1887

Abstract

Human herpesvirus-6 (HHV-6), the virus which causes roseola, has traditionally been associated with benign and self-limited childhood illness. However, HHV-6 establishes lifelong latency and can reactivate in immunocompromised adult patients. In about 1% of cases, it integrates into the human genome as inherited chromosomally integrated HHV-6 (iciHHV-6). We report the case of a 70-year-old man presenting with altered mental status and agitation. His infectious workup revealed a cerebrospinal fluid sample positive for HHV-6 with virus detectable in the blood as well. He was subsequently treated with ganciclovir. HHV-6 viremia (DNAemia) persisted, and the antiviral medications were switched to foscarnet under the assumption of treatment failure due to drug resistance. After several admissions to the hospital for the same complaint, and after noticing that DNAemia persisted despite adequate treatment for HHV-6, infectious disease specialists ordered testing for chromosomally integrated virus. Test results confirmed the presence of iciHHV-6, explaining his consistently elevated serum viral load. Primary HHV-6 infection in adults causes a transient increase in viral load with resolution and clearance after a few weeks while iciHHV-6 is characterized by persistent detection of viral DNA at a high copy number. Individuals with iciHHV-6 can develop HHV-6 disease and are at increased risk for active viral replication when treated with immunosuppressive medications, but only mRNA testing, which is not widely available can differentiate between latent and active infection. This makes the decision to treat challenging in this patient population. When faced with a positive HHV-6 DNA result in the setting of equivocal symptoms, clinicians should consider the possibility of chromosomally integrated virus rather than drug-resistant virus in order to reduce exposure to potentially toxic antiviral medications.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. The Microbiology Society waived the open access fees for this article.
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2021-08-04
2022-10-03
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References

  1. Zerr D, Meier A, Selke S, Frenkel L, Huang ML et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med 2005; 352:768–776 [View Article] [PubMed]
    [Google Scholar]
  2. Kotton CN, Hirsch MS. Cytomegalovirus and human herpesvirus types 6, 7, and 8. Jameson J, Fauci A, Kasper D, Hauser S, Longo D. eds In Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill Education; 2018
    [Google Scholar]
  3. Agut H, Bonnafous P, Gautheret-Dejean A. Human Herpesviruses 6A, 6B, and 7. Microbiol Spectr 4 2016
    [Google Scholar]
  4. Ablashi D, Agut H, Alvarez-Lafuente R, Clark DA, Dewhurst S et al. Classification of HHV-6A and HHV-6B as distinct viruses. Arch Virol 2014; 159:863–870 [View Article] [PubMed]
    [Google Scholar]
  5. Arbuckle JH, Medveczky MM, Luka J, Hadley SH, Luegmayr A et al. The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro. Proc Natl Acad Sci U S A 2010; 107:5563–5568 [View Article] [PubMed]
    [Google Scholar]
  6. Pellett P, Ablashi D, Ambros P, Agut H, Caserta M et al. Chromosomally integrated human herpesvirus 6: Questions and answers. Rev Med Virol 2012; 22:144–155 [View Article] [PubMed]
    [Google Scholar]
  7. Lee SO, Brown RA, Razonable R. Chromosomally integrated human herpesvirus-6 in transplant recipients. Transpl Infect Dis 2012; 14:346–354 [View Article] [PubMed]
    [Google Scholar]
  8. Pruksananonda P, Hall C, Insel R, McIntyre K, Pellett P et al. Primary Human Herpesvirus 6 Infection in Young Children. N Engl J Med 1992; 326:1445–1450 [View Article] [PubMed]
    [Google Scholar]
  9. Aimola G, Beythien G, Aswad A, Kaufer BB. Current understanding of human herpesvirus 6 (HHV-6) chromosomal integration. Antiviral Res 2020; 176:104720 [View Article] [PubMed]
