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Human herpesvirus-6 infection in solid organ and stem cell transplant recipients
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Journal of Clinical Virology 37 Suppl. 1 (2006) S87–S91 www.elsevier.com/locate/jcv
Human herpesvirus-6 infection in solid organ and stem cell transplant recipients Per Ljungmana, ° , Nina Singhb a Karolinska b University
University Hospital, Karolinska Institutet, Stockholm, Sweden of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
Abstract HHV-6 has in recent years become recognized as a potential significant pathogen in both solid organ and stem cell transplant recipients. HHV-6 infections are common after transplantation regardless of the utilized diagnostic technique. Several different clinical manifestations have been described including fever, bone marrow suppression, encephalitis, skin rash, and hepatitis. The most important end-organ disease is encephalitis in stem cell transplant recipients that has been reported to have a mortality of at least 40%. HHV-6 is also considered an immunomodulatory and immunosuppressive virus that may facilitate super-infections with other opportunistic pathogens such as CMV and fungal infections and thereby contribute to overall mortality. No established therapy exists but both ganciclovir and foscarnet have been reported to have in vitro and in vivo efficacy against HHV-6. © 2006 Elsevier B.V. All rights reserved.
1. Introduction HHV-6 has rendered substantial interest as a pathogen in transplant recipients. Several problems with the interpretation of published data exist due to the ubiquity of the virus and the diffuseness of the associated syndromes described. Most HHV-6 infections in transplant patients are considered to result from reactivation since the seroprevalence is high in adults and older children. HHV-6B has been much more frequently identified as the cause of disease in transplant recipients than HHV-6A although in many published studies determination of the subtype has not been performed. The transmission of HHV-6 from the donor with the allograft has been documented and mononuclear cells latently infected with HHV-6 in the donor allograft are believed to be the likely source of transmission (Lau et al., 1998).
2. Solid organ transplant recipients Overall, 38−55% of renal, 22−54% of liver, 36% of heart, and up to 57% of heart–lung transplant recipients have been shown to develop active HHV-6 infection (de Ona et al., 2002; Dockrell et al., 1997; Herbein et al., 1996; Lautenschlager et al., 2000; Morris et al., 1989; Okuno et al., 1990; Rogers et al., 2000). Most HHV-6 * Corresponding author. Tel.: +46 8 585 82507; Fax: +46 8 774 8725. E-mail address: [email protected] (P. Ljungman). 1590-8658/ $ – see front matter © 2006 Elsevier B.V. All rights reserved.
infections occur between 2 and 4 weeks after SOT; this characteristic timing distinguishes HHV-6 from other beta-herpesvirus infections that usually occur later posttransplantation (Singh and Carrigan, 1996). In a study in liver transplant recipients where HHV-6 and HHV-7 DNA detection was sought in the plasma, HHV-6 infections occurred in 38% (15/40) patients; 67% of the infections occurred at 2 weeks post-transplantation after which the frequency of viral genome detection in the plasma declined sharply (Ihira et al., 2001). Following liver transplantation, primary HHV-6 infection has been reported in 61-100% of the patients who were seronegative for HHV-6 prior to transplantation; the latter observation was in infants receiving liver grafts from their mothers (Dockrell et al., 1997; Yoshikawa et al., 2001b). Risk factors for HHV-6 infections in SOT recipients have not been fully defined. Receipt of OKT3 monoclonal antibodies or antithymocyte globulin has been associated with HHV-6 reactivation (Nash et al., 2004; Rossi et al., 2001). A HHV-6 seroconversion in one study was noted more frequently in patients who received immuosuppressive regimens containing sirolimus and IL-12 receptor antibodies as induction therapy (Deborska et al., 2003).
3. Stem cell transplant recipients HHV-6 was documented in 38% of SCT recipients by virus isolation (Yoshikawa et al., 2002). By using molecular
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techniques, detection of HHV-6 DNA has been documented in 40−70% in PBL or whole blood (Imbert-Marcille et al., 2000; Sashihara et al., 2002; Wang et al., 1996) and 47−70% in plasma or serum (Zerr et al., 2001, 2005). The peak in viral load does occur early after transplant and usually within the first four weeks after SCT (ImbertMarcille et al., 2000; Ljungman et al., 2000; Maeda et al., 2000; Yoshikawa et al., 2002). A recently recognized problem with the diagnosis of HHV-6 infection by PCR is the possibility to detect chromosomally integrated HHV-6 sequences (Clark et al., 2006; Ward et al., 2006). Risk factors associated with HHV-6 infection after SCT has been reported to be allogeneic SCT, advanced hematological disease, younger age, gender mismatch between donor and recipient, and treatment with corticosteroids (Imbert-Marcille et al., 2000; Yoshikawa et al., 2002; Zerr et al., 2005). A small study reported a high incidence of HHV-6 in patients undergoing cord blood transplantation (Sashihara et al., 2002).
4. Clinical manifestations Clinical sequelae of HHV-6 may result from symptoms directly attributable to the virus or from its immunomodulatory effects. Symptomatic infections seem to be more common in SCT than in SOT patients and vary from very limited clinical effects to a contributing effect on overall mortality. The risk for symptomatic disease seems to be associated to transplant type and intensity of immunosuppression. Liver transplant patients seem to be the group of SOT recipients most prone to develop symptomatic HHV-6 disease. In the group of SCT patients, high risk patients such as those receiving grafts from unrelated donors or patients with severe graft-versus-host disease are most prone to develop symptomatic disease. A nonspecific febrile syndrome occurring in the early post-transplant period is the most frequently observed clinical manifestation of HHV-6 infection in SOT recipients. Unexplained fever was described in 87% of the liver transplant recipients compared to 20% of those without HHV-6 infection (p < 0.01) (Yoshikawa et al., 2000). The febrile syndrome attributable to CMV in transplant recipients may, in fact, be related to a concurrent infection due to HHV-6 or -7 rather than CMV alone. Eighty-nine percent of the liver transplant recipients with CMV infections had concomitant HHV-6 variant B or HHV-7 infection (Razonable et al., 2003). Bone marrow suppression, most often manifesting as thrombocytopenia or leukopenia, has been associated with HHV-6 and has been seen both in SCT recipients (Carrigan and Knox, 1994; Imbert-Marcille et al., 2000; Ljungman et al., 2000; Wang et al., 1996; Zerr et al., 2005) and in SOT recipients (Singh et al., 1997). HHV-6 can infect hematological progenitor cells and reduce colony formation (Burd et al., 1993; Isomura et al., 1997). Increased levels
of HHV-6 DNA are associated with a delayed platelet engraftment (Ljungman et al., 2000; Maeda et al., 2000; Zerr et al., 2005) and increased requirement for platelet transfusions in SCT recipients (Ljungman et al., 2000; Zerr et al., 2005). HHV-6 has a propensity for the central nervous system (Caserta et al., 1994; Challoner et al., 1995), and although HHV-6 DNA can occasionally be detected in the CSF of asymptomatic SCT recipients (Wang et al., 1999; Zerr et al., 2001), several case reports and small patient series have given strong support for that HHV-6 is an important cause of encephalitis in SCT recipients. Approximately 40 cases have been published (Bethge et al., 1999; Bosi et al., 1998; Cole et al., 1998; De Almeida Rodrigues et al., 1999; Drobyski et al., 1994; Gorniak et al., 2006; Hentrich et al., 2005; Ljungman et al., 2000; MacLean and Douen, 2002; Mookerjee and Vogelsang, 1997; Muta et al., 2005; Rieux et al., 1998; Tanaka et al., 2005; Tiacci et al., 2000; Tsujimura et al., 1998; Wang et al., 1999; Visser et al., 2005; Yoshida et al., 2002; Zerr et al., 2001). Most cases of encephalitis have been caused by HHV-6B although also cases with HHV-6A have been documented. The reported mortality in these cases even with treatment is approximately 40%. In SOT patients, a number of well documented case reports and case-controlled studies and at least three studies that included concurrent controls have documented an association between HHV-6 and central nervous system complications of unidentifiable etiology (Bollen et al., 2001; Paterson et al., 1999; Rogers et al., 2000; Singh and Paterson, 2000). A study of liver transplant recipients showed that 15% had mental status changes of unknown etiology after transplantation and patients with HHV-6 viremia had a significantly higher incidence of unexplained mental status changes as compared to those without HHV-6 viremia (Rogers et al., 2000). The symptoms are frequently uncharacteristic with lethargy, confusion, convulsions, and decreased consciousness as the predominant clinical manifestations. Focal neurological findings are less common. The reports regarding CSF pleocytosis are conflicting. In one review CSF pleocytosis was present in 50% of the patients with HHV-6 encephalitis (Singh and Paterson, 2000) while Zerr et al. (2001) reported that increased protein levels were common but CSF pleocytosis was rare. Magnetic resonance imaging can show abnormalities but it can also be normal. The prognosis is poor unless the encephalitis is treated with antiviral drugs. There have been reports of HHV-6 as the cause of interstitial pneumonia in SCT patients (Cone et al., 1993; Hentrich et al., 2005). It has been difficult to assess the true relevance of HHV-6 since several other causes of pneumonia exist. Although HHV-6 has been detected in 9.4−14.6% of the bronchoalveolar lavage fluid samples in lung transplant recipients (Jacobs et al., 2003; Ross et al., 2001), its relevance as a pathogen in this setting is controversial.
