An international multicenter validation study of the Toronto listing criteria for pediatric intestinal transplantation.

Deciding which patients would benefit from intestinal transplantation (IT) remains an ethical/clinical dilemma. New criteria* were proposed in 2015: ≥2 intensive care unit (ICU) admissions, loss of ≥3 central venous catheter (CVC) sites, and persistently elevated conjugated bilirubin (CB ≥ 75 µmol/L) despite 6 weeks of lipid modification strategies. We performed a retrospective, international, multicenter validation study of 443 children (61% male, median gestational age 34 weeks [IQR 29-37]), diagnosed with IF between 2010 and 2015. Primary outcome measure was death or IT. Sensitivity, specificity, NPV, PPV, and probability of death/transplant (OR, 95% confidence intervals) were calculated for each criterion. Median age at IF diagnosis was 0.1 years (IQR 0.03-0.14) with median follow-up of 3.8 years (IQR 2.3-5.3). Forty of 443 (9%) patients died, 53 of 443 (12%) were transplanted; 11 died posttransplant. The validated criteria had a high predictive value of death/IT; ≥2 ICU admissions (p < .0001, OR 10.2, 95% CI 4.0-25.6), persistent CB ≥ 75 µmol/L (p < .0001, OR 8.2, 95% CI 4.8-13.9). and loss of ≥3 CVC sites (p = .0003, OR 5.7, 95% CI 2.2-14.7). This large, multicenter, international study in a contemporary cohort confirms the validity of the Toronto criteria. These validated criteria should guide listing decisions in pediatric IT.

Long-Term Cognitive Outcomes and Associated Quality of Life of Young Adults Who Experienced Liver Transplantation in Early Childhood.

We evaluated long term outcomes in infants born between 1992 and 2002 with cholestatic liver disease (CLD) who underwent successful liver transplantation (LT). A total of 160 children with CLD were identified: 68 had developmental assessments before and after LT of whom 32 were excluded because they were followed up elsewhere; 16/36 consented to complete measures of IQ, anxiety, depression, health related quality of life (HRQoL), and a habits/employment survey. Illness severity and developmental attainment prior to LT were comparable with the 32 excluded and 20 patients who declined to take part. The IQ of young adults after LT (mean score = 91.13, range 75-108, SD 10.4) was not significantly improved compared to pre-LT scores (mean score = 85.7 range 50-111, SD 17), but was inversely correlated with stunting of growth and duration of disease before LT, highlighting the need for timely LT in CLD. HRQoL scores ranged from 22 to 99 (mean 64.5 SD 20.7), comparable to scores in other LT recipients. Five (31%) had mild-moderate depression; 5 (31%) had moderate-severe anxiety associated with reduced HRQoL (P = 0.01 and P = 0.06, respectively); and nine had problematic fatigue which correlated with reduced HRQoL (r 2 = 0.4 P = 0.007). Reduced medication adherence was associated with fatigue (Spearman correlation r 2 = 0.267; P = 0.09) and anxiety (Spearman correlation r 2 = 0.597; P = 0.02). Raised body mass index was also associated with reduced and health-related quality of life scores PeLTQL© (r 2 = 0.379 P = 0.011). Fifteen (94%) were undergoing education or were employed. The long-term neuro-cognitive and psychosocial outcomes of young adults transplanted as babies is encouraging, although anxiety/depression was more common than in the healthy population. Psychosocial questionnaires help identify those young adult LT recipients who may benefit from support.

Trends in Pediatric Intestinal Failure: A Multicenter, Multinational Study.

OBJECTIVES: To assess the natural history and outcomes of children with intestinal failure in a large, multicenter, geographically diverse contemporary cohort (2010-2015) from 6 pediatric intestinal failure programs. STUDY DESIGN: Retrospective analysis of a multicenter intestinal failure cohort (n = 443). Competing-risk analysis was used to obtain cumulative incidence rates for the primary outcome (enteral autonomy, transplantation, or death). The χ2 test and Cox proportional hazard regression were used for bivariate and multivariable analyses. RESULTS: The study cohort comprised 443 patients (61.2% male). Primary etiologies included short bowel syndrome (SBS), 84.9%; dysmotility disorder, 7.2%; and mucosal enteropathy, 7.9%. Cumulative incidences for enteral autonomy, transplantation, and death at 6 years of follow-up were 53.0%, 16.7%, and 10.5%, respectively. Enteral autonomy was associated with SBS, ≥50% of small bowel length, presence of an ileocecal valve (ICV), absence of portal hypertension, and follow-up in a non-high-volume transplantation center. The composite outcome of transplantation/death was associated with persistent advanced cholestasis and hypoalbuminemia; age <1 year at diagnosis, ICV, and intact colon were protective. CONCLUSIONS: The rates of death and transplantation in children with intestinal failure have decreased; however, the number of children achieving enteral autonomy has not changed significantly, and a larger proportion of patients remain parenteral nutrition dependent. New strategies to achieve enteral autonomy are needed to improve patient outcomes.

