SHERLOCk: An integrative genomic approach to Solve tHe puzzle of sevERe (earLy-Onset) COPD

Chronic Obstructive Pulmonary Disease (COPD) is characterized by a chronic
airflow limitation associated with an abnormal inflammatory response of the
airways to inhaled noxious particles or gases. It is the third leading cause of
death worldwide, accounting for approximately 3 million deaths each year and
the prevalence is predicted to increase even further during the coming decade
(WHO 2015). In the last two decades, there has been a disappointing lack of
fundamental breakthroughs in the understanding of the pathophysiology of COPD
and there is currently no pharmacological treatment available that halts its
relentless progression. A clear alternative for describing COPD does not exist
either, while the identification of subgroups of COPD patients based on
clinical, genomic and epigenomic factors would be useful. A clinically relevant
phenotype with high potential of having a genetic cause is severe early-onset
COPD (SEO-COPD), defined by severe airflow obstruction (FEV1 <= 40% predicted)
at a relatively young age (<=53 years). In the UMCG, we have a continuous flow
of severe COPD patients who are referred to our hospital for bronchoscopic lung
volume reduction treatment or lung transplantation. Approximately 40-50% of
these patients fulfil the criteria for SEO-COPD. As part of a previously
approved study (*Phenotyping in COPD*, METc 2014/102), these patients are
routinely characterized when they are willing to participate in this study and
gave their written informed consent. Characterization is performed using lung
function (i.e. spirometry, body box), clinical (i.e. questionnaires, physical
examination, measurement of waist-hip ratio), radiologic (HRCT-scan) and
systemic parameters (venous blood collection). Moreover, the following
additional samples are being extracted: bronchial biopsies, bronchial brushes
and nasal brushes.
There are two objectives this study adds. The primary objective is to identify
the genetic and epigenetic mechanisms underlying SEO-COPD by using the
bronchial brushes and biopsies that are already extracted from the SEO-COPD
patients and add 125 patients with severe COPD. The secondary objective is to
add two control groups (i.e. mild-moderate COPD group and healthy non-COPD
control group) matched for age and smoking habits.
Hopefully, this will eventually explore COPD susceptibility and its genetic
cause, resulting in a more tailored treatment of this COPD subset.

The aim of this study is to identify why a subset of COPD patients develops
such a severe COPD at early age and with relatively few packyears smoking. This
will need a functional genomics approach integrating both whole genome DNA
sequencing data in blood and transcriptomics data in the bronchial epithelium
as well as epigenetic regulation. This will identify novel common and rare
genetic variants, genes, miR*s, and DNA methylation sites that contribute to
severe (early-onset) COPD.

This is a single-center, observational, cross-sectional study.

The 250 (ex-)smoking mild-moderate COPD patients and 150 (ex-) smokers without
COPD are characterized during the following three visites:
Visit 1: demographics, medical history, physical examination, bodycomposition
(waist-hip ratio), questionnaires (CCQ, CAT, SGRQ), peripheral blood, ECG,
spirometry with reversibility and sputuminduction.
Visit 2: diffusion capacity, bodybox and IOS, PC20 methacholine, FeNO, PeXA,
Multiple Breath Nitrogen Washout (MBNW), in- and expiration HRCT of the thorax.
Visit 3: nosebrushes, bronchoscopy.

Yearly visit: catch-up demographics, medical history, physical examination,
spirometry and reversibility.
Exacerbation visit: Catch up demographics and medical history, physical
examination, spirometry and sputum induction, nasal swab, peripheral blood
collection.

The 125 patients with severe COPD are mainly characterized during routine
clinical care. When included in the study, patients will fill in extra
questionnaires, do extra pulmonary function tests, will collect urine and stool
samples and during the bronchoscopy, samples will be collected for the study.
The bronchoscopy is performed for bronchoscopic lungvolume reduction therapy
and not planned for participation in this study.

The risk for participant in this study are:
1. Dyspnea during sputum induction and provocation test with methacholine.
2. Bronchospasm during bronchoscopy and / or desaturation during the
bronchoscopy
3. Bleeding during collection of bronchial biopsies, bronchial or nasal brushes.

Measures for treatment or prevention:
Ad 1. Before the sputum induction and after the methacholine provocation every
subject will be given inhaled salbutamol to prevent or treat dyspnea. Patients
with severe COPD or an FEV1 < 1,2 L will not do provocation tests or sputum
induction.
Ad 2. If bronchospasms occur during the bronchoscopy the procedure will be
stopped immediately and if necessary subject will be given extra bronchodilator
medication by inhalation. This will treat bronchospasm properly. Monitoring
oxygen saturation will be performed during the whole procedure. If necessary
the bronchoscopy will be stopped.
Ad 3. If hemostasis is necessary, xylometazoline will be applied locally.