The Efficacy of 4 Liters of Clear Liquids for Small Bowel Preparation Prior to Video Capsule Endoscopy.

BACKGROUND/AIMS: Optimal small bowel (SB) preparation for video capsule endoscopy (VCE) is controversial. Our study aimed to support the use of a specified volume of 4 liters of clear liquids for bowel preparation for VCE. METHODS: A retrospective review of 284 patients who underwent SB preparation with 2 liters of polyethylene glycol (PEG) and 284 patients who had 4 liters of clear liquid preparation. We analyzed image quality, endoscopic findings, completion rate, and transit times. RESULTS: The 4-liter clear liquid group had significantly higher mean image quality scores when compared to the PEG group (2.908±0.77 to 2.669±0.64, p<0.0001), as well as more studies with adequate preparation (72% to 64%, p=0.0214). Although the PEG group had more endoscopic findings on VCE (40% to 23%, p<0.0001), there was a significant difference in the indications for the procedure between the groups. There was no difference in the capsule completion rate or SB transit time. CONCLUSION: Our data demonstrate significantly higher mean image quality scores when using a specified volume of 4 liters of clear liquid compared to 2 liters of PEG. This study supports the growing evidence of the effectiveness of a 4-liter clear liquid SB preparation as opposed to PEG for VCE.

Delayed gastrointestinal-associated lymphoid tissue reconstitution in duodenum compared with rectum in HIV-infected patients initiating antiretroviral therapy.

BACKGROUND: We aimed to characterize the impact of antiretroviral therapy (ART) initiation on gastrointestinal-associated lymphoid tissue at various sites along the gastrointestinal site. METHODOLOGY: Peripheral blood and duodenal and rectal biopsies were obtained from 12 HIV to 33 treatment-naive HIV participants at baseline and after 9 months ART. Tissue was digested for immunophenotyping. Inflammatory, bacterial translocation and intestinal damage markers were measured in plasma. RESULTS: Twenty-six HIV patients completed follow-up. The lowest reconstitution of CD4 T cells and the lowest CD4/CD8 ratio during ART compared with blood were observed in the duodenum with the rectum being either intermediate or approaching blood levels. Regulatory T cells were in higher proportions in the duodenum than the rectum and neither declined significantly during ART. Several correlations with biomarkers of microbial translocation were observed including increases in lipoteichoic acid levels, which reflects Gram-positive bacterial translocation, correlated with increases in %CD4 T cells in the duodenum (Rho 0.773, P = 0.033), and with decreases in duodenal regulatory T-cell populations (Rho -0.40, P = 0.045). CONCLUSION: HIV-mediated immunological disruption is greater in the duodenum than rectum and blood before and during ART. Small intestine damage may represent a unique environment for T-cell depletion, which might be attenuated by interaction with Gram-positive bacteria.

Clear Liquids versus Polyethylene Glycol Preparation for Video Capsule Endoscopy of the Small Bowel: A Randomized Controlled Trial.

BACKGROUND: An effective bowel cleanse can improve the imaging quality of video capsule endoscopy (VCE). We aimed to further investigate the optimal small bowel cleanse method by comparing the efficacy of 4 L of clear liquids, 2 L of polyethylene glycol (PEG), and 4 L of PEG on the image quality of VCE. METHODS: A randomized controlled, non-inferiority trial was performed comparing 4 L of clear liquids (Group A), 2 L of PEG (Group B), and 4 L of PEG (Group C). The primary endpoint was image quality between the groups. The secondary endpoints included patient tolerability and side effects. RESULTS: Eighty-one patients were analyzed in group A, 84 patients were analyzed in group B, and 80 patients were analyzed in group C. Image quality scores revealed 4 L of clear liquids to be non-inferior to 2 L of PEG, and 2 L of PEG to be non-inferior to 4 L of PEG (p < 0.0167). Group A had a lower difficulty of completion rate than Group B and Group C and a lower rate of side effects when compared to Group C (p < 0.0167). CONCLUSION: Four liters of clear liquids should be considered a routine method for small bowel preparation prior to VCE.

Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

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

[This corrects the article DOI: 10.1371/journal.ppat.1005381.].

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.

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-ß) 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-ß1, is significantly increased in duodenal biopsies from HIV patients naïve to cART, and negatively correlated with subsequent peripheral CD4(+) recovery. The increase in TGF-ß1 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-ß1, 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.

Impact of water exchange colonoscopy on serum sodium and potassium levels: an observational study.

