Multidimensional Phenotype Classification in Grade 3 Bronchopulmonary Dysplasia

Bronchopulmonary Dysplasia (BPD), or chronic lung disease of prematurity, is the most consequential complication of preterm birth and is strong predictor of childhood pulmonary and neurodevelopmental disability, particularly in infants diagnosed with grade 3 BPD (ventilator dependence at 36 weeks' postmenstrual age), the most severe disease form. This study aims to (1) generate the first empirically defined phenotype classification system for grade 3 BPD developed using a rich array of objective and quantitative cardiopulmonary diagnostic, clinical, and biological data; and (2) define the association between phenotype subgroups and neurodevelopmental and respiratory outcomes through 2 years' corrected age.

Bronchopulmonary Dysplasia (BPD), or infant chronic lung disease, is the most consequential morbidity of prematurity. It affects \>50% of extremely preterm infants (\<30wk gestation) and can incur \>$1 million in costs per child. Among infants who develop grade 3 BPD (most severe grade, defined as invasive ventilation at 36 weeks' postmenstrual age), nearly 80% suffer life-long respiratory impairment and \>60% suffer severe developmental disability. Rates of grade 3 BPD are increasing and no proven therapies treat this disease. A key contributor to these gaps is the nearly singular reliance on the prescribed respiratory support to define BPD severity, select therapies, and assess prognosis. This subjective diagnostic approach masks heterogeneity in clinical presentation, treatment responsiveness, and outcomes. In other heterogenous lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and asthma, evidence-based phenotyping (identification of patient subgroups based on shared characteristics) objectively classifies disease sub-types, improves patient counseling, promotes discovery of novel pathological mechanisms, and leads to more effective, phenotype-targeted therapies. The central hypothesis of the present study is that deep, multidimensional phenotyping in grade 3 BPD is feasible with existing diagnostic technologies, will reliably characterize disease heterogeneity, and will improve outcome prediction. Confirmation of this hypothesis holds promise to promote a frameshift towards objective diagnostic approaches and first-of-their-kind phenotype-specific trials in infants with BPD.

Existing preliminary data support the feasibility of phenotyping in grade 3 BPD and suggest newer diagnostic techniques may improve disease characterization. Using data from lung computed tomography scan, cardiac echo, and bronchoscopy, researchers showed that preterm infants with grade 3 BPD can be classified into phenotypes based on the presence or absence of severe parenchymal lung disease, abnormal large airways, and pulmonary arterial hypertension. This classification scheme correlated with pre-discharge outcomes and suggested possible phenotype-specific therapies. Recent discoveries indicate that serial quantitative cardiopulmonary imaging and evaluation of mechanistic contributors to BPD including lung inflammation, gastroesophageal reflux, recurrent hypoxemia, and lung microbial dysbiosis may improve disease phenotyping and prediction of childhood neurodevelopmental and respiratory outcomes. This study builds on this information and uses multidimensional imaging, biological, and clinical data plus robust statistical techniques to propose an objective phenotype classification system for grade 3 BPD.

Enrolled infants will undergo baseline quantitative chest computed tomography with angiography (CTA), cardiac echocardiography, bronchoscopy with lavage, 24-hour esophageal pH-impedance testing, pulmonary mechanics testing, oximetry, and complete medical record review at enrollment. Repeat diagnostic testing will be performed 6-8wk later and cardiopulmonary monitoring and outcome data collected until discharge. These data will be used to empirically define phenotypes and assess phenotype stability. Enrolled participants will undergo validated neurodevelopmental and respiratory assessments through 2 years' corrected age. The diagnostic performance the empirically defined phenotype classification system for predicting 2 year outcomes will be determined.

Eligibility Criteria:
Inclusion Criteria (infant subjects):

* Male or female infant born with gestational age \<32 weeks
* Postmenstrual age between 36-65 weeks at enrollment
* Receiving invasive ventilation at enrollment
* Grade 3 BPD or grade 2 BPD with need for chronic invasive ventilation at enrollment
* Parental informed consent (provides the consent to participate)

Exclusion Criteria (infant subjects):

* Contraindication to 1 or more of the study diagnostic procedures
* Family unable/unlikely to commit to 2-year follow-up
* Unlikely to survive the 6-8-week diagnostic period
* Parental consent not provided (decline consenting for study)
* Aneuploidy or other severe congenital abnormality not-representative in BPD

At the time of consent, a parent or guardian caregiver will be invited to participate as an enrolled dyad using the following eligibility criteria:

Inclusion criteria (parents/guardians):

* Parent or legal guardian of an enrolled infant subject
* Informed consent

Exclusion criteria (parents/guardians):

* Unable/unlikely to complete study procedures