The association of tidal EFL with exercise performance, exacerbations, and death in COPD

Abstract

Background: Tidal expiratory flow limitation (EFL_T) is frequently found in patients with COPD and can be detected by forced oscillations when within-breath reactance of a single-breath is ≥0.28 kPa·s·L^-1. The present study explored the association of within-breath reactance measured over multiple breaths and EFL_T with 6-minute walk distance (6MWD), exacerbations, and mortality.

Methods: In 425 patients, spirometry and forced oscillation technique measurements were obtained on eight occasions over 3 years. 6MWD was assessed at baseline and at the 3-year visit. Respiratory symptoms, exacerbations, and hospitalizations were recorded. A total of 5-year mortality statistics were retrieved retrospectively. We grouped patients according to the mean within-breath reactance [Formula: see text], measured over several breaths at baseline, calculated as mean inspiratory-mean expiratory reactance over the sampling period. In addition to the established threshold of EFL_T, an upper limit of normal (ULN) was defined using the 97.5th percentile of [Formula: see text], of the healthy controls in the study; 6MWDs were compared according to [Formula: see text], as normal, ≥ ULN < EFL_T, or ≥ EFL_T. Annual exacerbation rates were analyzed using a negative binomial model in the three groups, supplemented by time to first exacerbation analysis, and dichotomizing patients at the ULN.

Results: In patients with COPD and baseline [Formula: see text] below the ULN (0.09 kPa·s·L^-1), 6MWD was stable. 6MWD declined significantly in patients with [Formula: see text]. Worse lung function and more exacerbations were found in patients with COPD with [Formula: see text], and patients with [Formula: see text] had shorter time to first exacerbation and hospitalization. A significantly higher mortality was found in patients with [Formula: see text] and FEV₁ >50%.

Conclusion: Patients with baseline [Formula: see text] had a deterioration in exercise performance, more exacerbations, and greater hospitalizations, and, among those with moderate airway obstruction, a higher mortality. [Formula: see text] is a novel independent marker of outcome in COPD.

Keywords: 6-minute walk test; COPD; exacerbations; forced oscillation technique; mortality; reactance.

Figure 1

Timeplot illustrating the variability of $\mathrm{\Delta }\overline{\text{Xrs}}$ measurements (splines) over the course of the study shown in the first 20 patients with COPD with complete visits, defined as having EFL_T at baseline $(\mathrm{\Delta }\overline{\text{Xrs}}>0.28\text{kPa}\cdot \mathrm{s}\cdot {\mathrm{L}}^{-1})$. The dotted line is set at 0.09 kPa·s·L⁻¹, the upper limit of normal and the solid line at EFL_T.

Figure 2

(A) Six-minute walk distance (6MWD) in patients with COPD (N=388) at different levels of FEV₁% predicted (A) and $\mathrm{\Delta }\overline{\text{Xrs}}$ (B) at baseline. Dotted lines set at 350 m (horizontal) and at $\mathrm{\Delta }\overline{\text{Xrs}}>0.09\text{kPa}\cdot \mathrm{s}\cdot {\mathrm{L}}^{-1}$, upper limit of normal (ULN), and $\mathrm{\Delta }\overline{\text{Xrs}}>0.28\text{kPa}\cdot \mathrm{s}\cdot {\mathrm{L}}^{-1}$, the threshold for tidal expiratory flow limitation (EFL_T). The solid lines represent the regression lines. (C) 6MWT at baseline and the 3-year visit presented by notchplots with quartiles, 95% central range and outliers among COPD patients of GOLD II–IV grades and categorized according to $\mathrm{\Delta }\overline{\text{Xrs}}$ (D) as normal (white), below EFL_T, but above ULN (light gray), and > EFL_T threshold (gray). Non-overlapping notched areas are likely to represent significant differences between groups. Solid lines are drawn between the mean 6MWD at baseline and the 3-year visit.

Figure 3

Time to first moderate or severe exacerbation (A) and to the first hospitalization (B) in COPD patients with $\mathrm{\Delta }\overline{\text{Xrs}}$ measurements above the upper limit of normal (ULN), 0.9 kPa·s·L⁻¹ (solid line), and below the ULN at the baseline visit. Dashed line at 25%.

Figure 4

Kaplan–Meier survival curves in COPD patients with normal $\mathrm{\Delta }\overline{\text{Xrs}}$ and in COPD patients with $\mathrm{\Delta }\overline{\text{Xrs}}$ measurements above the upper limit of normal (ULN). Test of equality of survival distributions was performed using log-rank test.