Multidimensional Phenotype Classification in Grade 3 Bronchopulmonary Dysplasia
- Conditions
- Bronchopulmonary Dysplasia
- Interventions
- Diagnostic Test: Chest computed tomography (CT) with angiographyDiagnostic Test: Bronchoscopy with bronchoalveolar lavageDiagnostic Test: EchocardiographyDiagnostic Test: 24 hour esophageal pH ("potential of hydrogen") - multichannel intraluminal impedance (MII) monitoring (reflux testing)
- Registration Number
- NCT06475976
- Lead Sponsor
- Children's Hospital of Philadelphia
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 130
Not provided
Not provided
Study & Design
- Study Type
- OBSERVATIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Diagnostic cohort Echocardiography Study participants will undergo the following diagnostic tests: Diagnostic cohort 24 hour esophageal pH ("potential of hydrogen") - multichannel intraluminal impedance (MII) monitoring (reflux testing) Study participants will undergo the following diagnostic tests: Diagnostic cohort Bronchoscopy with bronchoalveolar lavage Study participants will undergo the following diagnostic tests: Diagnostic cohort Chest computed tomography (CT) with angiography Study participants will undergo the following diagnostic tests:
- Primary Outcome Measures
Name Time Method Empirically defined phenotype subgroup Up to 26 months' corrected age The number and characteristics of phenotype subgroups will be empirically defined using cluster analyses applied to the collected cardiopulmonary diagnostic and clinical data. All recorded diagnostic and clinical information will be considered for inclusion in these analyses. Final study reports will indicate which diagnostic and clinical data were most associated with cluster classification. The strength of association between assigned cluster and neurodevelopmental and respiratory outcomes assessed through 26 months' corrected age will be defined.
- Secondary Outcome Measures
Name Time Method Mortality Up to 26 months' corrected age Death before anticipated 2 year follow-up
Health related quality of life Up to 26 months' corrected age Child health-related quality of life will be assessed using the Infant and Toddler Quality of Life Questionnaire Short Form (ITQOL-SF47). The ITQOL-SF47 has 47 questions and assesses domains such as the overall health, physical abilities, growth and development, bodily pain/discomfort, temperament and moods, general health perceptions, parent impact - emotional, parent impact - time and family cohesion with a score of 0 (worst) to 100 (best) for each of these domains.
Abnormal respiratory signs/symptoms Up to 26 months' corrected age Recent history of wheezing/whistling, limitations of daily activities due to wheezing, and persistent cough. This will be assessed using the International Study of Asthma and Allergies in Childhood (ISAAC) respiratory questionnaire which includes 6 questions based on the presence of wheeze, cough, night time respiratory signs, and limitations and activity.
Moderate to severe neurodevelopmental impairment (NDI) Up to 26 months' corrected age Moderate to severe NDI is a composite outcome that will be defined as the presence of one or more of the following outcomes at 22-26 month follow-up: Bayley Scale of Infant Development IV (BSID IV) cognitive score ≤84, Gross Motor Functional (GMF) level of 2-5, hearing deficit requiring amplification to understand commands or inability to understand commands despite amplification, blindness (\<20/200 vision) in one or both eyes based on visual acuity screening or medical history, and/or profound hearing loss (inability to understand commands despite amplification). The BSID is a standard series of developmental play tasks that are assessed by a trained clinician and takes between 45-60 minutes to complete. GMF is assessed using the 5-level Gross Motor Functional Classification System (GMFCS) that describes gross motor function on the basis of self initiated movement abilities.
Total problem behavior score Up to 26 months' corrected age Behavior difficulties will be assessed using the Child Behavior Checklist (CBCL) at 22-26 month follow-up. Parents/caregivers complete 100 questions from observations of their child's behaviors, using a 3-point scale (this behavior is: "not true", "somewhat true", "very or often true"). The mean and standard deviation is 50 ±10. Higher scores indicate increased behavioral problems. Estimated time to administer the CBCL is 10-15 minutes. The questions are grouped into Diagnostic and Statistical Manual (DSM) oriented scales (affective, anxiety, pervasive developmental, attention deficit/hyperactivity, and oppositional defiant problems). These scales are grouped into empirically based composite scales measuring internalizing and externalizing. These values will be aggregated to derive the total problem behavior score which will be the primary measure of child behavior difficulties for this study.
Moderate to severe respiratory compromise Up to 26 months' corrected age Moderate to severe respiratory compromise is a composite outcome that will be defined as one or more of the following:
* Tracheostomy placed any time between birth and 22-26 month follow-up
* home O2 therapy or positive airway pressure at 22-26 month follow-up
* ≥ 2 re-hospitalizations respiratory reasons - including viral respiratory infections through 22-26 month follow-up
* Respiratory medications (inhaled therapies, corticosteroids, diuretics) in the 3mo prior to 22-26 month follow-up.
* Home respiratory monitor (pulse oximeter, apnea monitor) use at 22-26 month follow-up.
Trial Locations
- Locations (1)
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States