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The multiple-breath washout (MBW) is a lung function test that measures the degree of ventilation inhomogeneity (VI). The test is used to identify small airway impairment in patients with lung diseases like cystic fibrosis. However, the physical and physiological factors that influence the test outcomes and differentiate health from disease are not well understood. Computational models have been used to better understand the interaction between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the tracer gas washout test in a whole. Thus, our aim was to create a lung model that simulates the entire MBW and investigate the role of lung morphology and tissue mechanics on the tracer gas washout procedure. To this end, we developed a multi-scale lung model to simulate the inert gas transport in airways of all size. We then applied systematically different modifications to geometrical and mechanical properties of the lung model (compliance, residual airway volume and flow resistance) which have been associated with VI. The modifications were applied to distinct parts of the model, and their effects on the gas distribution within the lung and on the gas concentration profile were assessed. We found that variability in compliance and residual volume of the airways, as well as the spatial distribution of this variability in the lung had a direct influence on gas distribution among airways and on the MBW pattern (washout duration, characteristic concentration profile during each expiration), while the effects of variable flow resistance were negligible. Based on these findings, it is possible to classify different types of inhomogeneities in the lung and relate them to specific features of the MBW pattern, which builds the basis for a more detailed association of lung function and structure., Author summary Obstructive lung diseases, like cystic fibrosis or primary ciliary dyskinesia, lead to inhomogeneous ventilation. The degree of observed inhomogeneity represents a clinical measure for the progression of the disease. The multiple-breath washout (MBW) is a lung function test that measures this inhomogeneity in the lung. However, the factors that influence the results of the test and differentiate between health and disease are not well understood. Computational models help us to understand better the relation between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the MBW test in whole. Our aim was to create a lung model that simulates the entire MBW test and study the role of lung structure and tissue mechanics on the washout procedure. We developed a multi-scale lung model to simulate the inert gas transport in all airways including the gas exchange area. Our model offers the opportunity to understand the ventilation distribution in the healthy lung. It can also mimic certain patterns of lung disease by applying modifications in mechanical properties out of the physiological limits. Thus, it can be used to study MBW characteristics in health and disease.

Background Multiple breath washout (MBW) is a lung function test that identifies the degree of ventilation inhomogeneity (VI) in the lungs. In vitro validation of MBW devices is recommended. So far, plastic lung models for MBW validation ignored variable degrees of VI. Our primary aim was to create a plastic lung model applicable for physiological lung volumes and variable VI. Methods A plastic box divided in two chambers was filled with water and ventilated in various lung volumes and respiratory rates. A ventilator was used for efficient gas distribution (model with low VI). An additional divider was inserted to create a model with high VI. The model was connected to commercial MBW devices and measurements were performed using different tracer gases and conditions. Primary outcome was the precision of generated functional residual capacity (FRC) and the ability to generate variable VI. The latter was estimated by lung clearance index (LCI) and expiratory phase III slopes (SIII). LCI was also compared to a mathematical model. Findings The intra-test variability for FRC was minimal, mean(SD) coefficient of variation 0.96(0.63)%, using different tracer gases under different conditions. Compared to the model with low VI, in the model with high VI LCI and washout SIII were significantly increased. LCI compared well to the mathematical model. Interpretation This novel lung model shows excellent precision in lung volumes and VI estimates independent of tracer gases and conditions. The model can mimic the lungs of patients with uneven gas distribution.

Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth-cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15–7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing., Unsupervised analysis of symptom dynamics during infancy identifies subjects susceptible to persistent airway disease http://ow.ly/r9xz30lDpHB

BackgroundThe 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.MethodsN2MBW 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).ResultsAnalysis 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.ConclusionWe 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.

Lung clearance index (LCI) is the main outcome of the multiple-breath washout (MBW) test. Current recommendations for LCI acquisition are based on low-grade evidence. The aim of this study was to challenge those recommendations using alternative methods for LCI analysis. Nitrogen MBW measurements from school-aged children, 20 healthy controls, 20 with cystic fibrosis (CF) and 17 with primary ciliary dyskinesia (PCD), were analysed using 1) current algorithms (standard), 2) three alternative algorithms to detect with higher precision the end of MBW testing and 3) two alternative algorithms to determine exhaled tracer gas concentrations. LCI values, intra-test repeatability, and ability to discriminate between health and lung disease were compared between these methods. The analysis methods strongly influenced LCI (mean±sd overall differences (%) between standard and alternative analysis methods: −4.9±5.7%; range: −66–19%), but did not improve intra-test variability. Discrimination between health and disease was comparable as areas under the receiver operator curves were not greater than that from standard analysis. This study supports current recommendations for LCI calculation in children. Alternative methods influence LCI estimates and hamper comparability between MBW setups. Alternative algorithms, whenever used, should be carefully reported., Lung clearance index values are strongly affected by the algorithms used for the analysis http://ow.ly/h2Rs30ktPiN

Primary ciliary dyskinesia (PCD) has been considered a relatively mild disease, especially compared to cystic fibrosis (CF), but studies on lung function in PCD patients have been few and small. This study compared lung function from spirometry of PCD patients to normal reference values and to published data from CF patients. We calculated z-scores and % predicted values for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) using the Global Lung Function Initiative 2012 values for 991 patients from the international PCD Cohort. We then assessed associations with age, sex, country, diagnostic certainty, organ laterality, body mass index and age at diagnosis in linear regression models. Lung function in PCD patients was reduced compared to reference values in both sexes and all age groups. Children aged 6–9 years had the smallest impairment (FEV1 z-score −0.84 (−1.03 to −0.65), FVC z-score −0.31 (−0.51 to −0.11)). Compared to CF patients, FEV1 was similarly reduced in children (age 6–9 years PCD 91% (88–93%) CF 90% (88–91%)), but less impaired in young adults (age 18–21 years PCD 79% (76–82%) CF 66% (65–68%)). The results suggest that PCD affects lung function from early in life, which emphasises the importance of early standardised care for all patients. Tweetable abstract @ERSpublications click to tweetPCD affects lung function from an early age, similarly to CF, thus early multidisciplinary management is crucial http://ow.ly/T9ch30kHXns 52 2

INTRODUCTION Multiple breath washout (MBW) is a sensitive test to measure lung volumes and ventilation inhomogeneity from infancy on. The commonly used setup for infant MBW, based on ultrasonic flowmeter, requires extensive signal processing, which may reduce robustness. A new setup may overcome some previous limitations but formal validation is lacking. AIM We assessed the feasibility of infant MBW testing with the new setup and compared functional residual capacity (FRC) values of the old and the new setup in vivo and in vitro. METHODS We performed MBW in four healthy infants and four infants with cystic fibrosis, as well as in a Plexiglas lung simulator using realistic lung volumes and breathing patterns, with the new (Exhalyzer D, Spiroware 3.2.0, Ecomedics) and the old setup (Exhalyzer D, WBreath 3.18.0, ndd) in random sequence. RESULTS The technical feasibility of MBW with the new device-setup was 100%. Intra-subject variability in FRC was low in both setups, but differences in FRC between the setups were considerable (mean relative difference 39.7%, range 18.9; 65.7, P = 0.008). Corrections of software settings decreased FRC differences (14.0%, -6.4; 42.3, P = 0.08). Results were confirmed in vitro. CONCLUSION MBW measurements with the new setup were feasible in infants. However, despite attempts to correct software settings, outcomes between setups were not interchangeable. Further work is needed before widespread application of the new setup can be recommended.