Ventilator strategies in congenital diaphragmatic hernia.

This review focuses on contemporary mechanical ventilator practices used in the initial management of neonates born with congenital diaphragmatic hernia (CDH). Both conventional and non-conventional ventilation modes in CDH are reviewed. Special emphasis is placed on the rationale for gentle ventilation and the current evidence-based clinical practice guidelines that are recommended for supporting these fragile infants. The interplay between CDH lung hypoplasia and other key cardiopulmonary elements of the disease, namely a reduced pulmonary vascular bed, abnormal pulmonary vascular remodeling, and left ventricular hypoplasia, are discussed. Finally, we provide insights into future avenues for mechanical ventilator research in CDH.

Cellular origins and translational approaches to congenital diaphragmatic hernia.

Congenital Diaphragmatic Hernia (CDH) is a complex developmental abnormality characterized by abnormal lung development, a diaphragmatic defect and cardiac dysfunction. Despite significant advances in management of CDH, mortality and morbidity continue to be driven by pulmonary hypoplasia, pulmonary hypertension, and cardiac dysfunction. The etiology of CDH remains unknown, but CDH is presumed to be caused by a combination of genetic susceptibility and external/environmental factors. Current research employs multi-omics technologies to investigate the molecular profile and pathways inherent to CDH. The aim is to discover the underlying pathogenesis, new biomarkers and ultimately novel therapeutic targets. Stem cells and their cargo, non-coding RNAs and agents targeting inflammation and vascular remodeling have produced promising results in preclinical studies using animal models of CDH. Shortcomings in current therapies combined with an improved understanding of the pathogenesis in CDH have given rise to novel promising experimental treatments that are currently being evaluated in clinical trials. This review provides insight into current developments in translational research, ranging from the cellular origins of abnormal cardiopulmonary development in CDH and the identification of novel treatment targets in preclinical CDH models at the bench and their translation to clinical trials at the bedside.

Isolated left hypoplasia of the pulmonary artery accompanied by lung hypoplasia and chronic bronchial disease in a cat.

A 2-year-old castrated Russian Blue cat presented with inappetence, depression, and labored respirations. Radiography findings suggested left lung atelectasis; however, the ultrasonography findings did not indicate lung atelectasis. The left pulmonary artery (PA) was abnormally small on echocardiography; further, there were no other cardiac anomalies. Computed tomography revealed an abnormally small left PA and left lung. Furthermore, bronchiectasis and tree-in-bud patterns were observed in the lung lobes. Based on these findings, the cat was diagnosed with isolated left PA hypoplasia, presumed left lung hypoplasia, and feline chronic bronchial disease. Early diagnosis of this disease is important because it can cause serious complications, including recurrent respiratory infection, bronchiectasis, massive hemoptysis, and pulmonary hypertension.

Imaging spectrum of horseshoe lung: A series of four cases.

Horseshoe lung (HL) is a rare congenital anomaly represented by the fusion of both lungs, posterior to the heart, and is typically associated with various bronchopulmonary and cardiovascular malformations. Multi-detector contrast enhanced CT is the imaging modality of choice to demonstrate the pathology and associated malformations. There has been inconsistency in the nomenclature used for such cases in literature. To resolve ambiguity, the authors emphasise that only two terms: HL and pseudo-HL be used on imaging to describe variants of this congenital malformation. Contribution: A description of the imaging features in four cases of HL, with their associated malformations and a review of the nomenclature.

[Congenital diaphragmatic hernia : Imaging-from diagnosis to aftercare]. / Kongenitale Zwerchfellhernie : Bildgebung von der Diagnose bis zur Nachsorge.

STANDARD RADIOLOGICAL METHODS: Fetal: Ultrasound and magnetic resonance imaging (MRI); postnatal: conventional X­ray diagnostics, computed tomography (CT) and MRI. METHODICAL INNOVATIONS: MRI-based lung ventilation and perfusion measurement. PRACTICAL RECOMMENDATIONS: Lifelong follow-up care should be provided, in which radiology is part of the treatment team.

