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On the immunological basis for stress-induced reactivation of colitis in the rat
April 1 9 9 5
• ON THE IMMUNOLOGICAL BASIS FOR STRESS-INDUCED REACTIVATION OF COLITIS IN THE RAT. K.Jacobson K.McHugh, H.P.Weingarten, E.Svensjo, R.Brattsand, and S.M.Collins. IDRP, Department of Psychology, McMaster University, Hamilton, Ontario, Canada, and Astra Draco, Lund, Sweden. We have recently shown in rats that mild restraint stress causes a reactivation of colitis induced 6 weeks previously by intrarectal (ir) administration of trinitrobermene sulfonic acid (TNB). In the present study we explored mechanisms underlying the stress-induced reactivationby determining whether the response could be prevented by corticosteroid administration during the interval between recovery from colitis and the induction of stress. We used a locally active steroid, budesonide, in order to minimize impact on the hypothalamicpituitary axis and the stress response per se. We also determined whether stress reactivation of colitis was dependent on T lymphocyte function by performing studies in athymic rats and their euthymic littermates. Colitis was induced by ir administration of TNB (30 mg in 0.25 ml of 50% ethanol) while control rats received 0.25 ml 50% ethanol. Mild restraint stress was applied on days 40-42 post-induction of colitis. Budesonide (300/zg/kg) was administered ir on days 28-32 post-colitis. Measurements of myeloperoxidase (MPO) activity in units/mg of tissue were used to monitor inflammation in the distal colon. Stress resulted in a > 5-fold increase in MPO activity in the distal colon of normal Sprague Dawley rats that received TNB 6 weeks previously, but did not alter MPO in ethanol-treated controls. Administration of budesonide 8 days prior to the application of stress resulted in a significant abrogation of the stress-induced changes in MPO activity; MPO activity fell from 1.975:0.55 in untreated oolitic rats to 0.265 +0.108 in budesonide-treated rats following stress, and this value was not statistically different from that observed in budesonidetreated control rats. In athymic rats, MPO activity was similar in both TNB treated and control athymics at day 42 (15.76_+5.6 vs 12.87+1.14) respectively; P>0.05). Mild restraint stress caused a decrease in MPO activity in both TNBtreated (from 15.76--+5.6 to 3.34+1.58) and in untreated athymic rats (from 12.87--+1.14 to 2.794-1.4, P=0.001), whereas stress produced the expected increase in MPO activity (from 0.46_+0.14 to 1.345:0.38, P=0.05) in TNBtreated euthymic rats. These results indicate that topical steroid pretreatment 8 days prior to stress prevented the reactivation of colitis, suggestingthat this reactivation process requires the presence of a steroid-sensitive cell in the colon. The absence of an increase in MPO activity in athymic rats after stress suggests that T lymphocytes are a pre-requisite for the expression of str&ss-induced reactivation of colitis in this model.
ABDOMINAL AND PELVIC ABSCESSES IN CROHN'S DISEASE: RESULTS OF NON4NVASNE AND SURGICAL MANAGEMENT. A Jawhari, C Ong, MA Kamm, A Forbes. St Mark's Hospital, London, UK. Intra-abdominal abscesses occur in up to 30% of patients with Crohn's disease, causing appreciable morbidity and mortality. Traditional management has been surgical, but percutaneous drainage offers an alternative. To determine optimum management we reviewed the outcome of both approaches. Methods: Patients with Cmhn's related abdominal and pelvic abscesses, were identif'md from a prospective database, comprising a total of 531 Crohn's patients admitted 1156 times between 1991 and 1994. Periana! abscesses and abscesses within 3 mooths of surgery were exclud~=,d.Mean follow up was for 18 months. Patients: Of 35 patients (14 male, median age 35 years, median disease duration 12 years) treated, 45% had extensive ileocolonic disease, 35% had Iocatised ileocacal or anastomotic disease and 20% had isolated colonic or small bowel disease. Abscesses were 61% abdominal, 22% retroperitoneal and 17% pelvic. 75% had chronic active disease, and 47% had been on steroids for more than 6 months. Abdominal mass was present in 22 patients (64%) and enterocutaneous fistula in 9 (26%). There was subacute obstruction in 6 patients (t8%). 75% had had previous surgery, including 36% with surgery for abscess or enterocutaneous fistula. Bowel to abscess communication was demonstrated radiologically in 21 cases (61%), and originated from a previous anastomosis In 12 (35%). Outcome: Percutaneous drainage was performed in 8. Four abscesses resolved (of whom 1 had a bowel to abscess communication), while 4 needed surgery for recurrent abscess (2), and enterocutaneous fistula (2). Overall surgery was required in 27 patients. A stoma was created in only 4 patients. Post-operative abscess recurrence occurred in 9 (27%), enterocutaneous fistula in 4 (11%, 2 new), short bowel in 6 (17%), bowel obstruction in 3 (8%). There were no deaths. At 3 months 64% were well. Pre-.operative. steroids did not influence complication rate. Conclusions: Pemutaneous drainage was successful in half the patients in whom it was performed. It has a role in management, especially if there is no bowel-abscess communication, and may obviate the need for surgery. Intra-abdominel abscesses have a high complication rate, but can be managed without mertality,
