Judy Park

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.

Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis.

BACKGROUND We hypothesized that the inflammatory response in the lungs of children with cystic fibrosis (CF) would vary with the type of infecting organism, being greatest with Pseudomonas aeruginosa and Staphylococcus aureus. METHODS A microbiological surveillance program based on annual bronchoalveolar lavage (BAL) collected fluid for culture and assessment of inflammation was conducted. Primary analyses compared inflammation in samples that grew a single organism with uninfected samples in cross-sectional and longitudinal analyses. RESULTS Results were available for 653 samples from 215 children with CF aged 24 days to 7 years. A single agent was associated with pulmonary infection (≥10(5) cfu/mL) in 67 BAL samples, with P. aeruginosa (n = 25), S. aureus (n = 17), and Aspergillus species (n = 19) being the most common. These microorganisms were associated with increased levels of inflammation, with P. aeruginosa being the most proinflammatory. Mixed oral flora (MOF) alone was isolated from 165 BAL samples from 112 patients, with 97 of these samples having a bacterial density ≥10(5) cfu/mL, and was associated with increased pulmonary inflammation (P < .001). For patients with current, but not past, infections there was an association with a greater inflammatory response, compared with those who were never infected (P < .05). However, previous infection with S. aureus was associated with a greater inflammatory response in subsequent BAL. CONCLUSIONS Pulmonary infection with P. aeruginosa, S. aureus, or Aspergillus species and growth of MOF was associated with significant inflammatory responses in young children with CF. Our data support the use of specific surveillance and eradication programs for these organisms. The inflammatory response to MOF requires additional investigation.

Early Respiratory Infection Is Associated with Reduced Spirometry in Children with Cystic Fibrosis

RATIONALE Pulmonary inflammation, infection, and structural lung disease occur early in life in children with cystic fibrosis. OBJECTIVES We hypothesized that the presence of these markers of cystic fibrosis lung disease in the first 2 years of life would be associated with reduced lung function in childhood. METHODS Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. We examined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalizations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model. MEASUREMENTS AND MAIN RESULTS Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of proinflammatory bacterial pathogens (Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, Aspergillus species, Streptococcus pneumoniae) in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%). CONCLUSIONS The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasizing the need for targeted therapeutic interventions in infancy to maximize functional outcomes later in life.

Respiratory impedance and bronchodilator responsiveness in healthy children aged 2-13 years

The forced oscillation technique (FOT) can be used in children as young as 2 years of age and in those unable to perform routine spirometry. There is limited information on changes in FOT outcomes in healthy children beyond the preschool years and the level of bronchodilator responsiveness (BDR) in healthy children. We aimed to create reference ranges for respiratory impedance outcomes collated from multiple centers. Outcomes included respiratory system resistance (Rrs) and reactance (Xrs), resonant frequency (Fres), frequency dependence of Rrs (Fdep), and the area under the reactance curve (AX). We also aimed to define the physiological effects of bronchodilators in a large population of healthy children using the FOT.

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.

Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF. Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life. Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150–0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484–1.612; p<0.001). Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF. Early life respiratory infections are detrimental to long-term lung function in children with cystic fibrosis http://ow.ly/PKaHn

Impact of lung disease on respiratory impedance in young children with cystic fibrosis

This study aimed to evaluate the ability of the forced oscillation technique (FOT) to detect underlying lung disease in preschool children with cystic fibrosis (CF) diagnosed following newborn screening. 184 children (aged 3–6 years) with CF underwent lung function testing on 422 occasions using the FOT to assess respiratory resistance and reactance at the time of their annual bronchoalveolar lavage collection and chest computed tomography scan. We examined associations between FOT outcomes and the presence and progression of respiratory inflammation, infection and structural lung disease. Children with CF who had pronounced respiratory disease, including free neutrophil elastase activity, infection with pro-inflammatory pathogens and structural lung abnormalities had similar FOT outcomes to those children without detectable lung disease. In addition, the progression of lung disease over 1 year was not associated with worsening FOT outcomes. We conclude that the forced oscillation technique is relatively insensitive to detect underlying lung disease in preschool children with CF. However, FOT may still be of value in improving our understanding of the physiological changes associated with early CF lung disease. Forced oscillation technique is insensitive in detecting lung disease in preschool children with cystic fibrosis http://ow.ly/R9rSU

Psychosocial characteristics and predictors of health-care use in families of young children with cystic fibrosis in Western Australia

Early childhood psychosocial experiences determine future health and health‐care use. Identifying psychosocial predictors in cystic fibrosis may inform intervention strategies that can reduce health‐care utilization.

Pulmonary infection in infants with cystic fibrosis (CF) leads to progressive ventilation inhomogenities

Background : The current guidelines for acceptable levels of ambient PM ( Methods : The PM fraction was extracted from surface soil samples from 4 communities across Western Australia. BALB/c 10 mice were intranasally exposed to 100 µg of PM . Control mice received 100 µg of polystyrene beads (2.5 µm) or vehicle 10 alone. Mice were assessed for inflammation (cellular influx, MIP-2, IL-6 and IL-1β), lung volume (plethysmography) and lung mechanics (forced oscillation technique) 6, 24 or 168 hours post-exposure. The physical and chemical characteristics of the particles were assessed by cascade impactor and ICP-MS/OES respectively. Principal component analysis of the outcome measures were used to construct lung impairment scores. Multivariate linear regression models were then used to identify the characteristics of the particles driving the lung responses. Results : Exposure to geogenic particles caused an acute inflammatory response (6 hours post-exposure), an acute impairment in lung mechanics (24 hours post-exposure) and a long term deficit in lung volume (168 hours post-exposure). Both the inflammatory response and long term deficits in lung volume were associated with the concentration of Fe and variability in particle size (GSD) while the impairment in lung mechanics was associated with Fe and particle size (MMAD). Conclusions : Despite the complex physico-chemical characteristics of geogenic dusts we were able to identify the concentration of Fe and physical dimensions of the particles as the key drivers of lung responses. Using these data we may be able to predict which communities are at greatest risk of adverse respiratory health due to high geogenic particle loads.