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Venkatesan A, Deb R, Nadeem Ahmed R, Vidgeon S, Ashok S, Kotsiopoulou S. Optimising Care for Haemophagocytic Lymphohistiocytosis in District General Hospitals: Best Practice Insights and Review of Literature. Cureus 2025; 17:e80957. [PMID: 40260338 PMCID: PMC12010027 DOI: 10.7759/cureus.80957] [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] [Accepted: 03/21/2025] [Indexed: 04/23/2025] Open
Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory syndrome characterised by widespread, uncontrolled T cell and histiocyte activation with accompanying cytokine storm. It can be inherited or acquired, with acquired forms triggered by infection, malignancy or autoimmune disease. There is high mortality, with patients commonly requiring critical care support. HLH is a relatively rare condition (though it is likely underdiagnosed), and there is an incomplete understanding of its pathogenesis, diagnosis and optimal management. As such, HLH presents a challenge to the critical care physician, particularly in a non-specialist centre. In our District General Hospital (DGH) intensive therapy unit, we experienced an unusually high volume of HLH cases in a short period. By presenting this case series and our improvement strategies, we aim to distil key lessons to other centres to improve the understanding of HLH for critical care physicians. There were seven confirmed cases of HLH between January 2022 and August 2024. We analysed each case, in turn, documenting the initial symptomatology, blood test results, including ferritin, and when specialist teams such as haematology and critical care became involved. We then noted when HLH treatment was started and the outcome of each case. We found that implementing a protocol to encourage early requests of an HLH blood test panel and, thereafter, early review and input by the local haematology teams, as well as critical care input for any patient with suspected HLH, improved patient outcomes: two patients died during admission pre-intervention. However, none of the patients died within their admission after our interventions. We also found that pharmacy input to ensure the emergency stock of medications used to treat HLH allowed more prompt administration of HLH treatment. Although the cornerstone of management for the critical care physician includes supportive care and organ support, HLH-specific treatments targeting the underpinning inflammation and the cytokine storm are also pivotal to controlling the disease process. Early escalation to the haematology team based on abnormally high ferritin levels and early critical care input was the cornerstone of the pathway we developed in our hospital. This system that has been developed will stand to be useful in other DGHs where HLH remains an unfamiliar condition that carries a high mortality rate.
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Affiliation(s)
| | - Rita Deb
- Department of Critical Care Medicine, Croydon University Hospital, London, GBR
| | - Rahim Nadeem Ahmed
- Department of Critical Care Medicine, Croydon University Hospital, London, GBR
| | - Steven Vidgeon
- Department of Critical Care Medicine, Croydon University Hospital, London, GBR
| | - Sundar Ashok
- Department of Critical Care Medicine, Croydon University Hospital, London, GBR
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Cavaillon JM, Chousterman BG, Skirecki T. Compartmentalization of the inflammatory response during bacterial sepsis and severe COVID-19. JOURNAL OF INTENSIVE MEDICINE 2024; 4:326-340. [PMID: 39035623 PMCID: PMC11258514 DOI: 10.1016/j.jointm.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 01/04/2024] [Accepted: 01/06/2024] [Indexed: 07/23/2024]
Abstract
Acute infections cause local and systemic disorders which can lead in the most severe forms to multi-organ failure and eventually to death. The host response to infection encompasses a large spectrum of reactions with a concomitant activation of the so-called inflammatory response aimed at fighting the infectious agent and removing damaged tissues or cells, and the anti-inflammatory response aimed at controlling inflammation and initiating the healing process. Fine-tuning at the local and systemic levels is key to preventing local and remote injury due to immune system activation. Thus, during bacterial sepsis and Coronavirus disease 2019 (COVID-19), concomitant systemic and compartmentalized pro-inflammatory and compensatory anti-inflammatory responses are occurring. Immune cells (e.g., macrophages, neutrophils, natural killer cells, and T-lymphocytes), as well as endothelial cells, differ from one compartment to another and contribute to specific organ responses to sterile and microbial insult. Furthermore, tissue-specific microbiota influences the local and systemic response. A better understanding of the tissue-specific immune status, the organ immunity crosstalk, and the role of specific mediators during sepsis and COVID-19 can foster the development of more accurate biomarkers for better diagnosis and prognosis and help to define appropriate host-targeted treatments and vaccines in the context of precision medicine.
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Affiliation(s)
| | - Benjamin G. Chousterman
- Department of Anesthesia and Critical Care, Lariboisière University Hospital, DMU Parabol, APHP Nord, Paris, France
- Inserm U942, University of Paris, Paris, France
| | - Tomasz Skirecki
- Department of Translational Immunology and Experimental Intensive Care, Centre of Postgraduate Medical Education, Warsaw, Poland
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Ruffer N, Kosch R, Weisel K, Kötter I, Krusche M. [Hemophagocytic lymphohistiocytosis and macrophage activation syndrome : A multidisciplinary challenge]. Z Rheumatol 2024; 83:376-386. [PMID: 38267764 DOI: 10.1007/s00393-023-01472-w] [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] [Accepted: 11/15/2023] [Indexed: 01/26/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that is characterized by hyperferritinemia, cytopenia, disseminated intravascular coagulopathy and functional disorders of the liver and the central nervous system. The term macrophage activation syndrome is predominantly used for secondary HLH in the context of autoimmune diseases (e.g., systemic juvenile idiopathic arthritis). In addition, malignancies and genetic inborn errors of immunity can predispose to the development of HLH. Infections (e.g., Epstein-Barr virus) in turn represent possible triggers of an acute episode. Due to the unspecific manifestation of the disease, a systematic evaluation of the organ systems is recommended in the clinical and laboratory analytical clarification of hyperinflammatory syndromes. In general, the treatment should be carried out by a multidisciplinary team with expertise in rheumatology, hematological oncology, infectious diseases and intensive care medicine. The primary treatment of HLH usually consists of glucocorticoids and in cases of a rapid deterioration of the condition anakinra (interleukin 1 block) and intravenous immunoglobulins can be employed. Treatment of the underlying disease should be consequently carried out in parallel, together with antimicrobial treatment.
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Affiliation(s)
- Nikolas Ruffer
- Sektion Rheumatologie und entzündliche Systemerkrankungen, III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.
| | - Ricardo Kosch
- II. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Katja Weisel
- II. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - Ina Kötter
- Sektion Rheumatologie und entzündliche Systemerkrankungen, III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland
- Klinik für Rheumatologie und Immunologie, Klinikum Bad Bramstedt, Bad Bramstedt, Deutschland
| | - Martin Krusche
- Sektion Rheumatologie und entzündliche Systemerkrankungen, III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland
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Scholz L, Posch F, Schulz E, Gornicec M, Wölfler A, Reisinger AC, Reinisch A, Eller P, Eisner F, Kreuzer P, Stradner M, Rosenkranz AR, Krammer F, Schilcher G, Krause R, Hatzl S. Ruxolitinib, IV Immunoglobulin, and High-Dose Glucocorticoids for Critically Ill Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-Center Observational Pilot Study. Crit Care Explor 2024; 6:e1046. [PMID: 38511127 PMCID: PMC10954049 DOI: 10.1097/cce.0000000000001046] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024] Open
Abstract
OBJECTIVES Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH. DESIGN Observational pilot study. SETTING Single-center tertiary academic ICU. PATIENTS Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria. INTERVENTION Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol. MEASUREMENT AND MAIN RESULTS Nine patients (median age: 42 yr [25th-75th percentile: 32-54]; male: n = 6 males, median H-score: 299 [255-304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th-75th percentile: 7-12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period. CONCLUSION In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.
