Acute Eosinophilic Colitis and Hypersensitivity Reaction Associated with Naproxen Therapy ALAN J. BRIDGES, M.D., JOHN B. MARSHALL, M.D., ALBERTOA.
onsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in clinical practice. The damaging effects of NSAIDs on gastroduodenal mucosa, which include ulceration and bleeding, are well known. Serious lower gastrointestinal tract side effects of NSAIDs are rare. We report a new lower gastrointestinal complication of NSAID therapy, acute eosinophilic colitis. The patient, who received naproxen (Naprosyne), also had manifestations of a generalized hypersensitivity reaction suggesting a common pathogenic mechanism.
She returned a week later for follow-up. Her symptoms and examination were unchanged. She had sustained a 5-kg weight loss. Laboratory evaluation included a white blood cell count of 14,800/ mm3 (with 40% eosinophils), hemoglobin 14.5 g/dL, platelet count 233,000/mm3, alkaline phosphatase 304 U/L (normal: 30 to 115 U/L), aspartate aminotransferase 69 U/L (normal: 0 to 40 U/L), and alanine aminotransferase 163 U/L (normal: 0 to 45 U/ L). Urinalysis was normal. A stool smear was positive for fecal leukocytes. Stool samples were negative for routine culture and for ova and parasites. A chest roentgenogram was normal. She was continued on symptomatic therapy. The diarrhea continued, and 3 weeks later flexible proctosigmoidoscopy was performed. This showed diffusely erythematous, mildly friable mucosa without frank ulcerations. Multiple biopsy specimens of the sigmoid colon were fixed in 10% buffered formalin and stained with hematoxylin and eosin. The sections showed extensive infiltration of the congested lamina propria by intact as well as degranulated eosinophils and a sprinkling of plasma cells. Acidic toluidine blue and Giemsa stains showed rare mucosal mast cells, some undergoing cellular degranulation. Eosinophilic exocytosis was noted in the mucosa and crypts with eosinophils also present in the luminal mucous (Figure 1). Naproxen was discontinued, and within 3 days the diarrhea had stopped. The liver function abnormalities had normalized when they were rechecked 1 week later. The eosinophil count was still elevated at that time (21% of 7,500 white blood cells). However, it was normal when rechecked 1 month later.
N
CASE REPORT A 57-year-old otherwise healthy woman was seen for hip and hand discomfort. Physical examination and radiographic evaluation revealed osteoarthritis. Naproxen was prescribed at a dose of 375 mg twice daily. She returned 3 weeks later, several days after the onset of watery non-bloody diarrhea, averaging 15 to 20 loose, small-volume stools per 24 hours. Her diarrhea was accompanied by mild abdominal cramping. She denied fever, chills, worsening of arthritic symptoms, unusual travel history, or exposure to others who were ill. There was no past history of allergies, asthma, or atopy. Her only medication was naproxen. At physical examination, her temperature was 365°C. The skin showed an erythematous macular rash on the neck, arms, buttocks, and lower extremities. Abdominal examination revealed mild distention, borborygmus, and mild diffuse tenderness without peritoneal signs. Rectal examination showed watery stool with semisolid fragments that were positive for occult blood. The remainder of the examination was negative. The patient was suspected of having infectious diarrhea and was treated with a liquid diet and Kaopectate. From the Divisions of ment of Medicine, (AJB. A), University of Missouri, Requests for reprints Department of Medicine, cine, One Hospital Drive, Manuscript submitted May 31, 1990.
