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Tian F, Xie N, Sun W, Zhang W, Zhang W, Chen J, Ruan Q, Song J. Risk Factors of Hemophagocytic Lymphohistiocytosis in Adults with Fever of Unknown Origin: A Retrospective Study. Int J Gen Med 2025; 18:321-330. [PMID: 39872968 PMCID: PMC11769724 DOI: 10.2147/ijgm.s504345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 01/14/2025] [Indexed: 01/30/2025] Open
Abstract
Purpose Hemophagocytic lymphohistiocytosis (HLH) is a critical syndrome with a high mortality rate. In clinical practice, some patients with fever of unknown origin (FUO) can develop HLH, further complicating the diagnosis and treatment. However, studies on HLH in adults with FUO are limited. This study aimed to investigate the clinical characteristics of adult patients with FUO to facilitate the early identification of those at high risk of developing HLH. Patients and Methods We collected data from hospitalized patients with FUO between January 2014 and December 2020. Risk factors for HLH in adults with FUO were analyzed using univariate and multivariate analysis. Results A total of 988 patients with FUO were included in the study. The incidence of HLH in adults with FUO was 6.4%, with hematological tumors being the primary cause. Multivariate analysis indicated that skin rash and elevated alanine aminotransferase, total bilirubin, triglycerides, lactate dehydrogenase, and ferritin levels were independent risk factors for HLH in adults with FUO. Conclusion This study revealed the incidence rate, etiology distribution, and risk factors for HLH in adults with FUO. Comprehensive assessment of clinical and laboratory data at admission can assist in the early identification of FUO patients at risk for HLH.
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Affiliation(s)
- Fangbing Tian
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Nana Xie
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Wenjin Sun
- Department of Infectious Diseases, Ezhou Central Hospital, Ezhou, People’s Republic of China
| | - Wencong Zhang
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Wenyuan Zhang
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jia Chen
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Qiurong Ruan
- Institute of Pathology, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
| | - Jianxin Song
- Department of Infectious Diseases, Tongji Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
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Zhao M, Guan Y, Lin J, Qiu Y, Zhao S, Duan M. Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis. Front Immunol 2024; 15:1396124. [PMID: 38957461 PMCID: PMC11217173 DOI: 10.3389/fimmu.2024.1396124] [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: 03/05/2024] [Accepted: 05/29/2024] [Indexed: 07/04/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.
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Affiliation(s)
- Mengya Zhao
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yiming Guan
- Department of Nephrology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jin Lin
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yu Qiu
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Shen Zhao
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Meili Duan
- Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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Nyvlt P, Schuster FS, Ihlow J, Heeren P, Spies C, Hiesgen J, Schenk T, von Brünneck AC, Westermann J, Brunkhorst FM, La Rosée P, Janka G, Lachmann C, Lachmann G. Value of hemophagocytosis in the diagnosis of hemophagocytic lymphohistiocytosis in critically ill patients. Eur J Haematol 2024; 112:917-926. [PMID: 38368850 DOI: 10.1111/ejh.14185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/24/2024] [Accepted: 01/25/2024] [Indexed: 02/20/2024]
Abstract
BACKGROUND Ferritin is an established biomarker in the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH), which is diagnosed by the HLH-2004 criteria. Among these criteria, detection of hemophagocytosis through invasive procedures may delay early life saving treatment. Our aim was to investigate the value of hemophagocytosis in diagnosing HLH in critically ill patients. METHODS In this secondary analysis of a retrospective observational study, we included all patients aged ≥18 years and admitted to any adult ICU at Charité-Universitätsmedizin Berlin between January 2006 and August 2018, who had hyperferritinemia (≥500 μg/L) and underwent bone marrow biopsy during their ICU course. RESULTS Two hundred fifty-two patients were included, of whom 31 (12.3%) showed hemophagocytosis. In multivariable logistic regression analysis, maximum ferritin was independently associated with hemophagocytosis. By removing hemophagocytosis from HLH-2004 criteria and HScore, prediction accuracy for HLH diagnosis was only marginally decreased compared to the original scores. CONCLUSIONS Our results strengthen the diagnostic value of ferritin and underline the importance of considering HLH diagnosis in patients with high ferritin but only four fulfilled HLH-2004 criteria, when hemophagocytosis was not assessed or not detectable. Proof of hemophagocytosis is not required for a reliable HLH diagnosis.
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Affiliation(s)
- Peter Nyvlt
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Friederike S Schuster
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Jana Ihlow
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Patrick Heeren
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Claudia Spies
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Josephine Hiesgen
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
| | - Thomas Schenk
- Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany
| | - Ann-Christin von Brünneck
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Pathology, Berlin, Germany
| | - Jörg Westermann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - Frank M Brunkhorst
- Center for Clinical Studies, Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Jena, Jena, Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - Gritta Janka
- Clinic of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany
| | - Cornelia Lachmann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Gunnar Lachmann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Berlin, Germany
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Masood M, Siddique A, Krishnamoorthi R, Kozarek RA. Liver Dysfunction in Adult Hemophagocytic Lymphohistiocytosis: A Narrative Review. Adv Ther 2024; 41:553-566. [PMID: 38145441 DOI: 10.1007/s12325-023-02768-8] [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: 11/07/2023] [Accepted: 12/08/2023] [Indexed: 12/26/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition that has been increasingly recognized in adults and is characterized by a hyperinflammatory state due to immune dysregulation. Its nonspecific presentation, the lack of clinician familiarity given its rarity, and shared clinical features with sepsis and other syndromes can lead to a delay in diagnosis and a poor prognosis. Significant liver function abnormalities as the initial manifestation of HLH are uncommon and can range from mild elevation of aminotransferases to fulminant hepatic failure with high mortality rates. The authors encountered a case of adult HLH mimicking acute viral hepatitis in which a markedly elevated ferritin level led to a prompt diagnosis, early initiation of treatment, and a successful outcome. Clinicians, including gastroenterologists and hepatologists, are often called upon to evaluate patients with abnormal liver tests and may lack experience in the early diagnosis and management of liver dysfunction in the context of HLH. Thus, we expand our reporting to a narrative review of literature which explores the pathogenesis of HLH, challenges associated with its diagnosis, previous reports of liver disease associated with the syndrome, recommended treatments for the familial and adult variations including the role of liver transplantation, and the outcomes of these treatments.
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Affiliation(s)
- Muaaz Masood
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Asma Siddique
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Rajesh Krishnamoorthi
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Richard A Kozarek
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA.
- Center for Interventional Immunology, Benaroya Research Institute, Virginia Mason Franciscan Health, 1201 Ninth Ave, Seattle, WA, 98101, USA.
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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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Dumas G, Arabi YM, Bartz R, Ranzani O, Scheibe F, Darmon M, Helms J. Diagnosis and management of autoimmune diseases in the ICU. Intensive Care Med 2024; 50:17-35. [PMID: 38112769 DOI: 10.1007/s00134-023-07266-7] [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: 06/23/2023] [Accepted: 11/01/2023] [Indexed: 12/21/2023]
Abstract
Autoimmune diseases encompass a broad spectrum of disorders characterized by disturbed immunoregulation leading to the development of specific autoantibodies, resulting in inflammation and multiple organ involvement. A distinction should be made between connective tissue diseases (mainly systemic lupus erythematosus, systemic scleroderma, inflammatory muscle diseases, and rheumatoid arthritis) and vasculitides (mainly small-vessel vasculitis such as antineutrophil cytoplasmic antibody-associated vasculitis and immune-complex mediated vasculitis). Admission of patients with autoimmune diseases to the intensive care unit (ICU) is often triggered by disease flare-ups, infections, and organ failure and is associated with high mortality rates. Management of these patients is complex, including prompt disease identification, immunosuppressive treatment initiation, and life-sustaining therapies, and requires multi-disciplinary involvement. Data about autoimmune diseases in the ICU are limited and there is a need for multicenter, international collaboration to improve patients' diagnosis, management, and outcomes. The objective of this narrative review is to summarize the epidemiology, clinical features, and selected management of severe systemic autoimmune diseases.
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Affiliation(s)
- Guillaume Dumas
- Medical Intensive Care Unit, Service de Médecine Intensive-Réanimation, CHU Grenoble-Alpes, Université Grenoble-Alpes, INSERM, U1042-HP2, Grenoble, France.
| | - Yaseen M Arabi
- Intensive Care Department, Ministry of the National Guard-Health Affairs, Riyadh, Kingdom of Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Kingdom of Saudi Arabia
- King Saud Bin Abdulaziz University for Health Sciences Riyadh, Riyadh, Kingdom of Saudi Arabia
| | - Raquel Bartz
- Department of Anesthesia, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Otavio Ranzani
- Barcelona Institute for Global Health, ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Pulmonary Division, Faculdade de Medicina, Heart Institute, InCor, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Franziska Scheibe
- Department of Neurology and Experimental Neurology, Charité- Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Michaël Darmon
- Medical Intensive Care Unit, APHP, Hôpital Saint-Louis, Famirea Study Group, ECSTRA Team, and Clinical EpidemiologyUMR 1153, Center of Epidemiology and Biostatistics, Sorbonne Paris Cité, CRESS, INSERM, Université Paris Cité, Paris, France
| | - Julie Helms
- Faculté de Médecine, Service de Médecine Intensive-Réanimation, Université de Strasbourg (UNISTRA), Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, 1 Place de L'Hôpital, Strasbourg, France
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Henter JI, von Bahr Greenwood T. Etoposide Therapy of Cytokine Storm Syndromes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:525-551. [PMID: 39117837 DOI: 10.1007/978-3-031-59815-9_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.
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Affiliation(s)
- Jan-Inge Henter
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital Solna, Stockholm, Sweden.
| | - Tatiana von Bahr Greenwood
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Astrid Lindgren Children's Hospital, Karolinska University Hospital Solna, Stockholm, Sweden
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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). Arthritis Rheumatol 2023; 75:1714-1732. [PMID: 37486733 PMCID: PMC11040593 DOI: 10.1002/art.42636] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [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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9
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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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10
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Zhang Y, Cheng Z, Hu Y, Tang LV. Management of Complex Infections in Hemophagocytic Lymphohistiocytosis in Adults. Microorganisms 2023; 11:1694. [PMID: 37512867 PMCID: PMC10383929 DOI: 10.3390/microorganisms11071694] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/20/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation and inflammatory response due to a variety of primary and secondary factors that can cause a range of clinical symptoms and, in severe cases, life-threatening conditions. Patients with HLH are at increased risk of infection due to their abnormal immune function as well as chemotherapy and immunosuppressive therapy at the time of treatment. At the same time, the lack of specific clinical features makes complex infections in HLH challenging to diagnose and treat. The management of complex infections in HLH requires a multidisciplinary and integrated approach including the early identification of pathogens, the development of anti-infection protocols and regimens, and the elimination of potential infection factors. Especially in HLH patients with septic shock, empirical combination therapy against the most likely pathogens should be initiated, and appropriate anti-infective regimens should be determined based on immune status, site of infection, pathogens, and their drug resistance, with timely antibiotic adjustment by monitoring procalcitonin. In addition, anti-infection prophylaxis for HLH patients is needed to reduce the risk of infection such as prophylactic antibiotics and vaccinations. In conclusion, complex infection in HLH is a serious and challenging disease that requires vigilance, early identification, and timely anti-infective therapy.
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Affiliation(s)
- Yi Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Zhipeng Cheng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
| | - Liang V Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Avenue, Wuhan 430022, China
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11
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Loubet D, Sarton B, Lelièvre L, Grouteau G, Iriart X, Chauvin P, Fillaux J, Valentin A, Berry A, Silva S, Bonneville F, Cassaing S, Guemas E. Fatal mucormycosis and aspergillosis coinfection associated with haemophagocytic lymphohistiocytosis: A case report and literature review. J Mycol Med 2023; 33:101325. [PMID: 36270214 DOI: 10.1016/j.mycmed.2022.101325] [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: 01/24/2022] [Revised: 07/08/2022] [Accepted: 08/05/2022] [Indexed: 11/15/2022]
Abstract
Invasive mould infections are life-threatening and mainly occur in immunocompromised patients. Whereas aspergillosis is described during haemophagocytic lymphohistiocytosis (HLH), only a few cases of concomitant mucormycosis with HLH have been reported. Here, we present an uncommon coinfection of mucormycosis and aspergillosis associated with HLH probably due to a varicella zoster virus (VZV) viraemia which was unresponsive to triple antifungal therapy (liposomal amphotericin B combined with isavuconazole and caspofungin). A review of the cases of mucormycosis with HLH showed that this uncommon association was always lethal and underscored the relevance of screening for mould infections in patients with HLH.
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Affiliation(s)
- Dorian Loubet
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France
| | - Benjamine Sarton
- Critical Care Unit, University Hospital of Purpan, Toulouse, France; Toulouse NeuroImaging Center, Unité Mixte de Recherche 1214, Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier, Toulouse, France
| | - Lucie Lelièvre
- Department of Infectious and Tropical Diseases, CHU Toulouse, Toulouse, France
| | - Gaspard Grouteau
- Department of Infectious and Tropical Diseases, CHU Toulouse, Toulouse, France
| | - Xavier Iriart
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France; Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse, CNRS UMR5051, INSERM UMR1291, UPS, Toulouse, France
| | - Pamela Chauvin
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France
| | - Judith Fillaux
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France
| | - Alexis Valentin
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France; PHARMA-Dev, UMR 152 IRD-UPS, Université Toulouse, France
| | - Antoine Berry
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France; Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse, CNRS UMR5051, INSERM UMR1291, UPS, Toulouse, France
| | - Stein Silva
- Critical Care Unit, University Hospital of Purpan, Toulouse, France; Toulouse NeuroImaging Center, Unité Mixte de Recherche 1214, Institut National de la Santé et de la Recherche Médicale, Université Paul Sabatier, Toulouse, France
| | - Fabrice Bonneville
- Neuroradiology Department, Pierre-Paul-Riquet/Purpan University Hospital, Toulouse, France
| | - Sophie Cassaing
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France; RESTORE Institute, UMR 1301-Inserm 5070-CNRS EFS Univ. P. Sabatier, Toulouse, France
| | - Emilie Guemas
- Department of Parasitology and Mycology, CHU Toulouse, Toulouse, France; Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse, CNRS UMR5051, INSERM UMR1291, UPS, Toulouse, France.
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12
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Zondag TCE, Lika A, van Laar JAM. The role of etoposide in the treatment of adult patients with hemophagocytic lymphohistiocytosis. Exp Hematol Oncol 2023; 12:2. [PMID: 36624539 PMCID: PMC9827679 DOI: 10.1186/s40164-022-00362-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/29/2022] [Indexed: 01/11/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal inflammatory clinical condition, in which an exaggerated immune response is ineffectively regulated. Although etoposide-containing regimens are generally recommended for children with HLH, the exact role of etoposide in the adult setting remains unclear. We performed a systematic review of the literature on the use of etoposide in adults with HLH. All articles written in English on the use of etoposide in adults with HLH available from seven databases and published on or before July 2021 were analyzed. Thirteen studies were found to be relevant to the search results. Ten of these studies report a statistical analysis on the effect of etoposide, of which five found etoposide-containing regimens superior to non-etoposide-containing regimens. Seven studies provided sufficient data to be included in the meta-analysis. For these data, the estimated logit relative risk of etoposide on survival was 1.06 (95% confidence interval: 0.92-1.21, standard error: 2.06). The pooled data of the meta-analysis did thus not support a beneficial effect of etoposide. It should be taken into account that the presented results are highly susceptible to bias and that the effect of etoposide differs between HLH-triggers. Although the meta-analysis does not support the effect of etoposide, we do not recommend abandoning etoposide as treatment modality. The limitations of the meta-analysis, together with several individual articles confirming the benefit of etoposide, justify etoposide for select cases in adults with HLH such as refractory or severe disease with (threatening) multiorgan failure.
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Affiliation(s)
- Timo C. E. Zondag
- grid.5645.2000000040459992XDepartment of Internal Medicine, Clinical Immunology Section, Erasmus University Medical Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
| | - Aglina Lika
- grid.5645.2000000040459992XDepartment of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands ,grid.5645.2000000040459992XDepartment of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, The Netherlands ,grid.5645.2000000040459992XDepartment of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jan A. M. van Laar
- grid.5645.2000000040459992XDepartment of Internal Medicine, Clinical Immunology Section, Erasmus University Medical Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands ,grid.5645.2000000040459992XDepartment of Immunology, Clinical Immunology Section, Erasmus University Medical Center, Rotterdam, The Netherlands
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13
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"A Dangerous Black Box:" Idiopathic Hemophagocytic Lymphohistiocytosis in Adult Patients-A Case Report and Review of the Literature. Case Rep Hematol 2022; 2022:5867129. [PMID: 36510501 PMCID: PMC9741541 DOI: 10.1155/2022/5867129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially life-threatening condition characterized by aberrant inflammation that can be related to genetic or sporadic forms. In both forms, triggering factors may be involved. Early detection of the underlying cause is crucial for therapeutic decision, while early intervention might be associated with better outcomes. The largest descriptions in the literature on HLH refer to pediatric cases. Adolescents and adults may also be affected, but there is scarce evidence regarding their diagnosis and management. We describe here the case of a 68-year-old Swiss woman with HLH, in whom an extensive search for underlying causes was performed, but neither trigger nor pathogenic variant was found. An early intervention first with dexamethasone and later with cyclosporine was performed. The patient showed a favorable response and did not require further hospitalization; however, one year after diagnosis, it was not possible to suspend cyclosporine due to recurrence of laboratory inflammation signs by drug tapering. The occurrence of HLH idiopathic forms represents a challenge; failure to identify the underlying triggering cause generates uncertainty, endless diagnostic investigations, and consequently additional delays in the treatment. This manuscript addresses the difficulties on this issue.
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14
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Roccatello D, Sciascia S, Barreca A, Naretto C, Alpa M, Quattrocchio G, Radin M, Fenoglio R. Renal involvement as a unique manifestation of hemophagocytic syndrome. Front Med (Lausanne) 2022; 9:796121. [PMID: 36275824 PMCID: PMC9579315 DOI: 10.3389/fmed.2022.796121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 08/25/2022] [Indexed: 11/21/2022] Open
Abstract
Renal-limited hemophagocytic syndrome (HPS) is a rare clinical setting characterized by abnormal activation of the immune system. Fever associated with pancytopenia, hepatosplenomegaly with liver dysfunction, and hypofibrinogenemia are usually observed in HPS. From a histological level, the presence of non-malignant macrophages infiltrating bone marrow and organs represents the hallmark of this condition. Non-malignant macrophages are associated with phagocytizing activities involving other blood cells. While primary HPS is usually associated with inherited dysregulation of the immune system, secondary HPS usually occurs in the context of infection or is linked to a neoplastic process. Clinical presentation varies and can potentially lead to life-threatening settings. While renal involvement has frequently been reported, however, detailed descriptions of the kidney manifestations of HPS are lacking. More critically, the diagnosis of HPS is rarely supported by renal biopsy specimens. We report four rare cases of biopsy-proven renal-limited HPS in patients presenting with acute kidney injury (AKI). The available evidence on this topic is critically discussed in light of the possible emergence of an autonomous entity characterized by an isolated kidney involvement.
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Affiliation(s)
- Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy,*Correspondence: Dario Roccatello
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | | | - Carla Naretto
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Mirella Alpa
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Giacomo Quattrocchio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Massimo Radin
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Roberta Fenoglio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
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15
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Li XY, Zhu SM, Li XY, Dong RS, Zhang AA, Li SJ, Geng YL. Reactive Hemophagocytic Lymphohistiocytosis Secondary to Ovarian Adenocarcinoma: A Rare Case Report. J Inflamm Res 2022; 15:5121-5128. [PMID: 36097636 PMCID: PMC9464022 DOI: 10.2147/jir.s376756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 08/09/2022] [Indexed: 11/23/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH), a syndrome of immune hyperactivation and abnormal regulation that causes life-threatening inflammation, is mainly characterized by fever, hepatosplenomegaly, cytopenia, and other symptoms. Reactive HLH (rHLH) is typically secondary to immune deregulation caused by underlying rheumatologic, infectious, or malignant conditions. Malignancy-associated HLH (M-HLH) continues to be a critical health problem worldwide. Most malignancies associated with HLH are hematologic tumors, and M-HLH in non-hematologic tumors very rarely occurs. Case Report A 34-year-old Chinese woman had a history of persistent fever, acute dizziness, and bicytopenia. She was found to have developed bilateral ovarian cancer. Additional tests showed splenomegaly, hemophagocytes in the bone marrow, low natural killer activity, and hyperferritinemia, which met the diagnostic criteria put forth in the Histiocyte Society HLH-2004. The patient was treated with correcting anemia, increased platelets, and glucocorticoid therapy but showed no response. She progressively deteriorated and died 55 days later. Conclusion Hemophagocytic lymphohistiocytosis related to a solid tumor is extremely rare. To the best of the authors’ knowledge, the present case was the first to report rHLH secondary to ovarian adenocarcinoma. It is very significant for a better understanding of the disease mechanisms of HLH and should attract the attention of hematologists and other clinicians as the condition progresses and the cost of treating it increases.
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Affiliation(s)
- Xiao-Yan Li
- Department of Laboratory Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Shu-Min Zhu
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Xin-Yuan Li
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Rui-Sheng Dong
- Department of Imaging Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Ai-Ai Zhang
- Department of Laboratory Medicine, Shanxi Province Fenyang Hospital, Fenyang, 032200, People's Republic of China
| | - Shu-Jing Li
- Department of Radiology, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
| | - Yu-Lan Geng
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050031, People's Republic of China
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16
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Naymagon L. Anakinra for the treatment of adult secondary HLH: a retrospective experience. Int J Hematol 2022; 116:947-955. [PMID: 35948764 PMCID: PMC9365216 DOI: 10.1007/s12185-022-03430-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/30/2022]
Abstract
Anti-cytokine therapies have been gaining attention as a means of improving outcomes in adult secondary HLH (asHLH), which currently has poor outcomes when treated with standard etoposide-based therapies. Anakinra is an interleukin-1 antagonist that is increasingly being used in the management of asHLH. Here is described a multi-hospital series of 16 adult patients with secondary HLH treated with anakinra. Provoking factors of secondary HLH included hematologic malignancy (n = 7, 44%), bacterial infection (n = 7, 44%), viral infection (n = 5, 31%), rheumatologic disorder (n = 4, 25%), and unknown (n = 1, 6%). Five patients remained alive at time of last follow-up (OS = 31%). Median OS was 1.7 months from initiation of anakinra (range 0.2–59). OS among patients with rheumatologic causes of secondary HLH was 75%, whereas only 17% of patients with other provoking factors survived (p = 0.0293). Anakinra was well tolerated, with only 1 patient experiencing associated toxicity (grade 3 liver injury). Anakinra may be useful in the management of asHLH provoked by rheumatologic conditions, although its benefit in asHLH provoked by other factors may be limited.
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Affiliation(s)
- Leonard Naymagon
- Mount Sinai School of Medicine, Tisch Cancer Institute, New York, NY, USA.
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17
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Ioannou M, Zacharouli K, Doukas SG, Diamantidis MD, Tsangari V, Karakousis K, Koukoulis GK, Vageli DP. Hemophagocytic lymphohistiocytosis diagnosed by bone marrow trephine biopsy in living post-COVID-19 patients: case report and mini-review. J Mol Histol 2022; 53:753-762. [PMID: 35699822 PMCID: PMC9192937 DOI: 10.1007/s10735-022-10088-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/31/2022] [Indexed: 12/15/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) constitutes a life-threatening inflammatory syndrome. Postmortem histological findings of bone marrow (BM) from COVID-19 patients showed histiocytosis and hemophagocytosis and supported the hypothesis that secondary HLH (sHLH) may be triggered by SARS-CoV-2 infection. However, there are a limited number of sHLH cases in which trephine has been performed in living post-COVID-19 patients. Here we present a recent case and a mini-review of sHLH diagnosed by trephine biopsy in living patients after COVID-19. An 81-year-old man with a past medical history of hypertension, diabetes, ischemic stroke, was referred to the hospital to evaluate leukocytosis, pyuria, and elevation of inflammatory markers four weeks after recovering from COVID-19. Computed tomography of the abdomen did not reveal focal signs of infection or hepatosplenomegaly. The patient received intravenous meropenem and two packed red blood cell units. Leukocytes and C-reactive protein were gradually decreased. A BM biopsy was performed and the patient was discharged on cefixime. BM smear revealed severe anemia, lymphopenia, and dysplastic morphologic findings of erythroblasts, neutrophils, and megakaryocytes. Trephine biopsy revealed hypercellular marrow dyserythropoiesis, plasmacytosis, lymphocytosis, histiocytosis, hemophagocytosis, and the absence of granulomas or carcinoma. Immunohistochemistry documented a mixed population of T lymphocytes (CD3+) and B lymphocytes (CD20+). Strong positivity for CD68 confirmed histiocytosis. CD138 κ, λ staining proved polyclonal plasmacytosis. Perl's staining showed excess hemosiderin deposits. Based on our findings, we document sHLH in trephine BM biopsy of a living post-COVID-19 patient and persistent leukocytosis, underscoring the diagnostic value of trephine biopsy in preventing life-threatening conditions such as COVID-19.
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Affiliation(s)
- Maria Ioannou
- Department of Pathology, Faculty of Medicine, Medical School, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Konstantina Zacharouli
- Department of Pathology, Faculty of Medicine, Medical School, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Sotirios G Doukas
- Department of Toxicology Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003, Heraklion, Greece
- Department of Medicine, Rutgers/Saint Peter's University Hospital, 08901, New Brunswick, NJ, USA
| | - Michael D Diamantidis
- Thalassemia and Sickle Cell Disease Unit, Department of Hematology, General Hospital of Larissa, Larissa, Greece
| | - Vaya Tsangari
- Department of Pathology, Faculty of Medicine, Medical School, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | | | - George K Koukoulis
- Department of Pathology, Faculty of Medicine, Medical School, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece
| | - Dimitra P Vageli
- Department of Pathology, Faculty of Medicine, Medical School, School of Health Sciences, University of Thessaly, Biopolis, 41500, Larissa, Greece.
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18
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Nam SH, Ahn SM, Oh JS, Hong S, Lee CK, Yoo B, Kim YG. Macrophage activation syndrome in rheumatic disease: Clinical characteristics and prognosis of 20 adult patients. PLoS One 2022; 17:e0267715. [PMID: 35522672 PMCID: PMC9075640 DOI: 10.1371/journal.pone.0267715] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 04/13/2022] [Indexed: 11/18/2022] Open
Abstract
Objectives
Macrophage activation syndrome (MAS) is a hyperinflammatory condition that is known to be secondary hemophagocytic lymphohistiocytosis (HLH) in patients with rheumatic disease. The aim of study was to evaluate the clinical manifestations and outcomes in patients with MAS with rheumatic disease.
Materials and methods
We performed a retrospective study of 20 adult patients who were diagnosed with MAS from 2012 to 2020. MAS was classified according to the HLH-2004 criteria. Patients’ information, including clinical features, laboratory findings, and treatment regimens, was collected, and the overall survival rate was estimated by the Kaplan–Meier method.
Results
Twenty patients (18 women, 35.6 ± 18.3 years) who met the HLH-2004 criteria also fulfilled the 2016 EULAR/ACR/PRINTO classification criteria for MAS, and HScore was higher than 169 (mean, 241.1). Fourteen patients with systemic lupus erythematosus and 6 patients with adult-onset Still’s disease were included. All patients were treated initially with corticosteroids, and 16 patients required additional immunosuppressants. The overall survival at 3 and 6 months was 75.2% and 64.3%. In survivors, renal impairment was less common (7.7% versus 71.4%, p = 0.007), the levels of AST (364.0 versus 81.0 IU/L, p = 0.019) and LDH (1346.0 versus 343.0IU/L, p = 0.014), and platelet count (90.0 versus 43.0 × 109/L, p = 0.02) were higher in compared to non-survivors. Nine patients had opportunistic infections, five of whom died during admission.
Conclusion
The mortality of patients with MAS associated with rheumatic disease remains high. Renal impairment, levels of AST and LDH, and platelet count might be associated with prognosis.
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Affiliation(s)
- So Hye Nam
- Division of Rheumatology, Department of Internal Medicine, Eulji University School of Medicine, Uijeongbu Eulji Medical Center, Uijeongbu, Gyeonggi-do, Korea
| | - Soo Min Ahn
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Ji Seon Oh
- Department of Information Medicine, Asan Medical Center, Seoul, Korea
| | - Seokchan Hong
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Chang-Keun Lee
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Bin Yoo
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Yong-Gil Kim
- Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
- * E-mail:
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Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults. Crit Care Med 2021; 50:860-872. [PMID: 34605776 DOI: 10.1097/ccm.0000000000005361] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. DATA SOURCES The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. DATA SYNTHESIS Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. CONCLUSIONS Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.
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Mirza M, Zafar M, Nahas J, Arshad W, Abbas A, Tauseef A. Hemophagocytic lymph histiocytosis (HLH): etiologies, pathogenesis, treatment, and outcomes in critically ill patients: a review article and literature to review. J Community Hosp Intern Med Perspect 2021; 11:639-645. [PMID: 34567455 PMCID: PMC8462863 DOI: 10.1080/20009666.2021.1954783] [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] [Indexed: 11/02/2022] Open
Abstract
Hemophagocytic lymph histiocytosis (HLH) is not an independent disease but is instead a clinical syndrome that occurs in many underlying conditions involving all age groups. HLH is the consequence of a severe, uncontrolled hyperinflammatory reaction that in most cases is triggered by an infectious agent. Acquired HLH is much more common than primary HLH syndrome but primary is more fatal, and it does have the worst prognosis with no definitive treatment available to date. This review article mentioned all the latest advancements regarding etiologies, pathogenesis, treatment, and outcomes in critically ill patients who got diagnosed with HLH syndrome in last 15 years.
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Affiliation(s)
- Mohsin Mirza
- Internal Medicine Department, Creighton University Hospital Program, Omaha, NE, USA
| | - Maryam Zafar
- Internal Medicine Department, Dow University of Health Sciences, DUHS, Karachi, Pakistan
| | - Joseph Nahas
- Internal Medicine Department, Creighton University Hospital Program, Omaha, NE, USA
| | - Wafa Arshad
- Internal Medicine Department, Dow University of Health Sciences, DUHS, Karachi, Pakistan
| | - Anum Abbas
- Internal Medicine Department, University of Nebraska Medical Center, Omaha, USA
| | - Abubakar Tauseef
- Internal Medicine Department, Creighton University Hospital Program, Omaha, NE, USA
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21
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Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment. METHODS For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charité - Universitätsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis. RESULTS Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (P = 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 μg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771-1.000; sensitivity 93.8%, specificity 78.9%). CONCLUSIONS Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring. TRIAL REGISTRATION The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.