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Affiliation(s)
- Laura Scholz
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Florian Posch
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Eduard Schulz
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Max Gornicec
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Albert Wölfler
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander C Reisinger
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Andreas Reinisch
- Division of Hematology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Philipp Eller
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Florian Eisner
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Philipp Kreuzer
- Emergency Department, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Martin Stradner
- Division of Rheumatology and Immunology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Alexander R Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Florian Krammer
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
- Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gernot Schilcher
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Robert Krause
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Stefan Hatzl
- Intensive Care Unit, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY
- Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, New York, NY
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Raimbault S, Monneret G, Gossez M, Venet F, Belot A, Zekre F, Remy S, Javouhey E. Elevated monocyte HLA-DR in pediatric secondary hemophagocytic lymphohistiocytosis: a retrospective study. Front Immunol 2023; 14:1286749. [PMID: 38077325 PMCID: PMC10704813 DOI: 10.3389/fimmu.2023.1286749] [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: 08/31/2023] [Accepted: 11/08/2023] [Indexed: 12/18/2023] Open
Abstract
Introduction Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, and its diagnosis may be challenging. In particular, some cases show close similarities to sepsis (fever, organ failure, and high ferritin), but their treatment, while urgent, differ: prompt broad-spectrum antibiotherapy for sepsis and immunosuppressive treatment for HLH. We questioned whether monocyte human leucocyte antigen (mHLA)-DR could be a diagnostic marker for secondary HLH (sHLH). Methods We retrospectively reviewed data from patients with a sHLH diagnosis and mHLA-DR quantification. mHLA-DR data from healthy children and children with septic shock, whose HLA-DR expression is reduced, from a previously published study were also included for comparison. Results Six patients with sHLH had mHLA-DR quantification. The median level of monocyte mHLA-DR expression in patients with sHLH [79,409 antibodies bound per cell (AB/C), interquartile range (IQR) (75,734-86,453)] was significantly higher than that in healthy children and those with septic shock (29,668 AB/C, IQR (24,335-39,199), and 7,493 AB/C, IQR (3,758-14,659), respectively). Each patient with sHLH had a mHLA-DR higher than our laboratory normal values. Four patients had a second mHLA-DR sampling 2 to 4 days after the initial analysis and treatment initiation with high-dose corticosteroids; for all patients, mHLA-DR decreased to within or close to the normal range. One patient with systemic juvenile idiopathic arthritis had repeated mHLA-DR measurements over a 200-day period during which she underwent four HLH episodes. mHLA-DR increased during relapses and normalized after treatment incrementation. Conclusion In this small series, mHLA-DR was systematically elevated in patients with sHLH. Elevated mHLA-DR could contribute to sHLH diagnosis and help earlier distinction with septic shock.
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Affiliation(s)
- Sylvain Raimbault
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de Réanimation Pédiatrique, Bron, France
| | - Guillaume Monneret
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire d’Immunologie, Lyon, France
| | - Morgane Gossez
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire d’Immunologie, Lyon, France
| | - Fabienne Venet
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Laboratoire d’Immunologie, Lyon, France
| | - Alexandre Belot
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de Néphrologie et Rhumatologie Pédiatrique, Centre de Référence RAISE (Rhumatismes Inflammatoires et Maladies Auto-Immunes Systémiques Rares de l’Enfant), ERN RITA (European Reference Network for Immunodeficiency, Autoinflammatory, Autoimmune and Paediatric Rheumatic Diseases), Bron, France
| | - Franck Zekre
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de Néphrologie et Rhumatologie Pédiatrique, Centre de Référence RAISE (Rhumatismes Inflammatoires et Maladies Auto-Immunes Systémiques Rares de l’Enfant), ERN RITA (European Reference Network for Immunodeficiency, Autoinflammatory, Autoimmune and Paediatric Rheumatic Diseases), Bron, France
| | - Solene Remy
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de Réanimation Pédiatrique, Bron, France
| | - Etienne Javouhey
- Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Service de Réanimation Pédiatrique, Bron, France
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Li X, Luo T, Yan H, Xie L, Yang Y, Gong L, Tang Z, Tang M, Zhang X, Huang J, Zheng M, Yao Z, Zang P, Zhu D, Xiao Z, Lu X. Proteomic Analysis of Pediatric Hemophagocytic Lymphohistiocytosis: a Comparative Study with Healthy Controls, Sepsis, Critical Ill, and Active Epstein-Barr virus Infection to Identify Altered Pathways and Candidate Biomarkers. J Clin Immunol 2023; 43:1997-2010. [PMID: 37653176 PMCID: PMC10661879 DOI: 10.1007/s10875-023-01573-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/20/2023] [Indexed: 09/02/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by excessive activation of the immune system, along with uncontrolled proliferation of activated macrophages and lymphocytes. The clinical features of HLH often overlap with the clinical features of other severe inflammatory conditions such as sepsis, hindering accurate and timely diagnosis. In this study, we performed a data-independent acquisition mass spectrometry-based plasma proteomic analysis of 33 pediatric patients with HLH compared with four control groups: 39 healthy children, 43 children with sepsis, 39 children hospitalized in the pediatric intensive care unit without confirmed infections, and 21 children with acute Epstein-Barr virus infection. Proteomic comparisons between the HLH group and each of the control groups showed that HLH was characterized by alterations in complement and coagulation cascades, neutrophil extracellular trap formation, and platelet activation pathways. We identified eight differentially expressed proteins in patients with HLH, including plastin-2 (LCP1), vascular cell adhesion protein 1, fibrinogen beta chain, fibrinogen gamma chain, serum amyloid A-4 protein, extracellular matrix protein 1, apolipoprotein A-I, and albumin. LCP1 emerged as a candidate diagnostic marker for HLH with an area under the curve (AUC) of 0.97 in the original cohort and an AUC of 0.90 (sensitivity = 0.83 and specificity = 1.0) in the validation cohort. Complement C1q subcomponent subunit B was associated with disease severity in patients with HLH. Based on comparisons with multiple control groups, this study provides a proteomic profile and candidate biomarkers of HLH, offering researchers novel information to improve the understanding of this condition.
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Affiliation(s)
- Xun Li
- Pediatrics Research Institute of Hunan Province & Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Ting Luo
- Pediatrics Research Institute of Hunan Province & Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Haipeng Yan
- General Emergency Ward & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Longlong Xie
- Pediatrics Research Institute of Hunan Province & Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Yufan Yang
- Pediatrics Research Institute of Hunan Province & Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Ling Gong
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Zhexuan Tang
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Minghui Tang
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Xinping Zhang
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Jiaotian Huang
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Mincui Zheng
- Department of Pediatric Hematology, Hunan Children's Hospital, Changsha, China
| | - Zhenya Yao
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Ping Zang
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Desheng Zhu
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Zhenghui Xiao
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China
| | - Xiulan Lu
- Department of Pediatric Intensive Care Unit & Hunan Provincial Key Laboratory of Emergency Medicine for Children, Hunan Children's Hospital, Changsha, China.
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An JH, Ahn JH. Postpartum hemophagocytic lymphohistiocytosis: A case report. World J Clin Cases 2023; 11:6183-6188. [PMID: 37731572 PMCID: PMC10507548 DOI: 10.12998/wjcc.v11.i26.6183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/12/2023] [Accepted: 08/15/2023] [Indexed: 09/08/2023] Open
Abstract
BACKGROUND Postpartum hemophagocytic lymphohistiocytosis (HLH) is a rare disease with unclear pathophysiology. It is a secondary HLH diagnosed using the pediatric diagnostic criteria; however, the clinical diagnosis of postpartum HLH remains challenging. Hence, HLH may remain undiagnosed, leading to poor patient prognosis. Therefore, improvements in the accuracy of postpartum HLH diagnoses and treatments are necessary. CASE SUMMARY We report the case of a 40-year-old female with postpartum HLH. The patient attended the postpartum care center for 3 wk after giving birth and underwent needle aspiration due to thyroid gland enlargement 11 d before an emergency department visit precipitated by fever and abdominal pain. Since no abnormal emergency room findings were noted, the patient was discharged with a prescription for broad-spectrum antibiotics. Three days later, she returned to the emergency room in a hemodynamically unstable state and was admitted to the intensive care unit with suspected sepsis or hematologic disease. The patient was treated, without effect, for sepsis using broad-spectrum antibiotics, and for suspected hematologic disease with steroid therapy. However, she died due to rapidly worsening symptoms. CONCLUSION Rapid recognition and appropriate treatment of postpartum HLH are needed to improve the prognosis.
