- Email: [email protected]
Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture
Clinical allergy-immunology rounds Supported by an unrestricted grant from Aventis Pharmaceuticals
Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture Brian E. Daikh, MD*; Charlotte K. Ryan, MD†; and Robert H. Schwartz, MD‡§
Background: Eosinophilic gastroenteritis (EG) is an uncommon entity of which the pathogenesis is unclear. As no controlled treatment trials exist, treatment of EG remains largely empiric. Limited results have been achieved with oral cromolyn, ketotifen, and other antihistamines. Oral corticosteroids are effective, but long-term use is complicated by side effects including growth retardation, diabetes, and osteoporosis. Objectives: We sought to determine whether treatment with montelukast would improve symptoms and decrease both peripheral blood and tissue eosinophilia (TE) in a patients with steroid-dependent EG for 20 years complicated by esophageal stricture. Methods: In an unblinded, n ⫽ 1 trial, we treated the patient for 5 months with montelukast (20 to 30 mg daily) while his baseline dose of prednisone (10 mg daily) was continued. Complete blood counts and symptoms were monitored weekly. Esophageal biopsies were obtained before and after 5 months of therapy with montelukast. After the posttreatment biopsy was obtained, montelukast was discontinued. Outcome measures included patient symptoms and peripheral and tissue eosinophil counts. Results: During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/L (average 28 determinations over 20 years; range 1,408 to 12,500 cells/L) to 1,195 cells/L (average 14 determinations over 16 weeks; range 556 to 2,193 cells/L), a 76% reduction. The corresponding TE as calculated from esophageal biopsies was 31 eosinophils/high power field before and 70 eosinophils/high power field after treatment. The patient noted no appreciable improvement in esophageal symptoms. Conclusions: Montelukast dramatically reduced peripheral blood eosinophilia, but did not affect TE or symptoms in this patient with severe, long-standing EG complicated by esophageal stricture. Ann Allergy Asthma Immunol 2003;90:23–27.
INTRODUCTION Eosinophilic gastroenteritis (EG) is an uncommon entity of which the pathogenesis is unclear.1 Less than 300 cases are reported in the medical literature; the first in 1937 by Kaijser.2 EG is characterized by eosinophilic infiltration of the gastrointestinal (GI) tract (most commonly the stomach and small bowel), GI symptoms, peripheral eosinophilia (75% of cases), and the absence of alternative causes (eg, parasitic infection).1 A subgroup of this condition is
University of Rochester/Strong Memorial Hospital Divisions of Allergy, Immunology, and Rheumatology*, Pathology†, and Pediatrics‡, Rochester, New York. § Allergy, Asthma, Immunology of Rochester (AAIR)/Allergy & Asthma Rochester, Resource Center (AARRC), Rochester, New York. Received for publication October 19, 2001. Accepted for publication in revised form March 15, 2002.
VOLUME 90, JANUARY, 2003
allergic EG in which patients have positive skin tests to food antigens, elevated total immunoglobulin (Ig)E, and specific IgE to food antigens.3 The treatment of EG remains largely empirical. To date, no controlled treatment trials exist. If food allergy is present, elimination of the potential offending foods is required. In some cases, basic amino acid diets have been successful.4 Limited results have been achieved with oral cromolyn, ketotifen, and other antihistamines.5,6 Oral corticosteroids are a very effective treatment,7 but long-term use can be complicated by side effects including growth retardation, diabetes, and osteoporosis. Recent studies with swallowed fluticasone delivered by metered-dose inhaler are promising.8 This method delivers steroid topically, but the high first-pass metabolism of the drug minimizes the systemic side effects. Future treatments may target helper T cells, inflammatory mediators such as leukotrienes,9 or cytokines important to
