ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults

Clinical manifestations, diagnosis, and treatment of human herpesvirus 6 infection in adults
Author:
Cécile Tremblay, MD
Section Editor:
Martin S Hirsch, MD
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Jan 2024.
This topic last updated: Sep 08, 2022.

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.)

  1. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986; 234:596.
  2. Ablashi DV, Salahuddin SZ, Josephs SF, et al. HBLV (or HHV-6) in human cell lines. Nature 1987; 329:207.
  3. International Committee on Taxonomy of Viruses. ICTV Master Species List 2011. http://talk.ictvonline.org/files/ictv_documents/m/msl/4090.aspx (Accessed on June 27, 2012).
  4. Akashi K, Eizuru Y, Sumiyoshi Y, et al. Brief report: severe infectious mononucleosis-like syndrome and primary human herpesvirus 6 infection in an adult. N Engl J Med 1993; 329:168.
  5. Niederman JC, Liu CR, Kaplan MH, Brown NA. Clinical and serological features of human herpesvirus-6 infection in three adults. Lancet 1988; 2:817.
  6. Maric I, Bryant R, Abu-Asab M, et al. Human herpesvirus-6-associated acute lymphadenitis in immunocompetent adults. Mod Pathol 2004; 17:1427.
  7. McCullers JA, Lakeman FD, Whitley RJ. Human herpesvirus 6 is associated with focal encephalitis. Clin Infect Dis 1995; 21:571.
  8. Birnbaum T, Padovan CS, Sporer B, et al. Severe meningoencephalitis caused by human herpesvirus 6 type B in an immunocompetent woman treated with ganciclovir. Clin Infect Dis 2005; 40:887.
  9. Isaacson E, Glaser CA, Forghani B, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 2005; 40:890.
  10. Yao K, Honarmand S, Espinosa A, et al. Detection of human herpesvirus-6 in cerebrospinal fluid of patients with encephalitis. Ann Neurol 2009; 65:257.
  11. Mekheal E, Tagliaferri AR, Vasquez KS, et al. A Rare Case of HHV-6 Encephalitis in an Immunocompetent Host: Case Report and Literature Review. Cureus 2022; 14:e23007.
  12. Hata A, Fujita M, Morishima T, et al. Acute cerebellar ataxia associated with primary human herpesvirus-6 infection: a report of two cases. J Paediatr Child Health 2008; 44:607.
  13. Troy SB, Blackburn BG, Yeom K, et al. Severe encephalomyelitis in an immunocompetent adult with chromosomally integrated human herpesvirus 6 and clinical response to treatment with foscarnet plus ganciclovir. Clin Infect Dis 2008; 47:e93.
  14. Whitley RJ, Lakeman FD. Human herpesvirus 6 infection of the central nervous system: is it just a case of mistaken association? Clin Infect Dis 2005; 40:894.
  15. Donati D, Akhyani N, Fogdell-Hahn A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology 2003; 61:1405.
  16. Fotheringham J, Donati D, Akhyani N, et al. Association of human herpesvirus-6B with mesial temporal lobe epilepsy. PLoS Med 2007; 4:e180.
  17. Kawamura Y, Nakayama A, Kato T, et al. Pathogenic Role of Human Herpesvirus 6B Infection in Mesial Temporal Lobe Epilepsy. J Infect Dis 2015; 212:1014.
  18. Abu Sitta E, Khazan A, Luttmann K, Hanrahan J. HHV-6: an unusual cause of cerebellar ataxia. BMJ Case Rep 2020; 13.
  19. Miyashita N, Endo T, Onozawa M, et al. Risk factors of human herpesvirus 6 encephalitis/myelitis after allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis 2017; 19.
  20. Shiroshita K, Mori T, Kato J, et al. Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention. Bone Marrow Transplant 2020; 55:939.
  21. Ueki T, Hoshi K, Hiroshima Y, et al. Analysis of five cases of human herpesvirus-6 myelitis among 121 cord blood transplantations. Int J Hematol 2018; 107:363.