A rare variant of scimitar syndrome characterised by right pulmonary vein drainage to portal vein with eventeration of diaphragm.

While infradiaphragmatic total anomalous pulmonary venous drainage to portal vein is well described, hemianomalous drainage of right pulmonary veins to portal vein in Scimitar syndrome has not yet been reported.

Dysregulation of CITED2 in abnormal lung development in the nitrofen rat model.

PURPOSE: CITED2 both modulates lung, heart and diaphragm development. The role of CITED2 in the pathogenesis of congenital diaphragmatic hernia (CDH) is unknown. We aimed to study CITED2 during abnormal lung development in the nitrofen model. METHODS: Timed-pregnant rats were given nitrofen on embryonic day (E) 9 to induce CDH. Fetal lungs were harvested on E15, 18 and 21. We performed RT-qPCR, RNAscope™ in situ hybridization and immunofluorescence staining for CITED2. RESULTS: We observed no difference in RT-qPCR (control: 1.09 ± 0.22 and nitrofen: 0.95 ± 0.18, p = 0.64) and in situ hybridization (1.03 ± 0.03; 1.04 ± 0.03, p = 0.97) for CITED2 expression in E15 nitrofen and control pups. At E18, CITED2 expression was reduced in in situ hybridization of nitrofen lungs (1.47 ± 0.05; 1.14 ± 0.07, p = 0.0006), but not altered in RT-qPCR (1.04 ± 0.16; 0.81 ± 0.13, p = 0.33). In E21 nitrofen lungs, CITED2 RNA expression was increased in RT-qPCR (1.04 ± 0.11; 1.52 ± 0.17, p = 0.03) and in situ hybridization (1.08 ± 0.07, 1.29 ± 0.04, p = 0.02). CITED2 protein abundance was higher in immunofluorescence staining of E21 nitrofen lungs (2.96 × 109 ± 0.13 × 109; 4.82 × 109 ± 0.25 × 109, p < 0.0001). CONCLUSION: Our data suggest that dysregulation of CITED2 contributes to abnormal lung development of CDH, as demonstrated by the distinct spatial-temporal distribution in nitrofen-induced lungs.

Overactivated Epithelial NF-κB Disrupts Lung Development in Congenital Diaphragmatic Hernia.

Abnormal lung development is the main cause of morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH), a common birth defect (1:2,500) of largely unknown pathobiology. Recent studies discovered that inflammatory processes, and specifically NF-κB-associated pathways, are enriched in human and experimental CDH. However, the molecular signaling of NF-κB in abnormal CDH lung development and its potential as a therapeutic target require further investigation. Using sections and hypoplastic lung explant cultures from the nitrofen rat model of CDH and human fetal CDH lungs, we demonstrate that NF-κB and its downstream transcriptional targets are hyperactive during abnormal lung formation in CDH. NF-κB activity was especially elevated in the airway epithelium of nitrofen and human CDH lungs at different developmental stages. Fetal rat lung explants had impaired pseudoglandular airway branching after exposure to nitrofen, together with increased phosphorylation and transcriptional activity of NF-κB. Dexamethasone, the broad and clinically applicable antiinflammatory NF-κB antagonist, rescued lung branching and normalized NF-κB signaling in hypoplastic lung explants. Moreover, specific NF-κB inhibition with curcumenol similarly rescued ex vivo lung hypoplasia and restored NF-κB signaling. Last, we showed that prenatal intraperitoneal dexamethasone administration to pregnant rat dams carrying fetuses with hypoplastic lungs significantly improves lung branching and normalizes NF-κB in vivo. Our results indicate that NF-κB is aberrantly activated in human and nitrofen CDH lungs. Antiinflammatory treatment with dexamethasone and/or specific NF-κB inhibition should be investigated further as a therapeutic avenue to target lung hypoplasia in CDH.

Does Prediction of Neonatal Mortality by the Observed/Expected Lung-To-Head Ratio Change during Pregnancy in Fetuses with Left Congenital Diaphragmatic Hernia?

INTRODUCTION: The aim of this study was to evaluate prediction of neonatal mortality in fetuses with isolated left congenital diaphragmatic hernia (CDH) when the observed/expected lung-to-head ratio (O/E LHR) was estimated at two different gestational time points during pregnancy. METHODS: Forty-four (44) fetuses with isolated left CDH were included. O/E LHR was estimated at the time of referral (first scan) and before delivery (last scan). The main outcome was neonatal death due to respiratory complications. RESULTS: There were 10/44 (22.7%) perinatal deaths. The areas under (AU) the ROC curves were: first scan, 0.76, best O/E LHR cut-off 35.5% with 76% sensitivity and 70% specificity; last scan, AU-ROC 0.79, best O/E LHR cut-off 35.2%, with 79.0% sensitivity and 80% specificity. Considering an O/E LHR cut-off ≤35% to define high-risk fetuses at any examination, prediction for perinatal mortality showed: 80% sensitivity, 73.5% specificity, 47.1% positive and 92.6% negative predictive values, and 3.02 (95% CI 1.59-5.73) positive and 0.27 (95% CI 0.08-0.96) negative likelihood ratios. Prediction was similar in the two evaluations as 16/21 (76.2%) of fetuses considered at risk had an O/E LHR ≤35% in the two examinations; in the remaining 5 cases, two were identified only in the first and three only in the last scan. CONCLUSION: The O/E LHR is a good predictor of perinatal death in fetuses with left isolated CDH. Approximately 80% of fetuses at risk of perinatal death can be identified with an O/E LHR ≤35%, and 90% of them will have similar O/E LHR values at the first and at the last ultrasound examinations prior to delivery. In general, 88.6% of all CDH fetuses have a similar severity classification based on the O/E LHR at the first diagnostic ultrasound or at the ultrasound examination prior to delivery.

Dynamics of pulmonary hypertension severity in the first 48†h in neonates with prenatally diagnosed congenital diaphragmatic hernia.

Introduction: Pulmonary hypertension (PH) is one of the major contributing factors to the high morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). The severity and duration of postnatal PH are an established risk factor for patient outcome; however, the early postnatal dynamics of PH have not been investigated. This study aims to describe the early course of PH in CDH infants, and its relation to established prognostic markers and outcome measures. Methods: We performed a monocentric retrospective review of neonates with prenatally diagnosed CDH, who received three standardized echocardiographic examinations at 2-6 h, 24, and 48 h of life. The degree of PH was graded as one of three categories: mild/no, moderate, or severe PH. The characteristics of the three groups and their course of PH over 48 h were compared using univariate and correlational analyses. Results: Of 165 eligible CDH cases, initial PH classification was mild/no in 28%, moderate in 35%, and severe PH in 37%. The course of PH varied markedly based on the initial staging. No patient with initial no/mild PH developed severe PH, required extracorporeal membrane oxygenation (ECMO)-therapy, or died. Of cases with initial severe PH, 63% had persistent PH at 48 h, 69% required ECMO, and 54% died. Risk factors for any PH included younger gestational age, intrathoracic liver herniation, prenatal fetoscopic endoluminal tracheal occlusion (FETO)-intervention, lower lung to head ratio (LHR), and total fetal lung volume (TFLV). Patients with moderate and severe PH showed similar characteristics, except liver position at 24- (p = 0.042) and 48 h (p = 0.001), mortality (p = 0.001), and ECMO-rate (p = 0.035). Discussion: To our knowledge, this is the first study to systematically assess the dynamics of PH in the first postnatal 48 h at three defined time points. CDH infants with initial moderate and severe PH have a high variation in postnatal PH severity over the first 48 h of life. Patients with mild/no PH have less change in PH severity, and an excellent prognosis. Patients with severe PH at any point have a significantly higher risk for ECMO and mortality. Assessing PH within 2-6 h should be a primary goal in the care for CDH neonates.

