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.
The lung clearance index (LCI) has strong intra-test repeatability; however, the inter-test reproducibility of the LCI is poorly defined. The aim of the present study was to define a physiologically meaningful change in LCI in preschool children, which discriminates changes associated with disease progression from biological variability. Repeated LCI measurements from a longitudinal cohort study of children with cystic fibrosis and age-matched controls were collected to define the inter-visit reproducibility of the LCI. Absolute change, the coefficient of variation, Bland–Altman limits of agreement, the coefficient of repeatability, intra-class correlation coefficient, and percentage changes were calculated. LCI measurements (n=505) from 71 healthy and 77 cystic fibrosis participants (aged 2.6–6 years) were analysed. LCI variability was proportional to its magnitude, such that reproducibility defined by absolute changes is biased. A physiologically relevant change for quarterly LCI measurements in health was defined as exceeding ±15%. In clinically stable cystic fibrosis participants, the threshold was higher (±25%); however, for measurements made 24 h apart, the threshold was similar to that observed in health (±17%). A percentage change in LCI greater than ±15% in preschool children can be considered physiologically relevant and greater than the biological variability of the test.
Cystic fibrosis (CF) infants are born with normal airway anatomy, and dilatation of mucus glands in smaller airways has been described as the earliest histological changes in the lung of patients. This and other evidence has led to the concept that the small airways may be the region demonstrating initial pathology. Studies clarifying this have been challenged by the lack of a clear definition of what constitutes "small airways" and the difficulties to find accurate measures to quantify and track abnormalities in this region of the lung. Dynamic lung function test are not ideally suited to capture small airway abnormalities as the overall surface area of the small airways is about 40 times greater than that of central airways. Measures that are linked to airway size therefore often fail to capture abnormalities in a disease such as cystic fibrosis that is unevenly distributed throughout the lung. This review summarizes our current understanding of the role of small airways in disease development in cystic fibrosis patients and describes the spectrum of diagnostic tools available to diagnose and follow small airway disease and highlight the opportunities as well as challenges of targeting small airways via aerosol therapy in CF patients.
CF lung disease arises from ion transport defect. Disease origins in small airways before 1 yr of age necessitate early intervention. Denufosol (DEN), a novel chloride channel activator, stimulates Cl − transport, inhibits Na + absorption and increases ciliary beat frequency. A Phase 3, double‐blind, placebo (PL)‐controlled trial (TIGER‐1) was conducted in 352 CF pts to compare inhaled DEN 60 mg TID to PL for 24 wks. Pts were ≥ 5 yrs (mean 14.6 yrs) and had FEV 1 ≥ 75% predicted (mean 92%). Pulmonary function tests and exacerbations, QOL measures and systemic exposure of DEN were evaluated. This work examines endpoints relevant to DEN use as an early intervention agent. The ability to reach small airways was confirmed by significant improvement in FEF 25%–75% in pts ≤ 110% predicted FEV 1 (p=0.025). There was little to no systemic exposure to denufosol, no accumulation with chronic dosing, and no evidence of systemic AEs including liver enzyme levels, blood biochemistry and differential cell counts. DEN's mechanism of action addressing the basic defect, the lack of systemic exposure and ability to target small airways makes this a potentially promising therapy for early intervention in CF lung disease.
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