Human Herpesvirus 6 in Transplant Recipients

Authors: Danielle M Zerr, Raymund R Razonable


HHV-6 is a member of the Roseolovirus genus of the β-herpesvirus subfamily of human herpesviruses. There are two subtypes of HHV-6: type A and type B. The two subtypes share certain biological properties and a high level of sequence homology, but are clearly distinct, both virologically and epidemiologically. HHV-6 infects multiple cell lines and tissues and establishes latent infection in mononuclear cells. HHV-6 DNA and gene transcription has been detected in normal brain tissue (4, 33) and HHV-6 DNA is found in the CSF with a high frequency (42%) in children with acute or past HHV-6 infection (2). In less than 1% of the individuals, HHV-6 persistence occurs as a result of the integration of the virus into the host chromosome and passage through the germ line (27, 48).


HHV-6 infects virtually all children within the first few years of life and like other herpesviruses, it establishes latency after primary infection. After transplantation, HHV-6 may exit the latent state and actively replicate. This active HHV-6 infection is estimated to occur in 20 to 50% of transplant recipients (18, 20, 54, 57). The estimates vary, presumably due to the populations and diagnostic methods studied, but have been relatively consistent (approximately 40% in studies of HSCT recipients) especially when PCR of plasma or serum is used. HHV-6 reactivation occurs relatively early, generally within the first 2-4 weeks after transplantation (20, 54, 57). Risk of HHV-6 end organ disease has been harder to quantify but is considered to be lower than the risk of reactivation of the virus as discussed further, below (Clinical Manifestations). Type B virus accounts for the vast majority of the documented primary infections in children as well as reactivation events in patients receiving transplants. The epidemiology of HHV-6A is less clear.

Risk factors for HHV-6 infections are not completely defined. Given the high seroprevalence, most infections after organ transplantation likely represent reactivation of latent viruses, especially in adults. It is therefore reasonable to assume that the intensity of pharmacologic immunosuppression may be a risk factor, potentially through prolonged suppression of memory responses. Certain specific agents, including muromunab-CD3 (OKT3), an investigational anti-CD3 monoclonal antibody (BC3), and alemtuzumab have been associated with active HHV-6 infection after transplantation (23, 34, 55). In the setting of HSCT, younger age, underlying disease, receipt of glucocorticoids, receipt of unrelated transplant, and receipt of cord blood transplant are identified risk factors for HHV-6 reactivation and HHV-6 end organ disease (17, 28, 43, 54, 57).

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Latent virus serves as the reservoir for endogenous viral reactivation after transplantation or as potential vectors of transmission to susceptible individuals via the transplanted organ itself. Given the high (90-95%) seroprevalence of HHV-6 in adults, most active infections after transplantation are thought to originate from reactivation of endogenous latent virus. Pediatric transplant recipients under 2 years of age, however, may be HHV-6 seronegative prior to transplantation and therefore may acquire HHV-6 from the transplanted organ (11). Primary infections, presumably of donor origin, may occur in seronegative transplant recipients, and a few patients have developed fatal primary HHV-6 infections (40, 42).

Clinical Manifestations

HHV-6 associated sequelae may be viewed as either direct effects of the infection or from the consequences of virus-induced immune modulation. Most cases of HHV-6 active infection and disease after transplantation have been due to HHV-6B, although a few cases of HHV-6A associated disease have been reported35.

Overt disease directly due to HHV-6 has been estimated to occur in less than 1% of patients receiving solid organ transplantation (3, 20). In this setting, HHV-6 disease may manifest as a febrile syndrome accompanied by some degree of bone marrow suppression, an illness similar to CMV syndrome (38). In some cases, HHV-6 has been detected in the blood of patients with clinical syndromes attributable to CMV disease (15, 16, 38). To what extent HHV-6 may be directly causing or contributing to the clinical symptoms in these patients is not clear. HHV6 has also been reported as a cause of febrile dermatosis (46), hepatitis (35), gastroduodenitis (36), colitis (7, 24), pneumonitis (31), and encephalitis (31, 44) after solid organ transplantation. HHV-6 reactivation (usually defined by detection of viral nucleic acids in serum or plasma or whole blood) in HSCT has been associated with subsequent bone marrow suppression, GVHD, and encephalitis (17, 28, 57).

