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.

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.

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 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.

Infection, inflammation, and lung function decline in infants with cystic fibrosis.

RATIONALE: Better understanding of evolution of lung function in infants with cystic fibrosis (CF) and its association with pulmonary inflammation and infection is crucial in informing both early intervention studies aimed at limiting lung damage and the role of lung function as outcomes in such studies. OBJECTIVES: To describe longitudinal change in lung function in infants with CF and its association with pulmonary infection and inflammation. METHODS: Infants diagnosed after newborn screening or clinical presentation were recruited prospectively. FVC, forced expiratory volume in 0.5 seconds (FEV(0.5)), and forced expiratory flows at 75% of exhaled vital capacity (FEF(75)) were measured using the raised-volume technique, and z-scores were calculated from published reference equations. Pulmonary infection and inflammation were measured in bronchoalveolar lavage within 48 hours of lung function testing. MEASUREMENTS AND MAIN RESULTS: Thirty-seven infants had at least two successful repeat lung function measurements. Mean (SD) z-scores for FVC were -0.8 (1.0), -0.9 (1.1), and -1.7 (1.2) when measured at the first visit, 1-year visit, or 2-year visit, respectively. Mean (SD) z-scores for FEV(0.5) were -1.4 (1.2), -2.4 (1.1), and -4.3 (1.6), respectively. In those infants in whom free neutrophil elastase was detected, FVC z-scores were 0.81 lower (P=0.003), and FEV(0.5) z-scores 0.96 lower (P=0.001), respectively. Significantly greater decline in FEV(0.5) z-scores occurred in those infected with Staphylococcus aureus (P=0.018) or Pseudomonas aeruginosa (P=0.021). CONCLUSIONS: In infants with CF, pulmonary inflammation is associated with lower lung function, whereas pulmonary infection is associated with a greater rate of decline in lung function. Strategies targeting pulmonary inflammation and infection are required to prevent early decline in lung function in infants with CF.

The role of geographical location and climate on recurrent Pseudomonas infection in young children with Cystic Fibrosis.

OBJECTIVES: To determine the association between residence and climate with risk of Pseudomonas aeruginosa (Pa) and other respiratory outcomes. METHODS: We performed regular bronchoalveolar lavage and upper airway cultures in young children with CF to identify Pa infection. Children were classified for residence as regional or metropolitan. Bronchiectasis was detected on periodic chest computed tomography scans. Multilocus sequence typing determined Pa genotype. Lung function was assessed using Multiple Breath Washout. RESULTS: Of infants diagnosed with CF between 2006 and 2017, 129 were included in the study. Seven patients moved between metropolitan and regional Victoria and were excluded from analysis. Of the remaining 122 subjects, seventy-four (61%) children resided in metropolitan areas and over half (54%) were male. There were 83 Pa episodes in the 122 children who lived consistently in a geographical location. The incidence rate was 0.15 episodes per person-years. We found weak evidence of a 15% increase in the rate of Pa episodes with increasing average annual maximum temperature (95%CI (0.98, 1.36); p = .086), while the rate of Pa acquision decreased with average annual 3 pm humidity (IRR = 0.96; 95%CI(0.92, 1.0008); p = .054). The rate of Pa episodes was 2.1 times higher in regional participants (95%CI (1.4, 3.1); p = .001) and risk of second episode was more than five times greater (HR 5.7; 95%CI 1.9, 17); p = .002). No difference between regions in lung clearance index and presence of bronchiectasis was detected. CONCLUSION: Regional residence is associated with risk of acquiring recurrent infection with Pseudomonas aeruginosa in young children with CF.

Single-breath washout and association with structural lung disease in children with cystic fibrosis.

BACKGROUND: In children with cystic fibrosis (CF) lung clearance index (LCI) from multiple-breath washout (MBW) correlates with structural lung disease. As a shorter test, single-breath washout (SBW) represents an attractive alternative to assess the ventilation distribution, however, data for the correlation with lung imaging are lacking. METHODS: We assessed correlations between phase III slope (SIII) of double-tracer gas SBW, nitrogen MBW indices (LCI and moment ratios for overall ventilation distribution, Scond, and Sacin for conductive and mainly acinar ventilation, respectively) and structural lung disease assessed by chest computed tomography (CT) in children with CF. RESULTS: In a prospective cross-sectional study data from MBW, SBW, and chest CT were obtained in 32 children with CF with a median (range) age of 8.2 (5.2-16.3) years. Bronchiectasis was present in 24 (75%) children and air trapping was present in 29 (91%). Median (IQR) SIII of SBW was -138.4 (150.6) mg/mol. We found no association between SIII with either the MBW outcomes or CT scores (n = 23, association with bronchiectasis extent r = 0.10, P = 0.64). LCI and Scond were associated with bronchiectasis extent (n = 23, r = 0.57, P = 0.004; r = 0.60, P = 0.003, respectively). CONCLUSIONS: Acinar ventilation inhomogeneity measured by SBW was not associated with structural lung disease on CT. Double-tracer SBW added no benefit to indices measured by MBW.