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22
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Treatment and Mortality of Hemophagocytic Lymphohistiocytosis in Adult Critically Ill Patients: A Systematic Review With Pooled Analysis. Crit Care Med 2021; 48:e1137-e1146. [PMID: 32947471 DOI: 10.1097/ccm.0000000000004581] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Hemophagocytic lymphohistiocytosis is a cytokine release syndrome caused by uncontrolled immune activation resulting in multiple organ failure and death. In this systematic review, we aimed to analyze triggers, various treatment modalities, and mortality in critically ill adult hemophagocytic lymphohistiocytosis patients. DATA SOURCES MEDLINE database (PubMed) at October 20, 2019. STUDY SELECTION Studies and case series of patients greater than or equal to 18 years old, of whom at least one had to be diagnosed with hemophagocytic lymphohistiocytosis and admitted to an ICU. DATA EXTRACTION Source data of studies and case series were summarized and analyzed on an individual basis. Multivariable logistic regression analysis was performed adjusting for age, sex, and trigger groups. Each single treatment agent was entered as a dichotomous variable to determine treatments associated with survival, regardless if given alone or in combination. DATA SYNTHESIS In total, 661 patients from 65 studies and case series were included. Overall mortality was 57.8%. Infections were the most frequent trigger (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%), unknown triggers (9.4%), and drugs (0.6%). Treatment with IV immunoglobulins was associated with improved survival (odds ratio, 0.548; 95% CI, 0.337-0.891; p = 0.015), while treatment with cyclosporine was associated with increased risk of death (odds ratio, 7.571; 95% CI, 3.702-15.483; p < 0.001). Considering different trigger groups separately, same results occurred only for infection-triggered hemophagocytic lymphohistiocytosis. No information was available on disease severity and other confounding factors. CONCLUSIONS Mortality of hemophagocytic lymphohistiocytosis in the ICU is high. Most common triggers were infections. Results of survival analyses may be biased by treatment indication and disease severity. Future studies prospectively investigating treatment tailored to critically ill hemophagocytic lymphohistiocytosis patients are highly warranted.
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Li Z, Liu J, Man Y, Liu F, Gao L, Hu P, Zhao R, Wang Y, Yang T. Analysis of cytokine risk factors in the early death of patients with secondary phagocytic lymphocytic histiocytosis. Am J Transl Res 2021; 13:2388-2398. [PMID: 34017397 PMCID: PMC8129357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 02/25/2021] [Indexed: 06/12/2023]
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is an excessive inflammatory response syndrome caused by immune abnormalities. Up to date, the risk factors for cytokines causing early death in sHLH patients have not been elucidated. Our study reviewed the cytokine expression levels in peripheral blood of 50 sHLH patients. Through Cox proportional hazard model analysis, we found that IL-17F ≥2.835 pg/mL (HR = 5.922, 95% CI = 1.793-19.558, P = 0.004) was an independent death risk factor in sHLH patients, and it was also 30 days (Cutoff-value = 2.890 pg/mL, HR = 16.568, 95% CI = 1.917-143.195, P = 0.011), 60 days (Cutoff-value = 2.890 pg/mL, HR = 7.559, 95% CI = 1.449-39.423, P = 0.016), 90 day death risk factor (Cutoff-value = 2.835 pg/mL, HR = 7.649, 95% CI = 1.965-29.778, P = 0.003); IL-10 ≥16.730 pg/mL (HR = 4.821, 95% CI = 1.151-20.116, P = 0.031) is not only a death risk factor within 90 days, but also within 10 days (Cutoff-value = 944.350 pg/mL, HR = 13.321, 95% CI = 1.123-158.03, P = 0.027); and IL-5 ≥2.495 pg/mL (HR = 15.687, 95% CI = 1.377-178.645, P = 0.04) was also a death risk factor within 10 days. Besides, IL-17F, IL-10, IL-5, and the previously reported common risk factors Age, platelets, activated partial thromboplastin time, triglyceride, and lactate dehydrogenase were analyzed together. It was found that the patient age ≥56 years-old is was an important risk factor for death within 30 days, IL-17 ≥2.89 pg/mL and IL-10 ≥16.73 pg/mL are important risk factors for patient death. In summary, our data indicate that age, IL-10 and IL-17F are important risk factors for early death in sHLH patients.
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Affiliation(s)
- Zengzheng Li
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
| | - Jianqiong Liu
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
| | - Yan Man
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
- Kunming University of Science and TechnologyKunming, China
| | - Fusheng Liu
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
- Kunming University of Science and TechnologyKunming, China
| | - Lili Gao
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
| | - Peng Hu
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
| | - Renbin Zhao
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
| | - Yajie Wang
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
- Kunming University of Science and TechnologyKunming, China
| | - Tonghua Yang
- Department of Hematology, The First People’s Hospital of Yunnan ProvinceKunming, China
- Yunnan Blood Disease Clinical Medical CenterKunming, China
- Yunnan Blood Disease HospitalKunming, China
- Kunming University of Science and TechnologyKunming, China
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24
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Khare N, Jinkala SR, Kanungo S. Performance of HScore in Reactive Hemophagocytic Lymphohistiocytosis. Indian J Hematol Blood Transfus 2021; 37:256-263. [PMID: 33867732 PMCID: PMC8012436 DOI: 10.1007/s12288-020-01342-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 08/26/2020] [Indexed: 01/07/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life threatening systemic hyperinflammatory disorder that leads to multiple organ damage. The most widely used diagnostic guidelines are the HLH 2004 guidelines proposed by the Histiocyte society. Recently, Fardet et al. has proposed a Scoring system, "HScore" for diagnosis of reactive HLH. To test the performance of "HScore" in diagnosis of reactive HLH and compare the credibility of the same with the existing gold standard 2004 guidelines in a cohort of Indian patients. This was a descriptive study of cases referred to the department of Pathology for bone marrow examination with suspicion or diagnosis of HLH from Jan 2015 to June 2017. The clinical records of these patients were analysed and diagnosed as positive and negative for HLH using the HLH 2004 guidelines and HScore, the scoring system developed by Fardet et al. Fifty cases fulfilled the inclusion criteria. The variables fever, hepato and /or splenomegaly, high triglyceride levels and marrow hemophagocytosis are highly significant to predict an individuals risk of HLH. We propose a cut-off of ≥ 166 for the diagnosis of HLH by using HScore. If 4 of the 7 criteria are fulfilled by HLH 2004 guidelines, there is an 80% probability of having HLH by HScore. The HScore is less restrictive in confirming a diagnosis of HLH compared to the HLH 2004 guidelines. HScore is a simple, and cost effective tool for diagnosis of reactive HLH. The higher the HScore, more is the probability of HLH.
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Affiliation(s)
- Neerav Khare
- VI Semester MBBS, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India
| | - Sree Rekha Jinkala
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India
| | - Srikanta Kanungo
- Department of Preventive and Social Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, 605006 India
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Al Nasrallah N, Al-Hader A, Samala N, Sears CR. Hemophagocytic Lymphohistiocytosis in the Medical ICU: A Single-Institution Cohort Study on Acute Liver Failure and Mortality. Crit Care Explor 2021; 3:e0318. [PMID: 33458685 PMCID: PMC7803668 DOI: 10.1097/cce.0000000000000318] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis is a life-threatening hyperinflammatory disorder that is associated with high morbidity and mortality in the ICU. It has also been associated with acute liver failure. DESIGN Retrospective observational study. SETTING Tertiary-care medical ICU. PATIENTS Thirty-one patients critically ill with hemophagocytic lymphohistiocytosis. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We performed a comprehensive review of critically ill hemophagocytic lymphohistiocytosis patients admitted to a tertiary-care medical ICU from January 2012 to December 2018. Most patients presented with constitutional symptoms and elevated liver enzymes and thrombocytopenia were common upon hospital admission. ICU admission laboratory and clinical variables were used to calculate Acute Physiology and Chronic Health Evaluation II, hemophagocytic syndrome diagnostic score, and model for end-stage liver disease. Mean age of the cohort was 48.1 years, and 45% were male. The mortality rate was 65% at 28 days and 77% at 1 year. About 28-day survivors were younger, had lower mean Acute Physiology and Chronic Health Evaluation II score (16.5 vs 23.0; p = 0.004), and higher mean hemophagocytic syndrome diagnostic score (249.1 vs 226.0; p = 0.032) compared with nonsurvivors. Survivors were less likely to receive mechanical ventilation, renal replacement therapy, or vasopressor support and were more likely to receive chemotherapy for hemophagocytic lymphohistiocytosis. In this ICU cohort, 29% were diagnosed with acute liver failure, of whom only 22% developed acute liver failure early during their hospital stay. Acute liver failure was associated with a higher model for end-stage liver disease score upon hospital admission. Available histology in those that developed acute liver failure showed massive hepatic necrosis, or histiocytic or lymphocytic infiltrates. CONCLUSIONS Patients admitted to the ICU with hemophagocytic lymphohistiocytosis have a high mortality. Those who survived had lower Acute Physiology and Chronic Health Evaluation scores, had higher hemophagocytic syndrome diagnostic scores, are more likely to receive hemophagocytic lymphohistiocytosis specific chemotherapy, and are less likely to have organ failure. Hemophagocytic lymphohistiocytosis can be associated with acute liver failure especially when model for end-stage liver disease score is elevated upon admission.
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Affiliation(s)
- Nawar Al Nasrallah
- Division of Pulmonary, Critical Care, Sleep & Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ahmad Al-Hader
- Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis, IN
| | - Niharika Samala
- Division of Gastroenterology, Indiana University School of Medicine, Indianapolis, IN
| | - Catherine R Sears
- Division of Pulmonary, Critical Care, Sleep & Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN
- Division of Pulmonary Medicine, Richard L. Roudebush VA Medical Center, Indianapolis, IN
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Kumar G, Hererra M, Patel D, Nanchal R, Guddati AK. Outcomes of adult critically ill patients with hemophagocytic lymphohistiocytosis in united states-analysis from an administrative database from 2007 to 2015. AMERICAN JOURNAL OF BLOOD RESEARCH 2020; 10:330-338. [PMID: 33489441 PMCID: PMC7811911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 09/25/2020] [Indexed: 06/12/2023]
Abstract
BACKGROUND Severe infections caused by the novel coronavirus 2 display similarities to secondary hemophagocytic lymphohistiocytosis (HLH). However, HLH is a rare disease and has not been well described in critically ill patients. METHODS We used the Nationwide Inpatient Sample (NIS), the largest all-payer inpatient care database publicly available in the United States to identify all adult discharges with Hemophagocytic syndrome (ICD-9 CM code 288.4) between 2007 and 2015. Critical illness was considered present if patient had either ICD-9 CM code indicating the requirement of invasive mechanical ventilation or the presence of shock. We used ICD-9-CM codes to identify various infections (inf-HLH), malignancies (mal-HLH) and autoimmune diseases associated with HLH (MAS-HLH) and classified them in their respective groups. Primary outcome was in-hospital mortality in critically ill patients. We developed multivariable regression model to examine variables associated with mortality in critically ill HLH patients. P value was kept at < 0.05. RESULTS Of the 7420 (95% CI 6959-7881) estimated discharges with HLH, 2313 (31%) were critically ill. Of the critically ill patients, 442 (34%) were mal-HLH, 422 (43.3%) were inf-HLH, 403 (30.7%) were MAS-HLH and 1046 (27.3%) were unable to be classified. In hospital mortality rates were 6.4% in non-critically ill and 48.4% in critically ill patients. Among the subtypes of HLH, in-hospital mortality was 53% in mal-HLH, 49.4% in inf-HLH, 26% in MAS-HLH and 54.6% in unclassified group. On multivariable regression analysis, development of acute renal failure requiring hemodialysis (OR 2.06, 95% CI 1.29-3.3, P=0.002) and acute hepatic failure (OR 2.21, 95% CI 1.38-3.52, P=0.001) were significantly associated with higher mortality. CONCLUSION Inpatient mortality of critically ill patients is remarkably high. Patients with MAS-HLH had better outcomes when compared to other groups of HLH.
