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1
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Fan F, Liu J, Liu S, Xu Y, Wang X, Yan Y, Zhang Z. Advances in diagnosis and treatment of lymphoma-associated hemophagocytic syndrome. Am J Transl Res 2025; 17:1604-1612. [PMID: 40225971 PMCID: PMC11982887 DOI: 10.62347/tvtb3045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Accepted: 01/13/2025] [Indexed: 04/15/2025]
Abstract
Hemophagocytic syndrome (HPS) is a rare clinical disorder characterized by persistent and ineffective activation of the immune system, leading to a severe systemic inflammatory response. Lymphoma-associated hemophagocytic syndrome (LAHS) refers to HPS caused either by lymphoma itself or by immunosuppression during lymphoma chemotherapy at present, there is no standardized consensus on the diagnosis and treatment of LAHS, both domestically and internationally. After remission induced by combination chemotherapy, hematopoietic stem cell transplantation (HSCT) is a commonly used treatment approach. This paper reviews the latest advancements in the diagnosis and treatment of LAHS, providing a reference for its clinical management.
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Affiliation(s)
- Fuli Fan
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Jian Liu
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Shanshan Liu
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Yujie Xu
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Xiaolin Wang
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Yuting Yan
- Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao UniversityQingdao 266000, Shandong, China
| | - Zhiqun Zhang
- Department of Oncology, Tongliao People’s HospitalTongliao 028000, Inner Mongolia Autonomous Region, China
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Zhu W, Zhou F, Song Y, Zhou S, Du F, Zhu Q, Wang Z, Bai L, Fu J, Ma X, Wu X, He X. Low-dose emapalumab combined with chemotherapy for adult patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Transpl Immunol 2025; 88:102162. [PMID: 39719162 DOI: 10.1016/j.trim.2024.102162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 08/20/2024] [Accepted: 12/11/2024] [Indexed: 12/26/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder with poor clinical outcomes. Use of emapalumab, an IFN-γ inhibitor, enables primary HLH control in over 85 % of affected children. However, data on emapalumab use for Epstein-Barr virus-associated HLH (EBV-HLH) are limited. This report presents the cases of three patients with EBV-HLH, highlighting the successful integration of low-dose emapalumab in combination with chemotherapy as a novel therapeutic approach for patients diagnosed with EBV-HLH. This regimen resulted in rapid disease symptom control and hematological parameter improvement and facilitated successful stem cell transplantation. This report highlights the potential of low-dose emapalumab combined with chemotherapy as an effective bridging therapy to allogenic hematopoietic stem cell transplantation in EBV-HLH patients.
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Affiliation(s)
- Wenjuan Zhu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Fei Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Yue Song
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Shiyuan Zhou
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Feng Du
- Soochow Hopes Hematonosis Hospital, Suzhou 215000, China
| | - Qian Zhu
- Soochow Hopes Hematonosis Hospital, Suzhou 215000, China
| | - Ziyi Wang
- Soochow Hopes Hematonosis Hospital, Suzhou 215000, China
| | - Liyun Bai
- Soochow Hopes Hematonosis Hospital, Suzhou 215000, China
| | - Jianhong Fu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Xiao Ma
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China
| | - Xiaojin Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China.
| | - Xuefeng He
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215000, China.
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Wang W, Yuan X, Yu L, Pei F. Emapalumab as a therapeutic intervention for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: A case series. Medicine (Baltimore) 2024; 103:e39880. [PMID: 39331881 PMCID: PMC11441857 DOI: 10.1097/md.0000000000039880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/10/2024] [Indexed: 09/29/2024] Open
Abstract
RATIONALE Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is characterized by a severe cytokine storm, heightened inflammatory response, and immune-mediated damage to tissues and organs. Standard treatment protocols for hemophagocytic lymphohistiocytosis often fall short in effectively controlling EBV-HLH, leading to a need for novel therapeutic options. Emapalumab, a monoclonal antibody targeting interferon-gamma, has shown promise due to its targeted cytokine modulation capabilities and favorable safety profile. This study aimed to evaluate the efficacy and safety of emapalumab in pediatric patients with EBV-HLH. PATIENT CONCERNS The case series involved 4 pediatric patients diagnosed with EBV-HLH who did not achieve disease control despite receiving comprehensive treatment. DIAGNOSES All 4 pediatric patients were diagnosed with EBV-HLH. INTERVENTIONS Emapalumab was introduced as an adjunctive therapeutic intervention alongside the HLH-94 or L-DEP regimens for these patients. OUTCOMES Among the 4 patients, 1 experienced severe multiorgan dysfunction and opted to discontinue therapy. The remaining 3 patients showed controlled disease progression with significant clinical improvements following emapalumab administration. These improvements included reduced levels of inflammatory markers, normalization of blood counts and liver function, and decreased Epstein-Barr virus viral load. LESSONS The findings suggest that emapalumab may be an effective and safe treatment option for pediatric EBV-HLH. However, further research is necessary to confirm these outcomes, especially in critically ill patients.
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Affiliation(s)
- Wen Wang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao Yuan
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Li Yu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fuyu Pei
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Verbist K, Nichols KE. Cytokine Storm Syndromes Associated with Epstein-Barr Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:227-248. [PMID: 39117818 DOI: 10.1007/978-3-031-59815-9_16] [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
Epstein-Barr virus (EBV) is a ubiquitous and predominantly B cell tropic virus. One of the most common viruses to infect humans, EBV, is best known as the causative agent of infectious mononucleosis (IM). Although most people experience asymptomatic infection, EBV is a potent immune stimulus and as such it elicits robust proliferation and activation of the B-lymphocytes it infects as well as the immune cells that respond to infection. In certain individuals, such as those with inherited or acquired defects affecting the immune system, failure to properly control EBV leads to the accumulation of EBV-infected B cells and EBV-reactive immune cells, which together contribute to the development of often life-threatening cytokine storm syndromes (CSS). Here, we review the normal immune response to EBV and discuss several CSS associated with EBV, such as chronic active EBV infection, hemophagocytic lymphohistiocytosis, and post-transplant lymphoproliferative disorder. Given the critical role for cytokines in driving inflammation and contributing to disease pathogenesis, we also discuss how targeting specific cytokines provides a rational and potentially less toxic treatment for EBV-driven CSS.
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Affiliation(s)
- Katherine Verbist
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Kim E Nichols
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
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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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al Waseem SMH, Antony T, Suresh S, Gopalan S. Haemophagocytic lymphohistiocytosis due to Burkholderia pseudomallei in a primigravida. Access Microbiol 2023; 5:000520.v3. [PMID: 37841105 PMCID: PMC10569653 DOI: 10.1099/acmi.0.000520.v3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 08/30/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative, saprophytic bacillus, commonly found in soil or contaminated water. As infection with this bacterium produces a wide variety of clinical manifestations the organism is aptly called the 'great mimicker'. Even though it is non-fastidious and an easily cultivable organism, it can be misidentified in automated identification systems. Case report A 24-year-old primigravida presented with complaints of fever and myalgia of 45 days' duration. She was diagnosed to have haemophagocytic lymphohistiocytosis (HLH) based on clinical and laboratory parameters. Blood and bone marrow culture sent to the microbiology laboratory grew non-fermenting Gram-negative bacilli which were misidentified as Burkholderia cepacia by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology. It was subsequently identified as B. pseudomallei by 16S rRNA gene sequencing. The patient was commenced on intensive phase therapy with intravenous ceftazidime for 2 weeks, followed by maintenance therapy with oral trimethoprim and sulfamethoxazole for 3 months. In view of HLH, she was treated with intravenous dexamethasone for 2 weeks which was later switched to oral dexamethasone for a period of 6 weeks. She responded well to the treatment, but had to undergo medical termination of her pregnancy as there was severe intrauterine growth restriction of the fetus. Conclusion Prognosis of melioidosis is excellent if early diagnosis and appropriate antibiotic treatment is provided. In this era of automation, it is important to determine if the suspected pathogen is listed in the database of the automated identification system.
