Human Herpesvirus 6 - HHV6

Human herpesvirus 6 (HHV6), a member of the β-herpesvirus subfamily, exists as two closely related variants, HHV6A and HHV6B. A large portion (>90%) of the population is infected with HHV early in life, at which time the virus can cause a mild, self-limited syndrome called roseola. In immunocompromised patients, HHV6 reactivation can cause life-threatening diseases such as myocarditis, liver failure, and encephalitis. Reactivated HHV6 can also facilitate activation of other viruses and allow the spread of fungal infection.

Tabs Content

Clinical Overview

Diagnosis

Indications for Testing

Severe viral illness in immunocompromised patients

Laboratory Testing

Immunocompromised patients
- Polymerase chain reaction (PCR)
  - More rapid and sensitive than antibody testing
  - Use in patients with suspected meningitis – cerebrospinal fluid (CSF) sample
  - Quantitative PCR may help identify acute vs. previous disease
  - Not useful for inherited chromosomally integrated human herpesvirus 6 (iciHHV6) – always positive
- Antibody testing – traditional testing of paired acute and convalescent antibody testing samples
  - Indirect fluorescent antibody (IFA) – recommended
    - Provides quantitative testing
    - Allows for evaluation of change over time
  - Enzyme-linked immunosorbent assay (ELISA) – qualitative testing; less useful
  - Not as useful as PCR in immunocompromised diagnoses
- Culture – not recommended due to difficulty and extended turnaround times
Young children – testing typically not performed; diagnosis based on clinical presentation
Concurrent testing for other viral etiologies based on symptoms
- Epstein-Barr virus
- Meningitis – arbovirus, lymphocytic choriomeningitis (LCM)
- Hepatitis – hepatitis A, B, C, cytomegalovirus (CMV)
- Bone marrow suppression – parvovirus
- Pneumonitis – herpes simplex virus (HSV), adenovirus

Differential Diagnosis

Exanthem
- Measles
- Rubella
- Parvovirus B19
Meningitis
- Other viral
  - HSV
  - Arbovirus
  - LCM
  - Mycobacterium tuberculosis
- Bacterial
- Parasitic
- Fungal
Viral fever/flulike illness
- Mononucleosis
- Hepatitis
- HIV
Seizures
- Seizure disorder
- Central nervous system (CNS) tumor
- Electrolyte abnormalities

Background

Epidemiology

Prevalence – most children >2 years are seropositive
Transmission
- Oral droplets
- Transfusion
- Organ transplantation
- Congenital

Organism

DNA virus – human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7) together constitute Roseolovirus of the Herpesviridae family
- HHV6B – most common agent
- HHV6A – may be responsible for neuromeningitis
Isolated in 1986 from patients with AIDS and lymphoproliferative disease
- Virus originally named human B-lymphotropic virus; now identified as T-lymphotropic
Following primary infection, the virus becomes latent in lymphocytes and monocytes
- May persist in various tissues with a low level of replication
Evidence suggests HHV6 may act as an opportunistic agent with reactivation found in
- Immunodeficient patients – after bone marrow or organ transplants
- HIV-infected patients – as primary infection, reactivation of latent infection, or persistent infection
- Other immunosuppressed patients

Clinical Presentation

Primary infection in children
- Fever ≥40°C persisting for 3-5 days
- Exanthem subitum (roseola infantum or sixth disease) – develops on trunk and spreads to extremities
- Diarrhea
- Respiratory symptoms
Primary infection or reactivation in immunocompromised patients (particularly in organ transplant patients)
- Meningitis/encephalitis – posttransplantation acute limbic encephalitis
- Fulminant or chronic hepatitis, gastritis, colitis
- Bone marrow suppression, hemophagocytosis syndrome
- Pneumonitis
- Organ transplant rejection
- Arthritis
- In transplant patient, increases risk for (Razonable, 2013)
  - Allograft dysfunction
  - Cytomegalovirus (CMV) disease after kidney or liver transplantation
  - Fungal disease
  - Higher mortality

ARUP Lab Tests

Detect and quantify HHV6 subtypes A and B in immunocompromised patients

The limit of quantification for this DNA assay is 3.0 log copies/mL (1,000 copies/mL)

If no virus is detected, result will be reported as “<3.0 log copies/mL (<1,000 copies/mL)”; if assay detects the presence of the virus but is not able to accurately quantify the number of copies, result will be reported as “Not Quantified”

Human Herpesvirus 6 (HHV-6A and HHV-6B) by Quantitative PCR 0060071

Method: Quantitative Polymerase Chain Reaction

Use in conjunction with HHV6, IgM screen with reflex to titer for diagnosis of HHV6 disease in immunocompromised adults

Consider HHV6 (HHV6A and HHV6B) by polymerase chain reaction (PCR) as an alternative, especially in cases of suspected meningitis

Herpesvirus 6 Antibody, IgG 2013423

Method: Quantitative Indirect Fluorescent Antibody

Use in conjunction with HHV6, IgG, for diagnosis of HHV6 disease in immunocompromised adults

Consider HHV6A and HHV6B by PCR as an alternative, especially in cases of suspected meningitis

Herpesvirus 6 Antibody, IgM by IFA, Serum 3001284

Method: Semi-Quantitative Indirect Fluorescent Antibody

Related Tests

May be helpful in differentiating bacterial from viral etiology

CBC with Platelet Count and Automated Differential 0040003

Method: Automated Cell Count/Differential

Assess metabolic derangement as cause of altered consciousness

Electrolyte Panel 0020410

Method: Quantitative Ion-Selective Electrode/Enzymatic

Panel includes sodium, serum or plasma; potassium, serum or plasma; chloride, serum or plasma; carbon dioxide, serum or plasma; anion gap

Identify bacteria in CSF

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106

Method: Stain/Culture/Identification

May be helpful in differentiating bacterial from viral etiology

Glucose, CSF 0020515

Method: Enzymatic

Diagnose and manage diabetes mellitus and other carbohydrate metabolism disorders

Glucose, Plasma or Serum 0020024

Method: Quantitative Enzymatic

Aid in differentiating bacterial from viral meningitis

Cell Count, CSF 0095018

Method: Cell Count/Differential

May be helpful in differentiating bacterial from viral etiology

Protein, Total, CSF 0020514

Method: Reflectance Spectrophotometry

Preferred initial serologic test to detect acute Epstein-Barr virus infectious mononucleosis

Heterophile Antibody (Infectious Mononucleosis) by Latex Agglutination, Qualitative 0050385

Method: Qualitative Latex Agglutination

Aid in the diagnosis of infection with arboviruses

Arbovirus Antibodies, IgG and IgM, Serum 2001594

Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Aid in the diagnosis of lymphocytic choriomeningitis (LCM) viral infection

Lymphocytic Choriomeningitis (LCM) Virus Antibodies, IgG & IgM 2001635

Method: Semi-Quantitative Indirect Fluorescent Antibody

Evaluate viral etiology in patients with acute hepatitis

Not recommended for screening asymptomatic patients

Hepatitis Panel, Acute with Reflex to HBsAg Confirmation 0020457

Method: Qualitative Chemiluminescent Immunoassay

Panel includes HAV IgM, HBV core antibody IgM, HBV surface antigen (HBsAg), HCV antibody

Reflex pattern: if results for HBsAg are repeatedly reactive with an index value between 1.00 and 50.00, then HBsAg confirmation will be added

Detect and quantify cytomegalovirus (CMV)

Cytomegalovirus by Quantitative PCR 0051813

Method: Quantitative Polymerase Chain Reaction

Aid in the diagnosis of parvovirus infection

Parvovirus B19 Antibodies, IgG and IgM 0065120

Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Preferred test for detecting herpes simplex virus (HSV) infection in CSF, neonates, or when rapid diagnostic test for suspected HSV infection is necessary

Herpes Simplex Virus by PCR 0060041

Method: Qualitative Polymerase Chain Reaction

Detect adenovirus groups A-F

Adenovirus by Qualitative PCR 2007473

Method: Qualitative Real-Time Polymerase Chain Reaction

Detect presence of IgG and IgM antibodies in individuals with a clinical suspicion of West Nile virus

West Nile Virus Antibodies, IgG and IgM by ELISA, Serum 0050226

Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Medical Experts

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 Pathology, University of Utah

References

General References

Agut H, Bonnafous P, Gautheret-Dejean A. Human herpesviruses 6A, 6B, and 7. Microbiol Spectr. 2016; 4(3): PubMed

Agut H, Bonnafous P, Gautheret-Dejean A. Laboratory and clinical aspects of human herpesvirus 6 infections. Clin Microbiol Rev. 2015; 28(2): 313-35. PubMed

Flamand L, Komaroff AL, Arbuckle JH, Medveczky PG, Ablashi DV. Review, part 1: Human herpesvirus-6-basic biology, diagnostic testing, and antiviral efficacy. J Med Virol. 2010; 82(9): 1560-8. PubMed

Pantry SN, Medveczky PG. Latency, integration, and reactivation of human herpesvirus-6. Viruses. 2017; 9(7): PubMed

Prober CG. Human herpesvirus 6. Adv Exp Med Biol. 2011; 697: 87-90. PubMed

Razonable RR. Human herpesviruses 6, 7 and 8 in solid organ transplant recipients. Am J Transplant. 2013; 13 Suppl 3: 67-77; quiz 77-8. PubMed

Tyler KL. Emerging viral infections of the central nervous system: part 1. Arch Neurol. 2009; 66(8): 939-48. PubMed

Yao K, Crawford JR, Komaroff AL, Ablashi DV, Jacobson S. Review part 2: Human herpesvirus-6 in central nervous system diseases. J Med Virol. 2010; 82(10): 1669-78. PubMed

Zamora MR. DNA viruses (CMV, EBV, and the herpesviruses). Semin Respir Crit Care Med. 2011; 32(4): 454-70. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Herrmann MG, Durtschi JD, Bromley K, Wittwer CT, Voelkerding KV. Amplicon DNA melting analysis for mutation scanning and genotyping: cross-platform comparison of instruments and dyes. Clin Chem. 2006; 52(3): 494-503. PubMed

Hymas W, Stevenson J, Taggart EW, Hillyard D. Use of lyophilized standards for the calibration of a newly developed real time PCR assay for human herpes type six (HHV6) variants A and B. J Virol Methods. 2005; 128(1-2): 143-50. PubMed

Rentz AC, Stevenson J, Hymas W, Hillyard D, Stoddard GJ, Taggart EW, Byington CL. Human herpesvirus 6 in the newborn intensive care unit. Eur J Clin Microbiol Infect Dis. 2007; 26(4): 297-9. PubMed

Content Review:

November 2017

Last Update: November 2019

Human Herpesvirus 6 - HHV6

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Organism

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Human Herpesvirus 6 - HHV6. ARUP Consult^©. Retrieved November 15, 2019, from: https://arupconsult.com/content/human-herpesvirus-6

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Human Herpesvirus 6 - HHV6

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Organism

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult