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Cytomegalovirus (CMV) is an immunomodulatory virus that indirectly increases the risk for bacterial, fungal, and viral infections. However, the pathogenesis of this phenomenon is poorly understood. We determined whether inflammatory responses to different Toll-like receptor (TLR) ligands are blunted during CMV infection in solid-organ transplant (SOT) patients. Peripheral blood mononuclear cells from 38 SOT patients with and without CMV were incubated in the presence of various viral, fungal, and bacterial TLR ligands. Cytokines were measured in the supernatant by multiplex enzyme-linked immunosorbent assay. Patients had blunted cytokine responses to bacterial, fungal, and viral ligands during CMV infection when compared to the absence of CMV infection. This was independent of viral load, clinical presentation of CMV infection or immunosuppression, supporting the clinical observation in SOT recipients that CMV infection increases susceptibility to bacterial, fungal, and other viral infections. Moreover, in the absence of CMV infection, patients with subsequent CMV infection had lower cytokines in response to TLR ligands compared to those without subsequent CMV infection, suggesting that inherent differences in patients not directly related to CMV also contribute to this increased susceptibility. In summary, these data provide novel ex vivo evidence to support indirect effects of CMV.

Background Cutaneous squamous cell carcinoma (cSCC) occurs 65–200 times more in immunosuppressed organ transplant patients than in the general population. T cells, which are targeted by the given immunosuppressive drugs, are involved in anti-tumor immune surveillance and are functionally regulated by DNA methylation. Prior to kidney transplantation, we aim to discover differentially methylated regions (DMRs) in T cells involved in de novo post-transplant cSCC development. Methods We matched 27 kidney transplant patients with a future de novo cSCC after transplantation to 27 kidney transplant patients without cSCC and studied genome-wide DNA methylation of T cells prior to transplantation. From 11 out of the 27 cSCC patients, the DNA methylation of T cells after transplantation was also examined to assess stability of the observed differences in DNA methylation. Raw methylation values obtained with the 450k array were confirmed with pyrosequencing. Results We found 16 DMRs between patients with a future cSCC and those who do not develop this complication after transplantation. The majority of the DMRs were located in regulatory genomic regions such as flanking bivalent transcription start sites and bivalent enhancer regions, and most of the DMRs contained CpG islands. Examples of genes annotated to the DMRs are ZNF577, coding for a zinc-finger protein, and FLOT1, coding for a protein involved in T cell migration. The longitudinal analysis revealed that DNA methylation of 9 DMRs changed significantly after transplantation. DNA methylation of 5 out of 16 DMRs was relatively stable, with a variation in beta-value lower than 0.05 for at least 50% of the CpG sites within that region. Conclusions This is the first study demonstrating that DNA methylation of T cells from patients with a future de novo post-transplant cSCC is different from patients without cSCC. These results were obtained before transplantation, a clinically relevant time point for cSCC risk assessment. Several DNA methylation profiles remained relatively stable after transplantation, concluding that these are minimally affected by the transplantation and possibly have a lasting effect on post-transplant cSCC development. Electronic supplementary material The online version of this article (10.1186/s13148-018-0519-7) contains supplementary material, which is available to authorized users.

We report a case of cytomegalovirus encephalitis in a hematopoietic stem cell transplant recipient. A previously uncharacterized V787E mutation in UL54 was identified in cerebrospinal fluid but not plasma specimens. For the V787E recombinant virus, the half maximal effective concentrations for ganciclovir, foscarnet, and cidofovir were 8.6-, 3.4- and 2.9-fold higher than for wild-type virus, and the replicative capacity was lower. The introduction of a bulkier and negatively charged glutamate residue at position 787 could destabilize the finger domain of UL54 DNA polymerase. Viral genotyping of cerebrospinal fluid is warranted in subjects with cytomegalovirus encephalitis, owing to the low penetration of antivirals in this compartment.

We report the first case of tocilizumab (TCZ)-attributable skin squamous cell carcinoma (SCC) in a 53-year-old male with rheumatoid arthritis (RA).Figure 1. (A) Ulceration: suspected carcinoma on t...

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

Copyright © Ordem dos Médicos 2017, The effects of immunodepression on several disease states have constituted an important area of research, leading to the identification of relevant associations between immunodepression and a vast set of comorbidities, including infectious diseases, cardiovascular diseases and cancer. Research on the effects of immunodepression has mostly been conducted in individuals under immunodepression by the human immunodeficiency virus and transplant recipients under pharmacological immunosuppression, due to the difficulties in obtaining relevant samples sizes in other contexts of immunodepression. Overall, immunosuppressed individuals tend to show increased incidence of malignancies, but only transplant recipients show significantly increased incidence of skin cancer; human immunodeficiency virus-infected individuals only show increased incidence of malignancies of infectious origin. This paper presents a literature review on the effects of immunodepression in the development of tumours in humans, with special emphasis on the development of the different types of skin cancer., Os efeitos da imunodepressão no desenvolvimento de estados de doença têm constituído uma importante área de investigação, tendo sido verificadas associações entre a imunodepressão e o desenvolvimento de um vasto conjunto de comorbilidades, entre as quais se destacam as doenças infeciosas, doenças cardiovasculares e o cancro. A investigação dos efeitos da imunodepressão em humanos tem sido sobretudo realizada em indivíduos imunodeprimidos pelo vírus da imunodeficiência humana e indivíduos sob imu- nossupressão farmacológica após transplante, devido aos constrangimentos associados à obtenção de amostras de número relevante noutros contextos. De um modo geral, doentes imunodeprimidos tendem a apresentar maior incidência de neoplasias malignas. No que respeita aos doentes transplantados, o cancro cutâneo tem uma incidência significativamente aumentada, ao passo que, entre doentes portadores da infeção com vírus da imunodeficiência humana, apenas as neoplasias de origem infeciosa apresentam in- cidência aumentada. Este artigo apresenta uma revisão da literatura relativa aos efeitos da imunodepressão no desenvolvimento de tumores em humanos, com especial enfâse no desenvolvimento dos diferentes tipos de cancro cutâneo.

Heart retransplantation is a considerable treatment option for some patients with graft failure. In the time of heart donor shortage it is of great importance to critically assess candidates for cardiac retransplantation. In this article we present a rare case of an adult patient who underwent successful urgent heart retransplantation due to severe toxic cardiomyopathy (anthracycline-induced) after posttransplant lymphoproliferative disease (PTLD) – diffuse large B-cell lymphoma.

The aim of this retrospective study was to assess the incidence of late complications occurring ≥2 years after allogeneic hematopoietic stem cell transplantation (HSCT) for malignant diseases using a T-cell depletion strategy.Between 1984 and 2004, 142 patients were eligible for the study. Total body irradiation (TBI) was carried out in 85% of the patients and T-cell depletion in 84%.Non-relapse mortality (NRM) was 3% (95% CI 0-11) at 10 years, and serious late events affected a substantial number of patients. The cumulative incidence (CI) of chronic graft-versus-host disease (cGvHD) was 30% (95% CI 23-40), and that of infectious complications was 17% (95% CI 11-23). Multivariate analysis showed a higher risk for late complications in patients with cGvHD (HR 1.9, 95% CI 1.2-3.2, P=0.011) and patients receiving methylprednisolone during conditioning (HR 1.9, 95% CI 1.1-3.3, P=0.019 1), patients with cGvHD also having a higher risk for NRM (HR 13.2, 95% CI 1.2-143, P=0.03), as well as those receiving steroids for3 months (HR 40.3, 95% CI 2.3-718, P=0.02) and those receiving antithymocyte globulin (HR 9.6, 95% CI 0.8-68, P=0.024).A significant proportion of long-term survivors of HSCT had late complications. cGvHD remained an important risk factor for late complications despite T-cell depletion resulting in immunosuppression and infectious complications.

From the Division of Primary Care Medicine, Department of Community Medicine and Primary Care, Geneva University Hospitals and University of Geneva; Service of Infectious Diseases, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne; Division of Cardiology, Department of Internal Medicine, Geneva University Hospitals and University of Geneva; Transplantation Center, Centre Hospitalier Universitaire Vaudois and University of Lausanne; and Institute of Microbiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.

Disseminated toxoplasmosis is a life-threatening infection in transplant recipients, which results either from reactivation of latent infection or from organ-transmitted primary infection. Preventive measures and diagnostic screening methods differ between countries and are related to the seroprevalence of Toxoplasma spp. in the general population. Here we report a case of disseminated toxoplasmosis in a heart transplant recipient with previous immunity that occurred after cotrimoxazole prophylaxis for the prevention of Pneumocystis jiroveci i pneumonia was stopped. Quantitative PCR proved useful for the diagnosis and monitoring of Toxoplasma infection. Decreasing parasitic burdens in sequential samples of cerebrospinal fluid, blood, and bronchoalveolar lavage fluid correlated with a favorable outcome and allowed modulation of the immunosuppressive drug regimen. The duration of anti- Toxoplasma treatment and the need for maintenance prophylaxis are discussed, as well as prophylaxis for solid-organ transplant recipients. Although a rare event in heart transplant recipients, Toxoplasma reactivation must be investigated promptly, since early treatment improves the prognosis.

Kidney transplant recipients are a growing population in ambulatory care. Medical follow up after the first post transplant year requires a tight collaboration between transplant centers, primary care physicians and community nephrologists. Although kidney transplantation is the treatment of choice for patients in end stage renal failure, no major improvement has been seen in long-term patient and graft survivals. Mortality of kidney transplant recipients remains higher than that of the general population, due to the high incidence of cardiovascular disease, infection and malignancies related to progressive renal failure and also to immunosuppressive treatment. We review here the optimal ambulatory medical care needed by these patients after the first post transplant year.

RATIONALE AND OBJECTIVES: Bone mineral status in recipients of renal grafts is related to preexisting renal osteodystrophy and immunosuppressive treatment. The authors assessed bone mineral status after renal transplantation. METHODS: Bone mineral status of 20 male graft recipients was evaluated using the following noninvasive techniques: 1) neutron activation analysis, to measure hand bone phosphorus (HBP); 2) single photon absorptiometry, to measure forearm bone mineral content (BMC); and 3) single energy spectrum quantitative computed tomography, to measure spinal trabecular bone equivalent density (TBED). RESULTS: The mean (+/- SD, P) HBP, BMC, and TBED were found to be respectively, 4.8% (+/- 8.3%, P = .02), 6.6% (+/- 14.6%, P = .07) and 52% (+/- 8.5%, P < .001) lower than that measured in matched normal controls. Renal graft recipients demonstrated mean HBP and BMC decrements that were similar to those observed in matched patients on extrarenal dialysis, although the decrement in TBED was significantly greater in the graft recipients (P < .001). Repeated measurements performed during a 3-year period showed no statistically significant changes. CONCLUSIONS: Renal transplantation was associated with minor degree of osteopenia in the primarily cortical bone tissue. We speculate that the remarkably low TBED values in graft recipients does not reflect a mean 52% decrement of spinal bone minerals, but rather may be attributed in part to the deposition of adipose tissue in the spine as a result of corticosteroid treatment. Invest Radiol