. He was weaned at 4 months of age, switched to cow milk-based formula and was now ingesting infant cereals, jarred fruits, and vegetables. PHYSICAL EXAMINATION On examination he was afebrile and vital signs were appropriate for age. He appeared non-toxic and well hydrated. He was strikingly thin in appearance. His growth measurements were: weight 7.5 kg. (⬍ 5th percentile), height 72.5 cm. (10th percentile), and head circumference 45 cm. (10th percentile). His head was normocephalic and atraumatic. Pupils were equal round and reactive to light. Conjunctiva were clear. Extraocular movements were intact. Nasal passages and the oral cavity were normal. Neck was supple. Lungs were clear. Heart rate was regular without murmurs. Abdomen was soft, bowel sounds were present and there was no organomegaly or masses. No ascites was
noted. Skin was without lesions. Extremities were without clubbing, cyanosis or edema. His neurologic exam was normal. INITIAL LABORATORY DATA A complete blood count (CBC) showed a white blood cell (WBC) count of 23,900/cubic millimeter with 15% neutrophils, 71% lymphocytes, 7% monocytes, and 7% eosinophils. His absolute eosinophil count was 1673/mm3. The hemoglobin was 13.9 g/dL. The serum electrolytes, blood urea nitrogen, and creatinine were normal. QUESTIONS Based on the initial history, physical exam and laboratory data, which of the following diagnoses might be consistent with progressively worsening vomiting and failure to thrive in an 11-month-old male infant? a. Urinary tract infection. b. Increased intracranial pressure with or without a space occupying lesion in the brain. c. Non-organic failure to thrive d. Eosinophilic gastroenteritis. e. Intestinal obstruction f. Gastroesophageal reflux. g. Inflammatory bowel disease. h. Hepatitis. i. Celiac Sprue j. Peptic ulcer disease. k. Diabetes Mellitus. l. Thyroid disease m. Metabolic disorders ADDITIONAL STUDIES AND INITIAL TREATMENT A computerized tomogram (CT scan) of the head was normal with no masses
349
or space occupying lesions. A barium swallow with small-bowel follow through showed mild gastroesophageal reflux but no intestinal obstruction or malrotation. A urine specimen obtained by straight catheterization revealed 5 to 10 WBC/high power field and grew greater than 100,000 colonies of non-hemolytic Streptococci. He was diagnosed with a urinary tract infection and was treated with cefixime. After the third dose he developed swelling of the lips consistent with angioedema but with no associated bronchospasm or urticaria. The cefixime was discontinued and he was switched to amoxicillin. The lip swelling persisted on amoxicillin and he was then switched to co-trimoxazole. FURTHER EVALUATION The vomiting persisted despite completing treatment for the urinary tract infection. A voiding cystourethrogram revealed grade 1 vesico-ureteric reflux on the left side. Further laboratory evaluation was initiated when no weight gain was noted at the 2-week follow-up visit. ADDITIONAL LABORATORY DATA Glucose, serum amylase, lactic acid, ammonia, and liver function tests were normal. Renal ultrasound was normal. A repeat CBC showed a WBC of 17,900/mm3 with 15% neutrophils, 59% lymphocytes, 24% eosinophils, and 2% monocytes. The absolute eosinophil count was now 4296/mm3. The hemoglobin was 13 g/dL. Stool exam for ova and parasites, occult blood, fat globules, and eosinophils were negative. FURTHER QUESTIONS With the persistence of the vomiting, normal metabolic laboratory tests, normal stool exam and the increased eosinophilia, what would you do next? a. pH probe b. Food allergy skin tests c. Endoscopy d. Hospital admission to observe feeding and follow weight gain e. NBT test
350
Endoscopic examination revealed the distal esophagus to be nodular. The gastric, duodenal, rectal and sigmoid mucosa appeared normal. There were no granulomas consistent with chronic granulomatous disease. The biopsy specimens obtained from the esophagus, gastric antrum, and recto-sigmoid areas showed marked eosinophilic infiltration consistent with the polyenteric form of eosinophilic gastroenteritis. These infiltrates were predominately in the mucosal layer. A serum IgE level was significantly elevated at 562 U/mL. Radioallergosorbant tests (RAST) obtained by the gastroenterologist were positive for egg white, milk, wheat, barley, oat, rice, soy, rye, corn, and casein. Subsequent food skin testing using the prick puncture technique confirmed positive reactions to milk, eggs, soy, wheat, and corn. He was started on oral prednisone. To gain immediate control of his symptoms, an extensive food elimination diet was initiated. The vomiting resolved and he started to gain weight. He was gradually tapered off of the oral steroids and he has continued to thrive on a milk-free and eggfree diet. The reintroduction of wheat and corn was unremarkable, however an attempt at reintroducing soy led to immediate vomiting and eosinophilia. DISCUSSION Eosinophilic gastroenteritis (EGE) is a rare gastrointestinal inflammatory disorder of unknown etiology. It is characterized by an eosinophilic inflammatory infiltrate in the gastrointestinal tract associated with gastrointestinal symptoms consisting of nausea, vomiting, diarrhea, abdominal pain, and failure to thrive. Protein losing enteropathy, intestinal blood loss, ascites, abdominal obstruction, and abdominal distention may also occur. Eosinophilic gastroenteritis was first reported in the medical literature by Kaijser in 1937.1 Eosinophilic gastroenteritis can affect all ages and races and is not an exclusively human disease.2 Pediatric EGE can be classified as idiopathic or protein-sensitive. Waldman et al described six patients (6
