Evaluation of serial monitoring of donor-specific antibodies in pediatric and adult intestinal/multivisceral transplant recipients.

BACKGROUND: The study purpose was to add to limited literature assessing anti-HLA donor-specific antibody (DSA) appearance, clearance, specificity, and impact in intestinal/multivisceral (MV) transplant as well as the value of serial monitoring following an institutional protocol shift implementing serial monitoring. METHODS: This single-center retrospective review included intestinal/MV recipients transplanted 1/1/15-9/31/17 with completed DSA testing. Patients were divided into groups based on DSA presence post-transplant. The primary outcome was biopsy-proven acute rejection (BPAR). Secondary outcomes included graft loss and death. Descriptive analysis of DSA was completed. RESULTS: Of the 35 intestinal/MV recipients (60% pediatric) with DSA testing, 24 patients had post-transplant DSA. Fifteen patients in the DSA(+) group had T-cell-mediated BPAR versus five in the DSA(-) group (63% vs 45%, p = .47). Days to BPAR were 25 [IQR 19-165] (DSA(+) group) versus 232 [IQR 25.5-632.5] (DSA(-) group) (p = .066). There were no differences between groups for graft loss or death. One hundred and five DSA were identified in the DSA(+) group with 63% being class II, and 54% cleared during follow-up. DSA were directed against 50 different HLA alleles, with the most common being directed against HLA- DQ (35%). Time to first DSA and to clearance did not differ between class I and II. CONCLUSION: Findings confirm previous data that suggest post-transplant DSA in this population may lead to increased BPAR or shorter time to BPAR, although not statistically significant. Most DSA were identified within the first month after transplant, and ahead of rejection identification on biopsy. DSA therefore may have utility as an early rejection biomarker and use may be considered in place of early protocol biopsies, particularly in pediatric patients. We identified novel findings of DSA directed against a large breadth of HLA in intestinal/MV patients.

Efficacy and safety of recombinant human growth hormone therapy in pediatric intestinal transplant recipients.

BACKGROUND: Recombinant human growth hormone (rhGH) is widely used to treat growth retardation in children. We aimed to examine the effect of rhGH therapy on growth and its impact on allograft function in children with growth retardation after intestinal transplant (IT). METHODS: We retrospectively included children younger than 19 years who had received an IT with or without the liver, were diagnosed with growth retardation, and have received rhGH between January 2010 and January 2021. Changes in the patient's anthropometric parameters between baseline and various time points were compared using the paired t-test or Wilcoxon signed-rank test, as appropriate. RESULTS: Seven patients (all males and prepubertal) received rhGH for the median duration of 2.3 years. The median age at rhGH start was 9.5 years. The median growth velocity z-score improved from -0.95 before treatment to 2.3 (p = .04) and 1.9 (p = .06) after 1 and 2 years of treatment, respectively. The median height-for-age z-score significantly improved from -3.4 at rhGH start to -1.3 (p = .005) at rhGH stop and remained above baseline at the last visit (-2.4, p = .002). The change in the first-year growth velocity was negatively correlated with the change in the second-year growth velocity (r = -.90, p = .04). No serious adverse effects or worsening allograft function were observed. CONCLUSIONS: Severely growth retarded children after IT could benefit from rhGH treatment. A larger, longitudinal study would be warranted to monitor the long-term effect and safety of rhGH and examine predictors of growth response to rhGH therapy in these pediatric IT recipients.

Valganciclovir for the treatment of cytomegalovirus infections in pediatric intestinal transplant recipients: A case series.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection post-transplant and is associated with significant morbidity and mortality. Currently, there are no FDA dosing recommendations for the use of valganciclovir for the treatment of CMV infections in pediatric patients. This case series describes the use of valganciclovir for the treatment of CMV infections in nine pediatric intestinal transplant recipients (pITR). METHODS: Retrospective review of pITR between January 2004 and December 2016. The primary outcome was resolution of CMV viremia. Secondary outcomes included time-to-resolution of viremia, relapse rate, incidence of resistance, hematologic adverse effects, rejection, graft loss, and death. RESULTS: Of 214 pITR, ten CMV infections were treated with valganciclovir. One patient was lost to follow-up while on treatment and was not included. Eight (89%) patients had resolution of CMV viremia. The average dose of valganciclovir was 14.3mg/kg (SD 0.82) twice daily. CMV resistance testing was completed in three (33.3%) patients; one patient had a documented mutation requiring leflunomide to clear viremia. Three (33.3%) patients experienced rejection within one month prior to or during treatment for CMV. Six (66.6%) experienced hematologic side effects. No patients died or experienced graft loss. CONCLUSION: This is the first study to assess the use of valganciclovir for the treatment of CMV in pITR. Based on these results, weight-based dosing of valganciclovir seems to be an appropriate option for the treatment of CMV in pITR. Given limited number of patients reviewed in this case series and the high incidence of hematologic side effects, further investigation is warranted.

