Lidija Turkovic

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.

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

Lung Function in African Infants in the Drakenstein Child Health Study: Impact of Lower Respiratory Tract Illness.

Rationale: Lower respiratory tract illness is a major cause of childhood morbidity and mortality. It is unknown whether infants are predisposed to illness because of impaired lung function or whether respiratory illness reduces lung function. Objectives: To investigate the impact of early life exposures, including lower respiratory tract illness, on lung function during infancy. Methods: Infants enrolled in the Drakenstein child health study had lung function at 6 weeks and 1 year. Testing during quiet natural sleep included tidal breathing, exhaled nitric oxide, and multiple breath washout measures. Risk factors for impaired lung health were collected longitudinally. Lower respiratory tract illness surveillance was performed and any episode investigated. Measurements and Main Results: Lung function was tested in 648 children at 1 year. One hundred and fifty (29%) infants had a lower respiratory tract illness during the first year of life. Lower respiratory tract illness was independently associated with increased respiratory rate (4%; 95% confidence interval [CI], 1.01‐1.08; P = 0.02). Repeat episodes further increased respiratory rate (3%; 95% CI, 1.01‐1.05; P = 0.004), decreased tidal volume (−1.7 ml; 95% CI, −3.3 to −0.2; P = 0.03), and increased the lung clearance index (0.13 turnovers; 95% CI, 0.04‐0.22; P = 0.006) compared with infants without illness. Tobacco smoke exposure, lung function at 6 weeks, infant growth, and prematurity were other independent predictors of lung function at 1 year. Conclusions: Early life lower respiratory tract illness impairs lung function at 1 year, independent of baseline lung function. Preventing early life lower respiratory tract illness is important to optimize lung function and promote respiratory health in childhood.

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis, but the mechanisms underlying this pathway are incompletely understood. Metabolites associated with neutrophilic inflammation were identified by discovery metabolomics on bronchoalveolar lavage fluid supernatant from 20 preschool children (2.9±1.3 years) with cystic fibrosis. Targeted mass-spectrometric detection of relevant metabolites was then applied to 34 children (3.5±1.5 years) enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) who underwent chest computed tomography and bronchoalveolar lavage from two separate lobes during 42 visits. Relationships between metabolites and localised structural lung disease were assessed using multivariate analyses. Discovery metabolomics identified 93 metabolites associated with neutrophilic inflammation, including pathways involved in metabolism of adenyl purines, amino acids and small peptides, cellular energy and lipids. In targeted mass spectrometry, products of adenosine metabolism, protein catabolism and oxidative stress were associated with structural lung disease and predicted future bronchiectasis, and activities of enzymes associated with adenosine metabolism were elevated in the samples with early disease. Metabolomics analyses revealed metabolites and pathways altered with neutrophilic inflammation and destructive lung disease. These pathways can serve as biomarkers and potential therapeutic targets for early cystic fibrosis lung disease. Metabolomics in preschool children with CF reveals biomarkers that correlate with and predict early disease http://ow.ly/c7rb303Lc9y

Induced sputum to detect lung pathogens in young children with cystic fibrosis

Induced sputum sampling holds promise as a method for obtaining samples representative of the lower airways in young children. Collection of induced sputum samples in young children differs from older children and adults’ as pharyngeal suctioning is often required. Our aim was to determine the sensitivity and specificity of induced sputum with and without airway clearance techniques to detect lower airway pathogens in children less than age 7 with cystic fibrosis.

Chest imaging in cystic fibrosis studies: What counts, and can be counted?

BACKGROUND The dawn of precision medicine and CFTR modulators require more detailed assessment of lung structure in cystic fibrosis (CF) clinical studies. Various imaging markers have emerged and are measurable, but clarity is needed to identify what markers should count for clinical studies. High-resolution chest computed tomography (CT) scoring has yielded sensitive markers for the study of CF disease progression. Once completed, CT scores from ongoing randomized controlled trials can be used to examine relationships between imaging endpoints and therapeutic effectiveness. Similarly, Magnetic Resonance Imaging (MRI) is in development to generate structural as well as functional markers. RESULTS The aim of this review is to characterize the role of currently available CT and MRI markers in clinical studies, and to discuss study design, data processing and statistical challenges unique to these endpoints in CF studies. Suggestions to overcome these challenges in CF studies are included. CONCLUSIONS To maximize the potential of CT and MRI markers in clinical studies and advance treatment of CF disease progression, efforts should be made to conduct longitudinal randomized controlled trials including these modalities, develop data repositories, promote standardization and conduct reproducible research.

Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children

The cystic fibrosis (CF) lung microbiome has been studied in children and adults; however, little is known about its relationship to early disease progression. To better understand the relationship between the lung microbiome and early respiratory disease, we characterized the lower airways microbiome using bronchoalveolar lavage (BAL) samples obtained from clinically stable CF infants and preschoolers who underwent bronchoscopy and chest computed tomography (CT). Cross-sectional samples suggested a progression of the lower airways microbiome with age, beginning with relatively sterile airways in infancy. By age two, bacterial sequences typically associated with the oral cavity dominated lower airways samples in many CF subjects. The presence of an oral-like lower airways microbiome correlated with a significant increase in bacterial density and inflammation. These early changes occurred in many patients, despite the use of antibiotic prophylaxis in our cohort during the first two years of life. The majority of CF subjects older than four harbored a pathogen dominated airway microbiome, which was associated with a further increase in inflammation and the onset of structural lung disease, despite a negligible increase in bacterial density compared to younger patients with an oral-like airway microbiome. Our findings suggest that changes within the CF lower airways microbiome occur during the first years of life and that distinct microbial signatures are associated with the progression of early CF lung disease.

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

Air trapping in early cystic fibrosis lung disease—Does CT tell the full story?

Mosaic attenuation on expiratory chest computed tomography (CT) is common in early life cystic fibrosis (CF) and often referred to as “air trapping”. It is presumed to be localized hyperinflation due to small airway obstruction. In order to test this assumption, we compared air trapping extent to lung volumes measured on CT in young children with CF.