INTRODUCTION — Human herpesvirus 6 (HHV-6) was first isolated and characterized from patients with lymphoproliferative disorders [1] and was originally named human B-lymphotropic virus. Its name was changed to human herpesvirus 6 as its tropism was further characterized [2].
There are two HHV-6 variants, HHV-6A and HHV-6B. Based on their distinctive biological properties and genome sequences, HHV-6A and HHV-6B have been classified as two distinct herpesvirus species [3]. The vast majority of documented primary infections and reactivation events are due to HHV-6B. HHV-6B infects most children within the first three years of life and, like other herpesviruses, it establishes latency after primary infection. HHV-6B may reactivate in immunocompromised hosts, especially following allogeneic hematopoietic cell transplantation. Little is known about the epidemiology or clinical implications of HHV-6A.
The clinical manifestations, diagnosis, and treatment of HHV-6 infection in adults will be presented here. The virology, pathogenesis, and epidemiology of HHV-6 infection, as well as clinical issues in children, are presented separately; HHV-6 infection in hematopoietic cell transplant recipients is also discussed elsewhere. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)
CLINICAL MANIFESTATIONS
Immunocompetent hosts — HHV-6 infections usually occur during childhood and result in generally mild, self-limited illnesses. Possible disease associations with HHV-6 in immunocompetent adults are not proven other than a few cases of primary infection. (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Clinical manifestations'.)
Primary infection — Primary infection in adults is rare. However, a mononucleosis-like syndrome of varying severity with prolonged lymphadenopathy has been described in association with HHV-6 seroconversion in adults [4-6]. Three adults with serologic evidence of HHV-6 infection had mild illnesses in association with bilateral, nontender, anterior, and posterior lymphadenopathy, which persisted for up to three months [5].
Clear confirmation of the diagnosis was documented in a study of two immunocompetent adults with a mono-like illness in whom lymph node biopsies revealed intranuclear and cytoplasmic inclusions in CD4+ T cells that were positive for HHV-6 antigen by immunohistochemistry [6]. Polymerase chain reaction (PCR) techniques and DNA sequencing confirmed the virus as HHV-6.
Encephalitis — Encephalitis of variable severity has been associated rarely with HHV-6 infection in immunocompetent patients [7-11]. Clinical presentations have included altered level of consciousness, seizures, psychosis, acute cerebellar ataxia, and focal neurological signs (ie, cranial nerve deficits or hemiparesis) [7,8,12,13]. Neurologic outcomes have varied from full recovery to death. Most cases are believed to represent reactivation disease, since primary infection in adults is rare [14].
In a study of 138 patients with encephalitis of unknown etiology, HHV-6 DNA was found in the cerebrospinal fluid (CSF) of nine patients [7]. The CSF profile in HHV-6 encephalitis is notable for the presence of a lymphocytic pleocytosis [8,9].
Encephalitis has also been described in immunocompromised hosts (eg, transplant recipients). (See 'Transplant recipients' below and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'HHV-6 encephalitis'.)
Mesial temporal lobe epilepsy — HHV-6 has been associated with mesial temporal lobe epilepsy (MTLE). HHV-6 DNA was recovered from brain biopsies from patients with MTLE more frequently than in controls, suggesting a pathogenic effect of the virus [15-17].
Transplant recipients — Immunosuppression secondary to solid organ or hematopoietic cell transplantation (HCT) may favor reactivation and replication of HHV-6, resulting in viremia and/or clinical illness. Clinical syndromes associated with HHV-6 in transplant recipients include pneumonitis, hepatitis, encephalitis [18,19], myelitis [20,21], and bone marrow suppression [22]. (See "Infection in the solid organ transplant recipient" and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)
Inherited chromosomally integrated HHV-6 (iciHHV-6) can cause a confusing clinical picture in the setting of allogeneic HCT and has been reported rarely in solid organ transplant recipients. A fatal case of horizontal transmission of iciHHV-6A from donor to recipient through liver transplantation has been reported [23]. Molecular analysis performed on three viral genes from the recipient and donor samples supports transmission of iciHHV-6A from the graft. Transmission was followed by viral reactivation, severe disease, and death. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection", section on 'Viral replication' and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Inherited chromosomally integrated HHV-6'.)
These hosts are frequently coinfected with other viruses, such as cytomegalovirus, or other opportunistic agents, which complicates establishing the pathogenicity of HHV-6. The high prevalence of viral DNA in peripheral blood mononuclear cells of healthy controls limits the use of qualitative PCR to discriminate between latency and active infection, and increases in antibody titers often occur against several viruses simultaneously.
These difficulties were illustrated in a review of 228 consecutive HCT recipients [24]. HHV-6 viremia was documented in 42 percent of patients and in 57 percent of all clinical specimens collected. However, few clinical syndromes could be definitively attributed to HHV-6 infection.
