Alicia Casey

Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity

Impaired exercise capacity is common after the Fontan procedure and is attributed to cardiovascular limits. The Fontan circulation, however, is also distinctively vulnerable to unfavorable lung mechanics. This study aimed to define the prevalence and physiological relevance of pulmonary dysfunction in patients with Fontan physiology. We analyzed data from the Pediatric Heart Network Fontan Cross-Sectional Study to assess the prevalence and pattern of abnormal spirometry in Fontan patients (6-18 yr old) and investigated the relationship between low forced vital capacity (FVC) and maximum exercise variables, including peak O2 consumption (Vo2peak), among those who demonstrated adequate effort (n = 260). Average ages at the time of exercise testing and Fontan completion were 13.2 ± 3.0 and 3.5 ± 2.2 yr old, respectively. Aerobic capacity was reduced (Vo2peak: 67.3 ± 15.6% predicted). FVC averaged 79.0 ± 14.8% predicted, with 45.8% having a FVC less then the lower limit of normal. Only 7.8% demonstrated obstructive spirometry. Patients with low FVC had lower Vo2peak (64.4 ± 15.9% vs. 69.7 ± 14.9% predicted, P < 0.01); low FVC independently predicted lower Vo2peak after adjusting for relevant covariates. Among those with Vo2peak < 80% predicted (n = 204/260), 22.5% demonstrated a pulmonary mechanical contribution to exercise limitation (breathing reserve < 20%). Those with both low FVC and ventilatory inefficiency (minute ventilation/CO2 production > 40) had markedly reduced Vo2peak (61.5 ± 15.3% vs. 72.0 ± 14.9% predicted, P < 0.01) and a higher prevalence of pulmonary mechanical limit compared with patients with normal FVC and efficient ventilation (36.1% vs. 4.8%). In conclusion, abnormal FVC is common in young patients after the Fontan procedure and is independently associated with reduced exercise capacity. A large subset has a pathologically low breathing reserve, consistent with a pulmonary mechanical contribution to exercise limitation.

Expiratory Volumetric MDCT Evaluation of Air Trapping in Pediatric Patients With and Without Tracheomalacia

OBJECTIVE The purpose of this study was to use paired inspiratory-expiratory volumetric MDCT to compare the frequency, severity, and pattern of air trapping in pediatric patients with tracheomalacia with the findings in children without tracheomalacia. MATERIALS AND METHODS The study group consisted of 15 consecutively registered pediatric patients (younger than 18 years) who had tracheomalacia, defined as 50% or greater reduction in tracheal cross-sectional luminal area between end inspiration and end expiration, diagnosed with MDCT and confirmed with bronchoscopy. The comparison group consisted of 15 consecutively registered pediatric patients without evidence of tracheomalacia at MDCT and bronchoscopy. Two blinded pediatric radiologists working in consensus interpreted the randomly viewed end-expiratory thin-section CT images of both groups of children for the presence, severity, and pattern of air trapping at three anatomic levels (upper, middle, and lower lung zones). The severity of air trapping was graded visually on a 5-point scale. The total air trapping scores, obtained by summing the values for the three anatomic levels for the study and comparison groups, were compared by Wilcoxons rank sum test. The pattern of air trapping was categorized as lobular, segmental, lobar, diffuse, or mixed, and the patterns in the two study groups were compared by Pearsons chi-square test. RESULTS The study cohort with tracheomalacia consisted of 15 patients (10 boys, five girls; mean age, 2.4 +/- 2.8 years; range, 1 month-11.8 years). The comparison group without tracheomalacia consisted of 15 patients (nine boys, six girls; mean age, 2.7 +/- 2.4 years; range, 1 month-8.1 years). Air trapping was identified in all 15 patients with tracheomalacia (median score, 5.0; range, 3-11) and in 10 of 15 children (67%) in the comparison group (median score, 3.0; range, 1-4). The median total air trapping score was significantly higher in the study cohort than in the comparison group (p = 0.002), but there were no significant differences in the air trapping patterns between the study groups (p = 0.53). CONCLUSION Pediatric patients with tracheomalacia have a higher frequency and greater severity of air trapping than do children without tracheomalacia.

