Signal-correction errors in the EasyOne Pro LAB multiple-breath washout device significantly impact outcomes in children and adults.

Multiple-breath washout (MBW) is an established technique to assess functional residual capacity (FRC) and ventilation inhomogeneity in the lung. Indirect calculation of nitrogen concentration requires accurate measurement of gas concentrations. To investigate the accuracy of the CO2 concentration and molar mass (MM) values used for the indirect calculation of nitrogen concentration in a commercial MBW device [EasyOne Pro LAB (EOPL), ndd Medizintechnik AG, Switzerland] and its impact on outcomes. We used high-precision gas mixtures to evaluate CO2 and MM sensor output in vivo and in vitro. We developed updated algorithms to correct observed errors and assessed the impact on MBW outcomes and FRC measurement accuracy compared with body plethysmography. The respiratory exchange ratio (RER)-based adjustment of the measured CO2 signal used in the EOPL led to an overestimated CO2 signal (range -0.1% to 1.0%). In addition, an uncorrected dependence on humidity was identified. These combined effects resulted in an overestimation of expired nitrogen concentrations (range -0.7% to 2.6%), and consequently MBW outcomes. Corrected algorithms reduced the mean (SD) cumulative expired volume by 15.8% (9.7%), FRC by 6.6% (3.0%), and lung clearance index by 9.9% (7.6%). Differences in FRC between the EOPL and body plethysmography further increased. Inadequate signal correction causes RER- and humidity-dependent expired nitrogen concentration errors and overestimation of test outcomes. Updated algorithms reduce average signal error, however, RER values far from the population average still cause measurement errors. Despite improved signal accuracy, the updated algorithm increased the difference in FRC between the EOPL and body plethysmography.NEW & NOTEWORTHY We investigated the accuracy of the molar mass (MM) and CO2 sensors of a commercial multiple-breath washout device (ndd Medizintechnik AG, Switzerland). We identified humidity and respiratory exchange ratio-dependent errors that in most measurements resulted in an overestimation of expired nitrogen concentrations, and consequently, MBW results. Functional residual capacity and lung clearance index decreased by 6.6% and 9.9%, respectively. Despite improved signal accuracy, the difference in FRC between the EOPL and body plethysmography increased.

European Respiratory Society/American Thoracic Society technical statement: standardisation of the measurement of lung volumes, 2023 update.

This document updates the 2005 European Respiratory Society (ERS) and American Thoracic Society (ATS) technical standard for the measurement of lung volumes. The 2005 document integrated the recommendations of an ATS/ERS task force with those from an earlier National Heart, Lung, and Blood Institute workshop that led to the publication of background papers between 1995 and 1999 and a consensus workshop report with more in-depth descriptions and discussion. Advancements in hardware and software, new research and emerging approaches have necessitated an update to the 2005 technical standard to guide laboratory directors, physiologists, operators, pulmonologists and manufacturers. Key updates include standardisation of linked spirometry, new equipment quality control and validation recommendations, generalisation of the multiple breath washout concept beyond nitrogen, a new acceptability and grading system with addition of example tracings, and a brief review of imaging and other new techniques to measure lung volumes. Future directions and key research questions are also noted.

Simultaneous multiple breath washout and oxygen-enhanced magnetic resonance imaging in healthy adults.

Lung function testing and lung imaging are commonly used techniques to monitor respiratory diseases, such as cystic fibrosis (CF). The nitrogen (N2) multiple-breath washout technique (MBW) has been shown to detect ventilation inhomogeneity in CF, but the underlying pathophysiological processes that are altered are often unclear. Dynamic oxygen-enhanced magnetic resonance imaging (OE-MRI) could potentially be performed simultaneously with MBW because both techniques require breathing of 100% oxygen (O2) and may allow for visualisation of alterations underlying impaired MBW outcomes. However, simultaneous MBW and OE-MRI has never been assessed, potentially as it requires a magnetic resonance (MR) compatible MBW equipment. In this pilot study, we assessed whether MBW and OE-MRI can be performed simultaneously using a commercial MBW device that has been modified to be MR-compatible. We performed simultaneous measurements in five healthy volunteers aged 25-35 years. We obtained O2 and N2 concentrations from both techniques, and generated O2 wash-in time constant and N2 washout maps from OE-MRI data. We obtained good quality simultaneous measurements in two healthy volunteers due to technical challenges related to the MBW equipment and poor tolerance. Oxygen and N2 concentrations from both techniques, as well as O2 wash-in time constant maps and N2 washout maps could be obtained, suggesting that simultaneous measurements may have the potential to allow for comparison and visualization of regional differences in ventilation underlying impaired MBW outcomes. Simultaneous MBW and OE-MRI measurements can be performed with a modified MBW device and may help to understand MBW outcomes, but the measurements are challenging and have poor feasibility.

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.

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.

Monitoring disease progression in childhood bronchiectasis.

Bronchiectasis (not related to cystic fibrosis) is a chronic lung disease caused by a range of etiologies but characterized by abnormal airway dilatation, recurrent respiratory symptoms, impaired quality of life and reduced life expectancy. Patients typically experience episodes of chronic wet cough and recurrent pulmonary exacerbations requiring hospitalization. Early diagnosis and management of childhood bronchiectasis are essential to prevent respiratory decline, optimize quality of life, minimize pulmonary exacerbations, and potentially reverse bronchial disease. Disease monitoring potentially allows for (1) the early detection of acute exacerbations, facilitating timely intervention, (2) tracking the rate of disease progression for prognostic purposes, and (3) quantifying the response to therapies. This narrative review article will discuss methods for monitoring disease progression in children with bronchiectasis, including lung imaging, respiratory function, patient-reported outcomes, respiratory exacerbations, sputum biomarkers, and nutritional outcomes.

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.

Shedding light into the black box of infant multiple-breath washout.

BACKGROUND: Multiple-breath inert gas washout (MBW) is a sensitive technique to assess lung volumes and ventilation inhomogeneity in infancy. Poor agreement amongst commercially available setups and a lack of transparency in the underlying algorithms for the computation of infant MBW outcomes currently limit the widespread application of MBW as a surveillance tool in early lung disease. METHODS: We determined all computational steps in signal processing and the calculation of MBW outcomes in the current infant WBreath/Exhalyzer D setup (Exhalyzer D device, Eco Medics AG; WBreath software version 3.28.0, ndd Medizintechnik AG; Switzerland). We developed a revised WBreath version based on current consensus guidelines and compared outcomes between the current (3.28.0) and revised (3.52.3) WBreath version. We analyzed 60 visits from 40 infants with cystic fibrosis (CF) and 20 healthy controls at 6 weeks and 1 year of age. RESULTS: Investigation into the algorithms in WBreath 3.28.0 revealed discrepancies from current consensus guidelines, which resulted in a potential overestimation of functional residual capacity (FRC) and underestimation of lung clearance index (LCI). We developed a revised WBreath version (3.52.3), which overall resulted in 6.7% lower FRC (mean (SD) -1.78 (0.99) mL/kg) and 14.1% higher LCI (1.11 (0.57) TO) than WBreath version 3.28.0. CONCLUSION: Comprehensive investigation into the signal processing and algorithms used for analysis of MBW measurements improves the transparency and robustness of infant MBW data. The revised software version calculates outcomes according to consensus guidelines. Future work is needed to validate and compare outcomes between infant MBW setups.

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.

The impact of segmentation on whole-lung functional MRI quantification: Repeatability and reproducibility from multiple human observers and an artificial neural network.

PURPOSE: To investigate the repeatability and reproducibility of lung segmentation and their impact on the quantitative outcomes from functional pulmonary MRI. Additionally, to validate an artificial neural network (ANN) to accelerate whole-lung quantification. METHOD: Ten healthy children and 25 children with cystic fibrosis underwent matrix pencil decomposition MRI (MP-MRI). Impaired relative fractional ventilation (RFV ) and relative perfusion (RQ ) from MP-MRI were compared using whole-lung segmentation performed by a physician at two time-points (At1 and At2 ), by an MRI technician (B), and by an ANN (C). Repeatability and reproducibility were assess with Dice similarity coefficient (DSC), paired t-test and Intraclass-correlation coefficient (ICC). RESULTS: The repeatability within an observer (At1 vs At2 ) resulted in a DSC of 0.94 ± 0.01 (mean ± SD) and an unsystematic difference of -0.01% for RFV (P = .92) and +0.1% for RQ (P = .21). The reproducibility between human observers (At1 vs B) resulted in a DSC of 0.88 ± 0.02, and a systematic absolute difference of -0.81% (P < .001) for RFV and -0.38% (P = .037) for RQ . The reproducibility between human and the ANN (At1 vs C) resulted in a DSC of 0.89 ± 0.03 and a systematic absolute difference of -0.36% for RFV (P = .017) and -0.35% for RQ (P = .002). The ICC was >0.98 for all variables and comparisons. CONCLUSIONS: Despite high overall agreement, there were systematic differences in lung segmentation between observers. This needs to be considered for longitudinal studies and could be overcome by using an ANN, which performs as good as human observers and fully automatizes MP-MRI post-processing.