  22. Dockrell DH, Paya CV. Human herpesvirus-6 and -7 in transplantation. Rev Med Virol 2001; 11:23.
  23. Bonnafous P, Marlet J, Bouvet D, et al. Fatal outcome after reactivation of inherited chromosomally integrated HHV-6A (iciHHV-6A) transmitted through liver transplantation. Am J Transplant 2018; 18:1548.
  24. Hentrich M, Oruzio D, Jäger G, et al. Impact of human herpesvirus-6 after haematopoietic stem cell transplantation. Br J Haematol 2005; 128:66.
  25. Yoshikawa T, Suga S, Asano Y, et al. A prospective study of human herpesvirus-6 infection in renal transplantation. Transplantation 1992; 54:879.
  26. Humar A, Malkan G, Moussa G, et al. Human herpesvirus-6 is associated with cytomegalovirus reactivation in liver transplant recipients. J Infect Dis 2000; 181:1450.
  27. Potenza L, Luppi M, Barozzi P, et al. HHV-6A in syncytial giant-cell hepatitis. N Engl J Med 2008; 359:593.
  28. Halme L, Arola J, Höckerstedt K, Lautenschlager I. Human herpesvirus 6 infection of the gastroduodenal mucosa. Clin Infect Dis 2008; 46:434.
  29. Nash PJ, Avery RK, Tang WH, et al. Encephalitis owing to human herpesvirus-6 after cardiac transplant. Am J Transplant 2004; 4:1200.
  30. Cone RW, Hackman RC, Huang ML, et al. Human herpesvirus 6 in lung tissue from patients with pneumonitis after bone marrow transplantation. N Engl J Med 1993; 329:156.
  31. Carrigan DR, Drobyski WR, Russler SK, et al. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. Lancet 1991; 338:147.
  32. Cone RW, Huang ML, Hackman RC. Human herpesvirus 6 and pneumonia. Leuk Lymphoma 1994; 15:235.
  33. Merlino C, Giacchino F, Segoloni GP, Ponzi AN. Human herpesvirus-6 infection and renal transplantation. Transplantation 1992; 53:1382.
  34. Volin L, Lautenschlager I, Juvonen E, et al. Human herpesvirus 6 antigenaemia in allogeneic stem cell transplant recipients: impact on clinical course and association with other beta-herpesviruses. Br J Haematol 2004; 126:690.
  35. Dietrich J, Blumberg BM, Roshal M, et al. Infection with an endemic human herpesvirus disrupts critical glial precursor cell properties. J Neurosci 2004; 24:4875.
  36. Challoner PB, Smith KT, Parker JD, et al. Plaque-associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci U S A 1995; 92:7440.
  37. Rotola A, Merlotti I, Caniatti L, et al. Human herpesvirus 6 infects the central nervous system of multiple sclerosis patients in the early stages of the disease. Mult Scler 2004; 10:348.
  38. Soldan SS, Leist TP, Juhng KN, et al. Increased lymphoproliferative response to human herpesvirus type 6A variant in multiple sclerosis patients. Ann Neurol 2000; 47:306.
  39. Alvarez-Lafuente R, De las Heras V, Bartolomé M, et al. Relapsing-remitting multiple sclerosis and human herpesvirus 6 active infection. Arch Neurol 2004; 61:1523.
  40. Alvarez-Lafuente R, De Las Heras V, Bartolomé M, et al. Beta-interferon treatment reduces human herpesvirus-6 viral load in multiple sclerosis relapses but not in remission. Eur Neurol 2004; 52:87.
  41. Alvarez-Lafuente R, de las Heras V, García-Montojo M, et al. Human herpesvirus-6 and multiple sclerosis: relapsing-remitting versus secondary progressive. Mult Scler 2007; 13:578.
  42. Tao C, Simpson-Yap S, Taylor B, et al. Markers of Epstein-Barr virus and Human Herpesvirus-6 infection and multiple sclerosis clinical progression. Mult Scler Relat Disord 2022; 59:103561.
  43. Lundström W, Gustafsson R. Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis. Front Immunol 2022; 13:840753.
  44. Tuke PW, Hawke S, Griffiths PD, Clark DA. Distribution and quantification of human herpesvirus 6 in multiple sclerosis and control brains. Mult Scler 2004; 10:355.