Immunology, Microbiology, and Inflammatory Disorders
A843
ASCITES AS A C L I N I C A L MANIFESTATION OF ANTIBIOTICASSOCIATED PSEUDOMEMBRANOUS COLITIS. S.F. Jafri and LB. Marshall. Division of Gastroenterology, University of Missouri School of Medicine and Harry S. Tt~]mzn VA Hospital, Columbia, MO. We recently saw a patient with severe pseudomembranous colitis (PMC) due to Clostridium difficile infection who had moderate ascites and diffuse thickening of the colon on an abdominal CT scan. The patient subsequently died; autopsy revealed no other source for ascites except for PMC. How often ascites complicates C. difficle infection and PMC is unknown and was the subject of this investigation. W e examined the charts of all inpatients who the laboratories at our hospitals reported as having a positive stool C. difficile toxin assay over a one year period. Of 228 such patients, 36 had an abdominal CT scan (n = 25) or ultrasound (n = 11) at about the time that the C. difficile infection was diagnosed. Twenty-one of these patients were noted to have ascites on their imaging study. In only one of the patients was PMC (which was clinically severe) clearly the cause of ascites. Thickening of the colon on CT was noted. The cause of ascites in the remaining patients was: congestive heart failure (n = 4), cirrhosis of the liver (n = 3), recent abdominal surgery or complications (11 = 5), Crohn's disease (n = 1), and diffuse anasarca due to sepsis (11 = 1). In 5 other patients, the cause of minimal or mild ascites was undetermined but felt unlikely to be due to C. difficile infection or PMC. Thickening of the colon was not noted on C T or US in any of these 5. We conclude: (1) In most patients with concomitant C. difficile infection and ascites, the latter is explanable on the basis of some other cause besides the C. difficile infection. (2) Ascites can directly complicate C. difficile infections of the GI tract, but is relatively uncommon. It implies severe PMC when it occurs. CT scanning in such patients shows associated nonspecific diffuse colonic thickening.
MICROSCOPIC COLITIS: WIDENING THE DEFINITION
A. Jawhar~, M. Sheaf, A. Forbes, M. A. Kamm, I. C. Talbot. St. Mark's Hospital, City Road, London. Microscopic Colitls refers to chronic idiopathic watery diarrhoea with histological but no radiological or endoscopic abnormality. The histological criteria, which embrace lymphocytic (LC) and collagenous colitis (CC), are: i n c r e a s e d intraepithelial and lamina propria lymphocytes, surface epithelial damage, and in CC a thickened collagen plate. We believe a histological variant can present with an identical clinical syndrome. Patients: (i) 12 patients (5 male, mean age 49 years) with diarrhea for more than six months had normal blood tests, macroscopic bowel appearance, and microbiology. Mean duration of symptoms 3 years (range 0.5-20 years). Associated conditions were: arthritis(4), hypothyroidism (i), and diabetes (1).Previous histology failed to fulfil criteria for LC or CC. (2) Results were compared with established cases of LC (7), and CC (5) (11 female, mean age of 55). Methods: Histology was reviewed independently by 2 pathologists, and only cases with histological conoensus included. Biopsies were assessed for: crypt distortion, subepithelial collagen band, surface epithelial damage, inflammatory infiltrate in epithelium, crypts & lamina propria. Results: The major finding in all 12 of group (i), was mixed inflammatory infiltrate in the lamina prepria, including 6 with excess eosinophils. Mild infiltrate only was seen in the surface epithelium (n=8),in the crypt epithelium (n=9), with mild crypt distortion (n=5). No biopsy had an abnormal collagen band. Group (2) had prominent epithelial inflammation and fulfilled standard criteria. Concl~sion: These patients with identical clinical features to LC and CC have distinct histology which may represent the milder end of the microscopic colitis spectrum. These histological findings, often regarded as non-specific, appear to be clinically significant.
