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.
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
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)
This study will enroll male and female infants born very premature and who are receiving prolonged invasive ventilation at the time of study enrollment between 36 and 65 weeks postmenstrual age for high grade (2 or 3) bronchopulmonary dysplasia. A parent or guardian caregiver will be enrolled as a dyad with the enrolled infant to facilitate collection of parental stress index data through 2 year follow-up.
Cohort
Prospective
Chest computed tomography (CT) with angiography
Diagnostic testA CT scan uses a doughnut-shaped machine to take x-rays in a circle around the body. CT scans help doctors learn about the structure of the lungs, heart, and blood vessels in the chest. A CT scan provides more information than regular x-rays. CT w/angiography - injection of intravenous contrast during the CT to image the blood vessels within the chest.
Bronchoscopy with bronchoalveolar lavage
Diagnostic testDuring a bronchoscopy, a lung doctor inserts a small flexible camera into the breathing tube and main branches of the airways within the lungs. During the test, a small amount of sterile fluid is placed into the lung and then retrieved (lavage). This fluid is tested for evidence of infection.
Echocardiography
Diagnostic testAn echo uses sound waves to create computer pictures of the heart.
24 hour esophageal pH ("potential of hydrogen") - multichannel intraluminal impedance (MII) monitoring (reflux testing)
Diagnostic test24 hour pH/MII testing is used to measure gastroesophageal reflux. A small feeding tube like catheter is passed through the nose or mouth into the esophagus. The catheter is used to measure the frequency and acidity of reflux episodes during a 24 hour monitoring period.
Empirically defined phenotype subgroup
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.
Moderate to severe neurodevelopmental impairment (NDI)
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
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.
Health related quality of life
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
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.
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Children's Hospital of Philadelphia
Lead sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborator
