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Case Presentation - Spring, 2010

Cytomegalovirus (CMV) Infection

NOTE: The diagnosis and analysis for this case study were provided by an independent physician. All conclusions and opinions are those of the physician and not Hologic, Inc.

History: 46 year old male, HIV positive

Specimen type: Bronchial lavage

Cytologic diagnosis: Consistent with Cytomegalovirus

Subsequent CMV positive biopsies: gastric, colon, anal

Case provided and edited by: Saint Joseph's Hospital, Atlanta, Georgia

GENERAL:
Human cytomegalovirus (CMV) is a member of the herpes virus family, which includes herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, human herpesviruses 6 and 7, and Kaposi sarcoma-associated herpesvirus (human herpesvirus 8). Herpes viruses have double-stranded DNA. CMV is the largest virus known to infect humans. CMV was first identified in a mouse strain (murine CMV), resulting in the beginning of modern clinical virology in 1954, and was first described in the salivary gland of a human in 1956 (salivary gland virus). Reports of congenital CMV appeared shortly thereafter (cytomegalic inclusion disease), but not reported to cause adult illness until 1965 in an infectious mononucleosis-like syndrome. Asymptomatic CMV infection is common, and 50% to 80% of the U.S. population has been exposed to the virus by age 40. After first or primary infection, the virus becomes dormant in a persistent, latent infection, apparently causing no cellular aberration.

As with all other herpes virus infections, latency is subject to reactivation into a secondary endogenous infection, and for CMV this is induced by an acquired defect in cellular immunity. Extreme symptoms are unusual in the immunocompetent individual. However, patients who are immunocompromised are at higher risk for more extreme and prolonged symptoms and signs, either from such diseases as AIDS, or secondary to the immunosuppression induced by malignancy, chemotherapy or organ transplantation regimens. Also at significant risk for disease severity are babies born to women with primary infection during pregnancy. The virus is known to be transmitted by bodily secretions, including saliva, tears, blood, breast milk, stool, vaginal secretions, and semen. Once transmitted, the virus can initially infect cells in the salivary glands, respiratory system, GI tract, liver, kidneys, adrenal glands, and reproductive organs. During the lifelong latent phase, various cells have been found to harbor the virus, including neutrophils, T lymphocytes, macrophages, endothelial cells, neural cells, smooth muscle cells, and epithelial cells of salivary gland and kidney. CMV is not known to be oncogenic. There is extensive research into the relationship of CMV and atherosclerosis, but thus far, no definitive cause and effect relationship between infection and atheromatous plaque formation has been forthcoming.

CLINICAL FEATURES:
Most healthy individuals have asymptomatic primary CMV infections. When primary infection is delayed until young adulthood, patients may develop fever, swollen lymph nodes, and lethargy, resulting in an infectious mononucleosis-like syndrome with peripheral blood lymphocytosis, but heterophil antibody is negative. (CMV is responsible for about 20% of infectious mononucleosis, the rest being Epstein-Barr virus.) In the few immunocompetent patients who develop signs and symptoms of clinically evident disease, patients may experience interstitial pneumonia, hepatitis, Guillain-Barre syndrome, meningoencephalitis, myocarditis, thrombocytopenia, hemolytic anemia, and skin rashes. For those patients suffering from an acquired immunodeficiency state such as AIDS, reactivation of latent infection may result in all of the above illnesses, as well as gastrointestinal ulcers, chorioretinitis, polyradiculopathy, seizures, coma, and death. Most solid organ and hematopoietic stem cell transplant recipients who develop CMV disease acquire the CMV strain responsible for the acute illness from the donor and therefore represent primary infections rather than endogenous reactivation.

CONGENITAL CMV:
A newborn exposed to CMV from a seropositive (but latently infected) mother's cervix during passage through the birth canal or during the perinatal period from breast milk is usually asymptomatic. There is low risk for development of symptoms or associated disabilities, although there is some evidence for long term risk of subtle decrease in intelligence and sensorineural hearing loss, which apparently drives the search for an effective vaccine. In contrast, a fetus exposed to CMV by active transplacental infection in utero from a seronegative mother (almost always related to the mother's acquisition of a primary CMV infection early in the pregnancy) is more likely to develop congenital CMV with clinically evident disease, exhibited by microcephaly, CNS calcifications, jaundice, purpuric skin rash, low birth weight, enlarged spleen and liver, pneumonia, and seizures. If the newborn infant survives, possible long term disabilities include hearing loss, visual disturbances, learning disabilities, lack of neuromuscular coordination, and seizures.

