Human Herpes Virus 6

Background

Human herpes virus type 6 (HHV-6) is a member of the herpes virus family. Most infections are asymptomatic and occurs in childhood before age 2 years. Seroprevalence in adults is near 100%. Symptomatic infections typically induces exanthema subitum, also known as roseola infantum.. More severe primary infections may include hepatitis, meningoencephalitis, interstitial pneumonitis, and mononucleosislike syndrome. In immunosuppressed patients (such as transplant recipients) HHV-6 primary infection or reactivation may induce a rejection of transplanted organs and death.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

AGE RANGE-MEDIAN Children<2 years

INCIDENCE/
PREVALENCE

Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women.

Baillargeon J, Piper J, Leach CT.

Departments of Pediatrics, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, USA.

J Clin Virol 2000 May;16(3):149-57 Abstract quote
BACKGROUND: Human herpesvirus 6 (HHV-6) is a ubiquitous virus primarily associated with benign conditions such as febrile syndromes and exanthem subitum (roseola infantum). Sexual, horizontal, and vertical transmission have been suggested. Little information is available regarding HHV-6 infection in women of reproductive age.

OBJECTIVE: Describe epidemiology of HHV-6 infection in pregnant and nonpregnant women.

STUDY DESIGN: The study sample consisted of 569 women, age 18-45, who attended a university family planning clinic (nonpregnant, n=224) and two obstetrics clinics (pregnant [first trimester], n=345) in San Antonio, TX between October 1995 and May 1998. Blood and a vaginal swab, as well as sociodemographic information, were collected from each participant. Plasma was tested for HHV-6 IgG antibodies using a standard immunofluorescence assay (IFA). Lysed material from vaginal swabs was tested for HHV-6 DNA by polymerase chain reaction (PCR). Products were screened by enzyme-linked immunosorbent assay and positive tests were confirmed by repeat PCR followed by Southern analysis. PCR-positive samples were subtyped using an established method.

RESULTS: All subjects were HHV-6 antibody positive. Geometric mean titers of HHV-6 antibodies were significantly higher among nonpregnant versus pregnant women. Moreover, a higher proportion of nonpregnant versus pregnant women had antibody titers >/=160 and >/=320. This association persisted even after adjusting for a number of sociodemographic and clinical factors. Low rates of HHV-6 shedding in the genital tract were observed for both groups (pregnant, 7/297 [2.0%]; nonpregnant, 8/214 [3.7%]). Of 14 samples subtyped, four (29%) were subtype A.

CONCLUSION: The present study showed that 100% of the study sample was infected with HHV-6. Higher HHV-6 antibody titers, however, were noted in nonpregnant women. Both groups shed virus at low rates in the genital tract. HHV-6 subtype A was identified more commonly than previously reported. Further longitudinal studies are required to assess the consequences of maternal HHV-6 infection.

TRANSMISSION

Human herpesviruses 6 and 7: effects on hematopoiesis and mode of transmission.

Yamada M.

Department of Virology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.
Jpn J Infect Dis 2001 Apr;54(2):47-54 Abstract quote
Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) were recently discovered, and are known as etiologic agents of exanthem subitum (roseola). HHV-6 and HHV-7 are T-lymphotropic, and have been classified as betaherpesviruses.

In monitoring of herpesviruses after hematopoietic stem cell transplantation, each herpesvirus had a unique temporal profile of detection. HHV-6 DNA was detected most frequently at 3 weeks, whereas cytomegalovirus and Epstein-Barr virus DNA were detected later. HHV-7 DNA was not detected throughout the observation period. In in vitro hematopoietic colony assays, HHV-6 suppressed all three lineages of hematopoiesis, i.e., erythroid, granulocyte/macrophage, and megakaryocyte, whereas HHV-7 did not have any suppressive effect. Molecular epidemiological analysis revealed that HHV-7 was transmitted horizontally from grandparents to parents to children through close contact within a household. Either parent could transmit HHV-7 to the children. Follow-up studies of the amount of viral DNA in saliva samples revealed that the amount of HHV-7 DNA was rather constant for each individual, and that "high producers" and "low producers" could be distinguished.

Transferred antibodies against HHV-7 tended to be higher and remain longer after birth than those of HHV-6, and these findings are consistent with the clinical observation that HHV-6 infection occurs earlier than HHV-7 infection.

Transfer of human herpesvirus 6 and 7 antibodies from mothers to their offspring.

Ohashi M, Ihira M, Suzuki K, Suga S, Asano Y, Yoshikawa T, Saito Y, Sakui H.

Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
Pediatr Infect Dis J 2001 Apr;20(4):449-50 Abstract quote
Placental transfer of maternal human herpesvirus (HHV) 6 and HHV 7 antibodies to infants was examined simultaneously in 69 paired plasma samples by an indirect immunofluorescence assay. All the mothers had antibodies to both viruses.

The mean HHV 6 and HHV 7 antibody titers of infants were significantly higher than those of the mothers. The mean ratio of cord blood antibody titer to the maternal titer for both viruses was 1.89, suggesting active transport by placenta.

GEOGRAPHY

BRAZIL

Outbreaks of human-herpes virus 6 (HHV-6) infection in day-care centers in Belem, Para, Brazil.

Freitas RB, Monteiro TA, Linhares AC.

Servico de Virologia Geral, Instituto Evandro Chagas, Fundacao Nacional de Saude, Ministerio da Saude, Belem, Para, Brasil.
Rev Inst Med Trop Sao Paulo 2000 Nov-Dec;42(6):305-11 Abstract quote
A total of 730 children aged less than 7 years, attending 8 day-care centers (DCCs) in Belem, Brazil were followed-up from January to December 1997 to investigate the occurrence of human-herpes virus 6 (HHV-6) infection in these institutional settings.

Between October and December 1997 there have been outbreaks of a febrile- and -exanthematous disease, affecting at least 15-20% of children in each of the DCCs. Both serum- and- plasma samples were obtained from 401 (55%) of the 730 participating children for the detection of HHV-6 antibodies by enzyme-linked immunosorbent assay (ELISA), and viral DNA amplification through the nested-PCR.

Recent HHV-6 infection was diagnosed in 63.8% (256/401) of them, as defined by the presence of both IgM and IgG-specific antibodies (IgM+/IgG+); of these, 114 (44.5%) were symptomatic and 142 (55.5%) had no symptoms (p = 0.03). A subgroup of 123 (30.7%) children were found to be IgM-/IgG+, whereas the remaining 22 (5.5%) children had neither IgM nor IgG HHV-6- antibodies (IgM-/IgG-). Of the 118 children reacting strongly IgM-positive (> or = 30 PANBIO units), 26 (22.0%) were found to harbour the HHV-6 DNA, as demonstrated by nested-PCR. Taken the ELISA-IgM- and- nested PCR-positive results together, HHV-6 infection was shown to have occurred in 5 of the 8 DCCs under follow-up.

Serological evidence of recent infections by Epstein-Barr virus (EBV) and parvovirus B19 were identified in 2.0% (8/401) and 1. 5% (6/401) of the children, respectively. Our data provide strong evidence that HHV-6 is a common cause of outbreaks of febrile/exanthematous diseases among children attending DCCs in the Belem area.

