Project Summary Neonates can now survive premature birth from as early as 22 weeks’ gestation, but often suffer from bron- chopulmonary dysplasia (BPD) – chronic lung disease of prematurity. BPD consists of several phenotypes – hyperdense lung consisting of fibrotic tissue or inflammation, hyperinflated airspaces, and airway collapse at various levels from the upper airway to the distal airways. However, even if a patient’s phenotypes are identified, there is no mechanism to calculate the relative contributions of the phenotypes to disease severity and symp- toms. Therefore, the goal of this proposal is to create and validate a tool to calculate the contribution of each BPD phenotype. Such a tool would allow patient-specific treatment based on an individual’s disease phenotypes. To address this clinical need, this proposal will create a tool to calculate the contribution of each phenotype of BPD to elevated breathing effort. Breathing effort, known as the work of breathing (WOB), is comprised of elastic work, which is used to expand the lungs and chest wall, and resistive work, which is used to move air through the airways. Resistive work can be further broken down into where in the airways the resistance occurs, e.g., upper airway, trachea, etc. Each component of WOB is related to a specific phenotype of BPD: hyperdense lung tissue will result in increased elastic WOB; hyperinflated airspaces indicate increased resistive WOB in the distal airways; obstruction or collapse in the bronchi, trachea, or upper airway will result in increased resistive WOB in each specified region. Specific Aim 1 of this proposal will validate each of these relationships between compo- nents of WOB and phenotypes of BPD and Specific Aims 2 and 3 will assess how they change in response to two common treatments for BPD – the bronchodilator albuterol and steroids, respectively. This proposal is innovative in its use of a novel, neonate-specific magnetic resonance imaging (MRI) scanner, which can be sited within a neonatal intensive care unit, novel MRI reconstruction techniques to assess lung parenchymal health, and computational fluid dynamics (CFD) simulations to assess respiratory airflow and re- sistance throughout the airway tract. We anticipate this study will result in more personalized diagnosis of premature neonates’ respiratory disease and more precise use of drugs used to treat them. Neither albuterol or steroids are effective in all neonates and may cause harm in some patients; for example, albuterol can exacerbate tracheal collapse by relaxing the pos- terior tracheal membrane, while steroids pose neurodevelopmental risks. This study will identify which patients will benefit from these treatments. In the long-term, the tools created for this study will be translated to other respiratory diseases with multiple levels of airway obstruction and lung issues, in which the main cause of res- piratory distress is challenging to identify, and may be used to titrate respiratory support, demonstrating the significance of this proposal to older pediatric and adult medicine, in addition to the target neonatal population.

Project Narrative Babies who are born extremely prematurely suffer from bronchopulmonary dysplasia (BPD), a disease that is characterized by respiratory difficulties due to underdeveloped lungs and airways, and is responsible for $13 billion per year in healthcare costs. BPD has several different characteristics (overly dense lungs, overinflated lungs, collapse in various parts of the airway, etc.), and each characteristic may require different treatment, but understanding which characteristics are causing the respiratory difficulties in a specific patient is challenging. This study will calculate the effort that patients with BPD use to breathe (known as the work of breathing) and will determine the contribution of each characteristic of BPD to the work of breathing, revealing which character- istic(s) are the most beneficial to treat in each individual infant with BPD.