Ultrastructural Characterization of Genetic Diffuse Lung Diseases in Infants and Children: A Cohort Study and Review

Pediatric diffuse lung diseases are rare disorders with an onset in the neonatal period or in infancy, characterized by chronic respiratory symptoms and diffuse interstitial changes on imaging studies. Genetic disorders of surfactant homeostasis represent the main etiology. Surfactant protein B and ABCA3 deficiencies typically cause neonatal respiratory failure, which is often lethal within a few weeks or months. Although heterozygous ABCA3 mutation carriers are mostly asymptomatic, there is growing evidence that monoallelic mutations may affect surfactant homeostasis. Surfactant protein C mutations are dominant or sporadic disorders leading to a broad spectrum of manifestations from neonatal respiratory distress syndrome to adult pulmonary fibrosis. The authors performed pathology and ultrastructural studies in 12 infants who underwent clinical lung biopsy. One carried a heterozygous SP-B mutation, 3 carried SP-C mutations, and 7 carried ABCA3 mutations (5 biallelic and 2 monoallelic). Optical microscopy made it possible to distinguish between surfactant-related disorders and other forms. One of the ABCA3 monoallelic carriers had morphological features of alveolar capillary dysplasia, a genetic disorder of lung alveolar, and vascular development. One patient showed no surfactant-related anomalies but had pulmonary interstitial glycogenosis, a developmental disorder of unknown origin. Electron microscopy revealed specific lamellar bodies anomalies in all SP-B, SP-C, and ABCA3 deficiency cases. In addition, the authors showed that heterozygous ABCA3 mutation carriers have an intermediate ultrastructural phenotype between homozygous carriers and normal subjects. Lung biopsy is an essential diagnostic procedure in unexplained diffuse lung disorders, and electron microscopy should be performed systematically, since it may reveal specific alterations in genetic disorders of surfactant homeostasis

Rapid and safe response to low-dose carbamazepine in neonatal epilepsy

To evaluate treatment responses in benign familial neonatal epilepsy (BFNE)

Dysregulation of locus coeruleus development in congenital central hypoventilation syndrome.

Human congenital central hypoventilation syndrome (CCHS), resulting from mutations in transcription factor PHOX2B, manifests with impaired responses to hypoxemia and hypercapnia especially during sleep. To identify brainstem structures developmentally affected in CCHS, we analyzed two postmortem neonatal-lethal cases with confirmed polyalanine repeat expansion (PARM) or Non-PARM (PHOX2B∆8) mutation of PHOX2B. Both human cases showed neuronal losses within the locus coeruleus (LC), which is important for central noradrenergic signaling. Using a conditionally active transgenic mouse model of the PHOX2B∆8 mutation, we found that early embryonic expression (<E10.5) caused failure of LC neuronal specification and perinatal respiratory lethality. In contrast, later onset (E11.5) of PHOX2B∆8 expression was not deleterious to LC development and perinatal respiratory lethality was rescued, despite failure of chemosensor retrotrapezoid nucleus formation. Our findings indicate that early-onset mutant PHOX2B expression inhibits LC neuronal development in CCHS. They further suggest that such mutations result in dysregulation of central noradrenergic signaling, and therefore, potential for early pharmacologic intervention in humans with CCHS

ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system

Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelic mutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as disease modifiers in lung diseases such as RDS of prematurity or associate with mutations in other surfactant-related genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology

COVID-19 : synthèse de la situation actuelle en néonatologie

Le début de cette année 2020 a été marqué par la propagation du SARS-CoV-2, un nouveau virus de la famille des bêta-coronavirus, au départ de la province de Hubei en Chine. Ce virus est responsable d’une pandémie mondiale de pneumonie et de syndrome de détresse respiratoire aigüe. Bien que l’infection (appelée COVID-19) semble être moins sévère dans la population pédiatrique, les nouveau-nés ont tendance à être plus fréquemment touchés que les autres enfants. Plusieurs cas d’infections néonatales au SARS-CoV-2 ont été rapportés à ce jour, dont un chez un prématuré extrême. Néanmoins, le tableau clinique parait moins sévère et la mortalité néonatale liée au COVID 19 n’a pas été rapportée à ce jour. Le mode de transmission par lequel une mère infecte son bébé n’est pas encore clairement identifié, la transmission verticale n’a pas été démontrée jusqu’à présent. L’allaitement maternel n’est pas contre-indiqué dans la plupart des pays. Le but de cet article est de faire le point sur la situation actuelle en pédiatrie, et particulièrement en néonatologie.[COVID-19 in neonatology: a synthesis of the current situation] The beginning of 2020 was marked by the spread of SARS-CoV-2 virus, a new virus from the beta-coronavirus family, from Hubei, China. This virus is responsible for a global pandemia of pneumonia with acute respiratory distress syndrome. Although the infection appears to be less acute in the pediatric population, neonates tend to be more frequently affected. Several cases of neonatal SARS-CoV-2 infections have been reported to date, including one in an extremely premature neonate. Nevertheless, the clinical picture seems to be less critical and neonatal mortality associated with COVID-19 has not been reported to date. The transmission mode from mother to infant has not been clearly demonstrated so far. Breastfeeding is allowed in most countries. The aim of this article is to summarize the epidemiological context and current knowledge on COVID-19 in infants and neonates

