Deborah R. Liptzin

The polymeric mucin Muc5ac is required for allergic airway hyperreactivity

In asthma, airflow obstruction is thought to result primarily from inflammation-triggered airway smooth muscle (ASM) contraction. However, anti-inflammatory and smooth muscle-relaxing treatments are often temporary or ineffective. Overproduction of the mucin MUC5AC is an additional disease feature that, while strongly associated pathologically, is poorly understood functionally. Here we show that Muc5ac is a central effector of allergic inflammation that is required for airway hyperreactivity (AHR) to methacholine (MCh). In mice bred on two well-characterized strain backgrounds (C57BL/6 and BALB/c) and exposed to two separate allergic stimuli (ovalbumin and Aspergillus extract), genetic removal of Muc5ac abolishes AHR. Residual MCh responses are identical to unchallenged controls, and although inflammation remains intact, heterogeneous mucus occlusion decreases by 74%. Thus, whereas inflammatory effects on ASM alone are insufficient for AHR, Muc5ac-mediated plugging is an essential mechanism. Inhibiting MUC5AC may be effective for treating asthma and other lung diseases where it is also overproduced.

Sex and the lung: Observations, hypotheses, and future directions

Sex‐related differences in a variety of lung diseases in infants and young children are reviewed, including respiratory distress syndrome, and chronic lung disease of prematurity, lower respiratory tract illnesses and wheezing, asthma, diffuse, and interstitial lung diseases, and cystic fibrosis. Differences in anatomy and physiology, such as airway size, airway muscle bulk, airway reactivity, airway tone, and cough reflexes may explain much of these sex differences. Better understanding of sex‐related lung differences could help personalize respiratory treatment. Pediatr Pulmonol. 2015; 50:1159–1169.

Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme

RATIONALE Childrens Interstitial and Diffuse Lung Disease (chILD) is a heterogeneous group of disorders that is challenging to categorize. In previous study, a classification scheme was successfully applied to children 0 to 2 years of age who underwent lung biopsies for chILD. This classification scheme has not been evaluated in children 2 to 18 years of age. OBJECTIVES This multicenter interdisciplinary study sought to describe the spectrum of biopsy-proven chILD in North America and to apply a previously reported classification scheme in children 2 to 18 years of age. Mortality and risk factors for mortality were also assessed. METHODS Patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease from 12 North American institutions were included. Demographic and clinical data were collected and described. The lung biopsies were reviewed by pediatric lung pathologists with expertise in diffuse lung disease and were classified by the chILD classification scheme. Logistic regression was used to determine risk factors for mortality. MEASUREMENTS AND MAIN RESULTS A total of 191 cases were included in the final analysis. Number of biopsies varied by center (5-49 biopsies; mean, 15.8) and by age (2-18 yr; mean, 10.6 yr). The most common classification category in this cohort was Disorders of the Immunocompromised Host (40.8%), and the least common was Disorders of Infancy (4.7%). Immunocompromised patients suffered the highest mortality (52.8%). Additional associations with mortality included mechanical ventilation, worse clinical status at time of biopsy, tachypnea, hemoptysis, and crackles. Pulmonary hypertension was found to be a risk factor for mortality but only in the immunocompetent patients. CONCLUSIONS In patients 2 to 18 years of age who underwent lung biopsies for diffuse lung disease, there were far fewer diagnoses prevalent in infancy and more overlap with adult diagnoses. Immunocompromised patients with diffuse lung disease who underwent lung biopsies had less than 50% survival at time of last follow-up.

Chronic ventilation in infants with surfactant protein C mutations: an alternative to lung transplantation.

