Follistatin-like 1 and Biomarkers of Neutrophil Activation Are Associated with Poor Short-Term Outcome after Lung Transplantation on VA-ECMO

SIMPLE SUMMARY: The determination of biomarkers linked to adverse outcome after lung transplantation is crucial to identify vulnerable recipients and to define targeted therapeutic options. In this study, we investigated the perioperative course of a cytokine that has been related to graft-versus-host disease named Follistatin-like 1 and cytokines associated with neutrophil activation. We included 42 consecutive patients with different etiologies of end-stage pulmonary disease undergoing double lung transplantation. We found that all cytokines increased immediately after surgery. Follistatin-like 1 was significantly reduced at baseline in patients developing primary graft dysfunction. Serum concentrations of neutrophil-derived cytokines were related to prolonged extracorporeal membrane oxygenation and increases sequential organ failure assessment. Follistatin-like 1 serum concentrations seem exhausted in patients developing primary graft dysfunction. This finding could be of great importance, especially since this protein appears to contribute to allograft tolerance. However, larger trials are necessary to assess the predictive power of each of these cytokines. ABSTRACT: The investigation of biomarkers associated with undesired outcome following lung transplantation (LuTX) is essential for a better understanding of the underlying pathophysiology, an earlier identification of susceptible recipients and the development of targeted therapeutic options. We therefore determined the longitudinal perioperative course of putative cytokines related to neutrophil activation (chemokine CC motif ligand 4 (CCL-4), interleukin (IL)-23 and Lipocalin 2 (LCN2)) and a cytokine that has been implicated in graft-versus-host disease (Follistatin-like 1 (FSTL1)) in 42 consecutive patients undergoing LuTX. We plotted receiver-operating curves (ROC) to assess the predictive power of the measured cytokines for short-term outcomes namely primary graft dysfunction (PGD), early complications requiring extracorporeal membrane oxygenation (ECMO), and a high postoperative sequential organ failure assessment (SOFA). All cytokines increased immediately after surgery. ROC analyses determined significant associations between CCL4 and a high SOFA score (area under the curve (AUC) 0.74 (95%CI:0.5–0.9; p < 0.05), between LCN2 and postoperative ECMO support (AUC 0.73 (95%CI:0.5–0.9; p < 0.05), and between FSTL1 and PGD (AUC 0.70 (95%CI:0.5–0.9; p < 0.05). The serum concentrations of the neutrophil-derived cytokines LCN2 and CCL4 as well as FSTL1 were all related to poor outcome after LuTX. The specific predictive power, however, still has to be assessed in larger trials. The potential role of FSTL1 as a biomarker in the development of PGD could be of great interest particularly since this protein appears to play a crucial role in allograft tolerance.