Updated: May 8, 2008
Of all the human herpesviruses described to date, cytomegalovirus (CMV) arguably causes the most morbidity and mortality. Although primary infection with this agent generally does not produce symptoms in healthy adults, several high-risk groups, including immunocompromised organ transplant recipients and individuals infected with human immunodeficiency virus (HIV), are at risk of developing life-threatening and sight-threatening CMV disease. In addition, CMV has emerged in recent years as the most important cause of congenital infection in the developed world, commonly leading to mental retardation and developmental disability.
In 1904, Ribbert first identified histopathological evidence of CMV, probably in tissues from a congenitally infected infant. Ribbert mistakenly assumed that the large inclusion-bearing cells he observed at autopsy were from protozoa (incorrectly named Entamoeba mortinatalium). In 1920, Goodpasture correctly postulated the viral etiology of these inclusions.1 Goodpasture used the term cytomegalia to refer to the enlarged, swollen nature of the infected cells. Human CMV (HCMV) was first isolated in tissue culture in 1956, and the propensity of this organism to infect the salivary gland led to its initial designation as a salivary gland virus.
In 1960, Weller designated the virus cytomegalovirus;2 during the 1970s and 1980s, knowledge of the role of CMV as an important pathogen with diverse clinical manifestations increased steadily.3 Although enormous progress has recently been made in defining and characterizing the molecular biology, immunology, and antiviral therapeutic targets for CMV, considerable work remains in devising strategies for prevention of CMV infection and in understanding the role of specific viral genes in pathogenesis.
Furthermore, development of a vaccine against this virus is a major public health priority (reviewed below).4
CMV is a member of a family of 8 human herpesviruses, designated as human herpesvirus 5 (HHV-5). Taxonomically, CMV is referred to as a Betaherpesvirinae, based on its propensity to infect mononuclear cells and lymphocytes and on its molecular phylogenetic relationship to other herpesviruses. CMV is the largest member of the herpesvirus family, with a double-stranded DNA genome of more than 240 kbp, capable of encoding more than 200 potential protein products. The function of most of these proteins remains unclear. As with the other herpesviruses, the structure of the viral particle is that of an icosahedral capsid, surrounded by a lipid bilayer outer envelope.
An understanding of the process of viral replication provides insights into molecular mechanisms of antiviral therapy and protective immunity. CMV replicates very slowly in cell culture, mirroring its very slow pattern of growth in vivo (in contrast to herpes simplex virus [HSV] infection, which progresses very rapidly). The replication cycle of CMV is temporally divided into the following 3 regulated classes: immediate early, early, and late.
Immediate early gene transcription occurs in the first 4 hours following viral infection, when key regulatory proteins that allow the virus to take control of cellular machinery are made. The major immediate early promoter of this region of the CMV genome is one of the most powerful eucaryotic promoters described in nature; this has been exploited in modern biotechnology as a useful promoter for driving gene expression in gene therapy and vaccination studies.
Following synthesis of immediate early genes, the early gene products are transcribed. Early gene products include DNA replication proteins and some structural proteins.
Finally, the late gene products are made approximately 24 hours after infection, and these proteins are chiefly structural proteins that are involved in virion assembly and egress. Synthesis of late genes is highly dependent on viral DNA replication and can be blocked by inhibitors of viral DNA polymerase, such as ganciclovir. The lipid bilayer outer envelope contains the virally encoded glycoproteins, which are the major targets of host neutralizing antibody responses. These glycoproteins are candidates for human vaccine design. The proteinaceous layer between the envelope and the inner capsid, the viral tegument, contains proteins that are major targets of host cell–mediated immune responses. The most important of these tegument proteins is the so-called major tegument protein, UL83 (phosphoprotein 65 [pp65]).
Another clinically important gene product, the UL97 gene product, is a phosphotransferase. Although the function of this protein in the viral life cycle is unknown, this gene is clinically important because a substrate of the kinase is the antiviral drug ganciclovir, which, once phosphorylated, becomes a highly effective CMV therapy.5
In clinical specimens, one of the classic hallmarks of CMV infection is the cytomegalic inclusion cell. These strikingly enlarged cells (the property of "cytomegaly," from which CMV acquires its name) contain intranuclear inclusions that have the histopathological appearance of owl's eyes. The presence of these cells indicates productive infection, although they may be absent even in actively infected tissues. In most cell lines, CMV is difficult to culture in the laboratory; however, in vivo infection seems to chiefly involve epithelial cells. In severe disseminated CMV disease, involvement can be observed in most organ systems.
