S. Azad

Ex Vivo Perfusion Treatment of Infection in Human Donor Lungs

Ex vivo lung perfusion (EVLP) is a platform to treat infected donor lungs with antibiotic therapy before lung transplantation. Human donor lungs that were rejected for transplantation because of clinical concern regarding infection were randomly assigned to two groups. In the antibiotic group (nu2009=u20098), lungs underwent EVLP for 12u2009h with high‐dose antibiotics (ciprofloxacin 400u2009mg or azithromycin 500u2009mg, vancomycin 15u2009mg/kg, and meropenem 2u2009g). In the control group (nu2009=u20097), lungs underwent EVLP for 12u2009h without antibiotics. A quantitative decrease in bacterial counts in bronchoalveolar lavage (BAL) was found in all antibiotic‐treated cases but in only two control cases. Perfusate endotoxin levels at 12u2009h were significantly lower in the antibiotic group compared with the control group. EVLP with broad‐spectrum antibiotic therapy significantly improved pulmonary oxygenation and compliance and reduced pulmonary vascular resistance. Perfusate endotoxin levels at 12u2009h were strongly correlated with levels of perfusates tumor necrosis factor α, IL‐1β and macrophage inflammatory proteins 1α and 1β at 12u2009h. In conclusion, EVLP treatment of infected donor lungs with broad‐spectrum antibiotics significantly reduced BAL bacterial counts and endotoxin levels and improved donor lung function.

Risk Factors for Voriconazole Hepatotoxicity at 12 Weeks in Lung Transplant Recipients

Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole‐associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53–12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K‐nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity.

Soluble Adhesion Molecules During Ex Vivo Lung Perfusion Are Associated With Posttransplant Primary Graft Dysfunction

Ex vivo lung perfusion (EVLP) enables assessment of marginal donor lungs for transplantation. We aimed to discover biomarkers in EVLP perfusate that could predict development of primary graft dysfunction (PGD). From September 2008 to August 2013, 100 clinical EVLPs were performed. Eleven patients developed PGD grade 3 within 72 h after transplant. The non‐PGD group consisted of 34 patients without PGD grade 3. Nonbilateral lung transplants or transplant after extracorporeal life support were excluded from analyses. Soluble intercellular adhesion molecule 1 (sICAM‐1), soluble VCAM‐1 (sVCAM‐1), and soluble E selectin (sE‐selectin) levels, as markers of endothelial activation, were measured in the perfusate of EVLP by enzyme‐linked immunosorbent assay and were correlated with clinical outcome. Levels of sICAM‐1 at 1 h and sVCAM‐1 at 1 and 4 h were significantly higher in the PGD group compared with the non‐PGD group. The sE selectin levels were not statistically different between the study groups. Higher levels of sVCAM‐1 at 1 and 4 h were statistically significantly associated with PGD either alone or after adjustment for other PGD risk factors. These adhesion molecules may help identify donor lungs at higher risk of PGD during EVLP.