Fellows Corner: Toward a Deeper Understanding of Neonatal Lung Disease

Jonathan Knowlton, MD PhD

Preterm infants born at less than 28 weeks gestation are exceedingly fragile due to the underdeveloped nature of every major organ system. Despite advances in neonatal intensive care that have improved survival in infants born at the thresholds of viability, the field has not made similar progress in improving rates of the most common morbidity associated with preterm birth: bronchopulmonary dysplasia (BPD).

BPD is a life-long chronic lung disease unique to preterm infants that is associated with abnormal and arrested lung development. Infants with BPD suffer from chronic respiratory failure that is associated with significant morbidity and mortality. Even after discharge from the hospital, infants with BPD are at a much higher risk of acute respiratory illnesses that frequently require rehospitalization.

The mechanisms underlying the pathophysiology of BPD are far from clear. Hypothesized drivers of BPD include prenatal factors such as preeclampsia, maternal environmental exposures, chorioamnionitis, and growth restriction, as well as postnatal factors, like exposure to high oxygen content, trauma from mechanical ventilation, malnutrition, and infections from pathogenic microorganisms. Because the pathogenesis of BPD is multifactorial, the disease manifests in heterogenous ways across individual infants, making management and treatment challenging. While personalized approaches to care are being sought, treatments targeting the underlying mechanisms of disease remain lacking and require further scientific and technological advances.

Normally, lung development in utero occurs in a sterile intra-amniotic environment. For infants born prematurely, microorganisms quickly colonize the upper respiratory tract. Moreover, intubation and mechanical ventilation, frequently required to support extremely premature infants, can introduce microbes into the lower respiratory tract. For chronically ventilated preterm infants, there is likely a steady exposure of the lower respiratory tract to microbial life. It is unclear how this collection of microorganisms that constitutes the airway microbiome affects ongoing lung development, although some early studies have identified microbial signatures unique to infants with severe BPD. Much remains to be discovered about the contribution of the airway microbiome to neonatal lung disease.

Role of bacteria and viruses in outcomes

While it is clear that in addition to the airway microbiome, specific microorganisms, commonly bacteria and viruses, can cause acute respiratory tract infections in hospitalized neonates. The incidence of respiratory tract infections in the NICU is variable, with younger gestational age and mechanical ventilation being important factors that increase infection risk. Bacterial and viral lung infections are associated with longer hospitalization and increased morbidity and mortality. Additionally, infectious lung disease early in life is a risk factor for future respiratory tract infections.

While it is clear that respiratory infections lead to worse clinical outcomes for infants born prematurely, the molecular mechanisms driving long-term changes to lung function remain poorly defined. I hope to begin answering these basic science questions through my work in the laboratory of Edward Morrisey, PhD, at the University of Pennsylvania. With a better understanding of how the lung fundamentally changes after infectious injuries during a developmentally sensitive period, we can begin to develop and test novel therapeutics to aid in tissue repair and ultimately improve the health of infants with BPD.

References and Suggested Reading

Jensen EA, Schmidt B. Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol. 2014;100(3):145-57.

Jobe AH. The new bronchopulmonary dysplasia. Curr Opin Pediatr. 2011;23(2):167-72.

Pammi M, Lal CV, Wagner BD, et al. Airway microbiome and development of bronchopulmonary dysplasia in preterm infants: a systematic review. J Pediatr. 2019;204:126-133.e2.

Pryhuber GS. Postnatal infections and immunology affecting chronic lung disease of prematurity. Clin Perinatol. 2015;42(4):697-718.