Benefit of Ketotifen in Patients with Eosinophilic Gastroenteritis ISAAC MELAMED, M.D., STEPHEN J. FEANNY, M.D., F.R.C.P., PHILIP
M. SHERMAN,
M.D., F.R.C.P.,
CHAIM M. ROIFMAN, M.D., Toronto, Ontario, Canada
PURPOSE: Eosinophilic gastroenteritis (EG) is a rare condition of unknown etiology characterized by vomiting, diarrhea, protein-losing enteropathy, a n d e o s i n o p h i l l c inf'fltration of the gastrointestinal mucosa. The potential association of EG with allergy and related mAlt-cell release of mediators led us to evaluate the ability of an antihi~tnmlne drug to modify the course of the disease. PATIENTS AND METHODS: Six patients with protracted gastrointestinal symptoms were diagnosed with EG because of histologic evidence of predominantly eosinophilic inf'fltrates in the gastrointestinni mucosa. Each patient was treated in an open trial for 12 months with ketotifen (Zaditen), an antihistamine of the HI class that is known to stabiliT~ ma.qt cells. , RESULTS:All six patients improved clinically;, four also gained weight. Total serum IgE levels decreased after 4 to 6 months of therapy. Clear° ing of eosinophilic inf'fltrates was documented in t h e four patients w h o u n d e r w e n t f o l l o w - u p m u c o s a l biopsies. CONCLUSION: W e c o n c l u d e that ketotifen treatment represents a safe and effective alternative to traditional systemic corticosteroid therapy for t r e a t m e n t o f EG.
From the Divisionsof Immunology/Allergy(IM, SJF,CMR) and Gastroenterology (PMS), Department of Pediatrics,The Hospitalfor Sick Children, Toronto, Ontario, Canada. This study was supported by the Leah Reichmann Immunodeticiency Fund, Toronto, Ontario, Canada. Requestsfor reprints shouldbe addressedto Chaim M. Roifman, M.D., Division of Immunology/Allergy,The Hospitalfor SickChildren, 555 University Avenue,Toronto, Ontario, CanadaM5G 1X8. Manuscript submitted June 19, 1990, and accepted in revised form November 19, 1990.
310
March 1991
E
osinophilic gastroenteritis (EG) is a chronic, recurrent disease of the gastrointestinal tract that is characterized by abdominal pain, nausea, vomiting, and diarrhea [1-4]. Other reported clinical manifestations include weight loss, anemia, melena, protein-losing enteropathy, esophagitis, and intestinal perforation [5-8]. Histologic evidence of a predominant eosinophilic infiltration of gastrointestinal mucosa in the absence of parasitic infection or extraintestinal disease confirms a diagnosis of EG [9]. EG has been classified into three forms [10]: mucosal, which generally acts like other inflammatory disorders of the bowel; submucosal, which may cause bowel obstructions; and serosal, which produces eosinophflic peritonitis. Various mucosal sites from the esophagus to the rectum may be involved and results in presenting symptoms and signs that range from mild abdominal discomfort to acute intestinal obstruction [11-13]. Although the primary cause of EG remains unknown, previously reported associations with allergy, allergic rhinitis, atopic dermatitis, and elevated IgE levels suggest an atopic predisposition in the pathogenesis of this disorder [14,15]. Other evidence suggests that mast cell degranulation plays a significant role [16]. One of the drugs that might modulate the release of mast cell mediators is ketotifen (Zaditen; Sandoz Pharmaceuticals, Basel, Switzerland), which has a histamine (H1) antagonist effect. Early studies with ketotifen, both in vivo and in vitro, demonstrated its capacity to inhibit the secretion of mast cell mediators such as histamine [17]. These mast cell products may contribute to the inflammation of intestinal tissue that is characteristic of EG [18]. On the basis of such findings, we initiated an open clinical trial to assess the efficacy of ketotifen therapy in the treatment of patients with histologically confirmed EG:
PATIENTS AND METHODS Six patients, four females and two males, ranging in age from 8 to 30 years (mean age, 16.9 years) were studied prospectively following histologic confir-
The American Journal of Medicine Volume 90
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL
mation of eosinophilic infiltrates confined to the gastrointestinal tract. Three of the six patients were previously (8 months to 5 years prior to study) treated with corticosteroids. Despite initial symptomatic relief, steroids were discontinued because of severe side effects (two patients) or frequent relapses (one patient). Laboratory studies included complete blood cell count and differential, erythrocyte sedimentation rate, eosinophil count, iron studies (serum ferritin, serum iron, total iron-binding capacity), serum glutamic-oxaloacetic transaminase, serum glutamatepyruvate transaminase, alkaline phosphatase, bilirubin, serum immunoglobulins, al-antitrypsin, C3, C4, total hemolytic complement (CHs0), antinuclear f a c t o r , p r o t e i n e l e c t r o p h o r e s i s , and immunoelectrophoresis. We screened each patient for atopy by measuring the total serum IgE with a radioallergosorbent test assay and modified prick test (Pharn~acia Phadebas Systems, Pharmacia, Montreal). In this skin test, we used 17 common allergens including three molds (Alternaria, Hormodendrum, and Aspergillus mix, OMEGA Laboratories, Montreal), egg, milk, wheat, house dust, mites, cat, dog, horse, grass mix, tree mix, and ragweed. Multiple stool samples were examined for the presence of occult blood and to exclude known intestinal parasites. As part of the initial clinical evaluation, upper and lower fiberoptic endoscopies were performed on all patients. During endoscopy, multiple biopsy s p e c i m e n s were o b t a i n e d for histologic examination. The six patients were treated with a dose of ketotifen between 2 and 4 mg daily for a period of 12 months. All patients were followed at 2- to 3-month intervals. At each assessment, their symptoms were reviewed and blood samples for total serum IgE, complete blood cell count, differential white blood cell count, and erythrocyte sedimentation rate were obtained. Each patient underwent a complete physical examination, and in four, endoscopic examinations with biopsies and histologic examination of the specimens were repeated.
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RESULTS All six patients in this study had abdominal pain. Additional clinical symptoms included persistent diarrhea (three patients), weight loss (four), and vomiting (one) due to partial gastric-outlet obstruction. The duration of symptoms prior to the use of ketotifen ranged from 2 months to 12 years (mean, 32.5 months). All patients had evidence of a peripheral eosinophilia (absolute counts ranging from 0.75
Before
After
Figure 1. A, effect of ketotifen treatment on weight (kg) in six patients over 12 months of treatment. B, effect of ketotifen treatment on the number of peripheral eosinophils in six patients. C, effect of ketotifen treatment on IgE levels in six patients over 12 months of treatment.
March 1991 The American Journal of Medicine Volume 90
311
KETOTIFENTREATMENTFOR EOSINOPHILICGASTROENTERITIS/ MELAMEDET AL
Figure 2. Left, the gastric mucosa is infiltrated by eosinophils focally clustered in the lamina propria (original magnification x50, reduced by 35%). Right, the gastric mucosa appears normal with only an occasional eosinophil in the lamina propria (original magnification X50, reduced by 35%).
to 1.20 × 103/L). Each of the six patients had a history of allergic rhinitis, but none had a positive history of food allergy, and only one patient had demonstrable IgE antibodies to any of the food-test antigens (a mild response to egg on modified prickskin test). Four of the six patients tested positive for occult blood, two of whom had evidence of a significant iron-deficiency anemia. Only one patient in our series had hypoalbuminemia that suggested significant protein-losing enteropathy. In all subjects, the presence of an eosinophilic infiltrate was confirmed by histologic examination of biopsy specimens of the gastrointestinal tract. Biopsies indicated predominantly proximal bowel involvement (stomach and duodenum) in three patients and predominantly distal colonic involvement in the other three cases. The results of all laboratory tests performed to exclude diagnoses other than EG were normal. Within 1 to 4 months of ketotifen therapy administered at a dose of 2.to 4 rag/day, all six patients reported symptomatic improvement including the
312
resolution of diarrhea, severe abdominal pain, and vomiting. Amelioration of symptoms coincided with a dramatic weight gain within 4 months of starting therapy (Figure 1A). In addition, in four of the six patients, total serum IgE levels decreased after 4 to 6 months of therapy (Figure 1B). The peripheral eosinophil count decreased in all six patients (Figure 1C). Clearing of eosinophilic infilt r a t e , was observed after treatment with ketotifen for 4 to 6 months of therapy (Figure 2) in the follow-up mucosal specimens of all four patients in whom repeat endoscopy and biopsy were performed. The resolution of symptoms was sustained in all patients for the study period of 12 months.