526
October
1990
COMMENTS Although diarrhea occurs in up to 2% of patients taking NSAIDs, serious lower gastrointestinal tract complications are rare. Nonspecific colitis, resembling ulcerative colitis, has been described as the result of therapy using various NSAIDs [1,2]. The use of NSAIDs has also been associated with activation of quiescent idiopathic inflammatory bowel disease [3], with ulcerations of the colon [4], and with collagenous colitis [5]. Eosinophilic colitis associated with the use of
Rheumatology, Gastroenterology. the DepartJBM), and the Department of Pathology (AADSchool of Medicine, Columbia, Mlssouri65212. should be addressed to Alan J. Bridges, M.D., MA427, University of Missouri, School of MediColumbia, Missouri 65212. April 26, 1990, and accepted in revised form
The American
Journal
of Medicine
Volume
DIAZ-ARIAS, M.D., Columbia, Missouri
69
EOSINOPHILIC
COLITIS
WITH NAPROXEN
/ BRIDGES
ET AL
ment of symptoms within 3 weeks, a diffuse skin rash, peripheral blood eosinophilia, liver function abnormalities, and rapid resolution after discontinuation of naproxen. However, acute eosinophilic colitis, which our patient had, has not, to our knowledge, been reported in this setting. The severity of her illness and patient preference precluded drug rechallenge. The relationship of the hypersensitivity reaction to accumulation of tissue eosinophils in this case is intriguing. The role of the mast cell in this response may have been critical [lo]. We visualized only rare mucosal mast cells in a typically mast cell-abundant tissue [lo]. Some of the mast cells present were undergoing degranulation. Since detection of the mast cell by metachromatic staining requires the presence of intact granules, our findings suggest local release of mast cell mediators, including eosinophil chemoattractants. Thus, the hypersensitivity reaction to naproxen with activation of gastrointestinal mucosa mast cells may have played a role in the accumulation of colonic eosinophils. This case serves to alert clinicians to less frequent complications of NSAID therapy. ACKNOWLEDGMENT Special thanks to Drs. Frank Graziano, Dan Malone, and M. J. Rosenholtz for their thoughtful review.
Figure 1. Top, intact colonic mucosa with eosinophils within the epithelium and bowel lumen (arrows). Lamina propria with intact and degranulated eosinophils as well as a few plasma cells. Bottom, eosinophils within crypts (arrow) and lamina propria (hematoxylin and eosin, 40X).
NSAIDs has not been reported. We describe a case of acute eosinophilic colitis associated with naproxen therapy that rapidly resolved when the medication was discontinued. Most cases of eosinophilic gastroenteritis and enterocolitis are chronic and of unknown cause, although an allergic basis is most likely [6,7]. Gold is the only drug we could identify as being associated with eosinophilic enterocolitis [a]. Hypersensitivity reactions to NSAID therapy with peripheral blood and tissue eosinophilia are well described [9]. A number of the clinical features experienced by our patient were very suggestive of a hypersensitivity reaction, including the develop-
REFERENCES 1. Ravi S. Keat AC, Keat ECB Colitis caused by non-steroidal anti-inflammatory drugs. Postgrad Med J 1986; 6.2: 773-6. 2. Tanner AR, Raghunath AS. Colonic inflammation and nonsteroidal anti-inflammatory drug administration: an assessment of the frequency of the problem. Digestion 1988; 41: 116-20. 3. Kaufmann HJ. Taubin HL. Nonsteroidal anti-inflammatory drug activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-6. 4. Uribe A, Johansson C. Slezak P. Rubio C. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc 1986; 32:
242-3. 5. Giardiello FM, Hansen FC Ill, Lazenby AJ, eta). Collagenous colitis in setting of nonsteroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990: 35: 257-
60. 6. Klein NC, Hargrove RL, Sleisenger MH. Jeffries GH. Eosinophilicgastroenteritis. Medicine (Baltimore) 1970; 49: 299-319. 7. Naylor AR, Pollet JE. Eosinophilic colitis. Dis Colon Rectum 1985; 28: 615-8. 8. Martin DM, Goldman JA, Gilliam J, Nasrallah SM. Gold-induced eosinophils enterocolitis: response to oral cromolyn sodium. Gastroenterology 1981; 80: 1567-70. 9. O’Brien WM. Bagby GF. Rare adverse reactions to non-steroidal anti-inflammatory drugs. J Rheumatol 1985; 12: 13-20, 347-53. 562-7, 785-90. 10. Lemanske RF Jr, Atkins FM, Metcalfe DD. Gastrointestinal mast cells in health and disease. J Pediatr 1983; 103: 177-84, 343-51.
