Evaluation of pediatric patients for intestinal transplantation in the modern era.

OBJECTIVES: To review recent evaluations of pediatric patients with intestinal failure (IF) for intestinal transplantation (ITx), waiting list decisions, and outcomes of patients listed and not listed for ITx at our center. METHODS: Retrospective chart review of 97 patients evaluated for ITx from January 2014 to December 2021 including data from referring institutions and protocol laboratory testing, body imaging, endoscopy, and liver biopsy in selected cases. Survival analysis used Kaplan-Meier estimates and Cox proportional hazards regression. RESULTS: Patients were referred almost entirely from outside institutions, one-third because of intestinal failure-associated liver disease (IFALD), two-thirds because of repeated infective and non-IFALD complications under minimally successful intestinal rehabilitation, and a single patient because of lost central vein access. The majority had short bowel syndrome (SBS). Waiting list placement was offered to 67 (69%) patients, 40 of whom for IFALD. The IFALD group was generally younger and more likely to have SBS, have received more parenteral nutrition, have demonstrated more evidence of chronic inflammation and have inferior kidney function compared to those offered ITx for non-IFALD complications and those not listed. ITx was performed in 53 patients. Superior postevaluation survival was independently associated with higher serum creatinine (hazard ratio [HR] 15.410, p = 014), whereas inferior postevaluation survival was associated with ITx (HR 0.515, p = 0.035) and higher serum fibrinogen (HR 0.994, p = 0.005). CONCLUSIONS: Despite recent improvements in IF management, IFALD remains a prominent reason for ITx referral. Complications of IF inherent to ITx candidacy influence postevaluation and post-ITx survival.

North American Biliary Stricture Management Strategies in Children After Liver Transplantation: A Multicenter Analysis From the Society of Pediatric Liver Transplantation (SPLIT) Registry.

Biliary strictures affect 4%-12% of pediatric liver transplantations. Biliary strictures can contribute to graft loss if left untreated; however, there remains no consensus on the best course of treatment. Study objectives included analyses of outcomes associated with biliary stricture management strategies via percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP), or surgery. We identified pediatric liver transplantation recipients (2011-2016) with biliary strictures from the Society of Pediatric Liver Transplantation (SPLIT) registry and retrieved imaging, procedural, and operative reports from individual centers. Subanalyses were performed to specifically evaluate PTC and ERCP for "optimal biliary outcome" (OBO), defined as graft survival with stricture resolution and without recurrence or surgery. A total of 113 children with a median follow-up of 3.9 years had strictures diagnosed 100 days (interquartile range, 30-290) after liver transplantation; 81% were isolated anastomotic strictures. Stricture resolution was achieved in 92% within 101 days, more frequently with isolated anastomotic strictures (96%). 20% of strictures recurred, more commonly in association with hepatic artery thrombosis (32%). Patient and graft survival at 1 and 3 years were 99% and 98% and 94% and 92%, respectively. In a subgroup analysis of 79 patients with extrahepatic strictures managed by PTC/ERCP, 59% achieved OBO following a median of 4 PTC, and 75% following a median of 3 ERCP (P < 0.001). Among patients with OBO, those with ERCP had longer time intervals between successive procedures (41, 47, 54, 62, 71 days) than for PTC (27, 31, 36, 41, 48 days; P < 0.001). Allograft salvage was successful across all interventions. Stricture resolution was achieved in 92%, with 20% risk of recurrence. Resolution without recurrence was highest in patients with isolated anastomotic strictures and without hepatic artery thrombosis.

Mismatch epitope load predicts de novo-DSA-free survival in pediatric liver transplantation.

