Exhaled Breath Particles in Lung Transplantation

Exhaled Breath Particles as a Clinical Indicator for Acute and Chronic Rejection After Lung Transplantation

Lung transplantation (LTx) is the only effective treatment for patients with end stage lung disease. Of the major organs transplanted, survival following LTx is the lowest with a mean of 5 years. Despite improvements, primary graft dysfunction (PGD) remains the leading cause of early mortality and contributes to the development of chronic lung allograft dysfunction (CLAD) that remains the leading cause of late mortality. Earlier detection of rejection after LTx is of substantial importance as it would improve the possibilities of treatment and could increase survival.

The investigators have shown in previous work that exhaled breath particles (EBP) reflect the composition of respiratory tract lining fluid (RTLF). EBP and particle flow rate (PFR) can be used as non-invasive methods for early detection and monitoring of airway diseases such as acute respiratory distress syndrome (ARDS). It has also been shown that the particle flow prolife after lung transplantation differs between patients who develop PGD and those who do not and that the composition of EBP differs between patients with and without bronchiolitis obliterans syndrome (BOS), an obstructive form of CLAD.

Samples of EBP and measurements of PFR will be collected from lung transplanted patients. Membranes with EBP will be saved for molecular analysis. The investigators aim to identify potential particle flow patterns and biomarkers for earlier detection of rejection after lung transplantation.

Study Overview

• Status: Recruiting
• Conditions: Lung Transplant Rejection; Chronic Rejection of Lung Transplant; Primary Graft Dysfunction

Detailed Description

Samples of EBP and measurement of PFR will be done on patients undergoing lung transplantation at Skåne University Hospital (SUS) Lund. Measurements of EBP and PFR and collection of blood will be done repeatedly postoperatively when the patient is still in the hospital, at three months post-transplantation, at six months post-transplantation, at 12 months post-transplantation and annually after that. An additional preoperative blood sample will also be obtained. Furthermore, the investigators will collect bronchoalveolar lavage fluid (BALF) and lung biopsies when the patient is scheduled for routine bronchoscopies in the follow-up period.

This study involves measurements of EBP and PFR done by the particles in exhaled air (PExA) system on lung transplanted patients with and without acute or chronic rejection. The patients who do not develop any form of rejection will serve as a control group to the ones who develop rejection. Furthermore, each patient will serve as their own control.

The purpose of this study is to find better means of identifying rejection of transplanted lungs in earlier stages, and to explore candidate biomarkers. Earlier diagnosis of rejection of the transplanted organ can lead to better treatment possibilities and a positive impact on survival after LTx.

• Study Type: Observational
• Enrollment (Anticipated): 150

Contacts and Locations

• Study Contact: Name: Sandra Lindstedt, MD, PhD; Phone Number: +46737220580; Email: sandra.lindstedt_ingemansson@med.lu.se

Study Locations

• Sweden
  • Skåne Län
    • Lund, Skåne Län, Sweden, 224 60
      • Recruiting
      • Skåne University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients undergoing lung transplantation at Skåne University Hospital, SUS Lund.

Description

Inclusion Criteria:

• Patients who have undergone LTx at Skåne University Hospital, SUS Lund

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
LTx rejection; Lung transplanted patients with acute or chronic rejection
LTx non-rejection; Lung transplanted patients without any form of rejection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	Pre-transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	Day 1-3 after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	1 month after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	3 months after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	6 months after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	9 months after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	12 months after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	18 months after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	2 years after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	3 years after lung transplantation
Concentration of proteins in EBP	Proteins from exhaled air are collected onto a membrane for subsequently molecular analysis. Analysis aims to identify candidate biomarker for acute and chronic rejection of transplanted lungs.	4 years after lung transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	Day 1-3 after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	1 month after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	3 months after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	6 months after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	9 months after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	12 months after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	18 months after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	2 years after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	3 years after transplantation
Particle flow rate from the airways (PFR)	PFR will be measured by the PExA device. The flow rate and the particle pattern will be analysed to find differences between groups of lung transplanted patients with and without rejection.	4 years after transplantation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	Pre-transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	Day 1 after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	Day 2 after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	Day 3 after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	1 month after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	3 months after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	6 months after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	9 months after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	12 months after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	18 months after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	2 years after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	3 years after lung transplantation
Concentration of proteins and other biomarkers in plasma	Concentration and composition of proteins and other biomarkers will be analysed in plasma	4 years after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	Day 1-3 after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	1 month after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	3 months after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	6 months after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	9 months after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	12 months after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	18 months after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	2 years after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	3 years after lung transplantation
Concentration of proteins and other biomarkers in BAL	Concentration and composition of proteins and other biomarkers will be analysed in BAL	4 years after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue. Both taken from the native lung and from the donor lung.	At the time of lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	1 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	3 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	6 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	9 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	12 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	18 months after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	2 years after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	3 years after lung transplantation
Concentration of proteins and other biomarkers in lung tissue	Concentration and composition of proteins and other biomarkers will be analysed in lung tissue	4 years after lung transplantation

Collaborators and Investigators

• Sponsor: Lund University Hospital
• Investigators: Principal Investigator: Sandra Lindstedt, MD, PhD, Region Skåne, Lund University

Publications and helpful links

General Publications

• Ericson PA, Mirgorodskaya E, Hammar OS, Viklund EA, Almstrand AR, Larsson PJ, Riise GC, Olin AC. Low Levels of Exhaled Surfactant Protein A Associated With BOS After Lung Transplantation. Transplant Direct. 2016 Aug 26;2(9):e103. doi: 10.1097/TXD.0000000000000615. eCollection 2016 Sep.
• Stenlo M, Hyllen S, Silva IAN, Bolukbas DA, Pierre L, Hallgren O, Wagner DE, Lindstedt S. Increased particle flow rate from airways precedes clinical signs of ARDS in a porcine model of LPS-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2020 Mar 1;318(3):L510-L517. doi: 10.1152/ajplung.00524.2019. Epub 2020 Jan 29.
• Broberg E, Hyllen S, Algotsson L, Wagner DE, Lindstedt S. Particle Flow Profiles From the Airways Measured by PExA Differ in Lung Transplant Recipients Who Develop Primary Graft Dysfunction. Exp Clin Transplant. 2019 Dec;17(6):803-812. doi: 10.6002/ect.2019.0187. Epub 2019 Oct 11.
• Behndig AF, Mirgorodskaya E, Blomberg A, Olin AC. Surfactant Protein A in particles in exhaled air (PExA), bronchial lavage and bronchial wash - a methodological comparison. Respir Res. 2019 Sep 26;20(1):214. doi: 10.1186/s12931-019-1172-1.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2018
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): September 1, 2026

Study Registration Dates

• First Submitted: May 10, 2022
• First Submitted That Met QC Criteria: May 10, 2022
• First Posted (Actual): May 16, 2022

Study Record Updates

• Last Update Posted (Actual): May 16, 2022
• Last Update Submitted That Met QC Criteria: May 10, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Lung transplantation; Primary Graft Dysfunction; Exhaled Breath Particles; PExA; Chronic Lug Allograft Dysfunction
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Postoperative Complications; Reperfusion Injury; Primary Graft Dysfunction
• Other Study ID Numbers: LTxPEx

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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