Genetic therapies and respiratory outcomes in patients with neuromuscular disease.

PURPOSE OF REVIEW: Genetic therapies made a significant impact to the clinical course of patients with spinal muscular atrophy and Duchenne muscular dystrophy. Clinicians and therapists who care for these patients want to know the changes in respiratory sequelae and implications for clinical care for treated patients. RECENT FINDINGS: Different genetic therapy approaches have been developed to replace the deficient protein product in spinal muscular atrophy and Duchenne muscular dystrophy. The natural history of these conditions needed to be understood in order to design clinical trials. Respiratory parameters were not the primary outcome measures for the clinical trials. The impact of these therapies is described in subsequent clinical trial reports or real-world data. SUMMARY: Genetic therapies are able to stabilize or improve the respiratory sequelae in patients with spinal muscular atrophy and Duchenne muscular dystrophy. Standardized reporting of these outcomes is needed to help inform the future revisions of clinical standards of care and practice guidelines.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined. Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001. Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Nocturnal Hypoventilation as a Respiratory Complication of Acute Flaccid Myelitis.

Detailed accounts of long-term respiratory complications among children with acute flaccid myelitis have not been reported systematically. We describe respiratory complications and outcomes in a single-center cohort of 19 children with acute flaccid myelitis. Significantly, 3 of the 19 children had a prolonged course of nocturnal hypoventilation that required intervention.

Gastrostomy Tubes Placed in Children With Neurologic Impairment: Associated Morbidity and Mortality.

BACKGROUND: Gastrostomy tube (G-tube) placement for children with neurologic impairment with dysphagia has been suggested for pneumonia prevention. However, prior studies demonstrated an association between G-tube placement and increased risk of pneumonia. We evaluate the association between timing of G-tube placement and death or severe pneumonia in children with neurologic impairment. METHODS: We included all children enrolled in California Children's Services between July 1, 2009, and June 30, 2014, with neurologic impairment and 1 pneumonia hospitalization. Prior to analysis, children with new G-tubes and those without were 1:2 propensity score matched on sociodemographics, medical complexity, and severity of index hospitalization. We used a time-varying Cox proportional hazard model for subsequent death or composite outcome of death or severe pneumonia to compare those with new G-tubes vs those without, adjusting for covariates described above. RESULTS: A total of 2490 children met eligibility criteria, of whom 219 (9%) died and 789 (32%) had severe pneumonia. Compared to children without G-tubes, children with new G-tubes had decreased risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39-0.55) but increased risk of the composite outcome (HR 1.21, CI 1.14-1.27). Sensitivity analyses using varied time criteria for definitions of G-tube and outcome found that more recent G-tube placement had greater associated risk reduction for death but increased risk of severe pneumonia. CONCLUSION: Recent G-tube placement is associated with reduced risk of death but increased risk of severe pneumonia. Decisions to place G-tubes for pulmonary indications in children with neurologic impairment should weigh the impact of severe pneumonia on quality of life.

Pneumonia Prevention Strategies for Children With Neurologic Impairment.

BACKGROUND: Children with neurologic impairment (NI) face high risk of recurrent severe pneumonia, with prevention strategies of unknown effectiveness. We evaluated the comparative effectiveness of secondary prevention strategies for severe pneumonia in children with NI. METHODS: We included children enrolled in California Children's Services between July 1, 2009, and June 30, 2014, with NI and 1 pneumonia hospitalization. We examined associations between subsequent pneumonia hospitalization and expert-recommended prevention strategies: dental care, oral secretion management, gastric acid suppression, gastrostomy tube placement, chest physiotherapy, outpatient antibiotics before index hospitalization, and clinic visit before or after index hospitalization. We used a 1:2 propensity score matched model to adjust for covariates, including sociodemographics, medical complexity, and severity of index hospitalization. RESULTS: Among 3632 children with NI and index pneumonia hospitalization, 1362 (37.5%) had subsequent pneumonia hospitalization. Only dental care was associated with decreased risk of subsequent pneumonia hospitalization (adjusted odds ratio [aOR]: 0.64; 95% confidence interval [CI]: 0.49-0.85). Exposures associated with increased risk included gastrostomy tube placement (aOR: 2.15; 95% CI: 1.63-2.85), chest physiotherapy (aOR: 2.03; 95% CI: 1.29-3.20), outpatient antibiotics before hospitalization (aOR: 1.42; 95% CI: 1.06-1.92), clinic visit before (aOR: 1.30; 95% CI: 1.11-1.52), and after index hospitalization (aOR: 1.72; 95% CI: 1.35-2.20). CONCLUSIONS: Dental care was associated with decreased recurrence of severe pneumonia. Several strategies, including gastrostomy tube placement, were associated with increased recurrence, possibly due to unresolved confounding by indication. Our results support a clinical trial of dental care to prevent severe pneumonia in children with NI.

Respiratory complications, management and treatments for neuromuscular disease in children.

PURPOSE OF REVIEW: To summarize current literature describing the respiratory complications of neuromuscular disease (NMD) and the effect of respiratory interventions and to explore new gene therapies for patients with NMD. RECENT FINDINGS: Measurements of respiratory function focus on vital capacity and maximal inspiratory and expiratory pressure and show decline over time. Management of respiratory complications includes lung volume recruitment, mechanical insufflation-exsufflation, chest physiotherapy and assisted ventilation. Lung volume recruitment can slow the progression of lung restriction. New gene-specific therapies for Duchenne muscular dystrophy and spinal muscular atrophy have the potential to preserve respiratory function longitudinally. However, the long-term therapeutic benefit remains unknown. SUMMARY: Although NMDs are heterogeneous, many lead to progressive muscle weakness that compromises the function of the respiratory system including upper airway tone, cough and secretion clearance and chest wall support. Respiratory therapies augment or support the normal function of these components of the respiratory system. From a respiratory perspective, the new mutation and gene-specific therapies for NMD are likely to confer long-term therapeutic benefit. More sensitive and standard tools to assess respiratory function longitudinally are needed to monitor respiratory complications in children with NMD, particularly the youngest patients.

Assessing Differences in Mortality Rates and Risk Factors Between Hispanic and Non-Hispanic Patients With Cystic Fibrosis in California.

BACKGROUND: Over the past 30 years, therapeutic advances have extended the median lifespan of patients with cystic fibrosis (CF). Hispanic patients are a vulnerable subpopulation with a high prevalence of risk factors for worse health outcomes. The consequences of these differences on health outcomes have not been well described. The objective of this study was to characterize the difference in health outcomes, including mortality rate, between Hispanic and non-Hispanic patients with CF. METHODS: This study is a retrospective analysis of CF Foundation Patient Registry data of California residents with CF, diagnosed during or after 1991, from 1991 to 2010. Ethnicity was self-reported. The primary outcome was mortality. Hazard ratios were estimated from a Cox regression model, stratified by sex, and adjusted for socioeconomic status, clinical risk factors, and year of diagnosis. RESULTS: Of 1,719 patients, 485 (28.2%) self-identified as Hispanic. Eighty-five deaths occurred, with an overall mortality rate of 4.9%. The unadjusted mortality rate was higher among Hispanic patients than among non-Hispanic patients (9.1% vs 3.3%, P < .0001). Compared with non-Hispanic patients, Hispanic patients had a lower survival rate 18 years after diagnosis (75.9% vs 91.5%, P < .0001). Adjusted for socioeconomic status and clinical risk factors, Hispanic patients had an increased rate of death compared with non-Hispanic patients (hazard ratio, 2.81; 95% CI, 1.70-4.63). CONCLUSIONS: Hispanic patients with CF have a higher mortality rate than do non-Hispanic patients, even after adjusting for socioeconomic status and clinical severity. Further investigation into the mechanism for the measured difference in lung function will help inform interventions and improve the health of all patients with CF.

Asthma, tobacco smoke and the indoor environment: a qualitative study of sheltered homeless families.

OBJECTIVE: Asthma is common in homeless children with an incidence of 28-40%. There are few published studies investigating asthma in homeless children. This study examines the perspectives of both caregivers and shelter staff regarding challenges and opportunities of caring for children with asthma. METHODS: A focus group of sheltered parents (n = 10) with children who have asthma was conducted to identify barriers to optimal asthma management. Key informant interviews (n = 6) were conducted with shelter staff to discuss the shelter systems and policies to address childhood asthma. Data were audio-recorded and transcribed. A representative analysis team performed qualitative theme analysis. RESULTS: Key themes across 5 domains were identified: asthma education, access to asthma medication and equipment, asthma action plans, structural barriers to asthma management and environmental triggers. Parents identified multiple asthma triggers present in the shelter environment but cited lack of control as a barrier to remediation. Shelter staff desired elimination of asthma triggers but refer to the lack of resources as the primary barrier. Shelter staff favored a smoking ban on shelter property but named challenges to policy implementation. Both parents and staff identified asthma education and increased access to medications would be helpful. CONCLUSIONS: Policies to reduce environmental exposures, such as a smoking ban, to asthma triggers has the potential to improve the health of sheltered children with asthma.