months to 14 years) with protein losing enteropathy, presenting as a syndrome of edema, anemia, hypoalbuminemia, eosinophilia, and growth failure.3 Four of the six patients had a personal or family history of allergy. Three of the six patients had significant amelioration of their clinical symptoms and resolution of their hypoalbuminemia on exclusion of milk proteins from the diet. Re-introduction of milk caused recurrence of the symptoms, the return of eosinophilia and their protein losing enteropathy. Katz et al4 described 12 children (1 month to 20 years) with gastrointestinal symptoms, protein losing enteropathy, blood and tissue eosinophilia. The patients in this study could be categorized in to two equal groups, namely the milk-sensitive EGE and the idiopathic EGE. The milk or proteinsensitive EGE group was composed of younger infants (mean age, 5 months ⫾ 3.9 months) with food allergies. Symptoms resolved after milk elimination. This form of the disease often resolved spontaneously over time. Protein-sensitive EGE occurred more frequently than the idiopathic form of the disease in both studies. Idiopathic EGE is a chronic, relapsing disorder, which may occur at any age, but most often the affects older children.4,5 In Katz’s study, the idiopathic EGE group had a mean age of 4 years (⫾3.3 years) and had chronic symptoms associated with failing to thrive. This group had a family history of allergy in nearly 50% of the cases or had other atopic diseases. Despite evidence of allergy as a predisposing factor, none of these children improved after dietary manipulation. Idiopathic EGE was responsive to corticosteroids in most cases. Eosinophilic gastroenteritis may also be classified as either diffuse or circumscribed granulomatous, defined by the extent of the eosinophilic infiltrate in the gastrointestinal tract seen at biopsy.6,7 Diffuse EGE can be further classified as polyenteric, monoenteric or regional. The polyenteric form of the disease involves the gastric antrum and variable parts of the small bowel,
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
and may have an extensive eosinophilic inflammatory infiltrate up to the serosa. The monoenteric form is present in the pylorus and extends in a retrograde fashion toward the rest of the stomach. The regional form affects either the stomach (pyloric or pre-pyloric) or an isolated segment of the small bowel. The eosinophilic inflammation in the regional type is often restricted to the submucosa. Pyloric obstruction occurred in all polyenteric and monoenteric patients described by Ureles et al.6 Klein et al7 described three patterns of clinical presentations in EGE based on the depth of maximum disease process: mucosal, muscular and serosal. The mucosal form of the disease is the most commonly encountered and presents as a malabsorption syndrome. The typical features of the malabsorption syndrome are diarrhea, weight loss, protein-losing enteropathy, and failure to thrive. Anemia due to occult blood in the stools may occur. Edema and hypoalbuminemia are features often associated with the protein-losing enteropathy. Presentation with bloody diarrhea is occasionally noted if there is colonic mucosal involvement. The muscular form of the disease leads to gastric outlet obstruction, the typical symptoms of which are anorexia, abdominal pain and vomiting. The serosal form of the disease is rare and is characterized by eosinophilic ascites. Naylor’s retrospective review of 220 cases of EGE from the preexisting medical literature is one of the largest descriptive case series of EGE.2 In that series the gastrointestinal involvement was monoenteric in 64% and polyenteric in 15%. The stomach was the most frequently involved site. The gastric antrum was universally affected if stomach was involved. Abdominal pain, vomiting, diarrhea and weight loss were the most frequently noted symptoms. Goldman and Proujansky8 also noted a similar constellation of symptoms in their pediatric case series. The duration of symptoms prior to diagnosis was less than 4 weeks in 33% of the children. Twenty-five percent had symptoms for greater than 5 years
VOLUME 85, NOVEMBER, 2000
prior to the diagnosis. A few patients have gone remarkably long periods of time with symptoms before a correct diagnosis was made.9 One patient was described as having symptoms for 32 years and required 38 hospitalizations before the diagnosis of EGE was finally made. In Naylor’s series there was a history of allergies in 52%, aggravation of symptoms with ingestion of certain foods in 8% and peripheral eosinophilia in 80% of patients.2 The exact etiology of EGE is unknown.2 The frequent history of atopic diseases, aggravation of symptoms with certain foods (especially milk) and rapid endoscopic and histologic changes with dietary challenge suggest an allergic and immunologic basis for EGE.2,10 The tissue and blood eosinophilia, correlation with IgE levels, skin and RAST positivity, and response to steroid therapy further imply an allergic etiology. The absence of allergies in 50% of patients, lack of peripheral eosinophilia in 20% of patients, and lack of response to dietary manipulation in 70% of patients, however, argue against an allergic etiology in many patients.2,11 As in asthma and atopic dermatitis, EGE appears to have two clinically distinguishable subtypes. One subtype reflects an IgE-mediated allergy and the other subtype has a currently unidentified mechanism which is responsible. The differential diagnosis of failure to thrive and vomiting is extensive and includes gastroesophageal reflux, infectious agents, intracranial processes, intestinal obstruction, pyschosocial failure to thrive, as well as a variety of metabolic and endocrine disorders. The initial diagnosis of a urinary tract infection as the cause of our patient’s symptoms was reasonable. When his symptoms of failure to thrive and vomiting did not resolve, however, other etiologies were considered. Other immunologic disorders that are associated with these symptoms would include inflammatory bowel disease, celiac sprue, and granulomatous obstruction of the duodenum caused by chronic granulomatous disease.
The diagnosis of eosinophilic gastroenteritis requires a high index of clinical suspicion. The diagnosis should be entertained in any patient with gastrointestinal symptoms and eosinophilia. Without question, the diagnosis of EGE is certainly more challenging in the absence of peripheral eosinophilia.12 Supportive evidence for EGE includes gastrointestinal blood loss suggested by guaiac positive stools. A positive d-xylose absorption test or hypoalbuminemia may indicate a protein-losing enteropathy and lead to this diagnosis.5 Gastrointestinal contrast studies tend to be non-specific but can rule out obstruction and be suggestive of EGE.13 An elevated serum IgE in this clinical situation may also suggest the diagnosis. Evidence of food sensitization by skin testing or RAST is also useful in the management and diagnosis of the protein-sensitive form of the disease. Patients with markedly elevated IgE levels may have positive tests to foods that are not clinically relevant. Documenting the eosinophilic inflammatory infiltrate of the affected gastrointestinal tract by endoscopic biopsy remains the gold standard test in the diagnosis of EGE. Gastric mucosal biopsies carry the highest yield for positive identification of EGE, however, biopsy of the colon is often diagnostic.8,14 The protein-sensitive form of EGE responds well to dietary elimination of food proteins.5,15 Milk proteins are often the offending agent and can be substituted with hypoallergenic or elemental formulas during the period of exclusion. Milk may be tolerated at a future time without recurrence of the disease. The idiopathic form of EGE often has a chronic relapsing course.8,12,16 Ketotifen and oral sodium cromoglycate have been used in some patients with EGE and found to possibly be of therapeutic value as steroidsparing agents.14,17,18 Montelukast, a leukotriene antagonist, has been recently reported to be of value in one adolescent female with the idiopathic type of this disease.19 Further research will be needed to determine whether this medication is of value for this dis-
351
order; however, idiopathic EGE is clearly a steroid responsive disease and this remains the primary treatment for this form of the disease. FINAL DIAGNOSIS Eosinophilic gastroenteritis. REFERENCES 1. Kaijser R. Zur kenntnis der allergischen affektionen des verdaungskanal vom standpunkt des chirurgen aus. Arch Klin Chir 1937;188:36 – 64. 2. Naylor AR. Eosinophilic gastroenteritis. Scottish Med J 1990;35:163–165. 3. Waldmann TA, Wochner RD, Laster L, Gordon RS. Allergic gastroenteropathy: a cause of excessive gastrointestinal protein loss. N Engl J Med 1967;276: 761–769. 4. Katz AJ, Twarog FJ. Zeiger RS, Falchuk ZM. Milk-sensitive and eosinophilic gastroenteropathy: similar clinical features with contrasting mechanisms and clinical course. J Allergy Clin Immunol. 1984;74:72–78. 5. Proujansky R. Eosinophilic gastroenteritis. In: Wyllie R, Hyams JS, eds. Pediatric gastrointestinal disease: pathophysiology, diagnosis, management. Philadelphia: WB Saunders, 1993:566 –572.
6. Ureles AL, Alschibaja T, Lodico D, Stabins SJ. Idiopathic eosinophilic gastrointestinal tract, diffuse and circumscribed. Am J Med 1961;30: 899 –909. 7. Klein NC, Hargrove RL, Sleisenger MH, Jeffries GH. Eosinophilic gastroenteritis. Medicine 1970;49:299 –319. 8. 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. 9. Weisberg SC, Crosson JT. Eosinophilic gastroenteritis, a report of a case of 32 years duration. Dig Dis Sci 1973; 18:1005–1014. 10. Caldwell JH, Tennenbaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. N Engl J Med. 1975; 292:1388 –1390. 11. Leinbach GE, Rubin CE. Eosinophilic gastroenteritis: a simple reaction to food allergens? Gastroenterology 1970;59:874 – 889. 12. Steffen RM, Wyllie R, Petras RE, et al. The spectrum of eosinophilic gastroenteritis: Report of six pediatric cases and review of the literature. Clin Pediatr 1991;30:404 – 411. 13. Teele RL, Katz AJ, Goldman H, Kettell RM. Radiographic features of eosinophilic gastroenteritis (allergic gas-
14.
15. 16.
17.
18.
19.
troenteropathy) of childhood. Am J Rad 1979;132:575–580 Katz AJ, Goldman H, Grand RD. Gastric mucosal biopsy in eosinophilic (allergic) gastroenteritis. Gastroenterology 1977;73:705–709. Moon A, Kleinman RE. Allergic gastroenteropathy in children. Ann Allergy Asthma Immunol 1995;74:5–12. Whitington PF, Whitington GL. Eosinophilic gastroenteropathy in childhood. J Pediatr Gastroenterol Nutr 1988;7:379 –385. Melamed I, Feanny S, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310 –314. Moots RD, Prouse P, Gumpel JM. Near fatal eosinophilic gastroenteritis responding to oral sodium cromoglycate. Gut 1988;29:1282–1285. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast. [Letter]. J Allergy Clin Immunol 1999;104:506.
Request reprint should be addressed to: Nevin W Wilson, MD Section of Pediatric Allergy & Immunology Department of Pediatrics West Virginia University School of Medicine Morgantown, WV 26 506-9214
Answers to CME examination—Annals of Allergy, Asthma, & Immunology (Identification N 2000-010) Moraes PSA and EA Taketomi: Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000;85:253–267. 1. d 6. b 11. c 16. b 2. b 7. e 12. a 17. c 3. c 8. d 13. c 18. a 4. a 9. b 14. b 19. b 5. e 10. a 15. c 20. d
352
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
Failure to thrive and two weeks of persistent vomiting in an 11-month-old infant Kumaravel Rajakumar, MD*; Mary Beth Hogan, MD†; and Nevin W Wilson, MD†
CHIEF COMPLAINT An 11-month-old male infant of Asian origin with failure to thrive was evaluated by his pediatrician for persistent vomiting of 2 weeks duration. HISTORY OF PRESENT ILLNESS This infant presented with a 2-week history of vomiting. Initially, the episodes of vomiting were infrequent and appeared to the parents to be possibly self-induced. They were often associated with tantrums. After 1 week, the episodes of emesis gradually became more frequent and copious. At the time of the initial evaluation, the vomiting was occurring about 4 to 5 times a day. There was no particular time of day or activity in which the vomiting occurred more frequently. There was no relationship with meals. The parents noted a gradual failure to gain weight over the previous 5 months. There was no associated history of fever, diarrhea, or constipation. His activity level was unchanged and he was developmentally appropriate for his age. There was no history of travel or exposure to any pets. He was on no medications. PAST MEDICAL HISTORY He was a 3.2 kg. term infant born after a non-complicated pregnancy, labor, Department of Pediatrics, Sections of General Pediatrics* and Pediatric Allergy and Immunology† West Virginia University, School of Medicine Morgantown, West Virginia. Received for publication December 6, 1999. Accepted for publication in revised form May 8, 2000.
