CYTOMEGALOVIRUS (CMV)

By Abelardo J. C. Campos, M.D.

INTRODUCTION

•	The human cytomegalovirus (CMV) is a herpes virus, the largest virus to infect humans. CMV infection is common in all human populations. (1)
•	CMV can be found in blood, urine, saliva, respiratory secretions, tears, feces, breast milk, semen and cervical secretions. (1)
•	CMV has the ability to establish a latent infection in the host after recovery from acute infection. (2)

EPIDEMIOLOGY

•	CMV is ubiquitous in humans. Around the world the mean seropositivity rate varies with location, race, socioeconomic status. However in any location, almost all the individuals eventually became infected, ranging from 60-70% in urban U.S. cities to 100 % in Africa. (1)

•	The congenital infection rate worldwide is constant between 0.5 and 2% of all newborns. (3)
•	Transmission can occur horizontally (by direct contact, person to person with virus containing secretions such as saliva, urine, cervical secretions or semen) and vertically (mother to newborn, before, during or after birth). (4)

CLINICAL MANIFESTATIONS

•	The manifestations may vary with age and immunocompetence of the host. Asymptomatic infections are the most common in healthy adults. (5)
•	In young adults, CMV infections can cause an infectious mononucleosis like syndrome with fever, lymphadenopathy and relative lymphocytosis. In CMV induced syndrome the symptoms may be more systemic, with fever predominating, and signs of enlarged lymph nodes or splenomegaly may be reduced.
•	Hematologic tests will show a relative lymphocytosis with more than 50 % of the peripheral white blood cell count composed of lymphocytes. From these 10 % or more are atypical lymphocytes. (5)
•	CMV is the most common cause of infection following solid organ or bone marrow transplantation. (6)
•	Mild liver function abnormalities are common, but severe hepatitis or jaundice is rare. (6)

DIAGNOSTIC TESTS

•

Laboratory diagnosis is frequently confounded by the ubiquity of the virus, high number of patients with asymptomatic infection, reactivated infections, and the development of IgM

•

The laboratory diagnosis is possible through a combination of: •   Viral isolation in tissue culture (human cells) from urine, pharynx, peripheral blood leukocytes, human milk, semen, cervical secretions, and body fluids. (4,7) •   Direct visualization of viral inclusion bodies. (4) •   Examination of urine for cells with intranuclear inclusions is useful in newborns. (7) •   Various serologic methods are used including fluorescence assays, indirect hemagglutination, latex agglutination and enzyme immunoassays.(4) •   The polymerase chain reaction (PCR) using primers in the gene encoding immediate early antigen or in the CMV DNA polymerase is a very sensitive technique to detect small amounts of virus in many body fluids and is especially useful in follow up of transplant patients (bone marrow, liver or kidney). (8,9)

COMPLICATIONS

In the healthy adult:
Prolonged fatigue, interstitial pneumonia, hepatitis, thrombocytopenia and hemolytic anemia, skin eruptions, meningoencephalitis, Guillain-Barré syndrome and myocarditis can occur in healthy adults but are usually mild and require little or no treatment. (5,10,11,12)

Immunocompromised adult (excluding transplant patients):

•	CMV is the most common opportunistic infection in patients with AIDS (Acquired Immunodeficiency Syndrome). (13)
•	CMV retinitis is the most common form of CMV disease in this population. (13) CMV retinitis causes an infection within the retina resulting in progressive retinal destruction with blindness in 4 to 6 months without treatment. (14)

CMV in transplanted patient

•	The immunosuppressive regimens used for transplanted patients predispose them to CMV disease. Infected organs or blood transfusions are the most common sources of infection. In these patients the severity of the disease is related to the degree of immunosuppression. (14) •   High doses of glucocorticosteroids predispose transplant patients to opportunistic infection, such as CMV. However, CMV was not a major cause of morbidity until the 1960s when myelosuppressive cytotoxic drugs were introduced. (15)
•	Morbidity due to donation from a seropositive donor to seronegative recipient is usually higher. (4)
•	CMV interstitial pneumonia is the most common, important and severe infectious complication of the bone marrow transplanted patients. Usually the onset is in the first 120 days after transplantation. The principal finding on chest radiographs is an interstitial nodular infiltrate. Usually CMV results in a rapid onset with fever, nonproductive cough and dyspnea. Hypoxia can occur in severe illness. The mortality rate is very high even with antiviral therapy. (16)
•	CMV hepatitis is more common after primary infection, usually arising after transplantation from a seropositive donor. Patients develop fever, hyperbilirubinemia, and elevated liver enzymes. Severe hepatitis can lead to liver failure and another transplantation. The signs of hepatitis (treated by antiviral therapy) can be difficult to distinguish from graft rejection (treated by increasing immunosuppression). (17)
•	Among kidney transplant patients CMV syndrome is common and consists of fever, leukopenia, atypical lymphocytosis, hepatosplenomegaly, myalgia and arthralgia. Prophylactic treatment with antiviral drugs prevents this syndrome. (18)
•	Although the incubation period for a horizontally transmitted infection is unknown, it is usually 3 to 12 weeks after blood transfusions and 4 weeks to 4 months after transplantation. (4)

In pregnancy:

•	During pregnancy a primary infection may present like mild mononucleosis syndrome or be asymptomatic. Recurrent infections do not cause symptoms. (4,6)

Congenital infections:

•	Congenital infection is more frequent among babies born to primiparous mothers with primary infections during pregnancy. (14)
•	The signs and symptoms in these babies can be jaundice, hepatosplenomegaly, petechial rash, microcephaly, motor disabilities, chorioretinitis, and cerebral calcifications. Survivors can exhibit mental retardation, microcephaly, motor disabilities, hearing loss and chronic liver disease. (6,19)
•	In infants whose mothers had primary infection during pregnancy, 10 to 20 % will have mental retardation or sensorineural deafness. Severe disease, with manifestations at birth, can appear in 5% of in-utero infected children. These children can excrete CMV in saliva and urine for 12 to 40 months. IgG antibody appears 2 to 3 weeks following a primary infection and persists for life in both children and adults. (4,6)

TRANSMISSION

•	Transmission can occur between persons by intimate contact including kissing and through transfusion of infected blood or blood products or transplantation of an infected organ. CMV is most prevalent between those who have multiple sexual partners. (1,6)
•	Vertical transmission to the infant can occur: in utero by transplacental passage of maternal blood borne virus (2%), or at birth by passage through an infected maternal genital tract (10 to 20%) or postnatally by ingestion of CMV positive human breast milk (50%). (4)
•	In healthcare workers: CMV can be found in blood, urine, saliva, respiratory secretions, tears, feces, breast, milk, semen and cervical secretions. Standards precautions are recommended by the CDC and the Johns Hopkins Hospital (INSERT LINK TO JHH CMV POLICY). Studies have shown that healthcare workers are at no greater risk than the general population. (4)

TREATMENT

Acquired CMV:
Ganciclovir IV 10 mg/kg/d in two divided doses for 14 to 21 days. For long term suppression, 5mg/kg/d for 5 to 7 d/week

Prophylaxis of CMV:
Ganciclovir 10 mg/kg/d in two doses for 1 week, then 5mg/kg/d in one dose for 100 days. (4)

PREVENTION

•	It is easy to deactivate the CMV virus with products such as soaps, detergents and alcohol. The virus is not stable in the environment. It lives 2 to 6 hours on surfaces. Low numbers may persist for 24 hours. Hand hygiene and standard precautions prevent transmission.
•	Healthcare workers: good hand hygiene, use of protective measures against secretions and body fluids to avoid direct contact.
•	Cytomegalovirus negative patients who receive tissue from CMV seropositive individuals are at high risk for CMV disease. (4)
•	Pregnant healthcare workers can work with patients who have CMV infection but must follow appropriate infection control precautions (as required of all healthcare workers)

References

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