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Affiliation(s)
- Ju Ho An
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon 16499, Gyeonggi-do, South Korea
| | - Jung Hwan Ahn
- Department of Emergency Medicine, Ajou University School of Medicine, Suwon 16499, Gyeonggi-do, South Korea
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Cao Y, Liu P, Song Q, Wang J. Case report: A case of sepsis caused by rickettsial infection-induced hemophagocytic syndrome. Front Med (Lausanne) 2023; 10:1209174. [PMID: 37608831 PMCID: PMC10440429 DOI: 10.3389/fmed.2023.1209174] [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: 04/20/2023] [Accepted: 07/17/2023] [Indexed: 08/24/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare histiocytic disorder characterized by reactive hyperplasia of the mononuclear phagocytic system, which is primarily caused by dysfunction of cytotoxic killer cells and natural killer cells, leading to antigen clearance barriers and the overactivation of the mononuclear phagocytic system due to continuous antigen stimulation. HLH encompasses a group of clinical syndromes marked by the overproduction of inflammatory cytokines. A 68-year-old Chinese man presented with persistent fever, chills, nausea, and vomiting; the patient had no history of any underlying conditions. Laboratory investigations revealed decreased levels of red blood cells, white blood cells, and platelets, along with reduced natural killer cell activity, increased CD25, hyperferritinemia, and the detection of Rickettsia DNA in his blood, meeting the diagnostic criteria of the Histiocyte Society HLH-2004 guidelines. The patient was treated with antibiotics, improving anemia, glucocorticoid therapy, and continuous renal replacement therapy (CRRT), temporarily improving his condition. However, the patient died after 2 years from chronic renal failure caused by septic shock.
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Affiliation(s)
| | | | | | - Jing Wang
- Department of Respiratory and Critical Care Medicine, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China
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Wi W, Yoon KW, Kim HJ. Secondary hemophagocytic lymphohistiocytosis associated with heat stroke: A case report and review of literature. Medicine (Baltimore) 2023; 102:e33842. [PMID: 37233425 PMCID: PMC10219742 DOI: 10.1097/md.0000000000033842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/04/2023] [Indexed: 05/27/2023] Open
Abstract
RATIONALE Hemophagocytic lymphohistiocytosis (HLH) is a syndrome with potentially fatal consequences that results from an excessive immune response caused by malfunctioning natural killer cells and cytotoxic T lymphocytes. Secondary HLH, which is the predominant type in adults, is associated with various medical conditions, including infections, malignancies, and autoimmune diseases. Secondary HLH associated with heat stroke has not been reported. PATIENT CONCERNS A 74-year-old male was admitted to the emergency department after being unconscious in a 42°C hot public bath. The patient was witnessed to be in the water for more than 4 hours. The patient's condition was complicated by rhabdomyolysis and septic shock, which were managed with mechanical ventilation, vasoactive agents, and continuous renal replacement therapy. The patient also showed evidence of diffuse cerebral dysfunction. DIAGNOSES While the patient's condition initially improved, the patient developed a fever, anemia, thrombocytopenia, and an acute rise in total bilirubin, which, we suspected, was caused by HLH. Further investigations revealed elevated serum ferritin and soluble interleukin-2 receptor levels. INTERVENTIONS The patient received 2 cycles of serial therapeutic plasma exchange to lower the endotoxin burden. To manage HLH, high-dose glucocorticoid therapy was done. OUTCOMES Despite the best efforts, the patient did not recover and expired from progressive hepatic failure. LESSONS We report a novel case of secondary HLH associated with heat stroke. Diagnosing secondary HLH can be difficult since clinical manifestations of the underlying disease and HLH may present simultaneously. Early diagnosis and prompt initiation of treatment is required to improve the prognosis of the disease.
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Affiliation(s)
- Wongook Wi
- Department of Anesthesiology and Pain Medicine, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Gyeonggi-do, Republic of Korea
| | - Kyoung Won Yoon
- Division of Critical Care, Department of Surgery, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Gyeonggi-do, Republic of Korea
| | - Hyo Jin Kim
- Department of Anesthesiology and Pain Medicine, Chung-Ang University Gwangmyeong Hospital, Gwangmyeong-si, Gyeonggi-do, Republic of Korea
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Benlamkaddem S, Doughmi D, Tlamçani I, Berdai MA, Harandou M. The Challenging Aspect of Macrophage Activation Syndrome in the Setting of Sepsis or Systemic Inflammatory Response Syndrome (SIRS). Cureus 2023; 15:e36228. [PMID: 37069877 PMCID: PMC10105518 DOI: 10.7759/cureus.36228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2023] [Indexed: 03/18/2023] Open
Abstract
Macrophage activation syndrome (MAS) is a rare but potentially fatal disease. It is characterized by hyperinflammation, including the proliferation and activation of immune cells (CD8 T cells and NK cells) associated with hypercytokinemia. Patients present with fever, splenomegaly, and cytopenia, associated with a hemophagocytosis picture in the bone marrow. It can progress to a multiorgan failure syndrome (MODS), mimicking sepsis or a systemic inflammatory response syndrome (SIRS). We report the case of an 8-year-old girl admitted to the pediatric intensive care unit for the management of major trauma due to a domestic accident. She presented with a protracted fever in the context of a septic shock, despite appropriate treatment. The association with bicytopenia, hyperferritinemia, hypofibrinogenemia, and hypertriglyceridemia was suggestive of MAS which was confirmed by a bone marrow puncture showing hemophagocytosis. A Bolus of corticotherapy was then added to the supportive treatment and broad-spectrum antibiotherapy, with a good outcome.
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Steed D, Collins J, Farris AB, Guarner J, Yarar D, Friedman-Moraco R, Doane T, Pouch S, Marshall Lyon G, Woodworth MH. Haemophagocytic lymphohistiocytosis associated with bartonella peliosis hepatis following kidney transplantation in a patient with HIV. THE LANCET. INFECTIOUS DISEASES 2022; 22:e303-e309. [PMID: 35500593 PMCID: PMC9942922 DOI: 10.1016/s1473-3099(22)00276-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 10/28/2021] [Accepted: 04/22/2022] [Indexed: 02/04/2023]
Abstract
Bacillary peliosis hepatis is a well recognised manifestation of disseminated Bartonella henselae infection that can occur in immunocompromised individuals. Haemophagocytic lymphohistiocytosis is an immune-mediated condition with features that can overlap with a severe primary infection such as disseminated Bartonella spp infection. We report a case of bacillary peliosis hepatis and secondary haemophagocytic lymphohistiocytosis due to disseminated Bartonella spp infection in a kidney-transplant recipient with well controlled HIV. The patient reported 2 weeks of fever and abdominal pain and was found to have hepatomegaly. He recalled exposure to a sick dog but reported no cat exposures. Laboratory evaluation was notable for pancytopenia and cholestatic injury. The patient met more than five of eight clinical criteria for haemophagocytic lymphohistiocytosis. Pathology review of a bone marrow core biopsy identified haemophagocytosis. A transjugular liver biopsy was done, and histopathology review identified peliosis hepatis. Warthin-Starry staining of the bone marrow showed pleiomorphic coccobacillary organisms. The B henselae IgG titre was 1:512, and Bartonella-specific DNA targets were detected by peripheral blood PCR. Treatment with doxycycline, increased prednisone, and pausing the mycophenolate component of his transplant immunosuppression regimen resulted in an excellent clinical response. Secondary haemophagocytic lymphohistiocytosis can be difficult to distinguish from severe systemic infection. A high index of suspicion can support the diagnosis of systemic Bartonella spp infection in those who present with haemophagocytic lymphohistiocytosis, especially in patients with hepatomegaly, immunosuppression, and germane animal exposures.