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eosinophil chemotaxis and eosinophilopoesis, such as interleukin (IL)-4 and IL-5.10 A 25-year-old male with EG has been followed by one of the authors (RHS) for 20 years. Because this patient’s condition was complicated by esophageal stricture requiring long-term daily prednisone for symptomatic relief and he had already experienced significant steroid-related side effects, we sought to investigate a novel therapy, the cysteinyl-leukotriene antagonist montelukast. In studies of asthmatic patients, treatment with the leukotriene antagonist montelukast, compared with placebo, significantly decreased peripheral blood eosinophils (PBEs) and bronchoalveolar lavage fluid eosinophils.11,12 The eosinophil decrease correlated with improvement in symptoms and forced expiratory volume in 1 second. A reduction in tissue eosinophilia (TE) has also been observed in transbronchial biopsies from asthmatic patients, although within-patient and within-biopsy variability has made it difficult to conclusively substantiate this histopathologic benefit of montelukast.13 A decrease in peripheral blood eosinophilia (574 to 342/L) and improved symptoms in a 13-year-old girl with biopsy-proven EG with 4 months of oral montelukast (10 mg/day) was recently reported.9 Posttreatment biopsies were not available, however. Based on this report, we treated the present patient with oral montelukast and sought to determine whether treatment with montelukast would improve symptoms and decrease both peripheral blood eosinophilia and TE. Case A 25-year-old male first presented at age 5 years with symptoms of vomiting after meals and progressive dysphagia with solid foods. Over a period of months he was noted to have a slowed rate of linear growth (third percentile). He was referred for evaluation of food allergy. Skin prick tests were positive to wheat, egg white, milk, fish, and peanut. A complete blood count was remarkable for a total white blood cell count (WBC) count of 18,300 cells/L with 45% eosinophils (absolute eosinophil count 8,235 cells/L; Table 1). The serum albumin was low at 3.3 mg/dL. The erythrocyte sedimentation rate was not elevated. A total serum IgE was 864 IU/mL and radioallergosorbent testing (Table 2) revealed the following: milk ⫽ 12.2 kU/L (class 3/6); ␣-lactalbumin ⫽ 5.41 kU/L (class 3/6); -lactoglobulin ⫽ 0.41 kU/L (class 1/6); casein ⫽ 14.84 kU/L (class 3/6); beef ⫽ 6.69 kU/L (class 3/6); egg ⫽ 2.94 kU/L (class 2/6); and wheat ⫽ 99.4 kU/L (class 5/6). Double-blind, placebo-controlled food chal-
Table 2. Patient Radioallergosorbent Test Data RAST test Milk ␣-lactalbumin -lactoglobulin Casein Egg Wheat
Class 12.2 kU/L 5.41 kU/L 0.41 kU/L 14.8 kU/L 2.94 kU/L 99.4 kU/L
3/6 1/6 1/6 3/6 2/6 5/6
RAST, radioallergosorbent test.
lenges were not conducted, but accidental exposure to egg, milk, and wheat resulted in immediate nausea, abdominal cramping, and diarrhea. Because of progressive dysphagia and regurgitation, at age 15, an esophagogastroduodenoscopy with biopsy was performed, which revealed esophageal edema with stricture. A biopsy of gastric antrum showed an intense eosinophilic infiltrate of the mucosa along with eosinophilic infiltration of glands and surface epithelium (Fig 1). There was no duodenal involvement, with normal appearing villi and crypt-to-villous ratio and without increased numbers of eosinophils. A workup revealed no evidence of malabsorption syndrome, parasitic infection, malignancy, or other organ involvement. Under supervision of a registered nutritionist, a rigorous avoidance diet was initiated that included explicit instructions to his parents. An elemental diet eliminating intact protein was not attempted. Despite this intervention, his dysphagia and peripheral eosinophilia persisted (mean 5,064 cells/L, 14 to 45% of total WBC; data collected during 20 years of clinical observation). Although the postprandial vomiting resolved with dietary intervention, he ultimately required oral prednisone as well as esophageal dilation on two occasions at age 15 for the obstructive symptoms. He has been unsuccessfully treated with oral cromolyn, ketotifen, cyproheptidine, ranitidine, and cetirizine. Twenty years later,
Table 1. Patient Laboratory Data WBC Eosinophils AEC Serum Albumin ESR Total Serum IgE
18,300 cells/L 45% 8232 cells/L 3.3 mg/dL Normal 864 IU/mL
WBC, white blood count; AEC, absolute eosinophil count; ESR, erythrocyte sedimentation rate.
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Figure 1. Gastric biopsy at the time of diagnosis of EG (1990). A marked eosinophilic infiltrate is present, diffusely involving the lamina propria of the mucosa (80 eosinophils/HPF; hematoxylin and eosin [H&E], magnification ⫻300).
