Viral Diseases - CYTOMEGALOVIRUS DISEASE

Most cytomegalovirus infections in healthy individuals are asymptomatic, with the virus remaining (exact cells of latency are not known). However the virus is isolable from up to 25% of salivary glands, 10% of uterine cervices, and 1% of neonatal urine samples. Seroprevalence increases with age and the number of sexual partners; detectable antibody is present in the serum of most homosexual men. Transmission is sexual, congenital, through or transplantation, and person-to-person (e.g., day care centers). Severe disease occurs primarily in the immunocompromised, especially those with AIDS and transplant patients.

DISEASE IN MAN:

A. Classification: There are three recognizable syndromes.
1. Perinatal disease and cytomegalovirus inclusion disease -- Intrauterine infection of infants whose mothers had a primary infection during pregnancy results in a neonatal syndrome of jaundice, hepatosplenomegaly, thrombocytopenia, periventricular central nervous system calcifications, mental retardation, motor disability, and purpura.  Confirmed by viruria within the first week after birth or serum IgM antibodies to cytomegalovirus. Hearing deficits occur in over 15% and mental retardation in up to 30%. Neonatally acquired disease may resemble mononucleosis; while it is often asymptomatic, neurologic deficits may ensue later in life.

2. Acute acquired cytomegalovirus infection -- This syndrome, akin to EBV-associated infectious mononucleosis, is characterized by fever, malaise, myalgias and arthralgias (but not pharyngitis or respiratory symptoms), atypical lymphocytes, and abnormal liver function tests. Unlike EBV-associated infectious mononucleosis, the heterophil antibody is not found. Transmission can be by sexual contact, by milk, by respiratory droplets (probably) among nursery or day care center attendants, and by (usually massive) transfusions of blood.

3. Disease in immunocompromised hosts -- Tissue and bone marrow transplant patients are at increased risk for CMV infection, especially in the first I 00 days after allograft transplantation. HIV-infected patients may have a variety of CMV manifestations. Cytomegalovirus is itself immunosuppressive and may worsen manifestations of HIV infection, including Pneumocystis carinii pneumonia.
    a. CMV retinitis-Retinitis due to CMV infection occurs primarily in AIDS patients. Screening for visual symptoms may be helpful, but ophthalmologic documentation of neovascular, proliferative lesions ("pizza-pie" retinopathy) is required for diagnosis.
    b. Gastrointestinal and hepatobiliary CMV-Serious gastrointestinal CMV disease occurs in AIDS and after organ transplantation, cancer chemotherapy, or steroid therapy. Esophagitis presents with odynophagia; small bowel disease may mimic inflammatory bowel disease or may present as ulceration or perforation. Colonic CMV disease causes diarrhea, hematochezia. abdominal pain, fever, and weight loss. Pancreatitis, when not due to pentamidine, didanosine, or (less often) zalcitabine is often due to cytomegalovirus; hepatobiliary involvement often includes other pathogens, including Cryptosporidium. Diagnosis is by mucosal biopsy that shows characteristic CMV histopathologic findings of intranuclear ("owl's eye") and intracytoplasmic inclusions.
    c. Pulmonary CMV-Pulmonary CMV infection occurs in about 15% of bone marrow transplant recipients: the mortality rate is 80-90% in this group. CMV seronegative blood products should be used in seronegative recipients of seronegative transplants. High-titer CMV immunoglobulins may be effective in preventing CMV pneumonia in the seronegative recipients. d. Neurologic CMV-Polyradiculopathy and encephalitis have been reported but are not common. When they do occur, there is often concomitant retinitis, which may be subclinical. Prolonged ganciclovir may be helpful, and treatment should be continued indefinitely.

DIAGNOSIS:

Cytomegalovirus is isolable from urine, cervical secretions, semen, saliva, blood, and other tissues, but virus isolation is most useful when combined with pathologic findings, including large cells with intranuclear and intracytoplasmic inclusions that resemble owl's eyes: cultures alone are of little use in diagnosing AIDS-related cytomegalovirus infections. Retinitis among aids patients is diagnosed clinically. The acute mononucleosis syndrome is associated with a lymphocytosis, often 2 weeks after the fever. Serologic tests (IFA and the anticomplement immunofluorescent antibody [ACIF]) are useful primarily in seroepidemiologic studies. In AIDS patients, titers may be depressed, and seroconversions are seldom documented, with most seroconversions having occurred in the past. Antigen detection by virus technology (including the polymerase chain reaction technique) must be interpreted in the context of clinical and pathologic findings.
 

TREATMENT:

Two antiviral agents with efficacy against cytomegalovirus are Ganciclovir, given in a dosage of 5 mg/kg IV every 12 hours for 14-21 days (maintenance: 5-7 mg/kg/day for 5 days each week, with dose reduction for renal impairment); and Foscarnet, given as a loading dose of 20 mg/kg IV and then 60 mg/kg every 8 hours over 2 weeks (maintenance: 120 mg/kg/day). The induction phase is essential for AIDS patients with cytomegalovirus disease involving critical parts of the retina; for less critical areas, maintenance therapy can be used from the outset. Both agents are effective in preventing progression of retinitis, and Ganciclovir is useful in cytomegalovirus colitis; treatment is usually lifelong in patients with AIDS. Complications include neutropenia with Ganciclovir (preventing concomitant Zidovudine therapy) and renal impairment with Foscarnet (often manageable with hydration).

CONTROL:

Cytomegalovirus hyperimmune globulin given to seronegative bone marrow or renal transplant recipients may be prophylactic. Limiting transfusions, using products filtered to remove leukocytes, and selecting cytomegalovirus-seronegative donors are all important in reducing the rate of cytomegalovirus transmission.