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Affiliation(s)
- Danielle Steed
- Division of Hospital Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jeffrey Collins
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
| | - Alton B Farris
- Department of Medicine, and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jeannette Guarner
- Department of Medicine, and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Dilek Yarar
- Kidney Specialists of Kentucky, Bowling Green, KY, USA
| | | | - Tristan Doane
- Department of Medicine, and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Stephanie Pouch
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
| | - G Marshall Lyon
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA
| | - Michael H Woodworth
- Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, USA.
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12
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Primary Bone Marrow HIV-Associated Hodgkin Lymphoma Complicated by Hemophagocytic Lymphohistiocytosis. Genes (Basel) 2022; 13:genes13091608. [PMID: 36140777 PMCID: PMC9498763 DOI: 10.3390/genes13091608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 08/30/2022] [Accepted: 09/05/2022] [Indexed: 11/17/2022] Open
Abstract
The presentation of human immunodeficiency virus (HIV)-associated Hodgkin lymphoma can differ from that of the general population. More specifically, primary bone marrow Hodgkin lymphoma is an uncommon presentation that is more often reported in patients with HIV. Given the many overlapping symptoms of Hodgkin lymphoma and HIV as well as HIV-associated infections, diagnosis can be difficult and delayed. We describe a case of primary bone marrow HIV-associated Hodgkin lymphoma complicated by hemophagocytic lymphohistiocytosis (HLH) where the initial work-up was inconclusive. Our case demonstrates the importance of early consideration of HLH as well as the need for an early bone marrow biopsy in a cytopenic patient with a fever of unknown origin.
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13
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Núñez-Torrón C, Ferrer-Gómez A, Moreno Moreno E, Pérez-Mies B, Villarrubia J, Chamorro S, López-Jiménez J, Palacios J, Piris-Villaespesa M, García-Cosío M. Secondary haemophagocytic lymphohistiocytosis in COVID-19: correlation of the autopsy findings of bone marrow haemophagocytosis with HScore. J Clin Pathol 2022; 75:383-389. [PMID: 33722841 PMCID: PMC7970658 DOI: 10.1136/jclinpath-2020-207337] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/19/2021] [Accepted: 02/15/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND Secondary haemophagocytic lymphohistiocytosis (sHLH) is characterised by a hyper activation of immune system that leads to multiorgan failure. It is suggested that excessive immune response in patients with COVID-19 could mimic this syndrome. Some COVID-19 autopsy studies have revealed the presence of haemophagocytosis images in bone marrow, raising the possibility, along with HScore parameters, of sHLH. AIM Our objective is to ascertain the existence of sHLH in some patients with severe COVID-19. METHODS We report the autopsy histological findings of 16 patients with COVID-19, focusing on the presence of haemophagocytosis in bone marrow, obtained from rib squeeze and integrating these findings with HScore parameters. CD68 immunohistochemical stains were used to highlight histiocytes and haemophagocytic cells. Clinical evolution and laboratory parameters of patients were collected from electronic clinical records. RESULTS Eleven patients (68.7%) displayed moderate histiocytic hyperplasia with haemophagocytosis (HHH) in bone marrow, three patients (18.7%) displayed severe HHH and the remainder were mild. All HScore parameters were collected in 10 patients (62.5%). Among the patients in which all parameters were evaluable, eight patients (80%) had an HScore >169. sHLH was not clinically suspected in any case. CONCLUSIONS Our results support the recommendation of some authors to use the HScore in patients with severe COVID-19 in order to identify those who could benefit from immunosuppressive therapies. The presence of haemophagocytosis in bone marrow tissue, despite not being a specific finding, has proved to be a very useful tool in our study to identify these patients.
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Affiliation(s)
| | | | | | - Belen Pérez-Mies
- Pathology, Hospital Ramón y Cajal, Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain
- CIBER-ONC, Instituto de Salud Carlos III, Madrid, Spain
| | | | | | - Javier López-Jiménez
- Hematology, Hospital Ramón y Cajal, Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain
| | - J Palacios
- Pathology, Hospital Ramón y Cajal, Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain
- CIBER-ONC, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Mónica García-Cosío
- Pathology, Hospital Ramón y Cajal, Madrid, Spain
- Faculty of Medicine, University of Alcalá de Henares, Madrid, Spain
- CIBER-ONC, Instituto de Salud Carlos III, Madrid, Spain
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14
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Li X, Yan H, Luo T, Xiao Z, Gong L, Huang J, Zhang X, Zheng M, Yao Z, Zang P, Zhu D, Lu X. Fulfillment status of hypertriglyceridemia and hypofibrinogenemia in children with hemophagocytic lymphohistiocytosis and risks of multiple organ dysfunction syndrome and early mortality. Orphanet J Rare Dis 2022; 17:161. [PMID: 35410268 PMCID: PMC8996201 DOI: 10.1186/s13023-022-02315-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 03/29/2022] [Indexed: 12/26/2022] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder. How to stratify high risk patients is one of the current challenges for the treatment of HLH. HLH patients usually fulfill multiple but not all eight diagnostic criteria. Different combinations of the fulfilled criteria may naturally cluster into previously undescribed subsets or phenotypes that may have different pathophysiology and demonstrate different risks for a poor outcome. The objectives of this study were to identify HLH subgroups according to the fulfillment of diagnostic criteria and evaluate the risk of multiple organ dysfunction syndrome (MODS) and 30-day mortality for subgroups. We retrospectively collect medical records of patients with discharge diagnosis of HLH between June 2015 and October 2018 from a tertiary children’s hospital in China. Latent class analysis was used to identify class defining variables from HLH diagnostic items, and subgroups were defined according to different combinations of the class defining variables. Results Triglyceride and fibrinogen were identified as the class defining variables. When evaluated in combinations, patients with hypertriglyceridemia and normal fibrinogen levels during hospitalization had the lowest risks for MODS (27.8%, OR = 1) and 30-day mortality (18.8%, OR = 1), and patients with normal triglyceride and hypofibrinogenemia had the highest risks for MODS (86.2%, OR = 16.24, P = 0.0002) and 30-day mortality (57.1%, OR = 5.78, P = 0.0187). The fulfillment status of hypertriglyceridemia and hypofibrinogenemia within 72 h of hospital admission was also associated with the risk of adverse outcomes. Conclusions The fulfillment status of hypertriglyceridemia and hypofibrinogenemia were associated with the risks of MODS and 30-day mortality among pediatric HLH patients. Further studies are needed to validate this association and investigate its clinical utility in the severity evaluation for HLH. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02315-8.
