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Background: Primary graft dysfunction (PGD) is the most important determinant of morbidity and mortality after lung transplantation, but its definition has evolved over the past decade. The implications of this refinement in clinical definition have not been evaluated. In this single-center study, we compared PGD incidence, risk factors, and outcomes using the 2005 and the updated-2016 International Society of Heart and Lung Transplantation guidelines for PGD grading in lung transplant patients. Methods: In this retrospective study, we extracted data from the medical records of 127 patients who underwent lung transplantation between 1/1/2016-12/31/2018. PGD was defined as PGD3 present at 48 and/or 72 hours post-reperfusion. We used the 2005 and the updated 2016 guidelines to assess clinical risk factors, outcomes, and baseline biomarkers for PGD. Results: On the basis of the 2016 and 2005 guidelines, we identified PGD in 37% and 26% of patients, respectively. PGD was significantly associated with extracorporeal life support, large body mass index, and restrictive lung disease using the 2016 but not the 2005 guidelines. Based on the 2016 guidelines, pretransplant levels of several biomarkers were associated with PGD; using the 2005 guidelines, only increased interleukin-2 levels were significantly associated with PGD. No preoperative biomarkers were associated with PGD using either guidelines after adjusting for clinical variables. Postoperative morbidity and 1-year mortality were similar regardless of guidelines used. Conclusions: Our findings suggest that refinements in the PGD scoring system have improved the detection of graft injury and associated risk factors without changing its ability to predict postoperative morbidity and mortality.

The clinical use of circulating biomarkers for primary graft dysfunction (PGD) after lung transplantation has been limited. In a prospective single-center cohort, we examined the use of plasma protein biomarkers as indicators of PGD severity and duration after lung transplantation. The study comprised 40 consecutive lung transplant patients who consented to blood sample collection immediately pretransplant and at 6, 24, 48, and 72 h after lung transplant. An expert grader determined the severity and duration of PGD and scored PGD at T0 (6 h after reperfusion), T24, T48, and T72 h post-reperfusion using the 2016 ISHLT consensus guidelines. A bead-based multiplex assay was used to measure 27 plasma proteins including cytokines, growth factors, and chemokines. Enzyme-linked immunoassay was used to measure cell injury markers including M30, M65, soluble receptor of advanced glycation end-products (sRAGE), and plasminogen activator inhibitor-1 (PAI-1). A pairwise comparisons analysis was used to assess differences in protein levels between PGD severity scores (1, 2, and 3) at T0, T24, T48, and T72 h. Sensitivity and temporal analyses were used to explore the association of protein expression patterns and PGD3 at T48–72 h (the most severe, persistent form of PGD). We used the Benjamini–Hochberg method to adjust for multiple testing. Of the 40 patients, 22 (55%) had PGD3 at some point post-transplant from T0 to T72 h; 12 (30%) had PGD3 at T48–72 h. In the pairwise comparison, we identified a robust plasma protein expression signature for PGD severity. In the sensitivity analysis, using a linear model for microarray data, we found that differential perioperative expression of IP-10, MIP1B, RANTES, IL-8, IL-1Ra, G-CSF, and PDGF-BB correlated with PGD3 development at T48–72 h (FDR < 0.1 and p < 0.05). In the temporal analysis, using linear mixed modeling with overlap weighting, we identified unique protein patterns in patients who did or did not develop PGD3 at T48–72 h. Our findings suggest that unique inflammatory protein expression patterns may be informative of PGD severity and duration. PGD biomarker panels may improve early detection of PGD, predict its clinical course, and help monitor treatment efficacy in the current era of lung transplantation.

End stage lung diseaseChronic lung disease is the fourth leading cause of death in the United States and is a major health burden worldwide (1). Lung transplant is a treatment option for patients with cystic fibrosis, chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary hypertension and other chronic lung diseases. There are approximately 4,500 lung transplants performed annually world-wide and the number continues to grow (2). Yet there are significant limitations with transplant. One of the biggest challenges is the critical organ shortage. Patients have a 15-30% chance of dying on the waiting list depending on their diagnosis and urgency (3). Currently, only 20% of organ offers are transplanted. Thus, 80% of lungs are discarded. Another challenge is primary graft dysfunction (PGD) which is described below. Finally, the quality of the organ at the time of transplant can contribute to chronic lung allograft dysfunction (CLAD), which occurs in 50% of patients by five years after transplant. PGDUp to 30% of transplanted lungs will develop PGD. PGD is graded from zero to three, with three being the worst category of graft dysfunction. PGD is associated with a high rate of mortality in the hospital and following discharge (4).An important donor risk factor for development of PGD is cigarette smoking. Other risk factors may include aspiration, chest trauma, lung contusions, undersized donors relative to recipient, and heavy alcohol use (5). Recipient risk factors for PGD include pre-transplant lung diseases other than COPD or cystic fibrosis, obesity and pulmonary hypertension. Importantly, prolonged cold ischemic time is associated with PGD. Ex vivo lung perfusion (EVLP)EVLP describes a concept of perfusing and ventilating a donor lung outside of the donor and recipient. Breathing lung transplantation is a form of EVLP. The Organ Care

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