October
1990
The American
Journal
of Medicine
Volume
89
527
onsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in clinical practice. The damaging effects of NSAIDs on gastroduodenal mucosa, which include ulceration and bleeding, are well known. Serious lower gastrointestinal tract side effects of NSAIDs are rare. We report a new lower gastrointestinal complication of NSAID therapy, acute eosinophilic colitis. The patient, who received naproxen (Naprosyne), also had manifestations of a generalized hypersensitivity reaction suggesting a common pathogenic mechanism.
She returned a week later for follow-up. Her symptoms and examination were unchanged. She had sustained a 5-kg weight loss. Laboratory evaluation included a white blood cell count of 14,800/ mm3 (with 40% eosinophils), hemoglobin 14.5 g/dL, platelet count 233,000/mm3, alkaline phosphatase 304 U/L (normal: 30 to 115 U/L), aspartate aminotransferase 69 U/L (normal: 0 to 40 U/L), and alanine aminotransferase 163 U/L (normal: 0 to 45 U/ L). Urinalysis was normal. A stool smear was positive for fecal leukocytes. Stool samples were negative for routine culture and for ova and parasites. A chest roentgenogram was normal. She was continued on symptomatic therapy. The diarrhea continued, and 3 weeks later flexible proctosigmoidoscopy was performed. This showed diffusely erythematous, mildly friable mucosa without frank ulcerations. Multiple biopsy specimens of the sigmoid colon were fixed in 10% buffered formalin and stained with hematoxylin and eosin. The sections showed extensive infiltration of the congested lamina propria by intact as well as degranulated eosinophils and a sprinkling of plasma cells. Acidic toluidine blue and Giemsa stains showed rare mucosal mast cells, some undergoing cellular degranulation. Eosinophilic exocytosis was noted in the mucosa and crypts with eosinophils also present in the luminal mucous (Figure 1). Naproxen was discontinued, and within 3 days the diarrhea had stopped. The liver function abnormalities had normalized when they were rechecked 1 week later. The eosinophil count was still elevated at that time (21% of 7,500 white blood cells). However, it was normal when rechecked 1 month later.
N
CASE REPORT A 57-year-old otherwise healthy woman was seen for hip and hand discomfort. Physical examination and radiographic evaluation revealed osteoarthritis. Naproxen was prescribed at a dose of 375 mg twice daily. She returned 3 weeks later, several days after the onset of watery non-bloody diarrhea, averaging 15 to 20 loose, small-volume stools per 24 hours. Her diarrhea was accompanied by mild abdominal cramping. She denied fever, chills, worsening of arthritic symptoms, unusual travel history, or exposure to others who were ill. There was no past history of allergies, asthma, or atopy. Her only medication was naproxen. At physical examination, her temperature was 365°C. The skin showed an erythematous macular rash on the neck, arms, buttocks, and lower extremities. Abdominal examination revealed mild distention, borborygmus, and mild diffuse tenderness without peritoneal signs. Rectal examination showed watery stool with semisolid fragments that were positive for occult blood. The remainder of the examination was negative. The patient was suspected of having infectious diarrhea and was treated with a liquid diet and Kaopectate. From the Divisions of ment of Medicine, (AJB. A), University of Missouri, Requests for reprints Department of Medicine, cine, One Hospital Drive, Manuscript submitted May 31, 1990.
