Cytomegalovirus (CMV), which was initially isolated from patients with congenital cytomegalic inclusion disease, is now recognized as an important pathogen in all age groups. In addition to inducing severe birth defects, CMV causes a wide spectrum of disorders in older children and adults, ranging from an asymptomatic subclinical infection to a mononucleosis syndrome in healthy individuals to disseminated disease in immunocompromised patients. Human CMV is one of several related species-specific viruses that cause similar diseases in various animals. All are associated with the production of characteristic enlarged cells—hence the name cytomegalovirus.
CMV, a β-herpesvirus, has double-stranded DNA, four species of mRNA, a protein capsid, and a lipoprotein envelope. Like other herpesviruses, CMV demonstrates icosahedral symmetry, replicates in the cell nucleus, and can cause either a lytic and productive or a latent infection. CMV can be distinguished from other herpesviruses by certain biologic properties, such as host range and type of cytopathology. Viral replication is associated with the production of large intranuclear inclusions and smaller cytoplasmic inclusions. CMV appears to replicate in a variety of cell types in vivo; in tissue culture it grows preferentially in fibroblasts. Although there is little evidence that CMV is oncogenic in vivo, it does transform fibroblasts in rare instances, and genomic transforming fragments have been identified.
CMV has a worldwide distribution. In many regions of the world, the vast majority of adults are seropositive for CMV, whereas only half of adults in the United States and Canada are seropositive. In regions where the prevalence of CMV antibody is high, immunocompromised adults are more likely to undergo reactivation disease rather than primary infection. Data generated in specific regions should be considered in the context of local seropositivity rates, when appropriate.
Of newborns in the United States, ~1% are infected with CMV; the percentages are higher in many less-developed countries. Communal living and poor personal hygiene facilitate spread. Perinatal and early childhood infections are common. CMV may be present in breast milk, saliva, feces, and urine. Transmission has occurred among young children in day-care centers and has been traced from infected toddler to pregnant mother to developing fetus. When an infected child introduces CMV into a household, 50% of susceptible family members seroconvert within 6 months.
CMV is not readily spread by casual contact but rather requires repeated or prolonged intimate exposure for transmission. In late adolescence and young adulthood, CMV is often transmitted sexually, and asymptomatic carriage in semen or cervical secretions is common. Antibody to CMV is present at detectable levels in a high proportion of sexually active men and women, who may harbor several strains simultaneously. Transfusion of blood products containing viable leukocytes may transmit CMV, with a frequency of 0.14–10% per unit transfused. Transfusion of leukocyte-reduced or CMV-seronegative blood significantly decreases the risk of CMV transmission.
Once infected, an individual generally carries CMV for life. The infection usually remains silent. CMV reactivation syndromes develop more frequently, however, when T lymphocyte–mediated immunity is compromised—for example, after organ transplantation, with lymphoid neoplasms and certain acquired immunodeficiencies (in particular, HIV infection; Chap. 97), or during critical illness in intensive care units. Most primary CMV infections in organ transplant recipients (Chap. 16) result from transmission via the graft. In CMV-seropositive transplant recipients, infection results from reactivation of latent virus or from infection by a new strain. CMV infection may also be associated with diseases as diverse as coronary artery stenosis and malignant gliomas, but these associations require further validation.
Congenital CMV infection can result from either primary or reactivation infection of the mother. However, clinical disease in the fetus or newborn is related almost exclusively to primary maternal infection (Table 91-1). The factors determining the severity of congenital infection are unknown; a deficient capacity to produce precipitating antibodies and to mount T cell responses to CMV is associated with relatively severe disease.
TABLE 91-1CMV DISEASE IN THE IMMUNOCOMPROMISED HOST ||Download (.pdf) TABLE 91-1 CMV DISEASE IN THE IMMUNOCOMPROMISED HOST
|POPULATION ||RISK FACTORS ||PRINCIPAL SYNDROMES ||TREATMENT ||PREVENTION |
|Fetus ||Primary maternal infection/early pregnancy ||Cytomegalic inclusion disease ||Ganciclovir for symptomatic neonates ||Avoidance of exposure; possibly, maternal treatment with CMV immunoglobulin during pregnancy |
|Organ transplant recipient ||Seropositivity of donor and/or recipient; potent immunosuppressive regimen; treatment of rejection ||Febrile leukopenia; gastrointestinal disease; pneumonia ||Ganciclovir or valganciclovir ||Prophylaxis or preemptive therapy with ganciclovir or valganciclovir |
|Hematopoietic stem cell transplant recipient ||Graft-vs.-host disease; older age of recipient; seropositive recipient; viremia ||Pneumonia; gastrointestinal disease ||Ganciclovir or valganciclovir or foscarnet, ± CMV immunoglobulin ||Prophylaxis or preemptive therapy with ganciclovir or valganciclovir |
|Person with AIDS ||<100 CD4+ T cells/μL; CMV seropositivity ||Retinitis; gastrointestinal disease; neurologic disease ||Ganciclovir, valganciclovir, foscarnet, or cidofovir ||Oral valganciclovir |
Primary infection with CMV in late childhood or adulthood is often associated with a vigorous T lymphocyte response that may contribute to the development of a mononucleosis syndrome similar to that which follows infection with Epstein-Barr virus (Chap. 90). The hallmark of such infection is the appearance of atypical lymphocytes in the peripheral blood; these cells are predominantly activated CD8+ T lymphocytes. Polyclonal activation of B cells by CMV contributes to the development of rheumatoid factors and other autoantibodies during mononucleosis.
Once acquired, CMV persists indefinitely in host tissues. The sites of persistent infection probably include multiple cell types and various organs. Transmission via blood transfusion or organ transplantation is due primarily to latent infections in these tissues. If the host’s T cell responses become compromised by disease or by iatrogenic immunosuppression, latent virus can reactivate to cause a variety of syndromes. Chronic antigenic stimulation in the presence of immunosuppression (for example, after organ transplantation) appears to be an ideal setting for CMV activation and CMV disease. Certain particularly potent suppressants of T cell immunity (e.g., antithymocyte globulin, alemtuzumab) are associated with a high rate of clinical CMV syndromes. CMV may itself contribute to further T lymphocyte hyporesponsiveness, which often precedes superinfection with other opportunistic pathogens such as bacteria, molds, and Pneumocystis.
Cytomegalic cells in vivo (presumed to be infected epithelial cells) are two to four times larger than surrounding cells and often contain an 8- to 10-μm intranuclear inclusion that is eccentrically placed and is surrounded by a clear halo, producing an “owl’s eye” appearance. Smaller granular cytoplasmic inclusions are demonstrated occasionally. Cytomegalic cells are found in a wide variety of organs, including the salivary gland, lung, liver, kidney, intestine, pancreas, adrenal gland, and central nervous system.
The cellular inflammatory response to infection consists of plasma cells, lymphocytes, and monocyte-macrophages. Granulomatous reactions occasionally develop, particularly in the liver. Immunopathologic reactions may contribute to CMV disease. Immune complexes have been detected in infected infants, sometimes in association with CMV-related glomerulopathies. Immune-complex glomerulopathy has also been observed in some CMV-infected patients after renal transplantation.
Fetal infections range from subclinical to severe and disseminated. Cytomegalic inclusion disease develops in ~5% of infected fetuses and is seen almost exclusively in infants born to mothers who develop primary infections during pregnancy. Petechiae, hepatosplenomegaly, and jaundice are the most common presenting features (60–80% of cases). Microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity are reported in 30–50% of cases. Inguinal hernias and chorioretinitis are less common. Laboratory abnormalities include elevated alanine aminotransferase levels in serum, thrombocytopenia, conjugated hyperbilirubinemia, hemolysis, and elevated protein levels in cerebrospinal fluid. The prognosis for severely infected infants is poor; the mortality rate is 20–30%, and few survivors escape intellectual or hearing difficulties later in childhood. The differential diagnosis of cytomegalic inclusion disease in infants includes syphilis, rubella, toxoplasmosis, infection with herpes simplex virus or enterovirus, and bacterial sepsis.