BACKGROUND: Our knowledge of de novo anti-HLA donor-specific antibodies (dnDSA) in liver transplantation continues to be defined. We hypothesized that differences of HLA-DR/DQ mismatches can improve precision in alloimmune risk categorization and be applied to tailor immunosuppression. METHODS: A retrospective chart review of 244 pediatric patients consecutively transplanted at our center between 2003 and 2019 was performed to identify patients tested for dnDSA. Records were queried for: demographics, pre-transplant diagnosis, biopsy-proven T-cell-mediated rejection (TCMR), radiology proven biliary complications, tacrolimus trough levels, dnDSA characteristics, and HLA typing. The eplet mismatch analyses were performed using HLAMatchmaker™ 3.1. All statistical analyses were conducted using R software version 3.40. RESULTS: There were 99 dnDSA-negative patients and 73 dnDSA-positive patients (n = 70 against class II and n = 3 against class I and II). ROC analysis identified optimal cutoff of eplet mismatch load for dnDSA and defined risk groups for an alloimmune outcome. Kaplan-Meier curves and log-rank tests showed high eplet mismatch load was associated with shorter dnDSA-free survival (log-rank p = .001). Multivariable Cox regression models showed that tacrolimus coefficient of variation and tacrolimus mean levels were significantly associated with dnDSA-free survival (p < .001 and p = .036). Fisher's exact test showed that dnDSA was associated with an increased likelihood of TCMR (OR 14.94; 95% CI 3.65 - 61.19; p < .001). Patients without TCMR were more likely to have dnDSA to HLA-DQ7 and less likely to have dnDSA to HLA-DQ2 (p = .03, p = .080). CONCLUSIONS: Mismatched epitope load predicts dnDSA-free survival in pediatric liver transplant, while dnDSA specificity may determine alloimmune outcome.

SARS-CoV-2 Infection in Pediatric Solid Organ Transplant Recipients: A Single Center Observation.

OBJECTIVES: This is a descriptive study to characterize rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric solid organ transplant (SOT) recipients during the early days of the pandemic. We hypothesized that asymptomatic infection may represent a large proportion of SARS-CoV-2 infection in pediatric SOT recipients. METHODS: We queried Organ Transplant Tracking Record (OTTR) for all pediatric SOT recipients followed at our center and reviewed medical records to identify patients tested for SARS-CoV-2 between March 15, 2020 and June 30, 2021. Patients were tested by polymerase chain reaction (PCR): prior to planned procedures or because of symptoms; OR: tested by measurement of IgG to spike protein with their routine labs q 2-monthly. A positive PCR was called acute infection. A positive IgG with negative PCR was called convalescence. For immunologic studies, blood was obtained when the PCR or IgG was positive. Statistical comparisons were made between (1) acute infection versus convalescence; (2) acute infection versus SOT recipients without infection (called healthy controls); (3) liver transplant (LT) versus small bowel (SB)/multivisceral transplant (MVT); (4) positive versus negative test result. RESULTS: Of 257 LT recipients, 99 were tested: 6 were PCR positive, 13 were antibody positive. Of 150 SB/MVT recipients, 55 were tested: 4 were PCR positive, 6 were antibody positive. Of 8 simultaneous liver, kidney transplant recipients, 3 were tested: 1 was PCR positive. Symptoms when present were mostly mild. Patients with a positive test result were younger (6.3 vs 10.0 years; P = 0.017). We observed a rapid decline in viral load within 96 hours without a change in immunosuppression. Antibody lasted >8 months beyond the time it was monitored. Acute infection was associated with increased CD4 and CD8 T EM cell frequency ( P = 0.04, P = 0.03, respectively), decreased interferon (IFN)-γ production from T-cells (2.8% vs 11.3%; P = 0.006), and decreased CD8 TEMRA frequency (4.56% vs 11.70%; P = 0.006). CONCLUSIONS: Early in the pandemic, COVID-19 disease was mostly mild in pediatric SOT recipients with no rejection, patient death, or graft loss observed.

CD69+ resident memory T cells are associated with graft-versus-host disease in intestinal transplantation.

