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
• Pretransplant screening
  • IgG for donor and recipient
  • CMV-specific CD8  T cells – determine risk of CMV infection post-transplant
• Diagnosis of 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
• Neonates
  • 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
• Immunocompromised patients
  • Serology not helpful
  • Quantitative measurement by PCR defines viral load
  • Culture of tissue is gold standard
• Culture
  • Gold standard for tissue screening prior to transplantation
  • Biopsy of affected tissue site or bronchoalveolar lavage in immunocompromised patients
• Interpretation of CMV laboratory tests (CDC)

Histology

• Tissue from affected site
• 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

• Congenital disease
  • Toxoplasma gondii
  • Herpes simplex virus (HSV)
  • Varicella-zoster virus (VZV)
  • Rubella virus
  • Treponema pallidum
  • Lymphocytic choriomeningitis
  • Echovirus
  • Filariasis
• Immunocompetent patients
  • Epstein-Barr virus (EBV)
  • T. gondii
  • Acute HIV infection
• Immunocompromised patients
  • EBV
  • T. gondii
  • Pneumocystis jirovecii
  • Fungal infection
  • Adenovirus
  • Parvovirus B19
• Transplant patients
  • Graft versus host disease
  • Rejection
  • EBV
  • T. gondii
  • P. jirovecii
  • Fungal infection
  • Adenovirus
  • Parvovirus B19
  • Herpesvirus 6

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 Production

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

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 (IUGR)
• Primary infection (immunocompetent adult)
  • Flu-like syndrome
  • Fever
  • Hepatitis
  • Mononucleosis-like syndrome
  • Often asymptomatic
• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
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: Chemiluminescent Immunoassay
Cytomegalovirus Antiviral Drug Resistance by Sequencing 2004760 Method: Polymerase Chain Reaction/Sequencing
TORCH Antibodies, IgG 0050772 Method: 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
Viral Culture, Non-Respiratory 2006498 Method: Cell Culture
Viral Culture, Respiratory 2006499 Method: Cell Culture
Viral Culture, Respiratory, and Cytomegalovirus Rapid Culture 2006497 Method: Cell Culture/Immunofluorescence