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Abstract: Background: There is lack of recent multicenter epidemiological data on invasive aspergillosis (IA) among solid organ transplant recipient (SOTr) in the mold‐acting antifungal era. We describe the epidemiology and outcomes of IA in a contemporary cohort of SOTr using the Swiss Transplant Cohort Study. Methods: All consecutive SOTr with proven or probable IA between 01.05.2008 and 31.12.2014 were included. A case‐control study to identify IA predictors was performed: 1‐case was matched with 3‐controls based on SOT type, transplant center, and time post‐SOT. Results: Among 2868 SOTr, 70 (2.4%) patients were diagnosed with proven (N: 30/70, 42.9%) or probable (N: 40/70, 57.1%) IA. The incidence of IA was 8.3%, 7.1%, 2.6%, 1.3%, and 1.2% in lung, heart, combined, kidney, and liver transplant recipients, respectively, Galactomannan immunoassay was positive in 1/3 of patients tested. Only 33/63 (52.4%) of patients presented with typical pulmonary radiographic findings. Predictors of IA included: renal insufficiency, re‐operation, and bacterial and viral infections. 12‐week mortality was higher in liver (85.7%, 6/7) compared to other (15.9%, 10/63; P < .001) SOTr. Conclusions: Invasive aspergillosis remains a rare complication post‐SOT, with atypical radiographic presentations and low positivity rates of biomarkers posing significant diagnostic challenges. Although overall mortality has decreased in SOTr, it remains high in liver SOTr. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

S. Gianella, L. Haeberli, B. Joos, B. Ledergerber, R.P. Wüthrich, R. Weber, H. Kuster, P.M. Hauser, T. Fehr, N.J. Mueller. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis 2010: 12: 1–10. All rights reserved Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised individuals. The epidemiology and pathogenesis of this infection are poorly understood, and the exact mode of transmission remains unclear. Recent studies reported clusters of PCP among immunocompromised patients, raising the suspicion of interhuman transmission. An unexpected increase of the incidence of PCP cases in our nephrology outpatient clinic prompted us to conduct a detailed analysis. Genotyping of 7 available specimens obtained from renal transplant recipients was performed using multi-locus DNA sequence typing (MLST). Fragments of 4 variable regions of the P. jirovecii genome (ITS1, 26S, mt26S, β-tubulin) were sequenced and compared with those of 4 independent control patients. MLST analysis revealed identical sequences of the 4 regions among all 7 renal allograft recipients with available samples, indicating an infection with the same P. jirovecii genotype. We observed that all but 1 of the 19 PCP-infected transplant recipients had at least 1 concomitant visit with another PCP-infected patient within a common waiting area. This study provides evidence that nosocomial transmission among immunocompromised patients may have occurred in our nephrology outpatient clinic. Our findings have epidemiological implications and suggest that prolonged chemoprophylaxis for PCP may be warranted in an era of more intense immunosuppression. [ABSTRACT FROM AUTHOR]

N.J. Mueller, M. Weisser, T. Fehr, R.P. Wüthrich, B. Müllhaupt, R. Lehmann, A. Imhof, J.-D. Aubert, M. Genoni, R. Kunz, M. Weber, J. Steiger. Donor-derived aspergillosis from use of a solid organ recipient as a multiorgan donor. Transpl Infect Dis 2010: 12: 54–59. All rights reserved The growing need for organs and the scarcity of donors has resulted in an increased use of extended criteria donors. We report a case where a recipient of a cardiac graft was used as an organ donor. Death of the recipient occurred 9 days after transplantation and was attributed to presumed cerebral hemorrhage, which post mortem was diagnosed as invasive aspergillosis of the brain. One recipient of a kidney transplant lost the graft due to infection with Aspergillus fumigatus, whereas prompt initiation of therapy successfully prevented disseminated aspergillosis in the other recipients. Despite the pressure to extend the use of organs by lowering the acceptance criteria, organs should only be accepted if the cause of death of the donors is unequivocally explained. [ABSTRACT FROM AUTHOR]

