Talk:Respiratory System - Abnormalities

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Cite this page: Hill, M.A. (2019, October 17) Embryology Respiratory System - Abnormalities. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Respiratory_System_-_Abnormalities

2019

Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway

Am J Hum Genet. 2019 Jan 2. pii: S0002-9297(18)30461-0. doi: 10.1016/j.ajhg.2018.12.010. [Epub ahead of print]

Karolak JA1, Vincent M2, Deutsch G3, Gambin T4, Cogné B2, Pichon O5, Vetrini F6, Mefford HC7, Dines JN8, Golden-Grant K9, Dipple K10, Freed AS8, Leppig KA11, Dishop M12, Mowat D13, Bennetts B14, Gifford AJ15, Weber MA16, Lee AF17, Boerkoel CF18, Bartell TM19, Ward-Melver C20, Besnard T2, Petit F21, Bache I22, Tümer Z23, Denis-Musquer M24, Joubert M24, Martinovic J25, Bénéteau C2, Molin A26, Carles D27, André G27, Bieth E28, Chassaing N28, Devisme L29, Chalabreysse L30, Pasquier L31, Secq V32, Don M33, Orsaria M34, Missirian C35, Mortreux J35, Sanlaville D36, Pons L36, Küry S2, Bézieau S2, Liet JM37, Joram N37, Bihouée T38, Scott DA39, Brown CW40, Scaglia F41, Tsai AC42, Grange DK43, Phillips JA 3rd44, Pfotenhauer JP44, Jhangiani SN45, Gonzaga-Jauregui CG46, Chung WK47, Schauer GM48, Lipson MH19, Mercer CL49, van Haeringen A50, Liu Q51, Popek E52, Coban Akdemir ZH51, Lupski JR53, Szafranski P51, Isidor B2, Le Caignec C54, Stankiewicz P55. Author information Abstract Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung. Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. KEYWORDS: 17q23.1q23.2 recurrent deletion; 5p12 deletion; T-box transcription factor 4; aplasia of lacrimal and salivary glands; fibroblast growth factor 10; lacrimoauriculodentodigital (LAAD) syndrome; lung hypoplasia; neonatal lung disease PMID: 30639323 DOI: 10.1016/j.ajhg.2018.12.010


Predictors of Long-Term Pulmonary Morbidity in Children with Congenital Diaphragmatic Hernia

Eur J Pediatr Surg. 2019 Feb;29(1):120-124. doi: 10.1055/s-0038-1676586. Epub 2018 Dec 24.

Wigen RB1, Duan W2, Moraes TJ2, Chiu PPL1. Author information

PURPOSE:  The aim is to identify prognostic markers of long-term pulmonary morbidity among congenital diaphragmatic hernia (CDH) survivors. METHODS:  A single-institution, retrospective review was performed on all CDH patients from 2000 and 2012 (REB#1000053383). Liver position, patch use, and pulmonary function tests (PFTs) (forced expiratory volume at 1 second [FEV1] and forced vital capacity [FVC] expressed as mean % predicted + SD) were recorded. Data were analyzed using analysis of variance. RESULTS:  Patients with acceptable and reproducible PFT (n = 72 for 202 total PFT) with patch repair and liver up (n = 28) had significantly lower FEV1 (72.4 + 17.6) than those with no patch and liver down (n = 98, FEV1= 86.3 + 15.9, p = 0.002). Patients with patch repair and liver down (n = 40) also had significantly lower FEV1 (76.6 + 14.4) than those with liver down and no patch (p = 0.0463). Patients with liver up and patch repair had PFT results consistent with moderate reduction of lung function, while the remainder had mild to no decrease in lung function. All CDH patients older than 14 years had a reduction in FEV1/FVC consistent with obstructive phenotype, with a mean FEV1/FVC = 62.3 for patch repair group and FEV1/FVC = 76.1 in the no patch group. CONCLUSION:  Decreased pulmonary function of CDH survivors correlated with the use of patch repair and liver position. CDH lung disease should be monitored in adulthood. Georg Thieme Verlag KG Stuttgart · New York. PMID: 30583297 DOI: 10.1055/s-0038-1676586

2018

Maternal asthma is associated with increased risk of perinatal mortality

PLoS One. 2018 May 18;13(5):e0197593. doi: 10.1371/journal.pone.0197593. eCollection 2018.

