The Oxford Pleural Infection Endotyping Study (TORPIDS-2)

Pleural Fluid Proteomics From Patients With Pleural Infection Shows Signatures of Diverse Neutrophilic Responses: The Oxford Pleural Infection Endotyping Study (TORPIDS 2)

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.

Study Overview

• Status: Completed
• Conditions: Pleural Diseases; Pleural Effusion; Pleural Infection; Pleural Empyema; Pleural Infection Bacterial; Pleural Infections and Inflammations

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.

• Study Type: Observational
• Enrollment (Actual): 80

Contacts and Locations

Study Locations

• United Kingdom
  • Oxfordshire
    • Oxford, Oxfordshire, United Kingdom, OX3 7FZ
      • Laboratory of Pleural Translational Research, Nuffield Department of Medicine, University of Oxford

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with evidence of pleural infection

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Enrolment; All samples were collect at patient enrolment for the PILOT study (PMID: 32675200, ISRCTN 50236700)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pleural infection endotypes	Discovery of pleural infection biological endotypes	12 months
Association between endotypes and microbiology	Investigate the association between pleural infection endotypes and microbiology	12 months
Association between endotypes and one-year survival	Investigate the association between pleural infection endotypes and one-year survival	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between endotypes and need for surgical treatment	Investigate the association between pleural infection endotypes and need for surgical treatment	12 months
Association between levels of pleural fluid plasminogen and neutrophil elastase	Investigate the association between pleural fluid plasminogen and neutrophil elastase protein levels	12 months

Collaborators and Investigators

• Sponsor: University of Oxford

Publications and helpful links

General Publications

• "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.

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2021
• Primary Completion (Actual): June 20, 2023
• Study Completion (Actual): June 20, 2024

Study Registration Dates

• First Submitted: July 16, 2024
• First Submitted That Met QC Criteria: July 16, 2024
• First Posted (Actual): July 22, 2024

Study Record Updates

• Last Update Posted (Actual): July 22, 2024
• Last Update Submitted That Met QC Criteria: July 16, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: respiratory; neutrophils; pleural infection; pleural
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Disease Attributes; Bacterial Infections and Mycoses; Suppuration; Inflammation; Infections; Communicable Diseases; Bacterial Infections; Pleural Effusion; Pleural Diseases; Empyema; Empyema, Pleural
• Other Study ID Numbers: R74885/RE001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymised and non-identifiable data could be shared with other researchers. The mass spectrometry data are deposited in PRIDE to share with other researchers.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No