Systemic Inflammation in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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COPD is ranked number 3 by the WHO list of important diseases worldwide and is the only disease with increasing mortality. The pathogenesis of cigarette smoke-induced COPD is obscure, therefore more insight is needed to design effective anti-inflammatory agents. Recently it has become clear that cigarette smoke-induced inflammation is not only present in the lungs but also in the blood, and that this systemic inflammation has important consequences for the clinical expression of COPD. The investigators hypothesize that healthy individuals who are susceptible to cigarette smoking demonstrate a higher and aberrant systemic inflammatory response to cigarette smoke. This susceptibility is caused by heterogeneous factors and is associated with various polymorphic genes that interact with each other and with the environment. Objective: To study systemic inflammation in individuals who are or are not susceptible to develop COPD. To characterize the switch to chronicity of the systemic inflmmatory response in COPD To determine whether the type and severity of the systemic inflammation contributes to the clinical outcome of COPD To compare between subjects who are or are not susceptible to develop COPD in peripheral blood, the corticosteroid responsiveness in vitro, and to unravel underlying mechanisms. To study the role of candidate genes that may play a role in the development of fixed airway obstruction, and to identify clues for patient's responsiveness to specific drugs To develop new biological and clinical markers for the early diagnosis and monitoring of COPD To define possible mediators involved in the early induction of COPD in susceptible smokers, and to define new drug targets

Official Title
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Acute and Chronic Inflammatory Responses Induced by Smoking in Individuals Being Susceptible and Non-Susceptible for Development of COPD: From Specific Disease Phenotyping Towards Novel Therapy (Study 2).

Conditions
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Chronic Obstructive Pulmonary Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 and ≤75 years Age, pack years, FEV1/FVC and FEV1% predicted must fit in one of the 9 groups of the study population Physically and mentally able to undergo the total study protocol Written informed consent Exclusion Criteria: Participation in another study Alpha-1-antitrypsin deficiency Selected grade 1-3 co-morbidity listed in the ACE-27 Active pulmonary infection like tuberculosis, pneumonia, flue, tracheobronchitis Active extra-pulmonary infection like hepatitis A-C, cystitis, gastro-enteritis etc Pulmonary diseases like sarcoidosis, pulmonary fibrosis, silicosis, hypersensitivity pneumonitis, asthma Life threatening diseases like carcinoma, AIDS (including HIV+), acute leukaemia etc Medication that may affect the results of the study: NSAID's, immunosuppressive agents like prednisolon, metotrexate, azathioprine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| A<br>20 healthy individuals not susceptible for COPD (age 18-40 years, 0 < pack years > 10, FEV1/FVC >70% , FEV1 >85% predicted) | |
| B<br>30 healthy individuals susceptible for COPD (age 40-75years, pack years >20, FEV1/FVC > 70%, FEV1 > 85% predicted) | |
| C<br>20 healthy individuals very susceptible for COPD (age 18-40 year, 0 < pack years > 10, FEV1/FVC > 70%, FEV1 > 85% predicted)and high prevalance of COPD in smoking family members older than 45 years | |
| D1<br>30 COPD patients with GOLD stage I (age 40-75 years, Pack years > 10, FEV1/FVC ≤ 70%, FEV1 > 80% predicted) | |
| D2<br>30 COPD patients with GOLD stage II (age 40-75 years, Pack years > 10, FEV1/FVC ≤ 70%, FEV1 50-80 predicted) | |
| D3<br>30 COPD patients with GOLD stage III (age 40-75 years, Pack years > 10, FEV1/FVC ≤ 70%, FEV1 30-50% predicted) | |
| D4<br>30 COPD patients with GOLD stage IV (age 40-75 years,Pack years > 10, FEV1/FVC ≤ 70%, FEV1 30% predicted) | |
| E<br>20 healthy individuels very susceptible for COPD ( Age 18-40 years,0 < Pack years > 10, FEV1/FVC >70%, FEV1 > 85% predicted, and one of the smoking family members has severe early onset COPD or mild COPD with very low smoke exposure | |
| F<br>30 COPD patients who are highly susceptible (age > 53 years with Pack years > 10 , FEV1/FVC ≤ 70% and FEV1 < 40% predicted) or (age >18 years with 0 < pack years > 5, FEV1/FVC ≤ 70% and FEV1 < 80% predicted) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic inflammation assessed by measurement of expression of established and newly developed markers on innate immune cells; genomic and proteomic analysis of innate immune cells and measurement of pro- and anti-inflammatory cytokines in plasma/serum |  | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extensive clinical characterisation of: a) young healthy individuals with low number of pack years who have a high and low familial risk to develop COPD; b) older individuals with higher number of pack years with either a normal lung function or COPD. |  | 4 years | 
| Important clinical endpoints include symptoms, lung function, Bode-index, CT-scanning of the lung. |  | 4 years | 
| Distribution of candidate genes (SNPs) for COPD between the different groups and relations with systemic inflammation. |  | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Inflammation, Smoking, Susceptibility