Interactions Between Cytomegalovirus, Human Herpesvirus-6, and the Recurrence of Hepatitis C After Liver Transplantation

Recurrence of hepatitis C (HCV) following liver transplantation is common. Herpesvirus reactivation following transplant may have an immunomodulatory effect resulting in increased HCV replication. We studied whether cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6) may be associated with HCV recurrence and viral load after transplant. We prospectively followed 66 HCV liver-transplant recipients with serial viral load testing for CMV and HHV-6. Infection and viral load were correlated with the development of biopsy-proven HCV recurrence and HCV viral loads. Histologic recurrence of HCV occurred in 41/66 (62.1%) patients. In the primary analysis, CMV infection and disease, and HHV-6 infection were not associated with HCV recurrence. Peak CMV and HHV-6 viral loads were not significantly different in patients with and without recurrence. No correlation was observed between HCV viral loads at 1 and 3 months post-transplant and peak HHV-6 or CMV viral loads. In a subgroup analysis, HHV-6 infection was associated with the development of more severe recurrence (hepatitis and/or fibrosis score > or = 2) (p = 0.01). Also, fibrosis scores at last follow up were higher in patients with CMV disease (1.67 vs. 0.56; p = 0.016) and in patients with HHV-6 infection (1.18 vs. 0.55; p = 0.031). In conclusion, HHV-6 and CMV infection and viral load were not associated with increased overall rates of HCV recurrence or HCV viral load after liver transplantation but may be associated with more severe forms of recurrence.     

Correlation between the intensity of cytomegalovirus infection and the amount of perivasculitis in aortic allografts

Abstract  We previously demonstrated that cytomegalovirus (CMV) infection enhanced perivascular inflammation in rat aortic allografts. In this study, we investigated the relationship between the CMV infection load and the magnitude of perivasculitis (chronic rejection) in aortic transplants. Rats received or-thotopic abdominal aortic grafts, different degrees of total body irradiation (TBI) for immunosuppres-sion and CMV inoculation. The spleens of the rats receiving 5 Gy of TBI contained more infectious virus and viral antigens than those of rats receiving 3 Gy of TBI or no TBI. Although the number of inflammatory cells infiltrating the perivascular area was decreased after TBI, CMV infection resulted in increased perivasculitis in rats that received 5 Gy of TBI as compared to non-infected animals. This virus-induced effect was characterized predominantly by an increased T-cell infiltration, including CD4 and CD8 T-cells. It is concluded that an enhanced systemic CMV infection during severe immunosuppressive therapy can accelerate the development of chronic rejection, which seems to be mediated mainly by T-cells.     

Rat Cytomegalovirus Infection Interferes with Anti-CD4 mAb-(RIB 5/2) Mediated Tolerance and Induces Chronic Allograft Damage

In order to assess the role of heterologous immunity on tolerance induction (TI) by signal 1 modification, the influence of rat cytomegalovirus infection (RCMVI) on TI by a non-depleting monoclonal anti-CD4 mAb (monoclonal antibody) (RIB 5/2) in a rat kidney transplant (KTx) model was investigated. Orthotopic rat KTx (Dark Agouty (DA)-->Lewis (LEW)) was performed after TI with RIB 5/2 [10 mg/kg body weight (BW); day -1, 0, 1, 2, 3; i.p. (intraperitoneal route)]. RCMVI (5x10E5 Plaque forming units [PFU] i.p.) was simultaneously conducted to KTx, 50 days after KTx, and 14 days before and after KTx. RIB 5/2 induced robust allograft tolerance even across the high-responder strain barrier. RCMVI broke RIB 5/2-induced tolerance regardless of the time of RCMVI but did not induce acute graft failure during the 120 days follow-up. RCMVI induced a significant chronic deterioration of allograft function (p<0.01) and enhanced morphological signs of chronic allograft damage (p<0.05). Cellular infiltrates and major histo-compatibility complex (MHC)-expression were more pronounced (p<0.05) in the infected groups. RCMVI induced not only RCMV-specific T-cell response but also enhanced the frequency of alloreactive T cells. RCMV interferes with anti-CD4 mAb-induced tolerance and leads to chronic allograft damage. The data we presented suggest a potentially important role of viral infections and their prophylaxis in clinical TI protocols.     

