Exhaled Markers in COPD during viral and/or bacterial induced Exacerbations

COPD patients frequently exacerbate. Consequently, clinicians often empirically
prescribe broad spectrum antibiotics, which may or may not have been indicated.
The origin of the exacerbation might indeed be bacterial but can also be viral,
in which antibiotics are not useful. Currently, information on the underlying
cause of an exacerbation can only be available after 3 days. Therefore, there
is an urgent need for a quick and reliable test at point-of-care to assess the
origin of an exacerbation. We hypothesize that comprehensive analysis of the
mixture of volatile organic compounds (VOCs) in exhaled air (breathprints)
qualifies for this.

The present study has two parts. Part I is clinically focused and is testing
the accuracy of exhaled VOC analysis in relation to bacterial infection at
single clinical presentation of a COPD exacerbation. Part II is
pathophysiologically oriented, examining the longitudinal changes in VOCs at
clinical recovery and the association of exhaled VOCs with respiratory virus
infection.

Part I (cross-sectional study)
1. To identify breathprints of VOCs by electronic nose in exhaled air that are
associated with a bacterial origin of an exacerbation in COPD patients.
2. To examine the critical VOCs of these breathprints in exhaled air by gas
chromatography and mass spectrometry (GC-MS).
3. To identify specific VOCs by GC-MS analysis of in vitro headspace samples
obtained from expectorated sputum.
4. To identify individual biomarkers in sputum and blood that are associated
with COPD exacerbations and electronic nose (eNose) and GC-MS breathprints to
help unravel the underlying pathophysiological pathways.

Part II (longitudinal study)
1. To identify breathprints of VOCs by electronic nose in exhaled air that are
associated with a viral, bacterial, viral and bacterial or other origin of an
exacerbation in COPD patients.
2. To identify within-subject changes in these breathprints of VOCs by
electronic nose in exhaled air between exacerbation and recovery.
3. Objectives 2, 3 and 4 described under part I also apply for the changes in
breathprints in part II.

Part I will be a cross-sectional, observational study, requiring 62 GOLD I-IV
COPD patients presenting with an acute exacerbation at the two referral
hospitals (MST and AMC). Part II will be a prospective follow-up study
including an exacerbation- and a recovery visit, requiring another 334 COPD
patients, adding up to 396 patients in total. Patients will be divided into a
training cohort (allowing internal validation) and a validation cohort (for
independent, external validation).

The burden of the study procedures can be considered minimal and without risks
for all patients. Part I: Adult patients will be asked for a spontaneous sputum
sample and venous blood sample (part of regular care) and an exhaled breath
sample and nasal-pharyngeal swab during an unscheduled visit to AMC or MST for
an exacerbation. Part II: During a second, regular monitoring visit (< 4 months
after exacerbation) at clinical recovery exhaled breath sampling will be
repeated, together with spontaneous sputum sample, a venous blood sample and a
nasal-pharyngeal swab. When there is no regular monitoring visit planned within
4 months after exacerbation, the patient will be contacted to schedule an extra
visit.