Human Herpesvirus 6 Infection 

Updated: Nov 29, 2018
Author: Michelle R Salvaggio, MD, FACP; Chief Editor: Burke A Cunha, MD 

Overview

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 lymphotropic virus with high affinity for CD4 lymphocytes.[1, 2]

A beta herpesvirus (like cytomegalovirus [CMV] and human herpesvirus 7 [HHV-7]), HHV-6 comprises 2 forms, A and B; as of 2012, HHV-6A and HHV-6B are officially considered distinct species rather than variants of 1 species. HHV-6B causes the childhood illness roseola infantum, whereas HHV-6A has been isolated mainly in immunocompromised hosts. Specific 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. (See Pathophysiology and Etiology.)

Primary HHV-6B 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 characterized by fever, lymphadenopathy, and hepatitis or encephalitis, with negative test results for CMV or Epstein-Barr virus (EBV).[3]

After primary infection, HHV-6 remains latent unless the immune system is compromised, at which time the virus may reactivate. HHV-6 remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. In immunocompetent hosts, 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, such cases are not common, and no causal relation has been established.[4]

In immunosuppressed hosts, HHV-6A reactivation is associated with a worse outcome.[5, 6] Such 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 (GVHD), and delayed engraftment. Although reactivation of HHV-6 accounts for most infections, transmissions of HHV-6 with the donor allograft, solid organ, or hematopoietic stem cell have also been reported.[7, 8, 9]

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 syndrome (DIHS),[10] or drug reaction with eosinophilia and systemic symptoms (DRESS)

  • Sjögren syndrome

  • Sarcoidosis

  • Systemic lupus erythematosus

  • Chronic fatigue syndrome (CFS)

  • Guillain-Barré syndrome

  • Multiple sclerosis (MS)

A causal relation has not been yet been established between HHV-6 and these conditions.

The great majority of HHV-6 infections are silent or appear as a general mild febrile illness (see Presentation). Laboratory diagnosis is rarely required in patients who are immunocompetent; most often, HHV-6 infection is diagnosed on the basis of its clinical features (see DDx and Workup).

No specific treatment for HHV-6 infection has been established. Treatment varies according to the presenting clinical situation and is usually unnecessary with primary infection in immunocompetent hosts. Supportive measures are the basis of care. Some infants may require hospitalization for atypical presentations. Antivirals such as ganciclovir and foscarnet have been suggested as possible therapies for acute disease, but they remain unproven. No vaccine exists. (See Treatment.)

For patient education resources, see the Bacterial and Viral Infections Center and the Children’s Health Center, as well as Mononucleosis and Skin Rashes in Children.

Pathophysiology

HHV-6 belongs to the Betaherpesvirinae subfamily and to the Roseolovirus genus. The virion particle has the typical structure of a herpesvirus, with a central core containing the viral DNA, a capsid, and a tegument layer that, in turn, is surrounded by a membrane.

At the molecular level, HHV-6 encodes proteins similar to immune mediators in the chemokine family. The functional chemokine is encoded by an open reading frame U83; U12 and U51 encode the 7 transmembrane proteins analogous to the chemokine receptors. This molecular mimicry seems to help HHV-6 in immune invasion and to contribute to long latency in the host cells.[11]

The exact mode by which HHV-6 is transmitted has yet to be elucidated fully. Studies indicate that primary HHV-6B infection is acquired during the first 24months of life. Children likely acquire infection through contact with adult caretaker saliva or from older siblings. DNA restriction enzyme profile studies have shown mothers’ isolates to be genetically similar to their infants’. Vertical transmission of HHV 6 has been documented; however, this mode of transmission represents only 1-2% of all births.[12]

HHV-6 chromosomal integration in immunocompetent patients has been found to result in high levels of viral DNA in blood, sera, and hair follicles.[13] These characteristically high HHV-6 DNA levels in chromosomal integration should be considered in the effort to establish accurate laboratory diagnosis methods.

In vivo, HHV-6 primarily infects and replicates in CD4 lymphocytes. The cellular receptor is CD46, a 52- to 57-kd 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. The virus is believed to invade the central nervous system (CNS), which may lead to such CNS complications as seizures and encephalitis.

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 upregulate CD4 lymphocytes and natural killer (NK) cells and to downregulate CD3 T cells. HHV-6 infection has been reported to induce down-regulation of CXC chemokine receptor 4 in CD4+ T lymphocytes.[14] NK cells seem to play a major role in resolving acute-phase HHV-6 infection[15] ; specific lymphocyte activity develops later. The lymphoproliferative response to phytohemagglutinin ratios suggests that HHV-6 infection has some impact on host T-cell immunity during the course of exanthema subitum.

