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.

Musculoskeletal deformities in children with congenital thoracic malformations: a population-based cohort study.

PURPOSE: It is unclear if musculoskeletal deformities observed in patients with congenital diaphragmatic hernia (CDH), congenital lung lesion (CLL) and esophageal atresia/tracheoesophageal fistula (EA/TEF) are associated with the anomaly or are a result of the surgery required to treat the anomaly. This study compared the prevalence of musculoskeletal deformities for: (1) children with congenital thoracic anomalies to controls; (2) CLL to EA/TEF both repaired via thoracotomy; and (3) CLL and EA/TEF to CDH repaired via laparotomy. METHODS: We performed a retrospective study of children with CLL, CDH or EA/TEF between 1990 and 2016. Date-of-birth-matched control groups were generated from a population-based dataset. International Classification of Disease codes were used to identify scoliosis and pectus anomalies. We determined Hazard ratios (HR) for cases versus controls. RESULTS: We included 167 cases (CDH n = 82; CLL n = 29; EA/TEF n = 56) and 1670 controls. EA/TEF had a greater risk of scoliosis (HR 5.52, 95%CI 1.49,13.73) and pectus deformities (HR 4.07, 95%CI 1.96,8.45). CDH showed more scoliosis (HR 5.03, 95%CI 1.99,12.74) but not pectus anomalies. Musculoskeletal deformities were not more common in CLL. CONCLUSION: Children born with CDH or EA/TEF, but not CLL, had more musculoskeletal deformities than controls. The inconsistent association between musculoskeletal deformities and the surgical approach suggested a congenital predisposition.

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.

Respiratory outcomes in the first 10 years of life in children with gastroschisis: A retrospective cohort study.

BACKGROUND: Little attention has been given to the long-term respiratory outcomes of children with gastroschisis. The purpose of this study was to determine if gastroschisis survivors have more respiratory illnesses in their first 10 years of life compared with age-matched controls. METHODS: We performed a retrospective cohort study of all gastroschisis children born in Manitoba between 1991 and 2017. Gastroschisis cases were identified from a clinical database, and a date of birth-matched control cohort was constructed from a population-based data repository. International Classification of Disease codes were used to compare the risk and frequency of respiratory diagnoses for children with gastroschisis to date of birth-matched controls from 0-5 years of age and 5-10 years of age. RESULTS: The 0-5 years of age analysis included 117 gastroschisis cases and 1205 date of birth-matched controls; children with gastroschisis had a higher risk of asthma (relative risk [RR] = 1.46; 95% confidence interval [CI]: 1.03, 2.55; p = .029), acute bronchitis/bronchiolitis (RR = 1.61; 95% CI: 1.27, 2.03; p < .001), pneumonia (RR = 1.99; 95% CI: 1.45, 2.72; p < .001), viral pneumonia (RR = 5.15; 95% CI: 1.79, 14.81; p = .007), and pneumonia due to unspecified organism (RR = 2.06; 95% CI: 1.45, 2.92; p < .001). Gastroschisis children 0-5 years of age were also diagnosed more frequently with bronchitis/bronchiolitis (RR = 2.14; 95% CI: 1.79, 2.57; p < .001) and viral pneumonia (RR = 8.10; 95% CI: 3.79, 17.31; p < .001). The 5-10 years of age analysis included 73 cases and 738 controls; no difference in the risk of respiratory illness was found for gastroschisis cases and controls in this age group. However, gastroschisis cases were more frequently diagnosed with bacterial pneumonia (RR = 3.03; 95% CI: 1.67, 5.51; p < .001) and influenza (RR = 3.03; 95% CI: 1.67, 5.51; p < .001). CONCLUSION: Our study shows that children with gastroschisis have an increased risk of asthma and respiratory infections compared with children without gastroschisis, most noticeably in the first 5 years of life.

The prevalence of hearing loss in children with congenital diaphragmatic hernia: A longitudinal population-based study.

BACKGROUND: The true prevalence of hearing loss among children with congenital diaphragmatic hernia (CDH) is unknown, with some studies reporting rates up to 60%. PURPOSE: The purpose of this study was to determine the prevalence of hearing loss among children with CDH and compare it to age-matched controls. METHODS: We used population-based datasets to compare the number of hearing loss diagnoses in children younger than 10 years-of-age born between 1992 and 2009 with CDH to date-of-birth matched controls without CDH. Factors associated with CDH disease severity were analyzed to determine their effect on the prevalence of hearing loss. A sensitivity analysis was performed to determine if selection bias of improved care over the course of the study affected hearing loss in CDH patients. The prevalences of hearing loss were compared using Fisher's exact tests and statistical significance was defined as p < 0.05. RESULTS: A total of 529 children, 38 CDH cases and their 491 date-of-birth matched controls, met the inclusion criteria. Hearing loss was found in 7 children with CDH (18.4%) compared to 26 (5.3%) controls; the risk ratio (RR) of hearing loss was 3.48 (95%CI = 1.61-7.49, p = 0.006). There was no association between CDH disease severity and hearing loss. CONCLUSIONS: CDH is associated with hearing loss compared to the general population. Our results suggest that congenital factors may contribute to hearing loss in CDH more than perinatal exposures. LEVEL OF EVIDENCE: 3.