CYTOLOGY AND HISTOLOGY:
Unlike the herpes simplex virus, CMV does not typically infect squamous cells. Multinucleated cells are not commonly found, but infected cells are usually enlarged-- thus the name "cytomegalo"-virus. The infected cells are often present below the surface, instead of involving the surface epithelium of the mucosa, but CMV infected cells can be visualized in certain cytology specimens, such as bronchial fluid because of infection of pneumocytes and in urine because of infection of renal tubular cells ("cytomegalic inclusion disease") using the standard Papanicolaou stain. CMV is more frequently visible in histology specimens using the standard H&E stain. Infected cells have a large, generally basophilic intranuclear inclusion surrounded by a prominent halo ("owl's eye"; Cowdry A type). The nuclear envelope is typically thickened due to peripheral condensation of chromatin. Granular cytoplasmic inclusions are also often visualized, and CMV is differentiated from other herpes viruses by the presence of both cytoplasmic and intranuclear inclusions. In sections, sometimes only cytoplasmic inclusions are visible because the plane of section misses the intranuclear inclusion. These cytoplasmic inclusions are positive by PAS and GMS stains. Immunohistochemistry stains yield more definitive positive results by marking CMV intranuclear inclusions with an antibody specific for CMV antigen pp65. Nucleic acid probes and in situ hybridization are also available to confirm CMV-DNA or RNA, but standard IHC is usually sufficient for establishing the nature of the virus.

DIAGNOSIS, TREATMENT AND PREVENTION:
Prior CMV exposure can be detected using a blood test to identify IgG antibodies to CMV, since seroconversion from negative to positive indicates infection. Active acute infection by CMV can be diagnosed by detecting a high or rising IgM titer. CMV viral load may be quantitatively identified in body fluids by PCR, detecting the gene for antigen pp65, and this is being used in evaluation of the blood and spinal fluid of AIDS patients and transplant patients. Tissue samples can be examined by standard cytological or histological procedures, or by immunofluorescence. CMV can be cultured in a human fibroblast cell line, which requires long cultivation time delay by conventional viral isolation techniques, but results are available in 48 hr by the rapid spin amplification shell vial technique utilizing monoclonal antibody.

Treatment is usually not necessary or recommended for healthy adults and children who are immunocompetent. Newborns, immunocompromised patients and occasional immunocompetent patients with significant symptoms are treated with antiviral drugs such as ganciclovir or foscarnet which block viral DNA polymerase.

Transmission of the virus usually requires direct contact and is not typically considered to be a significant airborne contagious risk, although aerosolized nasal secretions have been implicated in child daycare centers. Risk of transmission of CMV by blood transfusion can be reduced either by limiting blood units to seronegative donors, or by using leuko-reduced units.

Immunization for CMV by vaccine is currently in the research phase.

References:
  1. www.mayoclinic.com/health/cmv/DS00938
  2. www.cdc.gov/cmv
  3. Atkinson, Barbara; Silverman, Jan: Atlas of Difficult Diagnoses in Cytopathology. 1998: 117,133,207,226,233,237.
  4. Bibbo, Marluce: Comprehensive Cytotechnology 2nd Edition. 1997: 142,345, 418, 433, 454.
  5. DeMay, Richard: The Art & Science of Cytopathology – Exfoliative Cytology. 1996: 54, 112, 223, 237, 337, 354, 394-395, 1194.
  6. Geisinger, Kim; Silverman, Jan; Wakely Jr., Paul: Pediatric Cytopathology. 1994: 140-141, 154, 159.
  7. Lack, Ernest E, Chandler, Francis W, and Pearson, Gary R.: Cytomegalovirus Infection in Pathology of Infectious Diseases, 1997 (edited by Conner, Chandler, Schwartz, Manz, and Lack):91-99.
  8. Crumpacker, Clyde S. and Zhang, Jie Lin: Cytomegalovirus in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 7th ed, 2010 (edited by Mandell, Bennett, and Delin): 1971-1987.