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.

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.

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.

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.

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.

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.

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.

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.

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.

Pressurised metered dose inhaler-spacer technique in young children improves with video instruction.

UNLABELLED: The importance of good device technique to maximise delivery of aerosolised medications is widely recognised. Pressurised metered dose inhaler (pMDI)-spacer technique was investigated in 122 children, aged 2-7 years, with asthma. Eight individual steps of device technique were evaluated before and after viewing an instructional video for correct device technique. Video measurements were repeated every three months for nine months. Device technique improved directly after video instruction at the baseline study visit (p < 0.001) but had no immediate effect at subsequent visits. Additionally, pMDI-spacer technique improved with successive visits over one year for the group overall as evidenced by increases in the proportion of children scoring maximal (p = 0.02) and near-maximal (p = 0.04) scores. CONCLUSION: Repeated video instruction over time improves inhaler technique in young children. WHAT IS KNOWN: • Correct device technique is considered essential for sufficient delivery of inhaled medication. • Poor inhaler use is common in young asthmatic children using pressurised metered dose inhalers and spacers. What is New: • Video instruction could be used as a strategy to improve device technique in young children.