PATHOGENESIS CHARACTERIZATION

GENERAL

Human herpesvirus 6: molecular biology and clinical features.

Dockrell DH.

Division of Genomic Medicine, University of Sheffield School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK.
J Med Microbiol 2003 Jan;52(Pt 1):5-18 Abstract quote
Human herpesvirus 6 (HHV-6) exists as distinct variants HHV-6A and HHV-6B. The complete genomes of HHV-6A and HHV-6B have been sequenced. HHV-6B contains 97 unique genes. CD46 is the cell receptor for HHV-6, explaining its broad tissue tropism but its restricted host-species range. HHV-6 utilizes a number of strategies to down-regulate the host immune response, including molecular mimicry by production of a functional chemokine and chemokine receptors. Immunosuppression is enhanced by depletion of CD4 T lymphocytes via direct infection of intra-thymic progenitors and by apoptosis induction. Infection is widespread in infants between 6 months and 2 years of age. A minority of infants develop roseola infantum, but undifferentiated febrile illness is more common.

Reactivation from latency occurs in immunocompromised hosts. Organ-specific clinical syndromes occasionally result, but indirect effects including interactions with other viruses such as human immunodeficiency virus type 1 and human cytomegalovirus or graft dysfunction in transplant recipients may be more significant complications in this population. Recent advances in quantitative PCR are providing additional insights into the natural history of infection in paediatric populations and immunocompromised hosts.

RESERVOIR OF INFECTION

Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection.
Kondo K, Kondo T, Shimada K, Amo K, Miyagawa H, Yamanishi K.

Department of Microbiology, Osaka University Medical School, Osaka, Japan.
J Med Virol 2002 Jul;67(3):364-9 Abstract quote
Human herpesvirus 6 (HHV-6) encodes a viral chemokine and chemokine receptors that may modify the functions of monocytes/macrophages (MO/M phi) during productive HHV-6 infection.

The interactions between HHV-6 and MO/M phi during acute infection, however, remain poorly understood. In this study, we investigated the tropism of HHV-6 in peripheral blood mononuclear cells (PBMCs) during acute infection. We detected 637 +/- 273 copies of viral DNA in 10(4) MO/M phi. in contrast, in 10(4) CD4+ T cells, which have been reported to be viral carriers during the acute infection of HHV-6, we found only 115 +/- 42 copies of viral DNA.

Consistent with these data, virus was isolated from MO/M phi an order of magnitude more frequently than from CD4+ T cells. Viral mRNA U79/80, which indicates viral replication, was detectable in the MO/M phi. In addition, the mRNAs that encode viral chemokine receptors U12 and U51, which may modify the function of MO/M phi, were expressed in the cells.

Therefore, productively infected MO/M phi may be the dominant cell population that is responsible for HHV-6 viremia during acute HHV-6 infection. The strong interaction of HHV-6 with MO/M phi may be partly responsible for the pathogenesis of this virus.

Prevalence and Cellular Reservoir of Latent Human Herpesvirus 6 in Tonsillar Lymphoid Tissue

Karen S. Roush, MD
Rana K. Domiati-Saad, PhD
Linda R. Margraf, MD
Karen Krisher, PhD
Richard H. Scheuermann, PhD
Beverly Barton Rogers, MD
D. Brian Dawson, PhD

Am J Clin Pathol 2001;116:648-654 Abstract quote

There are few studies that examine prevalence, quantity, and cellular proclivity of latent human herpesvirus 6 (HHV-6) in healthy populations.

We examined 69 tonsils with paired blood specimens from children without evidence of acute infection. By polymerase chain reaction (PCR), HHV-6 was detected at low levels in 100% of tonsils and 39% of blood samples (n = 27), suggesting that prevalence of latent HHV-6 infection is high in children and may be underestimated by PCR analysis of blood. Although HHV-6A and HHV-6B were detected, HHV-6B predominated, being found in 97% of samples (n = 67). Tonsil sections from 7 cases were examined by in situ hybridization using 2 HHV-6 probes and immunohistochemical analysis. Using both in situ hybridization and immunohistochemical analysis, all tissues revealed marked HHV-6�specific staining in the squamous epithelium of the tonsillar crypts and rare positive lymphocytes.

We conclude that HHV-6 is present universally in tonsils of children, and tonsillar epithelium may be an important viral reservoir in latent infection.

DISEASE ASSOCIATIONS CHARACTERIZATION

ANTICONVULSANT HYPERSENSITIVITY SYNDROME

Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia.

Kano Y, Inaoka M, Shiohara T.

Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan.

Arch Dermatol. 2004 Feb;140(2):183-8 Abstract quote.

BACKGROUND: Anticonvulsant hypersensitivity syndrome (AHS) is a life-threatening, drug-induced, multiorgan system reaction. The identification of predisposing factors is clearly needed to predict the incidence and outcome of AHS; attention has recently been focused on reactivation of human herpesvirus 6 (HHV-6).

OBJECTIVE: To determine whether immunosuppressive conditions that can allow HHV-6 reactivation could be specifically detected in association with the onset of AHS. DESIGN: We analyzed patients with AHS who were treated during 1997-2002. Two groups of patients receiving anticonvulsants served as controls.

SETTING: Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan.Patients Ten patients with AHS.

MAIN OUTCOME MEASURES: The results of serologic tests for antibody titers for various viruses, including HHV-6, HHV-6 DNA detection by real-time polymerase chain reaction, immunoglobulin levels by turbidimetric immunoassay, IgG subclass levels by nephelometry, and CD19(+) B-cell counts by flow cytometric analysis, were sequentially assessed.

RESULTS: Serum IgG levels (mean, 745 mg/dL) and circulating B-cell counts (mean, 88/ micro L) in patients with AHS were significantly decreased at onset compared with control groups (P<.001 and P =.007, respectively). These alterations returned to normal on full recovery. Reactivation of HHV-6 as judged by a greater than 4-fold increase in HHV-6 IgG titers was exclusively detected in most patients with AHS associated with decreased IgG levels and B-cell counts.

CONCLUSIONS: A decrease in immunoglobulin levels and B-cell counts can be associated with HHV-6 reactivation and the subsequent onset of AHS. These immunological alterations might be a useful predictor of the development of AHS.

Human herpesvirus 6 encephalitis associated with hypersensitivity syndrome.

Fujino Y, Nakajima M, Inoue H, Kusuhara T, Yamada T.

Department of Neurology, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Johnan-ku, Fukuoka, Japan 814-0180.
Ann Neurol 2002 Jun;51(6):771-4 Abstract quote
Hypersensitivity syndrome, a serious systematic reaction to a limited number of drugs, is associated with the reactivation of human herpesvirus 6. A 56-year-old man developed acute limbic encephalitis followed by multiple organ failure during the course of toxic dermatitis induced by aromatic anticonvulsants.

The clinical features of skin eruptions, high fever, eosinophilia, and atypical lymphocytosis were compatible with drug hypersensitivity syndrome. The patient showed seroconversion for human herpesvirus 6, and polymerase chain reaction detected human herpesvirus 6 DNA in the cerebrospinal fluid.

To our knowledge, this is the first report of human herpesvirus 6 encephalitis associated with hypersensitivity syndrome.