Little is known about the molecular mechanisms responsible for the pathogenesis of tissue damage caused by CMV, particularly for congenital CMV infection. Although the CNS is the major target organ for tissue damage in the developing fetus, culturing CMV from the cerebrospinal fluid of symptomatic infants with congenital infection is surprisingly difficult. Because CMV can infect endothelial cells, some authors have postulated that a viral angitis may be responsible for perfusion failure in the developing brain with resultant maldevelopment. Others have postulated a direct teratogenic effect of CMV on the developing fetus. Observation of CMV-induced alternations in the cell cycle and CMV-induced damage to chromosomes supports this speculation; however, this hypothesis has been difficult to experimentally verify.
Immunity to CMV is complex and involves humoral and cell-mediated responses.Several CMV gene products are of particular importance in CMV immunity. The outer envelope of the virus, which is derived from the host cell nuclear membrane, contains multiple virally encoded glycoproteins. Glycoprotein B (gB) and glycoprotein H (gH) appear to be the major determinants of protective humoral immunity. Antibody to these proteins is capable of neutralizing virus, and gB and gH are targets of investigational CMV subunit vaccines; however, although humoral responses are important in control of severe disease, they are clearly inadequate in preventing transplacental infection, which can occur even in women who are CMV-seropositive.
The generation of cytotoxic T-cell (CTL) responses against CMV may be a more important host immune response in control of infection. In general, these CTLs involve major histocompatibility complex (MHC) class I restricted CD8+ responses. Although many viral gene products are important in generating these responses, most CMV-specific CTLs target an abundant phosphoprotein in the viral tegument, pp65, the product of the CMV UL83 gene. In passive transfer experiments involving high-risk bone marrow transplant recipients, the value of these responses was dramatically demonstrated using adoptive transfer of CMV-specific CD8+ T cells that target the CMV UL83gene, which was able to control CMV disease.
Recent investigations into the molecular biology of CMV have revealed the presence of many viral gene products, which appear to modulate host inflammatory and immune responses. Several CMV genes interfere with normal antigen processing and generation of cell-mediated immune responses. To date, 3 viral gene products have been identified that inhibit MHC class I antigen presentation. One is the US11 gene product, which exports the class I heavy chain from the endoplasmic reticulum (ER) to the cytosol (rendering it nonfunctional). Another is the US3gene product, which retains MHC molecules in the ER, preventing them from traveling to the plasma membrane. Finally, the US6 protein inhibits peptide translocation by transporters associated with antigen processing (TAP).
Other viral gene products, the UL33, US27, and US28 genes, are functional homologs of cellular G-protein coupled receptors which may, via molecular mimicry, subvert normal inflammatory responses and, in the process, promote tissue dissemination of the virus and interfere with host immune response. The CMV genome also encodes a homolog of the cellular major histocompatibility class I gene, which appears to contribute to the ability of CMV to evade host defense. The UL144 open reading frame found in clinical isolates of CMV encodes a structural homolog of the tumor necrosis factor receptor superfamily, which may contribute to the ability of HCMV to escape immune clearance.
Other CMV genes interfere with natural killer (NK) cell responses, including the UL18 gene product. A better understanding of the impact of viral immune evasion genes on the development of protective immunity to CMV infection should enable the design of improved vaccines.
Every mammal appears to be infected with its own species-specific CMV, and no evidence suggests that infections cross species. Hence, humans are the only natural host for HCMV infection. Although most adults eventually become infected with CMV, the epidemiology of this infection is complex, and the age at which an individual acquires CMV greatly depends on geographic location, socioeconomic status, cultural factors, and child-rearing practices.
In developing countries, most children acquire CMV infection early in life, with adult seroprevalence approaching 100% by early adulthood. In contrast, in developed countries, the seroprevalence of CMV approximates 50% in young adults of middle-upper socioeconomic status. This observation has important implications for congenital CMV epidemiology because women of childbearing age who are CMV seronegative are at major risk of giving birth to infants with symptomatic congenital infection if primary infection is acquired during pregnancy.
Transmission of CMV infection may occur throughout life, chiefly via contact with infected secretions.6 Acquisition of CMV in the newborn period is common. Approximately 1% (range, 0.5-2.5%) of all newborns are congenitally infected with CMV. Most of these infections occur in infants born to mothers with preexisting immunity and are clinically asymptomatic at birth; however, long-term sequelae, including deafness, can occur (see History).
The route of congenital infection is presumed to be transplacental. CMV may also be transmitted perinatally, both by aspiration of cervicovaginal secretions in the birth canal and by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV.7 Infants who are not infected congenitally or perinatally with CMV are at high risk to acquire infection in daycare centers. According to some studies, the prevalence of CMV infection in children who attend daycare, particularly children younger than 2 years, approximates 80%.
The virus may be readily transmitted to susceptible children via saliva, urine, and fomites; these children, in turn, may transmit infection to their parents. Such horizontal transmission of infection in daycare centers appears to play a major role in the epidemiology of many CMV infections in young parents.
In adulthood, sexual activity is probably the most important route of acquisition of CMV,8 although the observation that virus is present in saliva, cervicovaginal secretions, and semen obscures which route or routes of transmission are primarily responsible for establishment of infection. Saliva alone appears to be sufficient for transmission of CMV, and this route of transmission may be responsible for those cases of heterophile-negative mononucleosis, which are attributable to CMV. Kissing appears to be a way in which CMV is transmitted from toddlers to seronegative parents. Recent work by the Centers for Disease Control and Prevention (CDC) has emphasized the need for greater public awareness of these risks and for educational interventions for young women of childbearing age.
Other important routes of transmission include blood transfusion and solid organ transplantation. Before screening of blood products, transfusion-associated CMV was an important cause of morbidity and mortality in premature infants; however, the routine use in many neonatal intensive care units of CMV-negative blood products has largely eliminated this problem. Posttransfusion CMV is still a risk in CMV-seronegative trauma and in surgery patients, often manifesting as hepatitis.
The risk of congenital CMV infection is not well defined in the developing world. Because seroepidemiologic studies indicate that, in many developing countries, seroprevalence for CMV approaches 100% very early in childhood, little attention has been given to the question of potential morbidities in these populations.
CMV is a substantial cause of morbidity in newborns. As the most common so-called toxoplasmosis, rubella, CMV, and herpes simplex (TORCH) infection in the developed world, CMV accounts for extensive neurodevelopmental morbidity, including sensorineural deafness in infants. CMV also accounts for substantial mortality in immunocompromised patients.
The effects of race and genetics on clinical manifestations of CMV infection are not well understood. In some studies in the United States, prevalence of congenital CMV appears to be higher in infants born to black women.9 More work is required to understand the basis for the differences in the epidemiology of CMV infection in various ethnic groups in the United States.
Both sexes are equally susceptible to infection and morbidity from CMV, although only women are at risk for transplacental transmission of infection.
The annual seroconversion rate for acquisition of CMV infection is approximately 1%. However, two age groups have higher rates of acquisition of infection: toddlers who attend group daycare and adolescents. Accordingly, these represent two potential groups in which to implement vaccination.
The history must be tailored to the specific clinical circumstances and disease category. Specific disease categories are considered as follows:
- Congenital cytomegalovirus (CMV) infection: Current estimates suggest that 30,000-40,000 infants are born with congenital CMV infection annually in the United States, making CMV by far the most common and important of all congenital infections. The likelihood of congenital infection and the extent of disease in the newborn depend on maternal immune status. If primary maternal infection occurs during pregnancy, the average rate of transmission to the fetus is 40%; approximately 65% of these infants have CMV disease at birth. With recurrent maternal infection (ie, CMV infection that occurs in the context of preconceptual immunity), the risk of transmission to the fetus is lower, ranging from 0.5-1.5%; most of these infants appear normal at birth (ie, silent infection). Hence, congenital infection may be classified as symptomatic or asymptomatic in nature (see Media file 1).