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Affiliation(s)
- Gagan Kumar
- Department of Pulmonary & Critical Care, Northeast Georgia Health SystemGainesville, GA 30501, USA
| | - Martin Hererra
- Department of Internal Medicine, Northeast Georgia Health SystemGainesville, GA 30501, USA
| | - Dhaval Patel
- Department of Pulmonary & Critical Care, Northeast Georgia Health SystemGainesville, GA 30501, USA
| | - Rahul Nanchal
- Division of Pulmonary & Critical Care, Medical College of WisconsinMilwaukee 53226, USA
| | - Achuta K Guddati
- Department of Hematology and Oncology, Augusta UniversityAugusta, GA 30912, USA
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27
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Tudesq JJ, Valade S, Galicier L, Zafrani L, Boutboul D, de Bazelaire C, Munoz-Bongrand N, Canet E, Ardisson F, Lemiale V, Darmon M, Azoulay E, Mariotte E. Diagnostic strategy for trigger identification in severe reactive hemophagocytic lymphohistiocytosis: A diagnostic accuracy study. Hematol Oncol 2020; 39:114-122. [PMID: 33099794 DOI: 10.1002/hon.2819] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/01/2020] [Accepted: 10/19/2020] [Indexed: 12/14/2022]
Abstract
Reactive hemophagocytic lymphohistiocytosis (rHLH) management requires early recognition, trigger identification, and adequate treatment in order to reduce mortality. We assessed the diagnostic yield of tissue biopsies to identify trigger in severe rHLH. We included all consecutive patients presenting an rHLH diagnosis (HLH-2004 criteria) admitted to the intensive care unit (ICU) of a tertiary hospital. This retrospective diagnostic accuracy study was conducted according to the Standards for Reporting Diagnostic Accuracy Statement. Among the 134 included patients (median age 47 years [IQR 47-56]), an underlying immunodeficiency was previously known in 61.2%. rHLH trigger was identified in 127 patients (94.8%) (hematological disorder 75%, infection 16%, systemic disease 4%). Diagnostic yield of tissue biopsies was as follows: lymph node 75% (95% confidence interval [CI], 61-85), skin 50% (95% CI, 27-73), bone marrow 44% (95% CI, 34-55), liver 30% (95% CI, 15-49). Splenectomy (yield 77%; 95% CI, 46-95) was reserved to cases of diagnostic deadlock. Procedural severe adverse events included two cases of reversible hemorrhagic shock. Seventy-eight percent of patients received etoposide regarding to the rHLH severity, and 68% could receive trigger-specific treatment in the ICU. A comprehensive diagnostic workup led to an rHLH trigger identification in 95% of patients, allowing prompt initiation of appropriate therapy. Prospective studies to validate a standardized diagnostic approach are warranted.
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Affiliation(s)
- Jean-Jacques Tudesq
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France.,UFR Médecine Paris Nord, Université de Paris, Paris, France
| | - Sandrine Valade
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Lionel Galicier
- Immunologie Clinique, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Lara Zafrani
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France.,UFR Médecine Paris Nord, Université de Paris, Paris, France
| | - David Boutboul
- UFR Médecine Paris Nord, Université de Paris, Paris, France.,Immunologie Clinique, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Cédric de Bazelaire
- UFR Médecine Paris Nord, Université de Paris, Paris, France.,Imagerie Médicale, Hôpital Saint-Louis, AP-HP, Paris, France
| | | | - Emmanuel Canet
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Fanny Ardisson
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Virginie Lemiale
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Michael Darmon
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France.,UFR Médecine Paris Nord, Université de Paris, Paris, France
| | - Elie Azoulay
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France.,UFR Médecine Paris Nord, Université de Paris, Paris, France
| | - Eric Mariotte
- Médecine Intensive - Réanimation, Hôpital Saint-Louis, AP-HP, Paris, France
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Opoka-Winiarska V, Grywalska E, Roliński J. Could hemophagocytic lymphohistiocytosis be the core issue of severe COVID-19 cases? BMC Med 2020; 18:214. [PMID: 32664932 PMCID: PMC7360379 DOI: 10.1186/s12916-020-01682-y] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/25/2020] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly presents as fever, cough, dyspnea, and myalgia or fatigue. Although the majority of patients with COVID-19 have mild symptoms, some are more prone to serious outcomes, including pneumonia, acute respiratory distress syndrome (ARDS), and even death. Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening inflammatory syndrome associated with intense cytokine release (also known as a "cytokine storm"). Similar to COVID-19, HLH is characterized by aggressive course leading to multi-organ failure. MAIN TEXT The purpose of this review article is to draw attention to the possibility of the complication of HLH in patients with the severe course of COVID-19. Indeed, some of the clinical characteristics observed in the more severe cases of COVID-19 are reminiscent of secondary HLH (which can be triggered by infections, malignancies, rheumatological diseases, or autoimmune/immunodeficiency conditions). The pathogenesis of SARS-CoV-2 infection also suggests that HLH or a similar hyperinflammatory syndrome is the cause of the severe course of the infection. CONCLUSION The pathogenesis and clinical symptoms of severe COVID-19 indicate that an increased inflammatory response corresponding to HLH is occurring. Therefore, patients with severe COVID-19 should be screened for hyperinflammation using standard laboratory tests to identify those for whom immunosuppressive therapy may improve outcomes.
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Affiliation(s)
- Violetta Opoka-Winiarska
- Department of Paediatric Pulmonology and Rheumatology, Medical University of Lublin, Gębali 6, 20-093 Lublin, Poland
| | - Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland
- Department of Clinical Immunology, St. John’s Cancer Hospital, K. Jaczewskiego 7 St, 20–090 Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a Street, 20-093 Lublin, Poland
- Department of Clinical Immunology, St. John’s Cancer Hospital, K. Jaczewskiego 7 St, 20–090 Lublin, Poland
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Lachmann G, Knaak C, Vorderwülbecke G, La Rosée P, Balzer F, Schenk T, Schuster FS, Nyvlt P, Janka G, Brunkhorst FM, Keh D, Spies C. Hyperferritinemia in Critically Ill Patients. Crit Care Med 2020; 48:459-465. [PMID: 32205591 DOI: 10.1097/ccm.0000000000004131] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Hyperferritinemia is frequently seen in critically ill patients. A rather rare though life-threatening condition related to severely elevated ferritin is hemophagocytic lymphohistiocytosis. We analyze ferritin levels to differentiate hemophagocytic lymphohistiocytosis from other causes of hyperferritinemia in a mixed cohort of critically ill patients. DESIGN Retrospective observational study. SETTING Adult surgical, anesthesiologic, and medical ICUs of a university hospital. PATIENTS Critical care patients (≥ 18 yr old) admitted to any of the adult ICUs at Charité - Universitätsmedizin Berlin between January 2006 and August 2018 with at least one ferritin value and hyperferritinemia (≥ 500 µg/L). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients were categorized into hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other diagnoses. These were further categorized into 17 subgroups. Hemophagocytic lymphohistiocytosis diagnosis was based on Hemophagocytic Lymphohistiocytosis-2004 criteria and the HScore. Of 2,623 patients with hyperferritinemia, 40 were considered to have hemophagocytic lymphohistiocytosis (1.52%). Maximum ferritin levels were highest in hemophagocytic lymphohistiocytosis patients compared with all other disease groups (each p < 0.001). Sepsis and septic shock patients had higher maximum ferritin levels than patients with other diagnoses (each p < 0.001). A maximum ferritin value of 9,083 µg/L was at 92.5% sensitivity and 91.9% specificity for hemophagocytic lymphohistiocytosis (area under the curve, 0.963; 95% CI, 0.949-0.978). Of all subgroups with other diagnoses, maximum ferritin levels were highest in patients with varicella-zoster virus, hepatitis, or malaria (median, 1,935, 1,928, and 1,587 µg/L, respectively). Maximum ferritin levels were associated with increased in-hospital mortality (odds ratio, 1.518 per log µg/L [95% CI, 1.384-1.665 per log µg/L]; p < 0.001). CONCLUSIONS This is the largest study of patients with ferritin available in a mixed ICU cohort. Ferritin levels in patients with hemophagocytic lymphohistiocytosis, sepsis, septic shock, and other conditions were distinctly different, with the highest ferritin levels observed in hemophagocytic lymphohistiocytosis patients. Maximum ferritin of 9,083 µg/L showed high sensitivity and specificity and, therefore, may contribute to improved diagnosis of hemophagocytic lymphohistiocytosis in ICU. The inclusion of ferritin into the sepsis laboratory panel is warranted.
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Affiliation(s)
- Gunnar Lachmann
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
| | - Cornelia Knaak
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Gerald Vorderwülbecke
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II, Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
| | - Felix Balzer
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Thomas Schenk
- Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany
| | - Friederike S Schuster
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Peter Nyvlt
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Gritta Janka
- Clinic of Pediatric Hematology and Oncology, University Medical Center Eppendorf, Hamburg, Germany
| | - Frank M Brunkhorst
- Center for Clinical Studies, Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Jena, Jena, Germany
| | - Didier Keh
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Claudia Spies
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Augustenburger Platz 1, D-13353 Berlin, Germany
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Bauchmuller K, Manson JJ, Tattersall R, Brown M, McNamara C, Singer M, Brett SJ. Haemophagocytic lymphohistiocytosis in adult critical care. J Intensive Care Soc 2020; 21:256-268. [PMID: 32782466 DOI: 10.1177/1751143719893865] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation, characterised by extreme inflammation, fever, cytopaenias and organ dysfunction. HLH can be triggered by conditions such as infection, autoimmune disease and malignancy, among others. Both a familial and a secondary form have been described, the latter being increasingly recognised in adult patients with critical illness. HLH is difficult to diagnose, often under-recognised and carries a high mortality. Patients can present in a very similar fashion to sepsis and the two syndromes can co-exist and overlap, yet HLH requires specific immunosuppressive therapy. HLH should be actively excluded in patients with presumed sepsis who either lack a clear focus of infection or who are not responding to energetic infection management. Elevated serum ferritin is a key biomarker that may indicate the need for further investigations for HLH and can guide treatment. Early diagnosis and a multidisciplinary approach to HLH management may save lives.
