A Retrospective Analysis of Rituximab Treatment for B Cell Depletion in Different Pediatric Indications.

Background: Rituximab (RTX) is used in cancer therapy as well as in the treatment of autoimmune diseases and alloimmune responses after transplantation. It depletes the disease-causing B cells by binding to the CD (cluster of differentiation) 20 antigen. We evaluate different pediatric treatment protocols (via fixed treatment schedule, B cell- or symptom-controlled) and their therapeutic effects. Methods: Demographic information, clinical and laboratory characteristics, and special laboratory values such as immunoglobulin G (IgG), CD19 positive B cells and Epstein-Barr viral load were retrospectively analyzed in children treated with RTX between 2008 and 2016. Results: Seventy-six patients aged 1 to 19 (median 13) years were treated with 259 RTX infusions. The spectrum of diseases was very heterogeneous. RTX led to a complete depletion of the B cells. The reconstitution time varied between patients and was dependent on the application schedule (median 11.8 months). Fourteen out of 27 (52%) patients developed hypogammaglobulinaemia. The risk of IgG deficiency was 2.6 times higher in children under 4 years of age than in olderones. In the last group IgG deficiency developed in only 38% of the cases (n = 8). Recurrent and severe infections were observed each in 11/72 (15%) patients. Treatment-related reactions occurred in 24/76 (32%) cases; however, treatment had to be discontinued in only 1 case. In 16/25 (76%), the Epstein-Barr viral load dropped below the detection limit after the first RTX infusion. Conclusion: RTX is an effective and well-tolerated drug for the treatment of oncological diseases as well as autoimmune and alloimmune conditions in children. B cell depletion and reconstitution varies both intra- und interindividually, suggesting that symptom-oriented and B cell-controlled therapy may be favorable. Treatment-related reactions, IgG deficiency and infections must be taken into account.

Role of Tacrolimus C/D Ratio in the First Year After Pediatric Liver Transplantation.

Background: The calcineurin inhibitor (CNI) tacrolimus (TAC) is a cornerstone agent in immunosuppressive therapy in pediatric liver transplantation (LTX). Adverse effects limit the use of CNI. In adults, calculating the individual TAC metabolism rate allows to estimate the transplant recipient's risk for therapy-associated complications. Methods: A retrospective, descriptive data analysis was performed in children who had undergone LTX in 2009-2017 and had received TAC twice daily in the first year after LTX. A weight-adjusted concentration/dose ratio (C/D ratio) was calculated [TAC trough level/(daily TAC dose/body weight)] every 3 months after LTX to estimate the average individual TAC metabolism rate. Depending on the C/D ratio, all patients were divided into two groups: fast metabolizers (FM) and slow metabolizers (SM). Clinical and laboratory parameters were analyzed as risk factors in both groups. Results: A total of 78 children (w 34, m 44, median age at LTX 2.4; 0.4-17.0 years) were enrolled in the study. FM (SM) had a mean C/D ratio of <51.83 (≥51.83) ng/ml/(mg/kg). FM were younger at the time of LTX (median age 1.7; 0.4-15.8 years) than SM (5.1, 0.4-17.0), p = 0.008. FM were more likely to have biliary atresia (20/39, 51%) compared to SM (11/39, 28%), p = 0.038, whereas SM were more likely to have progressive familial intrahepatic cholestasis (9/39, 23%) vs. in FM (1/39, 3%), p = 0.014. Epstein-Barr virus (EBV) infection occurred more frequently in FM (27/39, 69%) than SM (13/39, 33%), p = 0.002. Three FM developed post-transplant lymphoproliferative disorder. The annual change of renal function did not differ in both groups (slope FM 1.2 ± 0.6; SM 1.4 ± 0.8 ml/min/1.73 m2 per year, and p = 0.841). Conclusions: Calculation of individual, weight-adjusted TAC C/D ratio is a simple, effective, and cost-efficient tool for physicians to estimate the risk of therapy-associated complications and to initiate individual preventive adjustments after pediatric LTX. Lower TAC levels are tolerable in FM, especially in the presence of EBV infection, reduced renal function, or when receiving a liver transplant in the first 2 years of life.

Changes of the microbial population structure in an overloaded fed-batch biogas reactor digesting maize silage.

Two parallel, stable operating biogas reactors were fed with increasing amounts of maize silage to monitor microbial community changes caused by overloading. Changes of microorganisms diversity revealed by SSCP (single strand conformation polymorphism) indicating an acidification before and during the pH-value decrease. The earliest indicator was the appearance of a Methanosarcina thermophila-related species. Diversity of dominant fermenting bacteria within Bacteroidetes, Firmicutes and other Bacteria decreased upon overloading. Some species became dominant directly before and during acidification and thus could be suitable as possible indicator organisms for detection of futurity acidification. Those bacteria were related to Prolixibacter bellariivorans and Streptococcus infantarius subsp. infantarius. An early detection of community shifts will allow better feeding management for optimal biogas production.