© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Clin Transplant 2014: 28: 540–545 DOI: 10.1111/ctr.12342
Clinical Transplantation
Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen Yamamoto W, Ogusa E, Matsumoto K, Maruta A, Ishigatsubo Y, Kanamori H. Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen.
Wataru Yamamotoa, Eriko Ogusaa, Kenji Matsumotoa, Atsuo Marutaa, Yoshiaki Ishigatsubob and Heiwa Kanamoria a
Abstract: Human herpesvirus-6 (HHV-6) encephalopathy is a serious complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although reactivation of HHV-6 is often observed after alloHSCT, encephalopathy only affects a few patients with HHV-6 reactivation. Human leukocyte antigen (HLA) class I is expressed by most somatic cells, and a relationship between some class I alleles and neurological diseases has been reported. The HHV-6 load at two, three, and four weeks after allo-HSCT was examined. HHV-6 encephalopathy was diagnosed from symptoms, results of cerebrospinal fluid examination, and magnetic resonance imaging findings. The relation between HHV-6 reactivation or encephalopathy and the HLA class I status of the recipients was investigated. In 130 patients, 147 allo-HSCT transplantation procedures were carried out. HHV-6 reactivation and encephalopathy occurred in 56 and nine procedures, respectively. HLA mismatch (p = 0.008) and unrelated donor (p = 0.001) were associated with HHV-6 reactivation, but not with HHV-6 encephalopathy. HHV-6 encephalopathy was more frequent in patients with HLA-B*40:06 (p = 0.027). In addition, HLA-A*26:01 and HLA-B*40:06 were found to be associated with each other (p = 0.089), while HLA-B*40:06 and HLAC*08:01 showed a significant association (p < 0.001). The HLA class I alleles of recipients may be associated with the occurrence of HHV-6 encephalopathy after allo-HSCT.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed for many hematological malignancies. After allo-HSCT, patients show immunosuppression because of both the conditioning regimen and the immunosuppressive effect of graft-versus-host disease (GVHD) prophylaxis. Accordingly, herpesvirus reactivation often becomes problematic in these patients. Encephalopathy due to human herpesvirus type-6 (HHV-6) sometimes occurs after allo-HSCT, and this disease is frequently lethal or causes severe sequelae that impair the quality of life (1–6). While reactivation of HHV-6 is often detected after allo-HSCT, only a few patients with reactivation develop encephalopathy, but the reason for this is still unclear. The human major histocompatibility gene complex contains the human leukocyte antigen (HLA) class I and II genes. Although HLA class II is expressed on the surface of only antigen-presenting cells,
540
Department of Hematology, Kanagawa Cancer Center and bDepartment of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Key words: encephalopathy – human herpesvirus-6 – human leukocyte antigen – reactivation – stem cell transplantation Corresponding author: Wataru Yamamoto, MD, Department of Hematology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan. Tel.: 81 45 520 2222; fax: 81 45 520 2202; e-mail: [email protected] Conflict of interest: None. Accepted for publication 21 February 2014
HLA class I is expressed on the surface of all nucleated cells and relate to the cytotoxic immune response. Some types of autoimmune and infectious disease are thought they were related to HLA class I. There are some neurological diseases that have an autoimmune basis, and they were previously reported about a relationship of HLA class I alleles, for example, progressive multifocal leukoencephalopathy (7), ocular Behcßet’s disease (8), and Rasmussen syndrome (9). On the other hand, HLA class I binds viral peptides and presents them on the surface of virus-infected cells. Some viruses have been reported about relationships of HLA class I in prevalence and severity, for example, JC virus in progressive multifocal leukoencephalopathy (7) and human immunodeficiency virus in acquired immunodeficiency disease (10). Therefore, we made a hypothesis that HLA class I relates to pathogenesis of HHV-6 encephalopathy as viral
HHV-6 encephalopathy and HLA infectious neurological disease. In this study, we investigated the relationship between the HLA class I alleles of recipients and the occurrence of HHV-6 encephalopathy after allo-HSCT. Patients and Methods
Patients who underwent allo-HSCT for hematological malignancies from April 2004 to May 2010 at Kanagawa Cancer Center in Japan were investigated retrospectively. A real-time quantitative polymerase chain reaction assay for HHV-6 was performed using the LightCycler FastStart DNA Master Hybridization Probes kit (Roche Diagnostics, Mannheim, Germany) according to the methodology of past reports (5, 11). We routinely measured the plasma HHV-6 load at two, three, and four weeks after allo-HSCT, and HHV-6 reactivation was defined as existing when the viral load exceeded 125 copies/mL. We thought that the cutoff line of HHV-6 load should be relatively low to reduce false-negative rate. HHV-6 encephalopathy was diagnosed from the symptoms, the results of cerebrospinal fluid examination including HHV-6 load, and the findings on magnetic resonance imaging according to past reports (5, 12). Then the relation between HHV-6 reactivation or encephalopathy and the HLA class I allele status of the recipients was investigated. We analyzed all alleles of HLA class I whether there was a significant difference in frequency of incidence of HHV-6 reactivation or HHV-6 encephalopathy or not. The influence of clinical factors, including the age, disease risk, HLA mismatch, GVHD prophylaxis, conditioning regimen, sex, donor type, and repeat allo-HSCT, was also investigated. Standard-risk disease was defined as acute leukemia in the firstor second-remission myelodysplastic syndrome (MDS) without leukemic transformation, and chronic myeloid leukemia (CML) in the chronic phase at transplantation, while all other diagnoses were considered to be high-risk disease. HLA mismatch was defined as the mismatch of at least one of six antigen classes among HLA-A, B, and DR. Myeloablative conditioning included cyclophosphamide with total body irradiation or busulfan plus cyclophosphamide, while reduced intensity conditioning was fludarabine plus melphalan with or without low-dose total body irradiation. Statistical analysis was performed with R software (version 2.11.1; R Development Core Team, Vienna, Austria). Differences between groups were analyzed by Fisher’s exact test, and multivariate logistic regression analysis was also performed. This study conformed to the ethical guidelines of the Japan Society for Hematopoietic Cell
Transplantation (http://www.jshct.com/organization/pdf/about_rinri.pdf). Results
A total of 147 allo-HSCT transplantation procedures were performed in 130 patients with hematological malignancies. The underlying disease was acute myeloid leukemia in 84 patients, acute lymphoblastic leukemia in 29, MDS in eight, CML in six, mixed phenotype acute leukemia in one, multiple myeloma in one, and primary myelofibrosis in one. Seventeen of the procedures were second or third transplantations for graft failure or disease relapse. There were 30 transplantations without analysis of HLA-C allele. HHV-6 reactivation and HHV-6 encephalopathy were detected in 56 (38.1%) and nine (6.1%) transplantation procedures, respectively. Median serum HHV-6 viral loads in patients with encephalopathy were higher than loads in patients without encephalopathy (4650 copies/mL [range, 1270–22 100] and 852 copies/mL [range, 168–290 000], respectively, p = 0.036). In nine patients with HHV-6 encephalopathy, there were six deaths, and the causes of death were HHV-6 encephalopathy in one patient, internal pneumonias in two, sepsis in one, gastrointestinal hemorrhage in one, and relapse in one. No relapse was observed in three survivors. All patients with HHV-6 encephalopathy had high fever and impaired consciousness. One of them developed a seizure. Focal hyperintensities on magnetic resonance imaging with the fluid attenuation inversion recovery were observed in hippocampus of seven patients, in left medial temporal lobe of one patient, and in cerebellum of one patient. Median HHV-6 load of cerebrospinal fluid was 50 900 copies/mL (range, 590–199 000). All patients were treated with foscarnet or ganciclovir for HHV-6 infection. All of the patients who developed HHV-6 encephalopathy also showed reactivation of HHV-6 infection. HLA mismatch (odds ratio [OR], 4.5; 95% confidence interval [95%CI], 1.5–13.7; p = 0.008) and unrelated donor were found to be risk factors (OR, 5.6; 95%CI, 2.0– 16.1; p = 0.001) for HHV-6 reactivation according to multivariate analysis (Table 1). However, neither one of these was a significant risk factor for HHV-6 encephalopathy according to multivariate analysis that included certain HLA alleles found in all of the patients (Table 2). According to multivariate analysis, possession of HLA-B*40:06 (OR, 31.1; 95%CI, 1.5–649.0; p = 0.027) was a significant risk factor for encephalopathy across all of the transplantation procedures (Table 2). In transplantation procedures that featured HHV-6
541
Yamamoto et al. Table 1. Relationships between HHV-6 reactivations and variables Univariate analysis Variables
Reactivation+
Age
Clin Transplant 2014: 28: 540–545 DOI: 10.1111/ctr.12342
Clinical Transplantation
Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen Yamamoto W, Ogusa E, Matsumoto K, Maruta A, Ishigatsubo Y, Kanamori H. Human herpesvirus-6 encephalopathy after hematopoietic stem cell transplantation and class I human leukocyte antigen.
Wataru Yamamotoa, Eriko Ogusaa, Kenji Matsumotoa, Atsuo Marutaa, Yoshiaki Ishigatsubob and Heiwa Kanamoria a
Abstract: Human herpesvirus-6 (HHV-6) encephalopathy is a serious complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Although reactivation of HHV-6 is often observed after alloHSCT, encephalopathy only affects a few patients with HHV-6 reactivation. Human leukocyte antigen (HLA) class I is expressed by most somatic cells, and a relationship between some class I alleles and neurological diseases has been reported. The HHV-6 load at two, three, and four weeks after allo-HSCT was examined. HHV-6 encephalopathy was diagnosed from symptoms, results of cerebrospinal fluid examination, and magnetic resonance imaging findings. The relation between HHV-6 reactivation or encephalopathy and the HLA class I status of the recipients was investigated. In 130 patients, 147 allo-HSCT transplantation procedures were carried out. HHV-6 reactivation and encephalopathy occurred in 56 and nine procedures, respectively. HLA mismatch (p = 0.008) and unrelated donor (p = 0.001) were associated with HHV-6 reactivation, but not with HHV-6 encephalopathy. HHV-6 encephalopathy was more frequent in patients with HLA-B*40:06 (p = 0.027). In addition, HLA-A*26:01 and HLA-B*40:06 were found to be associated with each other (p = 0.089), while HLA-B*40:06 and HLAC*08:01 showed a significant association (p < 0.001). The HLA class I alleles of recipients may be associated with the occurrence of HHV-6 encephalopathy after allo-HSCT.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed for many hematological malignancies. After allo-HSCT, patients show immunosuppression because of both the conditioning regimen and the immunosuppressive effect of graft-versus-host disease (GVHD) prophylaxis. Accordingly, herpesvirus reactivation often becomes problematic in these patients. Encephalopathy due to human herpesvirus type-6 (HHV-6) sometimes occurs after allo-HSCT, and this disease is frequently lethal or causes severe sequelae that impair the quality of life (1–6). While reactivation of HHV-6 is often detected after allo-HSCT, only a few patients with reactivation develop encephalopathy, but the reason for this is still unclear. The human major histocompatibility gene complex contains the human leukocyte antigen (HLA) class I and II genes. Although HLA class II is expressed on the surface of only antigen-presenting cells,
540
Department of Hematology, Kanagawa Cancer Center and bDepartment of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Key words: encephalopathy – human herpesvirus-6 – human leukocyte antigen – reactivation – stem cell transplantation Corresponding author: Wataru Yamamoto, MD, Department of Hematology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku, Yokohama 241-8515, Japan. Tel.: 81 45 520 2222; fax: 81 45 520 2202; e-mail: [email protected] Conflict of interest: None. Accepted for publication 21 February 2014
HLA class I is expressed on the surface of all nucleated cells and relate to the cytotoxic immune response. Some types of autoimmune and infectious disease are thought they were related to HLA class I. There are some neurological diseases that have an autoimmune basis, and they were previously reported about a relationship of HLA class I alleles, for example, progressive multifocal leukoencephalopathy (7), ocular Behcßet’s disease (8), and Rasmussen syndrome (9). On the other hand, HLA class I binds viral peptides and presents them on the surface of virus-infected cells. Some viruses have been reported about relationships of HLA class I in prevalence and severity, for example, JC virus in progressive multifocal leukoencephalopathy (7) and human immunodeficiency virus in acquired immunodeficiency disease (10). Therefore, we made a hypothesis that HLA class I relates to pathogenesis of HHV-6 encephalopathy as viral
HHV-6 encephalopathy and HLA infectious neurological disease. In this study, we investigated the relationship between the HLA class I alleles of recipients and the occurrence of HHV-6 encephalopathy after allo-HSCT. Patients and Methods
