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Infectious Diseases > MEDICAL TOPICS
Human Herpesvirus Type 6
Article Last Updated: Jun 9, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Peter S Miele, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Washington Hospital Center
Peter S Miele is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine and Infectious Diseases Society of America
Coauthor(s):
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
Editors: Thomas J Marrie, MD, Chair, Professor, Department of Medicine, Division of Infectious Diseases, University of Alberta College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Ronald A Greenfield, MD, Professor, Chief, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital; 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
Author and Editor Disclosure
Synonyms and related keywords:
HHV-6, roseola infantum, exanthema subitum, sixth disease
Background
Human herpesvirus 6 (HHV-6) is the sixth herpesvirus discovered. Isolated in 1986 during attempts to find novel viruses in patients with lymphoproliferative diseases, HHV-6 is now recognized as a T-cell lymphotrophic virus with high affinity for CD4 lymphocytes. A beta herpesvirus (like cytomegalovirus [CMV] and human herpesvirus type 7), HHV-6 had two variants, A and B. Variant B causes the childhood illness roseola infantum, while variant A has been isolated mainly in immunocompromised hosts. The disease manifestations of variant A are still undefined, but both variants may turn out to be pathogenic in the settings of transplantation and AIDS.
- Primary HHV-6 infection usually occurs in infants and is the most common cause of febrile-induced seizures in children aged 6-24 months. Acute infection in immunocompetent adults is rare but may present as a mononucleosislike illness with fever, lymphadenopathy, and hepatitis or encephalitis, with negative test results for CMV or Epstein-Barr virus (EBV).
- After primary infection, HHV-6 remains latent unless the immune system is compromised, at which time the virus may reactivate. The virus remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. In the immunocompetent host, this persistent infection is generally of no consequence.
- In the immunosuppressed host, HHV-6 reactivation is associated with a worse outcome. The virus has been shown to reactivate in 33-48% of patients undergoing hematopoietic stem cell transplantation. For example, in these patients, reactivation has been associated with reactivation and increased severity of CMV infection. Other clinical conditions associated with HHV-6 reactivation in this population include hepatitis, idiopathic pneumonitis, bone marrow suppression, encephalitis, fever and rash, graft versus host disease, and delayed engraftment.
- In patients infected with HIV, HHV-6 infection may up-regulate HIV replication and hasten the progression toward AIDS. HHV-6 also has been implicated in the pathogenesis of white matter demyelination in the AIDS dementia complex. However, the clear causality has yet to be demonstrated.
- HHV-6 has been linked to several other conditions, including the following:
- Kikuchi lymphadenitis
- Lymphoma
- Lymphadenopathy
- Drug-induced hypersensitivity syndrome
- Sjögren syndrome
- Sarcoidosis
- Systemic lupus erythematosus
- Chronic fatigue syndrome
- Guillain-Barré syndrome
- Multiple sclerosis (MS)
- Whether the detection of HHV-6 from tissue, cells, or fluid or antibodies to HHV-6 in these conditions reflects an etiologic role for the virus remains to be determined.
Pathophysiology
- The exact mode of transmission of HHV-6 has yet to be proven. Studies indicate that primary infection is acquired during the first 6 months of life.
- Infants likely acquire infection through contact with adult caretaker saliva. DNA restriction enzyme profile studies have shown mothers' isolates were genetically similar to their infants'.
- In vivo, HHV-6 primarily infects and replicates in CD4 lymphocytes. The cellular receptor is CD46, a 52- to 57-kDa type 1 transmembrane glycoprotein expressed on the surface of all cells. The cell attachment protein of HHV-6 has not been identified. Entry occurs through receptor-mediated endocytosis. Subsequent stages of viral replication are similar to those of CMV.
- During acute infection, replication occurs in lymphocytes, macrophages, histiocytes, endothelial cells, and epithelial cells. In vitro studies have demonstrated that HHV-6 also can replicate in glial cells.
- HHV-6 causes direct cytolysis. This may be responsible for roseola, as well as the heterophile-negative mononucleosis-like picture of acute infection.
- The virus has been shown to up-regulate CD4 lymphocytes and natural killer cells and down-regulate CD3 T cells. HHV-6 infection has been reported to induce down-regulation of CXC chemokine receptor 4 in CD4+ T lymphocytes.
- HHV-6 is also a powerful inducer of cytokines and triggers the release of interferon-alpha, tumor necrosis factor, and interleukin-1b, thus, potentially playing a role in the pathogenesis of HIV disease and other immunocompromised states.
- HHV-6 also may alter the natural history of other viral infections, such as CMV, EBV, and human papilloma virus.
- HHV-6 antigen has been found in the nuclei of oligodendrocytes in the plaques of patients with MS. Researchers have also found a strong association between anti-HHV-6 immunoglobulin M (IgM) antibodies and early MS compared with healthy controls and progressive MS. Some theorize that viral infection plays a role in the pathogenesis of MS through potential molecular mimicry. Cross-reactivity between myelin basic protein and HHV-6 has been suggested. Thus, the host response may be responsible rather than the viral infection. However, further investigation is needed to fully define the role of HHV-6 in MS.
