Pinelopi Anagnostopoulou

Lung clearance index and moment ratios at different cut-off values in infant multiple-breath washout measurements

Multiple‐breath washout (MBW) is increasingly used for infant lung function testing. Current guidelines recommend calculating lung clearance index (LCI) and functional residual capacity (FRC) at 2.5% of normalized tracer gas concentration, without clear recommendation for moment ratios (MR). Whether the 2.5% cut‐off has the highest discriminative power to detect ventilation inhomogeneity in infants with lung diseases is unknown.

Lower exhaled nitric oxide in infants with Cystic Fibrosis compared to healthy controls

Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.

Unexpected results in infant multiple breath washout: Is the truth hidden in the washin?

Recently, a refined software algorithm for infant multiple breath washout (MBW) analysis was proposed aiming to improve the accuracy of tracer gas evaluation. The use of this algorithm revealed high lung clearance index (LCI) values in infants with cystic fibrosis (CF) which were previously found to be normal. Foong et al. used this algorithm to retrospectively analyze infant MBW data from healthy, CF, and preterm infants and report an increase in LCI in CF and preterm groups. However, in the majority of healthy subjects they also found higher LCI values compared with those reported previously for healthy infants, measured either by massspectrometer or by ultrasonic flowmeter systems. Those high LCI values of up to 12 lung turnovers in healthy subjects are clearly counterintuitive. Besides algorithm-related errors, other factors can affect MBW indices, for example, insufficient foreign tracer gas washin. In MBW tests using foreign tracer gases (in this case, SF6) the tracer gas needs to equilibrate between inspired and expired tracer gas fractions before starting the washout. In the present setup for infant MBW, the operator manually stops the washin and starts the washout, but there is no clear online display of a complete washin. Thus, it is easily possible to terminate thewashin earlier than required. We hypothesized that a noncomplete tracer gas washin phase could lead to false washout outcomes. To examine this, we simulated different degrees of incomplete washin using a 4% SF6 MBW measurement from a healthy infant. We truncated the washin stepwise and conventionally analyzed the washout (see online supplement, OLS). Washin incompleteness resulted in increased LCI, functional residual capacity (FRC) and cumulative expired volume (CEV), using the proposed (manual modus) as well as the old algorithm (automatic modus). Using the manual modus, the increase was even more pronounced. Interestingly, the more incomplete the washin, the later the “target” washout breath (at 1/40th of the initial SF6 concentration) where LCI is calculated (linear regression analysis, R 0.79, P< 0.001) and the higher the washout outcomes. We were able to reproduce the same results in vitro using a Plexiglas infant lung model (see OLS). Based on the physiology of the MBW test, during an incomplete washin the tracer gas fraction within the lungs is lower and predominantly distributed in fast ventilated lung compartments. Depending on the algorithms for determining the “target” washout breath, using a relative (1/40th) or absolute tracer gas concentration step, incompletewashin will result in shorter or longer washout times, respectively. In systems that measure molar mass (MM) and calculate those steps based onMMdifferences, washin incompleteness leads to overestimations in LCI, FRC, CEV (Fig. 1). An incomplete washin leads to lower end-expiratory MM at the end of the washin (EEMMWI) compared with the complete washin. This relates to the specific MM of all gas fractions and in this case the SF6 fraction did not sufficiently replace the nitrogen fraction. LCI is calculated only when the EEMM difference between washin and washout (DEEMM: EEMMwiEEMMwo) reaches a certain fixed value [97.5% of end-inspiratory MM (EIMM)-step or EEMM-step, Figure 1 and OLS]. The more incomplete the washin, the later the washout target is reached and thus LCI is found elevated. The above findings underline the importance of a sufficient washin in MBWmeasurements and, taking into account the limitations of the software, we propose to use the washin completion as an additional quality criterion (see OLS). Of note, the current software always considers the washin as complete (end-washin SF6 concentration is set to 100%) and, according to this, it calculates the normalized SF6 concentration per washout breath.

Interrupter technique in infancy: Higher airway resistance and lower short‐term variability in preterm versus term infants

In preschool children, measurement of airway resistance using interrupter technique (Rint) is feasible to assess the degree of bronchial obstruction. Although some studies measured Rint in infancy, values of Rint and its variability in preterm infants are unknown. In this study, Rint and its variability was measured at infancy and compared between healthy term and preterm infants.

Infant multiple breath washout using a new commercially available device: Ready to replace the previous setup?

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.

Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth

BACKGROUND Lung impairment in cystic fibrosis (CF) starts in infancy. However, tools to monitor early lung disease are limited. Respiratory rate (RR) as a key vital sign is easy to assess during sleep and is elevated during acute respiratory disease. Thus, elevated RR could indicate early lung impairment and potentially serve as a diagnostic tool in disease monitoring. METHODS In a prospective cohort of infants with CF diagnosed by newborn screening and healthy controls RR was measured and respiratory symptoms reported weekly throughout infancy. Infants performed a lung function measurement within the first weeks of life. RESULTS The analyses included 5656 measurements from 153 infants (43 with CF). RR declined from 43.2 (40.5)/min at 6 weeks of age to 28.3 (24.6)/min at 50 weeks in infants with CF (healthy controls). Infants with CF had consistently higher RR than controls (mean difference: 4.15/min; (95% CI 2.86-5.44); p < .001). In both study groups, RR was increased throughout the study period in infants with higher lung clearance indices (LCI) and during episodes of respiratory infections. CONCLUSIONS Infants with CF have a higher RR compared to healthy controls during the first year of life. The association with early LCI measurements, the current gold standard to assess physiology of peripheral airways persisted throughout the study period. This may indicate tracking of lung function by RR. It might thus be an early subtle sign of functional respiratory deficit. Further studies will show if RR can be used as a sensitive and promising marker to monitor early CF lung disease.

Comparison of different analysis algorithms to calculate multiple-breath washout outcomes

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

An innovative lung model for multiple breath washout testing 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.