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1
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Povedano Medina MA, Arnau Prieto Á, Parra Zurutuza A, Martínez Amunarriz C, Bustinduy Odriozola MJ, Camino Ortiz de Barrón X, Pérez Santaolalla E, Maíz Alonso O, Benavente Claveras I, Rodrigo de Tomas MT. Hemophagocytic Lymphohistiocytosis in a Kidney Transplant Recipient: Case Report. Transplant Proc 2025; 57:90-92. [PMID: 39753491 DOI: 10.1016/j.transproceed.2024.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/15/2024] [Indexed: 02/14/2025]
Abstract
Hemophagocytic lymphohistiocytosis is a potentially fatal multisystemic inflammatory syndrome that is better understood in the pediatric population. Consequently, the diagnostic criteria for adults still derives from studies conducted in the pediatric population. Several genetic mutations and secondary causes, including infections, autoimmunity, and malignancy, have been reported as significant actors in this condition, especially in adults. It is of the utmost importance to identify these triggers, as the treatment of this condition is largely dependent on addressing the underlying cause. Those who have undergone transplantation and whose immune response is already compromised are particularly susceptible to this condition. We present the case of a 74-year-old kidney transplant recipient who was admitted due to a persistent fever of unknown origin, pancytopenia, and splenomegaly. The patient was ultimately diagnosed with hemophagocytic lymphohistiocytosis in our hospital secondary to Epstein-Barr virus, aspergillosis, and leishmania infections. Targeted treatments for the aforementioned conditions led to the resolution of the syndrome and the recovery of the patient. Lymphohistiocytosis is a rare, albeit serious, condition that should be considered a differential diagnosis in the early stages of critical illness in transplant recipient patients. Doing so enables target treatments to be administered as soon as possible.
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Affiliation(s)
| | | | | | | | | | | | | | - Olga Maíz Alonso
- Rheumatology, Hospital Universitario Donostia, San Sebastián, España
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2
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Qureshi Z, Altaf F, Jamil A, Siddique R. Rituximab as a Therapeutic Strategy in Hemophagocytic Lymphohistiocytosis: Efficacy, Outcomes, and Survival-Insights From a Systematic Review. Am J Clin Oncol 2024; 47:498-508. [PMID: 38934172 DOI: 10.1097/coc.0000000000001119] [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: 06/28/2024]
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a severe immunologic disorder that can be fatal if left untreated. The condition is characterized by excessive immune system activation and is often triggered by infections such as Epstein-Barr virus (EBV). Rituximab, an anti-CD20 monoclonal antibody, has been suggested as a treatment, particularly for EBV-associated HLH. METHODS A systematic review was conducted using PRISMA guidelines, with a literature search spanning PubMed, Scopus, Web of Science, and the Cochrane Library. The inclusion criteria focused on studies that assessed rituximab's efficacy in treating HLH. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal Checklist for Case Reports. RESULTS Of 783 identified records, 24 studies were included in the final analysis. Rituximab was typically administered at 375 mg/m 2 , with varying doses and treatment frequency. Clinical response, often seen within 1 month, was assessed by improvements in clinical symptoms and laboratory findings. Survival rates posttreatment displayed a wide range, with instances of complete remission and disease-free periods, as well as reports of relapse and mortality. CONCLUSIONS Rituximab demonstrates the potential for significant clinical benefit in treating HLH, particularly when associated with EBV, showing promise in reducing disease activity and contributing to remission. These findings encourage further research and clinical trials to refine the therapeutic protocols and better understand the long-term effects of rituximab in HLH management.
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Affiliation(s)
- Zaheer Qureshi
- Frank H. Netter M.D. School of Medicine at Quinnipiac University, Bridgeport, CT
| | - Faryal Altaf
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai/BronxCare Health System, New York
| | - Abdur Jamil
- Department of Medicine, Samaritan Medical Center
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Gioia C, Paroli M, Izzo R, Di Sanzo L, Rossi E, Pignatelli P, Accapezzato D. Pathogenesis of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Case Report and Review of the Literature. Int J Mol Sci 2024; 25:5921. [PMID: 38892108 PMCID: PMC11173133 DOI: 10.3390/ijms25115921] [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: 04/26/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.
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Affiliation(s)
| | | | | | | | | | | | - Daniele Accapezzato
- Division of Clinical Immunology, Department of Clinical, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy; (C.G.); (M.P.); (R.I.); (L.D.S.); (E.R.); (P.P.)
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Xu S, He K. Hemophagocytic lymphohistiocytosis after solid organ transplantation: A challenge for clinicians. Transpl Immunol 2024; 83:102007. [PMID: 38307154 DOI: 10.1016/j.trim.2024.102007] [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: 02/21/2023] [Revised: 01/29/2024] [Accepted: 01/30/2024] [Indexed: 02/04/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare inflammatory disorder with a high mortality rate and a wide range of symptoms. Solid organ transplantation, which provides patients with a unique immunosuppressive state, is a less common predisposing factor for HLH. HLH after solid organ transplantation (HLH-SOT) is very rare and fatal. It is hard to diagnose and treat and extremely understudied. The use of immunosuppressants makes the situation of HLH-SOT more complex. This review summarizes the existing literature on HLH after solid organ transplantation and describes its triggers and symptoms, focusing on its diagnosis and treatment. We performed a literature search of case reports, case series, letters to the editor, and clinical quizzes describing patients with HLH after solid organ transplantation (HLH-SOT). We provide recommendations on the diagnosis protocol and treatment strategy based on the existing evidence.
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Affiliation(s)
- Shanshan Xu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Engineering Research Center of Transplantation and Immunology, Shanghai, China; Shanghai Institute of Transplantation, Shanghai, China.
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5
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Carcillo JA, Shakoory B. Cytokine Storm and Sepsis-Induced Multiple Organ Dysfunction Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:441-457. [PMID: 39117832 DOI: 10.1007/978-3-031-59815-9_30] [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
There is extensive overlap of clinical features among familial or primary HLH (pHLH), reactive or secondary hemophagocytic lymphohistiocytosis (sHLH) [including macrophage activation syndrome (MAS) related to rheumatic diseases], and hyperferritinemic sepsis-induced multiple organ dysfunction syndrome (MODS); however, the distinctive pathobiology that causes hyperinflammatory process in each condition requires careful considerations for therapeutic decision-making. pHLH is defined by five or more of eight HLH-2004 criteria [1], where genetic impairment of natural killer (NK) cells or CD8+ cytolytic T cells results in interferon gamma (IFN-γ)-induced hyperinflammation regardless of triggering factors. Cytolytic treatments (e.g., etoposide) or anti-IFN-γ monoclonal antibody (emapalumab) has been effectively used to bridge the affected patients to hematopoietic stem cell transplant. Secondary forms of HLH also have normal NK cell number with decreased cytolytic function of varying degrees depending on the underlying and triggering factors. Although etoposide was uniformly used in sHLH/MAS in the past, the treatment strategy in different types of sHLH/MAS is increasingly streamlined to reflect the triggering/predisposing conditions, severity/progression, and comorbidities. Accordingly, in hyperferritinemic sepsis, the combination of hepatobiliary dysfunction (HBD) and disseminated intravascular coagulation (DIC) reflects reticuloendothelial system dysfunction and defines sepsis-associated MAS. It is demonstrated that as the innate immune response to infectious organism prolongs, it results in reduction in T cells and NK cells with subsequent lymphopenia even though normal cytolytic activity continues (Figs. 30.1, 30.2, 30.3, and 30.4). These changes allow free hemoglobin and pathogens to stimulate inflammasome activation in the absence of interferon-γ (IFN-γ) production that often responds to source control, intravenous immunoglobulin (IVIg), plasma exchange, and interleukin 1 receptor antagonist (IL-1Ra), similar to non-EBV, infection-induced HLH.