Most congenital CMV infections are clinically inapparent at birth. Of asymptomatically infected infants, 5–25% develop significant psychomotor, hearing, ocular, or dental abnormalities over the next several years.
The newborn may acquire CMV at delivery by passage through an infected birth canal or by postnatal contact with infected breast milk or other maternal secretions. Of infants who are breast-fed for >1 month by seropositive mothers, 40–60% become infected. Iatrogenic transmission can result from blood transfusion; use of leukocyte-reduced or CMV-seronegative blood products for transfusion into low-birth-weight seronegative infants or seronegative pregnant women decreases risk.
The great majority of infants infected at or after delivery remain asymptomatic. However, protracted interstitial pneumonitis has been associated with perinatally acquired CMV infection, particularly in premature infants, and occasionally has been accompanied by infection with Chlamydia trachomatis, Pneumocystis, or Ureaplasma urealyticum. Poor weight gain, adenopathy, rash, hepatitis, anemia, and atypical lymphocytosis may also be found, and CMV excretion often persists for months or years.
The most common clinical manifestation of CMV infection in immunocompetent hosts beyond the neonatal period is a heterophile antibody–negative mononucleosis syndrome, which may develop spontaneously or follow transfusion of leukocyte-containing blood products. Although the syndrome occurs at all ages, it most often involves sexually active young adults. With incubation periods of 20–60 days, the illness generally lasts for 2–6 weeks. Prolonged high fevers, sometimes with chills, profound fatigue, and malaise, characterize this disorder. Myalgias, headache, and splenomegaly are common, but in CMV (as opposed to Epstein-Barr virus) mononucleosis, exudative pharyngitis and cervical lymphadenopathy are rare. Occasional patients develop rubelliform rashes, often after exposure to ampicillin or certain other antibiotics. Less common are interstitial or segmental pneumonia, myocarditis, pleuritis, arthritis, and encephalitis. In rare cases, Guillain-Barré syndrome complicates CMV mononucleosis. The characteristic laboratory abnormality is relative lymphocytosis in peripheral blood, with >10% atypical lymphocytes. Total leukocyte counts may be low, normal, or markedly elevated. Although significant jaundice is uncommon, serum aminotransferase and alkaline phosphatase levels are often moderately elevated. Heterophile antibodies are absent; however, transient immunologic abnormalities are common and may include the presence of cryoglobulins, rheumatoid factors, cold agglutinins, and antinuclear antibodies. Hemolytic anemia, thrombocytopenia, and granulocytopenia complicate recovery in rare instances.
Most patients recover without sequelae, although postviral asthenia may persist for months. The excretion of CMV in urine, genital secretions, and/or saliva often continues for months or years. Rarely, CMV infection is fatal in immunocompetent hosts; survivors can have recurrent episodes of fever and malaise, sometimes associated with autonomic nervous system dysfunction (e.g., attacks of sweating or flushing).
CMV infection in the immunocompromised host
(Table 91-1) CMV is the viral pathogen most commonly complicating organ transplantation (Chap. 16). In recipients of kidney, heart, lung, liver, pancreas, and vascularized composite (hand, face, other) transplants, CMV induces a variety of syndromes, including fever and leukopenia, hepatitis, colitis, pneumonitis, esophagitis, gastritis, and retinitis. CMV disease is an independent risk factor for both graft loss and death. Without prophylaxis, the period of maximal risk is between 1 and 4 months after transplantation. Disease likelihood and viral replication levels generally are greater after primary infection than after reactivation. Molecular studies indicate that seropositive transplant recipients are susceptible to infection with donor-derived, genotypically variant CMV, and such infection often results in disease. Reactivation infection, although common, is less likely than primary infection to be important clinically. The risk of clinical disease is related to various factors, such as degree of immunosuppression, use of antilymphocyte antibodies, lack of anti-CMV prophylaxis, and co-infection with other pathogens. The transplanted organ is particularly vulnerable as a target for CMV infection; thus there is a tendency for CMV hepatitis to follow liver transplantation and for CMV pneumonitis to follow lung transplantation.
