Non-Invasive Monitoring of Infection and Rejection After Lung Transplantation

Abstracts S137 in 5 male patients (Sparing group) because lobar grafts were thought to be too small. This strategy was used when upper lobes or segments were preoperatively less impaired, compared with lower lobes. Unilateral upper lobe was spared in two patients and bilateral upper lobes or upper segments were spared in three patients. The indications for these 5 LDLLTs were idiopathic interstitial pneumonia (IIP) in two patients, and bronchiolitis obliterans (BO), chronic hypersensitivity pneumonitis (CHP), and idiopathic pulmonary artery hypertension (IPAH) in one, respectively. Results: There were no operative or hospital deaths. Extracorporeal circulation time and operative time (224 min, 472 min) of Sparing group were similar to those of conventional LDLLTs (248 min, 497 min). The length of ICU stay was also similar (12 vs. 13 days). The pulmonary artery pressure was immediately normalized in the IPAH patient. Late complications attributed to spared lungs were airway infection in one recipient, and pneumothorax in two, which were all conservatively managed. One recipient with IIP died at 3.3 years due to chronic graft dysfunction, and the other four are alive at 0.8, 1.2, 1.3, and 5 years with good performance status. The volumes of spared lungs measured by 3D-CT volumetry did not significantly change after LDLLT. Tc99-MAA lung perfusion scintigraphy performed at 6 to 12 months indicated remaining perfusion in the spared lungs in IIP and CHP patients, and almost no perfusion in BO and IPAH patients. These results suggested that spared lobes provided adequate chest cavity for small grafts and kept functioning in some patients. Conclusion: The new “lobar-sparing” strategy appears to be feasible and effective in LDLLT using small-for-size grafts for selected patients when upper lobes or segments are less impaired. 3( 54) Non-Invasive Monitoring of Infection and Rejection After Lung Transplantation I.D. Vlaminck,1 L. Martin,1 M. Kertesz,1 K.N. Patel ,2 M. Kowarsky,1 C. Strehl,3 G. Cohen,3 H. Luikart,3 N. Neff,1 J. Okamoto,1 M.N. Nicolls,2 D.N. Cornfield,2 D. Weill,2 H.A. Valantine,3 K.K. Khush,3 S.R. Quake.1  1Bioengineering and Applied Physics, Stanford University School of Medicine, Stanford, CA; 2Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA; 3Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA. Purpose: The survival rate following lung transplantation is among the lowest of all solid organ transplants, with only modest improvement over the past decade. Infection and rejection are often responsible for post-lung transplantation morbidity and mortality, but standard clinical tests often fail to distinguish between these two clinical complications. Methods: We used shotgun sequencing to simultaneously quantify transplant donor, transplant recipient, and infectious pathogen derived cell-free DNA in plasma samples (n= 398) collected from a prospective cohort of lung transplant recipients (n= 51). We distinguished donor and recipient derived cell-free DNA based upon SNP genotypes. We also isolated pathogen derived cell-free DNA by mapping reads to a database of non-human reference sequences. We evaluated the correlation between donor- and pathogen- derived cell-free DNA level and standard clinical tests for graft rejection and infection, respectively. Results: We found that an elevated level of donor-derived cell-free DNA correlated with standard clinical indicators of graft dysfunction and rejection (AUC= 0.9, performance against invasive transbronchial biopsy). By comparing donor-derived DNA to clinical tests for CMV infection, we found direct evidence of graft injury during cytomegalovirus (CMV) disease. We also found that clinical tests for CMV infection correlated with the level of CMV-derived cell-free DNA (AUC =  0.91), demonstrating that shotgun sequencing of cell-free DNA can be used for non-invasive monitoring of infectious diseases. We further used hypothesis-free screening of infectious pathogen derived cell-free DNA in order to identify un-diagnosed cases of infections. Conclusion: We demonstrate a novel, non-invasive, and sequencing-based diagnostic test that can help distinguish between infection and graft rejection, the two primary clinical complications associated with lung transplantation. We further demonstrate that hypothesis-free shotgun sequencing of pathogen derived cell-free DNA can reveal un-diagnosed cases of infectious disease, which may be broadly useful in clinical medicine.

