Effectiveness of preemptive therapy with ganciclovir in recipients of renal transplants at high risk (R-/D+) for the development of cytomegalovirus disease

Current management of renal transplant recipients who are CMV seronegative (R-) and receive an organ from a seropositive donor (D+) is controversial. These patients are at high risk for CMV disease and are usually treated with ganciclovir prophylaxis at variable dose and duration. An alternative to this approach is to administer ganciclovir only to those patients who are identified by virological markers to be at the highest risk to develop the disease (preemptive therapy). This prospective trial was conducted to asses the value of preemptive therapy to prevent CMV disease in R-/D+ kidney transplant recipients on triple drug immunosuppression without antilymphocyte induction. Sixteen adults receiving their first kidney transplant were enrolled and followed with pp65 antigenemia assay performed biweekly for the first 16 postransplant weeks, and then monthly to complete 12 months. Ganciclovir (5 mg/kg/day i.v., for 15 days) was administered as preemptive therapy upon detection of one or more antigen-positive cells per 150 x 10(3) peripheral blood leucocytes examined. For those receiving preemptive therapy, pp65 antigenemia was also repeated after completion of the regimen. CMV antigenemia was detected in 7/16 patients. At mean follow-up of 9 months (4-12 m) none of the 16 patients developed CMV disease. CMV serology (IgM) became positive in all patients after the first antigenemia result. The last follow-up mean serum creatinine (SCr) level was similar in both groups (1.35 mg/dL). In CMV R-/D+, the use of preemptive therapy guided by pp65 antigenemia is effective in preventing CMV disease. By using this strategy, 9 of 16 patients were spared ganciclovir prophylaxis with no effect on rejection or CMV disease. The clinical benefit and cost/effectiveness of this strategy should be evaluated against universal prophylaxis in these high-risk patients.     

ID4 Evaluation of the Cost-Effectiveness of Management Strategies in Cytomegalovirus Infection and Disease

OBJECTIVE: To develop a decision analytical model for current and anticipated management of cytomegalovirus infection and disease in renal transplant patients.
METHODS: We developed a decision analytical model for the US and UK, containing currently recognised management strategies for cytomegealovirus infection and disease in renal transplant patient. The model enables comparison of current management strategies, assessment of anticipated strategies, and the impact of country-specific practice. Outcomes are expressed as "number of cases avoided" and "quality-adjusted time without symptoms or toxicity" (Q-TWIST).
RESULTS: The model indicates that in the UK, for donor seropositive/recipient seronegative (D+/R−) patients, prophylaxis with IV ganciclovir cost an additional 27,000 GBP, whereas testing for virus and preemptive therapy with IV ganciclovir costs an additional 18,000 GBP per case of CMV avoided compared with a "wait and treat" strategy. Modeling indicates that prophlaxis with an efficacious oral drug could reduce these figures to 800 GBP per avoided case. In the US, preemptive therapy with IV ganciclovir is currently a dominant strategy compared with a "wait and treat" option with IV ganciclovir ($500 less expensive and avoids 18 CMV cases per 100). This reflects the trend to provide preemptive therapy in ambulatory settings. There is potential for new oral prophylactic therapies, of similar efficacy to existing therapies, that could result in further cost savings.
CONCLUSIONS: The model demonstrates the costeffectiveness of preemptive therapy in ambulatory settings compared with inpatient treatment of CMV disease (US), suggesting a potential cost-effectiveness of new oral prophylactic therapies.     

两种方案预防肾移植术后巨细胞病毒感染的临床观察

目的探讨针对性预防方案和普遍性预防方案在防治肾移植术后巨细胞病毒(CMV)感染中的临床疗效。方法回顾性分析128例肾移植受者的临床资料。按术后预防CMV感染方案的不同分为针对性预防组(56例)和普遍性预防组(72例)。针对性预防组:针对高危病例术后应用更昔洛韦预防CMV感染。普遍性预防组:所有病例术后常规应用更昔洛韦预防CMV感染。对两组受者的CMV感染率、耐药发生率、病死率及预防和治疗CMV感染的费用进行统计分析。结果针对性预防组CMV感染率为7.14%(4例)、耐药发生率为1.79%(1例),改用膦甲酸钠治愈;普遍性预防组CMV感染率为9.72%(7例)、耐药发生率为4.17%(3例),改用膦甲酸钠3例治愈,病死率为1.39%(1例)。两组受者的CMV感染率、耐药发生率及病死率差异均无统计学意义(P>0.05),普遍性预防组用于预防和治疗CMV感染的人均费用明显高于针对性预防组(P<0.01)。结论肾移植术后针对性预防方案临床疗效优于普遍性预防方案,而且针对性预防方案更为经济,适合于我国的肾移植受者。     

Hospitalizations for cytomegalovirus disease after renal transplantation in the United States

PURPOSE: Risk factors, sites, and mortality of hospitalized cytomegalovirus (CMV) disease in renal transplant recipients have not been studied in a national population. METHODS: Therefore, 33,479 renal transplant recipients in the United States Renal Data System from 1 July 1, 1994 to June 30, 1997 were analyzed in an historical cohort study of patients with a primary discharge diagnosis of CMV disease (ICD9 Code 078.5x). RESULTS: Renal transplant recipients had an incidence density of hospitalized CMV disease of 1.26/100 person years, and 79% of hospitalizations for CMV disease occurred in the first six months post transplant. The leading manifestation of hospitalized infection was pneumonia (17%). In logistic regression analysis controlling for transplant era, pre-transplant dialysis > or = 6 months, maintenance mycophenolate mofetil (MMF) therapy, and allograft rejection, but not induction antibody therapy, were significantly associated with hospitalized CMV disease. Compared with recipients with negative CMV serology (R-) who had donor kidneys with negative CMV serology (D-), D+/R- had the highest risk of hospitalization for CMV disease [adjusted odds ratio (AOR) 5.19, 95% confidence interval (CI) 3.89-6.93] followed by D+/R+ recipients, whereas D-/R+ were not at significantly increased risk. In Cox Regression analysis the relative risk of death associated with hospitalized CMV disease was 1.32 (95% CI 1.02-1.71). CONCLUSIONS: Even in modern era, renal transplant recipients were at high risk for hospitalizations for CMV disease, which were associated with decreased patient survival. Current prophylactic measures have apparently not reduced the high risk of D+/R- recipients. Prolonged pre-transplant dialysis and maintenance MMF should also be considered risk factors for hospitalized CMV infection, and prospective trials of prophylactic antiviral therapy should be performed in these subgroups.     

Hepatitis E virus infection without reactivation in solid-organ transplant recipients, France

Infections with hepatitis E virus (HEV) in solid-organ transplant recipients can lead to chronic hepatitis. However, the incidence of de novo HEV infections after transplantation and risk for reactivation in patients with antibodies against HEV before transplantation are unknown. Pretransplant prevalence of these antibodies in 700 solid-organ transplant recipients at Toulouse University Hospital in France was 14.1%. We found no HEV reactivation among patients with antibodies against HEV at the first annual checkup or by measuring liver enzyme activities and HEV RNA. In contrast, we found 34 locally acquired HEV infections among patients with no antibodies against HEV, 47% of whom had a chronic infection, resulting in an incidence of 3.2/100 person-years. Independent risk factors for HEV infection were an age <52 years at transplantation and receiving a liver transplant. Effective prophylactic measures that include those for potential zoonotic infections should reduce the risk for HEV transmission in this population.     

