Andrew A. Colin

Epidemiologic study of cystic fibrosis: Design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase‐IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site.

Passive respiratory mechanics: the occlusion techniques

The aim of this position paper is to define quality control and acceptance criteria for measuring passive respiratory mechanics in infants using the occlusion techniques to ensure that valid results are obtained. These guidelines cover numerous aspects including: 1) terminology and definitions; 2) equipment; 3) data acquisition; 4) data handling and analysis; 5) reporting of results. Adherence to these guidelines should ensure that measurement of passive respiratory mechanics in infants in different lung function laboratories could be performed with an acceptable degree of safety, precision, and reproducibility. This will facilitate multi-centre collection of data and performance of clinical investigations.

Lung abscess versus necrotizing pneumonia: implications for interventional therapy

Objective. To assess and contrast the role of interventional therapy for two types of cavitating pneumonias: lung abscess and necrotizing pneumonia. Materials and methods. We retrospectively reviewed the imaging, interventional therapy, and outcome of 14 children seen between February 1987 and January 1996 with lung abscess and 9 with necrotizing pneumonia. All children were treated with antibiotics prior to intervention. Pulmonary parenchymal fluid was percutaneously aspirated from ten lung abscesses and three necrotizing pneumonias. Percutaneous catheters drained five lung abscesses. Pleural drainage was performed for three lung abscesses and eight necrotizing pneumonias. Results. All 14 children with lung abscesses had positive Gram stains of the pulmonary fluid; 13 cultures were positive. All 14 defervesced within 48 h of intervention. None developed a bronchopleural fistula. All nine necrotizing pneumonias were presumed to be sequelae of prior pneumonia. Streptococcus pneumoniae was the only organism as documented by pleural fluid latex fixation in three patients, gram stain in two, and culture in only one. Seven of these children developed pneumatoceles, five developed bronchopleural fistulae, and three required long-term chest tubes for persistent pneumothoraces. Conclusion. Aggressive interventional therapy can be diagnostic and therapeutic in the infected lung abscess. Interventional therapy can be harmful in postinfectious necrotizing pneumonia.

Late Preterm Infants: Near Term But Still in a Critical Developmental Time Period

Late preterm (LP) infants are defined as those born at 34-0/7 to 36-6/7 weeks’ gestational age. LP infants were previously referred to as near term infants. The change in terminology resulted from the understanding that these infants are not fully mature and that the last 6 weeks of gestation represent a critical period of growth and development of the fetal brain and lungs, and of other systems. There is accumulating evidence of higher risks for health complications in these infants, including serious morbidity and a threefold higher infant mortality rate compared with term infants. This information is of critical importance because of its scientific merits and practical implications. However, it warrants a critical and balanced review, given the apparent overall uncomplicated outcome for the majority of LP infants. Others reviewed the characteristics of LP infants that predispose them to a higher risk of morbidity at the neonatal period. This review focuses on the long-term neurodevelopmental and respiratory outcomes, with the main aim to suggest putative prenatal, neonatal, developmental, and environmental causes for these increased morbidities. It demonstrates parallelism in the trajectories of pulmonary and neurologic development and evolution as a model for fetal and neonatal maturation. These may suggest the critical developmental time period as the common pathway that leads to the outcomes. Disruption in this pathway with potential long-term consequences in both systems may occur if the intrauterine milieu is disturbed. Finally, the review addresses the practical implications on perinatal and neonatal care during infancy and childhood.

Necrotising pneumonia is an increasingly detected complication of pneumonia in children

Necrotising pneumonia (NP) is a severe complication of community-acquired pneumonia characterised by liquefaction and cavitation of lung tissue. The present study describes the epidemiology, aetiology, management and outcomes of children hospitalised with NP over a 15-yr period. A retrospective observational study of NP cases was conducted from January 1990 to February 2005 analysing clinical presentation, laboratory data, hospital course and long-term follow-up. A total of 80 NP cases were identified, with the number of detected cases increasing from 12, in the period 1993–1996, to 40 in the period 2001–2004. In total, 69 (86%) cases had pleural effusion with a low pH (mean 7.08) and 38 (48%) patients had positive cultures, with Streptococcus pneumoniae as the predominant organism. Recently, other organisms, most notably methicillin-resistant Staphylococcus aureus, emerged. Patients had prolonged hospitalisations (median 12 days). A total of 69 patients required pleural interventions and those receiving chest drainage alone had similar outcomes to those managed surgically. All patients had full clinical resolution within 2 months of presentation. Necrotising pneumonia has increasingly been identified as a complication of paediatric pneumonia. Streptococcus pneumoniae remains the predominant organism, but since 2002, different bacteria have been isolated and the age range of cases has broadened. Despite the serious morbidity, massive parenchymal damage and prolonged hospitalisations, long-term outcome following necrotising pneumonia is excellent.