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Affiliation(s)
- Joseph A Carcillo
- Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Bita Shakoory
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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6
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Chen QT, Chen MH, Lin YK, Yeh RH, Lu CC, Hsiao PJ, Sung YF. Case report: Hemophagocytic lymphohistiocytosis complicated by multiple organ dysfunction syndrome following aseptic encephalitis. Front Immunol 2023; 14:1296575. [PMID: 38193074 PMCID: PMC10773876 DOI: 10.3389/fimmu.2023.1296575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening condition caused by excessive immune activation. Secondary HLH is usually triggered by infection, most often from viral infection or malignancy. Here, we present a case of secondary HLH, complicated by multiple organ dysfunction syndrome triggered by critical aseptic encephalitis. A 27-year-old man without any underlying disease presented to our hospital with fever, disturbance of consciousness, and generalized seizures. The patient was diagnosed with aseptic encephalitis with super-refractory status epilepticus. Although antiseizure medications and immunoglobulins were administered, the patient developed multiple organ dysfunction syndrome. HLH was later diagnosed based on hypertriglyceridemia, hyperferritinemia, splenomegaly, cytopenia, and phagocytosis of nucleated cells, as shown by a blood smear of bone marrow aspiration. Treatment with pulse steroid therapy and plasmapheresis was initiated rather than chemotherapy because of the patient's critical condition. However, the patient died of profound shock and multiple organ failure. Diagnosis of HLH is challenging in patients with severe infections because of similar clinical manifestations and laboratory findings. The early recognition of HLH provides patients with the opportunity to receive appropriate treatment, which can lead to increased survival and remission rates.
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Affiliation(s)
- Quan-Ting Chen
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Ming-Hua Chen
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Yu-Kai Lin
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ren-Hua Yeh
- Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chun-Chi Lu
- Division of Rheumatology/Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Po-Jen Hsiao
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Yueh-Feng Sung
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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7
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Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW. The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS). Arthritis Rheumatol 2023; 75:1714-1732. [PMID: 37486733 PMCID: PMC11040593 DOI: 10.1002/art.42636] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023]
Abstract
OBJECTIVE Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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Affiliation(s)
- Bita Shakoory
- Translational Autoinflammatory Diseases Section, NIH, Bethesda, Maryland
| | - Ashley Geerlinks
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, and Hematology/Oncology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Hematology/Oncology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Marta Wilejto
- Hematology/Oncology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Kate Kernan
- Pediatric Critical Care Medicine, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Melissa Hines
- Pediatric Critical Care Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Micol Romano
- Pediatrics, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - David Piskin
- Department of Epidemiology and Biostatistics, Western University and Department of Paediatrics, Lawson Health Research Institute, London, Ontario, Canada
| | - Angelo Ravelli
- Direzione Scientifica, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | | | - Daniel Aletaha
- Department of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Carl Allen
- Pediatric Oncology, Texas Children’s Hospital, Houston
| | - Hamid Bassiri
- Pediatric Infectious Diseases, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Edward M. Behrens
- Pediatric Rheumatology, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Joseph Carcillo
- Pediatric Critical Care Medicine, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Linda Carl
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Winn Chatham
- Rheumatology, University of Alabama at Birmingham
| | - Jeffrey I. Cohen
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
| | - Randy Q. Cron
- Pediatric Rheumatology, University of Alabama at Birmingham
| | - Erik Drewniak
- Autoinflammatory Alliance, San Francisco, California
| | - Alexei A. Grom
- Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Lauren A. Henderson
- Pediatric Immunology, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Annacarin Horne
- Department of Women’s and Children’s Health, Karolinska Institutet Cancerforskning KI, Stockholm, Sweden
| | - Michael B. Jordan
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Kim E. Nichols
- Division of Cancer Predisposition Department of Oncology, St. Jude Children’s Research Hospital Department of Oncology, Memphis, Tennessee
| | - Grant Schulert
- Pediatric Rheumatology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Sebastiaan Vastert
- Center for Translational Immunology Research, UMC Utrecht, Utrecht, The Netherlands
| | - Erkan Demirkaya
- Pediatrics, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | | | | | - Rebecca A. Marsh
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio
| | - Scott W. Canna
- Pediatric Rheumatology, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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8
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Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, Piskin D, Ravelli A, Sinha R, Aletaha D, Allen C, Bassiri H, Behrens EM, Carcillo J, Carl L, Chatham W, Cohen JI, Cron RQ, Drewniak E, Grom AA, Henderson LA, Horne A, Jordan MB, Nichols KE, Schulert G, Vastert S, Demirkaya E, Goldbach-Mansky R, de Benedetti F, Marsh RA, Canna SW. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis 2023; 82:1271-1285. [PMID: 37487610 PMCID: PMC11017727 DOI: 10.1136/ard-2023-224123] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/27/2023] [Indexed: 07/26/2023]
Abstract
OBJECTIVE Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
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Affiliation(s)
- Bita Shakoory
- Translational Autoinflammatory Diseases Section, National Institutes of Health, Bethesda, Maryland, USA
| | - Ashley Geerlinks
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
- Hematology/Oncology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Marta Wilejto
- Hematology/Oncology, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Kate Kernan
- Pediatric Critical Care Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Melissa Hines
- Pediatric Critical Care Medicine, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Micol Romano
- Pediatrics, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - David Piskin
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
- Department of Paediatrics, Lawson Health Research Institute, London, Ontario, Canada
| | - Angelo Ravelli
- Direzione Scientifica, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | | | - Daniel Aletaha
- Department of Rheumatology, Medical University of Vienna, Vienna, Austria
| | - Carl Allen
- Pediatric Oncology, Texas Children's Hospital, Houston, Texas, USA
| | - Hamid Bassiri
- Pediatric Infectious Diseases, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Edward M Behrens
- Pediatric Rheumatology, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Joseph Carcillo
- Pediatric Critical Care Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Linda Carl
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Winn Chatham
- Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeffrey I Cohen
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Randy Q Cron
- Pediatric Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Erik Drewniak
- Autoinflammatory Alliance, San Francisco, California, USA
| | - Alexei A Grom
- Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Lauren A Henderson
- Pediatric Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Annacarin Horne
- Department of Women's and Children's Health, Karolinska Institutet Cancerforskning KI, Stockholm, Sweden
| | - Michael B Jordan
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Kim E Nichols
- Division of Cancer Predisposition Department of Oncology, St Jude Children's Research Hospital Department of Oncology, Memphis, Tennessee, USA
| | - Grant Schulert
- Pediatric Rheumatology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Sebastiaan Vastert
- Center for Translational Immunology Research, UMC Utrecht, The Netherlands
| | - Erkan Demirkaya
- Pediatrics, University of Western Ontario Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Raphaela Goldbach-Mansky
- Translational Autoinflammatory Diseases Section, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Rebecca A Marsh
- Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio, USA
| | - Scott W Canna
- Pediatric Rheumatology, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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Benevenuta C, Mussinatto I, Orsi C, Timeus FS. Secondary hemophagocytic lymphohistiocytosis in children (Review). Exp Ther Med 2023; 26:423. [PMID: 37602304 PMCID: PMC10433411 DOI: 10.3892/etm.2023.12122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 06/16/2023] [Indexed: 08/22/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by hyperinflammation in an uncontrolled and ineffective immune response. Despite great improvement in diagnosis and treatment, it still represents a challenge in clinical management, with poor prognosis in the absence of an aggressive therapeutic approach. The present literature review focuses on secondary HLH at pediatric age, which represents a heterogeneous group in terms of etiology and therapeutic approach. It summarizes the most recent evidence on epidemiology, pathophysiology, diagnosis, treatment and prognosis, and provides a detailed description and comparison of the major subtypes of secondary HLH. Finally, it addresses the open questions with a focus on diagnosis and new treatment insights.
