Human Herpesvirus Type 6

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Human Herpesvirus Type 6 <http://www.healthverve.blogspot.com>

AUTHOR AND EDITOR INFORMATION

 

Author: Michelle R Salvaggio, MD, Assistant Professor, Department of

Internal Medicine, Section of Infectious Diseases, University of Oklahoma

College of Medicine; Medical Director of Infectious Diseases Institute,

University of Oklahoma Health Sciences Center

 

Michelle R Salvaggio is a member of the following medical societies:

American College of Physicians, American Medical Association, and Infectious

Diseases Society of America

 

Coauthor(s): Peter S Miele, MD, Fellow, Department of Internal Medicine,

Section of Infectious Diseases, Washington Hospital Center; 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, 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: human herpesvirus 6, human herpesvirus type

6, HHV-6, HHV6, human herpes virus 6, HHV-6A, HHV-6B, roseola infantum,

exanthema subitum, sixth disease

 

INTRODUCTION

 

Background

 

Human herpesvirus 6 (HHV-6) was 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 has two variants, A and B. HHV-6B causes the childhood illness

roseola infantum, while HHV-6A has been isolated mainly in immunocompromised

hosts. Specific disease manifestations of HHV-6A infection are still

undefined. However, both HHV-6A and HHV-6B may be pathogenic in the settings

of transplantation and AIDS.

 

- Primary HHV-6 infection usually occurs in infants and is the most

common cause of fever-induced seizures in children aged 6-24 months. Acute

HHV-6 infection is rare in immunocompetent adults but may manifest 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. Isolated cases of pulmonary failure in immunocompetent

patients have been attributed to HHV-6 when no other pathogens have been

isolated; however, these cases are not common and a causal relationship has

not been established.1

- In the immunosuppressed host, HHV-6 reactivation is associated with a

worse outcome. HHV-6 reactivation occurs in 33-48% of patients undergoing

hematopoietic stem cell transplantation. For example, in these patients,

reactivation of HHV-6 has been associated with CMV reactivation and

increased severity of CMV disease. 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. While reactivation of HHV-6

accounts for most infections, transmissions of HHV-6 with the donor

allograft, solid organ, or hematopoietic stem cell have been reported.2

- 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 persons with

AIDS dementia complex; however, causality has not been proven.

- HHV-6 has been isolated from various tissues, cells, and fluid in

association with the following conditions:

-

- Kikuchi lymphadenitis

- Lymphoma

- Lymphadenopathy

- Drug-induced hypersensitivity syndrome3

- Sjögren syndrome

- Sarcoidosis

- Systemic lupus erythematosus

- Chronic fatigue syndrome

- Guillain-Barré syndrome

- Multiple sclerosis (MS)

- A causal relationship has not been yet been established between HHV-6

and these conditions.

 

Pathophysiology

 

- The exact mode of transmission of HHV-6 has yet to be proven. Studies

indicate that primary HHV-6 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 effect may be responsible for

roseola, as well as the heterophile-negative mononucleosislike picture of

acute infection.

- HHV-6 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.4

- 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 may also alter the natural history of other viral infections,

such as those with CMV, EBV, and human papillomavirus.

- HHV-6 antigen has been found in the nuclei of oligodendrocytes in the

plaques of patients with MS.5 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.6 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 infection is ubiquitous worldwide, with greater than 90%

seropositivity reported in children older than 2 years.

Mortality/Morbidity

 

- HHV-6 infection is the most common cause of febrile seizures in

childhood (age 6-24 mo).

- Encephalitis may develop in children with HHV-6 infection.

- HHV-6 has a possible role in CNS infections and demyelinating

conditions.

- HHV-6 infection may increase the severity of CMV infection in

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 patients undergoing

hematopoietic stem cell or solid-organ transplantation.

 

Race

 

HHV-6 infection is found in people of all races.

Sex

 

HHV-6 infection has no sexual predilection.

Age

 

- HHV-6 Infection most commonly occurs after maternal antibodies have

waned, usually at age 6-24 months.

- Primary HHV-6 infection is rare in adults.

- Reactivation can occur at any age.

 

 

CLINICAL

 

History

 

Human herpesvirus 6 (HHV-6) infection is often asymptomatic. Symptomatic

manifestations occur predominately after primary infection in infants and

after either primary or reactivation disease in immunocompromised adults.

 

- Children: Approximately 20% of HHV-6 infections manifest as roseola,

with an 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 infection

may also manifest as a rash and no fever.