Viremia — HHV-6 viremia can occur after transplantation in patients with serologic evidence of prior infection. This was illustrated in a prospective study of 65 kidney transplant recipients and their donors; all had evidence of neutralizing antibodies to HHV-6 at the time of transplant, but none had viremia [25]. At two to four weeks after transplantation, new-onset HHV-6 viremia was detected in 14 percent of recipients.
Among liver transplant recipients, HHV-6 viremia has been associated with cytomegalovirus reactivation and symptomatic disease [26]. In addition, HHV-6 has been detected in the plasma and liver of a liver transplant recipient with syncytial giant-cell hepatitis [27]. HHV-6 has also been recovered from gastroduodenal tissue in association with HHV-6 viremia in liver transplant recipients, although the significance of this is unclear [28].
HHV-6 viremia is common following HCT. This is discussed in detail separately. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)
Encephalitis — Most cases of HHV-6 encephalitis have occurred in allogeneic HCT recipients, although it has also been reported rarely in solid organ transplant recipients [29] and in immunocompetent individuals (see 'Encephalitis' above). HHV-6 infection in HCT recipients is discussed in detail separately. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients".)
Pneumonitis — HHV-6 can cause pneumonitis in transplant recipients [24,30-32]. The association between HHV-6 and pneumonitis in HCT recipients is presented separately. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Other possible associations'.)
Possible association with graft rejection
Solid organ transplant — Studies in renal transplant recipients have noted significant post-transplantation increases in HHV-6 antibody titers, isolation of HHV-6 from peripheral blood leukocytes, and detection of HHV-6 antigen in biopsy tissue [25,33,34]. However, most reports have failed to show a correlation with rejection among solid organ transplant recipients [25,33].
Hematopoietic cell transplant — Among HCT recipients, delayed bone marrow engraftment and bone marrow suppression have been associated with HHV-6 infection. There are conflicting data regarding whether HHV-6 reactivation is associated with graft-versus-host disease among HCT recipients. These issues are discussed in detail elsewhere. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Bone marrow suppression' and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Other possible associations'.)
UNPROVEN ASSOCIATIONS — Associations between HHV-6 and several diseases have been proposed but not proven. These include multiple sclerosis, hepatic failure, chronic fatigue syndrome (CFS; also known as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]), neoplasia, and myocarditis.
Multiple sclerosis — HHV-6 has been implicated in both acute and chronic inflammatory demyelinating diseases. The following observations support a possible association of HHV-6 with multiple sclerosis (MS) [35-39]:
●HHV-6 is highly neurotropic and can infect oligodendrocytes associated with MS plaques as well as glial precursors leading to disruption of normal glial differentiation [35,36].
●HHV-6 mRNA has been isolated in the blood in 16 percent of 105 patients with relapsing-remitting MS (RRMS) compared with none in healthy blood donors [39]. Among the patients with RRMS and isolation of HHV-6, viral load increased during periods of disease exacerbation when compared with remission. On the other hand, the use of beta interferon has been associated with a reduction in HHV-6 viral load in patients with RRMS [40]. However, HHV-6A does not seem to play an active role in secondary progressive MS [41]. In a prospective study of 205 MS patients, high anti-HHV-6 immunoglobulin (Ig)G titers (>640) were significantly associated with MS severity score and strong positive trends with higher relapse and conversion risks [42].
Using a novel bead-based multiplex serology assay that can measure antibodies against the immediate early proteins IE1A (HHV-6A) and IE1B (HHV-6B) encoded by the open reading frame U90-U89, the antibody response against HHV-6A was increased and decreased against HHV-6B , compared with controls in a cohort of 8742 MS patients and 7215 controls [43].
Other reports have not supported an association between HHV-6 and MS [44-46]. These differences may be attributable to several factors including patient selection and the techniques used. Although viruses cause a number of demyelinating neurologic disorders, the association of HHV-6 to such disorders has not been proven (see "Manifestations of multiple sclerosis in adults"). This controversy will be difficult to resolve in view of the ubiquitous nature of HHV-6 infection and the need to discriminate between latency and active infection [45].
Fulminant hepatic failure — A possible role of HHV-6 as a cause of fulminant hepatic failure has been suggested [47-49]. As an example, in one study, 32 patients who underwent liver transplantation were tested for viruses in their explanted livers [47]. Fifteen of these patients had no known cause for liver failure. HHV-6 antigens were found in 12 patients (10 of whom also had HHV-6 viremia) compared with 4 of 17 patients with a known cause. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
Chronic fatigue syndrome — There are conflicting data as to whether there is [50,51] or is not [52,53] an association between CFS and increasing HHV-6 antibody titers. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome".)
