Cytomegalovirus (CMV)

Introduction

Cytomegalovirus (CMV) infections are common viral pathogens that generally produce “silent” or asymptomatic infections in immunocompetent individuals. However, infection has demonstrated a wide and diverse range of disease in immunocompromised hosts of all age groups.

Epidemiology

The CDC estimates that CMV infects between 50%-80% of people in the United States by age 40. Some estimates have predicted >90% prevalence among adults in the developing world.

Cytomegalovirus is the leading cause of congenital infections wordwide.

1 out of every 150 children is born with congenital CMV infection. 20% of those born with infection will develop permanent complications including developmental disabilities and neurocognitive deficits.

CMV is the most common, non-genetic cause of childhood hearing loss.

There is a 5% mortality rate among symptomatic newborns.

In the U.S., approximately 1%-4% of uninfected women have a primary (first) CMV infection during pregnancy. It is estimated that 25% of congenital CMV infections occur from primary maternal infection.

Seroprevalence is age-dependent. For example, in one U.S. based study 36% of children between the ages of 6 -11 possessed anti-CMV antibodies increasing to 91% of adults > 80.

Seroprevalence also varies by race and ethnicity, with 51.2% in non-Hispanic white persons, 75.8% in non-Hispanic black persons, and 81.7% in Mexican Americans.  

Studies have shown an inverse correlation between seroprevalence and socioeconomic development with regions of Africa, Asia and South America possessing the highest rates of infection.

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CMV seroplrevalence (shaded). Congenital CMV birth prevelance (circles).  http://cmr.asm.org/content/26/1/86/F7.expansion.html

Virology

Cytomegalovirus is a viral genus in the Hepesviridae family. It is also known as Human Herpesvirus-5 (HHV-5).

Replication is slow and the life cycle includes a lytic and latent phase.  It often takes days to weeks for host cells to show visible signs of infection under microscopic examination.

During the lytic cycle, viral replication disrupts the cystoskeleton causing massive cell enlargement.

CMV evades detection by encoding UL16, a protein that binds to and prevents expression of specific ligands on NKG2D, a cell surface receptor on NK cells. These NKG2D ligands are normally up-regulated during viral infections and by preventing up-regulation, CMV infected host cells avoid apoptotic signaling and NK response.

Characteristics include a double-stranded, linear DNA genome, icosahedral capsid, viral envelope (shown below).

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CMV structure.  http://drmhanna.com/cytomegalovirus-cmv/

Transmission

Transmission is presumed to occur through:

  • Contact with urine, saliva and nasopharyngeal secretions.
  • Sexual contact  - semen, cervical and vaginal secretions.
  • During delivery - Infants can become infected through ingestion or aspiration of cervicovaginal secretions.
  • Blood transfusions, organ transplantation and breast milk can also cause infection.

Pathophysiology - Immunocompetent Hosts

Immunocompetent hosts are usually asymptomatic but may present with mononucleosis syndrome. Patients present with protracted fever, fatigue or malaise. Lab values show increased WBC with absolute lymphocytosis > 50% mononuclear cells and > 10% atypical lymphocytes.

Rash may be present particularly after exposure to bet-lactam antibiotics such as ampicillin.

CMV can cause organ-specific complications (rare): CMV colitis, granulomatous hepatitis or transaminitis, encephalitis, Guillain-Barre syndrome, focal neurological deficits - transverse myelitis, Horner’s syndrome, and cranial nerve palsies.

Ocular manifestations include anterior uveitis

Mononucleosis: CMV vs. EBV

Mononucleosis syndrome associated with CMV infection differs from that caused by EBV.

13% – 17% patients with CMV-mononucleosis present with cervical lymphadenopathy, vs. 80% with EBV-associated mononucleosis.

CMV is not usually associated with tonsillopharyngitis and patients usually present with symptoms later in life.

Patients with CMV-related mononucleosis are heterophile antibody negative, unlike those infected with EBV.

Pregnant Mothers and Congenital Infections

Similar to infection in immunocompitent hosts, infection in pregnant mothers does not usually cause symptoms. When symptoms are present, they are non-specific and include rhinitis, pharyngitis, myalgia, arthralgia, headache and fatigue.

Infections in pregnant woman are classified as Primary and nonprimary infections.

Primary infections occur during pregnancy when a mother has not previously been exposed to, or been infected with CMV.

Nonprimary infections occur due to reactivation or infection with a second CMV strain in pregnant mothers who possess antibody to CMV prior to conception.

CMV infects placental cytotrophoblasts and then subsequently spreads to multiple tissues in the developing fetus.

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http://www.nlm.nih.gov/medlineplus/ency/imagepages/17144.htm

Most congenital infections are asymptomatic. However, between 5-20% of infants born to mothers with primary CMV infections are overtly symptomatic.

