Systemic manifestation and co-morbidity in COPD are associated with circulating markers of aging

Chronic obstructive pulmonary disease (COPD) is currently generally recognized
as a systemic disease with various extra-pulmonary features. There is currently
considerable scientific interest in exploring the role and utility of
biomarkers in insights in the outcome of COPD. Indeed, there is a need for
biomarkers in COPD to better diagnose and assess the severity of the disease.
Based on the parallelism between the manifestation of COPD and the process of
aging, the aim of the present study is to investigate if COPD can be described
as a syndrome of accelerated aging. Moreover, the underlying case for the
elevated presence of co-morbidity (cardiovascular co-morbidity, diabetes,
osteoporosis, muscle wasting, renal failure, metabolic syndrome and depressive
symptoms) is not known yet. It is likely that the systemic consequences of the
disease -systemic inflammation and oxidative stress- play a role in the
pathogenesis. In addition, the contribution of the liver induced adipokines
(hepatokines) to the extra-pulmonary manifestation of COPD will be
investigated. With increasing age, respiratory infections become more frequent
and severe. Colonization with respiratory pathogens, such as S. pneumoniae and
H. influenzae seem to play an important role in this. More recently, it was
found the both COPD patients, as healthy subjects, have a rich respiratory
microbiome, without symptoms of an infection, which is possibly related to
disease progression and exacerbations in COPD patients. Part III of the study
will focus on the respiratory microbiome of COPD patients, in comparison with
that of control subjects.

Part I of the study: I) to determine if one or a batch of aging marker(s)
is/are associated with the presence of objectively diagnosed COPD related
co-morbidity (muscle wasting, osteoporosis, cardiovascular risk, glucose
intolerance, renal failure, metabolic syndrome and depressive symptoms) or
systemic COPD phenotypes (systemic inflammation and oxidative stress) at
baseline in a COPD population admitted for pulmonary rehabilitation; II) to
determine if one or a batch of aging marker(s) can predict the presence of
objectively diagnosed COPD related co-morbidity (muscle wasting, osteoporosis,
cardiovascular risk, glucose intolerance, renal failure, metabolic syndrome and
depressive symptoms) at baseline in a COPD population admitted for pulmonary
rehabilitation; III) to determine if the change in aging markers over 2 years
if different in patients with COPD compared to healthy subjects. Part II of the
study: I) to determine if the hepatokines are associated with the
extra-pulmonary manifestation of COPD (co-morbidity and systemic COPD
phenotypes). Part III of the study: I) to define the respiratory microbiome of
stable COPD patients and compare this with the respiratory microbiome of
elderly smokers and non-smokers; II) to assess the microbial diversity of the
respiratory microbiome of stable COPD patients and compare this with that of
elderly smokers and non-smokers; III) to assess if there is a relationship
between the respiratory microbiome and clinical characteristics of COPD
patients (e.g. frequent exacerbations).

observational cross-sectional study with a longitudinal follow-up of two years.

Part I of the study: Participation includes two test days: Test day 1 at the
Center of expertise for chronic organ failure (Ciro) Horn: in the fasted state,
venous blood will be collected for the assessment of cardiovascular risk
markers, glucose intolerance, markers of systemic inflammation and oxidative
stress and the markers of accelerated aging. In total, about 50 ml venous blood
will be collected, an amount which is not of clinical relevance. Also in the
fasted state, urine will be collected, the electrocardiography and the pulse
wave velocity will also be measured and the dual x-ray absorptiometry scan will
be performed after emptying the bladder. After breakfast, a lung function
measurement and measuring the waist circumference will take place, and the HADs
questionnaire will be filled in. On the second day, all subjects will be
invited to the MUMC+ for a high resolution computed tomography (HRCT) scan of
the thorax. As the measurement of the lung function and body composition are
included in the assessment of the COPD patients, these tests do not have to
repeated during participation of the test. The test days will be planned before
the start of the rehabilitation for the COPD patients. Part II of the study: A
subgroup of 50 patients with COPD and 50 healthy subjects, hepatokines will be
analyzed during a second blood sampling during the second test day. Part III
of the study: a subgroup of 70 COPD patients and 70 healthy subjects, throat
swab and (induced) sputum will be collected at T1.

The performance of these tests are virtually without any risks. Blood sampling
will occur by venapunction and a bleu spot may occur. However, subjects who are
really frightened of blood sampling will be advised not to participate in the
study. During the assessment of the cardiovascular risk, blood flow of the arm
will be minimized for 5 minutes. This procedure can result in a tingling
feeling of the arm that disappears after the occlusion. The radiation dose of
the different scans (DEXA, HRCT) is very low and virtually without any risk.
The risks associated with collecting spontaneous sputum is negligible. The
risks associated with collecting induced sputum are dyspnoea, fear and cough.
However, induced sputum is performed according to internationally accepted
protocols, including frequent assessment of lung function in order to minimize
risks.The control subjects will receive a health check including lung function
measurements, body composition and cardiovascular risk assessment by
participating the study. Although this is not direct benefit of the study, it
may be interesting for the subjects to receive this information.