Pulmonary Medicine Research
The Division of Pulmonary Medicine has an active research program, striving to understand the root causes and develop new treatments to improve the lives of children with lung diseases. Some of our active studies are briefly described below:
- Multicenter study of effects of surgery on mild sleep-disordered breathing without actual obstructive sleep apnea (MSDB). This study will evaluate the effects of adenotonsillectomy on behavior, attention, and healthcare utilization in children with MSDB, as well as identify subgroups that are most likely to benefit. Site-PI: Ignacio Tapia, MD
- Impact of surgery on OSAS in children with Beckwith-Wiedemann syndrome and 22q11.2 deletion syndrome, among others. PI: Christopher Cielo, DO
- Implementing evidence-based behavioral sleep intervention in urban primary care, with adaptations to lower-socio-economic status (SES) preschoolers. PI: Arielle Williamson, PhD
- Participation in Phase 3 trials in spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). The neuromuscular program has the largest population of patients receiving nusinersen (Spinraza®, Biogen), which has dramatically altered the respiratory and overall natural history of patients with SMA. Because of this broad experience, a manuscript focusing on the respiratory outcomes has been submitted for publication. Pulmonary PI: Oscar (Hank) Mayer, MD
- Active participation in many clinical trials through the Cystic Fibrosis Therapeutics Development Network. PI: Ronald Rubenstein MD, PhD
Other Studies in Sleep Medicine
- Cerebral blood flow and neurocognition in children with obstructive sleep apnea syndrome (OSAS), using a novel, noninvasive optical device to measure cerebral blood flow and other determinants of brain metabolism during wakefulness and sleep in children with OSAS and controls. PI: Ignacio Tapia, MD
- Mechanisms of OSAS and the use of MRI imaging to better understand structural contributors to OSAS in infants with micrognathia. PI: Christopher Cielo, DO
- Clinical and molecular risk factors for obstructive sleep apnea in children with Beckwith-Wiedemann syndrome. PI: Christopher Cielo, DO
Research in Lung Physiology
- Forced oscillation technique (FOT) for assessing lung function in preschoolers to assess now-preschool former preterm infants with respiratory distress who received steroids or placebo soon after birth. PI: Sara Demauro, MD, MSCE, CHOP Neonatologist, with pulmonary coinvestigators from CHOP, Cincinnati, Indianapolis, and Kansas City
- Using FOT to assess the effects of air quality on children’s lung health in Philadelphia and Beijing, China. This is a collaborative study with Beijing Children’s Hospital and the Penn Center for Environmental Toxicology. PI: Julian Allen, MD
- The forced oscillation technique measures, among other things, the resonant frequency, fo, of the respiratory system. Just as in musical instruments, in which the resonant frequency falls as the instrument size increases (that is, just as a cello has a lower fo than a viola, which in turn has a lower fo than a violin), the resonant frequency of the respiratory system falls as lung volume increases. Therefore, adults have a lower fo than children. Resonant frequency also falls as the stiffness, or elastance, of a system decreases. Thus, preschool children with asthma have a lower fo after inhalation of bronchodilator medication.
Changes in resonance frequency of musical instruments (right) and the respiratory system (left) with increasing volume.
- Howard Panitch, MD, has been working with members of the Pulmonary Hypoplasia Program to study the health outcomes of 8- to 13-year-old children born with lesions that result in lung hypoplasia, like congenital diaphragmatic hernia, giant omphalocele, or congenital pulmonary airway malformation (CPAM). Lung function data from 97 school-aged children are currently being analyzed. Another group of children with the same lung lesions is undergoing study of changes in ventilation with position, using a non-invasive technique called electrical impedance tomography.
- Our Cystic Fibrosis Center's multidisciplinary Cystic Fibrosis Related Diabetes (CFRD) Research Group investigates the mechanisms underlying the development of CFRD, including the mechanism(s) by which insulin secretion is impaired in CF. This group demonstrated that the CFTR modulator, Ivacaftor, when given for clinically approved indication, resulted in improved insulin secretion over a 3-month time period. These data were published in 2019 in the American Journal of Respiratory and Critical Care Medicine. PIs: Ronald Rubenstein, MD, PhD, Pulmonary, and Andrea Kelly, MD, MSCE, Endocrinology
- The CFRD Research Group has also recently received additional grant funding from the CF Foundation to investigate the mechanisms by which insulin secretion in people with CF is impaired in response to the gut incretin hormone GIP (Glucose-stimulated Insulinotropic Polypeptide). This work may lead to additional novel strategies to improve insulin secretion in people with CF and CFRD. PIs: Ronald Rubenstein, MD, PhD, Pulmonary, and Andrea Kelly, MD, MSCE, Endocrinology
Lymphatic Disorders and Genomics
- Discovery of a novel set of mutations in pulmonary patients with generalized lymphatic disorders, which is a foundation for a new therapeutic development program. A recurrent gain-of-function ARAF mutation was identified in a 12-year-old male with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another unrelated young adult patient. Primary endothelial cell studies showed the mutation altered VE-cadherin organization, which were fully reversed by inhibition of MEK signaling. Functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, and remodeling of the patient’s lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements, and near normalization of daily activities. Subsequent findings suggest that up to 20% of patients unresponsive to sirolimus therapy, may respond to MEK inhibitors. PI: Hakon Hakonarson, MD, PhD, Attending, Division of Pulmonary Medicine, and Director, Center for Applied Genomics; co-PIs: Jean Belasco, MD, Attending, Division of Oncology; and Yoav Dori, MD, PhD, Director, Center for the Lymphatic Imaging and Interventions