CMV viremia occurs in roughly one-third of hematopoietic stem cell transplant recipients; the risk of severe disease may be reduced by prophylaxis or preemptive therapy with antiviral drugs. The risk is greatest 5–13 weeks after transplantation, and identified risk factors include certain types of immunosuppressive therapy, an allogeneic (rather than an autologous) graft, acute graft-versus-host disease, older age, and pretransplantation recipient seropositivity.
CMV is an important pathogen in patients with advanced HIV infection (Chap. 97), in whom it may cause retinitis or disseminated disease, particularly when peripheral-blood CD4+ T cell counts fall below 50–100/μL. As treatment for underlying HIV infection has improved, the incidence of serious CMV infections (e.g., retinitis) has decreased. However, during the first few weeks after institution of highly active antiretroviral therapy, acute flare-ups of CMV retinitis may occur secondary to an immune reconstitution inflammatory syndrome.
Syndromes produced by CMV in immunocompromised hosts often begin with prolonged fatigue, fever, malaise, anorexia, night sweats, and arthralgias or myalgias. Liver function abnormalities, leukopenia, thrombocytopenia, and atypical lymphocytosis may be observed during these episodes. The development of tachypnea, hypoxemia, and unproductive cough signals respiratory involvement. Radiologic examination of the lung often shows bilateral interstitial or reticulonodular infiltrates that begin in the periphery of the lower lobes and spread centrally and superiorly; localized segmental, nodular, or alveolar patterns are less common. The differential diagnosis includes Pneumocystis infection; other viral, bacterial, or fungal infections; pulmonary hemorrhage; and injury secondary to irradiation or to treatment with cytotoxic drugs.
Gastrointestinal CMV involvement may be localized or extensive and almost exclusively affects immunocompromised hosts. Colitis is the most common clinical manifestation in organ transplant recipients. Ulcers of the esophagus, stomach, small intestine, or colon may result in bleeding or perforation. CMV infection may lead to exacerbations of underlying ulcerative colitis. Hepatitis occurs frequently, particularly after liver transplantation. Acalculous cholecystitis and adrenalitis also have been described.
CMV rarely causes meningoencephalitis in otherwise healthy individuals. Two forms of CMV encephalitis are seen in patients with AIDS. One resembles HIV encephalitis and presents as progressive dementia; the other is a ventriculoencephalitis characterized by cranial-nerve deficits, nystagmus, disorientation, lethargy, and ventriculomegaly. In immunocompromised patients, CMV can also cause subacute progressive polyradiculopathy, which is often reversible if recognized and treated promptly.
CMV retinitis is an important cause of blindness in immunocompromised patients, particularly patients with advanced AIDS (Chap. 97). Early lesions consist of small, opaque, white areas of granular retinal necrosis that spread in a centrifugal manner and are later accompanied by hemorrhages, vessel sheathing, and retinal edema (Fig. 91-1). CMV retinopathy must be distinguished from that due to other conditions, including toxoplasmosis, candidiasis, and herpes simplex virus infection.
Cytomegalovirus infection in a patient with AIDS may appear as an arcuate zone of retinitis with hemorrhages and optic disk swelling. Often CMV is confined to the retinal periphery, beyond view of the direct ophthalmoscope.
Fatal CMV infections are often associated with persistent viremia and the involvement of multiple organ systems. Progressive pulmonary infiltrates, pancytopenia, hyperamylasemia, and hypotension are characteristic features that are frequently found in conjunction with a terminal bacterial, fungal, or protozoan superinfection. Extensive adrenal necrosis with CMV inclusions is often documented at autopsy, as is CMV involvement of many other organs.