526
October
1990
COMMENTS Although diarrhea occurs in up to 2% of patients taking NSAIDs, serious lower gastrointestinal tract complications are rare. Nonspecific colitis, resembling ulcerative colitis, has been described as the result of therapy using various NSAIDs [1,2]. The use of NSAIDs has also been associated with activation of quiescent idiopathic inflammatory bowel disease [3], with ulcerations of the colon [4], and with collagenous colitis [5]. Eosinophilic colitis associated with the use of
Rheumatology, Gastroenterology. the DepartJBM), and the Department of Pathology (AADSchool of Medicine, Columbia, Mlssouri65212. should be addressed to Alan J. Bridges, M.D., MA427, University of Missouri, School of MediColumbia, Missouri 65212. April 26, 1990, and accepted in revised form
The American
Journal
of Medicine
Volume
DIAZ-ARIAS, M.D., Columbia, Missouri
69
EOSINOPHILIC
COLITIS
WITH NAPROXEN
/ BRIDGES
ET AL
ment of symptoms within 3 weeks, a diffuse skin rash, peripheral blood eosinophilia, liver function abnormalities, and rapid resolution after discontinuation of naproxen. However, acute eosinophilic colitis, which our patient had, has not, to our knowledge, been reported in this setting. The severity of her illness and patient preference precluded drug rechallenge. The relationship of the hypersensitivity reaction to accumulation of tissue eosinophils in this case is intriguing. The role of the mast cell in this response may have been critical [lo]. We visualized only rare mucosal mast cells in a typically mast cell-abundant tissue [lo]. Some of the mast cells present were undergoing degranulation. Since detection of the mast cell by metachromatic staining requires the presence of intact granules, our findings suggest local release of mast cell mediators, including eosinophil chemoattractants. Thus, the hypersensitivity reaction to naproxen with activation of gastrointestinal mucosa mast cells may have played a role in the accumulation of colonic eosinophils. This case serves to alert clinicians to less frequent complications of NSAID therapy. ACKNOWLEDGMENT Special thanks to Drs. Frank Graziano, Dan Malone, and M. J. Rosenholtz for their thoughtful review.
Figure 1. Top, intact colonic mucosa with eosinophils within the epithelium and bowel lumen (arrows). Lamina propria with intact and degranulated eosinophils as well as a few plasma cells. Bottom, eosinophils within crypts (arrow) and lamina propria (hematoxylin and eosin, 40X).
NSAIDs has not been reported. We describe a case of acute eosinophilic colitis associated with naproxen therapy that rapidly resolved when the medication was discontinued. Most cases of eosinophilic gastroenteritis and enterocolitis are chronic and of unknown cause, although an allergic basis is most likely [6,7]. Gold is the only drug we could identify as being associated with eosinophilic enterocolitis [a]. Hypersensitivity reactions to NSAID therapy with peripheral blood and tissue eosinophilia are well described [9]. A number of the clinical features experienced by our patient were very suggestive of a hypersensitivity reaction, including the develop-
REFERENCES 1. Ravi S. Keat AC, Keat ECB Colitis caused by non-steroidal anti-inflammatory drugs. Postgrad Med J 1986; 6.2: 773-6. 2. Tanner AR, Raghunath AS. Colonic inflammation and nonsteroidal anti-inflammatory drug administration: an assessment of the frequency of the problem. Digestion 1988; 41: 116-20. 3. Kaufmann HJ. Taubin HL. Nonsteroidal anti-inflammatory drug activate quiescent inflammatory bowel disease. Ann Intern Med 1987; 107: 513-6. 4. Uribe A, Johansson C. Slezak P. Rubio C. Ulcerations of the colon associated with naproxen and acetylsalicylic acid treatment. Gastrointest Endosc 1986; 32:
242-3. 5. Giardiello FM, Hansen FC Ill, Lazenby AJ, eta). Collagenous colitis in setting of nonsteroidal anti-inflammatory drugs and antibiotics. Dig Dis Sci 1990: 35: 257-
60. 6. Klein NC, Hargrove RL, Sleisenger MH. Jeffries GH. Eosinophilicgastroenteritis. Medicine (Baltimore) 1970; 49: 299-319. 7. Naylor AR, Pollet JE. Eosinophilic colitis. Dis Colon Rectum 1985; 28: 615-8. 8. Martin DM, Goldman JA, Gilliam J, Nasrallah SM. Gold-induced eosinophils enterocolitis: response to oral cromolyn sodium. Gastroenterology 1981; 80: 1567-70. 9. O’Brien WM. Bagby GF. Rare adverse reactions to non-steroidal anti-inflammatory drugs. J Rheumatol 1985; 12: 13-20, 347-53. 562-7, 785-90. 10. Lemanske RF Jr, Atkins FM, Metcalfe DD. Gastrointestinal mast cells in health and disease. J Pediatr 1983; 103: 177-84, 343-51.
October
1990
The American
Journal
of Medicine
Volume
89
527
