Lymphoreticular and Hematopoetic Infections
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CYTOMEGALOVIRUS INFECTIONS

General Goal: To know the major cause of these diseases, how they are transmitted, and the major manifestations of the diseases.

Specific Educational Objectives: The student should be able to:

1. describe the family of virus this organism belongs to, what cells it infects and can establish latency in. Know how long the infection lasts.

2. describe the common means of transmission. Know what portion of the population is damaged the most by this virus.

2. describe the major manifestations of this infection.

3. describe how you diagnose, treat and prevent this infection.

Reading: MEDICAL MICROBIOLOGY by P.R. Murray, K.S. Rosenthal, G.S. Kobayashi and M.A. Pfaller, 3rd Edition. pp. 434-437.

Mosby's Color Atlas and Text of Infectious Diseases by Christopher P. Conlon and David R. Snydman. pp. 211-215.

Lecture: Dr. Neal R. Chamberlain

References:

Koffron AJ, Mueller KH, Kaufman DB, Stuart FP, Patterson B, Abecassis MI.1995. Direct evidence using in situ polymerase chain reaction that the endothelial cell and T-lymphocyte harbor latent murine cytomegalovirus. Scand J Infect Dis Suppl 99:61-2

Jarvis MA, Nelson JA. 2002. Human cytomegalovirus persistence and latency in endothelial cells and macrophages. Current Opin. Microbiol. 5(4):403-407.

OVERVIEW

Cytomegalovirus (CMV) causes asymptomatic infections, serious congenital infections, heterophile-negative mononucleosis in adults, and fever hepatitis syndrome in neonates and transplant recipients.

ETIOLOGY

CMV, a herpes virus (Human Herpes Virus 5; HHV-5)

EPIDEMIOLOGY

Incidence: CMV is ubiquitous, and at least 80% of adults (worldwide) have antibody to it. Infection rates are highest below age 6 and are elevated for young adults. The rate of CMV infection in adolescents of well-developed countries is about 10-15%, increasing to about 50% when 35 years old.

CMV is the most common viral cause of congenital defects.

Source: CMV has been isolated from urine, blood (harbored within leukocytes), throat washings, saliva, tears, breast milk, semen, stools, amniotic fluid, vaginal and cervical secretions, as well as tissues taken for transplantation.

Routes of transmission:

Congenital infection:

Perinatal infection: Approximately 20% of pregnant women at term harbor CMV in their cervix; mostly reactivation. Neonates may acquire CMV during passage through the birth canal or later from breast feeding.

Infection in adults.

Oral
Sexual transmission
Postneonatal CMV infection rates are increased under crowded living conditions, with some role for sexual transmission.
Posttransfusion infection.
Infection following transplantation. CMV may be transmitted by organ transplantation. Sero-positive recipients may reactivate the virus due to immunosuppressive therapy.

Major means by which CMV is transmitted; sexual route (heterosexual and homosexual), transfusions, and transplants.

PATHOGENESIS

Usually CMV infections are subclinical.

CMV infects epithelial cells and lymphocytes.

CMV is highly cell-associated and spreads to coalescing cells. This close cell-interaction protects the virus from antibody inactivation.

Latency: Eventually CMV attains a latent state and persistent infection within T-cells, endothelial cells and monocyte-derived macrophages.

Cell-mediated immunity is required for resolution of symptoms and also contributes to symptoms. Antibodies role is limited.
Suppression of cell-mediated immunity allows recurrence of symptoms and can result in severe disease.

Immunosuppression: The virus also has the ability to induce immunosuppression in the body.

MANIFESTATIONS

Congenital infection. 0.2% to 2% of all newborns are infected with CMV. Fetuses can be infected via their mother's bloodstream during a primary infection of the mother or by virus ascending from the cervix (during a recurrence). Symptoms of a congenital infection are usually less severe or can be prevented in the fetus of a seropositive mother. Approximately 10-15% (4000 per year) of infants infected in utero via a primary maternal infection show classic CMV inclusion disease and may exhibit teratogenesis:

microcephaly	thrombocytopenia with petechiae or purpura
intracerebral calcification	hepatosplenomegaly
chorioretinitis	rash
seizure disorders	jaundice
mental retardation and hearing loss (1-3% of cases)	interstitial pneumonia

Neonatal infection. As many as 20% of pregnant women harbor CMV in their cervix at term and are likely to experience reactivation of CMV during their pregnancy. About 50% of the neonates born through an infected cervix acquire CMV and become excreters of the virus at 3-4 wks. They may also acquire a CMV infection from maternal milk or colostrum. Healthy infants who acquire CMV at birth usually show NO symptoms of disease.

Neonates can also acquire CMV via blood transfusions. Of the seronegative neonates exposed to seropositive donor 13.5% acquire CMV. Significant clinical disease can occur in premature neonates who acquire CMV by blood transfusion. Most common manifestations include: pneumonia and hepatitis.

Infection in children and adults. Only 10-15% of adolescents are infected with CMV however this number increases to 50% by 35 years of age. CMV is sexually transmitted. 13 to 23% of women visiting venereal disease clinics have CMV isolated from their cervix. CMV concentrations in semen is the highest of all body secretions.

Young adults who are infected with CMV are generally asymptomatic, but may develop an infection resembling infectious mononucleosis called heterophile-negative mononucleosis syndrome: sore throat without exudative tonsillitis fever atypical lymphocytosis abnormal liver function tests

Transplant patients and posttransfusion infection. usually asymptomatic. Common manifestations include; In adults: mononucleosis-like syndrome after 3-5 weeks. pneumonia, hepatitis.

Immunocompromised patients. Both reactivation and primary infections can occur in this group of patients. Interstitial pneumonia is a common outcome in the immunosuppressed and can be fatal if not treated. Other manifestations include hepatitis, encephalitis, esophagitis (10% of AIDS patients), colitis (10% of AIDS patients), pancreatitis, cholecystitis, chorioretinitis (10-15% of AIDS patients; The first signs of CMV retinitis are vision problems such as moving black spots.), necrotizing adrenalitis.

DIAGNOSIS

Cytology. CMV-induced large-inclusion bodies in urine sediment diagnoses CMV infection in neonates, however 1/3 false negatives.

Histology. The owl's eye appearance of CMV infected cells can easily be seen in tissue or organ preparations from any part of the body. Cells are enlarged and contain intranuclear and intracytoplasmic inclusions and peripheralized chromatin.

Culture. The ability to culture CMV from the patient gives the most reliable diagnosis. CMV can be found in most body fluids and cultured on diploid fibroblast lines with positive results in 1-4 weeks. However, positive results can be visualized in 16-36 hours after inoculation by applying monoclonal antibodies and immunofluorescent staining.

Serology. CMV infected patients exhibit a negative heterophile antibody test. Complement fixation can be used to detect CMV-IgM antibodies in infants infected with CMV in utero.

THERAPY

The most effective treatment for CMV infections is ganciclovir (dihydroxy propoxymethyl guanine), an analog of acyclovir and foscarnet.

Hyperimmune human anti-CMV immunoglobulin has been used to reduce CMV disease associated with renal transplants.

PREVENTION

Safe sex practices as well as blood and tissue screening will help limit the spread of CMV.

An attenuated CMV vaccine is under development. It is targeted at preventing the most serious forms of CMV illness: primary infection of immunosuppressed patients and congenital infections.