Graft-versus-host disease (GvHD) is a common, morbid complication after intestinal transplantation (ITx) with poorly understood pathophysiology. Resident memory T cells (TRM ) are a recently described CD69+ memory T cell subset localizing to peripheral tissue. We observed that T effector memory cells (TEM ) in the blood increase during GvHD and hypothesized that they derive from donor graft CD69+TRM migrating into host blood and tissue. To probe this hypothesis, graft and blood lymphocytes from 10 ITx patients with overt GvHD and 34 without were longitudinally analyzed using flow cytometry. As hypothesized, CD4+ and CD8+CD69+TRM were significantly increased in blood and grafts of GvHD patients, alongside higher cytokine and activation marker expression. The majority of CD69+TRM were donor derived as determined by multiplex immunostaining. Notably, CD8/PD-1 was significantly elevated in blood prior to transplantation in patients who later had GvHD, and percentages of HLA-DR, CD57, PD-1, and naïve T cells differed significantly between GvHD patients who died vs. those who survived. Overall, we demonstrate that (1) there were significant increases in TEM at the time of GvHD, possibly of donor derivation; (2) donor TRM in the graft are a possible source; and (3) potential biomarkers for the development and prognosis of GvHD exist.

Rejection of intestinal allotransplants is driven by memory T helper type 17 immunity and responds to infliximab.

Intestinal transplantation (ITx) can be life-saving for patients with advanced intestinal failure experiencing complications of parenteral nutrition. New surgical techniques and conventional immunosuppression have enabled some success, but outcomes post-ITx remain disappointing. Refractory cellular immune responses, immunosuppression-linked infections, and posttransplant malignancies have precluded widespread ITx application. To shed light on the dynamics of ITx allograft rejection and treatment resistance, peripheral blood samples and intestinal allograft biopsies from 51 ITx patients with severe rejection, alongside 37 stable controls, were analyzed using immunohistochemistry, polychromatic flow cytometry, and reverse transcription-PCR. Our findings inform both immunomonitoring and treatment. In terms of immunomonitoring, we found that while ITx rejection is associated with proinflammatory and activated effector memory T cells in the blood, evidence of treatment efficacy can only be found in the allograft itself, meaning that blood-based monitoring may be insufficient. In terms of treatment, we found that the prominence of intra-graft memory TNF-α and IL-17 double-positive T helper type 17 (Th17) cells is a leading feature of refractory rejection. Anti-TNF-α therapies appear to provide novel and safer treatment strategies for refractory ITx rejection; with responses in 14 of 14 patients. Clinical protocols targeting TNF-α, IL-17, and Th17 warrant further testing.

De novo hepatocellular carcinoma 18 years after liver and small bowel transplantation in a one-year-old pediatric patient.

De novo HCC following transplantation in a child is a rare occurrence. Even within the adult liver transplantation population, there are a limited number of published cases. In this report, we present a case of de novo HCC found in a child, post-multivisceral transplantation. A 19-year-old boy, at the age of one, received liver and small bowel transplantation due to short gut syndrome secondary to midgut volvulus and total parenteral nutrition-associated liver disease. Eighteen years later, he was found to have a large mass involving the right hepatic dome consistent with HCC. To the best of our knowledge, this is the second reported case after gut transplantation and the third case post-liver transplantation in the pediatric population.

Anti-plasma cell treatment in refractory autoimmune hemolytic anemia in a child with multivisceral transplant.

BACKGROUND: Warm-antibody AIHA is known to complicate solid organ (SOT) and HSCT, the disease maybe refractory to standard therapy. Immunosuppressive therapies as well as IVIG, and rituximab have been the main stay of treatment. Over the past decade, B-lymphocyte targeted, anti-CD-20 antibody has been recognized in the treatment of autoimmune diseases and utilized in AIHA. Bortezomib, a proteasome inhibitor that causes apoptosis of plasma cells, is an appealing targeted therapy in secondary AIHA and has demonstrated efficacy in HSCT patients. From our experience, we advocate for early targeted therapy that combines B cell with plasma cell depletion. CASE REPORT: We describe a 4-year-old-girl with stage III neuroblastoma, complicated with intestinal necrosis needing multivisceral transplant developed warm AIHA 1-year after transplantation, and following an adenovirus infection. She received immunoglobulin therapy, rituximab, sirolimus, plasmapheresis, and long-term prednisolone with no sustained benefit while developing spinal fractures related to the latter therapy. She received bortezomib for intractable AIHA in combination with rituximab with no appreciable adverse effects. Three years later the child remains in remission with normal reticulocyte and recovered B cells. In the interim, she required chelation therapy for iron overload related to blood transfusion requirement during the treatment of AIHA. CONCLUSION: We propose early targeted anti-plasma cell therapy with steroid burst, IVIG, rituximab, and possible plasmapheresis may reduce morbidity in secondary refractory w-AIHA.

Efficacy and feasibility of ruxolitinib in chronic steroid-refractory GVHD in a pediatric intestine transplant.

Acute graft-versus-host disease (GvHD) has been a clinical problem in solid organ transplant that includes intestine due to the donor lymphoid tissue mass which accompanies the intestinal component of the graft. We report a case that demonstrated the efficacy and feasibility of ruxolitinib a JAK 1/2 inhibitor in the treatment of chronic steroid-refractory GVHD (SR-GVHD). The child developed SR-GVHD following a composite intestine transplant (small bowel, colon, liver, and pancreas). And after receiving ruxolitinib 1.25 mg (0.15 mg/kg/dose) per gastric tube (G-tube) daily, the child appeared to have improved skin rash and sigmoidoscopy was negative. Nonetheless, we encourage close monitoring of hematologic and infectious adverse effect during dose escalation, and individualizing patient maximum effective dose with the least adverse effect possible. We stress the importance of early diagnosis and hyper-alertness of GVHD in intestinal transplant patients.

The effects of child anxiety and depression on concordance between parent-proxy and self-reported health-related quality of life for pediatric liver transplant patients.

BACKGROUND: HRQOL is a key outcome following pediatric LT. Parent-proxy reports may substitute for patients unable to report their own HRQOL. This study compared parent-proxy and self-reported HRQOL in children who have undergone LT. METHODS: Pediatric LT recipients between the ages of 8 and 18 years, and a parent, completed self and proxy versions of the PeLTQL questionnaire, PedsQL Generic and Transplant modules, and standardized measures of depression and anxiety. RESULTS: Data from 129 parent-patient dyads were included. Median parent age was 44 years, and most (89%) were mothers. Median patient age was 2.5 years at LT and 13.6 years at the time of study participation. Parents had significantly lower scores than patients on PedsQL total generic (70.8 ± 18.5 and 74.3 ± 19.0, p = .01), PeLTQL coping and adjustment (63.0 ± 15.6 and 67.3 ± 16.2, p < .01), and social-emotional (66.3 ± 14.9 and 71.9 ± 15.6, p < .001) domains. Higher patient anxiety and depression were related to larger absolute differences between parent-proxy and self-reported scores on all HRQOL measures (all p < .05). In this disparity, parents reported higher HRQOL scores than their child as self-reported anxiety and depression scores increased. CONCLUSIONS: Differences in concordance between parent-proxy and self-reported HRQOL scores can be more prominent when children have more symptoms of anxiety and depression. Children's mental health symptoms should be queried, if feasible, when interpreting differences in parent and child reports of HRQOL.

Factors Associated With 5- and 10-Year Survival After Intestinal Transplantation in Infants and Children.