Kemppainen M1, Lahesmaa-Korpinen AM2, Kauppi P3,4, Virtanen M5, Virtanen SM6,7,8, Karikoski R9, Gissler M2,10, Kirjavainen T1.

Abstract

BACKGROUND: Asthma is the most common chronic disease during pregnancy and it may have influence on pregnancy outcome. OBJECTIVES: Our goal was to assess the association between maternal asthma and the perinatal risks as well as possible effects of asthma medication. METHODS: The study was based on a nationwide Finnish register-based cohort between the years 1996 and 2012 in the Drug and Pregnancy Database. The register data comprised 962 405 singleton live and stillbirths, 898 333 (93.3%) pregnancies in mothers with neither confirmed asthma nor use of asthma medication (controls), and 26 674 (2.8%) pregnancies with confirmed maternal asthma. 71% of mothers with asthma used asthma medication. The diagnosis of asthma was based on the mothers' right for subsidised medication which is carefully evaluated by strict criteria including pulmonary function testing. Odds ratio was used in comparison. Premature birth (PB), low birth weight, small for gestational age (SGA), neonatal death were the main outcome measures. RESULTS: Maternal asthma was associated with adjusted odds ratios (aORs) for perinatal mortality 1.24 (95% CI 1.05 to 1.46), preterm birth 1.18 (1.11 to 1.25), low birth weight 1.29 (1.21 to 1.37), fetal growth restriction (SGA) 1.32, (1.24 to 1.40), and asphyxia 1.09 (1.02 to 1.17). Asthma treatment reduced the increased risk of preterm birth aOR 0.85 (95% CI 0.76 to 0.96) but mothers with treated asthma had higher risks of fetal growth restriction (SGA) aOR 1.26 (1.10 to 1.45), and asphyxia aOR 1.37 (1.17 to 1.61) than mothers with untreated asthma. CONCLUSION: Asthma is associated with increased risks of perinatal mortality, preterm birth, low birth weight, fetal growth restriction (SGA), and asphyxia. Asthma treatment reduces the risk of preterm delivery, but it does not seem to reduce other complications such as perinatal mortality. PMID: 29775476 DOI: 10.1371/journal.pone.0197593

Longitudinal assessment of lung function in extremely prematurely born children

Pediatr Pulmonol. 2018 Jan 9. doi: 10.1002/ppul.23933.

Lo J1, Zivanovic S2,3, Lunt A2,3, Alcazar-Paris M2,3, Andradi G2,3, Thomas M4, Marlow N5, Calvert S6, Peacock J7,8, Greenough A2,3,8.

Abstract

OBJECTIVES: To assess longitudinally small airway function in children born extremely prematurely and whether there was a correlation between airway function in infancy and at 11-14 years. WORKING HYPOTHESES: There would be tracking of airways obstruction and small airway function would deteriorate during childhood in those born extremely prematurely. STUDY DESIGN: A longitudinal study. PATIENT-SUBJECT SELECTION: Thirty-five children with a mean gestational age of 26 weeks had lung function assessed at 1 year corrected and 11-14 years of age. METHODOLOGY: Lung volumes were measured by helium gas dilution (FRCHe ) and plethysmography (FRCpleth ) and small airway function assessed by calculating the FRCHe :FRCpleth ratio. Airway function was assessed at 1 year corrected by measurement of airway resistance (Raw ) and at 11-14 years by assessment of Raw , forced expiratory flow from 75% of vital capacity (FEF75 ), and forced expiratory volume at one second (FEV1 ). RESULTS: At the first assessment, the children had a mean (SD) FRCHe :FRCpleth of 0.90 (0.13) and at the second, 0.83 (0.12) (P = 0.035). There was a significant 0.54% decrease (95%CI: -1.02%, -0.06%) in FRCHe :FRCpleth for increased age per year after adjusting for birth weight, gestational age, sex, and bronchopulmonary dysplasia (P = 0.027). There were significant correlations between Raw at the first assessment and Raw (P = 0.012), FEF75 (P = 0.034), and FEV1 (P = 0.04) at 11-14 years. CONCLUSIONS: These results demonstrate in those born extremely prematurely there is tracking of airway function during childhood. © 2018 Wiley Periodicals, Inc. KEYWORDS: airway function; extreme prematurity; lung volume; small airway function

PMID: 29316378 DOI: 10.1002/ppul.23933

2017

Better understanding of childhood asthma, towards primary prevention - are we there yet? Consideration of pertinent literature

F1000Res. 2017 Dec 20;6:2152. doi: 10.12688/f1000research.11601.1. eCollection 2017.

Gur M1, Hakim F1,2, Bentur L1,2.

Abstract

Asthma is a chronic disease, characterized by reversible airway obstruction, airway inflammation and hyper-reactivity. The prevalence of asthma has risen dramatically over the past decade, affecting around 300,000,000 people. The etiology is multifactorial, with genetic, epigenetic, developmental and environmental factors playing a role. A complex interaction between the intrauterine environment, the developing immune system, the infant's microbiome and infectious organisms may lead to the development of allergic sensitization and asthma. Thus, a large number of studies have investigated the risk factors for childhood asthma, with a meticulous search of modifiable factors that could aid in primary prevention. We present a current literature review from 2014-2017, as well as older classic publications, on the pathogenesis and the potential modifiable factors for primary prevention of asthma. No ideal preventive measure has yet been found. Rather, creating favorable prenatal and postnatal environments, minimal exposure to hostile environmental factors, prevention of infections in early life, allergic desensitization and nutritional modifications could possibly reduce asthma inception. In the era of personalized medicine, identifying individual risk factors and tailoring specific preventive measures is warranted. KEYWORDS: Asthma; environmental; factors; prevention; wheezing PMID: 29333254 PMCID: PMC5749133 DOI: 10.12688/f1000research.11601.1


2015

Trends in treatment and in-hospital mortality for neonates with congenital diaphragmatic hernia

J Perinatol. 2015 May 7. doi: 10.1038/jp.2015.46.

Hagadorn JI1, Brownell EA1, Herbst KW2, Trzaski JM1, Neff S2, Campbell BT3.

Abstract

OBJECTIVE: We performed a retrospective cohort study in order to examine recent trends in use of post-partum treatments and in-hospital mortality for congenital diaphragmatic hernia (CDH). STUDY DESIGN: Included were infants with CDH, born in 2003 to 2012 and hospitalized at ⩽7 days of age at one of 33 United States tertiary referral children's hospitals with extracorporeal membrane oxygenation (ECMO) programs. In-hospital mortality as well as use of ECMO, surfactant and a variety of vasodilators were examined for trends during the study period. RESULT: Inclusion criteria were met by 3123 infants with CDH. Among 2423 term or near-term infants, odds of death decreased annually for those with isolated or complex CDH. For 700 premature or low-birth weight infants with CDH, in-hospital mortality did not change. Among treatments for CDH, increasing with time in the study cohort were use of milrinone and sildenafil individually, and use of multiple vasodilators during the hospitalization. CONCLUSION: Survival improved in large subgroups of term or near-term infants with CDH in this 10-year multicenter cohort, temporally associated with increasing use of multiple vasodilators. Use of vasodilators for infants with CDH is increasing despite a lack of evidence supporting efficacy or safety. Prospective research is needed to clarify specific causal effects contributing to improving survival in these infants.Journal of Perinatology advance online publication, 7 May 2015; doi:10.1038/jp.2015.46.

PMID 25950919

2014

The Robyn Barst Memorial Lecture: Differences between the fetal, newborn, and adult pulmonary circulations: relevance for age-specific therapies (2013 Grover Conference series)

Pulm Circ. 2014 Sep;4(3):424-40. doi: 10.1086/677371.

Abman SH1, Baker C1, Gien J1, Mourani P1, Galambos C2.