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Affiliation(s)
| | - Tessa Antony
- Department of Microbiology, Sri Ramachandra Medical College and Research Institute, Chennai, India
| | - Suchitra Suresh
- Past postgraduate, Department of Microbiology, Sri Ramachandra Medical College and Research Institute, Chennai, India
| | - Sowmya Gopalan
- Department of General Medicine, Sri Ramachandra Medical College and Research Institute, Chennai, India
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7
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Tejedor I, Tedbirt B, Carvalho P, Duval-Modeste AB, Joly P, Hébert V. Successful use of rituximab for refractory hemophagocytic lymphohistiocytosis in a melanoma patient treated with targeted therapy. Melanoma Res 2022; 32:485-487. [PMID: 36125885 DOI: 10.1097/cmr.0000000000000845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by aberrant immune hyperactivation of T CD8 lymphocytes and macrophages driven by cytokine dysfunction. We report a 64-year-old man, with advanced BRAF-mutant melanoma treated by combined targeted therapies who had a recalcitrant and cortico-dependent Epstein-Barr virus (EBV)-induced HLH. One rituximab cycle led to a rapid and prolonged HLH remission which allowed to switch the targeted therapy for immunotherapy rituximab thus makes it possible to limit the use of corticosteroids, which limits the effectiveness of immunotherapy. The patient finally died of a cerebral tumoral progression 2 years later. Despite secondary hypogammaglobulinemia, we did not observe any severe infections during this period. This case suggests that rituximab can be a valuable option for EBV-induced HLH to avoid the T-suppressive effects of high-dose of corticosteroids in immunotherapy-treated patients.
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Affiliation(s)
- Ines Tejedor
- Department of Dermatology, Rouen University Hospital, Rouen, France
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Qiu KY, Guo SY, Zeng YH, Liao XY, Lin SF, Fang JP, Zhou DH. Analysis of clinical characteristics and prognostic factors associated with EBV-associated HLH in children. HEMATOLOGY (AMSTERDAM, NETHERLANDS) 2022; 27:874-880. [PMID: 35950974 DOI: 10.1080/16078454.2022.2109328] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Purpose Our aim is to analyze the clinical characteristics and prognostic factors of Epstein-Barr (EB) virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children. Methods Children with newly diagnosed HLH were retrospectively analyzed. Results Finally, a total of 95 children with HLH were enrolled in this study, including 43 (45.3%) with EBV-HLH and 52 (54.7%) with non-EBV-HLH. Laboratory tests showed that the levels of absolute neutrophil count (ANC) decrease (P = 0.031) and triglycerides (TG) increase (P = 0.036) in the EBV-HLH group were statistically significant compared with those in the non-EBV-HLH group, respectively. We found that the remission rate during induction period in the EBV-HLH group and non-EBV-HLH group was 75.8% and 89.3%, respectively. The correlation analysis showed that the elevated degree of total bilirubin (TBIL) (P = 0.042), triglyceride (TG) (P = 0.009), serum ferritin (SF) (P = 0.008) and interleukin-8 (IL-8) (P = 0.004) were related with the remission rate during induction in the EBV-HLH group. Further univariate analysis showed that the elevated degree of TBIL (P = 0.048) and TG (P = 0.019) were significant risk factors for the remission rate during induction in the EBV-HLH group. In the multivariate analysis, we observed that there was statistical significance for the degree of TG elevation (P = 0.015) between the two groups. The correlation analysis showed that the elevated degree of TBIL (P = 0.030), the elevated degree of SF (P = 0.020) and the elevated degree of interleukin-6 (P = 0.010) were related to the induction mortality of children with EBV-HLH. Conclusion TBIL and TG are valid indicators to assess the efficacy and prognosis of EVBHLH among children in induction period.
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Affiliation(s)
- Kun-Yin Qiu
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Shu-Yi Guo
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Yang-Hui Zeng
- Shunde Woman & Children Hospital and Health Institute, Foshan, People's Republic of China
| | - Xiong-Yu Liao
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Shao-Fen Lin
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Jian-Pei Fang
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Dun-Hua Zhou
- Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China
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9
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Yang WC, Lin SF, Wu SC, Shu CW. Matrin3 (MATR3) Expression Is Associated with Hemophagocytosis. Biomedicines 2022; 10:biomedicines10092161. [PMID: 36140262 PMCID: PMC9495864 DOI: 10.3390/biomedicines10092161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/26/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by prolonged fever, cytopenia, hepatosplenomegaly, and hemophagocytosis. This occurs as a result of activated macrophages and impaired function of natural killer cells and/or cytotoxic T lymphocytes. The NF-κB pathway plays a crucial role in hyperinflammation. Matrin3 (MATR3) is a nuclear RNA/DNA-binding protein that plays multiple roles in the regulation of gene expression. We enroll 62 patients diagnosed with secondary HLH and hemophagocytosis. Peripheral blood (PB) from 25 patients and 30 healthy volunteers and good quality bone marrow (BM) samples from 47 patients are collected and used for analysis. Clinical parameters, including age, sex, etiology, ferritin, fibrinogen, triglyceride, and viral infection status, had no association with survival prediction. Patients with downregulation of NF-κB and MATR3mRNA expression in the BM had a higher mortality rate. MATR3mRNA expression in PB was lower in patients compared to that in healthy volunteers. We use shRNA-MATR3-KD-THP1 cells to determine the efficacy of phagocytosis. We note that shRNA-MATR3-KD-THP1 cells had a higher phagocytic effect on necrotic Jurkat E6 cells and carboxylate modified polystyrene latex beads. Herein, we provide evidence of a new marker for clinical translation that can serve as a potential treatment target for secondary HLH.
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Affiliation(s)
- Wen-Chi Yang
- Division of Hematology and Medical Oncology, Department of Internal Medicine, E-DA Hospital, Kaohsiung 824, Taiwan
- Faculty of School of Medicine, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan
- Correspondence: ; Tel.: +886-7-6151101 (ext. 5005); Fax: +886-7-3906595
| | - Sheng-Fung Lin
- Division of Hematology and Medical Oncology, Department of Internal Medicine, E-DA Hospital, Kaohsiung 824, Taiwan
| | - Shih-Chi Wu
- School of Medicine, China Medical University, Taichung 404, Taiwan
- Trauma and Emergency Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Chih-Wen Shu
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
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10
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Suolitiken D, Wang Y, Jin Z, Wang Z. EBV protection- and susceptibility-related HLA alleles and EBV status in the Chinese population: A single-center study. Immun Inflamm Dis 2022; 10:e666. [PMID: 35759244 PMCID: PMC9210551 DOI: 10.1002/iid3.666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Although most adults are infected by Epstein-Barr virus (EBV), some patients develop highly lethal diseases associated with EBV infection, including EBV-hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV infections (CAEBV), and lymphoma, the pathogeneses of which remain to be investigated. The human leukocyte antigen (HLA) complex may be associated with the viral infection pathway, and, therefore, HLA alleles may be associated with EBV-related diseases and subpopulations of infected cells, studies related to EBV-associated diseases, and subpopulations of infected cells that were conducted in China are scarce. METHODS In this study, we analyzed the high-resolution HLA genotypes of 269 patients with EBV-associated diseases and 213 EBV-seronegative hematopoietic stem cell donors using PCR-SBT assay and elucidated the associations of HLA-A, -B, -C, -DRB1, and -DQB1 alleles with EBV-associated diseases in the Chinese population, Benjamini-Hochberg correction to adjust for multiple testing. HLA genotypes were also analyzed in patients with EBV-associated diseases showing EBV-infected lymphocyte subpopulations. RESULTS We found that individuals carrying the following alleles showed the following levels of risks: HLA-DRB1*11 allele, reduced risk of EBV-related disease (OR [odds ratio]: 0.56; 95% confidence interval [95% CI]: 0.32-0.99; p < .05; Adjust p = .71); HLA-DQB1*06:02 allele, reduced risk (OR: 0.5699; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57); and HLA-B*15:01 allele, increased risk (OR: 1.763; 95% CI: 0.3486-0.9317; p < .05; Adjust p = .57). Patients with EBV-associated diseases showing the B*15:01 genotype had a higher risk of T-cell, NK-cell, and multicell infections than those with other genotype subgroups. CONCLUSIONS These findings highlight the importance of HLA genotype for assessing EBV infectivity.
