Oscar H. Mayer

An Official American Thoracic Society Workshop Report: Optimal Lung Function Tests for Monitoring Cystic Fibrosis, Bronchopulmonary Dysplasia, and Recurrent Wheezing in Children Less Than 6 Years of Age

Although pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions in children under 6 years of age, objective physiologic assessment is limited in the clinical care of infants and children less than 6 years old, due to the challenges of measuring lung function in this age range. Ongoing research in lung function testing in infants, toddlers, and preschoolers has resulted in techniques that show promise as safe, feasible, and potentially clinically useful tests. Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.

Early changes in pulmonary function after vertical expandable prosthetic titanium rib insertion in children with thoracic insufficiency syndrome.

BACKGROUND The vertical expandable prosthetic titanium rib (VEPTR) has been inserted in children with thoracic insufficiency syndrome for the last decade to expand and support the chest and allow for further lung growth. There are minimal published data evaluating the postoperative change in lung function after VEPTR insertion. We hypothesize that there will be a significant increase in lung function after VEPTR insertion, and the earlier the insertion, the greater the improvement. METHODS The Chest Wall Disorders Study Group Database, containing data before and after VEPTR insertion from 7 different centers, was queried for spirometry and lung volume measurements, and the data were analyzed to assess the short-term effect on lung function of VEPTR placement. RESULTS There was a statistically significant decrease in forced vital capacity, forced expiratory volume in 1 second as a percent of predicted, an increase in residual volume (RV) that did not reach statistical significance, and there was no change in total lung capacity at the first postoperative visit (7.7 +/- 4.8 months). There was a significant decrease in Cobb angle. There was no correlation between absolute change in any pulmonary function and Cobb angle age at the time of surgery. CONCLUSIONS Although there is a clinically and radiographically apparent expansion of the thorax after VEPTR insertion, there is no similar improvement in lung volume, and instead there is a decrease in forced vital capacity and increase in residual volume, the explanation for which requires further study. This lack of change in pulmonary function after VEPTR insertion suggests that the benefit of VEPTR insertion may lie more in stabilizing the thorax and improving respiratory mechanics measured in other ways.

Characterization of Pulmonary Function in Duchenne Muscular Dystrophy

Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5–24 years). Expiratory flow‐volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10–18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time. Pediatr Pulmonol. 2015; 50:487–494.

Lung function distinguishes preschool children with CF from healthy controls in a multi-center setting.

Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites.

Analysis of the associations between lung function and clinical features in preschool children with cystic fibrosis.

To analyze cross‐sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF).

Lung function in 3–5-year-old children with cystic fibrosis

It is well established that the lung disease of CF can occur early in life and may progress through the preschool years when accurate lung function assessment has been challenging to perform. We hypothesized that respiratory inductive plethysmography (RIP) and spirometry could be effectively performed in 3–6‐year‐old children and could be used to assess both longitudinal changes in lung function and the acute changes that occur during exacerbation of pulmonary disease. Both RIP and spirometry were equally feasible; however, the success rate for spirometry gradually increased with age to become higher than that for RIP in the 6‐year‐old subjects. Forty‐four subjects were studied longitudinally and demonstrated significant increases in FVC, FEV1, and FEV0.5, but not in FEF25–75 or RIP variables. There were significant differences in FVC, FEV1, and phase angle (a measure of thoracoabdominal asynchrony) during exacerbations of lung disease. Although both RIP and spirometry were able to show differences in lung function in subjects with acute clinical worsening, spirometry was more robust in demonstrating change in lung function longitudinally and in children who had an exacerbation of lung disease. Pediatr. Pulmonol. 2008; 43:1214–1223.

Respiratory Muscle Function in Infants With Spinal Muscular Atrophy Type I

To determine the feasibility and safety of respiratory muscle function testing in weak infants with a progressive neuromuscular disorder.

CHEST WALL ABNORMALITIES

Chest wall abnormalities can substantially impact the quality of breathing. Chest wall dysfunction can occur as a primary disorder due to congenital (e.g., VATER syndrome), genetic (e.g., Jarcho-Levin syndrome), or acquired (e.g., scoliosis) causes, or can occur as a secondary disorder due to conditions such as obesity, neuromuscular disease, or chronic obstructive pulmonary disease. Recently, much has been learned about the genetic mechanisms producing chest wall disorders. These mechanisms include dominant negative action (e.g., Marfan syndrome), gain-of-function mutation (e.g., achondroplasia), haploinsufficiency (e.g., Campomelic dysplasia), and loss-of-function mutations (e.g., Jarcho-Levin syndrome). Clinical features common to all these disorders include, in severe cases, respiratory insufficiency due to pulmonary hypoplasia or respiratory pump failure. There are a variety of noninvasive interventions to help counteract the effects of chest wall dysfunction; these improve airway clearance (mechanical percussion devices and cough assist devices) and improve ventilation (noninvasive or invasive nocturnal or continuous mechanical ventilation). Surgical interventions to correct or prevent further progression of the disorder include bracing, spinal fusion, and, more recently, introduction of the vertical expandable prosthetic titanium rib (VEPTR), which has the advantage of allowing for future spinal growth.

Characterization of pulmonary function in 10–18 year old patients with Duchenne muscular dystrophy

Pulmonary function loss in patients with Duchenne muscular dystrophy (DMD) is progressive and leads to pulmonary insufficiency. The purpose of this study in 10-18 year old patients with DMD is the assessment of the inter-correlation between pulmonary function tests (PFTs), their reliability and the association with the general disease stage measured by the Brooke score. Dynamic PFTs (peak expiratory flow [PEF], forced vital capacity [FVC], forced expiratory volume in one second [FEV1]) and maximum static airway pressures (MIP, MEP) were prospectively collected from 64 DMD patients enrolled in the DELOS trial (ClinicalTrials.gov, number NCT01027884). Baseline PEF percent predicted (PEF%p) was <80% and patients had stopped taking glucocorticoids at least 12 months prior to study start. At baseline PEF%p, FVC%p and FEV1%p correlated well with each other (Spearmans rho: PEF%p-FVC%p: 0.54; PEF%p-FEV1%p: 0.72; FVC%p-FEV1%p: 0.91). MIP%p and MEP%p correlated well with one another (MIP%p-MEP%p: 0.71) but less well with PEF%p (MIP%p-PEF%p: 0.40; MEP%p-PEF%p: 0.41) and slightly better with FVC%p (MIP%p-FVC%p: 0.59; MEP%p-FVC%p: 0.74). The within-subject coefficients of variation (CV) for successive measures were 6.97% for PEF%p, 6.69% for FVC%p and 11.11% for FEV1%p, indicating that these parameters could be more reliably assessed compared to maximum static airway pressures (CV for MIP%p: 18.00%; MEP%p: 15.73%). Yearly rates of PFT decline (placebo group) were larger in dynamic parameters (PEF%p: -8.9% [SD 2.0]; FVC%p: -8.7% [SD 1.1]; FEV1%p: -10.2% [SD 2.0]) than static airway pressures (MIP%p: -4.5 [SD 1.3]; MEP%p: -2.8 [SD 1.1]). A considerable drop in dynamic pulmonary function parameters was associated with loss of upper limb function (transition from Brooke score category 4 to category 5). In conclusion, these findings expand the understanding of the reliability, correlation and evolution of different pulmonary function measures in DMD patients who are in the pulmonary function decline phase.

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.