How to minimize central line-associated bloodstream infections in a neonatal intensive care unit: a quality improvement intervention based on a retrospective analysis and the adoption of an evidence-based bundle.

Central line-associated bloodstream infection (CLABSI) is a significant cause of morbidity and mortality in neonatal intensive care units (NICUs). A "bundle" is defined as a combination of evidence-based interventions that provided they are followed collectively and reliably, are proven to improve patient outcomes. The aim of this quasi-experimental study was to assess the impact of new central line insertion, dressing, and maintenance "bundles" on the rate of CLABSI and catheter-related complications. We performed a quality improvement (QI), prospective, before-after study. In the first 9-month period, the old "bundles" and pre-existing materials were used/applied. An intervention period then occurred with changes made to materials used and the implementation of new "bundles" related to various aspects of central lines care. A second 6-month period was then assessed and the CLABSI rates were measured in the NICU pre- and post-intervention period. The QI measures were the rate of CLABSI and catheter-related complications. Data are still being collected after the study to verify sustainability. The implementation of the new "bundles" and the change of certain materials resulted in a significantly decreased rate of CLABSI (8.4 to 1.8 infections per 1000 central venous catheter (CVC) days, p = 0.02,) as well as decreased catheter-related complications (47 to 10, p < 0.007).Conclusions: The analysis of pre-existing "bundles" and the implementation of updated central line "bundles" based on best practice recommendations are crucial for reducing the rate of CLABSI in the NICU. The implementation of the new evidence-based central line "bundles" was associated with a significant reduction in CLABSI rate in our unit soon after implementation. What is Known: • Central line-associated bloodstream infection (CLABSI) is a major cause of morbidity and mortality in the neonatal population. • The implementation of evidence-based "bundles" in the NICU is associated with a reduction in the incidence of CLABSI. What is New: • For the improvement in quality care in the NICU, audits are necessary to assess the existing systems. • The "Plan-Do-Study-Act cycle" is an effective tool to use when tackling challenges in an existing system. Using this tool assisted in the approach to reducing CLABSI in our NICU

Nutrients and Microbiota in Lung Diseases of Prematurity: The Placenta-Gut-Lung Triangle.

Cardiorespiratory function is not only the foremost determinant of life after premature birth, but also a major factor of long-term outcomes. However, the path from placental disconnection to nutritional autonomy is enduring and challenging for the preterm infant and, at each step, will have profound influences on respiratory physiology and disease. Fluid and energy intake, specific nutrients such as amino-acids, lipids and vitamins, and their ways of administration -parenteral or enteral-have direct implications on lung tissue composition and cellular functions, thus affect lung development and homeostasis and contributing to acute and chronic respiratory disorders. In addition, metabolomic signatures have recently emerged as biomarkers of bronchopulmonary dysplasia and other neonatal diseases, suggesting a profound implication of specific metabolites such as amino-acids, acylcarnitine and fatty acids in lung injury and repair, inflammation and immune modulation. Recent advances have highlighted the profound influence of the microbiome on many short- and long-term outcomes in the preterm infant. Lung and intestinal microbiomes are deeply intricated, and nutrition plays a prominent role in their establishment and regulation. There is an emerging evidence that human milk prevents bronchopulmonary dysplasia in premature infants, potentially through microbiome composition and/or inflammation modulation. Restoring antibiotic therapy-mediated microbiome disruption is another potentially beneficial action of human milk, which can be in part emulated by pre- and probiotics and supplements. This review will explore the many facets of the gut-lung axis and its pathophysiology in acute and chronic respiratory disorders of the prematurely born infant, and explore established and innovative nutritional approaches for prevention and treatment

ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system.

Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelic mutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as disease modifiers in lung diseases such as RDS of prematurity or associate with mutations in other surfactant-related genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology