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Chapter: Medical Microbiology: An Introduction to Infectious Diseases: Herpesviruses

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Cytomegalo Virus : Clinical Aspects

Worldwide, 1% of infants excrete CMV in urine or nasopharynx at delivery as a result of infection in utero.

CYTOMEGALO VIRUS : CLINICAL ASPECTS

MANIFESTATIONS

Worldwide, 1% of infants excrete CMV in urine or nasopharynx at delivery as a result of infection in utero. On physical examination, 90% of these infants appear normal or asymptomatic; however, long-term follow-up has indicated that 10 to 20% go on to develop sensory nerve hearing loss, psychomotor mental retardation, or both. Infants with symptomatic illness (about 0.1% of all births) have a variety of congenital defects or other disorders, such as hepatosplenomegaly, jaundice, anemia, thrombocytopenia, low birth weight, microcephaly, and chorioretinitis. Almost all infants with clinically evident congenital CMV infection are born of mothers who experienced primary CMV infection during pregnancy. The apparent explanation is that these babies are exposed to virus in the absence of maternal antibody. It is estimated that one third of maternal primary infections are transmitted to the fetus and that fetal damage is most likely to occur in the first trimester. Congenital infection frequently also results from reactivation in the mother with spread to the fetus, but such infection rarely leads to congenital abnormalities since the mother also transmits antibody to the fetus.

In contrast to the devastating findings with some congenital infections, neonatal infec-tion acquired during or shortly after birth appears to be rarely associated with an adverse outcome. Most population-based studies have indicated that 10 to 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 in-fants have no discernible illness unless the infant 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.

As with intrapartum acquisition of infection, most CMV infections during childhood and adulthood are totally asymptomatic. In healthy young adults, CMV may cause a mononucleosis-like syndrome. In immunosuppressed patients, both primary infection and reactivation may be severe. For example, in patients receiving bone marrow transplants, interstitial pneumonia caused by CMV is a leading cause of death (50–90% mortality) and in AIDS patients, CMV often disseminates to visceral organs, causing chorioretinitis, gastroenteritis, and neurologic disorders.

DIAGNOSIS

Laboratory diagnosis of CMV infection depends on (1) detecting CMV cytopathology, antigen, or DNA in infected tissues; (2) isolating the virus from tissue or secretions; or(3) demonstrating seroconversion. CMV can be grown readily in serially propagated diploid fibroblast cell lines. Demonstration of cytopathic effect generally requires 3 to 14 days, depending on the concentration of virus in the specimen and whether coverslip cultures in shell vials are used to speed detection. The presence of large inclusion-bearing cells in urine sediment may be detected in widespread CMV infection. This technique is insensitive, however, and provides positive results only when large quantities of virus are present in the urine. Culture of blood to detect viremia is now superseded by detection of CMV antigen in peripheral blood leukocytes or detection of CMV DNA in plasma or leukocytes. These procedures are more rapid and more sensitive than culture.

Because of the high prevalence of asymptomatic carriers and the known tendency of CMV to persist weeks or months in infected individuals, it is frequently difficult to associ-ate a specific disease entity with the 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 of CMV as the cause of that illness. CMV pneumonia or gas-trointestinal disease is best diagnosed by demonstrating CMV inclusions in biopsy tissue.

The procedures listed below are recommended to facilitate the diagnosis of CMV in-fection in specific clinical settings:

1.   Congenital infection. Virus culture or viral DNA assay positive at birth or within 1 to 2 weeks (to distinguish from natally or perinatally infected infants, who will not begin to excrete virus until 3 to 4 weeks after delivery).

 

2. Perinatal infection. Culture-negative specimens at birth but positive specimens at 4 weeks or more after birth suggest natal or early postnatal acquisition. Seronegative infants may acquire CMV from exogenous sources, e.g. blood transfusion.

 

3.   CMV mononucleosis in nonimmunocompromised patients. Seroconversion and pres-ence of IgM antibody specific for CMV are the best indicators of primary infection. Urine culture positivity supports the diagnosis of CMV infection but may reflect re-mote infection, because positivity may continue for months to years. A positive blood assay for CMV antigen or DNA, however, is diagnostic in this patient population.

 

4.   Immunocompromised patients. Demonstration of virus by viral antigen, DNA, or cul-ture in blood documents viremia. Demonstration of inclusions or viral antigen in diseased tissue (eg, lung, esophagus, or colon) establishes the presence of CMV infec-tion but does not provide proof that CMV is the cause of disease unless other pathogens are excluded. Seroconversion is diagnostic but rarely occurs, especially in AIDS patients, because more than 95% of these patients are seropositive for CMV be-fore infection with human immunodeficiency virus (HIV). CMV-specific IgM anti-body may not be present in immunocompromised patients, especially during reactiva-tion of virus. Conversely, in AIDS patients, this antibody frequently is present even when clinically important infection is absent.

 

TREATMENT

Ganciclovir, a nucleoside analog of acyclovir, has been shown to inhibit CMV replication; prevent CMV disease in AIDS patients and transplant recipients; and reduce the severity of some CMV syndromes, such as retinitis and gastrointestinal disease. Combining immune globulin with ganciclovir appears to reduce the very high mortality of CMV pneumonia in bone marrow transplant patients over that achieved with ganciclovir alone, but the progno-sis for long-term survival of these patients remains poor. Foscarnet, a second approved drug for therapy of CMV disease, is equally efficacious. Its toxic effects are primarily re-nal, whereas ganciclovir is most apt to inhibit bone marrow function. Ganciclovir inhibits CMV DNA polymerase, like foscarnet, but the two drugs act on different sites, and cross resistance is rare. In 1996, a third drug, cidofovir, a nucleotide analog, was approved for therapy of retinitis; it is also nephrotoxic.

PREVENTION

The use of blood from CMV-seronegative donors or blood that is treated to remove white cells decreases transfusion-associated CMV. 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 pneumonia associated with transplants. Safe sex practices including condom usage reduces transmis-sion. CMV vaccines have been developed, and are being evaluated in clinical trials.

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