Jeremy M. Woodward

The Role Of Chronic Norovirus Infection In The Enteropathy Associated With Common Variable Immunodeficiency

OBJECTIVES:A severe enteropathy of unknown etiology can be associated with common variable immunodeficiency (CVID).METHODS:Stool and archived small intestinal mucosal biopsies from patients with CVID enteropathy were analyzed by PCR for the presence of Norovirus RNA. The PCR products were sequenced to determine the relationship of viral isolates. Stool samples from 10 patients with CVID but no enteropathy served as controls.RESULTS:All eight patients in our CVID cohort with enteropathy showed persistent fecal excretion of Norovirus. Analysis of archived duodenal biopsies revealed a strong association between the presence of Norovirus and villous atrophy over a period of up to 8 years. Analysis of the viral isolates from each patient revealed distinct strains of genogroup II.4. Sequence analysis from consecutive biopsy specimens of one patient demonstrated persistence of the same viral strain over a 6-year period. CVID patients without enteropathy showed no evidence of Norovirus carriage. Viral clearance occurred spontaneously in one patient and followed oral Ribavirin therapy in two further patients, and resulted in complete symptomatic and histological recovery. However, Ribavirin treatment in two further patients was unsuccessful.CONCLUSIONS:Norovirus is an important pathogen for patients with CVID and a cause of CVID enteropathy, as viral clearance, symptom resolution, and histological recovery coincide. Ribavirin requires further evaluation as a potential therapy.

The skinny on cocaine: Insights into eating behavior and body weight in cocaine-dependent men ☆☆ ☆☆

Highlights • Low body weight in cocaine users may not be due to the appetite suppressing effects of the drug.• Chronic cocaine users report higher levels of uncontrolled food intake than healthy volunteers.• Imbalance in fat intake and storage may explain the excessive weight gain during abstinence.

Clinical application of magnetic resonance spectroscopy of the liver in patients receiving long-term parenteral nutrition.

BACKGROUND Intestinal failure-associated liver disease (IFALD) may have progressed to an advanced stage by the time it becomes evident via laboratory or physical signs. A safe, noninvasive technique for assessing the liver could significantly aid in monitoring the effects of therapeutic intervention, improve the timing of liver and small intestinal transplantation, and increase our understanding of the causes of IFALD. METHODS Six female patients fed intravenously for >1 year and 6 controls matched for body mass index (BMI) underwent liver magnetic resonance scanning with acquisition of (1)H and (31)P resonance spectra. Areas under the curve for lipid (the sum of CH, CH(2), and CH(3)), water, and choline peaks were calculated and expressed semi-quantitatively as ratios of lipid:water and choline:lipid. Phosphomonoester (PME) and phosphodiester (PDE) peak areas were similarly expressed as a ratio. Controls and cases were compared using Mann-Whitney U test; least squares regression analysis was used to compare the effect of measured variables on the lipid:water peak area ratio. RESULTS Patients and controls were well matched for BMI. Parenteral feeding was associated with a highly significant increase in lipid:water peak ratio (P < .005). Choline:lipid (P < .05) and choline:water (not significant) ratios were reduced in patients compared with controls. The increase in lipid:water ratios in patients was independent of BMI and choline:water ratios. A ratio of PME:PDE of >0.3 (and >3 SD from the control mean) predicted the 2 patients at most risk of advanced liver disease. CONCLUSIONS This pilot study confirms the potential of magnetic resonance spectroscopic techniques in evaluating IFALD and could contribute significantly to our understanding and management of this condition.