- Cytomegalic inclusion disease (CID)
- Approximately 10% of infants with congenital infection have clinical evidence of disease at birth. The most severe form of congenital CMV infection is referred to as CID.
- CID almost always occurs in women who have primary CMV infection during pregnancy, although rare cases are described in women with preexisting immunity who presumably have reactivation of infection during pregnancy.
- CID is characterized by intrauterine growth retardation, hepatosplenomegaly, hematological abnormalities (particularly thrombocytopenia), and various cutaneous manifestations, including petechiae and purpura (ie, blueberry muffin baby). However, the most significant manifestations of CID involve the CNS. Microcephaly, ventriculomegaly, cerebral atrophy, chorioretinitis, and sensorineural hearing loss are the most common neurological consequences of CID.
- Intracerebral calcifications typically demonstrate a periventricular distribution and are commonly encountered using CT scanning (see Media file 2). The finding of intracranial calcifications is predictive of cognitive and audiologic deficits in later life and predicts a poor neurodevelopmental prognosis.
- Most infants who survive symptomatic CID have significant long-term neurological and neurodevelopmental sequelae. Indeed, it has been estimated that congenital CMV may be second only to Down syndrome as an identifiable cause of mental retardation in children.
- Asymptomatic congenital CMV
- Most infants with congenital CMV infection are born to women who have preexisting immunity to CMV. These infants appear clinically healthy at birth; however, although infants with congenital CMV infection appear well, they may have subtle growth retardation compared to uninfected infants. Although asymptomatic at birth, these infants, nevertheless, are at risk for neurodevelopmental sequelae.
- The major consequence of inapparent congenital CMV infection is sensorineural hearing loss. Approximately 15% of these infants will have unilateral or bilateral deafness. Routine newborn audiologic screening may not detect cases of CMV-associated hearing loss because this deficit may develop months or even years after birth.10
- Cytomegalic inclusion disease (CID)
- Acquired CMV infection: In contrast to congenital infection, acquired CMV infection occurs postnatally. Primary infection in this context is generally asymptomatic, although CMV disease may occur in certain risk groups as follows:
- Perinatal infection
- Perinatal acquisition of CMV usually occurs secondary to exposure to infected secretions in the birth canal or via breastfeeding. Most infections are asymptomatic. Indeed, in some reviews, CMV acquired through breast milk has been referred to as a form of natural immunization.
- Some infants who acquire CMV infection perinatally may have signs and symptoms of disease, including lymphadenopathy, hepatitis, and pneumonitis, which may be severe. Disease secondary to acquisition by breast milk is generally limited to premature infants with low birth weight. These infants may suffer considerable morbidity. Whether interventions, such as freezing or pasteurization, are warranted to decrease the risk of transmission to these high-risk infants is unclear. More studies of long-term neurodevelopmental outcomes of premature infants who acquire CMV infection perinatally from breast milk are needed.
- CMV mononucleosis
- Typical CMV mononucleosis is a disease found in young adults. Although CMV mononucleosis may be acquired by blood transfusion or organ transplantation, CMV mononucleosis is usually acquired via person-to-person transmission.
- The hallmark symptoms of CMV mononucleosis are fever and severe malaise. An atypical lymphocytosis and mild elevation of liver enzymes are present.
- Clinically differentiating CMV mononucleosis from Epstein-Barr virus (EBV)-induced mononucleosis may be difficult. CMV mononucleosis is typically associated with lesspharyngitis and less splenomegaly. As with EBV mononucleosis, the use of b -lactam antibiotics in association with CMV mononucleosis may precipitate a generalized morbilliform rash.
- Transfusion-acquired CMV infection
- Posttransfusion CMV infection has a presentation similar to that of CMV mononucleosis. Incubation periods range from 20-60 days.
- The use of seronegative blood donors, frozen deglycerolized blood, or leukocyte-depleted blood can decrease the likelihood of transmission and is recommended for high-risk patients (eg, neonates, immunocompromised patients).
- Perinatal infection
- CMV infections in immunocompromised patients: CMV causes various clinical syndromes in immunocompromised patients. Disease manifestations vary in severity depending on the degree of host immunosuppression. Infection may occur because of reactivation of latent viral infection or may be newly acquired via organ or bone marrow transplant from a seropositive donor. Infections may also be mixed in nature, with donor and recipient isolates both present. Viral dissemination leads to multiple organ system involvement, with the most important clinical manifestations consisting of pneumonitis, GI disease, and retinitis.
- CMV pneumonitis
- CMV is a major cause of pneumonitis in immunosuppressed children and adults. This disease may be observed in the setting of HIV infection, congenital immunodeficiency, malignancy, and solid organ or bone marrow transplant.
- The mortality rate is based on the degree of immunosuppression, with mortality rates of at least 90% reported in bone marrow transplant recipients. Solid organ transplant recipients are at risk of developing CMV pneumonitis also, although mortality rates are lower.
- The illness usually begins 1-3 months following transplantation and starts with symptoms of fever and dry, nonproductive cough. The illness progresses quickly with retractions, dyspnea, and hypoxia becoming prominent.
- The illness is an interstitial pneumonitis, with a radiographic appearance of diffuse bilateral interstitial infiltrates. Because the differential diagnosis of pneumonitis is extensive in immunocompromised patients, consider performing a bronchoalveolar lavage or open lung biopsy to confirm the diagnosis and direct appropriate therapy.
- CMV GI disease
- GI tract disease caused by CMV can include esophagitis, gastritis, gastroenteritis, pyloric obstruction, hepatitis, pancreatitis, colitis, and cholecystitis. Characteristic signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea.
- Stool may be hemoccult positive or frankly bloody. Endoscopy and biopsy are warranted, and characteristic cytomegalic inclusion cells may be observed in GI endothelium or epithelium.
- Although CMV enteritis does not carry the same ominous prognosis as CMV pneumonitis, antiviral therapy is warranted.
- Differentiating CMV hepatitis from chronic rejection in liver transplant patients may be difficult, even with biopsy.
- CMV retinitis
- Before the advent of highly active antiretroviral therapy (HAART) for HIV infection, CMV retinitis was the most common cause of blindness in adult patients with acquired immunodeficiency syndrome (AIDS), with an overall lifetime prevalence of more than 90%.
- HIV-associated CMV retinitis in children, in contrast to adults, has been relatively rare, probably reflecting overall differences in CMV seroprevalence between the populations. Retinitis is less common in transplant patients.
- CMV produces a necrotic rapidly progressing retinitis with characteristic white perivascular infiltrate with hemorrhage (brushfire retinitis).
- Peripheral lesions may be asymptomatic, and even advanced disease does not cause pain. In children, strabismus or failure to fix and follow objects may be important clues to the diagnosis.
- The disease can progress to total blindness and retinal detachment if left untreated. CMV chorioretinitis is also observed in symptomatic infants with congenital infection infants, although the disease does not usually progress to vision loss. The presence of chorioretinitis in an infant with congenital infection infant indicates a poor neurodevelopmental prognosis.
- Other CMV syndromes
- Various syndromes have been attributed to CMV infection, although cause and effect relationships are often difficult to establish.
- Menetrier disease is a rare disorder characterized by hyperplasia and hypertrophy of the gastric mucous glands, which results in massive enlargement of the gastric folds. Most cases appear to be CMV associated, although the pathogenesis is unknown.
- In children with congenital HIV infection, co-infection with CMV appears to accelerate the HIV disease progression and HIV-associated neurological disease. Accumulating evidence suggests that CMV infection may be a cofactor in the pathogenesis of atherosclerosis. In addition, the phenomena of posttransplant vascular sclerosis and postangioplasty restenosis appear to be CMV-induced lesions.
- The long-term health consequences of CMV infection may include atherosclerosis, immunosenescence, and an increased risk of malignancy. These associations require further study but provide a potential justification for universal vaccination of both sexes against CMV.
- CMV pneumonitis
Physical examination findings depend on age, route of acquisition, and immune status of the patient. Findings are reviewed in a syndrome-specific fashion.
Risk factors for CMV-associated illness chiefly include age and immunodeficiency. These points are covered in case-by-case fashion in other sections of this article.
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