Hans H. Hirsch

PTX3 Polymorphisms and Invasive Mold Infections After Solid Organ Transplant

Donor PTX3 polymorphisms were shown to influence the risk of invasive aspergillosis among hematopoietic stem cell transplant recipients. Here, we show that PTX3 polymorphisms are independent risk factors for invasive mold infections among 1101 solid organ transplant recipients, thereby strengthening their role in mold infection pathogenesis and patients risk stratification.

KIR-associated protection from CMV replication requires pre-existing immunity: a prospective study in solid organ transplant recipients.

Previous studies have associated activating Killer cell Immunoglobulin-like Receptor (KIR) genes with protection from cytomegalovirus (CMV) replication after organ transplantation. Whether KIR-associated protection is operating in the context of primary infection, re-activation, or both, remains unknown. Here we correlated KIR genotype and CMV serostatus at the time of transplantation with rates of CMV viremia in 517 heart (n=57), kidney (n=223), liver (n=165) or lung (n=72) allograft recipients reported to the Swiss Transplant Cohort Study. Across the entire cohort we found B haplotypes—which in contrast to A haplotypes may contain multiple activating KIR genes—to be protective in the most immunosuppressed patients (receiving anti-thymocyte globulin induction and intensive maintenance immunosuppression) (hazard ratio after adjustment for covariates 0.46, 95% confidence interval 0.29–0.75, P=0.002). Notably, a significant protection was detected only in recipients who were CMV-seropositive at the time of transplantation (HR 0.45, 95% CI 0.26–0.77, P=0.004), but not in CMV seronegative recipients (HR 0.59, 95% CI 0.22–1.53, P=0.28). These data indicate a prominent role for KIR—and presumably natural killer (NK) cells—in the control of CMV replication in CMV seropositive organ transplant recipients treated with intense immunosuppression.

Cytomegalovirus infection management in solid organ transplant recipients across European centers in the time of molecular diagnostics: An ESGICH survey

Scant information is available about how transplant centers are managing their use of quantitative molecular testing (QNAT) assays for active cytomegalovirus (CMV) infection monitoring in solid organ transplant (SOT) recipients. The current study was aimed at gathering information on current practices in the management of CMV infection across European centers in the era of molecular testing assays.

Clostridium difficile Infection is Associated with Graft Loss in Solid Organ Transplant Recipients.

Clostridium difficile infection (CDI) is a leading cause of infectious diarrhea in solid organ transplant recipients (SOT). We aimed to assess incidence, risk factors, and outcome of CDI within the Swiss Transplant Cohort Study (STCS). We performed a case‐control study of SOT recipients in the STCS diagnosed with CDI between May 2008 and August 2013. We matched 2 control subjects per case by age at transplantation, sex, and transplanted organ. A multivariable analysis was performed using conditional logistic regression to identify risk factors and evaluate outcome of CDI. Two thousand one hundred fifty‐eight SOT recipients, comprising 87 cases of CDI and 174 matched controls were included. The overall CDI rate per 10 000 patient days was 0.47 (95% confidence interval ([CI] 0.38‐0.58), with the highest rate in lung (1.48, 95% CI 0.93‐2.24). In multivariable analysis, proven infections (hazard ratio [HR] 2.82, 95% CI 1.29‐6.19) and antibiotic treatments (HR 4.51, 95% CI 2.03‐10.0) during the preceding 3 months were independently associated with the development of CDI. Despite mild clinical presentations, recipients acquiring CDI posttransplantation had an increased risk of graft loss (HR 2.24, 95% CI 1.15‐4.37; P = .02). These findings may help to improve the management of SOT recipients.

Aktuelle Situation und neue diagnostische Entwicklungen: Überwachung der Poliomyelitis in der Schweiz

Ermutigt durch die Erfolge bei der Pockenbekampfung hat die Weltgesundheitsorganisation im Jahr 1988 die Global Polio Eradication Initiative formuliert. Ziel dieser Initiative ist, die Kinderlahmung durch Impfpravention weltweit auszurotten.

NK Cell Immunity Pre-Transplant as a Predictor for CMV Post-Transplant.: Abstract# 2167

2167 NK Cell Immunity Pre-Transplant as a Predictor for CMV PostTransplant. S. Keshwani,1 A. Humar,1 L. Lisboa,2 A. Egli,2 P. Bochud,2 H. Hirsch,2 M. Weisser,2 S. Husain,1 C. Garzoni,2 C. van Delden,2 O. Manuel,2 P. Meylan,2 K. Boggian,2 M. Stern,2 J. Rick,2 N. Mueller,2 D. Kumar.1 1UHN, Toronto, Canada; 2Swiss Transplant Cohort, Zurich, Switzerland. Introduction: NK cell responses are thought to play an important role in controlling CMV replication. The expansion of a specifi c subset of NK cells (NKG2C+) has been observed during CMV infection and this may be a “memory” subset of NK cells. We hypothesized that pre-transplant NK cell phenotypes would correlate with the development of CMV post-transplant. Methods: PBMCs were collected prior to transplant in a large cohort of patients. Patients were followed post-transplant for CMV viremia or disease. PBMCs were stimulated with CMV Towne strain and underwent surface and intracellular staining for CD56, CD16, NKG2C and IFN-γ and were divided into the following phenotypes: CD56brCD16dim, CD56brCD16neg, CD56dimCD16pos, CD56dimCD16neg as well as NKG2C positive or negative. Results: We enrolled 272 CMV seropositive transplant recipients (170 D+R+, 102 D-R+), predominantly kidney and liver. No patient received antiviral prophylaxis. Of these patients 123/272 (45.2%) developed CMV infection, 10/272 (3.7%) developed CMV disease and 83/272 (30.7%) required antiviral therapy. Patients with greater proportion of CD56brCD16dim NK cells were less likely to have CMV disease (cell frequency 0.23% vs. -3.9% in no disease vs. disease; p=0.018). In the D+/R+ subgroup CD56brCD16dim NK cell frequencies predicted CMV disease (median 0.41% in no disease and -4.0% in disease; p=0.007). In addition, the expression of NKG2C on CD56brCD16neg cells was upregulated after CMV stimulation in those who did not have CMV disease and downregulated in those who developed disease (+1.76% vs. -6.17%; p=0.025). The expression of NKG2C receptor on CD56brCD16dim NK cells was also related to the development of CMV viremia (5.2% vs. 0.47%; p=0.063). This was especially true for the D+R+ subgroup where lower pre-transplant expression of NKG2C on CD56brCD16neg cells was more likely to lead to CMV infection (1.5% vs -1.68%; p=0.033) and CMV disease (0.21% vs. -4.1%; p=0.045). CD56dimCD16pos NK cells that produced IFN-γ in response to CMV stimulation were also predictive of CMV disease (p=0.017). Conclusion: This study provides novel insight into pre-transplant evaluation of NK cell phenotypes and subsequent risk of CMV reactivation. The importance of the NKG2C+ phenotype as a CMV-specifi c subset of NK cells is also demonstrated and has the potential to be a biomarker for CMV infection post-transplant. DISCLOSURE: Humar, A.: Grant/Research Support, Roche, Other, Astellas, Advisory Board Member, Chimerix, Advisory Board Member. Kumar, D.: Grant/ Research Support, Roche, Astellas, Other, Oxford Immunotec, Advisory Board