HHV-6 is also a powerful inducer of cytokines and triggers the release of interferon alfa, 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 (HPV).

HHV-6 antigen has been found in the nuclei of oligodendrocytes in the plaques of patients with MS.[16] Researchers have also found a strong association between anti–HHV-6 immunoglobulin M (IgM) antibodies and early MS in comparison with healthy control subjects 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.[17] Thus, the host response may be responsible, rather than the viral infection itself. However, further investigation is needed before the role of HHV-6 in MS can be fully defined.[18]

Etiology

HHV-6 is the virus that most commonly causes the childhood disease roseola.[19] It includes 2 genetically distinct forms: HHV-6A and HHV-6B. These 2 forms were originally considered variants of a single species but are now considered separate species.[20] HHV-6B has been associated with a variety of viral illnesses, including exanthema subitum (roseola infantum), mononucleosis syndromes, focal encephalitis, and pneumonitis.[21] This virus shows the closest homology with CMV and HHV-7.

HHV-6B infection in infants is the most common cause of fever-induced seizures. In a prospective study involving children aged 1 month to 5 years, HHV-6B was found to be commonly associated with febrile status epilepticus (as was HHV-7, albeit to a lesser degree).[22]

Infection in adults is seen primarily in immunocompromised hosts who have undergone solid-organ or stem cell transplantation or in those with HIV infection.[23, 24]

To elucidate the roles of HHV-6 and HHV-7 in pityriasis rosea (PR), their DNA load in plasma, peripheral blood mononuclear cells (PBMCs), and tissues was evaluated by using a calibrated quantitative real-time polymerase chain reaction (PCR) assay.[25] In addition, HHV-6– and HHV-7–specific antigens in skin were evaluated by means of immunohistochemistry (IHC), and anti–HHV-7 neutralizing activity was assessed with a syncytia-inhibition test.

HHV-6 and HHV-7 DNA were found in 17% and 39% of PR plasmas, respectively, but in no controls.[25] HHV-6 levels in PBMCs were not higher in PR patients than in controls. HHV-6 and HHV-7 antigens were detected only in PR skin (17% and 67% of instances, respectively), presumably indicating a productive infection. These and other data strongly suggest a causal association between PR and active HHV-7 or, to a lesser extent, HHV-6 infection.

The reactivation of herpesviruses, including HHV-6 and EBV, is linked with a potentially serious drug eruption known as DRESS (drug reaction with eosinophilia and systemic symptoms; also referred to as DIHS).[26] A report of high-level HHV-6 viremia associated with the onset of Stevens-Johnson syndrome suggests an association.[27]

As noted (see Pathophysiology), the role of HHV-6 in MS remains controversial.[18]

An association between HHV-6 reactivation and CFS has been proposed. A high proportion of patients with CFS are infected with HHV-6 but have a low viral load. Study results to date have not supported HHV-6 reactivation in patients with CFS, though further investigation is required.[28]

Good prospective studies in patients with encephalitis, posttransplant pneumonia, and MS are needed.

It has been speculated that HHV-6 infection may act as an inducer of sporadic porphyria cutanea tarda, triggering it to become apparent clinically.[29]

Epidemiology

United States statistics

HHV-6 infection is ubiquitous. HHV-6B is the cause of most symptomatic HHV-6 infections. Although evidence of past HHV-6 infection is found in most people, initial infection usually occurs within the first 2 years of life; greater than 90% seropositivity reported in children older than 2 years. Roseola is estimated to affect as many as 30% of all children and is most common in spring and fall.

International statistics

HHV-6 has a worldwide distribution. In an HIV-1 endemic region of sub-Saharan Africa, the predominant form in infant infections was found to be HHV-6A.[30] In Europe and Japan, as in the United States, HHV-6B is the agent mainly responsible for infant infection; HHV-6A appears to be rare.

Seroprevalence is almost 100% in Europe and is close to 100% in the rest of the world—with certain exceptions, such as Morocco, which has 20% seroprevalence. Virus shedding evaluated by PCR in the saliva of healthy adults in Rio de Janeiro, Brazil, detected an HHV-6 prevalence of 9.8%, with HHV-6A detected in 7.1% of the samples and HHV-6B in 2.7%.[31]

Age-, sex, and race-related demographics

HHV-6 infection most commonly occurs after maternal antibodies have waned, usually between the ages of 6 months and 3 years (average, 9 months). The virus is shed in and probably spread through saliva of asymptomatic seropositive children.

Serologic studies demonstrate that HHV-6 infects approximately 90% of children by the age of 2 years.[32] A prospective study found that HHV-6 was acquired in infancy, was usually symptomatic, and often resulted in a medical evaluation. However, only a minority of these patients developed roseola or febrile seizures with primary HHV-6 infection. Older siblings and other care takers appeared to be a source of HHV-6 transmission.[12, 32]

Primary HHV-6 infection is rare in adults. However, reactivation can occur at any age.

HHV-6 infection has no sexual predilection and may occur in people of all races.

Prognosis

HHV-6 infections are mainly uncomplicated and have a self-limited course. They are usually asymptomatic. Even when HHV-6 leads to roseola, it is a mild illness in children who are immunocompetent. It usually resolves without any treatment; however, in some rare cases, patients who are immunocompetent may develop additional symptoms, including respiratory distress, seizures, and multiorgan involvement. One infection usually provides lifetime immunity, though HHV-6 may reactivate in patients who are immunocompromised.

Rarely, HHV-6 can be associated with fatal dissemination and death; 8 fatal cases have been reported. The causes of death were encephalitis, hepatitis,[33] sudden death in infancy, hemophagocytic lymphocytosis, and disseminated infections. In studies by Prezioso et al and Hoang et al, atypical monocyte infiltrate was found in multiple organs, including the brain, spleen, lungs, liver, heart, renal cortex, lymph nodes, and intestine.[34, 35]

In adults who are immunosuppressed (eg, those with AIDS), HHV-6A is a major source of morbidity and mortality, especially in those who do not take antiretroviral therapy; disseminated organ involvement and death can occur. In adults who are immunosuppressed because of undergoing a transplant, HHV-6 infection may cause multiorgan system involvement, accelerate organ rejection, and lead to death.

In adults who are immunocompetent, primary infection or reactivation with HHV-6 can produce a mononucleosislike illness and, more rarely, severe disease, including encephalitis.

HHV-6 may be associated with various complications, as follows:

  • HHV-6B infection is the most common cause of febrile seizures in childhood (age 6-24 months)

  • 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-6A infection induces bone marrow suppression, respiratory failure, GVHD, and encephalitis in patients undergoing hematopoietic stem cell or solid-organ transplantation[36, 37]

 

Presentation

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.

HHV-6 is the single most common cause of hospital visits in infants with fever. Approximately 20% of HHV-6 infections manifest as roseola, which is characterized by the abrupt onset of an initial febrile phase of 3-5 days, with temperatures reaching 40°C. With the fever, some children exhibit bilateral periorbital edema in the prodrome.

This initial phase may be 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.

Symptoms reported in children may include the following:

  • Irritability

  • Ear symptoms, otitis

  • Upper respiratory tract symptoms

  • Gastrointestinal (GI) symptoms, including liver dysfunction and hepatitis

  • Fever-induced seizures[38]

  • Bulging fontanelles

  • Symptoms of meningoencephalitis[39]

Symptoms reported in adults may include the following:

  • Fever with lymphadenopathy, a mononucleosislike disease with negative test results for acute cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection

  • Symptoms consistent with hepatitis

  • Symptoms consistent with encephalitis

It is possible that HHV-6 may play a role in multiple sclerosis (MS).[40] HHV-6 antigen has been demonstrated in the oligodendrocytes of patients with MS. In addition, HHV-6 DNA and high rates of immunoglobulin M (IgM) antibody to HHV-6 have been detected in patients with relapsing-remitting type MS, but not in those with chronic progressive MS disease or in control subjects.

Symptoms reported in immunocompromised hosts and transplant recipients may include the following:

  • Fever, usually very high

  • Symptoms of graft versus host disease (GVHD)

  • Symptoms of graft rejection

  • Symptoms of interstitial pneumonitis

  • Symptoms of meningoencephalitis or myelitis[41]

  • Rash

Symptoms reported in patients with HIV infection may include the following:

  • Fever

  • Rash

  • Symptoms of interstitial pneumonitis

  • Symptoms of meningoencephalitis

Physical Examination

Physical findings of HHV-6 infection are those expected with the symptoms described (see History). Most cases of HHV-6 infection are asymptomatic. Very few physical examination findings exist in children who are infected with HHV-6 until skin findings become apparent.