New Insights Into the Indications for Intestinal Transplantation: Consensus in the Year 2019.

In 2001, a Statement was published that described indications for intestinal transplantation in patients with intestinal failure expected to require parenteral nutrition indefinitely. Since 2001, advances in the management of intestinal failure including transplantation and patient survival, both on extended parenteral nutrition and after transplantation, have improved, leading to a reduction in the number of intestinal transplants worldwide from a peak of 270 per year in 2008 to 149 per year in 2017. These changes suggest that the original 2001 Statement requires reassessment. All patients with permanent intestinal failure should be managed by dedicated multidisciplinary intestinal rehabilitation teams. Under care of these teams, patients should be considered for intestinal transplantation in the event of progressive intestinal failure-associated liver disease, progressive loss of central vein access, and repeated life-threatening central venous catheter-associated infections requiring critical care. Additional indications for transplantation include large desmoid tumors and other intra-abdominal tumors with reasonable expectation of posttransplant cure, extensive mesenteric vein thrombosis and intestinal infarction, total intestinal aganglionosis, and nonrecoverable congenital secretory diarrhea. Quality of life typically improves after successful intestinal transplantation and may support the decision to proceed with transplantation when other indications are present. However, the requirement for life-long immunosuppression and its associated side effects preclude intestinal transplantation if motivated only by an expectation of improved quality of life. Increasing experience with intestinal transplantation and critical appraisal of transplant outcomes including graft survival and patient quality of life together with potential advances in immunosuppression can be expected to influence transplant practices in the future.

Comparison of Clinical Features and Outcome of Pediatric Posttransplant Lymphoproliferative Disorder in Recipients of Small Bowel Allograft Versus Isolated Liver Transplantation.

BACKGROUND: Higher incidence of posttransplant lymphoproliferative disorder (PTLD) is reported in the pediatric small bowel transplant (SBTx) population, which may be associated with more aggressive disease and poorer outcome as compared to liver transplant (LTx) recipients. We aim to compare the characteristics and outcome of PTLD in pediatric SBTx against LTx patients at a single center. METHODS: Retrospective review of pediatric SBTx and LTx patients diagnosed with PTLD from 1989 to 2016 was conducted. Diagnosis of PTLD was biopsy-proven based on World Health Organization histologic criteria. Treatment protocol consisted of reduction of immunosuppression (RIS), rituximab (from 2000), cytotoxic T-lymphocyte (CTL) therapy (available in 1999-2004 and from 2011), and chemotherapy. RESULTS: Thirty-seven PTLD patients were included following LTx (n = 23, incidence = 2.8%) and SBTx (n = 14, incidence = 14.9%). Monomorphic PTLD made up 64% of SBTx and 43% of LTx cases. RIS alone resulted in remission in 50% of LTx patients but none of the SBTx patients (P = 0.002). Poorer overall remission (57% versus 96%, P = 0.004), 2-year (46% versus 91%, P = 0.003), and 5-year survival rates (39% versus 90%, P = 0.002) were observed in the SBTx group. Risk factors associated with mortality following PTLD were SBTx (odds ratio [OR], 12.00; 95% confidence interval [CI], 2.34-61.45; P = 0.003), monomorphic histology (OR, 10.63; 95% CI, 1.88-60.25; P = 0.008), multisite involvement (OR, 6.38; 95% CI, 1.35-30.14; P = 0.019), and tumor involvement of allograft (OR, 5.33; 95% CI, 1.14-24.90; P = 0.033). Introduction of CTL therapy was associated with improved survival. CONCLUSIONS: Majority of PTLD following pediatric SBTx are of monomorphic subtype and associated with poorer outcome as compared to LTx patients. RIS is inadequate as a single strategy in managing PTLD in SBTx and prompt escalation to rituximab and CTL is recommended.

Hypogammaglobulinemia and bacterial infections following pediatric post-transplant lymphoproliferative disorder in the rituximab era.