Human herpesvirus 6 infection associated with anticonvulsant hypersensitivity syndrome and reactive haemophagocytic syndrome Br J Dermatol. 1997;137:605-608.

Human herpesvirus 6 infection as a risk factor for the development of severe drug-induced hypersensitivity syndrome. Arch Dermatol. 1998;134:1108-1112

Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms-DRESS)
Semin Cutan Med Surg. 1996;15:250-257.
J Clin Invest. 1988;82:1826-1832.

Criteria for diagnosis included:
Clinical manifestations (fever, facial edema, exfoliative dermatitis, or lymphadenopathy) and biological manifestations (hypereosinophilia, atypical circulating lymphocytes, or liver cytolysis)

DRUG REACTIONS

Association of Human Herpesvirus 6 Infection With Drug Reaction With Eosinophilia and Systemic Symptoms
Arch Dermatol. 2001;137:301-304 Abstract quote

Background:
There is a current debate regarding the association of human herpesvirus 6 (HHV-6) infection and drug reaction with eosinophilia and systemic symptoms (DRESS).

Methods:
Seven consecutive patients hospitalized with DRESS were enrolled in a prospective study to evaluate evidence of active HHV-6 infection.

Observations:
The imputable drugs were carbamazepine (5 patients), ibuprofen
(1 patient), and sulfasalazine (1 patient). All patients were seropositive for anti�HHV-6 IgG antibodies. Anti�HHV-6 IgM antibodies were detected in 4 of the 7 patients with a seroconversion in 2 patients. Neither anti-cytomegalovirus nor anti�Epstein-Barr virus early antigen IgM antibody was detected. Human herpesvirus 6 genome was not detected by polymerase chain reaction in the first serum sample of all patients. It was weakly detected in skin lesions in the last patient tested by polymerase chain reaction but was not found in uninvolved skin.

Conclusions:
The results suggest an association between HHV-6 active infection (primo-infection or reactivation) and severe DRESS. Absence of anti-cytomegalovirus or anti�Epstein-Barr virus early antigen IgM antibodies argues against a nonspecific viral reactivation. Human herpesvirus 6 infection may play a role in the development of DRESS in susceptible patients. Some drugs with reactive metabolites could favor reactivation and propagation of HHV-6.

GUILLAIN-BARRE SYNDROME

Guillain-Barre syndrome after exanthem subitum.

Miyake F, Yoshikawa T, Suzuki K, Ohashi M, Suga S, Asano Y.

Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
Pediatr Infect Dis J 2002 Jun;21(6):569-70 Abstract quote
A female infant developed Guillain-Barre syndrome 20 days after having exanthem subitum confirmed serologically as human herpesvirus 6 infection. DNA of human herpesvirus 6 was detected in peripheral blood mononuclear cells collected on admission.

LEUKEMIA

Antibody status to HHV-6 in children with leukaemia.

Salonen MJ, Siimes MA, Salonen EM, Vaheri A, Koskiniemi M.

Haartman Institute, Department of Virology, University of Helsinki, Helsinki, Finland.

Leukemia 2002 Apr;16(4):716-9 Abstract quote
Forty children with acute lymphoblastic (33) or myeloid leukaemia (seven) were studied for IgG and IgM antibodies and IgG avidity against human herpesvirus 6 (HHV-6) at the time of diagnosis, and compared with age-, sex- and season-matched children with various neurological diseases of suspected viral origin.

Of the children with leukaemia, 97.5% had IgG antibodies and 40% IgM antibodies to HHV-6 compared with 92.3% and 7.7% of reference subjects (P = 0.005). A seronegative child with leukaemia seroconverted 3 weeks after the diagnosis. The avidity of IgG antibodies (based on the resistance to urea treatment) was high in all children with leukaemia.

One reference child had HHV-6-specific IgG antibodies with low avidity, which together with his positive IgM indicated an acute infection. The presence of specific IgM antibodies in 40% of children with leukaemia and the high avidity of IgG suggest a reactivation or an inaproppriate primary response to HHV-6 infection.

The results support the conclusion of the role of the HHV-6 infection at the onset of childhood leukaemia.

LABORATORY/
RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

Neuroradiologic findings of brain lesions related to exanthema subitum.

Kimura S, Nezu A.

Department of Pediatrics, Urafune Hospital of Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
Pediatr Neurol 1998 Nov;19(5):343-6 Abstract quote
The neuroradiologic findings of the brain lesions in eight infants with exanthema subitum were normal in three, suspected vascular lesions in two, and symmetric thalamic lesions with or without diffuse brain edema in the other three.

In addition, diffuse brain edema or focal cerebral lesions were observed in 13 previously reported Japanese infants.

These findings suggest that the pathogeneses of the brain lesions related to exanthema subitum are variable.

LABORATORY MARKERS

COMPLETE BLOOD COUNT

Hematologic findings associated with thrombocytopenia during the acute phase of exanthem subitum confirmed by primary human herpesvirus-6 infection.

Hashimoto H, Maruyama H, Fujimoto K, Sakakura T, Seishu S, Okuda N.

Department of Pediatrics, Kanazawa National Hospital, Japan.

J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):211-4 Abstract quote
PURPOSE: To elucidate the mechanism underlying thrombocytopenia during the acute phase of exanthem subitum (ES), the associated hematological findings were investigated.

PATIENTS AND METHODS: Five infants with thrombocytopenia during the acute phase of ES serologically confirmed by primary human herpesvirus-6 (HHV-6) were examined and followed-up.

RESULTS: Thrombocytopenia was accompanied by neutropenia, leukopenia, and decreased reticulocyte fraction during the acute phase. These changes were self-limiting, and the sequential changes of platelet, neutrophil count, and reticulocyte fraction were closely linked. Slight but significant decreases in hemoglobin in the convalescent phase and mild increases in atypical lymphocytes after subsidence of the fever were observed. Hemophagocytosis and increase in atypical lymphocytes in the bone marrow suggested that bone marrow cells were influenced by primary HHV-6 infection. Platelet-associated immunoglobulin G and indirect antiplatelet antibody were negative. Plasma levels of fibrinogen and D-dimer of fibrinogen degradation products were within normal ranges.

CONCLUSIONS: Thrombocytopenia is a complication of ES, and this may result from bone marrow suppression rather than from immune-mediated peripheral consumption seen in acute idiopathic thrombocytopenic purpura or from disseminated intravascular coagulation.

ELISA

A mu-capture immunoassay for detection of human herpes virus-6 (HHV-6) IgM antibodies in human serum.

Nielsen L, Vestergaard BF.

Department of Virology, Statens Seruminstitut, Artillerivej 5, DK 2300, Copenhagen S, Denmark.
J Clin Virol 2002 Aug;25(2):145-54 Abstract quote
BACKGROUND: Human herpes virus-6 (HHV-6) was first isolated in 1986. It has been shown to cause exanthema subitum and has been associated with various other diseases. HHV-6 infection is widespread, and more than 90% of the population have antibodies against HHV-6 at the age of 2 years. Once acquired, the virus remains latent in the body. This makes it difficult to draw any conclusions about a causal relationship between the demonstration of HHV-6 and a specific disease.

OBJECTIVES: This work was to develop a mu-capture HHV-6 IgM enzyme linked immuno sorbent assay (ELISA) for use in routine diagnosis and for wide scale patient population analysis.

STUDY DESIGN: A mu-capture HHV-6 IgM ELISA was established. A total of 682 sera consisting of 585 sera from Danish blood donors and 97 sera from patients with autoimmune antibodies were analysed in the HHV-6 IGM ELISA. One hundred and ninety-two sera had earlier been analysed for total HHV-6 antibody content in a competitive ELISA, 94 sera were analysed for cytomegalovirus (CMV) IgM and 57 sera for Epstein Barr virus (EBV) antibodies, using different ELISA assays. The results for 12 primary infections with HHV-6 are also reported.

RESULTS: A HHV-6 IgM optical density (OD)-ratio was calculated according to a constant positive control. An empirical cut off of 0.5 HHV-6 IgM OD-ratio was chosen (with regard to the 10 HHV-6 seroconverters), which resulted in a specificity of 97.5% of the HHV-6 IgM ELISA. Two of the three donor sera with HHV-6 IgM OD-ratios more than 1.05 had total HHV-6 antibody titers significantly above the group with IgM OD-ratios below 0.7 consisting with HHV-6 reactivation. There was no cross reactions to EBV or CMV IgM positive sera.

CONCLUSION: The HHV-6 IgM ELISA seems valid to diagnose primary HHV-6 infection in particular in combination with the HHV-6 total antibody assay.

PCR

Quantitation of human herpesvirus 6 DNA in infant with exanthem subitum by microplate PCR-hybridization assay.

Abe T, Yoshikawa T, Ihira M, Suzuki K, Suga S, Nishida M, Nagata M, Asano Y.

Department of Pediatrics, Fujita Health University Hospital, Toyoake, Aichi, Japan.

Pediatr Int 2001 Aug;43(4):372-8 Abstract quote
BACKGROUND: Quantitative analysis of human herpesvirus 6 (HHV-6) genome is important for monitoring active virus infection. The purpose of our study is to evaluate the reliability of a hybridization-based microtiter plate assay (polymerase chain reaction enzyme-linked immunosorbent assay (PCR ELISA)) for quantifying the virus genome.

METHODS: Semiquantitative analysis of the virus genome was carried out in 31 (18 male and 13 female) infants with primary HHV-6 infection. If the HHV-6 virus could be isolated from the peripheral blood mononuclear cells (PBMC), the infants were defined as being infected with HHV-6. The PCR ELISA method was used to determine the virus load. A titration of the virus was also carried out in the samples obtained during the acute phase of exanthem subitum.

RESULTS: Specificity of the method was demonstrated by a lack of amplification of human herpesvirus 7 and cytomegalovirus DNA. The upper and lower detection limits of the method were 58 and 5800 copies of the virus genome, respectively. The quantity of HHV-6 DNA in the PBMC during the acute phase (879 +/- 975 copies/10(4) PBMC) was significantly higher than during the convalescent phase (54 +/- 76 copies/10(4) PBMC). Furthermore, the virus load in acute phase plasma (53 +/- 75 copies/microL) was also significantly higher than in the convalescent phase samples (2 +/- 9 copies/microL). Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 to 4 of the illness, but then decreased quickly. However, there was no significant association between virus load and the numbers of infected cells.

Conclusion: Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 and day 4 of the illness, respectively, then it decreased quickly. These results indicate that our PCR ELISA system is reliable for monitoring active HHV-6 infection in vivo.

Early diagnosis of primary human herpesvirus 6 infection in childhood: serology, polymerase chain reaction, and virus load.

Chiu SS, Cheung CY, Tse CY, Peiris M.

Department of Pediatrics and Microbiology, University of Hong Kong.
J Infect Dis 1998 Nov;178(5):1250-6 Abstract quote
Qualitative and quantitative polymerase chain reaction (PCR) for human herpesvirus 6 (HHV-6) DNA in whole blood and plasma was correlated with serology and clinical assessment in 143 children hospitalized for undifferentiated febrile illness to evaluate options for diagnosis of primary HHV-6 infection on the acute blood specimen. PCR and serology for HHV-7 were done in parallel to define serologic cross-reactions.

Using HHV-6 seroconversion as the reference standard, detection of HHV-6 DNA in whole blood in the absence of antibody in the plasma was the most reliable evidence of primary HHV-6 infection. Detection of HHV-6 DNA in plasma and a high virus load in whole blood (>3.3 log10 copies/5 microL) had a sensitivity of 90% and 100%, respectively, in diagnosing primary HHV-6 infection. However, both were occasionally found in patients with other infections, possibly associated with HHV-6 reactivation.

Maternal antibody may confound interpretation of serology in patients under 3 months of age.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

EXANTHEMA SUBITUM (ROSEOLA INFANTUM)

Uvulo-palatoglossal junctional ulcers--an early clinical sign of exanthem subitum due to human herpesvirus 6.

Chua KB, Lam SK, Sazaly AB, Lim ST, Paranjothy M.

Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur.
Med J Malaysia 1999 Mar;54(1):32-6 Abstract quote
A provisional clinical diagnosis of exanthem subitum was made in six febrile infants seen in the Paediatric Unit of Assunta Hospital, Petaling Jaya, Malaysia with uvulo-palatoglossal junctional ulcers prior to the eruption of maculopapular rash.

On follow-up, all six infants developed maculopapular rash with the subsidence of fever at the end of the fourth febrile day. Human herpesvirus 6 was isolated from the peripheral blood mononuclear cells during the acute phase of the illness and HHV 6 specific genome was also detected in these cells by nested polymerase chain reaction. All the six infants showed seroconversion for both specific IgG and IgM to the isolated virus.

This study suggests that the presence of uvulo-palatoglossal junctional ulcers could be a useful early clinical sign of exanthem subitum due to human herpesvirus 6.

VARIANTS

LYMPHADENITIS

Human herpesvirus-6-associated acute lymphadenitis in immunocompetent adults.

Maric I, Bryant R, Abu-Asab M, Cohen JI, Vivero A, Jaffe ES, Raffeld M, Tsokos M, Banks PM, Pittaluga S.

1Laboratory of Pathology, National Cancer Institute, National Institutes of Health; Bethesda, MD, USA.

Mod Pathol. 2004 Nov;17(11):1427-33. Abstract quote

In contrast to other causes of herpetic lymphadenitis, the histological features associated with human herpesvirus-6 (HHV-6) infection have remained elusive since its discovery in 1986.

We describe the histologic and phenotypic changes associated with acute HHV-6 lymphadenitis in two immunocompetent adults who presented with fever, fatigue, generalized lymphadenopathy, and elevated liver enzymes. Serologic tests for human immunodeficiency virus, acute Epstein-Barr virus, and cytomegalovirus infection were negative. Lymph node biopsies were consistent with viral lymphadenitis. Intranuclear and cytoplasmic inclusions were identified in CD4-positive T lymphocytes in expanded paracortical areas. Immunohistochemical staining with monoclonal antibody to the HHV-6 gp60/110 kDa envelope glycoprotein showed that the inclusions were positive for viral antigen. Electron microscopy demonstrated numerous viral particles in the cytoplasm and nucleus, characteristic of Herpesviridae family. Clustering of viral particles was observed, which has previously been reported only in infected tissue culture cells. PCR followed by sequencing of DNA extracted from the lymph nodes identified the virus as HHV-6, type B.

