Update on Additives to the Ex-Vivo Lung Perfusate

Three recent studies have investigated the effects of three additives to the perfusate during EVLP: Monoclonal antibodies, Perfluorocarbon-based oxygen carrier and Heat shock protein inhibitor.

A. Use of monoclonal antibodies to suppress Epstein Barr virus and reduce transmission.

The monoclonal antibody Rituximab has recently been successfully used(8) during ex-vivo lung perfusion to reduce the risk of lymphoproliferative disorder (PTLD), which can arise when an Epstein-Barr Virus (EBV) seropositive donor lung is transplanted into a seronegative recipient. Although most humans carry EBV in its latent form, immunosuppression in transplant recipients can trigger activation of EBV and subsequent risk of PTLD, which is a potentially lethal complication of transplantation. The antibody targets EBV infected B-cells in the donor lung, thereby reducing the risk of transferring EBV to select transplant recipients by removing latent infection.

The study compared two groups of rejected human lungs (with and without Rituximab). Rituximab resulted in an 8.75 x reduction in EBV B-cell receptors compared with controls. (p = 0.0002). No apparent safety concerns were seen based on markers associated with acute cell injury. EVLP thus seems an effective platform to administer monoclonal antibody-based therapies to treat donor lungs.

B. Addition of Perfluorocarbon-based Oxygen Carrier during EVLP improves donor lung quality and post-transplant outcome.

To investigate whether the addition of a perfluorocarbon (PFC) based oxygen carrier might improve lung function during and after ex-vivo lung perfusion (EVLP), the Zurich group devised a demanding porcine study(9) in which lungs were subjected to 24 hours of cold preservation with PERFADEX® followed by six hours of warm EVLP with or without PFC, and four hours of post-transplant reperfusion.

During EVLP, most physiological markers were comparable, irrespective of whether or not PFC was added. In the PFC groups, perfusate lactate levels, however, were lower; ATP levels were higher; and lung infiltrates were lower.

After transplantation, graft function improved somewhat in the PFC group. Gas exchange, however, was significantly better in the PFC group during the four-hour reperfusion period.

C. Heat Shock Protein inhibitor during EVLP reduces lung edema

Lungs donated after circulatory death (DCD) are particularly prone to ischemia-reperfusion injury due to prolonged warm ischemia. In a recent paper in Ann. Thor. Surg.(10) , the Montreal group reported their results with an innovative Heat Shock Protein Inhibitor HSP90i added to the EVLP perfusate to recondition DCD lungs. The group had previously utilized HSP90i as a cardioprotective agent in a DCD heart model.

Two groups of DCD pig lungs were placed on EVLP (with and without HSP90i) after cardiac arrest plus two hours of warm ischemia. The use of HSP90i reduced lung weight gain to ca 8.4 % compared with 26.6% in the control group (p < .05). Other parameters were not significantly different.

XVIVO Insights PB-2021-02-04


8. Terrance J.Y. Ku, et al: Ex-vivo delivery of monoclonal antibody (Rituximab) to treat human donor lungs prior to transplantation. EBioMedicine. 2020 Oct; 60: 102994. doi10.1016/j.ebiom.2020.102994PMCID: PMC7501077  PMID: 32950000 (link to Abstract)
9. Inci I, et al: Functional, Metabolic and Morphologic Results of Ex Vivo Donor Lung Perfusion with a Perfluorocarbon-Based Oxygen Carrier Nanoemulsion in a Large Animal Transplantation Model 2020 Nov 18;9(11):2501. doi: 10.3390/cells9112501. PMID: 33218154  Free PMC article. Cells 2020, 9(11), 2501; https://doi.org/10.3390/cells9112501 (link to Abstract)
10. Basil S Nasir, et al: HSP90 Inhibitor Improves Lung Protection in Porcine Model of Donation After Circulatory Arrest Ann Thorac Surg . 2020 Dec;110(6):1861-1868. doi: 10.1016/j.athoracsur.2020.05.079. Epub 2020 Jul 9. Montreal  PMID: 32652069 DOI: 10.1016/j.athoracsur.2020.05.079 (link to Abstract)