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Purpose Along with infections, rejection and graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of over 30% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population. Identification of biomarkers that assess post-transplant risk is needed to improve long-term outcomes following heart transplantation. Methods We performed a single center, cohort study of 281 heart transplant recipients followed for a mean time of 9.5 years (2-19 years post-transplant). Mean age was 54.5, male 71.5%. The primary endpoint was development of neoplasia (27.2%). 8.2% developed metastasis. We serially measured funcionally distinct lymphocyte subsets in peripheral blood. We correlated assay results with the outcomes of neoplasia and development of metastasis. Lymphocyte subsets were assessed by four-colour flow-cytometry before transplantation at the time of inclusion in waiting list, at day 7 and 30 after heart transplantation. Results Clinical risk factors of cancer were age, smoking, obesity, ischemic etiology and post-transplant infections. We observed the following abnormalities in heart recipients who developed cancer: lower percentages of naive B-cells and lower mean fluorescence intensity (MFI) of toll like receptor (TLR) 4 on B-cells before transplantation (p=0.01 and p=0.049, respectively); lower non switched memory B-cell percentages and lower MFI of TLR4 on B-cells at 7 days after transplantation (p Conclusion Immunological abnormalities of B-cells and of TLR4 expression on B-cells and CD8 T-cells were observed in heart recipients who developed cancer after heart transplantation. These results suggest a role of these abnormalities in the predisposition to cancer that warrants further evaluation.

BACKGROUND: Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. METHODS: We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. RESULTS: We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as

Purpose The identification of pre-transplant biomarkers to assess the risk of post transplant infections in lung transplantation is of interest. The anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in this study. Higher IL-10 plasma levels have been associated with prolonged CMV clearance in lung recipients. In other clinical setings higher IL-10 levels have been found to be a predictor of clinical outcome in sepsis. In this study we evaluated the relationship between pre-transplant IL-10 serum concentration and the development of infections occurring after lung transplantation. Methods In a prospective follow-up multicenter study, 87 patients in 5 centers were included to identify potential biomarkers of risk for development of post transplant infections. 82 patients were transplanted. 41 patients (50%) developed at least one infection episode that required intravenous drug therapy during the first 6 months after transplantation. Pre-transplant IL-10 was measured with an enzyme-linked immunosorbent assay in blood. IL-10 levels were then correlated with the prevalence of infections. Results The distribution of post transplant infections was as follows: bacterial (67,35%), fungal (20,41%), viral (10,20%). Patients who developed infections disclosed significantly higher levels of pre-transplant serum IL-10: 43,26 ± 39,55 pg/ml vs. 21,70 ± 23,34 pg/ml; p 29 pg/ml were at higher risk of having post transplant infections (Logistic regression relative hazard 3.64 (p= 0.021; 95% confidence interval: 1.28- 10.87). Conclusion We demostrated that in lung recipients with pre-transplant higher levels of serum IL-10, the prevalence of post-transplant infections was higher which suggest a potential role of individual anti-inflammatory responses in the predisposition to infection.

[Abstract] BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG

s S131 visits. A novel approach for quantifying dd-cfDNA using targeted amplification and next-generation sequencing was used to quantify dd-cfDNA on 109 plasma samples from these 24 patients. 3 to 10 samples were collected between 2 months and 1 year post-transplantation for each patient. Most plasma samples had endomyocardial biopsy rejection grades and geneexpression profiling (GEP) test scores available from the same clinic visits. Results: Median dd-cfDNA was 0.79% (interquartile range [0.38%, 1.30%]). Total between-patient variability (51% CV) was similar to within-patient variability (45% CV). Analytical variability was 17%. The ratio of betweenpatient variability to within-patient variability was 1.6 times lower for ddcfDNA than for GEP. No effect of recipient gender, age, CMV serologic status, or time post-transplantation was seen on % dd-cfDNA measurements. Conclusion: In this longitudinal study of non-rejecting heart transplant recipients, the withinand between-patient variabilities of dd-cfDNA were shown to be of similar size, and significantly larger than the analytical variability of the assay. The ratio of between-patient variability to within-patient variability was significantly less than in GEP, suggesting that dd-cfDNA does not depend as strongly on patient-specific factors as does GEP. dd-cfDNA showed no dependence on patient age, gender, CMV serologic status, or time since transplant in this cohort. Taken together, these characteristics indicate that dd-cfDNA is a stable analyte in non-rejecting patients. (Study sponsored by CareDx, Inc.)

(PD-1) and increased levels of the T-box factor eomesodermin (Eomes) unlike tetramer+ cells from controllers. While impaired effector function persisted in many relapsers from acute infection, the expression of high PD-1 levels on CMV-specific CD8+ T cells was only detected during chronic infection, and not acute primary infection, suggesting exhaustion. Conclusion: Thus, impaired CMV-specific T cell responses from relapsers are not for lack of CMV-specific cells, but rather, cells that are dysfunctional with an exhausted phenotype. Ongoing studies are focusing on whether effector function can be rescued in these CMV-specific CD8+ T cells.