Surinder K. Mann

Water-aided colonoscopy: a systematic review

BACKGROUND Water-aided methods for colonoscopy are distinguished by the timing of removal of infused water, predominantly during withdrawal (water immersion) or during insertion (water exchange). OBJECTIVE To discuss the impact of these approaches on colonoscopy pain and adenoma detection rate (ADR). DESIGN Systematic review. SETTING Randomized, controlled trial (RCT) that compared water-aided methods and air insufflation during colonoscope insertion. PATIENTS Patients undergoing colonoscopy. INTERVENTION Medline, PubMed, and Google searches (January 2008-December 2011) and personal communications of manuscripts in press were considered to identify appropriate RCTs. MAIN OUTCOME MEASUREMENTS Pain during colonoscopy and ADR. RCTs were grouped according to whether water immersion or water exchange was used. Reported pain scores and ADR were tabulated based on group assignment. RESULTS Pain during colonoscopy is significantly reduced by both water immersion and water exchange compared with traditional air insufflation. The reduction in pain scores was qualitatively greater with water exchange as compared with water immersion. A mixed pattern of increases and decreases in ADR was observed with water immersion. A higher ADR, especially proximal to the splenic flexure, was obtained when water exchange was implemented. LIMITATIONS Differences in the reports limit application of meta-analysis. The inability to blind the colonoscopists exposed the observations to uncertain bias. CONCLUSION Compared with air insufflation, both water immersion and water exchange significantly reduce colonoscopy pain. Water exchange may be superior to water immersion in minimizing colonoscopy discomfort and in increasing ADR. A head-to-head comparison of these 3 approaches is required.

Options for screening colonoscopy without sedation: a pilot study in United States veterans

Background  The direct and indirect costs of sedation limit access to screening colonoscopy amongst United States veterans.

Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribosomal DNA (rDNA) quantification and correlations with immune activation.

Background:The relationship between gut microbial community composition at the higher-taxonomic order level and local and systemic immunologic abnormalities in HIV disease may provide insight into how bacterial translocation impacts HIV disease. Methods:Antiretroviral-naive patients with HIV underwent upper endoscopy before and 9 months after starting antiretroviral treatment. Duodenal tissue was paraffin-embedded for immunohistochemical analysis and digested for fluorescence activated cell sorting for T-cell subsets and immune activation (CD38+/HLA-DR+) enumeration. Stool samples were provided from patients and control subjects for comparison. Metagenomic microbial DNA was extracted from feces for optimized 16S ribosomal RNA gene (rDNA) real-time quantitative polymerase chain reaction assays designed to quantify panbacterial loads and the relative abundances of proinflammatory Enterobacteriales order and the dominant Bacteroidales and Clostridiales orders. Results:Samples from 10 HIV subjects before initiating and from six subjects receiving antiretroviral treatment were available for analysis. There was a trend for a greater proportion of Enterobacteriales in HIV-positive subjects compared with control subjects (P = 0.099). There were significant negative correlations between total bacterial load and duodenal CD4+ and CD8+ T-cell activation levels (r = −0.74, P = 0.004 and r = −0.67, P = 0.013, respectively). The proportions of Enterobacteriales and Bacteroidales were significantly correlated with duodenal CD4+ T-cell depletion and peripheral CD8+ T-cell activation, respectively. Conclusions:These data represent the first report of quantitative molecular and cellular correlations between total/universal and order-level gut bacterial populations and gastrointestinal-associated lymphoid tissue levels of immune activation in HIV-infected subjects. The correlations between lower overall 16S rDNA levels and tissue immune activation suggest that the gut microbiome may contribute to immune activation and influence HIV progression.

