Search for human herpesvirus 6 and human cytomegalovirus in bronchoalveolar lavage from patients with human immunodeficiency virus-1 and respiratory disorders

Virus isolation and viral DNA detection by the polymerase chain reaction were used to investigate the presence of human herpesvirus 6 (HHV-6) and human cytomegalovirus (HCMV) in bronchoalveolar lavage from 34 human immunodeficiency virus-1 (HIV-1)-infected patients with respiratory disorders. The aim was to assess the presence of reactivated HHV-6 in lung tissues for a subsequent evaluation of the frequency of virus involvement in respiratory clinical manifestations in the course of HIV-1 infection. Bronchoalveolar lavage samples were tested for the presence of HCMV, as a routine investigation within a protocol monitoring opportunistic infections in symptomatic HIV-1 patients. Whereas HCMV DNA was detected by the polymerase chain reaction in 12 bronchoalveolar lavage specimens, 10 of which were also positive for virus isolation, all samples were negative for HHV-6 by both virological procedures. The HHV-6 DNA finding in bronchoalveolar lavage from an HIV-1-seronegative patient with renal carcinoma, investigated accidentally together with the bronchoalveolar lavage specimens from HIV-1 seropositive patients, stressed the HHV-6 polymerase chain reaction-negative results in the bronchoalveolar lavage samples under study. It is concluded that the lung may be a target organ for HCMV infection in HIV-1-seropositive patients affected by respiratory symptoms but that this does not seem to be the case for HHV-6. © 1996 Wiley-Liss, Inc.     

Persistent cytomegalovirus infection in kidney allografts is associated with inferior graft function and survival

The long-term effects of cytomegalovirus (CMV) infections on kidney allografts are unknown. We examined the impact of persistent intragraft CMV infection on long-term kidney allograft function and survival. CMV was diagnosed in 82/172 renal transplant recipients by antigenemia test and viral cultures. Biopsies from 48 of 82 patients taken after CMV infection and from 15 patients with no previous CMV infection detected were available for the immunohistochemical demonstration of CMV antigens and DNA hybridization in situ. Five-year follow-up data from these 63 patients were analysed. In 17 patients, CMV antigens and/or DNA persisted in the biopsy >2 months after the last positive finding in blood or urine. Patients with persistent intragraft CMV had reduced graft survival (P = 0.041) and Cox regression analysis showed persistent CMV as a risk factor for reduced graft survival (RR: 3.5). Recipients with persistent intragraft CMV had reduced creatinine clearance 1 and 2 years after transplantation (P = 0.007) and in multivariate logistic regression analyses including several potential pre- and posttransplant risk factors, persistent CMV was an independent risk factor for lower clearance at 1 and 2 years (OR: 4.4 and 4.9). Our novel findings show that persistent intragraft CMV infection was associated with reduced kidney allograft function and survival.     

De novo gastrointestinal tumours after renal transplantation: role of CMV and EBV viruses

The development of new and more effective immunosuppressive agents has provided long-term survival for transplant recipients, thereby increasing the risk of de novo malignancy in chronic immunocompromised hosts. While de novo post-transplant lymphoproliferative diseases and skin cancer has been shown to have an increased incidence in long-term surviving solid organ transplant recipients, the association with gastrointestinal (GI) cancer is controversial. Over 12 yr, 20 patients (5%) out of 395 renal transplant recipients developed 23 de novo tumours; 11 skin cancer and 12 non-skin cancer. Four patients (1%) developed de novo tumours of the GI tract (three colon, and one gastric cancer). Immediately after tumour's diagnosis, immunosuppressive therapy was reduced; all patients were shifted from cyclosporine to Rapamicine within 30 d. The tumour was surgically resected with curative intent in three cases, while one patient had only palliative surgery because of metastatic disease. The post-operative courses was uneventful. All patients maintained normal graft function. However, three out of four patients (75%) died of progression of the neoplasm, within a median time from the diagnosis of 12 months. Further, we investigated a possible correlations between de novo GI cancer and HCV, HBV status, infections, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation, episodes of rejection, and blood transfusions. All cases with GI de novo cancers reported in this paper developed CMV and EBV reactivation within three months after transplantation. Thereafter we suggest a closer follow-up for de novo GI cancer in renal transplants with early CMV and EBV reactivation in order to avoid delayed diagnosis.     

