Human herpesvirus (HHV)-6 and -7 are two of the

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1 REVIEW ARTICLE The Impact of Human Herpesvirus-6 and -7 Infection on the Outcome of Liver Transplantation Raymund R. Razonable * and Carlos V. Paya * Human herpesvirus (HHV)-6 and -7 are novel members of the -herpesvirus family that maintain latency in the human host after primary infection. Reactivation from latency and/or increased degree of viral replication occurs during periods of immune dysfunction. The clinical effect of HHV-6 and HHV-7 reactivation in recipients of liver transplants is now being recognized. Clinical illnesses such as fever, rash, pneumonitis, encephalitis, hepatitis, and myelosuppression have been described in a number of anecdotal reports. Moreover, a growing body of evidence suggests that the more important effect of HHV-6 and HHV-7 reactivation on the outcomes of liver transplantation may be mediated indirectly by their interactions with the other -herpesvirus cytomegalovirus (CMV). Coinfection among these three -herpesviruses in clinical syndromes that were classically ascribed to be solely caused by CMV has been shown and has raised substantial interest in the potential role of HHV-6 and HHV-7 as copathogens in the directand indirectillnesses caused by CMV. This article reviews the current scientific data on the role and the magnitude of impact of HHV-6 and HHV-7 infection on the outcomes of liver transplantation. (Liver Transpl 2002;8: ) Human herpesvirus (HHV)-6 and -7 are two of the recently recognized members of the Herpesviridae family. First isolated in 1986, 1 HHV-6 is the etiologic agent of a common childhood illness known as roseola infantum (also known as Exanthem subitum or sixth disease) 2 and has also been associated with nonspecific infantile febrile illnesses and febrile seizures in children. 3,4 HHV-6 is acquired early in life, most likely transmitted through saliva. More than 95% of the human population acquires the infection by 2 years of age, with peak incidence between 6 and 12 months of age. 3,4 Two variants of the virus exist variant A and B that differ from one another by up to 8% at the nucleotide level. 5,6 Both variants also differ in their clinical and epidemiologic features and possibly cytopathic potential. 7 Variant B is implicated in the majority of illnesses currently associated with HHV-6 infection, including roseola infantum, whereas variant A has been associated with various neurologic illnesses, reflecting its neurotropism. 8,9 HHV-7, another lymphotropic virus that was first identified in 1990, 10 is also a ubiquitous virus that is acquired early in life (usually during the first 5 years), presumably through contact with oropharyngeal secretions. 11 Like HHV-6, it affects more than 95% of the human population. 12 Its spectrum of clinical illness remains to be defined; however, it is believed to cause diseases similar to that caused by HHV-6, including a roseola-like illness. 13,14 Both HHV-6 and HHV-7 belong to the -herpesvirus family and have close homology with a third and closely related -herpesvirus, the cytomegalovirus (CMV). 15 Like all other members of the human herpesvirus family, the three -herpesviruses maintain latency or low-level viral replication in the human host after primary infection. This predisposes to reactivation or increased viral replication during periods of immune dysfunction. Indeed, all of the -herpesviruses have been shown to reactivate among patients receiving intense pharmacologic immunosuppression after transplantation, with benign as well as potentially serious consequences, as are described in this review. The role and the impact of CMV reactivation in posttransplantation clinical illnesses and outcomes are well characterized. Beyond the direct effects of CMV in target organs (such as pneumonitis, gastroenteritis, encephalitis, retinitis, and hepatitis) and the virus-associated febrile illness (CMV syndrome) that results from viral invasion and dissemination are myriad indirect consequences that include reduced patient survival, acute and chronic graft dysfunction, accelerated arteriosclerosis (in cardiac transplant recipients), and increased predisposition to bacterial and fungal infections as a result of the virus-induced immune modulation. 16 The increased appreciation of these effects has resulted in tremendous efforts in its diagnosis (ie, development of highly sensitive assays such as quantitative polymerase chain reaction [PCR]), 17 prevention (ie, universal prophylaxis 18 or pre-emptive antiviral therapy), 19 and treatment (ie, novel antiviral From the *Division of Infectious Diseases and Internal Medicine, and Transplant Center, Mayo Clinic and Foundation, Rochester, MN. Address reprint requests to Carlos V. Paya, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN Telephone: ; FAX: ; Paya@ mayo.edu Copyright 2002 by the American Association for the Study of Liver Diseases /02/ $35.00/0 doi: /jlts Liver Transplantation, Vol 8, No 8 (August), 2002: pp

