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Previous Volume 330:1356-1360 May 12, 1994 Number 19 Next

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Human herpesvirus-6 (HHV-6) is the causative agent of exanthem subitum¹ and febrile illnesses² in children. More recently, HHV-6 has been shown to infect the recipients of bone marrow transplants and has been implicated in interstitial pneumonitis^3,4 and bone marrow suppression⁵ after transplantation. The pathogenicity of HHV-6, however, has yet to be fully delineated in either immunocompetent or immunocompromised hosts. In some children with exanthem subitum, seizures, encephalopathy, and the detection of HHV-6 DNA in cerebrospinal fluid have provided circumstantial evidence that HHV-6 can infect the central nervous system^6,7. Nevertheless, these studies have failed to document the direct invasion of neural tissue. In this report, we describe a patient who died of HHV-6 encephalitis five months after undergoing allogeneic bone marrow transplantation for relapsed Hodgkin's disease.

Case Report

The patient was a 37-year-old woman who was seropositive for HHV-6 and cytomegalovirus who received an allogeneic bone marrow transplant from an HLA-identical sibling in June 1992 for the treatment of relapsed Hodgkin's disease. Conditioning was with a previously described regimen of cytarabine, cyclophosphamide, methylprednisolone, and total-body irradiation (14 Gy)⁸. Prophylaxis against graft-versus-host disease consisted of T-cell depletion with the / T-cell-receptor monoclonal antibody T₁₀B₉ and post-transplantation cyclosporine⁸. Weekly peripheral-blood samples were obtained for the first 100 days after transplantation for the isolation of cytomegalovirus, HHV-6, and other viral organisms.

Grade II graft-versus-host disease developed 14 days after transplantation and was confined to the skin. Treatment with cyclosporine and prednisone was instituted. Four weeks after transplantation, HHV-6 was isolated from the patient's peripheral blood. She was clinically asymptomatic and received no treatment. Two weeks later, cytomegalovirus viremia was documented. Treatment was begun with ganciclovir but was switched to foscarnet 10 days later because of ganciclovir-related myelosuppression. A total of seven weeks of antiviral therapy was administered. Follow-up samples of peripheral blood drawn for viral isolation during antiviral therapy were negative. All subsequent cultures for HHV-6 were negative. Two weeks after the completion of antiviral treatment, meningoencephalitis developed, characterized by disorientation, headache, and confusion. Computed tomography of the head and magnetic resonance imaging of the brain were negative. Analysis of the cerebrospinal fluid revealed 28 white cells per cubic millimeter, with a differential count of 51 percent lymphocytes, 43 percent monocytes, and 6 percent granulocytes. The glucose level was 52 mg per deciliter (2.9 mmol per liter) (normal range, 50 to 75 mg per deciliter [2.8 to 4.2 mmol per liter]) and the total protein level 153 mg per deciliter (normal range, 15 to 45 mg per deciliter). All cerebrospinal fluid and blood cultures for bacterial, fungal, and viral organisms were negative. The patient's symptoms resolved with supportive care, and her mental status returned to normal.

Recurrent cytomegalovirus viremia developed in September 1992, when the patient was receiving no antiviral therapy except prophylactic acyclovir (400 mg twice daily). She continued to receive immunosuppressive therapy with prednisone and cyclosporine for the treatment of extensive chronic graft-versus-host disease. Treatment with ganciclovir in conjunction with growth-factor therapy with granulocyte colony-stimulating factor was reinstituted. The patient received a total of eight weeks of antiviral therapy. All subsequent cultures for cytomegalovirus were negative. Two weeks after antiviral therapy was discontinued, the patient was admitted to the hospital with a progressive deterioration in mental status characterized by a profound loss of short-term memory, disorientation with regard to time and place, inability to perform self-care activities, somnolence, social withdrawal, and incontinence. Computed tomography of the head and magnetic resonance imaging were again negative. There were no metabolic abnormalities. Cerebrospinal fluid and blood cultures were negative for viral, fungal, and bacterial organisms. Analysis of the cerebrospinal fluid demonstrated 3 white cells per cubic millimeter, with a glucose level of 53 mg per deciliter (2.9 mmol per liter) and a protein level of 94 mg per deciliter. A neurologic consultation revealed no demonstrable focal motor, sensory, or cerebellar abnormalities. The patient's neurologic status deteriorated, and she died seven days after the onset of symptoms. An autopsy was performed.

