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Ono R, Sakamoto K, Doi T, Yanagisawa R, Morimoto A, Kanegane H, Nakazawa Y, Shioda Y. Dexamethasone palmitate for children with Epstein-Barr virus associated hemophagocytic lymphohistiocytosis. Int J Hematol 2025; 121:252-256. [PMID: 39630348 DOI: 10.1007/s12185-024-03892-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 02/01/2025]
Abstract
Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) has a wide range of clinical presentations and is sometimes life-threatening. It is often treated with systemic corticosteroids and etoposide, but no optimal treatment has been identified. Dexamethasone palmitate (DP) contains a combination of dexamethasone and a lipid emulsion and is selectively taken up by activated macrophages. Recently, a small case series reported the efficacy of dexamethasone palmitate (DP) in HLH. Here, we present the results of a nationwide survey in Japan detailing 14 cases of EBV-HLH treated with DP in children. One week after DP initiation, fever, cytopenia, and splenomegaly resolved in 77%, 38%, and 77% of patients (10, 5, and 10 of 13 patients, 1 missing). A 50% or greater reduction in ferritin levels was observed in 62% of patients (8 of 13 patients, 1 missing). In addition, the attending physician judged DP to be effective or partially effective in 12/14 (86%) patients. DP-related adverse events were uncommon, with only two infectious events reported. Thus, DP can be a therapeutic option for EBV-HLH.
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Affiliation(s)
- Rintaro Ono
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
| | - Kenichi Sakamoto
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Takehiko Doi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Ryu Yanagisawa
- Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan
| | - Akira Morimoto
- Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan
- Department of Pediatrics, Showa Inan General Hospital, Komagane, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yoko Shioda
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
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Henter JI, von Bahr Greenwood T. Etoposide Therapy of Cytokine Storm Syndromes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:525-551. [PMID: 39117837 DOI: 10.1007/978-3-031-59815-9_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.
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Affiliation(s)
- Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital Solna, Stockholm, Sweden.
| | - Tatiana von Bahr Greenwood
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital Solna, Stockholm, Sweden
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Benevenuta C, Mussinatto I, Orsi C, Timeus FS. Secondary hemophagocytic lymphohistiocytosis in children (Review). Exp Ther Med 2023; 26:423. [PMID: 37602304 PMCID: PMC10433411 DOI: 10.3892/etm.2023.12122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 06/16/2023] [Indexed: 08/22/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by hyperinflammation in an uncontrolled and ineffective immune response. Despite great improvement in diagnosis and treatment, it still represents a challenge in clinical management, with poor prognosis in the absence of an aggressive therapeutic approach. The present literature review focuses on secondary HLH at pediatric age, which represents a heterogeneous group in terms of etiology and therapeutic approach. It summarizes the most recent evidence on epidemiology, pathophysiology, diagnosis, treatment and prognosis, and provides a detailed description and comparison of the major subtypes of secondary HLH. Finally, it addresses the open questions with a focus on diagnosis and new treatment insights.
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Affiliation(s)
- Chiara Benevenuta
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Ilaria Mussinatto
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Cecilia Orsi
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Fabio S. Timeus
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
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Sakaguchi M, Nagata Y, Terasaki Y, Takeyoshi A, Yasuda S, Honma S, Kinoshita R, Marumo A, Asayama T, Yui S, Wakita S, Okamoto M, Kajimoto Y, Inokuchi K, Yamaguchi H. Epstein-Barr Virus-Related Hemophagocytic Lymphohistiocytosis with Central Nervous System Symptoms. J NIPPON MED SCH 2023; 90:126-135. [PMID: 36436914 DOI: 10.1272/jnms.jnms.2023_90-105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) involves pathological histiocytes and phagocytosis of normal blood cells through activation of inflammatory cytokines. We report a case of Epstein-Barr virus-HLH in a 75-year-old woman who presented with fever, thrombocytopenia, and loss of consciousness. Epstein-Barr virus-HLH was diagnosed after we identified massive hemophagocytosis in bone marrow and Epstein-Barr virus DNA in cerebrospinal fluid. The HLH-2004 protocol was applied, and lactate dehydrogenase levels-which reflect HLH disease status-decreased. However, persistent loss of consciousness and multiple organ failure led to the patient's death on day 18. Most cases of primary and secondary HLH involve pediatric patients; adult cases are rare. Few cases of central nervous system involvement in older adults have been reported. Therefore, accumulation of more data will help in developing better treatment strategies.
