Resistant cytomegalovirus in intestinal and multivisceral transplant recipients.

BACKGROUND: Intestinal and multivisceral transplantation can be complicated by cytomegalovirus (CMV)-related viremia and disease. Intravenous ganciclovir (GCV) and oral valganciclovir remain the treatment of choice in this setting. Limited data are available on GCV-resistant (GCV-R) CMV infection in small intestine and multivisceral transplant recipients. METHOD: A retrospective review was performed on all patients who underwent small intestine or multivisceral transplantation from November 8, 2003 through November 30, 2008. Those with CMV viremia and invasive disease were identified. GCV resistance was suspected in patients who continued to have viremic episodes or invasive disease despite appropriate GCV treatment. Genotypic analyses were performed to detect the presence of GCV resistance genes UL97 and UL54. RESULTS: During the study period, 88 small intestine or multivisceral transplants were performed on 85 patients. Of the 88 transplantations, 16 patients developed CMV viremia with or without end-organ disease (18.2%) and 5.7% developed GCV-R CMV infection. In patients diagnosed with CMV infection, 31.3% (5/16) had GCV-R CMV infection. Of patients with GCV-R CMV infection, 80% (4/5) developed CMV allograft enteritis, resulting in allograft explantation in 3 patients. All patients with GCV-R CMV infection were CMV donor positive/recipient negative. Patients with tissue-invasive CMV disease were 18 times more likely to be infected with GCV-R CMV (95% confidence interval 1.24-260.93; P-value 0.0341). CONCLUSION: Small intestinal and multivisceral transplant recipients have a higher rate of GCV-R CMV infection compared with other solid organ transplant recipients, which is often associated with tissue-invasive disease and allograft loss.

Intestinal transplant registry report: global activity and trends.

The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan-Meier survival curves and a multiple variable analysis. Eighty-two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune-suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.

Developing trends in the intestinal transplant waitlist.

The United Network for Organ Sharing database was examined for trends in the intestinal transplant (ITx) waitlist from 1993 to 2012, dividing into listings for isolated ITx versus liver-intestine transplant (L-ITx). Registrants added to the waitlist increased from 59/year in 1993 to 317/year in 2006, then declined to 124/year in 2012; Spline modeling showed a significant change in the trend in 2006, p < 0.001. The largest group of registrants, <1 year of age, determined the trend for the entire population; other pediatric age groups remained stable, adult registrants increased until 2012. The largest proportion of new registrants were for L-ITx, compared to isolated ITx; the change in the trend in 2006 for L-ITx was highly significant, p < 0.001, but not isolated ITx, p = 0.270. New registrants for L-ITx, <1 year of age, had the greatest increase and decrease. New registrants for isolated ITx remained constant in all pediatric age groups. Waitlist mortality increased to a peak around 2002, highest for L-ITx, in patients <1 year of age and adults. Deaths among all pediatric age groups awaiting L-ITx have decreased; adult L-ITx deaths have dropped less dramatically. Improved care of infants with intestinal failure has led to reduced referrals for L-ITx.

Isolated peritoneal donor-related plasmacytoma 3 years after liver transplantation: a case report.

Organ transplantation carries a risk of disease transmission from donor to recipient, primarily infection or malignancy. Although donors are thoroughly screened, donor-related malignancies are reported to occur in 0.01% of solid organ transplants. Plasma cell neoplasm, to the best of our knowledge, has not been reported as a donor-transmitted malignancy in liver transplantation. We describe a liver transplant from a donor with unrecognized plasmacytoma requiring retransplantation. Three years after the first transplant a single peritoneal mass was detected on surveillance imaging and radically excised; HLA phenotyping confirmed the mass to be an isolated extra-medullary plasmacytoma of chimeric donor and recipient origin.

Infection among adult small bowel and multivisceral transplant recipients in the 30-day postoperative period.