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
despite avoidance of foods to which he is allergic, he requires prednisone, 10 to 40 mg daily, to suppress his obstructive symptoms. He has achieved an adult height of 67 inches, approximating his predicted height, but has osteopenia by bone densitometry. METHODS The patient was treated for 5 months with montelukast 20 mg daily while his baseline dose of prednisone (10 mg daily) was continued. Complete blood cell counts and symptoms were monitored weekly. At the end of 2 months, the montelukast dose was increased to 30 mg daily. Esophageal biopsies were obtained before and after 5 months of therapy with montelukast. In each biopsy the number of eosinophils per high power field (HPF, magnification ⫻400) was determined by averaging the number of eosinophils in sequential HPFs over the entire area (one level) of the specimen. After the posttreatment biopsy was obtained, montelukast was discontinued. RESULTS Immediately before treatment, the PBE count was 6,480 cells/L with a mean pretreatment level of 5,064 cells/L (average 28 determinations over 20 years; range 1,408 to 12,500 cells/L). PBEs fell to a mean of 1,195 cells/L (average 14 determinations over 16 weeks; range 556 to 2,193 cells/L) during treatment, a 76% reduction. There was no appreciable change in the PBE count when montelukast was increased from 20 to 30 mg daily. The corresponding TE as calculated from esophageal biopsies was 31 eosinophils/HPF before and 70 eosinophils/HPF after treatment (Fig 2, A-C). The patient initially reported a mild reduction in stricture symptoms, but improvement was not sustained. After 5 months of therapy, he judged his symptoms to be no different from the beginning of treatment. No visual improvement of the stricture was observed on repeat esophagoscopy (data not shown). DISCUSSION The pathophysiology of EG, particularly what drives the chronic eosinophilic infiltration, is not understood. In those patients who are food-allergic, chronic antigenic stimulation leading to mast cell degranulation followed by eosinophil chemotaxis, similar to that seen in asthma, would be predicted. This hypothesis is supported by clinical and histologic improvement upon removal of the relevant foods in these patients. In nonallergic patients or allergic patients in which the suspected food allergen is removed from the diet and symptoms persist, the cause of persistent eosinophilia is unknown. This appears to be a local phenomenon, so unlike hypereosinophilic syndrome, there are local mechanisms at work. One possible explanation is that the relevant antigen has not been identified by history or skin testing, thereby preventing its elimination from the diet. Both in vitro and in vivo studies have identified many cytokines and chemokines, as well as leukotrienes and com-
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Figure 2. A) Esophageal biopsy before treatment with montelukast, 10 years after initial diagnosis (March 2000). Eosinophils infiltrate the squamous epithelium and aggregate in the superficial layers (31 eosinophils/HPF, H&E, magnification ⫻400). B and C) Esophageal biopsy after treatment with montelukast for 5 months (July 2000). B) Pronounced eosinophilia of the squamous epithelium with desquamation of the superficial layers (H&E, magnification ⫻175). C) Higher magnification of the same biopsy with numerous aggregated eosinophils clearly visible (70 eosinophils/HPF; H&E, magnification ⫻400).
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plement components, that are chemoattractant to eosinophils. IL-2, C5a, C3a, leukotriene (LT)D4, LTB4, platelet-activating factor, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are all eosinophil chemoattractants, as are the C-C chemokines RANTES, eotaxin, monocyte chemotactive protein-3 (MCP-3), and MCP-4.14,15 Local production of some or many of these factors because of unknown stimuli could lead to the influx and maintenance of tissue and peripheral eosinophilia in EG. The initial event leading to TE involves the release of the T helper 2 cytokines IL-4 and IL-5, as well as IL-3, by activated CD4⫹ T cells. Similarly, release of cytokines (IL-3, IL-4, IL-5, GM-CSF) and leukotrienes by activated tissue mast cells also contribute to the influx of eosinophils. Once present, eosinophils can release cytokines (IL-3 and IL-5) and growth factors (GM-CSF) with autocrine and paracrine activity that allows the eosinophils to regulate their own proliferation and differentiation. Increased levels of IL-3, IL-5, and GM-CSF in endoscopic biopsy specimens from patients with EG compared with controls have been identified by immunohistochemical techniques.16 The authors conclude that release of theses cytokines with autocrine and paracrine function may be involved in the persistent intestinal eosinophil infiltration observed in EG. IL-4, IL-5, and interferon-␥ are known to regulate IgE synthesis, whereas IL-5 regulates eosinophilopoesis in vitro. Increased numbers of T cells, increased levels of IL-4, and decreased levels of interferon-␥ were identified in biopsy specimens from three patients with EG compared with controls.3 There was higher in vitro