A randomized, controlled trial to confirm the beneficial effects of the water method on U.S. veterans undergoing colonoscopy with the option of on-demand sedation

BACKGROUND Sedation for colonoscopy discomfort imposes a recovery-time burden on patients. The water method permitted 52% of patients accepting on-demand sedation to complete colonoscopy without sedation. On-site and at-home recovery times were not reported. OBJECTIVE To confirm the beneficial effect of the water method and document the patient recovery-time burden. DESIGN Randomized, controlled trial, with single-blinded, intent-to-treat analysis. SETTING Veterans Affairs outpatient endoscopy unit. PATIENTS This study involved veterans accepting on-demand sedation for screening and surveillance colonoscopy. INTERVENTION Air versus water method for colonoscope insertion. MAIN OUTCOME MEASUREMENTS Proportion of patients completing colonoscopy without sedation, cecal intubation rate, medication requirement, maximum discomfort (0 = none, 10 = severe), procedure-related and patient-related outcomes. RESULTS One hundred veterans were randomized to the air (n = 50) or water (n = 50) method. The proportions of patients who could complete colonoscopy without sedation in the water group (78%) and the air group (54%) were significantly different (P = .011, Fisher exact test), but the cecal intubation rate was similar (100% in both groups). Secondary analysis (data as Mean [SD]) shows that the water method produced a reduction in medication requirement: fentanyl, 12.5 (26.8) μg versus 24.0 (30.7) μg; midazolam, 0.5 (1.1) mg versus 0.94 (1.20) mg; maximum discomfort, 2.3 (1.7) versus 4.9 (2.0); recovery time on site, 8.4 (6.8) versus 12.3 (9.4) minutes; and recovery time at home, 4.5 (9.2) versus 10.9 (14.0) hours (P = .049; P = .06; P = .0012; P = .0199; and P = .0048, respectively, t test). LIMITATIONS Single Veterans Affairs site, predominantly male population, unblinded examiners. CONCLUSION This randomized, controlled trial confirms the reported beneficial effects of the water method. The combination of the water method with on-demand sedation minimizes the patient recovery-time burden. ( CLINICAL TRIAL REGISTRATION NUMBER NCT00920751.).

Capsule endoscopy's impact on clinical management and outcomes: a single-center experience with 145 patients.

BACKGROUND:Capsule endoscopy (CE) is a new technology that has been shown to have superior diagnostic yield compared with other methods of evaluating the small bowel. However, there have not been many studies supporting capsule endoscopys impact on clinical outcomes. This study is a chart review evaluating the diagnostic yield and the impact of CE on management and clinical outcomes.METHODS:Retrospective chart review was performed on 145 patients who had undergone capsule endoscopy. Demographic characteristics, indication, prior diagnostic tests, capsule findings, interventions, and clinical outcomes up to 8 months following CE were evaluated. Indications included five main categories that were overt gastrointestinal (GI) bleed, occult GI bleed, abdominal pain, Crohns disease, and iron deficiency anemia. Findings on capsule endoscopy were classified into angiodysplasias, ulcers, gastritis and/or duodenitis, ulcers suggestive of Crohns and normal findings. Interventions performed based on capsule findings were recorded, which included the discontinuation of nonsteroidal anti-inflammatory drugs (NSAIDS), further diagnostic or therapeutic studies, increase in medications, and surgery. Positive outcomes including stabilization or improvement of hemoglobin, decreased need for transfusions, improved symptoms of pain, and a decrease in medications based on interventions were assessed.RESULTS:There were 145 patients who underwent CE. The indications for CE were overt GI bleed (38%), occult GI bleed (22%), abdominal pain (20%), Crohns (12%), iron deficiency anemia (2.7%), and miscellaneous (4%). Eighty percent achieved completion and 6 patients had complications of capsule retention with 4 requiring surgery. The overall diagnostic yield was 69% and included findings of angiodysplasias (24%), intestinal ulcers (13%) gastritis or duodenitis (13.8%), ulcers suggestive of Crohns disease (8.9%), and mass or polyp (3.4%). Based on capsule findings, 35.8% of patients had an intervention. Of the patients who received intervention, 71.7% had a positive clinical outcome (P = 0.032).CONCLUSIONS:The high diagnostic yield of CE influences clinical management leading to improved outcomes. However, the utility of CE may be greater in patients who are referred for certain indications or have specific findings. Additional studies are needed to clarify the role of capsule endoscopy in the evaluation of various indications as well as identify factors associated with positive outcomes.

