Susanne I. Fuchs

Consensus statement for inert gas washout measurement using multiple- and single- breath tests

Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.

An Official American Thoracic Society Workshop Report: Optimal Lung Function Tests for Monitoring Cystic Fibrosis, Bronchopulmonary Dysplasia, and Recurrent Wheezing in Children Less Than 6 Years of Age

Although pulmonary function testing plays a key role in the diagnosis and management of chronic pulmonary conditions in children under 6 years of age, objective physiologic assessment is limited in the clinical care of infants and children less than 6 years old, due to the challenges of measuring lung function in this age range. Ongoing research in lung function testing in infants, toddlers, and preschoolers has resulted in techniques that show promise as safe, feasible, and potentially clinically useful tests. Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies.

Sensitivity of lung clearance index and chest computed tomography in early cf lung disease

It is widely accepted that CF lung disease starts before clinical symptoms become apparent or spirometry deteriorates. Computed chest tomography (CT) is the reference method for identifying structural changes in CF; however, radiation exposure limits its use as a monitoring tool. It has been suggested that the Lung Clearance Index (LCI) measured by Multiple Breath Washout (MBW) for assessing ventilation inhomogeneity is a more sensitive surrogate marker than spirometry allowing non-invasive monitoring of CF lung disease. The aim of this study was to prospectively investigate the diagnostic accuracy of the LCI in comparison to CT in CF patients with early lung disease and normal FEV(1) (>80% pred.). MBW and ultra-low-dose CT were performed in 34 patients (6-26 years). LCI was abnormal in 76.5% subjects. LCI and CT correlated significantly in 82.3%. LCI was related to presence and extent of structural lung changes observed on CT with a sensitivity of 88%. Diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1) was good when compared to CT. Results indicate that structural changes are unlikely if a normal LCI is measured. We speculate that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose. The LCI may be a suitable surrogate marker for monitoring progression of CF lung disease and effect of treatment in both, clinical care and research settings.

Lung clearance index: Normal values, repeatability, and reproducibility in healthy children and adolescents†

There is increasing interest in using the Multiple Breath Washout technique and the lung clearance index (LCI) for detecting early pulmonary changes, for example, in cystic fibrosis lung disease. However, there are still limited data regarding equipment specific reference ranges, repeatability and reproducibility. The aim of this prospective study was to assess within‐test repeatability, short term reproducibility and long term reproducibility, and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor (EasyOne Pro, MBW Module, ndd Medical Technologies, Switzerland). Fourty‐four volunteers (5.3–20.3 years) were recruited for the 1st test. Twenty‐two out of 44 were measured on a 2nd test occasion after an interval of 1 hr (2nd test). Thirty‐four out of 44 agreed to come back for a follow up test 6–15 months later (3rd test). Mean LCI (SD) was 6.2 (0.4), 6.3 (0.4), and 6.0 (0.4) at the 1st, 2nd, and 3rd test. The upper limit of normal was 7.0 for all subjects. Within‐test repeatability was 5.1%. Short‐term reproducibility (1st test vs. 2nd test) was 4.2% with a mean difference of −0.13 (95% CI −0.350; 0.087). Long‐term reproducibility (1st test vs. 3rd test) was 5.1%, with a mean difference of 0.017 (95% CI −0.016; 0.348). With this low variability of the LCI for both, within and between tests, our study demonstrates reliability and robustness of equipment, protocol and analysis and the reliability of the MBW technique in general. The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases. Pediatr Pulmonol. 2009; 44:1180–1185.

Lung clearance index: clinical and research applications in children

Multiple breath washout (MBW) has been demonstrated to be sensitive for assessing ventilation inhomogeneity (VI). VI is supposed to reflect changes in peripheral airways which are not apparent using spirometry. The lung clearance index (LCI) is the most robust parameter to quantify VI, and is largely independent of age; therefore, it potentially qualifies as a surrogate outcome parameter for clinical and research purposes, particularly during childhood. This review summarizes the current evidence regarding the clinical value of measuring LCI in children. Feasibility, reproducibility and diagnostic accuracy have been demonstrated; available data confirm that LCI is superior to spirometry in detecting small air way disease. However, there is little information regarding the value in the individual patient, and sparse longitudinal data looking at its prognostic value. Currently, only in patients with Cystic Fibrosis, it appears likely that knowledge of LCI will be useful for routine clinical management.

Short-term effect of physiotherapy on variability of the lung clearance index in children with cystic fibrosis.

Multiple breath washout (MBW) for measuring the lung clearance index (LCI) has been proposed as a non‐invasive tool for detecting early cystic fibrosis (CF) lung disease. The LCI is highly repeatable and reproducible in healthy subjects. In patients with CF, within‐test variability is low. However, application of physiotherapy (PT) immediately preceding MBW may affect LCI variability in CF patients and thus interpretation of repeat measurements and treatment effects. Therefore, the aim of the present study was to prospectively assess the short‐term effect of PT on LCI in CF patients in order to address the question whether or not standardized timing of PT and MBW has to be considered when introducing MBW into clinical CF management. Twenty‐seven out of 32 patients (5.7–15.9 years) with CF successfully performed two technically acceptable MBW tests with the EasyOne Pro, MBW Module (ndd, Switzerland) at intervals of 1½ hr. Sixteen out of 27 received 30 min PT in between, whereas 11/27 did not.

Feasibility and Variability of Measuring the Lung Clearance Index in a Multi-Center Setting

The Lung Clearance Index (LCI) is superior to spirometry in detecting early lung disease in cystic fibrosis (CF) and correlates with structural lung changes seen on CT scans. The LCI has the potential to become a novel outcome parameter for clinical and research purposes. However longitudinal studies are required to further prove its prognostic value. Multi‐center design is likely to facilitate realization of such studies.

Tracking Lung Clearance Index and chest CT in mild cystic fibrosis lung disease over a period of three years

INTRODUCTION Lung disease remains the main cause of morbidity and mortality in patients with Cystic Fibrosis (CF). To detect lung disease before clinical symptoms become apparent, sensitive tools are essential. Spirometry is used for monitoring, but the FEV1 remains frequently normal throughout childhood. The Lung Clearance Index (LCI) calculated from Multiple Breath Washout (MBW) was introduced at the CF centre Innsbruck in 2007 for assessing ventilation inhomogeneity in patients with mild lung disease. We hypothesized that LCIs in 2007 are of prognostic value for the presence or absence of structural lung changes in later years. METHODS Between 2007 and 2010 MBW, spirometry and ultra-low-dose HR-CT were prospectively tracked in 36 patients (6-53 years) with a mean FEV1 ≥ 80% predicted in 2007. RESULTS At study start the majority of patients had abnormal CT scores and LCI results. While CT and spirometry remained largely stable throughout the study, LCI results slightly improved but still correlated with CT scores in 2010. LCI results in 2007 correlated with CT scores in 2010 while FEV1 did not. In 86% the LCI value in 2007 was indicative for the presence or absence of structural lung changes in 2010. CONCLUSION The LCI is a sensitive tool for detecting and tracking pulmonary changes. Extended structural changes are unlikely if the LCI is normal. The LCI has the potential to be used for monitoring the progression of early CF lung disease and assessing the effect of treatment in both clinical care and research settings.

Calculation of the capnographic index based on expiratory molar mass-volume-curves —A suitable tool to screen for cystic fibrosis lung disease

BACKGROUND Volumetric capnography reflecting the course of CO2-exhalation is used to assess ventilation inhomogeneity. Calculation of the slope of expiratory phase 3 and the capnographic index (KPIv) from expirograms allows quantification of extent and severity of small airway impairment. However, technical limitations have hampered more widespread use of this technique. Using expiratory molar mass-volume-curves sampled with a handheld ultrasonic flow sensor during tidal breathing is a novel approach to extract similar information from expirograms in a simpler manner possibly qualifying as a screening tool for clinical routine. The aim of the present study was to evaluate calculation of the KPIv based on molar mass-volume-curves sampled with an ultrasonic flow sensor in patients with CF and controls by assessing feasibility, reproducibility and comparability with the Lung Clearance Index (LCI) derived from multiple breath washout (MBW) used as the reference method. METHODS Measurements were performed in patients with CF and healthy controls during a single test occasion using the EasyOne Pro, MBW Module (ndd Medical Technologies, Switzerland). RESULTS Capnography and MBW were performed in 87/96 patients with CF and 38/42 controls, with a success rate of 90.6% for capnography. Mean age (range) was 12.1 (4-25) years. Mean (SD) KPIv was 6.94 (3.08) in CF and 5.10 (2.06) in controls (p=0.001). Mean LCI (SD) was 8.0 (1.4) in CF and 6.2 (0.4) in controls (p=<0.001) and correlated significantly with the KPIv (p=<0.001). CONCLUSION Calculation of the KPIv based on molar mass-volume-curves is feasible. KPIv is significantly different between patients with CF and controls and correlates with the LCI. However, individual data revealed a relevant overlap between patients and controls requiring further evaluation, before this method can be recommended for clinical use.

Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?

To assess whether long-term inhalation with hypertonic saline is able to halt the progression of mild CF lung disease, we analysed longitudinal data of lung clearance index (LCI) and spirometry. A total of 34 patients with mild lung disease (FEV1 ≥ 70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.