Cytomegalovirus - CMV

Diagnosis

Indications for Testing

  • Mononucleosis-like illness in immunocompetent patients
  • Suspected CMV infection based on presentation in immunocompromised patients
  • Congenital syndrome that presents with symptoms of CMV

Laboratory Testing

  • Acute disease in immunocompetent patients – acute and convalescent serology
    • Positive IgM provides evidence of current infection or reactivation
    • Observation of at least a fourfold increase in CMV-specific IgG titers in paired specimens obtained at least 2-4 weeks apart is suggestive of recent or acute infection
  • Acute disease in immunocompromised patients
    • Serology not helpful
    • Quantitative measurement by PCR defines viral load
    • Culture of tissue is gold standard
    • Biopsy of affected tissue site or bronchoalveolar lavage in immunocompromised patients
  • Pretransplant screening
    • IgG for donor and recipient
    • CMV-specific CD8  T cells – aids in determining risk of CMV infection post transplant
    • Gold standard for tissue screening prior to transplantation
  • Primary infection in pregnant women
    • Serology – IgG avidity testing to distinguish between primary and secondary infection
    • Perform acute and convalescent serology (IgM may remain positive for months and may occur in reactivated disease)
    • Use same criteria as immunocompromised patients for active infection
    • May also test amniotic fluid using PCR – most sensitive >21 weeks gestation
  • Neonatal disease
    • Rapid culture of urine (early antigen detection)
    • PCR on blood or body fluids (amniotic fluid for prenatal diagnosis)
    • Diagnose in first 3 weeks to exclude perinatal infection
    • May need to test for other congenital syndromes if CMV not clearly identified as etiology of congenital disease
  • Interpretation of CMV laboratory tests (CDC)

Histology

  • Presence of characteristic intranuclear and intracytoplasmic inclusions confirms diagnosis
  • Immunohistochemical – cytomegalovirus stain

Prognosis

  • Neonatal – poor outcome associated with the following
    • Cerebrospinal fluid protein >120 mg/dL
    • CT – calcifications/microcephaly
    • Fetal ultrasound – placentomegaly; observed fetal anatomic abnormalities

Differential Diagnosis

Clinical Background

Cytomegalovirus (CMV), generally asymptomatic in immunocompetent children and adults, is a potentially significant disease in immunocompromised hosts, neonates and pregnant females.

Epidemiology

  • Incidence  
    • ~70% of adults in the U.S. are seropositive
    • 1%-2% of U.S. population infected yearly
  • Transmission
    • Transplacental (congenital), perinatal (human milk, cervical secretions)
    • Blood transfusion
    • Organ transplantation (both solid and hematopoietic)
    • Infectious droplet (normal childhood route)
      • CMV excreted in all secretions except tears
    • Sexual contact

Organism

  • Largest member of the herpesvirus family; double-stranded DNA virus
  • Ability to remain latent (feature of all herpes viruses)
  • Large intranuclear and cytoplasmic inclusions produced in tissues by CMV are the hallmark of the disease

Risk Factors for Disease

  • HIV
  • Organ transplantation
  • Immunocompromised states
  • Congenital – maternal primary infection or reinfection

Clinical Presentation

  • Infection in utero or at birth (cytomegalic inclusion disease)
    • Congenital abnormalities include hepatosplenomegaly, microcephaly, developmental delay, chorioretinitis, sensorineural hearing loss, seizures, hypotonia, and “blueberry muffin” syndrome rash
    • Intrauterine growth restriction
  • Primary infection (immunocompetent adult)
  • CMV diseases and related syndromes

    CMV Diseases and Related Syndromes

    CMV disease

    Principal syndrome

    Risk factors

    AIDS

    Pulmonary disease – pneumonia
    Ophthalmic disease – retinitis
    GI disease – gastritis, colitis, esophagitis
    CNS disease – encephalopathy, neuropathy

    CD4+ cells <100/mL
    Previous CMV infection

    Congenital

    Cytomegalic inclusion disease

    Primary early maternal infection

    Organ transplant

    Pulmonary disease – pneumonia
    GI disease – esophagitis, gastritis, colitis, hepatitis
    Disseminated disease
    Tissue invasive disease – nephritis, myocarditis, cystitis, pancreatitis

    Seronegative recipient with seropositive donor (increased risk with intensive suppression)
    Immunosuppression

    Bone marrow transplant

    Enhanced graft vs host; rejection
    Pulmonary disease – pneumonitis
    GI disease – gastritis, colitis, hepatitis
    Disseminated disease

    Older age
    Seropositive recipient or seropositive donor

  • Associated illnesses – hepatitis, pneumonia or a mononucleosis-like illness with little or no exudative pharyngitis or adenopathy (heterophile antibody negative mononucleosis)

Treatment

  • CMV disease and related syndromes are often treatable
  • CMV prophylaxis is useful in high-risk patients

Prevention

  • Blood transfusions
    • Seronegative individuals transfused with blood from seropositive donors have a high risk of developing CMV infection
    • Serologic testing for CMV is important in screening blood for transfusion to neonates or to immunocompromised patients
    • Use of leukocyte-reduced blood products greatly reduces the risk of transfusion-associated transmission
  • Patients with altered cellular immunity (eg, AIDS, recipients of organ transplants or cancer patients in active treatment)
    • Serologic testing is important for screening organ donors and recipients
    • CMV infection is frequent and severe in transplant recipients
    • IgG titers are not a reliable means to detect reactivation of latent virus
      • Most AIDS patients are seropositive for CMV before HIV infection is diagnosed
    • Monitor viral loads with quantitative PCR

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cytomegalovirus Rapid Culture 0065004
Method: Cell Culture/Immunofluorescence

Rapid test to diagnose CMV infection

Recommended for detecting CMV in specimens other than CSF; gold standard test for tissue

High sensitivity and specificity

   
Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction

Standard of care for diagnosing CMV in CSF

Rapid test to diagnose CMV in immunocompromised patients or solid organ donors (not tissue donors)

May be performed on amniotic fluid

PCR on amniotic fluid should be performed >21 weeks gestation to reduce risk of false negatives

 
Cytomegalovirus by PCR, Whole Blood or Bone Marrow 0060031
Method: Qualitative Polymerase Chain Reaction

Rapid test to diagnose CMV infection

   
Cytomegalovirus, Quantitative PCR 0051813
Method: Quantitative Polymerase Chain Reaction

Diagnose CMV infection

Monitor disease state in solid organ transplant and HIV patients

Negative result does not rule out presence of PCR inhibitors or DNA concentrations below the level of detection

Limit of quantification for this DNA assay is 2.6 log copies/mL (390 copies/mL); if the assay DID NOT DETECT the virus, the test result will be reported as <2.6 log copies/mL (<390 copies/mL)  

If assay DETECTED presence of virus but was unable to accurately quantify number of copies, test result will be reported as not quantified

 
Cytomegalovirus, Quantitative PCR with Reflex to Drug Resistance Testing by Sequencing 2006966
Method: Quantitative Polymerase Chain Reaction/Sequencing

Diagnose CMV infection

Monitor disease state in solid organ transplant and HIV patients

Negative result does not rule out presence of PCR inhibitors or DNA concentrations below the level of detection

 
Cytomegalovirus Antibodies, IgG and IgM 0050622
Method: Semi-Quantitative Chemiluminescent Immunoassay

Diagnose pregnant women and infants possibly infected with CMV

Discriminate between current (IgM) and prior infections (IgG)

Not recommended for immunocompromised patients

Rise in CMV antibody level may occur in patients with measles, VZV or HSV due to antigenic cross-reactivity within the herpesvirus family

Infants may test positive during first 6 months due to maternal antibodies

 
Cytomegalovirus IgG Avidity (AviDx), ELISA 2003044
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Measure CMV IgG avidity to distinguish primary infection from non-primary infection during pregnancy

   
Cytomegalovirus (CMV) by Immunohistochemistry 2003833
Method: Immunohistochemistry

Aid in histologic diagnosis of CMV

Stained and returned to client pathologist for interpretation; consultation available if needed

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Cytomegalovirus Antibody, IgM 0050553
Method: Semi-Quantitative Chemiluminescent Immunoassay

CMV serology is not useful for the evaluation of active or reactivated infection in immunocompromised patients; molecular diagnostic tests (ie, PCR) are preferred in these cases

Cytomegalovirus Antibody, IgG 0050165
Method: Semi-Quantitative Chemiluminescent Immunoassay
Cytomegalovirus Antiviral Drug Resistance by Sequencing 2004760
Method: Polymerase Chain Reaction/Sequencing
TORCH Antibodies, IgG 0050772
Method: Semi-Quantitative Chemiluminescent Immunoassay/Quantitative Chemiluminescent Immunoassay
TORCH Antibodies, IgM 0050665
Method: Semi-Quantitative Chemiluminescent Immunoassay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay
Viral Culture, Non-Respiratory and Cytomegalovirus Rapid Culture 2006496
Method: Cell Culture/Immunofluorescence

Viruses that can be isolated – adenovirus, CMV, enterovirus, HSV, and VZV

Virus-specific tests are recommended

Viral Culture, Non-Respiratory 2006498
Method: Cell Culture

Viruses that can be isolated by culture – adenovirus, CMV, enterovirus, HSV, and VZV

Virus-specific tests are recommended

Viral Culture, Respiratory 2006499
Method: Cell Culture

Viruses that can be isolated – adenovirus; CMV; enterovirus; HSV; influenza A and B; parainfluenza types 1,2, and 3; RSV; and VZV

Virus-specific tests are recommended

Viral Culture, Respiratory and Cytomegalovirus Rapid Culture 2006497
Method: Cell Culture/Immunofluorescence

Viruses that can be isolated – adenovirus; CMV; enterovirus; HSV; influenza A and B; parainfluenza types 1,2, and 3; RSV; and VZV

Virus-specific tests are recommended