Newer immunosuppressive strategies have resulted in a marked reduction in graft rejection after transplantation, with the price being an increase of infectious complications, such as BK-related nephropathy. The targeting of new immunosuppressive pathways, such as interleukin-2–mammalian target of rapamycin inhibition, may have unexpected consequences for the immune response. Cell-depleting agents have long-lasting effects on cellular recovery and function, with the activation of latent viral infections and late viral and fungal infections. The multitude of different induction and maintenance protocols renders the detection of small increases of often rare infections very difficult. At the same time, preemptive and prophylactic strategies have gained widespread acceptance and may further offset small changes in infection rates. Other factors related to an increase or shift of infections may be of equal importance, such as increased use of marginal donors, older age at transplantation, or more patients receiving a second transplant. Not all the changes observed result in an increased immunosuppression. Steroid- and calcineurin inhibitor-sparing protocols may have a beneficial impact on infectious complications. Antimycotic or antiviral activity has been described for specific immunosuppressive agents, although the in vivo effect of these activities is uncertain. The possible role of specific drugs in the occurrence of infections is discussed, with emphasis on the antibodies and fusion proteins. The unequivocal attribution of a given infection to a specific drug is often impossible, as the risk of infection is dependent on the entirety of immunosuppression and the epidemiological pressure (‘net immunosuppression’). It is important to remain vigilant for unexpected infections, not only in the context of clinical studies with selected patients, but also in the routine follow-up of our transplant patients. [ABSTRACT FROM AUTHOR]

A cytomegalovirus (CMV) donor positive/recipient negative liver transplant recipient developed CMV syndrome with presumed colitis 2 weeks after discontinuing the standard 3 months of valganciclovir prophylaxis. Treatment with intravenous ganciclovir (GCV) reduced, but did not clear, CMV replication. A CMV UL97 mutation (M460V) conferring GCV resistance was identified. Reduction of immunosuppression was followed by rapidly rising lymphocyte counts as well as by clearance of CMV viremia and of clinical symptoms. However, bilateral chorioretinitis was diagnosed 2 weeks later and treated with foscarnet and cidofovir. Then, right eye vitritis occurred necessitating vitrectomy due to a partially rhegmatogeneous retinal detachment. Because chorioretinitis–vitritis after rising lymphocyte counts and clearance of CMV viremia was strongly suggestive of an immune reconstitution syndrome (IRS)-like disease, we investigated CMV-specific T-cells in the peripheral blood available during follow-up. We found strong CD8+ but only low CD4+ T-cell responses (4.77% vs.<0.1%) to the CMV immediate early pp72, while responses to CMV-lysate or CMV-pp65 (CD4+ <0.01%; CD8+<0.01%) were low. Over 16 weeks of follow-up, pp72-specific CD8+ responses declined, while responses to pp65 gradually increased (CD4+ 0.16%; CD8+ 0.76%) indicating a slowly adapting CMV-specific cellular T-cell response. Review of 12,653 published liver transplant patients identified only 14 (0.1%) reported cases of CMV-associated chorioretinitis at a median 41.7 weeks post transplant. CMV-associated opthalmologic complications late post transplantation may possibly involve 2 different entities of cytopathic retinitis and IRS-like chorioretinitis–vitritis. [ABSTRACT FROM AUTHOR]

Background. Varicella zoster virus (VZV) causes significant morbidity and mortality in immunocompromised patients. Subclinical reactivation has been described in solid organ recipients and has been associated with graft versus host disease in bone marrow transplantation. Newer studies assessing the prevalence and impact of subclinical VZV reactivation in solid organ transplant (SOT) recipients are lacking. Methods and results. In a first step we developed a highly sensitive quantitative polymerase chain reaction (qPCR) assay for VZV DNA with a detection limit of ≤20 copies/mL. Using this assay, we retrospectively analyzed plasma samples of different patient groups for VZV DNA. VZV DNA was found in 10/10 plasma samples of immunocompentent patients with herpes zoster (VZV copy numbers/mL: mean±SEM 1710±1018), in 1/1 sample of a human immunodeficiency virus-infected patient with primary VZV disease (15,192 copies/mL) and in 4/4 plasma samples of immunocompromised patients with visceral VZV disease (mean of first value 214,214±178,572). All 108 plasma samples of asymptomatic SOT recipients off any antiviral therapy, randomly sampled over 1 year, were negative for VZV DNA. Conclusion. Our qPCR assay proved to be highly sensitive (100%) in symptomatic VZV disease. We did not detect subclinical reactivation in asymptomatic SOT recipients during the first post-transplant year. Thus, subclinical VZV reactivation is either a rare event or does not exist. These data need to be confirmed in larger prospective trials. [ABSTRACT FROM AUTHOR]

The article presents the clinical trial of a 53-year-old HIV-positive female with a history of weakness, weight loss and fatigue. Since July 2004, the patient was medicated with combination antiretroviral therapy which consist of tenofovir, didanosine, and lopinavir-ritonavir. Combination antiretroviral therapy of the patient was discontinued in January 2006 when she was hospitalized due to abdominal discomfort, where her lactate level had increased.

Human cytomegalovirus (HCMV) infection or reactivation represents one of the most important infectious disease problems in allotransplantation . Transmission and activation of porcine cytomegalovirus in pig-to-baboon xenotransplantation is associated with xenograft injury and possibly an increased incidence of consumptive coagulopathy. However, stringent protocols used in the rearing of pig donors practically exclude a risk of porcine CMV. In contrast, in pig-to-human xenotransplantation, the porcine endothelium will inevitably be exposed to human pathogens such as HCMV, and the consequences of potential HCMV cross-species infection of porcine xenografts, in particular endothelial injury and immune activation, remain to be elucidated. Since it is of outmost importance to anticipate any detrimental consequence of this contact, the susceptibility of porcine endothelial cells (pEC) to HCMV infection and its effect on cell surface molecule expression and human leukocyte recruitment was evaluated. Clinical and laboratory HCMV strains, including an EC propagated (TB40/E) and two fibroblast-adapted (AD169 and TB40/F) strains, as well as UV-inactivated, or heparin-treated controls were inoculated to a panel of pEC stemming from different vascular beds. Infection at various MOI was analyzed by PCR, immediate early (IE), early and late antigen expression. To determine HCMV cytopathogenicity, morphological changes were monitored using live cell imaging and apoptosis was analyzed by flow cytometry. The capability of pEC to produce infectious virus was quantified by focus expansion assays. After inoculation, cell surface receptor expression was studied by flow cytometry on pEC bulk cultures and also differentially on IE-positive (infected) and IE-negative (bystander) pEC. Adhesion of human PBMC was tested on HCMV infected pEC monolayers and cell-free pEC supernatants were analyzed for their cytokine content, chemotactic activity, and stimulatory effect on resting secondary pEC cultures. All viral strains infected pEC with differences in the infection efficiency (percentage of IE-positive cells) and the kinetics of cytopathology. Moreover, differences in susceptibility of pEC derived from distinct vascular beds were observed. HCMV underwent a complete replication cycle in about 5% of the infected pEC. Comparing the permissiveness of pEC to human aortic EC (HAEC) revealed differences in strain susceptibility and lower rates of late antigen expression in pEC. Finally, HCMV-infected pEC were demonstrated to release viral progeny with a lower efficiency than infected HAEC. Cell-surface expression of E-selectin and VCAM-1 was upregulated not only in the IE-positive fractions (infected) of HCMV-inoculated cultures but also in the IE-negative fractions, presumably by bystander effects. In contrast, porcine MHC class I expression was downregulated in IE-positive, and upregulated in IE-negative cells. The receptor alterations in the IE-negative fraction were mediated by pEC-derived soluble factors and consequently both porcine IL-6 and IL-8 were detected in the supernatants. The increased adhesion receptor expression was paralleled by enhanced human leukocyte chemotaxis and adhesion to infected pEC cultures. Pretreatment of HCMV with heparin blocking viral entry, but not UV-inactivation blocking viral replication, prevented adhesion-receptor modulation, and reversed the increased adhesion and chemotaxis. In summary, HCMV may productively infect pEC following pig-to-human solid organ transplantation and may alter and activate the porcine endothelium, rendering the xenograft more susceptible to human leukocyte recruitment and rejection. Therefore, understanding the mechanisms of cross-species HCMV infection and finding strategies to render pEC resistant to HCMV infection will be essential for xenotransplantation to become a clinical reality. [ABSTRACT FROM AUTHOR]