Longitudinal course of clinical lung clearance index in children with cystic fibrosis.

BACKGROUND: Although the lung clearance index (LCI) is a sensitive marker of small airway disease in individuals with cystic fibrosis (CF), less is known about longitudinal changes in LCI during routine clinical surveillance. Here, our objectives were to describe the longitudinal course of LCI in children with CF during routine clinical surveillance and assess influencing factors. METHODS: Children with CF aged 3-18 years performed LCI measurements every 3 months as part of routine clinical care between 2011 and 2018. We recorded clinical data at every visit. We used a multilevel mixed effect model to determine changes in LCI over time and identify clinical factors that influence LCI course. RESULTS: We collected LCI measurements from 1204 visits (3603 trials) in 78 participants, of which 907 visits had acceptable LCI data. The average unadjusted increase in LCI for the entire population was 0.29 (95% CI 0.20-0.38) LCI units·year-1. The increase in LCI was more pronounced in adolescence (0.41 (95% CI 0.27-0.54) LCI units·year-1). Colonisation with either Pseudomonas aeruginosa or Aspergillus fumigatus, pulmonary exacerbations, CF-related diabetes and bronchopulmonary aspergillosis were associated with a higher increase in LCI over time. Adjusting for clinical risk factors reduced the increase in LCI over time to 0.24 (95% CI 0.16-0.33) LCI units·year-1. CONCLUSIONS: LCI measured during routine clinical surveillance is associated with underlying disease progression in children with CF. An increased change in LCI over time should prompt further diagnostic intervention.

A computerized tool for the systematic visual quality assessment of infant multiple-breath washout measurements.

Background: Multiple-breath washout (MBW) is a sensitive method for assessing lung volumes and ventilation inhomogeneity in infants, but remains prone to artefacts (e.g., sighs). There is a lack of tools for systematic retrospective analysis of existing datasets, and unlike N2-MBW in older children, there are few specific quality control (QC) criteria for artefacts in infant SF6-MBW. Aim: We aimed to develop a computer-based tool for systematic evaluation of visual QC criteria of SF6-MBW measurements and to investigate interrater agreement and effects on MBW outcomes among three independent examiners. Methods: We developed a software package for visualization of raw Spiroware (Eco Medics AG, Switzerland) and signal processed WBreath (ndd Medizintechnik AG, Switzerland) SF6-MBW signal traces. Interrater agreement among three independent examiners (two experienced, one novice) who systematically reviewed 400 MBW trials for visual artefacts and the decision to accept/reject the washin and washout were assessed. Results: Our tool visualizes MBW signals and provides the user with (i) display options (e.g., zoom), (ii) options for a systematic QC assessment [e.g., decision to accept or reject, identification of artefacts (leak, sigh, irregular breathing pattern, breath hold), and comments], and (iii) additional information (e.g., automatic identification of sighs). Reviewer agreement was good using pre-defined QC criteria (κ 0.637-0.725). Differences in the decision to accept/reject had no substantial effect on MBW outcomes. Conclusion: Our visual quality control tool supports a systematic retrospective analysis of existing data sets. Based on predefined QC criteria, even inexperienced users can achieve comparable MBW results.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening - A nationwide observational study.

BACKGROUND: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. METHODS: Lung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. RESULTS: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. CONCLUSIONS: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.

Variability of clinically measured lung clearance index in children with cystic fibrosis.

RATIONALE: The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance. OBJECTIVES: To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change. METHODS: In children aged 4-18 years with CF, LCI was measured every 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes. RESULTS: Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%. CONCLUSION: We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes.

Do clinimetric properties of LCI change after correction of signal processing?

BACKGROUND: The recently described sensor-crosstalk error in the multiple-breath washout (MBW) device Exhalyzer D (Eco Medics AG) could highly influence clinimetric properties and the current interpretation of MBW results. This study reanalyzes MBW data from clinical routine in the corrected software version Spiroware® 3.3.1 and evaluates the effect on outcomes. METHODS: We included nitrogen-MBW data from healthy children and children with cystic fibrosis (CF) from previously published trials and ongoing cohort studies. We specifically compared lung clearance index (LCI) analyzed in Spiroware 3.2.1 and 3.3.1 with regard to (i) feasibility, (ii) repeatability, and (iii) validity as outcome parameters in children with CF. RESULTS: (i) All previously collected measurements could be reanalyzed and resulted in unchanged feasibility in Spiroware 3.3.1. (ii) Short- and midterm repeatability of LCI was similar in both software versions. (iii) Clinical validity of LCI remained similar in Spiroware 3.3.1; however, this resulted in lower values. Discrimination between health and disease was comparable between both software versions. The increase in LCI over time was less pronounced with 0.16 LCI units/year (95% confidence interval [CI] 0.08; 0.24) versus 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CF transmembrane conductance-modulator therapy resulted in a comparable improvement in LCI, in both Spiroware versions. CONCLUSION: Our study confirms that clinimetric properties of LCI remain unaffected after correction for the cross-sensitivity error in Spiroware software.

Breath detection algorithms affect multiple-breath washout outcomes in pre-school and school age children.

BACKGROUND: Accurate breath detection is essential for the computation of outcomes in the multiple-breath washout (MBW) technique. This is particularly important in young children, where irregular breathing is common, and the designation of inspirations and expirations can be challenging. AIM: To investigate differences between a commercial and a novel breath-detection algorithm and to characterize effects on MBW outcomes in children. METHODS: We replicated the signal processing and algorithms used in Spiroware software (v3.3.1, Eco Medics AG). We developed a novel breath detection algorithm (custom) and compared it to Spiroware using 2,455 nitrogen (N2) and 325 sulfur hexafluoride (SF6) trials collected in infants, children, and adolescents. RESULTS: In 83% of N2 and 32% of SF6 trials, the Spiroware breath detection algorithm rejected breaths and did not use them for the calculation of MBW outcomes. Our custom breath detection algorithm determines inspirations and expirations based on flow reversal and corresponding CO2 elevations, and uses all breaths for data analysis. In trials with regular tidal breathing, there were no differences in outcomes between algorithms. However, in 10% of pre-school children tests the number of breaths detected differed by more than 10% and the commercial algorithm underestimated the lung clearance index by up to 21%. CONCLUSION: Accurate breath detection is challenging in young children. As the MBW technique relies on the cumulative analysis of all washout breaths, the rejection of breaths should be limited. We provide an improved algorithm that accurately detects breaths based on both flow reversal and CO2 concentration.

Multiple breath washout quality control in the clinical setting.

BACKGROUND: Multiple breath washout (MBW) is increasingly used in the clinical assessment of patients with cystic fibrosis (CF). Guidelines for MBW quality control (QC) were developed primarily for retrospective assessment and central overreading. We assessed whether real-time QC of MBW data during the measurement improves test acceptability in the clinical setting. METHODS: We implemented standardized real-time QC and reporting of MBW data at the time of the measurement in the clinical pediatric lung function laboratory in Bern, Switzerland, in children with CF aged 4-18 years. We assessed MBW test acceptability before (31 tests; 89 trials) and after (32 tests; 96 trials) implementation of real-time QC and compared agreement between reviewers. Further, we assessed the implementation of real-time QC at a secondary center in Zurich, Switzerland. RESULTS: Before the implementation of real-time QC in Bern, only 58% of clinical MBW tests were deemed acceptable following retrospective QC by an experienced reviewer. After the implementation of real-time QC, MBW test acceptability improved to 75% in Bern. In Zurich, after the implementation of real-time QC, test acceptability improved from 38% to 70%. Further, the agreement between MBW operators and an experienced reviewer for test acceptability was 84% in Bern and 93% in Zurich. CONCLUSION: Real-time QC of MBW data at the time of measurement is feasible in the clinical setting and results in improved test acceptability.

Correction of sensor crosstalk error in Exhalyzer D multiple-breath washout device significantly impacts outcomes in children with cystic fibrosis.

Nitrogen multiple-breath washout is an established technique to assess functional residual capacity and ventilation inhomogeneity in the lung. Accurate measurement of gas concentrations is essential for the appropriate calculation of clinical outcomes. We investigated the accuracy of oxygen and carbon dioxide gas sensor measurements used for the indirect calculation of nitrogen concentration in a commercial multiple-breath washout device (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and its impact on functional residual capacity and lung clearance index. High-precision calibration gas mixtures and mass spectrometry were used to evaluate sensor output. We assessed the impact of corrected signal processing on multiple-breath washout outcomes in a data set of healthy children and children with cystic fibrosis using custom analysis software. We found inadequate correction for the cross sensitivity of the oxygen and carbon dioxide sensors in the Exhalyzer D device. This results in an overestimation of expired nitrogen concentration and consequently, multiple-breath washout outcomes. Breath-by-breath correction of this error reduced the mean (SD) cumulative expired volume by 19.6% (5.0%), functional residual capacity by 8.9% (2.2%), and lung clearance index by 11.9% (4.0%). It also substantially reduced the level of the tissue nitrogen signal at the end of measurements. Inadequate correction for cross sensitivity in the oxygen and carbon dioxide gas sensors of the Exhalyzer D device leads to an overestimation of functional residual capacity and lung clearance index. Correction of this error is possible and could be applied by reanalyzing the measurements in an updated software version.NEW & NOTEWORTHY We investigated the sensor accuracy of a prominent nitrogen multiple-breath washout (N2MBW) device (Eco Medics AG, Duernten, Switzerland) as a possible cause of lack of comparability between outcomes of different MBW devices and methods. We identified an error in the nitrogen concentration calculation of this device, which results in a 10%-15% overestimation of primary outcomes, functional residual capacity, and lung clearance index. It also leads to a significant overestimation of nitrogen back-diffusion into the lungs.