P. Ljungman, N. Singh / Journal of Clinical Virology 37 Suppl. 1 (2006) S87–S91
Other clinical syndromes suggested being associated with HHV-6 infections are hepatitis and gastrointestinal disease (Appleton et al., 1995; Hentrich et al., 2005; Lautenschlager et al., 1998). Several other differential diagnoses for these conditions exist in transplant recipients especially GVHD and other infections making interpretation of HHV-6’s role in these conditions difficult.
5. Indirect sequelae HHV-6 is considered an immunomodulatory and immunosuppressive virus that may facilitate super-infections with other opportunistic pathogens and contribute to overall mortality (Dockrell et al., 1997; Flamand et al., 1995; Singh and Carrigan, 1996; Singh et al., 1997). A primary HHV-6 infection was identified as a significant risk factor for the development of a symptomatic CMV infection in liver transplant recipients (Dockrell et al., 1997). HHV-6 infections have also been reported as an independently significant predictor of invasive fungal infections in liver transplant recipients (Dockrell et al., 1997; Rogers et al., 2000). When controlled for the level of immunosuppression, HHV-6 infections increased the risk of opportunistic infections in liver transplant recipients. In SCT patients, detection of HHV-6 in plasma predicted for subsequent all-cause mortality (Zerr et al., 2005). Also liver transplant recipients with HHV-6 had a significantly higher mortality; the independent association between HHV-6 and late mortality approached statistical significance (Rogers et al., 2000). Similar observations were made in lung transplant recipients where patients with HHV-6 infections had a significantly higher mortality rate than those without HHV-6 (Jacobs et al., 2003). It is difficult to assess in all these studies whether there was a cause and effect association between HHV-6 and mortality or if they are instead parallel phenomena. HHV-6 infection has been shown to have a contributory role in the pathogenesis of hepatitis C disease (Humar et al., 2002; Singh et al., 2002). Although the HHV-6 viremia did not affect the overall rate of recurrence of hepatitis C, it was associated with a more severe form of recurrence. Other variables that may influence the outcome of hepatitis C recurrence such as the HCV genotype, alcohol use, CMV infections, and augmented immunosuppression, did not differ for patients who did or did not have HHV-6 viremia. There is conflicting data on the association of HHV-6 with rejection in SOT patients. HHV-6 infection has been associated with acute allograft rejection in some, but not in all reports (Griffiths et al., 1999; Lautenschlager et al., 2000; Rogers et al., 2000). HHV-6 infection and peak HHV-6 viral load in liver transplant recipients were associated with only those rejection episodes that occurred after day 30 post-transplantation (Rossi et al., 2001).
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HHV-6 has been associated with acute GVHD in SCT patients. Two possibilities exist. HHV-6 can induce a rash that can be confused with early acute skin GVHD. This association was first reported by Yoshikawa et al. (1991) and has since been reported in several subsequent studies (Yoshikawa et al., 2001a). HHV-6 might also interact with acute GVHD either by aggravating the condition or patients with more severe GVHD might be more likely to reactivate HHV-6. HHV-6 reactivation has been associated with the development of subsequent severe acute GVHD (Zerr et al., 2005). In another study it was found that HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%) (Appleton et al., 1995). Taken together, the indirect effects of HHV-6 appear to be the predominant clinical manifestation after SOT, whereas tissue invasive disease occurs less frequently. On the other hand, more direct clinical sequelae seem to be more prominent after SCT although indirect effects especially on acute GVHD and persistent impairment of T-helper cell response could contribute to the immunosuppressive effects of HHV-6 and possibly to overall mortality.