High-frequency vs. conventional ventilation at the time of CDH repair is not associated with higher mortality and oxygen dependency: a retrospective cohort study.

PURPOSE: The VICI-trial reported that in patients with congenital diaphragmatic hernia (CDH), mortality or bronchopulmonary dysplasia (BPD) were equivalent using conventional mechanical ventilation (CMV) and high-frequency oscillatory ventilation. The purpose of this study was to determine if the mode of ventilation at the time of CDH repair affected mortality or oxygen dependence at 28 days. METHODS: We performed a retrospective cohort study of infants born wih CDH from 1991 to 2015. A generalized linear model was applied to the data using a propensity score analysis. RESULTS: Eighty patients met the inclusion criteria; at the time of surgery 39 (48.8%) patients were on HFV and 41 (51.3%) patients were on CMV. In the HFV group, 16 (47.1%) patients remained oxygen dependent and there were 5 (12.8%) deaths at 28 days. In the CMV group, 5 (12.2%) patients remained oxygen dependent at 28 days but none had died. The base model demonstrated that the HFV group had increased rates of oxygen dependence [OR = 6.40 (2.13, 22.2), p = 0.002]. However, after propensity score analysis, we found no difference between HFV and CMV. CONCLUSION: Our study suggests that in infants with CDH, there is no significant difference between HFV and CMV in oxygen dependency or death.

Long-Term Health-Related Quality of Life in Survivors of Congenital Diaphragmatic Hernia.

The health-related quality of life (HRQoL) of survivors of congenital diaphragmatic hernia (CDH) is presently unknown. Literature prior to 2015 suggests that CDH survivors have worse HRQoL compared with the general population. However, due to changes in the diagnosis, management, and follow-up of CDH patients, this may no longer be true. The objective of this review was to determine what recent literature suggests regarding the HRQoL of CDH survivors. We reviewed all studies published between April 9, 2015, and April 6, 2020, that described the HRQoL of CDH survivors. Studies were identified using PubMed, and the references of the identified papers were searched for additional studies eligible for inclusion. Seven studies describing HRQoL in CDH survivors using validated measures of HRQoL for children, PedsQL (Pediatric Quality of Life Inventory), KIDSCREEN-52, and Comprehensive Quality of Life Scale - School Version were examined. The findings were disparate. One study suggested that CDH survivors had better than average HRQoL scores, three studies found patients and controls had equivalent scores, and two studies reported poor outcomes for CDH patients. The final study found no effect of disease severity on HRQoL, as determined by prenatal ultrasound. Evidence published between 2015 and 2020 suggests that CDH patients have an HRQoL equivalent to the general population.

The presence of a hernia sac in isolated congenital diaphragmatic hernia is associated with less disease severity: A retrospective cohort study.

INTRODUCTION: We aimed to determine if the presence of a hernia sac in neonates with isolated congenital diaphragmatic hernia (CDH) was associated with better clinical outcomes. METHODS: We performed a retrospective cohort study of infants with isolated CDH from 1991 to 2015. Primary outcome measures were oxygen-dependence and mortality at 28 days. Secondary measures were: inhaled nitric oxide use, vasoactive medication use, ventilator support, and recurrence rates. RESULTS: Seventy-one patients met the inclusion criteria: 14 patients (19.7%) had a hernia sac, and 57 patients (80.3%) did not. Mortality did not differ between the 2 groups [0 of 14 versus 3 of 57 (5.3%) (p = 1.000)]. Hernia sac patients had similar oxygen-dependence after 28 days [1 of 14 (7.1%) versus 14 of 57 (24.6%) (p = 0.273)]. Hernia sac children required less iNO (0.64 ±â€¯2.41 vs. 6.35 ±â€¯12.2 days, p = 0.002), vasoactive medications (2.79 ±â€¯3.07 vs. 5.36 ±â€¯5.52, p = 0.027), and time on ventilation (7.62 ±â€¯6.12 vs. 15.9 ±â€¯19.2, p = 0.010). Hernia sac children had similar recurrence rates within 2 years [0 of 14 versus 7 of 57 (12.3%) (p = 0.331)]. CONCLUSION: The presence of a hernia sac was not associated with lower rates of oxygen dependency or death at 28 days but was associated with decreased inhaled nitric oxide, vasoactive medication, and ventilator use. LEVEL OF EVIDENCE: III.