Exploring Novel Biomarkers for Emphysema Detection: the ENBED study

Chronic obstructive pulmonary disease (COPD) consists of two main phenotypes;
airway predominant COPD and emphysema predominant COPD There are novel drugs in
the therapeutic pipeline that specifically target one of these two specific
phenotypes of COPD. To assist in drug development targeting specific COPD
phenotypes it is necessary to reliably distinguish between these two COPD
phenotypes.

The reference standard for diagnosing emphysema is the high-resolution computed
tomography (HRCT) scan. Emphysema is characterized by permanently enlarged air
spaces with destruction of alveolar walls that can be visualized as focal areas
of low attenuation on the HR-CT scan, often without visible walls. Though many
studies nowadays include CT scanning for emphysema screening, such screening
exposes participants to radiation. Alternatives to HRCT scanning are pulmonary
function testing, of which body plethysmography is most suitable for detecting
emphysema.. Static hyperinflation (high total lung capacity and residual
volume) are markers for emphysema but not sensitive enough to predict
emphysema. Moreover, the technique of performing body plethysmography requires
an experienced pulmonary function laboratory and the device itself is not
portable, which hampers scalability of these screening methods. Third, specific
blood biomarkers , such as sRAGE have been linked to emphysema, but their
diagnostic accuracy has not yet been tested and this would still require the
sampling of venous blood. Novel, easy-to-use and preferably non-invasive ways
are necessary to detect emphysema in patients with COPD.

Speech analysis might be a first of such novel diagnostics. Dyspnea and cough
are common symptoms in COPD patients, and are likely to affect the vocal
features of the individuals. Studies have shown that voice biomarkers can be
used to differentiate COPD from healthy controls, and changes in voice are
associated with changes in symptoms in COPD. Also emphysema has a specific
speech characteristics when patient breath at a certain pace, putatively
reflecting dynamic hyperinflation. Though certain speech characteristics are
associated with COPD, particularly with emphysema, it is not yet known whether
speech can be used to distinguish between the two COPD phenotypes.

Besides speech, time-based capnometry might be another non-invasive,
breathing-based, diagnostic method for the detection of emphysema. Capnometry
analyzes the pattern of carbon dioxide (CO2) eliminated from the lungs as a
function of time. It produces a curve, the capnogram, which represents the
total amount of CO2 eliminated by the lungs during each breath. Features
extracted from the capnogram, such as the Slope of phase 2 (Slp2) and Slope of
phase 3 (Slp3) have been demonstrated to relate to airway obstruction and may
provide useful information about the heterogeneous involvement of lung
structures in COPD.(9) Slp2 represents the rapid increase in CO2 coming from
short paths to alveoli; it comes immediately after the elimination of the air
from the dead space. Slp3 is an important feature of gas washout curves and
contains information about gas transport in the alveolated airways of the lung
periphery. In volumetric capnography, emphysema patients reportedly have lower
ETCO2, Slp2, and Slp3 compared to COPD patients with predominantly airway
disease, and might thus be useful biomarkers to distinguish the two phenotypes
in time capnography.

The goal of the present study is to evaluate whether voice or capnometry, alone
or in combination with other (non-invasive) biomarkers, can be used to detect
emphysema predominant COPD phenotype (>=25% emphysematous lung tissue).

The present study will be a cross-sectional, single-center observational study
at the Department of Respiratory Medicine at Maastricht UMC+.

The present study will only include adult and capacitated patients with COPD
who are able to understand, read and write Dutch language. Risk and
inconveniences associated with this study are minimal and are limited to the
time investment associated with the non-invasive study measurements. The study
participants will undergo one venipuncture that poses a small risk of a local
hematoma, but is considered to be a very low risk procedure. The 5-STS is a
safe and low risk procedure for COPD patients to induce exercise(17) and might
be associated with feelings of dyspnea in those patients but this is generally
not considered as unpleasant (e.g. low BORG scores, < 4 on average).(18) The
NTC device that will be used in this study is a portable, handheld capnometer
(N-Tidal C Handset) through which patients can breathe freely without any
resistance, and will not be of substantial importance in diagnosing, curing,
mitigating, or treating disease, or otherwise preventing impairment of human
health in this study. The device used in this study will not otherwise present
a potential for serious risk to the health, safety, or welfare of a subject. We
will only include adult patients with stable disease and incapacitated patients
will not be able to participate.