spontaneous and mitogenstimulated production of IL-4 and IL-5 in these patients. The authors conclude that these findings are consistent with the eosinophilia and elevated serum IgE seen in EG, and that treatment targeting T cells may be efficacious in treating EG. Activated eosinophils are believed to be the effector cells in EG.17 The CC chemokine, eotaxin, plays a key role in the normal homing of eosinophils to the GI tract,18 but its role in inflammatory states such as EG is yet to be defined. There is significant eosinophil infiltration in the GI tract of patients with EG, and many have elevated PBEs. Similar to observations in asthma, oral corticosteroids significantly decrease both TE and PBEs in EG. The mechanism may be through accelerated eosinophil apoptosis,19 but other mechanisms may play a role. LTD4 may be an important eosinophil chemoattractant,15 and antileukotriene therapy decreases eosinophil survival in asthmatic patients.20 Thus, we hypothesized that montelukast could decrease PBE and TE in EG in a steroid-dependent patient. We observed a marked and sustained decrease in PBE after 3 weeks of treatment when montelukast was added to oral prednisone. However, regardless of the effect of montelukast on PBE counts, we did not observe any overall improvement in TE with treatment. This would suggest that either leukotrienes do not play a significant role in TE in EG or that more complete blockade of the leukotriene pathway is required. Further, and perhaps more significantly, the patient did not
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observe any appreciable improvement in his obstructive symptoms that would allow a decrease in his prednisone dosage. CONCLUSION Oral treatment with montelukast (20 to 30 mg daily for 5 months) diminished PBEs in an adult patient with childhoodonset EG complicated by esophageal stricture. However, obstructive symptoms did not improve and marked TE persisted. Although montelukast was not effective in treating this patient with steroid-dependent EG, the possible decrease in PBE counts suggests that further dose and duration treatment studies in patients with this condition should be explored. These studies could contribute to understanding the relationships between peripheral blood eosinophilia and TE. ACKNOWLEDGMENT The authors thank Dr. Martin S. Kleinman for performing esophagogastroduodenoscopy and endoscopic biopsy. REFERENCES 1. Lee M, Hodges WG, Huggins TL, Lee EL. Eosinophilic gastroenteritis. South Med J 1996;89:189 –194. 2. Kaijser R. Zur Kenntnis der Allergischen Affektioner desima Verdanungskanal von Standpunkt desima Chirurgen aus. Arch Klin Chir 1937;188:36 – 64. 3. Jaffe JS, James SP, Mullins GE, et al. Evidence for an abnormal profile of interleukin-4 (IL-4), IL-5, and ␥-interferon (␥-INF) in peripheral blood T cells from patients with allergic eosinophilic gastroenteritis. J Clin Immunol 1994;14:299 –309. 4. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109: 1503–1512. 5. Rothenburg ME. Mechanisms of disease: eosinophilia. N Engl J Med 1998;338:1592–1600. 6. Melamed I, Feanny SJ, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310 –314. 7. Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26: 380 –385. 8. Faubion WA Jr, Perrault J, Burgart LJ, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998;27:90 –93. 9. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast. J Allergy Clin Immunol 1999;104:506. 10. Shirai T, Hashimoto D, Suzuki K, et al. Successful treatment of eosinophilic gastroenteritis with suplatast tosilate. J Allergy Clin Immunol 2001;107:924 –925. 11. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998;158:1213–1220. 12. Zhang J, Chervinsky P, Edwards T, et al. Montelukast, a cys LT1 receptor antagonist, decreases peripheral blood eosinophils and improves signs and symptoms of asthma over a 3 month
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
period. J Allergy Clin Immunol 1997;99:S268. 13. Ramsey C, Li D, Wang D. Bronchial biopsy specimen variability: requirement for large sample size and repeated measurements to improve reliability. Am J Respir Crit Care Med 1999;159:A655. 14. Kita H, Adolphson CR, Gleich GJ. Biology of eosinophils. In: Middleton E Jr, Reed CF, Ellis EF, et al, editors. Allergy, Principles and Practice. St. Louis: Mosby, 1998:242–260. 15. Spada CS, Nieves AL, Krauss AH, Woodward DF. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 1994;55:183–191. 16. Desreumaux P, Bloget F, Seguy D, et al. Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis. Gastroenterology 1996;110: 768 –774. 17. Bischoff SC, Mayer J, Nguyen QT, et al. Immunohistological assessment of intestinal eosinophil activation in patients with eosinophilic gastroenteritis and inflammatory bowel disease. Am J Gastroenterol 1999;94:3521–3529.
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18. Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 1999;103:1719 –1727. 19. Fuller R, Johnson M, Bye A. Fluticasone propionate–an update on preclinical and clinical experience. Respir Med 1995; 89(Suppl):3–18. 20. Lee A, Robertson T, Smith J, et al. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med. 2000;161: 1881–1886.
