Prevention Of CMV Disease Research Articles

How we treat cytomegalovirus in hematopoietic cell transplant recipients

AbstractCytomegalovirus (CMV) continues to cause major complications after hematopoietic cell transplantation (HCT). Over the past decade, most centers have adopted preemptive antiviral treatment or prophylaxis strategies to prevent CMV disease. Both strategies are effective but also have shortcomings with presently available drugs. Here, we review aspects of CMV treatment and prevention in HCT recipients, including currently used drugs and diagnostics, ways to optimize preemptive therapy strategies with quantitative polymerase chain reaction assays, the use of prophylaxis, management of CMV disease caused by wild-type or drug-resistant strains, and future strategies.

Subdominant CD8 T-Cell Epitopes Account for Protection against Cytomegalovirus Independent of Immunodomination

Cytomegalovirus (CMV) infection continues to be a complication in recipients of hematopoietic stem cell transplantation (HSCT). Preexisting donor immunity is recognized as a favorable prognostic factor for the reconstitution of protective antiviral immunity mediated primarily by CD8 T cells. Furthermore, adoptive transfer of CMV-specific memory CD8 T (CD8-T(M)) cells is a therapeutic option for preventing CMV disease in HSCT recipients. Given the different CMV infection histories of donor and recipient, a problem may arise from an antigenic mismatch between the CMV variant that has primed donor immunity and the CMV variant acquired by the recipient. Here, we have used the BALB/c mouse model of CMV infection in the immunocompromised host to evaluate the importance of donor-recipient CMV matching in immundominant epitopes (IDEs). For this, we generated the murine CMV (mCMV) recombinant virus mCMV-DeltaIDE, in which the two memory repertoire IDEs, the IE1-derived peptide 168-YPHFMPTNL-176 presented by the major histocompatibility complex class I (MHC-I) molecule L(d) and the m164-derived peptide 257-AGPPRYSRI-265 presented by the MHC-I molecule D(d), are both functionally deleted. Upon adoptive transfer, polyclonal donor CD8-T(M) cells primed by mCMV-DeltaIDE and the corresponding revertant virus mCMV-revDeltaIDE controlled infection of immunocompromised recipients with comparable efficacy and regardless of whether or not IDEs were presented in the recipients. Importantly, CD8-T(M) cells primed under conditions of immunodomination by IDEs protected recipients in which IDEs were absent. This shows that protection does not depend on compensatory expansion of non-IDE-specific CD8-T(M) cells liberated from immunodomination by the deletion of IDEs. We conclude that protection is, rather, based on the collective antiviral potential of non-IDEs independent of the presence or absence of IDE-mediated immunodomination.

Preemptive vs prophylactic therapy for CMV disease prevention

Preemptive vs prophylactic therapy for CMV disease prevention

Preemptive vs prophylactic therapy for CMV disease prevention

Preemptive vs prophylactic therapy for CMV disease prevention

Optimal approach to prevent CMV disease

Optimal approach to prevent CMV disease

Expansion of cytomegalovirus-specific cytotoxic T lymphocytes after peptides stimulation

目的 研制一种扩增特异细胞毒性T淋巴细胞频数的方法.方法 用不同浓度的巨细胞病毒(CMV)特异的表位肽pp65刺激人外周血单个核细胞(PBMCs)使CMV特异CTLs在PBMCs中的百分比增高.用四聚体-PE和CD8-FITC双标记PBMCs中的CMV特异CTLs,然后用流式细胞仪分析.结果 这个方法能有效扩增CMV特异CTLs,使在外周血中占淋巴细胞百分比不到1%的CMV特异CTLs迅速增加到接近20%,占CD+8 T淋巴细胞的40%以上,并能从单份血样中获得大量特异CTLs用于流式分析.结论 肽刺激培养法简便、易操作,能有效扩增CMV特异CTLs,使不同人的数据更容易对比和连续的评价.该方法也为过继性免疫疗法治疗巨细胞病毒疾病打下了基础。

Prevention of CMV disease in pediatric kidney transplant recipients: Evaluation of pp67 NASBA‐based pre‐emptive ganciclovir therapy combined with CMV hyperimmune globulin prophylaxis in high‐risk patients

A new prevention strategy for CMV infection was evaluated in our pediatric kidney transplant unit. This approach comprises a pre-emptive therapy, based upon the monitoring of CMV pp67 mRNA in whole blood by the qualitative NASBA, combined with prophylactic CMV-IG in high risk (R-/D+) children. Thirty-one kidney transplant children were followed for six months with serial measurements of CMV pp67 mRNA in the blood. The R-/D+ patients were given prophylactic CMV-IG for the first 16 wk after transplantation. I.v. ganciclovir was administered upon CMV detection by NASBA and was discontinued after two consecutive negative results. CMV infection, detected by NASBA, developed in 11 (35%) recipients: one (33%) of the R+/D- patients and 10 (72%) of the R-/D+ patients. CMV disease developed in 9.6% of the patients (3/31), exclusively in the R-/D+ group. These three patients presented concurrently with CMV viremia and disease. It is noteworthy that two of the three patients could not receive a complete course of CMV-IG, and one of the latter two subjects had been treated for acute rejection 15 days before CMV infection. Ganciclovir was given for the 11 cases of primary infection, and for three cases of relapsed CMV infection. pp67 NASBA-based pre-emptive ganciclovir therapy, combined with prophylactic CMV-IG in high-risk patients leads to a lower rate of CMV disease, as long as a complete course of CMV-IG has been administered and ganciclovir is given during the period of treatment for acute rejection in high-risk populations.

118: Specific pattern of serum HGF and broncho-alveolar lavage MMP-9 in acute and chronic lung transplant rejection

single, 3 heart-lung) survived more than 3 months following transplant. Only 1 of 194 patients (0.05%) developed PTLD. The patient was EBV seropositive prior to transplant, but CMV negative with a CMV positive donor. She had complete resolution of PTLD with Rituximab, and upon autopsy, there was no evidence of recurrent PTLD. 122 of 194 patients (63%) were documented to be EBV seropositive prior to transplantation, while 20 (10%) were EBV seronegative. Repeat EBV serologies were available for 6 of 20 patients who were previously negative. 5 of the 6 became EBV seropositive following transplantation with no evidence of PTLD. Of the 113 living patients, 82 (72.6%) remain on valgancyclovir, 3 (2.7%) are on acyclovir, and 28 (24.8%) are no longer on antiviral therapy. Conclusions: The incidence of PTLD in patients undergoing lung transplantation at UCSF is only 0.05%, with 0% mortality secondary to PTLD, which is much lower than previously reported. Antiviral therapy may decrease the incidence of PTLD either by direct inhibitory effects on EBV or by indirectly preventing CMV disease. The implications of this study are limited by its small sample size and retrospective design, but further investigation is indicated to determine whether antiviral prophylaxis decreases the incidence of PTLD.

Antiviral drugs for cytomegalovirus in transplant recipients: advantages of preemptive therapy

Currently available, potent antiviral agents have proven highly effective for the prevention of CMV disease during the time that prophylaxis is employed. However, late-onset CMV disease, occurring in 5-18% of the patients, has emerged as a significant complication in organ transplant recipients receiving prophylaxis. Complete suppression of the virus with long-term use of a potent antiviral agent may be less conducive to antigen-induced priming of host responses, which may explain why there is a greater likelihood of late-onset CMV disease. On the other hand, allowing controlled low-level viral replication, implicit in the strategy of preemptive therapy, may facilitate CMV-specific immune reconstitution and have a mitigating effect on the risk of late-onset CMV disease. Preemptive therapy with valganciclovir appears less likely to be associated with CMV disease, largely due to a lower incidence of late-onset CMV disease. Emerging data, documenting that CMV disease in the era of prophylaxis with potent antiviral agents is an independent contributor to mortality, particularly infection-associated mortality, stands to challenge the notion that prophylaxis is more likely to have a beneficial effect on CMV-related secondary outcomes. Preemptive therapy is a more logical and theoretically more appealing approach for the prevention of CMV disease in transplant recipients.

Phase I Trial of Siplizumab in CD2-Positive Lymphoproliferative Disease.

Siplizumab is a humanized IgG1κ class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells. In an animal model of adult T-cell leukemia/lymphoma (ATL), fifty percent of animals survived tumor challenge with 4 weeks of siplizumab treatment and the life-span of tumor bearing animals treated for six months was equivalent to that of animals not challenged with tumors. A single-center phase I dose escalation trial to assess maximum tolerated dose (MTD) and safety in patients (pts) with CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocyte leukemia (LGL) is ongoing. Eligibility includes Karnofsky performance status ≥70%; life expectancy >2 months; appropriate hematological status and normal organ function; prior treatment with chemotherapy and monoclonal antibodies is allowed. Cohorts of 3 pts each receive escalating i.v. doses of siplizumab ranging from 0.4 to 4.8 mg/kg administered over 2–3 days per treatment week every other week for 16 weeks or until unacceptable toxicity or disease progression (PD). 16 pts have been enrolled into 5 cohorts: 0.4 (3 pts), 0.6 (3 pts), 0.8 (3 pts), 1.2 (4 pts) and 2.4 (3 pts) mg/kg per week with planned dose escalation to 3.4 and 4.8 mg/kg. Median number of courses received is 4 (range 1–8). Diagnoses include ATL (9), LGL (4), PTCL (1) and CTCL (2). Grade 1/2 infusional reactions primarily manifested as fever and chills were confined to the first dose of treatment in the majority of patients. Meperidine pretreatment significantly ameliorated infusional reactions. The median (range) percentage decrease in CD4, CD8, NK and malignant cell numbers in peripheral blood from baseline are 98(71–100%), 93(50–100%), 89(55–96%) and 88 (0–100%), respectively. No DLTs have occurred at this time. To date, 3 confirmed PRs have been observed (2 ATL, 1 LGL), 6 pts had stable disease, and 7 pts had PD. 1 pt discontinued therapy due to a siplizumab-related adverse event of polymyalgia rheumatica and 3 pts (2 ATL, 1 LGL) were removed due to CMV antigenemia (which was an off-treatment criterion at the time of study drug discontinuation). 4 patients have died during the one-year follow up period due to PD and 4 patients have completed all 8 courses of treatment. In conclusion-siplizumab has been well tolerated in this trial and the maximum tolerated dose has not been reached. The protocol has been amended to allow for treatment of CMV antigen positive patients provided oral antivirals are effective in preventing CMV disease and rising CMV levels. Anti-tumor activity has been observed in some patients. Enrollment in this study continues.

Prophylactic antivirals prevent CMV disease in transplant recipients

Prophylactic antivirals prevent CMV disease in transplant recipients

Efficacy and limitations of preemptive therapy against cytomegalovirus infections in heart transplant patients

ObjectivesCytomegalovirus (CMV) disease often represents a serious complication that promotes opportunistic infections in heart transplant recipients. In this study we evaluated the impact of preemptive gancylovir therapy, guided by pp65 antigenemia on the morbidity associated with viral reactivation. Patients and methodsWe have performed a CMV infection surveillance program since March 1999, with antigenemia pp65 determinations weekly for the first 2 months biweekly in the third months, and monthly to the sixth month. Patients with pp65 antigenemia value ≥ 10 positive cells per 2 × 105 polymorphonuclear cells (PMN) were treated with intravenous gancyclovir followed by 1 month of oral gancyclovir. ResultsAmong the 107 patients who underwent the virological monitoring, 80 were pp65 antigenemia-positive with preemptive therapy administered in 48 cases. Five patients displayed symptomatic CMV disease (4.7% vs 18% rate in the period of 1988 to 1998 before the introduction of virologic monitoring; P < .01). We observed only one case of gancyclovir-resistant pneumonia which was successfully treated with foscarnet. CMV recurrence in 10 patients required a second cycle of gancyclovir treatment. Our experience included 13 opportunistic infections (12.7%) with 11 antigenemia-positive. ConclusionsPreemptive therapy drastically reduces the incidence of CMV disease and the associated morbidity. Compared to universal prophylaxis, this approach may avoid unnecessary pharmacologic treatment in more than 50% of transplant recipients. Indeed, preemptive therapy does not fully prevent CMV disease, because it may manifest at the first antigenemia determination, and furthermore may select gancyclovir-resistant strains.

Cytomegalovirus (CMV) infection in allogeneic non-myeloablative stem cell transplantation recipients

Background: Non-myeloablative technique of allogeneic stem cell transplantation is recent and increasingly popular; data regarding CMV infection are limited in such transplant recipients. Methods: We examined our data on patients undergoing non-myeloablative transplantation (NMT) during Sept 2000-Dec 2002. Results: Thirty-one patients (men 16, mean age 54; women 15, mean age 47) underwent non-myeloablative transplantation (NMT) during Sept 2000-Dec 2002 (Number of patients: 3–2000; 16–2001; 12–2002). Major underlying diseases were renal cell carcinoma (11), myeloma (5), Non-Hodgkin’s lymphoma (5) and breast cancer (3). Of 31 patients, 10 received matched unrelated donor stem cells. Preparative regimens were Fludarabine with cyclophosphamide (19 patients) or fludarabine with total body irradiation (12 patients). Most (29/31) received peripheral blood stem cells. Mean duration of neutropenia was 6.6 days (range 0–16). Fifteen of 31 patients were CMV seropositive. None received prophylaxis against CMV; CMV antigen (pp65) test was routinely done once weekly. CMV antigenemia occurred in 12 patients (with viremia in 3), 9 of whom were seropositive and 3 seronegative, after a mean duration of 56 days (range 24–165) from transplant. Antigenemia after 100 days occurred in only 1 patient. Four of 12 patients with antigenemia had received stem cells form unrelated donors. None developed CMV disease. Of the total 31 patients transplanted, 19 died. CMV antigenemia was of low level in most patients with prompt response to IV ganciclovir. Conclusions: Our preliminary data demonstrate that CMV infection is common in NMT recipients; routine surveillance and pre-emptive therapy with ganciclovir are effective in preventing CMV disease.

Role of CMV antigenemia directed preemptive therapy with ganciclovir for the prevention of cmv disease at 6 months in lung transplant recipients

Role of CMV antigenemia directed preemptive therapy with ganciclovir for the prevention of cmv disease at 6 months in lung transplant recipients

Valacyclovir for the prevention of CMV disease after renal transplantation: A 5-year follow-up

Valacyclovir for the prevention of CMV disease after renal transplantation: A 5-year follow-up

Hyperimmune IVIG may be advantageous in comparison to intravenous ganciclovir as a preemptive antiviral therapy in CMV-positive heart transplant recipients

Introduction: We compared the effectiveness of preemptive antiviral therapy for prevention of CMV disease using hyperimmune IVIG (Cytogam®; Medimmune) versus intravenous ganciclovir (Cytovene®; Roche Pharmaceuticals) in CMV-positive heart transplant recipients. In a prospective randomized trial, we analyzed data from 18 adult patients who underwent primary heart transplantation from 1997 to 2000.

One year analysis of CMV-PCR surveillance data in lung transplant recipients

The optimal strategy for preventing CMV disease post transplantation (Tx) is unknown. In January 2000 we introduced quantitative CMV-PCR (QPCR) monitoring of CMV-IgG +ve and CMV-status mismatched patients (CMV-MM) post-Tx. All patients received aciclovir prophylaxis and CMV-MM also received oral ganciclovir (GCV) prophylaxis for 3 months.

Leukocyte depleted, unscreened blood products give a low risk for CMV infection and disease in CMV seronegative allogeneic stem cell transplant recipients with seronegative stem cell donors.

Leukocyte depletion (LD) by blood product filtration has been shown to be similarly effective to the use of screened, CMV seronegative blood products to prevent CMV disease in CMV seronegative allogeneic stem cell transplant (SCT) patients with CMV seronegative donors. The aim of this retrospective study was to determine the risk for development of CMV infection requiring preemptive therapy and for CMV disease if unscreened products treated by prestorage LD is used. Forty-nine consecutive patients transplanted after June 1995 were included. As a control group, 33 patients transplanted from January 1992 to June 1995 in whom a combination of CMV seronegative and LD blood products were given. All patients were monitored weekly by a leukocyte-based PCR for CMV DNA detection. Preemptive therapy was initiated after two consecutively positive tests. No patient developed CMV disease in either group. CMV DNA was detected in 6/49 (p = NS) in the study group and in 3/33 patients in the historical control group. Two patients in the study group were given preemptive therapy compared to one patient in the control group. This study suggests that the risk for CMV disease and the need for preemptive therapy against CMV is low in CMV seronegative allogeneic SCT patients receiving grafts from CMV seronegative stem cell donors receiving LD blood products. Thus, this strategy can be safely used together with PCR monitoring and preemptive therapy.

Flow cytometric quantitation and characterization of the T-lymphocyte memory response to CMV in healthy donors

Levels of circulating CMV Ag-specific lymphocytes determine CMV reactivation risk in immunocompromised individuals. Frequencies of T cells producing cytokines after stimulation by CMV Ag were measured in hematopoietic stem-cell donors using flow cytometry. In seropositive individuals (n = 75) the mean number of CD8(+) (CD8(bright), CD8(dim)) and CD4(+) cells producing IFN-gamma was respectively 3.1% (12.6/microL) and 0.38% (3.2/microL), over 10-fold higher than in seronegative subjects (n = 22). CMV stimulation induced tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in both CD4(+) and CD8(+) cells (usually together), with a shift from memory- to effector-cell phenotype, while only a small proportion of CD4(+) cells produced IL-4. Although the normal range was wide, neither age, sex nor HLA type affected the frequency. These quantitative studies and the recognition of CD4(+) cells as potential effectors of CMV immunity are of relevance for immunotherapeutic approaches to prevent CMV disease after stem-cell transplantation.

Cidofovir as primary pre-emptive therapy for post-transplant cytomegalovirus infections.

Pre-emptive antiviral therapy for CMV infection following allogeneic stem cell transplantation is an effective strategy for preventing CMV disease. This entails the logistic difficulty of daily intravenous therapy with ganciclovir or foscarnet to clinically asymptomatic patients. Cidofovir (CDV) is effective against CMV in vitro and has the practical advantage of weekly administration. However, there are limited data on the pre-emptive use of CDV in CMV infections. We carried out a pilot study exploring the efficacy and toxicity of CDV as primary pre-emptive therapy for CMV infections monitored by PCR-based assays. CDV was used at 5 mg/kg with probenecid and hydration, weekly for a maximum of 4 weeks, followed by fortnightly maintenance treatment. Four patients were treated with CDV and two of them responded. Both the non-responders developed CMV disease. There was no renal toxicity noted in any of the patients, but three patients had severe vomiting and one developed uveitis, which precluded maintenance treatment in the two responders. Following failure of CDV, foscarnet was effective in controlling the CMV infection in both patients, although the infection recurred in both. Thus, larger randomised studies are required before CDV can be recommended as a primary pre-emptive therapy for post-transplant CMV infections.