Proteomic Profiling of Hypoplastic Lungs Suggests an Underlying Inflammatory Response in the Pathogenesis of Abnormal Lung Development in Congenital Diaphragmatic Hernia.

The pathogenesis of lung hypoplasia in congenital diaphragmatic hernia (CDH), a common birth defect, is poorly understood. The diaphragmatic defect can be repaired surgically, but the abnormal lung development contributes to a high mortality in these patients. To understand the underlying pathobiology, we compared the proteomic profiles of fetal rat lungs at the alveolar stage (E21) that were either exposed to nitrofen in utero (CDH lungs, n=5) or exposed to vehicle only (non-CDH control lungs, n=5). Pathway analysis of proteomic datasets showed significant enrichment in inflammatory response proteins associated with cytokine signaling and Epstein Barr Virus in nitrofen CDH lungs. Among the 218 significantly altered proteins between CDH and non-CDH control lungs were Tenascin C, CREBBP, LYN, and STAT3. We showed that Tenascin C was decreased around the distal airway branches in nitrofen rat lungs and human CDH lungs, obtained from stillborn fetuses that did not receive pre- or postnatal treatment. In contrast, STAT3 was significantly increased in the airway epithelium of nitrofen lungs at E21. STAT3 inhibition after direct nitrofen exposure to fetal rat lung explants (E14.5) partially rescued the hypoplastic lung phenotype ex vivo by increasing peripheral lung budding. Moreover, we demonstrated that several STAT3-associated cytokines (IL-15, IL-9, andIL-2) are increased in fetal tracheal aspirates of CDH survivors compared with nonsurvivors after fetoscopic endoluminal tracheal occlusion. With our unbiased proteomics approach, we showed for the first time that downstream inflammatory processes are likely involved in the pathogenesis of abnormal lung development in CDH.

Congenital lung malformation patients experience respiratory infections after resection: A population-based cohort study.

PURPOSE: The benefit of elective resection of congenital lung malformations continues to be debated. Proponents of resection endorse a decreased risk of respiratory complications as one indication for surgery. Our study aimed to compare the prevalence of respiratory infections in cases, before and after resection of congenital lung malformations, to controls without a history of congenital lung malformation. METHODS: We performed a retrospective cohort study of children born from 1991 to 2007 who underwent congenital lung malformation resection. Patients were identified from Winnipeg´s Surgical Database of Outcomes and Management (WiSDOM), and a 10:1 date-of-birth matched control group was generated from a population-based administrative data repository. International Classification of Disease codes were used to assess pulmonary infection outcomes. Relative rates (RR) were calculated to compare the frequency of pneumonia, respiratory infections and influenza between cases and controls. RESULTS: We included 31 congenital lung malformation cases and 310 controls. Cases consisted of 14 (45.16%) congenital pulmonary airway malformations, 9 (29.03%) bronchopulmonary sequestrations and 8 (25.81%) hybrid lesions. Before resection, pneumonia was more common in cases than controls (RR 6.85; 95%CI 3.89, 11.9), while the risk of acute respiratory infections (RR 1.21; 95%CI 0.79, 1.79) and influenza (RR 0.46; 95%CI 0.01, 3.22) were similar to controls. Post-resection, the risk of pneumonia (RR 9.75; 5.06, 18.50) was still higher in cases than controls, and respiratory infections (RR 1.77; 95%CI 1.20, 2.53) and influenza (RR 3.98; 95%CI 1.48, 9.36) were more common in cases than controls. CONCLUSION: Our study demonstrated that after resection of congenital lung malformations, children experience more frequent respiratory infections compared to the general population. Resection does not eliminate the increased risk of pneumonia.

Educational outcomes in school age children with a history of isolated Hirschsprung disease are equivalent to their peers.

PURPOSE: The aim of this study was to assess real-world educational outcomes and developmental disorders in patients with a history of Hirschsprung disease compared to an age-matched control group. METHODS: With ethics approval (H2016:014) a retrospective cohort study of all children diagnosed with Hirschsprung disease at a single centre from 1992 to 2017 was performed. A 10:1 date-of-birth matched control cohort was constructed from a population-based directory. The educational outcomes were compared using the following measures: Early Developmental Instrument, Grades 3, 7, and 8 assessments, Grade 9 completion, Grade 9 performance, and high school graduation. Fisher's exact tests were used to compare the odds of failure between cases to controls. Only children who reached 4 years of age were included. RESULTS: A total of 75 cases with Hirschsprung disease patients were identified. Patients with Hirschsprung disease were at increased risk of failing to meet expectations on the Early Development Instrument. After entering elementary school, Hirschsprung patients were at no greater risk than their peers of failing to meet expectations on standardized testing or failing to graduate from high school. CONCLUSION: Using real-world measures of academic success as a surrogate for neurodevelopmental status, our study demonstrates that patients with a history of Hirschsprung disease demonstrated poor neurodevelopmental performance in pre-school, but the educational achievements of patients did not differ from controls once they started school. These promising data can be used to mitigate preconceived notions that patients with Hirschsprung disease require special education, which may be isolating and psychosocially damaging.