2 652 Razonable and Paya agents and use of quantitative PCR assays to guide duration of therapy). 17,20 Consequently, these have resulted in increased cost and overall transplant resource use. 21,22 In contrast to the well-described effects of CMV on transplant outcomes, the role and impact of the novel herpesviruses, HHV-6 and HHV-7, are less defined. In the hematopoietic stem cell transplant population, HHV-6 has been implicated in a variety of organ dysfunction syndromes such as pneumonitis, encephalitis, hepatitis, and bone marrow suppression (ie, delayed platelet engraftment and leukopenia) Several anecdotal reports have also implicated HHV-6 and possibly HHV-7 as causes of similar syndromes in solid organ transplant recipients In addition, many studies in kidney and liver transplant recipients have inferred that the interaction of HHV-6 and/or HHV-7 with CMV and their immune modulating properties are the more important factors in their illness-causing potential, 31,32 as suggested indirectly by the increased predisposition to other opportunistic infection. 33,34 As more scientific data based on many in vitro and in vivo observations are gathered through the years, it is becoming evident that these viruses are emerging pathogens or copathogens after transplantation. Consequent to this increasing appreciation of their potential impact on transplantation outcomes, their pathogenesis during the posttransplantation period, the methods for their diagnosis, and the evaluation of antiviral drugs and strategies for their prevention and treatment are now the subject of many investigations. In this review, we examine the scientific evidence, clinical or otherwise, on which is based our current understanding of the potential role that these new herpesviruses may play and their impact on the outcomes of liver transplantation procedures. Epidemiology Table 1. Mechanisms of Human Herpesvirus-6 and -7 Infection After Liver Transplantation Type of Infection Primary HHV-6 and HHV-7 infection Reactivation disease or infection Mixed infection Potential Mechanisms Transmission of HHV-6 and/or -7 to a susceptible recipient through the transplanted liver allograft Transmission through blood products Natural transmission through oropharyngeal secretions Reactivation of endogenous latent HHV-6 and/or -7 in a previously infected patient Increased replication of endogenous HHV-6 and/or -7 Combination of the above mechanisms resulting in infection with endogenous HHV-6 and/or -7 and a superimposed HHV-6 and/or -7 infection from the allograft and/ or blood donor NOTE. Reactivation disease or infection is likely the most common mechanism of infection. Primary infection is rare and occurs in susceptible HHV-6 and HHV-7 seronegative liver transplant recipients. Mechanisms of Posttransplantation HHV-6 and HHV-7 Infection The persistent nature of HHV-6 and HHV-7 infection results in their reactivation in the human host (ie, reactivation of endogenous virus in transplant recipients) and possibly in the transplanted organ during periods of immune dysfunction that are characteristic during the posttransplantation period. Because of the highly prevalent nature of these infections (more than 95% of the human population), it is assumed that the vast majority of HHV-6 and HHV-7 infections in the posttransplantation period are the result of endogenous viral reactivation or the enhancement of a persistent viral replication (Table 1). Primary HHV-6 and/or HHV-7 infection in a susceptible patient (HHV-6 and/or HHV-7 seronegative patient) who received a liver allograft and/or blood products from an HHV-6 and/or HHV-7 seropositive donor 35 and a mixed infection consisting of the reactivated endogenous HHV-6 and/or HHV-7 and the virus or viruses transmitted through the liver allograft or blood transfusion (ie, viral superinfection) 36 may also occur. Incidence and Risk Factors The incidence of HHV-6 and HHV-7 infection after liver transplantation has been reported as between 14% and 82% and up to 45%, respectively. 11,32,37 The wide variability of the reported incidence of HHV-6 and HHV-7 infection after liver transplantation results partly from the differences of the patient characteristics, the immunosuppressive regimen, and the methods of detection (eg, PCR, virus cultures, serology). Reactivation of HHV-6, mainly of variant B, and of HHV-7 occurs 2 to 8 weeks after liver transplantation, but HHV-6 infection as early as 10 days and as late as 5 years after liver transplantation has been reported. 30

