Conor Murray

Lung Disease at Diagnosis in Infants with Cystic Fibrosis Detected by Newborn Screening

RATIONALE The promise of newborn screening (NBS) for cystic fibrosis (CF) has not been fully realized, and the extent of improvement in respiratory outcomes is unclear. We hypothesized that significant lung disease was present at diagnosis. OBJECTIVES To determine the extent of lung disease in a geographically defined population of infants with CF diagnosed after detection by NBS. METHODS Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol. MEASUREMENTS AND MAIN RESULTS Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 x 10(3) cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectable free neutrophil elastase activity. Inflammation was increased in those with infection and respiratory symptoms; however, the majority of those infected were asymptomatic. Radiologic evidence of structural lung disease was common, with 46 (80.7%) having an abnormal CT; 11 (18.6%) had bronchial dilatation, 27 (45.0%) had bronchial wall thickening, and 40 (66.7%) had gas trapping. On multivariate analysis, free neutrophil elastase activity was associated with structural lung disease. Most children with structural lung disease had no clinically apparent lung disease. CONCLUSIONS These data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of NBS for CF is to be realized.

Bronchiectasis in Infants and Preschool Children Diagnosed with Cystic Fibrosis after Newborn Screening

OBJECTIVES To determine the prevalence of bronchiectasis in young children with cystic fibrosis (CF) diagnosed after newborn screening (NBS) and the relationship of bronchiectasis to pulmonary inflammation and infection. STUDY DESIGN Children were diagnosed with CF after NBS. Computed tomography and bronchoalveolar lavage were performed with anesthesia (n = 96). Scans were analyzed for the presence and extent of abnormalities. RESULTS The prevalence of bronchiectasis was 22% and increased with age (P = .001). Factors associated with bronchiectasis included absolute neutrophil count (P = .03), neutrophil elastase concentration (P = .001), and Pseudomonas aeruginosa infection (P = .03). CONCLUSIONS Pulmonary abnormalities are common in infants and young children with CF and relate to neutrophilic inflammation and infection with P. aeruginosa. Current models of care for infants with CF fail to prevent respiratory sequelae. Bronchiectasis is a clinically relevant endpoint that could be used for intervention trials that commence soon after CF is diagnosed after NBS.

Emphysema in young adult survivors of moderate-to-severe bronchopulmonary dysplasia

Improved survival following extreme preterm birth complicated by bronchopulmonary dysplasia (BPD) is resulting in an increasing number of affected infants surviving to adulthood. The aim of the present pilot study was to describe the functional and structural pulmonary sequelae of moderate and severe BPD in a population of adult survivors. All babies were cared for at one institution (King Edward Memorial Hospital, Subiaco, Australia). Subjects born between 1980 and 1987 with birthweight <1,500 g and requiring supplementary oxygen at 36 weeks post-menstrual age were identified from a complete neonatal database and recruited prospectively. Local physicians were concurrently asked to refer suitable patients. Demographics, respiratory symptoms and examination results, pulmonary function tests and computed tomography images were acquired. In total, 21 subjects were studied. Of these, 12 were female, the median (range) age was 19 (17–33) yrs and 15 (71%) had persistent respiratory symptoms. The median (range) forced expiratory volume in one second (FEV1) z-score was -0.77 (-8.20–1.37), the forced expiratory flow at 25–75% of forced vital capacity was -1.81 (-6.00–0.75) and the diffusing capacity of the lung for carbon monoxide was -5.04 (-13.17– -1.24). Computed tomography was carried out on 19 subjects and all had abnormal findings, with emphysema being the most common, present in 84% of subjects. The extent of radiological emphysema was inversely related to the FEV1 z-score. Young adult survivors of moderate and severe bronchopulmonary dysplasia may be left with residual functional and characteristic structural pulmonary abnormalities, most notably emphysema.

Progression of early structural lung disease in young children with cystic fibrosis assessed using CT

Background Cross-sectional studies implicate neutrophilic inflammation and pulmonary infection as risk factors for early structural lung disease in infants and young children with cystic fibrosis (CF). However, the longitudinal progression in a newborn screened population has not been investigated. Aim To determine whether early CF structural lung disease persists and progresses over 1 year and to identify factors associated with radiological persistence and progression. Methods 143 children aged 0.2–6.5 years with CF from a newborn screened population contributed 444 limited slice annual chest CT scans for analysis that were scored for bronchiectasis and air trapping and analysed as paired scans 1 year apart. Logistic and linear regression models, using generalised estimating equations to account for multiple measures, determined associations between persistence and progression over 1 year and age, sex, severe cystic fibrosis transmembrane regulator (CFTR) genotype, pancreatic sufficiency, current respiratory symptoms, and neutrophilic inflammation and infection measured by bronchoalveolar lavage. Results Once detected, bronchiectasis persisted in 98/133 paired scans (74%) and air trapping in 178/220 (81%). The extent of bronchiectasis increased in 139/227 (63%) of paired scans and air trapping in 121/264 (47%). Radiological progression of bronchiectasis and air trapping was associated with severe CFTR genotype, worsening neutrophilic inflammation and pulmonary infection. Discussion CT-detected structural lung disease identified in infants and young children with CF persists and progresses over 1 year in most cases, with deteriorating structural lung disease associated with worsening inflammation and pulmonary infection. Early intervention is required to prevent or arrest the progression of structural lung disease in young children with CF.