HHV-6-associated hepatitis, colitis, and pneumonitis have also been described in HSCT recipients, mainly as case reports and case series. HHV-6 encephalitis deserves special mention due to the relative strength and quantity of data which support a causal association and the potential severity of the condition. HHV-6 encephalitis as an entity has been defined through prospective surveillance studies and a number of case reports and case series (58). Encephalitis typically occurs within 4-6 weeks after transplantation and is characterized by confusion, loss of short term memory, and seizures. Patients will often have normal CSF profiles; elevated protein is the most common abnormality. Brain imaging is often abnormal with hallmark abnormalities found in the medial temporal lobes. Approximately a quarter of patients with HHV-6 encephalitis appear to die of their infection while a high proportion of the survivors experience long-term morbidity.

HHV-6 may cause important indirect effects, possibly as a result of the immunomodulatory effects of active viral infection. In this vein, HHV-6 has been associated with CMV disease (9, 20), (30), fungal and other opportunistic infections (10, 41), early fibrosis due to hepatitis C virus recurrence after liver transplantation (21, 47), bronchiolitis obliterans following lung transplantation (32, 42), graft versus host disease after HSCT (57), and a higher mortality rate after liver (41), heart-lung (22), and HSCT transplantation (57). There are conflicting data on the association between HHV-6 infections with allograft rejection and dysfunction (14, 20, 25, 26).

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Laboratory Diagnosis

Identifying clinically relevant HHV-6 is hampered by the ubiquitous nature of infection and the spectrum of tissues and cell types that support persistent or latent infection in vivo. In addition, HHV-6 may integrate into human chromosomes (6, 52). Integration has been estimated to occur in less than 1% of individuals (27, 48) and has also been described in the transplant setting (5). The possibility of integrated HHV-6 must be considered when interpreting HHV-6 results in any population.

The diagnostic tests available for the detection of HHV-6 include serology, culture, antigenemia, immunohistochemistry, and nucleic acid amplification assays (Table 1). In general, serology has inadequate sensitivity and specificity in identifying acute infection in immunocompromised transplant patients, who have impaired ability to mount an effective immune response. The high HHV-6 seroprevalence rates in adults further limit the potential usefulness of serology after transplantation. Instead, methods utilizing direct viral detection, such as the detection of nucleic acids by polymerase chain reaction (PCR), are preferred for the detection of HHV-6 after solid organ transplantation. PCR of peripheral blood mononuclear cells (PBMC) is the most sensitive technique for detecting these viruses, but this type of assay may not be able to distinguish latent from active infection. In addition, many patients are leukopenic in the first few weeks after transplantation, especially after hematopoietic transplantation, when HHV-6 reactivation peaks, potentially limiting applicability of such assays in this population. The use of non-cellular samples, quantitative PCR, or methods to detect messenger RNA is recommended for the diagnosis of active HHV-6 infections. Either quantitative or qualitative methods may be used on non-cellular samples (serum or plasma) while quantitative methods (or methods aimed at detecting messenger RNA) are preferred when using cellular samples such as PBMC. It is important to also consider the potential detection of chromosomally-integrated HHV-6, a form of viral persistence characterized by very high levels of HHV-6 in blood samples (usually in millions of copies per ml whole blood), which may be misinterpreted as substantial active infection leading to unnecessary treatment (5). Detecting HHV-6 by PCR of hair follicles samples also indicates chromosomally-integrated HHV-6 (27, 48).

Because of the apparent low rate of clinical disease and the relatively high rate of subclinical viral reactivations, routine monitoring for HHV-6 after solid organ transplantation is not recommended. However there are certain clinical scenarios, such as encephalitis, which should prompt testing for HHV-6 (8). Wang et al.(51) demonstrated that HHV-6 was detected more frequently in the CSF of transplant recipients with encephalitis (5 of 22, or 23%) than in immunocompromised patients without encephalitis (1 of 107, or 0.9%). Although, there have been patients described with HHV-6 DNA detected in the CSF who are asymptomatic or relatively asymptomatic (56), the data from Wang et al suggest that detection of HHV-6 DNA in CSF of an HCT recipient if not all transplant recipients is potentially meaningful and that patients with CNS signs and symptoms should have their CSF investigated for HHV-6 as well as other pathogens.

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Currently, no antiviral compounds are approved for the treatment of HHV-6 infections. Foscarnet, ganciclovir and cidofovir are used clinically, based on in vitro data and anecdotal clinical reports. In vitro, HHV-6 is sensitive to achievable concentrations of ganciclovir, foscarnet, and cidofovir, although HHV-6A and HHV-6B variants demonstrate different susceptibilities (1, 53). Both HHV-6 variants are resistant to acyclovir and penciclovir.