Requests for reprints should be addressed to: Brian E. Daikh, MD Rheumatology Associate 51 Sewall Street Portland, ME 04102 E-mail: [email protected]
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Montelukast reduces peripheral blood eosinophilia but not tissue eosinophilia or symptoms in a patient with eosinophilic gastroenteritis and esophageal stricture Brian E. Daikh, MD*; Charlotte K. Ryan, MD†; and Robert H. Schwartz, MD‡§
Background: Eosinophilic gastroenteritis (EG) is an uncommon entity of which the pathogenesis is unclear. As no controlled treatment trials exist, treatment of EG remains largely empiric. Limited results have been achieved with oral cromolyn, ketotifen, and other antihistamines. Oral corticosteroids are effective, but long-term use is complicated by side effects including growth retardation, diabetes, and osteoporosis. Objectives: We sought to determine whether treatment with montelukast would improve symptoms and decrease both peripheral blood and tissue eosinophilia (TE) in a patients with steroid-dependent EG for 20 years complicated by esophageal stricture. Methods: In an unblinded, n ⫽ 1 trial, we treated the patient for 5 months with montelukast (20 to 30 mg daily) while his baseline dose of prednisone (10 mg daily) was continued. Complete blood counts and symptoms were monitored weekly. Esophageal biopsies were obtained before and after 5 months of therapy with montelukast. After the posttreatment biopsy was obtained, montelukast was discontinued. Outcome measures included patient symptoms and peripheral and tissue eosinophil counts. Results: During treatment with montelukast, the mean peripheral blood eosinophil count fell from 5,064 cells/L (average 28 determinations over 20 years; range 1,408 to 12,500 cells/L) to 1,195 cells/L (average 14 determinations over 16 weeks; range 556 to 2,193 cells/L), a 76% reduction. The corresponding TE as calculated from esophageal biopsies was 31 eosinophils/high power field before and 70 eosinophils/high power field after treatment. The patient noted no appreciable improvement in esophageal symptoms. Conclusions: Montelukast dramatically reduced peripheral blood eosinophilia, but did not affect TE or symptoms in this patient with severe, long-standing EG complicated by esophageal stricture. Ann Allergy Asthma Immunol 2003;90:23–27.
INTRODUCTION Eosinophilic gastroenteritis (EG) is an uncommon entity of which the pathogenesis is unclear.1 Less than 300 cases are reported in the medical literature; the first in 1937 by Kaijser.2 EG is characterized by eosinophilic infiltration of the gastrointestinal (GI) tract (most commonly the stomach and small bowel), GI symptoms, peripheral eosinophilia (75% of cases), and the absence of alternative causes (eg, parasitic infection).1 A subgroup of this condition is
University of Rochester/Strong Memorial Hospital Divisions of Allergy, Immunology, and Rheumatology*, Pathology†, and Pediatrics‡, Rochester, New York. § Allergy, Asthma, Immunology of Rochester (AAIR)/Allergy & Asthma Rochester, Resource Center (AARRC), Rochester, New York. Received for publication October 19, 2001. Accepted for publication in revised form March 15, 2002.
VOLUME 90, JANUARY, 2003
allergic EG in which patients have positive skin tests to food antigens, elevated total immunoglobulin (Ig)E, and specific IgE to food antigens.3 The treatment of EG remains largely empirical. To date, no controlled treatment trials exist. If food allergy is present, elimination of the potential offending foods is required. In some cases, basic amino acid diets have been successful.4 Limited results have been achieved with oral cromolyn, ketotifen, and other antihistamines.5,6 Oral corticosteroids are a very effective treatment,7 but long-term use can be complicated by side effects including growth retardation, diabetes, and osteoporosis. Recent studies with swallowed fluticasone delivered by metered-dose inhaler are promising.8 This method delivers steroid topically, but the high first-pass metabolism of the drug minimizes the systemic side effects. Future treatments may target helper T cells, inflammatory mediators such as leukotrienes,9 or cytokines important to
23