肝肠联合移植受体巨细胞病毒感染临床病例报告

目的探讨肝肠联合移植术后受体巨细胞病毒(CMV)感染后的临床表现与检测方法。方法回顾性分析全国首例肝小肠整块联合移植CMV感染前后的临床资料。结果联合移植术后,受体发生疲乏,关节酸痛等临床症状;有白细胞、血小板降低,淋巴细胞增高现象;同时检测出CMV-IgG( )、CMV-PCR( ),证明受体存在CMV感染。结论需要结合临床与实验室检测技术才能有效早期诊断出CMV的感染。     

Beta-herpesviruses in febrile children with cancer

We conducted a cross-sectional study of beta-herpesviruses in febrile pediatric oncology patients (n = 30), with a reference group of febrile pediatric solid-organ transplant recipients (n = 9). One (3.3%) of 30 cancer patients and 3 (33%) of 9 organ recipients were PCR positive for cytomegalovirus. Four (13%) of 30 cancer patients and 3 (33%) of 9 transplant recipients had human herpesvirus 6B (HHV-6B) DNAemia, which was more common within 6 months of initiation of immune suppression (4 of 16 vs. 0 of 14 cancer patients; p = 0.050). HHV-6A and HHV-7 were not detected. No other cause was identified in children with HHV-6B or cytomegalovirus DNAemia. One HHV-6B-positive cancer patient had febrile disease with concomitant hepatitis. Other HHV-6B-positive children had mild "viral" illnesses, as did a child with primary cytomegalovirus infection. Cytomegalovirus and HHV-6B should be included in the differential diagnosis of febrile disease in children with cancer.     

肾移植受者巨细胞病毒感染检测的临床意义

目的　比较肾移植受者采用不同方法检测巨细胞病毒 (CMV)感染的意义。方法　比较肾移植受者和健康供肾者外周血中的CMV -IgM ,CMV -IgG和CMV抗原 (CMV -Ag)的阳性率及其与CMV病的关系。结果　 167例肾移植受者CMV -IgM阳性率为 1 8% ,CMV -IgG阳性率为 98 8% ,CMV -Ag阳性率为47 2 % ,平均阳性抗原指数 3 2个 /5万白细胞 ;对照组 13例CMV -IgM均阴性 ,CMV -IgG均阳性。观察组3 6例CMV肺炎中CMV -IgG均阳性 ,CMV -IgM5 6%阳性 ,CMV -Ag91 7%阳性 ,平均阳性抗原指数 3 6个 /5万白细胞。结论　肾移植受者以CMV -Ag检测诊断CMV活动性感染及CMV病敏感性及特异性优于CMV -IgM及CMV -IgG。     

Priorities for CMV vaccine development

A multidisciplinary meeting addressed priorities related to development of vaccines against cytomegalovirus (CMV), the cause of congenital CMV (cCMV) disease and of serious disease in the immunocompromised. Participants discussed optimal uses of a CMV vaccine, aspects of clinical study design, and the value of additional research. A universal childhood CMV vaccine could potentially rapidly reduce cCMV disease, as infected children are sources of viral transmission to seronegative and seropositive mothers. A vaccine administered to adolescents or adult women could also reduce cCMV disease by making them immune prior to pregnancy. Clinical trials of CMV vaccines in women should evaluate protection against cCMV infection, an essential precursor of cCMV disease, which is a more practical and acceptable endpoint for assessing vaccine effects on maternal-fetal transmission. Clinical trials of vaccines to evaluate prevention of CMV disease in stem cell transplant recipients could use CMV viremia at a level triggering pre-emptive antiviral therapy as an endpoint, because widespread use of pre-emptive and prophylactic antivirals has rendered CMV-induced disease too rare to be a practical endpoint for clinical trials. In solid organ transplant patients, CMV-associated disease is sufficiently common for use as a primary endpoint. Additional research to advance CMV vaccine development should include identifying factors that predict fetal loss due to CMV, determining age-specific incidence and transmission rates, defining the mechanism and relative contributions of maternal reactivation and re-infection to cCMV disease, developing assays that can distinguish between reactivation and re-infection in seropositive vaccinees, further defining predictors of sequelae from cCMV infection, and identifying clinically relevant immune response parameters to CMV (including developing validated assays that could assess CMV antibody avidity) that could lead to the establishment of immune correlates of protection.     

