Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

The history of workforce concerns in pediatric pulmonary Medicine.

Children are affected by a broad spectrum of acute and chronic respiratory disorders. The number of children with respiratory disease is increasing, as are the complexity of disease pathophysiology and the management demands on pediatric pulmonologists. Despite slowly increasing numbers of board-certified pediatric pulmonologists, large areas of the country are underserved and there is a perception of an impending workforce crisis. There are multiple reasons for these concerns. A joint effort between the Pediatric Pulmonology Division Directors Association and Pediatric Pulmonary Training Directors Association was undertaken to address these issues.

The chronically critically ill patient: pediatric considerations.

Whether defined as chronically critically ill, long-term mechanical ventilator dependent (or otherwise chronically medically supported), or medically fragile, a population of infants and children with chronic illness clearly exists. Infants and children with chronic healthcare needs are at an increased risk for physical, developmental, behavioral, and/or emotional conditions and generally require healthcare services of a type or amount beyond that of a general pediatric or adult population. This review will focus on the specific management and psychosocial needs associated with the healthcare of this subgroup of infants and children with chronic illness. Attention will be paid to defining the population, describing trends over time, reviewing their special needs, and discussing outcomes. Increased focus and an increasing quantity of resources for this subgroup of infants and children are needed, as the number of such pediatric patients continues to grow.

Extracorporeal membrane oxygenation for severe refractory respiratory failure secondary to 2009 H1N1 influenza A.

BACKGROUND: Respiratory failure and acute respiratory distress syndrome secondary to H1N1 influenza infection is a source of substantial morbidity and mortality, having caused over 265,000 hospitalizations in the United States in 2009. During the H1N1 pandemic, up to 31% of the H1N1 patients required intensive care unit admission, and many were refractory to maximal conventional therapies. These most critically ill patients may require extracorporeal membrane oxygenation (ECMO) for survival. METHODS: We retrospectively reviewed the medical records of the 7 patients with refractory hypoxemia due to H1N1 influenza who were treated with ECMO in our pediatric intensive care unit. RESULTS: Five of the 7 patients survived to hospital discharge. The cohort's mean age was 21 years, and 4 were female. At admission to the pediatric intensive care unit, 6 had at least one comorbid condition, 6 were mechanically ventilated, and one was in shock. All 7 patients were treated with oral oseltamivir, high-frequency oscillatory ventilation, and inhaled nitric oxide prior to ECMO. Five received intravenous steroids, and 2 were treated with compassionate-use intravenous zanamivir. The mean duration of pre-ECMO ventilation was 8.7 days (range 14 h to 25 d). Mean oxygenation index was 50 (range 26-73) at ECMO cannulation. Six received venovenous ECMO, and one received venoarterial ECMO. The mean duration of ECMO was 432 hours (range 192-890 h). CONCLUSIONS: This series suggests that ECMO is a viable treatment for refractory hypoxemia secondary to H1N1 influenza infection in both pediatric and adult patients.

Correlation between the clinical severity of laryngomalacia and endoscopic findings.

OBJECTIVE: To correlate the clinical severity of laryngomalacia (LM) with endoscopic findings, swallowing evaluations and polysomnography in a cohort of patients. Method: We conducted a retrospective analysis between 2017-2018 on a cohort of patients diagnosed with upper airway obstruction (UAO), stridor, noisy breathing or laryngomalacia. This study took place at the Pediatric Pulmonology Department, Riley Children's Hospital, Indianapolis, United States of America. RESULTS:   There were 157 patients with laryngomalacia included in the study. Patients with severe LM were significantly younger than those with mild LM (p=0.0214) and moderate LM (p=0.0220). Subjects with type I of LM were significantly older than type III (p=0.0051). When associations were tested between polysomnogram (PSG) variables and clinical severity, there were significant associations with age at PSG. The overall apnea-hypopnea index (AHI) in mild (p=0.0103) and moderate (p=0.0242) were significantly lower than the severe group. The rapid eye movement (REM) AHI was significantly lower in moderate cases than severe (p=0.0134). The end-tidal carbon dioxide (EtCO2) peak was significantly lower in mild cases than severe (p=0.0141). The total sleep time (TST) peripheral capillary oxygen saturation (SpO2) 90% occurs in both mild (p=0.0197) and moderate (p=0.0498) were significantly lower than the severe group. CONCLUSIONS: The severity of the clinical manifestations of LM did not correlate with the different endoscopic types in our study. The presence of cyanosis was associated with type III LM. Rapid eye movement AHI and EtCO2 in polysomnogram were remained significantly associated with clinical severity.

In children, the microbiota of the nasopharynx and bronchoalveolar lavage fluid are both similar and different.

RATIONALE: Sputum and bronchoalveolar lavage fluid (BALF) are often obtained to elucidate the lower airway microbiota in adults. Acquiring sputum samples from children is difficult and obtaining samples via bronchoscopy in children proves challenging due to the need for anesthesia and specialized procedural expertise; therefore nasopharyngeal (NP) swabs are often used as surrogates when investigating the pediatric airway microbiota. In adults, the airway microbiota differs significantly between NP and BALF samples however, minimal data exist in children. OBJECTIVES: To compare NP and BALF samples in children undergoing clinically indicated bronchoscopy. METHODS: NP and BALF samples were collected during clinically indicated bronchoscopy. Bacterial DNA was extracted from 72 samples (36 NP/BALF pairs); the bacterial V1-V3 region of the 16S rRNA gene was amplified and sequenced on the Illumina Miseq platform. Analysis was performed using mothur software. RESULTS: Compared to NP samples, BALF had increased richness and diversity. Similarity between paired NP and BALF (intra-subject) samples was greater than inter-subject samples (P = 0.0006). NP samples contained more Actinobacteria (2.2% vs 21%; adjusted P = 1.4 × 10-6 ), while BALF contained more Bacteroidetes (29.5% vs 3.2%; adjusted P = 1.2 × 10-9 ). At the genus level several differences existed, however Streptococcus abundance was similar in both sample types (NP 37.3% vs BAL 36.1%; adjusted P = 0.8). CONCLUSION: Our results provide evidence that NP samples can be used to distinguish differences between children, but the relative abundance of organisms may differ between the nasopharynx and lower airway in pediatric patients. Studies utilizing NP samples as surrogates for the lower airway should be interpreted with caution.

Survey of clinical infant lung function testing practices.

BACKGROUND: Data supporting the clinical use of infant lung function (ILF) tests are limited making the interpretation of clinical ILF measures difficult. OBJECTIVES: To evaluate current ILF testing practices and to survey users regarding the indications, limitations and perceived clinical benefits of ILF testing. METHODS: We created a 26-item survey hosted on the European Respiratory Society (ERS) website between January and May 2010. Notifications were sent to members of the ERS, American Thoracic Society and the Asian Pacific Society of Respirology. Responses were sought from ILF laboratory directors and pediatric respirologists. The survey assessed the clinical indications, patient populations, equipment and reference data used, and perceived limitations of ILF testing. RESULTS: We received 148 responses with 98 respondents having ILF equipment and performing testing in a clinical capacity. Centers in North America were less likely to perform ≥50 studies/year than centers in Europe or other continents (13% vs. 41%). Most respondents used ILF data to either "start a new therapy" (78%) or "help decide about initiation of further diagnostic workup such as bronchoscopy, chest CT or serological testing" (69%). Factors reported as limiting clinical ILF testing were need for sedation, uncertainty regarding clinical impact of study results and time intensive nature of the study. CONCLUSIONS: Clinical practices associated with ILF testing vary significantly; centers that perform more studies are more likely to use the results for clinical purposes and decision making. The future of ILF testing is uncertain in the face of the limitations perceived by the survey respondents.

A 2-year-old girl with co-inherited cystic fibrosis and sickle cell-ß+ thalassemia presenting with recurrent vaso-occlusive events during cystic fibrosis pulmonary exacerbations: a case report.

INTRODUCTION: This is the first published report of a young girl with co-inherited sickle cell-ß+ thalassemia and cystic fibrosis. Although a small subset of patients with co-inherited cystic fibrosis and other hemoglobinopathies have been reported, this patient developed early hematologic and pulmonary complications that were more severe than the previous cases. To assess pulmonary co-morbidities, we used infant pulmonary function testing through the raised volume rapid thoracoabdominal compression technique as both an established study of early cystic fibrosis and also as a newer study of mechanism for early sickle cell lung disease. This further serves as the first report of the raised volume rapid thoracoabdominal compression technique to determine raised volume forced expiratory flows and fractional lung volumes in a patient with a hemoglobinopathy. CASE PRESENTATION: A 2-year-old African-American girl with co-inherited cystic fibrosis and sickle cell-ß+ thalassemia developed severe hematologic complications (recurrent vaso-occlusive events, hepatic sequestration, and acute chest syndrome) during periods of cystic fibrosis pulmonary exacerbations and weight loss. Because cystic fibrosis and sickle cell-ß+ thalassemia both confer distinct patterns of pulmonary disease, infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique was used to define respiratory pathophysiology and guide treatment options. Infant pulmonary function testing data demonstrated moderate-to-severe lower airways obstruction, moderate air trapping, and no evidence of restrictive lung disease. CONCLUSIONS: Infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique guided therapy in this patient with cystic fibrosis and sickle cell-ß+ thalassemia. Although this is an original case report on a unique patient, this case highlights the need to evaluate early respiratory pathophysiology in a broader population of young patients with hemoglobinopathies and screen those at risk for early pulmonary co-morbidities.

Association of lower airway inflammation with physiologic findings in young children with cystic fibrosis.

BACKGROUND: The relationship between lower airway markers of inflammation and infection with physiologic findings is poorly understood in young children with cystic fibrosis (CF). The goal of this study was to evaluate the association of bronchoalveolar lavage fluid (BALF) markers of infection and inflammation, including mediators linked to airway remodeling, to infant lung function values in young children with CF undergoing clinically indicated bronchoscopy. METHODS: Plethysmography and the raised volume rapid thoracoabdominal compression (RVRTC) technique were performed in 16 sedated infants and young children with CF prior to bronchoscopy. BALF was collected and analyzed for pathogen density, cell count, % neutrophils, transforming growth factor beta 1 (TGF-beta(1)), matrix metalloproteinases (MMP), and interleukin-8 (IL-8). RESULTS: There was a significant direct correlation between functional residual capacity (FRC), the ratio of residual volume to total lung capacity (RV/TLC) and FRC/TLC with % neutrophils (P < 0.05). Forced expiratory flows were inversely correlated to % neutrophils (P < 0.01). Lung function parameters did not differentiate those with and without lower airway infection; however, pathogen density directly correlated with FRC and inversely correlated with flows (P < 0.05). In a subset of the population, MMP-2 directly correlated with RV/TLC and inversely correlated with flows (P < 0.05) and TGF-beta(1) directly correlated with FRC (P < 0.05). CONCLUSIONS: Results from this study suggest that lower airway inflammation as well as mediators linked to airway remodeling play an active role in pulmonary deterioration in CF infants and young children undergoing clinically indicated bronchoscopy.