Airway epithelium respiratory illnesses and allergy (AERIAL) birth cohort: study protocol.

Introduction: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. Methods: The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to 5 years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to 6 weeks, 1, 3, and 5 years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Discussion: The AERIAL study will provide a comprehensive longitudinal assessment of factors influencing the association between epithelial dysfunction and respiratory morbidity in early life, and hopefully identify novel targets for diagnosis and early intervention.

Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) birth cohort: study protocol.

Introduction: Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. Methods and Analysis: The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to five years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to six weeks, one, three, and five years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. Ethics and Dissemination: Ethical approval has been obtained from Ramsey Health Care HREC WA-SA (#1908). Results will be disseminated through open-access peer-reviewed manuscripts, conference presentations, and through different media channels to consumers, ORIGINS families, and the wider community.

A screening tool to identify risk for bronchiectasis progression in children with cystic fibrosis.

BACKGROUND: The marked heterogeneity in cystic fibrosis (CF) disease complicates the selection of those most likely to benefit from existing or emergent treatments. OBJECTIVE: We aimed to predict the progression of bronchiectasis in preschool children with CF. METHODS: Using data collected up to 3 years of age, in the Australian Respiratory Early Surveillance Team for CF cohort study, clinical information, chest computed tomography (CT) scores, and biomarkers from bronchoalveolar lavage were assessed in a multivariable linear regression model as predictors for CT bronchiectasis at age 5-6. RESULTS: Follow-up at 5-6 years was available in 171 children. Bronchiectasis prevalence at 5-6 was 134/171 (78%) and median bronchiectasis score was 3 (range 0-12). The internally validated multivariate model retained eight independent predictors accounting for 37% (adjusted R2 ) of the variance in bronchiectasis score. The strongest predictors of future bronchiectasis were: pancreatic insufficiency, repeated intravenous treatment courses, recurrent lower respiratory infections in the first 3 years of life, and lower airway inflammation. Dichotomizing the resulting prediction score at a bronchiectasis score of above the median resulted in a diagnostic odds ratio of 13 (95% confidence interval [CI], 6.3-27) with positive and negative predictive values of 80% (95% CI, 72%-86%) and 77% (95% CI, 69%-83%), respectively. CONCLUSION: Early assessment of bronchiectasis risk in children with CF is feasible with reasonable precision at a group level, which can assist in high-risk patient selection for interventional trials. The unexplained variability in disease progression at individual patient levels remains high, limiting the use of this model as a clinical prediction tool.

BAL Inflammatory Markers Can Predict Pulmonary Exacerbations in Children With Cystic Fibrosis.

BACKGROUND: Pulmonary exacerbations in cystic fibrosis are characterized by airway inflammation and may cause irreversible lung damage. Early identification of such exacerbations may facilitate early initiation of treatment, thereby potentially reducing long-term morbidity. RESEARCH QUESTION: Is it possible to predict pulmonary exacerbations in children with cystic fibrosis, using inflammatory markers obtained from BAL fluid? STUDY DESIGN AND METHODS: A longitudinal analysis was conducted of children aged 0 to 7 years included in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) study between 2005 and 2015. The association between inflammatory markers from annual BAL fluid and time to pulmonary exacerbation requiring hospital admission in the 6-month period post-BAL was analyzed using Kaplan-Meier curves and Weibull regression, adjusting for annually repeated measurements. Admissions for Pseudomonas eradication were excluded in the main analysis, because of the standard policy in participating centers to treat Pseudomonas in-hospital. RESULTS: Nine hundred seventy-six BAL samples from 308 children were analyzed. After exclusion of admissions for Pseudomonas eradication (n = 43), there were 145 pulmonary exacerbations recorded within 6 months of BAL; median time to exacerbation was 31 days (interquartile range, 9-100). In univariate analyses, high IL-8 (hazard ratio [HR], 2.25 for 75th vs 25th percentile; 95% CI, 1.87-2.72), neutrophil elastase (HR, 3.00; 95% CI, 2.03-4.42), and high neutrophil percentage (HR, 1.80 for 75th vs 25th percentile; 95% CI, 1.56-2.04) were all significantly associated with risk for a pulmonary exacerbation (P < .001). The inflammatory markers remained significant predictors after adjustment for clinical predictive variables. INTERPRETATION: Inflammatory markers in BAL fluid are significant predictors of pulmonary exacerbations in young children with cystic fibrosis. The development of noninvasive measures of lung inflammation may facilitate routine surveillance of cystic fibrosis.

Structural determinants of long-term functional outcomes in young children with cystic fibrosis.

BACKGROUND: Accelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients. METHODS: Annual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5-6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean±sd age 9.3±2.1 years). RESULTS: Children with a total CT score above the median at age 5-6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV1) (adjusted hazard ratio 2.67 (1.06-6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change -0.17 (-0.26 - -0.07) p<0.001 and -0.09 (-0.14 - -0.04) p<0.001, respectively). DISCUSSION: Chest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.

Aspergillus Infections and Progression of Structural Lung Disease in Children with Cystic Fibrosis.

Rationale: Recent data show that Aspergillus species are prevalent respiratory infections in children with cystic fibrosis (CF). The biological significance of these infections is unknown.Objectives: We aimed to evaluate longitudinal associations between Aspergillus infections and lung disease in young children with CF.Methods: Longitudinal data on 330 children participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis surveillance program between 2000 and 2018 who underwent annual chest computed tomography (CT) imaging and BAL were used to determine the association between Aspergillus infections and the progression of structural lung disease. Results were adjusted for the effects of other common infections, associated variables, and repeated visits. Secondary outcomes included inflammatory markers in BAL, respiratory symptoms, and admissions for exacerbations.Measurements and Main Results:Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa, and Aspergillus infections were all associated with worse CT scores in the same year (Poverall < 0.05). Only P. aeruginosa and Aspergillus were associated with progression in CT scores in the year after an infection and worse CT scores at the end of the observation period. P. aeruginosa was most significantly associated with development of bronchiectasis (difference, 0.9; 95% confidence interval, 0.3-1.6; P = 0.003) and Aspergillus with trapped air (difference, 3.2; 95% confidence interval, 1.0-5.4; P = 0.004). Aspergillus infections were also associated with markers of neutrophilic inflammation (P < 0.001) and respiratory admissions risk (P = 0.008).Conclusions: Lower respiratory Aspergillus infections are associated with the progression of structural lung disease in young children with CF. This study highlights the need to further evaluate early Aspergillus species infections and the feasibility, risk, and benefit of eradication regimens.

The cumulative effect of inflammation and infection on structural lung disease in early cystic fibrosis.

INTRODUCTION: Pulmonary inflammation and infection are important clinical and prognostic markers of lung disease in cystic fibrosis (CF). However, whether in young children they are transient findings or have cumulative, long-term impacts on respiratory health is largely unknown. We aimed to determine whether their repeated detection has a deleterious effect on structural lung disease. METHODS: All patients aged <6 years with annual computed tomography (CT) and bronchoalveolar lavage (BAL) were included. Structural lung disease on CT (%Disease) was determined using the PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) method. The number of times free neutrophil elastase (NE) and infection were detected in BAL were counted, to determine cumulative BAL history. Linear mixed model analysis, accounting for repeat visits and adjusted for age, was used to determine associations. RESULTS: 265 children (683 scans) were included for analysis, with BAL history comprising 1161 visits. %Disease was significantly associated with the number of prior NE (0.31, 95% CI 0.09-0.54; p=0.007) but not infection (0.23, 95% CI -0.01-0.47; p=0.060) detections. Reference equations were determined. CONCLUSIONS: Pulmonary inflammation in surveillance BAL has a cumulative effect on structural lung disease extent, more so than infection. This provides a strong rationale for therapies aimed at reducing inflammation in young children.

Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis.

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography-defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared "permanent" because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but not N-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

Changing Prevalence of Lower Airway Infections in Young Children with Cystic Fibrosis.

Rationale: Historical studies suggest that airway infection in cystic fibrosis initiates with Staphylococcus aureus and Haemophilus influenzae, with later emergence of Pseudomonas aeruginosa. Aspergillus species are regarded as relatively infrequent, late-occurring infections.Objectives: To assess the prevalence and change in prevalence of early lower airway infections in a modern cohort of children with cystic fibrosis.Methods: All infants diagnosed with cystic fibrosis after newborn screening participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) cohort study between 2000 and 2018 were included. Participants prospectively underwent BAL at 3-6 months, 1 year, and annually up to 6 years of age. Lower airway infection prevalence was described. Changes in prevalence patterns were assessed longitudinally using generalized estimating equations controlling for age and repeated visits.Measurements and Main Results: A total of 380 infants underwent 1,759 BALs. The overall prevalence and median age of first acquisition of the most common infections were as follows: S. aureus, 11%, 2.5 years; P. aeruginosa, 8%, 2.4 years; Aspergillus species, 11%, 3.2 years; and H. influenzae, 9%, 3.1 years. During the study, a significant decrease in prevalence of P. aeruginosa (P < 0.001) and S. aureus (P < 0.001) was observed with a significant change toward more aggressive treatment. Prevalence of Aspergillus infections did not significantly change (P = 0.669).Conclusions:Aspergillus species and P. aeruginosa are commonly present in the lower airways from infancy. The decrease in prevalence of P. aeruginosa and S. aureus since 2000, coinciding with a more aggressive therapeutic approach, has resulted in Aspergillus becoming the most commonly isolated pathogen in young children. Further research is warranted to understand the implication of these findings.

Intra-breath measures of respiratory mechanics in healthy African infants detect risk of respiratory illness in early life.

Lower respiratory tract illness (LRTI) is a leading cause of mortality and morbidity in children. Sensitive and noninvasive infant lung function techniques are needed to measure risk for and impact of LRTI on lung health. The objective of this study was to investigate whether lung function derived from the intra-breath forced oscillation technique (FOT) was able to identify healthy infants at risk of LRTI in the first year of life.Lung function was measured with the novel intra-breath FOT, in 6-week-old infants in a South African birth cohort (Drakenstein Child Health Study). LRTI during the first year was confirmed by study staff. The association between baseline lung function and LRTI was assessed with logistic regression and odds ratios determined using optimal cut-off values.Of the 627 healthy infants with successful lung function testing, 161 (24%) had 238 LRTI episodes subsequently during the first year. Volume dependence of respiratory resistance (ΔR) and reactance (ΔX) was associated with LRTI. The predictive value was stronger if LRTI was recurrent (n=50 (31%): OR 2.5, ΔX), required hospitalisation (n=38 (16%): OR 5.4, ΔR) or was associated with wheeze (n=87 (37%): OR 3.9, ΔX).Intra-breath FOT can identify healthy infants at risk of developing LRTI, wheezing or severe illness in the first year of life.

Predicting disease progression in cystic fibrosis.

INTRODUCTION: Progressive lung disease is the major cause of morbidity and mortality in patients with cystic fibrosis (CF). Methods of correctly predicting the future progression of lung disease in patients with CF are essential for directing aggressive treatment to prevent loss of lung function and end stage respiratory failure. Areas covered: This review addresses predictors of respiratory disease progression in patients with CF. We searched Web of Science and Medline, with no restriction on publication date, with the search terms 'cystic fibrosis' and 'disease progression', 'lung function decline', 'prognosis', 'prediction/predictive', 'prediction/prognostic scores', 'risk factors', 'outcome measures/endpoints/disease surrogate', 'longitudinal/long term', 'statistical model', and 'survival'. Expert commentary: Forced expiratory volume in 1 sec (FEV1) and rate of FEV1 decline, remain the most significant predictors of mortality in patients with CF while CT scores and airway secretion biomarkers are the main predictors of early CF lung disease. Comprehensive scores incorporating clinical, lung function, imaging and laboratory data will become essential in the future for predicting disease progression and for use in clinical trials. Early interventions may delay the progression of structural lung disease.

Lung function trajectories throughout childhood in survivors of very preterm birth: a longitudinal cohort study.

BACKGROUND: Data on longitudinal respiratory follow-up after preterm birth in the surfactant era are scarce and of increasing importance, with concerns that preterm survivors are destined for early onset chronic obstructive airway disease. We aimed to comprehensively assess lung function longitudinally from early childhood to mid-childhood in very preterm children (≤32 weeks gestation), and to explore factors negatively impacting on lung function trajectories. METHODS: Preterm children (with and without bronchopulmonary dysplasia) and healthy term children as controls were studied. All preterm participants were born at 32 weeks' gestation or earlier at King Edward Memorial Hospital, Perth, WA, Australia, between 1997 and 2003. Bronchopulmonary dysplasia was defined as at least 28 days of supplemental oxygen requirement as assessed at 36 weeks' post-menstrual age. Spirometry, oscillatory mechanics, gas exchange, lung volumes, and respiratory symptoms were assessed at three visits, two in early childhood (4-8 years) and one in mid-childhood (9-12 years). CT of the chest was done in preterm children in mid-childhood. Respiratory symptoms were documented via questionnaire at each visit. Data were analysed longitudinally using linear mixed models. FINDINGS: 200 very preterm children (126 with bronchopulmonary dysplasia and 74 without bronchopulmonary dysplasia) and 67 healthy term control children attended 458 visits between age 4 and 12 years. Chest CT was done on 133 preterm children at a mean age of 10·9 (SD 0·6) years. Preterm children, with and without bronchopulmonary dysplasia, had declines in spirometry z-scores over time compared with controls: forced expiratory volume in 1 s (FEV1), forced expiratory flow at 25-75% of the pulmonary volume, and FEV1/forced vital capacity all declined by at least 0·1 z-score per year in children with bronchopulmonary dysplasia (all p<0·001). Respiratory mechanics and gas exchange also deteriorated over time in children with bronchopulmonary dysplasia (relative to term controls, respiratory system reactance at 8 Hz decreased by -0·05 z-score per year [95% CI -0·08 to -0·01; p=0·006] and diffusing capacity of the lungs for carbon monoxide decreased by -0·03 z-score per year [95% CI -0·06 to -0·01; p=0·048]). Preterm children with bronchial wall thickening on chest CT (suggestive of inflammation) had bigger decreases in spirometry outcomes through childhood. For example, children with bronchial wall thickening on chest CT had an FEV1 z-score decline of -0·61 (95% CI -1·03 to-0·19; p=0·005) more than those without. Similarly, children exposed to tobacco smoke, those with earlier gestation, or those requiring more neonatal supplemental oxygen declined at a faster rate. INTERPRETATION: Lung function trajectories are impaired in survivors of very preterm birth. Survivors with bronchopulmonary dysplasia, ongoing respiratory symptoms, or CT changes reflecting inflammation have the poorest trajectories and might be at increased risk of lung disease in later life. Close targeted pulmonary follow-up of these individuals is necessary. FUNDING: National Health and Medical Research Council grants APP634519, APP1073301 (to SJS), APP1077691 (to JJP), and APP1025550 (to GLH), Princess Margret Hospital Foundation, and Raine Medical Foundation.

Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis.

BACKGROUND: Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF. METHODS: Bronchoalveolar lavage fluid (BALf) from 102 children with CF were used to determine IL-1α, IL-1ß, IL-8 levels and neutrophil elastase (NE) activity, which were then correlated to structural lung changes observed on chest computed tomography (CT) scans. RESULTS: IL-1α and IL-1ß were detectable in BAL in absence of infection, increased in the presence of bacterial infection and correlated with IL-8 (p < 0.0001), neutrophils (p < 0.0001) and NE activity (p < 0.01 and p < 0.001). IL-1α had the strongest association with structural lung disease (p < 0.01) in the absence of infection (uninfected: p < 0.01 vs. infected: p = 0.122). CONCLUSION: Our data associates IL-1α with early structural lung damage in CF and suggests this pathway as a novel anti-inflammatory target.

The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials.

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3-6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible.

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.

The association between Staphylococcus aureus and subsequent bronchiectasis in children with cystic fibrosis.

BACKGROUND: Staphylococcus aureus (S. aureus) may be related to more rapid progression of cystic fibrosis (CF) lung disease. METHODS: In the AREST CF cohort study, children diagnosed with CF undergo annual bronchoscopies with bronchoalveolar lavage and ultra-low-dose, chest computed tomography (CT) up to 6-years-old. Spirometry was assessed 3-monthly from the age of 4years. Associations between de novo S. aureus acquisition before school age and CT and lung function at ages 5-7years were investigated. Models were adjusted for multiple markers of disease severity at baseline. RESULTS: De novo S. aureus acquisition at 3-years-old (n/N=12/122) was associated with increased bronchiectasis score at age 5-6years. This association decreased but remained significant after adjustment for confounders. S. aureus at 3 was associated with significantly reduced FEF25-75 at age 5-7years, but not with FEV1-%-predicted. CONCLUSION: De novo S. aureus acquisition at age 3 is associated with later bronchiectasis and FEF25-75 in children with CF.

Quantitative assessment of airway dimensions in young children with cystic fibrosis lung disease using chest computed tomography.

OBJECTIVE: To evaluate lung disease progression using airway and artery (AA) dimensions on chest CT over 2-year interval in young CF patients longitudinally and compare to disease controls cross-sectionally. METHODS: Retrospective analysis of pressure controlled end-inspiratory CTs, 12 routine baseline (CT1 ) and follow up (CT2 ) from AREST CF cohort; 12 disease controls with normal CT. All visible AA-pairs were measured perpendicular to the airway axis. Inner and outer airway diameters and wall (outer-inner radius) thickness were divided by adjacent arteries to compute Ain A-, Aout A-, and AWT A-ratios, respectively. Differences between CF and control data were assessed using mixed effects models predicting AA-ratios per segmental generation (SG). Power calculations were performed with 80% power and ɑ = 0.05. RESULTS: CF, median age CT1 2 years; CT2 3.9 years, 5 males. Controls, median age 2.9 years, 10 males. Total of 4798 AA-pairs measured. Cross-sectionally: Ain A-ratio showed no difference between controls and CF CT1 or CT2 . Aout A-ratio was significantly higher in CF CT1 (SG 2-4) and CT2 (SG 2-5) compared to controls. AWT A-ratio was increased for CF CT1 (SG 1-5) and CT2 (SG 2-6) compared to controls. CF longitudinally: Ain A-ratio was significantly higher at CT2 compared to CT1 . Increase in Aout A-ratio at CT2 compared to CT1 was visible in SG ≥4. Sample sizes of 21 and 58 would be necessary for 50% and 30% Aout A-ratio reductions, respectively, between CF CT2 and controls. CONCLUSION: AA-ratio differences were present in young CF patients relative to disease controls. Aout A-ratio as an objective parameter for bronchiectasis could reduce sample sizes for clinical trials.

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

INTRODUCTION: 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. MATERIALS AND METHODS: Children aged below 7 years undergoing inspiratory/expiratory CT were recruited from the Australian Respiratory Early Surveillance Team for Cystic Fibrosis cohort. Automated lung segmentation was used to determine functional residual capacity (FRC), total lung capacity (TLC), and their ratio (FRC/TLC). Structural lung disease (%Disease) and air trapping (%TrappedAir) extent were assessed using PRAGMA-CF. Lung clearance index (LCI), an index of ventilation heterogeneity, was measured. Linear mixed model analysis was used to determine associations. RESULTS: Seventy-three scans from 55 patients were obtained. %TrappedAir was associated with %Disease (0.19 [0.07, 0.31]; P = 0.003) and LCI (0.22 [0.04, 0.39]; P = 0.016), but not FRC/TLC (0.00 [-0.02, 0.02]; P = 0.931). DISCUSSION: CT mosaic attenuation is associated with CF lung disease, however it is not always accompanied by physiologic hyperinflation. Other pathologies may contribute to mosaic attenuation. A better understanding of these factors could guide future therapies.

Multiple-Breath Washout Outcomes Are Sensitive to Inflammation and Infection in Children with Cystic Fibrosis.

RATIONALE: The lung clearance index is a measure of ventilation distribution derived from the multiple-breath washout technique. The lung clearance index is increased in the presence of lower respiratory tract inflammation and infection in infants with cystic fibrosis; however, the associations during the preschool years are unknown. OBJECTIVES: We assessed the ability of the lung clearance index to detect the presence and extent of lower respiratory tract inflammation and infection in preschool children with cystic fibrosis. METHODS: Ventilation distribution outcomes were assessed at 82 visits with 58 children with cystic fibrosis and at 38 visits with 31 healthy children aged 3-6 years. Children with cystic fibrosis also underwent bronchoalveolar lavage fluid collection for detection of lower respiratory tract inflammation and infection. Associations between multiple-breath washout indices and the presence and extent of airway inflammation and infection were assessed using linear mixed effects models. RESULTS: Lung clearance index was elevated in children with cystic fibrosis (mean [SD], 8.00 [1.45]) compared with healthy control subjects (6.67 [0.56]). In cystic fibrosis, the lung clearance index was elevated in individuals with lower respiratory tract infections (difference compared with uninfected [95% confidence interval], 0.62 [0.06, 1.18]) and correlated with the extent of airway inflammation. CONCLUSIONS: These data suggest that the lung clearance index may be a useful surveillance tool for monitoring the presence and extent of lower airway inflammation and infection in preschool children with cystic fibrosis.