3 HHV-6 and HHV-7 Infection After Liver Transplantation 653 Factors associated with HHV-6 reactivation are acute allograft rejection and receipt of high doses of steroids, 28,30 whereas variables associated with HHV-7 reactivation are less well defined. Clinical Syndromes DirectEffects The clinical impact of HHV-6 and HHV-7 infection after liver transplantation has been mostly supported by anecdotal and observational studies. A reflection of the preponderance of HHV-6 as compared with HHV-7 studies, the majority of the direct illnesses discussed in this review have been associated with HHV-6 and less commonly with HHV-7 infection. Some of these clinical illnesses that have been proposed to be directly associated with HHV-6 and possibly HHV-7 infection are rash, fever, leukopenia, encephalitis, hepatitis, and interstitial pneumonitis (Table 2). Fever, rash, and -herpesvirus syndrome. HHV-6 has been implicated as the most frequently reported viral cause of febrile illness in liver transplant recipients. 29 A case of febrile dermatosis associated with thrombocytopenia and encephalopathy in a patient with HHV-6 reactivation after liver transplantation has also been reported. 28 In a recent study of 200 liver transplant recipients, 38 the two (1%) patients that presented with clinical illness directly attributed to HHV-6 infection (in the absence of other pathogens such as CMV) manifested with unexplained fever (and leukopenia and thrombocytopenia). In some instances, these febrile illnesses have been misdiagnosed as CMV syndromes. In Table 2. Clinical Syndromes That Have Been Proposed to be Associated With HHV-6 and HHV-7 Infection After Liver Transplantation Mechanism Clinical Syndrome (References) Direct effects Fever and rash (28, 29, 38) Myelosuppression (28, 38, 39) Hepatitis (30, 38) Encephalitis (28, 33) Pneumonitis (39) Viral syndrome (CMV syndrome) (27, 38) Indirect effects CMV syndrome and invasive CMV disease (31, 32, 43, 56-58) Other virus interactions (see text) Increased opportunistic infections (eg, invasive fungal disease) (33, 34, 38) Allograft dysfunction (30, 38, 58, 60) Acute cellular rejection (30, 38, 58, 60) our evaluation of 21 episodes of clinically presumed CMV disease, 27 we show that the clinical specimens from patients with febrile illnesses that were clinically presumed to be caused by CMV contain HHV-6 and/or HHV-7. Thus, the use of the term -herpesvirus syndrome may be more appropriate (instead of CMV syndrome) when the specific etiology is being investigated. Hepatitis. Using serology and by showing HHV-6 specific antigens (with the use of monoclonal antibodies and immunoperoxidase staining) in liver biopsy specimens, Lautenschlager et al 30 have documented posttransplantation HHV-6 infection in eight (6.7%) liver transplant recipients (out of the total population of 121 patients) associated with graft dysfunction, acute rejection, and lymphocytic infiltration. These patients had significant elevation in serum transaminase levels and bilirubin at the time of serologic diagnosis. 30 Likewise, in one of the two patients with HHV-6 infection as described by Humar et al, 38 lymphocytic infiltration in the liver was associated with significant elevation in serum transaminases. Myelosuppression. Whereas HHV-6 has been reported as a common cause of bone marrow suppression and delayed engraftment in hematopoietic stem cell transplant recipients, 23,24 it has also been suggested as an important cause of myelosuppression in liver transplant recipients. 39 The four patients described by Singh et al 39 (two patients required transplantation because of alcoholic cirrhosis and two because of cryptogenic cirrhosis) presented with idiopathic bone marrow suppression at a median of 50 days (range, days) after transplantation; one patient presented with late-onset bone marrow suppression. The white blood cell lineage is most commonly affected, but the other cell lines may also be involved. 39 Pneumonitis. HHV-6 associated interstitial pneumonitis has been shown in bone marrow transplant patients. 25,26 In one of the four liver transplantation patients described by Singh et al, 39 HHV-6 infection presented with leukopenia 25 days after liver transplantation (or 2 days after treatment of allograft rejection) associated with interstitial pneumonitis, as documented by positive immunostaining of the lung biopsy specimen. Encephalitis. The neurotropism 40 of HHV-6 has led to marked interest in the role of the virus in previously undefined neurologic syndromes during the posttransplantation period. 41 A large body of data implicating HHV-6 as a cause of posttransplantation encephalitis exists in the bone marrow transplant patient population. 42 In contrast, the evidence of the neuropathogenic