eosinophil chemotaxis and eosinophilopoesis, such as interleukin (IL)-4 and IL-5.10 A 25-year-old male with EG has been followed by one of the authors (RHS) for 20 years. Because this patient’s condition was complicated by esophageal stricture requiring long-term daily prednisone for symptomatic relief and he had already experienced significant steroid-related side effects, we sought to investigate a novel therapy, the cysteinyl-leukotriene antagonist montelukast. In studies of asthmatic patients, treatment with the leukotriene antagonist montelukast, compared with placebo, significantly decreased peripheral blood eosinophils (PBEs) and bronchoalveolar lavage fluid eosinophils.11,12 The eosinophil decrease correlated with improvement in symptoms and forced expiratory volume in 1 second. A reduction in tissue eosinophilia (TE) has also been observed in transbronchial biopsies from asthmatic patients, although within-patient and within-biopsy variability has made it difficult to conclusively substantiate this histopathologic benefit of montelukast.13 A decrease in peripheral blood eosinophilia (574 to 342/L) and improved symptoms in a 13-year-old girl with biopsy-proven EG with 4 months of oral montelukast (10 mg/day) was recently reported.9 Posttreatment biopsies were not available, however. Based on this report, we treated the present patient with oral montelukast and sought to determine whether treatment with montelukast would improve symptoms and decrease both peripheral blood eosinophilia and TE. Case A 25-year-old male first presented at age 5 years with symptoms of vomiting after meals and progressive dysphagia with solid foods. Over a period of months he was noted to have a slowed rate of linear growth (third percentile). He was referred for evaluation of food allergy. Skin prick tests were positive to wheat, egg white, milk, fish, and peanut. A complete blood count was remarkable for a total white blood cell count (WBC) count of 18,300 cells/L with 45% eosinophils (absolute eosinophil count 8,235 cells/L; Table 1). The serum albumin was low at 3.3 mg/dL. The erythrocyte sedimentation rate was not elevated. A total serum IgE was 864 IU/mL and radioallergosorbent testing (Table 2) revealed the following: milk ⫽ 12.2 kU/L (class 3/6); ␣-lactalbumin ⫽ 5.41 kU/L (class 3/6); -lactoglobulin ⫽ 0.41 kU/L (class 1/6); casein ⫽ 14.84 kU/L (class 3/6); beef ⫽ 6.69 kU/L (class 3/6); egg ⫽ 2.94 kU/L (class 2/6); and wheat ⫽ 99.4 kU/L (class 5/6). Double-blind, placebo-controlled food chal-
Table 2. Patient Radioallergosorbent Test Data RAST test Milk ␣-lactalbumin -lactoglobulin Casein Egg Wheat
Class 12.2 kU/L 5.41 kU/L 0.41 kU/L 14.8 kU/L 2.94 kU/L 99.4 kU/L
3/6 1/6 1/6 3/6 2/6 5/6
RAST, radioallergosorbent test.
lenges were not conducted, but accidental exposure to egg, milk, and wheat resulted in immediate nausea, abdominal cramping, and diarrhea. Because of progressive dysphagia and regurgitation, at age 15, an esophagogastroduodenoscopy with biopsy was performed, which revealed esophageal edema with stricture. A biopsy of gastric antrum showed an intense eosinophilic infiltrate of the mucosa along with eosinophilic infiltration of glands and surface epithelium (Fig 1). There was no duodenal involvement, with normal appearing villi and crypt-to-villous ratio and without increased numbers of eosinophils. A workup revealed no evidence of malabsorption syndrome, parasitic infection, malignancy, or other organ involvement. Under supervision of a registered nutritionist, a rigorous avoidance diet was initiated that included explicit instructions to his parents. An elemental diet eliminating intact protein was not attempted. Despite this intervention, his dysphagia and peripheral eosinophilia persisted (mean 5,064 cells/L, 14 to 45% of total WBC; data collected during 20 years of clinical observation). Although the postprandial vomiting resolved with dietary intervention, he ultimately required oral prednisone as well as esophageal dilation on two occasions at age 15 for the obstructive symptoms. He has been unsuccessfully treated with oral cromolyn, ketotifen, cyproheptidine, ranitidine, and cetirizine. Twenty years later,
Table 1. Patient Laboratory Data WBC Eosinophils AEC Serum Albumin ESR Total Serum IgE
18,300 cells/L 45% 8232 cells/L 3.3 mg/dL Normal 864 IU/mL
WBC, white blood count; AEC, absolute eosinophil count; ESR, erythrocyte sedimentation rate.
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Figure 1. Gastric biopsy at the time of diagnosis of EG (1990). A marked eosinophilic infiltrate is present, diffusely involving the lamina propria of the mucosa (80 eosinophils/HPF; hematoxylin and eosin [H&E], magnification ⫻300).