This is the first report that documents distinctive histologic features of HHV-6 lymphadenitis and demonstrates that the cells harboring the virus in vivo are CD4-positive T lymphocytes.

MENINGOENCEPHALITIS

Fatal human herpesvirus 6-associated multifocal meningoencephalitis in an adult female patient.

Beovic B, Pecaric-Meglic N, Marin J, Bedernjak J, Muzlovic I, Cizman M.

Department of Infectious Diseases, University Medical Centre, Ljubljana, Slovenia
Scand J Infect Dis 2001;33(12):942-4 Abstract quote
Human herpesvirus 6 (HHV 6) is a known cause of central nervous system infection in immunocompromised patients. Less is known about the clinical course of HHV 6 encephalitis in immunocompetent patients. We report a case of meningoencephalitis in a 42-y-old immunocompetent patient associated with HHV 6 infection.

MYOCARDITIS

Fatal acute myocarditis in an infant with human herpesvirus 6 infection.

Yoshikawa T, Ihira M, Suzuki K, Suga S, Kito H, Iwasaki T, Kurata T, Tanaka T, Saito Y, Asano Y.

Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
J Clin Pathol 2001 Oct;54(10):792-5 Abstract quote
A 5 month old girl had typical clinical features of acute myocarditis just after the febrile period of exanthem subitum and died immediately. She had been healthy, with normal development, and there was no family history of particular note. Myocardial postmortem findings were compatible with acute myocarditis.

Although the isolation of human herpesvirus 6 (HHV-6) was not attempted, positive IgM antibody to HHV-6 was detected in the patient's serum. Moreover, HHV-6 variant B DNA was detected in several tissues, including myocardium, by the polymerase chain reaction (PCR). In contrast, antibody responses to human herpesvirus 7, another causal agent of exanthem subitum, were not found, and enteroviral RNA was not detected in myocardial tissues by reverse transcription PCR. Apoptotic changes were seen in infiltrating cells within the myocardial tissues by means of the TUNEL method.

HHV-6 antigen was not detected in several tissues (including myocardium) by immunohistochemical analysis. In conclusion, HHV-6 may have been the causative agent of fatal acute myocarditis in this infant.

NEONATAL

Human herpesvirus-6 infection in neonates: Not protected by only humoral immunity.

Sugimoto T, Tanaka-Taya K, Ono J, Miyoshi H, Okada S, Yamanishi K.

Division of Pediatrics,Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan.

Pediatr Int 2002 Jun;44(3):281-5 Abstract quote
BACKGROUND: Infants are usually protected from various viral infections, including human herpesvirus-6 (HHV-6) and human herpesvirus-7 (HHV-7) infections, during the early infantile period by antibodies transferred from their mothers. However, rare cases of exanthem subitum (ES) in neonates have been described in published reports.

METHODS: From the infantile patients of febrile illness, HHV-6 and HHV-7 DNA were examined by the polymerase chain reaction method. Antibodies to HHV-6 and HHV-7 were detected by indirect immuno-fluorescence assay and neutralization test. Viral isolation was attempted from the patient's peripheral blood mononuclear cells (PBMC) during the acute phase of febrile illness.

RESULTS: Human herpesvirus-6 was verified virologically in two neonates who were clinically diagnosed as ES within the first month of life. Although high copies of HHV-6 DNA were detected in their PBMC during the acute phase, the isolation of HHV-6 from their PBMC was not successful. Neutralizing antibodies to HHV-6 were detected in sera of the acute phase, and those antibodies were considered to be transferred from their mothers. Antibody titers showed fourfold elevation in sera of the convalescent phase. The HHV-6 infection occurred despite the presence of pre-existing maternal antibody. Human herpesvirus-7 and HHV-7 DNA were not detected from their clinical samples.

CONCLUSIONS: This observation suggests that HHV-6 infection could not be protected by only humoral immunity.

SEIZURES

Frequent seizures with elevated interleukin-6 at the eruptive stage of exanthema subitum.

Go T, Nakamura K.

Department of Paediatrics, Otsu Red Cross Hospital, Otsu, Japan.

Eur J Paediatr Neurol 2002;6(4):221-3 Abstract quote
A 15-month-old girl developed frequent seizures at the eruptive stage of exanthema subitum.

The eruption persisted for 2 weeks. Serum immunoglobulin G antibody to human herpes virus type 6 (HHV-6) increased markedly. Interleukin-6 was elevated whereas HHV-6 deoxyribonucleic acid was not detected in cerebrospinal fluid.

These findings suggest that immune-mediated reactions after HHV-6 infection rather than direct action of active HHV-6 are responsible for frequent seizures in this case.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

LIVER

Are there histopathologic characteristics particular to fulminant hepatic failure caused by human herpesvirus-6 infection? A case report and discussion.

Aita K, Jin Y, Irie H, Takahashi I, Kobori K, Nakasato Y, Kodama H, Yanagawa Y, Yoshikawa T, Shiga J.

Department of Pathology, Central Laboratory for Electron Microscopy, Teikyo University School of Medicine, Tokyo, Japan.
Hum Pathol 2001 Aug;32(8):887-9 Abstract quote
An 8-month-old boy was admitted to a neighboring hospital for severe liver dysfunction and drowsiness 4 days after a diagnosis of exanthem subitum.

A diagnosis of fulminant hepatic failure was made, and liver biopsy was performed during the acute stage. The presence of human herpesvirus-6 variant B (HHV-6B) DNA was shown in liver tissue by polymerase chain reaction (PCR) and in the endothelium of the portal vein by in situ hybridization (ISH).

Histologic examination showed microvesicular steatosis resembling that of Reye's syndrome, even though aspirin had not been prescribed. We considered HHV-6 to be the causative agent in this case and report what is perhaps the first precise histologic description of fulminant hepatic failure caused by HHV-6.

PROGNOSIS CHARACTERIZATION

GENERAL

Risk factors for the early acquisition of human herpesvirus 6 and human herpesvirus 7 infections in children.

Lanphear BP, Hall CB, Black J, Auinger P.

Children's Hospital Medical Center and the Department of Pediatrics, University of Cincinnati, OH 45229-3039, USA.
Pediatr Infect Dis J 1998 Sep;17(9):792-5 Abstract quote
OBJECTIVE: Human herpesviruses 6 and 7 (HHV-6 and HHV-7) are common infections in children, but risk factors for their early acquisition have not been described.

METHODS: Excess sera from children 12 to 31 months of age enrolled in a cross-sectional, random survey were tested for human herpesviruses 6 and 7 infection, as measured by using immuno-blot and immunofluorescence assays.

RESULTS: Of 164 children 131 (80%) had antibody to HHV-6, and 79 (47%) of 167 had antibody to HHV-7. In logistic regression analysis low income [odds ratio (OR), 2.9; 95% confidence intervals (CI), 1.02 to 8.7] and having more than 1 sibling (OR=2.1, 95% CI=0.9 to 5.1) were risk factors for HHV-6 infection after adjusting for age, whereas month of test (OR=2.7, 95% CI=1.3 to 5.9) and Black race (OR=2.0, 95% CI=0.9, 4.6) were associated with a higher prevalence of HHV-7 infection. In contrast having ever been breast-fed appeared to protect against HHV-7 infection (OR=0.5, 95% CI=0.3 to 1.1).