4 654 Razonable and Paya potential of HHV-6 after liver transplantation is currently limited. A liver transplant recipient with encephalopathy associated with fever, thrombocytopenia, and rash has been described. 28 In a study of 80 liver transplant recipients, central nervous complications of undefined etiology (ie, mental status changes of unidentifiable etiology) were significantly more likely to occur in patients with HHV-6 infection. 33 However, a recent study of 200 liver transplant recipients contrasts with this observation because it did not find any significant association between HHV-6 and various neurologic illnesses. 38 The differences in the neurotropic characteristics between the two variants (with variant A as the neurotropic variant) may have confounded the analysis of the role of HHV-6 in neurologic illnesses after transplantation and may account for the conflicting results of these two studies. Thus, the association between HHV-6 and encephalitis may be further elucidated if the two variants are analyzed as separate variables in future investigations. IndirectEffects Although the majority of the reported clinical syndromes related to HHV-6 and HHV-7 infection during the posttransplantation period are based on anecdotal reports, there are better designed studies, albeit observational, suggesting that the major impact of both HHV-6 and HHV-7 reactivation on liver transplantation is related to their indirect effects (Table 2). The principal indirect effect of HHV-6 and HHV-7 infection in association with organ transplantation results from their potential to exacerbate CMV infection and disease 32,43-46 and their influence on the occurrence of other opportunistic infections such as invasive fungal disease. 33,34 These indirect effects of HHV-6 and HHV-7 infection are partly influenced by their impact on the host immune system All the three -herpesviruses share tropism for immune cells, a feature that may likely play an important part in the immunomodulating properties of these viruses. HHV-6, by using CD46 as a cellular receptor, 51 has tropism for CD4 T lymphocytes, and it also interacts with other cells of the immune system such as natural killer cells and CD8 T lymphocytes; such interaction with the immune system results in decreased interleukin-2 levels and enhanced susceptibility to apoptosis. 48,52,53 HHV-7 uses CD4 as the cellular receptor to infect T cells. 54 The role of virus-induced immunomodulation as the sole or primary predictor of increased opportunistic infections has, however, been confounded by the iatrogenic pharmacologic immunomodulation that is inherent during the posttransplantation period. Although attempts have been made to control for this variable in previous studies, the lack of a standardized method to measure the degree of pharmacologic immunosuppression has limited such analyses. It is, however, suggested that the degree of pharmacologic immunosuppression, which leads to viral reactivation, is further enhanced by the immunomodulating properties of the reactivated viruses (CMV, HHV-6, and HHV-7). -herpesvirus coinfections and interactions. Interactions among viruses have the potential to alter the natural history of defined viral infections. This may be mediated by a direct virus-virus interaction or by an indirect mechanism. HHV-6 has been shown to predispose cells to superinfection by other viruses, 55 and the HHV-6 and/or HHV-7 induced immunosuppression may predispose to the increased pathogenicity and consequently may modify the clinical presentation of defined viral diseases. Several studies have implicated HHV-6 and HHV-7 as agents that may influence the pathogenesis of CMV. Using a serologic assay 34 and a sensitive semiquantitative PCR assay, 32 our group raised the potential interaction between the -herpesviruses after transplantation. Primary and secondary HHV-6 seroconversion after liver transplantation was found to be associated with predisposition to invasive and symptomatic CMV infection, particularly in CMV-seropositive recipients of organs from CMV-seropositive donors. In this study, 20 of 33 liver transplant patients with documented primary HHV-6 seroconversion after liver transplantation had significantly higher incidence of invasive and symptomatic CMV disease as compared with those who did not seroconvert. 