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Objective: To evaluate the potential impact of molecular phenotyping of transbronchial biopsies in lung transplant recipients with allograft dysfunction, and the potential for developing a safer endobronchial mucosal biopsy format.
The current standard for biopsy-based diagnoses of dysfunction of lung transplants is the International Society of Heart and Lung Transplantation (ISHLT) classification applied to transbronchial biopsies, which represents an arbitrary international consensus. Recent data-driven approaches using molecular and conventional technologies indicate that this system produces frequently incorrect diagnoses with potential harm to patients due to inappropriate treatment. especially in relationship to the correct diagnosis of chronic lung allograft dysfunction is a pressing need. To address this unmet need and improve diagnostics in the area of organ transplantation, the Alberta Transplant Applied Genomics Centre (ATAGC, University of Alberta) has developed a new diagnostic system - the Molecular Microscope® Diagnostic System (MMDx) that interprets biopsies in terms of their molecular phenotype. The MMDx, developed first in kidney transplant biopsies with thoroughly established phenotypes, will now be adapted to lung transplant transbronchial biopsies (TBBs). Microarray analysis of lung allograft biopsy specimens will be compared to conventional allograft phenotyping, including clinical, physiologic, radiographic and histological assessment. The present study will use the MMDx™ system to assess and report TBBs, and validate and refine this system in 300 unselected prospectively collected lung TBBs. A subset of the study will examine the third bifurcation mucosal endobronchial biopsies (3BMBs) paired with TBBs from 50 patients to see if the safer 3BMBs can substitute for the TBB to be used by MMDx™. Due to a considerable interest and support from participating Centers, the study is further extended and collected 1032 TBBs and 602 3BMBs from 849 patients. This this is the extension of the INTERLUNG study - INTERLUNGEX.
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lung transplant biopsy bites. | Procedure | In the second phase of the study, two biopsy bites from the same patient will be collected to assess tissue sampling variability. |
| Measure | Description | Time Frame |
|---|---|---|
| Report the molecular scores (probability) of lung transplant disease in a reference set of 600 transbronchial biopsies. | Molecular classifier predicts antibody mediated and T cell mediated rejection, and chronic allograft dysfunction. | two years |
| Report the molecular diagnoses of the MMDx-TBB system | Compare MMDx readings to standard-of-care TBB histology and clinical diagnosis of CLAD. | two years |
| Measure | Description | Time Frame |
|---|---|---|
| Report the molecular scores (probability) of lung transplant disease in a reference set of 600 mucosal endobronchial biopsies. | Molecular classifier predicts antibody mediated and T cell mediated rejection, and chronic allograft dysfunction. | two years |
| Report the molecular diagnoses of the MMDx-3BMB system |
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Inclusion Criteria:
Exclusion Criteria:
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Patients with functioning lung transplant biopsied to determine their graft dysfunction or to confirm good function as per standard of care.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Konrad S Famulski, PhD | Contact | 1 780 492 1725 | konrad@ualberta.ca | |
| Robert Polakowski, PhD | Contact | 1 780 492 5091 | polakows@ualberta.ca |
| Name | Affiliation | Role |
|---|---|---|
| Philip F Halloran, MD, PhD | Faculty of Medicine and Dentistry, University of Alberta | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Joseph's Hospital and Medical Center 350 West Thomas Road, Floor 8HLT | Recruiting | Phoenix | Arizona | 85013 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38819301 | Background | Madill-Thomsen KS, Halloran PF. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope(R) Diagnostic System (MMDx). Clin Sci (Lond). 2024 Jun 5;138(11):663-685. doi: 10.1042/CS20220530. | |
| 30773443 | Result | Halloran KM, Parkes MD, Chang J, Timofte IL, Snell GI, Westall GP, Hachem R, Kreisel D, Trulock E, Roux A, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran PF. Molecular assessment of rejection and injury in lung transplant biopsies. J Heart Lung Transplant. 2019 May;38(5):504-513. doi: 10.1016/j.healun.2019.01.1317. Epub 2019 Feb 6. |
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Lung transplant biopsies taken as per local standard of care.
Compare MMDx-3BMB readings to MMDx-TBB readings and clinical diagnosis of CLAD |
| two years |
| Report the molecular changes over time in medically indicated follow-up biopsies | Predict and monitor response to anti-rejection treatment. | two years |
| University of Maryland School of Medicine | Completed | Baltimore | Maryland | 21201 | United States |
| Division of Pulmonary and Critical Care, Washington University School of Medicine | Completed | St Louis | Missouri | 63110 | United States |
| University of Texas at San Antonio | Completed | San Antonio | Texas | 21201 | United States |
| The Alfred Hospital, Monash University | Completed | Melbourne | Australia |
| Department of Thoracic Surgery, Medical University of Vienna | Completed | Vienna | Austria |
| Alberta Transplant Applied Genomics Centre, University of Alberta | Recruiting | Edmonton | Alberta | T6G 2E1 | Canada |
|
| Department of Medicine, University of Alberta | Recruiting | Edmonton | Alberta | T6G 2G3 | Canada |
|
| University Health Network, Toronto General Hospital | Completed | Toronto | Ontario | M5G 2C4 | Canada |
| Charles University/Hospital Motol | Recruiting | Prague | Czechia |
|
| Thoracic Surgery Transplant Clinic | Completed | Szczecin | 70891 | Poland |
| 32943286 | Result | Halloran K, Parkes MD, Timofte I, Snell G, Westall G, Havlin J, Lischke R, Hachem R, Kreisel D, Levine D, Kubisa B, Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Hirji A, Weinkauf J, Halloran PF. Molecular T-cell-mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss. J Heart Lung Transplant. 2020 Dec;39(12):1327-1337. doi: 10.1016/j.healun.2020.08.013. Epub 2020 Aug 26. |
| 31679176 | Result | Halloran K, Parkes MD, Timofte IL, Snell GI, Westall GP, Hachem R, Kreisel D, Levine D, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Hirji A, Weinkauf J, Halloran PF. Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants. Am J Transplant. 2020 Apr;20(4):954-966. doi: 10.1111/ajt.15685. Epub 2019 Dec 1. |
| 34850543 | Result | Parkes MD, Halloran K, Hirji A, Pon S, Weinkauf J, Timofte IL, Snell GI, Westall GP, Havlin J, Lischke R, Zajacova A, Hachem R, Kreisel D, Levine D, Kubisa B, Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran PF. Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants. Am J Transplant. 2022 Apr;22(4):1054-1072. doi: 10.1111/ajt.16895. Epub 2021 Dec 16. |
| 36163162 | Result | Halloran K, Mackova M, Parkes MD, Hirji A, Weinkauf J, Timofte IL, Snell GI, Westall GP, Lischke R, Zajacova A, Havlin J, Hachem R, Kreisel D, Levine D, Kubisa B, Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran PF. The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa. J Heart Lung Transplant. 2022 Dec;41(12):1689-1699. doi: 10.1016/j.healun.2022.08.014. Epub 2022 Aug 27. |
| 37295720 | Result | Gauthier PT, Mackova M, Hirji A, Weinkauf J, Timofte IL, Snell GI, Westall GP, Havlin J, Lischke R, Zajacova A, Simonek J, Hachem R, Kreisel D, Levine D, Kubisa B, Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran K, Halloran PF. Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies. Am J Transplant. 2023 Dec;23(12):1922-1938. doi: 10.1016/j.ajt.2023.06.003. Epub 2023 Jun 7. |
| 41242356 | Result | Mackova M, Gauthier P, Chang J, Hirji A, Weinkauf J, Juvet S, Keshavjee S, Havlin J, Lischke R, Zajacova A, Snell G, Westall G, Halloran PF, Halloran K. Molecular biopsy features associated with baseline lung allograft dysfunction in a multicenter international cohort. J Heart Lung Transplant. 2026 Mar;45(3):403-414. doi: 10.1016/j.healun.2025.11.005. Epub 2025 Nov 14. |
| 33595110 | Derived | Halloran PF. Integrating molecular and histologic interpretation of transplant biopsies. Clin Transplant. 2021 Apr;35(4):e14244. doi: 10.1111/ctr.14244. Epub 2021 Feb 17. No abstract available. |