Bronchial Atresia Is Common to Extralobar Sequestration, Intralobar Sequestration, Congenital Cystic Adenomatoid Malformation, and Lobar Emphysema

Congenital cystic adenomatoid malformation (CCAM), intralobar sequestration (ILS), extralobar sequestration (ELS), and lobar emphysema (LE) are well-accepted entities; however, certain findings are common to all, particularly the parenchymal maldevelopment characterizing CCAM. Isolated reports have described bronchial atresia (BA) in some specimens in all 4 entities, but this finding has not been evaluated in a prospective manner. With the aid of a dissecting microscope, we prospectively examined 47 lung specimens resected during the past 4 years and submitted with the clinical impression of ELS (n = 11), ILS (n = 11), CCAM (n = 20), LE (n = 4), and airway-esophageal communication (n = 1). Most lesions were detected by prenatal ultrasound and were resected during infancy. The clinical impression and pathologic findings were compared. Pathologic examination revealed atresia of a lobar, segmental, or subsegmental bronchus in 100% of ELS, 82% of ILS, 70% of CCAM, and 50% of LE (those clinically recognized to have BA or minor CCAM) cases. Parenchymal maldevelopment that characterizes CCAM was present in 100% of CCAM cases (as expected by definition) as well as in 91% of ELS, 91% of ILS, and 50% of LE (those with BA) cases. Bronchial atresia is present in all ELS, most ILS and CCAM, and some LE cases, and its detection is greatly enhanced with the dissecting microscope. Bronchial atresia and CCAM nearly always coexist. It may be that both have the same etiopathogenesis with anatomic differences accounted for by aberrant genetic programs or other insults, perhaps modified by time of onset or duration.

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.

The pediatric pulmonary and cardiovascular complications of vertically transmitted human immunodeficiency virus (P2C2 HIV) infection study: Design and methods

The P2C2 HIV Study is a prospective natural history study initiated by the National Heart, Lung, and Blood Institute in order to describe the types and incidence of cardiovascular and pulmonary disorders that occur in children with vertically transmitted HIV infection (i.e., transmitted from mother to child in utero or perinatally). This article describes the study design and methods. Patients were recruited from five clinical centers in the United States. The cohort is composed of 205 infants and children enrolled after 28 days of age (Group I) and 612 fetuses and infants of HIV-infected mothers, enrolled prenatally (73%) or postnatally at age < 28 days (Group II). The maternal-to-infant transmission rate in Group II was 17%. The HIV-negative infants in Group II (Group IIb) serves as a control group for the HIV-infected children (Group IIa). The cohort is followed at specified intervals for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. In Group IIa, the cumulative loss-to-follow-up rate at 3 years was 10.5%, and the 3-year cumulative mortality rate was 24.9%. The findings will be relevant to clinical and epidemiologic aspects of HIV infection in children.

Posterior spinal fusion for scoliosis in Duchenne muscular dystrophy diminishes the rate of respiratory decline

Study Design. To assess the rate of decline in pulmonary function in Duchenne muscular dystrophy (DMD) before and after posterior spinal fusion for scoliosis. Objective. To compare the rate of respiratory decline using percent normal forced vital capacity (%FVC) measurements before and after posterior spinal fusion. Summary of Background Data. Posterior spinal fusion for scoliosis is used widely in DMD, although the long-term pulmonary effects have not been well established. Methods. Fifty-six patients were assessed. Percent forced vital capacity was the outcome parameter with data analysis using a mixed-model repeated-measures ANOVA and paired t tests. Group 1: Inclusion criteria were a diagnosis of DMD, 2 or more pulmonary function tests presurgery, and 2 or more postsurgery. Group 2: The rates of respiratory decline before and after spinal fusion for the whole study population were determined by within- subjects mixed-model regression analysis to account for the varying number of FVC studies between patients and unequal spacing between tests. Results. Group 1: 20 patients. Mean length of time of respiratory value determination was 2.5 ± 1.0 years presurgery and 5.6 ± 2.8 years postsurgery. Mean rate of decline presurgery was 8.0% ± 4.1% per year, which decreased to 3.9% ± 1.9% per year postsurgery (paired t test = 4.58, P < 0.0001). Group 2: 56 patients. The respiratory value determinations ranged from 4 years presurgery to 8 years postsurgery. The rates of respiratory decline based on the whole study population were 4% per year presurgery, which decreased to 1.75% per year postsurgery (F-test comparison of slopes = 19.71, P < 0.0001). Conclusions. Posterior spinal fusion for scoliosis in DMD is associated with a significant decrease in the rate of respiratory decline postsurgery compared with presurgery rates.

Predictors of mucoid Pseudomonas colonization in cystic fibrosis patients

Chronic mucoid Pseudomonas aeruginosa within the airway in cystic fibrosis (CF) patients can determine prognosis. Understanding the risk factors of mucoid P. aeruginosa acquisition may change how we deliver care. This study aims to evaluate whether presence of risk factors reported to predict disease severity including gender, CFTR genotype, bacterial organisms in airway cultures, and serum levels of vitamins A and E, albumin, C‐reactive protein, alpha 1‐antitrypsin, and immunoglobulins increased the risk of mucoid P. aeruginosa acquisition.