34 Using a more sensitive semiquantitative assay, we confirmed the previous association between HHV-6 and CMV disease 32 and further expanded the observation to implicate HHV-7 as a potential copathogen. 32 Recently, we have also shown that coinfection among these viruses occurs at the time of active CMV disease. 27 In a study of 19 episodes of CMV viremia or disease (the majority of patients are liver transplant recipients), coinfection with HHV-6 and/or HHV-7 was observed in 17 (90%) of these episodes. 27 Consistent with the results from our group, several investigators have also reported that infection with HHV-6 (and the degree of HHV-6 replication) and HHV-7 are associated with increased predisposition to invasive and symptomatic CMV disease Hepatitis C virus interaction. A potential interaction between HHV-6 and HHV-7 with other viral pathogens such as hepatitis C virus (HCV) may also exist. We hypothesized that because of the significant interaction between the three -herpesviruses, 32 the previously

5 HHV-6 and HHV-7 Infection After Liver Transplantation 655 observed effect of CMV on the progression of HCVrelated fibrosis after liver transplantation 59 may also be influenced by HHV-6 and/or HHV-7. In a study of 93 patients who received a liver transplant because of liver disease caused by HCV, we observed no significant interaction between the -herpesviruses and that CMV but not HHV-6 influenced the pathogenesis of HCV (Razonable R, unpublished data, January 2002). These novel observations illustrate the complex interactions not only between -herpesviruses but also with other viral pathogens. Whether CMV directly accelerates the pathogenesis of HCV infection and whether HCV negates the interactions among the -herpesviruses are subject to further investigations. Increased opportunistic infections. Using HHV-6 quantitative PCR, HHV-6 infection and the degree of HHV-6 replication were found to be significantly associated with the development of opportunistic infections (a composite of CMV disease, invasive fungal disease, Epstein-Barr virus associated posttransplantation lymphoproliferative disorder, multidermatomal zoster, invasive pneumococcal disease, and mycobacterial disease). 38 HHV-6 infection, as determined by serologic conversion after transplantation, has also been shown to be an independent predictor of invasive fungal infections during the first 90 days after transplantation. 34 In a study of 247 patients, patients with HHV-6 seroconversion had twice the incidence of invasive fungal infection as patients with no documented seroconversion. 34 Because HHV-6 was found to be a stronger predictor of subsequent invasive fungal disease than CMV in this study, it was hypothesized that the increased fungal infection that has previously been described in association with CMV infection may actually be an indirect effect of an unrecognized HHV-6 infection. This observation is now supported by a recent study, which found that HHV-6 infection and viral load, but not CMV, was associated with increased incidence of opportunistic infections. 38 Graft dysfunction and rejection. HHV-6 could directly participate in the rejection process by exacerbating the inflammatory response; alternatively, its presence could just be a manifestation of its reactivation after a critical illness and/or the result of the immunosuppression used to treat the rejection. HHV-6 infection (and the degree of its replication) was found to be the only factor associated with biopsy-proven acute allograft rejection beyond 30 days after transplantation. 38 In a study by Griffiths et al, 58 infection with HHV-6 (and CMV) but not with HHV-7 was independently associated with biopsy-proven graft rejection after liver transplantation. Likewise, the association between HHV-6 and allograft dysfunction has been shown in two observational studies by Lautenschalger et al. 30,60 Diagnosis Conventional methods for the diagnosis of HHV-6 and HHV-7 infection consist of the isolation of the virus or viruses in cell cultures 7,39 or by showing the viral antigens in tissue specimens. 30 The use of serology is limited by the almost universal seroprevalence of HHV-6 and HHV-7 in the human population. However, the potential utility of serologic assays for the detection of HHV-6 infection has been evaluated in the assessment of its direct 30 and indirect effects. 