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Affiliation(s)
| | | | - Yasuhiro Terasaki
- Department of Analytic Human Pathology, Nippon Medical School.,Division of Pathology, Nippon Medical School Hospital
| | | | | | | | | | | | | | | | | | | | - Yusuke Kajimoto
- Department of Analytic Human Pathology, Nippon Medical School
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Cui T, Wang J, Wang Z. The Outcome of Induction Therapy for EBV-Related Hemophagocytic Lymphohistiocytosis: A Model for Risk Stratification. Front Immunol 2022; 13:876415. [PMID: 35860246 PMCID: PMC9289144 DOI: 10.3389/fimmu.2022.876415] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundEpstein–Barr virus (EBV)–related hemophagocytic lymphohistiocytosis (HLH) is an abnormal inflammation caused by EBV infection, which has high mortality during induction therapy.ObjectivesThis study is aimed to build a model to predict the risk of death during induction therapy.MethodsThe patients with EBV-HLH admitted from January 2015 to December 2018 were retrospectively reviewed. The primary outcome was death during induction therapy. The interval from receiving therapy to death or the end of induction therapy was the observing time. The patients admitted from January 2015 to December 2017 were assigned to the primary group, and the patients admitted from January to December 2018 were assigned to the validation group.ResultsWe included 234 patients with EBV-HLH, of whom 65 (27.4%) died during induction therapy. The middle observing time was 25 days. On the basis of the primary group, the multivariate Cox analysis demonstrated age >18 years, blood urea nitrogen, procalcitonin >2 µg/L, serum CD25, and EBV-DNA in peripheral blood mononuclear cell as the risk factors of death during induction therapy. We developed a nomogram integrating the above factors with high predictive accuracy (c-statistic, 0.86) and stratified all patients into the high-risk and the low-risk groups. On the basis of the validation group, the high-risk patients had a higher risk of death (hazard ratio, 4.93; P = 0.012). In the subgroup analysis based on patients receiving etoposide-based strategy, the mortality in high-risk and low-risk patients was 43.9 and 3.1 per 100 person-weeks, respectively.ConclusionWe developed a nomogram for risk stratification of patients with EBV-HLH receiving induction therapy.
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Ono R, Sakamoto K, Doi T, Yanagisawa R, Tamura A, Hashimoto H, Kanegane H, Ishii E, Nakazawa Y, Shioda Y. A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial. Int J Hematol 2022; 116:434-441. [PMID: 35524025 DOI: 10.1007/s12185-022-03357-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/14/2022] [Accepted: 04/14/2022] [Indexed: 11/24/2022]
Abstract
Although clinical trials have reported an improvement in the prognosis of hemophagocytic lymphohistiocytosis (HLH), current treatment outcomes are unsatisfactory, especially in severe cases. Most clinical trial patients with severe disease discontinue participation due to complications associated with HLH or treatment-related toxicity. A retrospective survey of patients who discontinued participation in the JPLSG HLH-2004 clinical trial was conducted to review the detailed course of these cases to optimize HLH treatment and supportive care. Findings in these patients were compared with those of 45 patients who completed the protocol treatment. The 3 year overall survival rate of patients who completed treatment was 86.7%, versus 50.7% for those who did not complete treatment. Incidence of serious adverse events, such as infections, coagulopathy, and posterior reversible encephalopathy syndrome, during the initial 8 weeks of treatment was much higher in patients who did not complete treatment than in patients who completed treatment. To improve overall outcomes of patients with HLH, it is important to not only optimize HLH-directed therapy but also provide appropriate supportive care.
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Affiliation(s)
- Rintaro Ono
- Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan
| | - Kenichi Sakamoto
- Department of Pediatrics, Shiga University of Medical Science, Seta Tsukinowa-Cho, Otsu, Japan.
| | - Takehiko Doi
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Ryu Yanagisawa
- Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan
| | - Akihiro Tamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroya Hashimoto
- Core Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Imabari City Hospital, Ehime, Japan
| | - Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yoko Shioda
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
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Xu L, Guo X, Guan H. Serious consequences of Epstein-Barr virus infection: Hemophagocytic lymphohistocytosis. Int J Lab Hematol 2021; 44:74-81. [PMID: 34709704 DOI: 10.1111/ijlh.13736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 09/24/2021] [Accepted: 09/29/2021] [Indexed: 12/23/2022]
Abstract
Human is the host of the Epstein-Barr virus (EBV) especially in childhood and adolescence. Most of them are asymptomatic infection and self-limiting. However, for those patients who suffer from immune dysfunction, EBV infection will be life-threatening. Epstein-Barr virus-associated hemophagocytic lymphohistocytosis (EBV-HLH) is one of the severe effects. The diagnosis and differential diagnosis of EBV-HLH and other EBV infectious diseases are mentioned in this paper. The molecular biology mechanism and complications of EBV-HLH are equally briefly presented. It also provides a practical method for the genetic diagnosis of such diseases and the differential diagnosis with other human immunodeficiency diseases for medical scientists in routine clinical practice.
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Affiliation(s)
- Lingyue Xu
- Department of Clinical Hematology, Qingdao University School of Medicine, Qingdao, China
| | - Xiaofang Guo
- Department of Clinical Hematology, Qingdao University School of Medicine, Qingdao, China
| | - Hongzai Guan
- Department of Clinical Hematology, Qingdao University School of Medicine, Qingdao, China
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Imashuku S, Morimoto A, Ishii E. Virus-triggered secondary hemophagocytic lymphohistiocytosis. Acta Paediatr 2021; 110:2729-2736. [PMID: 34096649 DOI: 10.1111/apa.15973] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/18/2021] [Accepted: 06/04/2021] [Indexed: 12/16/2022]
Abstract
Primary (familial/hereditary) and secondary (non-familial/hereditary) hemophagocytic lymphohistiocytosis (HLH) are hyperinflammatory and hypercytokinemic syndromes. Secondary HLH includes infection- (eg viral/bacterial/fungal/parasitic) and non-infection- (eg collagen disease or malignancy) related diseases. Viral HLH is the major type among all age groups. Secondary viral HLH and primary HLH must be differentiated carefully because primary HLH can be associated with viral infection(s), and the outcome is dismal without a timely diagnosis and hematopoietic stem cell transplantation (HSCT). Epstein-Barr virus (EBV)-related HLH (EBV-HLH) is the most common type of viral HLH in childhood. For non-EBV-HLH, appropriate treatment of viral infection, followed by immunomodulatory agent(s) such as corticosteroids, intravenous immunoglobulin or cyclosporine A, is usually successful; however, recent SARS-CoV-2-related HLH may become life-threatening. EBV-HLH may occur heterogeneously associated with the primary infection, with chronic active EBV infection or with underlying primary HLH. Although immunomodulatory agent(s) are effective in the majority of EBV-HLH cases, management differs from that of non-EBV-HLH because severe and refractory cases may require etoposide-containing HLH-1994/2004 regimens or other experimental agents. The novel agent, emapalumab (an anti-IFN-γ monoclonal antibody) can be used to treat EBV-HLH cases to avoid the risk of secondary malignancy due to etoposide. Finally, HSCT is required for refractory EBV-HLH cases and can also be curative in some other cases.
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Affiliation(s)
- Shinsaku Imashuku
- Department of Laboratory Medicine Uji‐Tokushukai Medical Center Uji Kyoto Japan
| | - Akira Morimoto
- Department of Pediatrics Jichi Medical University School of Medicine Shimotsuke, Tochigi Japan
| | - Eiichi Ishii
- Director Imabari City Hospital Imabari, Ehime Japan
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Meng GQ, Wang JS, Wang YN, Wei N, Wang Z. Rituximab-containing immuno-chemotherapy regimens are effective for the elimination of EBV for EBV-HLH with only and mainly B lymphocytes of EBV infection. Int Immunopharmacol 2021; 96:107606. [PMID: 33826999 DOI: 10.1016/j.intimp.2021.107606] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/16/2021] [Accepted: 03/19/2021] [Indexed: 11/27/2022]
Abstract
Patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) have a poor prognosis. This study investigated the efficacy of rituximab-containing immuno-chemotherapy regimens for EBV-HLH. In this study, 15 patients were treated with rituximab-containing regimens. The treatment efficacy and adverse events were evaluated. In 10 patients, EBV DNA became negative after the first course of treatment. The lymphocyte types infected by EBV in the 10 patients were only infected with B cells and mainly infected with B cells. In the other 5 patients, the EBV DNA of peripheral blood mononuclear cells (PBMC) before and after treatment with the regimens had no statistical difference (P = 0.111). In addition, in these 5 patients, EBV mainly infected T and NK cells. Among the 5 patients without a significant decline in EBV DNA of PBMC, 2 patients received allogeneic hematopoietic stem cell transplantation and turned negative for EBV DNA. This study suggests that rituximab-containing regimens are effective therapy for EBV-HLH with only and mainly B lymphocytes infected by EBV, especially for eliminating EBV.
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Affiliation(s)
- Guang-Qiang Meng
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| | - Jing-Shi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| | - Yi-Ni Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| | - Na Wei
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
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Opoka-Winiarska V, Grywalska E, Roliński J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BMC Med 2020; 18:214. [PMID: 32664932 PMCID: PMC7360379 DOI: 10.1186/s12916-020-01682-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/25/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly presents as fever, cough, dyspnea, and myalgia or fatigue. Although the majority of patients with COVID-19 have mild symptoms, some are more prone to serious outcomes, including pneumonia, acute respiratory distress syndrome (ARDS), and even death. Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening inflammatory syndrome associated with intense cytokine release (also known as a "cytokine storm"). Similar to COVID-19, HLH is characterized by aggressive course leading to multi-organ failure. MAIN TEXT The purpose of this review article is to draw attention to the possibility of the complication of HLH in patients with the severe course of COVID-19. Indeed, some of the clinical characteristics observed in the more severe cases of COVID-19 are reminiscent of secondary HLH (which can be triggered by infections, malignancies, rheumatological diseases, or autoimmune/immunodeficiency conditions). The pathogenesis of SARS-CoV-2 infection also suggests that HLH or a similar hyperinflammatory syndrome is the cause of the severe course of the infection. CONCLUSION The pathogenesis and clinical symptoms of severe COVID-19 indicate that an increased inflammatory response corresponding to HLH is occurring. Therefore, patients with severe COVID-19 should be screened for hyperinflammation using standard laboratory tests to identify those for whom immunosuppressive therapy may improve outcomes.
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Affiliation(s)
- Violetta Opoka-Winiarska
- Department of Paediatric Pulmonology and Rheumatology, Medical University of Lublin, Gębali 6, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland
- Department of Clinical Immunology, St. John’s Cancer Hospital, K. Jaczewskiego 7 St, 20–090 Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland
- Department of Clinical Immunology, St. John’s Cancer Hospital, K. Jaczewskiego 7 St, 20–090 Lublin, Poland
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Zhao Y, Li Z, Zhang L, Lian H, Ma H, Wang D, Zhao X, Zhang Q, Wang T, Zhang R. L‐DEP regimen salvage therapy for paediatric patients with refractory Epstein‐Barr virus‐associated haemophagocytic lymphohistiocytosis. Br J Haematol 2020; 191:453-459. [DOI: 10.1111/bjh.16861] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Accepted: 05/16/2020] [Indexed: 11/30/2022]
Affiliation(s)
- Yunze Zhao
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Zhigang Li
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Li Zhang
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Hongyun Lian
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Honghao Ma
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Dong Wang
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Xiaoxi Zhao
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Qing Zhang
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Tianyou Wang
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
| | - Rui Zhang
- Beijing Key Laboratory of Paediatric Haematology Oncology National Key Discipline of Paediatrics (Capital Medical University) Key Laboratory of Major Diseases in Children, Ministry of Education Haematology Oncology Center Beijing Children’s HospitalCapital Medical UniversityNational Center for Children’s Health Beijing China
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Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, Hines M, Eckstein O, Ladisch S, Nichols KE, Rodriguez-Galindo C, Wistinghausen B, McClain KL. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer 2019; 66:e27929. [PMID: 31339233 PMCID: PMC7340087 DOI: 10.1002/pbc.27929] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/10/2019] [Accepted: 06/28/2019] [Indexed: 12/15/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.
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Affiliation(s)
- Michael B. Jordan
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Carl E. Allen
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Jay Greenberg
- Division of Hematology, Children’s National Medical Center, Washington, DC
| | - Michael Henry
- Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, University of Arizona College of Medicine, Tucson, Arizona
| | - Michelle L. Hermiston
- Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, California
| | - Ashish Kumar
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Melissa Hines
- Division of Critical Care, Department of Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, Tennessee
| | - Olive Eckstein
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Stephan Ladisch
- Center for Cancer and Immunology Research, Children’s National Medical Center and George Washington University School of Medicine, Washington, DC
| | - Kim E. Nichols
- Division of Cancer Predisposition, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Carlos Rodriguez-Galindo
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Birte Wistinghausen
- Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Health System, Washington, DC
| | - Kenneth L. McClain
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Additional corresponding author, Kenneth L. McClain, 6701 Fannin St. Suite 1510, Houston, TX 77030,
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Song Y, Wang Y, Wang Z. Requirement for etoposide in the initial treatment of Epstein‐Barr virus–associated haemophagocytic lymphohistiocytosis. Br J Haematol 2019; 186:717-723. [PMID: 31115044 DOI: 10.1111/bjh.15988] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/25/2019] [Indexed: 01/25/2023]
Affiliation(s)
- Yue Song
- Department of Haematology Beijing Friendship Hospital Capital Medical University Beijing China
| | - Yini Wang
- Department of Haematology Beijing Friendship Hospital Capital Medical University Beijing China
| | - Zhao Wang
- Department of Haematology Beijing Friendship Hospital Capital Medical University Beijing China
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14
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Yanagaisawa R, Matsuda K, Ohga S, Kanegane H, Morimoto A, Okamoto Y, Ohara A, Fukushima K, Sotomatsu M, Nomura K, Saito AM, Horibe K, Ishii E, Nakazawa Y. Factors predicting the recurrence of Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis in children after treatment using the HLH-2004 protocol. Int J Hematol 2019; 109:612-617. [DOI: 10.1007/s12185-019-02612-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 02/05/2019] [Accepted: 02/05/2019] [Indexed: 12/13/2022]
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15
