The respiratory tract microbiome : a potential predictor for acute exacerbations of chronic obstructive pulmonary disease?
Authors:   , Endres Adrian 
Published: November 2024

Chronic obstructive pulmonary disease (COPD) is the most common chronic respiratory disease and the third leading cause of death globally. Clinically stable periods can be disrupted by acute exacerbations (AECOPD), defined as episodes of acute worsening of respiratory symptoms resulting in additional therapy. AECOPD are major causes for the morbidity and mortality of COPD patients and are the main drivers of COPD-associated healthcare costs. Early identification of AECOPD would ensure timely initiation of appropriate treatment, and reliable prediction of AECOPD risk could enable a stratified preventative pharmaco-therapy. Therefore, there is a high unmet medical need to predict AECOPD risk in advance. The respiratory tract microbiome is known to differ between COPD patients and healthy controls. Additionally, in COPD patients the microbiome is suspected to differ between AECOPD and stable disease state. However, its value as a biomarker for AECOPD prediction is unclear so far. The aims of this thesis are - first, to evaluate non-invasive respiratory tract microbiome sampling techniques and assess self-sampling by patients. Second, to investigate the respiratory tract microbiome in patients with COPD during stable disease state and its relation to exacerbation history, clinical parameters, and prospective exacerbation rate. Third, identify differences in the respiratory tract microbiome between stable disease state and AECOPD. Lastly, as AECOPD are often triggered by respiratory viruses, another goal is to examine whether and how a bacterial pathogen can influence viral infections. Throat swabs and sputum samples were identified as adequate non-invasive sampling types for lung microbiome analysis because their microbiome composition was similar to bronchoalveolar lavage fluid samples. In contrast, nasal swabs showed a distinct microbiome composition with a higher relative abundance of FAFV on phylum level and Staphylococcus on genus level. Self- sampling of throat swabs by patients at home was found to be a good substitute for professionally sampled throat swabs as there were no significant differences in any microbiome parameter. In COPD patients at stable disease state neither overall microbiome composition, α-diversity, nor phylum level characteristics differed between clinical risk groups (airway obstruction, symptom scores, exacerbation history, prospective exacerbation rate). Relative intensities of Neisseria were higher and Streptococcus lower in patients who later developed an exacerbation compared to those who did not. There was no difference in any microbiome parameter between samples taken at stable disease state and patient-matched samples during AECOPD. Respiratory viruses were found more frequently during AECOPD than stable disease state, underlining the importance of viral pathogens as triggers for AECOPD. In this context, it is of high relevance whether the bacterial microbiome can influence the susceptibility and course of viral infections. Utilizing an in-vitro model of Pseudomonas aeruginosa (PA) – human rhinovirus co-infection, a PA strain-specific alteration of the inflammatory response was observed in epithelial cells previously infected with PA, compared to virus infection alone. A serine protease dependent degradation of Interleukin- 6 (IL-6) was identified as a key driver of this process. IL-6 dependent epithelial repair pathways were hampered and consequently a disruption of the epithelial barrier function was observed. Whole proteome analysis showed differences in host and bacterial proteomes during co-infections, distinct from changes induced by single pathogens, however Reactome network pathway analysis did not reveal specific pathway enrichment. The results of this thesis could lead to more frequent utilization of respiratory tract microbiome data in clinical studies. In-vitro experiments have demonstrated that even a single bacterium can influence viral airway infections, emphasizing the role of the bacterial microbiome on virus-triggered AECOPD. However, respiratory tract microbiome analysis is so far not suitable as a single biomarker for prediction of AECOPD. Further, larger studies are needed to determine its benefit in complex models including clinical data and blood biomarkers.