CONCLUSIONS: Despite studies linking both HHV-6 and HHV-7 with exanthem subitum, risk factors for the early acquisition of HHV-6 and HHV-7 are distinct. Subsequent studies investigating the transmission of HHV-6 should explore family size and other factors associated with poverty, whereas breast-feeding should be examined as a protective factor for HHV-7 infection.

TRANSPLANTATION

Human herpesvirus 6 infection in transplantation.

Yoshikawa T.

Laboratory of Virology, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Nagoya J Med Sci 2001 May;64(1-2):11-8 Abstract quote
Human herpesvirus 6 (HHV-6) is ubiquitous in the human population and causes exanthem subitum, a benign disease seen in infancy. The virus remains latent in the body after primary infection, and reactivates in immunocompromised patients. Infection occurs in nearly half of all bone marrow or solid organ transplant recipients 2-3 weeks following the procedure.

It has been suggested that the viral infection and activation result in clinical symptoms including fever, skin rash, pneumonia, bone marrow suppression, encephalitis, and rejection.

In order to control the viral infection, several studies investigating the route of viral transmission and diagnostic procedures have been carried out.

TREATMENT CHARACTERIZATION

GENERAL Supportive

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated November 3, 2004

EPIDEMIOLOGY	CHARACTERIZATION
AGE RANGE-MEDIAN	Children<2 years
INCIDENCE/ PREVALENCE
Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women. Baillargeon J, Piper J, Leach CT. Departments of Pediatrics, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, USA.	J Clin Virol 2000 May;16(3):149-57 Abstract quote BACKGROUND: Human herpesvirus 6 (HHV-6) is a ubiquitous virus primarily associated with benign conditions such as febrile syndromes and exanthem subitum (roseola infantum). Sexual, horizontal, and vertical transmission have been suggested. Little information is available regarding HHV-6 infection in women of reproductive age. OBJECTIVE: Describe epidemiology of HHV-6 infection in pregnant and nonpregnant women. STUDY DESIGN: The study sample consisted of 569 women, age 18-45, who attended a university family planning clinic (nonpregnant, n=224) and two obstetrics clinics (pregnant [first trimester], n=345) in San Antonio, TX between October 1995 and May 1998. Blood and a vaginal swab, as well as sociodemographic information, were collected from each participant. Plasma was tested for HHV-6 IgG antibodies using a standard immunofluorescence assay (IFA). Lysed material from vaginal swabs was tested for HHV-6 DNA by polymerase chain reaction (PCR). Products were screened by enzyme-linked immunosorbent assay and positive tests were confirmed by repeat PCR followed by Southern analysis. PCR-positive samples were subtyped using an established method. RESULTS: All subjects were HHV-6 antibody positive. Geometric mean titers of HHV-6 antibodies were significantly higher among nonpregnant versus pregnant women. Moreover, a higher proportion of nonpregnant versus pregnant women had antibody titers >/=160 and >/=320. This association persisted even after adjusting for a number of sociodemographic and clinical factors. Low rates of HHV-6 shedding in the genital tract were observed for both groups (pregnant, 7/297 [2.0%]; nonpregnant, 8/214 [3.7%]). Of 14 samples subtyped, four (29%) were subtype A. CONCLUSION: The present study showed that 100% of the study sample was infected with HHV-6. Higher HHV-6 antibody titers, however, were noted in nonpregnant women. Both groups shed virus at low rates in the genital tract. HHV-6 subtype A was identified more commonly than previously reported. Further longitudinal studies are required to assess the consequences of maternal HHV-6 infection.
TRANSMISSION
Human herpesviruses 6 and 7: effects on hematopoiesis and mode of transmission. Yamada M. Department of Virology, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan.	Jpn J Infect Dis 2001 Apr;54(2):47-54 Abstract quote Human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7) were recently discovered, and are known as etiologic agents of exanthem subitum (roseola). HHV-6 and HHV-7 are T-lymphotropic, and have been classified as betaherpesviruses. In monitoring of herpesviruses after hematopoietic stem cell transplantation, each herpesvirus had a unique temporal profile of detection. HHV-6 DNA was detected most frequently at 3 weeks, whereas cytomegalovirus and Epstein-Barr virus DNA were detected later. HHV-7 DNA was not detected throughout the observation period. In in vitro hematopoietic colony assays, HHV-6 suppressed all three lineages of hematopoiesis, i.e., erythroid, granulocyte/macrophage, and megakaryocyte, whereas HHV-7 did not have any suppressive effect. Molecular epidemiological analysis revealed that HHV-7 was transmitted horizontally from grandparents to parents to children through close contact within a household. Either parent could transmit HHV-7 to the children. Follow-up studies of the amount of viral DNA in saliva samples revealed that the amount of HHV-7 DNA was rather constant for each individual, and that "high producers" and "low producers" could be distinguished. Transferred antibodies against HHV-7 tended to be higher and remain longer after birth than those of HHV-6, and these findings are consistent with the clinical observation that HHV-6 infection occurs earlier than HHV-7 infection.
Transfer of human herpesvirus 6 and 7 antibodies from mothers to their offspring. Ohashi M, Ihira M, Suzuki K, Suga S, Asano Y, Yoshikawa T, Saito Y, Sakui H. Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.	Pediatr Infect Dis J 2001 Apr;20(4):449-50 Abstract quote Placental transfer of maternal human herpesvirus (HHV) 6 and HHV 7 antibodies to infants was examined simultaneously in 69 paired plasma samples by an indirect immunofluorescence assay. All the mothers had antibodies to both viruses. The mean HHV 6 and HHV 7 antibody titers of infants were significantly higher than those of the mothers. The mean ratio of cord blood antibody titer to the maternal titer for both viruses was 1.89, suggesting active transport by placenta.
GEOGRAPHY
BRAZIL
Outbreaks of human-herpes virus 6 (HHV-6) infection in day-care centers in Belem, Para, Brazil. Freitas RB, Monteiro TA, Linhares AC. Servico de Virologia Geral, Instituto Evandro Chagas, Fundacao Nacional de Saude, Ministerio da Saude, Belem, Para, Brasil.	Rev Inst Med Trop Sao Paulo 2000 Nov-Dec;42(6):305-11 Abstract quote A total of 730 children aged less than 7 years, attending 8 day-care centers (DCCs) in Belem, Brazil were followed-up from January to December 1997 to investigate the occurrence of human-herpes virus 6 (HHV-6) infection in these institutional settings. Between October and December 1997 there have been outbreaks of a febrile- and -exanthematous disease, affecting at least 15-20% of children in each of the DCCs. Both serum- and- plasma samples were obtained from 401 (55%) of the 730 participating children for the detection of HHV-6 antibodies by enzyme-linked immunosorbent assay (ELISA), and viral DNA amplification through the nested-PCR. Recent HHV-6 infection was diagnosed in 63.8% (256/401) of them, as defined by the presence of both IgM and IgG-specific antibodies (IgM+/IgG+); of these, 114 (44.5%) were symptomatic and 142 (55.5%) had no symptoms (p = 0.03). A subgroup of 123 (30.7%) children were found to be IgM-/IgG+, whereas the remaining 22 (5.5%) children had neither IgM nor IgG HHV-6- antibodies (IgM-/IgG-). Of the 118 children reacting strongly IgM-positive (> or = 30 PANBIO units), 26 (22.0%) were found to harbour the HHV-6 DNA, as demonstrated by nested-PCR. Taken the ELISA-IgM- and- nested PCR-positive results together, HHV-6 infection was shown to have occurred in 5 of the 8 DCCs under follow-up. Serological evidence of recent infections by Epstein-Barr virus (EBV) and parvovirus B19 were identified in 2.0% (8/401) and 1. 5% (6/401) of the children, respectively. Our data provide strong evidence that HHV-6 is a common cause of outbreaks of febrile/exanthematous diseases among children attending DCCs in the Belem area.