    [Google Scholar]
  10. Epstein LG, Shinnar S, Hesdorffer DC, Nordli DR, Hamidullah A et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia 2012; 53:1481–1488 [View Article] [PubMed]
    [Google Scholar]
  11. Ward KN, Hill JA, Hubacek P, Camara R de la, Crocchiolo R et al. Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematologic malignancies and after hematopoietic stem cell transplantation. Haematologica 2019; 104:2155–2163 [View Article] [PubMed]
    [Google Scholar]
  12. Dougan C, Ormerod I. A neurologist’s approach to the immunosuppressed patient. J Neurol Neurosurg Psychiatry 2004; 75:i43–i49
    [Google Scholar]
  13. Razonablea RR, Zerrb DM. HHV-6, HHV-7 and HHV-8 in solid organ transplant recipients. Am J Transplant 2009; 9:S100–S103
    [Google Scholar]
  14. Lautenschlager I, Razonable R. Human herpesvirus-6 infections in kidney, liver, lung, and heart transplantation: Review. Transpl Int 2012; 25:493–502 [View Article] [PubMed]
    [Google Scholar]
  15. Kesely KR, Pantaleo A, Turrini FM, Olupot-Olupot P, Low PS. Inhibition of an erythrocyte tyrosine kinase with imatinib prevents Plasmodium falciparum egress and Terminates parasitemia. PLoS One 2016; 11:e0164895 [View Article] [PubMed]
    [Google Scholar]
  16. Hall CB, Caserta MT, Schnabel K, Shelley LM, Marino AS et al. Chromosomal integration of human herpesvirus 6 is the major mode of congenital human herpesvirus 6 infection. Pediatrics 2008; 122:513–520 [View Article] [PubMed]
    [Google Scholar]
  17. Clark DA. Clinical and laboratory features of human herpesvirus 6 chromosomal integration. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2016; 22:333–339
    [Google Scholar]
  18. Luppi M, Marasca R, Barozzi P, Ferrari S, Ceccherini-Nelli L et al. Three cases of human herpesvirus-6 latent infection: Integration of viral genome in peripheral blood mononuclear cell DNA. J Med Virol 1993; 40:44–52 [View Article] [PubMed]
    [Google Scholar]
  19. Endo A, Watanabe K, Ohye T, Suzuki K, Matsubara T et al. Molecular and virological evidence of viral activation from chromosomally integrated human herpesvirus 6A in a patient with X-linked severe combined immunodeficiency. Clin Infect Dis an Off Publ Infect Dis Soc Am 2014; 59:545–548 [View Article]
    [Google Scholar]
  20. Ohye T, Kawamura Y, Inagaki H, Yoshikawa A, Ihira M et al. A simple cytogenetic method to detect chromosomally integrated human herpesvirus-6. J Virol Methods 2016; 228:74–78 [View Article] [PubMed]
    [Google Scholar]
  21. Miura H, Kawamura Y, Kudo K, Ihira M, Ohye T et al. Virological analysis of inherited chromosomally integrated human herpesvirus-6 in three hematopoietic stem cell transplant patients. Transpl Infect Dis 2015; 17:728–731 [View Article] [PubMed]
    [Google Scholar]
  22. Torelli G, Barozzi P, Marasca R, Cocconcelli P, Merelli E et al. Targeted integration of human herpesvirus 6 in the p arm of chromosome 17 of human peripheral blood mononuclear cells in vivo. J Med Virol 1995; 46:178–188 [View Article] [PubMed]
    [Google Scholar]
  23. Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT et al. Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. J Infect Dis 2006; 193:912–916 [View Article] [PubMed]
    [Google Scholar]
  24. Strenger V, Caselli E, Lautenschlager I, Schwinger W, Aberle SW et al. Detection of HHV-6-specific mRNA and antigens in PBMCs of individuals with chromosomally integrated HHV-6 (ciHHV-6. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2014; 20:1027–1032
    [Google Scholar]
  25. Mori T, Tanaka-Taya K, Satoh H, Aisa Y, Yamazaki R et al. Transmission of chromosomally integrated human herpesvirsus 6 (HHV-6) variant A from a parent to children leading to misdiagnosis of active HHV-6 infection. Transpl Infect Dis 2009; 11:503–506 [View Article] [PubMed]
    [Google Scholar]
