Robert G. Castile

Longitudinal Assessment of Pseudomonas aeruginosa in Young Children with Cystic Fibrosis

Pseudomonas aeruginosa lung infection is an important cause of morbidity and mortality in cystic fibrosis (CF). Longitudinal assessment of the phenotypic changes in P. aeruginosa isolated from young children with CF is lacking. This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 CF patients during the first 3 years of life; antibody response was also examined. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally nonmucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.

Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis

The objective of this study was to assess the diagnostic accuracy of oropharyngeal (OP) cultures relative to simultaneous bronchoalveolar lavage (BAL) cultures in very young children with CF, and to examine the effects of bacterial density, age, and study cohort on diagnostic accuracy. Respiratory culture data were analyzed from three independent, prospective studies involving simultaneous collection of 286 OP and BAL cultures from 141 children with CF <5 years of age.

Adult-type pulmonary function tests in infants without respiratory disease.

A new method that permits the measurement of adult‐type maximal expiratory flow‐volume curves and fractional lung volumes in sedated infants was recently described. The purpose of this study was to define the normal range for these new measures of pulmonary function in infants and young children. Measurements of forced expiratory flows and fractional lung volume were made on 35 occasions in 22 children (ages 3–120 weeks) without respiratory disease. Maximal expiratory flow‐volume curves were measured by the raised lung volume, thoracoabdominal compression technique. Functional residual capacity (FRC) was measured plethysmographically.

Technique and clinical applications of full-inflation and end-exhalation controlled-ventilation chest CT in infants and young children

Background. The inability of young children to cooperate with breath holding limits the usefulness of chest CT. Objective. To describe the technique and utility of a non-invasive method called controlled-ventilation CT (CVCT) for obtaining motion-free full-inflation and end-exhalation images of the lung in infants and young children. Materials and methods. Eighty-seven children (ages 1 week to 5 years, mean 2 years) underwent CVCT of the chest during suspended respiration at full-lung inflation and end-exhalation for a variety of clinical indications. Respiratory pauses were produced using conscious sedation and positive-pressure face-mask ventilation. Forty-one of 87 children had recordings of respiratory motion during CVCT. Results. Respiratory pause lengths increased with age (P < 0.003), were highly reproducible (r = 0.85), and lasted sufficiently long to be practical for full-inflation (24 ± 9 s) and end-exhalation (12 ± 5 s) CT scanning. Full-inflation CVCT was useful in evaluating tracheal and bronchial stenosis, bronchial wall thickening, early bronchiectasis, bronchial fistula, extent of interstitial fibrosis, and lung nodules. End-exhalation CVCT was useful in evaluating tracheomalacia and air trapping. Conclusion. Controlled-ventilation chest CT is a practical and reliable technique that promises to be clinically useful for a number of clinical indications in infants and young children.

Multicenter Evaluation of Infant Lung Function Tests as Cystic Fibrosis Clinical Trial Endpoints

RATIONALE The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Immunogenicity of a new purified fusion protein vaccine to respiratory syncytial virus: A multi-center trial in children with cystic fibrosis

A third generation, purified fusion protein (PFP-3) vaccine was developed to prevent severe respiratory syncytial virus (RSV) disease in high-risk groups. A phase II, multi-center, adjuvant-controlled trial was performed in RSV seropositive children with cystic fibrosis (CF); 151 received the adjuvant-control and 143 received the vaccine. Details of the vaccine-induced immune response are presented. At enrollment, RSV-specific, serum antibodies were comparable between both groups. A highly sensitive and specific serum antibody vaccine profile was established for the PFP-3 vaccine. At post-vaccination and end-of-study, RSV-specific, neutralizing antibody (Nt Ab) and binding antibody (Bd Ab) to the fusion (F) protein were significantly higher in PFP-3 vaccinees. After 28 days post-vaccination, Nt Ab and Bd Ab to F protein titers declined slowly at rates of 0.23 and 0.37 log2 per month, respectively. The PFP-3 vaccine-induced a robust immune response that lasted throughout the RSV season.

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.

Lateral thoracic expansion for jeune syndrome: Evidence of rib healing and new bone formation

BACKGROUND Lateral thoracic expansion is a procedure that has been described to enlarge the thoracic cage in patients with Jeunes asphyxiating thoracic dystrophy. The procedure involves separating ribs from their periosteum and plating them together in an expanded fashion with titanium struts. We have speculated that the ribs heal in this situation, despite the absence of surrounding periosteum, and that new rib formation occurs in the liberated periosteum. METHODS Radiographic studies of patients who have undergone lateral thoracic expansion were reviewed for evidence of rib healing or periosteal new bone formation. RESULTS This study presents radiologic evidence that rib healing actually occurs, as does periosteal ossification. CONCLUSIONS Lateral thoracic expansion creates additional chest wall that is formed of autologous tissue, fully healed, and not ultimately dependent on titanium struts.

Lateral thoracic expansion for Jeune’s syndrome: midterm results

BACKGROUND In 1995, we reported the use of lateral thoracic expansion in a patient with symptomatic Jeunes asphyxiating thoracic dystrophy. We have subsequently used lateral thoracic expansion 16 times on 10 patients during 7 years. This article reports our outcomes and provides surgical details. METHODS Charts of all patients undergoing lateral thoracic expansion were reviewed. Eight of the 10 patients had symptomatic Jeunes syndrome. The other 2 had similar thoracic deformities limiting thoracic capacity. In half of the patients the procedures were performed bilaterally. RESULTS All patients older than 1 year of age were symptomatically benefited by lateral thoracic expansion. Functional and anatomic measurements documented thoracic enlargement in several patients who had comparable preoperative and postoperative studies. However, 2 infants with significant underlying airway disease did not improve and went on to succumb to that aspect of their disease despite enlargement of the thorax. Fracture of the titanium ministruts has been a recurrent problem, and we now use larger struts. CONCLUSIONS Lateral thoracic expansion is a safe and effective procedure in selected patients with Jeunes syndrome older than 1 year of age as judged by short-term and midterm follow-up. More experience and longer follow-up are required to discern the place of the lateral thoracic expansion in the overall management of these patients.

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.