Multivisceral Transplant Recipients Research Articles

Risk Factors Associated with PTLD Related Mortality in Adult Multivisceral Transplant Recipients - A Single Centre Cohort Study.

Background: PTLD is a heterogeneous group of lymphoproliferative diseases which can add significant mortality following multivisceral transplantation (MVTx). Our study aimed to identify potential risk factors of mortality in adult MVTx recipients who developed PTLD. Methods: All adult recipients of intestinal-containing grafts transplanted in our institution between 2013 and 2022, and who developed PTLD, were included in the study. Results: PTLD-associated mortality was 28.6% (6/21). Increased relative risk of mortality was associated with Stage 3 ECOG performance score (p=0.005; HR 34.77; 95%CI 2.94-410.91), if the recipients had a splenectomy (p=0.036; HR 14.36; 95%CI 1.19-172.89), or required retransplantation (p=0.039; HR 11.23; 95% CI 1.13-112.12). There was a significant trend for increased risk of PTLD mortality with higher peak EBV load (p=0.008), longer time from MVTx to PTLD diagnosis (p=0.008), and higher donor age (p 0.001). Peak LDH before treatment commencement was significantly higher in the mortality group vs the survival group (520.3 +- 422.8 IU/L vs 321.8 +- 154.4 IU/L; HR 1.00, 95%CI 1.00 to 1.01, p=0.019). Peak viral load prior to treatment initiation (Cycle Threshold (CT) cutoff = 32) correlated with the relative risk of death in MVTx patients who developed PTLD [29.4 (3.5) CTs in survivors compared to 23.0 (4.0) CTs in the mortality group]. Conclusions: This is the first study to identify risk factors for PTLD-associated mortality in an adult MVTx recipient cohort. Validation in larger multicentre studies and subsequent risk stratification according to these risk factors may contribute to better survival in this group of patients.

Clinical Utility of 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in Multivisceral Transplant Patients.

Multivisceral transplant (MVTx) refers to a composite graft from a cadaveric donor, which often includes the liver, the pancreaticoduodenal complex, and small intestine transplanted en bloc. It remains rare and is performed in specialist centres. Post-transplant complications are reported at a higher rate in multivisceral transplants because of the high levels of immunosuppression used to prevent rejection of the highly immunogenic intestine. In this study, we analyzed the clinical utility of 28 18F-FDG PET/CT scans in 20 multivisceral transplant recipients in whom previous non-functional imaging was deemed clinically inconclusive. The results were compared with histopathological and clinical follow-up data. In our study, the accuracy of 18F-FDG PET/CT was determined as 66.7%, where a final diagnosis was confirmed clinically or via pathology. Of the 28 scans, 24 scans (85.7%) directly affected patient management, of which 9 were related to starting of new treatments and 6 resulted in an ongoing treatment or planned surgery being stopped. This study demonstrates that 18F-FDG PET/CT is a promising technique in identifying life-threatening pathologies in this complex group of patients. It would appear that 18F-FDG PET/CT has a good level of accuracy, including for those MVTx patients suffering from infection, post-transplant lymphoproliferative disease, and malignancy.

Cytomegalovirus Infection Management in Multivisceral and Intestinal Transplant: A Dual Institution Study

Intestinal transplant and multivisceral transplant were originally in pediatric populations and are relatively new procedures in adults. Despite increasing success rates in the immediate post-transplant period, infectious complications and acute and chronic rejection remain significant causes of morbidity and mortality. Previous research has shown cytomegalovirus (CMV) is the main cause of infection in this population. Due to the limited patient population, incidence of CMV viremia ranges widely and there is lack of universal protocol for treatment. This dual institution retrospective chart review between Henry Ford Hospital and Duke University analyzed adult intestinal and multivisceral transplant recipients between 2009 and 2019. Of the 32 patients identified and included in the study, 15 had CMV infection (46.9%). Of those with CMV infection, 5 (33.3%) had donor positive (D+)/recipient positive (R+) status; 5 had D-/R+; 4 had D+/R-; and one had D-/R-. There was no significant difference between mortality in those who had reported infection and not (80% vs 76.5%). The data from this study show significant rates of CMV viremia in patients undergoing intestinal transplant/multivisceral transplant with almost half of our study population having documented infection within 1 year of transplant, stressing the importance for universal protocol into CMV viremia treatment.

Shear wave elastography-based liver fibrosis assessment in patients with chronic hepatitis E displays elevated liver stiffness regardless of previous antiviral therapy.