3( 55) Exposure to Moxifloxacin and Cytomegalovirus Replication Is Associated With Squamous Cell Carcinoma Development in Lung Transplant Recipients S.R. Gerber,1 B. Seifert,2 I. Inci,3 A.L. Serra,4 M. Kohler,1 C. Benden,1 G.F. Hofbauer,5 M.M. Schuurmans .1  1Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland; 2Division of Biostatistics, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; 3Division of Thoracic Surgery, University Hospital Zurich, Zurich, Switzerland; 4Division of Nephrology, University Hospital Zurich, Zurich, Switzerland; 5Division of Dermatology, University Hospital Zurich, Zurich, Switzerland. Purpose: Solid organ transplant recipients are at increased risk for malignancies. A number of factors have been found to significantly increase the risk for skin cancer including immunosuppression and ultraviolet radiation. In addition, lung transplant recipients (LTR) are subject to recurring and prolonged high dose antibiotic, antifungal and antiviral treatment in order to prevent or treat infections. Few data are available on the use of photosensitizing drugs and immunosuppressants in relation to the incidence of skin cancer in this population. The objective of this study is to analyse of incidence and tumor-load of squamous cell carcinoma (SCC) and to identify possible risk factors in LTR. Methods: In this retrospective study, we examined incidence and potential risk factors for SCC in LTR transplanted between 1992 and 2010. Cumulative incidence and Cox proportional hazards regression models were used to evaluate risk factors for SCC formation. Risk factors present in the first year post-transplant were evaluated. Results: In 205 analyzed LTR, 46 patients were diagnosed with SCC during a median follow-up of 4.9 years (interquartile range 2.4-8.6). Median time to first SCC was 4.8 years. The cumulative incidences of first SCC were 16.7%, 34.1%, and 59.9% for 5, 10, and 15 years post-transplantation, respectively. Multivariable analysis, corrected for age at transplantation and gender, identified CMV replication (HR 7.69, 95% CI 2.93-20.2, p< 0.001) and moxifloxacin exposure (HR 2.35, 95% CI 1.15-4.81, p =  0.020) during the first year post-transplantation as independent risk factors for SCC development during follow-up. Conclusion: SCC development is a relevant long-term risk for LTR. In our cohort, moxifloxacin use and CMV reactivations during the first year posttransplantation were associated with increased risk for SCC. These newly identified risk factors for SCC require confirmation in larger cohorts and prospective studies. 3( 56) The Impact of High-Risk Lung Donors on the Survival of Lung Recipients With Interstitial Pulmonary Fibrosis P.G. Sanchez ,1 M. Mulligan,1 C. Evans,1 S. Rahimpour,1 I. Timofte,2 J. Kim,2 K. Rajagopal,1 A.T. Iacono,2 R. Reed,2 J.S. Gammie,1 B.P. Griffith,1 S.M. Pham.1  1Cardiac Surgery, University of Maryland, Baltimore, MD; 2Medicine, University of Maryland, Baltimore, MD. Purpose: Matching donors and recipients is largely based on experience. With the implementation of the LAS, candidates with IPF have the highest provability of being transplanted after listing. As centers are extending their donor acceptance criteria we investigated if the use of high-risk donors (HR) affects survival of IPF lung transplant candidates. Methods: Using the UNOS dataset we identified IPF candidates listed for lung transplantation from 2005-13. Using Cox regression we stratified donor and recipient risk for increased mortality. A HR donor is defined as having one of the following: PaO2 ≤  300 and history of smoking ≥  20 pack-year, PaO2 ≤  300 and age ≥  60, or history of diabetes. A high-risk IPF had an LAS and age ≥  60. Donors and IPF candidates that did not match these criteria were considered low-risk. Our primary outcome was one-year survival from the time the candidate was listed for transplantation. We also investigated one-year survival after transplant. Results: Of a total of 4,164 IPF patients on the UNOS waitlist, 2,998 ( 72 %) were transplanted within one year of being listed, and 349 received lungs from HR donors. One-year post listing survival in IPFs with an LAS and age ≤  60 was not compromised by using HR or LR donors (0.87 vs 0.88; p= 0.80) Figure A, and was significantly higher than in not