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Affiliation(s)
- Dina Suolitiken
- Department of Hematology, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople's Republic of China
| | - Yini Wang
- Department of Hematology, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople's Republic of China
| | - Zhili Jin
- Department of Hematology, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople's Republic of China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship HospitalCapital Medical UniversityBeijingPeople's Republic of China
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11
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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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12
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El-Mallawany NK, Curry CV, Allen CE. Haemophagocytic lymphohistiocytosis and Epstein-Barr virus: a complex relationship with diverse origins, expression and outcomes. Br J Haematol 2021; 196:31-44. [PMID: 34169507 DOI: 10.1111/bjh.17638] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/22/2022]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non-familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X-linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non-neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders and lymphomas can cause neoplasia-associated HLH. The present review will discern between EBV-associated familial and non-familial HLH and highlight diagnostic and therapeutic considerations. Non-familial EBV-associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non-neoplastic EBV-HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV-positive T-cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV-related complications is desperately needed to improve survival for patients with neoplasia-associated HLH.
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Affiliation(s)
- Nader Kim El-Mallawany
- Department of Paediatrics, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Cancer and Haematology Centres, Houston, TX, USA
| | - Choladda V Curry
- Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Hospital, Houston, TX, USA
| | - Carl E Allen
- Department of Paediatrics, Baylor College of Medicine, Houston, TX, USA.,Texas Children's Cancer and Haematology Centres, Houston, TX, USA
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Kim YR, Kim DY. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res 2021; 56:S17-S25. [PMID: 33935031 PMCID: PMC8094004 DOI: 10.5045/br.2021.2020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
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Affiliation(s)
- Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dae-Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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14
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Sun SR, Wu M, Wulipan F, Shen L, Ma JX, Chen PP, Hu YW, Zhang HD, Xie YH. [Clinical features and treatment outcome of patients with non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:324-331. [PMID: 33979978 PMCID: PMC8120126 DOI: 10.3760/cma.j.issn.0253-2727.2021.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Indexed: 11/23/2022]
Abstract
Objective: To investigate the clinical features and effect of prognostic factors in patients with different pathological types of non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis. Methods: We collected and analyzed the clinical data of 89 patients with non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis who were treated at Huadong Hospital from March 2013 to May 2020. The data were analyzed via log-rank and Cox multivariate analyses. Results: The median overall survival time of the 89 cases was 10.2 months. Patients with B-cell lymphoma-associated hemophagocytic lymphohistiocytosis did not reach the median overall survival time. The median overall survival times of T-cell lymphoma-associated hemophagocytic lymphohistiocytosis and NK-cell lymphoma-associated hemophagocytic lymphohistiocytosis were 10.2 and 3.0 months, respectively. The pathological type of non-Hodgkin lymphoma (OS: P=0041, PFS: P=0.015) , ECOG score ≥ 3 (OS: P=0.031, PFS: P=0.030) , hematopoietic stem cell transplantation (OS: P=0.005, PFS: P=0.040) , lymphadenopathy (OS: P=0.007, PFS: P=0.012) , and splenomegaly (OS: P=0.276, PFS: P=0.324) were related to the overall survival and progression-free survival of patients with non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis. Splenectomy could improve the prognosis of patients with lymphoma-associated hemophagocytic lymphohistiocytosis, especially T-cell lymphoma-associated hemophagocytic lymphohistiocytosis. Conclusion: The clinical characteristics of patients with different pathological types of non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis were similar but were different in the overall survival rate and the effect of prognostic factors. We suggested that patients with non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis should receive more than combined chemotherapy. To improve the prognosis and survival rate of patients, those with B-cell lymphoma-associated hemophagocytic lymphohistiocytosis and NK-cell lymphoma-associated hemophagocytic lymphohistiocytosis promptly require hematopoietic stem cell transplantation. Moreover, patients with T-cell lymphoma-associated hemophagocytic lymphohistiocytosis should consider splenectomy.
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Affiliation(s)
- S R Sun
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - M Wu
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Fulati Wulipan
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - L Shen
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - J X Ma
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - P P Chen
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Y W Hu
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - H D Zhang
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
| | - Y H Xie
- Department of Hematology, Huadong Hospital, Fudan University, Shanghai 200040, China
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15
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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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16
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Perricone C, Triggianese P, Bursi R, Cafaro G, Bartoloni E, Chimenti MS, Gerli R, Perricone R. Intravenous Immunoglobulins at the Crossroad of Autoimmunity and Viral Infections. Microorganisms 2021; 9:121. [PMID: 33430200 PMCID: PMC7825648 DOI: 10.3390/microorganisms9010121] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/24/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023] Open
Abstract
Intravenous immunoglobulins (IVIG) are blood preparations pooled from the plasma of donors that have been first employed as replacement therapy in immunodeficiency. IVIG interact at multiple levels with the different components of the immune system and exert their activity against infections. Passive immunotherapy includes convalescent plasma from subjects who have recovered from infection, hyperimmune globulin formulations with a high titer of neutralizing antibodies, and monoclonal antibodies (mAbs). IVIG are used for the prevention and treatment of several infections, especially in immunocompromised patients, or in case of a poorly responsive immune system. The evolution of IVIG from a source of passive immunity to a powerful immunomodulatory/anti-inflammatory agent results in extensive applications in autoimmune diseases. IVIG composition depends on the antibodies of the donor population and the alterations of protein structure due to the processing of plasma. The anti-viral and anti-inflammatory activity of IVIG has led us to think that they may represent a useful therapeutic tool even in COVID-19. The human origin of IVIG carries specific criticalities including risks of blood products, supply, and elevated costs. IVIG can be useful in critically ill patients, as well as early empirical treatment. To date, the need for further well-designed studies stating protocols and the efficacy/tolerability profile of IVIG and convalescent plasma in selected situations are awaited.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Paola Triggianese
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
| | - Roberto Bursi
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Maria Sole Chimenti
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, 06129 Perugia, Italy; (C.P.); (R.B.); (G.C.); (E.B.); (R.G.)
| | - Roberto Perricone
- Rheumatology, Allergology and Clinical Immunology, Department of “Medicina dei Sistemi”, University of Rome, 00133 Rome, Italy; (M.S.C.); (R.P.)
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17
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A Rapid Cytologic Double Staining of Epstein-Barr Virus-encoded Small RNA and Cell Surface Markers for Diagnosis of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis. J Pediatr Hematol Oncol 2020; 42:e756-e758. [PMID: 31743316 DOI: 10.1097/mph.0000000000001647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.