Patients who underwent allo-HSCT for hematological malignancies from April 2004 to May 2010 at Kanagawa Cancer Center in Japan were investigated retrospectively. A real-time quantitative polymerase chain reaction assay for HHV-6 was performed using the LightCycler FastStart DNA Master Hybridization Probes kit (Roche Diagnostics, Mannheim, Germany) according to the methodology of past reports (5, 11). We routinely measured the plasma HHV-6 load at two, three, and four weeks after allo-HSCT, and HHV-6 reactivation was defined as existing when the viral load exceeded 125 copies/mL. We thought that the cutoff line of HHV-6 load should be relatively low to reduce false-negative rate. HHV-6 encephalopathy was diagnosed from the symptoms, the results of cerebrospinal fluid examination including HHV-6 load, and the findings on magnetic resonance imaging according to past reports (5, 12). Then the relation between HHV-6 reactivation or encephalopathy and the HLA class I allele status of the recipients was investigated. We analyzed all alleles of HLA class I whether there was a significant difference in frequency of incidence of HHV-6 reactivation or HHV-6 encephalopathy or not. The influence of clinical factors, including the age, disease risk, HLA mismatch, GVHD prophylaxis, conditioning regimen, sex, donor type, and repeat allo-HSCT, was also investigated. Standard-risk disease was defined as acute leukemia in the firstor second-remission myelodysplastic syndrome (MDS) without leukemic transformation, and chronic myeloid leukemia (CML) in the chronic phase at transplantation, while all other diagnoses were considered to be high-risk disease. HLA mismatch was defined as the mismatch of at least one of six antigen classes among HLA-A, B, and DR. Myeloablative conditioning included cyclophosphamide with total body irradiation or busulfan plus cyclophosphamide, while reduced intensity conditioning was fludarabine plus melphalan with or without low-dose total body irradiation. Statistical analysis was performed with R software (version 2.11.1; R Development Core Team, Vienna, Austria). Differences between groups were analyzed by Fisher’s exact test, and multivariate logistic regression analysis was also performed. This study conformed to the ethical guidelines of the Japan Society for Hematopoietic Cell
Transplantation (http://www.jshct.com/organization/pdf/about_rinri.pdf). Results
A total of 147 allo-HSCT transplantation procedures were performed in 130 patients with hematological malignancies. The underlying disease was acute myeloid leukemia in 84 patients, acute lymphoblastic leukemia in 29, MDS in eight, CML in six, mixed phenotype acute leukemia in one, multiple myeloma in one, and primary myelofibrosis in one. Seventeen of the procedures were second or third transplantations for graft failure or disease relapse. There were 30 transplantations without analysis of HLA-C allele. HHV-6 reactivation and HHV-6 encephalopathy were detected in 56 (38.1%) and nine (6.1%) transplantation procedures, respectively. Median serum HHV-6 viral loads in patients with encephalopathy were higher than loads in patients without encephalopathy (4650 copies/mL [range, 1270–22 100] and 852 copies/mL [range, 168–290 000], respectively, p = 0.036). In nine patients with HHV-6 encephalopathy, there were six deaths, and the causes of death were HHV-6 encephalopathy in one patient, internal pneumonias in two, sepsis in one, gastrointestinal hemorrhage in one, and relapse in one. No relapse was observed in three survivors. All patients with HHV-6 encephalopathy had high fever and impaired consciousness. One of them developed a seizure. Focal hyperintensities on magnetic resonance imaging with the fluid attenuation inversion recovery were observed in hippocampus of seven patients, in left medial temporal lobe of one patient, and in cerebellum of one patient. Median HHV-6 load of cerebrospinal fluid was 50 900 copies/mL (range, 590–199 000). All patients were treated with foscarnet or ganciclovir for HHV-6 infection. All of the patients who developed HHV-6 encephalopathy also showed reactivation of HHV-6 infection. HLA mismatch (odds ratio [OR], 4.5; 95% confidence interval [95%CI], 1.5–13.7; p = 0.008) and unrelated donor were found to be risk factors (OR, 5.6; 95%CI, 2.0– 16.1; p = 0.001) for HHV-6 reactivation according to multivariate analysis (Table 1). However, neither one of these was a significant risk factor for HHV-6 encephalopathy according to multivariate analysis that included certain HLA alleles found in all of the patients (Table 2). According to multivariate analysis, possession of HLA-B*40:06 (OR, 31.1; 95%CI, 1.5–649.0; p = 0.027) was a significant risk factor for encephalopathy across all of the transplantation procedures (Table 2). In transplantation procedures that featured HHV-6
541
Yamamoto et al. Table 1. Relationships between HHV-6 reactivations and variables Univariate analysis Variables
Reactivation+
Age
