Louise King

The influence of sighing respirations on infant lung function measured using multiple breath washout gas mixing techniques

There is substantial interest in studying lung function in infants, to better understand the early life origins of chronic lung diseases such as asthma. Multiple breath washout (MBW) is a technique for measuring lung function that has been adapted for use in infants. Respiratory sighs occur frequently in young infants during natural sleep, and in accordance with current MBW guidelines, result in exclusion of data from a substantial proportion of testing cycles. We assessed how sighs during MBW influenced the measurements obtained using data from 767 tests conducted on 246 infants (50% male; mean age 43 days) as part of a large cohort study. Sighs occurred in 119 (15%) tests. Sighs during the main part of the wash‐in phase (before the last 5 breaths) were not associated with differences in standard MBW measurements compared with tests without sighs. In contrast, sighs that occurred during the washout were associated with a small but discernible increase in magnitude and variability. For example, the mean lung clearance index increased by 0.36 (95% CI: 0.11–0.62) and variance increased by a multiplicative factor of 2 (95% CI: 1.6–2.5). The results suggest it is reasonable to include MBW data from testing cycles where a sigh occurs during the wash‐in phase, but not during washout, of MBW. By recovering data that would otherwise have been excluded, we estimate a boost of about 10% to the final number of acceptable tests and 6% to the number of individuals successfully tested.

Lack of transparency in software used to analyze multiple breath washout data

The multiple breath washout (MBW) is an exciting new technique that is increasingly used to detect lung function abnormalities, and to monitor progress and response to interventions in people with respiratory conditions. For example, in cystic fibrosis an increase in the lung clearance index (LCI) is associated with the identification of bronchiectasis on chest computed tomography and the technique has been used to study changes in response to treatment with mucolytics. Although the technique is used increasingly in multi-centre studies there are few commercial devices available andmany technical aspects in relation to validity and performance remain undocumented. WBreath (ndd Medizintechnik AG, Zurich, Switzerland) is a major commercial software package used to analyze raw inert gas MBW data for mainly research but also clinical purposes. Methodological development of tests using sulfur hexafluoride (SF6) MBW data collected via mainstream gas analyzer relies heavily on WBreath to transform the raw data into usable form and produce measures of lung function. This is problematic because the algorithms encoded in WBreath’s software are not publicly available (see Fig. 1). It seems likely that other software has a similar lack of transparency although our direct experience is limited to WBreath. A typical MBW analysis using WBreath begins by loading a file containing data including flow rate,measured assuming “ambient temperature pressure saturated” (ATPS) conditions, and native molar mass, both sampled at 200Hz. Additional patient and environmental metadata are also included in this file. The metadata are used along with various user inputs to run algorithms that modify the data to represent “body temperature pressure saturation” (BTPS) conditions, and to correct for changes in temperature and response in the ultrasonic device. These modifications are intended to account for the complexities in measuring molar mass and flow. The resulting data used for analysis—BTPS flow rate and a finalmolar mass signal measured at 200 Hz—are typically substantially different to the input raw data. The analysis that follows these data transformations uses algorithms to detect individual breaths and to calculate end-tidal quantities such as gas concentration and expired gas and air volumes. These quantities are in turn used in various algorithms to derive indices of lung function such as functional residual capacity (FRC) and LCI. Whether WBreath calculates instantaneous gas concentration as part of this analysis, or if such a calculation is indeed possible with SF6 data collected using a mainstream gas analyzer, is unclear. As experienced users of WBreath, it remains difficult for us to establish clear connections between WBreath’s inputs and outputs. While there is information available regarding some aspects of WBreath’s operation, including the user manual and a number of related application notes, the software remains proprietary and many of the aforementioned algorithms are either undocumented, or not documented in sufficient detail to allow results to be reproduced from the rawSF6MBWdatawith user-written software. Furthermore, questions remain about the internal accuracy of the software. Recent studies have found that normal use of WBreath with SF6 MBW data may provide either inaccurate LCI values in infants with cystic fibrosis, or significantly different LCI values when using different versions. Measurement bias introduced by minor changes to MBW software settings has also been demonstrated in software similar to WBreath (Spiroware 3.1.6, Ecomedics AG, Duernten, Switzerland), which will have implications for long-term and multi-centre studies and further reinforces the need for greater transparency. We are concerned that the lack of software transparency may stall methodological development of tests using SF6 MBW data, hinder overall reproducibility, and mask

Lack of small colony variants of Staphylococcus aureus from lower respiratory tract specimens

Small‐colony variants (SCVs) of Staphylococcus aureus are associated with worse lung disease in children with Cystic Fibrosis (CF), exhibit a higher resistance to antibiotics and co‐colonize more commonly with Pseudomonas aeruginosa compared to the normal phenotype. The prevalence of SCVs in lower airway specimens from children with CF is largely unknown.

Bone mineral density is related to lung function outcomes in young people with cystic fibrosis—A retrospective study

Improvements in the medical management of cystic fibrosis (CF) in recent years have resulted in increased prevalence of long‐term sequelae of the condition, such as low bone mineral density (BMD) and hence an increased risk of fractures in later life.

The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials

The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3–6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible. Two multiple-breath washout test trials are sufficient to determine lung clearance index in early CF lung disease http://ow.ly/YHxu30hnrl2