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18
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Pediatric hemophagocytic lymphohistiocytosis. Blood 2020; 135:1332-1343. [PMID: 32107531 DOI: 10.1182/blood.2019000936] [Citation(s) in RCA: 285] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 02/27/2020] [Indexed: 12/13/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome describing patients with severe systemic hyperinflammation. Characteristic features include unremitting fever, cytopenias, hepatosplenomegaly, and elevation of typical HLH biomarkers. Patients can develop hepatitis, coagulopathy, liver failure, central nervous system involvement, multiorgan failure, and other manifestations. The syndrome has a high mortality rate. More and more, it is recognized that while HLH can be appropriately used as a broad summary diagnosis, many pediatric patients actually suffer from an expanding spectrum of genetic diseases that can be complicated by the syndrome of HLH. Classic genetic diseases in which HLH is a typical and common manifestation include pathogenic changes in familial HLH genes (PRF1, UNC13D, STXBP2, and STX11), several granule/pigment abnormality genes (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4, CDC42, and the Epstein-Barr virus susceptibility diseases. There are many other genetic diseases in which HLH is an infrequent complication of the disorder as opposed to a prominent manifestation of the disease caused directly by the genetic defect, including other primary immune deficiencies and inborn errors of metabolism. HLH can also occur in patients with underlying rheumatologic or autoinflammatory disorders and is usually designated macrophage activation syndrome in those settings. Additionally, HLH can develop in patients during infections or malignancies without a known (or as-yet-identified) genetic predisposition. This article will attempt to summarize current concepts in the pediatric HLH field as well as offer a practical diagnostic and treatment overview.
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Ma H, Zhang R, Zhang L, Wei A, Zhao X, Yang Y, Liu W, Li Z, Qin M, Wang T. Treatment of pediatric primary hemophagocytic lymphohistiocytosis with the HLH-94/2004 regimens and hematopoietic stem cell transplantation in China. Ann Hematol 2020; 99:2255-2263. [PMID: 32766934 DOI: 10.1007/s00277-020-04209-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 07/27/2020] [Indexed: 12/21/2022]
Abstract
We aimed to clarify the clinical characteristics, prognostic factors, and effectiveness of the HLH-94/2004 regimens and hematopoietic stem cell transplantation (HSCT) in pediatric patients with primary hemophagocytic lymphohistiocytosis (pHLH) in China. A retrospective analysis was performed on 38 patients with pHLH at Beijing Children's Hospital. PRF1 (34.2%) and UNC13D (31.6%) were the most common mutations in the pHLH. Thirty-eight patients were treated with the HLH-94/2004 regimens after diagnosis. Twenty-six patients (72.2%) responded to first-line treatment (complete response: 55.5%, partial response: 16.7%). The median survival time was 23 months. The overall survival (OS) rate at 3 years was 74.7%. There was no significant difference in the response rate (72% vs. 63.6%, P = 0.703) or 3-year OS (83.6% vs. 66.7%, P = 0.443) between the patients treated with the HLH-94 regimen and those treated with the HLH-2004 regimen. The incidences of all side effects in patients treated with the HLH-94 or HLH-2004 regimen were 32.0% and 18.2%, respectively (P = 0.394). Among 15 patients treated with HSCT, neither the preconditioning regimen nor the donor type affected patient prognosis (P = 0.205 and P = 0.161, respectively). The disease status (remission or nonremission) before preconditioning did not affect prognosis or the incidence of GVHD. Furthermore, a higher bilirubin level (≥ 30 μmol/L) was correlated with a poorer prognosis in pHLH patients (P = 0.026). The effectiveness rates of the HLH-94 and HLH-2004 regimens, chemotherapy, and HSCT were similar in pHLH patients. A bilirubin level ≥ 30 μmol/L might be an adverse prognostic factor in pHLH.
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Affiliation(s)
- Honghao Ma
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Rui Zhang
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Liping Zhang
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Ang Wei
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Xiaoxi Zhao
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Ying Yang
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China
| | - Wei Liu
- Department of Hematology, Children's Hospital of Zhengzhou City, Zhengzhou, 450053, China
| | - Zhigang Li
- Hematology and Oncology Laboratory, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Pediatric Research Institute, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China.
| | - Maoquan Qin
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China.
| | - Tianyou Wang
- Department of Hematology and Oncology, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Oncology, Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics, Beijing Children's Hospital Affiliated to Capital Medical University, Nanlishi Road No. 56, Xicheng District, Beijing, 100045, People's Republic of China.
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Xu XJ, Tang YM. Dilemmas in diagnosis and management of hemophagocytic lymphohistiocytosis in children. World J Pediatr 2020; 16:333-340. [PMID: 31506890 DOI: 10.1007/s12519-019-00299-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 07/26/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening entity which is characterized by severe hyperinflammation. Now the HLH-2004 protocol has been widely accepted and clinically used; however, many questions still remain in clinical practice. In this review, we discuss the dilemmas in the diagnosis and treatment of HLH in children. DATA SOURCES Original research for articles and literature reviews published in PubMed was carried out using the key term "hemophagocytic lymphohistiocytosis". RESULTS As the gene sequencing technology progresses, the range of causal mutations and primary HLH has been redefined. The monoallelic variants may contribute to the pathogenesis of the disease. Many conditions without defective cytotoxicity of T or NK cells may lead to HLH, such as primary immunodeficiency (PID) and dysregulated immune activation or proliferation (DIAP). HLH shares overlapping clinical and laboratory characteristics with severe sepsis, but usually the single values are more pronounced in HLH than sepsis. H score is another approach to help the diagnosis of secondary HLH. Specific Th1/Th2 cytokine patterns are very helpful tools to differentiate HLH (reactivation of HLH) from sepsis. Moreover, it also has been used successfully to stratify the therapy intensity. The treatment of HLH should consider underlying diseases, triggers and severity. HLH-94 is recommended for patients who need etoposide-based therapy. CONCLUSIONS Dramatic progress has been made during the past decades in understanding the pathophysiology of HLH. However, diagnosis and treatment of HLH remain with many dilemmas because of the heterogeneous nature of the disease. Better understanding new gene defects and more effective diagnostic approaches and salvage regimens are goals for the future.
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Affiliation(s)
- Xiao-Jun Xu
- Division of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics of Ministry of Education, Zhejiang University, Hangzhou, 310003, China
| | - Yong-Min Tang
- Division of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, Key Laboratory of Reproductive Genetics of Ministry of Education, Zhejiang University, Hangzhou, 310003, China.
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Song Y, Wang J, Wang Y, Wang Z. HLA-mismatched GPBSC infusion therapy in refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis: an observational study from a single center. Stem Cell Res Ther 2020; 11:265. [PMID: 32611452 PMCID: PMC7329501 DOI: 10.1186/s13287-020-01779-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/24/2020] [Accepted: 06/18/2020] [Indexed: 11/22/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory state. Epstein–Barr virus (EBV) infection-associated HLH (EBV-HLH) is one of the most common secondary HLH and suffers a very poor prognosis. Allo-HSCT is often required for refractory EBV-HLH, but some patients still cannot proceed to the next allo-HSCT due to various factors. This study aimed to observe the efficacy of HLA-mismatched granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (GPBSCs) infusion for refractory EBV-HLH. Methods A retrospective case-control study of refractory EBV-HLH patients with GPBSC infusion from HLA-mismatched donors after chemotherapy (as GPBSC group) and sole chemotherapy (as control group) was performed. Efficacy was evaluated 2 and 4 weeks and all patients were followed-up until March 1, 2018. Results There were 18 cases who accepted infusion between March 2016 and Sep 2017 and 19 were randomly selected from refractory EBV-HLH patients who underwent salvage therapy during the same period for the control group. In GPBSC group, WBC (p = 0.017), Fbg (p = 0.040), and ferritin (p = 0.039) improved significantly after treatment. The overall response rate was 66.7% (CR 22.2%, PR 44.4%). However, there are no significant differences in changes of WBC, HGB, PLT, TG, Fbg, Ferritin, AST, ALT, and T-bil between two groups. Only the Fbg level was recovered better in the GPBSC infusion group (p = 0.003). In the GPBSC group, EBV-DNA decreased significantly after 2 weeks (p = 0.001) and 4 weeks (p = 0.012) after treatment, and the effect of the decrease was significantly better than that of the chemotherapy alone group in 2 weeks but not 4 weeks (p2w = 0.011, p4w = 0.145). The median survival time in the infusion group was 20.4 weeks [95% CI 10.9, 29.9], and the median survival time in the control group was 10.8 weeks [95% CI 0–24.34]. In the short-term, the infusion group’s survival rate was better (2-month 88.89% vs. 52.63%, p = 0.008; 3-month 83.33% vs. 47.09%, p = 0.012), but there was no difference in OS (p = 0.287). Conclusions Infusing GPBSCs combined with chemotherapy is effective, especially in decreasing EBV-DNA, performs better than chemotherapy alone, and improves short-term survival rate. GPBSC infusion is suggested as a bridging treatment method to allo-HSCT.