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Yoon JH, Park SS, Jeon YW, Lee SE, Cho BS, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Lee JW. Treatment outcomes and prognostic factors in adult patients with secondary hemophagocytic lymphohistiocytosis not associated with malignancy. Haematologica 2019; 104:269-276. [PMID: 30213834 PMCID: PMC6355492 DOI: 10.3324/haematol.2018.198655] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 09/11/2018] [Indexed: 11/09/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis is an overwhelming systemic inflammatory process that is life-threatening if not treated appropriately. We analyzed prognostic factors in patients with secondary hemophagocytic lymphohistiocytosis excluding malignancy. In this retrospective study, we analyzed 126 adult cases between 2001 and 2017. Treatment was based on dexamethasone with or without etoposide and cyclosporine. Patients who achieved a complete response by 4 weeks were defined as early stable responders, those who failed to achieve a complete response but showed continuous improvement until 8 weeks were defined as late responders, and those whose conditions waxed and waned until 8 weeks were defined as unstable responders. Patients with hemophagocytic lymphohistiocytosis caused by Epstein-Barr virus had a worse 5-year overall survival compared to those whose disease was secondary to autoimmune disease, other infections, or unknown causes (25.1% versus 82.4%, 78.7% and 55.5%, respectively; P<0.001). We observed that the overall response rate at 4 weeks was similar, but decreased at 8 weeks in the Epstein-Barr virus subgroup from 75.5% to 51.0%, and finally decreased to 30.6%. Multivariate analysis revealed that 8-week treatment response was the most relevant factor for overall survival. Excluding 8-week response, the presence of Epstein-Barr virus, old age, hyperferritinemia, and thrombocytopenia were associated with poor survival. We established a prognostic model with the parameters: low-risk (score 0-1), intermediate-risk (score 2), and high-risk (score ≥3). These groups had 5-year overall survival rates of 92.1%, 36.8%, and 18.0%, respectively (P<0.001). We found that 8-week treatment response was a good predictor for overall survival, and that Epstein-Barr virus, old age, thrombocytopenia, and hyperferritinemia were associated with poor survival outcomes. Physicians should take care to identify high-risk patients for appropriate treatment strategies.
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Affiliation(s)
- Jae-Ho Yoon
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Soo Park
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Young-Woo Jeon
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung-Eun Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Byung-Sik Cho
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ki-Seong Eom
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yoo-Jin Kim
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Hee-Je Kim
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang-Ki Min
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seok-Goo Cho
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong Wook Lee
- Department of Hematology, Catholic Blood and Marrow Transplantation Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Yanagisawa R, Nakazawa Y, Matsuda K, Yasumi T, Kanegane H, Ohga S, Morimoto A, Hashii Y, Imaizumi M, Okamoto Y, Saito AM, Horibe K, Ishii E. Outcomes in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan. Int J Hematol 2018; 109:206-213. [PMID: 30535855 DOI: 10.1007/s12185-018-02572-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/26/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.
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Affiliation(s)
- Ryu Yanagisawa
- Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Kazuyuki Matsuda
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Takahiro Yasumi
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Morimoto
- Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Yoshiko Hashii
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masue Imaizumi
- Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan
| | - Yasuhiro Okamoto
- Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akiko M Saito
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Keizo Horibe
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan
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Eguchi K, Ishimura M, Sonoda M, Ono H, Shiraishi A, Kanno S, Koga Y, Takada H, Ohga S. Nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis in MonoMAC syndrome. Pediatr Blood Cancer 2018; 65:e27017. [PMID: 29493060 DOI: 10.1002/pbc.27017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/24/2018] [Accepted: 01/24/2018] [Indexed: 01/17/2023]
Affiliation(s)
- Katsuhide Eguchi
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masataka Ishimura
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoshi Sonoda
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroaki Ono
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Shiraishi
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shunsuke Kanno
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuhki Koga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hidetoshi Takada
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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18
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Lai W, Wang Y, Wang J, Wu L, Jin Z, Wang Z. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents-a life-threatening disease: analysis of 133 cases from a single center. ACTA ACUST UNITED AC 2018; 23:810-816. [PMID: 29957156 DOI: 10.1080/10245332.2018.1491093] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis is the most common type of infection-associated HLH. Previous studies were focused on pediatric EBV-HLH patients, therefore there lack of adult data. METHOD We performed a retrospective analysis of 133 EBV-HLH patients (≥14 years old) in Beijing Friendship Hospital from March 2009 to April 2016 to evaluate the clinical manifestation and the effects and prognosis of existing regimens of EBV-HLH in adult and adolescents. RESULTS Of these patients, 91 male and 42 female cases had a median age of 26 (14-77) years. EBV-DNA load on admission was at a median of 6.6E + 05 IU/ml. The one-year mortality of these patients was 78%. 112 patients received the HLH-94/04 regimen as the initial treatment, 52 patients (46.43%) had response. Of the 6 patients who received the L-DEP regimen as the initial treatment, 5 patients (83.33%) had response. The rest 15 patients received initial treatment without etoposide, 5 cases achieved PR. 69 refractory or relapsed patients received DEP or L-DEP regimen, 55 (79.71%) cases had response. In addition, who received the L-DEP regimen, with the overall response rate significantly higher than the DEP regimen (88.37% VS 65.38%, P = 0.031). 36 out of 133 EBV-HLH patients eventually received allo-HSCT, with the overall survival rate of 52.78%. In summary, EBV-HLH is a highly lethal disease. CONCLUSION DEP/L-DEP was a good salvage treatment. L-DEP might be a more effective first-line initial regimen than HLH-94/04 regimen for EBV-HLH. Finally, allo-HSCT is an effective radical treatment for EBV-HLH.