The majority of HHV-6 infections are subclinical and transient, and therefore treatment of asymptomatic viral reactivation is not recommended. Treatment directed against HHV-6 should be initiated in the setting of HHV-6 encephalitis and should be considered for other clinical syndromes attributable to HHV-6. The International Herpes Management Forum recommends that HHV-6 be considered a cause of encephalitis, particularly in immunocompromised patients (8). The forum goes on to recommend ganciclovir and foscarnet either alone or in combination as first line therapy for treatment of HHV-6 related central nervous system illness. Cidofovir was not recommended as first line therapy in part because of potential toxicities.

Studies in order to define precise dosing and duration recommendations have not been performed. Dosing typical for CMV disease is often used ( Table 2 ). In the setting of HHV-6 encephalitis, some clinicians base duration of therapy on a minimum course of 3-4 weeks and factor in the patient’s clinical course and viral levels over time to define the ultimate course. It should be recognized however, that active viral replication in brain tissue may persist after levels in blood and cerebrospinal fluid have resolved (12). While chromosomally integrated HHV-6 is not treatable with antiviral agents (5, 19), a case of severe encephalomyelitis apparently successfully treated with foscarnet and ganciclovir in the setting of chromosomally integrated HHV-6 has been reported (50). Although the authors acknowledge the lack of certainty that HHV-6 caused the encephalitis in this case, it raises the possibility that HHV-6 may be able to cause disease and be treated in a patient with chromosomal integration. As in the treatment of most cases of opportunistic infections, strong consideration should be given to reducing the degree of pharmacologic immunosuppression when treating HHV-6 disease. This will allow the immune system to develop HHV-6 specific immunity that is needed for adequate control of infection. Although there is no direct evidence to support this strategy, it is assumed that the degree of immunosuppression is a risk factor that led to HHV-6 reactivation and clinical disease.


There have been no studies performed to define endpoints for monitoring therapy.

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There are no vaccines currently available.


There is insufficient evidence to recommend the routine use of antiviral prophylaxis or preemptive therapy for HHV-6 infection. Since the majority of HHV-6 infections after transplantation are subclinical, antiviral prophylaxis or preemptive therapy are currently of questionable benefit. However, indirect evidence suggests that anti-CMV prophylaxis with ganciclovir-containing regimens has been associated with a lower rate and degree of HHV-6 detection (29, 37, 39, 49), although this finding has not been uniform (13). Hence, the true in vivo efficacy of current antiviral agents on HHV-6 infection and replication has not been conclusively or directly demonstrated, thereby raising further questions on the potential clinical benefit or utility of prophylaxis or preemptive therapy.


HHV-6 is ubiquitous and the vast majority of older children and adults are infected with latent virus. The virus is present in multiple cell and tissue types and it is shed in saliva. Special isolation precautions are not required for patients with HHV-6. The Centers for Disease Control and Prevention’s “Standard Precautions” are based on the principle that all blood, body fluids, secretions, excretions except sweat, non-intact skin, and mucous membranes may contain transmissible infectious agents (45). Standard Precautions include infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which healthcare is delivered. Standard precautions call for the use of personal protective equipment depending on the anticipated exposure and should be adequate for preventing transmission of HHV-6 in the healthcare setting.

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1. Akhyani N, Fotheringham J, Yao K, Rashti F, Jacobson S. Efficacy of antiviral compounds in human herpesvirus-6-infected glial cells. J Neurovirol 2006;12:284-93. [PubMed] 

2. Caserta MT, Hall CB, Schnabel K, McIntyre K, Long C, Costanzo M, Dewhurst S, Insel R, Epstein LG. Neuroinvasion and persistence of human herpesvirus 6 in children. J Infect Dis 1994;170:1586-9. [PubMed] 

3. Cervera C, Marcos MA, Linares L, Roig E, Benito N, Pumarola T, Moreno A. A prospective survey of human herpesvirus-6 primary infection in solid organ transplant recipients. Transplantation 2006;82:979-82. [PubMed] 

4. Chan PK, Ng HK, Hui M, Cheng AF. Prevalence and distribution of human herpesvirus 6 variants A and B in adult human brain. J Med Virol 2001;64:42-6. [PubMed] 