Whole genome sequencing analysis of four patients: Are de novo copy number variations in non-coding region responsible for microtia with lung hypoplasia?

BACKGROUND: Microtia is a congenital malformation of the out ear, occurring either as an isolated defect or part of a specific pattern of multiple congenital anomalies. The etiology of microtia is poorly understood. Four patients with microtia and lung hypoplasia were reported by our team in a previous article. The purpose of this study was to identify the underlying genetic basis, mainly focusing on de novo copy number variations (CNVs) embedded in the noncoding region, in the four subjects. METHODS: DNA samples from all four patients and their unaffected parents were extracted for whole-genome sequencing on the Illumina platform. All variants were obtained through data quality control, variant calling and bioinformatics analysis. De novo strategy was used to prioritize the variants, and candidate variants were verified by PCR amplification combined with Sanger sequencing and visual inspection of bam file. RESULTS: Whole gene sequencing following bioinformatics analysis showed no potential de novo pathogenic variants in the coding region. Nonetheless, four de novo CNVs in the non-coding region, intronic or intergenic, were identified in each subject, ranging in size from 10 Kb to 12.5 Kb, and all are deletions. Case 1 had a de novo deletion of 10 Kb on chromosome10q22.3, located in the intronic region of the LRMDA gene. The other three cases all had a de novo deletion in intergenic regions, located on chromosome 20q11.21, 7q31.1 and 13q12.13, respectively. CONCLUSIONS: This study reported multiple long-lived cases of microtia with pulmonary hypoplasia and provided genome-wide genetic analysis focusing on de novo mutations. Whether the de novo CNVs identified are responsible for the rare phenotypes remains an open question. However, the results of our study provided a new perspective that the unsolved etiology of microtia might involve in non-coding sequences, which have long been ignored.

Fetal lung hypoxia and energetic cell failure in the nitrofen-induced congenital diaphragmatic hernia rat model.

PURPOSE: Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development. METHODS: To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1. RESULTS: The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase. CONCLUSION: Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

Pneumonectomy in an elderly patient with congenital unilateral lung hypoplasia and recurrent Aspergillus: a case report.

Background: Congenital lung disorders encompass a spectrum of several conditions, one of which is lung hypoplasia. While hypoplasia is typically identified and intervened upon in the neonatal period, some patients can remain asymptomatic or even be diagnosed as adults. Given the rarity of the condition persisting in adults though, it is not clear what medical or surgical interventions may be helpful if respiratory status declines. Case Description: In this report, we describe an elderly man with a history of right lung hypoplasia, pulmonary artery agenesis, and bronchial atresia who developed progressive dyspnea and worsening cough. His condition was complicated by multiple Aspergillus infections for which he received prolonged courses of anti-fungal therapy. He was also treated for bacterial pneumonia many times over a 10-year period. However, as his symptoms remained refractory to medical management, he underwent pneumonectomy, which revealed diffuse cystic changes in the right lung. He is currently doing well post-operatively with resolution of his dyspnea. Conclusions: Although hypoplastic lung disorders have been described in asymptomatic adults, this report highlights the successful utilization of pneumonectomy in an individual with refractory symptoms much later in adulthood. This case additionally describes possible complications of cystic lung disease in this patient population, serving as further rationale for aggressive intervention.

A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia.

