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.

Lecture: Dr. Neal R. Chamberlain

References: 

P.R. Murray, K.S. Rosenthal, and M.A. Pfaller. 2009. Medical Microbiology. 6th Edition. pg. 534-537. Mosby Elsevier, Philadephia, PA.

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.

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

EPIDEMIOLOGY

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: virus ascends from the cervix (viral reactivation in immune mothers) or invades from the maternal blood (mothers with primary 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.

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

CMV infections are usually subclinical. CMV is acquired from contaminated blood, tissue, and most body secretions. The virus infects epithelial cells, macrophages, and T lymphocytes. Epithelial cells when infected by CMV produce more virus. CMV is highly cell-associated and causes cells to coalesce. The close cell interaction protects the virus from antibody inactivation. Cell-mediated immunity is required for resolution of symptoms and contributes to symptoms.CMV eventually becomes latent within T lymphocytes, endothelial cells, and macrophages.

Suppression of cell-mediated immunity (e.g., HIV infection, corticosteroid use) allows recurrence of symptoms and can result in severe disease. The virus has the ability to induce immunosuppression during primary infections and reactivation of latent infections. CMV prevents expression of MHC I on the cell surface of an infected cell. It can also block cytokine-induced production of MHC-II on antigen presenting cells.  This virus can also produce an IL-10 analogue that inhibits TH1 protective responses.

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

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.

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. The inclusions can be visualized with Papanicolaou or hematoxylin-eosin staining.

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. Viral antigens can be detected with an immunofluorescence assay. An ELISA can be used to detect antibodies to CMV in the serum.

DNA Probe Techniques. PCR or in situ DNA probe hybridization assays can be used to detect viral DNA in biopsies, blood, bronchoalveolar lavages, and urine samples.

Ganciclovir, valganciclovir, cidofovir, and foscarnet have all been approved to treat diseases caused by CMV in immunocompromised patients.

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

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.