BACKGROUND: Intestinal transplantation is a potential option for patients with short gut syndrome (SGS), and infection is common in the postoperative period. The aim of our study was to identify the incidence and characteristics of bacterial and fungal infections of adult small bowel or multivisceral (SB/MV) transplantation recipients in the 30-day postoperative period. METHODS: This retrospective chart review assessed the incidence and characteristics of bacterial and fungal infections in patients who underwent SB/MV transplant at our center between April 2004 and November 2008. Patient data were retrieved from computerized databases, flow-charts, and medical records. RESULTS: A total of 40 adult patients with a mean age of 38.7 ± 13.4 years received transplants during this period: 27 patients received isolated SB, 12 received MV, and 1 received SB and kidney. Our immunosuppressive regimen included basiliximab for induction, and tacrolimus, sirolimus, and methylprednisolone for maintenance therapy. The most common indications for transplant were SGS, intestinal ischemia, Crohn's disease, trauma, motility disorders, and Gardner's syndrome. We report a 30-day postoperative infection rate of 57.5% and mean time to first infection of 10.78 ± 8.99 days. A total of 36 infections were documented in 23 patients. Of patients who developed infections, 56.5% developed 1 infection, 30.4% developed 2 infections, and 13% developed 3 infections. The most common site of infection was the abdomen, followed by blood, urine, lung, and wound infection. The isolates were gram-negative bacteria in 49.3%, gram-positive bacteria in 39.4%, and 11.3% were fungi. The most common organisms were Pseudomonas (19%), Enterococcus (15%), and Escherichia coli (13%). Overall, 47% of infections were due to drug-resistant pathogens; 31% of E. coli and Klebsiella species were extended-spectrum beta-lactamase-producing organisms, 36% of Pseudomonas was multidrug resistant (MDR), 75% of Enterococcus was vancomycin resistant, and 100% of Staphylococcus aureus was methicillin resistant. CONCLUSION: These findings demonstrate that bacterial and fungal infections remain an important complication in SB/MV transplant recipients within the early postoperative period. Infections due to MDR organisms have emerged as an important clinical problem in this patient population.

Abnormal CX3CR1⁺ lamina propria myeloid cells from intestinal transplant recipients with NOD2 mutations.

Although progress has been made in intestinal transplantation, chronic inflammation remains a challenge. We have reported that the risk of immunological graft loss is almost 100-fold greater in recipients who carry any of the prevalent NOD2 polymorphisms associated with Crohn's disease, and have shown that the normal levels of a key antimicrobial peptide produced by the Paneth cells of the allograft, fall as the graft becomes repopulated by hematopoietic cells of the NOD2 mutant recipient. These studies are extended in this report. Within several months following engraftment into a NOD2 mutant recipient the allograft loses its capacity to prevent adherence of lumenal microbes. Despite the significantly increased expression of CX3CL1, a stress protein produced by the injured enterocyte, NOD2 mutant CX3CR1(+) myeloid cells within the lamina propria fail to exhibit the characteristic morphological phenotype, and fail to express key genes required expressed by NOD2 wild-type cells, including Wnt 5a. We propose that the CX3CR1(+) myeloid cell within the lamina propria supports normal Paneth cell function through expression of Wnt 5a, and that this function is impaired in the setting of intestinal transplantation into a NOD2 mutant recipient. The therapeutic value of Wnt 5a administration in this setting is proposed.

Metabolomics of human intestinal transplant rejection.

Surveillance endoscopy with biopsy is the standard method to monitor intestinal transplant recipients but it is invasive, costly and prone to sampling error. Early noninvasive biomarkers of intestinal rejection are needed. In this pilot study we applied metabolomics to characterize the metabolomic profile of intestinal allograft rejection. Fifty-six samples of ileostomy fluid or stool from 11 rejection and 45 nonrejection episodes were analyzed by ultraperformance liquid chromatography in conjunction with Quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS). The data were acquired in duplicate for each sample in positive ionization mode and preprocessed using XCMS (Scripps) followed by multivariate data analysis. We detected a total of 2541 metabolites in the positive ionization mode (mass 50-850 Daltons). A significant interclass separation was found between rejection and nonrejection. The proinflammatory mediator leukotriene E4 was the metabolite with the highest fold change in the rejection group compared to nonrejection. Water-soluble vitamins B2, B5, B6, and taurocholate were also detected with high fold change in rejection. The metabolomic profile of rejection was more heterogeneous than nonrejection. Although larger studies are needed, metabolomics appears to be a promising tool to characterize the pathophysiologic mechanisms involved in intestinal allograft rejection and potentially to identify noninvasive biomarkers.

Successful isolated intestinal transplantation in sensitized recipients with the use of virtual crossmatching.

We evaluated virtual crossmatching (VXM) for organ allocation and immunologic risk reduction in sensitized isolated intestinal transplantation recipients. All isolated intestine transplants performed at our institution from 2008 to 2011 were included in this study. Allograft allocation in sensitized recipients was based on the results of a VXM, in which the donor-specific antibody (DSA) was prospectively evaluated with the use of single-antigen assays. A total of 42 isolated intestine transplants (13 pediatric and 29 adult) were performed during this time period, with a median follow-up of 20 months (6-40 months). A sensitized (PRA ≥ 20%) group (n = 15) was compared to a control (PRA < 20%) group (n = 27) to evaluate the efficacy of VXM. With the use of VXM, 80% (12/15) of the sensitized patients were transplanted with a negative or weakly positive flow-cytometry crossmatch and 86.7% (13/15) with zero or only low-titer (≤ 1:16) DSA. Outcomes were comparable between sensitized and control recipients, including 1-year freedom from rejection (53.3% and 66.7% respectively, p = 0.367), 1-year patient survival (73.3% and 88.9% respectively, p = 0.197) and 1-year graft survival (66.7% and 85.2% respectively, p = 0.167). In conclusion, a VXM strategy to optimize organ allocation enables sensitized patients to successfully undergo isolated intestinal transplantation with acceptable short-term outcomes.

Six-month incidence of bloodstream infections in intestinal transplant patients.

BACKGROUND: Intestinal transplantation has emerged as an established treatment for life-threatening intestinal failure. The most common complication and cause of death is infection. Risk of infection is highest during the first 6 months, as a consequence of maximal immunosuppression, greater than that required for any other organ allograft. METHODS: We performed a retrospective chart review of all (56) adult and pediatric (<18 years) small bowel transplant patients at our institution between November 2003 and July 2007, and analyzed the 6-month post-transplant incidence of bloodstream infections (BSIs). We evaluated multiple risk factors, including inclusion of a colon or liver, total bilirubin >5, surgical complications, and acute rejection. RESULTS: A BSI developed in 34 of the 56 patients, with a total of 85 BSI episodes. Of these BSI episodes, 65.9% were due to gram-positive organisms, 34.1% gram-negative organisms, and 2.4% due to fungi. The most common isolates were Enterococcus species, Enterobacter species, Klebsiella species, and coagulase-negative staphylococci. Inclusion of the liver and/or a preoperative bilirubin >5 mg/dL appeared to increase the incidence of BSI (P = 0.0483 and 0.0005, respectively). Acute rejection and colonic inclusion did not appear to affect the incidence of BSI (P = 0.9419 and 0.8248, respectively). The BSI incidence was higher in children (P = 0.0058). CONCLUSIONS: BSIs are a common complication of intestinal transplantation. Risk factors include age <18, inclusion of the liver, and pre-transplant bilirubin >5. Acute rejection and colon inclusion do not appear to be associated with increased BSI risk.

Complex arterial reconstruction in multivisceral transplantation.

We report the case of a successful multivisceral transplant in which both donor and recipient presented aberrant anatomy of the celiac-mesenteric axis requiring five separate arterial anastomoses to reconstruct the blood inflow to the graft.

Long term outcomes of abdominal wall reconstruction using open component separation and biologic mesh in the liver, kidney, and small bowel transplant population.

PURPOSE: The aim of this study is to critically examine the multidisciplinary approach to abdominal wall reconstruction (AWR) in the solid organ transplant (SOT) population at our institution, MedStar Georgetown University Hospital, using a modified component separation technique (CST). METHODS: A retrospective review of AWR utilizing modified open CST with biologic mesh in SOT patients was performed from January 2010 to June 2018. Patient demographics, comorbidities, operative details, complications, and outcomes were recorded. Descriptive statistics, logistic and linear regression analyses were performed to appraise outcomes. RESULTS: Thirty-five patients were included; mean age was 53 years. Patient demographics and comorbidities were: 82.9% male, 45.7% history of tobacco use, and 28.6% diabetes. Fifty-one percent had undergone prior hernia repair. Transplant types were: kidney (9), liver (16), liver/kidney (1), small bowel (7), multivisceral (2). All were on an immunosuppressive regimen at time of surgery; 22.9% included steroids. Average defect size was 361 cm2. Additional soft tissue procedures were performed in 65.7% (n = 23) of patients. Median time to healing was 29.0 days. Complication rate was 31.4% (n = 11); six patients required reoperation within 90 days. Recurrence rate was 5.7% (n = 2) at mean of follow up of 3.0 years. Additional soft tissue procedures were statistically significant for healing time (p = 0.037). Steroid use was statistically significant for reoperation within 90 days (OR = 12.500; 95% CI 1.694-92.250); however, steroid use was not significant after correction for confounders. CONCLUSION: Modified open CST with biologic mesh is a safe, efficacious approach to complex AWR in the SOT population with recurrence rates comparable to the general population.