CMV infection usually cannot be diagnosed reliably on clinical grounds alone. Isolation of CMV or detection of its antigens or DNA in appropriate clinical specimens is the preferred approach. The most common method of detection is quantitative nucleic acid testing (QNAT) for CMV by polymerase chain reaction (PCR) technology, for which blood or other specimens can be used; some centers use a CMV antigenemia test, an immunofluorescence assay that detects CMV antigens (pp65) in peripheral-blood leukocytes. Such assays may yield a positive result several days earlier than culture methods. QNAT may predict the risk for disease progression, particularly in immunocompromised hosts. CMV DNA in cerebrospinal fluid is useful in the diagnosis of CMV encephalitis or polyradiculopathy. Considerable variation exists among assays and laboratories; a recently introduced international testing standard should help reduce variation in PCR test results.
Virus excretion or viremia is readily detected by culture of appropriate specimens on human fibroblast monolayers. If CMV titers are high, as is common in congenital disseminated infection and in AIDS, characteristic cytopathic effects may be detected within a few days. However, in some situations (e.g., CMV mononucleosis), viral titers are low, and cytopathic effects may take several weeks to appear. Many laboratories expedite diagnosis with an overnight tissue-culture method (shell vial assay) involving centrifugation and an immunocytochemical detection technique employing monoclonal antibodies to an immediate-early CMV antigen. Isolation of virus from urine or saliva does not, by itself, constitute proof of acute infection, since excretion from these sites may continue for months or years after illness. Detection of viremia is a better predictor of acute infection.
A variety of serologic assays detect antibody to CMV. An increased level of IgG antibody to CMV may not be detectable for up to 4 weeks after primary infection. Detection of CMV-specific IgM is sometimes useful in the diagnosis of recent or active infection; however, circulating rheumatoid factors may result in occasional false-positive IgM tests. Serology is especially helpful when used to predict risk of CMV infection and disease in transplant recipients.
Prevention of CMV in organ and hematopoietic stem cell transplant recipients is usually based on one of two methods: universal prophylaxis or preemptive therapy. With universal prophylaxis, antiviral drugs are used for a defined period, often 3 or 6 months. One clinical trial demonstrated that, in CMV-seronegative recipients with seropositive donors, prophylaxis was more effective at prevention when given for 200 days rather than 100 days. With preemptive therapy, patients are monitored weekly for CMV viremia, and antiviral treatment is initiated once viremia is detected. Because of the bone marrow–suppressive effects of universal prophylaxis, preemptive therapy is more commonly employed in hematopoietic stem cell transplant recipients. For patients with advanced HIV infection (CD4+ T cell counts of <50/μL), some experts have advocated prophylaxis with valganciclovir (see below). However, side effects, lack of proven benefit, possible induction of viral resistance, and high cost have precluded the wide acceptance of this practice. Preemptive therapy is under study in HIV-infected patients.
Several additional measures are useful for the prevention of CMV transmission to CMV-naïve, high-risk patients. The use of CMV-seronegative or leukocyte-depleted blood greatly decreases the rate of transfusion-associated transmission. In a placebo-controlled trial, a CMV glycoprotein B vaccine reduced infection rates among 464 CMV-seronegative women; this outcome raises the possibility that this experimental vaccine will reduce rates of congenital infection, but further studies must validate this approach. A CMV glycoprotein B vaccine with MF59 adjuvant appeared effective in reducing the risk and duration of viremia in both seropositive and seronegative renal transplant recipients at risk for CMV infection. CMV immune globulin has been reported to prevent congenital CMV infection in infants of women with primary infection during pregnancy. Studies in hematopoietic stem cell transplant recipients have produced conflicting results.
Prophylactic acyclovir or valacyclovir may reduce rates of CMV infection and disease in renal transplant recipients, although neither drug is effective in the treatment of active CMV disease.
