Warwick Selby

Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND Most patients with Crohns disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohns disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patients study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohns disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohns Colitis Australia, and the National Health and Medical Research Council.

Diagnosis and outcome of small bowel tumors found by capsule endoscopy: a three-center Australian experience.

OBJECTIVE:The objective of the study was to examine diagnosis and outcome in a series of patients with small bowel tumors detected by capsule endoscopy (CE) in three Australian centers.METHODS:Review of prospectively collected data from 416 CEs identified 27 tumors in 26 patients. Clinical parameters, tumor histology, and follow-up are reported.RESULTS:Twenty-seven tumors were identified in 26 patients (mean age 61 ± 13.7 yr). Indications for CE were obscure gastrointestinal (GI) bleeding (21), suspected tumor (3), abdominal pain (1), diarrhea (1). Prior radiology found a possible lesion in 8 of 23 (35%). Nine tumors were proven benign: hamartoma (4), cystic lymphangioma (1), primary amyloid (1), lipoma (1). Two lesions were non-neoplastic: heterotopic gastric mucosa and inflammatory fibroid polyp. Seventeen tumors were malignant: five adenocarcinomas, six carcinoids, two melanoma metastases, two gastrointestinal stromal tumors (GIST), one colon carcinoma metastasis, one non-Hodgkins lymphoma. Tumors were surgically resected in 23 patients. Resection was considered curative in 12 (52%). Mean duration of follow-up was 26 ± 13.7 months. Of the five patients with primary adenocarcinoma only one remains disease free. Three of the six with carcinoid tumors have had no recurrence up to 51 months postresection. Both patients with GIST are disease free. Anemia resolved after surgery in the patients with melanoma.CONCLUSIONS:Small bowel tumors are a significant finding at CE and are often missed by other methods of investigation. In many patients, detection of a tumor alters management and improves outcome. Even in malignant lesions, treatment is potentially curative in the absence of metastatic disease.

Complete small-bowel transit in patients undergoing capsule endoscopy: determining factors and improvement with metoclopramide

BACKGROUND Passage of the capsule endoscope to the colon occurs in only approximately three quarters of patients. This study assessed factors that might influence the completeness of small-bowel transit, including orally administered metoclopramide. METHODS Clinical and procedural parameters were recorded prospectively for 150 patients undergoing capsule endoscopy. Metoclopramide was not administered to the first 83 patients (Group 1) but was given orally (10 mg) to the subsequent 67 (Group 2). RESULTS Small-bowel transit was complete in 63 patients in Group 1 (76%). Gastric transit time was significantly longer when the capsule did not reach the colon than when it did (114.9 +/- 32.6 minutes vs. 26.6 +/- 2.9 minutes; p=0.007). Small-bowel transit time also was longer. The likelihood of complete small-bowel passage was not predicted by any clinical or procedural factor. In Group 2 (metoclopramide), the capsule reached the colon in 65 (97%) patients (OR 10.3: 95% CI[2.32, 93.55], p <0.001). This improvement was associated with a significant reduction in gastric transit time (47.9 +/- 9.0 minutes vs. 30.8 +/- 7.5 minutes; p=0.025). CONCLUSIONS Metoclopramide increases the likelihood of a complete small-bowel examination in patients undergoing capsule endoscopy.

Malignancy in a 19-Year Experience of Adult Celiac Disease

Malignancy has developed in 10 of 93 patients with celiac disease who attended this hospital from 1959 to 1978. Four patients developed lymphoma, 5 a squamous carcinoma of the esophagus, and 1 an adenocarcinoma of the ileum. Because the majority of patients were ingesting varying amounts of gluten at the time of their follow-up no conclusion can be drawn about the possible role of a gluten-free diet in the prevention of malignancy.

Use of 6-mercaptopurine in patients with inflammatory bowel disease previously intolerant of azathioprine

Both azathioprine and its active metabolite, 6-mercaptopurine, are of benefit in the treatment of inflammatory bowel disease, either in resistant cases, or for their steroid-sparing effect. Azathioprine treatment is limited in some patients by hypersensitivity reactions or other side effects. We report our experience in 11 patients previously unable to tolerate azathioprine for a variety of reasons, who were switched to 6-mercaptopurine. Of seven patients with ulcerative colitis and four patients with Crohns disease who were treated with 6-mercaptopurine following failed azathioprine therapy, six were able to successfully tolerate the substitute medication, with good response. Where patients have previously been intolerant of azathioprine yet ongoing indications for immunosuppressive therapy remain, a trial of 6-mercatopurine may be warranted. Given the similar efficacies of the two drugs in inflammatory bowel disease, these findings also favor the use of 6-mercaptopurine rather than the parent compound as initial therapy.