Bone Marrow-Derived Multipotent Stromal Cells Attenuate Inflammation in Obliterative Airway Disease in Mouse Tracheal Allografts

Obliterative bronchiolitis (OB) remains the most significant cause of death in long-term survival of lung transplantation. Using an established murine heterotopic tracheal allograft model, the effects of different routes of administration of bone marrow-derived multipotent stromal cells (MSCs) on the development of OB were evaluated. Tracheas from BALB/c mice were implanted into the subcutaneous tissue of major histocompatibility complex- (MHC-) disparate C57BL/6 mice. At the time of transplant, bone marrow-derived MSCs were administered either systemically or locally or via a combination of the two routes. The allografts were explanted at various time points after transplantation and were evaluated for epithelial integrity, inflammatory cell infiltration, fibrosis, and luminal obliteration. We found that the most effective route of bone marrow-derived MSC administration is the combination of systemic and local delivery. Treatment of recipient mice with MSCs suppressed neutrophil, macrophage, and T-cell infiltration and reduced fibrosis. These beneficial effects were observed despite lack of significant MSC epithelial engraftment or new epithelial cell generation. Our study suggests that optimal combination of systemic and local delivery of MSCs may ameliorate the development of obliterative airway disease through modulation of immune response.

Pharmacokinetics and safety of cavosonstat (N91115) in healthy and cystic fibrosis adults homozygous for F508DEL-CFTR

BACKGROUND Cavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators. METHODS A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects. RESULTS Cavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (-4.1mmol/L; P=0.032) at day 28. CONCLUSIONS The favorable safety and clinical profile warrant further study of cavosonstat in CF. ClinicalTrials.gov Numbers: NCT02275936, NCT02013388, NCT02500667.

Lung Pathology in Pediatric Pulmonary Vein Stenosis

Pulmonary vein stenosis is a rare progressive narrowing of the extrapulmonary pulmonary veins, presenting predominantly in infancy and virtually always lethal. It typically arises following repair of congenital heart disease, particularly anomalous pulmonary venous return. Histologic characterization of pediatric pulmonary vein stenosis, not previously well described, may provide insight into the disease pathobiology. We retrieved archival lung specimens (biopsy, explant, or autopsy) from patients with pediatric pulmonary vein stenosis. Medical records were reviewed. Microscopic examination included hematoxylin and eosin (H&E)–stained slides, and for a subset of patients, elastic, trichrome, smooth-muscle actin, and D2-40. Groups with different clinical disease features were compared using Fishers exact test. A total of 33 patients (median age, 7 months) had available tissue and 52% had congenital heart disease; 18% were premature. Within the lungs, interlobular septal veins showed thickened muscular coats (in 58%), proliferation/tortuosity (in 6%), and fibromyxoid intimal proliferation (in 3%). Associated arterial hypertensive changes were seen in 30 (91%). The one patient with intrapulmonary venous fibromyxoid intimal proliferation was the only patient with apparent primary familial disease. Lymphangiectasia and arterial medial hypertrophy were histologic features that correlated with clinical grouping. We conclude that in pediatric pulmonary vein stenosis, intrapulmonary pulmonary veins commonly show muscular thickening, best interpreted as venous hypertensive remodeling. Fibromyxoid intimal proliferation resembling that of the extrapulmonary pulmonary veins is uncommon. Awareness of intrapulmonary features in various clinical subtypes of pulmonary vein stenosis may be diagnostically and therapeutically informative considering that current catheter-based and surgical therapy is directed at the extrapulmonary component of pulmonary vein stenosis.

