Overcoming Primary Graft Dysfunction After Lung Transplantation

In this issue of Transplantation, Sommer et al. from the University of Hannover present their experience with the use of C1-esterase-inhibitor (C1-INH) as a novel approach to treat primary graft dysfunction (PGD) after clinical lung transplantation in a prospectively designed, retrospectively reviewed single-center study (1). C1-INH is a serin-protease-inhibitor and is involved in the first part of the classical complement pathway. It is available for clinical use in the treatment of hereditary angioedema. It displays anti-inflammatory properties by decreasing vascular permeability as outlined in several clinical and preclinical models (2). The authors administered C1-INH to a cohort of 24 lung transplant patients displaying poor gas exchanges (PaO2/FiO2 ratio<100) immediately after reperfusion in the operative room and compared this cohort (a) with a group of patients who did not receive C1-INH but who developed grade 3 PGD at a later stage and (b) with a control group of patients who did not develop PGD at all. Interestingly, oxygenation improved immediately after administration of C1-INH and up to 72 hr postoperatively, together with a rapid decline of the grade of PGD. Ventilation time in the C1-INH treatment group was also significantly shorter compared with the PGD 3 patients who did not receive any treatment (105 versus 483 hr, P=0.03). Intensive care unit stay was also reduced in the treatment arm compared with nontreated PGD 3 patients (9 versus 29 days), although this difference did not reach statistical significance. Three-month and 1-year survival in the C1-INH treated patients was 82.5%, which compared worse with the control group (95%, P=0.001) but did not differ significantly from the nontreated, PGD 3 group. Nevertheless, the survival of the patients who received C1-INH compare reasonably well with the 1-year survival benchmark of the International Society for Heart and Lung Transplantation. Importantly, the study sets the basis for a promising and innovative approach to treating severe PGD in the very early phase of lung transplantation. The design of the study has some obvious limitations: the drug has been used as an off-label treatment without a randomized prospective clinical trial. A recent analysis of 1255 lung recipients enrolled between 2002 and 2010 in a prospective cohort study in the U.S. lung transplant centers showed an overall incidence of grade 3 PGD at any time point in the first 72 hr of 30.8% (3). Primary graft dysfunction grade 3 was also associated with greater 30-, 90-, and 1-year mortality and with the development of bronchiolitis obliterans syndrome (BOS). Primary graft dysfunction after lung transplantation is still a significant issue affecting patients’ outcome after lung transplantation. Despite the ISHLT standardized classification of PGD in 2005, the incidence of this phenomenon varies significantly, reflecting different practice, patterns, and different risk factor distributions across centers (4). The pathogenesis of PGD is complex and is influenced by donor, recipient, and technical factors and by the different combinations of all the above. It is driven by an inflammatory response as well as by immunological (both innate and cell-mediated) processes. Several strategies have been investigated over the years to prevent and treat PGD after lung transplantation. To quote a few, the instillation of surfactant, the use of inhaled nitric oxide, and the use of platelet activating factor antagonists: some of these studies demonstrated a significant beneficial effect on clinical outcomes. Attempts at modulating complement response to prevent PGD after lung transplantation were presented by the Toronto group in a randomized, placebo-controlled clinical trial testing the use of P-10 (solubile complement-receptor-1-inhibitor) and resulted in a significant reduction in ventilation time after surgery in the treated arm (5) Over the last few years, the development of innovative techniques such as ex vivo lung perfusion (EVLP) or the refinement in artificial support methods such as ECMO also contributed to treat and redefine the outcome of patients with PGD. What do we have at the end of the day? It is very unlikely that a single, highly effective drug, or treatment will resolve the issue of preventing or treating PGD after lung transplantation. This study certainly raises some important points for the transplant community to improve our approach to PGD. Controlled clinical trials for all possible strategies to treat PGD, such as the use of C1-INH, are advocated. Further standardization of the PGD is required. Should the very early (reperfusion) and late (>72 hr) phases included into the PGD score? Should a histologic definition of PGD used for assessment and research? The quest is for addressing these questions within dedicated, active working forces.

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