PATHOGENESIS	CHARACTERIZATION
GENERAL
Human herpesvirus 6: molecular biology and clinical features. Dockrell DH. Division of Genomic Medicine, University of Sheffield School of Medicine and Biomedical Sciences, Beech Hill Road, Sheffield S10 2RX, UK.	J Med Microbiol 2003 Jan;52(Pt 1):5-18 Abstract quote Human herpesvirus 6 (HHV-6) exists as distinct variants HHV-6A and HHV-6B. The complete genomes of HHV-6A and HHV-6B have been sequenced. HHV-6B contains 97 unique genes. CD46 is the cell receptor for HHV-6, explaining its broad tissue tropism but its restricted host-species range. HHV-6 utilizes a number of strategies to down-regulate the host immune response, including molecular mimicry by production of a functional chemokine and chemokine receptors. Immunosuppression is enhanced by depletion of CD4 T lymphocytes via direct infection of intra-thymic progenitors and by apoptosis induction. Infection is widespread in infants between 6 months and 2 years of age. A minority of infants develop roseola infantum, but undifferentiated febrile illness is more common. Reactivation from latency occurs in immunocompromised hosts. Organ-specific clinical syndromes occasionally result, but indirect effects including interactions with other viruses such as human immunodeficiency virus type 1 and human cytomegalovirus or graft dysfunction in transplant recipients may be more significant complications in this population. Recent advances in quantitative PCR are providing additional insights into the natural history of infection in paediatric populations and immunocompromised hosts.
RESERVOIR OF INFECTION
Strong interaction between human herpesvirus 6 and peripheral blood monocytes/macrophages during acute infection. Kondo K, Kondo T, Shimada K, Amo K, Miyagawa H, Yamanishi K. Department of Microbiology, Osaka University Medical School, Osaka, Japan.	J Med Virol 2002 Jul;67(3):364-9 Abstract quote Human herpesvirus 6 (HHV-6) encodes a viral chemokine and chemokine receptors that may modify the functions of monocytes/macrophages (MO/M phi) during productive HHV-6 infection. The interactions between HHV-6 and MO/M phi during acute infection, however, remain poorly understood. In this study, we investigated the tropism of HHV-6 in peripheral blood mononuclear cells (PBMCs) during acute infection. We detected 637 +/- 273 copies of viral DNA in 10(4) MO/M phi. in contrast, in 10(4) CD4+ T cells, which have been reported to be viral carriers during the acute infection of HHV-6, we found only 115 +/- 42 copies of viral DNA. Consistent with these data, virus was isolated from MO/M phi an order of magnitude more frequently than from CD4+ T cells. Viral mRNA U79/80, which indicates viral replication, was detectable in the MO/M phi. In addition, the mRNAs that encode viral chemokine receptors U12 and U51, which may modify the function of MO/M phi, were expressed in the cells. Therefore, productively infected MO/M phi may be the dominant cell population that is responsible for HHV-6 viremia during acute HHV-6 infection. The strong interaction of HHV-6 with MO/M phi may be partly responsible for the pathogenesis of this virus.
Prevalence and Cellular Reservoir of Latent Human Herpesvirus 6 in Tonsillar Lymphoid Tissue Karen S. Roush, MD Rana K. Domiati-Saad, PhD Linda R. Margraf, MD Karen Krisher, PhD Richard H. Scheuermann, PhD Beverly Barton Rogers, MD D. Brian Dawson, PhD	Am J Clin Pathol 2001;116:648-654 Abstract quote There are few studies that examine prevalence, quantity, and cellular proclivity of latent human herpesvirus 6 (HHV-6) in healthy populations. We examined 69 tonsils with paired blood specimens from children without evidence of acute infection. By polymerase chain reaction (PCR), HHV-6 was detected at low levels in 100% of tonsils and 39% of blood samples (n = 27), suggesting that prevalence of latent HHV-6 infection is high in children and may be underestimated by PCR analysis of blood. Although HHV-6A and HHV-6B were detected, HHV-6B predominated, being found in 97% of samples (n = 67). Tonsil sections from 7 cases were examined by in situ hybridization using 2 HHV-6 probes and immunohistochemical analysis. Using both in situ hybridization and immunohistochemical analysis, all tissues revealed marked HHV-6�specific staining in the squamous epithelium of the tonsillar crypts and rare positive lymphocytes. We conclude that HHV-6 is present universally in tonsils of children, and tonsillar epithelium may be an important viral reservoir in latent infection.