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Affiliation(s)
- Wenyuan Lai
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
| | - Yini Wang
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
| | - Jingshi Wang
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
| | - Lin Wu
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
| | - Zhili Jin
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
| | - Zhao Wang
- a Department of Hematology , Beijing Friendship Hospital, Capital Medical University , Beijing , People's Republic of China
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19
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Sawada A, Inoue M. Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders. Front Pediatr 2018; 6:334. [PMID: 30460216 PMCID: PMC6232123 DOI: 10.3389/fped.2018.00334] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/16/2018] [Indexed: 12/19/2022] Open
Abstract
Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy), and step 3 (allogeneic hematopoietic stem cell transplantation; HSCT) for CAEBV and its related diseases. Allogeneic HSCT is the only cure for CAEBV with few exceptions. Primary-EBV infection-associated hemophagocytic lymphohistiocytosis (primary-EBV HLH) is also an EBV+ T/NK-cell lymphoproliferation. The nature of EBV+ T/NK cells in CAEBV and those in primary-EBV HLH differ. In primary-EBV HLH, most patients need step 1 only and some require step 2 for the successful induction of apoptosis in EBV-infected T cells; however, some exceptional patients require HSCT. We herein present our single institutional experience of CAEBV and primary-EBV HLH, together with that of post-transplant EBV+ T/NK-cell lymphoproliferative disease. We also discuss some practical points on HCST with a review of the literature.
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Affiliation(s)
- Akihisa Sawada
- Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan
| | - Masami Inoue
- Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan
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20
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Lin M, Park S, Hayden A, Giustini D, Trinkaus M, Pudek M, Mattman A, Schneider M, Chen LYC. Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review. Ann Hematol 2017; 96:1241-1251. [PMID: 28497365 DOI: 10.1007/s00277-017-2993-y] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/11/2017] [Indexed: 12/22/2022]
Abstract
The serum-soluble interleukin-2 receptor (sIL-2r) level is considered an important diagnostic test and disease marker in hemophagocytic syndromes/hemophagocytic lymphohistiocytosis (HPS/HLH). However, this cytokine receptor is rarely measured in clinical practice and has been excluded from recent diagnostic/classification criteria such as the HScore and macrophage activation syndrome (MAS) 16. We performed a systematic scoping review of 64 articles (1975-2016) examining the clinical utility of sIL-2r in HPS/HLH. Twenty-two articles describe sIL-2r as a sensitive diagnostic marker for HLH, but only three distinct datasets actually address sensitivity. The original HLH-2004 Guidelines reported sensitivity of 93% and specificity of 100% for sIL-2r ≥ 2400, based on a pediatric dataset (n = 152) which is published for the first time in this review. Two pediatric studies reported sensitivity of 89% for sIL-2r ≥ 2400 in diagnosis of MAS complicating juvenile idiopathic arthritis (JIA) (n = 27) and 88% for secondary HLH in acute liver failure (n = 9). Twenty articles described sIL-2r as a dynamic marker of disease activity that falls with response to treatment, and 15 described high initial sIL-2r levels >10,000 U/mL as a poor prognostic marker. The ability of sIL-2r to distinguish between subtypes of HPS/HLH was inconsistent. This review confirms the importance of soluble IL-2r as a diagnostic and disease marker in HPS/HLH, but also reveals the need for more primary data about its performance characteristics, particularly in adults. More emphasis should be made in including this simple, inexpensive test in clinical practice and studies of HPS/HLH.