COMMENTS Although the pathogenesis of EG is not fully understood, an allergic mechanism appears to play a significant role in the disease. An excessive accumulation of eosinophils may cause the characteristic destruction of intestinal epithelium [19]. The principal pre-formed products released after the de-
March 1991 The American Journal of Medicine Volume 90
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL
granulation of eosinophils, including major basic protein, eosinophilic cationic protein, and eosinophilic peroxidase, may prove relevant in the pathogenesis of gastrointestinal inflammation [20,21]. Since each of the eosinophil granule proteins are potent toxins that are cytotoxic to eukaryotic cells in vitro, eosinophils are likely major effector cells mediating mucosal inflammation in EG [22]. Mast cell degranulation is also involved in mucosal injury [23]. The vasoactive substances, proteases, and pro-inflammatory mediators that are released after the activation of mucosal mast cells and the release of chemoattractants such as eosinophilic chemotactic factor of anaphylaxis (ECF-A) increase vascular permeability. To modulate the allergic mechanisms that lead to gastrointestinal inflammation, various treatment regimens have been employed. Corticosteroids have been the mainstay of therapy with generally good s y m p t o m a t i c responses [24]. However, steroid treatment is associated with a high percentage of relapses and significant side effects [25]. Trial elimination diets have occasionally been successful, but relapse is also common [26]. The value of oral sodium chromoglycate remains controversial [27]. In general, however, the results of treatment with this agent have not been impressive [27]. Because the goal of our treatment for EG was to modulate the release of inflammatory mediators such as ECF-A by mast cell degranulation, we chose ketotifen, an HI class of antihistamine that stabilizes mast cells and possibly impairs eosinophil migration to target organs [17]. The therapeutic efficacy of ketotifen in the treatment of EG likely also includes its ability to inhibit both histamine release and leukotriene production [28]. Ketotifen also stabilizes the mast cell membrane and prevents increases in vascular permeability caused by both chemical and immunologic stimuli. An ability to reduce calcium influx may play a key role in its ability to inhibit the action of inflammatory mediators. The striking symptomatic improvement, subsequent weight gain, and histologic evidence of eosinophilic clearing in repeat biopsies performed on our patients are all suggestive of the beneficial effect of ketotifen. Equally important was the significant lack of adverse side effects, apart from transient drowsiness, during therapy with ketotifen. The paucity of cases of EG greatly limits the ability to conduct double-blind, placebo-controlled studies that could delineate clearly the efficacy of new therapeutic agents for use in patients with EG. In the absence of a control group in our study, factors influencing the response of our patients to a placebo
effect or the variable history of the disease cannot be ruled out absolutely. We conclude that the therapeutic effect of ketotifen treatment in our patients demonstrates a safe and effective alternative to traditional systemic corticosteroid therapy for EG.
ACKNOWLEDGMENT We thank Dr. C. Cullinane and Mike Starr from the Department of Pathology for preparation of the pathologic materials and Sharon Nancekivell and Denise Purcell for editorial and secretarial assistance.
REFERENCES 1. Trounce JQ, Tanner MS. Eosinophilic gastroenteritis. Arch Dis Child 1985; 60: 1186-8.
