Solid organ transplant recipients

Overall, 38-55% of renal, 22-54% of liver, 36% of heart and up to 57% of heart-lung lung transplant recipients have been shown to develop HHV-6 infection (Morris et al., 1989; Okuno et al., 1990; Herbein et al., 1996; Dockrell et al., 1997; Lautenschlager et al., 2000; Rogers et al., 2000; de Ona et al., 2002). Following living related liver transplantation, HHV-6 infection has been documented in 48% of the patients; these included 4/4 patients who were seronegative and 42% (15/36) of those who were seropositive for HHV-6 prior to living related transplantation (Ihira et al., 2001).

Most HHV-6 infections occur between 2 and 4 weeks after SOT; this characteristic timing distinguishes HHV-6 from other betaherpesvirus infections that usually occur later post-transplantation (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 sharply declined (Ihira et al., 2001). In contrast, only 31% of the HHV-7 infections were detected at 2 weeks with no distinctive peak in time to detection. Further, HHV-7 DNA remained detectable in 10-20% of the patients until 8 weeks post-transplant. A study of the temporal sequence of infections with the 3 betaherpesviruses in organ transplant recipients showed that

HHV-6 reactivation occurred at a median of 20 days, followed by HHV-7 (median 26 days) and cytomegalovirus (CMV) (median 36 days) (Griffiths et al., 1999).

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 (Rossi et al., 2001; Nash et al., 2004). An HHV-6 seroconversion in one study was noted more frequently in patients who received immunosuppressive regimens containing sirolimus and IL-12 receptor antibodies as induction therapy (Deborska et al., 2003).

Stem cell transplant recipients

By virus isolation, HHV-6 was documented in 38% of SCT recipients (Yoshikawa et al., 2002). Detection of HHV-6 DNA has been documented in 40-70% by studies of PBL or whole blood (Wang et al., 1996; Imbert-Marcille et al., 2000; Sashihara et al., 2002) and 47-70% by studies of plasma or serum (Zerr et al., 2001, 2005). The peak in viral load does similarly in SOT patients, which occurs early after transplant, usually within the first 4 weeks after SCT (Imbert-Marcille et al., 2000; Ljungman et al., 2000; Maeda et al., 2000; Yoshikawa et al., 2002).

Risk factors associated with HHV-6 infection after SCT has been reported to be allogeneic rather than autologous SCT, transplantation for leukemia or lymphoma, advanced hematological disease, younger age, sex mismatch between donor and recipient and treatment with corticosteroids (Imbert-Marcille et al., 2000; Yoshikawa et al., 2002; Zerr et al., 2005) It has been reported that patients receiving peripheral blood SCT are more frequently PCR positive than patients receiving bone marrow grafts (Maeda et al., 2000) but this has not been confirmed by other studies (Imbert-Marcille et al., 2000; Ljungman et al., 2000; Zerr et al., 2005). A small study reported a high incidence of HHV-6 in patients undergoing cord blood transplantation (Sashihara et al., 2002)

Clinical manifestations

Clinical sequelae of HHV-6 may result from symptoms directly attributable to the virus or from its immunomodulatory effects. Table 1 shows a summary over the clinical syndromes that has been suggested being associated with HHV-6. Symptomatic infections seem to be more common in SCT than in SOT patients although published reports vary from very limited clinical effects of HHV-6 to a contributing effect on overall mortality. A fever of unknown origin; with or without a skin rash; bone marrow suppression, and encephalitis are the most frequently observed clinical features of HHV-6 (Carrigan et al., 1991; Drobyski et al., 1993; Carrigan and Knox, 1995; Wang et al., 1999; Ljungman et al., 2000; Zerr et al., 2001). Less commonly, interstitial pneumonitis, gastrointestinal disease, and hepatitis have been reported (Cone et al., 1993; Singh et al., 1997; Rossi et al., 2001; Hentrich et al., 2005).

Table 1

Association of HHV-6 with clinical sequelae and the level of supportive evidence

I. Supportive evidence from cohort studies

A. Febrile syndrome

B. Encephalitis

C. Bone marrow suppression

D. Association with fungal infections

E. Association with cytomegalovirus infection

F. Aggressive recurrence of hepatitis C virus after liver transplantation

G. Mortality

II. Evidence from case reports

A. Interstitial pneumonitis

B. Hepatitis

C. Gastroduodenitis

D. Leukocytoclastic vasculitis

III. Proposed association with conflicting supportive evidence

A. Allograft rejection

B. Obliterative bronchitis

A non-specific febrile syndrome occurring in the early post-transplant period is the most frequently observed clinical manifestation of HHV-6 infection in organ transplant recipients. Unexplained fever was documented in 87% of the liver transplant recipients with HHV-6 infections compared to 20% of those without it (p< 0.01) (Yoshikawa et al., 2000). The febrile mononucleosis syndrome attributable to CMV in transplant recipients may, in fact, be related to a concurrent infection due to HHV-6 and 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; Wang et al., 1996; Imbert-Marcille et al., 2000; Ljungman, et al., 2000; 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 CNS (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 30 cases have been published (Drobyski et al., 1994; Mookerjee and Vogelsang, 1997; Bosi et al., 1998; Cole et al., 1998; Rieux et al., 1998; Tsujimura et al., 1998; Bethge et al., 1999; De Almeida Rodrigues et al., 1999; Wang et al., 1999; Ljungman et al., 2000; Tiacci et al., 2000; Zerr et al., 2001; MacLean and Douen, 2002; Yoshida et al., 2002; Hentrich et al., 2005). A summary of published information around these cases regarding patient characteristics, diagnostic findings, and outcome of HHV-6 CNS disease in SCT patients is shown in Table 2. It should be noted that not all data are available for all patients. 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 CNS complications of unidentifiable etiology (Paterson et al., 1999; Rogers et al., 2000; Singh and Paterson, 2000; Bollen et al., 2001). A study of liver transplant recipients showed that 15% (12/80) of the patients had mental status changes of unknown etiology after transplantation and patients with HHV-6 viremia had a significantly higher incidence of mental status changes of unidentifiable etiology (29%, 9/31) as compared to those without HHV-6 viremia (6%, 3/49, p — 0.008) (Rogers et al., 2000). The symptoms are frequently uncharacteristic with lethargy, confusion, convulsions, and decreased consciousness as the predominant clinical

Table 2

Patient characteristics, diagnostic findings, therapy and outcome of SCT patients with suspected or proven HHV-6 encephalitis

Patient characteristics

Patient characteristics, diagnostic findings, therapy and outcome of SCT patients with suspected or proven HHV-6 encephalitis

Patient characteristics

Median age

36 (12-56)

Type of transplant

Was this article helpful?

0 0

Post a comment