Efficacy and safety of preemptive anti-CMV therapy with valganciclovir after kidney transplantation

BACKGROUND: CMV infections still pose a potentially serious threat to kidney transplant recipients and have a significant impact on graft as well as patient survival. The antiviral agent valganciclovir (VGCV) has a greater bioavailability after oral administration than oral ganciclovir (GCV) and can be considered a substitute for GCV. The substance is approved in North America and Europe for anti-CMV prophylaxis after organ transplantation. In this pilot study, we examined if VGCV could also be administered in preemptive treatment of CMV infections. METHODS: Twenty-eight renal transplant recipients suffering from 32 asymptomatic episodes of CMV infection were treated with VGCV and followed up. CMV infection was diagnosed by routine controls of pp65-antigenemia in pre-defined intervals. All patients received sequential quadruple immunosuppression. VGCV was given for up to 12 wk in a dosage adapted to renal graft function. Efficacy and safety parameters were monitored for 16 wk. RESULTS: Twenty-seven episodes of CMV antigenemia, two patients progressing to CMV syndrome and three patients progressing to CMV disease were treated. Primary efficiency was 79%, Four patients relapsed and were treated with a second course resulting in serological recovery. Two patients did not respond to oral VCGV and were switched to another antiviral agent. Graft function remained stable during and after treatment. Serious side effects were seen in seven patients, four patients complained of diarrhea and gastrointestinal pain, three patients suffered from leucopenia, in one of these treatment had to be temporary paused. Fifty-nine percent of all episodes were treated in a completely ambulatory setting. CONCLUSIONS: VGCV can be considered as an option also for preemptive treatment of CMV infections after renal transplantation. The antiviral potency seems to be adequate, potential side effects are comparable with IV GCV. Because of the improved pharmacokinetics of VGCV the substance can be used to abbreviate or even completely avoid in-hospital care of CMV infections.     

Cytomegalovirus Latency Promotes Cardiac Lymphoid Neogenesis and Accelerated Allograft Rejection in CMV Naïve Recipients

Human cytomegalovirus (HCMV) infection is associated with the acceleration of transplant vascular sclerosis (TVS) and chronic allograft rejection (CR). HCMV‐negative recipients of latently HCMV infected donor grafts are at highest risk for developing CMV disease. Using a rat heart transplant CR model, we have previously shown that acute rat CMV (RCMV) infection following transplantation significantly accelerates both TVS and CR. Here, we report that RCMV‐naïve recipients of heart allografts from latently RCMV‐infected donors undergo acceleration of CR with similar kinetics as acutely infected recipients. In contrast to acutely infected recipients, treatment of recipients of latently infected donor hearts with ganciclovir did not prevent CR or TVS. We observed the formation of tertiary lymphoid structures (TLOs) containing macrophages and T cells in latently infected hearts prior to transplantation but not in uninfected rats. Moreover, pathway analysis of gene expression data from allografts from latently infected donors indicated an early and sustained production of TLO‐associated genes compared to allografts from uninfected donors. We conclude that RCMV‐induced TLO formation and alteration of donor tissue T cell profiles prior to transplantation in part mediate the ganciclovir‐insensitive rejection of latently infected donor allografts transplanted into naïve recipients by providing a scaffold for immune activation.     

Induction of antiviral cytotoxic T cells by plasmacytoid dendritic cells for adoptive immunotherapy of posttransplant diseases

Virus-associated hematologic malignancies (EBV lymphoproliferative disease) and opportunistic infections (CMV) represent a major cause of hematopoietic stem cell and solid organ transplantation failure. Adoptive transfer of antigen-specific T lymphocytes appears to be a major and successful immunotherapeutic strategy, but improvements are needed to reliably produce high numbers of virus-specific T cells with appropriate requirements for adoptive immunotherapy that would allow extensive clinical use. Since plasmacytoid dendritic cells (pDCs) are crucial in launching antiviral responses, we investigated their capacity to elicit functional antiviral T-cell responses for adoptive cellular immunotherapy using a unique pDC line and antigens derived from Influenza, CMV and EBV viruses. Stimulation of peripheral blood mononuclear cells from HLA-A*0201(+) donors by HLA-A0201 matched pDCs pulsed with viral-derived peptides triggered high levels of multi-specific and functional cytotoxic T-cell responses (up to 99% tetramer(+) CD8 T cells) in vitro. Furthermore, the central/effector memory cytotoxic T cells elicited by the pDCs strongly display antiviral activity upon adoptive transfer into a humanized mouse model that mimics a virus-induced malignancy. We provide a simple and potent method to generate virus-specific CTL with the required properties for adoptive cellular immunotherapy of post-transplant diseases.     

Incidence of and Risk Factors for Posttransplant Diabetes Mellitus after Pancreas Transplantation

Posttransplant diabetes mellitus (PTDM) after pancreas transplantation (PTX) has not been extensively examined. This single center, retrospective analysis of 674 recipients from 1994 to 2005 examines the incidence of and risk factors for PTDM after PTX. PTDM was defined by fasting plasma glucose level ≥126 mg/dL, confirmed on a subsequent measurement or treatment with insulin or oral hypoglycemic agent for ≥30 days. The incidence of PTDM was 14%, 17% and 25% at 3, 5 and 10 years after PTX, respectively and was higher (p = 0.01) in solitary pancreas (PAN) versus simultaneous kidney pancreas (SPK) recipients (mean follow‐up 6.5 years). In multivariate analysis, factors associated with PTDM were: older donor age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03–1.06, p < 0.001), higher recipient body mass index (HR 1.07,CI 1.01–1.13, p = 0.01), donor positive/recipient negative CMV status (HR 1.65,CI 1.03–2.6, p = 0.04), posttransplant weight gain (HR 4.7,CI 1.95–11.1, p < 0.001), pancreas rejection (HR 1.94.CI 1.3–2.9, p < 0.001) and 6 month fasting glucose (HR 1.01,CI 1.01–1.02, p < 0.001), hemoglobin A₁c, (HR 1.12,CI 1.05–1.22, p = 0.002) and triglyceride to high‐density lipoprotein (TG/HDL) ratio (HR 0.94,CI 0.91–0.96, p < 0.001). This study delineates the incidence and identifies risk factors for PTDM after PTX.     

Efficacy and safety of conventional antiviral agents in preventive strategies for cytomegalovirus infection after kidney transplantation: a systematic review and network meta-analysis

Cytomegalovirus (CMV) infection is common in kidney transplantation (KT). Antiviral-agents are used as universal prophylaxis. Our purpose aimed to compare and rank efficacy and safety. MEDLINE, Embase, SCOPUS, and CENTRAL were used from inception to September 2020 regardless language restriction. We included randomized clinical trials (RCTs) comparing the CMV infection/disease prophylaxis among antiviral-agents in adult KT recipients. Of 24 eligible RCTs, prophylactic valganciclovir (VGC) could significantly lower the overall CMV infection and disease risks than placebo with pooled risk differences (RDs) [95% confidence interval (CI)] of −0.36 (−0.54, −0.18) and −0.28 (−0.48, −0.08), respectively. Valacyclovir (VAC) and ganciclovir (GC) significantly decreased risks with the corresponding RDs of −0.25 (−0.32, −0.19) and −0.30 (−0.37, −0.22) for CMV infection and −0.26 (−0.40, −0.12) and −0.22 (−0.31, −0.12) for CMV disease. For subgroup analysis by seropositive-donor and seronegative-recipient (D+/R−), VGC and GC significantly lowered the risk of CMV infection/disease with RDs of −0.42 (−0.84, −0.01) and −0.35 (−0.60, −0.12). For pre-emptive strategies, GC lowered the incidence of CMV disease significantly with pooled RDs of −0.33 (−0.47, −0.19). VGC may be the best in prophylaxis of CMV infection/disease follow by GC. VAC might be an alternative where VGC and GC are not available.     

Monitoring human cytomegalovirus infection in pediatric hematopoietic stem cell transplant recipients: using an affordable in‐house qPCR assay for management of HCMV infection under limited resources

Quantitative real‐time PCR (qPCR) assay is accepted as the method of choice for monitoring human cytomegalovirus (HCMV) infection in hematopoietic stem cell transplant recipients, but the high cost of commercial kits has hampered its use in many developing countries. In this study, an affordable in‐house qPCR was used to manage HCMV infection in pediatric patients and the diagnostic value of this method was compared with the conventional pp65 antigenemia assay. A total number of 1179 samples from 82 recipients were used in this study, and the effect of some potential risk factors on HCMV reactivation was evaluated. The qPCR was able to detect HCMV reactivation earlier and with higher sensitivity than antigenemia assay. Forty‐six episodes of reactivation were detected in 39 patients, of which all were detected by the qPCR assay, while only 21 episodes were diagnosed by antigenemia. The DNAemia level of 1284 IU/ml plasma was defined as the optimal cutoff value for starting pre‐emptive therapy. It was shown that the acute GVHD severity and the relationship of donor and recipient are the most significant risk factors for HCMV reactivation. The data suggest that the antigenemia method for monitoring HCMV reactivation could be substituted by the qPCR assay.