34 Qualitative nucleic acid detection assays often are not able to distinguish between latent and active HHV-6 and HHV-7 infection. Thus, the recent availability of quantitative PCR assays 9,38 with real-time detection may offer the advantage of correlating HHV-6 and HHV-7 load, similar to what has been shown in CMV infection, with clinical disease and its response to antiviral therapy. The clinical evaluation of these quantitative PCR assays in the diagnosis and management of HHV-6 and HHV-7 reactivation in transplant recipients is currently underway. We anticipate that these novel assays will further define the impact of these novel viruses on the outcome of liver transplantation. Prevention and Treatment There is no randomized and controlled trial assessing the efficacy of antiviral drugs for the prevention and treatment of HHV-6 and HHV-7 infection after liver transplantation. Current data on antiviral efficacy, although overwhelmingly suggestive of the susceptibility of HHV-6 and HHV-7 to the drugs used for the treatment of CMV infection, are conflicting Whereas in vitro studies suggest that ganciclovir, cidofovir, and foscarnet are effective and acyclovir has limited activity for the treatment of HHV-6 infection, there is a scarcity of data supporting their efficacy in vivo. In a case series of four patients, 39 the use of ganciclovir or foscarnet led to the recovery of HHV-6 induced myelosuppression in three of the four patients. Data from a recent prospective study indirectly infer the in vivo susceptibility of HHV-6 to ganciclovir because patients receiving ganciclovir prophylaxis have lower risk of HHV-6 reactivation. 38 Likewise, the data on the susceptibility of HHV-7 to ganciclovir are conflicting. Although ganciclovir susceptibility has been reported, other investigators have suggested that the replication

6 656 Razonable and Paya of HHV-7 is not affected by the use of oral ganciclovir prophylaxis. 27,65,66 The conflicting data on the efficacy of antiviral therapy for HHV-6 and HHV-7 infection are partly attributed to the lack of a widely accepted standard definition of HHV-6 and HHV-7 disease (unlike CMV), the lack of a specific antiviral agent for HHV-6 and HHV-7, and the lack of a widely available standard diagnostic assay that could monitor response to treatment (unlike CMV). Partly because of these reasons, and the common occurrence of coinfection of these viruses with CMV, it is difficult to implement randomized and controlled studies assessing the efficacy of antiviral drugs on these viruses in the posttransplantation period. However, with recent advances in diagnostic technology, 9,38 these unresolved issues of antiviral efficacy may be elucidated. Conclusions The novel human -herpesviruses HHV-6 and HHV-7 are now being recognized increasingly as important pathogens and copathogens after liver transplantation. Although many anecdotal reports have implicated these viruses as direct causes of many clinical syndromes of fever and rash, hepatitis, myelosuppression, and encephalopathy, a growing body of scientific evidence suggests that the more significant effect of these viruses on the outcomes of liver transplantation may be mediated indirectly by their interactions with CMV. Coinfection among these -herpesviruses in clinical syndromes that were classically ascribed to be solely caused by CMV have been shown and have raised significant interest in the potential role of HHV-6 and HHV-7 as copathogens in the direct and indirect illnesses caused by CMV. Evidence implicating HHV-6 as an independent risk factor for invasive fungal infection and other opportunistic infections has been reported. Whether HHV-6 or HHV-7 also influences the other indirect effects of CMV, including resource use and reduced patient survival, remains to be defined. As more evidence-based data are gathered with the increasing clinical suspicion of their pathogenic potential coupled with improved diagnostic technology, the exact role and the magnitude of the impact of these novel viruses on the outcome of liver transplantation will be realized. Acknowledgments The authors acknowledge the assistance of Ms. Teresa Hoff in the preparation of this manuscript. References 1. Salahuddin SZ, Ablashi DV, Markham PD, Josephs SF, Sturzenegger S, Kaplan M, et al. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 1986;234: Yamanishi K, Okuno T, Shiraki K, Takahashi M, Kondo T, Asano Y, Kurata T. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1988;1: Pruksananonda P, Hall CB, Insel RA, McIntyre K, Pellett PE, Long CE, et al. 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