MMDx-Lung System

Investigators: Drs. Philip F Halloran, Kieran Halloran, and the MMDx-Lung Study Group ( NCT02812290)

Currently, lung transplant rejection is diagnosed by using transbronchial biopsies (TBB), piercing the lung tissue up to 10 times with an instrument inserted into the airway. TBB tissue is stained and examined by a pathologist under the microscope. This method not only poses risks of complications for patients but also TBB tests have poor reproducibility (inter-observer kappa value of 0.18) for T cell-mediated rejection (TCMR) and cannot assess antibody-mediated rejection (ABMR). Sometimes all of the TBB tissue is un-interpretable. Incorrect and missed diagnoses can harm patients, and TBB cannot even be performed in the sickest patients who most need accurate treatment, because the risks are too high. There is a safer biopsy alternative - the mucosal biopsy (MB), which samples the airway lining (mucosa), but is not used by pathologists.

We want to change the diagnostics for lung transplants. The Alberta Transplant Applied Genomics Centre at the University of Alberta, Canada developed the Molecular Microscope® Diagnostic System (MMDx) to assess organ transplant biopsies. Instead of using a regular microscope, we measure the expression of thousands of genes in the biopsy. MMDx is already in use for diagnosing rejection and injury in kidney (MMDx-Kidney) and heart transplants (MMDx-Heart). The present project adapts the MMDx-Kidney to assess the molecular phenotypes of rejection and injury in lung biopsies.

We have developed a first-generation MMDx-Lung system for diagnosing rejection in single TBB pieces. Using both supervised and un-supervised assessment of global gene expression in a large cohort of single TBB bites collected in eight centers (Canada, US, Europe, and Australia), we identified four principal molecular groups of TBB: no rejection, TCMR, ABMR-like state, and lung injury phenotype.

We explored the possibility that donor bronchial mucosa might be a similar source of information, even though histology cannot read it. We analyzed a large number of single bite MB and found that molecular changes in MB correlated with those in paired TBB. We also identified two principal molecular groups of MB: no rejection and rejection.

We conclude that MMDx-Lung when fully developed will be able to diagnose rejection more accurately than pathology and will greatly improve patient safety. We also believe that MMDx has promise for assessing MB, offering even greater improvement in safety, especially for sickest patients.


MMDx-Lung Publications:

  1. Halloran KM, Parkes MD, Chang J, Timofte IL, Snell GI, Westall GP, et al. Molecular assessment of rejection and injury in lung transplant biopsies. J Heart Lung Transplant. 2019;38(5):504-13.
  2. Halloran K, Parkes MD, Timofte IL, Snell GI, Westall GP, Hachem R, et al. Molecular phenotyping of rejection-related changes in mucosal biopsies from lung transplants. Am J Transplant. 2020;20(4):954-66.
  3. Parkes MD, Halloran K, Hirji A, Pon S, Weinkauf J, Timofte IL, et al. Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants. Am J Transplant. 2021;22(4):1054-72.
  4. Halloran K, Mackova M, Parkes MD, Hirji A, Pon S, Weinkauf J, et al. The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa. J Heart Lung Transplant. 2022 Dec;41(12):1689-1699.