• ON THE IMMUNOLOGICAL BASIS FOR STRESS-INDUCED REACTIVATION OF COLITIS IN THE RAT. K.Jacobson K.McHugh, H.P.Weingarten, E.Svensjo, R.Brattsand, and S.M.Collins. IDRP, Department of Psychology, McMaster University, Hamilton, Ontario, Canada, and Astra Draco, Lund, Sweden. We have recently shown in rats that mild restraint stress causes a reactivation of colitis induced 6 weeks previously by intrarectal (ir) administration of trinitrobermene sulfonic acid (TNB). In the present study we explored mechanisms underlying the stress-induced reactivationby determining whether the response could be prevented by corticosteroid administration during the interval between recovery from colitis and the induction of stress. We used a locally active steroid, budesonide, in order to minimize impact on the hypothalamicpituitary axis and the stress response per se. We also determined whether stress reactivation of colitis was dependent on T lymphocyte function by performing studies in athymic rats and their euthymic littermates. Colitis was induced by ir administration of TNB (30 mg in 0.25 ml of 50% ethanol) while control rats received 0.25 ml 50% ethanol. Mild restraint stress was applied on days 40-42 post-induction of colitis. Budesonide (300/zg/kg) was administered ir on days 28-32 post-colitis. Measurements of myeloperoxidase (MPO) activity in units/mg of tissue were used to monitor inflammation in the distal colon. Stress resulted in a > 5-fold increase in MPO activity in the distal colon of normal Sprague Dawley rats that received TNB 6 weeks previously, but did not alter MPO in ethanol-treated controls. Administration of budesonide 8 days prior to the application of stress resulted in a significant abrogation of the stress-induced changes in MPO activity; MPO activity fell from 1.975:0.55 in untreated oolitic rats to 0.265 +0.108 in budesonide-treated rats following stress, and this value was not statistically different from that observed in budesonidetreated control rats. In athymic rats, MPO activity was similar in both TNB treated and control athymics at day 42 (15.76_+5.6 vs 12.87+1.14) respectively; P>0.05). Mild restraint stress caused a decrease in MPO activity in both TNBtreated (from 15.76--+5.6 to 3.34+1.58) and in untreated athymic rats (from 12.87--+1.14 to 2.794-1.4, P=0.001), whereas stress produced the expected increase in MPO activity (from 0.46_+0.14 to 1.345:0.38, P=0.05) in TNBtreated euthymic rats. These results indicate that topical steroid pretreatment 8 days prior to stress prevented the reactivation of colitis, suggestingthat this reactivation process requires the presence of a steroid-sensitive cell in the colon. The absence of an increase in MPO activity in athymic rats after stress suggests that T lymphocytes are a pre-requisite for the expression of str&ss-induced reactivation of colitis in this model.
ABDOMINAL AND PELVIC ABSCESSES IN CROHN'S DISEASE: RESULTS OF NON4NVASNE AND SURGICAL MANAGEMENT. A Jawhari, C Ong, MA Kamm, A Forbes. St Mark's Hospital, London, UK. Intra-abdominal abscesses occur in up to 30% of patients with Crohn's disease, causing appreciable morbidity and mortality. Traditional management has been surgical, but percutaneous drainage offers an alternative. To determine optimum management we reviewed the outcome of both approaches. Methods: Patients with Cmhn's related abdominal and pelvic abscesses, were identif'md from a prospective database, comprising a total of 531 Crohn's patients admitted 1156 times between 1991 and 1994. Periana! abscesses and abscesses within 3 mooths of surgery were exclud~=,d.Mean follow up was for 18 months. Patients: Of 35 patients (14 male, median age 35 years, median disease duration 12 years) treated, 45% had extensive ileocolonic disease, 35% had Iocatised ileocacal or anastomotic disease and 20% had isolated colonic or small bowel disease. Abscesses were 61% abdominal, 22% retroperitoneal and 17% pelvic. 75% had chronic active disease, and 47% had been on steroids for more than 6 months. Abdominal mass was present in 22 patients (64%) and enterocutaneous fistula in 9 (26%). There was subacute obstruction in 6 patients (t8%). 75% had had previous surgery, including 36% with surgery for abscess or enterocutaneous fistula. Bowel to abscess communication was demonstrated radiologically in 21 cases (61%), and originated from a previous anastomosis In 12 (35%). Outcome: Percutaneous drainage was performed in 8. Four abscesses resolved (of whom 1 had a bowel to abscess communication), while 4 needed surgery for recurrent abscess (2), and enterocutaneous fistula (2). Overall surgery was required in 27 patients. A stoma was created in only 4 patients. Post-operative abscess recurrence occurred in 9 (27%), enterocutaneous fistula in 4 (11%, 2 new), short bowel in 6 (17%), bowel obstruction in 3 (8%). There were no deaths. At 3 months 64% were well. Pre-.operative. steroids did not influence complication rate. Conclusions: Pemutaneous drainage was successful in half the patients in whom it was performed. It has a role in management, especially if there is no bowel-abscess communication, and may obviate the need for surgery. Intra-abdominel abscesses have a high complication rate, but can be managed without mertality,
Immunology, Microbiology, and Inflammatory Disorders
A843
ASCITES AS A C L I N I C A L MANIFESTATION OF ANTIBIOTICASSOCIATED PSEUDOMEMBRANOUS COLITIS. S.F. Jafri and LB. Marshall. Division of Gastroenterology, University of Missouri School of Medicine and Harry S. Tt~]mzn VA Hospital, Columbia, MO. We recently saw a patient with severe pseudomembranous colitis (PMC) due to Clostridium difficile infection who had moderate ascites and diffuse thickening of the colon on an abdominal CT scan. The patient subsequently died; autopsy revealed no other source for ascites except for PMC. How often ascites complicates C. difficle infection and PMC is unknown and was the subject of this investigation. W e examined the charts of all inpatients who the laboratories at our hospitals reported as having a positive stool C. difficile toxin assay over a one year period. Of 228 such patients, 36 had an abdominal CT scan (n = 25) or ultrasound (n = 11) at about the time that the C. difficile infection was diagnosed. Twenty-one of these patients were noted to have ascites on their imaging study. In only one of the patients was PMC (which was clinically severe) clearly the cause of ascites. Thickening of the colon on CT was noted. The cause of ascites in the remaining patients was: congestive heart failure (n = 4), cirrhosis of the liver (n = 3), recent abdominal surgery or complications (11 = 5), Crohn's disease (n = 1), and diffuse anasarca due to sepsis (11 = 1). In 5 other patients, the cause of minimal or mild ascites was undetermined but felt unlikely to be due to C. difficile infection or PMC. Thickening of the colon was not noted on C T or US in any of these 5. We conclude: (1) In most patients with concomitant C. difficile infection and ascites, the latter is explanable on the basis of some other cause besides the C. difficile infection. (2) Ascites can directly complicate C. difficile infections of the GI tract, but is relatively uncommon. It implies severe PMC when it occurs. CT scanning in such patients shows associated nonspecific diffuse colonic thickening.
MICROSCOPIC COLITIS: WIDENING THE DEFINITION
A. Jawhar~, M. Sheaf, A. Forbes, M. A. Kamm, I. C. Talbot. St. Mark's Hospital, City Road, London. Microscopic Colitls refers to chronic idiopathic watery diarrhoea with histological but no radiological or endoscopic abnormality. The histological criteria, which embrace lymphocytic (LC) and collagenous colitis (CC), are: i n c r e a s e d intraepithelial and lamina propria lymphocytes, surface epithelial damage, and in CC a thickened collagen plate. We believe a histological variant can present with an identical clinical syndrome. Patients: (i) 12 patients (5 male, mean age 49 years) with diarrhea for more than six months had normal blood tests, macroscopic bowel appearance, and microbiology. Mean duration of symptoms 3 years (range 0.5-20 years). Associated conditions were: arthritis(4), hypothyroidism (i), and diabetes (1).Previous histology failed to fulfil criteria for LC or CC. (2) Results were compared with established cases of LC (7), and CC (5) (11 female, mean age of 55). Methods: Histology was reviewed independently by 2 pathologists, and only cases with histological conoensus included. Biopsies were assessed for: crypt distortion, subepithelial collagen band, surface epithelial damage, inflammatory infiltrate in epithelium, crypts & lamina propria. Results: The major finding in all 12 of group (i), was mixed inflammatory infiltrate in the lamina prepria, including 6 with excess eosinophils. Mild infiltrate only was seen in the surface epithelium (n=8),in the crypt epithelium (n=9), with mild crypt distortion (n=5). No biopsy had an abnormal collagen band. Group (2) had prominent epithelial inflammation and fulfilled standard criteria. Concl~sion: These patients with identical clinical features to LC and CC have distinct histology which may represent the milder end of the microscopic colitis spectrum. These histological findings, often regarded as non-specific, appear to be clinically significant.