Viral enteritis in intestinal transplant recipients.

Intestinal transplant recipients (ITR) are at high risk for infections due to the high level of immunosuppression required to prevent rejection. There are limited data regarding viral enteritis post-intestinal transplantation. We retrospectively reviewed ITR transplanted between January 2008 and December 2016. Descriptive statistics, including mean (standard deviation) and median (range), were performed. Sixty-one (43.9%) of the 139 transplanted patients had viral enteritis: 26% norovirus, 25% adenovirus, and 9% each rotavirus and sapovirus. The median age of pediatric patients was 1.6 years (0.4-16.9) and for adults 36.3 years (27.1-48.2). Fifty-seven (58%) of 99 pediatric ITR had viral enteritis compared to 4 (10%) of 40 adult ITR. Median time-to-clinical resolution of enteritis for all patients was 5 days (1-92). Standard of care therapies administered: anti-motility agents (10%), anti-emetics agents (14%), and intravenous fluids (42%). There was a higher incidence of viral enteritis in pediatric compared to adults ITR. The majority of viral enteritis episodes resolved within 1 week and were treated with supportive therapy.

Respiratory syncytial virus lower respiratory tract infection in a pediatric liver transplant recipient treated with oral ribavirin.

The mainstay of therapy for RSV disease is supportive care, although aerosolized ribavirin has been used to treat infants and young children with severe lower respiratory tract infections. Aerosolized ribavirin has adverse effects, high cost and teratogenic potential. We report the case of a pediatric liver transplant recipient diagnosed with lower respiratory RSV infection, who was successfully treated with oral ribavirin.

Cidofovir in pediatric solid organ transplant recipients: University of Nebraska experience.

BACKGROUND: Clinical experience with cidofovir in pediatric solid organ transplantation is limited. We assessed the effect of cidofovir use on renal function in pediatric solid organ transplant recipients. METHODS: Wilcoxon signed-rank tests were used to determine if changes in renal function were significant, Wilcoxon rank-sum tests to test the association between changes in glomerular filtration rate and potential confounding factors, and MacNemar tests to compare the proportions of patients at different time points. RESULTS: We included 25 patients with a mean age of 4.2 years (SD 4.6). More patients were receiving renal replacement therapy while being treated with cidofovir compared with baseline (24% vs. 4%; P = 0.03). For patients not receiving renal replacement therapy, there was no evidence of a significant median change in glomerular filtration rate from baseline to 1 month after cidofovir treatment (P = 0.32) or to the end of cidofovir treatment (P = 0.23) or in creatinine from baseline to the end of cidofovir therapy (P = 0.2). There was a marginal decreased median change in creatinine from baseline to 1 month after cidofovir treatment (P = 0.06). Fewer patients had proteinuria (72.2% vs. 27.8%; P = 0.02) and hematuria (22.2% vs. 0%) after cidofovir treatment. CONCLUSION: In our pediatric transplant cohort, cidofovir did not significantly change renal function reflected by creatinine, glomerular filtration rate, hematuria or proteinuria, but a significant number of patients required renal replacement therapy because of fluid overload.

Development of CMX001 (Brincidofovir) for the treatment of serious diseases or conditions caused by dsDNA viruses.

CMX001 (hexadecyloxypropyl-cidofovir, Brincidofovir) is a broad spectrum, lipid conjugate of cidofovir that is converted intracellularly into the active antiviral, cidofovir diphosphate. The lipid conjugation results in oral bioavailability, higher intracellular concentrations of active drug, lower plasma concentrations of cidofovir and increased antiviral potency against dsDNA viruses.