Hepatitis E virus (HEV) infection especially in immunocompromised individuals can lead to chronic hepatitis. Aggressive courses of chronic hepatitis E leading to liver cirrhosis in a short period of time have been described, but evidence on the degree of liver involvement in chronic hepatitis E is rare. We therefore aimed to quantify liver fibrosis in patients with chronic active hepatitis E compared to patients with sustained virological response after ribavirin (RBV) treatment using 2D-shear wave elastography (2D-SWE) to measure liver stiffness. Patients with chronic hepatitis E underwent 2D-SWE, B-mode and Doppler ultrasound and laboratory testing in order to assess severity of liver involvement. In this cross-sectional study, we included 14 patients of whom 8 had ongoing chronic hepatitis E and 6 patients had been successfully treated for chronic hepatitis E. The most frequent cause for immunosuppression was prior kidney transplantation (n=12), one patient was a multivisceral transplant recipient, one had been treated for lymphoma. Five patients cleared HEV after RBV therapy, one patient reached viral clearance after reduction of his immunosuppressive medication. Using 2D-SWE measurement, 71.4% displayed increased stiffness indicative of liver fibrosis: 57.1% classified as significant fibrosis and 14.3% as severe fibrosis. Liver stiffness did not differ between patients with active chronic hepatitis E and in patients who had cleared HEV (1.59 and 1.54 m/s respectively). Compared with a control group of kidney transplant recipients without hepatitis E (1.44 m/s), the patients with a history of hepatitis E displayed a significantly higher liver stiffness (P=0.04). In our cohort of chronic hepatitis E patients, elevated liver stiffness indicating liver fibrosis was common and significantly higher than in controls. This is consistent with prior sparse reports of the presence of liver fibrosis or cirrhosis in chronic hepatitis E and emphasizes the need for HEV testing, therapy and research on new therapeutic options. As elevated liver stiffness was also present in patients after HEV treatment, continuous liver surveillance including elastography and ultrasound should be considered.

Multidrug-resistant organisms: A significant cause of severe sepsis in pediatric intestinal and multi-visceral transplantation

Severe sepsis in immunocompromised children is associated with increased mortality. This paper describes the epidemiology landscape, clinical acuity, and outcomes for severe sepsis in pediatric intestinal (ITx) and multi-visceral (MVTx) transplant recipients requiring admission to the pediatric intensive care unit (PICU). Severe sepsis episodes were retrospectively reviewed in 51 ITx and MVTx patients receiving organs between 2009 and 2015. Twenty-nine (56.8%) patients had at least one sepsis episode (total of 63 episodes) through December 2016. Bacterial etiologies accounted for 66.7% of all episodes (n=42), occurring a median of 122.5days following transplant (IQR 59-211.8days). Multidrug-resistant organisms (MDROs) accounted for 73.8% of bacterial infections; extended spectrum beta-lactamase producers, vancomycin-resistant enterococcus, and highly-resistant Pseudomonas aeruginosa were the most commonly identified. Increased mechanical ventilation and vasoactive requirements were noted in MDRO episodes (OR 3.03, 95% CI 1.09-8.46 and OR 3.07, 95% CI 1.09-8.61, respectively; p<.05) compared to non-MDRO episodes. PICU length of stay was significantly increased for MDRO episodes (7 vs. 3days, p=.02). Graft loss was 24.1% (n=7) and mortality was 24.1% (n=7) in patients who experienced severe sepsis. Further attention is needed for MDRO risk mitigation and modification of sepsis treatment guidelines to ensure MDRO coverage for this population.

Bloodstream infections among intestinal and multivisceral transplant recipients.