5. Clark DA, Nacheva EP, Leong HN, Brazma D, Li YT, Tsao EH, Buyck HC, Atkinson CE, Lawson HM, Potter MN, Griffiths PD. Transmission of integrated human herpesvirus 6 through stem cell transplantation: implications for laboratory diagnosis. J Infect Dis 2006;193:912-6. [PubMed] 

6. Daibata M, Taguchi T, Nemoto Y, Taguchi H, Miyoshi I. Inheritance of chromosomally integrated human herpesvirus 6 DNA. Blood 1999;94:1545-9. [PubMed] 

7. Delbridge MS, Karim MS, Shrestha BM, McKane W. Colitis in a renal transplant patient with human herpesvirus-6 infection. Transpl Infect Dis 2006;8:226-8. [PubMed] 

8. Dewhurst S. Human herpesvirus type 6 and human herpesvirus type 7 infections of the central nervous system. Herpes 2004;11 Suppl 2:105A-111A. [PubMed] 

9. Dockrell DH, Prada J, Jones MF, Patel R, Badley AD, Harmsen WS, Ilstrup DM, Wiesner RH, Krom RA, Smith TF, Paya CV. Seroconversion to human herpesvirus 6 following liver transplantation is a marker of cytomegalovirus disease. J Infect Dis 1997;176:1135-40. [PubMed] 

10. Dockrell DH, Mendez JC, Jones M, Harmsen WS, Ilstrup DM, Smith TF, Wiesner RH, Krom RA, Paya CV. Human herpesvirus 6 seronegativity before transplantation predicts the occurrence of fungal infection in liver transplant recipients. Transplantation 1999;67:399-403. [PubMed] 

11. Feldstein AE, Razonable RR, Boyce TG, Freese DK, El-Youssef M, Perrault J, Paya CV, Ishitani MB. Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients. Pediatr Transplant 2003;7:125-9. [PubMed] 

12. Fotheringham J, Akhyani N, Vortmeyer A, Donati D, Williams E, Oh U, Bishop M, Barrett J, Gea-Banacloche J, Jacobson S. Detection of active human herpesvirus-6 infection in the brain: correlation with polymerase chain reaction detection in cerebrospinal fluid. J Infect Dis 2007;195:450-4. [PubMed] 

13. Galarraga MC, Gomez E, de Ona M, Rodriguez A, Laures A, Boga JA, Melon S. Influence of ganciclovir prophylaxis on citomegalovirus, human herpesvirus 6, and human herpesvirus 7 viremia in renal transplant recipients. Transplant Proc 2005;37:2124-6. [PubMed] 

14. Griffiths PD, Ait-Khaled M, Bearcroft CP, Clark DA, Quaglia A, Davies SE, Burroughs AK, Rolles K, Kidd IM, Knight SN, Noibi SM, Cope AV, Phillips AN, Emery VC. Human herpesviruses 6 and 7 as potential pathogens after liver transplant: prospective comparison with the effect of cytomegalovirus. J Med Virol 1999;59:496-501. [PubMed] 

15. Harma M, Loginov R, Piiparinen H, Halme L, Hockerstedt K, Lautenschlager I. HHV-6-DNAemia related to CMV-DNAemia after liver transplantation. Transplant Proc 2005;37:1230-2. [PubMed] 

16. Harma M, Hockerstedt K, Lyytikainen O, Lautenschlager I. HHV-6 and HHV-7 antigenemia related to CMV infection after liver transplantation. J Med Virol 2006;78:800-5. [PubMed] 

17. Hentrich M, Oruzio D, Jager G, Schlemmer M, Schleuning M, Schiel X, Hiddemann W, Kolb HJ. Impact of human herpesvirus-6 after haematopoietic stem cell transplantation. Br J Haematol 2005;128:66-72. [PubMed] 

18. Herbein G, Strasswimmer J, Altieri M, Woehl-Jaegle ML,Wolf P, Obert G. Longitudinal study of human herpesvirus 6 infection in organ transplant recipients. Clin Infect Dis 1996;22:171-3. [PubMed] 

19. Hubacek P, Muzikova K, Hrdlickova A, Cinek O, Hyncicova K, Hrstkova H, Sedlacek P, Stary J. Prevalence of HHV-6 integrated chromosomally among children treated for acute lymphoblastic or myeloid leukemia in the Czech Republic. J Med Virol 2009; 81:258-63. [PubMed] 