The rate of infection has been shown to increase with advancing gestational age. However, symptoms appear to be less severe the later transmission occurs during gestation.

Symptomatic newborns present with a variety of abnormalities including low birth weight, microcephaly, seizure, chorioretinitis hepatomegaly, hepatitis, jaundice, thrombocytopenia, petechiae, and characteristic  “blueberry muffin” rash due to increased extramedullary hematopoiesis.

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CMV “blueberry muffin” rash - http://fashions-cloud.com/pages/b/blueberry-muffin-rash/

Immunocompromised Hosts

CMV infection can carry severe morbidity and mortality in patients with underlying HIV infections, and those receiving immunosuppressive drugs for organ transplantation, graft survival or cancer treatment.

Disease can present in many different ways including fever, pneumonia, pneumonitis, colitis, hepatitis, myocarditis, esophagitis, GI ulcerations, diarrhea, retinitis, visual impairment, blindness, polyradiculopathy, transverse myelitis, encephalopathy, encephalitis, seizures, and coma.

Patients with weakened immunes systems are particularly susceptible to reactivation of latent CMV infection. 

Diagnosis

Serology

Acute or recent infection

  • Detection of CMV-specific IgM antibodies – detected within the first two weeks after symptom onset
  • Fourfold increase in CMV-specific IgG antibodies

Past infection

  • Decection of CMV-specific IgG antibodies (threshold determined by type of diagnostic test)
  • CMV-IgG antibodies are not detectable until 2-3 weeks after onset of symptoms

These tests have limited value in immunocompromised patients due to decreased antibody and cell-mediated immune response.

Molecular Assays

  • Quantitative real-time PCR: this test is very sensitive for detecting viral DNA and is helpful in diagnosing active disease, determining viral load, and assessing response to treatment.

CMV Antigenemia Assays

Rapid and direct detection of CMV proteins in peripheral blood leukocytes. This test uses fluorescently-labeled monoclonal antibodies to CMV protein pp65 (shown below).

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CMV immunofluorescence - http://www.komabiotech.co.kr

Histopathology

Tissue invasive disease - infected cells are identified on H & E stain by characteristic features including a large cell nucleus with peri-nuclear clearing, and basophilic staining cytoplasmic inclusion bodies which are often referred to as the “owl’s eye” appearance.

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http://perridermatology.com/blog/2010/11/9/viruses-cytomegalovirus.html

Shell Vial Culture

Rapid culture method that detects early CMV antigen in blood, CSF, bronchoalveolar lavage, urine and biopsy specimens however sensitivity of blood samples is inadequate for clinical use.  Most useful for congenital and tissue invasive disease

Treatment

Antivirals: ganciclovir, valganciclovir, foscarnet cidofovir

Hyperimmunoglobulin: Recent studies have shown that administration of CMV-specific hyperimmune globulin to pregnant women with primary CMV infection was associated with significant reduction in maternal-to-fetal transmission and severity of congenital infection.

References

  1. Cannon MJ. Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol. 2009 Dec;46 Suppl 4:S6-10.
  2. Kraft CS1, Armstrong WS, Caliendo AM. Interpreting quantitative cytomegalovirus DNA testing: understanding the laboratory perspective. Clin Infect Dis. 2012 Jun;54(12):1793-7.
  3. Manicklal S1, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The "silent" global burden of congenital cytomegalovirus. Clin Microbiol Rev. 2013 Jan;26(1):86-102.
  4. Nigro G1, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med. 2005 Sep 29;353(13):1350-62.
  5. Nigro G1, Adler SP, Parruti G, Anceschi MM, Coclite E, Pezone I, Di Renzo GC. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy--a case-control study of the outcome in children. J Infect Dis. 2012 Jan 15;205(2):215-27.
  6. Picone O1, Vauloup-Fellous C, Cordier AG, Guitton S, Senat MV, Fuchs F, Ayoubi JM, Grangeot Keros L, Benachi A. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenat Diagn. 2013 Aug;33(8):751-8.
  7. Staras SA1, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis. 2006 Nov 1;43(9):1143-51.
  8. Visentin S1, Manara R, Milanese L, Da Roit A, Forner G, Salviato E, Citton V, Magno FM, Orzan E, Morando C, Cusinato R, Mengoli C, Palu G, Ermani M, Rinaldi R, Cosmi E, Gussetti N. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis. 2012 Aug;55(4):497-503.
  9. Welte SA1, Sinzger C, Lutz SZ, Singh-Jasuja H, Sampaio KL, Eknigk U, Rammensee HG, Steinle A. Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein. Eur J Immunol. 2003 Jan;33(1):194-203.
  10. http://www.cdc.gov/cmv/clinical/