Clinical trial NCT06513689: The Oxford Pleural Infection Endotyping Study
Official title: Pleural Fluid Proteomics From Patients With Pleural Infection Shows Signatures of Diverse Neutrophilic Responses: The Oxford Pleural Infection Endotyping Study (TORPIDS 2)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Pleural Infection
Pleural Diseases
Pleural Effusion
Pleural Empyema
Pleural Infection Bacterial
Pleural Infections and Inflammations
Keywords: pleural
pleural infection
respiratory
neutrophils
Lead sponsor: University of Oxford
Sponsor class: OTHER
First posted: 2024-07-22
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with evidence of pleural infection

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.

Eligibility 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.

Primary outcomes:
measure: Pleural infection endotypes
timeFrame: 12 months
measure: Association between endotypes and microbiology
timeFrame: 12 months
measure: Association between endotypes and one-year survival
timeFrame: 12 months
Secondary outcomes:
measure: Association between endotypes and need for surgical treatment
timeFrame: 12 months
measure: Association between levels of pleural fluid plasminogen and neutrophil elastase
timeFrame: 12 months
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: Laboratory of Pleural Translational Research, Nuffield Department of Medicine, University of Oxford
state: Oxfordshire
Study officials:
References:
citation: "Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study." John P. Corcoran, Ioannis Psallidas, Stephen Gerry, Francesco Piccolo, Coenraad F. Koegelenberg, Tarek Saba, Cyrus Daneshvar, Ian Fairbairn, Richard Heinink, Alex West, Andrew E. Stanton, Jayne Holme, Jack A. Kastelik, Henry Steer, Nicola J. Downer, Mohammed Haris, Emma H. Baker, Caroline F. Everett, Justin Pepperell, Thomas Bewick, Lonny Yarmus, Fabien Maldonado, Burhan Khan, Alan Hart-Thomas, Georgina Hands, Geoffrey Warwick, Duneesha De Fonseka, Maged Hassan, Mohammed Munavvar, Anur Guhan, Mitra Shahidi, Zara Pogson, Lee Dowson, Natalia D. Popowicz, Judith Saba, Neil R. Ward, Rob J. Hallifax, Melissa Dobson, Rachel Shaw, Emma L. Hedley, Assunta Sabia, Barbara Robinson, Gary S. Collins, Helen E. Davies, Ly-Mee Yu, Robert F. Miller, Nick A. Maskell and Najib M. Rahman. Eur Respir J 2020; 56: 2000130. Eur Respir J. 2020 Dec 17;56(6):2050130. doi: 10.1183/13993003.50130-2020. Print 2020 Dec. No abstract available.