Cytomegalovirus - CMV

Cytomegalovirus (CMV) is generally asymptomatic in immunocompetent children and adults, but is a potentially significant disease in immunocompromised hosts, neonates, and pregnant females. The approach to laboratory testing depends on whether the patient is immunocompetent or immunocompromised. Serology is used in immunocompetent persons, but is not helpful in immunocompromised patients. For these patients, PCR and culture (gold standard) are more helpful.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Mononucleosis-like illness in immunocompetent patients who test negative for EBV
Suspected CMV infection in immunocompromised patients
Congenital syndromes suspicious for CMV
Pretransplant and posttransplant screening

Laboratory Testing

Acute disease confirmation in immunocompetent patients – order acute and convalescent serology
- Elevated IgM provides evidence of current infection or reactivation
  - Four-fold increase in IgG titers using paired specimens 10-14 days apart is suggestive of recent infection
Acute disease in immunocompromised patients – serology not helpful
- Quantitative measurement by PCR defines viral load
- Gold standard – tissue culture
  - Biopsy of affected tissue site or bronchoalveolar lavage
Transplant patients
- Pretransplant screening
  - IgG testing of donor and recipient
  - CMV-specific CD8 T cells – aids in determining risk of CMV infection posttransplant
    - Gold standard for tissue screening prior to transplantation
- Posttansplant screening
  - Hematopoietic stem cell (HSCT) (Tomblyn, 2009)
    - Screen 7-10 days posttransplant
    - Screen until at least 100 days posttransplant
  - Renal transplant (KIDGO, 2009)
    - Viral load monitoring for patients deemed moderate risk for CMV
Primary infection in pregnant women
- CMV IgG avidity testing to distinguish between primary and secondary infection
  - Low avidity suggests CMV infection within last 3-4 months (increased risk for infant with congenital CMV)
- Acute and convalescent serology – may be less helpful than avidity testing
  - IgM may remain positive for months
  - IgM may elevate in reactivated disease
  - Use same criteria as immunocompromised patients for active infection
- Amniotic fluid – PCR testing
  - Most sensitive >21 weeks gestation
Congenital disease
- Rapid culture of urine (early antigen detection)
- PCR on blood or body fluids
- Test within first 3 weeks to exclude perinatal infection
- Consider testing 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
Cytomegalovirus IHC stain may be useful in tissue

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 virus
- Echovirus
- Filariasis
- Parvovirus B19
- HIV
Immunocompetent patients
- Epstein-Barr virus (EBV)
- Toxoplasma gondii
- Acute HIV infection
Immunocompromised patients
- EBV
- Toxoplasma gondii
- Pneumocystis jirovecii
- Fungal infection
- Adenovirus
- Parvovirus B19
Transplant patients
- Graft versus host disease
- Rejection
- EBV
- Toxoplasma gondii
- Pneumocystis jirovecii
- Fungal infection
- Adenovirus
- Parvovirus B19
- Human herpesvirus 6

Background

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 status
Maternal infections or reinfections – leads to congenital disease

Clinical Presentation

CMV diseases and related syndromes

CMV Diseases and Related Syndromes
CMV disease	Principal syndrome	Risk factors
Primary infection in immunocompetent individual	Often asymptomatic, fever, myalgies, flu-like syndrome, mononucleosis-like syndrome, hepatitis
AIDS/HIV	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 – hepatosplenomegaly, microcephaly, periventricular calcifications, developmental delay, sensorineural hearing loss, seizures, hypotenia, blueberry muffin syndrome (petechiae and purpura), intrauterine growth restriction, chorioretinitis, myocarditis	Early maternal primary infection or reinfection (first trimester)
Organ transplantation	Pulmonary disease – pneumonia GI disease – esophagitis, gastritis, colitis, hepatitis Disseminated disease Tissue invasive disease – nephritis, myocarditis, cystitis, pancreatitis	Seronegative recipient with seropositive donor (risk increased most with intensive suppression) Immunosuppression
Bone marrow transplant	Enhanced graft vs host disease; rejection Pulmonary disease – pneumonitis GI disease – gastritis, colitis, hepatitis Disseminated disease	Older age Seropositive recipient Seropositive donor

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

ARUP Lab Tests

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.

Cytomegalovirus Rapid Culture 0065004
Method: Cell Culture/Immunofluorescence

Recommended Use

Aids in diagnosis of active cytomegalovirus infection

Molecular testing is generally preferred

Cytomegalovirus by Qualitative PCR 0060040
Method: Qualitative Polymerase Chain Reaction

Recommended Use

Detect cytomegalovirus but does not quantify viral load; potentially useful for specimen types other than blood

CMV by quantitative PCR on plasma is preferred for most clinical indications

Limitations

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

Cytomegalovirus by Quantitative PCR 0051813
Method: Quantitative Polymerase Chain Reaction

Recommended Use

Detect and quantify cytomegalovirus (CMV)

Limitations

The quantitative range of this test is 2.6-6.6 log copies/mL (390-3,900,000 copies/mL) or 2/4-6.4 log IU/mL (227-2,270,000 IU/mL)

One IU/mL of CMV DNA is ~1.72 copies/mL

Negative result (<2.6 log copies/mL [<390 copies/mL] OR <2.4 log IU/mL [<227 IU/mL]) does not rule out presence of PCR inhibitors or DNA concentrations below the level of detection

Inhibition may also lead to underestimation of viral quantitation

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

Recommended Use

Detect and quantify cytomegalovirus

Determine antiviral drug resistance to cidofovir, foscarnet sodium, and ganciclovir

Reflex pattern – if CMV quantitative PCR result is ≥3.2 log (1600 copies/mL), then CMV antiviral drug resistance by sequencing will be added

Limitations

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

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

Cytomegalovirus Antibody, IgG Avidity 2011813
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended Use

Aid in the determination of recent (previous 3-4 months) or past (>3 months) CMV infection, particularly in pregnant females

Limitations

Avidity index cannot be calculated for patients who are negative for CMV IgG antibodies

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

Recommended Use

Aid in discriminating between current and past cytomegalovirus infection in immunocompetent individuals

Limitations

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 (CMV) by Immunohistochemistry 2003833
Method: Immunohistochemistry

Recommended Use

Aid in histologic diagnosis of CMV

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

Medical Reviewers

Couturier, Marc Roger, PhD, D(ABMM), Medical Director, Microbial Immunology, Parasitology and Fecal Testing, and Infectious Disease Antigen Testing at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

Schlaberg, Robert, MD, MPH, Medical Director, Microbial Amplified Detection, Virology, and Fecal Chemistry; and Assistant Medical Director, Virology and Molecular Infectious Disease at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

References

Guidelines

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009; 9 Suppl 3: S1-155. PubMed

Tomblyn M, Chiller T, Einsele H, Gress R, Sepkowitz K, Storek J, Wingard JR, Young JH, Boeckh MJ, Boeckh MA, Center for International Blood and Marrow Research, National Marrow Donor program, European Blood and MarrowTransplant Group, American Society of Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Disease Canada, Centers for Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15(10): 1143-238. PubMed

General References

Bhatia P, Narang A, Minz RW. Neonatal cytomegalovirus infection: diagnostic modalities available for early disease detection. Indian J Pediatr. 2010; 77(1): 77-9. PubMed

Boeckh M, Geballe AP. Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest. 2011; 121(5): 1673-80. PubMed

Crough T, Khanna R. Immunobiology of human cytomegalovirus: from bench to bedside. Clin Microbiol Rev. 2009; 22(1): 76-98, Table of Contents. PubMed

de Jong EP, Vossen AC, Walther FJ, Lopriore E. How to use... neonatal TORCH testing. Arch Dis Child Educ Pract Ed. 2013; 98(3): 93-8. PubMed

Del Pizzo J. Focus on diagnosis: congenital infections (TORCH). Pediatr Rev. 2011; 32(12): 537-42. PubMed

DeVries J. The ABCs of CMV. Adv Neonatal Care. 2007; 7(5): 248-55; quiz 256-7. PubMed

Hirsch M, et al. Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8. In Kasper D et al, eds. Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill, 2005.

Lazzarotto T, Guerra B, Lanari M, Gabrielli L, Landini MP. New advances in the diagnosis of congenital cytomegalovirus infection. J Clin Virol. 2008; 41(3): 192-7. PubMed

Neu N, Duchon J, Zachariah P. TORCH infections. Clin Perinatol. 2015 Mar;42(1):77-103, viii. PubMed

Plosa EJ, Esbenshade JC, Fuller P, Weitkamp J. Cytomegalovirus infection. Pediatr Rev. 2012; 33(4): 156-63; quiz 163. PubMed

Yinon Y, Farine D, Yudin MH. Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv. 2010; 65(11): 736-43. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Hanson KE, Swaminathan S. Cytomegalovirus antiviral drug resistance: future prospects for prevention, detection and management Future Microbiol. 2015; 10(10): 1545-8. PubMed

Kim JH, Goulston C, Sanders S, Lampas M, Zangari M, Tricot G, Hanson KE. Cytomegalovirus reactivation following autologous peripheral blood stem cell transplantation for multiple myeloma in the era of novel chemotherapeutics and tandem transplantation. Biol Blood Marrow Transplant. 2012; 18(11): 1753-8. PubMed

Owen WE, Martins TB, Litwin CM, Roberts WL. Performance characteristics of six IMMULITE 2000 TORCH assays. Am J Clin Pathol. 2006; 126(6): 900-5. PubMed

Prince HE, Lapé-Nixon M, Brenner A, Pitstick N, Couturier MR. Potential impact of different cytomegalovirus (CMV) IgM assays on an algorithm requiring IgM reactivity as a criterion for measuring CMV IgG avidity. Clin Vaccine Immunol. 2014; 21(6): 813-6. PubMed

Ravkov EV, Pavlov IY, Hanson KE, Delgado JC. Validation of cytomegalovirus immune competence assays for the characterization of CD8(+) T cell responses posttransplant. Clin Dev Immunol. 2012; 2012: 451059. PubMed

Last Update: April 2018


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	Cytomegalovirus - CMV. ARUP Consult^©. Retrieved May 14, 2018, from: https://arupconsult.com/content/cytomegalovirus

Cytomegalovirus - CMV

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Prognosis

Differential Diagnosis

Background

Epidemiology

Organism

Risk Factors for Disease

Clinical Presentation

Prevention

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

References from the ARUP Institute for Clinical and Experimental Pathology^®