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15
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Hardage J, Otto NB, Skaggs J, Travis S. Prompt Recognition of Hemophagocytic Lymphohistiocytosis in an Afebrile Patient with Lupus and Staphylococcus aureus Bacteremia. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e934092. [PMID: 34750340 PMCID: PMC8591524 DOI: 10.12659/ajcr.934092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Patient: Male, 43-year-old
Final Diagnosis: Hemophagocytic lymphohistiocytosis (HLH)
Symptoms: Acute kidney injury • anorexia • dyspnea • epistaxis • heart murmur • hepatosplenomegaly • murmur • weakness • weight loss
Medication: —
Clinical Procedure: Bone marrow biopsy • CT scan • echocardiography • plasmapharesis • renal biopsy • ultrasonography
Specialty: Hematology • General and Internal Medicine • Nephrology • Pathology • Rheumatology
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Affiliation(s)
- Joshua Hardage
- Department of Internal Medicine, University of Oklahoma College of Medicine, OU Health Sciences Center, Oklahoma City, OK, USA
| | - Natalie B Otto
- Department of Internal Medicine, University of Oklahoma College of Medicine, OU Health Sciences Center, Oklahoma City, OK, USA
| | - Joanne Skaggs
- Department of Internal Medicine, University of Oklahoma College of Medicine, OU Health Sciences Center, Oklahoma City, OK, USA.,Department of Medicine, OU Health Sciences Center, Oklahoma City, OK, USA
| | - Stephen Travis
- Department of Internal Medicine, University of Oklahoma College of Medicine, OU Health Sciences Center, Oklahoma City, OK, USA.,Department of Medicine and Pediatrics, OU Health Sciences Center, Oklahoma City, OK, USA
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16
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Elalfy MS, Ragab IA, AbdelAal NM, Mahfouz S, Rezk AR. Study of the diagnostic criteria for hemophagocytic lymphohistiocytosis in neonatal and pediatric patients with severe sepsis or septic shock. Pediatr Hematol Oncol 2021; 38:486-496. [PMID: 33622175 DOI: 10.1080/08880018.2021.1887983] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Septic shock is a major public health concern. However, the clinical and laboratory criteria for sepsis overlap with those for hemophagocytic lymphohistiocytosis (HLH), and their differentiation can be challenging. The aim of this study was to compare HLH criteria among patients diagnosed with neonatal sepsis and childhood sepsis and to study the outcomes in patients fulfilling the diagnostic criteria for HLH. A cross-sectional study included 50 neonates and children with severe sepsis and/or septic shock. Clinical and laboratory data and HLH diagnostic criteria were studied in relation to patients outcome. Of all patients, 18% fulfilled three of the eight HLH diagnostic criteria, 2% fulfilled four criteria, and 4% fulfilled five criteria. All patients who fulfilled three or more of the criteria died. Mortality was higher in the presence of more positive HLH criteria and in pediatric age groups. However, the distributions of the HLH criteria were comparable for pediatric and neonatal patients with severe sepsis/septic shock, and their mortality rates were not significantly different when based on the criteria.
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Affiliation(s)
- Mohsen S Elalfy
- Department of Pediatrics, Department of Hematology-Oncology, Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, Ain Shams University, Cairo, Egypt
| | - Iman A Ragab
- Department of Pediatrics, Department of Hematology-Oncology, Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, Ain Shams University, Cairo, Egypt
| | - NourEldin M AbdelAal
- Department of Pediatrics, Department of Hematology-Oncology, Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, Ain Shams University, Cairo, Egypt
| | - Sara Mahfouz
- Department of Pediatrics, Department of Hematology-Oncology, Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, Ain Shams University, Cairo, Egypt
| | - Ahmed R Rezk
- Department of Pediatrics, Department of Hematology-Oncology, Neonatal Intensive Care Unit and Pediatric Intensive Care Unit, Ain Shams University, Cairo, Egypt
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17
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Widjaja G, Turki Jalil A, Sulaiman Rahman H, Kamal Abdelbasset W, Bokov DO, Suksatan W, Ghaebi M, Marofi F, Gholizadeh Navashenaq J, Jadidi-Niaragh F, Ahmadi M. Humoral immune mechanisms involved in protective and pathological immunity during COVID-19. Hum Immunol 2021; 82:733-745. [PMID: 34229864 PMCID: PMC8245343 DOI: 10.1016/j.humimm.2021.06.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/13/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022]
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 is associated with excessive inflammation, as a main reason for severe condition and death. Increased inflammatory cytokines and humoral response to SARS-CoV-2 correlate with COVID-19 immunity and pathogenesis. Importantly, the levels of pro-inflammatory cytokines that increase profoundly in systemic circulation appear as part of the clinical pictures of two overlapping conditions, sepsis and the hemophagocytic syndromes. Both conditions can develop lethal inflammatory responses that lead to tissue damage, however, in many patients hemophagocytic lymphohistiocytosis (HLH) can be differentiated from sepsis. This is a key issue because the life-saving aggressive immunosuppressive treatment, required in the HLH therapy, is absent in sepsis guidelines. This paper aims to describe the pathophysiology and clinical relevance of these distinct entities in the course of COVID-19 that resemble sepsis and further highlights two effector arms of the humoral immune response (inflammatory cytokine and immunoglobulin production) during COVID-19 infection.
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Affiliation(s)
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq; Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Dmitry O Bokov
- Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok 10210, Thailand
| | - Mahnaz Ghaebi
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Faroogh Marofi
- Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Majid Ahmadi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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18
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El-Sayed ZA, El-Owaidy RH, Khamis MA, Rezk AR. Screening of hemophagocytic lymphohistiocytosis in children with severe sepsis in pediatric intensive care. Sci Prog 2021; 104:368504211044042. [PMID: 34519554 PMCID: PMC10402287 DOI: 10.1177/00368504211044042] [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] [Indexed: 11/17/2022]
Abstract
BACKGROUND We sought to screen for clinical and laboratory features of hemophagocytic lymphohistiocytosis among pediatric patients with severe sepsis. METHODS We conducted a retrospective study that analyzed the clinical and laboratory data of 70 pediatric patients who died of severe sepsis. Medical records were revised for the presence of fever, splenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia. Soluble CD25 was measured in stored samples. RESULTS Patients' ages ranged between 0.5 and 11 years with median (interquartile range) 2 (1-5). All patients had fever (≥38.5 °C) and pancytopenia, 58 (82.9%) hepatosplenomegaly, 36 (51.4%) lymphadenopathy, 37 (52.9%) had ferritin >500 ng/ml, 20 (28.6%) had fibrinogen <1.5 mg/ml, 14 (20%) had fasting triglycerides >264 mg/dl while 5 (7.1%) had soluble CD25 >2400 U/ml. Twenty-five (35.7%) patients fulfilled at least 5/6 of the hemophagocytic lymphohistiocytosis-2004 diagnostic criteria. Multivariate backward binary logistic regression analysis revealed lymphadenopathy as an independent predictor for hemophagocytic lymphohistiocytosis criteria fulfilment with odds ratio of 23.9. Fibrinogen had the best performance in discriminating hemophagocytic lymphohistiocytosis fulfilling from non-fulfilling groups (cut-off value: <1.8 mg/ml), followed by ferritin/erythrocyte sedimentation rate ratio (cut-off value: >17). CONCLUSION There is a significant clinical and laboratory overlap between hemophagocytic lymphohistiocytosis and severe sepsis, making the syndromes difficult to distinguish. The use of current hemophagocytic lymphohistiocytosis-2004 diagnostic criteria should be applied cautiously in those patients.
