Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation

Abstract

Summary:We report two cases of human herpesvirus-6 (HHV-6)-associated encephalitis in patients after BMT. Both patients reported distinct neurological symptoms with disorientation, sleepiness and loss of short-term memory. Diagnosis was based on PCR analysis of the cerebrospinal fluid (CSF) positive for HHV-6 variant B-DNA. After institution of therapy with foscarnet in both cases, neurological symptoms improved and in one patient clearance of HHV-6-DNA from CSF was demonstrated. These cases show that HHV-6 infection has to be considered in patients with neurological symptoms following BMT and effective treatment of HHV-6 encephalitis is possible if instituted early. Keywords: human herpesvirus-6; bone marrow transplantation; encephalitis; foscarnet Human herpesvirus-6 (HHV-6) is a member of the betaherpesvirus subfamily causing exanthem subitum in children. 1 Since its discovery in 1986, HHV-6 has been an emerging pathogen, especially in the immunocompromised host. In patients after BMT the reported incidence based on screening blood samples post transplant by polymerase chain reaction (PCR) is between 38-60%. 2 Infection occurs by reactivation of latent virus or exogenous infection. HHV-6 infection in transplant patients had been associated clinically with skin rash and fever, marrow suppression, interstitial pneumonitis and encephalitis. 1 Furthermore, there are reports that HHV-6 infection is associated with an increased incidence of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection 3 and the occurrence of graft-versus-host disease (GVHD). 4 To date, there are only three reports of HHV-6-associated encephalitis in patients after bone marrow transplantation in the literature and two proved to be fatal, demonstrating the potential morbidity and mortality of this infection. [5][6][7] As HHV-6 is susceptible to ganciclovir and foscarnet but less sensitive to acyclovir, 1 clinical disease caused by this virus is potentially treatable. Here, we report two cases of HHV-6 encephalitis after allogeneic BMT successfully treated with foscarnet. Case reports Patient 1A 34-year-old man received an allogeneic unrelated BMT for relapsed acute lymphoblastic leukemia in January 1998. The conditioning regimen consisted of total body irradiation (12 Gy), etoposide 40 mg/kg and cyclophosphamide 120 mg/kg. GVHD prophylaxis consisted of antithymocyte globulin (ATG) (Thymoglobulin; Meriéux, Leimen, Germany) 3.5 mg/kg/day from day 4 (−4) before transplantation to day −1, cyclosporin A 5 mg/kg from day −1, prednisone 0.5 mg/kg from days +7 to 14, prednisone 1 mg/kg from days +14 to +28 and mycophenolate from day +0. The patient received ofloxacin, fluconazole and polyvalent immunoglobulin preparations every 3 weeks post BMT as antimicrobial prophylaxis. The recipient and donor were CMV seropositive. The patient was screened weekly by PCR for CMV-DNA. The early post-transplant period was without severe complications, in particular, no signs of GVHD. Two months after transplantation the patient developed CMV viremia and in ...

Human herpesvirus type 6 reactivation after haematopoietic stem cell transplantation

“…This was also confirmed in vitro. 50 Foscarnet on the other hand appears to be active against HHV6 both in vitro and in vivo, 51,52 but can cause severe nephrotoxicity when administered at therapeutic levels. 53 Cidofovir showed excellent anti HHV6 activity in vitro, 54 and seems to be the most effective Methylenecyclopropane analog Good activity 7.8 Preclinical phase a EC50: 50% antiviral effective concentration.…”

Ganciclovir is effective for prophylaxis and treatment of human herpesvirus-6 in allogeneic stem cell transplantation

“…Human herpesvirus-6 (HHV-6) shares many biological characteristics with CMV, including viral protein products (ෂ67% homology), 1 antigenic reactivity, and in vitro growth characteristics. 2 Several studies have suggested that HHV-6 is associated with fever, skin rash, 3 graft-versus-host disease (GVHD), 4 interstitial pneumonitis, 5 encephalitis, 6,7 thrombotic microangiopathy (TMA), 8 and suppression of engraftment, 9 in bone marrow transplant recipients.…”

Human herpesvirus-6 encephalitis followed by severe acute GVHD after a stem cell transplant from a microchimeric non-inherited maternal antigen (NIMA)-mismatched sibling

“…Moreover, severe acute GVHD was not reported in four patients receiving stem-cell grafts from NIMAcomplementary sibling donors. [7][8]10 A temporal relationship between HHV-6 infection and severe acute GVHD in our patient suggests that acute GVHD could be triggered by HHV-6 infection after allogeneic stem cell transplantation. As for CMV infection, the elevated interferon gamma enhances expression of the major histocompatibility class I and class II antigens, giving rise to activation of alloreactive donor T cells, and thus inducing acute GVHD.…”

“…12 There were 14 fatalities in patients developing HHV-6 encephalitis, among which five patients died of acute GVHD. 2,9,10,[13][14][15][16] Although the direct association between HHV-6 infection and acute GVHD cannot be proven on the basis of a single case report, our experience suggests that careful management of acute GVHD against HHV-6 encephalitis and any subsequent GVHD may be important in the setting of non-T-celldepleted stem cell transplantation from an HLA-haploidentical NIMA-mismatched family member, even if long-term feto-maternal microchimerism is detected in the donor. …”