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Affiliation(s)
- Yue Song
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China
| | - Jingshi Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China
| | - Yini Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China.
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Abstract
OBJECTIVES The objectives of this study were to describe the clinical and etiologic profile and outcomes of children with hemophagocytic lymphohistiocytosis (HLH) in a tertiary care hospital in South India. METHODS This is a combined 2-year prospective (2017 to 2018) and 5-year retrospective (2012 to 2016) descriptive study in which children from birth to 18 years who satisfied the HLH-2004 diagnostic criteria were included. Case details from patient records were analyzed. RESULTS Fifty-three cases were enrolled of which 20 were prospective and 33 were retrospective. Fever, hepatomegaly, anemia, and hyperferritinemia were the common presentations. Infectious triggers were found in 33 (62%) cases. Five cases were secondary to rheumatic diseases, and 8 were primary HLH. Bacterial (14 cases) followed by viral infections (10 cases) were the leading triggers. Scrub typhus (6 cases) and dengue (4 cases) were the most common infectious agents. Major complications include febrile neutropenia (38%) and multiorgan dysfunction (26%). One child developed secondary malignancy. The most frequently used immunosuppressive drug for the treatment of HLH was steroid (70%), while 28% of cases recovered with only supportive therapy. The overall mortality was 41%. CONCLUSIONS Infections were the most common triggers for HLH of which tropical infectious agents constituted the majority. Treatment with steroids alone or regimens without cytotoxic drugs may result in resolution of secondary HLH with mild to moderate disease activity. Without stem cell transplant, primary HLH has a high mortality rate.
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Yoon HS. A Recent Update on Histiocytic Disorder in Children: Focus on Diagnosis and Treatment. CLINICAL PEDIATRIC HEMATOLOGY-ONCOLOGY 2020. [DOI: 10.15264/cpho.2020.27.1.32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Hoi Soo Yoon
- Department of Pediatrics, Kyung Hee University College of Medicine, Seoul, Korea
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Kumar V, Eulitt PJ, Bermudez A, Khagi S. Hemophagocytic lymphohistiocytosis in a patient with glioblastoma: a case report. CNS Oncol 2019; 8:CNS45. [PMID: 31777271 PMCID: PMC6912850 DOI: 10.2217/cns-2019-0013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Adult onset hemophagocytic lymphohistiocytosis (HLH) is a rare condition, usually secondary to either a precipitating infective or hematologic malignancy. We present a case of Epstein–Barr virus associated HLH in a 55-year-old female receiving treatment for a glioblastoma (GBM). It is possible that HLH is under recognized, as patients with GBM often have features of a nonspecific systemic inflammatory response syndrome, multiorgan failure and cognitive decline. A high index of suspicion and increased awareness can help improve timeliness of diagnosis. Therapeutically, Epstein–Barr virus associated HLH in patients with solid organ malignancy poses significant challenges. An individualized, multidisciplinary approach is essential when managing adult-onset HLH and providers will need to be mindful of the high mortality rate despite treatment.
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Affiliation(s)
- Vaibhav Kumar
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Patrick J Eulitt
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Ana Bermudez
- Division of Internal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Simon Khagi
- Division of Hematology & Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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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: 26] [Impact Index Per Article: 4.3] [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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Song Y, Wang Z, Hao Z, Li L, Lu J, Kang H, Lu Y, You Y, Li L, Chen Q, Chen B. Requirement for etoposide in the treatment of pregnancy related hemophagocytic lymphohistiocytosis: a multicenter retrospective study. Orphanet J Rare Dis 2019; 14:50. [PMID: 30777105 PMCID: PMC6380007 DOI: 10.1186/s13023-019-1033-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 02/11/2019] [Indexed: 11/20/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare severe clinical syndrome. HLH manifesting during pregnancy has been paid much attention in recent years. Despite the specificity of pregnancy-related HLH, there has not been any consensus regarding its treatment. According to a previous study, corticosteroid/IVIG is the mainstream therapy; however, the efficacy is controversial. Etoposide is an important agent in the HLH-94 regimen; nevertheless, its use is limited because of possible toxicity to the fetus. Methods: In this study, we summarized 13 cases from 4 medical institutions from April 2011 to April 2018. Treatment regimens and outcomes were observed. Results The median age was 26 (20–36) years old. The median gestational age was 28 (10–35) weeks. In these 13 patients, 10 were treated with methylprednisolone/IVIG and was effective in only two patients. In 6 patients who used etoposide during their treatment, all achieved remission. The median time from onset of disease to use of etoposide was 36 (17–131) days. Five of these 6 patients were treated with corticosteroids with/without IVIG before etoposide. One patient with pulmonary tuberculosis and one with lymphoma were treated according to etiology and achieved long survival. Conclusion For treatment of pregnancy-related HLH, particularly for patients who do not respond to corticosteroids/IVIG therapy, etoposide should be used bravely. Nevertheless, suitable dosages and toxic and side-effects require further clinical observation.
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Affiliation(s)
- Yue Song
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, YongAn Road 95th Xicheng District, Beijing, 100050, China.
| | - Zengping Hao
- Department of Obstetrics and Gynecology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lihong Li
- Department of Hematology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Junli Lu
- Department of Obstetrics and Gynecology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Hongjun Kang
- Department of Hematology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yanping Lu
- Department of Obstetrics and Gynecology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yanqin You
- Department of Obstetrics and Gynecology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Lijuan Li
- Department of Intensive Care Unit, China-Japan Friendship Hospital, Beijing, China
| | - Qingyun Chen
- Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China
| | - Bo Chen
- Department of Obstetrics and Gynecology, China-Japan Friendship Hospital, Beijing, China
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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: 70] [Impact Index Per Article: 11.7] [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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Song Y, Pei RJ, Wang YN, Zhang J, Wang Z. Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Analysis of 96 Patients in a Single Center. Chin Med J (Engl) 2018; 131:776-783. [PMID: 29578120 PMCID: PMC5887735 DOI: 10.4103/0366-6999.228234] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome. Central nervous system (CNS) involvement is a severe complication, which can lead to rapid disease development and higher morality. However, this has not been given enough attention in adult HLH. Therefore, we carried out this study to analyze the clinical features, laboratory findings, treatment outcomes, and other characteristics of adult HLH with CNS involvement. Methods A retrospective analysis of 96 adult patients with HLH combined with CNS involvement between June 2003 and December 2016 was conducted. Clinical features, cerebrospinal fluid (CSF) features, image changes, and therapeutic outcomes were analyzed. Results Among the 96 patients, 86 had various CNS symptoms and 33 (38.4%) had already presented symptoms before the HLH diagnosis was confirmed. A total of 59 patients received CSF examinations and showed abnormalities in 23 patients (39.0%). Seventy patients received imaging examinations and the results showed fifty patients with imaging changes (71.4%). Fifty-seven patients received multiple rounds of repeated intrathecal injection therapy and 35 patients improved (61.4%). As for the multiple analyses of effective factors on survival time, the results showed that the effects of combined Epstein-Barr virus (EBV) infection (P = 0.026, Exp(B) = 2.309, 95% confidence interval [CI] [1.108, 4.823) and intrathecal injection therapy (P = 0.013, Exp(B) = 0.422, 95% CI [0.214, 0.831]) on the survival time of the CNS-HLH patients were significant. Conclusions Complication with EBV infection is a risk factor, and intrathecal injection is a protective factor. CNS involvement in HLH is not rare, which can result in a poor prognosis. Multiple rounds of repeated intrathecal injection therapy can improve the prognosis of CNS-HLH patients.
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Affiliation(s)
- Yue Song
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Rui-Jun Pei
- 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
| | - Jia Zhang
- 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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Ehl S, Astigarraga I, von Bahr Greenwood T, Hines M, Horne A, Ishii E, Janka G, Jordan MB, La Rosée P, Lehmberg K, Machowicz R, Nichols KE, Sieni E, Wang Z, Henter JI. Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 6:1508-1517. [PMID: 30201097 DOI: 10.1016/j.jaip.2018.05.031] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/14/2018] [Accepted: 05/24/2018] [Indexed: 12/16/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.
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Affiliation(s)
- Stephan Ehl
- Center for Chronic Immunodeficiency, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
| | - Itziar Astigarraga
- Servicio de Pediatria, BioCruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country UPV/EHU, Barakaldo, Spain
| | - Tatiana von Bahr Greenwood
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's and Women's Health, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Melissa Hines
- Division of Critical Care Medicine, St. Jude Children's Research Hospital, Memphis, Tenn
| | - AnnaCarin Horne
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's and Women's Health, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan
| | - Gritta Janka
- Clinic of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany
| | - Michael B Jordan
- Divisions of Immunobiology and Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Paul La Rosée
- Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - Kai Lehmberg
- Clinic of Pediatric Hematology and Oncology, Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Eppendorf, Hamburg, Germany
| | - Rafal Machowicz
- Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Kim E Nichols
- Division of Cancer Predisposition, St. Jude Children's Research Hospital, Memphis, Tenn
| | - Elena Sieni
- Department of Pediatric Hematology Oncology, Azienda Ospedaliero Universitaria A. Meyer Children Hospital, Firenze, Italy
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's and Women's Health, Karolinska University Hospital Solna, Stockholm, Sweden.
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Mehta B, Kasturi S, Teruya-Feldstein J, Horwitz S, Bass AR, Erkan D. Adult-Onset Still's Disease and Macrophage-Activating Syndrome Progressing to Lymphoma: A Clinical Pathology Conference Held by the Division of Rheumatology at Hospital for Special Surgery. HSS J 2018; 14:214-221. [PMID: 29983666 PMCID: PMC6031528 DOI: 10.1007/s11420-018-9606-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 02/01/2018] [Indexed: 02/07/2023]
Affiliation(s)
- Bella Mehta
- 0000 0001 2285 8823grid.239915.5Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA ,000000041936877Xgrid.5386.8Weill Cornell Medicine, New York, NY USA
| | - Shanthini Kasturi
- 0000 0000 8934 4045grid.67033.31Tufts Medical Center, Boston, MA USA
| | - Julie Teruya-Feldstein
- 0000 0000 9963 6690grid.425214.4Icahn School of Medicine, Mount Sinai Health System, New York, NY USA
| | - Steven Horwitz
- 0000 0001 2171 9952grid.51462.34Memorial Sloan Kettering Cancer Center, New York, NY USA
| | - Anne R. Bass
- 0000 0001 2285 8823grid.239915.5Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA ,000000041936877Xgrid.5386.8Weill Cornell Medicine, New York, NY USA
| | - Doruk Erkan
- 0000 0001 2285 8823grid.239915.5Hospital for Special Surgery, 535 East 70th Street, New York, NY 10021 USA ,000000041936877Xgrid.5386.8Weill Cornell Medicine, New York, NY USA
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31
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Ko YH. Epstein-Barr virus-positive T/NK-cell lymphoproliferative diseases in children and adolescents. PRECISION AND FUTURE MEDICINE 2018. [DOI: 10.23838/pfm.2017.00198] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
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Matsuda K, Toyama K, Toya T, Ikemura M, Nakamura F, Kurokawa M. Reactivation of Hemophagocytic Lymphohistiocytosis Triggered by Antithymocyte Globulin. Intern Med 2018; 57:583-586. [PMID: 29225252 PMCID: PMC5849557 DOI: 10.2169/internalmedicine.9226-17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
A 16-year-old boy with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (HLH) underwent allogeneic hematopoietic stem cell transplantation after conditioning with fludarabine, melphalan, total body irradiation, and rabbit antithymocyte globulin (ATG). A severe, persistent infusion reaction occurred after the initial administration of ATG. Investigations showed a rapid increase in the levels of liver enzymes and ferritin, and the reactivation of HLH was confirmed by marked hemophagocytosis in the bone marrow. Treatment with pulse glucocorticoid therapy resulted in the improvement of HLH. This is the first case of HLH reactivation triggered by ATG. Physicians should therefore be cautious of HLH reactivation, especially when a severe and prolonged infusion reaction occurs.
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Affiliation(s)
- Kensuke Matsuda
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Kazuhiro Toyama
- Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Japan
| | - Takashi Toya
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Masako Ikemura
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Fumihiko Nakamura
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Mineo Kurokawa
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Japan
- Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, Japan
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Allen C, Rooney CM, Gottschalk S. Infectious Mononucleosis and Other Epstein-Barr Virus–Associated Diseases. Hematology 2018. [DOI: 10.1016/b978-0-323-35762-3.00054-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Prognostic factors of early death in children with hemophagocytic lymphohistiocytosis. Cytokine 2017; 97:80-85. [PMID: 28582648 DOI: 10.1016/j.cyto.2017.03.013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/10/2017] [Accepted: 03/31/2017] [Indexed: 11/20/2022]
Abstract
Hemophagocytic lymphohistiocytosis is a rapidly progressing and fatal disease. Early identification of early death for HLH patients based on the laboratory findings at the time of diagnosis could improve the overall survival. A retrospective study was performed on 95 Chinese pediatric patients with HLH. Patients' data including clinical features and laboratory findings at diagnosis were collected. In a multivariate Cox proportional hazard regression model analysis, albumin≤27.75g/L (hazard ratio (HR)=11.82, 95% confidence interval (CI) 2.58-54.23; P=0.001), LDH≥3707.5 U/L (HR=4.15, 95%CI 1.43-12.01; P=0.009), and IL-10≥456pg/ml (HR=12.39, 95%CI 1.59-96.79; P=0.016) at diagnosis were independent prognostic factors of early death. The risk of early death was 33-fold increase in patients with three risk factors (HR=33.33; 95%CI 8.40-125.00; P<0.001), and 12-fold increase in patients with two risk factors (HR=12.80; 95%CI 2.34-69.80; P=0.002) when compared to it in patients with zero to one risk factor. Our results reveal that HLH patients with the risk of early death can be identified by laboratory findings at diagnosis, which may help guide the treatment decision making for this disease.
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Similar but not the same: Differential diagnosis of HLH and sepsis. Crit Rev Oncol Hematol 2017; 114:1-12. [PMID: 28477737 DOI: 10.1016/j.critrevonc.2017.03.023] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2016] [Revised: 03/17/2017] [Accepted: 03/20/2017] [Indexed: 12/12/2022] Open
Abstract
Differential diagnosis of hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) and sepsis is critically important because the life-saving aggressive immunosuppressive treatment, required in the effective HLH therapy, is absent in sepsis guidelines. Moreover, HLH may be complicated by sepsis. Hyperinflammation, present in both states, gives an overlapping clinical picture including fever and performance status deterioration. The aim of this review is to provide aid in this challenging diagnostic process. Analysis of clinical features and laboratory results in multiple groups of patients (both adult and pediatric) with either HLH or sepsis allows to propose criteria differentiating these two conditions. The diagnosis of HLH is supported by hyperferritinemia, splenomegaly, marked cytopenias, hypofibrinogenemia, low CRP, characteristic cytokine profile and, only in adults, hypertriglyceridemia. In the presence of these parameters (especially the most characteristic hyperferritinemia), the other HLH criteria should be assessed. Genetic analyses can reveal familial HLH. Hemophagocytosis is neither specific nor sensitive for HLH.