Abstract

Pulmonary arterial hypertension (PAH) contributes to poor outcomes in diverse diseases in newborns, infants, and children. Many aspects of pediatric PAH parallel the pathophysiology and disease courses observed in adult patients; however, critical maturational differences exist that contribute to distinct outcomes and therapeutic responses in children. In comparison with adult PAH, disruption of lung vascular growth and development, or angiogenesis, plays an especially prominent role in the pathobiology of pediatric PAH. In children, abnormalities of lung vascular development have consequences well beyond the adverse hemodynamic effects of PAH alone. The developing endothelium also plays critical roles in development of the distal airspace, establishing lung surface area for gas exchange and maintenance of lung structure throughout postnatal life through angiocrine signaling. Impaired functional and structural adaptations of the pulmonary circulation during the transition from fetal to postnatal life contribute significantly to poor outcomes in such disorders as persistent pulmonary hypertension of the newborn, congenital diaphragmatic hernia, bronchopulmonary dysplasia, Down syndrome, and forms of congenital heart disease. In addition, several studies support the hypothesis that early perinatal events that alter lung vascular growth or function may set the stage for increased susceptibility to PAH in adult patients ("fetal programming"). Thus, insights into basic mechanisms underlying unique features of the developing pulmonary circulation, especially as related to preservation of endothelial survival and function, may provide unique therapeutic windows and distinct strategies to improve short- and long-term outcomes of children with PAH.

KEYWORDS: Down syndrome; alveolarization; angiogenesis; bronchopulmonary dysplasia; congenital diaphragmatic hernia; pediatric pulmonary hypertension; persistent pulmonary hypertension of the newborn; pulmonary vascular development PMID: 25621156 PMCID: PMC4278602 DOI: 10.1086/677371

Urinary metabolomics of bronchopulmonary dysplasia (BPD): preliminary data at birth suggest it is a congenital disease

J Matern Fetal Neonatal Med. 2014 Oct;27 Suppl 2:39-45. doi: 10.3109/14767058.2014.955966.

Fanos V1, Pintus MC, Lussu M, Atzori L, Noto A, Stronati M, Guimaraes H, Marcialis MA, Rocha G, Moretti C, Papoff P, Lacerenza S, Puddu S, Giuffrè M, Serraino F, Mussap M, Corsello G.

Abstract

OBJECTIVE: Bronchopulmonary dysplasia (BPD) or chronic lung disease is one of the principal causes of mortality and morbidity in preterm infants. Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. The trigger cause of the disease comprehends the impairment of the alveolar development and the increased angiogenesis. Nevertheless, the molecular pathways characterizing the disease are still unclear. Therefore, the use of the metabolomics technique, due to the capability of identifying instantaneous metabolic perturbation, might help to recognize metabolic patterns associated with the condition. METHODS: The purpose of this study is to compare urinary metabolomics at birth in 36 newborns with a gestational age below 29 weeks and birth weight <1500 g (very low birth weight - VLBW), admitted in Neonatal Intensive Care Unit (NICU) divided into two groups: the first group (18 cases) consisting of newborns who have not yet developed the disease, but who will subsequently develop it and the second group (18 controls) consisting of newborns not affected by BPD. Urine samples were collected within 24-36 h of life and immediately frozen at -80 °C. RESULTS: The (1)H-NMR spectra were analyzed using a partial least squares discriminant analysis (PLS-DA) model coupled with orthogonal Signal Correction. Using this approach it was possible with urine at birth to discriminate newborns that will be later have a diagnosis of BPD with a high statistics power. In particular, we found five important discriminant metabolites in urine in BPD newborns: lactate, taurine, TMAO, myoinositol (which increased) and gluconate (which decreased). CONCLUSION: These preliminary results seem to be promising for the identification of predictor's biomarkers characterizing the BPD condition. These data may suggest that BPD is probably the result of an abnormal development (respiratory bud, vascular tree, hypodysplasia of pneumocytes) and could be considered a congenital disease (genetics plus intrauterine epigenetics). Early identification of infants at the greater risk of developing BPD may allow a targeted approach for reducing disease severity and complications. KEYWORDS: 1H-NMR; Bronchopulmonary dysplasia; metabolites; metabolomics; multivariate statistical analysis

PMID 25284176

2013

Prenatal diagnosis and postnatal findings of bronchogenic cyst

Case Rep Pulmonol. 2013;2013:483864. doi: 10.1155/2013/483864. Epub 2013 May 23.

Rios LT1, Araujo Júnior E, Nardozza LM, Moron AF, Martins Mda G.

Abstract

Bronchogenic cysts arise from abnormal buds from the primitive esophagus and tracheobronchial tree, which do not extend to the site where alveolar differentiation occurs. Bronchogenic cysts are typically unilocular mucus field lesions arising from posterior membranous wall of the air way. The prenatal diagnosis usually is realized by two-dimensional ultrasound showing the large unilocular cystic image in the chest fetus. The prenatal percutaneous aspiration can reduce the risk of heart compression and permit better respiratory conditions to newborn. We present a case of a primiparous pregnant 23 year-old-woman prenatal ultrasound showed a large unilocular cyst in the left hemithorax with compression of the normal left lung tissue and contralateral mediastinal shift. This cyst was percutaneously aspirated without subsequent reaccumulation of fluid. The newborn did not have respiratory distress and the computed tomography scan confirmed the finding of a fluid-filled cyst in the left chest. The chest X-ray showed the displacement of the heart and the mediastinum from the left to the right. The prenatal diagnosis of bronchogenic cyst is very important to assess the degree of the compression of the normal lung and the mediastinum shift. Furthermore, the prenatal diagnosis permits planning delivery in the tertiary hospital with multidisciplinary team because of the risk of respiratory distress.

PMID 23762726

http://www.hindawi.com/journals/cripu/2013/483864/

2012

Laryngo-tracheo-oesophageal clefts

Orphanet J Rare Dis. 2011 Dec 7;6:81.

Leboulanger N, Garabédian EN. Source Paediatric Otolaryngology-Head and Neck surgery Department, UPMC-Paris VI University, Armand-Trousseau Children's Hospital, Paris, France. nicolas.leboulanger@trs.aphp.fr

Abstract

A laryngo-tracheo-esophageal cleft (LC) is a congenital malformation characterized by an abnormal, posterior, sagittal communication between the larynx and the pharynx, possibly extending downward between the trachea and the esophagus. The estimated annual incidence of LC is 1/10,000 to 1/20,000 live births, accounting for 0.2% to 1.5% of congenital malformations of the larynx. These incidence rates may however be underestimated due to difficulty in diagnosing minor forms and a high mortality rate in severe forms. A slightly higher incidence has been reported in boys than in girls. No specific geographic distribution has been found. Depending on the severity of the malformation, patients may present with stridor, hoarse cry, swallowing difficulties, aspirations, cough, dyspnea and cyanosis through to early respiratory distress. Five types of laryngo-tracheo-esophageal cleft have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms: Type 0 laryngo-tracheo-esophageal cleft to Type 4 laryngo-tracheo-esophageal cleft. LC is often associated with other congenital abnormalities/anomalies (16% to 68%), mainly involving the gastro-intestinal tract, which include laryngomalacia, tracheo-bronchial dyskinesia, tracheo-bronchomalacia (mostly in types 3 and 4), and gastro-esophageal reflux disease (GERD). The syndromes most frequently associated with an LC are Opitz/BBB syndrome, Pallister Hall syndrome, VACTERL/VATER association, and CHARGE syndrome. Laryngeal clefts result from failure of fusion of the posterior cricoid lamina and abnormal development of the tracheo-esophageal septum. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial. LC appears to be mostly sporadic although some familial cases with suspected autosomal dominant transmission have been reported. The age of diagnosis depends mainly on the severity of the clinical symptoms and therefore on the extent of the LC. Diagnosis is made either based on clinical manifestations or on investigations, such as endoscopy, X-ray, CT scan, performed for other conditions. Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal reflux disease and neurological swallowing disorders, as well as laryngomalacia and laryngeal palsy. Prenatal diagnosis of LC has never been reported, although associated anomalies may be detected on fetal ultrasonography. Once the cleft is diagnosed, it is essential to determine its length to orient the management and treatment approach. Management involves maintenance of satisfactory ventilation, prevention of secondary pulmonary complications as a result of repeated aspirations, and adequate feeding. Endotracheal intubation may be required for respiratory distress in severe cases. Treatment requires endoscopic or external surgery to close the cleft. Surgery should be performed as early as possible to avoid complications related to aspiration and gastric reflux, except in type 0 and type 1 cases in which conservative measures must first be attempted. The prognosis is variable depending on the severity of the LC and associated malformations. Early diagnosis and appropriate treatment and management help to reduce mortality and morbidity.

PMID 22151899

http://www.ojrd.com/content/6/1/81

© 2011 Leboulanger and Garabédian; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes

Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2978-83. Epub 2012 Feb 6.

Russell MK, Longoni M, Wells J, Maalouf FI, Tracy AA, Loscertales M, Ackerman KG, Pober BR, Lage K, Bult CJ, Donahoe PK. Source Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA 02114, USA.

Abstract

Congenital diaphragmatic hernia (CDH) is a common (1 in 3,000 live births) major congenital malformation that results in significant morbidity and mortality. The discovery of CDH loci using standard genetic approaches has been hindered by its genetic heterogeneity. We hypothesized that gene expression profiling of developing embryonic diaphragms would help identify genes likely to be associated with diaphragm defects. We generated a time series of whole-transcriptome expression profiles from laser captured embryonic mouse diaphragms at embryonic day (E)11.5 and E12.5 when experimental perturbations lead to CDH phenotypes, and E16.5 when the diaphragm is fully formed. Gene sets defining biologically relevant pathways and temporal expression trends were identified by using a series of bioinformatic algorithms. These developmental sets were then compared with a manually curated list of genes previously shown to cause diaphragm defects in humans and in mouse models. Our integrative filtering strategy identified 27 candidates for CDH. We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects. Our study demonstrates the utility of genetic characterization of normal development as an integral part of a disease gene identification and prioritization strategy for CDH, an approach that can be extended to other diseases and developmental anomalies.

PMID 22315423

Congenital diaphragmatic hernia

Orphanet J Rare Dis. 2012 Jan 3;7:1.

Tovar JA. Source Universidad Autonoma de Madrid, Department of Pediatric Surgery, Hospital Universitario La Paz, Madrid, Spain. jatovar.hulp@salud.madrid.org

Abstract

Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an orifice in the diaphragm, more often left and posterolateral that permits the herniation of abdominal contents into the thorax. The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality. About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects. CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes. Some chromosomal anomalies involve CDH as well. The incidence is < 5 in 10,000 live-births. The etiology is unknown although clinical, genetic and experimental evidence points to disturbances in the retinoid-signaling pathway during organogenesis. Antenatal diagnosis is often made and this allows prenatal management (open correction of the hernia in the past and reversible fetoscopic tracheal obstruction nowadays) that may be indicated in cases with severe lung hypoplasia and grim prognosis. Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction. The best hospital series report 80% survival but it remains around 50% in population-based studies. Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors. Much more research on several aspects of this severe condition is warranted.

PMID 22214468

http://www.ojrd.com/content/7/1/1

2011

Laryngo-tracheo-oesophageal clefts

Orphanet J Rare Dis. 2011 Dec 7;6:81. doi: 10.1186/1750-1172-6-81.

Leboulanger N1, Garabédian EN. Author information

Abstract A laryngo-tracheo-esophageal cleft (LC) is a congenital malformation characterized by an abnormal, posterior, sagittal communication between the larynx and the pharynx, possibly extending downward between the trachea and the esophagus. The estimated annual incidence of LC is 1/10,000 to 1/20,000 live births, accounting for 0.2% to 1.5% of congenital malformations of the larynx. These incidence rates may however be underestimated due to difficulty in diagnosing minor forms and a high mortality rate in severe forms. A slightly higher incidence has been reported in boys than in girls. No specific geographic distribution has been found. Depending on the severity of the malformation, patients may present with stridor, hoarse cry, swallowing difficulties, aspirations, cough, dyspnea and cyanosis through to early respiratory distress. Five types of laryngo-tracheo-esophageal cleft have been described based on the downward extension of the cleft, which typically correlates with the severity of symptoms: Type 0 laryngo-tracheo-esophageal cleft to Type 4 laryngo-tracheo-esophageal cleft. LC is often associated with other congenital abnormalities/anomalies (16% to 68%), mainly involving the gastro-intestinal tract, which include laryngomalacia, tracheo-bronchial dyskinesia, tracheo-bronchomalacia (mostly in types 3 and 4), and gastro-esophageal reflux disease (GERD). The syndromes most frequently associated with an LC are Opitz/BBB syndrome, Pallister Hall syndrome, VACTERL/VATER association, and CHARGE syndrome. Laryngeal clefts result from failure of fusion of the posterior cricoid lamina and abnormal development of the tracheo-esophageal septum. The causes of the embryological developmental anomalies leading to LC are not known but are thought to be multifactorial. LC appears to be mostly sporadic although some familial cases with suspected autosomal dominant transmission have been reported. The age of diagnosis depends mainly on the severity of the clinical symptoms and therefore on the extent of the LC. Diagnosis is made either based on clinical manifestations or on investigations, such as endoscopy, X-ray, CT scan, performed for other conditions. Differential diagnoses include tracheo-bronchial fistula, gastro-esophageal reflux disease and neurological swallowing disorders, as well as laryngomalacia and laryngeal palsy. Prenatal diagnosis of LC has never been reported, although associated anomalies may be detected on fetal ultrasonography. Once the cleft is diagnosed, it is essential to determine its length to orient the management and treatment approach. Management involves maintenance of satisfactory ventilation, prevention of secondary pulmonary complications as a result of repeated aspirations, and adequate feeding. Endotracheal intubation may be required for respiratory distress in severe cases. Treatment requires endoscopic or external surgery to close the cleft. Surgery should be performed as early as possible to avoid complications related to aspiration and gastric reflux, except in type 0 and type 1 cases in which conservative measures must first be attempted. The prognosis is variable depending on the severity of the LC and associated malformations. Early diagnosis and appropriate treatment and management help to reduce mortality and morbidity.

