Established Cytomegalovirus Research Articles

Letermovir and Maribavir for the Treatment and Prevention of Cytomegalovirus Infection in Solid Organ and Stem Cell Transplant Recipients.

Until recently, available drugs for cytomegalovirus (CMV) prevention and treatment in transplant patients included (val)ganciclovir, foscarnet, and cidofovir. Use of these drugs is limited by toxicity and the development of resistance. The 2017 approval of letermovir for prevention of CMV after stem cell transplant marked the first approval of an anti-CMV agent since 2003. The role of letermovir in treatment of established CMV infection or disease remains largely unstudied, although early reports suggest that a low barrier to resistance will likely limit efficacy as primary therapy for patients with refractory or resistant disease. The investigational agent maribavir has shown promise as preemptive treatment; in patients with refractory or resistant disease the emergence of resistance while on treatment has been observed and ongoing studies will define efficacy in this population. Both agents have unique mechanisms of action limiting cross resistance, and neither exhibit myelotoxicity or nephrotoxicity.

The effect of induction therapy on established CMV specific T cell immunity in living donor kidney transplantation.

Cytomegalovirus (CMV) infection influences both short and long term outcomes in immunosuppressed organ transplant recipients. The aim of this study was to evaluate the effect of different induction immunosuppression regimens on CMV specific T cell response in patients with already established CMV immunity. In 24 seropositive living donor kidney recipients, the frequency of CMV specific T cells was determined by ELISPOT (Enzyme-Linked ImmunoSpot) assay prior and 6 months after transplantation. Recipients' peripheral blood mononuclear cells were stimulated with immediate-early (IE1) and phosphoprotein 65 (pp65) CMV-derived peptide pools and the number of cells producing interferon gamma (IFN-gamma) was assessed. Patients received quadruple immunosuppression based either on depletive rabbit antithymocyte globulin (rATG) or non-depletive basiliximab induction and tacrolimus/mycophenolate mofetil/steroids. Patients with rATG induction received valgancyclovir prophylaxis. No effects of different induction agents on CMV specific T cell immunity were found at sixth month after kidney transplantation. There were no associations among dialysis vintage, pretransplant CMV specific T cell immunity, and later CMV DNAemia. Similarly, no effect of CMV prophylaxis on CMV specific T cell immunity was revealed. This study shows no effect of posttransplant immunosuppression on CMV specific T cell immunity in living donor kidney transplant recipients with CMV immunity already established, regardless of lymphocyte depletion and CMV prophylaxis.

1168Use of First Positive Cytomegalovirus (CMV) PCR Determination to Differentiate a Viral Blip From Established CMV Infection in Transplant Recipients

1168Use of First Positive Cytomegalovirus (CMV) PCR Determination to Differentiate a Viral Blip From Established CMV Infection in Transplant Recipients

CMV and transfusions, an old story that's not quite over yet

CMV and transfusions, an old story that's not quite over yet Krishna G BadamiNew Zealand Blood Service, Christchurch, New ZealandAbstract: Cytomegalovirus (CMV), or human herpes virus 5, can cause a serious infection in immunocompromised patients. Primary infection can be vertical or horizontal – the latter includes transfusion-transmitted CMV (TT-CMV). The immune response against CMV involves both innate (eg, natural killer cells) and adaptive (humoral and cell-mediated) immunity. Through elaborate immune evasion mechanisms, CMV manages to stay latent, mainly in myeloid blood cells. T lymphocytes are mainly responsible for maintaining latency and preventing reactivation. In otherwise healthy individuals, the CMV infection is mild or subclinical. In immunocompromised patients (but also others), primary or reactivated CMV infection can cause significant disease. In addition to direct effects, a range of indirect effects – inflammatory, vasculopathic, etc – can be caused. Some of the indirect effects of CMV may be important even in immunocompetent but ill individuals. In immunocompromised patients, prophylaxis – either universal prophylaxis or preemptive treatment using antiviral drugs, such as ganciclovir against CMV – may be appropriate. The treatment of established CMV infection normally employs the same drugs. The role of intravenous immunoglobulin or CMV-specific hyperimmune globulin in prophylaxis and treatment is uncertain. New anti-CMV drugs, T-cell immunotherapy, and a vaccine are all being developed. From a transfusion medicine perspective, it is important to have a certain background knowledge of CMV, including: an understanding of its epidemiology; the immune response to it; and its clinical features. More specific areas of interest are blood donor selection using methodologies such as routine serology and, possibly, nucleic acid testing, to identify those who pose significant risks of TT-CMV. What are the ways of preventing TT-CMV even from potentially infective donors? The answer may, potentially, be achieved through leukoreduction and pathogen reduction technology.Keywords: cytomegalovirus, transfusion, infection, Herpesviridae, reactivation, transfusion medicine, leucoreduction

Adoptive T cell immunotherapy for cytomegalovirus

Cytomegalovirus (CMV) is a major opportunistic pathogen following allogeneic transplantation, reflecting the inability of depressed host immunity to contain viral replication. Current antiviral drugs are limited by toxicities and lack of efficacy in established CMV disease, making adoptive immunotherapeutic strategies aimed at hastening virus-specific immune reconstitution attractive alternatives. A number of relatively small Phase I-II studies have demonstrated the feasibility of transferring CMV-specific T cells, varying in composition in terms of CD4+ and CD8+ T cell content. They have all suggested to varying degrees that restoration of CMV-specific immunity can be accelerated without an obvious effect on rates of graft-versus-host disease in those with CMV-seropositive donors. The majority also infer that recovery of laboratory measures of CMV-specific immunity correlate with clinical protection. Direct isolation of cells from donor blood now allows consideration of more widespread availability outside of a few academic centres, and equally importantly the delivery of randomised studies to establish the true efficacy of these strategies.

Gastrointestinal cytomegalovirus infections in organ transplant recipients

Cytomegalovirus (CMV) is a major pathogen for immunocompromised organ transplant recipients. 80 to 90% of all transplant recipients are infected by the virus; however, the incidence of CMV disease is 30 to 40%. Gastrointestinal CMV disease involving any part of the digestive tract occurs in about 10% of all patients receiving solid organ transplantation. Mucosal injury, ulcerations, erosions, haemorrhage, disorders of digestive tract motility, rarely gastrointestinal mass and perforation are the most common pathological findings in CMV disease. Diagnostics is based on endoscopy with mucosal biopsy. Histopathological examination of biopsy samples must look for specific cytomegalic cells with intranuclear (“owl's eye”) and intracytoplasmatic inclusions. Various microbiological, immunohistochemical and molecular biological assays can be performed to detect CMV in the mucosa. In established gastrointestinal CMV disease both gastroenterological and antiviral treatments are needed including intravenous ganciclovir and/or oral valganciclovir. Prevention of disease should be achieved by general prophylaxis in high-risk patients (oral valganciclovir, in special cases hyperimmune globulin); and in medium risk patients by pre-emptive therapy using microbiological surveillance.

The CARI guidelines. CMV disease and kidney transplant: treatment of cytomegalovirus disease in renal transplant recipients.

The CARI guidelines. CMV disease and kidney transplant: treatment of cytomegalovirus disease in renal transplant recipients.

Cytomegalovirus and Lung Transplantation

Cytomegalovirus (CMV) infection remains a serious problem in lung transplant recipients. Development of potent oral antiviral agents, molecular techniques for the detection of infection and its response to therapy and the emergence of isolates with antiviral resistance have had significant impacts on the approach to CMV in these patients. This article discusses the following issues as part of a comprehensive CMV management strategy in lung transplant recipients: (1) Prevention strategies in the era of potent oral antiviral agents, (2) the role of new diagnostic techniques in the management of CMV, (3) treatment regimens for established CMV infection or disease, (4) the potential impact of treatment of CMV on the indirect effects on long-term allograft function, and (5) the incidence, risk factors for and impact of ganciclovir resistance following lung transplantation.

Antibody inhibition of cytomegalovirus: the role of natural killer and macrophage effector cells.

To explore mechanisms by which antibody might inhibit cytomegalovirus (CMV), we measured the ability of intravenous CMV-IgG (CytoGam) to reduce viral yield in the presence of effector cells. Foreskin fibroblasts were infected with a clinical strain of CMV, and CytoGam was added along with effector cells consisting of either unfractionated peripheral blood mononuclear cells (PBMCs), natural killer (NK) cells, or macrophages. The combination of CytoGam and either of the effector cell types markedly inhibited established CMV infection in vitro. In addition, CytoGam combined with effector cells protected the monolayer from CMV-induced cytopathic effects. Antibody-dependent, effector cell-mediated functions may underlie the ability of CytoGam to prevent or modulate CMV infection in vivo.

Clinical significance of viral load in the diagnosis of cytomegalovirus disease after liver transplantation.

In a cohort of 43 liver transplant recipients who did not receive antiviral prophylaxis, qualitative and quantitative polymerase chain reactions (PCRs) from peripheral blood were prospectively compared to determine their value in the diagnosis of established cytomegalovirus (CMV) disease and for the early detection of CMV replication as a marker for preemptive antiviral therapy. Using a cutoff of 7000 copies of CMV DNA per sample, the specificity and positive predictive values of qualitative PCR for the diagnosis of established CMV disease increased from 33% to 89% and from 54% to 82%, respectively, without reducing the 100% sensitivity and negative predictive value. By contrast, quantification of viral load provided no additional advantage to qualitative PCR for the early diagnosis of CMV infection before development of disease.

Antiviral Immunotherapy

Unselected intramuscular (IM) and intravenous (IV) immunoglobulins, as well as virus-specific hyperimmune globulins, occupy important roles as immunotherapy for viral infections. Standard IM immunoglobulins may be utilised in selected, susceptible patients for the prevention of hepatitis A and measles. Hyperimmune globulins to varicella zoster virus (VZV), hepatitis B virus and rabies have established indications for use as post-exposure prophylaxis. Cytomegalovirus (CMV) hyperimmune globulin has an indication for the prevention of primary CMV-associated disease in kidney transplantation and has been shown to decrease severe CMV-associated disease in liver transplantation. More recently, respiratory syncytial virus (RSV) hyperimmune globulin has been developed and is being utilised to prevent RSV disease in high risk infants and children during months of maximum risk for RSV infection. Unselected IV immunoglobulins (IVIg) have proven beneficial in preventing CMV-associated disease and graft-versus-host-disease in allogeneic bone marrow transplant recipients. In addition, IVIg plus ganciclovir is effective therapy for established CMV disease in both bone marrow and solid organ transplantation. IVIg for chronic anaemia associated with parvovirus B19 infection is gaining acceptance, as is the use of IVIg and intraventricular immunoglobulin for chronic meningoencephalitis associated with agammaglobulinaemia. Immunotherapy for the prevention or treatment of several other viral infections has been explored, but without clear conclusions. The use of human immunodeficiency virus (HIV) hyperimmune globulins in HIV-infected patients has yielded inconsistent results and the role of such therapy in the era of highly active antiretroviral therapy is uncertain. Oral immunoglobulins appear successful for rotaviral infections, but their exact use requires further clarification. Other immunotherapeutic modalities, such as monoclonal antibodies against CMV, RSV and HIV, have been developed but these agents have not undergone extensive clinical evaluation.

Cytomegalovirus: genetics of drug resistance.

Human cytomegalovirus (CMV) shares the characteristic ability of other herpesviruses to establish persistence or life-long latency following primary infection, and to reactivate subsequently as host cell-mediated immunity diminishes.1 However, CMV has clearly evolved unique strategies for intracellular replication, pathogenesis and persistence in the host. The regulatory mechanisms and biological sites for viral persistence and reactivation of CMV are poorly understood, but clearly they do not involve the neurotropic pathways employed by herpes simplex virus (HSV) or varicella zoster virus (VZV). CMV infections in immunocompromised patients, especially bone marrow and organ transplant recipients and patients with AIDS, are a major cause of morbidity and mortality. These infections most commonly are reactivations of prior latent infection. Reactivation likely begins with a viremic phase, during which virus can be detected in blood mononuclear cells, followed by symptoms and signs of organ involvement, such as retinitis, pneumonitis, or colitis. Individuals may be infected with multiple strains of CMV, which can reactivate sequentially or simultaneously.2, 3 Different strains or populations of virus may be present at different body sites, with variable accessibility to individual antiviral drugs. Currently approved therapies for the suppression and treatment of CMV include ganciclovir (GCV), foscarnet (PFA), and acyclovir (ACV). Acyclovir is less active in treatment of established CMV infections, but it can reduce the reactivation of latent infection, and resulting CMV disease, in bone marrow and solid organ transplant patients. Several factors point to the likelihood of drug-resistant strains of CMV developing Most disease occurs in immunocompromised patients, who have a high viral load and for whom control of the infection depends almost solely on antiviral therapy. In addition, chronic therapy is frequently necessaryKeywordsHuman CytomegalovirusUL97 GeneSolid Organ Transplant PatientPhosphonoacetic AcidUL97 MutationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Current management of cytomegalovirus disease

Cytomegalovirus (CMV) is an important pathogen for the fetus, for allograft recipients, and for acquired immunodeficiency syndrome (AIDS) patients; the clinical features in each of these groups of patients are described. CMV may also act as a cofactor to accelerate the rate at which the human immunodeficiency virus (HIV) causes AIDS. Active CMV infection in immunocompromised patients is best managed by routine laboratory screening of patients at risk using assays that provide prognostic information. Antiviral therapy can then be considered under one of four headings: For prophylaxis, the drug is given to all patients from a particular time point, e.g., time of transplantation. Successful trials have been reported for interferon (renal transplant), acyclovir (renal transplant and bone marrow transplant), and ganciclovir (heart transplant and bone marrow transplant). For suppression, the drug is given once CMV excretion has been detected in peripheral sites of particular patients. A successful trial of ganciclovir in bone marrow transplant patients has been reported. For pre-emptive therapy, the drug is given once CMV has been detected systemically. A successful trial of ganciclovir in bone marrow transplant patients has been reported. Regarding treatment, a controlled comparison of ganciclovir and foscarnet for CMV retinitis in AIDS patients has shown that both drugs are equally effective but that foscarnet has a survival benefit. Open studies suggest that the combination of immunoglobulin and ganciclovir is of benefit for treatment of established CMV pneumonitis. In open studies other treatments have been tried, with no clinical success, despite control of viral replication in some cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Management and prevention of cytomegalovirus infection after renal transplantation.

We reviewed the epidemiologic characteristics, diagnosis, clinical features, and management of cytomegalovirus (CMV) infection after renal transplantation. CMV, the major viral pathogen after renal transplantation, increases patient morbidity and mortality. The spectrum of CMV infection ranges from latent infection to asymptomatic viral shedding to life-threatening multisystem disease. The two major risk factors for the development of CMV infection in renal transplant recipients are (1) preexisting CMV antibody seropositivity of either the organ donor or the recipient and (2) host immunosuppression. Blood cultures (but not urine cultures) positive for CMV predict the progression of asymptomatic infection to CMV disease, characterized by fever, malaise, myalgia, leukopenia, abnormal transaminase levels, and often involvement of the lung and gut. New genomic methods of viral detection now offer diagnostic advantages, including methods of detecting only actively replicating CMV. No evidence shows that CMV directly causes allograft rejection or glomerulonephritis, but patients with tissue-invasive CMV disease have higher rates of allograft loss and mortality than do those without the disease. Therapy for established CMV disease includes decreasing the immunosuppressive therapy and administering the antiviral agent ganciclovir sodium. Proven prophylactic strategies include limitation of exposure to the virus from CMV seropositive blood or organ donors, administration of CMV-specific immune globulin, and use of high-dose acyclovir therapy. Preemptive therapy with ganciclovir is a promising alternative to prophylaxis for patients at highest risk for progression to symptomatic CMV disease, such as those with CMV viremia and seropositive recipients receiving antilymphocyte therapy.

Treatment of acquired immune deficiency syndrome (AIDS)related pneumonitis with foscarnet: A double-blind placebo controlled study

A double-blind placebo controlled trial of foscarnet was conducted in 32 Human Immunodeficiency Virus (HIV) antibody positive male homosexuals with a presumed AIDS pneumonia. The study was designed to evaluate the importance of treating cytomegalovirus (CMV) as a possible lung pathogen of these patients and as a toxicity study of foscarnet. Trial subjects were randomised to receive either foscarnet or placebo as a continuous intravenous infusion for 2 weeks along with conventional therapy against Pneumocystis carinii (PC) pneumonia. Bronchoscopy or post-mortem showed PC to be present in 24 patients and the bronchoalveolar lavage fluid had early antigen foci of CMV in nine, five of these being double infections. The incidence of CMV infection in this group of patients was not sufficiently high to prove or disprove that treatment of CMV speeds recovery or improves prognosis in AIDS pneumonias. Overall however foscarnet was well tolerated with a slight increase in adverse reactions in the treated groups. This agent is therefore a relatively non-toxic drug to use in the treatment of established CMV disease.

Prevention of Cytomegalovirus Infection After Marrow Transplantation

Primary infection with cytomegalovirus (CMV) in seronegative patients is acquired most commonly from blood products or marrow taken from seropositive donors, whereas recurrent infection in seropositive patients appears to be derived predominantly from reactivation of latent endogenous virus. Not all infected patients develop symptomatic CMV disease; the factors that determine severity of infection and recovery are not yet fully defined. The epidemiology of CMV infection indicates that primary infection is preventable by use of seronegative blood products, including marrow. Such techniques should be implemented immediately. Leukocyte depletion of blood products is a potential alternative, but both efficacy and logistics of implementation require further study in patients who need large quantities of blood products. The efficacy of passive immunoprophylaxis with immunoglobulins remains uncertain, and this modality cannot be recommended until additional data are available. Among seropositive patients, antiviral agents may be used to suppress CMV infection until periods of improved immunocompetence. Although not effective for the treatment of established CMV infection, intravenous acyclovir significantly reduced the probability of CMV infection and disease and improved survival in a controlled trial. The newer antiviral agents ganciclovir and foscarnet should provide better protection, although the marrow toxicity of ganciclovir is problematic. Future directions will include attempts to restore specific immune responses with subunit or recombinant vaccines and adoptive immunotherapy with CMV-specific effector cells generated in vitro.

Liver transplantation in children: The initial Toronto experience

The Hospital for Sick Children's initial 2-year experience with pediatric liver transplantation is reviewed. Patients are divided into high- and low-risk groups according to certain criteria. The high-risk group includes patients under 10 kg in weight, those with extrahepatic biliary atresia (EHBA), those with portal vein atresia or thrombosis, and those in hepatic coma. All others were considered low risk. Twenty-nine patients were assessed for transplantation: 18 were transplanted and 6 (21% of total referred) died while on the waiting list. Eighteen patients received 23 transplants. Of the 18 recipients, nine had EHBA, four had fulminant hepatic failure, two had tyrosinemia, one had glycogen storage disease, one had Indian childhood cirrhosis, and one had idiopathic cirrhosis. Seven of the 13 patients in the high-risk group survived (55% survival) with 1 to 23 month follow-up. Survival was significantly higher (80%) in the low-risk group (P less than 0.05). Four patients were retransplanted and two survived. Early deaths occurred from prolonged warm ischemia, recurrent portal vein thrombosis, and brain death in a patient who had been transplanted in hepatic coma. Late deaths occurred from cytomegalovirus (CMV) disease (2 patients), acute rejection (1 patient), and myocardial infarction (1 patient). The incidence of primary nonfunction was 4.3% (1 of 23) and of arterial thrombosis was 13% (3 of 23). Survival in patients transplanted for EHBA (67%) was slightly higher than it was for the rest of the group, although not as good as it was in the low-risk group.(ABSTRACT TRUNCATED AT 250 WORDS)

Prophylaxis and treatment of cytomegalovirus infections in the bone marrow transplant recipient

Almost all viral infections after bone marrow transplant (BMT) are attributable to reactivation of latent DNA viruses, especially those of the Herpesvirus family. The first to reactivate is herpes simplex virus, followed by cytomegalovirus (CMV) with a reported peak incidence between 60 and 90 days in most studies and varicella zoster virus about three to 18 months after BMT. Epstein-Barr virus rarely causes detectable illness after BMT and reactivation is only seen in the most profoundly immunosuppressed. The most lethal infection and indeed the most prominent cause of failure overall after allogenic BMT is interstitial pneumonitis which is frequently due to CMV infection. This article considers prophylactic measures against viral infection and preliminary studies of regimens for the treatment of established CMV infections.

In vivo application of recombinant interleukin 2 in the immunotherapy of established cytomegalovirus infection.

We have shown in a murine model system for cytomegalovirus (CMV) disease in the immunocompromised host that in vivo application of recombinant human IL-2 (rhIL-2) can enhance the antiviral effect of a limited number of CD8+T lymphocytes, not only in prophylaxis, but also in therapy, when virus has already colonized host tissues. The observed net effect of IL-2 was consistent with the assumption of daily effector population doublings. The prospects for IL-2-supported immunotherapy of established CMV infection depend upon the tissues involved in disease. It appears that the prospects for controlling established CMV adrenalitis are less promising than for a therapy of interstitial CMV pneumonia.

Toxicity and efficacy of human leukocyte interferon for treatment of cytomegalovirus pneumonia after marrow transplantation.

Eight recipients of marrow transplants with cytomegalovirus (CMV) pneumonia diagnosed by open lung biopsy were treated with doses of human leukocyte interferon of 2 X 10(4)--6.4 X 10(5) units/kg per day to evaluate its toxicity after marrow transplant and its effectiveness against CMV infection. All eight patients died from pneumonia, and virus was still present in lung tissue from seven patients cultured after death. Interferon doses of less than or equal to 1.6 X 10(5) units/kg per day did not affect the circulating granulocyte count. Patients treated with higher doses had a decrease in circulating granulocyte count, but study of granulocyte-macrophage colony-forming cells in culture showed no evidence of toxicity to granulocyte progenitor cells. The effect on in vitro lymphocyte function was variable. Antibody production was not impaired. Interferon was not effective against established CMV infection. However, there was less hematologic toxicity than was anticipated, and the prophylactic use of interferon after marrow transplant is feasible.