Pleural Diseases, Pleural Effusion, Pleural Empyema, Pleural Infection, Pleural Infection Bacterial, Pleural Infections and Inflammations
Conditions
Keywords
pleural, pleural infection, respiratory, neutrophils
Brief summary
Pleural infection is a severe disease with increasing incidence worldwide. The subphenotypes of pleural infection remain unknown.We designed a study to endotype the disease and assess the association between patient phenotype, microbiology and clinical outcome. We subjected 80 pleural fluid samples to unlabelled mass spectrometry. Pathway analysis of the differentially expressed proteins identified the neutrophil degranulation, glycolysis, pentose phosphate pathway, and the liver and retinoid X receptors (LXR-RXR) activation. Higher neutrophil degranulation was associated with increased glycolysis and pentose phosphate activation. Pleural infection patients exhibit proteomic signatures indicating diverse responses of neutrophil mediated immunity, glycolysis, and pentose phosphate activation.
Detailed description
Pleural infection is a common and severe disease with increasing incidence worldwide. The endotypes of pleural infection remain unknown. A better understanding of patient variation in underlying biological response to infection may lead to improved treatments and clinical outcomes. We designed a study with the aim to endotype the disease and assess the association between patient phenotype, microbiology and clinical outcome. We subjected 80 pleural fluid samples from the PILOT study, a prospective study on pleural infection, to unlabelled mass spectrometry. Proteins were retained if they were detected in at least 50% of the samples resulting in a total of 449 proteins. Unsupervised hierarchical clustering and UMAP analyses were used to cluster samples, Spearman and exact Fischer's methods were used for correlation assessment and protein expression was correlated with clinical outcomes. UMAP plotting separated the samples in to two different and distinct cohorts. Pathway analysis of the differentially expressed proteins identified neutrophil degranulation, glycolysis, the pentose phosphate pathway, and the liver and retinoid X receptors (LXR-RXR) activation. Higher neutrophil degranulation was associated with increased glycolysis and pentose phosphate activation. Specimens dominated by Streptococcus Pneumoniae exhibited high neutrophil degranulation. Increased activity of the LXR-RXR pathway was associated with better survival. Pleural infection patients exhibit proteomic signatures indicating diverse responses of neutrophil mediated immunity, glycolysis, and pentose phosphate activation which were associated with microbiology. Therapeutic targeting the LXR-XRX pathway with agonists may improve survival.
Interventions
None listed
Sponsors
University of Oxford
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Samples collected for the PILOT clinical trial (DOI: 10.1183/13993003.00130-2020) used for the TORPIDS-2 study. Patients were included if they had a clinical presentation consistent with pleural infection and any of the following criteria: 1. pleural fluid that was macroscopically purulent; or 2. pleural fluid that was positive on culture for bacterial infection; or 3. pleural fluid that demonstrated bacteria on Gram staining; or 4. pleural fluid with a pH ≤7.2 (measured by blood gas analyser) or low glucose level (≤3 mmol·L-1 or ≤55 mg·dL-1) in a patient with clinical evidence of infection; or 5. contrast-enhanced computed tomography (CT) evidence of pleural infection (consolidation of underlying lung with enhancing pleural collection) in a patient with clinical evidence of infection, alongside exclusion of other sources of infection. Evidence of infection was assessed by the recruiting physician on the basis of fever, an elevated peripheral blood white-cell count, or elevated serum inflammatory markers such as C-reactive protein (CRP). Study
Exclusion criteria
were as follows: 1. age \<18 years; 2. no pleural fluid available for analysis; 3. previous pneumonectomy on the side of pleural infection; and 4. expected survival of \<3 months due to co-morbid disease, as judged by the recruiting physician.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pleural infection endotypes | 12 months | Discovery of pleural infection biological endotypes |
| Association between endotypes and microbiology | 12 months | Investigate the association between pleural infection endotypes and microbiology |
| Association between endotypes and one-year survival | 12 months | Investigate the association between pleural infection endotypes and one-year survival |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Association between endotypes and need for surgical treatment | 12 months | Investigate the association between pleural infection endotypes and need for surgical treatment |
| Association between levels of pleural fluid plasminogen and neutrophil elastase | 12 months | Investigate the association between pleural fluid plasminogen and neutrophil elastase protein levels |
Countries
United Kingdom
Outcome results
None listed