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Human Herpesvirus 6 Infection Workup

  • Author: Michelle R Salvaggio, MD, FACP; Chief Editor: Burke A Cunha, MD  more...
 
Updated: Nov 10, 2015
 

Approach Considerations

Human herpesvirus 6 (HHV-6) may be diagnosed by means of viral culture, serologic testing, or polymerase chain reaction (PCR) assay.[50, 51, 52] However, because of the self-limiting nature of primary HHV-6 infection, laboratory diagnosis is rarely required in patients who are immunocompetent. Most often, such infection is diagnosed on the basis of its clinical features. Leukopenia with lymphocytosis may suggest the diagnosis. Transaminase elevations, cholestasis, and thrombocytopenia may be noted.

Diagnoses in patients who are recipients of organ transplants or patients with immunodeficiency, encephalitis, or hepatitis are performed by different laboratory methods.

HHV-6 can be isolated from the blood for the first 5 days and later is found intermittently or persistently in saliva, stool, and, rarely, urine. One study showed that HHV-6 and HHV-7 antigenemia usually occurred together with symptomatic cytomegalovirus (CMV) infection after liver transplantation.[53] HHV-6 infection preceded CMV infection, but HHV-7 infection appeared together with CMV infection. However, further investigation of the clinical significance of HHV-6 and HHV-7 antigenemia in organ transplant patients is necessary.

Other studies used in the diagnosis of HHV-6 infection include diagnostic imaging, bronchoscopy, lumbar puncture (LP), and tissue biopsy.

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Laboratory Studies

Routine tests

Routine laboratory studies used to evaluate for HHV-6 depend on the clinical presentation and setting—for example, whether the host is immunocompetent or immunocompromised.

The complete blood count (CBC) may show leukopenia and varying degrees of cytopenia (thrombocytopenia or anemia), especially in the setting of transplantation. In active infection, a CBC with differential shows leukopenia with relative leukocytosis.

Electrolyte concentrations should be evaluated and renal function tests performed, especially in renal transplant patients. Liver function tests may reveal hepatitis or liver dysfunction.

Culture

Standard peripheral cell culture, which takes 5-21 days and is labor-intensive, and shell vial assay culture, which takes 1-3 days, are available (albeit on a limited basis) for isolating HHV-6. The virus causes a characteristic finding of balloonlike syncytia on cell culture as a consequence of its cytopathic effects. The rapid shell vial assay yields a sensitivity of 86% and a specificity of 100%.

Immunohistochemistry

Immunohistochemical stains are available for detecting HHV-6 in formalin-fixed paraffin-embedded tissues. Only cells with active infection, as opposed to latent infection, stain positively with these antibodies. Immunohistochemical staining can be performed on tissue and cytologic samples. For biopsy and cytologic specimens, results are available in 1-3 days.

Serology

Primary infection can be demonstrated by seroconversion from immunoglobulin G (IgG)-negative to IgG-positive or by the presence of immunoglobulin M (IgM) to HHV-6. Active HHV-6 disease (primary or reactivated) is indicated by a 4-fold increase in IgG on immunofluorescence or a 1.6-fold increase in antibody on enzyme immunoassay (EIA). Distinguishing primary infection from reactivation can be difficult.

Immunofluorescent techniques include both indirect and anticomplement methods; results are operator-dependent and may lack objectivity. In general, EIA methods are more easily quantified and less subjective. Note that increases in HHV-6 antibody levels have been observed in other herpesvirus infections. CMV antibodies can cross-react with HHV-6 antibodies; hence, exclusion of CMV is required. CMV and HHV-6 are closely related on a genomic level.

Polymerase chain reaction assay

PCR assays can be performed on either cellular or acellular specimens. Acellular samples, including CSF, have been suggested to be more helpful in distinguishing active from latent infection.

Rapid diagnosis of HHV-6 primary infections or reactivations can be facilitated by using quantitative PCR assays.[54] Detection of co-infections with multiple herpesviruses can also be accomplished, with quantitative results enabling monitoring of virus load during antiviral therapy.

Neither qualitative nor quantitative PCR of plasma is sufficient to distinguish between active viral replication and chromosomal integration with HHV-6. A higher specificity may be obtained by using reverse transcriptase PCR (RT-PCR) when evaluating samples for active HHV-6 replication.[55, 56]

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Radiography and Computed Tomography

Chest radiography or computed tomography (CT) of the chest should be performed in patients with respiratory symptoms. These may show evidence of pneumonitis or pneumonia.

A head CT scan, with and without contrast, should be obtained to rule out other treatable diseases.

Indications for these and other diagnostic procedures depend on the clinical presentation, especially in immunocompromised patients.

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Other Studies

Clinicians should have a low threshold for ordering certain diagnostic procedures, including bronchoscopy, LP, and tissue biopsy.

In cases of respiratory distress, bronchoalveolar lavage (BAL) or biopsy samples can be sent for immunohistochemical staining to identify HHV-6 infection.

In patients with central nervous system (CNS) symptoms, LP can be performed to rule out other etiologies. In cases of febrile seizures due to HHV-6 infection, the cerebrospinal fluid (CSF) may reveal a mild pleocytosis with elevated protein levels, but it is often noteworthy for a complete lack of inflammatory response. CSF can be sent for HHV-6 PCR studies. A positive result may indicate active HHV-6 infection in the CNS. The virus has not been shown to grow in CSF samples sent for viral culture.

Tissue biopsy is especially relevant in solid-organ or bone-marrow transplant recipients who have evidence of graft rejection and in immunocompromised patients with severe hepatitis or hepatic failure. Samples should be sent for immunohistochemical staining and cell culture to identify HHV-6 infection. Skin biopsies have failed to show the presence of HHV-6 in cases of rash. If the etiology of a rash is in doubt, skin biopsy should be obtained to rule out other causes.

On histologic analysis, typical balloonlike cells (cells that show cytoplasmic swelling with a loss of intercellular bridges) may be seen in all affected organs.

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Contributor Information and Disclosures
Author

Michelle R Salvaggio, MD, FACP Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, Director, Clinical Trials Unit, Director, Ryan White Programs, Department of Medicine, University of Oklahoma Health Sciences Center; Attending Physician, Infectious Diseases Consultation Service, Infectious Diseases Institute, OU Medical Center

Michelle R Salvaggio, MD, FACP is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Received honoraria from Merck for speaking and teaching.

Chief Editor

Burke A Cunha, MD Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Ruchir Agrawal, MD Chief, Allergy and Immunology, Aurora Sheboygan Clinic

Ruchir Agrawal, MD, is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and American Medical Association

Disclosure: Nothing to disclose.

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Franklin Flowers, MD Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, Affiliate Associate Professor of Pediatrics and Pathology, University of Florida College of Medicine

Franklin Flowers, MD, is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology

Disclosure: Nothing to disclose.

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Cris Jagar, MD Staff Physician, Department of Psychiatry, Trinitas Regional Medical Center

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology and Society for Investigative Dermatology

Disclosure: Elsevier Royalty Other

Sue J Jue, MD Associate Professor, Department of Pediatrics, Section of Infectious Diseases, East Carolina University

Disclosure: Nothing to disclose.

Ewa Koziorynska, MD Assistant Professor of Neurology, Comprehensive Epilepsy Center, State University of New York Downstate Medical Center

Ewa Koziorynska, MD is a member of the following medical societies: Sigma Xi

Disclosure: Nothing to disclose.

Leonard R Krilov, MD Chief of Pediatric Infectious Diseases and International Adoption, Vice Chair, Department of Pediatrics, Professor of Pediatrics, Winthrop University Hospital

Leonard R Krilov, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Medimmune Grant/research funds Clinical trials; Medimmune Honoraria Speaking and teaching; Medimmune Consulting fee Consulting

Larry I Lutwick, MD Professor of Medicine, State University of New York Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus

Larry I Lutwick, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Thomas J Marrie, MD Dean of Faculty of Medicine, Dalhousie University Faculty of Medicine, Canada

Thomas J Marrie, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society for Microbiology, Canadian Infectious Disease Society, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society

Disclosure: Nothing to disclose.

Peter S Miele, MD Medical Officer, Division of Antiviral Products, US Food and Drug Administration

Peter S Miele, MD is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Margo A Smith, MD Associate Program Director, Department of Medicine, Washington Hospital Center; Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, George Washington University

Margo A Smith, MD is a member of the following medical societies: American Society for Microbiology

Disclosure: Nothing to disclose.

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture (adhesive bandage), with normal cerebrospinal fluid analysis results. He was admitted to hospital
9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk.
9-month-old infant boy presented with 1-day history of high-grade fever and irritability. In emergency department, patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to hospital. High-grade fever abruptly resolved on day 3 of hospitalization. Within a few hours, erythematous, pink papular (roseola) nonpruritic rash appeared, mainly on trunk. Patient was playful after supportive therapy. Antibiotics were discontinued after 2 days of negative culture.
 
 
 
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