  45. Rotola A, Cassai E, Tola MR, et al. Human herpesvirus 6 is latent in peripheral blood of patients with relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 1999; 67:529.
  46. Hay KA, Tenser RB. Leukotropic herpesviruses in multiple sclerosis. Mult Scler 2000; 6:66.
  47. Härmä M, Höckerstedt K, Lautenschlager I. Human herpesvirus-6 and acute liver failure. Transplantation 2003; 76:536.
  48. Chevret L, Boutolleau D, Halimi-Idri N, et al. Human herpesvirus-6 infection: a prospective study evaluating HHV-6 DNA levels in liver from children with acute liver failure. J Med Virol 2008; 80:1051.
  49. Charnot-Katsikas A, Baewer D, Cook L, David MZ. Fulminant hepatic failure attributed to infection with human herpesvirus 6 (HHV-6) in an immunocompetent woman: A case report and review of the literature. J Clin Virol 2016; 75:27.
  50. Sairenji T, Yamanishi K, Tachibana Y, et al. Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology 1995; 38:269.
  51. Ablashi DV, Eastman HB, Owen CB, et al. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol 2000; 16:179.
  52. Gold D, Bowden R, Sixbey J, et al. Chronic fatigue. A prospective clinical and virologic study. JAMA 1990; 264:48.
  53. Levine PH, Jacobson S, Pocinki AG, et al. Clinical, epidemiologic, and virologic studies in four clusters of the chronic fatigue syndrome. Arch Intern Med 1992; 152:1611.
  54. Di Luca D, Dolcetti R, Mirandola P, et al. Human herpesvirus 6: a survey of presence and variant distribution in normal peripheral lymphocytes and lymphoproliferative disorders. J Infect Dis 1994; 170:211.
  55. Yadav M, Chandrashekran A, Vasudevan DM, Ablashi DV. Frequent detection of human herpesvirus 6 in oral carcinoma. J Natl Cancer Inst 1994; 86:1792.
  56. Chi J, Gu B, Zhang C, et al. Human herpesvirus 6 latent infection in patients with glioma. J Infect Dis 2012; 206:1394.
  57. Comar M, D'Agaro P, Campello C, et al. Human herpes virus 6 in archival cardiac tissues from children with idiopathic dilated cardiomyopathy or congenital heart disease. J Clin Pathol 2009; 62:80.
  58. Stefanski HE, Thibert KA, Pritchett J, et al. Fatal Myocarditis Associated With HHV-6 Following Immunosuppression in Two Children. Pediatrics 2016; 137.
  59. Brennan Y, Gottlieb DJ, Baewer D, Blyth E. A fatal case of acute HHV-6 myocarditis following allogeneic haemopoietic stem cell transplantation. J Clin Virol 2015; 72:82.
  60. Seitz A, Martínez Pereyra V, Hubert A, et al. Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis. Int J Cardiol 2022; 360:1.
  61. Colombo D, Cecannecchia C, Albore M, et al. Post-mortem differential diagnosis from COVID-19: A case of fulminant myocarditis HHV-6 related. Pathol Int 2022; 72:75.
  62. Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): a multiorgan antiviral T cell response. Sci Transl Med 2010; 2:46ra62.
  63. Ozcan D, Seçkin D, Bilezikçi B, Arslan H. The role of human herpesvirus-6, Epstein–Barr virus and cytomegalovirus infections in the etiopathogenesis of different types of cutaneous drug reactions. Int J Dermatol 2010; 49:1250.
  64. Goto M, Shimizu F, Takeo N, et al. Drug-induced hypersensitivity syndrome due to carbapenem antibiotics. J Dermatol 2010; 37:374.
  65. Gentile I, Talamo M, Borgia G. Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpesvirus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review. BMC Infect Dis 2010; 10:49.
  66. Saida S, Yoshida A, Tanaka R, et al. A case of drug-induced hypersensitivity syndrome-like symptoms following HHV-6 encephalopathy. Allergol Int 2010; 59:83.