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY
despite avoidance of foods to which he is allergic, he requires prednisone, 10 to 40 mg daily, to suppress his obstructive symptoms. He has achieved an adult height of 67 inches, approximating his predicted height, but has osteopenia by bone densitometry. METHODS The patient was treated for 5 months with montelukast 20 mg daily while his baseline dose of prednisone (10 mg daily) was continued. Complete blood cell counts and symptoms were monitored weekly. At the end of 2 months, the montelukast dose was increased to 30 mg daily. Esophageal biopsies were obtained before and after 5 months of therapy with montelukast. In each biopsy the number of eosinophils per high power field (HPF, magnification ⫻400) was determined by averaging the number of eosinophils in sequential HPFs over the entire area (one level) of the specimen. After the posttreatment biopsy was obtained, montelukast was discontinued. RESULTS Immediately before treatment, the PBE count was 6,480 cells/L with a mean pretreatment level of 5,064 cells/L (average 28 determinations over 20 years; range 1,408 to 12,500 cells/L). PBEs fell to a mean of 1,195 cells/L (average 14 determinations over 16 weeks; range 556 to 2,193 cells/L) during treatment, a 76% reduction. There was no appreciable change in the PBE count when montelukast was increased from 20 to 30 mg daily. The corresponding TE as calculated from esophageal biopsies was 31 eosinophils/HPF before and 70 eosinophils/HPF after treatment (Fig 2, A-C). The patient initially reported a mild reduction in stricture symptoms, but improvement was not sustained. After 5 months of therapy, he judged his symptoms to be no different from the beginning of treatment. No visual improvement of the stricture was observed on repeat esophagoscopy (data not shown). DISCUSSION The pathophysiology of EG, particularly what drives the chronic eosinophilic infiltration, is not understood. In those patients who are food-allergic, chronic antigenic stimulation leading to mast cell degranulation followed by eosinophil chemotaxis, similar to that seen in asthma, would be predicted. This hypothesis is supported by clinical and histologic improvement upon removal of the relevant foods in these patients. In nonallergic patients or allergic patients in which the suspected food allergen is removed from the diet and symptoms persist, the cause of persistent eosinophilia is unknown. This appears to be a local phenomenon, so unlike hypereosinophilic syndrome, there are local mechanisms at work. One possible explanation is that the relevant antigen has not been identified by history or skin testing, thereby preventing its elimination from the diet. Both in vitro and in vivo studies have identified many cytokines and chemokines, as well as leukotrienes and com-
VOLUME 90, JANUARY, 2003
Figure 2. A) Esophageal biopsy before treatment with montelukast, 10 years after initial diagnosis (March 2000). Eosinophils infiltrate the squamous epithelium and aggregate in the superficial layers (31 eosinophils/HPF, H&E, magnification ⫻400). B and C) Esophageal biopsy after treatment with montelukast for 5 months (July 2000). B) Pronounced eosinophilia of the squamous epithelium with desquamation of the superficial layers (H&E, magnification ⫻175). C) Higher magnification of the same biopsy with numerous aggregated eosinophils clearly visible (70 eosinophils/HPF; H&E, magnification ⫻400).
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plement components, that are chemoattractant to eosinophils. IL-2, C5a, C3a, leukotriene (LT)D4, LTB4, platelet-activating factor, IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are all eosinophil chemoattractants, as are the C-C chemokines RANTES, eotaxin, monocyte chemotactive protein-3 (MCP-3), and MCP-4.14,15 Local production of some or many of these factors because of unknown stimuli could lead to the influx and maintenance of tissue and peripheral eosinophilia in EG. The initial event leading to TE involves the release of the T helper 2 cytokines IL-4 and IL-5, as well as IL-3, by activated CD4⫹ T cells. Similarly, release of cytokines (IL-3, IL-4, IL-5, GM-CSF) and leukotrienes by activated tissue mast cells also contribute to the influx of eosinophils. Once present, eosinophils can release cytokines (IL-3 and IL-5) and growth factors (GM-CSF) with autocrine and paracrine activity that allows the eosinophils to regulate their own proliferation and differentiation. Increased levels of IL-3, IL-5, and GM-CSF in endoscopic biopsy specimens from patients with EG compared with controls have been identified by immunohistochemical techniques.16 The authors conclude that release of theses cytokines with autocrine and paracrine function may be involved in the persistent intestinal eosinophil infiltration observed in EG. IL-4, IL-5, and interferon-␥ are known to regulate IgE synthesis, whereas IL-5 regulates eosinophilopoesis in vitro. Increased numbers of T cells, increased levels of IL-4, and decreased levels of interferon-␥ were identified in biopsy specimens from three patients with EG compared with controls.3 There was higher in vitro spontaneous and mitogenstimulated production of IL-4 and IL-5 in these patients. The authors conclude that these findings are consistent with the eosinophilia and elevated serum IgE seen in EG, and that treatment targeting T cells may be efficacious in treating EG. Activated eosinophils are believed to be the effector cells in EG.17 The CC chemokine, eotaxin, plays a key role in the normal homing of eosinophils to the GI tract,18 