2. Johnstone JM. Morson 8C. Eosinophilic gastroenteritis. Histopathology 1978; 2: 335--48. 3. Cello JP. Eosinophilic gastroenteritis--a complex disease entity. Am J Med 1979; 67: ]097-1104. 4. Whitington PF, Whitington GL. Eosinophilic gastroenteropathy in childhood. J Pediatr Gastroenterol Nutr 1988; 7: 379-85. 5. Felt-Bersma RJ. Meuwissen SG, van Velzu D. Perforation of the small intestine due to eosinophilic 8astroenteritis. Am J Gastroenterol 1984; 79: 442-5. 6. Greenberger NJ, Tennenbaum JI, Ruppert RD. Protein-losing enteropathy associated with gastrointestinal allergy. Am J Med 1967; 43: 777-84. 7. Haberkern CM. Christie DL, Haas JE. Eosinophilic gastroenteritis presenting as ileocolitis. Gastroenterology 1978: 74: 896-9. 8. Kuipers FC, van Thiel PH, Rodenberg W, Wielinga WJ. Roskam RT. Eosinophilic phlegmon of the alimentary tract caused by a worm. Lancet ] 960: 2:117 ]-3. 9. Blackshaw AJ, Levison DA. Eosinophilic infiltrates of the gastrointestinal tract. J Clin Pathol 1986; 39: 1-7. 10. Klein NC, Hargrove RL; Sleisenger MH. Jeffries GH. Eosinophilic gastroenteritis. Medicine (Baltimore) 1970: 49: 299-319. 11. Zora JA, O'Connell EJ, Sachs MI, Hoffman AD. Eosinophilic gastroenteritis: a case report and review of the literature. Ann Allergy 1984; 53: 45-7. 12. Steele RJ, Wright RG, Gilmore HM Eosinophilic gastroenteritis presenting as acute intestinal obstruction. Scott Med J 1983; 28: 183-4. 13. Caldwell JH, Mekhjian H8, Hurtubise PE, Beman FM. Eosinophylic gastroenteritis with obstruction. Immunological studies of seven patients. Gastroenterology 1978; 74: 825-8. 14. Metcalfe DD. Food hypersensitivity. J Allergy Clin Immuno11984; 73: 74962. 15. Caldwell JH, Tennebaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. Response to intestinal challenge in two cases. N Engl J Med 1975; 292: 1388-90. 16. Lee TDG, Swieter M, 8efus D. Mast cells, eosinophils and gastrointestinal hypersensitivity. Immunol Allergy Clin 1988; 8: 469-83. 17. MacDonald GF. An overview of ketotifen. Chest 1982; 82 (Suppl 1): 30S32S. 18. Lee TD, Swieter M, Bienenstock J. Befus AD. Heterogeneity in mast cell populations. Clin Immunol Rev 1985; 4: ]43-99. 19. Keshavarzian A, Saverymuttu SH, Tai P-C, et aL Activated eosinophils in familial eosinophilic gastroenteritis. Gastroenterology 1985; 88: 1041-9. 20. Capron M, Khalife J, Gleich GJ, et aL Mediators released after activation of human eosinophils [Abstract]. In: Proceedings of the 17th Symposium of the College of International Allergists, 1987: 5A. 21. Gleich GJ, Adolphson CR. The eosinophil leukocyte: structure and function. Adv Immunol 1986; 39: 177-253. 22. Kay AB. Eosinophils as effector cells in immunity and hypersensitivity disorders. Clin Exp Immunol 1985; 62: 1-12. 23. Befus AD, Dyck N, Goodacre R, Bienenstock J. Mast cells from human intestinal lamina propria. Isolation, histochemical subtypes, and functional char-
March 1991
The American Journal of Medicine Volume 90
313
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL acterization. J Immunol 1987: 138: 2604-10. 24. Robert F, Omura E, Durant JR. Mucosal eosinophilic gastroenteritis with systemic involvement. Am J Med 1977; 62: 139-43. 25. Greenberger N. Allergic disorder of the intestine and eosinophilic gastroenteritis. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease, 3rd ed. Philadelphia: WB Saunders, 1983: 1069-76. 26. Leinbach GE, Rubin CE. Eosinophilic gastroenteritis: a simple reaction to
314
food allergens? Gastroenterology 1970: 59: 874-89. 27. Heatley RV, Harris A, Atkinson M. Treatment of a patient with clinical features of both eosinophilic gastroenteritis and polyarteritis nodosa with oral sodium cromoglycate. Dig Dis Sci 1980: 25: 470-2. 28. Martin U, Greenwood C, Crops L, Ba88iolini M. Ketotifen. In: Goldberg ME, ed. Pharmacological and biochemical properties of drug substances. Vol 3. Washington: Academy of Pharmaceutical Sciences, 1981: 424.
March 1991 The American Journal of Medicine Volume 90
M. SHERMAN,
M.D., F.R.C.P.,
CHAIM M. ROIFMAN, M.D., Toronto, Ontario, Canada
PURPOSE: Eosinophilic gastroenteritis (EG) is a rare condition of unknown etiology characterized by vomiting, diarrhea, protein-losing enteropathy, a n d e o s i n o p h i l l c inf'fltration of the gastrointestinal mucosa. The potential association of EG with allergy and related mAlt-cell release of mediators led us to evaluate the ability of an antihi~tnmlne drug to modify the course of the disease. PATIENTS AND METHODS: Six patients with protracted gastrointestinal symptoms were diagnosed with EG because of histologic evidence of predominantly eosinophilic inf'fltrates in the gastrointestinni mucosa. Each patient was treated in an open trial for 12 months with ketotifen (Zaditen), an antihistamine of the HI class that is known to stabiliT~ ma.qt cells. , RESULTS:All six patients improved clinically;, four also gained weight. Total serum IgE levels decreased after 4 to 6 months of therapy. Clear° ing of eosinophilic inf'fltrates was documented in t h e four patients w h o u n d e r w e n t f o l l o w - u p m u c o s a l biopsies. CONCLUSION: W e c o n c l u d e that ketotifen treatment represents a safe and effective alternative to traditional systemic corticosteroid therapy for t r e a t m e n t o f EG.
From the Divisionsof Immunology/Allergy(IM, SJF,CMR) and Gastroenterology (PMS), Department of Pediatrics,The Hospitalfor Sick Children, Toronto, Ontario, Canada. This study was supported by the Leah Reichmann Immunodeticiency Fund, Toronto, Ontario, Canada. Requestsfor reprints shouldbe addressedto Chaim M. Roifman, M.D., Division of Immunology/Allergy,The Hospitalfor SickChildren, 555 University Avenue,Toronto, Ontario, CanadaM5G 1X8. Manuscript submitted June 19, 1990, and accepted in revised form November 19, 1990.
310
March 1991
E
osinophilic gastroenteritis (EG) is a chronic, recurrent disease of the gastrointestinal tract that is characterized by abdominal pain, nausea, vomiting, and diarrhea [1-4]. Other reported clinical manifestations include weight loss, anemia, melena, protein-losing enteropathy, esophagitis, and intestinal perforation [5-8]. Histologic evidence of a predominant eosinophilic infiltration of gastrointestinal mucosa in the absence of parasitic infection or extraintestinal disease confirms a diagnosis of EG [9]. EG has been classified into three forms [10]: mucosal, which generally acts like other inflammatory disorders of the bowel; submucosal, which may cause bowel obstructions; and serosal, which produces eosinophflic peritonitis. Various mucosal sites from the esophagus to the rectum may be involved and results in presenting symptoms and signs that range from mild abdominal discomfort to acute intestinal obstruction [11-13]. Although the primary cause of EG remains unknown, previously reported associations with allergy, allergic rhinitis, atopic dermatitis, and elevated IgE levels suggest an atopic predisposition in the pathogenesis of this disorder [14,15]. Other evidence suggests that mast cell degranulation plays a significant role [16]. One of the drugs that might modulate the release of mast cell mediators is ketotifen (Zaditen; Sandoz Pharmaceuticals, Basel, Switzerland), which has a histamine (H1) antagonist effect. Early studies with ketotifen, both in vivo and in vitro, demonstrated its capacity to inhibit the secretion of mast cell mediators such as histamine [17]. These mast cell products may contribute to the inflammation of intestinal tissue that is characteristic of EG [18]. On the basis of such findings, we initiated an open clinical trial to assess the efficacy of ketotifen therapy in the treatment of patients with histologically confirmed EG:
PATIENTS AND METHODS Six patients, four females and two males, ranging in age from 8 to 30 years (mean age, 16.9 years) were studied prospectively following histologic confir-
The American Journal of Medicine Volume 90
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL
mation of eosinophilic infiltrates confined to the gastrointestinal tract. Three of the six patients were previously (8 months to 5 years prior to study) treated with corticosteroids. Despite initial symptomatic relief, steroids were discontinued because of severe side effects (two patients) or frequent relapses (one patient). Laboratory studies included complete blood cell count and differential, erythrocyte sedimentation rate, eosinophil count, iron studies (serum ferritin, serum iron, total iron-binding capacity), serum glutamic-oxaloacetic transaminase, serum glutamatepyruvate transaminase, alkaline phosphatase, bilirubin, serum immunoglobulins, al-antitrypsin, C3, C4, total hemolytic complement (CHs0), antinuclear f a c t o r , p r o t e i n e l e c t r o p h o r e s i s , and immunoelectrophoresis. We screened each patient for atopy by measuring the total serum IgE with a radioallergosorbent test assay and modified prick test (Pharn~acia Phadebas Systems, Pharmacia, Montreal). In this skin test, we used 17 common allergens including three molds (Alternaria, Hormodendrum, and Aspergillus mix, OMEGA Laboratories, Montreal), egg, milk, wheat, house dust, mites, cat, dog, horse, grass mix, tree mix, and ragweed. Multiple stool samples were examined for the presence of occult blood and to exclude known intestinal parasites. As part of the initial clinical evaluation, upper and lower fiberoptic endoscopies were performed on all patients. During endoscopy, multiple biopsy s p e c i m e n s were o b t a i n e d for histologic examination. The six patients were treated with a dose of ketotifen between 2 and 4 mg daily for a period of 12 months. All patients were followed at 2- to 3-month intervals. At each assessment, their symptoms were reviewed and blood samples for total serum IgE, complete blood cell count, differential white blood cell count, and erythrocyte sedimentation rate were obtained. Each patient underwent a complete physical examination, and in four, endoscopic examinations with biopsies and histologic examination of the specimens were repeated.
A
m A
Is
10
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~---
5
0-
B
12oo IOO0
800
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24°° . . . .
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. . . .
I
. . . .
I
. . . .
I
. . . .
I
. . . .
I
6000 5000 4000
c
w
3000 2000 1000
RESULTS All six patients in this study had abdominal pain. Additional clinical symptoms included persistent diarrhea (three patients), weight loss (four), and vomiting (one) due to partial gastric-outlet obstruction. The duration of symptoms prior to the use of ketotifen ranged from 2 months to 12 years (mean, 32.5 months). All patients had evidence of a peripheral eosinophilia (absolute counts ranging from 0.75
Before
After
Figure 1. A, effect of ketotifen treatment on weight (kg) in six patients over 12 months of treatment. B, effect of ketotifen treatment on the number of peripheral eosinophils in six patients. C, effect of ketotifen treatment on IgE levels in six patients over 12 months of treatment.
March 1991 The American Journal of Medicine Volume 90
311
KETOTIFENTREATMENTFOR EOSINOPHILICGASTROENTERITIS/ MELAMEDET AL
Figure 2. Left, the gastric mucosa is infiltrated by eosinophils focally clustered in the lamina propria (original magnification x50, reduced by 35%). Right, the gastric mucosa appears normal with only an occasional eosinophil in the lamina propria (original magnification X50, reduced by 35%).
to 1.20 × 103/L). Each of the six patients had a history of allergic rhinitis, but none had a positive history of food allergy, and only one patient had demonstrable IgE antibodies to any of the food-test antigens (a mild response to egg on modified prickskin test). Four of the six patients tested positive for occult blood, two of whom had evidence of a significant iron-deficiency anemia. Only one patient in our series had hypoalbuminemia that suggested significant protein-losing enteropathy. In all subjects, the presence of an eosinophilic infiltrate was confirmed by histologic examination of biopsy specimens of the gastrointestinal tract. Biopsies indicated predominantly proximal bowel involvement (stomach and duodenum) in three patients and predominantly distal colonic involvement in the other three cases. The results of all laboratory tests performed to exclude diagnoses other than EG were normal. Within 1 to 4 months of ketotifen therapy administered at a dose of 2.to 4 rag/day, all six patients reported symptomatic improvement including the
312
resolution of diarrhea, severe abdominal pain, and vomiting. Amelioration of symptoms coincided with a dramatic weight gain within 4 months of starting therapy (Figure 1A). In addition, in four of the six patients, total serum IgE levels decreased after 4 to 6 months of therapy (Figure 1B). The peripheral eosinophil count decreased in all six patients (Figure 1C). Clearing of eosinophilic infilt r a t e , was observed after treatment with ketotifen for 4 to 6 months of therapy (Figure 2) in the follow-up mucosal specimens of all four patients in whom repeat endoscopy and biopsy were performed. The resolution of symptoms was sustained in all patients for the study period of 12 months.