  26. Hill JA, Ikoma M, Zerr DM, Basom RS, Peddu V et al. RNA sequencing of the in vivo human Herpesvirus 6B transcriptome to identify targets for clinical assays distinguishing between latent and active infections. J Virol 2019; 93: [View Article] [PubMed]
    [Google Scholar]
  27. Ward K, Leong HN, Nacheva E, Howard J, Atkinson C et al. Human Herpesvirus 6 chromosomal integration in immunocompetent patients results in high levels of viral DNA in blood, SERA, and hair follicles. J Clin Microbiol 2006; 44:1571–1574 [View Article] [PubMed]
    [Google Scholar]
  28. Ljungman P. Chromosomally integrated HHV-6: a new piece of the puzzle. Blood 2017; 130:961–962 [View Article] [PubMed]
    [Google Scholar]
  29. Leber AL, Everhart K, Balada-Llasat JM, Cullison J, Daly J et al. Multicenter evaluation of Biofire Filmarray Meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol 2016; 54:2251–2261 [View Article] [PubMed]
    [Google Scholar]
  30. Green DA, Pereira M, Miko B, Radmard S, Whittier S et al. Clinical significance of human herpesvirus 6 positivity on the Filmarray meningitis/encephalitis panel. Clin Infect Dis 2018; 67:1125–1128 [View Article]
    [Google Scholar]
  31. Takano K, Ogata M, Kawano R, Satou T, Nashimoto Y et al. Comparison of HHV-6 DNA detection in plasma and whole blood in allogeneic hematopoietic stem cell transplant recipients: frequent false-positive results for active HHV-6 infection using whole blood samples. Int J Hematol 2018; 108:535–542 [View Article] [PubMed]
    [Google Scholar]
  32. Greninger AL, Naccache SN, Pannaraj P, Jerome KR, Dien Bard J et al. The brief case: inherited chromosomally integrated human herpesvirus 6 (HHV-6) in the age of multiplex HHV-6 testing. J Clin Microbiol 2019; 57: [View Article] [PubMed]
    [Google Scholar]
  33. Zerr DM, Fann JR, Breiger D, Boeckh M, Adler AL et al. HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients. Blood 2011; 117:5243–5249 [View Article] [PubMed]
    [Google Scholar]
  34. Prichard MN, Whitley RJ. The development of new therapies for human herpesvirus 6. Current Opinion in Virology 2014; 9:148–153 [View Article]
    [Google Scholar]
  35. Komatsu TE, Pikis A, Naeger LK, Harrington PR. Resistance of human cytomegalovirus to ganciclovir/valganciclovir: a comprehensive review of putative resistance pathways. Antiviral Res 2014; 101:12–25 [View Article] [PubMed]
    [Google Scholar]
  36. Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin Microbiol Rev 2010; 23:689–712 [View Article]
    [Google Scholar]
  37. Hiramatsu H, Suzuki R, Yamada S, Ihira M, Isegawa Y et al. Analysis of ganciclovir-resistant human herpesvirus 6B clinical isolates using quenching probe PCR methodology. Antimicrob Agents Chemother 2015; 59:2618–2624 [View Article]
    [Google Scholar]
  38. Rodriguez J, Casper K, Smallwood G, Stieber A, Fasola C et al. Resistance to combined ganciclovir and foscarnet therapy in a liver transplant recipient with possible dual-strain cytomegalovirus coinfection. Liver Transpl 2007; 13:1396–1400 [View Article]
    [Google Scholar]
  39. Bonnafous P, Naesens L, Petrella S, Gautheret-Dejean A, Boutolleau D et al. Different mutations in the HHV-6 DNA polymerase gene accounting for resistance to foscarnet. Antivir Ther 2007; 12:877–888 [PubMed]
    [Google Scholar]
  40. Eyal S, Yagen B, Sobol E, Altschuler Y, Shmuel M et al. The activity of antiepileptic drugs as histone deacetylase inhibitors. Epilepsia 2004; 45:737–744 [View Article] [PubMed]
    [Google Scholar]
  41. Granit A, Tetro N, Shmuel M, Peretz T, Eyal S. Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro. Epilepsia open 2018; 3:535–539 [View Article] [PubMed]
    [Google Scholar]
  42. Politikos I, McMasters M, Bryke C, Avigan D, Boussiotis VA. Possible reactivation of chromosomally integrated human herpesvirus 6 after treatment with histone deacetylase inhibitor. Blood Adv 2018; 2:1367–1370 [View Article] [PubMed]
    [Google Scholar]
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