cytomegalovirus

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Cytomegalovirus
CMV infection of a lung pneumocyte.
Virus classification
Group:	Group I (dsDNA)
Family:	Herpesviridae
Subfamily:	Betaherpesvirinae
Genus:	Cytomegalovirus
Species
see text

Cytomegalovirus (from the Greek cyto-, "cell", and -megalo-, "large") is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV (HCMV) or human herpesvirus-5 (HHV-5), and is the most studied of all cytomegaloviruses.^[1] Within Herpesviridae, CMV belongs to the Betaherpesvirinae subfamily, which also includes the genera Muromegalovirus and Roseolovirus (HHV-6 and HHV-7).^[2] It is related to other herpesviruses within the subfamilies of Alphaherpesvirinae that includes herpes simplex viruses (HSV)-1 and -2 and varicella-zoster virus (VZV), and the Gammaherpesvirinae subfamily that includes Epstein–Barr virus.^[1] All herpesviruses share a characteristic ability to remain latent within the body over long periods. Although they may be found throughout the body, CMV infections are frequently associated with the salivary glands in humans and other mammals.^[2] Other CMV viruses are found in several mammal species, but species isolated from animals differ from HCMV in terms of genomic structure, and have not been reported to cause human disease.

Species

Several species of cytomegalovirus have been identified and classified for different mammals.^[2] The most studied is human CMV (HCMV), which is also known as human herpesvirus-5 (HHV-5). Other primate CMV species include chimpanzee CMV (CCMV) that infects chimpanzees and orangutans, and simian CMV (SCCMV) and rhesus CMV (RhCMV) that infect macaques; CCMV is known as both panine herpesvirus-2 (PaHV-2) and pongine herpesvirus-4 (PoHV-4), SCCMV is also called cercopithecine herpesvirus-5 (CeHV-5) and RhCMV is also called cercopithecine herpesvirus-8 (CeHV-8). A further two viruses found in the night monkey are tentatively placed in the cytomegalovirus genus, and are called Herpesvirus aotus 1 and Herpesvirus aotus 3. Rodents also have viruses previously called cytomegaloviruses that are now reclassified under the genus muromegalovirus; this genus contains mouse CMV (MCMV) is also known as murid herpesvirus 1 (MuHV-1) and the closely related murid herpesvirus 2 (MuHV-2) that is found in rats. In addition, there many other viral species with the name cytomegalovirus identified in distinct mammals that are as yet not completely classified; these were predominantly isolated from primates and rodents.

Cytomegalovirus, also a herpesvirus, causes retinitis that leads progressively to complete blindness without treatment. CMV is a lytic virus that causes a cytopathic effect in vitro and in vivo. The pathologic hallmark of CMV infection is an enlarged cell with viral inclusion bodies. Cells that exhibit cytomegaly are also seen in infections caused by other Betaherpesvirinae. The microscopic description given to these cells is most commonly an "owl's eye," depicted in the image below . Although considered diagnostic, such histological findings may be minimal or absent in infected organs.

Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan. When the host is infected, CMV DNA can be detected with polymerase chain reaction (PCR) in all the different cell lineages and organ systems in the body. Upon initial infection, CMV infects the epithelial cells of the salivary gland, resulting in a persistent infection and viral shedding. Infection of the genitourinary system leads to clinically inconsequential viruria. Despite ongoing viral replication in the kidney, renal dysfunction is rare except in renal transplant recipients, in whom CMV is associated with rare cases of glomerulopathy and possible graft rejection.

Immunology Primary CMV infection is defined as infection in an individual who was previously CMV seronegative.[4] In these patients, CMV immunoglobulin M (IgM) antibodies may be found as early as 4-7 weeks after initial infection and may persist as long as 16-20 weeks. Most neutralizing antibodies are directed against an envelope glycoprotein gB. Studies have shown that more than 50% of neutralizing activity in convalescent serum is attributable to glycoprotein gB. However, virion tegument proteins such as pp150, pp28, and pp65 evoke strong and durable antibody responses. CMV is an immunomodulatory virus and may aggravate underlying immune disorders (eg, SLE). CMV DNAemia and viruria are commonly found in healthy CMV seropositive women. Naturally acquired immunity to the virus does not seem to prevent reinfection or the duration of viral shedding.[9] Cell-mediated immunity is considered the most important factor in controlling CMV infection. Patients deficient in cell-mediated immunity are at greatest risk for CMV disease. CMV-specific CD4+ and CD8+ lymphocytes play an important role in immune protection after primary infection or reactivation of latent disease. Studies of bone marrow transplant recipients have revealed that those who do not develop CMV-specific CD4+ or CD8+ cells are at higher risk for CMV pneumonitis. Additionally, no cases of CMV pneumonia have been reported in allogeneic marrow transplant recipients receiving infusions of CMV-specific CD8+cells.[10]