PMID 22151899

Choriodecidual group B streptococcal inoculation induces fetal lung injury without intra-amniotic infection and preterm labor in Macaca nemestrina

PLoS One. 2011;6(12):e28972. doi: 10.1371/journal.pone.0028972. Epub 2011 Dec 21.

Adams Waldorf KM, Gravett MG, McAdams RM, Paolella LJ, Gough GM, Carl DJ, Bansal A, Liggitt HD, Kapur RP, Reitz FB, Rubens CE. Source Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA. adamsk@u.washington.edu Abstract BACKGROUND: Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. METHODOLOGY/PRINCIPAL FINDINGS: Ten chronically catheterized pregnant monkeys (Macaca nemestrina) at 118-125 days gestation (term=172 days) received one of two treatments: 1) choriodecidual and intra-amniotic saline (n=5), or 2) choriodecidual inoculation of Group B Streptococcus (GBS) 1×10(6) colony forming units (n=5). Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6) and fetal plasma (IL-8) were detected in GBS animals and correlated with lung injury (p<0.05). Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (~10 samples tested/animal), maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. CONCLUSIONS/SIGNIFICANCE: A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without symptoms and before the onset of the fetal systemic inflammatory response syndrome. © 2011 Adams Waldorf et al.

PMID 22216148 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3244436/

http://dx.plos.org/ambra-doi-resolver/10.1371/journal.pone.0028972

Congenital lung malformations

J Bras Pneumol. 2011 Apr;37(2):259-71.

[Article in English, Portuguese] Andrade CF, Ferreira HP, Fischer GB. Source Santo Antônio Children's Hospital, Santa Casa Sisters of Mercy Hospital Complex, Porto Alegre, Brazil. cristianofa@cirurgiatoracica.net

Abstract

Congenital lung malformations are rare and vary widely in their clinical presentation and severity, depending mostly on the degree of lung involvement and their location in the thoracic cavity. They can manifest at any age and can be the source of significant morbidity and mortality in infants and children. Individuals with congenital lung malformations can present with respiratory symptoms at birth or can remain asymptomatic for long periods. Recently, there has been an increase in the early diagnosis of these malformations, a change that is attributable to the routine use of prenatal ultrasound. The clinical manifestation of these malformations varies from respiratory distress in the immediate postnatal period to an incidental finding on chest X-rays. Early diagnosis and prompt treatment offer the possibility of absolutely normal lung development. The treatment of asymptomatic patients with lung malformations is controversial, because the prognosis of these diseases is unpredictable. The management of these lesions depends on the type of malformation and symptoms. Because of the risk of complications, most authors recommend resection of the lesion at the time of diagnosis. Lobectomy is the procedure of choice and yields excellent long-term results. This article describes the principal congenital lung malformations, their diagnosis, and the controversies regarding treatment.

PMID 21537663


2010

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. annick.clement@trs.aphp.fr

Abstract

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

2009

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.

PMID 19252722

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629012

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. susan.wert@cchmc.org

Abstract

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.

PMID 19220077

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. dm.deluca@fastwebnet.it

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.

PMID 22067747

2007

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. bthebaud@ualberta.ca

Abstract

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.

PMID 17272782

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747658/

2005

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. dominic.hartl@med.uni-muenchen.de

Abstract

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.

PMID 15819986

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