Detection of persistent vegetative bacteria and amplified viral nucleic acid from in-use testing of gastrointestinal endoscopes

Hospital-acquired infection attributed to inadequate decontamination of gastrointestinal endoscopes prompted an in use evaluation of recommended procedures. Specimens were obtained from the internal channels of 123 endoscopes before, during and after decontamination by flushing with saline and brushing with a sterile brush, and examined for vegetative bacteria by broth and plate culture. Four endoscopy units were tested; the chemical disinfectants used were: 2% glutaraldehyde in Centres 1 and 2 (automated) and Centre 3 (manual); peracetic acid in Centre 4 (automated). Samples from patients in Centre 1 with known chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV-1) infection were also examined for viral nucleic acid by ultracentrifugation, nucleic acid extraction, reverse transcription (for RNA) and polymerase chain reaction (PCR). No persistent vegetative bacteria were found following standard manual cleaning and disinfection for 20 min in 2% glutaraldehyde in Centres 2 and 3 (N = 37). At Centre 1, while plate culture yielded no growth, 34% of samples (10/29) grew vegetative bacteria in broth culture after cleaning and disinfection for 20 min in 2% glutaraldehyde. Investigation revealed an error in manual cleaning; no bacteria were detected in 37 samples taken after this was corrected. At Centre 4, despite the use of peracetic acid as a sterilant, three out of 20 (15%) of post decontamination samples grew bacteria; one contained persistent bacteria. HBV and HCV PCR analysis detected viral nucleic acid in three out of four and four out of six samples from viraemic patients undergoing endoscopy in Centre 1 during the period of improper manual washing. After proper cleaning was instituted, samples from nine out of nine HCV viraemic patients were negative. HIV RNA was detected in five of 14 samples taken from endoscopes after use on HIV positive patients but all post decontamination samples were negative. Detection of bacteria in washes from endoscope channels is a useful warning of a breakdown in decontamination practice. Inadequate brushing of internal channels may result in persistent HCV and HBV viral nucleic acid, the significance of which is not clear. These results reinforce the importance of adequate manual cleaning of endoscopes before chemical disinfection.

Non-small-bowel lesions detected by capsule endoscopy in patients with obscure GI bleeding

BACKGROUND Approximately two thirds of patients undergoing capsule endoscopy for obscure GI bleeding will have an abnormality found in the small intestine. This report describes 9 patients (4 men, 5 women) of 140 with obscure bleeding in whom a source of their blood loss was found in the stomach or the colon at capsule endoscopy. METHODS A review was made of a prospective database of 140 consecutive patients undergoing capsule endoscopy for obscure GI bleeding at a single center. Patients with a definite or likely cause of bleeding within reach of conventional upper or lower GI endoscopy were identified. RESULTS Three patients had gastric antral vascular ectasia and another an inflamed pyloric canal polyp. Two patients had actively bleeding cecal carcinoma, missed at previous colonoscopies. Two others had bleeding cecal angiodysplasia. The final patient had severe nonspecific cecal inflammation. The identification of these lesions was aided by the suspected blood indicator. All patients underwent endoscopic therapy or surgery for their non-small-bowel lesions. CONCLUSIONS Like push enteroscopy, capsule endoscopy also can identify lesions within reach of conventional endoscopy and colonoscopy. These subsequently can be treated successfully. The reasons why these lesions have been missed are unclear.

Can clinical features predict the likelihood of finding abnormalities when using capsule endoscopy in patients with GI bleeding of obscure origin

BACKGROUND Capsule endoscopy is becoming the investigation of choice for GI bleeding of obscure etiology. This study examined whether clinical or other features predict an increased likelihood of finding a lesion in patients with this type of bleeding. METHODS Clinical and other data were collected prospectively for 92 patients undergoing capsule endoscopy for GI bleeding of obscure origin. Patients were divided into two groups: those with overt bleeding (42 patients) and those with anemia alone (50 patients). The relationship between these data and the findings at capsule endoscopy was examined. RESULTS A definite or probable cause of bleeding was found in 60 patients (angiodysplasias 47, tumor 7, ulcer 3, gastric antral vascular ectasia 2). There was no difference between the two groups with respect to age, gender, mode of presentation, duration of bleeding, or need for transfusion. Lesions were found as often in patients who had only one preceding endoscopy and colonoscopy as in those who had multiple procedures. Colonic cleansing and cecal imaging by the capsule did not influence the result. Hospitalized patients were more likely to have an actively bleeding lesion detected. CONCLUSIONS Capsule endoscopy is equally useful in patients with overt and occult GI bleeding of obscure origin. Capsule endoscopy should be performed early in the evaluation of these patients.

Early Australian experience with infliximab, a chimeric antibody against tumour necrosis factor-α, in the treatment of Crohn's disease: is its efficacy augmented by steroid-sparing immunosuppressive therapy?

Abstract