COMMENTS Although the pathogenesis of EG is not fully understood, an allergic mechanism appears to play a significant role in the disease. An excessive accumulation of eosinophils may cause the characteristic destruction of intestinal epithelium [19]. The principal pre-formed products released after the de-
March 1991 The American Journal of Medicine Volume 90
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL
granulation of eosinophils, including major basic protein, eosinophilic cationic protein, and eosinophilic peroxidase, may prove relevant in the pathogenesis of gastrointestinal inflammation [20,21]. Since each of the eosinophil granule proteins are potent toxins that are cytotoxic to eukaryotic cells in vitro, eosinophils are likely major effector cells mediating mucosal inflammation in EG [22]. Mast cell degranulation is also involved in mucosal injury [23]. The vasoactive substances, proteases, and pro-inflammatory mediators that are released after the activation of mucosal mast cells and the release of chemoattractants such as eosinophilic chemotactic factor of anaphylaxis (ECF-A) increase vascular permeability. To modulate the allergic mechanisms that lead to gastrointestinal inflammation, various treatment regimens have been employed. Corticosteroids have been the mainstay of therapy with generally good s y m p t o m a t i c responses [24]. However, steroid treatment is associated with a high percentage of relapses and significant side effects [25]. Trial elimination diets have occasionally been successful, but relapse is also common [26]. The value of oral sodium chromoglycate remains controversial [27]. In general, however, the results of treatment with this agent have not been impressive [27]. Because the goal of our treatment for EG was to modulate the release of inflammatory mediators such as ECF-A by mast cell degranulation, we chose ketotifen, an HI class of antihistamine that stabilizes mast cells and possibly impairs eosinophil migration to target organs [17]. The therapeutic efficacy of ketotifen in the treatment of EG likely also includes its ability to inhibit both histamine release and leukotriene production [28]. Ketotifen also stabilizes the mast cell membrane and prevents increases in vascular permeability caused by both chemical and immunologic stimuli. An ability to reduce calcium influx may play a key role in its ability to inhibit the action of inflammatory mediators. The striking symptomatic improvement, subsequent weight gain, and histologic evidence of eosinophilic clearing in repeat biopsies performed on our patients are all suggestive of the beneficial effect of ketotifen. Equally important was the significant lack of adverse side effects, apart from transient drowsiness, during therapy with ketotifen. The paucity of cases of EG greatly limits the ability to conduct double-blind, placebo-controlled studies that could delineate clearly the efficacy of new therapeutic agents for use in patients with EG. In the absence of a control group in our study, factors influencing the response of our patients to a placebo
effect or the variable history of the disease cannot be ruled out absolutely. We conclude that the therapeutic effect of ketotifen treatment in our patients demonstrates a safe and effective alternative to traditional systemic corticosteroid therapy for EG.
ACKNOWLEDGMENT We thank Dr. C. Cullinane and Mike Starr from the Department of Pathology for preparation of the pathologic materials and Sharon Nancekivell and Denise Purcell for editorial and secretarial assistance.
REFERENCES 1. Trounce JQ, Tanner MS. Eosinophilic gastroenteritis. Arch Dis Child 1985; 60: 1186-8.
