Jonathan D. Finder

Cystic Fibrosis Pulmonary Guidelines: Treatment of Pulmonary Exacerbations

The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

Role of IL-17A, IL-17F, and the IL-17 Receptor in Regulating Growth-Related Oncogene-α and Granulocyte Colony-Stimulating Factor in Bronchial Epithelium: Implications for Airway Inflammation in Cystic Fibrosis

IL-17R signaling is critical for pulmonary neutrophil recruitment and host defense against Gram-negative bacteria through the coordinated release of G-CSF and CXC chemokine elaboration. In this study, we show that IL-17R is localized to basal airway cells in human lung tissue, and functional IL-17R signaling occurs on the basolateral surface of human bronchial epithelial (HBE) cells. IL-17A and IL-17F were potent inducers of growth-related oncogene-α and G-CSF in HBE cells, and significant synergism was observed with TNF-α largely due to signaling via TNFRI. The activities of both IL-17A and IL-17F were blocked by a specific anti-IL-17R Ab, but only IL-17A was blocked with a soluble IL-17R, suggesting that cell membrane IL-17R is required for signaling by both IL-17A and IL-17F. Because IL-17A and IL-17F both regulate lung neutrophil recruitment, we measured these molecules as well as the proximal regulator IL-23p19 in the sputum of patients with cystic fibrosis (CF) undergoing pulmonary exacerbation. We found significantly elevated levels of these molecules in the sputum of patients with CF who were colonized with Pseudomonas aeruginosa at the time of pulmonary exacerbation, and the levels declined with therapy directed against P. aeruginosa. IL-23 and the downstream cytokines IL-17A and IL-17F are critical molecules for proinflammatory gene expression in HBE cells and are likely involved in the proinflammatory cytokine network involved with CF pathogenesis.

The respiratory management of patients with duchenne muscular dystrophy: a DMD care considerations working group specialty article.

In 2001, the Muscular Dystrophy Community Assistance, Research and Education Amendments (MD‐CARE Act) was enacted, which directed federal agencies to coordinate the development of treatments and cures for muscular dystrophy. As part of the mandate, the Centers for Disease Control and Prevention (CDC) initiated surveillance and educational activities, which included supporting development of care considerations for Duchenne muscular dystrophy (DMD) utilizing the RAND/UCLA Appropriateness Method (RAM). This document represents the consensus recommendations of the projects 10‐member Respiratory Panel and includes advice on necessary equipment, procedures and diagnostics; and a structured approach to the assessment and management of the respiratory complications of DMD via assessment of symptoms of hypoventilation and identification of specific thresholds of forced vital capacity, peak cough flow and maximum expiratory pressure. The document includes a set of Figures adaptable as “pocket guides” to aid clinicians. This article is an expansion of the respiratory component of the multi‐specialty article originally appearing in Lancet Neurology, comprising respiratory recommendations from the CDC Care Considerations project. Pediatr. Pulmonol. 2010; 45:739–748.

Contemporary Cardiac Issues in Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder diagnosed in childhood. It affects ≈1 in every 5000 live male births (≈20 000 new cases worldwide each year).1,2 This results in a US prevalence of 1.3 to 1.8 per 10 000 males 5 to 24 years of age. DMD is caused by mutations in the gene encoding the dystrophin protein. The loss of dystrophin results in a cascade of events leading to progressive loss of muscle function. Without supportive care, young men with DMD typically die in their late teens and early 20s. Historically, the most common cause of death has been respiratory failure. However, with improved respiratory support, an increasingly important source of morbidity and mortality is cardiomyopathy leading to heart failure and arrhythmias.3,4 There are important differences in DMD cardiomyopathy compared with other types of pediatric dilated cardiomyopathy.5 DMD cardiomyopathy is similar to the cardiomyopathy seen in some forms of limb girdle muscular dystrophy and congenital muscular dystrophy. In particular, a shared cardiomyopathic process is seen in those disorders in which the primary mutation alters components that directly or indirectly interact with dystrophin. There is less left ventricular (LV) enlargement at diagnosis in DMD. Only 30% of boys with DMD have cardiac symptoms at diagnosis (far fewer than other dilated cardiomyopathy). DMD cardiomyopathy is less often treated at the time of diagnosis. However, treatment rates have increased over time. Finally, there is a higher mortality for DMD cardiomyopathy than for other dilated cardiomyopathies. The DMD Care Considerations published in 2010 addressed cardiac care recommendations based on minimal surveillance standards with echocardiography.6,7 However, echocardiography has known limitations in DMD patients.8 Since the 2010 publication of the DMD Care Considerations,6,7 there have been significant advances in the understanding …

Liver Transplantation in Children with Cystic Fibrosis: A Long-Term Longitudinal Review of a Single Center's Experience

BACKGROUND Improved long-term survival in cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, end-stage liver disease is a significant cause of morbidity and mortality with liver transplantation being the only effective therapy. METHODS Records of all CF pediatric liver transplant recipients were reviewed. RESULTS Twelve children with CF were the recipients of 16 allografts. The 1- and 5-year survival was 91.6% and 75%, respectively. There were 5 deaths at a mean interval of 6.8 +/- 6.3 years. All of these deaths were related to pulmonary disease. Pulmonary function improved or remained stable in 8 of 9 patients tested. Despite an 83% incidence of positive sputum cultures, there was only one early mortality related to pulmonary sepsis in the setting of primary liver allograft nonfunction. CONCLUSIONS Liver transplantation is acceptable treatment for children with CF and end-stage liver disease. Long-term survival is comparable to liver transplantation performed for other indications. Although posttransplant morbidity and mortality is related to lung disease, the authors speculate that as therapeutic improvements prolong the survival in CF, it is expected that longer survival after liver transplantation in this patient population may also be anticipated.

Management of pulmonary complications in neuromuscular disease.

Restrictive lung disease occurs commonly in patients with neuromuscular disease. The earliest sign of respiratory compromise in the patient with neuromuscular disease is nocturnal hypoventilation, which progresses over time to include daytime hypoventilation and eventually the need for full-time mechanical ventilation. Pulmonary function testing should be done during regular follow-up visits to identify the need for assistive respiratory equipment and initiate early noninvasive ventilation. Initiation of noninvasive ventilation can improve quality of life and prolong survival in patients with neuromuscular disease.

Airway clearance modalities in neuromuscular disease

Airway clearance consists of two linked processes: mucociliary clearance and cough clearance. Patients with neuromuscular weakness are at risk for impaired cough clearance and therefore the development of pneumonia and atelectasis. Aiding airway clearance in the patient with neuromuscular weakness is critical to the maintenance of health and the prevention of significant respiratory morbidity. This can be achieved using both manual and mechanical techniques. This review will discuss the physiology of cough and the mechanics of aiding cough clearance in the patient with neuromuscular weakness. In addition, technologies and techniques used to improve mucociliary clearance will also be discussed. Newer technologies such as mechanical insufflation-exsufflation have gained widespread acceptance in the management of airway clearance in the patient with neuromuscular weakness.

An Official American Thoracic Society Clinical Practice Guideline: Pediatric Chronic Home Invasive Ventilation.

BACKGROUND Children with chronic invasive ventilator dependence living at home are a diverse group of children with special health care needs. Medical oversight, equipment management, and community resources vary widely. There are no clinical practice guidelines available to health care professionals for the safe hospital discharge and home management of these complex children. PURPOSE To develop evidence-based clinical practice guidelines for the hospital discharge and home/community management of children requiring chronic invasive ventilation. METHODS The Pediatric Assembly of the American Thoracic Society assembled an interdisciplinary workgroup with expertise in the care of children requiring chronic invasive ventilation. The experts developed four questions of clinical importance and used an evidence-based strategy to identify relevant medical evidence. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to formulate and grade recommendations. RESULTS Clinical practice recommendations for the management of children with chronic ventilator dependence at home are provided, and the evidence supporting each recommendation is discussed. CONCLUSIONS Collaborative generalist and subspecialist comanagement is the Medical Home model most likely to be successful for the care of children requiring chronic invasive ventilation. Standardized hospital discharge criteria are suggested. An awake, trained caregiver should be present at all times, and at least two family caregivers should be trained specifically for the childs care. Standardized equipment for monitoring, emergency preparedness, and airway clearance are outlined. The recommendations presented are based on the current evidence and expert opinion and will require an update as new evidence and/or technologies become available.

A 2009 perspective on the 2004 American Thoracic Society statement, "respiratory care of the patient with Duchenne muscular dystrophy".

This is a summary of the presentation “A 2009 Perspective on the 2004 American Thoracic Society Statement, ‘Respiratory Care of the Patient With Duchenne Muscular Dystrophy,’” presented as part of the program on pulmonary management of pediatric patients with neuromuscular disorders at the 30th annual Carrell-Krusen Neuromuscular Symposium on February 20, 2008.

Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary

Abstract Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.