INTRODUCTION: Treatment of PTLD using immune-depleting agents such as RTX may be associated with increased risk of infections. The aim of this report was to describe the incidence of hypogammaglobulinemia and bacterial infections in children with PTLD after SOT at a single center since the introduction of RTX. METHODS: A retrospective review was conducted over a study period of 2000-2016 in pediatric patients diagnosed with biopsy-proven PTLD based on the WHO histologic criteria. Hypogammaglobulinemia was defined by serum IgG <4 g/L; CPBI was defined by clinically significant infection by an identified pathogenic bacteria isolated from a normally sterile body site. RESULTS: Twenty-eight patients were included, comprising 16 LTx and 12 ITx patients, and 17 patients received RTX therapy. Total of 31 episodes of CPBI occurred in 16 patients. Incidence of CPBI was 31.4 infections per 100 patient-years in RTX-treated patients, as compared to 8.4 infections per 100 patient-years in non-RTX-treated patients (P < 0.001). Hypogammaglobulinemia was significantly more prevalent after 6 months (P = 0.001) and 2 years (P = 0.005) in RTX-treated patients, as compared to none in the group that did not receive RTX. Hypogammaglobulinemia (P = 0.047), ITx (P = 0.027), and monomorphic PTLD (P = 0.024) were significantly associated with recurrent (≥2) CPBI and/or CPBI-related deaths within the first year post-PTLD. CONCLUSION: While RTX is an effective treatment for PTLD, hypogammaglobulinemia can persist for up to 2 years following RTX therapy, which may be associated with the higher cumulative rates of CPBI observed in RTX-treated patients.

Long-term Effects of Cholestatic Liver Disease in Childhood on Neuropsychological Outcomes and Neurochemistry.

OBJECTIVES: Children with liver disease have increased risk of long-term cognitive deficits. We differentiated between the effects of chronic liver disease from that associated with transplantation by recruiting children with cholestatic liver disease (CLD) with and without transplantation. METHODS: Psychometric measures and magnetic resonance spectroscopy were obtained for 3 groups of children: stable liver disease without transplantation; CLD from birth with transplantation; and individuals healthy to 18 months of age, before transplantation for acute liver failure. RESULTS: Cognitive outcomes between children with different disease histories were significantly associated with the duration of liver disease but not the effects of transplantation, including that of immunosuppression. Lower intellectual ability was most frequently observed in the CLD group, whereas all of the acute liver failure group scored within the normal range. Myoinositol and glutamate/glutamine concentrations in cortex were significantly associated with disease duration across the cohort. Neurometabolite profiles in stable liver disease were consistent with subclinical encephalopathy. Impaired growth in early childhood was associated with later cognitive performance. CONCLUSION: Children with prolonged liver disease had the poorest cognitive outcomes despite successful transplantation, suggesting that prolonged cholestasis before transplantation adversely affects neurodevelopment, and reinforces the need for timely interventions.

Cytotoxic T-lymphocyte therapy for post-transplant lymphoproliferative disorder after solid organ transplantation in children.

EBV-CTL immunotherapy targets EBV antigens expressed by tumor cells in PTLD. Data on outcome of EBV-CTL in pSOT patients are limited. The aim of the study is to describe our experience with allogeneic, third-party EBV-CTL for the treatment of PTLD in pSOT patients in a single tertiary center. Retrospective review was performed of all pSOT patients who received EBV-CTL for PTLD. PTLD was diagnosed using World Health Organization histologic criteria. EBV-CTLs were derived from human leukocyte antigen-typed, EBV-seropositive third-party donors, and cryopreserved and maintained by an accredited national blood transfusion service. Ten patients received EBV-CTL for histologically proven PTLD from 1999 to 2016 following liver (n=5), combined intestinal/liver (n=4), and liver/kidney (n=1) transplantation. PTLD occurred at median age of 40 months (range: 12-144) and median post-transplant interval of 8 months (range: 2-107). Seven had monomorphic, two had polymorphic, and one had Hodgkin-type PTLD. All were of B-cell origin and EBV-positive on histology. EBV-CTL achieved an overall remission rate of 80% (8 of 10). Transient adverse effects included fever, tachycardia, and vomiting. None developed graft-versus-host disease or opportunistic infections. EBV-CTL is an effective treatment for PTLD in pSOT patients, with good remission rate and minimal toxicity.

Total Parenteral Nutrition-Induced Cholestasis: Prevention and Management.

When cholestasis occurs in patients receiving total parenteral nutrition, it is the result of many pathogenic pathways converging on the hepatic acinus. The result may be a temporary rise in liver function tests. The resulting fibrosis, portal hypertension, and jaundice are hallmarks of type 3 intestinal-associated liver disease to which children are more susceptible than adults. The key to prevention is in identifying high-risk scenarios, meticulous monitoring, and personalized prescription of parenteral nutrition solutions combined with an active approach in reducing the impact of inflammatory events when they occur by prompt use of antibiotics and line locks.