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Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) has well been studied as a genetic disorder in children (primary HLH). Mutations in the regulatory complex of the cellular immune synapse lead to a loss of function of cytotoxic T‑cells and natural killer cells with excessive inflammation based on a cytokine storm. During the last decade, an increasing number of adult HLH patients without a family history of HLH (secondary or acquired HLH) have been reported. Various triggers - infections, malignancies or autoimmune diseases - result in an acquired loss of function of these cells and a sepsis-like disease. Missed or late diagnosis is believed to be a major cause of the high mortality. OBJECTIVES To describe the current knowledge on HLH and to raise awareness. MATERIALS AND METHODS Analysis of case reports, current studies, and expert recommendations. RESULTS Increased vigilance in identifying the adult form of HLH resulted in an increasing number of case reports over the past few years. HLH patients typically present with a clinical phenotype resembling severe sepsis or septic shock with fever, cytopenia, and organomegaly, which do not or insufficiently respond to anti-infective treatment. Early recognition of HLH distinction from sepsis, and prompt initiation of treatment - which is fundamentally different from sepsis - are crucial for improved outcome. A promising diagnostic parameter is ferritin, which has gained sufficient specificity, but only in the context of the triad of fever, cytopenia, and organomegaly. Treatment of adult HLH patients requires immunosuppression, with strict therapeutic guidance derived from the triggering disease. CONCLUSIONS Because of the similar clinical presentation to that of sepsis, HLH is often not recognized, resulting in a fatal outcome. In "sepsis" patients on the ICU with deterioration despite a standard of care, HLH needs to be considered by testing for ferritin when considering differential diagnoses. The complexity of the illness requires interdisciplinary patient care with specific integration of the hematologist in the diagnostic workup and therapeutic management, because of the frequent use of chemotherapy-based immunosuppression.
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Clinically Mild Encephalitis/Encephalopathy With a Reversible Splenial Lesion Accompanied by Epstein-Barr Virus Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature. J Pediatr Hematol Oncol 2017; 39:e92-e96. [PMID: 27879539 DOI: 10.1097/mph.0000000000000708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Central nervous system involvement in hemophagocytic lymphohistiocytosis (HLH) is associated with a poor outcome. For such patients, it is unknown whether more aggressive therapies, such as intrathecal methotrexate or hydrocortisone, are inevitably required. We present a very rare case of 3-year-old Japanese girl who developed mild encephalitis/encephalopathy with a reversible splenial lesion, accompanied by Epstein-Barr virus-associated HLH, and review previous similar reports. Our case and previous reports suggest that mild encephalitis/encephalopathy with a reversible splenial lesion accompanied by Epstein-Barr virus-associated HLH has a relatively good prognosis, even in the absence of intrathecal treatments.
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38
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Hu S, Bansal P, Lynch D, Rojas Hernandez CM, Dayao Z. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature. J Med Case Rep 2016; 10:365. [PMID: 27998299 PMCID: PMC5175318 DOI: 10.1186/s13256-016-1143-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Accepted: 11/10/2016] [Indexed: 12/28/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis is becoming an increasingly recognized disorder in adults. Classical Hodgkin lymphoma is a relatively uncommon etiology of hemophagocytic lymphohistiocytosis and may complicate treatment options. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin are discussed here as a treatment regimen. Case presentation A 66-year-old Hispanic man previously in good health presented with a 1-month history of recurrent fevers, chills, and night sweats and a 3-week history of new onset jaundice. A bone marrow biopsy revealed a normocellular bone marrow with increased histiocytes with areas of hemophagocytic activity. He met five out of eight criteria for hemophagocytic lymphohistiocytosis diagnosis including fevers, pancytopenia, hemophagocytosis, ferritin of 23,292 ng/mL (>500 ng/mL), and soluble-CD25 of 15,330 pg/mL (>1033 pg/mL). A right cervical lymph node biopsy revealed CD15, CD30, MUM-1, and Epstein–Barr virus-encoded small ribonucleic acid-positive cells with morphologic findings of classical Hodgkin lymphoma, lymphocyte-rich subtype. He completed 2 weeks of hemophagocytic lymphohistiocytosis-directed therapy with etoposide and dexamethasone, but then was switched to rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin due to minimal improvement in his pancytopenia and hepatic impairment. He completed one full cycle of rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin with notable improvement in serial hepatic function panels and had an undetectable Epstein–Barr virus viral load. However, he eventually died due to complications of Enterococcus faecalis bacteremia and colonic microperforation in the setting of persistent pancytopenia. Conclusions This case discusses the challenges facing treatment of adult malignancy-associated hemophagocytic lymphohistiocytosis. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin may be a viable option for patients with secondary hemophagocytic lymphohistiocytosis and Hodgkin lymphoma who cannot tolerate standard therapies due to hepatic impairment. Targeted therapy and immunotherapy are promising new areas of developing treatments.
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Affiliation(s)
- Steve Hu
- Department of Internal Medicine, University of New Mexico, MSC10 5550, 1 University of New Mexico, 87131, Albuquerque, NM, USA.
| | - Pranshu Bansal
- University of New Mexico Comprehensive Cancer Center, 1201 Camino de Salud NE, Room 3618, 87131, Albuquerque, NM, USA
| | - David Lynch
- Department of Pathology, University of New Mexico, MSC08 4640, 1 University of New Mexico, 87131, Albuquerque, NM, USA
| | | | - Zoneddy Dayao
- University of New Mexico Comprehensive Cancer Center, 1201 Camino de Salud NE, Room 3618, 87131, Albuquerque, NM, USA
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Stefanou C, Tzortzi C, Georgiou F, Timiliotou C. Combining an antiviral with rituximab in EBV-related haemophagocytic lymphohistiocytosis led to rapid viral clearance; and a comprehensive review. BMJ Case Rep 2016; 2016:bcr-2016-216488. [PMID: 27941111 DOI: 10.1136/bcr-2016-216488] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Epstein-Barr virus (EBV)-related haemophagocytic lymphohistiocytosis (EBVr-HLH) has a better prognosis when the virus is rapidly cleared, but the best antiviral approach is controversial. We present a patient to whom the therapeutic standard rituximab was co-administered with valacyclovir and an HLH-specific treatment with favourable viral and clinical responses. We conducted an extensive literature review and contacted several world reference centres and experts to inquire about their approaches and experience. We conclude that antivirals are infrequently used for EBVr-HLH, despite their laboratory-proven and likely clinical beneficial effect on some EBV-related diseases. However, the role of antivirals remains obscure. Concerns about their lack of efficacy are based on observational data and reports of the cellular tropism of EBV. Therefore, the adjunct use of antivirals may be considered when myelotoxicity is not the primary concern, and related outcomes should be systematically recorded to produce higher quality evidence.
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40
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Otsubo K, Fukumura A, Hirayama M, Morimoto T, Kato M, Mochizuki H. Hemophagocytic lymphohistiocytosis caused by systemic herpes simplex virus type 1 infection: Successful treatment with dexamethasone palmitate. Pediatr Int 2016; 58:390-393. [PMID: 27076380 DOI: 10.1111/ped.12817] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 08/11/2015] [Accepted: 08/19/2015] [Indexed: 11/29/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition resulting from an uncontrolled and ineffective immune response. Here, we report a case of HLH caused by disseminated herpes simplex virus (HSV)-1 infection. The patient was initially treated with prednisolone and high-dose acyclovir. Although liver enzymes, coagulation abnormalities, and inflammatory markers were remarkably improved, the platelet count remained low. Prednisolone was therefore switched to dexamethasone palmitate. Thereafter, the platelet count normalized. Inflammatory markers normalized 30 days after admission and serum HSV-DNA became undetectable on day 41. The patient was discharged on day 91 and no developmental delay was evident at 7 months of age. These findings suggest that dexamethasone palmitate is effective for neonatal HLH.