Neoplasia — HHV-6 antigens and DNA have been detected in a number of types of malignant tissue, including those from non-Hodgkin lymphomas, Hodgkin lymphoma, oral carcinomas, glioma, and others [54-56]. Although isolated studies have suggested an association between HHV-6 and certain malignancies, these have not been subsequently confirmed.
Myocarditis — Some studies have suggested that HHV-6 may also be implicated in the pathogenesis of myocarditis with subsequent cardiomyopathy [57-61]. (See "Myocarditis: Causes and pathogenesis".)
Drug reaction with eosinophilia and systemic symptoms — Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as drug-induced hypersensitivity syndrome [DIHS]) has been associated with reactivation of HHV-6 as well as human herpesvirus 7, Epstein-Barr virus, and cytomegalovirus [62-67], although a causal link between these viruses and DRESS has not been demonstrated. One hypothesis is that the rash could be mediated by an increase in activated CD8+ and CD4+ T lymphocytes directed against these viruses [62]. Suppression of T cell proliferation by tofacitinib results in disease control, implicating the JAK-STAT signaling pathway in disease pathogenesis [68]. (See "Drug reaction with eosinophilia and systemic symptoms (DRESS)".)
Other possible associations — Other possible associations being studied include autoimmune thyroiditis [69-72], infertility [73], spontaneous abortion [74], pre-eclampsia [75], Alzheimer disease [76], and acute alithiasic cholecystitis [77].
HHV-6 pneumonitis has been diagnosed in a 68-year-old man with relapsed follicular lymphoma [78]. Eighteen months after achieving second complete remission by salvage therapy with rituximab, the patient developed pneumonia. HHV-6 was identified by polymerase chain reaction on his bronchoalveolar lavage, and he improved on ganciclovir therapy. A severe interstitial pneumonitis with concomitant detection of HHV-6 was also reported in a nivolumab-treated patient with non-small cell lung cancer [79].
DIAGNOSIS — Since HHV-6 infection is common in childhood, most adults demonstrate antibodies to the virus. Most illnesses in adults are due to immunosuppression and reactivation of latent infection.
The diagnosis of acute clinical syndromes, like encephalitis or pneumonitis, requires isolation of HHV-6 or detection of HHV-6 DNA in clinical specimens such as cerebrospinal fluid (CSF), respiratory secretions, or brain or lung tissue. In suspected HHV-6 encephalitis, brain magnetic resonance imaging may be normal or demonstrate focal findings, such as enhancement in the temporal lobes [9].
Serodiagnosis — A variety of tests are available for the detection of HHV-6 IgG antibody responses. These include indirect immunofluorescence assays, anti-complement immunofluorescence, competitive radioimmunoassay, and neutralization and enzyme immunoassays [80-82]. The sensitivity of these assays varies. They do not distinguish between the HHV-6A and -B variants, and there is cross-reactivity with human herpesvirus 7.
Because most people over two years of age are seropositive for HHV-6, a single positive result cannot be interpreted. Paired sera need to be collected, with a ≥4-fold rise in titers considered diagnostic. Seroconversion from negative to positive is good evidence of primary infection.
HHV-6 IgM develops within four to seven days of infection. However, approximately 5 percent of healthy adults are IgM positive at any given time, making this test unreliable for a definitive diagnosis. The mu-capture immunoassay appears to perform more accurately than older-generation assays and does not cross-react with Epstein-Barr virus or cytomegalovirus IgM-positive sera [83].
Virus detection — Testing of tissue for virus is feasible with monoclonal antibodies against specific HHV-6A and -B antigens as well as a polyclonal antibody against HHV-6 U90 protein [84]. Qualitative DNA polymerase chain reaction (PCR) assays are also available and can detect HHV-6 from several tissues [6,85-88]. However, because HHV-6 causes latent infection, the clinical significance of this finding needs to be better defined. Quantitation of cell-free virus in serum, plasma, and CSF by real-time PCR is used to diagnose active HHV-6 infections [89-93]. One study has shown that reverse-transcriptase PCR performed using peripheral blood mononuclear cells may be more specific for detecting active infection compared with qualitative PCR or real-time PCR [94]. The diagnosis of HHV-6 encephalitis in hematopoietic cell transplant recipients is discussed in detail separately (see "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Diagnosis'). Film-array meningitis/encephalitis might be a useful sensitive tool to screen and diagnose CSF infections in transplant recipients [95].
Clinicians need to be aware that, aside from latent infection in peripheral blood mononuclear cells, HHV-6 can also be integrated into chromosomes, which may lead to inaccuracies in HHV-6 diagnosis. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'Detecting inherited chromosomal integration'.)
TREATMENT AND PREVENTION — HHV-6 infections in immunocompetent patients are generally not treated, since most cases are self-limited and antiviral therapy has not been studied in such patients. In severe cases of HHV-6 encephalitis in immunocompetent children, ganciclovir therapy has been used, although there was no evidence of benefit in a small case series [96].
Certain HHV-6 infections in immunocompromised hosts (eg, encephalitis in hematopoietic cell transplant recipients [HCT]) are often treated with antiviral agents given the high morbidity of such infections, although efficacy data are limited and no controlled trials have been reported. The treatment of HHV-6 encephalitis in HCT recipients is discussed in detail separately [97]. (See "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on 'HHV-6 encephalitis'.)
In vitro, HHV-6 has a susceptibility pattern similar to cytomegalovirus. Foscarnet is active against both HHV-6A and -B, whereas ganciclovir is active against HHV-6B but, in some reports, HHV-6A was relatively resistant [98,99]. Mutations in the polymerase gene U69 at codon M318V and in the gene U38 (P462S and A565V) are associated with a ganciclovir-resistant phenotype and with treatment failure [100,101]. Cidofovir-resistant mutants have also been selected in vitro, resulting in the R798I mutation, which confers a 200-fold increase in IC50 [102]. One study in hematopoietic cell transplant recipients suggested that ganciclovir modestly reduced HHV-6 in saliva compared with no therapy [103].
Although these studies suggest that certain antivirals may have some effect on HHV-6 replication, there are no controlled clinical trials to show benefits in humans. Several anecdotal case reports and case series have suggested improvement in presumed HHV-6 encephalitis after administration of foscarnet or ganciclovir [8,29,104]. However, these findings require confirmation in carefully controlled trials.
Efforts are ongoing for the development of a vaccine against HHV-6B. A tetrameric glycoprotein complex gH/gL/gQ1/gQ2 was successful at inducing immunity in a mouse model [105].
SUMMARY AND RECOMMENDATIONS
●Background − Human herpesvirus 6 (HHV-6) was first isolated and characterized from patients with lymphoproliferative disorders and was originally named human B-lymphotropic virus. Its name was changed to human herpesvirus 6 as its tropism was further characterized. Like most herpesviruses, HHV-6 may remain latent in certain host cells after primary infection but can be reactivated in immunocompromised patients. (See 'Introduction' above.)
●Primary infection − HHV-6 infections usually occur during childhood and result in generally mild, self-limited illnesses. Primary infection in adults is rare. However, a mononucleosis-like syndrome of varying severity with prolonged lymphadenopathy has been described in association with HHV-6 seroconversion in adults. (See 'Immunocompetent hosts' above.)
●Encephalitis − Encephalitis of variable severity has been associated rarely with HHV-6 infection in immunocompetent patients. Clinical presentations have included altered level of consciousness, seizures, psychosis, acute cerebellar ataxia, and focal neurological signs (eg, cranial nerve deficits or hemiparesis). Neurologic outcomes have varied from full recovery to death. (See 'Encephalitis' above.)
●Mesial temporal lobe epilepsy − HHV-6 has been associated with mesial temporal lobe epilepsy (MTLE). HHV-6 DNA was recovered from brain biopsies from patients with MTLE more frequently than in controls, suggesting a pathogenic effect of the virus. (See 'Mesial temporal lobe epilepsy' above.)
●Viral reactivation in immunosuppressed patients − Immunosuppression secondary to solid organ or hematopoietic cell transplantation (HCT) favors reactivation and replication of HHV-6 and may result in viremia and/or clinical illness. Clinical syndromes associated with HHV-6 in transplant recipients include pneumonitis, hepatitis, encephalitis, and bone marrow suppression. (See 'Transplant recipients' above.)
●Putative associations − Associations between HHV-6 and several diseases have been proposed but not proven. These include multiple sclerosis, hepatic failure, chronic fatigue syndrome (CFS; also known as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]), neoplasia, and myocarditis. (See 'Unproven associations' above.)
●Diagnosis − Since HHV-6 infection is common in childhood, most adults demonstrate antibodies to the virus. Most illnesses in adults result from immunosuppression and reactivation of latent infection. The diagnosis of acute HHV-6 clinical syndromes, like encephalitis or pneumonitis, requires isolation of the virus or detection of HHV-6 DNA in clinical specimens such as cerebrospinal fluid, respiratory secretions, or brain or lung tissue. (See 'Diagnosis' above.)
●Treatment
•Immunocompetent patients − HHV-6 infections in immunocompetent patients are generally not treated, since most cases are self-limited and antiviral therapy has not been carefully studied in such patients. In severe cases of HHV-6 encephalitis in immunocompetent children, ganciclovir therapy has been used, although there was no evidence of benefit in a small case series. (See 'Treatment and prevention' above.)
•Immunocompromised patients − Certain HHV-6 infections in immunocompromised hosts (eg, encephalitis in HCT recipients) are often treated with antiviral agents, such as foscarnet or ganciclovir, given the high morbidity of such infections, although efficacy data are limited and no controlled trials have been reported. (See 'Treatment and prevention' above.)
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