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Affiliation(s)
- Kris Bauchmuller
- Department of Critical Care and Anaesthesia, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Jessica J Manson
- Department of Rheumatology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Rachel Tattersall
- Department of Rheumatology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.,Department of Paediatric and Adolescent Rheumatology, Sheffield Children's NHS Trust, Sheffield, UK
| | - Michael Brown
- Hospital for Tropical Diseases, University College London Hospitals NHS Foundation Trust, London, UK.,Clinical Research Department, London School of Hygiene and Tropical Medicine, London, UK
| | - Christopher McNamara
- Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Mervyn Singer
- Division of Medicine, Bloomsbury Institute of Intensive Care Medicine, University College London, London, UK
| | - Stephen J Brett
- Department of Surgery and Cancer, Imperial College London, London, UK
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von Bahr Greenwood T, Palmkvist-Kaijser K, Chiang SC, Tesi B, Bryceson YT, Hjelmqvist H, Henter JI. Elevated ferritin and soluble CD25 in critically ill patients are associated with parameters of (hyper) inflammation and lymphocyte cytotoxicity. Minerva Anestesiol 2019; 85:1289-1298. [DOI: 10.23736/s0375-9393.19.13534-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Georgiadou S, Gatselis NK, Stefos A, Zachou K, Makaritsis K, Rigopoulou EI, Dalekos GN. Efficient management of secondary haemophagocytic lymphohistiocytosis with intravenous steroids and γ-immunoglobulin infusions. World J Clin Cases 2019; 7:3394-3406. [PMID: 31750324 PMCID: PMC6854401 DOI: 10.12998/wjcc.v7.i21.3394] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/20/2019] [Accepted: 10/15/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Secondary haemophagocytic lymphohistiocytosis (sHLH) is a rare life-threatening condition mainly associated with underlying infections, malignancies, and autoimmune or immune-mediated diseases.
AIM To analyse all sHLH cases that were diagnosed and managed under real-world circumstances in our department focusing on the treatment schedule and the outcome.
METHODS Prospectively collected data from all adult patients fulfilling the criteria of sHLH who diagnosed and managed from January 1, 2010 to June 1, 2018, in our department of the tertiary care university hospital of Larissa, Greece, were analysed retrospectively (n = 80; 52% male; median age: 55 years). The electronic records and/or written charts of the patients were reviewed for the demographic characteristics, clinical manifestations, underlying causes of sHLH, laboratory parameters, treatment schedule and 30-d-mortality rate. Most of patients had received after consent intravenous γ-immunoglobulin (IVIG) for 5 d (total dose 2 g/kg) in combination with intravenous steroid pulses followed by gradual tapering of prednisolone.
RESULTS Seventy-five patients (94%) reported fever > 38.5 °C, 47 (59%) had liver or spleen enlargement and 76 (95%) had ferritin > 500 ng/mL including 20 (25%) having considerably high levels (> 10000 ng/mL). Anaemia and thrombocytopenia occurred in 72% and leucopoenia in 47% of them. Underlying infections were diagnosed in 59 patients (74%) as follows: leishmaniasis alone in 15/80 (18.9%), leishmaniasis concurrently with Coxiella Burnetti or non-Hodgkin lymphoma in 2/80 (2.5%), bacterial infections in 14/80 (17.5%) including one case with concurrent non-Hodgkin lymphoma, viral infections in 13/80 (16.3%), fungal infections in 2/80 (2.5%), infections by mycobacteria in 1/80 (1.3%) and unidentified pathogens in 12/80 (15%). Seventy-two patients (90%) had received combination treatment with IVIG and intravenous steroids. Overall, sHLH resolved in 76% of patients, 15% died within the first month but 82.5% of patients were still alive 6 mo after diagnosis. Univariate analysis showed older age, anaemia, thrombocytopenia, low fibrinogen, disseminated intravascular coagulation (DIC), and delay of diagnosis as factors that negatively affected remission. However, multivariate analysis showed low platelets and DIC as the only independent predictors of adverse outcome.
CONCLUSION sHLH still carries a remarkable morbidity and mortality. Underlying infections were the major cause and therefore, they should be thoroughly investigated in patients with sHLH. Early recognition and combination treatment with IVIG and corticosteroids seem an efficient treatment option with successful outcome in this life-threatening condition.
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Affiliation(s)
- Sarah Georgiadou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
| | - Nikolaos K Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, University Hospital of Larissa, Larissa 41447, Greece
| | - Aggelos Stefos
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
| | - Kalliopi Zachou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, University Hospital of Larissa, Larissa 41447, Greece
| | - Konstantinos Makaritsis
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, University Hospital of Larissa, Larissa 41447, Greece
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, University Hospital of Larissa, Larissa 41447, Greece
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, University Hospital of Larissa, Larissa 41110, Greece
- Institute of Internal Medicine and Hepatology, University Hospital of Larissa, Larissa 41447, Greece
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Lachmann G, Knaak C, von Haefen C, Paeschke N, Meisel C, Nyvlt P, Schuster FS, Piper SK, Kruppa J, Vorderwülbecke G, Balzer F, La Rosée P, Schenk T, Unterwalder N, Kölsch U, Lachmann N, Akyüz L, Brunkhorst FM, Volk HD, Keh D, Spies C. Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol. BMJ Open 2019; 9:e032695. [PMID: 31666276 PMCID: PMC6830715 DOI: 10.1136/bmjopen-2019-032695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
INTRODUCTION Haemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early diagnosis and specific immune suppressive treatment are mandatory to avoid fatal outcome, but the diagnostic criteria (HLH-2004) are adopted from paediatric HLH and have not been validated in adults. Experimental studies suggest biomarkers to sufficiently diagnose HLH. However, biomarkers for the diagnosis of adult HLH have not yet been investigated. METHODS AND ANALYSIS The HEMICU (Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients) study aims to estimate the incidence rate of adult HLH among suspected adult patients in intensive care units (ICUs). Screening for HLH will be performed in 16 ICUs of Charité - Universitätsmedizin Berlin. The inclusion criteria are bicytopaenia, hyperferritinaemia (≥500 µg/L), fever or when HLH is suspected by the clinician. Over a period of 2 years, we expect inclusion of about 100 patients with suspected HLH. HLH will be diagnosed if at least five of the HLH-2004 criteria are fulfilled, together with an expert review; all other included patients will serve as controls. Second, a panel of potential biomarker candidates will be explored. DNA, plasma and serum will be stored in a biobank. The primary endpoint of the study is the incidence rate of adult HLH among suspected adult patients during ICU stay. Out of a variety of measured biomarkers, this study furthermore aims to find highly potential biomarkers for the diagnosis of adult HLH in ICU. The results of this study will contribute to improved recognition and patient outcome of adult HLH in clinical routine. ETHICS AND DISSEMINATION The institutional ethics committee approved this study on 1 August 2018 (Ethics Committee of Charité - Universitätsmedizin Berlin, EA4/006/18). The results of the study will be disseminated in an international peer-reviewed journal and presented at international conferences. TRIAL REGISTRATION NUMBER NCT03510650.
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Affiliation(s)
- Gunnar Lachmann
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Cornelia Knaak
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Clarissa von Haefen
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Nadine Paeschke
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Christian Meisel
- Department of Immunology, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany
| | - Peter Nyvlt
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Friederike S Schuster
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Sophie K Piper
- Berlin Institute of Health, Berlin, Germany
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Jochen Kruppa
- Berlin Institute of Health, Berlin, Germany
- Institute of Biometry and Clinical Epidemiology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Gerald Vorderwülbecke
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Felix Balzer
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Paul La Rosée
- Klinik für Innere Medizin II, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany
| | - Thomas Schenk
- Department of Hematology and Oncology, Universitätsklinikum Jena, Jena, Germany
| | - Nadine Unterwalder
- Department of Immunology, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany
| | - Uwe Kölsch
- Department of Immunology, Labor Berlin - Charité Vivantes GmbH, Berlin, Germany
| | - Nils Lachmann
- Institute for Transfusion Medicine, H&I Laboratory, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Levent Akyüz
- Institute for Medical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Frank M Brunkhorst
- Center for Clinical Studies, Department of Anesthesiology and Intensive Care Medicine, Universitätsklinikum Jena, Jena, Germany
| | - Hans-Dieter Volk
- Institute for Medical Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Didier Keh
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Claudia Spies
- Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis in adults (aHLH) is a rare life-threatening hyperinflammatory syndrome caused by excessive activation of macrophages and CD8+ T-cells. Due to the clinical overlap with severe sepsis, aHLH often remains undiagnosed resulting in poor outcome. Here, we present a retrospective study of incidence, clinical findings, and the outcome of aHLH in intensive care units (ICUs). METHODS This retrospective analysis was performed at the university hospital Charité - Universitätsmedizin Berlin. We gathered data from 556 out of 46,532 patients admitted to our anesthesiological ICUs between 2006 and 2013, who had at least one plasma ferritin measurement during ICU treatment, and were at least 18 years old. Of these, 244 patients with ferritin at least 500 μg/L and available datasets of at least 4 HLH-2004 criteria were included. HLH-2004 diagnostic criteria and the recently published HScore were used. An aHLH expert team retrospectively reviewed the potential aHLH cases. RESULTS Seventy-one of the included 244 patients died; 9 out of the 244 patients were retrospectively classified as aHLH of whom 4 patients had died (44.4%). Two of the 9 aHLH patients had been correctly diagnosed and had received specific aHLH treatment. Thus, 7 out of 9 patients (77.8%) remained undetected. ICU patients with at least 1 captured ferritin value and hyperferritinemia showed an aHLH rate of 3.7%, which rises up to 5.6% when only deceased patients are considered. Mortality in this selected cohort is 44.4%. CONCLUSIONS Overall, 7 out of 9 patients (77.8%) suffering from aHLH remained undiagnosed. Awareness of this life-threatening syndrome, especially in ICUs, should be raised. The inclusion of ferritin into the admission lab panel for ICU is warranted.Clinical trial registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016. As this is a retrospective study, trial registration was after final data collection date.