Combined liver-intestine grafts compared with isolated intestinal transplantation in children: a single-center experience.

BACKGROUND: Intestinal transplantation is known to be associated with a high risk of early complications and mortality. METHODS: We analyzed prospective data of 51 primary small bowel transplantations from December 1999 to August 2009 and identified perioperative factors that impact on early mortality (≤6 months after transplantation) after isolated intestinal (IITx; n=12) and combined liver-intestinal transplantation (CLITx group; n=39). RESULTS: Ten patients died during the first 6 months after transplantation, all of them in CLITx group (n=10/51, 19%). Multivariate analyses demonstrated intraoperative red blood cell transfusion greater than 70 mL/kg (P=0.019, odds ratio [OR]=13.79) and base excess 30-min after reperfusion less than -16 (P=0.001, OR=14.05), thrombocytopenia (<50,000 per dL) between day 1 and day 15 after transplantation (P=0.047, OR=5.22), and occurrence of vascular complications (P=0.003, OR=8.96) during the posttransplantation period as predictors of early mortality in CLITx group. CONCLUSION: Risk of mortality at 6 months after intestinal transplantation increased when the liver is included as combined graft. Strategies to reduce mortality such as refining selection for transplantation and early referral before the development of liver failure should be a priority.

Paediatric Hepatology Dependency score (PHD score): an audit tool.

BACKGROUND: The aim was to develop a tool that measures patient dependency and disease severity in children with mild to severe liver disease. METHODS: The initial pilot score was based on known markers of disease severity in acute and chronic liver disease. Between 1997 and 2001, the score was modified 4 times and reduced to comprise 10 key parameters: aspartate transaminase, prothrombin time, albumin, bilirubin, ascites, nutritional support, organ dysfunction, blood product support, sepsis and intravenous access. The score's face validity, internal consistency, interobserver agreement and construct validity were evaluated statistically and by the use of endpoints such as survival and transplant after 6 months. RESULTS: The final 10 variable score was tested on 71 children admitted over two 3-month periods. The Cronbach's alpha score (a test for internal consistency) for the total score was 0.72. Serial data paralleled clinical deterioration and response to interventions. A Paediatric Hepatology Dependency score >15 had an odds ratio of 7 (P = 0.0125) for death or transplant at 6 months. The score was also found to agree with the paediatric end-stage liver disease score for the 12 patients being listed for liver transplantation (r = 0.660, P < 0.05). CONCLUSION: The Paediatric Hepatology Dependency score is valid and internally consistent and is a convenient measure of dependency and disease severity in a heterogeneous group of patients with liver disease. It also allows admissions to be audited for comparison between eras and for monitoring the progress of patients while on the ward.

An economic evaluation of pediatric small bowel transplantation in the United Kingdom.

BACKGROUND: Small bowel transplantation (SBTx) offers an alternative to parenteral nutrition (PN) for the treatment of chronic intestinal failure in children: this study estimated its cost-effectiveness in the early phase of a U.K. program. METHODS: Children assessed for SBTx were categorized as: 1) requiring SBTx following PN-related complications (n=23), 2) stable at home not requiring SBTx (n=24), and 3) terminally ill and unsuitable for SBTx (n=6). Costs were estimated from detailed resource-use data. Two comparisons were used for effectiveness: actual survival following transplantation (n=14) compared to: 1) estimated survival without transplantation using a prognostic model, and 2) the waiting list experiences of all patients listed for SBTx (n=23). RESULTS: Mean costs up to 30 months were pounds sterling 207,000 for those transplanted or on the waiting list, pounds sterling 159,000 for those stable on home PN, and pounds sterling 56,000 for those terminally ill. The prognostic model estimated a mean survival gain from transplantation of 0.12 years over 30 months, and suggested that transplantation was cost-saving. The second approach suggested that transplantation reduced survival by 0.24 years at an additional cost of pounds sterling 131,000. CONCLUSIONS: Firm conclusions on cost-effectiveness of SBTx are not possible given the two different estimates. The prognostic model approach (suggesting that pediatric SBTx may provide a small survival benefit at a small reduction in costs) should be less subject to bias, but the model requires external validation. Meanwhile, children at risk of fatal PN-complications should be given the opportunity to receive a SBTx only within a continuing formal assessment of the technology.