  67. Descamps V, Ranger-Rogez S. DRESS syndrome. Joint Bone Spine 2014; 81:15.
  68. Kim D, Kobayashi T, Voisin B, et al. Targeted therapy guided by single-cell transcriptomic analysis in drug-induced hypersensitivity syndrome: a case report. Nat Med 2020; 26:236.
  69. Seyyedi N, Dehbidi GR, Karimi M, et al. Human herpesvirus 6A active infection in patients with autoimmune Hashimoto's thyroiditis. Braz J Infect Dis 2019; 23:435.
  70. Sultanova A, Cistjakovs M, Gravelsina S, et al. Association of active human herpesvirus-6 (HHV-6) infection with autoimmune thyroid gland diseases. Clin Microbiol Infect 2017; 23:50.e1.
  71. Sultanova A, Cistjakovs M, Sokolovska L, et al. HHV-6 Infection and Chemokine RANTES Signaling Pathway Disturbance in Patients with Autoimmune Thyroiditis. Viruses 2020; 12.
  72. Rizzo R, Zatelli MC, Rotola A, et al. Increase in Peripheral CD3-CD56brightCD16- Natural Killer Cells in Hashimoto's Thyroiditis Associated with HHV-6 Infection. Adv Exp Med Biol 2016; 897:113.
  73. Marci R, Gentili V, Bortolotti D, et al. Presence of HHV-6A in Endometrial Epithelial Cells from Women with Primary Unexplained Infertility. PLoS One 2016; 11:e0158304.
  74. Miura H, Kawamura Y, Ohye T, et al. Inherited Chromosomally Integrated Human Herpesvirus 6 Is a Risk Factor for Spontaneous Abortion. J Infect Dis 2021; 223:1717.
  75. Gaccioli F, Lager S, de Goffau MC, et al. Fetal inheritance of chromosomally integrated human herpesvirus 6 predisposes the mother to pre-eclampsia. Nat Microbiol 2020; 5:901.
  76. Romanescu C, Schreiner TG, Mukovozov I. The Role of Human Herpesvirus 6 Infection in Alzheimer's Disease Pathogenicity-A Theoretical Mosaic. J Clin Med 2022; 11.
  77. Gomes MM, Antunes H, Lobo AL, et al. Acute Alithiasic Cholecystitis and Human Herpes Virus Type-6 Infection: First Case. Case Rep Pediatr 2016; 2016:9130673.
  78. Kuwahara-Ota S, Chinen Y, Mizuno Y, et al. Human herpesvirus-6 pneumonitis in a patient with follicular lymphoma following immunochemotherapy with rituximab. Infect Drug Resist 2018; 11:701.
  79. Foukas PG, Tsiodras S, Economopoulou P, et al. Concomitant Human Herpes Virus 6 and nivolumab-related pneumonitis: Potential pathogenetic insights. IDCases 2018; 11:101.
  80. Couillard M, Joly JR, Deschênes L, Richer G. Evaluation of variables in immunofluorescence procedures for the detection of antibodies against human herpesvirus 6 (HHV-6). Diagn Microbiol Infect Dis 1992; 15:313.
  81. Robert C, Agut H, Aubin JT, et al. Detection of antibodies to human herpesvirus-6 using immunofluorescence assay. Res Virol 1990; 141:545.
  82. Chou SW, Scott KM. Rises in antibody to human herpesvirus 6 detected by enzyme immunoassay in transplant recipients with primary cytomegalovirus infection. J Clin Microbiol 1990; 28:851.
  83. Nielsen L, Vestergaard BF. A mu-capture immunoassay for detection of human herpes virus-6 (HHV-6) IgM antibodies in human serum. J Clin Virol 2002; 25:145.
  84. Nishimura N, Yoshikawa T, Ozaki T, et al. In vitro and in vivo analysis of human herpesvirus-6 U90 protein expression. J Med Virol 2005; 75:86.
  85. Norton RA, Caserta MT, Hall CB, et al. Detection of human herpesvirus 6 by reverse transcription-PCR. J Clin Microbiol 1999; 37:3672.