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Gastrointestinal-associated lymphoid tissue immune reconstitution in a randomized clinical trial of raltegravir versus non-nucleoside reverse transcriptase inhibitor-based regimens.

Objectives:To examine immune restoration in duodenal tissue and correlates of reduction of immune activation in chronic HIV-infected patients randomized to different treatment regimens. Design:Randomized clinical trial (RCT) comparing raltegravir to a non-nucleoside reverse transcriptase inhibitor-based regimen, both with fixed-dose tenofovir difumerate/emtricitabine. Methods:Antiretroviral therapy (ART)-naive volunteers underwent upper endoscopy for duodenal biopsies before and after 9 months of therapy. Tissue was paraffin-embedded for immunohistochemistry or digested into single-cell suspensions for flow cytometry of lymphocyte subsets and activation phenotype. Plasma-soluble CD14 levels were measured as a surrogate for bacterial translocation. Results:Sixteen HIV-positive and seven control individuals completed study procedures. Small increases in duodenal lamina propria CD4+ T-cell numbers were observed, especially when viewed relative to populations in control volunteers, with no differences between treatment arms. The increase in CD4+ T-cell percentage was due largely to declines in CD8+ T-cell numbers, which were disproportionately increased compared to peripheral blood and controls. Patients randomized to the raltegravir arm had consistent declines in both sCD14 levels and CD8+ T-cell numbers in the duodenal tissue lamina propria. Conclusions:This first RCT of lymphocyte population restoration in duodenal tissue demonstrates more modest increases in CD4+ T-cell numbers during the first 9 months of therapy than when considering CD3/CD4 percentages only. Although reduced after 9 months of ART, disproportional increased CD8 populations persist in duodenal gastrointestinal-associated lymphoid tissue (GALT). Local rather than systemic antigenic stimulation appears to be driving expanded CD8+ T lymphocytes in GALT. Factors other than viral-induced CD8 expansion may be contributing to this local immunologic response.

Extended flexible sigmoidoscopy performed by colonoscopists for colorectal cancer screening: a pilot study

Background  Caecal intubation can be achieved by extended flexible sigmoidoscopy in 32% of patients.

Improved diagnostic yield with severity of bleeding

OBJECTIVE:  Video capsule endoscopy (VCE) is an important tool for non‐invasive imaging of the small bowel. Whether there is a dose‐related effect of anemia severity on the diagnostic yield of VCE is unknown. The aim of this study was to determine the influence of anemia severity on VCE outcome measures.

Role of Intestinal Myofibroblasts in HIV-Associated Intestinal Collagen Deposition and Immune Reconstitution following Combination Antiretroviral Therapy

Objective:To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in gut-associated lymphoid tissue. Design:Profibrotic changes within the secondary lymphoid organs and mucosa have been implicated in failed immune reconstitution following effective combination antiretroviral therapy (cART). Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are nonprofessional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen. Methods:Duodenal biopsies, obtained from patients naive to cART, underwent trichrome staining and were examined for tissue growth factor-beta (TGF-&bgr;) expression. Combined immunostaining and second harmonic generation analysis were used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine IMF activation and Toll-like receptor (TLR)4 expression. Finally, primary IMF cultures were stimulated with lipopolysaccharide to demonstrate the expression of the inflammatory biomarkers. Results:The expression of the fibrosis-promoting molecule, TGF-&bgr;1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4+ recovery. The increase in TGF-&bgr;1 coincided with an increase in collagen deposition in the duodenal mucosa in the tissue area adjacent to the IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-&bgr;1, and interleukin-6. Conclusion:Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes, and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.