Air Trapping on Chest CT Is Associated with Worse Ventilation Distribution in Infants with Cystic Fibrosis Diagnosed following Newborn Screening

Background In school-aged children with cystic fibrosis (CF) structural lung damage assessed using chest CT is associated with abnormal ventilation distribution. The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF. Methods Data of infants and young children with CF diagnosed following newborn screening consecutively reviewed between August 2005 and December 2009 were analysed. Ventilation distribution (lung clearance index and the first and second moment ratios [LCI, M1/M0 and M2/M0, respectively]), chest CT and airway pathology from bronchoalveolar lavage were determined at diagnosis and then annually. The chest CT scans were evaluated for the presence or absence of bronchiectasis and air trapping. Results Matched lung function, chest CT and pathology outcomes were available in 49 infants (31 male) with bronchiectasis and air trapping present in 13 (27%) and 24 (49%) infants, respectively. The presence of bronchiectasis or air trapping was associated with increased M2/M0 but not LCI or M1/M0. There was a weak, but statistically significant association between the extent of air trapping and all ventilation distribution outcomes. Conclusion These findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of LCI could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research in which both MBW and chest CT outcomes are obtained is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.

PRAGMA-CF. A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis

RATIONALE Chest computed tomography (CT) is the gold standard for demonstrating cystic fibrosis (CF) airway disease. However, there are no standardized outcome measures appropriate for children younger than 6 years. OBJECTIVES We developed the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), a quantitative measure of airway disease, and compared it with the commonly used CF-CT scoring method. METHODS CT scans from the Australian Respiratory Early Surveillance Team for CF (AREST CF) cohort in Western Australia were included. PRAGMA-CF was performed by annotating a grid overlaid on 10 axial slices for the presence of bronchiectasis, mucous plugging, or other airway abnormalities (inspiratory scans) and trapped air (expiratory scans). The separate proportions of total disease (%Dis), bronchiectasis (%Bx), and trapped air (%TA) were determined. Thirty scans were used for observer reliability, and 30 paired scans obtained at 1 and 3 years old were used for comparison with a validated standard and biologic plausibility. MEASUREMENTS AND MAIN RESULTS Intraobserver, intraclass correlation coefficients (95% confidence interval) for %Dis, %Bx, and %TA were 0.93 (0.86-0.97), 0.93 (0.85-0.96), and 0.96 (0.91-0.98), respectively. The change in %Dis (P = 0.004) and %Bx (P = 0.001) with PRAGMA-CF was related to neutrophil elastase presence at age 3, whereas only the change in bronchiectasis score was related to neutrophil elastase (P < 0.001) with CF-CT. Sample-size calculations for various effect sizes are presented. CONCLUSIONS PRAGMA-CF is a sensitive and reproducible outcome measure for assessing the extent of lung disease in very young children with CF.

Lung Clearance Index and Structural Lung Disease on Computed Tomography in Early Cystic Fibrosis

RATIONALE The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. It has been suggested as a surrogate for chest computed tomography to detect structural lung abnormalities in individuals with cystic fibrosis (CF); however, the associations between lung clearance index and early structural lung disease are unclear. OBJECTIVES We assessed the ability of the lung clearance index to reflect structural lung disease on the basis of chest computed tomography across the entire pediatric age range. METHODS Lung clearance index was assessed in 42 infants (ages 0-2 yr), 39 preschool children (ages 3-6 yr), and 38 school-age children (7-16 yr) with CF before chest computed tomography and in 72 healthy control subjects. Scans were evaluated for CF-related structural lung disease using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis quantitative outcome measure. MEASUREMENTS AND MAIN RESULTS In infants with CF, lung clearance index is insensitive to structural disease (κ = -0.03 [95% confidence interval, -0.05 to 0.16]). In preschool children with CF, lung clearance index correlates with total disease extent. In school-age children, lung clearance index correlates with extent of total disease, bronchiectasis, and air trapping. In preschool and school-age children, lung clearance index has a good positive predictive value (83-86%) but a poor negative predictive value (50-55%) to detect the presence of bronchiectasis. CONCLUSIONS These data suggest that lung clearance index may be a useful surveillance tool to monitor structural lung disease in preschool and school-age children with CF. However, lung clearance index cannot replace chest computed tomography to screen for bronchiectasis in this population.