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Affiliation(s)
- Molly Lin
- Division of Hematology, Department of Medicine, University of British Columbia, 2775 Laurel St, 10th Floor Room 10245, Vancouver, BC, V5Z 1M9, Canada
| | - Sujin Park
- Division of Hematology, Department of Medicine, University of British Columbia, 2775 Laurel St, 10th Floor Room 10245, Vancouver, BC, V5Z 1M9, Canada
| | - Anna Hayden
- Division of Hematology, Department of Medicine, University of British Columbia, 2775 Laurel St, 10th Floor Room 10245, Vancouver, BC, V5Z 1M9, Canada
| | - Dean Giustini
- Biomedical Branch Library, University of British Columbia, Vancouver, Canada
| | - Martina Trinkaus
- Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
| | - Morris Pudek
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
| | - Andre Mattman
- Adult Metabolic Disease Clinic, Vancouver General Hospital, Vancouver, Canada
| | - Marion Schneider
- Division of Experimental Anesthesiology, University Hospital Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany
| | - Luke Y C Chen
- Division of Hematology, Department of Medicine, University of British Columbia, 2775 Laurel St, 10th Floor Room 10245, Vancouver, BC, V5Z 1M9, Canada.
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Wang J, Wang Y, Wu L, Zhang J, Lai W, Wang Z. PEG-aspargase and DEP regimen combination therapy for refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Hematol Oncol 2016; 9:84. [PMID: 27613189 PMCID: PMC5017041 DOI: 10.1186/s13045-016-0317-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 09/03/2016] [Indexed: 12/15/2022] Open
Abstract
Background Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH. Methods In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment. Results Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 105 (1.5 × 104 − 1 × 109) copies/mL and 2.2 × 105 (3.8 × 102 − 1.2 × 107) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment (P = 0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders. Conclusions This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).
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Affiliation(s)
- Jingshi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yini Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lin Wu
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jia Zhang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wenyuan Lai
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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22
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Morimoto A, Nakazawa Y, Ishii E. Hemophagocytic lymphohistiocytosis: Pathogenesis, diagnosis, and management. Pediatr Int 2016; 58:817-25. [PMID: 27289085 DOI: 10.1111/ped.13064] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 06/03/2016] [Accepted: 06/09/2016] [Indexed: 12/14/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is classified into primary and secondary HLH. Primary HLH consists of monogenic disorders that mainly affect the perforin-mediated cytotoxicity of cytotoxic T lymphocytes and natural killer cells. Secondary HLH occurs as a complication in various settings such as infection, malignancy, autoimmune disease, and post-allogeneic hematopoietic stem cell transplantation. Both primary and secondary HLH are characterized by uncontrolled hypercytokinemia that results in myelosuppression and vascular endothelium damage. More than 10% of patients with HLH die within 2 months of diagnosis due to bleeding in the visceral organs, opportunistic infection due to neutropenia, or multiple organ failure. The most obvious presentations of HLH are persistent fever refractory to antimicrobial agents and hyperferritinemia due to hypersecretion of various cytokines. The first rule is not to overlook signs of hypercytokinemia and to settle the hyperactivated immunological state as soon as possible. In addition, to improve outcome, it is essential to identify the disorders underlying HLH and provide disorder-appropriate treatment.
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Affiliation(s)
- Akira Morimoto
- Department of Pediatrics, Jichi Medical University of Medicine, Shimotsuke, Tochigi, Japan.
| | - Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan
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23
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Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis: Study protocol of a prospective pilot study. World J Hematol 2015; 4:69-75. [DOI: 10.5315/wjh.v4.i4.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/06/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
In this manuscript, a number of debatable issues related to the diagnosis and treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) will be addressed. Considering the heterogeneous nature of EBV-HLH, diagnostic efforts are required to clarify the precise nature of the disease at diagnosis, the number of EBV genome copies in peripheral blood, and localization of the EBV genome in lymphoid cells (B, T, or natural killer cells). Although the majority of cases of EBV-HLH develop without evidence of immunodeficiency, some cases have been found to be associated with chronic active EBV infection, genetic diseases such as X-linked lymphoproliferative disease (XLP, type 1, or type 2), or familial HLH (FHL, types 2-5). Due to such background heterogeneity, the therapeutic results of EBV-HLH have also been found to vary. Patients have been found to respond to corticosteroids alone or an etoposide-containing regimen, whereas other patients require hematopoietic stem cell transplantation. Thus, decision-making for optimal treatment of EBV-HLH and its eventual outcome requires evaluation in consideration of the precise nature of the disease. A protocol for a pilot study on the treatment of patients with EBV-HLH is presented here.