OBJECTIVES: Intestinal transplantation is an option for permanent intestinal failure with parenteral nutrition intolerance. We sought to determine long-term intestinal graft survival in pediatric patients at our center and to identify factors influencing survival. METHODS: Retrospective chart review of 86 patients transplanted between 2003 and 2013, targeting potential explanatory variables related to demographics, perioperative factors, and postoperative complications. RESULTS: Intestinal graft survival was 71% and 65% after 5 and 10 years, respectively. Five-year graft survival was attained in 79% of patients with a history of anatomic intestinal failure compared with 45% with functional intestinal failure (P = 0.0055). Compared with nonsurvival, 5-year graft survival was also associated with reduced incidences of graft-versus-host disease (2% vs 16%, P = 0.0237), post-transplant lymphoproliferative disorder (3% vs 24%, P = 0.0067), and de novo donor-specific antibodies (19% vs 57%, P = 0.0451) plus a lower donor-recipient weight ratio (median 0.727 vs 0.923, P = 0.0316). Factors not associated with 5-year intestinal graft survival included graft rejection of any severity and inclusion of a liver graft. Factors associated with graft survival at 10 years were similar to those at 5 years. CONCLUSIONS: In our experience, outcomes in pediatric intestinal transplantation have improved substantially for anatomic but not functional intestinal failure. Graft survival depends on avoidance of severe infectious and immunological complications including GVHD, whereas inclusion of a liver graft provides no obvious survival benefit. Reduced success with functional intestinal failure may reflect inherently increased susceptibility to complications in this group.

Long-term survival in visceral transplant recipients in the new era: A single-center experience.

There is a paucity of data on long-term outcomes following visceral transplantation in the contemporary era. This is a single-center retrospective analysis of all visceral allograft recipients who underwent transplant between November 2003 and December 2013 with at least 3-year follow-up data. Clinical data from a prospectively maintained database were used to assess outcomes including patient and graft survival. Of 174 recipients, 90 were adults and 84 were pediatric patients. Types of visceral transplants were isolated intestinal transplant (56.3%), combined liver-intestinal transplant (25.3%), multivisceral transplant (16.1%), and modified multivisceral transplant (2.3%). Three-, 5-, and 10-year overall patient survival was 69.5%, 66%, and 63%, respectively, while 3-, 5-, and 10-year overall graft survival was 67%, 62%, and 61%, respectively. In multivariable analysis, significant predictors of survival included pediatric recipient (P = .001), donor/recipient weight ratio <0.9 (P = .008), no episodes of severe acute rejection (P = .021), cold ischemia time <8 hours (P = .014), and shorter hospital stay (P = .0001). In conclusion, visceral transplantation remains a good option for treatment of end-stage intestinal failure with parenteral nutritional complications. Proper graft selection, shorter cold ischemia time, and improvement of immunosuppression regimens could significantly improve the long-term survival.

Successful long-term outcome after combined hematopoietic stem cell transplantation and small bowel transplantation: A case report and review of the literature.

Combining HSCT with SOT is an unusual and challenging undertaking given the complexities of immune modulation, the need to balance comorbidities, and the cumulative potential for complications. Early life-threatening complications include infections and related effects, graft rejection, and GVHD can be expected to be increased especially if the HSCT is indicated for high-risk cases such as individuals with severe combined immune deficiency and SOT that includes an intestine graft. Herein, we report such a case. Our patient is unique as a long-term survivor. We review the literature and the features of our case, especially the timing of transplants and human leukocyte antigen matching for HSCT that resulted in a successful outcome and discuss how this may be applied to others in the future.

Visceral transplantation in patients with intestinal-failure associated liver disease: Evolving indications, graft selection, and outcomes.

Intestinal failure (IF)-associated liver disease (IFALD) is widely recognized as a lethal complication of long-term parenteral nutrition. The pathophysiology of IFALD is poorly understood but appears to be multifactorial and related to the inflammatory state in the patient with IF. Visceral transplant for IFALD includes variants of intestine, liver, or combined liver-intestine allografts. Graft selection for an individual patient depends on the etiology of IF, abdominal and vascular anatomy, severity of IFALD, and potential for intestinal rehabilitation. The past decade has witnessed dramatic improvement in the management of IFALD, principally due to improved lipid emulsion formulations and the multidisciplinary care of the patient with IF. As the recognition and treatment of IFALD continue to improve, the requirement of liver-inclusive visceral grafts appears to be decreasing, representing a paradigm shift in the care of the patient with IF. This review highlights the current indications, graft selection, and outcomes of visceral transplantation for IFALD.

World's smallest combined en bloc liver-pancreas transplantation.

We present a case of a 2-year-old child who underwent a combined en bloc liver and pancreas transplant following complications of WRS. WRS is characterized clinically through infantile insulin-dependent diabetes mellitus, neutropenia, recurrent infections, propensity for liver failure following viral infections, bone dysplasia, and developmental delay. Usually, death occurs from fulminant liver and concomitant kidney failure. Few cases with WRS are reported in the literature, mostly from consanguineous parents. To the best of our knowledge, combined en bloc liver and pancreas transplant has not been performed in small children.

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 320 months. FPE determination most distant from SBT was 6.1 years. 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 (>200 µg/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 30 days 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 2 years 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.

Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation.

FV is primarily produced in the liver, and congenital FV deficiency is a disorder with an incidence of one in 1 million. Standard care is to treat severe bleeding phenotypes with FFP as there is no recombinant or plasma-derived FV concentrate. We present a case of a neonate with known severe FV deficiency diagnosed after prolonged bleeding after circumcision who represented at age 2 months with a large left intraparenchymal hemorrhage. His bleed was treated with FFP, platelet transfusion, recombinant VIIa, and emergent evacuation. He was maintained on plasma infusions but was unable to space his infusions beyond 48 hours. Liver transplantation was considered as a definitive treatment for this condition. While awaiting a suitable liver, his FV trough levels occasionally dropped below 5%, and he suffered from a second acute intracranial bleed. He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post-transplantation and has had no further bleeding episodes. Liver transplantation should be considered as definitive treatment early in the course for patients with severe FV deficiency and first time life-threatening bleed.

Incidence of Biliary Atresia and Timing of Hepatoportoenterostomy in the United States.

OBJECTIVE: To evaluate the incidence, trends, seasonality, and age at the time of hepatoportoenterostomy (Kasai procedure) for biliary atresia in the US. STUDY DESIGN: The triennial Health Cost and Utilization Project-Kids' Inpatient Database for 1997-2012 was used to perform a retrospective analysis of biliary atresia in the US. Infants aged <1 year of age with a diagnosis of biliary atresia who underwent a Kasai procedure were included. Nationwide infant population data were used to calculate incidence and evaluate trends. Age at the time of the Kasai procedure and the seasonality of biliary atresia were evaluated as well. RESULTS: The incidence of biliary atresia in the US was 4.47 per 100 000 and was higher in females (risk ratio [RR], 1.43; 95% CI, 1.27-1.62), Asian/Pacific Islanders (RR, 1.89; 95% CI, 1.44-2.47), and blacks (RR, 1.30; 95% CI, 1.06-1.58) compared with whites. The incidence of biliary atresia increased by an average of 7.9% per year from 1997 to 2012 (P <.001). The median age at the time of the Kasai procedure was 63 days, with no improvement over the study period (P = .64). There was no evidence of seasonality (P = .69). CONCLUSION: The incidence of biliary atresia has increased over the past 15 years, with the median age at the time of the Kasai procedure now outside the optimal window. Implementation of systematic screening measures for biliary atresia in the US are needed.

Successful venoarterial extracorporeal membrane oxygenation for prolonged hepatopulmonary syndrome following pediatric liver transplantation: A case report and review of the literature.

HPS is a major complicating feature of end-stage liver disease. Diagnosis is clinical, and LT is the only definitive treatment. While the general impression is that HPS improves quickly after transplantation, it may not always be the case. We describe the smallest reported child with HPS prior to LT and requiring prolonged venoarterial extracorporeal membrane oxygenation after LT; especially as it is a rare occurrence, physician managing such cases should be aware of the circumstances under which HPS may require specific treatment.