Findings in infants that may suggest HHV-6 infection include the following (see the images below):

  • High-grade fever (>39.5°C [103°F]), typically persisting for 3-5 days and then resolving abruptly; undifferentiated febrile illness without rash or localizing signs is possible

  • Erythematous macular or maculopapular rash on the trunk, arms, neck, and face, and later on the lower extremities – The rash commonly appears during or within a few hours after defervescence; it is nonpruritic and mildly elevated, consists of rose-pink papules, and blanches on pressure; it usually fades in 1-2 days

  • Inflamed tympanic membranes

  • Signs of upper and, occasionally, lower respiratory tract involvement

  • Hepatomegaly (a common GI sign)

  • Central nervous system (CNS) manifestations – Most children are playful despite high-grade fever; however, anorexia, irritability, and listlessness may be presenting signs; febrile seizures occur in 10-15% of primary infections; HHV-6 is a major precipitant of seizures in infants, not merely because of the high fever but also because HHV-6 replicates in the CNS

    Nine-month-old infant boy presented with one-day h Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture (adhesive bandage), with normal cerebrospinal fluid analysis results. He was admitted to the hospital.
    Nine-month-old infant boy presented with one-day h Nine-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the 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.
    N-month-old infant boy presented with one-day hist N-month-old infant boy presented with one-day history of high-grade fever and irritability. In the emergency department, the patient underwent septic workup, including lumbar puncture, with normal cerebrospinal fluid analysis results. He was admitted to the 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 cultures.

HHV-6 infection in adults can have a wide variety of manifestations, which may range from mild to severe. Findings in healthy adults may include the following:

  • Fever

  • Lymphadenopathy

  • Hepatosplenomegaly

  • CNS manifestations (eg, meningismus and mental status changes)

Reports of encephalitis as a complication of exanthema subitum and the appreciation that HHV-6 is highly neurotropic predicted that the virus might be associated with encephalitis in other settings as well. Current controversy exists regarding reports of HHV-6 in the brains of patients with MS. Active HHV-6 infection in the CNS has been postulated to promote inflammatory injury and demyelination, but this is far from proven.

Findings in immunocompromised individuals may include the following:

  • Fever

  • Rash

  • Signs of pneumonitis

  • Hepatosplenomegaly

  • Mental status changes or meningismus

Immunocompromised individuals with HHV-6 infection may experience organ failure and death. Patients who have undergone transplantation may experience accelerated rejection of the transplant.[42]

 

DDx

Diagnostic Considerations

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. Misdiagnosis of a condition more serious than roseola is a pitfall. Many differential diagnoses exist that can present with a rash and a fever.

In immunocompetent adults with symptomatic HHV-6 disease, the illness closely resembles mononucleosis. Infection with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) should be excluded.

Recognizing HHV-6 infection in patients who are immunocompromised, especially patients with AIDS and recipients of organ transplants, is important. In immunocompromised patients with symptomatic HHV-6 disease, CMV infection is often present and must be diagnosed and managed.

Illnesses associated with HHV-6 (eg, encephalitis and pneumonitis) present as reactivated HHV-6 infection. Reactivation of HHV-6 in patients with AIDS can be serious, with fever, meningeal compromise, seizures, and encephalitis possible developments.[43]

In addition to the conditions in the differential diagnosis, other problems to be considered include the following:

  • Drug eruptions[44]

  • Parvovirus (B-19)

  • Pneumococcemia

HHV-6 is among the factors implicated in the severity of drug reaction with eosinophilia and systemic symptoms (DRESS), or drug-induced hypersensitivity syndrome (DIHS).[45, 46] Early demonstration of HHV-6 reactivation may represent a prognostic factor for identifying patients at higher risk for severe DRESS.

HHV-6 transcripts were found in carbamazepine-induced hypersensitivity syndrome by in-situ hybridization in 1 patient.[47] HHV-8 reactivation has also been linked with DRESS caused by other medications, including lamotrigine.[48] Another report linked carbamazepine with DRESS.[49] Additionally, a study cited trichloroethylene exposure in DRESS.[50]

Differential Diagnoses

 

Workup

Approach Considerations

Human herpesvirus 6 (HHV-6) may be diagnosed by means of viral culture, serologic testing, or polymerase chain reaction (PCR) assay.[51, 52, 53] 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.[54] 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.

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.[55] 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.[56, 57]

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.

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.