VOLUME 85, NOVEMBER, 2000
and delivery. At 5 months of age he developed scaly, erythematous macular, papular rash on his face and arms which was consistent with atopic dermatitis. This was successfully treated with topical emollients and steroids. FAMILY HISTORY There were no siblings. The parents were non-consanguineous. There was a family history of allergy. There was no family history of inherited metabolic disorders or immunologic problems. DIETARY HISTORY He was initially breastfed and no dietary restrictions were practiced by the mother. He was weaned at 4 months of age, switched to cow milk-based formula and was now ingesting infant cereals, jarred fruits, and vegetables. PHYSICAL EXAMINATION On examination he was afebrile and vital signs were appropriate for age. He appeared non-toxic and well hydrated. He was strikingly thin in appearance. His growth measurements were: weight 7.5 kg. (⬍ 5th percentile), height 72.5 cm. (10th percentile), and head circumference 45 cm. (10th percentile). His head was normocephalic and atraumatic. Pupils were equal round and reactive to light. Conjunctiva were clear. Extraocular movements were intact. Nasal passages and the oral cavity were normal. Neck was supple. Lungs were clear. Heart rate was regular without murmurs. Abdomen was soft, bowel sounds were present and there was no organomegaly or masses. No ascites was
noted. Skin was without lesions. Extremities were without clubbing, cyanosis or edema. His neurologic exam was normal. INITIAL LABORATORY DATA A complete blood count (CBC) showed a white blood cell (WBC) count of 23,900/cubic millimeter with 15% neutrophils, 71% lymphocytes, 7% monocytes, and 7% eosinophils. His absolute eosinophil count was 1673/mm3. The hemoglobin was 13.9 g/dL. The serum electrolytes, blood urea nitrogen, and creatinine were normal. QUESTIONS Based on the initial history, physical exam and laboratory data, which of the following diagnoses might be consistent with progressively worsening vomiting and failure to thrive in an 11-month-old male infant? a. Urinary tract infection. b. Increased intracranial pressure with or without a space occupying lesion in the brain. c. Non-organic failure to thrive d. Eosinophilic gastroenteritis. e. Intestinal obstruction f. Gastroesophageal reflux. g. Inflammatory bowel disease. h. Hepatitis. i. Celiac Sprue j. Peptic ulcer disease. k. Diabetes Mellitus. l. Thyroid disease m. Metabolic disorders ADDITIONAL STUDIES AND INITIAL TREATMENT A computerized tomogram (CT scan) of the head was normal with no masses
349
or space occupying lesions. A barium swallow with small-bowel follow through showed mild gastroesophageal reflux but no intestinal obstruction or malrotation. A urine specimen obtained by straight catheterization revealed 5 to 10 WBC/high power field and grew greater than 100,000 colonies of non-hemolytic Streptococci. He was diagnosed with a urinary tract infection and was treated with cefixime. After the third dose he developed swelling of the lips consistent with angioedema but with no associated bronchospasm or urticaria. The cefixime was discontinued and he was switched to amoxicillin. The lip swelling persisted on amoxicillin and he was then switched to co-trimoxazole. FURTHER EVALUATION The vomiting persisted despite completing treatment for the urinary tract infection. A voiding cystourethrogram revealed grade 1 vesico-ureteric reflux on the left side. Further laboratory evaluation was initiated when no weight gain was noted at the 2-week follow-up visit. ADDITIONAL LABORATORY DATA Glucose, serum amylase, lactic acid, ammonia, and liver function tests were normal. Renal ultrasound was normal. A repeat CBC showed a WBC of 17,900/mm3 with 15% neutrophils, 59% lymphocytes, 24% eosinophils, and 2% monocytes. The absolute eosinophil count was now 4296/mm3. The hemoglobin was 13 g/dL. Stool exam for ova and parasites, occult blood, fat globules, and eosinophils were negative. FURTHER QUESTIONS With the persistence of the vomiting, normal metabolic laboratory tests, normal stool exam and the increased eosinophilia, what would you do next? a. pH probe b. Food allergy skin tests c. Endoscopy d. Hospital admission to observe feeding and follow weight gain e. NBT test
350
Endoscopic examination revealed the distal esophagus to be nodular. The gastric, duodenal, rectal and sigmoid mucosa appeared normal. There were no granulomas consistent with chronic granulomatous disease. The biopsy specimens obtained from the esophagus, gastric antrum, and recto-sigmoid areas showed marked eosinophilic infiltration consistent with the polyenteric form of eosinophilic gastroenteritis. These infiltrates were predominately in the mucosal layer. A serum IgE level was significantly elevated at 562 U/mL. Radioallergosorbant tests (RAST) obtained by the gastroenterologist were positive for egg white, milk, wheat, barley, oat, rice, soy, rye, corn, and casein. Subsequent food skin testing using the prick puncture technique confirmed positive reactions to milk, eggs, soy, wheat, and corn. He was started on oral prednisone. To gain immediate control of his symptoms, an extensive food elimination diet was initiated. The vomiting resolved and he started to gain weight. He was gradually tapered off of the oral steroids and he has continued to thrive on a milk-free and eggfree diet. The reintroduction of wheat and corn was unremarkable, however an attempt at reintroducing soy led to immediate vomiting and eosinophilia. DISCUSSION Eosinophilic gastroenteritis (EGE) is a rare gastrointestinal inflammatory disorder of unknown etiology. It is characterized by an eosinophilic inflammatory infiltrate in the gastrointestinal tract associated with gastrointestinal symptoms consisting of nausea, vomiting, diarrhea, abdominal pain, and failure to thrive. Protein losing enteropathy, intestinal blood loss, ascites, abdominal obstruction, and abdominal distention may also occur. Eosinophilic gastroenteritis was first reported in the medical literature by Kaijser in 1937.1 Eosinophilic gastroenteritis can affect all ages and races and is not an exclusively human disease.2 Pediatric EGE can be classified as idiopathic or protein-sensitive. Waldman et al described six patients (6
months to 14 years) with protein losing enteropathy, presenting as a syndrome of edema, anemia, hypoalbuminemia, eosinophilia, and growth failure.3 Four of the six patients had a personal or family history of allergy. Three of the six patients had significant amelioration of their clinical symptoms and resolution of their hypoalbuminemia on exclusion of milk proteins from the diet. Re-introduction of milk caused recurrence of the symptoms, the return of eosinophilia and their protein losing enteropathy. Katz et al4 described 12 children (1 month to 20 years) with gastrointestinal symptoms, protein losing enteropathy, blood and tissue eosinophilia. The patients in this study could be categorized in to two equal groups, namely the milk-sensitive EGE and the idiopathic EGE. The milk or proteinsensitive EGE group was composed of younger infants (mean age, 5 months ⫾ 3.9 months) with food allergies. Symptoms resolved after milk elimination. This form of the disease often resolved spontaneously over time. Protein-sensitive EGE occurred more frequently than the idiopathic form of the disease in both studies. Idiopathic EGE is a chronic, relapsing disorder, which may occur at any age, but most often the affects older children.4,5 In Katz’s study, the idiopathic EGE group had a mean age of 4 years (⫾3.3 years) and had chronic symptoms associated with failing to thrive. This group had a family history of allergy in nearly 50% of the cases or had other atopic diseases. Despite evidence of allergy as a predisposing factor, none of these children improved after dietary manipulation. Idiopathic EGE was responsive to corticosteroids in most cases. Eosinophilic gastroenteritis may also be classified as either diffuse or circumscribed granulomatous, defined by the extent of the eosinophilic infiltrate in the gastrointestinal tract seen at biopsy.6,7 Diffuse EGE can be further classified as polyenteric, monoenteric or regional. The polyenteric form of the disease involves the gastric antrum and variable parts of the small bowel,