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Abstract
Half a century has passed since Epstein-Barr virus (EBV) particles were isolated from the cultured lymphoblasts of Burkitt lymphoma. During the period, molecular biology, hematology/immunology, and transplantation medicine made amazing progress, that clarified the mode of infection and pathophysiology of the virus in human diseases. Research strategies on the relationship between EBV and human have expanded to the epidemiology, structures and functions of both genomes, regulatory genes including microRNA, and the nature of epigenetics. Although no animal models of EBV infection long hampered the completion of in vivo experiments, humanized mice have broken through a barrier of in vitro study on EBV-infected cell lines. Our understanding of the life cycle of EBV has continued to deepen about the infection via the CD21 receptor expressed on B cells, the latency, reactivation/reinfection, and transformation, and also the dynamics of T-cell immune response and the intracellular immunosurveillance beyond acquired and innate immunity. On the other hand, the disease entity of life-threatening lymphoproliferative disease of EBV-infected T cells or NK cells is on controversial. The other parts of this special issue include the recent topics of the basic and clinical researches of EBV as the oncogenic virus. Then, we herewith overview the research history of EBV with special reference to the infected cells and host immune responses in EBV-associated diseases.
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25
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Domínguez-Pinilla N, Baro-Fernández M, González-Granado LI. Hemophagocytic lymphohistiocytosis secondary to Epstein Barr virus and Leishmania co-infection in a toddler. J Postgrad Med 2015; 61:44-45. [PMID: 25511219 PMCID: PMC4944368 DOI: 10.4103/0022-3859.147052] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 02/13/2014] [Accepted: 04/07/2014] [Indexed: 11/06/2022] Open
Abstract
This is the report of an EBV+Leishmanial co-infection. The patient developed hemophagocytic syndrome (HLH) and was treated with the standard HLH-2004 protocol. However, PCR in bone marrow discovered this secondary cause for HLH. In endemic countries, visceral leishmaniasis should be considered in the differential diagnosis even in EBV-related HLH, as chemotherapy toxicity may be avoided.
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Affiliation(s)
- N Domínguez-Pinilla
- Department of Pediatrics, Hematology and Oncology Unit. Hospital Universitario “12 de Octubre”, Carretera Andalucia km 5,400, Postal code 28041, Madrid, Spain
| | - M Baro-Fernández
- Department of Pediatrics, Hematology and Oncology Unit. Hospital Universitario “12 de Octubre”, Carretera Andalucia km 5,400, Postal code 28041, Madrid, Spain
| | - LI González-Granado
- Department of Pediatrics, Hematology and Oncology Unit. Hospital Universitario “12 de Octubre”, Carretera Andalucia km 5,400, Postal code 28041, Madrid, Spain
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Síndrome de ativação macrofágica em paciente com artrite idiopática juvenil sistêmica. REVISTA BRASILEIRA DE REUMATOLOGIA 2015; 55:79-82. [DOI: 10.1016/j.rbr.2014.02.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Revised: 01/05/2014] [Accepted: 02/10/2014] [Indexed: 11/22/2022] Open
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Imashuku S. Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment. World J Hematol 2014; 3:71-84. [DOI: 10.5315/wjh.v3.i3.71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Revised: 05/09/2014] [Accepted: 06/18/2014] [Indexed: 02/05/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that develops as a primary (familial/hereditary) or secondary (non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell (CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH (familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of (signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome (XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis (e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease (especially EBV-HLH).
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Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, Nichols KE. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol 2013; 162:376-82. [PMID: 23692048 DOI: 10.1111/bjh.12386] [Citation(s) in RCA: 150] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2013] [Accepted: 03/20/2013] [Indexed: 12/13/2022]
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a life threatening complication of Epstein-Barr virus (EBV) infection. The anti-CD20 antibody rituximab depletes B cells, leading to improved outcomes for patients with EBV-associated B-lymphoproliferative disorders. To gather data on the use of rituximab in EBV-HLH, we performed a retrospective investigation involving 42 EBV-HLH patients who had received treatment with rituximab-containing regimens. On average, patients received 3 rituximab infusions (range 1-10) at a median dose of 375 mg/m(2) . In all patients, rituximab was administered with other HLH-directed medications, including steroids, etoposide and/or ciclosporin. Rituximab-containing regimens appeared well tolerated and improved clinical status in 43% of patients. Examination of laboratory data obtained prior to and within 2-4 weeks after the first rituximab dose revealed significant reductions in EBV load (median load pre-rituximab: 114,200 copies/ml, median post-rituximab: 225 copies/ml, P = 0.0001) and serum ferritin levels (median ferritin pre-rituximab: 4260 μg/l, median post-rituximab: 1149 μg/l, P = 0.001). Thus, when combined with conventional HLH-directed therapies, rituximab improves symptoms, reduces viral load and diminishes inflammation. These data support the incorporation of rituximab into future prospective clinical trials for patients with EBV-HLH.
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