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

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: 50MBWtest 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

Correcting for tissue nitrogen excretion in multiple breath washout measurements - Fig 6

<p><b>Relationship between the contribution of tissue N₂ to LCI_N2 and length of washout calculated at a) the traditional 2.5% washout cut-off and b) the 5% washout cut-off.</b> The contribution of tissue N₂ to LCI_N2 calculated at the 2.5% cut-off (LCI_uncorr−LCI_Cournand) increased as washout time increased. However, this relationship was no longer observed at the earlier 5% cut-off.</p

Within-subject difference in FRC measured by multiple breath nitrogen washout (FRC_N2) and body plethysmography (FRC_pleth).

<p>The mean within-subject difference FRC_N2—FRC_pleth decreased after the three tissue N₂ excretion equations were applied to washout data from healthy and CF populations.</p

Estimates of tissue N₂ contribution to MBW outcomes at the 2.5% washout cut-off.

<p>Values are presented as the mean within-subject difference (95% CI) of the uncorrected–corrected MBW_N2 outcome. Outcomes were corrected by applying either the Cournand or Lundin tissue N₂ excretion equations.</p

Effect of applying Lundin and Cournand correction equations to previously published observational MBW data.

<p>Data are shown as pre-treatment and post-treatment LCI with paired treatment effect. Values are presented as mean (SD) unless otherwise indicated.</p

Within-subject difference between uncorrected LCI_N2 and LCI_N2 corrected for tissue N₂ excretion (LCI_Cournand) at different washout cut-offs.

<p>The difference was progressively smaller when calculated at earlier cut-offs of the washout in both health and CF.</p

Average slopes of the second half of all uncorrected, Lundin-corrected and Cournand-corrected FRC_N2/breath number curves (depicted graphically in Fig 4) for healthy subjects and those with CF.

<p>Average paired difference (uncorrected-corrected) in absolute and relative (percent of uncorrected slope) terms are shown. Data are expressed as mean 95% confidence interval) unless otherwise stated.</p

Relationship between the contribution of tissue N₂ to FRC_N2 and the difference between FRC as measured by MBW_N2 and MBW_SF6.

<p>FRC_N2 became disproportionately greater than FRC_SF6 as the contribution of tissue N₂ estimated by the within-subject difference FRC_N2—FRC_Cournand increased.</p