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Affiliation(s)
- Chiara Benevenuta
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Ilaria Mussinatto
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Cecilia Orsi
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
| | - Fabio S. Timeus
- Department of Pediatrics, Azienda Sanitaria Locale Torino 4, Chivasso Hospital, I-10034 Turin, Italy
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10
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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: 42] [Impact Index Per Article: 10.5] [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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11
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Abstract
Macrophage activation syndrome is a severe yet under-recognized complication encountered in pediatric rheumatology. It manifests as secondary hemophagocytic lymphohistiocytosis leading to a hyper-inflammatory state resulting from an underlying cytokine storm. If unchecked, it may lead to multiorgan failure and mortality. Early diagnosis and timely initiation of specific therapy is pivotal for a successful outcome. This review outlines the key clinical and laboratory features and management of macrophage activation syndrome.
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Affiliation(s)
- Narendra Kumar Bagri
- Division of Pediatric Rheumatology, Department of Pediatrics, AIIMS, New Delhi; India. Correspondence to: Dr Narendra Kumar Bagri, Associate Professor, Division of Pediatric Rheumatology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 027, India.
| | - Latika Gupta
- Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Ethan S Sen
- Department of Pediatric Rheumatology, Great North Children's Hospital, and Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - A V Ramanan
- Department of Pediatric Rheumatology, University Hospitals Bristol NHS Foundation Trust and Translational Health Sciences, University of Bristol, Bristol, UK
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12
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Abstract
Primary immune regulatory disorders (PIRDs) are a group of diseases belonging to inborn errors of immunity. They usually exhibit lymphoproliferation, autoimmunities, and malignancies, with less susceptibility to recurrent infections. Unlike classical primary immune deficiencies, in autoimmune manifestations, such as cytopenias, enteropathy can be the first symptom of diseases, and they are typically resistant to treatment. Increasing awareness of PIRDs among specialists and a multidisciplinary team approach would provide early diagnosis and treatment that could prevent end-organ damage related to the diseases. In recent years, many PIRDs have been described, and understanding the immunological pathways linked to these disorders provides us an opportunity to use directed therapies for specific molecules, which usually offer better disease control than known classical immunosuppressants. In this review, in light of the most recent literature, we will discuss the common PIRDs and explain their clinical symptoms and recent treatment modalities.
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Affiliation(s)
- Burcu Kolukısa
- Marmara University Faculty of Medicine, Division of Pediatric Allergy and Immunology, İstanbul, Turkey,İstanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, İstanbul, Turkey,The Işıl Berat Barlan Center for Translational Medicine, İstanbul, Turkey
| | - Safa Barış
- Marmara University Faculty of Medicine, Division of Pediatric Allergy and Immunology, İstanbul, Turkey,İstanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, İstanbul, Turkey,The Işıl Berat Barlan Center for Translational Medicine, İstanbul, Turkey
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13
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Pediatric hemophagocytic lymphohistiocytosis. Blood 2020; 135:1332-1343. [PMID: 32107531 DOI: 10.1182/blood.2019000936] [Citation(s) in RCA: 271] [Impact Index Per Article: 54.2] [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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14
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Canna SW, Cron RQ. Highways to hell: Mechanism-based management of cytokine storm syndromes. J Allergy Clin Immunol 2020; 146:949-959. [PMID: 33007328 PMCID: PMC7522622 DOI: 10.1016/j.jaci.2020.09.016] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/23/2020] [Accepted: 09/23/2020] [Indexed: 12/12/2022]
Abstract
Since the first textbook devoted to cytokine storm syndromes (CSSs) was published in 2019, the world has changed dramatically and the term’s visibility has broadened. Herein, we define CSSs broadly to include life/organ-threatening systemic inflammation and immunopathology regardless of the context in which it occurs, recognizing that the indistinct borders of such a definition limit its utility. Nevertheless, we are focused on the pathomechanisms leading to CSSs, including impairment of granule-mediated cytotoxicity, specific viral infections, excess IL-18, and chimeric antigen receptor T-cell therapy. These mechanisms are often reflected in distinct clinical features, functional tests, and/or biomarker assessments. Moreover, these mechanisms often indicate specific, definitive treatments. This mechanism-focused organization is vital to both advancing the field and understanding the complexities in individual patients. However, increasing evidence suggests that these mechanisms interact and overlap. Likewise, the utility of a broad term such as “cytokine storm” is that it reflects a convergence on a systemic inflammatory phenotype that, regardless of cause or context, may be amenable to “inflammo-stabilization.” CSS research must improve our appreciation of its various mechanisms and their interactions and treatments, but it must also identify the signs and interventions that may broadly prevent CSS-induced immunopathology.
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Affiliation(s)
- Scott W Canna
- University of Pittsburgh/UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pa.
| | - Randy Q Cron
- University of Alabama, Birmingham/Children's of Alabama, Birmingham, Ala
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15
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Griffin G, Shenoi S, Hughes GC. Hemophagocytic lymphohistiocytosis: An update on pathogenesis, diagnosis, and therapy. Best Pract Res Clin Rheumatol 2020; 34:101515. [PMID: 32387063 DOI: 10.1016/j.berh.2020.101515] [Citation(s) in RCA: 182] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening state of immune hyperactivation that arises in the setting of genetic mutations and infectious, inflammatory, or neoplastic triggers. Sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms. Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy. HLH is likely under-recognized, and mortality remains high, especially in adults; thus, prompt diagnosis and treatment are essential. Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation. HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A. In other forms of HLH, addressing the underlying trigger is essential. There remains a pressing need for more sensitive, context-specific diagnostic tools. Safer, more effective therapies will arise with improved understanding of the cellular and molecular mechanisms of HLH.
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Affiliation(s)
- Georgia Griffin
- Division of Rheumatology, Seattle Children's Hospital, Seattle, WA, USA.
| | - Susan Shenoi
- Division of Rheumatology, Seattle Children's Hospital, Seattle, WA, USA
| | - Grant C Hughes
- Division of Rheumatology, University of Washington, Seattle, WA, USA
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16
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Jordan MB, Allen CE, Greenberg J, Henry M, Hermiston ML, Kumar A, Hines M, Eckstein O, Ladisch S, Nichols KE, Rodriguez-Galindo C, Wistinghausen B, McClain KL. Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO). Pediatr Blood Cancer 2019; 66:e27929. [PMID: 31339233 PMCID: PMC7340087 DOI: 10.1002/pbc.27929] [Citation(s) in RCA: 240] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/10/2019] [Accepted: 06/28/2019] [Indexed: 12/15/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.