Methods

Microbiologic Surveillance and Viral-Isolation Studies

Throat-gargle, urine, and buffy-coat samples were obtained at least weekly for the first 100 days for routine viral isolation using fibroblasts, primary monkey-kidney cells, and A549 cells. All specimens were also inoculated onto monolayers of human fibroblasts in shell vials and processed by indirect immunofluorescence with a monoclonal antibody specific for one of the immediate early antigens of cytomegalovirus (Dupont Specialty Diagnostic, Billerica, Mass.). Peripheral-blood cultures for HHV-6 were obtained before transplantation and weekly for 14 weeks thereafter. The cell-culture procedure for the isolation of HHV-6 has previously been described⁹.

DNA Isolation, Polymerase Chain Reaction, and Sequence-Specific Oligonucleotide-Probe Hybridization

Genomic DNA was extracted by sodium dodecyl sulfate and proteinase K digestion followed by ethanol precipitation. DNA was amplified with use of the polymerase chain reaction and primers specific for HHV-6. Amplified DNA was then hybridized to variant-specific and consensus probes. The reaction conditions, primer sequences, washing and hybridization temperatures, and nucleotide sequences for the variant A, variant B, and consensus probes have been reported elsewhere¹⁰.

Immunohistochemical Studies

Astrocytes were detected by immunohistochemical staining with a rabbit antiserum specific for glial-filament acidic protein (Dako, Carpinteria, Calif.). Myelin was stained with Luxol fast blue. A previously described avidin-biotin immunohistochemical staining procedure⁹ was used to detect cells infected with HHV-6 in formalin-fixed, paraffin-embedded brain tissue. The results of immunohistochemical staining were confirmed with a murine monoclonal antibody reactive with the p101 structural protein of HHV-6¹¹. This antibody, which is specific for variant B of HHV-6, was obtained from Dr. Philip Pellett (Centers for Disease Control and Prevention, Atlanta).

Control antiserum, monoclonal antibodies, and oligonucleotide probes specific for human cytomegalovirus (monoclonal antibodies DDG9 and CCH2, Dako), herpes simplex virus (rabbit antiserum B114, Dako), varicella-zoster virus (rabbit antiserum, Lee Biomolecular Research, San Diego, Calif.), Epstein-Barr virus (EBER probes, Dako), JC virus (rabbit antiserum raised against purified virus), measles virus (rabbit antiserum raised against purified virus), and human immunodeficiency virus (HIV) (p24-specific monoclonal antibody M857, Dako) were used to exclude the possibility of other central nervous system pathogens.

Results

Examination of the brain at autopsy revealed no recurrent Hodgkin's disease. There was no evidence of cerebellar or uncal herniation, perivascular cuffing, or leptomeningeal inflammation. Immunohistochemical staining of brain tissue was negative for measles virus, cytomegalovirus, herpes simplex virus types 1 and 2, varicella-zoster virus, JC virus, and HIV p24 antigen. In situ hybridization for Epstein-Barr virus EBER RNA was negative. No viral inclusions were seen.

Two distinct regions of disease were observed. The first consisted of extensive necrosis of the deep white matter of the frontal lobe of the cerebral cortex. The most severe focus is depicted in Figure 1A. Radiating outward from this focus was an area of destruction ranging from essentially complete loss of myelin in tissue immediately adjacent to the main lesion (Figure 1B) to intact myelinated tissue at more distal sites (Figure 1C). Bodian staining of areas of abnormal white matter revealed that axonal degeneration correlated roughly with the loss of myelin (data not shown). Immunohistochemical staining with the rabbit hyperimmune serum demonstrated the presence of HHV-6-infected cells throughout the diseased white matter (Figure 2). A similar pattern of staining was seen with the murine monoclonal antibody reactive against the p101 protein. Most of the HHV-6-infected cells in the white-matter lesion appeared to be astrocytes, although the possibility of infected oligodendrocytes could not be excluded. No infected cells were seen in the white matter that appeared normal. A diffuse loss of astrocytes was also observed throughout the diseased white matter (data not shown). The degree of astrocyte loss correlated closely with the severity of myelin damage. A reactive gliosis was present in the morphologically intact tissue immediately adjacent to the demyelinated regions. Other regions of the cerebral cortex, subcortical structures, cerebellum, brain stem, and spinal cord showed no pathologic changes.