To examine the etiologies, risk factors, and microbiology of bloodstream infections (BSIs) among intestinal and multivisceral transplant recipients in the 2-year post-operative period. A retrospective medical record review of adult intestinal or multivisceral transplant recipients between 2003 and 2015. Descriptive statistics were used to describe cohort data. Logistic regression was used to assess factors related to BSIs using a backward selection process. One-hundred and six intestinal or multivisceral transplants were performed in 103 individuals. Fifty-eight percent (n=62) developed a BSI in the 2-year post-operative period with a median time to first BSI of 53days (interquartile range [IQR] 15, 169). The majority of BSIs were catheter related 38% (n=58) when the source was known. Common microbiological isolates included enterococcus 20% (n=36/174), coagulase-negative staphylococcus 14% (n=23), and 12% Klebsiella spp (n=21). Forty-seven percent (n=17) of the enterococci were resistant to vancomycin, and 14% (n=10/70) of the gram negatives were extended spectrum beta-lactamase (ESBL) producers. In adjusted analyses, (OR: 0.200 95% CI: 0.2, 0.514, P=.009) men were less likely to have a BSI. Transplant recipient age, allograft type, comorbidities, rejection, and length of stay were not noted to be risk factors for development of BSIs in our cohort. Mortality at 2-years post-transplant was similar for those who did not develop a BSI and those that developed infection, P=.5028. BSIs are a common complication of intestinal transplantation, and central venous catheters were a common source. Interventions such as early catheter removal should be implemented to prevent infections in this population. Female sex association with BSI requires further investigation.

553 Clinical characteristics of acute graft-versus-host disease in small bowel and multi-visceral transplant recipients

Acute graft-versus-host disease (aGVHD) following stem cell transplantation is characterized by rash, liver dysfunction, and diarrhea. Although aGVHD is uncommon following solid organ transplantation, we find higher rates of aGVHD after intestinal (ITx) and multi-visceral transplantation (MVT). In these cases we find a unique presentation as the donor liver (if present) and intestine are spared, leaving skin as the main target. Between 2013 and 2019, we diagnosed 17 cases of aGVHD following ITx (n=9) and MVT including both intestine and liver (n=8). Median time to onset of aGVHD was 37 days. Erythema on the trunk, palms, or both was the most common presenting skin finding (15/17 patients). All patients had skin biopsies at the time of diagnosis. Patients presented with grade 1 (7/17), grade 2 (8/17), grade 3 (1/17), and grade 4 (1/17) aGVHD. Peripheral blood chimerism studies obtained in 11 patients revealed donor CD3+ lymphocytes in 5 (45%). Two patients had passenger lymphocyte syndrome, and partial donor stem cell engraftment was diagnosed in a third patient. Native GI tract involvement (usually rectosigmoid), was found in 7/17 patients; other sites included bone marrow, and native liver. In all, 6/17 patients had no evidence of extra-cutaneous aGVHD. Treatment strategies included systemic and topical corticosteroids, anti-thymocyte globulin, extracorporeal photopheresis, and/or JAK inhibitors. Complications of immunosuppression including opportunistic infections (aspergillosis and toxoplasmosis) and post-transplant lymphoproliferative disorder occurred in 7/17 patients. In summary, rash is typically the first, and may be the only, manifestation of aGVHD following luminal organ transplants. Diagnosis may be aided by time of onset of cutaneous manifestations, extra-cutaneous signs, and peripheral blood chimerism.

Clostridioides difficile Infections in Adult and Pediatric Intestinal and Multivisceral Transplant Patients

Background Solid organ transplant (SOT) recipients are at increased risk of Clostridioides difficile infection (CDI). Studies addressing the epidemiology of CDI in intestinal and multivisceral transplant are limited. Since 2013, our center greatly expanded its intestinal and multivisceral transplant program, providing the consummate opportunity to examine CDI in this vulnerable population. Methods We conducted a retrospective study of all intestinal and multivisceral transplant recipients between 2009 and 2018. Results We identified 86 patients who underwent a total of 94 transplants. There were 60 isolated intestinal transplants (64%), 21 intestine/pancreas/liver (22%), 10 intestine/pancreas (11%), 2 intestine/pancreas/liver/kidney (2%), and 1 intestine/kidney transplant (1%). All but 3 patients received perioperative metronidazole. Four patients (5%) had CDI before transplant, but none experienced recurrence in the first 6 months posttransplant. Five patients suffered 7 mild-moderate episodes of early CDI (attack rate, 5.9%). Three patients (60%) with early CDI developed rejection, similar to the observed incidence (70%) in patients without CDI. Two patients with early CDI developed recurrent infection; both of these patients underwent intestinal retransplant. Overall, 1-year mortality was similar (20% among patients with early CDI vs. 23% among those without early CDI). Conclusions For certain solid organ transplant recipients, an association between CDI and allograft loss, rejection, and mortality has been shown. Although limited by sample size, we observed that early CDI was not associated with those outcomes in the present investigation. Multicenter studies are merited to explore risk factors for CDI and associations with transplant-related outcomes in intestinal and multivisceral transplant recipients.

