[DEFI-ALPHA cohort and POLYGEN DEFI-ALPHA clinical research hospital programme. A study about clinical, biological and genetics factors associated with the occurrence and the evolution of hepatic complications in children with alpha-1 antitrypsin deficiency]. / Cohorte DEFI-ALPHA et projet hospitalier de recherche clinique POLYGEN DEFI-ALPHA. Étude des facteurs cliniques, biologiques et génétiques associés à l'apparition et à l'évolution de complications hépatiques chez les enfants présentant un déficit en alpha-1 antitrypsine.

INTRODUCTION: The alpha-1 antitrypsin (α1-AT) deficiency, most frequently caused by homozygosity for the Z variant (SERPINA1: c.1096 G>A; Glu342Lys), can give rise to two clinical patterns: (i) respiratory impairment with emphysema (mainly in adulthood) because of a pulmonary quantitative defect in anti-elastase activity; (ii) hepatic impairment (mainly in childhood) due to the misfolding of the PiZ protein which accumulates in hepatocytes thus providing cytotoxicity. CURRENT KNOWLEDGE: To date, the clinical and genetic factors responsible for the development of major hepatic injuries (fibrosis and portal hypertension) during childhood in PiZ patients are not known. METHODS: The DEFI-ALPHA cohort, created in 2008, aims to inventory and prospectively study all α1-AT deficient children diagnosed and included after occurrence of a hepatic sign. The POLYGEN DEFI-ALPHA PHRC has recently (2013) been added to the project to identify modifiers genes by two complementary approaches: (i) the candidate genes strategy with the SERPINA1, CFTR (cystic fibrosis gene), MAN1B1 and SORL1 genes, these two latter being implied in the degradation of misfolding proteins; (ii) the whole exome sequencing (WES) strategy in families in which the PiZ proband has a PiZ brother or sister free of any hepatic sign. EXPECTED RESULTS: The clinical parameter we want to explain is the apparition of a portal hypertension in PiZ children. In the DEFI-ALPHA project, three criteria will be tested: (i) age of inclusion in the cohort, (ii) the way of inclusion (neo-natal icterus or later hepatic impairment) and (iii) treatment or not with ursodesoxycholic acid and, if so, its duration. Genetically, polymorphisms on the SERPINA1 and MAN1B1 genes have already been associated in the literature with different clinical evolutions of the A1ATD but very inconstantly. Our study thus aims to confirm or not this association. The CFTR and SORL1 genes have never been studied in the α1-AT deficiency. Finally, the whole exome sequencing strategy could allow the discovery of new unexpected modifiers genes in this disease.

Paediatric liver transplanted patients and prevalence of hepatitis E virus.

BACKGROUND: Hepatitis E is an emerging disease in developed countries and is usually asymptomatic, particularly in children. Chronic infection is possible in immunocompromised individuals. In the context of a liver transplant, it can simulate a rejection. In this case, antiviral therapy may be considered, thus highlighting the need to diagnose hepatitis E virus (HEV) infection in this population. OBJECTIVES: Given the lack of data in France, we have studied the the prevalence of antibodies to HEV in the paediatric liver transplant population. STUDY DESIGN: This was a retrospective study, carried out in Lyon between 1st January 2010 and 31 May 2013. HEV serology (anti-HEV IgM &IgG) and HEV PCR were studied in 96 children who had undergone liver transplants (84 isolated liver and 12 combined liver and kidney transplants). RESULTS: Eight patients (8.3%; 62.5% girls; mean age:12.3 years) were HEV seropositive. The mean period since their transplantation was 10 years (range:2-21.8 years). Biliary atresia was the principal indication for transplantation. Seven of these eight children had received liver transplants. There were no differences between the epidemiological and clinical data concerning these patients and the remainder of the study population, particularly with respect to immunosuppression(7/8 tacrolimus; 50% dual immunosuppression). No cases of chronic hepatitis E were found, but 1/8 had chronic cytolysis(EBV&adenovirus infection). In all the patients tested(4/8), seroconversion had occurred after the transplant. There was no significant differences between the age groups in this study. CONCLUSIONS: This study showed that in France, the prevalence of antibodies to HEV in paediatric liver and combined liver and kidney transplant patients is 8.3%, as has been found by other European authors.

Implementation of a computerized system in pediatric wards to improve nutritional care: a cluster randomized trial.

BACKGROUND/OBJECTIVES: Malnutrition occurs frequently in hospitalized children. We aimed to assess whether a computerized system could lead to improved clinical practices in malnourished children. SUBJECTS/METHODS: Healthcare workers (242) from six departments in a pediatric university hospital participated in a cluster randomized trial, studying 1457 malnourished children hospitalized from September 2009 to August 2011. Following a baseline observational pre-intervention period, all departments were randomized into either intervention or control arms. A computerized malnutrition-screening system was implemented in the intervention group to automatically trigger a dietetic referral in real time. Furthermore, the nutrition support team conducted an awareness campaign with healthcare workers and a leadership-based strategy to reinforce the message during the entire study period. Adherence to practice guidelines (daily weights, investigation of etiology for malnutrition, management by a dietitian and application of refeeding protocols) was compared between pre- and post-intervention periods in both the intervention and trial arms. RESULTS: When compared with the pre-intervention period, the clinical practices were significantly improved within the intervention arm for every outcome (P<0.01), whereas remained unchanged in the control arm. In addition, during the post-intervention period, malnutrition etiology investigation by physicians (adjusted odds ratio (OR) of 4.4, 95% confidence interval (CI) 1.7-11.8, P=0.003) and management by a dietitian (OR 2.7, 95% CI 1.0-6.9, P=0.046) occurred more frequently in the intervention clusters. CONCLUSIONS: Implementation of an electronic system to detect malnutrition in real time was associated with a rapid improvement in clinical practices for better care of hospitalized children.