6. Prevention and therapy In vitro studies show that ganciclovir, cidofovir, and foscarnet inhibit HHV-6. Tokimasa et al. (2002) reported a lower rate of HHV-6 reactivations in patients receiving ganciclovir as CMV prophylaxis. Antiviral therapy with ganciclovir or foscarnet has been shown to lead to reduction in HHV-6 viral load in CSF (Zerr et al., 2002) and blood (Mendez et al., 2001; Zerr et al., 2002). Ganciclovir can reduce HHV-6 viral load in saliva (own unpublished results). Both ganciclovir and foscarnet have been reported being effective against HHV-6 meningo-encephalitis after transplantation and the superiority of either ganciclovir or foscarnet over the other has not been established. However, the success rate of therapy is only approximately 60% as assessed from a summary of published case reports and small patient series. It should also be acknowledged that in several of these cases therapy was frequently instigated rather late in the course of the disease. Co-morbid clinical conditions such as renal failure or marrow suppression may also dictate whether ganciclovir or foscarnet is employed as therapy for HHV-6. The choice of the antiviral drug might be based on the side-effect profile of the different antivirals. Foscarnet may be preferable in patients with marrow suppression since it does not possess the myelosuppressive effect of ganciclovir. All three available agents are nephrotoxic so the choice in patients with renal dysfunction is not obvious.
Acknowledgment The Swedish Children’s Cancer Foundation.
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P. Ljungman, N. Singh / Journal of Clinical Virology 37 Suppl. 1 (2006) S87–S91 Rossi C, Delforge ML, Jacobs F, et al. Fatal primary infection due to human herpesvirus 6 variant A in a renal transplant recipient. Transplantation 2001;71:288−92. Sashihara J, Tanaka-Taya K, Tanaka S, et al. High incidence of human herpesvirus 6 infection with a high viral load in cord blood stem cell transplant recipients. Blood 2002;100:2005−11. Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996;124:1065−71. Singh N, Paterson DL. Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus. Transplantation 2000;69:2474−79. Singh N, Carrigan DR, Gayowski T, et al. Human herpesvirus-6 infection in liver transplant recipients: documentation of pathogenicity. Transplantation 1997;64:674−8. Singh N, Husain S, Carrigan DR, et al. 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. Tanaka M, Taguchi J, Hyo R, et al. Human herpesvirus-6 encephalitis after unrelated cord blood transplantation. Leuk Lymphoma 2005;46:561−6. Tiacci E, Luppi M, Barozzi P, et al. Fatal herpesvirus-6 encephalitis in a recipient of a T-cell-depleted peripheral blood stem cell transplant from a 3-loci mismatched related donor. Haematologica 2000;85:94−7. Tokimasa S, Hara J, Osugi Y, et al. Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation. Bone Marrow Transplant 2002;29:595−8. Tsujimura H, Iseki T, Date Y, et al. Human herpesvirus-6 encephalitis after bone marrow transplantation: magnetic resonance imaging could identify the involved sites of encephalitis [letter]. Eur J Haematol 1998; 61:284−5. Visser AM, van Doornum GJ, Cornelissen JJ, et al. Severe amnesia due to HHV-6 encephalitis after allogenic stem cell transplantation. Eur Neurol 2005;54:233−4. Wang FZ, Dahl H, Linde A, et al. Lymphotropic herpesviruses in allogeneic bone marrow transplantation. Blood 1996;88:3615−20.
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Journal of Clinical Virology 37 Suppl. 1 (2006) S87–S91 www.elsevier.com/locate/jcv
Human herpesvirus-6 infection in solid organ and stem cell transplant recipients Per Ljungmana, ° , Nina Singhb a Karolinska b University
University Hospital, Karolinska Institutet, Stockholm, Sweden of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
Abstract HHV-6 has in recent years become recognized as a potential significant pathogen in both solid organ and stem cell transplant recipients. HHV-6 infections are common after transplantation regardless of the utilized diagnostic technique. Several different clinical manifestations have been described including fever, bone marrow suppression, encephalitis, skin rash, and hepatitis. The most important end-organ disease is encephalitis in stem cell transplant recipients that has been reported to have a mortality of at least 40%. HHV-6 is also considered an immunomodulatory and immunosuppressive virus that may facilitate super-infections with other opportunistic pathogens such as CMV and fungal infections and thereby contribute to overall mortality. No established therapy exists but both ganciclovir and foscarnet have been reported to have in vitro and in vivo efficacy against HHV-6. © 2006 Elsevier B.V. All rights reserved.
1. Introduction HHV-6 has rendered substantial interest as a pathogen in transplant recipients. Several problems with the interpretation of published data exist due to the ubiquity of the virus and the diffuseness of the associated syndromes described. Most HHV-6 infections in transplant patients are considered to result from reactivation since the seroprevalence is high in adults and older children. HHV-6B has been much more frequently identified as the cause of disease in transplant recipients than HHV-6A although in many published studies determination of the subtype has not been performed. The transmission of HHV-6 from the donor with the allograft has been documented and mononuclear cells latently infected with HHV-6 in the donor allograft are believed to be the likely source of transmission (Lau et al., 1998).
2. Solid organ transplant recipients Overall, 38−55% of renal, 22−54% of liver, 36% of heart, and up to 57% of heart–lung transplant recipients have been shown to develop active HHV-6 infection (de Ona et al., 2002; Dockrell et al., 1997; Herbein et al., 1996; Lautenschlager et al., 2000; Morris et al., 1989; Okuno et al., 1990; Rogers et al., 2000). Most HHV-6 * Corresponding author. Tel.: +46 8 585 82507; Fax: +46 8 774 8725. E-mail address: [email protected] (P. Ljungman). 1590-8658/ $ – see front matter © 2006 Elsevier B.V. All rights reserved.
infections occur between 2 and 4 weeks after SOT; this characteristic timing distinguishes HHV-6 from other beta-herpesvirus infections that usually occur later posttransplantation (Singh and Carrigan, 1996). In a study in liver transplant recipients where HHV-6 and HHV-7 DNA detection was sought in the plasma, HHV-6 infections occurred in 38% (15/40) patients; 67% of the infections occurred at 2 weeks post-transplantation after which the frequency of viral genome detection in the plasma declined sharply (Ihira et al., 2001). Following liver transplantation, primary HHV-6 infection has been reported in 61-100% of the patients who were seronegative for HHV-6 prior to transplantation; the latter observation was in infants receiving liver grafts from their mothers (Dockrell et al., 1997; Yoshikawa et al., 2001b). Risk factors for HHV-6 infections in SOT recipients have not been fully defined. Receipt of OKT3 monoclonal antibodies or antithymocyte globulin has been associated with HHV-6 reactivation (Nash et al., 2004; Rossi et al., 2001). A HHV-6 seroconversion in one study was noted more frequently in patients who received immuosuppressive regimens containing sirolimus and IL-12 receptor antibodies as induction therapy (Deborska et al., 2003).
3. Stem cell transplant recipients HHV-6 was documented in 38% of SCT recipients by virus isolation (Yoshikawa et al., 2002). By using molecular
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techniques, detection of HHV-6 DNA has been documented in 40−70% in PBL or whole blood (Imbert-Marcille et al., 2000; Sashihara et al., 2002; Wang et al., 1996) and 47−70% in plasma or serum (Zerr et al., 2001, 2005). The peak in viral load does occur early after transplant and usually within the first four weeks after SCT (ImbertMarcille et al., 2000; Ljungman et al., 2000; Maeda et al., 2000; Yoshikawa et al., 2002). A recently recognized problem with the diagnosis of HHV-6 infection by PCR is the possibility to detect chromosomally integrated HHV-6 sequences (Clark et al., 2006; Ward et al., 2006). Risk factors associated with HHV-6 infection after SCT has been reported to be allogeneic SCT, advanced hematological disease, younger age, gender mismatch between donor and recipient, and treatment with corticosteroids (Imbert-Marcille et al., 2000; Yoshikawa et al., 2002; Zerr et al., 2005). A small study reported a high incidence of HHV-6 in patients undergoing cord blood transplantation (Sashihara et al., 2002).