Intra-abdominal infections among adult intestinal and multivisceral transplant recipients in the 2-year post-operative period.

Intestinal and multivisceral transplantations are treatment options for patients with intestinal failure. Transplantation is often complicated by abdominal and/or bloodstream infections in the post-operative period. A retrospective chart review of all adults who underwent intestinal or multivisceral transplantation at our institution from 2003 to 2015 was performed. Data were collected for 2years post transplant. A total of 106 intestinal or multivisceral transplants were performed in 103 patients. The median age at the time of transplant was 44 (IQR: 34-52) with 55% (n=58) male and 45% (n=48) female. There were 46 (43%) intra-abdominal infections post transplant among the 103 patients, and six transplant recipients (13%) developed concurrent bloodstream infections. The median time to first intra-abdominal infection was 23days (IQR: 10-48). For those with organisms isolated in culture, forty-seven percent of the isolates were gram negative, 39% gram positive, 7% anaerobes, and 7% yeast. The most common isolates were enterococci at 28%, E.coli at 14%, and Klebsiella spp at 13%. Sixty-three percent of the enterococci were vancomycin-resistant enterococci (VRE), and 22% of the gram-negative isolates were extended spectrum beta-lactamases (ESBLs). Patients with intra-abdominal infections had longer hospital post-transplant length of stays at a median of 35days (IQR: 25-48) vs 23days (IQR: 17-33) for those without infections, P=.0012. There was no difference in all-cause mortality in patients with or without intra-abdominal infections, P=.654. Intra-abdominal infections are common in intestinal or multivisceral transplant recipients, but despite this complication, we found no increased risk of mortality. These transplant recipients are also at risk for infection with drug-resistant organisms.

310.7: Spleen preservation attenuates GVHD in multivisceral transplant recipients.

Purpose: The immunological benefits of the spleen are well acknowledged, but splenectomy is often performed in recipients of multivisceral transplantation. Technical reason and the lack of room in the abdominal cavity are the key arguments to justify removal of the native spleen. We aimed to analyze the beneficial role of the spleen in MVTx recipients in a series of pediatric intestinal transplantation. Patients and methods: A total of 103 IT (55MV, 25SB, 22CLSB, 3MMV) were performed in 84 patients (male-60%-, mean age 5.3yrs) between 1999 and 2018. Mean time on the waiting list was 272days waiting list mortality was 25%. Main indications for the transplant on the first instance were short bowel syndrome (69%), motility disorders(12%) and epithelial diseases(9.5%). For the present study we included only pediatric (<18 years) cases that underwent multivisceral transplantation. Patients were divided patients in three groups, native spleen preservation, native spleen removal and spleen graft inclusion. We analyzed survival, GVHD, hemolytic disorders. Results: From the whole series, only 55 patients were included, all of them received a multivisceral graft. The spleen was included in the graft in 18.1% of patients, splenectomy was performed in 40%, in several of them after failed attempt of preservation; and native spleen was preserved in 41.8% Rejection in different forms was more frequent in patients who preserved the spleen, 4% presented humoral rejection, and acute cellular rejection was two times and chronic rejection four times more frequent compared with patients who underwent splenectomy. None of the patients with the spleen included in the graft presented humoral or chronic rejection, PTLD was also (1.8 times) more frequent in this group. The proportion of GVHD was significantly lower in the group of spleen preservation compared to splenectomy and graft spleen (RR 2.75, OR 3.33) (p<0.05). We also found a trend towards less hemolytic disorders in patients with spleen preservation. Conclusion: Native spleen preservation demonstrated to attenuate the occurrence and severity of GVHD in pediatric MVTx recipients. This technique should be considered in all patients, although technical difficulties, prolonged ischemia of the graft and other factors can preclude the success of the procedure.

P1.24: Vascular stenting for mycotic aneurysm in multivisceral transplant recipients

P1.24: Vascular stenting for mycotic aneurysm in multivisceral transplant recipients

Graft Loss Due to Thrombosis of an Aortic Conduit in a Pediatric Multivisceral Transplant Recipient.

Graft Loss Due to Thrombosis of an Aortic Conduit in a Pediatric Multivisceral Transplant Recipient.