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
and may have an extensive eosinophilic inflammatory infiltrate up to the serosa. The monoenteric form is present in the pylorus and extends in a retrograde fashion toward the rest of the stomach. The regional form affects either the stomach (pyloric or pre-pyloric) or an isolated segment of the small bowel. The eosinophilic inflammation in the regional type is often restricted to the submucosa. Pyloric obstruction occurred in all polyenteric and monoenteric patients described by Ureles et al.6 Klein et al7 described three patterns of clinical presentations in EGE based on the depth of maximum disease process: mucosal, muscular and serosal. The mucosal form of the disease is the most commonly encountered and presents as a malabsorption syndrome. The typical features of the malabsorption syndrome are diarrhea, weight loss, protein-losing enteropathy, and failure to thrive. Anemia due to occult blood in the stools may occur. Edema and hypoalbuminemia are features often associated with the protein-losing enteropathy. Presentation with bloody diarrhea is occasionally noted if there is colonic mucosal involvement. The muscular form of the disease leads to gastric outlet obstruction, the typical symptoms of which are anorexia, abdominal pain and vomiting. The serosal form of the disease is rare and is characterized by eosinophilic ascites. Naylor’s retrospective review of 220 cases of EGE from the preexisting medical literature is one of the largest descriptive case series of EGE.2 In that series the gastrointestinal involvement was monoenteric in 64% and polyenteric in 15%. The stomach was the most frequently involved site. The gastric antrum was universally affected if stomach was involved. Abdominal pain, vomiting, diarrhea and weight loss were the most frequently noted symptoms. Goldman and Proujansky8 also noted a similar constellation of symptoms in their pediatric case series. The duration of symptoms prior to diagnosis was less than 4 weeks in 33% of the children. Twenty-five percent had symptoms for greater than 5 years
VOLUME 85, NOVEMBER, 2000
prior to the diagnosis. A few patients have gone remarkably long periods of time with symptoms before a correct diagnosis was made.9 One patient was described as having symptoms for 32 years and required 38 hospitalizations before the diagnosis of EGE was finally made. In Naylor’s series there was a history of allergies in 52%, aggravation of symptoms with ingestion of certain foods in 8% and peripheral eosinophilia in 80% of patients.2 The exact etiology of EGE is unknown.2 The frequent history of atopic diseases, aggravation of symptoms with certain foods (especially milk) and rapid endoscopic and histologic changes with dietary challenge suggest an allergic and immunologic basis for EGE.2,10 The tissue and blood eosinophilia, correlation with IgE levels, skin and RAST positivity, and response to steroid therapy further imply an allergic etiology. The absence of allergies in 50% of patients, lack of peripheral eosinophilia in 20% of patients, and lack of response to dietary manipulation in 70% of patients, however, argue against an allergic etiology in many patients.2,11 As in asthma and atopic dermatitis, EGE appears to have two clinically distinguishable subtypes. One subtype reflects an IgE-mediated allergy and the other subtype has a currently unidentified mechanism which is responsible. The differential diagnosis of failure to thrive and vomiting is extensive and includes gastroesophageal reflux, infectious agents, intracranial processes, intestinal obstruction, pyschosocial failure to thrive, as well as a variety of metabolic and endocrine disorders. The initial diagnosis of a urinary tract infection as the cause of our patient’s symptoms was reasonable. When his symptoms of failure to thrive and vomiting did not resolve, however, other etiologies were considered. Other immunologic disorders that are associated with these symptoms would include inflammatory bowel disease, celiac sprue, and granulomatous obstruction of the duodenum caused by chronic granulomatous disease.
