Difference between revisions of "Talk:Respiratory System - Abnormalities"
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===Genetic disorders of surfactant dysfunction===
===Genetic disorders of surfactant dysfunction===
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Cite this page: Hill, M.A. (2019, December 7) Embryology Respiratory System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Respiratory_System_-_Abnormalities
Interstitial lung diseases in children
Orphanet J Rare Dis. 2010 Aug 20;5:22.
Clement A, Nathan N, Epaud R, Fauroux B, Corvol H. Source Pediatric Pulmonary Department, Reference Center for Rare Lung Diseases, AP-HP, Hôpital Trousseau, Inserm UMR S-938, Université Pierre et Marie Curie-Paris 6, Paris, F-75012 France. firstname.lastname@example.org
Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.
PMID 20727133 PMCID: PMC2939531
Surfactant Metabolism Dysfunction and Childhood Interstitial Lung Disease (chILD)
Ulster Med J. 2009 Jan;78(1):7-9.
McFetridge L, McMorrow A, Morrison PJ, Shields MD. Source Royal Belfast Hospital for Sick Children, Queens University Belfast, Grosvenor Road, Belfast BT12 6BA, UK.
Abstract Surfactant deficiency and the resultant respiratory distress syndrome (RDS) seen in preterm infants is a major cause of respiratory morbidity in this population. Until recently, the contribution of surfactant to respiratory morbidity in infancy was limited to the neonatal period. It is now recognised that inborn errors of surfactant metabolism leading to surfactant dysfunction account for around 10% of childhood interstitial lung disease (chILD). These abnormalities can be detected by blood sampling for mutation analysis, thereby avoiding the need for lung biopsy in some children with chILD.
Genetic disorders of surfactant dysfunction
Pediatr Dev Pathol. 2009 Jul-Aug;12(4):253-74.
Wert SE, Whitsett JA, Nogee LM. Source Perinatal Institute, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and the Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA. email@example.com
Mutations in the genes encoding the surfactant proteins B and C (SP-B and SP-C) and the phospholipid transporter, ABCA3, are associated with respiratory distress and interstitial lung disease in the pediatric population. Expression of these proteins is regulated developmentally, increasing with gestational age, and is critical for pulmonary surfactant function at birth. Pulmonary surfactant is a unique mixture of lipids and proteins that reduces surface tension at the air-liquid interface, preventing collapse of the lung at the end of expiration. SP-B and ABCA3 are required for the normal organization and packaging of surfactant phospholipids into specialized secretory organelles, known as lamellar bodies, while both SP-B and SP-C are important for adsorption of secreted surfactant phospholipids to the alveolar surface. In general, mutations in the SP-B gene SFTPB are associated with fatal respiratory distress in the neonatal period, and mutations in the SP-C gene SFTPC are more commonly associated with interstitial lung disease in older infants, children, and adults. Mutations in the ABCA3 gene are associated with both phenotypes. Despite this general classification, there is considerable overlap in the clinical and histologic characteristics of these genetic disorders. In this review, similarities and differences in the presentation of these disorders with an emphasis on their histochemical and ultrastructural features will be described, along with a brief discussion of surfactant metabolism. Mechanisms involved in the pathogenesis of lung disease caused by mutations in these genes will also be discussed.
Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study
BMC Pediatr. 2011 Nov 8;11:101.
De Luca D, Capoluongo E, Rigo V; Study group on Secretory Phospholipase in Paediatrics (SSPP). Collaborators (19) Source Pediatric Intensive Care Unit, Dept of Emergency and Intensive Care, University Hospital A.Gemelli, Catholic University of the Sacred Heart-Rome, Italy. firstname.lastname@example.org
Abstract BACKGROUND: Secretory phospholipase A2 (sPLA2) is a group of enzymes involved in lung tissue inflammation and surfactant catabolism. sPLA2 plays a role in adults affected by acute lung injury and seems a promising therapeutic target. Preliminary data allow foreseeing the importance of such enzyme in some critical respiratory diseases in neonates and infants, as well. Our study aim is to clarify the role of sPLA2 and its modulators in the pathogenesis and clinical severity of hyaline membrane disease, infection related respiratory failure, meconium aspiration syndrome and acute respiratory distress syndrome. sPLA2 genes will also be sequenced and possible genetic involvement will be analysed. METHODS/DESIGN: Multicentre, international, translational study, including several paediatric and neonatal intensive care units and one coordinating laboratory. Babies affected by the above mentioned conditions will be enrolled: broncho-alveolar lavage fluid, serum and whole blood will be obtained at definite time-points during the disease course. Several clinical, respiratory and outcome data will be recorded. Laboratory researchers who perform the bench part of the study will be blinded to the clinical data. DISCUSSION: This study, thanks to its multicenter design, will clarify the role(s) of sPLA2 and its pathway in these diseases: sPLA2 might be the crossroad between inflammation and surfactant dysfunction. This may represent a crucial target for new anti-inflammatory therapies but also a novel approach to protect surfactant or spare it, improving alveolar stability, lung mechanics and gas exchange.
Bronchopulmonary dysplasia: where have all the vessels gone? Roles of angiogenic growth factors in chronic lung disease
Am J Respir Crit Care Med. 2007 May 15;175(10):978-85. Epub 2007 Feb 1.
Thébaud B, Abman SH. Source Department of Pediatrics, Division of Neonatology, Vascular Biology Group, University of Alberta, HMRC 407, Edmonton, AB, T6G 2S2, Canada. email@example.com
Bronchopulmonary dysplasia and emphysema are significant global health problems at the extreme stages of life. Both are characterized by arrested alveolar development or loss of alveoli, respectively. Both lack effective treatment strategies. Knowledge about the genetic control of branching morphogenesis in mammals derives from investigations of the respiratory system in Drosophila, but mechanisms that regulate alveolar development remain poorly understood. Even less is known about regulation of the growth and development of the pulmonary vasculature. Understanding how alveoli and the underlying capillary network develop, and how these mechanisms are disrupted in disease states, are critical for developing effective therapies for lung diseases characterized by impaired alveolar structure. Recent observations have challenged old notions that the development of the blood vessels in the lung passively follows that of the airways. Rather, increasing evidence suggests that lung blood vessels actively promote alveolar growth during development and contribute to the maintenance of alveolar structures throughout postnatal life. Our working hypothesis is that disruption of angiogenesis impairs alveolarization, and that preservation of vascular growth and endothelial survival promotes growth and sustains the architecture of the distal airspace. Furthermore, the explosion of interest in stem cell biology suggests potential roles for endothelial progenitor cells in the pathogenesis or treatment of lung vascular disease. In this Pulmonary Perspective, we review recent data on the importance of the lung circulation, specifically examining the relationship between dysmorphic vascular growth and impaired alveolarization, and speculate on how these new insights may lead to novel therapeutic strategies for bronchopulmonary dysplasia. Comment in Am J Respir Crit Care Med. 2007 Oct 1;176(7):724-5; author reply 725.
Interstitial lung disease in children -- genetic background and associated phenotypes
Respir Res. 2005 Apr 8;6:32.
Hartl D, Griese M. Source Pediatric Pneumology, Childrens' hospital of the Ludwig-Maximilians-University, Munich, Germany. firstname.lastname@example.org
Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice.
Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia
Pediatrics. 2005 Sep;116(3):e356-63. Outcomes of congenital diaphragmatic hernia: a population-based study in Western Australia. Colvin J, Bower C, Dickinson JE, Sokol J.
Department of Neonatal Pediatrics, Women's and Children's Health Service, Perth, Australia. Erratum in:
Pediatrics. 2006 May;117(5):1870. Abstract OBJECTIVES: There have been many recent reports of improved survival rates for congenital diaphragmatic hernia (CDH), largely derived from institution-based data. These are often flawed by case selection bias. The objectives of this study were to document the true incidence, management, and outcomes of CDH in a geographically defined population over a 12-year period and to determine the changing trends in these over time. We also sought to ascertain the prenatal and postnatal factors associated with morbidity and death among these infants.
METHODS: A retrospective study of all cases of CDH in Western Australia from 1991 to 2002 was conducted. Cases were identified from 5 independent databases within the Western Australian health network, including the Western Australian Birth Defects Registry. All fetuses and neonates diagnosed with CDH in Western Australia during this period were identified, including miscarriages, stillbirths, and terminations of pregnancies in which a diagnosis of fetal CDH had been made, as well as those diagnosed postnatally. Cases not known to involve CDH until diagnosis at autopsy were also included. Infants with diaphragmatic eventration were excluded from the study. Detailed information was obtained from review of maternal and infant medical records.