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.

Associations between ambient PM2.5 concentrations and respiratory symptoms in Melbourne, 1998-2005.

Particulate matter (PM) has been widely associated with adverse effects on respiratory health, both overseas and in Australia. This study aimed to investigate the impacts of ambient particles of <2.5 microm diameter (PM2.5) in Melbourne on adverse respiratory symptoms. Two cohorts of adults were recruited in 1992-1998, and completed detailed respiratory questionnaires in 1998-1999 and 2004-2005. The mean age at baseline was 37.2 years, 55% were female, and the mean time lapsed between the baseline and follow-up questionnaires was 5.2 years. PM2.5 exposure was assessed from gravimetric data and routine nephelometry at monitoring stations located centrally with respect to the residence of most participants. Daily exposures to PM2.5 were averaged over the previous 12 months and mean daily exposure was 6.8 microg/m3. Logistic regression models were used to examine associations between PM2.5 exposure and adverse respiratory symptoms. Adjustment was made for age, gender, current smoking status, and medication use, but further adjustment for atopy did not alter the results. There was insufficient variability in PM2.5 exposure among participants over the study period to provide convincing evidence for or against associations between PM2.5 and adverse respiratory symptoms.

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.

Multiple breath washout cannot be used for tidal breath parameter analysis in infants.

BACKGROUND: Multiple breath washout (MBW) testing with SF6 gas mixture is routinely used to assess ventilation distribution in infants. It is currently unknown whether SF6 changes tidal breathing parameters during MBW in infants. We investigated if SF6 does change tidal breathing parameters in infants and whether a separate tidal breathing trace prior to MBW testing is necessary. METHODS: Tidal breathing during MBW was compared to standard tidal breathing in room air in healthy infants (n = 38), preterm infants (n = 41), and infants with cystic fibrosis (n = 41). Outcomes included inspiratory and expiratory times (TI and TE ), time to peak tidal inspiratory and expiratory flow (tPTIF and tPTEF), tidal volume (VT ), respiratory rate (f), and minute ventilation (VE ). RESULTS: Breath times were all significantly increased for both healthy (TE : -0.0790 [-0.10566, -0.05217]; mean difference [95% confidence intervals]) and CF (-0.109 [-0.15235, -0.06607]) infants during the MBW wash-in (P < 0.001). Healthy infants and those with CF showed decreased f during MBW wash-in (P < 0.001); however, no change in VT, resulting in a decreased VE (0.154 (0.086, 0.222) and 0.128 (0.069, 0.186) for healthy and CF infants, respectively, P < 0.001). Preterm infants experienced a decreased VE during both wash-in (0.134 [0.061, 0.207]; P < 0.001) and wash-out phases of MBW (P < 0.05). CONCLUSION: There are differences in tidal breathing parameters during MBW testing with SF6 in infants. It is, therefore, important to measure a separate tidal breathing trace in room air, prior to MBW testing to ensure rigour of tidal breath indices derived from analysis.

Induced sputum compared to bronchoalveolar lavage in young, non-expectorating cystic fibrosis children.

BACKGROUND: Induced sputum (IS) is feasible and safe in young CF children and is a readily accessible, non-invasive technique. However, it has not been compared to bronchoalveolar lavage (BAL), the gold standard for diagnosing lower airway infection. METHODS: We compared bacterial yield from IS and BAL in 11 non-expectorating CF children, aged 3 to 7.4 years. IS samples were obtained in 10/11 cases. RESULTS: Eight out of ten had the same predominant bacteria cultured from IS and BAL: Pseudomonas aeruginosa and Stenotrophomonas maltophilia[1], Staphylococcus aureus[3], and upper respiratory tract flora [4]. In one, Serratia marcescens and Haemophilus parainfluenzae were cultured from IS alone, whereas in one, non-group B Haemophilus influenzae was cultured from BAL alone. CONCLUSIONS: As proof of principle, IS samples showed good bacteriologic correlation with BAL. Larger studies are recommended to confirm IS as a clinically valuable tool and measure for early intervention studies in young CF children.