 

Treatment

Approach Considerations

Treatment of human herpesvirus 6 (HHV-6) infection varies according to the presenting clinical situation. Therapy is usually unnecessary for primary infection in immunocompetent hosts. In infants with roseola infantum only, treatment is mainly supportive. Infants who present with other manifestations of HHV-6 infection (eg, febrile seizures or CNS involvement) must be admitted to the hospital; overall, about 13% of infants with acute HHV-6 infection require hospitalization.

Treatment of individuals with acute HHV-6 infection remains under investigation. Some experts recommend ganciclovir and foscarnet in severe incidents.

Note that infection with HHV-6 cannot be prevented; no vaccine exists. According to guidelines regarding donor sepsis, HHV-6 may be transmitted to recipients but is not screened for.[58]

Advise rest for children with roseola until the fever breaks and the rash appears. Consult a pediatrician for evaluation of any atypical findings. No further outpatient care for roseola is necessary once the eruption appears (if presentation is typical).

Supportive Care

Supportive therapy is indicated for patients with symptomatic HHV-6 infection. In roseola, symptomatic treatment of the fever is recommended, including baths, lightweight clothing, and rest. Adequate fluid balance should be ensured.

Acetaminophen or ibuprofen should be administered to patients with high-grade fever, patients who are uncomfortable, or patients who have a previous history of febrile seizures; avoid aspirin in children, because of the risk of Reye syndrome. If the patient has a febrile seizure, no seizure medication is necessary.

Antiviral Therapy

For immunosuppressed hosts with documented 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. The effectiveness of ganciclovir was evaluated against HHV-6 excreted in saliva in stem-cell transplant recipients[59] ; ganciclovir was found to be capable of decreasing the HHV-6 viral load in saliva.

Ganciclovir can worsen bone-marrow suppression in patients who have undergone bone-marrow transplantation. Foscarnet may be used, but renal function and calcium levels must be monitored closely.

To evaluate the influence of ganciclovir prophylaxis on HHV-6 replication in renal transplant recipients, Galarraga et al[60] studied 3 groups: (1) patients not receiving ganciclovir, (2) patients receiving short-term (< 30 days) ganciclovir prophylaxis, and (3) patients receiving long-term (>60 days) ganciclovir prophylaxis.[60] The antiviral did not affect the prevalence of HHV-6 (67.2%), but HHV-6 viremia appeared later and was of shorter duration among patients on long-term prophylaxis.

Because HHV-6 and HHV-7 are possibly associated with pityriasis rosea (PR), it has been suggested that systemic administration of drugs directed against HHV may hasten the recovery of patients who have PR. High-dose acyclovir may be effective for treating PR, especially in patients treated in the first week from onset, when the replicative viral activity of HHV is probably very high.[61]

 

Medication

Medication Summary

Drug therapy specific to the infection is not currently a component of the standard of care for human herpesvirus 6 (HHV-6) infection. Supportive therapy, using antipyretics such as acetaminophen or ibuprofen, is indicated. Although HHV-6 is inhibited by several antiviral drugs (eg, ganciclovir and foscarnet) in the laboratory, no clinical trials have assessed their benefit, and their role in the treatment of HHV-6 infection remains to be determined. No seizure medication is indicated for febrile seizures.

Antivirals

Class Summary

Nucleoside analogues are initially phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate, resulting in the inhibition of viral replication.

Ganciclovir (Cytovene)

Ganciclovir is an acyclic nucleoside analogue of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.

Foscarnet (Foscavir)

Foscarnet is an organic analogue of inorganic pyrophosphate that inhibits replication of known herpesviruses. It inhibits viral replication at pyrophosphate-binding sites on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance.

Analgesics

Class Summary

Control of pain and fever is essential to quality patient care. Antipyretics inhibit central synthesis and release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus; thus, they promote the return of the set-point temperature to normal.

Nonsteroidal anti-inflammatory agents (NSAIDs) such as ibuprofen have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is unknown, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other possible mechanisms include inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Acetaminophen (Tylenol, FeverAll, Aspirin-Free Anacin Extra)

Acetaminophen is used as an antipyretic and analgesic. It reduces fever by acting directly on hypothalamic heat-regulating centers, thereby increasing dissipation of body heat via vasodilation and sweating.

Ibuprofen (Motrin, Advil, Ibu)

Ibuprofen is used as an antipyretic and analgesic. It inhibits inflammatory reactions, fever, and pain by decreasing prostaglandin synthesis. It is not recommended for children younger than 6 months.