Endoplasmic Reticulum Stress Is Implicated in Intestinal Failure–Associated Liver Disease

BACKGROUND Intestinal failure-associated liver disease (IFALD) is the most serious consequence of long-term parenteral nutrition for intestinal failure. Little is known about the pathogenesis of IFALD, although many of the risk factors are also linked to endoplasmic reticulum stress (ERS). We propose that ERS may have a role in the development of IFALD. METHODS Archived liver tissue from patients with early and late IFALD, as well as from normal controls, was used for RNA extraction and immunohistochemistry to demonstrate the presence of ERS markers. RESULTS Mean relative RNA levels of glucose regulatory protein 78 in normal liver (n = 3), early IFALD (n = 15), and late IFALD (n = 5) were 0.5, 37.86, and 212.11, respectively. Mean relative expression of ERDj4 (ER DnaJ homologue 4, a downstream ERS effector) in normal liver, early IFALD, and late IFALD was 5.51, 216.68, and 213.22, respectively. The degree of splicing of X-box binding protein 1 in IFALD compared with normal liver was significantly higher (mean, 0.0779 normal, 0.102 early IFALD, 0.2063 late IFALD). CONCLUSIONS This is the first description of ERS in IFALD. This information may open up new therapeutic possibilities in the form of chemical chaperones known to ameliorate ERS.

Addition of Insulin to Parenteral Nutrition for Control of Hyperglycemia

Administration of parenteral nutrition (PN) may result in hyperglycemia in patients with preexisting diabetes or disease-related insulin resistance, and it can be associated with increased rates of complications. Treatment requires insulin therapy. Insulin can be administered subcutaneously, intravenously via a variable rate sliding scale, or by adding it directly to the PN. The last method is a potentially attractive technique for a number of reasons-it could deliver the insulin intravenously at a steady rate alongside carbohydrates, and in malnourished patients with little subcutaneous tissue, it may prevent the need for frequent insulin injections. Despite such potential advantages, the addition of insulin to PN remains controversial, largely with respect to the bioavailability of insulin in PN and resultant concerns of the risk of hypoglycemia. There is a paucity of long-term quality controlled studies to address this question. The available literature suggests that, at least in the short term, insulin addition to PN can achieve reasonable glycemic control with low rates of hypoglycemia, and the technique compares favorably with the use of long-acting insulin preparations. This literature review finds a wide range of values reported for insulin availability via PN, ranging from 44% to 95% depending on the type of PN container material used and the presence of added vitamins and trace elements. Few studies looking at glycemic control among patients receiving home PN were found, and larger prospective trials are needed to assess the efficacy and safety of this technique in this patient group.

PTU-160 Successful clearance of chronic noroviral infection by ribavirin in a patient with common variable immunodeficiency-associated enteropathy results in complete symptomatic and histopathological resolution

Introduction We have recently demonstrated an association between chronic Noroviral infection and Common Variable Immunodeficiency-associated (CVID) enteropathy. Here we describe a patient with CVID enteropathy treated with Ribavirin. Methods A 33-year-old lady with known CVID presented to our service in 2003 with 20% weight loss, nausea and profuse diarrhoea. Investigations revealed classical appearances of CVID enteropathy with subtotal duodenal villous atrophy, but no evidence of bacterial, enteroviral or parasitic infection. Treatment with gluten withdrawal, elemental diet, and budesonide were largely ineffective and she required parenteral nutrition for malabsorption and anti-TNFα therapy with Infliximab and subsequently Humira for symptom relief. No therapy changed the degree of villous atrophy. Following 6 years of symptoms, stool was noted to be positive on PCR for Norovirus RNA. Retrospective analysis of archived duodenal biopsies revealed the presence of Noroviral RNA in all biopsies from 2003 to 2009 and RNA sequencing showed this to be the same strain of virus throughout. In view of reported in vitro activity of Ribavirin against Norovirus, this agent was commenced with therapeutic level monitoring and quantitative stool PCR for Norovirus excretion. Results Once Ribavirin levels were >1000 ng/ml, quantitative PCR demonstrated a reduction in Noroviral excretion which then became undetectable. Simultaneously, the patient reported dramatic symptomatic relief with a change from profuse diarrhoea to two formed motions a day, no nausea and return of appetite. Parenteral nutrition and Humira were stopped. Duodenal biopsies after 3 months showed complete resolution of villous morphology and were negative for Norovirus on PCR. Stool remained negative for Noroviral RNA. After 6 months Ribavirin therapy was stopped. The patient has remained asymptomatic for the subsequent 9 months with no evidence of recurrent Noroviral excretion. Conclusion Complete resolution of symptoms and duodenal villous atrophy with clearance of the Norovirus suggests that the association of Norovirus infection with CVID enteropathy is causal. Ribavirin may have activity against Norovirus in vivo and this first ever demonstration of a cure for this condition requires confirmation in other cases. Competing interests None declared.

Fatal breakthrough mucormycosis in a multivisceral transplant patient receiving micafungin: Case report and literature review

Introduction Antifungal agents are routinely used in the post-transplant setting for both prophylaxis and treatment of presumed and proven fungal infections. Micafungin is an echinocandin-class antifungal with broad antifungal cover and favorable side effect profile but, notably, it has no activity against molds of the order Mucorales. Presentation of case A 47-year-old woman underwent multivisceral transplantation for intestinal failure-associated liver disease. She had a prolonged post-operative recovery complicated by invasive candidiasis and developed an intolerance to liposomal amphotericin B. In view of her immunosuppression, she was commenced on micafungin as prophylaxis to prevent invasive fungal infection. However, she developed acute graft versus host disease with bone marrow failure complicated by disseminated mucormycosis which was only diagnosed post mortem. Discussion Non-Aspergillus breakthrough mold infections with micafungin therapy are rare with only eight other cases having been described in the literature. Breakthrough infections have occurred within one week of starting micafungin. Diagnosis is problematic and requires a high degree of clinical suspicion and microscopic/histological examination of an involved site. The management of these aggressive infections involves extensive debridement and appropriate antifungal cover. Conclusion A high level of suspicion of invasive fungal infection is required at all times in immunosuppressed patients, even those receiving antifungal prophylaxis. Early biopsy is required. Even with early recognition and aggressive treatment of these infections, prognosis is poor.

Nasal unsedated seated percutaneous endoscopic gastrostomy (nuPEG): a safe and effective technique for percutaneous endoscopic gastrostomy placement in high-risk candidates

Objective Percutaneous endoscopic gastrostomy (PEG) tube placement is associated with a high risk of cardiorespiratory complications in patients with significant respiratory compromise. This study reports a case series of high-risk patients undergoing PEG placement using a modified technique—nasal unsedated seated PEG (nuPEG) placement. Design Retrospective review of 67 patients at high risk of complications undergoing PEG placement between September 2012 and December 2016. Setting UK specialist tertiary centre for clinical nutrition support. Interventions Patients underwent ‘push’ PEG placement using nasal endoscopy without sedation in a seated position. Main outcome measures Procedural success and tolerability, short term (within 24 hours), medium term (24 hours to 30 days) complications and survival were recorded. Results 67 patients underwent 68 nuPEG placements. The majority had motor neuron disease (46/67). One patient developed a lower respiratory tract infection the following day. Two patients experienced accidental displacement of their PEG within 2 weeks. One patient died within 30 days of nuPEG insertion due to reasons unrelated to the procedure. Endoscopic comfort scores of 1 or 2 (98.0%) indicated good tolerance. A failure rate of 10.5% was attributed to intrathoracic displacement of the stomach, almost certainly due to the advanced stage of the neurological disease and associated diaphragmatic weakness. Conclusions Our experience with the nuPEG technique suggests that it is safe and well tolerated in high-risk patients. As a result, it has now entirely supplanted radiologically inserted gastrostomy insertion in our institution and we recommend it as the method of choice for gastrostomy tube insertion in such patients.

