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 $(\mathrm{\Delta }\overline{\text{Xrs}})$, 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 $\mathrm{\Delta }\overline{\text{Xrs}}$, of the healthy controls in the study; 6MWDs were compared according to $\mathrm{\Delta }\overline{\text{Xrs}}$, 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 $\mathrm{\Delta }\overline{\text{Xrs}}$ below the ULN (0.09 kPa·s·L⁻¹), 6MWD was stable. 6MWD declined significantly in patients with $\mathrm{\Delta }\overline{\text{Xrs}}\ge \text{ULN}$. Worse lung function and more exacerbations were found in patients with COPD with $\mathrm{\Delta }\overline{\text{Xrs}}\ge \text{ULN}$, and patients with $\mathrm{\Delta }\overline{\text{Xrs}}\ge \text{ULN}$ had shorter time to first exacerbation and hospitalization. A significantly higher mortality was found in patients with $\mathrm{\Delta }\overline{\text{Xrs}}\ge \text{ULN}$ and FEV₁ >50%.

Conclusion

Patients with baseline $\mathrm{\Delta }\overline{\text{Xrs}}\ge \text{ULN}$ had a deterioration in exercise performance, more exacerbations, and greater hospitalizations, and, among those with moderate airway obstruction, a higher mortality. $\mathrm{\Delta }\overline{\text{Xrs}}$ is a novel independent marker of outcome in COPD.

Keywords:

• forced oscillation technique
• reactance
• COPD
• exacerbations
• 6-minute walk test
• mortality

Supplementary materials

Figure S1 Scatterplot of $\mathrm{\Delta }\overline{\text{Xrs}}$ plotted against FEV₁ % predicted in healthy controls (N=229). Mean represented by the solid line. The dashed line represents the 97.5th percentile, the upper limit of normal (ULN).

Table S1 Baseline characteristics in men and women (N=425)

Acknowledgments

The study was sponsored by GlaxoSmithKline. The sponsor had no role in the design of the study, collection and analysis of the data, nor in the preparation of the manuscript.

The work was performed at Haukeland University Hospital. The authors thank all participants who took part in the study, all members of the Bergen Respiratory Research Group who contributed to the data collection, and offer special thanks to Lene Svendsen, Rita Oppedal, Tina Endresen-Vinsjevik, and Eli Nordeide who performed/supervised the pulmonary function tests.

Author contributions

The corresponding author BBA wrote the manuscript, had access to all of the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. PMAC was in the ECLIPSE Scientific Committee and PSB in the ECLIPSE Steering Committee. They both contributed to the development of the research design. PSB, JAH, and TMLE also contributed in the data collection. All authors, including RLJ and RD, contributed to the data analysis, the clinical interpretation of the data, and to reviewing the final submission.

Disclosure

The authors report no conflicts of interest in this work.