-

- Irritability

- Ear symptoms, otitis

- Upper respiratory tract symptoms

- Gastrointestinal symptoms, including liver dysfunction and hepatitis

- Fever-induced seizures

- Bulging fontanelles

- Symptoms of meningoencephalitis

- Adults

-

- Fever with lymphadenopathy, a mononucleosislike 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. In addition, HHV-6

DNA and high

rates of IgM 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 or myelitis7

- Rash

- HIV infection

-

- Fever

- Rash

- Symptoms of interstitial pneumonitis

- Symptoms of meningoencephalitis

- Rising HIV viral load

- Falling CD4 count

 

Physical

 

Physical findings of HHV-6 infection are those expected with the symptoms

listed above. Most cases of HHV-6 infection are asymptomatic. The following

findings 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/or seizures

- Adults

-

- Fever

- Lymphadenopathy

- Hepatosplenomegaly

- CNS symptoms - Meningismus and mental status changes

- Immunocompromised individuals

-

- Fever

- Rash

- Signs of pneumonitis

- Hepatosplenomegaly

- Mental status changes or meningismus

 

 

DIFFERENTIALS

 

Bone Marrow Failure

Chronic Fatigue Syndrome

Cytomegalovirus

Early Symptomatic HIV Infection

Fever of Unknown Origin

Herpes Simplex

Infectious Mononucleosis

Meningitis

Parvovirus (B19)

Pneumonia, Viral

 

Other Problems to be Considered

 

In infants with signs and symptoms of classic roseola infantum, human

herpesvirus 6 (HHV-6) is the causative agent. However, other causes for

fever and rash should be excluded.

 

In immunocompetent adults with symptomatic HHV-6 disease, the illness

closely resembles mononucleosis. EBV infection and CMV infection should be

excluded.

 

In immunocompromised patients with symptomatic HHV-6 disease, CMV infection

is often present and needs to be diagnosed and managed accordingly.

 

WORKUP

 

Lab Studies

 

- Routine laboratory studies used to evaluate for human herpesvirus 6

(HHV-6) 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 yields a sensitivity of 86% and a

specificity of

100%. Availability of culture or shell vial assays is limited.

- 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 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.

- 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

that can detect actively infected cells has been described.

 

Imaging Studies

 

- Chest radiography or CT scanning should be obtained 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.

 

Procedures

 

- Indications for procedures depend on the clinical presentation,

especially in 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 be

used to rule out other etiologies. In cases of febrile seizures

due to HHV-6

infection, the CSF may reveal a mild pleocytosis with elevated protein

levels but 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

-

- 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.

 

Histologic Findings

 

Immunohistochemical staining can be performed on tissue and cytologic

samples to identify HHV-6 infection.

 

TREATMENT

 

Medical Care

 

- Treatment of human herpesvirus 6 (HHV-6) infection varies according to

the presenting clinical situation.

- In infants with roseola infantum only, treatment is mainly supportive.

- Infants who present with other manifestations of HHV-6 infection (eg,

febrile seizures, CNS involvement) require hospitalization.

- About 13% of infants with acute HHV-6 infection require

hospitalization.

 

 

 

MEDICATION

 

 

- The role of antiviral therapy for human herpesvirus 6 (HHV-6) infection

has yet to be determined.

- Therapy is usually unnecessary in primary infection in immunocompetent

hosts.

- In immunosuppressed hosts in whom active HHV-6 infection has been

documented, 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 are initially phosphorylated by viral thymidine kinase to

eventually form a nucleoside triphosphate, resulting in the inhibition of

viral replication.

Drug NameGanciclovir (Cytovene, Vitrasert) DescriptionAcyclic nucleoside

analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both

in vitro and in vivo. Adult Dose10 mg/kg IV qd over 1 h, usually divided

bid; course of therapy depends on clinical scenario; therapeutic dose

monitoring may be helpful in some situations (Janoly-Duménil, 2006) Pediatric

DoseNot established; therapeutic dose monitoring used in pediatric

population with some success (Janoly-Duménil, 2006) ContraindicationsDocumented

hypersensitivity; pancytopenia; may be contraindicated in patients who

received as prophylaxis and failed InteractionsConcomitant 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 levels 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 PregnancyC - Fetal risk

revealed in studies in animals but not established or not studied in humans;

may use if benefits outweigh risk to fetus

PrecautionsClinical toxicity of ganciclovir includes granulocytopenia,

anemia, and thrombocytopenia; because oral ganciclovir is associated with

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 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 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

 

Drug NameFoscarnet (Foscavir) DescriptionOrganic 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. Adult Dose120 mg/kg/d IV early in

treatment in patients who can tolerate the drug well; individualize dosing

based on renal function status Pediatric DoseNot established

ContraindicationsDocumented hypersensitivity InteractionsCoadministration

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 PregnancyC - Fetal risk revealed in studies in animals but not

established or not studied in humans; may use if benefits outweigh risk to

fetus

PrecautionsMay 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 occur; granulocytopenia and anemia may

occur (regularly monitor CBC count); 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

 

 

FOLLOW-UP

 

Further Inpatient Care

 

- Infants infected with human herpesvirus 6 (HHV-6) who present with

findings such as febrile seizures or CNS involvement require

hospitalization.

- About 13% of infants with acute HHV-6 infection require

hospitalization.

 

 

MISCELLANEOUS

 

Medical/Legal Pitfalls

 

Ganciclovir can worsen bone marrow suppression in patients who have

undergone bone marrow transplant. Foscarnet may be used, but renal function

and calcium levels need to be monitored closely.

 

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