View larger version (157K): [in this window] [in a new window]   Figure 1. Histopathological Changes in the Subcortical White Matter of the Patient's Cerebral Cortex. Panel A (hematoxylin and eosin) shows an area of necrosis involving all elements of the brain parenchyma in the frontal cerebral cortex. In Panel B (Luxol fast blue), white matter adjacent to the lesion shown in Panel A reveals a striking loss of myelin with relative preservation of the underlying tissue. Panel C (Luxol fast blue) shows white matter in the uninvolved occipital cerebral cortex, with normal staining of myelinated fibers.

 

View larger version (53K): [in this window] [in a new window]   Figure 2. HHV-6-Infected Cells (Arrowheads) in the White Matter of the Patient's Frontal (Panel A) and Parietal (Panel B) Cerebral Cortex. Tissues were immunohistochemically stained with a rabbit antiserum specific for HHV-6-infected cells. (Vector Red reaction product with hematoxylin counterstain.).

 
The second area of abnormality consisted of necrosis in the gray matter of the left hippocampal gyrus (Figure 3). A nearly complete loss of neurons was evident throughout the pyramidal-cell layer in association with a prominent reactive gliosis. The few remaining neurons were located primarily in the CA4 region. There were also two small foci of neuronal destruction in the dentate region. The right hippocampal gyrus and remaining gray matter were free of any abnormality. Immunohistochemical staining for HHV-6-infected cells revealed dense neuronal infection in the CA4 region of the hippocampal gyrus (Figure 3). In addition to neuronal infection, HHV-6-infected cells that were morphologically identical to those observed in the infected white matter were seen. These cells appeared to be astrocytes.

View larger version (120K): [in this window] [in a new window]   Figure 3. Histopathological Changes and HHV-6-Infected Cells in the Hippocampal Gyrus. Panel A shows a section of the CA4 region of the hippocampus. Neurons are virtually absent, and have been replaced by astrocytes. The arrowhead indicates a single remaining neuron. In Panel B, a section of the CA1 region of the hippocampus shows an acute pathologic process consisting of necrosis and prominent reactive astrocytosis. Panel C shows a section of the CA4 region of the hippocampus that was less involved than that shown in Panel A after immunohistochemical staining for the p101 protein of HHV-6 with a murine monoclonal antibody. Note the prominent staining of a cluster of infected neurons (arrowheads). Panel D shows a section of the CA1 region of the hippocampus after immunohistochemical staining with a rabbit antiserum specific for HHV-6-infected cells. Arrowheads indicate two infected cells similar in appearance to those observed in the patient's white matter.

 
We identified the variant of HHV-6 responsible for the initial viremia and the terminal episode of encephalitis by amplifying DNA from the week 4 clinical isolate and from tissue removed at autopsy from the frontal cerebral cortex. The results, which are shown in Figure 4, demonstrate that at both points in the patient's clinical course her HHV-6 infection was due to variant B. Confirmation of variant B infection was provided by immunohistochemical staining of HHV-6-infected cells in the hippocampus with the variant B-specific p101 monoclonal antibody (Figure 3C). In contrast, HHV-6 DNA could not be detected by the polymerase chain reaction in brain tissue from six recipients of bone marrow transplants who died of causes other than encephalitis (data not shown).

View larger version (13K): [in this window] [in a new window]   Figure 4. Dot Blot Hybridization of HHV-6 Amplified DNA Derived from a Clinical Isolate and Brain Tissue with Variant A, Variant B, or Consensus Probes. HHV-6GS (variant A) and HHV-6Z29 (variant B) were included as positive controls. Uninfected MRC-5 fibroblasts were used as a negative control.

 
Discussion

This report demonstrates that HHV-6 is able to infect the central nervous system and implicates HHV-6 as a novel etiologic agent of encephalitis in recipients of bone marrow transplants. We confirmed HHV-6 infection in this patient's brain using two independent HHV-6-specific antibodies along with oligonucleotide-probe hybridization of DNA amplified by the polymerase chain reaction. Our detection of HHV-6-infected cells in affected brain tissue coincided with profound neurologic deterioration in the patient, providing clinical evidence that HHV-6 had a pathogenic role. Furthermore, extensive microbiologic testing before the patient's death and careful examination of brain tissue removed at autopsy failed to implicate any other etiologic agents. These data all support the premise that HHV-6 was the causative agent of the patient's neurologic illness.

The initial HHV-6 infection in this patient was documented early after transplantation. It is not clear, however, whether the interval between the initial viremia and the patient's death represented the progressive continuum of a single infectious episode that became localized in the brain or whether the patient had recurrent episodes of HHV-6 infection. It is possible that the two distinctive regions of disease in the gray and white matter were due to both acute and chronic infections rather than a single process. The patient's earlier episode of idiopathic meningoencephalitis raises the possibility that an undiagnosed chronic HHV-6 infection of the brain may have become established several months before the patient's terminal neurologic illness.

Immunohistochemical studies showed that astrocytes were the most commonly infected cell type in the white-matter lesions, whereas neuronal cells were predominantly affected in the gray matter. The presence of the p101 protein in HHV-6-infected cells indicated that infection was productive as opposed to latent in these cell types, since structural proteins are not produced in latently infected cells. Infected cells were observed in close proximity to demyelinated areas and regions of astrocyte depletion. This pattern, which has been described in experimental models of herpes simplex encephalitis,¹² suggests that HHV-6 may have been responsible for both the loss of astrocytes and the destruction of myelin.

HHV-6 infection was also observed in the hippocampus and appeared to be responsible for substantial neuronal destruction. This region of the brain is important to memory, and its destruction would provide an explanation for the patient's loss of short-term memory. A predilection of HHV-6 infection for the hippocampus would also provide a pathophysiologic basis for the occurrence of seizures in some patients with exanthem subitum. No other gray-matter lesions were seen in the patient's brain tissue, suggesting that HHV-6, like other herpesviruses, may have a propensity to infect the limbic system.

Both initially and on postmortem study, HHV-6 infection in this patient was found to be due to variant B. We determined this with oligonucleotide probes that recognize polymorphisms in a defined region of the HHV-6 genome¹³ and with the p101 monoclonal antibody, which is specific for variant B¹⁴. Although the relative prevalence of variant A and variant B infections has not been studied extensively in patients undergoing bone marrow transplantation, variant B has been the most frequently isolated subtype to date¹⁰. In a few immunocompetent patients, infection with both strains has been described¹⁵. Although we cannot definitively exclude the possibility of coinfection in our patient, the detection of only variant B HHV-6 in amplified DNA from brain tissue and immunohistochemical staining with a variant B-specific monoclonal antibody argue against it.

In summary, this study directly implicates HHV-6 as an etiologic agent in encephalitis. Immunocompromised patients may be at particular risk for this complication, given the high seroprevalence of HHV-6 in the general population¹³ and their predilection for acquiring life-threatening infections from other herpesviruses. Since HHV-6 may be susceptible to antiviral agents,^14,16 HHV-6 infection should be considered in the diagnostic evaluation of immunocompromised patients with unexplained neurologic illness.

Supported by a grant (EDT 19) from the American Cancer Society.

We are indebted to Ms. Jennifer Olson for assistance in the preparation of the manuscript.

Source Information

From the Departments of Medicine (W.R.D., D.M.) and Pathology (K.K.K., D.R.C.) and the Bone Marrow Transplant Program (W.R.D., D.M.), Medical College of Wisconsin, Milwaukee.

Address reprint requests to Dr. Drobyski at the Bone Marrow Transplant Program, Box 176, 8700 W. Wisconsin Ave., Milwaukee, WI 53226.

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