Rationale: Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm and lung hypoplasia. The pathophysiology of lung defects in CDH is poorly understood. Objectives: To establish a translational model of human airway epithelium in CDH for pathogenic investigation and therapeutic testing. Methods: We developed a robust methodology of epithelial progenitor derivation from tracheal aspirates of newborns. Basal stem cells (BSCs) from patients with CDH and preterm and term non-CDH control subjects were derived and analyzed by bulk RNA sequencing, assay for transposase accessible chromatin with sequencing, and air-liquid interface differentiation. Lung sections from fetal human CDH samples and the nitrofen rat model of CDH were subjected to histological assessment of epithelial defects. Therapeutics to restore epithelial differentiation were evaluated in human epithelial cell culture and the nitrofen rat model of CDH. Measurements and Main Results: Transcriptomic and epigenetic profiling of CDH and control BSCs reveals a proinflammatory signature that is manifested by hyperactive nuclear factor kappa B and independent of severity and hernia size. In addition, CDH BSCs exhibit defective epithelial differentiation in vitro that recapitulates epithelial phenotypes found in fetal human CDH lung samples and fetal tracheas of the nitrofen rat model of CDH. Furthermore, blockade of nuclear factor kappa B hyperactivity normalizes epithelial differentiation phenotypes of human CDH BSCs in vitro and in nitrofen rat tracheas in vivo. Conclusions: Our findings have identified an underlying proinflammatory signature and BSC differentiation defects as a potential therapeutic target for airway epithelial defects in CDH.

A Fetus with 17q23.1-q23.2 Microdeletion Presents with Primary Bilateral Lung Hypoplasia in Utero.

Background:Patients with 17q23.1-q23.2 microdeletion syndrome have common features, including mild to moderate developmental delay; microcephaly; heart defects; and hand, foot, and limb abnormalities. Case Report: We describe a fetus with 2.14 Mb microdeletion involving 17q23.1-q23.2 and presenting with primary bilateral lung hypoplasia in utero. The fetal biometry measurement and estimated fetal weight had a two-week delay but they were still above the 10th percentile. There were no other structural abnormalities. Primary lung hypoplasia is infrequent and has a poor prognosis, especially when bilateral. There are no reports of fetal survival with primary bilateral lung hypoplasia. Conclusion: This is the first report of the coexistence of primary lung hypoplasia and chromosome 17q23.1-q23.2 microdeletion detected during fetal life.

A Rare Case of Lung Hypoplasia in a 1-Year-Old Girl.

Pulmonary hypoplasia is a rare form of the congenital disorder that leads to lung underdevelopment. It is more common in children and infrequently noticed in adulthood. While congenital lung abnormalities are frequently discovered in the early years of life, these conditions are also often detected incidentally following routine radiographic imaging and investigations. We report the case of a 1-year-old girl who presented to the emergency department with a three-day history of cough, shortness of breath, fever, and respiratory distress. Investigations revealed right lung hypoplasia, left lung hyperinflation, and an invisible pulmonary artery and vein. A diagnosis of right lung hypoplasia as an incidental finding with associated anomalies was made. She was admitted to the pediatric ward and received supportive care and empirical antibiotics. She was then discharged in a good condition with supportive management for follow-up. This case report aims to describe a rare condition occurring in children with various clinical pictures and presentations to aid future early detection to achieve better diagnostic outcomes.

Expected small left heart size in the presence of congenital diaphragmatic hernia: Fetal values and Z-scores for infants confirmed to have no heart disease postnatally.