but its role in inflammatory states such as EG is yet to be defined. There is significant eosinophil infiltration in the GI tract of patients with EG, and many have elevated PBEs. Similar to observations in asthma, oral corticosteroids significantly decrease both TE and PBEs in EG. The mechanism may be through accelerated eosinophil apoptosis,19 but other mechanisms may play a role. LTD4 may be an important eosinophil chemoattractant,15 and antileukotriene therapy decreases eosinophil survival in asthmatic patients.20 Thus, we hypothesized that montelukast could decrease PBE and TE in EG in a steroid-dependent patient. We observed a marked and sustained decrease in PBE after 3 weeks of treatment when montelukast was added to oral prednisone. However, regardless of the effect of montelukast on PBE counts, we did not observe any overall improvement in TE with treatment. This would suggest that either leukotrienes do not play a significant role in TE in EG or that more complete blockade of the leukotriene pathway is required. Further, and perhaps more significantly, the patient did not
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observe any appreciable improvement in his obstructive symptoms that would allow a decrease in his prednisone dosage. CONCLUSION Oral treatment with montelukast (20 to 30 mg daily for 5 months) diminished PBEs in an adult patient with childhoodonset EG complicated by esophageal stricture. However, obstructive symptoms did not improve and marked TE persisted. Although montelukast was not effective in treating this patient with steroid-dependent EG, the possible decrease in PBE counts suggests that further dose and duration treatment studies in patients with this condition should be explored. These studies could contribute to understanding the relationships between peripheral blood eosinophilia and TE. ACKNOWLEDGMENT The authors thank Dr. Martin S. Kleinman for performing esophagogastroduodenoscopy and endoscopic biopsy. REFERENCES 1. Lee M, Hodges WG, Huggins TL, Lee EL. Eosinophilic gastroenteritis. South Med J 1996;89:189 –194. 2. Kaijser R. Zur Kenntnis der Allergischen Affektioner desima Verdanungskanal von Standpunkt desima Chirurgen aus. Arch Klin Chir 1937;188:36 – 64. 3. Jaffe JS, James SP, Mullins GE, et al. Evidence for an abnormal profile of interleukin-4 (IL-4), IL-5, and ␥-interferon (␥-INF) in peripheral blood T cells from patients with allergic eosinophilic gastroenteritis. J Clin Immunol 1994;14:299 –309. 4. Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: improvement with an amino acid-based formula. Gastroenterology 1995;109: 1503–1512. 5. Rothenburg ME. Mechanisms of disease: eosinophilia. N Engl J Med 1998;338:1592–1600. 6. Melamed I, Feanny SJ, Sherman PM, Roifman CM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310 –314. 7. Liacouras CA, Wenner WJ, Brown K, Ruchelli E. Primary eosinophilic esophagitis in children: successful treatment with oral corticosteroids. J Pediatr Gastroenterol Nutr 1998;26: 380 –385. 8. Faubion WA Jr, Perrault J, Burgart LJ, et al. Treatment of eosinophilic esophagitis with inhaled corticosteroids. J Pediatr Gastroenterol Nutr 1998;27:90 –93. 9. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with montelukast. J Allergy Clin Immunol 1999;104:506. 10. Shirai T, Hashimoto D, Suzuki K, et al. Successful treatment of eosinophilic gastroenteritis with suplatast tosilate. J Allergy Clin Immunol 2001;107:924 –925. 11. Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma: a multicenter, randomized, double-blind trial. Montelukast Clinical Research Study Group. Arch Intern Med 1998;158:1213–1220. 12. Zhang J, Chervinsky P, Edwards T, et al. Montelukast, a cys LT1 receptor antagonist, decreases peripheral blood eosinophils and improves signs and symptoms of asthma over a 3 month
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period. J Allergy Clin Immunol 1997;99:S268. 13. Ramsey C, Li D, Wang D. Bronchial biopsy specimen variability: requirement for large sample size and repeated measurements to improve reliability. Am J Respir Crit Care Med 1999;159:A655. 14. Kita H, Adolphson CR, Gleich GJ. Biology of eosinophils. In: Middleton E Jr, Reed CF, Ellis EF, et al, editors. Allergy, Principles and Practice. St. Louis: Mosby, 1998:242–260. 15. Spada CS, Nieves AL, Krauss AH, Woodward DF. Comparison of leukotriene B4 and D4 effects on human eosinophil and neutrophil motility in vitro. J Leukoc Biol 1994;55:183–191. 16. Desreumaux P, Bloget F, Seguy D, et al. Interleukin 3, granulocyte-macrophage colony-stimulating factor, and interleukin 5 in eosinophilic gastroenteritis. Gastroenterology 1996;110: 768 –774. 17. Bischoff SC, Mayer J, Nguyen QT, et al. Immunohistological assessment of intestinal eosinophil activation in patients with eosinophilic gastroenteritis and inflammatory bowel disease. Am J Gastroenterol 1999;94:3521–3529.
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18. Mishra A, Hogan SP, Lee JJ, et al. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. J Clin Invest 1999;103:1719 –1727. 19. Fuller R, Johnson M, Bye A. Fluticasone propionate–an update on preclinical and clinical experience. Respir Med 1995; 89(Suppl):3–18. 20. Lee A, Robertson T, Smith J, et al. Leukotriene receptor antagonists and synthesis inhibitors reverse survival in eosinophils of asthmatic individuals. Am J Respir Crit Care Med. 2000;161: 1881–1886.
Requests for reprints should be addressed to: Brian E. Daikh, MD Rheumatology Associate 51 Sewall Street Portland, ME 04102 E-mail: [email protected]
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