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Affiliation(s)
- Zeinab A El-Sayed
- Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Egypt
| | - Rasha H El-Owaidy
- Pediatric Allergy and Immunology Unit, Children’s Hospital, Ain Shams University, Egypt
| | - Mohammed A Khamis
- Pediatric Nephrology Unit, Children’s Hospital, Ain Shams University, Egypt
| | - Ahmed R Rezk
- Pediatric Intensive Care Unit, Children’s Hospital, Ain Shams University, Egypt
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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: 27] [Impact Index Per Article: 6.8] [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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20
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Analysis of the occurrence of hemophagocytic lymphohistiocytosis (HLH) features in patients with sepsis: a prospective study. Sci Rep 2021; 11:10529. [PMID: 34006913 PMCID: PMC8131636 DOI: 10.1038/s41598-021-90046-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 05/06/2021] [Indexed: 11/16/2022] Open
Abstract
HLH syndrome may mimic sepsis but requires entirely different treatment. The aim of the study was to assess the occurrence of HLH features in patients with sepsis and the influence these exert on the patients’ prognosis. The prospective study included 108 patients with suspected sepsis who were routinely evaluated according to HLH criteria. They were divided into group I (SOFA = 2, n = 57) and group II (SOFA ≥ 3, n = 51). Four patients were excluded from analysis: 1 with real HLH, 2 with Still’s disease and 1 with lymphoma. The median (IQR) concentration of ferritin was 613.4 (850.3) ng/mL, however 6 patients revealed a remarkedly high ferritin concentration > 3000 ng/mL, including 2 with ferritin > 10,000 ng/mL. In total, 21 patients met ≥ 4/8 HLH criteria and were found to have sepsis with HLH-like syndrome (SHLS). Out of these, 19 responded to antimicrobials, 2 died due to infection. The sepsis patients presented with the following HLH criteria: fever (95.2%), hyperferritinemia (57.3%), splenomegaly (43.4%), reduced NK cell activity (35.2%), high sCD25 activity (27.4%) and rarely: hypertriglyceridemia (14.4%), duopenia (5.8%), hypofibrinogenemia (1.9%). Although group II patients had higher odds for SHLS presentation (OR 3.26, p = 0.026) and for death (OR 14.3, p = 0.013), SHLS occurrence had no impact on the risk of death (OR 0.77, p = 0.75). Sepsis patients can present with SHLS exclusively due to severe infection. Duopenia, hypertriglyceridemia, hypofibrinogenemia and high level of sCD25 are unusual in sepsis and might indicate real HLH syndrome. Hyperferritinemia, even as high as in real HLH syndrome, can occur in sepsis patients.
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21
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Kim YR, Kim DY. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res 2021; 56:S17-S25. [PMID: 33935031 PMCID: PMC8094004 DOI: 10.5045/br.2021.2020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.
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Affiliation(s)
- Yu Ri Kim
- Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dae-Young Kim
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
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22
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Platelets parameters in septic shock: clinical usefulness and prognostic value. Blood Coagul Fibrinolysis 2021; 31:421-425. [PMID: 33065574 DOI: 10.1097/mbc.0000000000000937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
: Septic shock is a common cause of admission in the ICUs. Despite tremendous improvement in the management modalities, mortality remains high. Early diagnosis and prompt resuscitation are required to improve prognosis. Therefore, identifying a biomarker that could reveal the sepsis at its earlier stage is of paramount importance. In this regards, platelet parameters, such as mean platelet volume, immature platelet fraction and platelet-derived microparticles have been investigated as possible sepsis biomarkers. In fact, haemostasis disturbances are one of the hallmark of septic shock where platelets play a pivotal role in orchestrating the inflammatory response of the host. Moreover, these parameters could have a prognostic value as the severity of the multiorgan dysfunction is correlated with the inflammatory reaction.
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23
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Hakamifard A, Mardani M, Gholipur‐Shahraki T. Hemophagocytic lymphohistiocytosis presented with fever of unknown origin: A case study and literature review. Clin Case Rep 2021; 9:2350-2355. [PMID: 33936693 PMCID: PMC8077318 DOI: 10.1002/ccr3.4033] [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: 12/02/2020] [Revised: 02/06/2021] [Accepted: 02/22/2021] [Indexed: 11/30/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening clinical syndrome, which may present with FUO. The possible diagnosis of HLH must be considered in the differential diagnosis when a patient presents with FUO.
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Affiliation(s)
- Atousa Hakamifard
- Infectious Diseases and Tropical Medicine Research CenterShahid Beheshti University of Medical SciencesTehranIran
- Department of Infectious DiseasesSchool of MedicineIsfahan University of Medical SciencesIsfahanIran
| | - Masoud Mardani
- Infectious Diseases and Tropical Medicine Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Tahereh Gholipur‐Shahraki
- Department of Clinical Pharmacy and Pharmacy PracticeSchool of Pharmacy and Pharmaceutical SciencesIsfahan University of Medical SciencesIsfahanIran
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Chu R, van Eeden C, Suresh S, Sligl WI, Osman M, Cohen Tervaert JW. Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis. Int J Mol Sci 2021; 22:2967. [PMID: 33803997 PMCID: PMC8001312 DOI: 10.3390/ijms22062967] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 02/12/2021] [Accepted: 03/10/2021] [Indexed: 12/15/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.
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Affiliation(s)
- Raymond Chu
- Division of Rheumatology, Department of Medicine, The Ottawa Hospital, University of Ottawa, Ottawa, ON K1H 7W9, Canada;
| | - Charmaine van Eeden
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
| | - Sneha Suresh
- Division of IHOPE, Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, AB T6G 1C9, Canada;
| | - Wendy I. Sligl
- Department of Critical Care Medicine and Division of Infectious Diseases, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2B7, Canada;
| | - Mohammed Osman
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
| | - Jan Willem Cohen Tervaert
- Division of Rheumatology, Department of Medicine, University of Alberta Hospital, University of Alberta, Edmonton, AB T6G 2R3, Canada; (C.v.E.); (M.O.)
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Laudanski K. Humanized Mice as a Tool to Study Sepsis-More Than Meets the Eye. Int J Mol Sci 2021; 22:2403. [PMID: 33673691 PMCID: PMC7957591 DOI: 10.3390/ijms22052403] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 02/20/2021] [Accepted: 02/23/2021] [Indexed: 12/22/2022] Open
Abstract
(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This is a narrative, comprehensive review of humanized mice and sepsis literature to understand the model's benefits and shortcomings. (3) Results: Studies involving humanized models of sepsis include bacterial, viral, and protozoan etiology. Humanized mice provided several unique insights into the etiology and natural history of sepsis and are particularly useful in studying Ebola, and certain viral and protozoan infections. However, studies are relatively sparse and based on several different models of sepsis and humanized animals. (4) Conclusions. The utilization of humanized mice as a model for sepsis presents complex limitations that, once surpassed, hold some potential for the advancement of sepsis etiology and treatment.
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Affiliation(s)
- Krzysztof Laudanski
- Department of Anesthesiology and Critical Care, Department of Neurology, Leonard Davis Institute of Healthcare Economics, University of Pennsylvania, Philadelphia, PA 19194, USA
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26
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Wijeratne T, Gillard Crewther S, Sales C, Karimi L. COVID-19 Pathophysiology Predicts That Ischemic Stroke Occurrence Is an Expectation, Not an Exception-A Systematic Review. Front Neurol 2021; 11:607221. [PMID: 33584506 PMCID: PMC7876298 DOI: 10.3389/fneur.2020.607221] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/30/2020] [Indexed: 12/27/2022] Open
Abstract
Clinical reports of neurological manifestations associated with severe coronavirus disease 2019 (COVID-19), such as acute ischemic stroke (AIS), encephalopathy, seizures, headaches, acute necrotizing encephalitis, cerebral microbleeds, posterior reversible leukoencephalopathy syndrome, hemophagocytic lymphohistiocytosis, peripheral neuropathy, cranial nerve palsies, transverse myelitis, and demyelinating disorders, are increasing rapidly. However, there are comparatively few studies investigating the potential impact of immunological responses secondary to hypoxia, oxidative stress, and excessive platelet-induced aggregation on the brain. This scoping review has focused on the pathophysiological mechanisms associated with peripheral and consequential neural (central) inflammation leading to COVID-19-related ischemic strokes. It also highlights the common biological processes shared between AIS and COVID-19 infection and the importance of the recognition that severe respiratory dysfunction and neurological impairments associated with COVID and chronic inflammation [post-COVID-19 neurological syndrome (PCNS)] may significantly impact recovery and ability to benefit from neurorehabilitation. This study provides a comprehensive review of the pathobiology of COVID-19 and ischemic stroke. It also affirms that the immunological contribution to the pathophysiology of COVID-19 is predictive of the neurological sequelae particularly ischemic stroke, which makes it the expectation rather than the exception. This work is of fundamental significance to the neurorehabilitation community given the increasing number of COVID-related ischemic strokes, the current limited knowledge regarding the risk of reinfection, and recent reports of a PCNS. It further highlights the need for global collaboration and research into new pathobiology-based neurorehabilitation treatment strategies and more integrated evidence-based care.
