Renee Jensen

Hypertonic saline improves the LCI in paediatric patients with CF with normal lung function

Background and aims Sensitive outcome measures to assess the efficacy of therapeutic interventions in patients with cystic fibrosis (CF) with mild lung disease are currently lacking. Our objective was to study the ability of the lung clearance index (LCI), a measure of ventilation inhomogeneity, to detect a treatment response to hypertonic saline inhalation in paediatric patients with CF with normal spirometry. Methods In a crossover trial, 20 patients with CF received 4 weeks of hypertonic saline (HS) and isotonic saline (IS) in a randomised sequence separated by a 4 week washout period. The primary end point was the change in the LCI due to HS versus IS. Results Baseline characteristics including the LCI were not significantly different between both study periods. Four weeks of twice-daily HS inhalation significantly improved the LCI compared with IS (1.16, 95% CI 0.26 to 2.05; p=0.016), whereas other outcome measures such as spirometry and quality of life failed to reach statistical significance. Randomisation order had no significant impact on the treatment effect. Conclusions The LCI, but not spirometry was able to detect a treatment effect from HS inhalation in patients with CF with mild disease and may be a suitable tool to assess early intervention strategies in this patient population. Clinical trial number NCT00635141.

The effect of dornase alfa on ventilation inhomogeneity in patients with cystic fibrosis

Outcome measures to assess therapeutic interventions in cystic fibrosis (CF) patients with mild lung disease are lacking. Our aim was to determine if the lung clearance index (LCI) can detect a treatment response to dornase alfa in paediatric CF patients with normal spirometry. CF patients between 6–18 yrs of age with FEV1 ≥80% pred were eligible. In a crossover design, 17 patients received 4 weeks of dornase alfa and placebo in a randomised sequence separated by a 4-week washout period. The primary end-point was the change in LCI from dornase alfa versus placebo. A mixed model approach incorporating period-dependent baselines was used. The mean±sd age was 10.32±3.35 yrs. Dornase alfa improved LCI versus placebo (0.90±1.44; p = 0.022). Forced expiratory flow at 25–75% expired volume measured by % pred and z-scores also improved in subjects on dornase alfa (6.1%±10.34%; p = 0.03 and 0.28±0.46 z-score; p = 0.03). Dornase alfa significantly improved LCI. Therefore the LCI may be a suitable tool to assess early intervention strategies in this patient population.

Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline.

RATIONALE Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF). OBJECTIVES To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. METHODS The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect. MEASUREMENTS AND MAIN RESULTS A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025). CONCLUSIONS MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.

Multiple Breath Nitrogen Washout: A Feasible Alternative to Mass Spectrometry

Background The lung clearance index (LCI), measured by multiple breath washout (MBW), reflects global ventilation inhomogeneity and is a sensitive marker of early cystic fibrosis (CF) lung disease. Current evidence is based on a customized mass spectrometry system that uses sulfur hexafluoride (SF6) as a tracer gas, which is not widely available. Nitrogen (N2) washout may be better suited for clinical use and multi-center trials. Objective To compare the results obtained from a N2 washout system to those generated by the SF6 based system in healthy children and children with CF. Methods Children with CF were recruited from outpatient clinics; healthy children were recruited from the Research4Kids online portal. Participants performed MBWSF6 (Amis 2000, Innovision, Denmark) and MBWN2 (ExhalyzerD, EcoMedics, Switzerland) in triplicate, in random order on the same day. Agreement between systems was assessed by Bland-Altman plot. Results Sixty-two healthy and 61 children with CF completed measurements on both systems. In health there was good agreement between systems (limits of agreement −0.7 to 1.9); on average N2 produced higher values of LCI (mean difference 0.58 (95% CI 0.42 to 0.74)). In CF the difference between systems was double that in health with a clear bias towards disproportionately higher LCIN2 compared to LCISF6 at higher mean values of LCI. Conclusion LCIN2 and LCISF6 have similar discriminative power and intra-session repeatability but are not interchangeable. MBWN2 offers a valid new tool to investigate early obstructive lung disease in CF, but requires independent normative values.

Progression of Lung Disease in Preschool Patients with Cystic Fibrosis

Rationale: Implementation of intervention strategies to prevent lung damage in early cystic fibrosis (CF) requires objective outcome measures that capture and track lung disease. Objectives: To define the utility of the Lung Clearance Index (LCI), measured by multiple breath washout, as a means to track disease progression in preschool children with CF. Methods: Children with CF between the ages of 2.5 and 6 years with a confirmed diagnosis of CF and age‐matched healthy control subjects were enrolled at three North American CF centers. Multiple breath washout tests were performed at baseline, 1, 3, 6, and 12 months to mimic time points chosen in clinical care and interventional trials; spirometry was also conducted. A generalized linear mixed‐effects model was used to distinguish LCI changes associated with normal growth and development (i.e., healthy children) from the progression of CF lung disease. Measurements and Main Results: Data were collected on 156 participants with 800 LCI measurements. Although both LCI and spirometry discriminated health from disease, only the LCI identified significant deterioration of lung function in CF over time. The LCI worsened during cough episodes and pulmonary exacerbations, whereas similar symptoms in healthy children were not associated with increased LCI values. Conclusions: LCI is a useful marker to track early disease progression and may serve as a tool to guide therapies in young patients with CF.

Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term tolerability, adherence, and safety†‡

Inhaled hypertonic saline (HS) is an attractive agent for chronic maintenance therapy in infants and toddlers with cystic fibrosis (CF) because it improves defective mucociliary clearance. Prior to undertaking a clinical trial of HS efficacy in young children with CF, tolerability, adherence, and safety must be established.

Effect of equipment dead space on multiple breath washout measures.

Multiple breath inert gas washout (MBW) systems are designed to minimize equipment dead space volume (Vd). Animal and infant studies have demonstrated the impact of increased Vd on MBW measurements. In this study, we investigate the effect of Vd of a nitrogen (N2) MBW system on MBW measurements in preschool children.

A Systematic Approach to Multiple Breath Nitrogen Washout Test Quality

Background Accurate estimates of multiple breath washout (MBW) outcomes require correct operation of the device, appropriate distraction of the subject to ensure they breathe in a manner representative of their relaxed tidal breathing pattern, and appropriate interpretation of the acquired data. Based on available recommendations for an acceptable MBW test, we aimed to develop a protocol to systematically evaluate MBW measurements based on these criteria. Methods 50 MBW test occasions were systematically reviewed for technical elements and whether the breathing pattern was representative of relaxed tidal breathing by an experienced MBW operator. The impact of qualitative and quantitative criteria on inter-observer agreement was assessed across eight MBW operators (n = 20 test occasions, compared using a Kappa statistic). Results Using qualitative criteria, 46/168 trials were rejected: 16.6% were technically unacceptable and 10.7% were excluded due to inappropriate breathing pattern. Reviewer agreement was good using qualitative criteria and further improved with quantitative criteria from (κ = 0.53–0.83%) to (κ 0.73–0.97%), but at the cost of exclusion of further test occasions in this retrospective data analysis. Conclusions The application of the systematic review improved inter-observer agreement but did not affect reported MBW outcomes.

Lung clearance index response in patients with CF with class III CFTR mutations

Ivacaftor (KALYDECO) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that increases transmembrane chloride flux in vitro and leads to significant benefits in patients with cystic fibrosis (CF) with class III gating mutations.1–5 Ivacaftor is associated with sustained improvement in FEV1 and weight as well as reduced time to next pulmonary exacerbation.5–7 It has also been shown that 4 weeks of ivacaftor improves the lung clearance index (LCI) in patients with CF with preserved lung function.8 It is presently unclear whether LCI, a measure of ventilation inhomogeneity, provides additional information among patients with more impaired lung function as well as whether the sustained effectiveness of ivacaftor as demonstrated by improvements in the previously mentioned outcomes is also evident in the LCI response. The aim of this observational study was to assess the LCI before and after initiation of ivacaftor treatment over 6 months in patients with CF with a wider range of …

Correcting for tissue nitrogen excretion in multiple breath washout measurements

Nitrogen excreted from body tissues impacts the calculation of multiple breath nitrogen washout (MBWN2) outcomes. The aim of this study was to determine the effect of tissue N2 on MBWN2 outcomes in both healthy subjects and patients with CF and to assess whether it is possible to correct for tissue N2. The contribution of tissue N2 to MBWN2 outcomes was estimated by comparing MBWN2-derived functional residual capacity (FRCN2) to FRC measured by body plethysmography (FRCpleth) and by comparing MBW outcome measures derived from MBWN2 and sulfur hexafluoride MBW (MBWSF6). Compared to plethysmography and MBWSF6, MBWN2 overestimated FRC and lung clearance index (LCI). Application of mathematical tissue N2 corrections reduced FRCN2 values closer to FRCpleth in health and reduced LCIN2 in both health and CF, but did not explain all of the differences observed between N2-dependent and -independent techniques. Use of earlier washout cut-offs could reduce the influence of tissue N2. Applying tissue N2 corrections to LCIN2 measurements did not significantly affect the interpretation of treatment effects reported in a previously published interventional trial. While tissue N2 excretion likely has an impact on MBWN2 outcomes, better understanding of the nature of this phenomenon is required before routine correction can be implemented into current MBWN2 protocols.