Case Report Successful Treatment of Human Herpesvirus-6 Encephalitis After Bone Marrow Transplantation

Home , Ganciclovir, Herpes simplex virus, Human herpesvirus 6

Bone Marrow Transplantation, (1999) 24, 1245–1248  1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt Case report Successful treatment of human herpesvirus-6 encephalitis after bone marrow transplantation

W Bethge1, R Beck2, G Jahn2, P Mundinger3, L Kanz1 and H Einsele1

Departments of 1Hematology/Oncology/Immunology and Rheumatology, 2Medical Virology, and 3Neuroradiology, University of Tu¨bingen, Germany

Summary: Here, we report two cases of HHV-6 encephalitis after allogeneic BMT successfully treated with foscarnet. We report two cases of human herpesvirus-6 (HHV-6)- associated encephalitis in patients after BMT. Both patients reported distinct neurological symptoms with Case reports 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- Patient 1 DNA. After institution of therapy with foscarnet in both cases, neurological symptoms improved and in one A 34-year-old man received an allogeneic unrelated BMT patient clearance of HHV-6-DNA from CSF was dem- for relapsed acute lymphoblastic leukemia in January 1998. onstrated. These cases show that HHV-6 infection has The conditioning regimen consisted of total body to be considered in patients with neurological symptoms irradiation (12 Gy), etoposide 40 mg/kg and cyclophos- following BMT and effective treatment of HHV-6 phamide 120 mg/kg. GVHD prophylaxis consisted of anti- encephalitis is possible if instituted early. thymocyte globulin (ATG) (Thymoglobulin; Merieúx, Lei- Keywords: human herpesvirus-6; bone marrow trans- men, Germany) 3.5 mg/kg/day from day 4 (−4) before plantation; encephalitis; foscarnet 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 Human herpesvirus-6 (HHV-6) is a member of the beta- polyvalent immunoglobulin preparations every 3 weeks herpesvirus subfamily causing exanthem subitum in chil- post BMT as antimicrobial prophylaxis. The recipient and 1 dren. Since its discovery in 1986, HHV-6 has been an donor were CMV seropositive. The patient was screened emerging pathogen, especially in the immunocompromised weekly by PCR for CMV-DNA. The early post-transplant host. In patients after BMT the reported incidence based period was without severe complications, in particular, no on screening blood samples post transplant by polymerase signs of GVHD. Two months after transplantation the 2 chain reaction (PCR) is between 38–60%. Infection occurs patient developed CMV viremia and in spite of treatment by reactivation of latent virus or exogenous infection. with foscarnet this progressed to pneumonitis. Treatment HHV-6 infection in transplant patients had been associated was escalated with combined use of foscarnet and ganciclo- clinically with skin rash and fever, marrow suppression, vir, broad-spectrum antibiotics and systemic amphotericin 1 interstitial pneumonitis and encephalitis. Furthermore, B. The patient subsequently improved and the pneumonitis there are reports that HHV-6 infection is associated with resolved. One hundred days post transplantation he an increased incidence of cytomegalovirus (CMV) and presented with fever, nausea, slight headaches and pro- 3 Epstein–Barr virus (EBV) infection and the occurrence of gressive retrograde amnesia. There was no history of fits, 4 graft-versus-host disease (GVHD). To date, there are only paralysis or other focal neurologic symptoms. He reported three reports of HHV-6-associated encephalitis in patients having a febrile episode with a generalized rash a week after bone marrow transplantation in the literature and two before admission. An MRI study of the brain showed no proved to be fatal, demonstrating the potential morbidity abnormality apart from focal signal abnormalities in the 5–7 and mortality of this infection. As HHV-6 is susceptible subcortical white matter; there were no signs of herpes 1 to ganciclovir and foscarnet but less sensitive to acyclovir, encephalitis. A lumbar puncture was performed yielding clinical disease caused by this virus is potentially treatable. mild pleocytosis with slight elevation of lactate, normal protein and glucose suggestive of viral meningoencephal- Correspondence: PD Dr H Einsele, Clinic for Internal Medicine, Univer- itis. All