Human herpesvirus 6: An emerging pathogen.

Infections with human herpesvirus 6 (HHV-6), a beta-herpesvirus of which two variant groups (A and B) are recognized, is very common, approaching 100% in seroprevalence. Primary infection with HHV-6B causes roseola infantum or exanthem subitum, a common childhood disease that resolves spontaneously. After primary infection, the virus replicates in the salivary glands and is shed in saliva, the recognized route of transmission for variant B strains; it remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. Not usually associated with disease in the immunocompetent, HHV-6 infection is a major cause of opportunistic viral infections in the immunosuppressed, typically AIDS patients and transplant recipients, in whom HHV-6 infection/reactivation may culminate in rejection of transplanted organs and death. Other opportunistic viruses, human cytomegalovirus and HHV-7, also infect or reactivate in persons at risk. Another disease whose pathogenesis may be correlated with HHV-6 is multiple sclerosis. Data in favor of and against the correlation are discussed.     

Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity

A cytomegalovirus (CMV) vaccine that is effective at preventing congenital infection and reducing CMV disease in transplant patients remains a high priority as no approved vaccines exist. While the precise correlates of protection are unknown, neutralizing antibodies and antigen-specific T cells have been implicated in controlling infection. We demonstrate that the immunization of mice and nonhuman primates (NHPs) with lipid nanoparticles (LNP) encapsulating modified mRNA encoding CMV glycoproteins gB and pentameric complex (PC) elicit potent and durable neutralizing antibody titers. Since the protective correlates in pregnant women and transplant recipients may differ, we developed an additional mRNA vaccine expressing the immunodominant CMV T cell antigen pp65. Administration of pp65 vaccine with PC and gB elicited robust multi-antigenic T cell responses in mice. Our data demonstrate that mRNA/LNP is a versatile platform that enables the development of vaccination strategies that could prevent CMV infection and consequent disease in different target populations.     

Cytomegalovirus infection in non-immunosuppressed critically ill patients

Cytomegalovirus (CMV) is an important and common cause of mortality and morbidity in immunocompromised patients such as those with HIV/AIDS, transplant recipients on immunosuppressive therapy, and malignant hematological disease. After primary infection with CMV the virus becomes latent in multiple organs and can later be reactivated during severe dysregulation of the immune system. A large population carry dormant virus and are thus at risk for reactivation. However, reactivation of CMV has been reported in "non-immunosuppressed patients" such as severe trauma, sepsis, shock, burns, cirrhosis and other critically ill patients lying in the intensive care units. Therefore, the intensivists are increasingly facing a dilemma of identifying such patients to treat and there is a debate if there is a scientific justification for prophylaxis in such immunocompetent patients.     

Diabetes following kidney transplantation. Report of 35 cases

Post-transplant diabetes mellitus (PTDM) is a frequent complication of renal transplantation. It has a prevalence rate ranging from 3 to 46%. We undertook a retrospective study of 175 nondiabetic renal transplant recipients to determine the prevalence rate, clinical characteristics, and risk factors of PTDM in kidney transplant recipients in our region. Thirty five patients (20%) developed PTDM, 50% were diagnosed by 3 months post transplantation. Eight patients (22.8%) were insulin recurrent. PTDM was independent of kidney source, family history of diabetes, age, sex, incidence of acute rejection, body weight gain, steroid or cyclosporine dose, use of beta-blockers and cytomegalovirus infection. Acturial 5 years survival was 79.4% in the diabetic compared to 80.5% in the control group. Patient survival was similar in the two groups. We conclude that PTDM is frequent in our patients. No significant risk factors of PTDM were identified in this study.     