TREATMENT Cytomegalovirus Infection
Ganciclovir is a guanosine derivative that has considerably more activity against CMV than its congener acyclovir. After intracellular conversion by a viral phosphotransferase encoded by CMV gene region UL97, ganciclovir triphosphate is a selective inhibitor of CMV DNA polymerase. Several clinical studies have indicated response rates of 70–90% among patients with AIDS who are given ganciclovir for the treatment of CMV retinitis or colitis. In severe infections (e.g., CMV pneumonia in hematopoietic stem cell transplant recipients), ganciclovir is often combined with CMV immune globulin. Prophylactic or suppressive ganciclovir may be useful in high-risk hematopoietic stem cell or organ transplant recipients (e.g., those who are CMV-seropositive before transplantation). In many patients with AIDS, persistently low CD4+ T cell counts, and CMV disease, clinical and virologic relapses occur promptly if treatment with ganciclovir is discontinued. Therefore, prolonged maintenance regimens are recommended for such patients. Resistance to ganciclovir is more common among patients treated for >3 months and is usually related to mutations in the CMV UL97 gene (or, less commonly, the UL54 gene).
Valganciclovir is an orally bioavailable prodrug that is rapidly metabolized to ganciclovir in intestinal tissues and the liver. Approximately 60–70% of an oral dose of valganciclovir is absorbed. An oral valganciclovir dose of 900 mg results in ganciclovir blood levels similar to those obtained with an IV ganciclovir dose of 5 mg/kg. Valganciclovir appears to be as effective as IV ganciclovir for both CMV induction (treatment) and maintenance regimens, while providing the ease of oral dosing. Furthermore, the adverse-event profiles and rates of resistance for the two drugs are similar.
Ganciclovir or valganciclovir therapy for CMV disease consists of a 14- to 21-day induction course (5 mg/kg IV twice daily for ganciclovir or 900 mg PO twice daily for valganciclovir), sometimes followed by maintenance therapy (e.g., valganciclovir, 900 mg/d). Peripheral-blood neutropenia develops in roughly one-quarter of treated patients but may be ameliorated by granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Whether to use maintenance therapy should depend on the overall level of immunocompromise and the risk of recurrent disease. Discontinuation of maintenance therapy should be considered in patients with AIDS who, while receiving antiretroviral therapy, have a sustained (3- to 6-month) increase in CD4+ T cell counts to >100/μL.
For treatment of CMV retinitis, ganciclovir may also be administered via a slow-release pellet sutured into the eye. Although this intraocular device provides good local protection, contralateral eye disease and disseminated disease are not affected, and early retinal detachment is possible. A combination of intraocular and systemic therapy may be better than the intraocular implant alone.
Foscarnet (sodium phosphonoformate) inhibits CMV DNA polymerase. Because this agent does not require phosphorylation to be active, it is also effective against most ganciclovir-resistant isolates. Foscarnet is less well tolerated than ganciclovir and causes considerable toxicity, including renal dysfunction, hypomagnesemia, hypokalemia, hypocalcemia, genital ulcers, dysuria, nausea, and paresthesia. Moreover, foscarnet administration requires the use of an infusion pump and close clinical monitoring. With aggressive hydration and dose adjustments for renal dysfunction, the toxicity of foscarnet can be reduced. The use of foscarnet should be avoided when a saline load cannot be tolerated (e.g., in cardiomyopathy). The approved induction regimen is 60 mg/kg every 8 h for 2 weeks, although 90 mg/kg every 12 h is equally effective and no more toxic. Maintenance infusions should deliver 90–120 mg/kg once daily. No oral preparation is available. Foscarnet-resistant virus may emerge during extended therapy. This drug is used more frequently after hematopoietic stem cell transplantation than in other situations to avoid the myelosuppressive effects of ganciclovir; in general, foscarnet is also the first choice for infections with ganciclovir-resistant CMV.
Cidofovir is a nucleotide analogue with a long intracellular half-life that allows intermittent IV administration. Induction regimens of 5 mg/kg weekly for 2 weeks are followed by maintenance regimens of 3–5 mg/kg every 2 weeks. Cidofovir can cause severe nephrotoxicity through dose-dependent proximal tubular cell injury; however, this adverse effect can be tempered somewhat by saline hydration and probenecid. Cidofovir is used primarily for ganciclovir-resistant virus.