Primary cytomegalovirus infection and viremia In most hosts, primary CMV infection is clinically silent. The presentation of symptomatic primary infection is addressed in Adult Cytomegalovirus Infection in the Immunocompetent Host. Primary CMV infection of the immunocompromised host carries the greatest risk for CMV disease. Viremia is diagnosed by isolation of CMV in culture (either via standard or shell vial culture; see Laboratory studies).[4] CMV excretion in the saliva and urine is common in immunocompromised patients and is generally of little consequence. In contrast, viremia in organ transplant recipients identifies those at greatest risk for CMV disease. The sensitivity of CMV viremia as a marker for CMV pneumonia is 60%-70% in allogeneic marrow transplant recipients. Having no evidence of virus in the bloodstream has a high negative predictive value for CMV disease. Prophylactic or preemptive antiviral therapy against CMV disease in transplant recipients typically relies on the detection of CMV in the blood by shell vial cultures, CMV antigenemia, and PCR amplification.

Congenital cytomegalovirus disease Congenital CMV infection is one of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and HSV), which carry a risk of significant symptomatic disease and developmental defects in newborns. The clinical syndrome of congenital cytomegalic inclusion disease includes jaundice, splenomegaly, thrombocytopenia, intrauterine growth retardation, microcephaly, and retinitis. The most common clinical findings of congenital CMV infection include petechiae (71%), jaundice (67%), microcephaly (53%), and small size for gestational age (50%). Common laboratory abnormalities include hyperbilirubinemia (81%), increased levels of hepatocellular enzymes (83%), thrombocytopenia (77%), and increased CSF protein levels (77%). Studies have shown that asymptomatic children with neurological findings are more likely to have CMV IgM antibody. Many cases of hearing loss in children may be caused by CMV infection. CMV excretion is common in children with congenital infection and may represent a reservoir for infection in other children and daycare workers. The CMV immune status of the woman is important in determining the risk of placental infection and subsequent symptomatic disease in the child or fetus. Symptomatic CMV congenital disease is less likely to occur in women with pre-existing immune responses to CMV than in CMV-naïve individuals. One in ten cases of acute CMV infection during pregnancy is estimated to result in congenital CMV disease.

Cytomegalovirus pneumonia CMV pneumonia is defined as signs and symptoms of pulmonary disease in combination with detection of CMV in bronchoalveolar fluid or lung tissue.[4] CMV detection should be performed via culture, histopathology, immunohistochemical analysis, or in situ hybridization, as CMV DNA PCR testing alone is too sensitive for diagnosing CMV pneumonia.[4] Approximately 0%-6% of adults who present with CMV infection as a mononucleosis syndrome develop pneumonia. One study found that the incidence of CMV pneumonia in immunocompetent patients was 19%. In most cases, CMV pneumonia is found on chest radiography and is of no clinical significance, rapidly resolving with the disappearance of the primary infection. Life-threatening CMV pneumonia may develop in immunocompromised patients (see Adult Cytomegalovirus Infection in the Immunocompromised Host). The highest rate of CMV pneumonia, as well as the greatest severity, occurs among lung transplant recipients, who are at an overall 50% risk of developing CMV illness (infection or disease).

Cytomegalovirus hepatitis CMV hepatitis is defined as elevated bilirubin and/or liver enzymes levels in combination with the detection of CMV in the absence of other causes for hepatitis.[4] CMV may be detected via culture, histopathology, immunohistochemistry, or in situ hybridization. CMV PCR alone is not satisfactory for diagnosis, as a positive result may reflect transient viral shedding.[4] The first described case of CMV hepatitis involved a child with chorioretinitis, hepatosplenomegaly, and cerebral calcifications. Hepatitis has been commonly observed in patients with primary CMV infection and mononucleosis. levels of hepatocellular enzymes may be mildly and transiently increased, and, in rare cases, jaundice may develop. The prognosis of CMV hepatitis in immunocompetent hosts is typically favorable, but death has been reported in immunosuppressed patients. Histology typically reveals mononuclear cell infiltration of the portal areas but may also reveal granulomatous inflammation.[11]

Cytomegalovirus gastritis and colitis CMV GI disease is defined as the combination of symptoms of the upper and lower GI tract, mucosal lesions visible on endoscopy, and detection of CMV via culture, histopathology, immunohistochemistry, or in situ hybridization.[4] CMV colitis was first described in 1985 in two homosexual men who presented with abdominal pain, diarrhea, and hematochezia.[12] CMV PCR alone is insufficient for diagnosis, as a positive result may

simply reflect transient viral shedding. CMV may infect the GI tract from the oral cavity through the colon. The typical manifestation of disease is ulcerative lesions. In the oral cavity, these may be indistinguishable from ulcers caused by HSV or aphthous ulceration. Gastritis may present as abdominal pain and even hematemesis, whereas colitis more frequently presents as a diarrheal illness. CMV disease of the GI tract is often shorter-lived than that of other organ systems because of the frequent sloughing of infected cells of the GI mucosa.