RESULTS: One hundred sixteen cases of CDH were identified. Of these, 71 (61%) infants were born alive and 37 survived beyond 1 year of age (52% of live-born infants, 32% of all cases of CDH). Pregnancies involving 38 (33%) fetuses were terminated electively, 4 (3%) fetuses were aborted spontaneously, and 3 (3%) fetuses were stillborn. Another major congenital anomaly was present in 54 (47%) cases. Twenty-one (18%) cases had other anomalies that were likely to be fatal. Of all cases with an additional major anomaly, 42 (78%) died. Twenty-seven (71%) of 38 fetuses for whom the pregnancy was terminated had another major anomaly. Twenty-three (32%) live-born infants had another major anomaly (4 of which were considered fatal conditions); however, this did not affect their survival rates. Fifty-three percent of cases were diagnosed prenatally, and 49% of these pregnancies were then terminated. Of live-born infants with prenatally diagnosed CDH, 10 (33%) survived beyond 1 year of age. The gestational age at diagnosis did not affect the survival rate for live-born infants. Postnatal diagnosis occurred in 55 (47%) cases. Of these, 41 (74%) case subjects were born alive and diagnosed on clinical grounds after birth. In the remaining 14 cases, the diagnosis was made in postmortem examinations of fetuses from pregnancies that were terminated for other reasons (8 cases) or after spontaneous abortion or stillbirth (5 cases). Significant differences were found between prenatally and postnatally diagnosed live-born infants. Among live-born infants, prenatal diagnosis was associated with a significantly reduced survival rate (33%, compared with 66% for postnatally diagnosed infants). Prenatally diagnosed live-born infants were of lower birth weight and were born at an earlier gestational age. There was no statistically significant difference between the 2 groups in the onset of labor (spontaneous or induced) or in the rate of elective cesarean sections. Prenatally diagnosed live-born infants were more likely to be delivered in a tertiary perinatal center and were intubated more commonly at delivery. No difference was found in the Apgar scores at either 1 or 5 minutes between the groups. Of 71 live-born infants, 37 (52%) survived to 1 year of age. The majority of deaths occurred within the first 7 days of life (44%). Preoperative air leaks occurred for 16 (22%) infants, of whom 14 (88%) died. Factors found to predict death of live-born infants included prenatal diagnosis, right-sided hernia, major air leak, earlier gestational age at birth, lower birth weight, and lower Apgar scores at 1 and 5 minutes. Over the course of the decade, there were significant increases in the proportion of cases in which the diagnosis of CDH was made with prenatal ultrasonography and in the number of live-born infants born at the tertiary perinatal center. The mortality rate for all cases, the mortality rate for live-born infants, and the proportion of pregnancies involving prenatally diagnosed cases that were terminated electively were all greater in the later epoch but not significantly so.
CONCLUSIONS: This was a comprehensive, population-based study of CDH, with full case ascertainment, large sample size, and complete outcome data for all cases. The majority of published studies of CDH examined specific patient populations, such as neonates referred to tertiary pediatric surgical centers. Invariably, those studies failed to detect the demise of cases with CDH before arrival at the referral center, whether through termination of pregnancy, in utero fetal demise, or postnatal death occurring before transfer. Exclusion of these cases from calculations of mortality rates results in significant case selection bias. In our study, 35% of live-born infants died before referral or transport. The population of infants reaching the tertiary surgical center represented only 40% of the total cases of CDH. Wide variations in reported survival rates occur throughout the literature. These differences reflect the influence of this case selection bias, as well as variable referral policies and management practices. For our study population, survival rates differed vastly depending on the subgroup analyzed. Ninety-two percent of postoperative infants survived beyond 1 year of age, as did 80% of infants who reached the surgical referral center. However, only 52% of live-born infants, 32% of all cases, and 16% of all prenatally diagnosed cases survived. Therefore, the overall mortality rate for this condition remains high, despite increased prenatal detection, transfer to tertiary institutions for delivery, and advances in neonatal care, and is influenced significantly by the rate of prenatal termination. In our study, 33% of all cases of CDH and 49% of prenatally diagnosed fetuses underwent elective termination of pregnancy. This large number of fetal terminations confounds the accurate assessment of the true outcomes of this condition.
PMID 16140678 http://www.ncbi.nlm.nih.gov/pubmed/16140678