2. Johnstone JM. Morson 8C. Eosinophilic gastroenteritis. Histopathology 1978; 2: 335--48. 3. Cello JP. Eosinophilic gastroenteritis--a complex disease entity. Am J Med 1979; 67: ]097-1104. 4. Whitington PF, Whitington GL. Eosinophilic gastroenteropathy in childhood. J Pediatr Gastroenterol Nutr 1988; 7: 379-85. 5. Felt-Bersma RJ. Meuwissen SG, van Velzu D. Perforation of the small intestine due to eosinophilic 8astroenteritis. Am J Gastroenterol 1984; 79: 442-5. 6. Greenberger NJ, Tennenbaum JI, Ruppert RD. Protein-losing enteropathy associated with gastrointestinal allergy. Am J Med 1967; 43: 777-84. 7. Haberkern CM. Christie DL, Haas JE. Eosinophilic gastroenteritis presenting as ileocolitis. Gastroenterology 1978: 74: 896-9. 8. Kuipers FC, van Thiel PH, Rodenberg W, Wielinga WJ. Roskam RT. Eosinophilic phlegmon of the alimentary tract caused by a worm. Lancet ] 960: 2:117 ]-3. 9. Blackshaw AJ, Levison DA. Eosinophilic infiltrates of the gastrointestinal tract. J Clin Pathol 1986; 39: 1-7. 10. Klein NC, Hargrove RL; Sleisenger MH. Jeffries GH. Eosinophilic gastroenteritis. Medicine (Baltimore) 1970: 49: 299-319. 11. Zora JA, O'Connell EJ, Sachs MI, Hoffman AD. Eosinophilic gastroenteritis: a case report and review of the literature. Ann Allergy 1984; 53: 45-7. 12. Steele RJ, Wright RG, Gilmore HM Eosinophilic gastroenteritis presenting as acute intestinal obstruction. Scott Med J 1983; 28: 183-4. 13. Caldwell JH, Mekhjian H8, Hurtubise PE, Beman FM. Eosinophylic gastroenteritis with obstruction. Immunological studies of seven patients. Gastroenterology 1978; 74: 825-8. 14. Metcalfe DD. Food hypersensitivity. J Allergy Clin Immuno11984; 73: 74962. 15. Caldwell JH, Tennebaum JI, Bronstein HA. Serum IgE in eosinophilic gastroenteritis. Response to intestinal challenge in two cases. N Engl J Med 1975; 292: 1388-90. 16. Lee TDG, Swieter M, 8efus D. Mast cells, eosinophils and gastrointestinal hypersensitivity. Immunol Allergy Clin 1988; 8: 469-83. 17. MacDonald GF. An overview of ketotifen. Chest 1982; 82 (Suppl 1): 30S32S. 18. Lee TD, Swieter M, Bienenstock J. Befus AD. Heterogeneity in mast cell populations. Clin Immunol Rev 1985; 4: ]43-99. 19. Keshavarzian A, Saverymuttu SH, Tai P-C, et aL Activated eosinophils in familial eosinophilic gastroenteritis. Gastroenterology 1985; 88: 1041-9. 20. Capron M, Khalife J, Gleich GJ, et aL Mediators released after activation of human eosinophils [Abstract]. In: Proceedings of the 17th Symposium of the College of International Allergists, 1987: 5A. 21. Gleich GJ, Adolphson CR. The eosinophil leukocyte: structure and function. Adv Immunol 1986; 39: 177-253. 22. Kay AB. Eosinophils as effector cells in immunity and hypersensitivity disorders. Clin Exp Immunol 1985; 62: 1-12. 23. Befus AD, Dyck N, Goodacre R, Bienenstock J. Mast cells from human intestinal lamina propria. Isolation, histochemical subtypes, and functional char-
March 1991
The American Journal of Medicine Volume 90
313
KETOTIFEN TREATMENT FOR EOSINOPHILIC GASTROENTERITIS / MELAMED ET AL acterization. J Immunol 1987: 138: 2604-10. 24. Robert F, Omura E, Durant JR. Mucosal eosinophilic gastroenteritis with systemic involvement. Am J Med 1977; 62: 139-43. 25. Greenberger N. Allergic disorder of the intestine and eosinophilic gastroenteritis. In: Sleisenger MH, Fordtran JS, eds. Gastrointestinal disease, 3rd ed. Philadelphia: WB Saunders, 1983: 1069-76. 26. Leinbach GE, Rubin CE. Eosinophilic gastroenteritis: a simple reaction to
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March 1991 The American Journal of Medicine Volume 90