Cytomegalovirus Disease in High-Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis

The clinical patterns and predictors of cytomegalovirus (CMV) disease in kidney and/or pancreas transplant patients on ganciclovir (1.0 g po t.i.d.) or valganciclovir (450 mg po q.d.) prophylaxis were studied. This is a retrospective analysis of 129 transplant recipients. Median follow up was 12 months (range, 6-18 months). The overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive). Seventeen of 18 patients were diagnosed with CMV after completion of 3 months' prophylaxis (median 8 weeks, range, 2-28 weeks). Induction treatment with thymoglobulin, and Donor +/Recipient - CMV status were the strongest predictors for the development of CMV disease. Cytomegalovirus incidence was not different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively). Valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. High-risk individuals might require higher doses or longer duration of valganciclovir treatment.     

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.     

Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults     

异基因造血干细胞移植后巨细胞病毒的检测及临床意义

目的 为了降低异基因造血干细胞移植（allo-HSCT）后巨细胞病毒（CMV）感染的相关死亡率，寻求一种更快捷、更特异的诊断CMV感染的分子生物学方法。方法 2001年4月至2003年4月，从79例接受异基因造血干细胞移植的患者中采集了135份外周血标本。采用巢式聚合酶链反应（nested-PCR）方法检测患者外周血中CMVgB DNA，阳性标本做酶切分型，部分行序列测定。结果CMVgB DNA检测中有42例患者（53．9％）的66份标本（48．9％）阳性；对其中阳性患者的45份标本进行了酶切分型，结果 CMV gB1型21例（46．7％），CMV gB2型14例（31．1％），CMV gB3型7例（15．6％），CMV gB4型3例（6．7％）。先后有2种型别的CMV感染者有3例（3．8％）。经分析，CMV gB阳性和CMV gB阴性患者GVHD的发生率分别为81．0％和32．4％（P＜0.01）；CMV gB1、gB2、gB3以及gB4型Ⅱ～Ⅳ度急性GVHD及慢性GVHD的发生率分别为：81．0％、50．0％、42．9％和0。结论 Nested-PCR方法可快捷特异地检测CMV感染。CMVgB1、2型中，重度急性GVHD和慢性GVHD发生率较高。CMV gB基因分型检测可有效地指导临床抗病毒治疗，且对移植后患者的临床转归有一定的预测价值。     

Three clinical reports of Kikuchi's lymphadenitis combined with systemic lupus erythematosus

Summary The authors describe three cases of systemic lupus erythematosus (SLE) associated with Kikuchi's histiocitic necrotizing lymphadenitis (HNL). Two patients presented a cytomegalovirus infection concomitantly with Kikuchi's lymphadenitis; in one of them the onsets of SLE and HNL were simultaneous. In the third case an inguinal HNL was concomitant with vaginitis of unknown aetiology.     

巨细胞病毒感染对动脉粥样硬化的影响

目的：研究巨细胞病毒(CMV)感染和动脉粥样硬化的关系，并探讨其可能机制。方法：通过一个大样本从血清流行病学(ELISA检测患者血清中抗CMV的IgG抗体)和分子生物学(PCR检测动脉粥样硬化病变中CMV特异性基因)方面探讨巨细胞病毒感染和动脉粥样硬化的关系，并检测CMV感染对内皮细胞趋化因子表达的影响。结果：动脉粥样硬化组血清中CMV的阳性率显著高于非动脉粥样硬化组(分别为82．2％和61．0％，P=0．02)；而且动脉粥样硬化斑块中HCMV基因出现率显著高于正常血管组织(13／15和2／7，P=0．01)；CMV感染还可上调内皮细胞：ECV-304表达MCP-1。结论：CMV感染参与动脉粥样硬化的形成和发生，这可能与CMV上调内皮细胞趋化因子表达有关。     

Neuroradiology and clinical aspects of Usher syndrome

We describe the neurological evaluation and MRI analysis of 30 patients, belonging to 16 families with Usher syndrome (US) type I and type II (US1 and US2). In addition to the classic visual and audiological abnormalities seen in these patients, we observed abnormal gait in 88.9% of US1 and in 66.7% of US2 patients and abnormal coordination in 33.4% of US1, and in 58.3% of US2. Borderline mental retardation, depression or bipolar affective disorder were observed in 16.7% of US1 and 33.3% of US2 patients. MRI analysis showed cerebellar abnormalities in 50% of US 1 and 75% of US2 patients, but no clear correlation was observed between structural abnormalities and clinical findings. A pattern for the MRI classification of US patients is suggested.