Rejection reversibly alters enteroendocrine cell renewal in the transplanted small intestine.

Acute small intestinal allograft rejection presents clinically as an abrupt increase in ileal fluid output in the absence of extensive inflammation. We questioned whether acute intestinal rejection might be accompanied by a disturbance of normal intestinal stem cell differentiation. We examined the intestinal epithelial secretory cell lineage among patients experiencing early rejection before and during rejection as well as following corrective therapy. Lineage-specific progenitors were identified by their expression of stage-specific transcription factors. Progenitors of the enteroendocrine cell (EEC) expressing neurogenin-3 (NEUROG3) were found to be disproportionately reduced in numbers, along with their more mature EEC derivatives expressing neuro D; the enteric hormone PYY was the most profoundly depleted of all the EEC products evaluated. No change in the numbers of goblet or Paneth cells was observed. Steroid treatment resulted in resolution of clinical symptoms, restoration of normal patterns of EEC differentiation and recovery of normal levels of enteric hormones. Acute intestinal rejection is associated with a loss of certain subtypes of EEC, most profoundly, those expressing PYY. Deficiency of the mature EECs appears to occur as a consequence of a mechanism that depletes NEUROG3 EEC progenitors. Our study highlights the dynamics of the EEC lineage during acute intestinal rejection.

Nonhemolytic passenger lymphocyte syndrome: donor-derived anti-M in an M+ recipient of a multiorgan transplant.

Passenger lymphocyte syndrome (PLS) is a well-recognized complication that may follow a hematopoietic progenitor cell or solid-organ transplant. Typically, the syndrome presents as acute hemolysis of the recipient's RBCs, which have become serologically incompatible with blood group antibodies formed by passively transfused donor-origin B lymphocytes. Most cases involve anti-A or anti-B. However, there are cases involving non-ABO serologic incompatibility, as well as cases in which the serologic incompatibility was not associated with clinical evidence of hemolysis. This report describes a case of passenger lymphocyte syndrome in an M+ recipient who developed anti-M after receiving a multiorgan transplant from an M- cadaver donor. Although the temporal events and serologic findings were consistent with a diagnosis of PLS, there was no evidence of in vivo hemolysis associated with the identification of a newly formed anti-M. This report includes a literature review of other case reports of PLS associated with non-ABO antibodies in solid-organ and hematopoietic progenitor cell transplant recipients.

NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine.

BACKGROUND: Intestinal allograft rejection resembles Crohn's disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn's disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. METHODS: The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. RESULTS: An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation. CONCLUSIONS: Crohn's disease-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunological risk factor for intestinal allograft rejection. Compromised epithelial defences precede visible epithelial injury and inflammatory infiltration. The association of impaired epithelial immunity with the recipient's genotype suggests that certain NOD2-expressing cells of haematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial AMPs within the allograft.

Unusual Cystic Fibrosis Transmembrane Conductance Regulator Mutations and Liver Disease: A Case Series and Review of the Literature.

Cystic fibrosis (CF) is caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene, deranging the activity of chloride channels on the epithelial cell surface. Herein we describe end-stage liver disease in 3 infants with rare CFTR gene mutations; 2 of them were heterozygous. Case 1 was a premature male infant with negative CF screening at birth who developed a small bowel obstruction in the neonatal period requiring an ileostomy, with subsequent cholestatic liver disease and portal hypertension. In addition, he was noted to have frequent respiratory infections prompting a sweat test, which was positive. Genetic testing revealed that he was heterozygous for P.1177F. He then underwent a successful liver transplant. Case 2 was a female infant who developed progressive cholestasis with poor weight gain and was found to have neonatal hepatitis on liver biopsy. A sweat test was negative and genetic testing revealed she was heterozygous for CFTR and PEX26 gene mutations. She subsequently developed pneumatosis involving the cecum that was treated conservatively, followed by a successful liver transplant. Case 3 was a male infant who developed progressive liver disease, with liver biopsy showing neonatal hepatitis. He was extensively investigated but had a negative sweat test on repeated studies. Genetic testing revealed that the patient was heterozygous P.K186N-variant in the AKRID1 gene and homozygous P.R75Q-variant in the CFTR gene. Unfortunately, he succumbed to an acute upper gastrointestinal hemorrhage. Rare and unusual CFTR mutations, even in the heterozygous form, may be a feature in otherwise undiagnosed end-stage liver disease of infancy.

Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation.

Transforming growth factor-beta (TGF-beta) signaling members, TGF-beta receptor type II (TBRII), Smad2, Smad4 and Smad adaptor, embryonic liver fodrin (ELF), are prominent tumor suppressors in gastrointestinal cancers. Here, we show that 40% of elf(+/-) mice spontaneously develop hepatocellular cancer (HCC) with markedly increased cyclin D1, cyclin-dependent kinase 4 (Cdk4), c-Myc and MDM2 expression. Reduced ELF but not TBRII, or Smad4 was observed in 8 of 9 human HCCs (P<0.017). ELF and TBRII are also markedly decreased in human HCC cell lines SNU-398 and SNU-475. Restoration of ELF and TBRII in SNU-398 cells markedly decreases cyclin D1 as well as hyperphosphorylated-retinoblastoma (hyperphosphorylated-pRb). Thus, we show that TGF-beta signaling and Smad adaptor ELF suppress human hepatocarcinogenesis, potentially through cyclin D1 deregulation. Loss of ELF could serve as a primary event in progression toward a fully transformed phenotype and could hold promise for new therapeutic approaches in human HCCs.

Impact of positive preoperative surveillance blood cultures from chronic indwelling catheters in cadaveric intestinal transplant recipients.

Recurrent bloodstream infections are a common indication for intestinal transplantation (ITx). Often, clinical symptoms may be absent in the setting of bacteremia, especially in patients with chronic liver disease. This study investigated the incidence and impact of positive blood cultures (BCx) obtained from central venous catheters used for total parenteral nutrition (TPN) in asymptomatic patients immediately prior to cadaveric ITx. Of 13 consecutive patients transplanted between November 2003 and November 2004, 12 underwent preoperative surveillance BCx with four positives (33%). Isolates included Staphylococcus epidermidis (n = 2), methicillin-resistant Staphylococcus aureus, and Citrobacter freundii. All four patients with positive BCx displayed liver dysfunction at the time of transplant (> or = grade 2 fibrosis, total bilirubin >8.0 g/dL), three of whom were inpatients. In contrast, only three of eight nonbacteremic patients showed liver disease of comparable severity. Liver dysfunction and inpatient status at the time of transplant appear to predict positive blood cultures. Postoperative length of stay and time on the ventilator were significantly longer among bacteremic as compared with nonbacteremic patients, but there were no differences in intraoperative blood use, time to total parenteral nutrition independence, or operative time between bacteremic and nonbacteremic patients. Our study showed that occult bacteremia in asymptomatic pre-intestinal transplant patients was not uncommon and may increase postoperative morbidity. Preemptive removal of long-term central venous catheters should be considered prior to ITx.

Multi-Visceral Transplantation in a 21-Year-Old Man with Prior Pancreatoblastoma.

Organ transplantation in patients with prior malignancy increases the risk of tumor recurrence post-transplantation due to immunosuppression. Only two cases of liver transplantation have so far been reported in children with hepatic metastases from pancreatoblastoma, a rare malignant neoplasm originating from the epithelial exocrine cells of the pancreas. Herein, we describe a case of a successful multi-visceral transplant in a man with intestinal failure after surgical resection of pancreatoblastoma.

Hospital Readmissions After Intestinal and Multivisceral Transplantation.

BACKGROUND: Intestinal transplant recipients require frequent hospital readmission after a successful transplantation, but the reasons for readmission have not been characterized in detail. METHODS: We reviewed our single-center experience to characterize the patterns of readmissions and to identify preventable causes. Among 87 adult patients who received an intestinal or multivisceral transplant, 65 patients (35 males, 30 females; median age, 42 years [range, 19-66]) with a follow-up of at least 1 year were included in this study. Readmissions were defined as any unplanned inpatient hospital stay of 24 hours or longer occurring within 1 year after discharge from the transplantation admission and were classified as early (<1 month) and late (months 2-12) readmissions. RESULTS: Forty-four (68%) patients required early, and 59 (91%) patients required late readmission. A total of 333 readmissions (median, 4 readmissions/patient [0-20]) occurred within the first year post-transplantation; 69 were early (21%) and 264 were late (79%), resulting in a total of 4089 days of hospital stay (median, 7 days/readmission [2-136]). The three most frequent causes of readmission were dehydration, infection, and surgical complications. CONCLUSIONS: These findings suggest that the rate of hospital readmission after intestinal transplantation could potentially be reduced by optimizing fluid balance and hydration status after discharge.