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.

Effect of breastfeeding duration on lung function, respiratory symptoms and allergic diseases in school-age children.

BACKGROUND: A positive effect of breastfeeding on lung function has been demonstrated in cohorts of children with asthma or risk for asthma. We assessed the impact of breastfeeding on lung function and symptoms at the age of 6 years in an unselected, healthy birth cohort. METHODS: We prospectively studied healthy term infants from the Bern-Basel Infant Lung Development (BILD) cohort from birth up to 6 years. Any breastfeeding was assessed by weekly phone calls during the first year of life. Risk factors (eg, smoking exposure, parental history of allergic conditions, and education) were obtained using standardized questionnaires. The primary outcomes were lung function parameters measured at 6 years of age by spirometry forced expiratory volume in 1 second, body plethysmography (functional residual capacity [FRCpleth ], the total lung capacity [TLCpleth ], and the effective respiratory airway resistance [Reff ]) and fractional exhaled nitric oxide (FeNO). Secondary outcomes included ever wheeze (between birth and 6 years), wheeze in the past 12 months, asthma, presence of allergic conditions, atopic dermatitis, rhinitis, and positive skin prick test at the age of 6 years. RESULTS: In 377 children the mean breastfeeding duration was 36 weeks (SD 14.4). We found no association of breastfeeding duration with obstructive or restrictive lung function and FeNO. After adjustment for confounders, we found no associations of breastfeeding duration with respiratory symptoms or the presence of allergic conditions. CONCLUSION: This study found no evidence of an association between breastfeeding and comprehensive lung function in unselected healthy children with long-term breastfeeding. Our findings do not support the hypothesis that the duration of breastfeeding has a direct impact on lung function in a healthy population with low asthmatic risk.

Normative data for multiple breath washout outcomes in school-aged Caucasian children.

BACKGROUND: The multiple breath nitrogen washout (N2MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N2MBW outcomes in a cohort of healthy Caucasian school-aged children. METHODS: N2MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI2.5%) and at 5% (LCI5%) of the initial nitrogen concentration and for moment ratios (M1/M0 and M2/M0). A prediction equation was generated for functional residual capacity (FRC). RESULTS: Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year-1 for LCI2.5%) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI2.5%, 5.73 for LCI5%, 1.75 for M1/M0 and 6.15 for M2/M0, respectively. Height and weight were found to be independent predictors of FRC. CONCLUSION: We report reference values for N2MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Endotracheal tube mucus as a source of airway mucus for rheological study.

Muco-obstructive lung diseases (MOLDs), like cystic fibrosis and chronic obstructive pulmonary disease, affect a spectrum of subjects globally. In MOLDs, the airway mucus becomes hyperconcentrated, increasing osmotic and viscoelastic moduli and impairing mucus clearance. MOLD research requires relevant sources of healthy airway mucus for experimental manipulation and analysis. Mucus collected from endotracheal tubes (ETT) may represent such a source with benefits, e.g., in vivo production, over canonical sample types such as sputum or human bronchial epithelial (HBE) mucus. Ionic and biochemical compositions of ETT mucus from healthy human subjects were characterized and a stock of pooled ETT samples generated. Pooled ETT mucus exhibited concentration-dependent rheologic properties that agreed across spatial scales with reported individual ETT samples and HBE mucus. We suggest that the practical benefits compared with other sample types make ETT mucus potentially useful for MOLD research.

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.