The COP:TRIN vision 

Chronic obstructive pulmonary disease (COPD) is a frequent condition worldwide that impairs breathing, causes coughing and mucus hyper secretion. In Denmark, the prevalence of COPD has been estimated at 430,000, of whom 40,000 have severe to very severe disease.

Our vision is to establish a nationwide respiratory medicine research collaboration consisting of highly skilled entities within biomarkers, genetics and clinical trials. The aim is to perform urgently needed pathophysiological, genetic and clinical trials in an academic and independent research environment, building on strengths in Danish clinical research as well as biomarker technology.

 

 

BACKGROUND

APPROACH

ORIGINALITY


BACKGROUND

Chronic obstructive pulmonary disease (COPD) is a frequent condition worldwide that impairs breathing, causes coughing and mucus hyper secretion. Acute Exacerbation of COPD (AECOPD), a condition often caused by lower airway infection, is characterized by hyper-inflammation in the lungs and increased symptoms leading to physical disability, anxiety, depression and premature death. Despite the high incidence of AECOPD worldwide and the devastating personal consequences, little is known about how—on an individual level—to reduce the frequency and severity of exacerbations and mortality rate in the subgroup of COPD patients who are “frequent exacerbators”. In this area there are several important unresolved issues:

  1. One of the most frequently used treatments, systemic corticosteroids in moderate to high doses, causes severe side-effects such as osteoporosis, diabetes, haemorrhages and psychiatric disorders and has no apparent effect on mortality or other hard endpoints, and only a modest effect on the recovery of pulmonary function during the acute phase. Recent data show that treatment with systemic corticosteroids may have an effect in patients with an elevated level of eosinophils in sputum or peripheral blood, thus suggesting that the majority of patients (those without eosinophilia) do not benefit from this therapy, thus suffering harm without effect.
  2. Small observational studies show a strong association between colonization with certain bacteria (Pseudomonas aeruginosa) and disease progression and death; however, it is not known whether this colonization is a marker of advanced disease as such or a contributing cause to poor prognosis. Genetic analyses can reveal whether COPD patient are colonized for long periods of time with the same clonal P. aeruginosa, or rather suffer from repeated infections with clonally different bacteria.
  3. Autopsy studies of COPD patients show that as many as two-thirds of patients who die in a clinical picture of COPD exacerbation, actually die from thromboembolic complications such as pulmonary embolism and myocardial infarction. However, no systematic approach has been taken to identify patients at especially high risk of fatal thromboembolic events during AECOPD. If advanced coagulation status analysis can identify patients at risk of such events, the rationale for an intervention study is present.
  4. The most severely ill patients with AECOPD often have pneumonia—for patients without respiratory acidosis, it is not known whether these patients benefit from up front continuous positive airway pressure (CPAP) or non-invasive ventilation (NIV) to prevent respiratory fatigue, atelectases and hyper-secretion challenges.

APPROACH

Initial studies

Genetics and pathophysiology: Through state of the art genetic, pathophysiological and large scale epidemiological studies to increase the understanding of the diversity of disease processes taking place in different patients with AECOPD and thereby identifying specific patients in need of interventions targeted towards the specific pathophysiological processes taking place in an individual patient.
Evidence providing studies

Randomized controlled trials: On the basis of this knowledge (microbiomic profile, characterization of thrombosis risk, identification of patients at risk of persistent respiratory failure via biomarker studies) conduct randomized Good Clinical Practice controlled trials with interventions personalized to patients with specific pathophysiologic processes and only recruiting patients with a specific profile matching the pathophysiological and microbiomic profile, built on the knowledge reached in the studies on AECOPD. To intervene in a personalized manner, towards specific pathophysiological processes taking place in this certain patient.

ORIGINALITY

No systematic, large scale approach to answer the above genetic, pathophysiological and clinical questions has so far been conducted. More knowledge of how to personalize therapy in this large patient group is urgently needed.

We will attempt to do this using our organization of

  1. The largest departments of respiratory medicine in Denmark
  2. Centre for Genomic Medicine
  3. Foreign top-quality university capacities (Univ. of Manchester, Prof Jørgen Vestbo)
  4. Top-quality Danish biomarker-development SME (Nordic BioScience).