  86. Fujiwara N, Namba H, Ohuchi R, et al. Monitoring of human herpesvirus-6 and -7 genomes in saliva samples of healthy adults by competitive quantitative PCR. J Med Virol 2000; 61:208.
  87. Blumberg BM, Mock DJ, Powers JM, et al. The HHV6 paradox: ubiquitous commensal or insidious pathogen? A two-step in situ PCR approach. J Clin Virol 2000; 16:159.
  88. Ihira M, Ohta A, Sugata K, et al. Loop-mediated isothermal amplification for discriminating between human herpesvirus 6 A and B. J Virol Methods 2008; 154:223.
  89. Fotheringham J, Akhyani N, Vortmeyer A, et al. Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid. J Infect Dis 2007; 195:450.
  90. Canto CL, Sumita LM, Machado AF, et al. Optimization of the Sybr Green real time PCR for the detection of Human Herpes Virus type 6 (HHV-6). Rev Inst Med Trop Sao Paulo 2008; 50:61.
  91. Deback C, Agbalika F, Scieux C, et al. Detection of human herpesviruses HHV-6, HHV-7 and HHV-8 in whole blood by real-time PCR using the new CMV, HHV-6, 7, 8 R-gene kit. J Virol Methods 2008; 149:285.
  92. Engelmann I, Petzold DR, Kosinska A, et al. Rapid quantitative PCR assays for the simultaneous detection of herpes simplex virus, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus 6 DNA in blood and other clinical specimens. J Med Virol 2008; 80:467.
  93. Flamand L, Gravel A, Boutolleau D, et al. Multicenter comparison of PCR assays for detection of human herpesvirus 6 DNA in serum. J Clin Microbiol 2008; 46:2700.
  94. Caserta MT, Hall CB, Schnabel K, et al. Diagnostic assays for active infection with human herpesvirus 6 (HHV-6). J Clin Virol 2010; 48:55.
  95. Mori T, Koda Y, Kato J, et al. Usefulness of the FilmArray Meningitis/Encephalitis Panel in diagnosis of central nervous system infection after allogeneic hematopoietic stem cell transplantation. Support Care Cancer 2022; 30:5.
  96. Crawford JR, Kadom N, Santi MR, et al. Human herpesvirus 6 rhombencephalitis in immunocompetent children. J Child Neurol 2007; 22:1260.
  97. Toomey D, Phan TL, Nguyen V, et al. Retrospective case analysis of antiviral therapies for HHV-6 encephalitis after hematopoietic stem cell transplantation. Transpl Infect Dis 2021; 23:e13443.
  98. Williams MV. HHV-6: response to antiviral agents. In: Human herpesvirus-6: epidemiology, molecular biology, and clinical pathology, Ablashi DV, Krueger RF, Salahuddin SZ (Eds), Elsevier Biomedical Press, Amsterdam p.317.
  99. Manichanh C, Olivier-Aubron C, Lagarde JP, et al. Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo. J Gen Virol 2001; 82:2767.
  100. De Bolle L, Manichanh C, Agut H, et al. Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance. Antiviral Res 2004; 64:17.
  101. Isegawa Y, Hara J, Amo K, et al. Human herpesvirus 6 ganciclovir-resistant strain with amino acid substitutions associated with the death of an allogeneic stem cell transplant recipient. J Clin Virol 2009; 44:15.
  102. Bonnafous P, Boutolleau D, Naesens L, et al. Characterization of a cidofovir-resistant HHV-6 mutant obtained by in vitro selection. Antiviral Res 2008; 77:237.
  103. Ljungman P, Dahl H, Xu YH, et al. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant 2007; 39:497.
  104. Olli-Lähdesmäki T, Haataja L, Parkkola R, et al. High-dose ganciclovir in HHV-6 encephalitis of an immunocompetent child. Pediatr Neurol 2010; 43:53.
  105. Wang B, Hara K, Kawabata A, et al. Tetrameric glycoprotein complex gH/gL/gQ1/gQ2 is a promising vaccine candidate for human herpesvirus 6B. PLoS Pathog 2020; 16:e1008609.
Topic 8320 Version 23.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