Objectives: In fetuses with left-sided congenital diaphragmatic hernia (CDH), left heart structures may appear small, but usually normalize after birth in the absence of structural cardiac anomalies. To decrease the possibility of an erroneous diagnosis of structural heart disease, we identify normal values for left heart structures in the presence of left CDH and secondarily investigate the relationship of left heart size and survival to neonatal hospital discharge. Methods: Left heart structures [mitral valve (MV) and aortic valve (AoV) annulus diameter, left ventricle (LV) length and width] were measured by fetal echocardiogram in fetuses with left CDH and no congenital heart disease. We generated linear regression models to establish the relationship of gestational age for each left heart structure using data from fetuses who survived after birth. We calculated z-scores (normalized to gestational age), and assessed the relationship of survival to the size of each structure. Results: One hundred forty-two fetuses underwent fetal echocardiogram (median 25 weeks' gestation, IQR 23, 27 weeks). Left heart structures were deemed small when using published normative data from unaffected fetuses (z-scores: MV -1.09 ± 1.35, AoV -2.12 ± 1.16, LV length -1.36 ± 1.24, LV width -4.79 ± 0.79). CDH-specific models derived from log-transformed values yielded left-shifted distributions, reflecting the small structures (mean z-score lower by: MV 0.99 ± 0.30, AoV 2.04 ± 0.38, LV length 1.30 ± 0.36, and LV width 4.69 ± 0.28; p < 0.0001 for all comparisons). Non-survivors had worse z-scores than survivors for all measurements, but this did not reach statistical significance. Conclusions: Log-transformed linear models generated new normative data for fetal left heart structures in left CDH, which may be used to allay antenatal concerns regarding structural left heart anomalies. There were no significant differences in z-scores between survivors and non-survivors, suggesting that in the absence of true structural disease, cardiac evaluation is not predictive in isolation and that causes of mortality are likely multifactorial in this population.

Impact of fetal treatments for congenital diaphragmatic hernia on lung development.

The extent of lung hypoplasia impacts the survival and severity of morbidities associated with congenital diaphragmatic hernia (CDH). The alveoli of CDH infants and in experimental models of CDH have thickened septa with fewer type II pneumocytes and capillaries. Fetal treatments of CDH-risk preterm birth. Therefore, treatments must aim to balance the need for increased gas exchange surface area with the restoration of pulmonary epithelial type II cells and the long-term respiratory and neurodevelopmental consequences of prematurity. Achievement of sufficient lung development in utero for successful postnatal transition requires adequate intra-thoracic space for lung growth, maintenance of sufficient volume and appropriate composition of fetal lung fluid, regular fetal breathing movements, appropriate gas exchange area, and ample surfactant production. The review aims to examine the rationale for current and future therapeutic strategies to improve postnatal outcomes of infants with CDH.

Swyer-James syndrome: A cause of adult-onset dyspnea in a patient with adult polycystic kidney disease.

Swyer-James syndrome (SJS) is a rare lung condition characterized by abnormal lung growth secondary to childhood post-infectious bronchiolitis obliterans. Usually, one lung is affected more than the other leading to asymmetrical lungs with one lung being significantly smaller. The disease can lead to pulmonary obstructive airflow physiology, bronchiectasis, and fibrosis. Dyspnea usually presents early on in infancy and symptoms can mimic asthma, however, they can go unnoticed until adulthood. We present a case of SJS in a patient with adult polycystic kidney disease (ADPKD) and color vision deficiency. The patient presented to our clinic for evaluation for progressively worsening dyspnea and cough. His imaging revealed a hypoplastic left lung with fibrosis, cystic airway disease, and a small left pulmonary artery. His spirometry revealed an obstructive defect. A Ventilation-Perfusion scan (V/Q) showed a significant reduction of ventilation and perfusion to his left lung confirming the diagnosis of SJS. Both conditions - SJS and ADPKD-are not pathologically or genetically related and are very rare. Having both conditions is even rarer yielding interesting radiological imaging.

Unusual association of isolation of right pulmonary artery in absent pulmonary valve syndrome.

Absence of arterial duct, a sixth aortic arch derivative, plays an important etiologic role in Tetralogy of Fallot with absent pulmonary valve syndrome. When fetal ductus is absent, the large right ventricular stroke volume dilates the pulmonary trunk leading to pulmonary regurgitation. A proximal extension of the embryonic insult to the entire left sixth arch causes absence of the left pulmonary artery, a common association of absent pulmonary valve syndrome. On the contrary, absence of right pulmonary artery is not reported in absent pulmonary valve syndrome. A rare combination of tetralogy, absent pulmonary valve syndrome and isolation of a hypoplastic right pulmonary artery offered challenges to diagnosis and management.