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Affiliation(s)
- Keisuke Otsubo
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Akiko Fukumura
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Mariko Hirayama
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Tsuyoshi Morimoto
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Masahiko Kato
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
| | - Hiroyuki Mochizuki
- Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
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41
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Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016; 127:2672-81. [PMID: 26966089 DOI: 10.1182/blood-2016-01-690636] [Citation(s) in RCA: 962] [Impact Index Per Article: 106.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 03/02/2016] [Indexed: 12/11/2022] Open
Abstract
The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.
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Korbi M, Youssef M, Ben Brahim H, Chaabane A, Mohamed M, Akkari H, Belhadjali H, Zili J. DRESS à l’allopurinol compliqué d’un syndrome d’activation macrophagique. Ann Dermatol Venereol 2015; 142:767-70. [DOI: 10.1016/j.annder.2015.03.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 01/09/2015] [Accepted: 03/31/2015] [Indexed: 12/11/2022]
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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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Clonal CD8+ T Lymphocytic Proliferation and Karyotypical Abnormalities in an EBV Associated Hemophagocytic Lymphohistiocytosis. Case Rep Pathol 2015; 2015:513968. [PMID: 26451265 PMCID: PMC4588316 DOI: 10.1155/2015/513968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 08/27/2015] [Indexed: 11/18/2022] Open
Abstract
EBV associated hemophagocytic lymphohistiocytosis and EBV-positive T cell lymphoproliferative disease of childhood share many histologic and clinical features, which sometimes makes it very difficult to render a definitive diagnosis. In this report, we present a 16-year-old male who developed symptoms clinically consistent with EBV associated hematophagocytic lymphohistiocytosis including fulfilling most of HLH diagnostic criteria and responding promptly to HLH targeted therapy. However, histologic and cytogenetics features of this case are very concerning for EBV-positive T cell lymphoproliferative disease of childhood. This case demonstrates an ambiguous boundary of these two disease entities and emphasizes the importance of comprehensive evaluation and clinical correlation with cases suspicious of EBV driven hemophagocytic or lymphoproliferative process.
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Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal syndrome of pathologic immune dysregulation characterized by clinical signs and symptoms of extreme inflammation. HLH can occur as a genetic or sporadic disorder and, though seen as an inherited condition affecting primarily a pediatric population, can occur at any age and can be encountered in association with a variety of underlying diseases. Clinically the syndrome, whether genetic or acquired, is characterized by fever, hepatosplenomegaly, cytopenias, and activated macrophages in hematopoietic organs. Therapy centers on suppression of this hyperinflammatory state with cytotoxic, immunosuppressive therapy and treatment of any existing HLH triggers.
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Affiliation(s)
| | - Nancy Berliner
- Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Mid-Campus 3, 75 Francis Street, Boston, MA 02115, USA.
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Saidi W, Gammoudi R, Korbi M, Aounallah A, Boussofara L, Ghariani N, Sriha B, Braham N, Denguezli M, Belajouza C, Nouira R. Hemophagocytic lymphohistiocytosis: an unusual complication of leprosy. Int J Dermatol 2015; 54:1054-9. [DOI: 10.1111/ijd.12792] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/02/2014] [Accepted: 06/22/2014] [Indexed: 12/24/2022]
Affiliation(s)
- Wafa Saidi
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | - Rima Gammoudi
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | - Mouna Korbi
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | - Amina Aounallah
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | - Lobna Boussofara
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | - Najet Ghariani
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
| | | | - Nejia Braham
- Department of Hematology Laboratory; Farhat Hached Hospital; Sousse Tunisia
| | | | | | - Rafia Nouira
- Department of Dermatology; Farhat Hached Hospital; Sousse Tunisia
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47
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Inoue S, Mangat C, Rafe'e Y, Sharman M. Forme Fruste of HLH (haemophagocytic lymphohistiocytosis): diagnostic and therapeutic challenges. BMJ Case Rep 2015; 2015:bcr-2014-206190. [PMID: 25634853 DOI: 10.1136/bcr-2014-206190] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Infants and young children often present with a persistent febrile episode, sick appearance and negative infectious disease work-up. These patients present serious diagnostic and therapeutic problems to those who provide medical care, particularly since these children are clinically sick. We present a 13 month old child who presented with this clinical challenge. She was ultimately thought to have an incomplete form of HLH with underlying pathophysiology of hypercytokinemia, but also could have been a case of incomplete form of Kawasaki disease. She responded to IVIG, but this does not differentiate one diagnosis from another. Unfortunately we failed to obtain tests to exclude genetic etiologies of HLH, which would be important for predicting severity and risks of future recurrence. We wish to present this case so that one should do a thorough work up to establish a firm diagnosis of HLH and to search for genetic causes of this disorder.
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Affiliation(s)
- Susumu Inoue
- Department of Hematology/Oncology, Hurley Children's Hospital, Flint, Michigan, USA
| | - Chetna Mangat
- Department of Pediatrics, Hurley Children's Hospital, Flint, Michigan, USA
| | - Yaseen Rafe'e
- Department of Infectious Disease, Hurley Children's Hospital, Flint, Michigan, USA
| | - Mahesh Sharman
- Department of Intensive Care, Hurley Children's Hospital, Flint, Michigan, USA
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Abstract
Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related life-threatening conditions featuring ineffective immunity characterized by an uncontrolled hyperinflammatory response. HLH is often triggered by infection. Familial forms result from genetic defects in natural killer cells and cytotoxic T-cells, typically affecting perforin and intracellular vesicles. HLH is likely under-recognized, which contributes to its high morbidity and mortality. Early recognition is crucial for any reasonable attempt at curative therapy to be made. Current treatment regimens include immunosuppression, immune modulation, chemotherapy, and biological response modification, followed by hematopoietic stem-cell transplant (bone marrow transplant). A number of recent studies have contributed to the understanding of HLH pathophysiology, leading to alternate treatment options; however, much work remains to raise awareness and improve the high morbidity and mortality of these complex conditions.
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Affiliation(s)
- Melissa R George
- Department of Pathology, Penn State Milton S Hershey Medical Center, Hershey, PA, USA
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49
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Santos JA, Neves JF, Venâncio P, Gouveia C, Varandas L. Hemophagocytic lymphohistiocytosis secondary to Falciparum malaria in a 5 year-old boy. Ann Hematol 2014; 94:161-3. [PMID: 24880248 DOI: 10.1007/s00277-014-2118-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Accepted: 05/20/2014] [Indexed: 02/08/2023]
Affiliation(s)
- Joana Almeida Santos
- Pediatric Department, Hospital Dona Estefânia, Centro Hospitalar Lisboa Central, EPE, Rua Jacinta Marto, 1169-045, Lisbon, Portugal,
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Morel Z, Ramírez A. Autoimmune response in children with dengue. Case reports. ACTA ACUST UNITED AC 2014; 10:257-9. [PMID: 24666813 DOI: 10.1016/j.reuma.2013.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2012] [Revised: 06/18/2013] [Accepted: 07/03/2013] [Indexed: 10/25/2022]
Abstract
Dengue is an infectious disease caused by the dengue virus (DV), which can progress to dengue hemorrhagic fever and dengue shock syndrome. DV causes the production of auto-antibodies against human cells. A variety of factors have been associated with macrophage activation syndrome, including infections, drugs and autoimmune pathologies (systemic lupus erythematosus, systemic onset juvenile idiopathic arthritis). We present three cases of patients that clinically developed an autoimmune response related to a DV infection. Our country currently has endemic cases of dengue, with hyperimmune responses. Therefore, the physician should consider this possibility in the presence of unusual conditions.
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Affiliation(s)
- Zoilo Morel
- Servicio de Pediatría, Reumatología Pediátrica, Hospital Central del Instituto de Previsión Social, Asunción, Paraguay.
| | - Andrea Ramírez
- Servicio de Pediatría, Hospital Central del Instituto de Previsión Social, Asunción, Paraguay
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