Cytomegalovirus CNS disease CMV CNS disease is defined as CNS symptoms in combination with CMV detection in CSF (culture, PCR) or brain biopsy tissue (culture, histopathology, immunohistochemistry, in situ hybridization).[4] The association between CMV and Guillain-Barré Syndrome involves 2 groups. Younger patients (typically < 35 y) present with sensory defects and facial palsy, antiganglioside (GM2) IgM response, and milder long-term sequelae.[13] A second group includes women older than 50 years. These observations were made in France and thus may not be applicable to other populations due to different ages of primary CMV exposure.

Cytomegalovirus retinitis CMV retinitis is one of the most common opportunistic infection in persons with AIDS, typically those with CD4+ lymphocyte counts below 50 cells/µL. Although the number of cases has decreased with the use of HAART, new cases continue to be reported. Individuals with CMV retinitis typically exhibit a progressive decrease in visual acuity, which may progress to blindness if untreated. Unilateral and bilateral disease may exist. Long-term CMV treatment is necessary to prevent retinitis relapse. All lesions suspected to be CMV retinitis must be confirmed by an ophthalmologist. Immune reconstitution syndrome (IRIS) is reported in 16%-63% of HIV-infected patients with CMV retinitis following the initiation of HAART.[14, 15, 16] In one study, the median time to IRIS following HAART initiation was 43 weeks but has been reported as early as 4 weeks or as late as 4 years in some cases.[17, 15]CMV IRIS may manifest as painless floaters, blurred vision, photopia, decreased visual acuity, or ocular pain. Some patients may develop macular edema leading to vision loss or proliferative vitreoretinopathy, spontaneous vitreal hemorrhage, and retinal detachment.

Cytomegalovirus nephritis CMV nephritis is defined as CMV detection in combination with a renal biopsy showing CMV-associated changes in the setting of renal failure.[4] CMV PCR alone is inadequate for diagnosis. Of note, detection of CMV in the urine of a patient with renal failure does not meet diagnostic criteria for CMV nephritis.[4]CMV viremia has been associated with acute glomerular injury.[18]

Cytomegalovirus syndrome In general, it is better to avoid this term in stem cell transplant recipients, as other viruses (eg, HHV-6) can also cause fever and bone marrow suppression.[4]However, in solid organ transplant recipients, CMV syndrome is better defined: fever (>38°C) for at least 2 days within a 4-day period, CMV detection in blood, and either neutropenia or thrombocytopenia.[4]

Graft versus host disease CMV infection has been associated with acute graft verus host disease in bone marrow transplant recipients. Multiple genotypes (gB 1-4) of CMV exist, each with variations in the gene encoding envelope glycoprotein gB. The association of gB types with acute graft versus host disease and death related to myelosuppression has been examined. Taking into account disease type, donor-recipient HLA matching, donor CMV serostatus, and age, Torok-Storb et al (1997) found that gB3 and gB4 were linked to a higher degree of myelosuppression and death.[19] Interestingly, no specific CMV genotypes were linked to worse outcome in solid organ transplant recipients, although mixed gB genotype infections were associated with higher viral loads and delayed viral clearance.[20]

HCMV

Human cytomegalovirus is a species of virus that belongs to the viral family known as Herpesviridae or herpesviruses. It is typically abbreviated as HCMV and is alternatively known as human herpesvirus-5 (HHV-5).^[1] Within Herpesviridae, HCMV belongs to the Betaherpesvirinae subfamily, which also includes cytomegaloviruses from other mammals.^[2]

Although they may be found throughout the body, HCMV infections are frequently associated with the salivary glands.^[2] HCMV infection is typically unnoticed in healthy people, but can be life-threatening for the immunocompromised, such as HIV-infected persons, organ transplant recipients, or new born infants.^[1] After infection, HCMV has an ability to remain latent within the body over long periods. A prevention by hygienic measures is included in information given to pregnant women.^[3]

HCMV is found throughout all geographic locations and socioeconomic groups, and infects between 50% and 80% of adults in the United States (40% worldwide^[4]) as indicated by the presence of antibodies in much of the general population.^[1] Seroprevalence is age-dependent: 58.9% of individuals aged 6 and older are infected with CMV while 90.8% of individuals aged 80 and older are positive for HCMV.^[5] HCMV is also the virus most frequently transmitted to a developing fetus. HCMV infection is more widespread in developing countries and in communities with lower socioeconomic status and represents the most significant viral cause of birth defects in industrialized countries. CMV "seems to have a large impact on immune parameters in later life and may contribute to increased morbidity and eventual mortality."^[6]

References