Cytomegalovirus vaccine: persistence of humoral immunity following immunization of renal transplant candidates

A randomized, placebo-controlled, double-blind trial of Towne live, attenuated cytomegalovirus (CMV) vaccine in renal transplant candidates underway since January 1979 has enabled us to assess the durability of humoral immunity after immunization. Among 53 seronegative subjects, Towne vaccine elicited a geometric mean indirect immunofluorescent (IF) antibody titre of 72.3, but titres in patients either not transplanted or given kidneys from seronegative donors declined substantially by one year postimmunization. Vaccine boosted the geometric mean IF antibody titre in 21 seropositive untransplanted subjects from 66.5 pre-immunization to 91.0 approximately three months later. Seventeen seronegative subjects given a seropositive kidney and 27 subjects seropositive before immunization experienced a sharp boost in geometric mean antibody titre posttransplant signifying reactivation of their own CMV strain or acquisition of virus from the donor kidney. These data indicate that Towne vaccine is immunogenic in renal transplant candidates but does not completely prevent posttransplant infections.     

非亲缘异基因造血干细胞移植后出血性膀胱炎的防治策略

目的探讨常规预防方案干预下,非亲缘异基因造血干细胞移植(Allogenetic hematopoietic stem cell trans-plantation,Allo-HSCT)后出血性膀胱炎(hemorrhagic cystitis,HC)的发病情况、危险因素和有效的防治方法。方法对10例恶性血液病患者行非亲缘Allo-HSCT的回顾性分析,移植过程中均进行常规的HC、移植物抗宿主病(graft versus host dis-ease,GVHD)和巨细胞病毒(cytomegalovirus,CMV)感染的预防。分析移植后HC发生的特点及与移植类型、其他临床特征的关系和防治效果。结果共8例发生HC(8/10),平均发病时间为26.88天,平均病程为19.3天;其中5例发生CMV感染同时合并aGVHD,1例仅出现aGVHD,另2例两者皆无。经治疗后7例完全缓解,1例死亡。结论非亲缘Allo-HSCT在采取充分的预防措施后,HC多为早期发生,程度较轻,治疗效果良好;其发病与供者类型、HLA的匹配程度、aGVHD和CMV感染密切相关。     

Relationship between cytomegalovirus and colonization of the oropharynx by gram-negative bacilli following renal transplantation.

Numerous investigators have reported an increased incidence of pneumonia caused by Gram-negative bacilli and other secondary pathogens in transplant recipients infected by cytomegalovirus (CMV). To determine if CMV infections are related to colonization of the upper respiratory tract by Gram-negative bacilli, we examined prospectively 22 renal transplant recipients with sequential bacteriological, virological and biochemical examinations performed just prior to and at various times after transplantation. Only 11% of subjects had Gram-negative bacilli isolated from gargle specimens prior to transplantation, as compared to 54% after transplantation. More importantly, after transplantation, subjects with active CMV infections were more likely to have prolonged oropharyngeal carriage of Gram-negative bacilli than subjects without CMV infections (36% v. 25%). During active CMV infections, the rate at which Gram-negative bacilli were isolated from gargle specimens rose from 28 to 47%. During culture-positive CMV infections, the isolation rate reached 57% and was significantly different from that of CMV-negative samples (P less than 0.01). The increased rate of Gram-negative bacillary isolation from gargle specimens during CMV infections was not a function of type of immunosuppressive agents used, rejection episodes, antibiotic administration, concomitant hepatitis B, Epstein-Barr (EBV) virus, or herpes simplex virus infections, or alterations in salivary fibronectin concentrations.     

肾移植患者巨细胞病毒感染并发急性呼吸窘迫综合征

目的 探索肾移植患者巨细胞病毒(CMV)感染的诱因和治疗措施。方法 对4例CMV感染并发急性呼吸窘迫综合征(ARDS)的病例进行回顾性分析。结果 CMV感染并发ARDS死亡率高，75％病例死亡。结论 治疗CMV感染并发ARDS的关键是早期诊断、尽早治疗、适当调整免疫抑制剂。     

Cost-effectiveness of a new combined immunosuppressive and anti-infectious regimen in kidney transplantation

OBJECTIVES: The aims of this study were to assess the 1-year cost-effectiveness of a new combined immunosuppressive and anti-infectious regimen in kidney transplantation to prevent both rejection and infectious complications. METHODS: Patients (pts) transplanted from January 2000 to March 2003 (Group A) and treated with a conventional protocol were compared with pts submitted to a combined regimen including universal cytomegalovirus (CMV) prophylaxis between April 2003 and July 2005 (Group B). Costs were computed from the hospital accounting system for hospital stays, and official tariffs for outpatient visits. Patients with incomplete costs data were excluded from analysis. RESULTS: Fifty-three patients were analyzed in Group A, and 60 in Group B. Baseline characteristics including CMV serostatus were not significantly different between the two groups. Over 12 months after transplantation, acute rejections decreased from 41.5 percent in Group A to 6.7 percent in Group B (p < .001), and CMV infections from 47 percent to 15 percent (p < .001). Overall, readmissions decreased from 68 percent to 55 percent (p = .160), and average hospital days from 28 +/- 19 to 20 +/- 11 days (p < .007). The average number of outpatient visits decreased from 49 +/- 10 to 39 +/- 8 (p < .001). Average 1-year immunosuppressive and CMV prophylaxis costs (per patient) increased from CHF20,402 +/- 7,273 to 27,375 +/- 6,063 (p < .001), graft rejection costs decreased from CHF4,595 +/- 10,182 to 650 +/- 3,167 (p = .005), CMV treatment costs from CHF2,270 +/- 6,161 to 101 +/- 326 (p = .008), and outpatient visits costs from CHF8,466 +/- 1'721 to 6,749 +/- 1,159 (p < .001). Altogether, 1-year treatment costs decreased from CHF39'957 +/- 16,573 to 36,204 +/- 6,901 (p = .115). CONCLUSIONS: The new combined regimen administered in Group B was significantly more effective, and its additional costs were more than offset by savings associated with complications avoidance.     

移植患者免疫抑制剂治疗后感染多瘤病毒及巨细胞病毒的现状

目的 探讨移植患者在接受免疫抑制剂他克莫司(FK506)治疗后感染多瘤病毒(BKV)与巨细胞病毒(CMV)情况,为器官移植研究提供流行病学依据.方法 采用FQ-PCR检测605例肝、肾、骨髓移植患者BKV和CMV的感染载量,ELISA检测患者FK506的血药浓度,并对结果进行统计分析.结果 605份标本中,共检测BKV感染者79例,感染率为13.06％,CMV感染148例,感染率为24.46％,双重病毒感染者为35例,感染率为5.79％;肝移植患者感染BKV和CMV阳性率为12.61％和15.97％,肾移植则分别为13.33％和27.08％,而6例骨髓移植标本则未发现病毒感染;CMV感染阳性率明显高于BKV,而病毒感染阳性者,则其FK506血药浓度较高(P＜0.05).结论 移植患者在使用免疫抑制剂FK506后易感染BKV和CMV,并且感染程度与FK506血药浓度相关.     

Infections in solid organ transplant recipients

The main problems in solid organ transplant recipients are rejection and infections. The new immunosuppressive regimens have lowered the risk of rejection, however, infections continue to be one of the most important determinants for morbidity and mortality in these patients. The survival of the transplanted organ is also impacted by the different infectious diseases that occur in the post-transplant period. These infections are of viral, bacterial, fungal and parasitic origin, and their presentation occurs characteristically within well defined risk periods after the transplant. The clinical presentation is commonly atypical; therefore for optimal management, it is necessary to have a through knowledge of the epidemiology and clinical manifestations of these problems, but most importantly, the experience of the clinician in the clinical approach and early detection will result in better outcomes. We review recent information regarding the infectious diseases that affect solid organ recipients according to the type of transplant, the post-transplant, risk factors before the transplant and the type of immunosuppressive therapy used, which are the main determinants for these complications and their prognosis.