Dawn M. Simon

Endoscopic repair of laryngeal cleft type I and type II: When and why?

To evaluate the clinical features of children with type I and type II laryngeal cleft and the role of conservative monitoring versus endoscopic repair in their management.

Fibroblast Growth Factor Receptors Control Epithelial–Mesenchymal Interactions Necessary for Alveolar Elastogenesis

RATIONALE The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation. OBJECTIVES To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation. METHODS Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes. MEASUREMENTS AND MAIN RESULTS Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor-1, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology. CONCLUSIONS Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.

Lipid-Laden Macrophage Index Is Not an Indicator of Gastroesophageal Reflux-Related Respiratory Disease in Children

BACKGROUND. The lipid-laden macrophage index has been used to evaluate for gastroesophageal reflux-related respiratory disease, but the relationship between reflux detected by pH probe and the lipid-laden macrophage index is uncertain despite widespread use of the lipid-laden macrophage index in clinical decision-making. It was the aim of this study to correlate reflux as detected by multichannel intraluminal impedance with the lipid-laden macrophage index. METHODS. Patients undergoing both pH multichannel intraluminal impedance testing and bronchoscopy between January 2002 and January 2006 were identified. Baseline characteristics were compared by using parametric and nonparametric testing. Reflux profiles were correlated with the lipid-laden macrophage index by using Spearman correlations. RESULTS. There was no significant correlation between the lipid-laden macrophage index and the number of acid or nonacid reflux events. There also was no significant correlation between the lipid-laden macrophage index and the amount of full-column reflux. There was no significant difference between the mean lipid-laden macrophage index in patients with and without esophagitis. Finally, in patients who underwent fundoplication (n = 13) for intractable respiratory disease, there was no significant difference in any of the reflux parameters between patients who did and did not experience clinical improvement after fundoplication. There was, however, a higher lipid-laden macrophage index in patients with no symptomatic improvement compared with patients with symptomatic improvement. CONCLUSIONS. Lipid-laden macrophage index lacks the specificity necessary to detect reflux-related respiratory disease.

Use of flexible bronchoscopy in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support

Critically ill children treated with extracorporeal membrane oxygenation (ECMO) support frequently have respiratory complications amenable to evaluation by flexible bronchoscopy (FB). The safety and efficacy of FB in this setting has not been well described in children.

Role of PPARs and Retinoid X Receptors in the Regulation of Lung Maturation and Development

Understanding lung development has significant importance to public health because of the fact that interruptions in the normal developmental processes can have prominent effects on childhood and adult lung health. It is widely appreciated that the retinoic acid (RA) pathway plays an important role in lung development. Additionally, PPARs are believed to partner with receptors of this pathway and therefore could be considered extensions of retinoic acid function, including during lung development. This review will begin by introducing the relationship between the retinoic acid pathway and PPARs followed by an overview of lung development stages and regulation to conclude with details on PPARs and the retinoic acid pathway as they may relate to lung development.

Risk Factors for Development of Pulmonary Hypertension in Infants with Bronchopulmonary Dysplasia: Systematic Review and Meta-Analysis

OBJECTIVES Preterm infants with bronchopulmonary dysplasia (BPD) are at increased risk for development of Pulmonary Hypertension (PHT). We performed a systematic review and meta-analysis to identify risk factors for development of PHT in infants with BPD. STUDY DESIGN A systematic review identified risk factors for the development of PHT in infants with BPD. A meta-analysis of the pooled data was performed for each individual risk factor. RESULT Of the 20 risk factors identified, 10 were repeated more than once in nine studies. Meta analysis showed that duration of mechanical ventilation, length of stay, oligohydramnios, use of high frequency ventilation, small for gestational age, sepsis and severity of BPD were significant risk factors; while birth weight and gestational age were inversely related. CONCLUSION Several clinical variables are predictive of the development of PHT in infants with BPD. Prospective studies are needed to transform these risk factors into a risk-based scoring system.