20. Humar A, Kumar D, Caliendo AM, Moussa G, Ashi-Sulaiman A, Levy G, Mazzulli T. Clinical impact of human herpesvirus 6 infection after liver transplantation. Transplantation 2002; 73:599-604. [PubMed] 

21. Humar A, Kumar D, Raboud J, Caliendo AM, Moussa G, Levy G, Mazzulli T. Interactions between cytomegalovirus, human herpesvirus-6, and the recurrence of hepatitis C after liver transplantation. Am J Transplant 2002; 2:461-6. [PubMed]   

22. Jacobs F, Knoop C, Brancart F, Gilot P, Melot C, Byl B, Delforge ML, Estenne M, Liesnard C. Human herpesvirus-6 infection after lung and heart-lung transplantation: a prospective longitudinal study. Transplantation 2003; 75:1996-2001. [PubMed] 

23. Jacobs U, Ferber J, Klehr HU. Severe allograft dysfunction after OKT3-induced human herpes virus-6 reactivation. Transplant Proc 1994; 26:3121. [PubMed] 

24. Lamoth F, Jayet PY, Aubert JD, Rotman S, Mottet C, Sahli R, Lautenschlager I, Pascual M, Meylan P. Case report: human herpesvirus 6 reactivation associated with colitis in a lung transplant recipient. J Med Virol 2008; 80:1804-7. [PubMed] 

25. Lautenschlager I, Hockerstedt K, Linnavuori K, Taskinen E. Human herpesvirus-6 infection after liver transplantation. Clin Infect Dis 1998; 26:702-7. [PubMed] 

26. Lautenschlager I, Linnavuori K, Hockerstedt K. Human herpesvirus-6 antigenemia after liver transplantation. Transplantation 2000; 69:2561-6. [PubMed] 

27. Leong HN, Tuke PW, Tedder RS, Khanom AB, Eglin RP, Atkinson CE, Ward KN, Griffiths PD, Clark DA. The prevalence of chromosomally integrated human herpesvirus 6 genomes in the blood of UK blood donors. J Med Virol 2007; 79:45-51. [PubMed] 

28. Ljungman P, Wang FZ, Clark DA, Emery VC, Remberger M, Ringden O, Linde A. High levels of human herpesvirus 6 DNA in peripheral blood leucocytes are correlated to platelet engraftment and disease in allogeneic stem cell transplant patients. Br J Haematol 2000; 111:774-81. [PubMed] 

29. Ljungman P, Dahl H, Xu YH, Larsson K, Brytting M, Linde A. Effectiveness of ganciclovir against human herpesvirus-6 excreted in saliva in stem cell transplant recipients. Bone Marrow Transplant 2007; 39:497-9. [PubMed] 

30. Mendez JC, Dockrell DH, Espy MJ, Smith TF, Wilson JA, Harmsen WS, Ilstrup D, Paya CV. Human beta-herpesvirus interactions in solid organ transplant recipients. J Infect Dis 2001; 183:179-184. [PubMed] 

31. Nash PJ, Avery RK, Tang WH, Starling RC, Taege AJ, Yamani MH. Encephalitis owing to human herpesvirus-6 after cardiac transplant. Am J Transplant 2004; 4:1200-3. [PubMed] 

32. Neurohr C, Huppmann P, Leuchte H, Schwaiblmair M, Bittmann I, Jaeger G, Hatz R, Frey L, Uberfuhr P, Reichart B, Behr J. Human herpesvirus 6 in bronchalveolar lavage fluid after lung transplantation: a risk factor for bronchiolitis obliterans syndrome? Am J Transplant 2005; 5:2982-91. [PubMed] 

33. Opsahl ML, Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 2005; 128:516-27. [PubMed] 

34. Peleg AY, Husain S, Kwak EJ, Silveira FP, Ndirangu M, Tran J, Shutt KA, Shapiro R, Thai N, Abu-Elmagd K, McCurry KR, Marcos A, Paterson DL. Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody. Clin Infect Dis 2007; 44:204-12. [PubMed] 

35. Potenza L, Luppi M, Barozzi P, Rossi G, Cocchi S, Codeluppi M, Pecorari M, Masetti M, Di Benedetto F, Gennari W, Portolani M, Gerunda GE, Lazzarotto T, Landini MP, Schulz TF, Torelli G, Guaraldi G. HHV-6A in syncytial giant-cell hepatitis. N Engl J Med 2008; 359:593-602. [PubMed] 

36. Randhawa PS, Jenkins FJ, Nalesnik MA, Martens J, Williams PA, Ries A, Pham S, Demetris AJ. Herpesvirus 6 variant A infection after heart transplantation with giant cell transformation in bile ductular and gastroduodenal epithelium. Am J Surg Pathol 1997; 21:847-53. [PubMed] 

37. Rapaport D, Engelhard D, Tagger G, Or R, Frenkel N. Antiviral prophylaxis may prevent human herpesvirus-6 reactivation in bone marrow transplant recipients. Transpl Infect Dis 2002;4:10-6. [PubMed] 

38. Razonable RR, Rivero A, Brown RA, Hart GD, Espy MJ, van Cruijsen H, Wilson J, Groettum C, Kremers W, Smith TF, Paya CV. Detection of simultaneous beta-herpesvirus infections in clinical syndromes due to defined cytomegalovirus infection. Clin Transplant 2003;17:114-20. [PubMed] 

39. Razonable RR, Brown RA, Humar A, Covington E, Alecock E, Paya CV. Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease. J Infect Dis 2005;192:1331-9. [PubMed] 

40. Revest M, Camus C, D'Halluin PN, Cha S, Compagnon P, Boudjema K, Colimon R, Thomas R. Fatal human herpes virus 6 primary infection after liver transplantation. Transplantation 2007;83:1404-5. [PubMed] 

41. Rogers J, Rohal S, Carrigan DR, Kusne S, Knox KK, Gayowski T, Wagener MM, Fung JJ, Singh N. Human herpesvirus-6 in liver transplant recipients: role in pathogenesis of fungal infections, neurologic complications, and outcome. Transplantation 2000;69:2566-73. [PubMed]

42. Rossi C, Delforge ML, Jacobs F, Wissing M, Pradier O, Remmelink M, Byl B, Thys JP, Liesnard C. Fatal primary infection due to human herpesvirus 6 variant A in a renal transplant recipient. Transplantation 2001; 71:288-92. [PubMed]

43. Sashihara J, Tanaka-Taya K, Tanaka S, Amo K, Miyagawa H, Hosoi G, Taniguchi T, Fukui T, Kasuga N, Aono T, Sako M, Hara J, Yamanishi K, Okada S. High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood 2002; 100:2005-11. [PubMed]

44. Seeley WW, Marty FM, Holmes TM, Upchurch K, Soiffer RJ, Antin JH, Baden LR, Bromfield EB. Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 2007; 69:156-65. [PubMed]

45. Siegel JD, Rhinehart E, Jackson M, Chiarello L. 2007 Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Health Care Settings. Am J Infect Control 2007; 35:S65-164. [PubMed]

46. Singh N, Carrigan DR, Gayowski T, Singh J, Marino IR. Variant B human herpesvirus-6 associated febrile dermatosis with thrombocytopenia and encephalopathy in a liver transplant recipient. Transplantation 1995; 60:1355-7.[PubMed]

47. Singh N, Husain S, Carrigan DR, Knox KK, Weck KE, Wagener MM, Gayowski T. Impact of human herpesvirus-6 on the frequency and severity of recurrent hepatitis C virus hepatitis in liver transplant recipients. Clin Transplant 2002; 16:92-6. [PubMed]

48. Tanaka-Taya K, Sashihara J, Kurahashi H, Amo K, Miyagawa H, Kondo K, Okada S, Yamanishi K. Human herpesvirus 6 (HHV-6) is transmitted from parent to child in an integrated form and characterization of cases with chromosomally integrated HHV-6 DNA. J Med Virol 2004; 73:465-73. [PubMed]

49. Tokimasa S, Hara J, Osugi Y, Ohta H, Matsuda Y, Fujisaki H, Sawada A, Kim JY, Sashihara J, Amou K, Miyagawa H, Tanaka-Taya K, Yamanishi K, Okada S. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant 2002; 29:595-8. [PubMed]

50. Troy SB, Blackburn BG, Yeom K, Caulfield AK, Bhangoo MS, Montoya JG. 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:e93-6. [PubMed]

51. Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A, Ljungman P. Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: does it have clinical significance? Clin Infect Dis 1999; 28:562-8.  [PubMed]

52. Ward KN, Leong HN, Nacheva EP, Howard J, Atkinson CE, Davies NW, Griffiths PD, Clark DA. 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; 44:1571-4. [PubMed]