1487. Variability of Pneumocystis jirovecii Prophylaxis Use Among Pediatric Solid Organ Transplant Providers

Background Pneumocystis jirovecii pneumonia (PJP) prophylaxis after pediatric solid-organ transplant (SOT) is routinely recommended, but practice patterns vary.MethodsIn 2018, an online survey was sent to 707 members of the International Pediatric Transplant Association.Results105 responded, representing 47 institutions in 18 countries. Majority were transplant physicians (66%) or transplant surgeons (20%). Remainder were nurse practitioners (6%), infectious disease physicians (5%) or pharmacists (4%). Routine PJP prophylaxis was reported by 87%, while 13% do not routinely administer any prophylaxis. The majority not using PJP prophylaxis performed only renal transplants (67%) and listed low incidence of PJP infection as the primary reason (88%). Trimethoprim/sulfamethoxazole (TMP/SMX) was the preferred first-line agent (97%). Common second-line agents were dapsone (33%), inhaled pentamidine (33%), and atovaquone (12%). Of those that provide PJP prophylaxis following renal transplant (n = 51), the majority (51%) provide 4–6 months (Figure 1). Durations following liver transplant (n = 25) were similar; and heart transplant providers (n = 24) most commonly give 4–6 months (42%) as well. Majority of abdominal multivisceral (MVS) providers (55%) give 10–12 months and most lung transplant responders provide lifelong prophylaxis (81%). Across all organs, at least 20% provide lifetime prophylaxis. After completion of PJP prophylaxis, 36% do not restart for any reason and 54% would restart for treatment of acute graft rejection.Figure 1:Duration of PJP Prophylaxis.Reported PJP infections were uncommon with 80% reporting no PJP cases in the prior 12 months and 15% reporting 1–5 infections. Only 2% reported a case of PJP infection on prophylaxis.ConclusionPJP prophylaxis remains routine for the majority of pediatric SOT patients; albeit with notable practice variations. The most common duration of PJP prophylaxis following renal, liver and heart transplant was 4–6 months; while in abdominal multivisceral and lung transplant recipients, durations of either 10–12 months or lifelong prophylaxis were common. There remains a lack of evidence-based guidelines balancing the utility of PJP prevention against potential treatment side effects and unnecessary medication use.Disclosures All authors: No reported disclosures.

Role of Graft-derived Graft-versus-Host T cells in Facilitating Multilineage Blood Chimerism after Human Intestinal Transplantation

Long-term multilineage chimerism often appears in blood following human intestinal transplantation (ITx), especially in multivisceral transplant (MVTx) recipients. Patients with donor T cell macrochimerism (>4%) in blood, frequently without graft-versus-host disease (GVHD), displayed less graft rejection and donor-specific antibody (DSA) production and slower graft T cell replacement by the recipient. To address the hypothesis that the balance of graft-versus-host (GvH) and host-versus-graft (HvG) alloreactivity might underly these relationships, we analyzed the phenotype, repertoire and alloreactivity of donor- and recipient-derived T cells in the intestinal allograft, peripheral blood and bone marrow (BM) of ITx recipients. We identified GvH and HvG clones on the basis of high throughput TCRβ CDR3 sequencing from pre-Tx donor and recipient mixed lymphocyte reactions as we have described1. Enrichment of GvH compared to HvG clones in early intestinal biopsies and absence of Class I DSA were associated with donor T cell macrochimerism. Local expansion of GvH clones in the graft was likely driven by uniformly rapid replacement of recipient antigen presenting cells (APCs) within allografts early post-Tx. Cumulative frequency of GvH clones in blood early post-Tx was positively correlated with the peak level of donor T cell chimerism (Fig.1).Unlike donor ileal lymphocytes, which display a tissue-resident memory phenotype, long-term circulating donor T cells were markedly enriched for the recent thymic emigrant phenotype compared with recipient cells, and GvH clones were undetectable among these late circulating naïve donor-derived T cells. Enrichment of donor circulating naïve B cells and T cells and recurrent myeloid chimerism late post-Tx are consistent with our observation that donor-derived hematopoietic stem and progenitor cells are present in intestinal allografts and are detectable in the circulation of patients with macrochimerism. Multilineage chimerism might reflect a lymphohematopoietic GvH response (LGVHR) migrating from recipient circulation to the BM, making “space” for engraftment of progenitor cells from the graft. Indeed, 0.0356% of CD45+ cells in the BM of an MVTx patient on day 105 post-Tx were donor-derived, among which 72.9% were T cells and 1.37% were CD34+ progenitors. TCR sequencing of sorted donor cells in recipient BM identified donor-mappable clones, among CD4s of which 60% by frequency were GvH-reactive. GvH CD4 cells did not show marked enrichment in donor-mappable PBMCs on the same day. (Fig.2)Together, these data suggest that donor GvH-reactive T cells expanding within the graft in response to recipient APCs entering the graft migrate into the recipient circulation and BM, playing a key role in promoting and maintaining mixed chimerism. LGVHR without GVHD in ITx recipients suggests a novel approach to achieving intestinal allograft tolerance. 1. Zuber et al., 2016 Science Immunology. The study was funded by the National Institute of Allergy and Infectious Diseases grant P01 AI106697. Research reported in this study was performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10RR027050 and S10OD020056.

