Advances in Pediatric Pulmonology

Some 40 percent of individuals born with congenital diaphragmatic hernia (CDH) are affected by additional anomalies, including structural heart defects and musculoskeletal malformations. Indeed, anomalies of almost every organ also have been noted in association with CDH. Despite advances in improved prenatal diagnosis, fetal interventions, extracorporeal membrane oxygenation (ECMO), and gentle ventilation, CDH continues to be associated with at least 20 percent mortality and significant morbidity from related conditions. These include pulmonary hypertension and other respiratory complications, feeding difficulties, and neurocognitive deficits.

At NewYork-Presbyterian Morgan Stanley Children’s Hospital, the Congenital Diaphragmatic Hernia Clinic was established some 17 years ago, comprising a team of experts in a range of pediatric subspecialties who provide the highest level of care for children and support for families coping with this diagnosis. The CDH team is also actively involved in research that seeks to improve diagnosis, treatment, and long-term care. Columbia was among the first to study outcomes of patients who underwent CDH repair to help establish standardized follow-up care. The high-volume center enables the team to compile vast data to improve the understanding of long-term outcomes and help guide interventions.

Dr. Aliva De

“The CDH Clinic was originally spearheaded by pediatric surgeons, but today includes representatives from cardiology, gastroenterology, pulmonology, and genetics,” says Aliva De, MD, a pediatric pulmonologist at NewYork-Presbyterian Morgan Stanley Children’s Hospital and a member of the CDH team. “Our research has shined a light on new concepts and paradigms of mechanisms that can cause CDH and pulmonary disease manifestations.”

The Genetic Link in Pulmonary Development

Although the role of genetics in the pathogenesis of CDH is known, only a small number of disease-associated genes have been identified. In an effort to further understand the genetics of CDH, Columbia researchers took part in an international, multicenter study to analyze de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. Their findings, which were published in the October 7, 2021, issue of the American Journal of Human Genetics, identified LONP1 and ALYREF as candidate risk genes. The study also established LONP1 as a genome-wide significant candidate gene contributing to CDH risk through both de novo and inherited damaging variants.

The researchers found that individuals with CDH who have heterozygous ultra-rare damaging variants in LONP1 have clinical phenotypes that commonly include CDH or skeletal anomalies. They frequently require ECMO and have a higher mortality than the rest of the CDH cohort. In a mouse model with knockout of Lonp1 only in the embryonic lung epithelium and with an intact diaphragm, the researchers demonstrated reduced pulmonary growth and branching resulting in perinatal lethality. This finding suggests that the higher mortality rate and need for ECMO in humans is due to a primary effect of LONP1 on pulmonary development in addition to abnormal diaphragm development. Additionally, the study confirmed MYRF and ZFPM2 as genes associated with CDH.

The authors noted, “The identification of specific highly risk genes would enhance prenatal or early postnatal counseling and decision-making, especially with rapid turnaround of whole genome sequencing or exome sequencing results.”

“Traditional thinking was that the diaphragmatic hernia defect led to hypoplastic lungs or small lungs that brought other consequences over time,” says Dr. De. “But this research identified novel mutations in the genes of babies born with CDH showing that these specific mutations were more related to severe lung disease. This new knowledge has reversed our whole concept of the pulmonary manifestations in CDH. Children with CDH are already predisposed to having smaller lungs in addition to the effects of the hernia. However, these novel mutations, which are unique to this population, makes their pulmonary problems even worse.”

Dr. De believes this information is critically important for clinicians and pulmonologists in that it explains why some babies fare worse than others. “Having this knowledge available before birth is extremely helpful for clinicians in preparing for these deliveries,” says Dr. De. “It also impacts the future care of these newborns because they will require extra respiratory support and care.”

Optimizing Outcomes of Hernia Repair

Dr. De and her CDH Clinic colleagues recently presented the long-term outcomes of 193 patients who underwent CDH repair at NewYork-Presbyterian Morgan Stanley Children’s Hospital and discussed standardization of follow-up care. The study, which was published in the April 2022 issue of the Journal of Pediatric Surgery, is a retrospective review of patients followed from January 1, 2005, to December 1, 2020. Their findings showed:

• Left-sided defects were most common (75.7 percent), followed by right-sided defects (20.7 percent)
• Median age at repair was 4 days and 59.6 percent of all defects required patch repair
• Median length of stay was 29 days
• Median length of follow-up was 49 months with 25 patients followed for more than 12 years
• Long-term outcomes included:
  • gastroesophageal reflux disease (42.0 percent)
  • neurodevelopmental delay (28.6 percent)
  • asthma (23.6 percent)
  • chest wall deformity (15.5 percent)
  • scoliosis (11.4 percent)
  • diaphragmatic hernia recurrence (10.9 percent)
  • attention deficit hyperactivity disorder (7.3 percent)
  • inguinal hernia (6.7)
  • autism (1.6. percent)

According to Dr. De, some children with CDH may outgrow the need for respiratory support, however, they can still be prone to pulmonary deficits in the future and therefore should continue to be followed. “Surgery at birth is not the end of the story with CDH, and I think that’s important for physicians and community practitioners to recognize. They should continue to encourage parents to follow up with subspecialists,” she says.

Surgically Improving Lung Growth

Columbia pediatric surgeons will soon begin a study of an investigational surgical device that could potentially help to improve lung growth in utero. “Occluding the respiratory system in utero provides stimulus for the lungs to grow against that occlusion, which can help offset some of the pulmonary consequences after birth,” explains Dr. De. “The expectation is that the fetus’s lungs would be more developed at birth and their need for more intense respiratory support would be lessened. Some patients require ECMO and very sophisticated respiratory support that can perhaps be obviated by doing this procedure. We hope that the study demonstrates outcomes that support this procedure as a potential therapeutic option for the future.”

Importance of Ongoing Monitoring

The researchers agree that as survival of patients with CDH improves, long-term care must be continuously studied and fine-tuned to ensure appropriate surveillance and optimization of outcomes. “We also monitor for a recurrence, as these children can have relapses and future events can impact their pulmonary function,” says Dr. De. “It’s difficult to think of the human body in terms of isolated organ systems as there is so much overlap and blending of one system into the other. There also can be secondary effects of an initial problem. For example, a gastrointestinal issue, which is so common in this group of babies, can lead to secondary pulmonary effects such as aspiration and aspiration-related chronic lung injuries. Having a multidisciplinary clinic and being able to collaborate with each other helps us to make the best treatment decisions for our patients.”