To the Editor: We report a series of patients with surfactant protein C (SFTPC) dysfunction mutations who presented with severe and persistent respiratory failure in early infancy, resulting in discussions of lung transplantation and withdrawal of support. All three patients were successfully chronically ventilated and weaned off mechanical ventilation (MV). Institutional review board consent was obtained at the University of Colorado. SFTPC mutations were first recognized in 2001, when a 6-week-old child presented with respiratory distress and a family history of lung disease, and genetic studies revealed the SFTPC mutation (1). Symptom onset in SFTPC dysfunction mutations varies from during the neonatal period to in senior citizens (2–4). In addition, outcomes vary tremendously, from asymptomatic family members to respiratory failure leading to transplant or death (5–9). Hydroxychloroquine has been associated with weaning patients off oxygen, significant weight gain, and improvements in chest radiography (10). However, once a child requires persistent MV, typically discussions arise around withdrawal of support versus transplantation. A case report was recently published of an infant who required persistent MV and was able to wean completely off all support (11). Patient 1 Patient 1 was born full-term, with no perinatal complications. She was noted to be cyanotic at birth but was stable for discharge at 3 days of life. She had multiple admissions for respiratory distress, and at 2.5 months of age, a chest computed tomography (CT) scan (Figure 1) showed diffuse ground-glass opacities and septal thickening; a biopsy was consistent with a mutation in SFTPC: diffuse alveolar proteinosis with type II cell hyperplasia, lipid and iron-laden macrophages, septal widening and fibrosis, and scattered necrotic debris. With this diagnosis, she was started on medical therapies (Table 1). The patient was unable to be weaned from MV. After discussions about tracheostomy with chronic MV versus withdrawal of support versus transplantation, the family elected to proceed with chronic MV at 3.5 months of age. She was ultimately discharged on a home ventilator at 19 months of age and was decannulated by age 6 years (Table 1). She has had subsequent illness but never required reintubation. She has autism and has been unable to cooperate with pulmonary function tests. Her most recent CT scan showed nonspecific interstitial pneumonia findings, diffuse ground-glass opacities, and bronchiectasis (Figure 1). The diagnosis of a surfactant protein C mutation (c.545 G>C, .pGly182Arg) was confirmed by genetic testing once available. Patient 1 had a family history of a maternal uncle dying of pneumonia at 6 months of age and a maternal grandfather dying of lung disease at 49 years of age, but neither one had genetic studies performed. Figure 1. Initial and most recent computed tomography (CT) scan for each patient. (A) Patient 1 initial CT scan with diffuse ground-glass opacities and septal thickening. (B) Patient 1 recent CT scan with nonspecific interstitial pneumonia findings, diffuse ground-glass ... Table 1. Summary of Patients’ Clinical Courses Patient 2 Patient 2 was born at 36 weeks and 6 days with an antenatal course complicated by preterm labor at 27 weeks and preeclampsia. At 4 hours of life, she developed respiratory failure necessitating intubation and high-frequency oscillation for 3 months. After discussions about tracheostomy with ventilation versus withdrawal of support versus transplantation, the family elected to proceed with chronic ventilation. Her initial hospitalization (at an outside facility) lasted 10 months, and she was ultimately discharged on a home ventilator. Because her lung disease remained undiagnosed, she had a repeat CT scan at 22 months (Figure 1), which showed marked interstitial prominence with alveolar disease and a subsequent lung biopsy. The biopsy showed focal mild fibrosis in areas of endogenous lipoid pneumonia, consistent with a mutation in SFTPC. She was started on therapies and successfully decannulated by 5 years (Table 1). She was subsequently lost to follow up. She initially had delayed milestones, but she was catching up rapidly. Genetic testing, once available, confirmed the SFTPC mutation (c.563 T>A, p. Leu188Gln). No family history of lung disease was reported. Patient 3 Patient 3 was born at 39 weeks and 3 days with a perinatal course complicated by chorioamnionitis. He was noted to be tachypneic at 10 minutes of life and required noninvasive ventilation. A CT scan (Figure 1) revealed ground-glass opacities, and subsequent genetic testing revealed a SFTPC mutation (c.567 C>G, p.Cys189Trp). He was discharged home on medical therapies with nasal cannula oxygen (Table 1). In the subsequent months, he developed respiratory failure requiring high-frequency oscillation. After discussions about tracheostomy with MV versus withdrawal of support versus transplantation, the family elected to proceed with chronic MV. He was discharged home at 8 months on a home ventilator with medical therapies and was decannulated at age 3 years (Table 1). Since decannulation, he has not had any pulmonary-related hospitalizations, he takes only azithromycin, and he does not require any oxygen therapy. His development is unremarkable. There is no family history of lung disease. Discussion We present three patients with SFTPC mutations and respiratory failure. Withdrawal of support and lung transplantation were offered to each family, and each family elected to proceed with chronic MV. Different medication regimens were used in these patients, although systemic steroids in some form, dose, and duration were universal to all. Expert opinion and case reports (10, 11) have governed disease treatment, with attention to antiinflammatory agents (steroids, azathioprine, and hydroxychloroquine). The natural history of patients with SFTPC mutations is poorly understood and varies considerably, even within families (2–4). Early respiratory failure appears to resolve over time, and it is unknown whether this is secondary to medical therapies or just the natural history of the disease. Lung transplantation has been a solution for infants with SFTPC mutations and persistent respiratory failure. Because lung transplantation has a high risk for complication and mortality, with a median survival of 4.9 years for pediatric lung transplants (12), we propose that chronic MV may be a better option for infants and young children with SFTPC mutations because of this potential for recovery over time. With chronic MV, infants with respiratory failure can grow, develop, and ultimately be at home weaning off of ventilatory support without the chronic medications and potential for fatal outcomes with lung transplantation.

Weaning nocturnal ventilation and decannulation in a pediatric ventilator care program.

Children with chronic respiratory failure and upper airway disorders may require tracheostomy placement and long‐term mechanical ventilation, yet many improve to permit ventilator weaning and decannulation.

Evolution of Asthma Self-Management Programs in Adolescents: From the Crisis Plan to Facebook

Self-management programs for chronic illnesseswere first described regarding children with asthma at The Children’s Asthma Research Institute and Hospital. This groupapproached asthmacare by involving thepatient inhis/her own illnessmanagement. The importance of self-management for improved asthma care has long been recognized. In 1976, 3 programswere fundedby theNationalHeart,Lung, andBlood Institute (NHLBI) to develop self-management programs in pediatric asthma: Columbia University, the National Asthma Center, and the American Institutes of Research. Considerable energy and funding have been dedicated to creating and evaluating self-management programs to improve asthma care, and this has been a priority for the Global Initiative forAsthma and the NHLBI. These self-management approaches have evolved over time, and novel technologies are being used for asthma self-management. We review self-management programs in general and specifically the use of technology as an asthma self-management tool in the adolescent population.

MUC5B expression and location in surfactant protein C mutations in children

Mutations in Surfactant Protein C (SFTPC) can lead to fibrotic interstitial lung disease (ILD) with variable phenotypes, especially in children. The sources of phenotype variability are incompletely understood. A common MUC5B promoter variant rs35705950 is associated with adult Idiopathic Pulmonary Fibrosis (IPF). We examined whether MUC5B is similarly linked to ILD secondary to SFTPC mutations.

Pulmonary Screening in Subjects after the Fontan Procedure

Objectives To review the pulmonary findings of the first 51 patients who presented to our interdisciplinary single‐ventricle clinic after undergoing the Fontan procedure. Study design We performed an Institutional Review Board–approved retrospective review of 51 patients evaluated following the Fontan procedure. Evaluation included history, physical examination, pulmonary function testing, and 6‐minute walk. Descriptive statistics were used to describe the population and testing data. Results Sixty‐one percent of the patients had a pulmonary concern raised during the visit. Three patients had plastic bronchitis. Abnormal lung function testing was present in 46% of patients. Two‐thirds (66%) of the patients had significant desaturation during the 6‐minute walk test. Patients who underwent a fenestrated Fontan procedure and those who underwent unfenestrated Fontan were compared in terms of saturation and 6‐minute walk test results. Sleep concerns were present in 45% of the patients. Conclusions Pulmonary morbidities are common in patients after Fontan surgery and include plastic bronchitis, abnormal lung function, desaturations with walking, and sleep concerns. Abnormal lung function and obstructive sleep apnea may stress the Fontan circuit and may have implications for cognitive and emotional functioning. A pulmonologist involved in the care of patients after Fontan surgery can assist in screening for comorbidities and recommend interventions.

Pulmonary interstitial glycogenosis: Diagnostic evaluation and clinical course

We sought to describe the phenotype for patients with P.I.G. including presentation, evaluation, cardiac co‐morbidities, high resolution computed tomography findings, and outcomes.

Sleeping chILD: Neuroendocrine cell hyperplasia of infancy and polysomnography

Neuroendocrine cell hyperplasia of infancy (NEHI) is a childrens interstitial and diffuse lung disease of unknown etiology that presents in infancy with characteristic findings of tachypnea, retractions, crackles, and hypoxemia. At the present, the mainstay of treatment is oxygen supplementation to normalize oxygen saturations and decrease work of breathing. There are characteristic pulmonary function, radiographic, and histologic findings, but polysomnography (PSG) data has not been reported. We sought to report PSG data and implications for management and treatment of NEHI patients.