Fecal pancreatic elastase-1 in the evaluation of pancreatic function after pediatric intestinal transplantation.

Fat malabsorption is common after SBT. To identify whether anatomic variant transplants differ in occurrence of exocrine pancreatic insufficiency that could contribute to fat malabsorption, we measured FPE repeatedly in 54 recipients of a SBT, ages 6.2 to 320months. FPE determination most distant from SBT was 6.1years. Of the 54, 39% received an isolated intestinal graft (native pancreas only), 48% received an en bloc liver-intestinal-pancreas graft (native and graft pancreas), and 13% received a multivisceral graft (graft pancreas only). Initial FPE was normal (>200μg/g) in 15 of the 54 at a median of 22 (11-61) days after SBT. Recipients of a liver-intestine-pancreas transplant were more likely to have normal FPE within 30days after SBT than were isolated intestinal or multivisceral transplant recipients (47%, 19%, and 0%, respectively, P=.049). Of the remaining 39 patients, 34 eventually demonstrated a normal FPE at a median of 168 (31-943) days after SBT. Type of SBT did not influence the likelihood of achieving a normal FPE level or time when it occurred. Five (9%) patients failed to achieve normal FPE, including 3 who died within 2years after SBT. In conclusion, possessing both graft and native pancreas as in transplantation of an en bloc liver-intestinal-pancreas graft facilitates early normalization of FPE that eventually occurs in most patients irrespective of transplant type. Failure to recover normal pancreatic function may be associated with severe post-transplant complications.

Myeloid-derived suppressor cells increase and inhibit donor-reactive T cell responses to graft intestinal epithelium in intestinal transplant patients.

Recent advances in immunosuppressive regimens have decreased acute cellular rejection (ACR) rates and improved intestinal and multivisceral transplant (ITx) recipient survival. We investigated the role of myeloid-derived suppressor cells (MDSCs) in ITx. We identified MDSCs as CD33+ CD11b+ lineage(CD3/CD56/CD19)- HLA-DR-/low cells with 3 subsets, CD14- CD15- (e-MDSCs), CD14+ CD15- (M-MDSCs), and CD14- CD15+ (PMN-MDSCs), in peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the grafted intestinal mucosa. Total MDSC numbers increased in PBMCs after ITx; among MDSC subsets, M-MDSC numbers were maintained at a high level after 2months post ITx. The MDSC numbers decreased in ITx recipients with ACR. MDSC numbers were positively correlated with serum interleukin (IL)-6 levels and the glucocorticoid administration index. IL-6 and methylprednisolone enhanced the differentiation of bone marrow cells to MDSCs in vitro. M-MDSCs and e-MDSCs expressed CCR1, -2, and -3; e-MDSCs and PMN-MDSCs expressed CXCR2; and intestinal grafts expressed the corresponding chemokine ligands after ITx. Of note, the percentage of MDSCs among intestinal mucosal CD45+ cells increased after ITx. A novel in vitro assay demonstrated that MDSCs suppressed donor-reactive T cell-mediated destruction of donor intestinal epithelial organoids. Taken together, our results suggest that MDSCs accumulate in the recipient PBMCs and the grafted intestinal mucosa in ITx, and may regulate ACR.

Long-term Persistence of Innate Lymphoid Cells in the Gut After Intestinal Transplantation.

Little is known about innate lymphoid cell (ILC) populations in the human gut, and the turnover of these cells and their subsets after transplantation has not been described. Intestinal samples were taken from 4 isolated intestine and 3 multivisceral transplant recipients at the time of any operative resection, such as stoma closure or revision. ILCs were isolated and analyzed by flow cytometry. The target population was defined as being negative for lineage markers and double-positive for CD45/CD127. Cells were further stained to define ILC subsets and a donor-specific or recipient-specific HLA marker to analyze chimerism. Donor-derived ILCs were found to persist greater than 8 years after transplantation. Additionally, the percentage of cells thought to be lymphoid tissue inducer cells among donor ILCs was far higher than that among recipient ILCs. Our findings demonstrate that donor-derived ILCs persist long-term after transplantation and support the notion that human lymphoid tissue inducer cells may form in the fetus and persist throughout life, as hypothesized in rodents. Correlation between chimerism and rejection, graft failure, and patient survival requires further study.

Surgical Challenges in the Long Term Follow-up after Intestinal and Multivisceral Transplantation

Background: Intestinal and multivisceral transplant recipients have often undergone mulitple operations prior to and early after transplantation. In addition, they receive high amounts of immunosupression. Thus abdominal surgery at a later stage posttransplant is very challenging and may increase the morbidity and mortality of these fragile patients. Methods: We retrospectively studied 69 patients (27 female, 42 male, 37±9 years) with isolated intestinal (ITX, n=48), modified (mMVTX, n=7) or typical multivisceral transplantation (MVTX, n=15) in 2 large european transplant centres. 4 grafts included a kidney and 17 included the abdominal wall. Maintenance immunosuppression consisted of either Tacrolimus Monotherapy in 31 patients or a double combination of Tacrolimus/MMF, Tacrolimus/Sirolimus, Tacrolimus/Everolimus. We recorded all intraabdominal interventions, which were performed after the first year posttransplant, and subdivided them into 2 groups depending on whether or not they were related to the intestinal graft. Results: The median follow-up time posttransplant was 8 years [1;15]. 20 intraabdominal operations were reported in 15 patients after a median of 5 years [1;13] posttransplant. 81% were emergency operations: Graft-related surgery was required due to graft ischeamia (n=2), adhesive ileus (n=3) and encapsulating ileus (n=2). Surgery for these patients included partial graft resection (n=5), graft explantation (n=4) and intestinal retransplantation (n=1). Non graft-related operations did not affect the graft or graft function and were: native colon resection due to Volvulus (n=1), native nephrectomy due to outflow obstruction (n=1), kidney transplantation due to CNI-toxicity (n=1), cholecystectomy due to necrotic cholecystitis (n=1), caesarian (n=1), post-mortem kidney/liver donation (n=1). There were no deaths related to surgery. 19% was elective surgery: Incisional herniotomy at the previous stoma-site (n=3) and a bilateral inguinal herniotomy without incarceration(n=1). A conservative treatment was attempted in 4 patients with: rectovaginal fistula in a stapled rectum stump (n=1), neutropenic colitis (n=1) and upper GI-haemorrhage (n=2). The latter 2 patients died. The median hospital stay following surgery was 27 days [7;210]. Six patients had to undergo repeated surgery (median number of operations 3 [2;13]). Conclusion: Abdominal surgery in ITX and (m)MVTX-recipients is challenging but feasible. Especially graft-related surgery was accompanied with a high risk of graft-loss but not with mortality. Non graft-related surgery did not affect graft function or longterm survival.

Could Sentinel Skin Transplants Have Some Utility in Solid Organ Transplantation?

Accurate diagnosis of allograft rejection can be hazardous and challenging. A strategy that has emerged from experience with vascularized composite allografts (VCAs) is the use of sentinel skin transplants (SSTs)-portions of donor skin transplanted synchronously to an allograft. Work in nonhuman animal models and experience with VCAs suggest concordance between rejection occurring in the primary allograft and the SST, and that appearance of rejection in the SST may precede rejection in the primary allograft, permitting early therapeutic intervention that may improve outcomes with lower rates of chronic rejection. The encouraging findings reported in VCA transplantation raise the possibility that SST may also be useful in solid organ transplantation. Some evidence is provided by experience with abdominal wall transplantation in some intestinal and multivisceral transplant recipients. Results from those reports raise the possibility that rejection may manifest in the skin component before emergence in the intestinal allograft, providing a "lead time" during which treatment of rejection of the abdominal wall could prevent the emergence of intestinal rejection. It is plausible that these findings may be extrapolated to other solid organ allografts, especially those for which obtaining an accurate diagnosis of acute rejection can be hazardous and challenging, such as the lung or pancreas. However, more data are required to support widespread adoption of this technique.

Resistant cytomegalovirus in intestinal and multivisceral transplant recipients.

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. 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. 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). 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.