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[Hemophagocytic lymphohistiocytosis in unspecific virus infection]. Anaesthesist 2019; 68:626-632. [PMID: 31396675 PMCID: PMC7079861 DOI: 10.1007/s00101-019-00634-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/17/2019] [Accepted: 07/14/2019] [Indexed: 12/28/2022]
Abstract
Die Hämophagozytische Lymphohistiozytose (HLH), in der Literatur auch Hämophagozytosesyndrom oder Makrophagenaktivierungssyndrom im Rahmen einer rheumatologischen Vorerkrankung, wird auf Intensivstationen aufgrund des sepsisähnlichen Krankheitsbildes in über 70 % der Fälle nicht erkannt. Es wird von einem 30-jährigen, zuvor gesunden Patienten berichtet, der nach einer 3‑monatigen Asien- und Südamerikareise mit unklarem Fieber zunächst auf die infektiologische Normalstation der Charité – Universitätsmedizin Berlin aufgenommen und nach 3 Tagen bei respiratorischer Insuffizienz auf die Intensivstation verlegt wurde. Durch die sofortige HLH-Diagnostik mit Initiierung der spezifischen immunsupprimierenden Therapie mittels Dexamethason, Immunglobulinen und Anakinra konnte der Patient nach insgesamt 14-tägigem Krankenhausaufenthalt vollständig genesen in die Häuslichkeit entlassen werden. Es werden weiterhin aktuelle diagnostische und therapeutische Möglichkeiten diskutiert. Ferritin als entscheidender diagnostischer Marker sollte bei jedem Patienten mit unklarem Organversagen bestimmt werden.
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Diagnosis, Treatment, and Management of Hemophagocytic Lymphohistiocytosis in the Critical Care Unit. CRITICAL CARE OF THE PEDIATRIC IMMUNOCOMPROMISED HEMATOLOGY/ONCOLOGY PATIENT 2019. [PMCID: PMC7123852 DOI: 10.1007/978-3-030-01322-6_9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Karakike E, Giamarellos-Bourboulis EJ. Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis. Front Immunol 2019; 10:55. [PMID: 30766533 PMCID: PMC6365431 DOI: 10.3389/fimmu.2019.00055] [Citation(s) in RCA: 206] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 01/10/2019] [Indexed: 12/13/2022] Open
Abstract
Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra.
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Affiliation(s)
- Eleni Karakike
- Fourth Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Kapoor S, Morgan CK, Siddique MA, Guntupalli KK. Intensive care unit complications and outcomes of adult patients with hemophagocytic lymphohistiocytosis: A retrospective study of 16 cases. World J Crit Care Med 2018; 7:73-83. [PMID: 30596029 PMCID: PMC6305525 DOI: 10.5492/wjccm.v7.i6.73] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Revised: 10/21/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To study the management, complications and outcomes of adult patients admitted with hemophagocytic lymphohistiocytosis (HLH) in the intensive care unit (ICU).
METHODS We performed a retrospective observational study of adult patients with the diagnosis of “HLH” admitted to the two academic medical ICUs of Baylor College of Medicine between 01/01/2013 to 06/30/2017. HLH was diagnosed using the HLH-2004 criteria proposed by the Histiocyte Society.
RESULTS Sixteen adult cases of HLH were admitted to the medical ICUs over 4 years. Median age of presentation was 49 years and 10 (63%) were males. Median Sequential Organ Failure Assessment (SOFA) score at the time of ICU admission was 10. Median ICU length of stay (LOS) was 11.5 d and median hospital LOS was 29 d. Septic shock and acute respiratory failure accounted for majority of diagnoses necessitating ICU admission. Septic shock was the most common ICU complication seen in (88%) patients, followed by acute kidney injury (81%) and acute respiratory failure requiring mechanical ventilation (75%). Nine patients (56%) developed disseminated intravascular coagulation and eight (50%) had acute liver failure. 10 episodes of clinically significant bleeding were observed. Multi system organ failure was the most common cause of death seen in 12 (75%) patients. The 30 d mortality was 37% (6 cases) and 90 d mortality was 81% (13 cases). There was no difference in mortality based on age (above or less than 50 years), SOFA score on ICU admission (more than or less than 10), immunosuppression, time to diagnose HLH or direct ICU admission versus floor transfer.
CONCLUSION HLH is a devastating disease associated with poor outcomes in ICU. Intensivists need to have a high degree of clinical suspicion for HLH in patients with septic shock/multi system organ failure and progressive bi/pancytopenia who are not responding to standard management in ICU.
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Affiliation(s)
- Sumit Kapoor
- Department of Critical Care Medicine, Montefiore Medical Center, Bronx, NY 10467, United States
| | - Christopher K Morgan
- Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX 77030, United States
| | - Muhammad Asim Siddique
- Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX 77030, United States
| | - Kalpalatha K Guntupalli
- Department of Pulmonary, Critical Care and Sleep, Baylor College of Medicine, Houston, TX 77030, United States
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Brito-Zerón P, Kostov B, Moral-Moral P, Martínez-Zapico A, Díaz-Pedroche C, Fraile G, Pérez-Guerrero P, Fonseca E, Robles A, Vaquero-Herrero MP, Calvo MA, Forner MJ, Morcillo C, Larrañaga J, Rodriguez-Carballeira M, Ruiz-Muñoz M, Hurtado-García R, Prieto-González S, Aguilar AA, Caminal-Montero L, Hernández-Jiménez P, Fernández-Viagas CR, Castro P, Massó VM, Flores-Chavez A, Ramos-Casals M. Prognostic Factors of Death in 151 Adults With Hemophagocytic Syndrome: Etiopathogenically Driven Analysis. Mayo Clin Proc Innov Qual Outcomes 2018; 2:267-276. [PMID: 30225460 PMCID: PMC6132215 DOI: 10.1016/j.mayocpiqo.2018.06.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 06/24/2018] [Accepted: 06/27/2018] [Indexed: 01/09/2023] Open
Abstract
Objective To characterize the etiologies and clinical features at diagnosis of patients with hemophagocytic lymphohistiocytosis (HLH) and correlate these baseline features with survival using an etiopathogenically guided multivariable model. Patients and Methods The Spanish Group of Autoimmune Diseases HLH Study Group, formed in 2013, is aimed at collecting adult patients with HLH diagnosed in internal medicine departments between January 3, 2013, and October 28, 2017. Results The cohort consisted of 151 patients (91 men; mean age, 51.4 years). After a mean follow-up of 17 months (range, 1-142 months), 80 patients died. Time-to-event analyses for death identified a worse survival curve for patients with neoplasia (P<.001), mixed microbiological infections (P=.02), and more than 1 infection (P=.01) and glucocorticoid monotherapy (P=.02). According to univariate analyses, platelets of less than 100,000/mm3 (hazard ratio [HR], 3.39; 95% CI, 1.37-8.40), leukopenia (HR, 1.81; 95% CI, 1.01-3.23), severe hyponatremia (HR, 1.61; 95% CI, 1.02-2.54), disseminated intravascular coagulation (HR, 1.87; 95% CI, 1.05-3.34), bacterial infection (HR, 1.99; 95% CI, 1.09-3.63), mixed microbiological infections (HR, 3.42; 95% CI, 1.38-8.46), and 2 or more infectious triggers (HR, 2.95; 95% CI, 1.43-6.08) were significantly associated with death. In contrast, peripheral adenopathies (HR, 0.63; 95% CI, 0.40-0.98) and the immunosuppressive drug/intravenous immunoglobulin/biological therapies (HR, 0.44; 95% CI, 0.20-0.96) were protective against all-cause mortality. Multivariable Cox proportional hazards regression analysis identified 2 or more infectious triggers (HR, 3.14; 95% CI, 1.28-7.68) as the only variable independently associated with death. Conclusion The mortality rate of adult patients diagnosed with HLH exceeds 50%. Infection with more than 1 microbiological agent was the only independent variable associated with mortality irrespective of the underlying disease, epidemiological profile, clinical presentation, and therapeutic management.
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Affiliation(s)
- Pilar Brito-Zerón
- Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA-Sanitas, Barcelona, Spain
| | - Belchin Kostov
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain.,Primary Healthcare Transversal Research Group, IDIBAPS, Barcelona, Spain
| | - Pedro Moral-Moral
- Immunopathology Section, Department of Internal Medicine, Hospital Universitari i Politècnic La Fe, Departament de Salut Valencia La Fe, Valencia, Spain
| | - Aleida Martínez-Zapico
- Autoimmune Diseases Unit, UGC Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Carmen Díaz-Pedroche
- Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Guadalupe Fraile
- Department of Internal Medicine, Hospital Ramón y Cajal, Madrid, Spain
| | | | - Eva Fonseca
- Department of Internal Medicine, Hospital de Cabueñes, Gijón, Spain
| | - Angel Robles
- Department of Internal Medicine, Hospital La Paz, Madrid, Spain
| | - María P Vaquero-Herrero
- Department of Internal Medicine, Complejo Asistencial Universitario de Salamanca, Salamanca, Spain
| | - María Andrés Calvo
- Department of Internal Medicine, Hospital Rio Hortega Valladolid, Valladolid, Spain
| | - María José Forner
- Department of Internal Medicine, Hospital Clínico de Valencia, Valencia, Spain
| | - Cesar Morcillo
- Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA-Sanitas, Barcelona, Spain
| | - José Larrañaga
- Department of Internal Medicine, Hospital Xeral, Vigo, Spain
| | | | - Manuel Ruiz-Muñoz
- Department of Internal Medicine, Hospital Universitario Fundacion Alcorcón, Alcorcón, Spain
| | | | | | - Asun Aljibe Aguilar
- Immunopathology Section, Department of Internal Medicine, Hospital Universitari i Politècnic La Fe, Departament de Salut Valencia La Fe, Valencia, Spain
| | - Luis Caminal-Montero
- Autoimmune Diseases Unit, UGC Internal Medicine, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | | | - Pedro Castro
- Medical Intensive Care Unit, Department of Medicine, ICMiD, Hospital Clínic, Barcelona, Spain
| | - Victoria Morell Massó
- Immunopathology Section, Department of Internal Medicine, Hospital Universitari i Politècnic La Fe, Departament de Salut Valencia La Fe, Valencia, Spain
| | - Alejandra Flores-Chavez
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain.,Biomedical Research Unit 02, Clinical Epidemiology Research Unit, UMAE, Specialties Hospital, Western Medical Center, Mexican Institute for Social Security (IMSS), Guadalajara, Mexico.,Postgraduate Program of Medical Science, University Center for Biomedical Research (CUIB), University of Colima, Colima, Mexico
| | - Manuel Ramos-Casals
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain.,Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain.,Department of Medicine, University of Barcelona, Barcelona, Spain
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Chang Y, Cui M, Fu X, Han L, Zhang L, Li L, Li X, Sun Z, Wu J, Zhang X, Li Z, Nan F, Yan J, Sheng G, Zhang M. Lymphoma associated hemophagocytic syndrome: A single-center retrospective study. Oncol Lett 2018; 16:1275-1284. [PMID: 30061947 DOI: 10.3892/ol.2018.8783] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Accepted: 04/03/2018] [Indexed: 12/20/2022] Open
Abstract
To improve the understanding of lymphoma associated hemophagocytic syndrome (LAHS) and find an effective treatment for this fatal disease, 57 patients with LAHS were retrospectively reviewed. The most common histopathological type was extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) (45.61%). Patients with B-cell LAHS were significantly older (P<0.001), and exhibited a higher triglyceride level (P=0.012), lower serum ferritin level (P=0.014) and lower plasma Epstein-Barr virus DNA (P<0.001) compared with patients with T/NK-cell LAHS. The median survival time of all patients was 43 days, and patients with B-cell (n=14) and T/NK-cell (n=43) LAHS had a median survival time of 55 and 40 days, respectively (P=0.797). Compared with patients who were treated based on HLH-2004 protocols combined with multidrug chemotherapy, those without chemotherapy had a reduced prognosis (P=0.002). The patients that underwent hematopoietic stem cell transplantation (HSCT) following chemotherapy had a significantly improved overall survival (OS) compared with patients that did not undergo HSCT (P=0.001). Patients with B-cell LAHS treated with rituximab (P=0.015) and patients with ENKL treated with L-asparaginase/pegaspargase (L-asp/peg) (P=0.009) had an improved prognosis compared with patients not treated with these drugs. In the T/NK-cell LAHS group, patients treated with chemotherapy containing gemcitabine did not exhibit an improved OS compared with those not treated with gemcitabine (P=0.326). Furthermore, multivariate analysis demonstrated that long diagnosis time and poor performance status were independent prognosis factors for all patients with LAHS. The present study indicated that survival time does not differ between patients with B-cell LAHS and patients with T/NK-cell LAHS. Early diagnosis and appropriate immunochemotherapy plus HSCT are essential to achieve improved outcomes. The outcome of patients with B-cell LAHS may be significantly improved following treatment with rituximab. L-asp/peg-containing regimens are promising treatments for patients with NK/T-cell LAHS.