4. Clinical manifestations Clinical sequelae of HHV-6 may result from symptoms directly attributable to the virus or from its immunomodulatory effects. Symptomatic infections seem to be more common in SCT than in SOT patients and vary from very limited clinical effects to a contributing effect on overall mortality. The risk for symptomatic disease seems to be associated to transplant type and intensity of immunosuppression. Liver transplant patients seem to be the group of SOT recipients most prone to develop symptomatic HHV-6 disease. In the group of SCT patients, high risk patients such as those receiving grafts from unrelated donors or patients with severe graft-versus-host disease are most prone to develop symptomatic disease. A nonspecific febrile syndrome occurring in the early post-transplant period is the most frequently observed clinical manifestation of HHV-6 infection in SOT recipients. Unexplained fever was described in 87% of the liver transplant recipients compared to 20% of those without HHV-6 infection (p < 0.01) (Yoshikawa et al., 2000). The febrile syndrome attributable to CMV in transplant recipients may, in fact, be related to a concurrent infection due to HHV-6 or -7 rather than CMV alone. Eighty-nine percent of the liver transplant recipients with CMV infections had concomitant HHV-6 variant B or HHV-7 infection (Razonable et al., 2003). Bone marrow suppression, most often manifesting as thrombocytopenia or leukopenia, has been associated with HHV-6 and has been seen both in SCT recipients (Carrigan and Knox, 1994; Imbert-Marcille et al., 2000; Ljungman et al., 2000; Wang et al., 1996; Zerr et al., 2005) and in SOT recipients (Singh et al., 1997). HHV-6 can infect hematological progenitor cells and reduce colony formation (Burd et al., 1993; Isomura et al., 1997). Increased levels
of HHV-6 DNA are associated with a delayed platelet engraftment (Ljungman et al., 2000; Maeda et al., 2000; Zerr et al., 2005) and increased requirement for platelet transfusions in SCT recipients (Ljungman et al., 2000; Zerr et al., 2005). HHV-6 has a propensity for the central nervous system (Caserta et al., 1994; Challoner et al., 1995), and although HHV-6 DNA can occasionally be detected in the CSF of asymptomatic SCT recipients (Wang et al., 1999; Zerr et al., 2001), several case reports and small patient series have given strong support for that HHV-6 is an important cause of encephalitis in SCT recipients. Approximately 40 cases have been published (Bethge et al., 1999; Bosi et al., 1998; Cole et al., 1998; De Almeida Rodrigues et al., 1999; Drobyski et al., 1994; Gorniak et al., 2006; Hentrich et al., 2005; Ljungman et al., 2000; MacLean and Douen, 2002; Mookerjee and Vogelsang, 1997; Muta et al., 2005; Rieux et al., 1998; Tanaka et al., 2005; Tiacci et al., 2000; Tsujimura et al., 1998; Wang et al., 1999; Visser et al., 2005; Yoshida et al., 2002; Zerr et al., 2001). Most cases of encephalitis have been caused by HHV-6B although also cases with HHV-6A have been documented. The reported mortality in these cases even with treatment is approximately 40%. In SOT patients, a number of well documented case reports and case-controlled studies and at least three studies that included concurrent controls have documented an association between HHV-6 and central nervous system complications of unidentifiable etiology (Bollen et al., 2001; Paterson et al., 1999; Rogers et al., 2000; Singh and Paterson, 2000). A study of liver transplant recipients showed that 15% had mental status changes of unknown etiology after transplantation and patients with HHV-6 viremia had a significantly higher incidence of unexplained mental status changes as compared to those without HHV-6 viremia (Rogers et al., 2000). The symptoms are frequently uncharacteristic with lethargy, confusion, convulsions, and decreased consciousness as the predominant clinical manifestations. Focal neurological findings are less common. The reports regarding CSF pleocytosis are conflicting. In one review CSF pleocytosis was present in 50% of the patients with HHV-6 encephalitis (Singh and Paterson, 2000) while Zerr et al. (2001) reported that increased protein levels were common but CSF pleocytosis was rare. Magnetic resonance imaging can show abnormalities but it can also be normal. The prognosis is poor unless the encephalitis is treated with antiviral drugs. There have been reports of HHV-6 as the cause of interstitial pneumonia in SCT patients (Cone et al., 1993; Hentrich et al., 2005). It has been difficult to assess the true relevance of HHV-6 since several other causes of pneumonia exist. Although HHV-6 has been detected in 9.4−14.6% of the bronchoalveolar lavage fluid samples in lung transplant recipients (Jacobs et al., 2003; Ross et al., 2001), its relevance as a pathogen in this setting is controversial.
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Other clinical syndromes suggested being associated with HHV-6 infections are hepatitis and gastrointestinal disease (Appleton et al., 1995; Hentrich et al., 2005; Lautenschlager et al., 1998). Several other differential diagnoses for these conditions exist in transplant recipients especially GVHD and other infections making interpretation of HHV-6’s role in these conditions difficult.