53. Yoshida M, Yamada M, Tsukazaki T, Chatterjee S, Lakeman FD, Nii S, Whitley RJ. Comparison of antiviral compounds against human herpesvirus 6 and 7. Antiviral Res 1998; 40:73-84. [PubMed]

54. Yoshikawa T, Asano Y, Ihira M, Suzuki K, Ohashi M, Suga S, Kudo K, Horibe K, Kojima S, Kato K, Matsuyama T, Nishiyama Y. Human herpesvirus 6 viremia in bone marrow transplant recipients: clinical features and risk factors. J Infect Dis 2002; 185:847-53. [PubMed]

55. Zerr DM, Gooley TA, Yeung L, Huang ML, Carpenter P, Wade JC, Corey L, Anasetti C. Human herpesvirus 6 reactivation and encephalitis in allogeneic bone marrow transplant recipients. Clin Infect Dis 2001; 33:763-71. [PubMed]

56. Zerr DM, Gupta D, Huang ML, Carter R, Corey L. Effect of antivirals on human herpesvirus 6 replication in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34:309-17. [PubMed]

57. Zerr DM, Corey L, Kim HW, Huang ML, Nguy L, Boeckh M. Clinical outcomes of human herpesvirus 6 reactivation after hematopoietic stem cell transplantation. Clin Infect Dis 2005; 40:932-40. [PubMed]

58. Zerr DM. Human herpesvirus 6 and central nervous system disease in hematopoietic cell transplantation. J Clin Virol 2006; 37 Suppl 1:S52-6.  [PubMed]back to top

Table 1: Methods for diagnosis of HHV-6 and their advantages and disadvantages

Assay Advantages Disadvantages/Limitations
Culture Positive results represent active infection or replication
Allows to distinguish between subtypes A and B
Technically difficult
Long turn-around time does not allow for real-time clinical management
PCR Sensitive and specific for HHV-6
Rapid turn-around time to allow real-time clinical management


Risk of contamination (use of closed PCR system reduces this risk)
Lack of standardization among PCR assays
Plasma Correlates well with diagnostic and clinical indicators of active viral  infection and with virus isolation after transplantation
Technically easy
Allows to distinguish between subtypes A and B


PBMC Allows to distinguish between subtypes A and B If not using RT-PCR, need to distinguish between latent and active infection by quantitative cut points or by setting sensitivity threshold
Negative results may be difficult to interpret in lymphopenic patients (HCT recipients early after transplant)
RT-PCR Positive results represent active infection or replication




Immunocompromised populations do not reliably mount antibody response
Interference of maternal antibody around time of primary infection
Does not distinguish between types A and B
Avidity Assays Avidity assays are able to distinguish between antibody associated with primary versus established infection. Does not distinguish between types A and B
RT = reverse transcription, PBMC = peripheral blood mononuclear cell, HCT = hematopoietic cell transplantation

Table 2:  Antiviral agents with HHV-6 activity.  Rigorous studies have not been performed to define optimal dosing and duration of therapy. 

Dosing typical for CMV disease is often used and is represented in this table

Agent Indication Dose Duration
Ganciclovir* 1st line therapy for HHV-6 associated disease 5 mg/kg every 12 hours Not defined, but should be guided by clinical and virologic assessments
Foscarnet 1st line therapy for HHV-6 associated disease 90 mg/kg every 12 hours (or 60 mg/kg every 8 hours) Not defined, but should be guided by clinical and virologic assessments
Cidofovir Consider if concern for resistance is present (rare) 5 mg/kg every week Not defined, but should be guided by clinical and virologic assessment
 * There is variable in vitro susceptibility of HHV-6 variants A and B to ganciclovir. Valganciclovir has not been used for the treatment of established HHV-6 associated disease. Oral ganciclovir should not be used for treatment because of its poor oral bioavailability.

Singh N,  Carrigan DR. Human Herpesvirus-6

Funk GA, et al. Viral dynamics in transplant patients: implications for disease. Lancet Infectious Diseases 2007;7:460-472.

Sun HY, et al.  Pharmacotherapy of post-transplant viral infections.  Expert Opin Pharmacother 2008;9(14):2409-2421.



Clinical Manifestations




Berger S.  Emergence of Infectious Diseases into the 21st Century, 2008.


Human Herpesvirus 6 in Transplant Infections