Novel volumetric capnography indices measure ventilation inhomogeneity in cystic fibrosis

BackgroundVolumetric capnography (VCap) is a simpler alternative of multiple-breath washout (MBW) to detect ventilation inhomogeneity (VI) in patients with cystic fibrosis (CF). However, its diagnostic performance is influenced by breathing dynamics. We introduce two novel VCap indices, the Capnographic Inhomogeneity Indices (CIIs) that may overcome this limitation and explore their diagnostic characteristics in a cohort of CF patients.MethodsWe analysed 320 N2-MBW trials from 50 CF patients and 65 controls (age 4-18 years) and calculated classical VCap indices, such as slope III (SIII) and the capnographic index (KPIv). We introduced novel CIIs based on a theoretical lung model, and assessed their diagnostic performance compared to classical VCap indices and the lung clearance index (LCI).ResultsBoth CIIs were significantly higher in CF patients compared with controls (mean±SD CII1 5.9±1.4% versus 5.1±1.0%, p=0.002; CII2 7.7±1.8% versus 6.8±1.4%, p=0.002) and presented strong correlation with LCI (CII1 R2=0.47 and CII2 R2=0.44 in CF patients). Classical VCap indices showed inferior discriminative ability (SIII 2.3±1.0%/L versus 1.9±0.7%/L, P=0.013; KPIv 3.9±1.3% versus 3.5±1.2%, P=0.071), while the correlation with LCI was weak (SIII R2=0.03; KPIv R2=0.08 in CF patients). CIIs showed lower intra-subject inter-trial variability, calculated as coefficient of variation for three and relative difference for two trials, than classical VCap indices, but higher than LCI (CII1 11.1±8.2% and CII2 11.0±8.0% versus SIII 16.3±13.5%; KPIv 15.9±12.8%; LCI 5.9%±4.2%).ConclusionCIIs detect VI better than classical VCap indices and correlate well with LCI. However, further studies on their diagnostic performance and clinical utility are required.

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, Duernten, Switzerland) 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 CF from previously published trials and ongoing cohort studies. We specifically compared LCI analyzed in Spiroware 3.2.1 and 3.3.1 with regards 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, 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% CI 0.08; 0.24) vs. 0.30 LCI units/year (95% CI 0.21; 0.38) in 3.2.1. Response to intervention in children receiving CFTR-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.

Lung clearance index: a new measure of ventilation inhomogeneity in childhood respiratory diseases

: Conventional spirometry has long been considered the primary test for assessing respiratory function deficits in children and adults. However, the need to perform forced breathing maneuvers can make it challenging to perform these examinations in an uncooperative child. For these reasons, techniques such as gas dilutions and the multiple-breath-washout (MBW) method have been implemented because they allow for early assessment of damage to the small airways. These methods permit the determination of the possible presence of ventilatory inhomogeneity in the lungs by analyzing the clearance of an inert gas used as a tracer. The equipment consists of a mass spectrometer combined with a flow meter. The Lung Clearance Index (LCI) is most often used to evaluate ventilatory inhomogeneity. This narrative review aimed to review the literature on technical and practical aspects of the MBW test and evaluate the clinical implications of the LCI in pediatric respiratory disease.

Effect of Salbutamol on Lung Ventilation in Children with Cystic Fibrosis: Comprehensive Assessment Using Spirometry, Multiple-Breath Washout, and Functional Lung Magnetic Resonance Imaging

<b><i>Background:</i></b> Inhalation therapy is one of the cornerstones of the daily treatment regimen in patients with cystic fibrosis (CF). Recommendations regarding the addition of bronchodilators, especially salbutamol are conflicting due to the lack of evidence. New diagnostic measures such as multiple-breath washout (<underline>MBW)</underline> and functional magnetic resonance imaging (MRI) have the potential to reveal new insights into bronchodilator effects in patients with CF. <b><i>Objective:</i></b> The objective of the study was to comprehensively assess the functional response to nebulized inhalation with salbutamol in children with CF. <b><i>Methods:</i></b> Thirty children aged 6–18 years with stable CF performed pulmonary function tests, MBW, and matrix pencil-MRI before and after standardized nebulized inhalation of salbutamol. <b><i>Results:</i></b> Lung clearance index decreased (improved) by −0.24 turnover (95% confidence interval [CI]: −0.53 to 0.06; <i>p</i> = 0.111). Percentage of the lung volume with impaired fractional ventilation and relative perfusion decreased (improved) by −0.79% (CI: −1.99 to 0.42; <i>p</i> = 0.194) and −1.31% (CI: −2.28 to −0.35; <i>p</i> = 0.009), respectively. Forced expiratory volume (FEV₁) increased (improved) by 0.41 z-score (CI: 0.24–0.58; <i>p</i> &#x3c; 0.0001). We could not identify specific clinical factors associated with a more pronounced effect of salbutamol. <b><i>Conclusions:</i></b> There is a positive short-term effect of bronchodilator inhalation on FEV₁ in patients with CF, which is independent of ventilation inhomogeneity. Heterogeneous response between patients suggests that for prediction of a therapeutic effect this should be tested by spirometry in every patient individually.

Model-based Bayesian inference of the ventilation distribution in patients with Cystic Fibrosis from multiple breath washout, with comparison to ventilation MRI

BackgroundIndices of ventilation heterogeneity (VH) from multiple breath washout (MBW) have been shown to correlate well with VH indices derived from hyperpolarised gas ventilation MRI. Here we report the prediction of ventilation distributions from MBW data using a mathematical model, and the comparison of these predictions with imaging data.MethodsWe developed computer simulations of the ventilation distribution in the lungs to model MBW measurement with 3 parameters: σV, determining the extent of VH; V0, the lung volume; and VD, the dead-space volume. These were inferred for each individual from supine MBW data recorded from 25 patients with cystic fibrosis (CF) using approximate Bayesian computation. The fitted models were used to predict the distribution of gas imaged by 3He ventilation MRI measurements collected from the same visit.ResultsThe MRI indices measured (I1/3, the fraction of pixels below one-third of the mean intensity and ICV, the coefficient of variation of pixel intensity) correlated strongly with those predicted by the MBW model fits (r = 0.93, 0.87 respectively). There was also good agreement between predicted and measured MRI indices (mean bias ± limits of agreement: I1/3: 0.002 ± 0.112 and ICV: −0.001 ± 0.293). Fitted model parameters were robust to truncation of MBW data.ConclusionWe have shown that the ventilation distribution in the lung can be inferred from an MBW signal, and verified this using ventilation MRI. The Bayesian method employed extracts this information with fewer breath cycles than required for LCI, reducing acquisition time required, and gives uncertainty bounds, which are important for clinical decision making.New and NoteworthyThis paper demonstrates that the ventilation distribution observed by ventilation MRI in cystic fibrosis patients can be inferred using multiple breath washout data. The Bayesian method used quantifies prediction uncertainty. This has the potential to be used in the analysis of washout data in the clinic to give greater physiological insight more efficiently. The predictions also remained robust to truncation of the washout dataset, meaning that data-capture time can be significantly reduced using this method.

Lower airways clinical outcome measures for use in primary ciliary dyskinesia research, a scoping review

ObjectivesDisease-specific, well-defined, and validated clinical outcome measures are essential in designing research studies. Poorly defined outcome measures hamper pooling of data and comparisons between studies. We aimed to identify and describe pulmonary outcome measures that could be used for follow-up of patients with primary ciliary dyskinesia (PCD).MethodsWe conducted a scoping review by systematically searching Medline, Embase and Cochrane Systematic Review online databases for studies published from 1996 to 2020 that included ≥10 PCD adult and/or paediatric patients.ResultsWe included 102 studies (7289 patients). Eighty-three studies reported on spirometry, 11 on body plethysmography, 15 on multiple breath washout, 36 on high-resolution computed tomography (HRCT), 57 on microbiology, and 17 on health-related quality of life. Measurement and reporting of outcomes varied considerably between studies (e.g. different scoring systems for chest HRCT scans). Additionally, definitions of outcome measures varied (e.g. definition of chronic colonisation by respiratory pathogen), impeding direct comparisons of results.ConclusionsThis review highlights the need for standardisation of measurements and reporting of outcome measures to enable comparisons between studies. Defining a core set of clinical outcome measures is necessary to ensure reproducibility of results and for use in future trials and prospective cohorts.