Prospective longitudinal association between repeated multiple breath washout measurements and computed tomography scores in children with cystic fibrosis.

BACKGROUND: Progression of structural lung disease (SLD) is a major risk factor for morbidity in patients with cystic fibrosis (CF). We studied changes in SLD and correlations with spirometry and nitrogen multiple breath washout (N2MBW) outcomes to explore associations in contemporary evolution between structural and functional abnormalities in CF lung disease. METHODS: Spirometry-controlled chest-CTs using PRAGMA-CF for scoring extent of SLD, spirometry, and N2MBW were performed at two-year intervals in school-age children with CF. RESULTS: Fifty-seven children aged 6-18 years were included. No significant progression in mean PRAGMA-CF scores was observed. Half of the children showed improvement in the proportion of bronchiectasis (%Bx). Lung Clearance Index (LCI) and the second moment ratio (M2) increased significantly and baseline values correlated significantly with SLD at follow-up (p ≤ 0.0002). The correlation between the change in M2 (∆M2) and the change in total SLD was R = 0.27 (p = 0.048). We found high negative predictive values (100%) for ∆M2<10% to exclude progression in SLD. For stable or improving values of LCI and M2, the predicted probability for progression in SLD was 16% and 14%, respectively (upper 95% confidence limit: 33%). Evolution in N2MBW and CT outcomes was discordant in half of the children. CONCLUSIONS: We found no progression in SLD over 2 years in school-age children with CF, in contrast to both LCI and M2, which along with discordant outcomes in half of the children underlines that N2MBW and CT assess different aspects of CF lung disease. However, stable outcomes from N2MBW were associated with stable structural lung disease.

Lung clearance index-triggered intervention in children with cystic fibrosis - A randomised pilot study.

HYPOTHESIS: Using increase in the lung clearance index (LCI) as a trigger for bronchoalveolar lavage (BAL) and associated antimicrobial treatment might benefit clinical outcomes in children with cystic fibrosis (CF). METHODS: A 2-year, longitudinal, interventional, randomized, controlled pilot study with quarterly visits in 5-18 years old children with CF. LCI and z-scores for the forced expired volume in 1 s (zFEV1) and body mass index (zBMI) were obtained at every visit, CF Questionnaire-revised (CFQ-R) yearly and BAL and chest computed tomography at first and last visit. Children in the intervention group had BAL performed if LCI increased >1 unit from a fixed baseline value established at first visit. If the presence of a pathogen was documented in the BAL fluid, treatment was initiated/altered accordingly. RESULTS: Twenty-nine children with CF were randomized to the control (n = 14) and intervention group (n = 15). The median (interquartile range) number of BAL procedures per child was 2.5 (2.0; 3.0) and 6.0 (4.0; 7.0) in the control and intervention group, respectively. There was no significant difference between groups in slope for the primary outcome LCI; difference was 0.21 (95% confidence interval: -0.45; 0.88) units/year. Likewise, there was no significant difference between groups in slope for the secondary outcomes zFEV1, zBMI, CFQ-R respiratory symptom score and the proportion of total disease and trapped air on chest computed tomography. CONCLUSIONS: LCI-triggered BAL and associated antimicrobial treatment did not benefit clinical outcomes in a small cohort of closely monitored school-age children with CF.

The effect of time-of-day and chest physiotherapy on multiple breath washout measures in children with clinically stable cystic fibrosis.

BACKGROUND: In this pilot study we investigated daytime variation of multiple breath nitrogen washout (N2MBW) measures in children with clinically stable cystic fibrosis. To our knowledge the effect of time-of-day on multiple breath washout measures in patients with cystic fibrosis has not previously been reported. Furthermore, we assessed the influence of chest physiotherapy on N2MBW measures. METHODS: Ten school children with cystic fibrosis performed N2MBW followed by spirometry and plethysmography in the morning and afternoon at three visits that were one month apart. Chest physiotherapy was performed immediately before the afternoon measurements at visit 2 and immediately before morning and afternoon measurements at visit 3. The influence of time-of-day and chest physiotherapy on the measures was evaluated using linear mixed models. RESULTS: There were adequate quality data from 8 children with median age (range) 9.6 (6.0; 15.1) years. Baseline lung clearance index (LCI) (range) was 9.0 (7.1; 13.0) and baseline FEV1% predicted was 97.5 (78.5; 117.9). No N2MBW measures were significantly influenced by time-of-day or chest physiotherapy. LCI (95% confidence interval) decreased non-significantly 0.05 (-0.32; 0.22) during the day and increased non-significantly 0.08 (-0.26; 0.42) after chest physiotherapy. All spirometric measures were unaffected by time-of-day and chest physiotherapy. For plethysmographic measures FRCpleth decreased significantly (p<0.01) 110 mL during the day, whereas a borderline significant (p = 0.046) decrease in ΔFRCpleth-MBW during the day and a borderline significant (p = 0.03) increase in TLC after CPT were observed. CONCLUSION: This study demonstrated that the time-of-day as well as chest physiotherapy performed immediately prior to N2MBW had no consistent or significant influence on N2MBW measures. However, we emphasize that further studies of the effect of both daytime variation and the effect of chest physiotherapy on multiple breath washout measures are warranted.

Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis.

BACKGROUND: Knowledge of between-session variability of nitrogen multiple-breath washout (N2MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N2MBW as end-point. Such information is currently sparse. METHODS: Monthly triplets of N2MBW were prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N2MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint® vs. Spiroware®). RESULTS: Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages (p=0.18); however, variability was significantly higher using Spiroware®. CONCLUSIONS: We report between-session variability of LCI using N2MBW in school-age children and adolescents with CF. LCI changes exceeding 25% may be considered clinically relevant. TestPoint® and Spiroware® can be used interchangeably in longitudinal studies.

Association between spirometry controlled chest CT scores using computer-animated biofeedback and clinical markers of lung disease in children with cystic fibrosis.

Background: Computed tomography (CT) of the lungs is the gold standard for assessing the extent of structural changes in the lungs. Spirometry-controlled chest CT (SCCCT) has improved the usefulness of CT by standardising inspiratory and expiratory lung volumes during imaging. This was a single-centre cross-sectional study in children with cystic fibrosis (CF). Using SCCCT we wished to investigate the association between the quantity and extent of structural lung changes and pulmonary function outcomes, and prevalence of known CF lung pathogens. Methods: CT images were analysed by CF-CT scoring (expressed as % of maximum score) to quantify different aspects of structural lung changes including bronchiectasis, airway wall thickening, mucus plugging, opacities, cysts, bullae and gas trapping. Clinical markers consisted of outcomes from pulmonary function tests, microbiological cultures from sputum and serological samples reflecting anti-bacterial and anti-fungal antibodies. Results: Sixty-four children with CF, median age (range) of 12.7 (6.4-18.1) years, participated in the study. The median (range) CF-CT total score in all children was 9.3% (0.4-46.8) with gas trapping of 40.7% (3.7-100) as the most abundant finding. Significantly higher median CF-CT total scores (21.9%) were found in patients with chronic infections (N = 12) including Gram-negative infection and allergic bronchopulmonary aspergillosis (ABPA) exhibiting CF-CT total scores of 14.2% (ns) and 24.0% (p < 0.01), respectively, compared to 8.0% in patients with no chronic lung infection. Lung clearance index (LCI) derived from multiple breath washout exhibited closest association with total CF-CT scores, compared to other pulmonary function outcomes. Conclusions: The most prominent structural lung change was gas trapping, while CF-CT total scores were generally low, both showing close association with LCI. Chronic lung infections, specifically in the form of ABPA, were associated with increased scores in lung changes. Further investigation of impact of infections with different microorganisms on extent and progression of structural CF lung disease is needed.

Abbreviation modalities of nitrogen multiple-breath washout tests in school children with obstructed lung disease.

RATIONALE: Nitrogen multiple-breath washout (N2 MBW) is a promising tool for assessing early lung damage in children with chronic obstructive pulmonary disease, but it can be a time-consuming procedure. We compared alternative test-shortening endpoints with the most commonly reported N2 MBW outcome, the lung clearance index, calculated as lung volume turnovers required to reach 2.5% of the starting N2 concentration (LCI2.5 ). METHODS: Cross-sectional study of triplicate N2 MBW measurements obtained in cystic fibrosis (CF) patients (N = 60), primary ciliary dyskinesia (PCD) patients (N = 28), and matched healthy controls (N = 48) aged 5-18 years. Bland-Altman analysis was used to compare LCI2.5 with earlier LCI endpoints (3%, 4%, 5%, 7%, and 9% of starting N2 concentration), Cn@TO6 (defined as % of N2 starting concentration when reaching six lung volume turnovers), and LCI derived from only two N2 MBW runs in each session. N2 MBW endpoints were analyzed as z-scores calculated from healthy controls. RESULTS: In PCD, Cn@TO6 and LCI2.5 exhibited similar values (mean [95%CI] difference: 0.33 [-0.24; 0.90] z-scores), reducing the test duration by one-third (5.4 min; 95%CI: 4.0; 6.8). All other tested alternative endpoints exhibited increasing disagreement with increasing LCI2.5 . With an average reduction in test duration of 40%, LCI2.5 derived from two runs exhibited good agreement in all children. CONCLUSIONS: Cn@TO6 may be suggested as a potential test-shortening endpoint in school children with PCD. In CF, early test termination may reduce measurement power with advancing pulmonary disease, suggesting differences in underlying pathophysiology. Two technically acceptable N2 MBW runs may be sufficient in school children irrespective of diagnosis with CF or PCD. Pediatr Pulmonol. 2016;51:624-632. © 2015 Wiley Periodicals, Inc.

Improved air trapping evaluation in chest computed tomography in children with cystic fibrosis using real-time spirometric monitoring and biofeedback.

BACKGROUND: The quality of chest Computed Tomography (CT) images in children is dependent upon a sufficient breath hold during CT scanning. This study evaluates the influence of spirometric breath hold monitoring with biofeedback software on inspiratory and expiratory chest CT lung density measures, and on trapped air (TA) scoring in children with cystic fibrosis (CF). This is important because TA is an important component of early and progressive CF lung disease. METHODS: A cross sectional comparison study was completed for chest CT imaging in two cohorts of CF children with comparable disease severity, using spirometric breath hold monitoring and biofeedback software (Copenhagen (COP)) or unmonitored breath hold manoeuvres (Gothenburg (GOT)). Inspiratory-expiratory lung density differences were calculated, and TA was scored to assess the difference between the two cohorts. RESULTS: Eighty-four chest CTs were evaluated. Mean (95%CI) change in inspiratory-expiratory lung density differences was 436 Hounsfield Units (HU) (408 to 464) in the COP cohort with spirometric breath hold monitoring versus 229 HU (188 to 269) in the GOT cohort with unmonitored breath hold manoeuvres (p<0.0001). The Mean TA (95%CI) score was 6.93 (6.05 to 7.82) in COP patients and 3.81 (2.89 to 4.73) in GOT (p<0.0001) patients. CONCLUSIONS: In children with comparable CF lung disease, spirometric breath hold monitoring during examination yielded a large difference in lung volume between inhalation and exhalation, and allowed for a significantly greater measured change in lung density and TA score, compared to unmonitored breath hold maneuvers. This has implications to the clinical use of chest CT, especially in children with early CF lung disease.

Radiology, histology and short-term outcome of asymptomatic congenital thoracic malformations.

AIM: The aim of this study was to evaluate the safety and short-term outcome of our management of asymptomatic children with antenatally diagnosed congenital thoracic malformations (CTM), compared with recommendations from a recent review and meta-analysis. METHODS: Twenty-two asymptomatic children with CTM, born in January 1, 2002 to January 8, 2009 were reviewed. Data on complications and respiratory symptoms were collected. RESULTS: No severe respiratory symptoms were recorded. Seventeen children were referred to surgery. Complications were seen in one child. The final diagnoses were congenital pulmonary airway malformation (CPAM) in 13 children, two had sequestrations, and two had other significant malformations. Five children had minor malformations and did not undergo surgery. No malignancies were reported. CONCLUSION: Elective surgery at 1 year of age is safe and carries no apparent risk to asymptomatic children with CTM. The rate of complications was equal to that reported in a recent review and meta-analysis.