BACKGROUND: Concerns over the hypothetical adverse effects of water absorption and the disturbance of serum sodium and potassium levels prompted a quality assurance evaluation of water exchange (WE) colonoscopy. AIM: The purpose of this study was to evaluate the balance of water infused and suctioned in WE colonoscopy, and to quantify the acute impact on serum levels of sodium and potassium. METHODS: Prospectively collected quality monitoring data of patients undergoing screening and surveillance colonoscopy at the Sacramento Veterans Affairs Medical Center were analyzed. Measurements were made of volume infused and suctioned during, and blood samples drawn 10 min before the start of and 10 min after completion of WE colonoscopy. Outcome measures included volume of water infused and suctioned, and serum levels of sodium and potassium. RESULTS: A total of 140 patients (134M:6F), mean age of 59, underwent WE colonoscopy. Mean total volume of water infused was 1,839 mL. A negative balance of an average of 22 mL was documented. The mean (standard deviation) values (in meq/L) of serum levels of sodium 139.33 (2.27) and 139.28 (2.32), and potassium 3.86 (0.36) and 3.91 (0.39), before and after colonoscopy, respectively, showed no significant change. CONCLUSION: The WE method allowed most of the water infused during colonoscopy to be recovered by suction at the completion of colonoscopy. Serum sodium and potassium levels did not change significantly within 10 min after completion. The WE method appears to be safe with minimal water retention and is devoid of acute fluctuations in serum levels of sodium and potassium.

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.

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.

First Case of Small Bowel Sarcomatoid Carcinoma Found by Video Capsule Endoscopy.

Sarcomatoid carcinoma of the small bowel is extremely rare. We report the first case of sarcomatoid carcinoma identified by video capsule endoscopy in a patient referred for obscure gastrointestinal bleeding. Computed tomography and small bowel follow through failed to identify the tumor. The tumor was visualized initially on video capsule endoscopy examination and a 6 x 3 cm polypoid, fungating mass with irregular borders was retrieved on surgical resection. Microscopic examination showed sheets of pleomorphic spindled to epitheliod cells staining positive for cytokeritin and vimentin, indicative of sarcomatoid carcinoma. Forty-one months after surgical resection the patient continued to be free of metastatic disease.

Indigocarmine added to the water exchange method enhances adenoma detection - a RCT.

PURPOSE: Chromoendoscopy with dye spray and the water method both increase adenoma detection. HYPOTHESIS: Adding indigocarmine to the water method will enhance further the effectiveness of the latter in adenoma detection. METHODS: Screening colonoscopy was performed with the water method (control) or with 0.008% indigocarmine added (study) by two endoscopists. Randomization was based on computer-generated codes contained in blocks of pre-arranged opaque sealed envelopes. High resolution colonoscopes were used. Upon insertion into the rectum, air was suctioned. With the air pump turned off, water was infused using a blunt needle adaptor connected to the scope channel and a foot pump to facilitate scope insertion until the cecum was reached. Residual stool causing cloudiness was suctioned followed by infusion of clear or colored water (water exchange) to facilitate scope passage with minimal distention of the colonic lumen. Upon seeing the appendix opening under water, water was suctioned and air was insufflated to facilitate inspection on scope withdrawal. STATISTICS: Sample size calculation revealed 168 patients (84/group) needed to be randomized. Study was IRB-approved and registered (NCT01383265). RESULTS: There were no significant differences in mean age, gender distribution, BMI, and family history of colon cancer. Cecal intubation success rate was 100% in both groups. The overall adenoma detection rate was 44% (water only) versus 62% (water with indigocarmine), respectively (p=0.03). One cancer was detected in each group. CONCLUSION: In a RCT, indigocarmine at 0.008% concentration, added to the water method, significantly enhanced further the effectiveness of the latter in detecting adenomas.

Interim report of a randomized cross-over study comparing clinical performance of novice trainee endoscopists using conventional air insufflation versus warm water infusion colonoscopy.

BACKGROUND: The applicability of water method colonoscopy in trainee education is not known. AIM: To compare the water method vs. usual air method in teaching novice trainee colonoscopy. METHOD: An IRB approved prospective randomized cross-over study (NCT01482546) in a university setting with diverse patient population. DESIGN: Three first year GI fellows consented to participate in the study. Trainees were randomized to learn with either usual air method or the water method in performing colonoscopy with a dedicated endoscopy attending during their weekly outpatient endoscopy clinics for the initial six months of training and then cross-over to the other method for the remaining six months. PATIENTS: Patients undergoing screening, surveillance or diagnostic colonoscopy. RESULTS: The interim data revealed no significant difference in age, gender, and body mass index (BMI). Trainees rated the water method colonoscopy as significantly easier to learn compared to the air method (p=0.007). CONCLUSIONS: The interim data demonstrate positive effects of using the water method in training novice endoscopists who reported a significant ease of learning colonoscopy using this method. Training programs could consider joining us in evaluating the use of warm water infusion in colonoscopy education.

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. METHODS: VCE studies from the Sacramento Veterans Affairs Medical Center for 300 consecutive patients were retrospectively screened. Those with anemia were selected. Patients were grouped as mildly, moderately or severely bleeding. Outcomes data including completion of study, diagnostic yield and further intervention were compared. RESULTS: Of the 300 patients, 210 (70%) were found to have anemia. Overall 32 (15.24%) patients were mildly, 145 (69.05%) were moderately and 33 (15.71%) were severely bleeding. The diagnostic yield was significantly higher in severe (72.73%) relative to moderate (32.41%) and mild bleeding (12.50%); P = 0.0001. Significantly more angioectasias were detected in severely bleeding patients (42.42%) than in those bleeding moderately (14.48%) and mildly (0.00%), P = 0.0001. The ability of VCE to guide further intervention was significantly higher in patients bleeding severely (69.70%, P = 0.006). CONCLUSIONS: Our data showed a significant increase in diagnostic yield with the increasing degree of anemia. Relative difference in hemoglobin rather than absolute values may be a better predictor. The ability of VCE to guide further intervention reached significance in severely bleeding patients. The hypothesis that use of VCE prior to esophagogastroduodenoscopy or colonoscopy in the severely bleeding group deserves to be evaluated.

The water method significantly enhances detection of diminutive lesions (adenoma and hyperplastic polyp combined) in the proximal colon in screening colonoscopy - data derived from two RCT in US veterans.

PURPOSE: Emerging data indicate a colonoscopist-controlled method is needed to avoid missing proximal colon pre-malignant lesions. Screening colonoscopy does not prevent all proximal colon cancers. Even diminutive lesions in the proximal colon harbor dysplasia. In addition to adenomas (presumptive cancer precursors), recent proposals to reevaluate proximal colon hyperplastic polyps as serrated polyps which could be pre-malignant or harbingers of interval neoplasia dramatize the importance of attending to these lesions. The finding that the water method increased yield of proximal diminutive adenomas prompted assessment of the hypothesis that the water method increases yield of all proximal diminutive lesions (adenoma and hyperplastic polyp) in screening cases. METHODS: Two RCT assessed the water method with primary outcome of completion of unsedated colonoscopy when the option of scheduled, unsedated or sedation on demand was used. Diminutive (<10 mm) lesions proximal to the splenic flexure were tracked. RESULTS: In screening cases, 31% and 6% of the water and air group had at least one proximal diminutive lesion (p=0.0012). Regression analysis revealed withdrawal time, method and volume of water used were significant predictors of proximal diminutive lesions. Effect of the water method on detection of proximal diminutive lesions was independent of age, body mass index, endoscopist, sedation, cecal intubation rate, bowel cleanliness score on withdrawal and total procedure time. LIMITATION: Male subject predominance, analysis of secondary outcomes of pooled RCT data. CONCLUSION: The hypothesis that the water method effectively enhances proximal diminutive lesion detection in screening colonoscopy in diverse clinical settings should be tested.

The water method combined with chromoendoscopy enhances adenoma detection.

BACKGROUND: The water method is easy-to-learn and improves colonoscopy outcomes. Dye-spray chromoendoscopy enhances ADR but has not been widely accepted for routine application in screening or surveillance colonoscopy. HYPOTHESIS: With dye added to the water used in the water method, ADR can be enhanced compared with the water or air method alone. OBJECTIVE: To compare ADR determined by the air method, water method alone, and water method with indigo carmine (0.008%) added. DESIGN: Review of prospectively collected data in a performance improvement program. SETTING: VA endoscopy unit. PATIENT: Screening or surveillance colonoscopy. METHODS: Patients (n=50/group) underwent colonoscopy with each of the three methods. Water method involved warm water infusion in lieu of air insufflation coupled with removal of residual air by suction and residual feces by water exchange. ADR and procedural data were collected prospectively to monitor performance. MAIN OUTCOME MEASUREMENTS: ADR. RESULTS: ADR in the air method, water method alone and water method with indigo carmine were 36%, 40% and 62%, respectively. Water method with indigo carmine produced significantly higher ADR than the air or water method alone (p<0.05). LIMITATIONS: Non-randomized data, single VA site, retrospective comparison. Absence of significant difference between air and water methods could be a type II error due to small number of patients CONCLUSIONS: The approach with indigo carmine added to the water used in the water method yielded significantly higher ADR than the water or the air method alone. The data suggest that a prospective RCT to compare the different methods is warranted.

DDW 2011 cutting edge colonoscopy techniques - state of the art lecture master class - warm water infusion/CO(2) insufflation for colonoscopy.

Pain limits the success of cecal intubation in unsedated patient. Carbon dioxide infusion instead of air insufflation and water infusion as an adjunction to air insufflation have both been investigated as modalities to minimize pain associated with colonoscopy. Multiple RCT support an effect of carbon dioxide in reducing pain after colonoscopy. A modern method of water infusion as the sole modality for aiding colonoscope insertion has been shown to reduce pain during and after colonoscopy. Favorable effects in reducing discomfort have been documented in both sedated and unsedated patients. Because of the need to perform water exchange in the patients with suboptimal bowel perparation, a serendipitous consequence of salvage cleansing is evident with application of the water method. The associated increase in adenoma detection especially in the proximal colon is most intriguing. The hypothesis that the water method during insertion combined with carbon dioxide insufflation during withdrawal will optimally decrease colonoscopy pain should be evaluated. The implications of increased adenoma detection by the water method also deserve to be studied.