Airway epithelial cell PPARγ modulates cigarette smoke-induced chemokine expression and emphysema susceptibility in mice.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent, chronic inflammatory lung disease with limited existing therapeutic options. While modulation of peroxisome proliferator-activating receptor (PPAR)-γ activity can modify inflammatory responses in several models of lung injury, the relevance of the PPARG pathway in COPD pathogenesis has not been previously explored. Mice lacking Pparg specifically in airway epithelial cells displayed increased susceptibility to chronic cigarette smoke (CS)-induced emphysema, with excessive macrophage accumulation associated with increased expression of chemokines, Ccl5, Cxcl10, and Cxcl15. Conversely, treatment of mice with a pharmacological PPARγ activator attenuated Cxcl10 and Cxcl15 expression and macrophage accumulation in response to CS. In vitro, CS increased lung epithelial cell chemokine expression in a PPARγ activation-dependent fashion. The ability of PPARγ to regulate CS-induced chemokine expression in vitro was not specifically associated with peroxisome proliferator response element (PPRE)-mediated transactivation activity but was correlated with PPARγ-mediated transrepression of NF-κB activity. Pharmacological or genetic activation of PPARγ activity abrogated CS-dependent induction of NF-κB activity. Regulation of NF-κB activity involved direct PPARγ-NF-κB interaction and PPARγ-mediated effects on IKK activation, IκBα degradation, and nuclear translocation of p65. Our data indicate that PPARG represents a disease-relevant pathophysiological and pharmacological target in COPD. Its activation state likely contributes to NF-κB-dependent, CS-induced chemokine-mediated regulation of inflammatory cell accumulation.

False-Positive Sweat Chloride Test in a Child with Pyelonephritis in a Single Kidney

683 for a nontoxic child with left costovertebral angle tenderness. Labs were significant for a blood urea nitrogen of 80 mg/dL (normal 5-25 mg/dL), creatinine of 2.3 mg/dL (normal 0.5-0.7 mg/dL), and C-reactive protein of 33.6 mg/dL (normal <1.0 mg/ dL). Urinalysis was positive for nitrites and leukocyte esterase, and microscopic evaluation revealed 50 white blood cells per high-powered field and 2+ bacteria. Urine culture was obtained. He was admitted to a community hospital, where treatment included fluid resuscitation, empiric treatment with intravenous cefepime and ampicillin, and antipyretic therapy with ibuprofen and acetaminophen. Past medical history included placement of tympanostomy tubes, bilateral branchial cleft cyst removal during the first year of life, and a tonsillectomy and adenoidectomy at 3 years. Family history revealed that his father had polycystic kidney disease. His older sister has recurrent urinary tract infections without evidence of vesicoureteral reflux. There was no family history of cystic fibrosis. A renal ultrasound revealed absence of the left kidney and hypertrophy of the right kidney at 9.4 cm in length (normal 7.5-8.5 cm). The right kidney was echogenic, but there was no evidence of hydronephrosis or abscess. The urine culture from the pediatrician’s office grew >100 000 colony forming units of Pseudomonas species. The urine culture result with Pseudomonas prompted the physician to obtain a sweat chloride test to evaluate for cystic fibrosis. The sweat chloride test was abnormal at 68 mmol/L. The patient continued to have daily fevers with intermittent vomiting despite completing 48 hours of antibiotic therapy. He was subsequently transferred to our tertiary care center for further management. Sweat chloride testing was repeated to confirm the results from the referring hospital. Adequate Sweat chloride determination remains the primary screening test for children suspected of having cystic fibrosis. There are a number of potential causes of false-positive results, including adrenal insufficiency and pseudohypoaldosteronism. The absence of aldosterone or an inability to respond to aldosterone prevents the cells of the sweat gland from reabsorbing sodium normally, which causes an elevation in sweat sodium and its accompanying anion, chloride. We report a case of a child with a transient false-positive sweat chloride test associated with pyelonephritis in a single kidney. We postulate that the false-positive test was due to hyporeninemic hypoaldosteronism.

Aicardi goutières syndrome is associated with pulmonary hypertension

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

Inhaled treprostinil via the Tyvaso Inhalation System through a tracheostomy

A 20-year-old man with pulmonary arterial hypertension secondary to systemic sclerosis was admitted to our hospital. Prior to admission, his PAH had been successfully managed with the use of tadalafil, ambrisentan and inhaled Tyvaso. Owing to respiratory failure from vocal cord paralysis, he underwent an emergent tracheotomy. The delivery of inhaled Tyvaso through a tracheostomy tube was explored. Post-tracheostomy, the patient continued his ability to self-administer the medication. His WHO functional classification, brain natriuretic peptide levels, and echocardiograms were not significantly different when Tyvaso was administered via tracheostomy compared with oral administration. This case report summarises the method used to deliver Tyvaso via a tracheostomy tube, which proved to be successful in this patient.