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Affiliation(s)
- Michael B. Jordan
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Carl E. Allen
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Jay Greenberg
- Division of Hematology, Children’s National Medical Center, Washington, DC
| | - Michael Henry
- Center for Cancer and Blood Disorders, Phoenix Children’s Hospital, University of Arizona College of Medicine, Tucson, Arizona
| | - Michelle L. Hermiston
- Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, California
| | - Ashish Kumar
- Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Melissa Hines
- Division of Critical Care, Department of Pediatric Medicine, St Jude Children’s Research Hospital, Memphis, Tennessee
| | - Olive Eckstein
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Stephan Ladisch
- Center for Cancer and Immunology Research, Children’s National Medical Center and George Washington University School of Medicine, Washington, DC
| | - Kim E. Nichols
- Division of Cancer Predisposition, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Carlos Rodriguez-Galindo
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Birte Wistinghausen
- Division of Oncology, Center for Cancer and Blood Disorders, Children’s National Health System, Washington, DC
| | - Kenneth L. McClain
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
- Additional corresponding author, Kenneth L. McClain, 6701 Fannin St. Suite 1510, Houston, TX 77030,
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17
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García-Cadenas I, Yáñez L, Jarque I, Martino R, Pérez-Simón JA, Valcárcel D, Sanz J, Bermúdez A, Muñoz C, Calderón-Cabrera C, García E, Alonso L, Suárez-Lledó M, González Vicent M, Heras I, Viguria MC, Batlle M, Vázquez L, López J, Solano C. Frequency, characteristics, and outcome of PTLD after allo-SCT: A multicenter study from the Spanish group of blood and marrow transplantation (GETH). Eur J Haematol 2019; 102:465-471. [DOI: 10.1111/ejh.13226] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/21/2019] [Accepted: 02/23/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Irene García-Cadenas
- Department of Hematology of the: Hospital de la Santa Creu I Sant Pau, Biomedical Research Institute (IIB Sant-Pau); Autonomous University of Barcelona; Barcelona Spain
| | | | | | - Rodrigo Martino
- Department of Hematology of the: Hospital de la Santa Creu I Sant Pau, Biomedical Research Institute (IIB Sant-Pau); Autonomous University of Barcelona; Barcelona Spain
| | - Jose Antonio Pérez-Simón
- HU. Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC); Universidad de Sevilla; Sevilla Spain
| | | | | | | | | | - Cristina Calderón-Cabrera
- HU. Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC/CIBERONC); Universidad de Sevilla; Sevilla Spain
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18
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Yanagisawa R, Nakazawa Y, Matsuda K, Yasumi T, Kanegane H, Ohga S, Morimoto A, Hashii Y, Imaizumi M, Okamoto Y, Saito AM, Horibe K, Ishii E. Outcomes in children with hemophagocytic lymphohistiocytosis treated using HLH-2004 protocol in Japan. Int J Hematol 2018; 109:206-213. [PMID: 30535855 DOI: 10.1007/s12185-018-02572-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/26/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.
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Affiliation(s)
- Ryu Yanagisawa
- Division of Blood Transfusion, Shinshu University Hospital, Matsumoto, Japan
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Yozo Nakazawa
- Department of Pediatrics, Shinshu University School of Medicine, 3-1-1, Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Kazuyuki Matsuda
- Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan
| | - Takahiro Yasumi
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Morimoto
- Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan
| | - Yoshiko Hashii
- Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masue Imaizumi
- Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan
| | - Yasuhiro Okamoto
- Department of Pediatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Akiko M Saito
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Keizo Horibe
- Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan
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19
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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 2018; 104:269-276. [PMID: 30213834 PMCID: PMC6355492 DOI: 10.3324/haematol.2018.198655] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [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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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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21
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Ragab G, Atkinson TP, Stoll ML. Macrophage Activation Syndrome. THE MICROBIOME IN RHEUMATIC DISEASES AND INFECTION 2018. [PMCID: PMC7123081 DOI: 10.1007/978-3-319-79026-8_14] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH), or termed macrophage activation syndrome (MAS) when associated with rheumatic disorders, is a frequently fatal complication of infections, rheumatic disorders, and hematopoietic malignancies. Clinically, HLH/MAS is a life-threatening condition that is usually diagnosed among febrile hospitalized patients (children and adults) who commonly present with unremitting fever and a shock-like multiorgan dysfunction scenario. Laboratory studies reveal pancytopenia, elevated liver enzymes, elevated markers of inflammation (ESR, CRP), hyperferritinemia, and features of coagulopathy. In about 60% of cases, excess hemophagocytosis (macrophages/histiocytes engulfing other hematopoietic cell types) is noted on biopsy specimens from the bone marrow, liver, lymph nodes, and other organs. HLH/MAS has been hypothesized to occur when a threshold level of inflammation has been achieved, and genetic and environmental risk factors are believed to contribute to the hyperinflammatory state. A broad variety of infections, from viruses to fungi to bacteria, have been identified as triggers of HLH/MAS, either in isolation or in addition to an underlying inflammatory disease state. Certain infections, particularly by members of the herpesvirus family, are the most notorious triggers of HLH/MAS. Treatment for infection-triggered MAS requires therapy for both the underlying infection and dampening of the hyperactive immune response.
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Affiliation(s)
- Gaafar Ragab
- Faculty of Medicine, Cairo University, Cairo, Egypt
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22
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Ruscitti P, Cipriani P, Di Benedetto P, Liakouli V, Carubbi F, Berardicurti O, Ciccia F, Guggino G, Triolo G, Giacomelli R. Advances in immunopathogenesis of macrophage activation syndrome during rheumatic inflammatory diseases: toward new therapeutic targets? Expert Rev Clin Immunol 2017; 13:1041-1047. [PMID: 28837367 DOI: 10.1080/1744666x.2017.1372194] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Macrophage activation syndrome (MAS) is a severe, hyperinflammatory life-threatening syndrome, generally complicating different rheumatic diseases. Despite the severity of the disease, little is known about the pathogenic mechanisms and, thus, possible targeted therapies in the management of these patients. Areas covered: In this review, we aimed to update the current pathogenic knowledge of MAS, during rheumatic diseases, focusing mainly on immunologic abnormalities and on new possible therapeutic strategies. Expert commentary: The difficult pathogenic scenario of MAS, in which genetic defects, predisposing diseases, and triggers are mixed together with the high mortality rate, make it difficult to manage these patients. Although most efforts have been focused on investigating the disease in children, in recent years, several studies are trying to elucidate the possible pathogenic mechanism in adult MAS patients. In this context, genetic and immunological studies might lead to advances in the knowledge of pathogenic mechanisms and possible new therapeutic targets. In the future, the results of ongoing clinical trials are awaited in order to improve the management and, thus, the survival of these patients.
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Affiliation(s)
- Piero Ruscitti
- a Division of Rheumatology , University of L'Aquila , L'Aquila , Italy
| | - Paola Cipriani
- a Division of Rheumatology , University of L'Aquila , L'Aquila , Italy
| | | | - Vasiliky Liakouli
- a Division of Rheumatology , University of L'Aquila , L'Aquila , Italy
| | - Francesco Carubbi
- a Division of Rheumatology , University of L'Aquila , L'Aquila , Italy
| | | | - Francesco Ciccia
- b Division of Rheumatology , University of Palermo , Palermo , Italy
| | - Giuliana Guggino
- b Division of Rheumatology , University of Palermo , Palermo , Italy
| | - Giovanni Triolo
- b Division of Rheumatology , University of Palermo , Palermo , Italy
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23
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Wang H, Xiong L, Tang W, Zhou Y, Li F. A systematic review of malignancy-associated hemophagocytic lymphohistiocytosis that needs more attentions. Oncotarget 2017; 8:59977-59985. [PMID: 28938698 PMCID: PMC5601794 DOI: 10.18632/oncotarget.19230] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 06/29/2017] [Indexed: 12/11/2022] Open
Abstract
As an infrequent but potentially life-threatening hyperinflammatory syndrome, hemophagocytic lymphohistiocytosis (HLH) is clinically characterized with prolonged fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia and hemophagocytosis in bone marrow, liver, spleen or lymph nodes. Malignancy-associated HLH (M-HLH), one type of acquired HLH, usually presents variable overlaps of symptoms with other types of HLH, thus resulting in higher incidence of misdiagnosis and mortality. In recent years, with the increasing awareness to this disease, the diagnosis and management of HLH have gained more and more attention, and improvements have been made accordingly. As a result, the survival of patients is greatly prolonged. However, there is still no consensus on the diagnostic criteria and treatment strategies due to lack of large samples or prospective clinical trials. In order to improve recognition and diagnosis, and provide guidance regarding the treatment of M-HLH, the Study Group in HLH Subtypes of the Histiocyte Society has developed consensus recommendations for the diagnosis and management of M-HLH in 2015. In the present article, we summarized and discussed some updated understandings in M-HLH.
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Affiliation(s)
- Hongluan Wang
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.,Medical College, Nanchang University, Nanchang, Jiangxi 330006, China.,Department of Respiratory, Jiangxi Provincial People's Hospital, Nanchang, Jiangxi 330006, China
| | - Lixia Xiong
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.,Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Weiping Tang
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China.,Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Ying Zhou
- Medical College, Nanchang University, Nanchang, Jiangxi 330006, China
| | - Fei Li
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China
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Weaver LK, Behrens EM. Weathering the storm: Improving therapeutic interventions for cytokine storm syndromes by targeting disease pathogenesis. CURRENT TREATMENT OPTIONS IN RHEUMATOLOGY 2017; 3:33-48. [PMID: 28944163 DOI: 10.1007/s40674-017-0059-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cytokine storm syndromes require rapid diagnosis and treatment to limit the morbidity and mortality caused by the hyperinflammatory state that characterizes these devastating conditions. Herein, we discuss the current knowledge that guides our therapeutic decision-making and personalization of treatment for patients with cytokine storm syndromes. Firstly, ICU-level supportive care is often required to stabilize patients with fulminant disease while additional diagnostic evaluations proceed to determine the underlying cause of cytokine storm. Pharmacologic interventions should be focused on removing the inciting trigger of inflammation and initiation of an individualized immunosuppressive regimen when immune activation is central to the underlying disease pathophysiology. Monitoring for a clinical response is required to ensure that changes in the therapeutic regimen can be made as clinically warranted. Escalation of immunosuppression may be required if patients respond poorly to the initial therapeutic interventions, while a slow wean of immunosuppression in patients who improve can limit medication-related toxicities. In certain scenarios, a decision must be made whether an individual patient requires hematopoietic cell transplantation to prevent recurrence of disease. Despite these interventions, significant morbidity and mortality remains for cytokine storm patients. Therefore, we use this review to propose a clinical schema to guide current and future attempts to design rational therapeutic interventions for patients suffering from these devastating conditions, which we believe speeds the diagnosis of disease, limits medication-related toxicities, and improves clinical outcomes by targeting the heterogeneous and dynamic mechanisms driving disease in each individual patient.
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Affiliation(s)
- Lehn K Weaver
- Division of Pediatric Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Edward M Behrens
- Division of Pediatric Rheumatology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Horne A, Wickström R, Jordan MB, Yeh EA, Naqvi A, Henter JI, Janka G. How to Treat Involvement of the Central Nervous System in Hemophagocytic Lymphohistiocytosis? Curr Treat Options Neurol 2017; 19:3. [PMID: 28155064 PMCID: PMC5290057 DOI: 10.1007/s11940-017-0439-4] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OPINION STATEMENT Central nervous system (CNS)-hemophagocytic lymphohistiocytosis (HLH) is not a disease in itself, but it is part of a systemic immune response. The vast majority of patients with CNS-HLH also have systemic HLH and a large number of patients with primary and secondary HLH have CNS involvement. Reactivations within the CNS are frequent during the course of HLH treatment and may occur concomitant with or independent of systemic relapses. It is also important to consider primary HLH as an underlying cause of "unknown CNS inflammation" as these patients may present with only CNS disease. To initiate proper treatment, a correct diagnosis must be made. A careful review of the patient's history and a thorough neurological examination are essential. In addition to the blood tests required to make a diagnosis of HLH, a lumbar puncture with cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) should always be done in all cases regardless of the presence or absence of neurological signs or symptom. Treatment options for CNS-HLH include, but are not limited to, those commonly used in systemic HLH, including corticosteroids, etoposide, cyclosporine A, alemtuzumab, and ATG. In addition, intrathecal treatment with methotrexate and corticosteroids has become a standard care and is likely to be beneficial. Therapy must be initiated without inappropriate delay to prevent late effects in HLH. An interesting novel approach is an anti-IFN-gamma antibody (NI-0501), which is currently being tested. Hematopoietic stem cell transplantation (HSCT) also represents an important CNS-HLH treatment; patients with primary HLH may benefit from immediate HSCT even if there is active disease at time of transplantation, though care should be taken to monitor CNS inflammation through HSCT and treat if needed. Since CNS-HLH is a condition leading to the most severe late effects of HLH, early expert consultation is recommended.
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Affiliation(s)
- AnnaCarin Horne
- Department of Women's and Children's Health, Karolinska Institute, Division of Pediatrics Karolinska University Hospital, Stockholm, Sweden.
| | - Ronny Wickström
- Department of Women's and Children's Health, Karolinska Institute, Division of Pediatrics Karolinska University Hospital, Stockholm, Sweden
| | - Michael B Jordan
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - E Ann Yeh
- Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Ahmed Naqvi
- Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Jan-Inge Henter
- Department of Women's and Children's Health, Karolinska Institute, Division of Pediatrics Karolinska University Hospital, Stockholm, Sweden
| | - Gritta Janka
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
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26
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Papageorgiou SG, Tsiodras S, Siakallis G, Bazani E, Spathis A, Poulakou G, Korkolopoulou P, Panayiotides I, Pappa V. Epstein barr virus hemophagocytic lymphohistiocytosis related to rituximab use and immunopathogenetic insights. Pathol Res Pract 2016; 212:1194-1198. [DOI: 10.1016/j.prp.2016.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 08/17/2016] [Accepted: 10/13/2016] [Indexed: 01/07/2023]
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27
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Ruscitti P, Cipriani P, Ciccia F, Masedu F, Liakouli V, Carubbi F, Berardicurti O, Guggino G, Di Benedetto P, Di Bartolomeo S, Valenti M, Triolo G, Giacomelli R. Prognostic factors of macrophage activation syndrome, at the time of diagnosis, in adult patients affected by autoimmune disease: Analysis of 41 cases collected in 2 rheumatologic centers. Autoimmun Rev 2016; 16:16-21. [PMID: 27664384 DOI: 10.1016/j.autrev.2016.09.016] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 07/29/2016] [Indexed: 12/21/2022]
Abstract
Macrophage activation syndrome (MAS) is a rare, life-threatening disease in which early diagnosis and aggressive therapeutic strategy may improve the outcome. Due to its rarity, epidemiologic data are still lacking. Hyperferritinemia is frequently associated with MAS and might modulate the cytokine storm, which is involved in the development of multiple organ failure. In this paper, we investigated clinical data, treatments, and outcome of a homogeneous cohort of 41 adult MAS patients, complicating autoimmune rheumatic diseases. MAS-related death occurred in 17 patients (42.5%) during the follow-up, and older age and increased serum ferritin levels, at the time of diagnosis, were significantly associated with mortality. In conclusion, adult MAS is associated with high mortality rate. Some clinical features at diagnosis may be predictive of MAS-associated death.
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Affiliation(s)
- Piero Ruscitti
- Division of Rheumatology, University of L'Aquila, L'Aquila, Italy
| | - Paola Cipriani
- Division of Rheumatology, University of L'Aquila, L'Aquila, Italy
| | | | - Francesco Masedu
- Division of Medical Statistic Unit, University of L'Aquila, L'Aquila, Italy
| | | | | | | | | | | | | | - Marco Valenti
- Division of Medical Statistic Unit, University of L'Aquila, L'Aquila, Italy
| | - Giovanni Triolo
- Division of Rheumatology, University of Palermo, Palermo, Italy
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Abstract
Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic diseases such as systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus. It is often considered a type of secondary hemophagocytic lymphohistiocytosis (HLH) and results from over-activation of T lymphocytes and macrophages leading to a "cytokine storm". Characteristic features are persistent fever, lymphadenopathy, hepatosplenomegaly, cytopenias (anemia, leucopenia, thrombocytopenia), raised C-reactive protein, falling erythrocyte sedimentation rate, hypofibrinogenemia, transaminitis, hypertriglyceridemia and extreme hyperferritinemia often associated with multi-organ impairment. Key to its management is early recognition of MAS which may be difficult due to similarity to systemic sepsis or flares of the underlying rheumatic disease. To aid with this process, criteria for the diagnosis of MAS in patients with sJIA derived by international consensus have been published. Although bone marrow biopsy showing hemophagocytosis is strongly supportive it is not essential for diagnosis. Together with appropriate supportive care, first-line treatment is high-dose intravenous corticosteroids with cyclosporin or intravenous immunoglobulin (IVIg) added if there is not initial response. Although etoposide is used by hematologists in treatment of HLH, there are concerns regarding organ toxicity and bone marrow suppression which weigh against its use in initial management of MAS. With increasing understanding of the pathogenesis of MAS, use of drugs targeting specific cytokines has been reported in case series. The relatively rapid effectiveness of anakinra, a recombinant IL-1 receptor antagonist, has been documented. Further studies of this and other biologic agents are required to identify the most effective and safest treatment option for refractory MAS.
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Affiliation(s)
- Ethan S Sen
- Department of Pediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ, UK
- School of Clinical Sciences, University of Bristol, Bristol, UK
| | - Sarah L N Clarke
- Department of Pediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ, UK
- School of Clinical Sciences, University of Bristol, Bristol, UK
| | - Athimalaipet V Ramanan
- Department of Pediatric Rheumatology, Bristol Royal Hospital for Children, Upper Maudlin Street, Bristol, BS2 8BJ, UK.
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29
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Ishii E. Hemophagocytic Lymphohistiocytosis in Children: Pathogenesis and Treatment. Front Pediatr 2016; 4:47. [PMID: 27242976 PMCID: PMC4865497 DOI: 10.3389/fped.2016.00047] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 04/28/2016] [Indexed: 12/13/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder in children that is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia. Increased levels of various cytokines and soluble interleukin-2 receptor are biological markers of HLH. HLH can be classified into two major forms: primary and secondary. Familial hemophagocytic lymphohistiocytosis (FHL), a type of primary HLH, is an autosomal recessive disorder that typically occurs in infancy and can be classified into five different subtypes (FHL types 1-5). In Japan, >80% of patients with FHL have either PRF1 (FHL type 2) or UNC13D (FHL type 3) defects. FHL is considered to be a disorder of T-cell function because the activity of NK cells or cytotoxic T lymphocytes as target cells is usually impaired. Moreover, Epstein-Barr virus-associated HLH (EBV-HLH) is considered a major subtype of secondary HLH. Any genetic background could have an effect on the pathogenesis of secondary HLH because EBV-HLH is considered to be particularly prevalent in Asian countries. For primary HLH, hematopoietic stem cell transplantation is the only accepted curative therapy, although cord blood transplantation with a reduced-conditioning regimen has been used with superior outcomes. For secondary HLH, including EBV-HLH, immunochemotherapy based on the HLH-2004 protocol has been used. In the near future, the entire mechanism of HLH should be clarified to establish less toxic therapies, including cell therapy and gene targeting therapy.
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Affiliation(s)
- Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine , Toon, Ehime , Japan
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30
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Imashuku S. Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis: Study protocol of a prospective pilot study. World J Hematol 2015; 4:69-75. [DOI: 10.5315/wjh.v4.i4.69] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 09/06/2015] [Accepted: 10/13/2015] [Indexed: 02/05/2023] Open
Abstract
In this manuscript, a number of debatable issues related to the diagnosis and treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) will be addressed. Considering the heterogeneous nature of EBV-HLH, diagnostic efforts are required to clarify the precise nature of the disease at diagnosis, the number of EBV genome copies in peripheral blood, and localization of the EBV genome in lymphoid cells (B, T, or natural killer cells). Although the majority of cases of EBV-HLH develop without evidence of immunodeficiency, some cases have been found to be associated with chronic active EBV infection, genetic diseases such as X-linked lymphoproliferative disease (XLP, type 1, or type 2), or familial HLH (FHL, types 2-5). Due to such background heterogeneity, the therapeutic results of EBV-HLH have also been found to vary. Patients have been found to respond to corticosteroids alone or an etoposide-containing regimen, whereas other patients require hematopoietic stem cell transplantation. Thus, decision-making for optimal treatment of EBV-HLH and its eventual outcome requires evaluation in consideration of the precise nature of the disease. A protocol for a pilot study on the treatment of patients with EBV-HLH is presented here.
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Abstract
Macrophage activation syndrome (MAS) is a potentially life-threatening complication of rheumatic disorders that occurs most commonly in systemic juvenile idiopathic arthritis. In recent years, there have been several advances in the understanding of the pathophysiology of MAS. Furthermore, new classification criteria have been developed. Although the place of cytokine blockers in the management of MAS is still unclear, interleukin-1 inhibitors represent a promising adjunctive therapy, particularly in refractory cases.
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Affiliation(s)
- Angelo Ravelli
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Head, Center of Rheumatology, University of Genoa and G. Gaslini Institute, via G. Gaslini 5, Genoa 16147, Italy.
| | - Sergio Davì
- Second Pediatric Division and Rheumatology, G. Gaslini Institute, via G. Gaslini 5, Genoa 16147, Italy
| | - Francesca Minoia
- Second Pediatric Division and Rheumatology, G. Gaslini Institute, via G. Gaslini 5, Genoa 16147, Italy
| | - Alberto Martini
- Department of Pediatrics and Second Pediatric Division and Rheumatology, University of Genoa and G. Gaslini Institute, via G. Gaslini 5, Genoa 16147, Italy
| | - Randy Q Cron
- Director, Division of Pediatric Rheumatology, Children's Hospital of Alabama and University of Alabama at Birmingham, Children's Park Place, Ste. 210 1601 4th Avenue South Birmingham, AL 35233, USA
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32
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Esmaili H, Mostafidi E, Mehramuz B, Ardalan M, Mohajel-Shoja M. An update on renal involvement in hemophagocytic syndrome (macrophage activation syndrome). J Nephropathol 2015; 5:8-14. [PMID: 27047804 PMCID: PMC4790190 DOI: 10.15171/jnp.2016.02] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 07/03/2015] [Indexed: 12/16/2022] Open
Abstract
Context: Hemophagocytic syndrome (HPS) is mainly characterized by massive infiltration of bone marrow by activated macrophages and often presents with pancytopenia. Thrombotic microangiopathy (TMA) is also present with thrombocytopenia and renal involvement. Both conditions could coexist with each other and complicate the condition.
Evidence Acquisition: Directory of Open Access Journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science with keywords relevant to; Hemophagocytic syndrome, macrophage activation syndrome, interferon-gamma and thrombotic microangiopathy, have been searched.
Results: Viral infection, rheumatologic disease and malignancies are the main underlying causes for secondary HPS. calcineurin inhibitors and viral infections are also the main underlying causes of TMA in transplant recipients. In this review, we discussed a 39-year-old male who presented with pancytopenia and renal allograft dysfunction. With the diagnosis of HPS induced TMA his renal condition and pancytopenia improved after receiving intravenous immunoglobulin (IVIG) and plasmapheresis therapy.
Conclusions: HPS is an increasingly recognized disorder in the realm of different medical specialties. Renal involvement complicates the clinical picture of the disease, and this condition even is more complex in renal transplant recipients. We should consider the possibility of HPS in any renal transplant recipient with pancytopenia and allograft dysfunction. The combination of HPS with TMA future increases the complexity of the situation.
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Affiliation(s)
- Haydarali Esmaili
- Department of Pathology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elmira Mostafidi
- Department of Pathology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahareh Mehramuz
- Department of Pathology, Al-Zahra Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
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Alternative therapy for epstein-barr virus related hemophagocytic lymphohistiocytosis. Case Rep Oncol Med 2015; 2015:508387. [PMID: 25737788 PMCID: PMC4337264 DOI: 10.1155/2015/508387] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 01/24/2015] [Indexed: 01/14/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rapidly fatal condition characterized by excessive immune activation. HLH can occur as a familial or sporadic acquired disorder. Acquired HLH is more frequently found in adults and is commonly secondary to infections, malignancies, or autoimmune diseases. Diagnosing HLH is challenging because of the rare occurrence, variable presentation, and nonspecific findings of this disorder. Diagnosis of HLH can be based on the diagnostic criteria which were used in the HLH-2004 trial. Given the rarity of this disease, protocols for its treatment have developed slowly, and obtaining adequate short-term and long-term control of the disease continues to be a challenge. Conventional induction therapy for HLH is dexamethasone and etoposide (VP-16), followed by or with cyclosporine. Intrathecal methotrexate ± hydrocortisone is given to those with central nervous system disease. We are reporting a patient who was diagnosed with Epstein-Barr virus (EBV) related HLH. He achieved complete remission with rituximab alone. To our knowledge, this is the first case of an adult patient with EBV related HLH who went into remission with rituximab therapy alone, without using the conventional chemotherapy.
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Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med 2014; 66:145-59. [PMID: 25386930 DOI: 10.1146/annurev-med-061813-012806] [Citation(s) in RCA: 279] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Macrophage activation syndrome (MAS) is an acute episode of overwhelming inflammation characterized by activation and expansion of T lymphocytes and hemophagocytic macrophages. In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus. The main clinical manifestations include cytopenias, liver dysfunction, coagulopathy resembling disseminated intravascular coagulation, and extreme hyperferritinemia. Clinically and pathologically, MAS bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it. Central to its pathogenesis is a cytokine storm, with markedly increased levels of numerous proinflammatory cytokines including IL-1, IL-6, IL-18, TNFα, and IFNγ. Although there is evidence that IFNγ may play a central role in the pathogenesis of MAS, the role of other cytokines is still not clear. There are several reports of SJIA-associated MAS dramatically benefiting from anakinra, a recombinant IL-1 receptor antagonist, but the utility of other biologics in MAS is not clear. The mainstay of treatment remains corticosteroids; other medications, including cyclosporine, are used in patients who fail to respond.
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Affiliation(s)
- Grant S Schulert
- Division of Pediatric Rheumatology, Children's Hospital Medical Center, Cincinnati, Ohio 45229; ,
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Weber T, Wickenhauser C, Monecke A, Gläser C, Stadler M, Desole M, Ligeti K, Behrmann C, Müller-Tidow C, Müller LP. Treatment of rare co-occurrence of Epstein-Barr virus-driven post-transplant lymphoproliferative disorder and hemophagocytic lymphohistiocytosis after allogeneic stem cell transplantation. Transpl Infect Dis 2014; 16:988-92. [PMID: 25179757 DOI: 10.1111/tid.12287] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 03/28/2014] [Accepted: 06/28/2014] [Indexed: 12/14/2022]
Abstract
In both conditions, post-transplant lymphoproliferative disorder (PTLD) and hemophagocytic lymphohistiocytosis (HLH), infection with Epstein-Barr virus (EBV) is a key mechanism: almost all PTLD in allogeneic stem cell transplantation (alloSCT) is caused by EBV-related neoplastic lymphoproliferation, and secondary HLH is most frequently triggered by EBV infection. Therefore, concomitant EBV-driven PTLD and HLH early after alloSCT require an approach to eliminate EBV and balance immune activation simultaneously. We report on a patient who developed simultaneous PTLD and signs of HLH on day 64 after alloSCT. Treatment was comprised of stopping cyclosporine, short-course dexamethasone, and 3 courses of rituximab. The patient showed full recovery and complete remission of lymphadenopathy. This result indicates that immediate reduction in EBV-carrying B cells by rituximab, suppression of general inflammation, and parallel support of reconstitution of long-term T-cell function, might be an appropriate therapeutic approach in this rare situation.
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Affiliation(s)
- T Weber
- Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
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Imashuku S. Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment. World J Hematol 2014; 3:71-84. [DOI: 10.5315/wjh.v3.i3.71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Revised: 05/09/2014] [Accepted: 06/18/2014] [Indexed: 02/05/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that develops as a primary (familial/hereditary) or secondary (non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell (CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH (familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of (signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome (XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis (e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease (especially EBV-HLH).
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Kogawa K, Sato H, Asano T, Ohga S, Kudo K, Morimoto A, Ohta S, Wakiguchi H, Kanegane H, Oda M, Ishii E. Prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in children: report of the Japan Histiocytosis Study Group. Pediatr Blood Cancer 2014; 61:1257-62. [PMID: 24535916 DOI: 10.1002/pbc.24980] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Accepted: 01/17/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND Despite several advances in the treatment of Epstein-Barr virus (EBV) in recent years, patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients. PROCEDURE Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH. RESULTS The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels. CONCLUSIONS These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis.
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Affiliation(s)
- Kazuhiro Kogawa
- Tsuchiya Children's Hospital, Kuki, Saitama, Japan; HLH/LCH Committees in the Japanese Society of Pediatric Hematology, Tokyo, Japan
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38
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Abstract
Haemophagocytic syndromes (haemophagocytic lymphohistiocytosis) have a wide range of causes, symptoms, and outcomes, but all lead to a hyperinflammatory response and organ damage--mainly reported in paediatric patients, but reports of adult presentation are increasing. Analysis of the genetic and molecular pathophysiology of these syndromes have improved the understanding of the crosstalk between lymphocytes and histiocytes and their regulatoty mechanisms. Clinical presentations with a broad differential diagnosis, and often life-threatening outcome, complicate the management, which might include supportive intensive care, immunosuppressive and biological treatments, or haemopoietic stem cell transplantation. Insufficient knowledge of these syndromes could contribute to poor prognosis. Early diagnosis is essential to initiate appropriate treatment and improve the quality of life and survival of patients with this challenging disorder.
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Affiliation(s)
- Manuel Ramos-Casals
- Josep Font Laboratory of Autoimmune Diseases-CELLEX, Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Pilar Brito-Zerón
- Josep Font Laboratory of Autoimmune Diseases-CELLEX, Department of Autoimmune Diseases, Institut Clínic de Medicina i Dermatologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Armando López-Guillermo
- Department of Haematology, Institut Clínic de Malalties Hematològiques i Oncològiques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Munther A Khamashta
- Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, King's College University, London, UK
| | - Xavier Bosch
- Department of Internal Medicine, Institut Clínic de Medicina i Dermatologia, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
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Abstract
Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.
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Affiliation(s)
- Grant S Schulert
- Division of Pediatric Rheumatology, Children's Hospital Medical Center, MLC 4010, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
| | - Alexei A Grom
- Division of Pediatric Rheumatology, Children's Hospital Medical Center, MLC 4010, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
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40
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Jayakody Arachchillage D, Hurst E, Carey P, Moses S, O'Brien SG, Menne T, Keenan F, Wallis JP. Haemophagocytic lymphohistiocytosis following fludarabine/cyclophosphamide chemotherapy for chronic lymphocytic leukaemia. Br J Haematol 2014; 166:142-5. [PMID: 24628491 DOI: 10.1111/bjh.12822] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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41
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So MW, Koo BS, Kim YJ, Kim YG, Lee CK, Yoo B. Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus. Mod Rheumatol 2014; 24:855-7. [PMID: 24517558 DOI: 10.3109/14397595.2013.874740] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
High-dose steroids, immunosuppressants such as cyclophosphamide and cyclosporine, and high-dose intravenous immunoglobulin have all been used to control hemophagocytic lymphohistiocytosis (HLH) or autoimmune hemolytic anemia (AIHA) associated with systemic lupus erythematosus (SLE); however, some patients are refractory to treatment. Rituximab has successfully resolved many of the refractory manifestations of SLE. Here, we report a case of HLH and AIHA associated with SLE that was refractory or intolerable to conventional therapy, but was successfully treated with rituximab.
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Affiliation(s)
- Min Wook So
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
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42
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Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol 2014; 6:137-54. [PMID: 20383897 DOI: 10.1586/eci.09.58] [Citation(s) in RCA: 118] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Sumit Gupta
- Division of Haematology/Oncology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
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43
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Advances in the pathogenesis and treatment of systemic juvenile idiopathic arthritis. Pediatr Res 2014; 75:176-83. [PMID: 24213625 DOI: 10.1038/pr.2013.187] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 07/11/2013] [Indexed: 11/08/2022]
Abstract
Systemic juvenile idiopathic arthritis (s-JIA) is clinically distinct from other types of JIA. It is typified by extraarticular features such as quotidian fevers, rash, splenomegaly, lymphadenopathy, laboratory abnormalities (including leukocytosis, thrombocytosis, anemia, hyperferritinemia, and elevated inflammatory markers), and a close association with the macrophage activation syndrome. Recent investigations have highlighted dysregulation of the innate immune system as the critical pathogenic driver of s-JIA. Key innate immune mediators of s-JIA are the macrophage-derived cytokines interleukin-1 (IL-1) and IL-6. Increased understanding of the roles of IL-1 and IL-6 in the pathogenesis of s-JIA has led to major changes in therapeutic options. Until recently, the most commonly used medications included corticosteroids, methotrexate, and tumor necrosis factor (TNF) inhibitors, which are incompletely effective in most cases. Newer biologic agents targeting IL-1 and IL-6 have proven very effective in treating s-JIA and in minimizing corticosteroid exposure. Here we review recent advances in the understanding of the pathogenesis of s-JIA and the recent clinical trials that have revolutionized the care of children with s-JIA.
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44
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Bakshi J, Hassan S, D’Cruz D, Chan A. Rituximab therapy in refractory macrophage activation syndrome secondary to systemic lupus erythematosus. Lupus 2013; 22:1544-6. [DOI: 10.1177/0961203313504634] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- J Bakshi
- Rheumatology Department, Royal Berkshire Hospital, Reading, UK
| | - S Hassan
- Haematology Department, Royal Berkshire Hospital, Reading, UK
| | - D D’Cruz
- Rheumatology Department, St Thomas’ Hospital, London, UK
| | - A Chan
- Rheumatology Department, Royal Berkshire Hospital, Reading, UK
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45
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Imashuku S, Kudo N, Kubo K, Yachie A. Are regimens containing rituximab effective in the initial treatment of Epstein-Barr virus-positive natural killer cell lymphoproliferative disease-associated hemophagocytic lymphohistiocytosis? Int J Hematol 2013; 98:375-7. [PMID: 23975519 DOI: 10.1007/s12185-013-1419-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 08/09/2013] [Accepted: 08/12/2013] [Indexed: 12/12/2022]
Affiliation(s)
- Shinsaku Imashuku
- Division of Hematology, Takasago-seibu Hospital, 1-10-41 Nakasuji, Takasago, 676-0812, Japan,
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46
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Affiliation(s)
- Maciej Machaczka
- Hematology Center Karolinska
- Division of Hematology, Department of Medicine at Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
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47
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Evans CM, Kudesia G, McKendrick M. Management of herpesvirus infections. Int J Antimicrob Agents 2013; 42:119-28. [PMID: 23820015 DOI: 10.1016/j.ijantimicag.2013.04.023] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 04/24/2013] [Indexed: 12/19/2022]
Abstract
Management of human herpesviruses remains a considerable clinical challenge, in part due to their ability to cause both lytic and latent disease. Infection with the Herpesviridae results in lifelong infection, which can reactivate at any time. Control of herpesviruses is by the innate and adaptive immune systems. Herpesviruses must evade the host innate immune system to establish infection. Once infected, the adaptive immune response, primarily CD8(+) T-cells, is crucial in establishing and maintaining latency. Latent herpesviruses are characterised by the presence of viral DNA in infected cells and limited or no viral replication. These characteristics provide a challenge to clinicians and those developing antiviral agents. The scope of this review is two-fold. First, to provide an overview of all antivirals used against herpesviruses, including their mechanism of action, pharmacokinetics, side effects, resistance and clinical uses. And second, to address the management of each of the eight herpesviruses both in the immunocompetent and immunocompromised host, providing evidence for clinical management and therapeutic options, which is important to the clinician engaged in the management of these infections.
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Affiliation(s)
- Cariad M Evans
- Department of Virology, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
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48
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Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder resulting from immune dysfunction reflecting either primary immune deficiency or acquired failure of normal immune homeostasis. Familial HLH includes autosomal recessive and X-linked disorders characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines, secondary to defects in genes encoding proteins involved in granule-dependent cytolytic pathways. In older children and adults, HLH is associated more often with infections, malignancies, autoimmune diseases, and acquired immune deficiencies. HLH, macrophage activation syndrome, sepsis, and systemic inflammatory response syndrome are different clinical entities that probably represent a common immunopathological state, termed cytokine storm. These conditions may be clinically indistinguishable; all include massive inflammatory response, elevated serum cytokine levels, multi-organ involvement, haemophagocytic macrophages, and often death. Tissues of haematopoietic and lymphoid function are directly involved; other organs are secondarily damaged by circulating cytokines and chemokines. Haemophagocytic disorders are now increasingly diagnosed in the context of severe inflammatory reactions to viruses, malignancies and systemic connective tissue diseases. Many of these cases may reflect underlying genetic predispositions to HLH. The detection of gene defects has contributed considerably to our understanding of HLH, but the mechanisms leading to acquired HLH have yet to be fully determined.
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Affiliation(s)
- G Naheed Usmani
- Division of Pediatric Hematology and Oncology, University of Massachusetts Medical Center, Worcester, MA, USA
| | - Bruce A Woda
- Department of Pathology, UMass Memorial Medical Center, Worcester, MA, USA
| | - Peter E Newburger
- Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA
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49
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Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus. Mod Rheumatol 2013. [DOI: 10.1007/s10165-013-0838-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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50
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Debate around infection-dependent hemophagocytic syndrome in paediatrics. BMC Infect Dis 2013; 13:15. [PMID: 23324497 PMCID: PMC3549728 DOI: 10.1186/1471-2334-13-15] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 01/11/2013] [Indexed: 02/08/2023] Open
Abstract
Background Hemophagocytic syndrome (HPS) is clinically defined as a combination of fever, liver dysfunction, coagulation abnormalities, pancytopenia, progressive macrophage proliferation throughout the reticuloendothelial system, and cytokine over-production, and may be primary or secondary to infectious, auto-immune, and tumoral diseases. The most consistent association is with viral infections but, as it is still debated whether any micro-organisms are involved in its pathogenesis, we critically appraised the literature concerning HPS and its relationship with infections. Discussion Infection-dependent HPS has been widely observed, but there are no data concerning its incidence in children. A better understanding of the pathophysiology of HPS may clarify the interactions between the immune system and the variously implicated potential infectious agents. Epstein-Barr virus (EBV) infection has been prominently associated with HPS, with clonal proliferation and the hyperactivation of EBV-infected T cells. However, a number of other viral, bacterial, fungal, and parasitic infections have been reported in association with HPS. In the case of low-risk HPS, corticosteroids and/or intravenous immunoglobulin or cyclosporine A may be sufficient to control the biological process, but etoposide is recommended as a means of reversing infection-dependent lymphohistiocytic dysregulation in high-risk cases. Summary HPS is a potential complication of various infections. A polymerase chain reaction search for infectious agents including EBV, cytomegalovirus and Leishmania is recommended in clinical settings characterised by non-remitting fever, organomegaly, cytopenia and hyperferritinemia.
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