Phenotyping of COPD exacerbations

Phenotyping of COPD exacerbations

Exacerbation, i.e. a period of worsening of disease, has a profound impact on disease progression in COPD. The frequency of exacerbations has been linked to the rate of lung function decline and health-related quality of life in COPD. Severe (hospitalised) exacerbations increase the mortality rate, where fewer than half of the patients survive for a further 5-years after a severe exacerbation. Thus, there is an urgent need to better understand exacerbation pathobiology in order to develop better treatment options for patients.

The etiology of exacerbations is complex and multifactorial, as the interactions between the host immune response and the plethora of exacerbation triggers are likely to dictate the outcomes. In some patients, this might lead to an unrestrained cycle of infection and inflammation with long lasting adverse consequences on lung function. The majority of COPD exacerbations are caused by bacteria and viral infections, which alter lung microbiome homeostasis and cause epithelial damage. Although the association between changes in lung microbiome and worsening of lung function has been described in COPD, the mechanisms by which these changes lead to lung damage and disease progression are not well understood.

Lung epithelium constitutes the first line of defense against invading pathogens. Pathogenic alterations in the lung epithelium in COPD has been documented at the transcriptomic and protein levels, where some of the transcriptomic changes could be reflected in the nasal epithelium as they are part of the continuum of the airway structure. Nasal brushing can be an alternative source of biomarkers as it is closer to the site of disease manifestations compared to blood biomarkers but is less invasive in terms of sample collection compared to bronchoscopy. Additionally, since bronchoscopy is not a feasible procedure at the time of exacerbation, nasal brushing represents the most proximal route in the airway to examine epithelial changes during exacerbation.

In depth profiling of the airway inflammatory profile, including the sputum microbiome and  the nasal brush transcriptome at exacerbation and stable disease could improve our mechanistic understanding of the molecular pathways and the infectious triggers involved in exacerbation, chronic inflammation, patient reported daily symptoms and COPD disease progression, such that novel pathways could be explored as therapeutic targets and biomarkers.

SPECIFIC AIMS

Specific Aim 1: Assess whether exacerbation frequency or type (severity in symptoms, duration, or treatment, molecular phenotype by pathogen or inflammatory profile) is associated with disease pathway biomarkers or lung microbiome composition in stable disease and at exacerbation.

Specific Aim 2: Assess whether accelerated lung function decline in COPD is associated with disease pathway biomarkers or lung microbiome composition

Specific Aim 3: Determine if changes in the lung micro-environment following exacerbations could be reflected in the nasal compartment and are associated with changes in systemic biomarkers

Specific Aim 4: Evaluate the prognostic value of HRCT PRM-fSAD for exacerbations and FEV1 decline expected to lead to identification of novel therapeutic targets for COPD and chronic mucus hypersecretion in particular as well as biomarkers for those patients at risk to progress to severe disease.

 

Summary
Exacerbation, i.e. a period of worsening of disease, has a profound impact on disease progression in COPD. The frequency of exacerbations has been linked to the rate of lung function decline and health-related quality of life in COPD.1 Severe (hospitalised) exacerbations increase the mortality rate,1 where fewer than half of the patients survive for a further 5-years after a severe exacerbation.2 Thus, there is an urgent need to better understand exacerbation pathobiology in order to develop better treatment options for patients. In depth profiling of the airway inflammatory profile, including the sputum microbiome and the nasal brush transcriptome at exacerbation and stable disease will improve the mechanistic understanding of the molecular pathways and the infectious triggers involved in exacerbation, chronic inflammation, patient reported daily symptoms and COPD disease progression, such that novel pathways could be explored as therapeutic targets and biomarkers.
Technology Readiness Level (TRL)
3 - 3
Time period
60 months
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