One Step at a Time: A Pediatric Case of Primary Two Staged Liver Transplantation in a Child with ESLD

Toxic liver syndrome is a rare condition with multiorgan failure in end-stage liver disease (ESLD), and a two-stage LT following hepatectomy with a prolonged anhepatic phase is an accepted approach to bridge to transplant. This primary approach has not been described for toxic liver syndrome in children with ESLD. We report a 6-year-old boy who developed toxic liver syndrome with multiorgan failure while awaiting LT for ESLD from biliary atresia and failed Kasai at the age of 2 years. Deemed too sick to transplant, he underwent full hepatectomy and portocaval shunt placement. The child was then transplanted hemodynamically stable after an anhepatic phase of 10 h and 30 min. Although his initial graft showed primary liver dysfunction and he needed re-transplantation after 14 days, he was able to leave the hospital 4 months following 2nd LT and is well with a fully working graft 5 years later. Primary two stage LT is feasible in children in dire situations

Identification of novel immune phenotypes for allergic and nonallergic childhood asthma

BACKGROUND Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success. OBJECTIVE We sought to identify novel immune phenotypes for childhood AA and NA. METHODS The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4- to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and TH17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes. RESULTS The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL-5, IL-13, and IFN-γ secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1), important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1β levels, neutrophil counts, and IL-17-shifted immunity. In parallel, expressions of anti-inflammatory IL37, proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), and the neutrophil-associated genes CD93, triggering receptor expressed on myeloid cells 1 (TREM1), and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared TH2 immunity was present in both asthma phenotypes. CONCLUSION Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17-shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention

Ca 2+ and innate immune pathways are activated and differentially expressed in childhood asthma phenotypes

Background Asthma is the most common chronic disease in children. Underlying immunologic mechanisms—in particular of different phenotypes—are still just partly understood. The objective of the study was the identification of distinct cellular pathways in allergic asthmatics (AA) and nonallergic asthmatics (NA) vs healthy controls (HC). Methods Peripheral blood mononuclear cells (PBMCs) of steroid‐naïve children (n(AA/NA/HC) = 35/13/34)) from the CLARA study (n = 275) were stimulated (anti‐CD3/CD28, LpA) or kept unstimulated. Gene expression was investigated by transcriptomics and quantitative RT‐PCR. Differentially regulated pathways between phenotypes were assessed after adjustment for sex and age (KEGG pathways). Networks based on correlations of gene expression were built using force‐directed graph drawing. Results Allergic asthmatics vs NA and asthmatics overall vs HC showed significantly different expression of Ca2+ and innate immunity‐associated pathways. PCR analysis confirmed significantly increased Ca2+‐associated gene regulation (ORMDL3 and ATP2A3) in asthmatics vs HC, most prominent in AA. Innate immunity receptors (LY75, TLR7), relevant for virus infection, were also upregulated in AA and NA compared to HC. AA and NA could be differentiated by increased ATP2A3 and FPR2 in AA, decreased CLEC4E in AA, and increased IFIH1 expression in NA following anti‐CD3/28 stimulation vs unstimulated (fold change). Conclusions Ca2+ regulation and innate immunity response pattern to viruses were activated in PBMCs of asthmatics. Asthma phenotypes were differentially characterized by distinct regulation of ATP2A3 and expression of innate immune receptors (FPR2, CLEC4E, IFIH1). These genes may present promising targets for future in‐depth investigation with the long‐term goal of more phenotype‐specific therapeutic interventions in asthmatics