cerebrospinal fluid and blood cultures for bacterial, sity of Tu¨bingen, Otfried-Mu¨ller-Str. 10, 72076 Tu¨bingen, Germany fungal and viral organisms were negative as were serologic Received 1 February 1999; accepted 6 May 1999 studies for herpes simplex virus (HSV), VZV, EBV and a Successful treatment of HHV-6 after BMT W Bethge et al 1246 variety of other viruses. CMV- and HHV-6-specific IgG headaches, tremor, nystagmus and ataxia. Magnetic reson- and CMV-specific IgM were detectable in serum whereas ance imaging (MRI) showed slight signal abnormalities in assays for HHV-6-specific IgM were negative. PCR analy- the left cerebellum, suspicious of cerebellar ischemia or sis of the CSF was positive for HHV-6-DNA (Figure 1) but drug toxicity, and cyclosporin A was stopped. Because of negative for HSV-, EBV-, CMV-, VZV- and JC-virus fever, diarrhoea and a rise in bilirubin (2.5 mg/dl) typical (JCV)-DNA. Furthermore, HHV-6-DNA could be detected for GVHD the dose of corticosteroids was increased to in peripheral blood leukocytes, whereas PCR analysis of 2 mg/kg per day. Again, the fever and clinical condition of the plasma was negative. Restriction fragment analysis of the patient improved. Two weeks later the patient com- the PCR product obtained from CSF allowed classification plained of profound sleepiness, progressive loss of short- of the isolate as HHV-6-variant B. The patient was started term memory and disorientation without focal neurological on 3 × 60 mg/kg foscarnet. Neurological symptoms symptoms. Over the following days her neurological situ- improved rapidly within 2 weeks and a second CSF exam- ation deteriorated further with progressive loss of con- ination 14 days after institution of antiviral therapy was sciousness. A MRI study showed bilateral foci of signal negative for HHV-6-DNA by PCR. After 3 weeks of ther- abnormalities in the region of the hippocampus suggesting apy with foscarnet the patient was discharged with neuro- viral encephalitis (Figure 2). A lumbar puncture was perfor- logical disturbances completely resolved. med yielding mild pleocytosis but normal levels for protein, lactate and glucose. PCR analysis of cerebrospinal fluid (CSF) showed negative results for CMV-, EBV-, HSV- and Patient 2 JCV-DNA but was positive for HHV-6-DNA. Restriction A 54-year-old woman received an allogeneic BMT from an fragment analysis of the PCR product obtained from CSF HLA-identical sibling in March 1995 for chronic myeloid classified the isolate as HHV-6-variant B. All cerebrospinal leukemia. Conditioning was with busulfan 16 mg/kg and fluid and blood cultures for bacterial, fungal and viral cyclophosphamide 120 mg/kg. GVHD prophylaxis con- organisms were negative. IgG specific for CMV and HHV- sisted of cyclosporin A 5 mg/kg from dayϪ1 and metho- 6 was detectable in serum, whereas assays for the detection trexate 15 mg/m2 on day +1, respectively, 10 mg/m2 on of CMV-specific IgM and HHV-6-specific IgM were nega- days +3 and +6. For antimicrobial prophylaxis she received tive. Serological studies for a variety of other viruses were ofloxacin, fluconazole and polyvalent immunoglobulin negative. PCR analysis for HHV-6-DNA in serum samples preparations every 3 weeks post BMT. The recipient was were negative throughout her illness. Treatment with CMV-seropositive and was screened weekly by PCR for 3 × 60 mg/kg foscarnet was initiated and the neurological CMV-DNA in blood samples. After isolation of HSV by symptoms improved with full recovery of consciousness, cell culture from throat washings acyclovir (3 × 5 mg/kg) orientation and short-term memory after 2 weeks. Foscarnet was started. Grade II GVHD developed on day +10 with was continued for a total of 3 weeks. Subsequently, the skin rash and fever; symptoms rapidly improved when patient developed increasingly severe GVHD of bowel and corticosteroids (1 mg/kg) were started but on day +15 fever liver resistant to intensive immunosuppressive treatment. recurred. Chest X-ray showed a pulmonary lesion, highly She finally died of bowel GVHD with severe bleeding. suspicious of invasive pulmonary aspergillosis. Broad-spec- Autopsy was refused. trum antibiotics and amphotericin B (1 mg/kg) were started and after an initial response her temperature rose again on day +23 up to 39°C. In addition, the patient complained of