The diagnosis of eosinophilic gastroenteritis requires a high index of clinical suspicion. The diagnosis should be entertained in any patient with gastrointestinal symptoms and eosinophilia. Without question, the diagnosis of EGE is certainly more challenging in the absence of peripheral eosinophilia.12 Supportive evidence for EGE includes gastrointestinal blood loss suggested by guaiac positive stools. A positive d-xylose absorption test or hypoalbuminemia may indicate a protein-losing enteropathy and lead to this diagnosis.5 Gastrointestinal contrast studies tend to be non-specific but can rule out obstruction and be suggestive of EGE.13 An elevated serum IgE in this clinical situation may also suggest the diagnosis. Evidence of food sensitization by skin testing or RAST is also useful in the management and diagnosis of the protein-sensitive form of the disease. Patients with markedly elevated IgE levels may have positive tests to foods that are not clinically relevant. Documenting the eosinophilic inflammatory infiltrate of the affected gastrointestinal tract by endoscopic biopsy remains the gold standard test in the diagnosis of EGE. Gastric mucosal biopsies carry the highest yield for positive identification of EGE, however, biopsy of the colon is often diagnostic.8,14 The protein-sensitive form of EGE responds well to dietary elimination of food proteins.5,15 Milk proteins are often the offending agent and can be substituted with hypoallergenic or elemental formulas during the period of exclusion. Milk may be tolerated at a future time without recurrence of the disease. The idiopathic form of EGE often has a chronic relapsing course.8,12,16 Ketotifen and oral sodium cromoglycate have been used in some patients with EGE and found to possibly be of therapeutic value as steroidsparing agents.14,17,18 Montelukast, a leukotriene antagonist, has been recently reported to be of value in one adolescent female with the idiopathic type of this disease.19 Further research will be needed to determine whether this medication is of value for this dis-
351
order; however, idiopathic EGE is clearly a steroid responsive disease and this remains the primary treatment for this form of the disease. FINAL DIAGNOSIS Eosinophilic gastroenteritis. REFERENCES 1. Kaijser R. Zur kenntnis der allergischen affektionen des verdaungskanal vom standpunkt des chirurgen aus. Arch Klin Chir 1937;188:36 – 64. 2. Naylor AR. Eosinophilic gastroenteritis. Scottish Med J 1990;35:163–165. 3. Waldmann TA, Wochner RD, Laster L, Gordon RS. Allergic gastroenteropathy: a cause of excessive gastrointestinal protein loss. N Engl J Med 1967;276: 761–769. 4. Katz AJ, Twarog FJ. Zeiger RS, Falchuk ZM. Milk-sensitive and eosinophilic gastroenteropathy: similar clinical features with contrasting mechanisms and clinical course. J Allergy Clin Immunol. 1984;74:72–78. 5. Proujansky R. Eosinophilic gastroenteritis. In: Wyllie R, Hyams JS, eds. Pediatric gastrointestinal disease: pathophysiology, diagnosis, management. Philadelphia: WB Saunders, 1993:566 –572.
6. Ureles AL, Alschibaja T, Lodico D, Stabins SJ. Idiopathic eosinophilic gastrointestinal tract, diffuse and circumscribed. Am J Med 1961;30: 899 –909. 7. Klein NC, Hargrove RL, Sleisenger MH, Jeffries GH. Eosinophilic gastroenteritis. Medicine 1970;49:299 –319. 8. 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. 9. Weisberg SC, Crosson JT. Eosinophilic gastroenteritis, a report of a case of 32 years duration. Dig Dis Sci 1973; 18:1005–1014. 10. Caldwell JH, Tennenbaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. N Engl J Med. 1975; 292:1388 –1390. 11. Leinbach GE, Rubin CE. Eosinophilic gastroenteritis: a simple reaction to food allergens? Gastroenterology 1970;59:874 – 889. 12. Steffen RM, Wyllie R, Petras RE, et al. The spectrum of eosinophilic gastroenteritis: Report of six pediatric cases and review of the literature. Clin Pediatr 1991;30:404 – 411. 13. Teele RL, Katz AJ, Goldman H, Kettell RM. Radiographic features of eosinophilic gastroenteritis (allergic gas-
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troenteropathy) of childhood. Am J Rad 1979;132:575–580 Katz AJ, Goldman H, Grand RD. Gastric mucosal biopsy in eosinophilic (allergic) gastroenteritis. Gastroenterology 1977;73:705–709. Moon A, Kleinman RE. Allergic gastroenteropathy in children. Ann Allergy Asthma Immunol 1995;74:5–12. Whitington PF, Whitington GL. Eosinophilic gastroenteropathy in childhood. J Pediatr Gastroenterol Nutr 1988;7:379 –385. Melamed I, Feanny S, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310 –314. Moots RD, Prouse P, Gumpel JM. Near fatal eosinophilic gastroenteritis responding to oral sodium cromoglycate. Gut 1988;29:1282–1285. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast. [Letter]. J Allergy Clin Immunol 1999;104:506.
Request reprint should be addressed to: Nevin W Wilson, MD Section of Pediatric Allergy & Immunology Department of Pediatrics West Virginia University School of Medicine Morgantown, WV 26 506-9214
Answers to CME examination—Annals of Allergy, Asthma, & Immunology (Identification N 2000-010) Moraes PSA and EA Taketomi: Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000;85:253–267. 1. d 6. b 11. c 16. b 2. b 7. e 12. a 17. c 3. c 8. d 13. c 18. a 4. a 9. b 14. b 19. b 5. e 10. a 15. c 20. d
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