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Affiliation(s)
- Yu Chang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Meng Cui
- Department of Head and Neck and Thyroid, Henan Cancer Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xiaorui Fu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lijuan Han
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Lei Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Ling Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xin Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhenchang Sun
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jingjing Wu
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Xudong Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Zhaoming Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Feifei Nan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jiaqin Yan
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Guangyao Sheng
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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Calvet L, Pereira B, Sapin AF, Mareynat G, Lautrette A, Souweine B. Contribution to diagnosis and treatment of bone marrow aspirate results in critically ill patients undergoing bone marrow aspiration: a retrospective study of 193 consecutive patients. J Intensive Care 2017; 5:67. [PMID: 29225888 PMCID: PMC5715543 DOI: 10.1186/s40560-017-0263-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Accepted: 11/16/2017] [Indexed: 11/10/2022] Open
Abstract
Background The purpose of the work was to assess the contribution to diagnosis and/or treatment (CDT) of bone marrow aspiration (BMA) in the critically ill patient. Methods The retrospective study included 193 patients. On the basis of BMA findings, contribution to diagnosis was defined by one of four previously unestablished diagnoses (maturation arrest of granulocyte precursors, hemophagocytic lymphohistiocytosis, hematological malignancy, marrow infiltration with cancer cells) and to treatment as the initiation or withdrawal of a specific treatment including the decision to forgo life-sustaining treatment (DFLST). Results A CDT of BMA was observed in 40/193 patients (20.7%). BMA contributed to diagnosis in 37 cases (granulocyte precursor maturation arrest, N = 10; hemophagocytic lymphohistiocytosis, N = 12; hematological malignancy, N = 15) and to treatment in 14, including three DFLSTs. In multivariate analysis, the factors associated with a CDT were hematological malignancy, cancer or non-malignant hematological abnormality known on admission, indication for BMA excluding isolated thrombocytopenia, higher pre-BMA HScore (calculated prior to BMA), and higher SOFA score with or without platelet-count SOFA subscore. In the 160 patients without hematological malignancy or cancer known on admission, non-malignant hematological abnormality known on admission, indication for BMA excluding isolated thrombocytopenia, higher pre-BMA HScore, and higher SOFA score calculated with or without platelet-count SOFA subscore were independently associated with a CDT of BMA. Conclusion BMA can have a significant CDT in ICU patients with or without a known hematological malignancy or cancer on admission. An HScore calculated before BMA can be a valuable tool for predicting a CDT of BMA. Electronic supplementary material The online version of this article (10.1186/s40560-017-0263-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Laure Calvet
- Service de Réanimation Médicale, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, BP 69, 63003 Clermont-Ferrand, Cedex 1, France
| | - Bruno Pereira
- Département de biostatistique, CHU de Clermont-Ferrand, Clermont-Ferrand, France
| | | | - Gabrielle Mareynat
- Laboratoire d'hématologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France
| | - Alexandre Lautrette
- Service de Réanimation Médicale, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, BP 69, 63003 Clermont-Ferrand, Cedex 1, France.,Université Clermont Auvergne, CNRS, LMGE, F-63000 Clermont-Ferrand, France
| | - Bertrand Souweine
- Service de Réanimation Médicale, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, BP 69, 63003 Clermont-Ferrand, Cedex 1, France.,Université Clermont Auvergne, CNRS, LMGE, F-63000 Clermont-Ferrand, France
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Wong M, Rao A, Nemunaitis J, Czuchlewski D, Sagheer S, Arana-Yi C. Hemophagocytosis lymphocytosis presenting as pulmonary-renal syndrome: a case report and literature review. Clin Case Rep 2017; 5:1486-1489. [PMID: 28878910 PMCID: PMC5582273 DOI: 10.1002/ccr3.1082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 06/06/2017] [Indexed: 12/13/2022] Open
Abstract
Hemophagocytosis Lymphocytosis (HLH) is a rare and life-threatening illness that is more commonly seen in infants; however, its incidence in adults is becoming more common. Recognizing HLH in a complicated clinical scenario is key to early recognition, treatment, as well as improved morbidity and mortality.
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Affiliation(s)
- Morgan Wong
- Department of Internal Medicine University of New Mexico MSC10-5550 Albuquerque 87131 New Mexico
| | - Arpit Rao
- Division of Hematology and Oncology Department of Internal Medicine University of New Mexico Comprehensive Cancer Center MSC07-4025 Albuquerque 87131 New Mexico
| | - Jacklyn Nemunaitis
- Division of Hematology and Oncology Department of Internal Medicine University of New Mexico Comprehensive Cancer Center MSC07-4025 Albuquerque 87131 New Mexico
| | - David Czuchlewski
- Department of Pathology University of New Mexico MSC10-5550 Albuquerque 87131 New Mexico
| | - Shazib Sagheer
- Department of Internal Medicine University of New Mexico MSC10-5550 Albuquerque 87131 New Mexico
| | - Cecilia Arana-Yi
- Division of Hematology and Oncology Department of Internal Medicine University of New Mexico Comprehensive Cancer Center MSC07-4025 Albuquerque 87131 New Mexico
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Wohlfarth P, Agis H, Gualdoni GA, Weber J, Staudinger T, Schellongowski P, Robak O. Interleukin 1 Receptor Antagonist Anakinra, Intravenous Immunoglobulin, and Corticosteroids in the Management of Critically Ill Adult Patients With Hemophagocytic Lymphohistiocytosis. J Intensive Care Med 2017. [PMID: 28631531 DOI: 10.1177/0885066617711386] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) causes multiple organ dysfunction frequently leading to intensive care unit (ICU) referral and/or death. We report on a series of critically ill adult patients treated with a non-etoposide-based regimen including interleukin 1 antagonist anakinra, intravenous immunoglobulin (IVIG), and/or corticosteroids (CS) for HLH. METHODS Eight adult (≥18 years) ICU patients having received treatment with anakinra ± IVIG ± CS for HLH between March 2014 and March 2016 at a large tertiary care university hospital (Medical University of Vienna, Vienna, Austria) were retrospectively analyzed. RESULTS Eight patients (median age: 38 years; range: 20-58 years; 4 males and 4 females) received anakinra together with IVIG (n = 7) and/or high-dose CS (n = 5) for suspected reactive HLH (median H-score: 214; range: 171-288). Seven (88%) patients required vasopressors and invasive mechanical ventilation and 6 (75%) patients required renal replacement therapy (median Sequential Organ Failure Assessment [SOFA] score at HLH diagnosis: 9.5; range: 6-14). Six patients showed a significant decline in the SOFA score at 1 and 2 weeks following treatment initiation (P = .03), and the remainder 2 patients experienced early death. Five patients survived to ICU discharge, 4 of them could further be discharged from hospital (hospital survival rate: 50%). No overt treatment-related toxicity was noted. CONCLUSION Anakinra in combination with IVIG and/or CS resulted in a hospital survival rate of 50% in 8 critically ill adult patients with HLH despite a vast degree of organ dysfunction and the need for aggressive ICU treatment. Further research on non-etoposide-based treatment strategies for HLH in critically ill adults is warranted.
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Affiliation(s)
- Philipp Wohlfarth
- 1 Intensive Care Unit 13i2, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Hermine Agis
- 1 Intensive Care Unit 13i2, Department of Medicine I, Medical University of Vienna, Vienna, Austria.,2 Clinical Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Guido A Gualdoni
- 3 Clinical Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Johannes Weber
- 4 Department of Anesthesia and Intensive Care Medicine, Medical University of Vienna, Vienna, Austria
| | - Thomas Staudinger
- 1 Intensive Care Unit 13i2, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Schellongowski
- 1 Intensive Care Unit 13i2, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Oliver Robak
- 1 Intensive Care Unit 13i2, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Filippone EJ, Farber JL. Hemophagocytic lymphohistiocytosis: an update for nephrologists. Int Urol Nephrol 2016; 48:1291-1304. [DOI: 10.1007/s11255-016-1294-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Accepted: 04/11/2016] [Indexed: 12/11/2022]
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Cesarine J, Filippone LM, Filippone EJ. Hemophagocytic lymphohistiocytosis in the ED. Am J Emerg Med 2016; 34:2057.e5-2057.e8. [PMID: 27066745 DOI: 10.1016/j.ajem.2016.03.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 03/11/2016] [Indexed: 12/17/2022] Open
Affiliation(s)
- Joseph Cesarine
- Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ
| | - Lisa M Filippone
- Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ
| | - Edward J Filippone
- Division of Nephrology, Department of Medicine, Sydney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA 19107.
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