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
Neuroradiologic findings of brain lesions related to exanthema subitum. Kimura S, Nezu A. Department of Pediatrics, Urafune Hospital of Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.	Pediatr Neurol 1998 Nov;19(5):343-6 Abstract quote The neuroradiologic findings of the brain lesions in eight infants with exanthema subitum were normal in three, suspected vascular lesions in two, and symmetric thalamic lesions with or without diffuse brain edema in the other three. In addition, diffuse brain edema or focal cerebral lesions were observed in 13 previously reported Japanese infants. These findings suggest that the pathogeneses of the brain lesions related to exanthema subitum are variable.
LABORATORY MARKERS
COMPLETE BLOOD COUNT
Hematologic findings associated with thrombocytopenia during the acute phase of exanthem subitum confirmed by primary human herpesvirus-6 infection. Hashimoto H, Maruyama H, Fujimoto K, Sakakura T, Seishu S, Okuda N. Department of Pediatrics, Kanazawa National Hospital, Japan.	J Pediatr Hematol Oncol 2002 Mar-Apr;24(3):211-4 Abstract quote PURPOSE: To elucidate the mechanism underlying thrombocytopenia during the acute phase of exanthem subitum (ES), the associated hematological findings were investigated. PATIENTS AND METHODS: Five infants with thrombocytopenia during the acute phase of ES serologically confirmed by primary human herpesvirus-6 (HHV-6) were examined and followed-up. RESULTS: Thrombocytopenia was accompanied by neutropenia, leukopenia, and decreased reticulocyte fraction during the acute phase. These changes were self-limiting, and the sequential changes of platelet, neutrophil count, and reticulocyte fraction were closely linked. Slight but significant decreases in hemoglobin in the convalescent phase and mild increases in atypical lymphocytes after subsidence of the fever were observed. Hemophagocytosis and increase in atypical lymphocytes in the bone marrow suggested that bone marrow cells were influenced by primary HHV-6 infection. Platelet-associated immunoglobulin G and indirect antiplatelet antibody were negative. Plasma levels of fibrinogen and D-dimer of fibrinogen degradation products were within normal ranges. CONCLUSIONS: Thrombocytopenia is a complication of ES, and this may result from bone marrow suppression rather than from immune-mediated peripheral consumption seen in acute idiopathic thrombocytopenic purpura or from disseminated intravascular coagulation.
ELISA
A mu-capture immunoassay for detection of human herpes virus-6 (HHV-6) IgM antibodies in human serum. Nielsen L, Vestergaard BF. Department of Virology, Statens Seruminstitut, Artillerivej 5, DK 2300, Copenhagen S, Denmark.	J Clin Virol 2002 Aug;25(2):145-54 Abstract quote BACKGROUND: Human herpes virus-6 (HHV-6) was first isolated in 1986. It has been shown to cause exanthema subitum and has been associated with various other diseases. HHV-6 infection is widespread, and more than 90% of the population have antibodies against HHV-6 at the age of 2 years. Once acquired, the virus remains latent in the body. This makes it difficult to draw any conclusions about a causal relationship between the demonstration of HHV-6 and a specific disease. OBJECTIVES: This work was to develop a mu-capture HHV-6 IgM enzyme linked immuno sorbent assay (ELISA) for use in routine diagnosis and for wide scale patient population analysis. STUDY DESIGN: A mu-capture HHV-6 IgM ELISA was established. A total of 682 sera consisting of 585 sera from Danish blood donors and 97 sera from patients with autoimmune antibodies were analysed in the HHV-6 IGM ELISA. One hundred and ninety-two sera had earlier been analysed for total HHV-6 antibody content in a competitive ELISA, 94 sera were analysed for cytomegalovirus (CMV) IgM and 57 sera for Epstein Barr virus (EBV) antibodies, using different ELISA assays. The results for 12 primary infections with HHV-6 are also reported. RESULTS: A HHV-6 IgM optical density (OD)-ratio was calculated according to a constant positive control. An empirical cut off of 0.5 HHV-6 IgM OD-ratio was chosen (with regard to the 10 HHV-6 seroconverters), which resulted in a specificity of 97.5% of the HHV-6 IgM ELISA. Two of the three donor sera with HHV-6 IgM OD-ratios more than 1.05 had total HHV-6 antibody titers significantly above the group with IgM OD-ratios below 0.7 consisting with HHV-6 reactivation. There was no cross reactions to EBV or CMV IgM positive sera. CONCLUSION: The HHV-6 IgM ELISA seems valid to diagnose primary HHV-6 infection in particular in combination with the HHV-6 total antibody assay.
PCR
Quantitation of human herpesvirus 6 DNA in infant with exanthem subitum by microplate PCR-hybridization assay. Abe T, Yoshikawa T, Ihira M, Suzuki K, Suga S, Nishida M, Nagata M, Asano Y. Department of Pediatrics, Fujita Health University Hospital, Toyoake, Aichi, Japan.	Pediatr Int 2001 Aug;43(4):372-8 Abstract quote BACKGROUND: Quantitative analysis of human herpesvirus 6 (HHV-6) genome is important for monitoring active virus infection. The purpose of our study is to evaluate the reliability of a hybridization-based microtiter plate assay (polymerase chain reaction enzyme-linked immunosorbent assay (PCR ELISA)) for quantifying the virus genome. METHODS: Semiquantitative analysis of the virus genome was carried out in 31 (18 male and 13 female) infants with primary HHV-6 infection. If the HHV-6 virus could be isolated from the peripheral blood mononuclear cells (PBMC), the infants were defined as being infected with HHV-6. The PCR ELISA method was used to determine the virus load. A titration of the virus was also carried out in the samples obtained during the acute phase of exanthem subitum. RESULTS: Specificity of the method was demonstrated by a lack of amplification of human herpesvirus 7 and cytomegalovirus DNA. The upper and lower detection limits of the method were 58 and 5800 copies of the virus genome, respectively. The quantity of HHV-6 DNA in the PBMC during the acute phase (879 +/- 975 copies/10(4) PBMC) was significantly higher than during the convalescent phase (54 +/- 76 copies/10(4) PBMC). Furthermore, the virus load in acute phase plasma (53 +/- 75 copies/microL) was also significantly higher than in the convalescent phase samples (2 +/- 9 copies/microL). Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 to 4 of the illness, but then decreased quickly. However, there was no significant association between virus load and the numbers of infected cells. Conclusion: Virus load in both PBMC and plasma gradually increased after the onset of exanthem subitum until about day 3 and day 4 of the illness, respectively, then it decreased quickly. These results indicate that our PCR ELISA system is reliable for monitoring active HHV-6 infection in vivo.
Early diagnosis of primary human herpesvirus 6 infection in childhood: serology, polymerase chain reaction, and virus load. Chiu SS, Cheung CY, Tse CY, Peiris M. Department of Pediatrics and Microbiology, University of Hong Kong.	J Infect Dis 1998 Nov;178(5):1250-6 Abstract quote Qualitative and quantitative polymerase chain reaction (PCR) for human herpesvirus 6 (HHV-6) DNA in whole blood and plasma was correlated with serology and clinical assessment in 143 children hospitalized for undifferentiated febrile illness to evaluate options for diagnosis of primary HHV-6 infection on the acute blood specimen. PCR and serology for HHV-7 were done in parallel to define serologic cross-reactions. Using HHV-6 seroconversion as the reference standard, detection of HHV-6 DNA in whole blood in the absence of antibody in the plasma was the most reliable evidence of primary HHV-6 infection. Detection of HHV-6 DNA in plasma and a high virus load in whole blood (>3.3 log10 copies/5 microL) had a sensitivity of 90% and 100%, respectively, in diagnosing primary HHV-6 infection. However, both were occasionally found in patients with other infections, possibly associated with HHV-6 reactivation. Maternal antibody may confound interpretation of serology in patients under 3 months of age.

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HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
LIVER
Are there histopathologic characteristics particular to fulminant hepatic failure caused by human herpesvirus-6 infection? A case report and discussion. Aita K, Jin Y, Irie H, Takahashi I, Kobori K, Nakasato Y, Kodama H, Yanagawa Y, Yoshikawa T, Shiga J. Department of Pathology, Central Laboratory for Electron Microscopy, Teikyo University School of Medicine, Tokyo, Japan.	Hum Pathol 2001 Aug;32(8):887-9 Abstract quote An 8-month-old boy was admitted to a neighboring hospital for severe liver dysfunction and drowsiness 4 days after a diagnosis of exanthem subitum. A diagnosis of fulminant hepatic failure was made, and liver biopsy was performed during the acute stage. The presence of human herpesvirus-6 variant B (HHV-6B) DNA was shown in liver tissue by polymerase chain reaction (PCR) and in the endothelium of the portal vein by in situ hybridization (ISH). Histologic examination showed microvesicular steatosis resembling that of Reye's syndrome, even though aspirin had not been prescribed. We considered HHV-6 to be the causative agent in this case and report what is perhaps the first precise histologic description of fulminant hepatic failure caused by HHV-6.