Nécessité d'un suivi à long terme des enfants atteints de glomérulonéphrite extra-membraneuse néonatale par alloimmunisation foeto-maternelle

Le mécanisme d alloimmunisation fœto-maternelle tissulaire a récemment été mis en évidence chez des enfants atteints de glomérulonéphrite extra-membraneuse (GEM) néonatale. L endopeptidase neutre (EPN), protéine présente au niveau des glomérules, a pu être identifiée comme l antigène-cible de cette pathologie. Les allo-anticorps anti-EPN maternels étant transmis au fœtus pendant la grossesse, les lésions débutent in utero, et l enfant naît avec une symptomatologie rénale plus ou moins sévère. Ainsi, trois familles comportant des cas de GEM allo-immune ont été répertoriées à ce jour, et le recul est maintenant de plusieurs années pour les enfants atteints. L objectif de ce travail a été d évaluer le devenir à moyen terme de ces enfants présentant une GEM néonatale par alloimmunisation fœto-maternelle, et notamment le retentissement sur leur fonction rénale. Après analyse des données cliniques et biologiques de ces familles, il s avère que certains de ces enfants ont une protéinurie pathologique persistante, bien que leur fonction rénale soit encore conservée. Chez le patient pour lequel nous avons le plus de recul, une insuffisance rénale terminale s est déclarée à l âge de 20 ans, aboutissant à une transplantation. Il semble donc nécessaire de poursuivre un suivi à long terme chez tous ces patients, susceptibles d évoluer défavorablement. De plus, il n existe pas à l heure actuelle de thérapeutique spécifique permettant la neutralisation des anticorps maternels anti-EPN. Ce traitement est cependant envisageable, et fait aujourd hui l objet de travaux de recherche.LIMOGES-BU Médecine pharmacie (870852108) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Anomalies génétiques d'ABCA3 dans les détresses respiratoires néonatales sévères et les pathologies alvéolo-interstitielles de l'enfant

ABCA3 (ATP-binding cassette subfamily A, member 3) est un transporteur transmembranaire exprimé à la surface des corps lamellaires dans les pneumocytes II, et joue un rôle important dans le stockage et la régulation du surfactant pulmonaire. Des mutations du gène ABCA3 ont été décrites en association avec une détresse respiratoire néonatale (DRNN) sévère ou une pathologie alvéolo-interstitielle (PAI) de l enfant. L objectif de ces travaux était de rechercher des mutations d ABCA3 chez 50 patients présentant une DRNN et/ou une PAI. Le séquençage d ABCA3 a été réalisé chez 50 patients et chez 23 témoins indemnes de pathologie respiratoire : 13 enfants ont été identifiés comme porteurs de mutations d ABCA3; 4 à l état homozygote et 9 à l état hétérozygote. Parmi ces patients porteurs de mutations d ABCA3, 7 sont décédés en période néonatale and 6 ont développé une PAI. L expression des protéines spécifiques du surfactant SP-B et SP-C analysée par Western blot chez ces patients porteurs de mutations d ABCA3 a révélé des profils d expression variables. Les études fonctionnelles réalisées pour les mutations homozygotes p.D253H et p.T1173R ont révélé des mécanismes d action différents: la mutation p.D253H entraîne la formation de corps lamellaires anormaux, alors que la mutation p.T1173R est plutôt associée à une sécrétion accrue d IL-8 in vitro. Nous avons donc identifié 13 nouvelles mutations d ABCA3 chez des patients ayant présenté une DRNN sévère inexpliquée et/ou une PAI non étiquetée. Les études fonctionnelles réalisées semblent mettre en évidence des mécanismes physiopathologiques différents malgré un phénotype clinique identique chez les enfants atteintsPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

Impact of COVID-19 on pediatric clinical research in France

International audienc

The Prognostic Value of Neonatal Conventional-EEG Monitoring in~Hypoxic-Ischemic Encephalopathy during Therapeutic Hypothermia.

International audienceAIM: To determine the prognostic value of conventional electroencephalography (EEG) monitoring in neonatal hypoxic-ischemic encephalopathy (HIE). METHOD: In this multicentre retrospective study, 95 full-term neonates (mean of 39.3wks gestational age [SD~~1.4], 36 [38%] females, 59 [62%] males) with HIE (2013-2016) undergoing therapeutic hypothermia were divided between favourable or adverse outcomes. Background EEG activity (French classification scale: 0-1-2-3-4-5) and epileptic seizure burden (epileptic seizure scale: 0-1-2) were graded for seven 6-hour periods. Conventional EEG monitoring was investigated by principal component analysis (PCA), with clustering methods to extract prognostic biomarkers of development at 2\,years and infant death. RESULTS: Eighty-one per cent of infants with an adverse outcome had a French classification scale equal to or greater than 3 after H48 (100% at H6-12). The H6-12 epileptic seizure scale was equal to or greater than 1 for 39%, increased to 52% at H30-36 and then remained equal to or greater than 1 for 39% after H48. Forty-five per cent of infants with a favourable outcome had a H6-12 French classification scale equal to or greater than 3, which dropped to 5% after H48; 13% had a H6-12 epileptic seizure scale equal to or greater than 1 but no seizures after H48. Clustering methods based on PCA showed the high efficiency (96%) of conventional EEG monitoring for outcome prediction and allowed the definition of three prognostic EEG biomarkers: H6-78 French classification scale mean, H6-78 French classification scale slope, and H30-78 epileptic seizure scale mean. INTERPRETATION: Early lability and recovery of physiological features is prognostic of a favourable outcome. Seizure onset from the second day should also be considered to accurately predict neurodevelopment in HIE and support the importance of conventional EEG monitoring in HIE in infants cooled with therapeutic hypothermia