OC-033 Outcomes following small intestinal and multivisceral transplantation at addenbrooke’s hospital, cambridge

Introduction Small intestinal transplantation was first undertaken in Cambridge in 1991 and with advances in immunosuppression agents, outcomes have improved. We present our survival figures from 2006 to 2014. Method A prospective database is used to record all patients who undergo small intestine (SB), liver/small intestine (LSB), modified multivisceral (MMVT – intestine and stomach) and multivisceral (MVT – intestine, stomach and liver) transplantation at Addenbrooke’s Hospital. All grafts may also contain pancreas, kidney and colon. The NHS Blood and Transplant service derived Kaplan-Meier survival curves for all patients undergoing their first transplant procedure between January 2006 and December 2014. Results 56 transplant procedures were performed on 50 patients (6 were re-transplanted, all are still alive). 1-year survival in patients transplanted is 92% (SB), 83% (MMVT), 67% (LSB) and 69% (MVT). 5-year survival is 92% (SB), 63% (MMVT) and 27% (MVT) – this data is not available for LSB transplants due to small numbers and follow-up duration of only 14 m. These data compare favourably with international transplant registry 5-year survival figures of 59% (SB) and 22% (MVT).1Overall 1-year survival for all patients transplanted in our unit is 76% and 5-year survival is 46%. Conclusion Cambridge is one of 2 UK centres performing intestinal transplantation in adults and we are undertaking an increasing number of procedures – 16 in 2013 and 10 in 2014. We are particularly encouraged by our 92% 5-year survival in patients undergoing isolated SB transplantation and would advocate early referral for assessment in patients with Type 3 intestinal failure who develop complications from home parenteral nutrition. Colon is routinely included in the graft to aid fluid balance and does not preclude regular endoscopic surveillance for rejection. We have performed continuity surgery in a number of patients post transplant (transplanted colon to native colon anastomosis) with good outcomes and no anastomotic leaks. Due to complications of the oesophagogastric anastomosis, gastroparesis and increased morbidity and mortality of MVT we are moving towards performing more LSB transplants and will monitor outcomes with interest. Detailed pre-operative assessment, individualised procedures, patient optimisation and an emphasis on the multidisciplinary team are essential when managing these complex patients. Disclosure of interest None Declared. Reference Intestinal Transplant Registry (ITR) – http://www.intestinaltransplant.org/itr/(Accessed May 2014)

OC-112 Nupeg (nasal unsedated seated peg) is safer and better tolerated than rig (radiologically-inserted gastrostomy) in very high risk gastrostomy candidates

Introduction Endoscopic gastrostomy (PEG) placement in patients with severe respiratory or neuromuscular compromise carries a high risk of mortality through aspiration and radiological placement (RIG) is usually preferred in this setting. We have used ‘push-PEG’ placement in high risk patients guided by nasal endoscopy, unsedated and seated at 30–45° and here we report the outcomes of this technique compared to RIG placement in high risk patients. Method Records were analysed retrospectively for all ‘push-PEGs’ placed since 2008 and compared with records of RIG placements since 2010. Indications, completion rates and complications were compared. Results 296 push-PEGs have been placed since 2008 (mostly for head and neck malignancy). 242 were placed by standard per-oral endoscopic guidance and 54 using transnasal endoscopy using a Pentax transnasal endoscope. Of the 54, 27 (50%) were NuPEGs and the other 50% received intravenous sedation (SenPEG). 53/54 (98%) were placed successfully and without complication. One sedated patient experienced a respiratory arrest that required emergency intubation and led to the development of the NuPEG technique, since when no complications have been reported. From 2010–2014, 46 RIGs have been placed. Of these, 89% were successful and uncomplicated with one colonic perforation identified. In two patients where RIG failed due to anxiety or inability to lie flat, NuPEG was performed uneventfully. As a result, NuPEG has entirely replaced RIG in our institution where no RIGs have been placed since 2013. Conclusion NuPEG is safer and better tolerated than RIG in patients with respiratory or neuromuscular compromise and is the technique of choice in high risk patients requiring gastrostomy placement. Disclosure of interest None Declared.