Essentials of Diagnosis
- “Owl eye” cells in tissue biopsy, cytology
- Cultured in diploid fibroblast cells
- Antibody detection of those patients seroconverting or at risk for reactivation
- CMV detection in blood or bodily fluids by antigenemia, PCR, or other DNA-based assays, eg hybrid capture, or by culture
General Considerations
Epidemiology
CMV is ubiquitous, and in developed countries ~50% of adults have developed antibody (Box 7). Age-specific prevalence rates show that ~ 10-15% of children are infected by CMV during the first 5 years of life, after which the rate of new infections levels off. The rate subsequently increases during young adulthood, probably through close personal contact or sexual transmission of the virus. CMV has been isolated from saliva, cervical secretions, semen, urine, and white blood cells.
Excretion of virus is prolonged after congenital and perinatal infections, probably because of immunologic tolerance, and high titers of virus may be shed for more than 5 years after birth. Transmission of infection in daycare centers has been shown to occur from asymptomatic excretors to other children and, in turn, to seronegative parents. Infected adults, especially immunocompromised adults, also excrete virus for prolonged periods after primary infection or reactivation of latent infection. Latent infection, which may reside in leukocytes and their precursors, can be transmitted by transfusion and organ transplantation.
Microbiology
Human CMV possesses the largest genome of the herpesviruses (~240 kilobase pairs), and its replication, although slow, is similar to that of HSV with the sequential appearance of immediate early, early, and late gene products. Strains of CMV demonstrate considerable genomic and phenotypic heterogeneity, and restriction endonuclease analysis of viral DNA has been useful for distinguishing strains epidemiologically. Antigenic variations have been observed but are not of clinical importance.
Pathogenesis and Immunity
Cytomegalovirus infects epithelial cells and leukocytes. In vitro, CMV DNA can be demonstrated in monocytes showing no cytopathology, indicating a restricted growth potential in these cells. In addition to nuclear inclusions (“owl eye cells”), CMV produces perinuclear cytoplasmic inclusions and enlargement of the cell (cytomegaly), a property which gives the virus its name.
After primary CMV infection, the virus becomes latent. The exact site(s) of latency and the mechanisms of persistence are not completely understood, but leukocytes, especially mononuclear leukocytes, are suspected to contain latent virus and account for transmission of the virus by blood and leukocyte transfusions. Also, organs such as the kidneys and heart harbor the virus, but the exact cell is not known. Latent CMV infection appears to be reactivated by immunosuppression (eg, by corticosteroids or HIV infection) and possibly by allogeneic stimulation (ie, the host response to transfused or transplanted cells). Cellular damage appears to be caused directly by the viral lytic infection or indirectly by the immune response of the host. An example of cellular damage resulting from a direct cytopathic effect is retinitis in severely immunocompromised AIDS patients, in which blindness occurs as a result of a necrotizing infection by the virus. The beneficial effects of ganciclovir therapy support this notion. In contrast, HCMV pneumonitis in transplant recipients frequently manifests subtle histologic alterations in the face of life-threatening clinical symptomatology and extensive inflammation accompanied by mild viral replication, suggesting that immune-mediated injury is the primary pathologic mechanism. In other instances, both direct and immunopathogenic mechanisms seem to be at work.
Clinical Findings
Congenital
Worldwide, 1% of infants excrete CMV in urine at delivery, as a result of infection in utero. On physical examination, 90% of these infants appear normal; however, long-term follow-up has indicated that up to 20% go on to develop sensory nerve hearing loss, psychomotor mental retardation, or both. The infants with symptomatic illness (~ 0.1% of all births) may have a variety of congenital defects or other disorders (such as hepatosplenomegaly, jaundice, anemia, thrombocytopenia, low birth weight, microcephaly, and chorioretinitis). Almost all babies with clinically evident congenital CMV infection are born of mothers who experience primary CMV infection during the pregnancy. Congenital infection frequently also results from reactivation in the mother with spread to the fetus, but such infection rarely leads to congenital abnormalities due to protection by passively transferred maternal antibody.
Perinatal
Most population-based studies have indicated that 10-15% of all mothers are excreting CMV from the cervix at delivery. Approximately one-third to one-half of all infants born to these mothers acquire infection. Almost all of these perinatally infected infants have no discernible illness unless the baby is premature or immunocompromised. CMV can also be efficiently transmitted from mother to child by breast milk, but these postpartum infections are also usually benign.
Post neonatal
As with intrapartum acquisition of infection, most CMV infections during childhood and adulthood are totally asymptomatic. In adults, CMV may cause a mononucleosis-like syndrome. In immunosuppressed patients, latent CMV may be reactivated and cause very serious disease. In patients receiving bone marrow transplants, interstitial pneumonia caused by CMV is the leading cause of death (90% mortality). In AIDS patients with low CD4 lymphocyte counts CMV often disseminates to visceral organs, causing chorioretinitis, gastroenteritis, neurologic disorders, and disease in other organs.
Diagnosis
Laboratory diagnosis of CMV infection depends on (1) detecting CMV cytopathology, antigen, or DNA in infected tissues or bodily fluids, (2) isolating the virus from tissue or bodily fluids, or (3) demonstrating seroconversion. CMV can be grown in serially propagated diploid fibroblast cell lines but generally requires 3-14 days, depending on the concentration of virus in the specimen. The time for detection can be shortened by centrifugation and immune staining, but culture of blood is less sensitive than antigenemia or DNA-based assays.
Because of the high prevalence of asymptomatic carriers and the known tendency of CMV to persist weeks or months in infected individuals, it may be difficult to attribute a specific disease to CMV by isolation of the virus from a peripheral site. Thus, the isolation of CMV from urine of immunosuppressed patients with interstitial pneumonia does not constitute evidence for CMV as the etiology of that illness. CMV pneumonia or gastrointestinal disease is best diagnosed by demonstrating CMV inclusions in biopsy tissue.
Treatment
Ganciclovir, a nucleoside analog of acyclovir (INN: Aciclovir), inhibits CMV replication and reduces the severity of CMV syndromes, such as retinitis and gastrointestinal disease (Box 8). When given with hyper immune globulin, ganciclovir is thought to reduce the mortality of CMV pneumonia in transplant recipients.
Foscarnet is an approved drug for therapy of CMV retinitis. Its toxic effects are primarily renal with electrolyte disturbances, whereas ganciclovir is most apt to inhibit bone marrow function. Ganciclovir inhibits CMV DNA polymerase as does foscarnet, but they act on different sites and cross-resistance is rare. Cidofovir is a third approved anti-CMV drug and is the first nucleotide analog to be used in clinical practice. It has a long half-life, which allows it to be given every 2 weeks during maintenance treatment of CMV retinitis, but it is significantly nephrotoxic.
Prevention & Control
The use of blood from CMV seronegative donors or blood that is treated to remove white cells decreases transfusion-associated CMV (Box 9). Similarly, the disease can be avoided in seronegative transplant recipients by using organs from CMV-seronegative donors. Hyperimmune human anti-CMV globulin has been used to ameliorate CMV disease associated with renal and hepatic transplants. Prophylactic or preemptive ganciclovir and valacyclovir reduce the frequency of CMV disease in both transplant and AIDS patients. There are experimental and clinical data indicating that the use of condoms decreases sexual transmission of CMV. CMV vaccines are being evaluated in clinical trials.
Ganciclovir