Frequency
United States
HHV-6 is a worldwide ubiquitous infection, with greater than 90% seropositivity reported in children older than 2 years.
Mortality/Morbidity
- HHV-6 is the most common cause of febrile seizures in childhood (age 6-24 mo).
- Encephalitis may develop in the pediatric population.
- HHV-6 has a possible role in CNS infections and demyelinating conditions.
- HHV-6 infection may increase the severity of CMV infection in the immunocompromised and transplant populations.
- HHV-6 has a possible role in lymphoproliferative syndromes.
- HHV-6 infection induces bone marrow suppression, respiratory failure, graft versus host disease, and encephalitis in transplantation.
Race
HHV-6 is found to affect people of all races.
Sex
HHV-6 infection affects males and females in equal numbers.
Age
- Infection most commonly occurs after maternal antibodies have waned, usually at age 6-24 months.
- Primary infection in adults is rare.
History
HHV-6 infection often is asymptomatic. Symptomatic disease occurs predominately after primary infection in infants and after either primary or reactivation disease in immunocompromised adults.
- Children: Approximately 20% of infection presents as roseola, with the abrupt onset of high fever that lasts 3-5 days; this is followed by an erythematous maculopapular rash that appears when the temperature normalizes. The rash starts at the trunk and spreads centrifugally to the face and limbs. More commonly, the infection presents as an acute nonspecific febrile illness in a child younger than 2 years. HHV-6 also may present with rash and no fever.
- Irritability
- Ear symptoms, otitis
- Upper respiratory tract symptoms
- Gastrointestinal symptoms, including liver dysfunction and hepatitis
- Febrile seizures
- Bulging fontanelles
- Symptoms of meningoencephalitis
- Adults
- Fever with lymphadenopathy, a mononucleosis-like disease with negative test results for acute CMV and EBV infection
- Symptoms consistent with hepatitis
- Symptoms consistent with encephalitis
- Possible role for HHV-6 in MS
- HHV-6 antigen has been demonstrated in the oligodendrocytes of patients with MS
- HHV-6 DNA and high rates of immunoglobulin (Ig) M antibody to HHV-6 have been detected in patients with relapsing-remitting type MS, but not chronic, progressive MS disease or controls.
- Immunocompromised hosts and transplant recipients (bone marrow and solid organ)
- Fever, usually very high
- Cytopenia, in particular leukopenia
- Symptoms of graft-versus-host disease
- Symptoms of graft rejection
- Symptoms of interstitial pneumonitis
- Symptoms of meningoencephalitis
- Rash
- HIV infection
- Fever
- Rash
- Symptoms of interstitial pneumonitis
- Symptoms of meningoencephalitis
- Rising viral load
- Falling CD4 count
Physical
Physical findings are those to be expected with the above listed symptoms. In most cases, infection may be asymptomatic. The following are findings that may suggest HHV-6 infection.
- Infants
- High fever
- Erythematous macular or maculopapular rash on trunk and face and, later, lower extremities
- Inflamed tympanic membranes
- Signs of upper and, occasionally, lower respiratory tract involvement
- Hepatomegaly (common GI sign)
- CNS symptoms - May include bulging fontanelles, irritability, stupor, meningismus, and seizure
- Adults
- Fever
- Lymphadenopathy
- Hepatosplenomegaly
- CNS symptoms - Meningismus and mental status changes
- Immunocompromised individuals
- Fever
- Rash
- Signs of pneumonitis
- Hepatosplenomegaly
- Mental status changes or meningismus
Bone Marrow Failure
Chronic Fatigue Syndrome
Cytomegalovirus
Fever of Unknown Origin
Herpes Simplex
Meningitis
Pneumonia, Viral
Other Problems to be Considered
In infants with signs and symptoms of classic roseola infantum, HHV-6 is the causative agent. Other causes for fever and rash, however, should be excluded.
In immunocompetent adults with symptomatic disease, the illness closely resembles mononucleosis. EBV infection and CMV infection should be excluded.
In immunocompromised patients with symptomatic disease, CMV infection often is present and needs to be diagnosed and managed accordingly.
Lab Studies
- Routine laboratory studies depend on the clinical presentation and setting, such as immunocompetent versus immunocompromised host.
- CBC count may show leukopenia and varying degrees of cytopenia (thrombocytopenia or anemia), especially in the setting of transplantation.
- Obtain electrolytes and renal function tests, especially in renal transplant patients.
- Liver function tests may show hepatitis or liver dysfunction.
- Specific tests to diagnose HHV-6 infection include the following:
- 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 for isolating HHV-6. The virus causes a characteristic finding of balloonlike syncytia on cell culture due to its cytopathic effects. The rapid shell vial assay has a sensitivity of 86% and a specificity of 100%.
- Immunohistochemical stains: 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. For biopsy and cytologic specimens, results are available in 1-3 days.
- Serology: Primary infection can be demonstrated by seroconversion from IgG negative to positive or the presence of IgM to HHV-6. Active disease is indicated by a 4-fold increase in IgG by immunofluorescence or a 1.6-fold increase in antibody by 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 with other herpesvirus infections.
- Polymerase chain reaction (PCR): PCR 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. A quantitative technique to determine viral load still is investigational. A sensitive, semiquantitative technique that cannot detect latent virus but can detect actively infected cells has been described.
Imaging Studies
- A chest radiograph or CT scan should be obtained in patients presenting 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.
Procedures
- Carry out procedures according to the clinical presentation, especially with immunocompromised patients.
- Clinicians should have a low threshold for certain procedures, including the following:
- Bronchoscopy: In cases of respiratory distress, bronchioalveolar lavage (BAL) or biopsy samples can be sent for immunohistochemical staining to identify HHV-6 infection.
- Lumbar puncture (LP): In patients with CNS symptoms, an LP can rule out other etiologies. In cases of febrile seizures due to HHV-6, the CSF often shows a complete lack of inflammatory response. CSF can be sent for HHV-6 PCR studies. A positive result indicates active HHV-6 infection in the CNS. The virus has not been shown to grow in CSF samples sent for viral culture.
- Tissue biopsy
- It is especially relevant in solid organ or bone marrow transplant recipients with 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 a question exists as to the etiology of a rash, skin biopsy should be obtained to rule out other causes.
Histologic Findings
Immunohistochemical staining can be performed on tissue and cytologic samples to identify HHV-6 infection.
Medical Care
- Treatment varies according to the presenting clinical situation.
- In infants with roseola infantum only, treatment mainly is supportive.
- Infants presenting with other findings, such as febrile seizures or CNS involvement, will require hospitalization.
- About 13% of infants with acute HHV-6 infection require hospitalization.
- The role of antiviral therapy for HHV-6 infection has yet to be determined.
- Therapy is usually not necessary in primary infection of immunocompetent hosts.
- In immunosuppressed hosts who have documentation of active HHV-6 infection, some studies have suggested using antiviral therapy in cases of hepatitis, bone marrow suppression, pneumonitis, or encephalitis. In particular, they recommend ganciclovir or foscarnet. Ganciclovir has also been reported to be beneficial against HHV-6 reactivation in patients undergoing stem cell transplantation.
Drug Category: Antivirals
Nucleoside analogs initially are phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate, resulting in the inhibition of viral replication.
| Drug Name | Ganciclovir (Cytovene, Vitrasert) |
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| Description | Acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. |
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| Adult Dose | 6 mg/kg IV qd over 1 h for 5 d |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Concomitant administration with cytotoxic drugs such as dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole combinations, or other nucleoside analogs may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem-cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability of ganciclovir may decrease in presence of zidovudine, while bioavailability of zidovudine is increased in presence of ganciclovir |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Clinical toxicity of ganciclovir includes granulocytopenia, anemia, and thrombocytopenia; because oral ganciclovir is associated with a higher rate of CMV retinitis progression compared to IV formulation, use only when benefits outweigh risks (advanced HIV disease); half-life and plasma/serum concentrations of ganciclovir may be increased as a result of reduced renal clearance; dosages > 6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; administration of ganciclovir should be accompanied by adequate hydration; photosensitization (photoallergy or phototoxicity) may occur |
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| Drug Name | Foscarnet (Foscavir) |
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| Description | Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses. Inhibits viral replication at pyrophosphate-binding site on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance. |
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| Adult Dose | 120 mg/kg/d IV early in treatment in patients who can tolerate the drug well; individualize dosing based on renal function status |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Coadministration with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) may increase nephrotoxicity (do not administer unless potential benefits outweigh risks); coadministration with IV pentamidine may cause hypocalcemia |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | May cause decline in renal function; for correct dosing, obtain 24-h serum creatinine at baseline and continue to monitor (discontinue if serum creatinine <0.4 mL/min/kg); hydration may reduce nephrotoxicity; carefully monitor electrolytes (eg, calcium, magnesium); assess for electrolyte and mineral level abnormalities if mild perioral numbness, paresthesias symptoms, or seizures occurs; granulocytopenia and anemia may occur (regularly monitor CBC); infuse foscarnet solutions into veins with adequate blood flow to avoid local irritation; to avoid toxicity do not administer by rapid or bolus IV injection |
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Further Inpatient Care
- Infants presenting with findings such as febrile seizures or CNS involvement will require hospitalization.
- About 13% of infants with acute HHV-6 infection require hospitalization.
Medical/Legal Pitfalls
- Ganciclovir can worsen bone marrow suppression in patients who have received a bone marrow transplant. Foscarnet may be used, but renal function and calcium levels need to be monitored closely.
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Human Herpesvirus Type 6 excerpt Article Last Updated: Jun 9, 2006
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