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.

Idiopathic Ileal Ulceration After Intestinal Transplantation.

Background: Idiopathic ileal ulceration after intestinal transplantation (ITx) has been discussed infrequently and has an uncertain natural history and relation to graft rejection. Herein, we review our experience with this pathology. Methods: We retrospectively reviewed 225 ITx in 217 patients with minimum 1 y graft survival. Routine graft endoscopy was conducted up to twice weekly within the first 90 d after ITx, gradually decreasing to once yearly. Risks for ulceration over time were evaluated using Cox regression. Results: Of 93 (41%) patients with ulcers, 50 were found within 90 d after ITx mostly via ileoscopy; delayed healing after biopsy appeared causal in the majority. Of the remaining 43 patients with ulcers found >90 d after ITx, 36 were after ileostomy closure. Multivariable modeling demonstrated within 90-d ulcer associations with increasing patient age (hazard ratio [HR], 1.027; P < 0.001) and loop ileostomy (versus Santulli ileostomy; HR, 0.271; P < 0.001). For ulcers appearing after ileostomy closure, their sole association was with absence of graft colon (HR, 7.232; P < 0.001). For ulcers requiring extended anti-microbial and anti-inflammatory therapy, associations included de novo donor-specific antibodies (HR, 3.222; P < 0.007) and nucleotide oligomerization domain mutations (HR, 2.772; P < 0.016). Whole-cohort post-ITx ulceration was not associated with either graft rejection (P = 0.161) or graft failure (P = 0.410). Conclusions: Idiopathic ulceration after ITx is relatively common but has little independent influence on outcome; risks include ileostomy construction, colon-free ITx, immunologic mutation, and donor sensitization.

Graft Versus Host Disease After Intestinal Transplantation: A Single-center Experience.

BACKGROUND: Graft versus host disease (GVHD) is an uncommon but highly morbid complication of intestinal transplantation (ITx). In this study, we reviewed our 17-y experience with GVHD focusing on factors predicting GVHD occurrence and survival. METHODS: Retrospective review of 271 patients who received 1 or more ITx since program inception in 2003 with survival analysis using Cox proportional hazard modeling. RESULTS: Of 271 patients, 28 developed GHVD 34 (18-66) d after ITx presenting with rash or rash with fever in 26, rectosigmoid disease in 1, and hemolysis in 1; other sites, mainly rectosigmoid colon, were involved in 13. Initial skin biopsy demonstrated classic findings in 6, compatible findings in 14, and no abnormalities in 2. Additional sites of GVHD later emerged in 14. Of the 28 patients, 16 died largely from sepsis, the only independent hazard for death (hazard ratio [HR], 37.4181; P = 0.0008). Significant (P < 0.0500) independent hazards for occurrence of GVHD in adults were pre-ITx functional intestinal failure (IF) (HR, 15.2448) and non-IF diagnosis (HR, 20.9952) and early post-ITx sirolimus therapy (HR, 0.0956); independent hazards in children were non-IF diagnosis (HR, 4.3990), retransplantation (HR, 4.6401), donor:recipient age ratio (HR, 7.3190), and graft colon omission (HR, 0.1886). Variant transplant operation was not an independent GVHD hazard. CONCLUSIONS: Initial diagnosis of GVHD after ITx remains largely clinical, supported but not often confirmed by skin biopsy. Although GVHD risk is mainly recipient-driven, changes in donor selection and immunosuppression practice may reduce incidence and improve survival.

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.

Association Between Vancomycin Trough Concentrations and Duration of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children.

In a multicenter retrospective study, we sought to determine the optimal vancomycin trough concentration that would impact the duration of methicillin-resistant Staphylococcus aureus bacteremia in children. We found that a median vancomycin trough concentration of <10 µg/mL within the first 72 hours may be associated with a longer duration of bacteremia compared to a median trough concentration of ≥10 µg/mL.

Risk Factors for Non-Therapeutic Initial Steady-State Vancomycin Trough Concentrations in Children and Adolescents Receiving High Empiric Doses of Intravenous Vancomycin.

BACKGROUND: Achieving vancomycin troughs of 15-20 µg/mL remains challenging in children. Our objective was to identify risk factors associated with non-therapeutic initial vancomycin troughs in children. METHODS: We conducted a retrospective cohort study of children who received intravenous vancomycin with at least one initial steady-state trough obtained. Patients who achieved therapeutic troughs (15-20 µg/mL in the 20-mg/kg/dose sub-cohort and 10-15 µg/mL in the 15-mg/kg/dose sub-cohort) were compared with those with subtherapeutic troughs (<15 and <10 µg/mL, respectively) and supratherapeutic troughs (>20 and >15 µg/mL, respectively) separately to determine risk factors associated with non-therapeutic troughs. RESULTS: A total of 153 vancomycin courses in 140 patients met study eligibility criteria. Of 45 patients who received 20 mg/kg/dose of empiric vancomycin, 60, 16, and 24% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73 m2 increase in initial creatinine clearance (CrCl) was associated with a 47% increase in the odds of an initial subtherapeutic trough (adjusted odds ratio [aOR] 1.47; 95% CI 0.98-2.22). Of 108 patients who received 15 mg/kg/dose of empiric vancomycin, 62, 19, and 19% were subtherapeutic, therapeutic, and supratherapeutic, respectively. Each 10-mL/min/1.73 m2 increase in initial CrCl was associated with an 18% increase in the odds of an initial subtherapeutic trough (aOR 1.18; 95% CI 1.02-1.37). CONCLUSION: Achieving vancomycin troughs of 15-20 µg/mL for severe Gram-positive infections continues to be challenging in children, even at higher empiric doses of 20 mg/kg/dose IV every 6-8 h. Children with higher initial CrCls are particularly susceptible to subtherapeutic initial steady-state vancomycin troughs.