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
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.
At least 80% of adults worldwide carry antibody to the CMV virus. CMV causes asymptomatic infections, serious congenital infections, heterophile antibody-negative mononucleosis in adults, and fever hepatitis syndrome in neonates and transplant recipients.
CMV, or HHV-5, is a herpes virus. As is seen with all herpes viruses, infection is lifelong.
Fetuses can be infected with CMV via the mother’s bloodstream during a primary infection of the mother or by virus ascending from the cervix following reactivation of a prior infection. Symptoms of a congenital infection are usually less severe or can be prevented in the fetus of a seropositive mother (reactivation). Approximately 10–15% (4000 per year) of infants infected in utero via a primary maternal infection show CMV inclusion disease and may exhibit teratogenesis (Table L-16).
Table L-16. Manifestations of Congenital Cytomegalovirus Inclusion Disease
Neonates can acquire CMV following blood transfusions. Of all seronegative neonates exposed to a seropositive donor, 13.5% acquire CMV. Significant clinical disease can occur in premature neonates who acquire CMV by blood transfusion. The most common manifestations include pneumonia and hepatitis.
Healthy full-term infants who acquire CMV at birth usually exhibit no symptoms of disease.
Young adults who are infected with CMV are generally asymptomatic, but they may develop a disease resembling infectious mononucleosis called heterophile-negative mononucleosis syndrome. Symptoms of this disease include sore throat without exudative tonsillitis, fever, and atypical lymphocytosis. Fever is usually much higher than is seen with heterophile positive mononucleosis. Cervical lymphadenopathy is less commonly seen in heterophile-negative mononucleosis.The results of liver function tests are abnormal.
Patients who have undergone transplantations and had posttransfusion infections usually experience asymptomatic infections. If disease occurs, manifestations include mononucleosis-like syndrome, pneumonia, or hepatitis in adults
.Both reactivation and primary CMV infections can cause disease in immuno-compromised patients. Interstitial pneumonia is a common outcome in the immunocompromised and can be fatal if not treated. Other manifestations include hepatitis, encephalitis, esophagitis (in 10% of AIDS patients), colitis (in 10% of AIDS patients), pancreatitis, cholecystitis, chorioretinitis (in 10–15% of AIDS patients), and necrotizing adrenalitis.
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 to form large cells. 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.
Diagnosis of a CMV infection can be confirmed by detection of CMV-induced large inclusion bodies present in urine sediment. 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. An atypical lymphocytosis is also present in a complete blood count. The ability to culture CMV from the patient is the most reliable diagnosis.
CMV can be found in most body fluids and cultured on eukaryotic diploid fibroblast cells. Viral growth in tissue culture can be visualized 16–36 hours after inoculation by applying monoclonal antibodies and immunofluorescent staining. Patients infected with CMV who have symptoms of mononucleosis (i.e., fever, cervical lymphadenopathy, pharyngitis) do not have a heterophile antibody response. Patients who are positive for heterophile antibodies have mononucleosis due to EBV and not due to CMV.
Viral antigens can be detected with an immunofluorescence assay. An ELISA can be used to detect antibodies to CMV in the serum. PCR or in situ DNA probe hybridization assays can be used to detect viral DNA in biopsies, blood, bronchoalveolar lavages, and urine samples. Complement fixation can be used to detect CMV-IgM antibodies in infants infected with CMV in utero.
Therapy and Prevention
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 in combination with anti-viral medications to reduce CMV disease associated with renal and bone marrow transplantations. Safe-sex practices as well as blood and tissue screening will help limit the spread of CMV.
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