Role of high-resolution computed tomography in the detection of early cystic fibrosis lung disease

High-resolution computed tomography (HRCT) has been demonstrated to be sensitive at detecting early lung disease in cystic fibrosis (CF), often before it is apparent clinically. There is emerging evidence that structural changes in the lung occur earlier in life than previously appreciated. Despite this, the role of HRCT in young children with CF has yet to be defined, principally because the repeated exposure of children to X-ray doses several multiples that of a standard chest X-ray raises the concern of the long-term risks of ionizing radiation. With the challenges of acquiring HRCT images in young children in mind, we review scanning protocols and settings specific to young children, and review the best available evidence that describes early structural lung disease in young children with CF. The role of CT scoring and quantitative measures of CF lung disease are reviewed. The challenge for the future is to develop techniques that provide clinically useful information at the lowest possible radiation risk.

Assessment of Early Bronchiectasis in Young Children With Cystic Fibrosis Is Dependent on Lung Volume

OBJECTIVE The aim of this study was to determine whether assessment of early CT scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume. METHODS This study, approved by the hospital ethics committee, included 40 young children with CF from a newborn screened population contributing paired volume-controlled inspiratory and expiratory volumetric chest CT scans acquired under general anesthesia while clinically stable. Bronchiectasis was assessed with a semiquantitative CT scan score in inspiration and expiration, and the sensitivity of the expiratory CT scan to detect bronchiectasis was compared with the inspiratory CT scan by sensitivity and intraclass correlation coefficient analysis and Bland-Altman plots. Matched inspiratory and expiratory airway-vessel measurements were obtained in a subset of 10 children, and the relationship between lung volume and airway:vessel ratio after adjusting for age and vessel size was examined with the use of a linear regression model with generalized estimating equations. The number of visible airways in inspiration and expiration was compared in all 40 children by Wilcoxon signed rank test. RESULTS Expiratory scans had poor sensitivity (0.46) to detect bronchiectasis, underestimating disease extent (P < .001). Airway:vessel ratios were consistently higher in inspiration, independent of age and vessel size (P < .001), with significantly more airways visible in inspiration than in expiration, independent of age (median, 71 vs 28, respectively; P < .001). CONCLUSIONS In young children with CF, radiologic assessment of early bronchiectasis with chest CT scan depends on lung volume; thus, expiratory scans may not be appropriate for evaluating bronchiectasis in this population. Lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children.

A randomized trial of catheters of different lengths to achieve right atrium versus superior vena cava placement for continuous renal replacement therapy

BACKGROUND The aim was to assess whether inserting a longer soft silicone short-term dialysis catheter targeting tip placement in the right atrium could improve dialyzer circuit life span compared with inserting a shorter dialysis catheter targeting tip placement in the superior vena cava. STUDY DESIGN Randomized unblinded controlled study. SETTING & PARTICIPANTS A tertiary multidisciplinary intensive care unit enrolling 100 critically ill patients requiring continuous renal replacement therapy (CRRT). INTERVENTION Placement of longer (20-24 cm) versus shorter dialysis catheters (15-20 cm) within one of the major thoracic veins for initiation of CRRT. OUTCOMES The primary study outcome was duration of dialysis circuit life span. Secondary outcomes included delivered daily dialysis dose, incidence and cause of CRRT circuit failure, complications potentially related to the position of the short-term dialysis catheter, mortality, and patient length of stay. RESULTS Placing the longer dialysis catheters was associated with an increased average dialyzer life span of 6.5 hours (24 hours [25th-75th percentile, 11-32] vs 17.5 hours [25th-75th percentile, 8-23]; P = 0.001), improved delivered daily dialysis dose (91% [25th-75th percentile, 85%-100%] vs 81% [25th-75th percentile, 72%-97%]; P < 0.001), and reduced number of dialyzers clotted (2.3 vs 3.6; P = 0.04) or circuits taken down due to vascular access problem (0.19 vs 0.53; P = 0.04) per patient compared with placing shorter dialysis catheters. The incidence of atrial arrhythmias was similar between groups (28% vs 21%; P = 0.6) and the only mechanical complication was the malposition of one dialysis catheter tip in the longer dialysis catheter group. LIMITATIONS Single-center study design. CONCLUSIONS The use of longer soft silicone short-term dialysis catheters targeting right atrial placement appeared to be safe and could improve dialyzer life span and daily dialysis dose of CRRT delivered compared with the use of shorter catheters targeting superior vena cava placement.