Geographical differences in first acquisition of Pseudomonas aeruginosa in cystic fibrosis.

RATIONALE: Risk of infection with Pseudomonas aeruginosa in cystic fibrosis (CF) may be associated with environmental factors. OBJECTIVES: To determine whether residential location is associated with risk of first acquisition of P. aeruginosa. METHODS: We performed bronchoalveolar lavage and upper airway cultures in children newly diagnosed with CF to identify infection with P. aeruginosa during infancy and early childhood. Children were assessed according to their residence in a regional or metropolitan area. Multilocus sequence typing was used to determine P. aeruginosa genotype. An environmental questionnaire was also administered. MEASUREMENTS AND MAIN RESULTS: A total of 105 of 120 (87.5%) infants diagnosed with CF were included in this study. Diagnosis in 65 infants (61.9%) followed newborn screening at mean age of 4.6 weeks. Sixty subjects (57.1%) were homozygous ΔF508, and 47 (44.8%) were female. Fifty-five (52.3%) infants were regional, of whom 26 (47.3%), compared with 9 of 50 (18.0%) metropolitan children, acquired infection with P. aeruginosa (odds ratio, 4.084; 95% confidence interval, 1.55-11.30). Age at acquisition was similar (regional: median, 2.31 yr; range, 0.27-5.96 yr; metropolitan: median, 3.10 yr, range, 0.89-3.70 yr). Strain typing identified P. aeruginosa genotypes often encountered in different ecological settings and little evidence of cross-infection. Ninety questionnaires (85.7%) were completed. Those who acquired P. aeruginosa were more likely to be living in a household that used water sprinkler systems (P = 0.032), but no differences were identified to explain increased risk of acquisition of P. aeruginosa in regional children. CONCLUSIONS: Geographical difference in residence of children with CF was associated with increased risk of first acquisition of P. aeruginosa, usually with strains associated with the environment rather than with cross-infection.

Lung function in preschool children with a history of wheezing measured by forced oscillation and plethysmographic specific airway resistance.

RATIONALE: Wheezing is common in preschool children, but objective evidence for airway obstruction and its reversibility are rarely available in clinical practice. We assessed whether abnormalities of lung function and bronchodilator response can be detected in preschool children using the forced oscillation technique and measurements of specific airway resistance. METHODS: Fifty-nine children with a history of wheeze and 24 healthy controls aged 3-6 years were recruited. Resistance and reactance at 6 and 8 Hz (Rrs6, Rrs8, Xrs6 and Xrs8, respectively) were measured using the forced oscillation technique and specific airway resistance was measured in a plethysmograph. z-Scores were calculated from published reference data. Tests were repeated 15 min after 400 mcg salbutamol. Bronchodilator response was expressed as the log-transformed ratio of postbronchodilator/prebronchodilator values. RESULTS: Technically acceptable measurements using the forced oscillation technique were obtained in n = 77 (93%) of children and in n = 56 (68%) using plethysmography. There was no significant difference in baseline lung function or bronchodilator response, assessed by either technique, between those with a history of wheeze and healthy controls. CONCLUSION: Measurement of lung function is feasible in preschool children, but neither of these techniques was able to identify diminished lung function or reversibility to bronchodilator in children with a history of wheeze.

Identifying peroxidases and their oxidants in the early pathology of cystic fibrosis.

We aimed to determine whether myeloperoxidase (MPO) is the main peroxidase present in the airways of children with cystic fibrosis (CF) and to assess which oxidants it produces and whether they are associated with clinical features of CF. Children with CF (n=54) and without CF (n=16) underwent bronchoscopy and bronchoalveolar lavage (BAL) for assessment of pulmonary infection and inflammation. BAL fluid was analyzed for MPO, halogenated tyrosines as markers of hypohalous acids, thiocyanate, and protein carbonyls. MPO was the only peroxidase detected in BAL samples from children with CF and its concentration was markedly higher than in controls. Levels of 3-chlorotyrosine and 3-bromotyrosine in proteins were higher in the CF group. They correlated with neutrophils and MPO. The concentration of thiocyanate in BAL samples was below 1µM. Protein carbonyl levels correlated with MPO and halogenated tyrosines in patients with CF. Levels of MPO and halogenated tyrosines were higher in children with infections, especially Pseudomonas aeruginosa, and in the presence of respiratory symptoms. They also correlated with the Kanga clinical score. Our findings suggest that MPO produces hypobromous acid as well as hypochlorous acid in the airways of children with CF and that these oxidants are involved in the early pathogenesis of CF.