5. Indirect sequelae HHV-6 is considered an immunomodulatory and immunosuppressive virus that may facilitate super-infections with other opportunistic pathogens and contribute to overall mortality (Dockrell et al., 1997; Flamand et al., 1995; Singh and Carrigan, 1996; Singh et al., 1997). A primary HHV-6 infection was identified as a significant risk factor for the development of a symptomatic CMV infection in liver transplant recipients (Dockrell et al., 1997). HHV-6 infections have also been reported as an independently significant predictor of invasive fungal infections in liver transplant recipients (Dockrell et al., 1997; Rogers et al., 2000). When controlled for the level of immunosuppression, HHV-6 infections increased the risk of opportunistic infections in liver transplant recipients. In SCT patients, detection of HHV-6 in plasma predicted for subsequent all-cause mortality (Zerr et al., 2005). Also liver transplant recipients with HHV-6 had a significantly higher mortality; the independent association between HHV-6 and late mortality approached statistical significance (Rogers et al., 2000). Similar observations were made in lung transplant recipients where patients with HHV-6 infections had a significantly higher mortality rate than those without HHV-6 (Jacobs et al., 2003). It is difficult to assess in all these studies whether there was a cause and effect association between HHV-6 and mortality or if they are instead parallel phenomena. HHV-6 infection has been shown to have a contributory role in the pathogenesis of hepatitis C disease (Humar et al., 2002; Singh et al., 2002). Although the HHV-6 viremia did not affect the overall rate of recurrence of hepatitis C, it was associated with a more severe form of recurrence. Other variables that may influence the outcome of hepatitis C recurrence such as the HCV genotype, alcohol use, CMV infections, and augmented immunosuppression, did not differ for patients who did or did not have HHV-6 viremia. There is conflicting data on the association of HHV-6 with rejection in SOT patients. HHV-6 infection has been associated with acute allograft rejection in some, but not in all reports (Griffiths et al., 1999; Lautenschlager et al., 2000; Rogers et al., 2000). HHV-6 infection and peak HHV-6 viral load in liver transplant recipients were associated with only those rejection episodes that occurred after day 30 post-transplantation (Rossi et al., 2001).
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HHV-6 has been associated with acute GVHD in SCT patients. Two possibilities exist. HHV-6 can induce a rash that can be confused with early acute skin GVHD. This association was first reported by Yoshikawa et al. (1991) and has since been reported in several subsequent studies (Yoshikawa et al., 2001a). HHV-6 might also interact with acute GVHD either by aggravating the condition or patients with more severe GVHD might be more likely to reactivate HHV-6. HHV-6 reactivation has been associated with the development of subsequent severe acute GVHD (Zerr et al., 2005). In another study it was found that HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%) (Appleton et al., 1995). Taken together, the indirect effects of HHV-6 appear to be the predominant clinical manifestation after SOT, whereas tissue invasive disease occurs less frequently. On the other hand, more direct clinical sequelae seem to be more prominent after SCT although indirect effects especially on acute GVHD and persistent impairment of T-helper cell response could contribute to the immunosuppressive effects of HHV-6 and possibly to overall mortality.
6. Prevention and therapy In vitro studies show that ganciclovir, cidofovir, and foscarnet inhibit HHV-6. Tokimasa et al. (2002) reported a lower rate of HHV-6 reactivations in patients receiving ganciclovir as CMV prophylaxis. Antiviral therapy with ganciclovir or foscarnet has been shown to lead to reduction in HHV-6 viral load in CSF (Zerr et al., 2002) and blood (Mendez et al., 2001; Zerr et al., 2002). Ganciclovir can reduce HHV-6 viral load in saliva (own unpublished results). Both ganciclovir and foscarnet have been reported being effective against HHV-6 meningo-encephalitis after transplantation and the superiority of either ganciclovir or foscarnet over the other has not been established. However, the success rate of therapy is only approximately 60% as assessed from a summary of published case reports and small patient series. It should also be acknowledged that in several of these cases therapy was frequently instigated rather late in the course of the disease. Co-morbid clinical conditions such as renal failure or marrow suppression may also dictate whether ganciclovir or foscarnet is employed as therapy for HHV-6. The choice of the antiviral drug might be based on the side-effect profile of the different antivirals. Foscarnet may be preferable in patients with marrow suppression since it does not possess the myelosuppressive effect of ganciclovir. All three available agents are nephrotoxic so the choice in patients with renal dysfunction is not obvious.
Acknowledgment The Swedish Children’s Cancer Foundation.
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