Cytomegalovirus Infections: An overview

Special features of cytomegalovirus

Cytomegalovirus (CMV, human herpesvirus type 5) is also commonly spread in human population.

Nowadays CMV agent is a global leading cause of congenital infections, followed by childhood hearing loss and neurodevelopmental delay with mental retardation.

Cytomegaloviruses exhibit a number of characteristic traits:

– viruses are strictly adapted to human host; CMV propagates only in human cells;

– CMVs contain the largest genome of human herpesviruses with marked genetic variability;

– viruses demonstrate slow replication rate; the length of viral replication cycle is over 70 h, this leads to long incubation period of CMV infection;

– high variety of clinical manifestations affecting various organs and tissues with special emphasis to CNS;

– generally low pathogenicity for immunocompetent individuals;

– propagating within immune cells, CMVs suppress cell-mediated immune response;

– lifelong persistency with repeated subclinical reactivations;

– evident teratogenicity resulting in high rate of congenital abnormalities;

– CMV produces characteristic cytopathic effect in cell cultures – the affected cells become enlarged, nuclear cytoplasmic inclusions appear.

Pathogenesis, clinical findings and immunity in CMV infections

CMV infection is largely a social health problem. In developing countries and resource-limited communities the contraction of the infection occurs in early childhood primarily due to infected breast milk feeding, poor living conditions (overcrowdness) and generally low attention of health authorities to CMV burden.

In industrialized countries the prevalence of CMV infection in women of childbearing age exceeds 50%, whereas in developing countries it is usually above 90%.

Three main clinical groups of infections are caused by CMV:

congenital disorders in newborns and infants;

generalized (systemic) viral infections and CMV pneumonia in immunocompromised individuals (e.g., in AIDS patients);

– CMV infections in graft recipients after organ transplantation.

Humans are the only known hosts and sources of infection for cytomegalovirus.

Airborne and oral transmissions are the most common in cytomegalovirus spread.

It can also be transmitted vertically from mother to child, by contact route via contaminated fomites, by organ transplantation, via blood transfusion, or by sexual intercourse.

CMV infection in immunocompetent adults is usually mild or subclinical disease.

Incubation period lasts about 30-40 days. Manifested disease reveals mononucleosis-like syndrome with viremia, fever, lymphocytosis, and moderate hepatitis.

The virus is capable of invading virtually any type of host cells – endotheliocytes, leukocytes, epithelial cells, fibroblasts, parenchymatous cells of inner organs. CMV inhibits apoptosis of infected cells maintaining viral survival. During infection CMV actively sheds with saliva, genital secretions and urine, breast milk.

After 2-4 weeks the symptoms of the disease decline, as the virus is actively eliminated by reactions of humoral and cell-mediated immunity, and CMV comes into state of latency.

Latent infection is lifelong. The virus persists in CD14+monocytes and bone marrow progenitors. The genome of virus stays as episome within infected cells.

Reactivations of virus may be common but host immune response withstands viral propagation, preventing infection recurrence. Reactions of cell-mediated immunity are mandatory for efficient protection.

Congenital and perinatal CMV infections are characterized by CMV transmission across placenta in pregnancy, during delivery, and with infected breast milk after birth.

Cytomegalic disease of newborns often demonstrates systemic severe course with encephalitis and CNS damage. Lethality may achieve 30%.

The most common complications are sensorineural hearing loss (deafness), ocular abnormalities, and infant neurodevelopmental delay with mental retardation.

Severe generalized CMV infections develop in AIDS (AIDS indicator disease). They affect at least 15% of AIDS patients. CMV accounts for death of 10-20% of individuals with AIDS.

Finally, CMV produces life-threatening infections after organ transplantations, being one of the substantial causes of death of graft recipients.

Laboratory diagnosis of CMV infections

Laboratory confirmation of CMV infection is of great value due to its non-specific clinical manifestations.

Specimens of throat washings, urine, saliva, blood, or autopsy materials are taken for examination. For rapid cytomegalovirus detection immunofluorescence assay, ELISA and PCR are used. PCR is the most reliable laboratory test in routine clinical practice for CMV identification.

Virus isolation is performed in human embryonated cell lines (e.g. fibroblast culture). In 1-2 weeks swollen cells with large intranuclear inclusion bodies (known as “owl’s eye”) are detected under microscopy.

Rapid identification of CMV isolates in cell cultures is made by immunofluorescence and PCR.

In serological testings specific anti-CMV antibodies are detected by ELISA. Detection of antibodies of IgM class indicates primary CMV infection.

Principles of treatment and prophylaxis of CMV infection

Ganciclovir, a nucleoside structurally related to acyclovir, is used successfully to treat life-threatening cytomegaloviral infections in immunosuppressed patients. Donor’s high-titer CMV immune globulin can be administered for pregnant women with active CMV infection.

Specific prophylaxis by vaccination is still not available for prevention of cytomegalovirus infection. Several candidate vaccines undergo clinical trials. Non-speciic prophylaxis includes the maintenance of high personal hygienic conditions. Isolation of newborns with systemic CMV from other infants helps to prevent infection spread. Screening for cytomegalovirus infection is mandatory for graft donors and recipients.