Use of EEG in neonatal hypoxic-ischemic encephalopathy: A French survey of current practice and perspective for improving health care

International audienceObjectives: Controlled therapeutic hypothermia (CTH) is a standard of care in the management of neonatal hypoxic-ischemic encephalopathy HIE in newborns after 36 weeks of gestational age (WGA) in France. The electroencephalogram (EEG) plays a major role in HIE diagnosis and follow-up. We conducted a French national survey on the current use of EEG in newborn undergoing CTH.Methods: Between July and October 2021, an email survey was sent to the heads of the Neonatal intensive care units (NICUs) in metropolitan and overseas French departments and territories.Results: Out of 67, 56 (83%) of NICUs responded. All of them performed CTH in children born after 36 WGA with clinical and biological criteria of moderate to severe HIE. 82% of the NICUs used conventional EEG (cEEG) before 6 h of life (H6), prior to CTH being performed, to inform decisions about its use. However, half of the 56 NICUs had limited access after regular working hours. 51 of the 56 centers (91%) used cEEG, either short-lasting or continuous monitoring during cooling, while 5 centers conducted only amplitude EEG (aEEG). Only 4 of 56 centers (7%) used cEEG systematically both prior to CTH and for continuous monitoring under CTH.Discussion: The use of cEEG in the management of neonatal HIE was widespread in NICUs, but with significant disparities when considering 24-hour access. The introduction of a centralized neurophysiological on-call system grouping several NICUs would be of major interest for most centers which do not have the facility of EEG outside working hours

Impact of early life nutrition on gut health in children: a prospective clinical study

International audienceIntroduction: The first 1000 days of life could contribute to individual susceptibility to the later development of chronic non-communicable diseases. Nutrition in early life appears to be an important determinant factor for a sustainable child's health. In this study, we propose to investigate the impact of exclusive breast feeding on gut health in children.Methods and analysis: A prospective cohort of newborns (n=350) will be recruited at birth and followed up to 4 years of age. The main objective is to evaluate the link between exclusive breast feeding for at least 3 months and the gut health of the child at 4 years. The primary endpoint of assessment of gut health will be based on the non-invasive measurement of faecal secretory IgA (sIgA) as a sensitive biomarker of the intestinal ecosystem. The presence of gastrointestinal disorders will be defined according to the clinical criteria of Rome IV. Information on parent's nutritional habits and life style, breastfeeding duration and child's complementary feeding will be collected along the follow-up. Cord blood cells and plasma at birth will be purified for further analysis. The meconium and stools collected at birth, 6 months, 2 years and 4 years of age will allow sIgA analysis.Ethics and dissemination: This clinical study has obtained the approval from the national ethical committee. We plan to publish the results of the study in peer-review journals and by means of national and international conference.Trial registration number: NCT04195425

New surfactant protein C gene mutations associated with diffuse lung disease

International audienceMutations in the surfactant protein C gene () have been recently associated with the development of diffuse lung disease, particularly sporadic and familial interstitial lung disease (ILD). We have investigated the prevalence and the spectrum of mutations in a large cohort of infants and children with diffuse lung disease and suspected with surfactant dysfunction. One hundred twenty-one children were first screened for the common mutation, p.Ile73Thr (I73T). Ten unrelated patients were shown to carry this mutation. The I73T mutation was inherited in 6 cases, and appeared in 4. The 111 patients without the I73T mutation were screened for the entire coding sequence of . Of these, eight (seven unrelated) subjects were shown to carry a novel mutant allele of . All these seven new mutations are located in the BRICHOS domain except the p.Val39Ala (V39A) mutation, which is in the surfactant protein C (SP-C) mature peptide. Our results confirm that mutations are a frequent cause of diffuse lung disease, and that I73T is the most frequent mutation associated with diffuse lung disease

An educational programme in neonatal intensive care units (SEPREVEN): a stepped-wedge, cluster-randomised controlled trial

International audienceBackgroundPatients in neonatal intensive care units (NICUs) are at high risk of adverse events. The effects of medical and paramedical education programmes to reduce these have not yet been assessed.MethodsIn this multicentre, stepped-wedge, cluster-randomised controlled trial done in France, we randomly assigned 12 NICUs to three clusters of four units. Eligible neonates were inpatients in a participating unit for at least 2 days, with a postmenstrual age of 42 weeks or less on admission. Each cluster followed a 4-month multifaceted programme including education about root-cause analysis and care bundles. The primary outcome was the rate of adverse events per 1000 patient-days, measured with a retrospective trigger-tool based chart review masked to allocation of randomly selected files. Analyses used mixed-effects Poisson modelling that adjusted for time. This trial is registered wit

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children

International audienceABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died short-ly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysio-logical mechanisms despite similar clinical phenotypes