Impact of Cilia Ultrastructural Examination on the Diagnosis of Primary Ciliary Dyskinesia

Ultrastructural examination of cilia is the “gold standard” for diagnosing primary ciliary dyskinesia. There is little evidence suggesting the most effective method of procuring a ciliary biopsy and scant benchmark data on rates of conclusive biopsies or on the diagnostic impact of such biopsies. To critically assess rates of inconclusive, positive, and negative ciliary biopsies and to identify clinical factors associated with conclusive results, we reviewed ciliary biopsies submitted for electron microscopy from 2006 to 2011, noting whether specimens were adequate for analysis and whether the ciliary structure was normal. The biopsy site, method used, procedurists specialty, and clinical diagnoses were determined. Biopsy findings were categorized by diagnostic impact. Over 5 years, 187 patients had 211 biopsies. Conclusive results were obtained on 133/211 biopsies (63%); the remainder were insufficient. The rate of inconclusive biopsies did not vary significantly (P > 0.05; Fishers exact) among sampling methods. Abnormal results were identified in 8/133 (6.0%) of the adequate specimens. Forceps compared to brush biopsies (abnormal in 4/12 versus 4/121 of the adequate specimens, P = 0.002), along with multiple biopsy samples (taken on same or different days) compared with a single biopsy sample (abnormal in 3/12 versus 1/110 of the adequate specimens, P = 0.01), were more likely to yield an abnormal result. Only 63% of pediatric ciliary biopsies provide adequate morphology for analysis, the large majority of these samples showing normal ciliary anatomy. The method of obtaining biopsies did not significantly affect result conclusiveness. Understanding the diagnostic impact of ultrastructural analysis is important as new diagnostic algorithms are developed for primary ciliary dyskinesia.

Chest radiographic and CT evaluation of lung abnormalities in pediatric patients with laryngeal cleft

The purpose of this study was to (1) evaluate chest radiography (CR) and computed tomography (CT) findings in pediatric patients with laryngoscopically confirmed laryngeal cleft and (2) determine whether CT provided additional information over CR in evaluating lung abnormalities in pediatric patients with laryngeal cleft.

Current Update on Interstitial Lung Disease of Infancy: New Classification System, Diagnostic Evaluation, Imaging Algorithms, Imaging Findings, and Prognosis.

Childhood interstitial lung disease represents a rare and heterogeneous group of diseases that can result in significant morbidity and mortality, some leading to death during infancy. CT is the imaging test of choice. Although many CT findings are nonspecific and a definitive diagnosis usually cannot be reached by CT alone, the interpreting radiologist is instrumental in defining disease extent and refining the diagnosis. Chest CTs are of key importance in guiding site selection for lung biopsy and for following disease progression and response to treatment. Thus, from the radiologists perspective, ensuring maximal quality of CT imaging and interpretation is paramount.

Pulmonary hemorrhage in infancy: A 10-year single-center experience

Pulmonary hemorrhage in infancy is rare, with challenges in determining its incidence, causes, and outcomes across diverse groups. Our aim was to better understand the incidence and identified causes. We further analyzed the subgroup of patients meeting criteria for acute idiopathic pulmonary hemorrhage of infancy (AIPHI) to determine recurrence, mortality, and treatment.

ATS Core Curriculum 2017: Part II. Pediatric pulmonary medicine series editor: Jason T. Poston Part II Editors: Paul E. Moore and Jessica Pittman

Paul E. Moore, Jason T. Poston, Debra Boyer, Emily Barsky, Jonathan Gaffin, Kathleen B. Boyne, Kristie R. Ross, Laura Beth Mann Dosier, Timothy J. Vece, Alicia M. Casey, Sebastian K. Welsh, J. Wells Logan, Edward G. Shepherd, Pelton A. Phinzy, Howard B. Panitch, Christina M. Papantonakis, Eric D. Austin, Amir B. Orandi, Maleewan Kitcharoensakkul, Mark K. Abe, Amjad Horani, Jordan S. Rettig, and Jessica Pittman Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Pulmonary and Critical Care Medicine, Department of Medicine, and Section of Critical Care, Department of Pediatrics, University of Chicago, Chicago, Illinois; Division of Respiratory Diseases and Division of Critical Care Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts; Rainbow Babies and Children’s Hospital, Case Western Reserve University, Cleveland, Ohio; Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina; Division of Pediatric Pulmonology, University of North Carolina–Chapel Hill, Chapel Hill, North Carolina; Division of Neonatology, Nationwide Children’s Hospital, Columbus, Ohio; Division of Pulmonary Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; and Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri