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Cytomegalovirus (CMV)

  • CMV is a double-stranded, DNA herpesvirus that infects man and other species, producing unique large cells with inclusion bodies.
  • Hunan CMV is also known as human herpesvirus # 5 or HHV-5.
  • In immunocompentent individuals, most CMV infections are mild and may produce a viral syndrome resembling infectious mononucleosis.
  • CMV infections occur mainly early in life. Approximately 30 - 90% of immunocompetent adults >40 years old have antibodies (IgG) to CMV, and are described as having positive CMV serology.
  • In otherwise healthy adults, CMV remains inactive or latent, but ready to be become active under favorable conditions.
  • In immunocompromised or immunosuppressed patients, CMV reactivation can result in invasive CMV disease such as pneumonitis, esophagitis, encephalitis, hepatitis, pacreatitis, adrenalitis, esophagitis, gastritis, enteritis, colitis, and retinitis.
  • CMV can be found in blood, tissues, saliva, vaginal secretions, semen, breast milk, and urine.
  • CMV can be transmitted via transplanted tissue, blood transfusion, perinatally, and through sexual contact.
  • Seronegative, immunosuppressed patients are particularly vulnerable to primary CMV infection and symptomatic CMV disease (CMVD) upon exposure to the virus. This newly acquired or primary CMV infection may result from the introduction of the virus into the human host via a donor positive (D+) allograft or via transfused blood products or through the skin or mucous membranes. Following the infection, the CMV DNA enters the nucleus of the host cells and begins the process of replication and shedding, leading to the release of new viruses into the blood and other body fluids (see Figure 1).

    The replication cycle takes approximately 24 hours and consists of 3 phases:

    1. Immediate early phase (4 hrs) during which regulatory proteins are made;
    2. Early phase ( 8 hrs) during which viral DNA polymerase is made;
    3. Late phase ( 12 hrs) during which structural proteins are made and new viruses (virions) are assembled.

    In an immunocompetent host, most of the virus is destroyed (by CMV-specific cytotoxic T cells) and the infectious process is often asymptomatic. The presence of asymptomatic CMV infection is based on the detection of CMV in body fluids or based on seroconversion. The latter is defined as the appearance of CMV IgM or a 400% increase in the level of CMV IgG. However, in immunocompromised patient not receiving prophylactic treatment against CMV, symptomatic CMV infection (i.e., CMV disease or CMVD) and organ involvement may result. A definitive diagnosis of invasive CMVD is based on viral culture and histopathology (see diagnosis below). The presence of organ involvement is based on clinical assessment, hematology, clinical biochemistry, and radiographic evidence (X-rays, CT scan, ultrasound, MRI, etc.). In the solid organ transplant recipient, the graft is the organ that is most often involved. Unless promptly and aggressively treated, invasive, disseminated CMVD may be fatal

CMV diagnosis

There are several tools for the detection of CMV:
  • Conventional viral cultures of tissue biopsy or body fluid [buffy coat (WBCs), plasma, urine, respiratory secretions, or stool]. The specimen is incubated with fibroblasts at 36o C for 1-3 weeks, and the fibroblasts are then examined under the microscope for cytopathic changes. The identification of cytomegalic inclusion bodies in tissue specimens is still considered the gold standard for the diagnosis of CMVD. However, this technique requires a long incubation period and may take several weeks to yield results. Traditional viral culture is often used together with more rapid techniques such as PCR (see below).
  • The shell vial culture technique (aka rapid isolation) in which the specimen is placed onto the fibroblast monolayer and centrifuged to help the virus penetrate the fibroblast, increasing the viral yield 4-fold. The monolayer is stained 24 - 48 hrs later using monoclonal antibodies against a CMV protein produced during the immediate early phase of viral replication. The shell vial is best used for tissue specimens, urine, or respiratory fluid such as bronchoalveolar lavage (BAL); it is not recommended for specimens of leukocytes (buffy coat), where it has a relatively low sensitivity (<50%). In many centers, the shell vial technique has largely been supplanted by more sensitive methods (see below).
  • PP-65 antigenemia test in which specific monoclonal antibodies are used to detect, in PMN leukocytes, a CMV matrix phosphoprotein known as pp-65. It is relatively rapid, yielding results within ~ 6 hours and it has been used as a quantitative tool (measuring the number of positive or infected leukocytes). Antigenemia results are obtained ~5 days before the onset of symptomatic CMVD.
  • CMV DNA PCR (Polymerase Chain Reaction) is a highly sensitive, rapid (~ 6 hrs) technique based on selective amplification of specific nucleic acid sequences. The PCR method is used either qualitatively (diagnostic PCR) or quantitatively to measure the viral load, which is proportional to the level of CMV DNA. Ljungman and coworkers demonstrated a direct relationship between the viral load as estimated by PCR and the risk for subsequent development of CMVD. With the PCR method CMV infection may be detected as early as two weeks before the onset of symptomatic CMVD. This advantage has given impetus to the preemptive therapy strategy for the prevention of CMVD in high-risk patients (see below). Development and evaluation of more accurate tools combining PCR with other techniques are in progress (Aitken et al '99; Pelligrin et al '99).
  • CMV Serology Anti-CMV antibody (IgG and IgM) titers are routinely measured in both donor and recipient, primarily for the purpose of assessing the patient's risk for future development of CMVD.

 

Who is most susceptible to CMV infections ?

  • Immunocompromized patients (AIDS patients, infants, patients with leukemia or lymphoma, especially children, BM transplant recipients)
  • Organ transplant recipients due to immunosuppressive therapy. In this patient population, the risk for the development of CMVD varies depending on many factors:
    1. The type of organ transplant: The lung & heart-lung and small bowel recipients have the highest frequency of CMVD, followed by liver and pancreas recipients, followed by the kidney recipients. Cadaveric organs and re-transplants carry additional risk.
    2. The donor (D) / recipient (R) CMV serology: There are four possible combinations:

       D-/R-, D+/R+, D+/R-, and D-/R+

      The D+/R- combination, which account for about 20% of all solid organ transplants, bears the highest risk (50-70%) for CMVD. In virtually all of these cases, the disease is due to the reactivation of the virus latent in the allograft, and the viral load is proportional to the mass of the organ (liver >> kidney).

    3. The D+/R+ and the D-/R+ combinations, together account for about 70% of all kidney and liver transplants. For these two groups together there is a 10 - 20 % chance of developing CMVD. However, the risk appears to be twice as high in the D+/R+ group compared to D-/R+ group. Thus, a seronegative donor organ carries the least risk regardless of the recipient serologic status.
    4. Pro-inflammatory cytokines released in various clinical situations (sepsis, acute rejection, surgical trauma, and use of anti-lymphocyte antibodies such as Thymoglobulin and OKT3) cause a several-fold increase in the risk for CMVD in all recipients except D-/R-. The incidence of CMVD in solid organ transplant recipients who were CMV seropositive prior to transplantation is increased at least 3-fold following treatment with ALAs. This is the basis for the preemptive therapy strategy used in some transplant centers.

 

CMV in transplant patients

  • CMV is by far the most common infection in solid organ transplant recipients, with over half of the patients showing evidence of active CMV infection (viral replication).
  • In addition to the debilitating effects of direct, organ-specific syndromes such as bilateral interstitial pneumonia, disseminated CMVD is widely believed to cause graft injury and shorten graft survival.
  • CMV is an immunomodulator and CMVD exacerbates the net state of immunosuppression in the transplant patient, increasing the risk for bacterial and fungal infections, as well as opportunistic infections such as Nocardia asteroides, Mycoplasma, and Pneumocystis Carinii. Consequently, considering both of its direct and indirect effects (see figure below), CMVD is a significant cause of morbidity, mortality, and rising healthcare cost. It has been estimated that CMVD can add ~ 40% to the cost of transplant

    consequences of CMV disease

  • CMV is the cause of considerable morbidity & mortality in organ transplant recipients.
  • CMV is associated with a decreased survival rate.
  • Over half of all transplant patients are actively infected by CMV. These patients either reactivate a latent infection or acquire a primary infection via the transplanted organ.
  • CMV is responsible for 30% of all episodes of fever, 35% of all leukopenia, and 20% of all graft failure in transplant patients.

 

Timing of CMV Disease

    Generally, CMVD occurs within the first three months after solid organ transplantation. However, the timing of CMVD may be influenced by many factors. These include the D/R serologic combination, the course of the transplant operation, how debilitated or ill the patient was prior to the transplant, the use of ALAs induction therapy, the use of different prevention strategies, and the type of organ transplant. Liver transplant recipients may develop CMV disease as early as 10 days after transplantation and as late as 120 days. By contrast, kidney transplant recipients tend to develop CMVD between the second and fourth months post-transplant. Seronegative patients usually develop primary CMV infection within the first 60 days, whereas R+ patients tend to develop reactivation infection somewhat later. The use of ganciclovir (or valganciclovir) prophylaxis or preemptive therapy tends to delay the onset of CMV infection.

    timeline of infections

 

Preventive Strategies

    In view of the impact of CMVD on graft function, morbidity, and healthcare cost, many transplant centers have dedicated a great deal of resources to evaluate different strategies for the management of CMV infection in the transplant recipient. These strategies are continually being reassessed and modified as new therapeutic agents and diagnostic tools become available. Each preventive protocol must be evaluated in terms of its efficacy, safety, and cost-effectiveness. Theoretically, there are three main strategies for the prevention of CVMD:
    • Minimizing the risk for primary CMV infection by using CMV-free allograft and blood products in CMV seronegative recipients (R-). This protective serologic matching is impractical and perhaps unethical because it would drastically limit the donor pool for the seronegative (R-) patients.
    • Vaccination and/or enhancement of CMV-specific cell mediated immunity (CD8+ cytotoxic T-lymphocytes). These options are still in the development stage, and are unlikely to become available in the near future.
    • The use of antiviral therapy to prevent or control viral replication following reactivation infection or primary CMV infection. The bulk of clinical research appears to be concentrated in this area. As illustrated in the figure below management of CMV infection is either prophylactic or therapeutic. The administration of antiviral agents as prophylaxis, during the first few months after transplantation, to all transplant patients regardless of their risk for developing CMV infection represents a non-selective or universal prophylaxis protocol. The advantages of this approach are:
      • It is independent of subjective risk assessment
      • It does not require close viral surveillance
      • Antiviral action is exerted at the very beginning of the process of viral activation when it is most effective.
      • It minimizes the risk of CMVD after primary infection.
      • It minimizes potential, CMV-related graft rejection or injury.

    Disadvantages of universal prophylaxis include adverse drug effects, cost, complacency, and the possibility of promoting the emergence of resistant strains of CMV.

    Selective prophylaxis strategies exclude patients with low risk such as the D-/R- patients and the stable, uncomplicated D-/R+ renal or hepatic transplant recipients. This approach requires minimal viral surveillance and has the advantage of averting the side effects and expense associated with an unnecessary therapy. Selective prophylaxis has no disadvantage and carries no significant risk, except the risk of developing resistant strains of CMV. The latter has not been a significant problem for the solid organ transplant recipient, presumably because in these patients prophylactic treatment is required only for the limited post-transplant period of 3 - 4 months. Preemptive therapy refers to the early treatment of patients for CMVD (using full treatment doses) based on:

    • The earliest sign of CMV infection (usually positive CMV PCR).
    • The anticipation of CMV reactivation infection because of ALAs therapy and/or acute rejection, or sepsis In these instances, preemptive therapy represents a form of selective prophylaxis.
    In either case, a full treatment regimen is used consisting usually of IV ganciclovir (or valganciclovir) either alone or in combination with CMV immunoglobulin (CMVIG) (CytoGam ) in selected high-risk cases. Apparent advantages of the preemptive strategy are:
    • Antiviral therapy is given only to patients who need it. Untreated, these patients would most likely develop symptomatic CMVD. This approach is likely to reduce drug-related expenses and unnecessary exposure to adverse drug reactions.
    • Exposure of patients to subtherapeutic levels of antiviral agents is significantly reduced. This is likely to prevent the development of resistant strains of CMV.
    Although the preemptive strategy has been used successfully in many centers, it is not without shortcomings:
    • Requires close monitoring of the patient and intensive viral surveillance.
    • Requires the ability to identify and constantly reassess the changing risk factors of an individual patient for developing active CMV infection.
    • Depends highly on the availability of a sensitive and specific diagnostic tool with a high positive predictive value. This would permit the clinician to detect viral replication at its inception so that preemptive therapy is started in a timely manner
    However, these apparent shortcomings are not relevant to the use of preemptive therapy as selective prophylaxis accompanying antilymphocyte antibody therapy.

     

    Most of the clinical research in the area of CMV management has involved the use of antiviral agents such as acyclovir, valacyclovir, ganciclovir, valganciclovir, intravenous immunoglobulin (IVIG), and hyper-immunoglobulin. The latter consists of IVIG preparations (such as CytoGam ) that are enriched 4-8 fold with anti-CMV IgG.
    Ideally, a prophylactic regimen should consist of a single oral (PO) agent that has:

    • Excellent in vivo antiviral activity against all or most human herpesviruses;
    • Excellent oral bioavailability;
    • No significant side effects;
    • No significant interactions (with other drugs or with food);
    • A long duration of action so that it may be dosed once daily or even less frequently.
    • Low cost.

    CMV Immunoglobulin (CytoGam)

      Prophylaxis with IVIG, specifically CMVIG (CytoGam ) may provide some degree of immunity against CMVD and may be useful particularly in the high-risk (D+/R-) cadaveric allograft recipients. The FDA has recently expanded the approved indications of CytoGam to include prophylaxis of CMVD associated with transplantation of lung, liver, pancreas and heart [see CytoGam PI ]. Prophylactic CMVIG should be combined with ganciclovir. Although CMVIG has the advantage of infrequent dosing, it may not be cost-effective. For this reason, in most transplant centers, the use of CMVIG (in combination with IV ganciclovir) is reserved to the treatment of invasive CMVD in high-risk patients (small bowel or lung recipients, children, etc.). So far, there is no evidence that the addition of CytoGam to iv ganciclovir (or oral valganciclovir) confers additionnal protection against CMV infection in transplant patients.

    Acyclovir

      When used in vitro at the concentrations normally achieved in vivo, acyclovir shows inadequate anti-CMV activity. The transplant literature is replete with studies of variable quality and contradictory results concerning the efficacy of acyclovir for CMV prophylaxis in solid organ transplant recipients. Some studies [Balfour et al '89] demonstrated significant benefits from the prophylactic use of high dose PO acyclovir, while others [Kletzmayr et al '96; Rostaing et al..'97] showed no significant benefits. Also, most studies indicate that little or no benefit is obtained by administering acyclovir to transplant patients receiving antilymphocyte antibodies. Oral acyclovir is attractive to use because it is relatively inexpensive and well tolerated. However, at the present, its role in CMV management is primarily of historical value. In some centers oral acyclovir is used in low risk patients to provide protection against herpes simplex infections.

    Valacyclovir (Valtrex® )

      The valine ester (prodrug) of acyclovir, valacyclovir, has twice the bioavailability of oral acyclovir (55% vs 25%). An adult dosage of 2 g qid is estimated to provide the same area under the curve as 10 mg/kg tid of IV acyclovir. Valacyclovir has recently been evaluated for CMV prophylaxis in a randomized placebo-controlled trial [Lowance et al '99] in renal transplant recipients [208 D+R- and 408 R+; no D-/R- patients were included]. For 90 days, the patients received either placebo or valacyclovir (2 g qid; adjusted according to the patient's estimated creatinine clearance). The results were reported according to the serologic status of the recipient:

      Incidence of CMVD
      (P = Placebo; V = Valacyclovir)
      At 90 daysAt 180 days
      D+/R-R+D+/R- R+
      PVPVPVPV
      45%3%6%0%45%16%6% 1%

      In addition to reduced incidence of CMVD (45% vs 16%), there was a significant reduction in the incidence of biopsy-proven acute rejection in D+/R- patients (26% vs 52%), but not in the seropositive recipients. Thus, valacyclovir appears to provide adequate protection against CMV with the secondary benefit of reduced biopsy-proven acute rejection in the D+/R- patients. However, the drug had to be dosed four times daily and at a relatively high dose (2 g). The estimated cost of this regimen ($1,634 / month) does not compare favorably with oral ganciclovir at 1 g three times daily ($1585 /month). Hallucinations and confusion were reported as significant side effects of valacyclovir.

    Ganciclovir (Cytovene® )

      Ganciclovir is the first antiviral agent that is specific for the treatment of CMV. Intravenous ganciclovir is generally considered first line therapy for symptomatic CMVD. Most of the earlier studies involving the use of IV ganciclovir for prophylaxis were not well planned, lacking placebo control. Some studies compared IV ganciclovir to acyclovir, IVIG, CMVIG, or a combination regimen, and others combined data from different transplant types (kidney, liver, heart, etc.) In some studies, the therapy was either too short or was administered during an incorrect time window based on our current knowledge of the timing of CMV infection in different transplants. As in the case of acyclovir, these studies yielded contradictory results that are difficult to interpret. However, there is now convincing evidence that extended courses of IV ganciclovir reduce both the incidence and the severity of CMVD in heart, liver, and lung transplants . Evidence is also mounting that, in most types of transplants (except lung, heart-lung, and perhaps small bowel-liver), a 4-month prophylactic course of oral ganciclovir (1g tid or bid) is an effective strategy, reducing the incidence and severity of CMVD. In a randomized placebo-controlled, multinational trial [Gane et al '97] involving a total of 304 liver transplant recipients, 150 pts (including 21 D+R-) received ganciclovir 1 g PO tid x 98 days, and 154 patients (25 D+R-) received placebo. The incidence of CMVD was 4.8% in the ganciclovir group compared to18.9% in the placebo group (p<0.001). A similar degree of protection (65-75% reduction in the incidence of CMVD) was found in the high-risk group patients (D+/R- or those receiving ALA therapy). There was also a significant drop in HSV symptomatic infections, but there was no significant difference in mortality. These findings are generally corroborated by data obtained by different groups (Table 2). Thus, at least in the kidney and liver recipients, oral ganciclovir, despite its poor bioavailability, appears to be an effective prophylactic agent. High-risk transplant types (lung and heart-lung, etc.) probably require prolonged prophylaxis with IV ganciclovir. Valganciclovir, the valine ester (prodrug) of ganciclovir, is currently being tested in the AIDS population, and may in the next few years prove to be an effective alternative to IV ganciclovir in the high-risk solid organ transplant recipients. Parenteral agents such as foscarnet and cidofovir are extremely nephrotoxic and should be reserved for the treatment of ganciclovir-resistant strains of CMV. Despite its proven efficacy, ganciclovir is far from the perfect prophylactic agent whose attributes were listed above:
      • It has a very low bioavailability (F = 0.07)
      • It is not effective against all or most herpesviruses
      • It has some significant side effects, including neutropenia
      • It has to be dosed three times daily
      • It is still fairly expensive

      An effective alternative is valganciclovir.

     

References
  1. Anaizi N. Prevention and Treatment of Cytomegalovirus (CMV) in Solid Organ Transplantation
  2. Multiple authors / Dedicated supplement. Transpl Infect Dis. 2001;3 Suppl 1
  3. CytoGam P.I.: www.medimmune.com/medimmune/products/cytopi1.htm.
  4. Reinke P et al. Mechanisms of human cytomegalovirus (HCMV) (re)activation and its impact on organ transplant patients. Transpl Infect Dis. 1999;1(3):157-64.
  5. Rasmussen L. Molecular pathogenesis of human cytomegalovirus infection. Transpl Infect Dis. 1999;1(2):127-34.
  6. van der Bij W, Speich R. Management of cytomegalovirus infection and disease after solid-organ transplantation. Clin Infect Dis. 2001;33 Suppl 1:S32-7.
  7. Singh N. Preemptive therapy versus universal prophylaxis with ganciclovir for cytomegalovirus in solid organ transplant recipients. Clin Infect Dis. 2001;32(5):742-51.

 

 

 

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