M1 2 34 5 67

Figure 1 Analysis of HHV-6-DNA-PCR products of patient 1 by aga- rose gel electrophoresis after staining with ethidium bromide. Lane M: Size marker (123 bp ladder). Lane 1: Positive control (pVGUdel, kindly provided by F Neipel, Erlangen). Lane 2 and 5: Negative controls. Lane 3 and 4: Native CSF (3) and CSF after isolation of DNA (4) yielding HHV-6-DNA fragments of the expected size (709 bp). Lane 6 and 7: Figure 2 MRI of the brain of Patient 2. T2 weighted fluid attenuated Detection of HHV-6-DNA in peripheral blood leukocytes (7) but not in inversion recovery (FLAIR) sequences. Coronal image at the level of the plasma (6). Note that PCR product derived from pVGUdel is 60 bp smaller hippocampus demonstrating signal intensifications in the region of the in size as compared to clinical isolates. hippocampus. Successful treatment of HHV-6 after BMT W Bethge et al 1247 Discussion abnormalities in the hippocampal region could be demonstrated on MRI scan (Figure 2). There are also reports of HHV-6 is an increasingly recognized pathogen in the white matter demyelination caused by HHV-6, producing immunocompromised patient. The two cases reported here lesions similar to multiple sclerosis10 or progressive multi- demonstrate the potential role of HHV-6 in central nervous focal leukoencephalopathy as found in patient 2. The skin system infections in patients after BMT. rash reported by patient 1 one week before admission might Humans are the primary host for the known eight mem- also be attributed to HHV-6, since in 33% of HHV-6 bers of the herpes virus family. The HHV-6 entity consists infected patients after BMT a skin rash and fever was of two closely related but distinct viruses named human present in one study.11 Diagnosis in our patients was based herpes virus-6 variant A (HHV-6A) and B (HHV-6B). on PCR analysis of CSF. As PCR also detected HHV-6 Infection normally occurs in early childhood by close con- DNA in peripheral blood lymphocytes of patient 1, one tact or respiratory transmission resulting in a rate of seropo- might argue the PCR assay used detected latent HHV-6 sitivity of over 95% in people older than 2 years. So far DNA of lymphocytes found in the CSF. However, detection HHV-6A has rarely been found to cause any clinically rel- of HHV-6 DNA in peripheral blood lymphocytes is done evant disease whereas HHV-6B is the etiologic agent of by analysis of large numbers of lymphocytes and special exanthem subitum, related febrile illnesses and is increas- separation techniques not used in our PCR assay from CSF. ingly described as a pathogen in the immunocompromised PCR analysis of the CSF has been described as the first-line host.1 In patients after BMT an incidence of 38–60% for diagnostic test for patients with herpes-simplex-encephalitis HHV-6 infection, predominantly variant B, is described by superior to brain biopsy.12 Furthermore, 14 days after initi- PCR analysis.2 In these patients an association of HHV-6 ating treatment with foscarnet in this patient, HHV-6 DNA infection with interstitial pneumonitis, marrow suppression, was no longer detectable in the CSF. Both patients were acute GVHD and fatal encephalitis has been found.1 positive for HHV-6-specific IgG before onset of neurologi- As well as in CD4+ T cells, HHV-6 has been found in cal symptoms suggesting reactivation of the virus. The fail- lymph nodes, in salivary glands, lymphocytes, macro- ure to develop HHV-6-specific IgM could be explained by phages, monocytes and kidney tubule endothelial cells.1 In reactivation of latent virus and/or the post-transplant setting the CNS, viral gene products have been demonstrated in with a severely impaired immune response. neurons, astrocytes5 and oligodendrocytes.8 CNS disease HHV-6 has been tested for susceptibility to various anti- caused by HHV-6 is described in immunocompetent as well viral agents in vitro. The data indicate greater susceptibility as in immunocompromised patients. In children with exan- of HHV-6 to ganciclovir and foscarnet than to acyclovir. them subitum febrile seizures, distention of the anterior fon- The susceptibility of variant A strains to ganciclovir varies tanelle, hemiplegia and meningoencephalitis are described in different reports with relative resistance in some.1 suggesting direct invasion of the CNS during primary infec- Foscarnet might be preferable to ganciclovir if the HHV-6 tion. There are also reports of fulminant encephalitis caused variant and susceptibility are not known. In addition, by HHV-6 in immunocompromised patients with AIDS.9 In foscarnet is found in higher concentrations in the CSF patients after BMT there have been three reports of HHV-6- than ganciclovir. associated encephalitis to date, and two proved to be Clinical experience with the treatment of HHV-6-asso- fatal.5–7 ciated encephalitis in BMT patients is limited. There is only We describe two further cases of HHV-6-associated one report of successful treatment with ganciclovir so far encephalitis in BMT patients (Table 1). Both patients in the literature.6 We report the successful treatment of two developed characteristic neurological symptoms, namely cases of encephalitis in this setting by foscarnet. As early loss of short-term memory, headaches, sleepiness and dis- treatment is vital for a successful outcome, institution of orientation. These symptoms were most likely due to antiviral treatment should occur on an empirical basis invasion of the limbic system by HHV-6 as described for before diagnostic test results are available, as happened in other herpesviruses. In patient 2 correspondant signal these cases. The high seroprevalence in the general popu-

Table 1 Summary and comparison of the essential facts of the two patients

Patient 1 Patient 2

Presenting complaint fever, nausea, slight headaches, progressive profound sleepiness, progressive loss of retrograde amnesia, generalised rash short-term memory, progressive dimming of consciousness, disorientation, no focal neurological symptoms Days after BMT 100 45 MRI imaging focal signal abnormalities in subcortical bilateral foci of signal abnormality in white matter hippocampus Diagnostic test positive PCR for HHV-6-variant B-DNA positive PCR for HHV-6-variant B-DNA in CSF in CSF Treatment foscarnet foscarnet Follow-up diagnostics PCR for HHV-6 DNA in CSF negative not done Outcome complete recovery complete recovery Successful treatment of HHV-6 after BMT W Bethge et al 1248 lation and potential mortality and morbidity caused in post- 5 Drobyski WR, Knox KK, Majewski D et al. Brief report: fatal transplant patients makes routine surveillance of these encephalitis due to variant B human herpesvirus-6 infection patients an issue. Weekly assessment of blood samples by in a bone marrow-transplant recipient. New Engl J Med 1994; PCR for HHV-6 could be recommended in the first 330: 1356–1360. 3 months after transplantation, allowing early institution of 6 Mookerjee BP, Vogelsang G. Human herpes virus-6 encepha- 2 litis after bone marrow transplantation: successful treatment treatment if the criteria proposed by Singh and Carrigan with ganciclovir. Bone Marrow Transplant 1997; 20: 905– are met. 906. In summary, we describe two patients after BMT suffer- 7 Bosi A, Zazzi M, Amantini A et al. Fatal herpesvirus 6 ing from HHV-6-associated encephalitis successfully encephalitis after unrelated bone marrow transplant. Bone treated by foscarnet. HHV-6 infection should be considered Marrow Transplant 1998; 22: 285–288. in patients with neurological symptoms following BMT and 8 Luppi M, Barozzi P, Maiorana A et al. Human herpesvirus- early institution of antiviral treatment is mandatory. Further 6: a survey of presence and distribution of genomic sequences research into the role of HHV-6 as a pathogen in transplant in normal brain and neuroglial tumors. J Med Virol 1995; 47: patients and adequate prophylactic or therapeutic treatment 105–111. should be undertaken. 9 Knox KK, Harrington DP, Carrigan DR. Fulminant human herpesvirus six encephalitis in a human immunodeficiency virus-infected infant. J Med Virol 1995; 45: 288–292. References 10 Carrigan DR, Harrington D, Knox KK. Subacute leukoence- phalitis caused by CNS infection with human herpesvirus-6 1 Braun DK, Dominguez G, Pellett PE. Human herpesvirus 6. manifesting as acute multiple sclerosis. Neurology 1996; 47: Clin Microbiol Rev 1997; 10: 521–567. 145–148. 2 Singh N, Carrigan DR. Human herpesvirus-6 in transplan- 11 Frenkel N, Katsafanas GC, Wyatt LS et al. Bone marrow tation: an emerging pathogen. Ann Intern Med 1996; 124: transplant recipients harbor the B variant of human herpes- 1065–1071. virus 6. Bone Marrow Transplant 1994; 14: 839–843. 3 Flamand L, Stefanescu I, Ablashi DV et al. Activation of the 12 Lakeman FD, Whitley RJ and the National Institute of Allergy Epstein–Barr virus replicative cycle by human herpesvirus 6. and Infectious Diseases Collaborative Antiviral Study Group. J Virol 1993; 67: 6768–6777. Diagnosis of herpes simplex encephalitis: application of poly- 4 Cone RW, Hackman RC, Huang ML et al. Human herpesvirus merase chain reaction to cerebrospinal fluid from brain bio- 6 in lung tissue from patients with pneumonitis after bone psied patients and correlation with disease. J Infect Dis 1995; marrow transplantation. New Engl J Med 1993; 329: 156–161. 171: 857–863.