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Affiliation(s)
- Tissa Wijeratne
- School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia
- Department of Neurology, Western Health and University Melbourne, Australian Institute of Muscular Skeletal Sciences (AIMSS), Level Three, Western Health Centre for Research and Education (WHCRE), Sunshine Hospital, Melbourne, VIC, Australia
- Department of Medicine, Faculty of Medicine, University of Rajarata, Anuradhapura, Sri Lanka
| | - Sheila Gillard Crewther
- School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia
- Department of Neurology, Western Health and University Melbourne, Australian Institute of Muscular Skeletal Sciences (AIMSS), Level Three, Western Health Centre for Research and Education (WHCRE), Sunshine Hospital, Melbourne, VIC, Australia
| | - Carmela Sales
- Department of Neurology, Western Health and University Melbourne, Australian Institute of Muscular Skeletal Sciences (AIMSS), Level Three, Western Health Centre for Research and Education (WHCRE), Sunshine Hospital, Melbourne, VIC, Australia
- Department of Medicine, Faculty of Medicine, University of Rajarata, Anuradhapura, Sri Lanka
| | - Leila Karimi
- School of Psychology and Public Health, La Trobe University, Melbourne, VIC, Australia
- Department of Neurology, Western Health and University Melbourne, Australian Institute of Muscular Skeletal Sciences (AIMSS), Level Three, Western Health Centre for Research and Education (WHCRE), Sunshine Hospital, Melbourne, VIC, Australia
- Faculty of Social and Political Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi, Georgia
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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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Li X, Yan H, Zhang X, Huang J, Xiang ST, Yao Z, Zang P, Zhu D, Xiao Z, Lu X. Clinical profiles and risk factors of 7-day and 30-day mortality among 160 pediatric patients with hemophagocytic lymphohistiocytosis. Orphanet J Rare Dis 2020; 15:229. [PMID: 32867836 PMCID: PMC7456759 DOI: 10.1186/s13023-020-01515-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 08/19/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a relatively rare and life-threatening disorder. Early mortality remains significantly high among patients with HLH. Our aim was to investigate clinical features and risk factors associated with 7-day and 30-day mortality among pediatric HLH patients. We retrospectively collected medical records of patients with discharge diagnosis of HLH between August 2014 and October 2018 from a tertiary children's hospital in China. The main outcome measures were the 7-day and 30-day outcome after hospital admission. The associations between symptoms, concomitant diagnoses, laboratory test results, and the risk of 7-day and 30-day mortality were examined. RESULTS Among 160 pediatric HLH patients, 18 (11.3%) patients were deceased within 7 days after admission, and 46 (28.8%) patients were deceased within 30 days. The identified strong risk factors (OR > 10 and p < 0.05) for 30-day mortality were myocardial damage, severe pneumonia, respiratory failure, coagulopathy, gastrointestinal disorder, and multiple organ dysfunction syndrome (MODS). Factors strongly associated with 7-day mortality were sepsis, myocardial damage, shock, and respiratory failure. All patients deceased within 7 days developed hepatic dysfunction, coagulopathy, and MODS. CONCLUSIONS The identified risk factors could help to stratify patients with high risk of early death, and need to be considered in the development of treatment protocols. As early mortality of HLH remains high, studies are needed to investigate how to initiate adequate HLH-directed treatment strategies for patients at higher risk of early death.
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Affiliation(s)
- Xun Li
- Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, University of South China, Changsha, China
| | - Haipeng Yan
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Xinping Zhang
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Jiaotian Huang
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Shi-Ting Xiang
- Pediatrics Research Institute of Hunan Province, Hunan Children's Hospital, University of South China, Changsha, China
| | - Zhenya Yao
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Ping Zang
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Desheng Zhu
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China
| | - Zhenghui Xiao
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China.
| | - Xiulan Lu
- Department of Pediatric Intensive Care Unit, Hunan Children's Hospital, University of South China, Changsha, China.
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Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe form of immune dysregulation often presenting as unremitting fever, cytopenia, hepatosplenomegaly, coagulopathy, and elevation of typical HLH biomarkers. HLH is universally fatal, if left untreated. The HLH-2004 criteria are widely used to diagnose this condition, but there is growing concerns across different settings that its application may result in undertreatment of certain patients. There is an expanding spectrum of genetic conditions that can be complicated by HLH. This review summarizes the current concepts in HLH, the lessons learned from the past, and provide an overview of the latest diagnostic and treatment modalities.
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30
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Etoposide and Corticosteroid Combination Therapy Improves Acute Respiratory Distress Syndrome in Mice. Shock 2020; 52:83-91. [PMID: 30028782 DOI: 10.1097/shk.0000000000001231] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Excessive inflammation reactions with a cytokine storm in the lungs have historically been thought as the primary cause of fatal acute respiratory distress syndrome (ARDS). However, interruption of inflammatory cytokine activation failed to attenuate ARDS, suggesting that other therapies are required to treat this illness and improve survival. Etoposide (ET), a cytotoxic agent, and prednisolone (PSL), a corticosteroid with strong anti-inflammatory activity, have been used to treat other disease involving similar cytokine-activated macrophages and hemophagocytic activity. However, they have not been previously tested as ARDS therapeutics alone or in combination. In the present study, we used a fatal ARDS mouse model induced via administration of α-galactosylceramide and lipopolysaccharide, which resulted in the development of severe lung injury with hypercytokinemia and hemophagocytosis, all of which were observed in ARDS patients infected with highly pathogenic respiratory viruses. The ET and PSL combination therapy, but not ET or PSL alone, reduced the recruitment and activation of inflammatory cells including macrophages, natural killer T cells, and neutrophils, and significantly improved the survival rate in this model. Furthermore, whereas ET alone improved lung edema, it did not increase the survival rate, indicating the necessity of PSL in the treatment of ARDS. Surprisingly, combination therapy did not reduce the production of cytokines and chemokines in the lungs, demonstrating that inflammatory cells, rather than hypercytokinemia, are the direct target of these compounds and primary cause of ARDS-related death. Thus, combination therapy with ET and PSL that targets inflammatory cells has the potential to attenuate fatal ARDS.
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31
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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: 62] [Impact Index Per Article: 12.4] [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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32
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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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34
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Pandey PK, Kaul E, Agarwal N, Goel S. Effectiveness of therapeutic plasma exchange in a critically ill child with secondary hemophagocytic lymphohistiocytosis. Asian J Transfus Sci 2019; 13:145-147. [PMID: 31896925 PMCID: PMC6910033 DOI: 10.4103/ajts.ajts_45_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 03/26/2019] [Indexed: 01/07/2023] Open
Abstract
Currently, the ASFA has not included TPE in the management of HLH but many cases reports have reported successful role of TPE in HLH. Here we are presenting a case in which HLH was managed successfully with TPE. Diagnosis of HLH is based on the HLH 2004 diagnostic criteria proposed by HLH society. TPE was done using COM. TEC (Fresenius Kabi, Germany). Patient required three sessions of TPE. After three sessions of TPE patient's clinical condition improved remarkably and he was switched to IV Dexamethasone as maintenance treatment. One standard TPE procedure was 1.5 plasma volume exchanges. In view of deranged coagulation profile fresh frozen plasma was used as a replacement fluid. During follow up after one month of discharge, patient was absolutely normal. In developing countries like India, where infections are still a prime concern to the physicians, making an accurate diagnosis of HLH is a great concern. High suspicion, timely diagnosis and early start of TPE can be life saving in such patients.
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Affiliation(s)
- Prashant Kumar Pandey
- Department of Transfusion Medicine, Histocompatibility and Molecular Biology, Jaypee Hospital, Noida, Uttar Pradesh, India
| | - Esha Kaul
- Department of Clinical Hematology and BMT, Jaypee Hospital, Noida, Uttar Pradesh, India, India
| | - Nitin Agarwal
- Department of Transfusion Medicine, Histocompatibility and Molecular Biology, Jaypee Hospital, Noida, Uttar Pradesh, India
| | - Shalendra Goel
- Department of Critical Care Medicine, Jaypee Hospital, Noida, Uttar Pradesh, India
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35
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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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36
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Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, Pham HP, Schneiderman J, Witt V, Wu Y, Zantek ND, Dunbar NM, Schwartz GEJ. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice - Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher 2019; 34:171-354. [PMID: 31180581 DOI: 10.1002/jca.21705] [Citation(s) in RCA: 864] [Impact Index Per Article: 144.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Eighth Edition of the JCA Special Issue continues to maintain this methodology and rigor in order to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Eighth Edition, like its predecessor, continues to apply the category and grading system definitions in fact sheets. The general layout and concept of a fact sheet that was introduced in the Fourth Edition, has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease entity or medical condition. The Eighth Edition comprises 84 fact sheets for relevant diseases and medical conditions, with 157 graded and categorized indications and/or TA modalities. The Eighth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease.
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Affiliation(s)
- Anand Padmanabhan
- Medical Sciences Institute & Blood Research Institute, Versiti & Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Laura Connelly-Smith
- Department of Medicine, Seattle Cancer Care Alliance & University of Washington, Seattle, Washington
| | - Nicole Aqui
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rasheed A Balogun
- Department of Medicine, University of Virginia, Charlottesville, Virginia
| | - Reinhard Klingel
- Apheresis Research Institute, Cologne, Germany & First Department of Internal Medicine, University of Mainz, Mainz, Germany
| | - Erin Meyer
- Department of Hematology/Oncology/BMT/Pathology, Nationwide Children's Hospital, Columbus, Ohio
| | - Huy P Pham
- Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Jennifer Schneiderman
- Department of Pediatric Hematology/Oncology/Neuro-oncology/Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, Illinois
| | - Volker Witt
- Department for Pediatrics, St. Anna Kinderspital, Medical University of Vienna, Vienna, Austria
| | - Yanyun Wu
- Bloodworks NW & Department of Laboratory Medicine, University of Washington, Seattle, Washington, Yale University School of Medicine, New Haven, Connecticut
| | - Nicole D Zantek
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Nancy M Dunbar
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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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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Successful Modified Therapy in a Patient with Probable Infection-Associated Hemophagocytic Lymphohistiocytosis. Case Rep Oncol Med 2019; 2019:9781065. [PMID: 31583147 PMCID: PMC6754915 DOI: 10.1155/2019/9781065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 07/02/2019] [Accepted: 08/27/2019] [Indexed: 11/17/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, hyperinflammatory syndrome characterized by clinical signs and symptoms of extreme inflammation. In adults, HLH is typically a complication of infections, autoimmune diseases, and malignancies. While the disease is often fatal, classic management of HLH revolves around early diagnosis and initiation of protocolized therapy. We present a case of a previously healthy 56-year-old female who developed distributive shock requiring intubation, vasopressors, and continuous venovenous hemofiltration. In the setting of multiple infectious syndromes, severe cytopenias, and rising direct hyperbilirubinemia, her diagnosis of HLH was confirmed. Therapy was initiated with dexamethasone and two doses of reduced-intensity etoposide based on the patient's clinical course. Over the next few weeks, she continued to improve on dexamethasone monotherapy and has maintained remission up to the present with complete resolution of her cytopenias and return of baseline renal function. Our case highlights the variability in the management of probable infection-associated HLH (IHLH) with a good patient outcome. We demonstrate the potential to treat IHLH with partial protocols and minimal chemotherapeutics.
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39
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Cavaillon JM, Giamarellos-Bourboulis EJ. Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients. Shock 2019; 52:307-317. [PMID: 30239420 DOI: 10.1097/shk.0000000000001266] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.
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40
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Pneumococcal Bacteremia Complicated by Hemophagocytic Lymphohistiocytosis. J Gen Intern Med 2019; 34:1653-1657. [PMID: 31011972 PMCID: PMC6667527 DOI: 10.1007/s11606-019-05001-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 11/29/2018] [Accepted: 03/05/2019] [Indexed: 10/27/2022]
Abstract
From pneumonia to pericarditis, from sepsis to splenic abscess, Streptococcus pneumoniae is the causative agent of a diverse array of pyogenic disease. With the introduction of vaccines and effective antibiotic treatments, the incidence of complicated streptococcal infection has declined. We report a case of S. pneumoniae bacteremia, in the setting of occult sinusitis, complicated by hemophagocytic lymphohistiocytosis (HLH), disseminated intravascular coagulation (DIC), and recurrent pneumococcal infection. Although severe streptococcal infection has been associated with immunodeficiency or splenectomy, no such predisposition was identified in our patient. We discuss the association of streptococcal infection with HLH and DIC and review occult sinusitis as a source of pneumococcal bacteremia, with the goal of enhancing the "illness scripts" of general medical practitioners to include such entities.
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41
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Dong J, Xie F, Jia L, Li J, Hu Z, Zhu Y, Yu H, Zhao Y, Yao Q, Meng Q. Clinical characteristics of liver failure with hemophagocytic lymphohistiocytosis. Sci Rep 2019; 9:8125. [PMID: 31148551 PMCID: PMC6544643 DOI: 10.1038/s41598-019-43909-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/02/2019] [Indexed: 12/13/2022] Open
Abstract
Liver failure with hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome with high mortality. The aim of this study was to decipher clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis after definite diagnosis of liver failure and to provide clues for early diagnosis and treatment of HLH in patients with liver failure. Eleven patients diagnosed with liver failure and HLH were retrospectively investigated in this study. All patients presented with jaundice, persistent high-grade fever, pancytopenia, splenomegaly, evidence of hemophagocytes in the bone marrow and laboratory abnormalities indicating HLH. The average interval from the earliest diagnosis of liver failure to a definitive diagnosis of HLH was 17.27 days. Six (54.55%) patients died during follow-up. For patients with liver failure after admission and subsequently definitively diagnosed with HLH, bilirubin and INR were significantly decreased. HLH is definitely diagnosed at an intermediate or late stage when patients have already suffered from liver failure. The initial dose of glucocorticoid (methylprednisolone) was decreased to 1-1.5 mg/kg/d and gradually reduced thereafter. In conclusion, for patients with liver failure, HLH should be screened as early as possible upon persistent fever, splenomegaly and unexplained pancytopenia. For patients with liver failure and HLH, the dosage of glucocorticoid should be reduced to avoid serious side effects.
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Affiliation(s)
- Jinling Dong
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Fang Xie
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Lin Jia
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Juan Li
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Zhongjie Hu
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yueke Zhu
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Hongwei Yu
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yujuan Zhao
- Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qinwei Yao
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Qinghua Meng
- Department of Severe Liver Disease Medical Center, Beijing You An Hospital, Capital Medical University, Beijing, China.
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42
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Coelho S, Marques P, Lourenço P, Bettencourt P. Hemophagocytic syndrome in adults. Experience of a tertiary center. GAZZETTA MEDICA ITALIANA ARCHIVIO PER LE SCIENZE MEDICHE 2019. [DOI: 10.23736/s0393-3660.18.03798-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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43
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Burton JL, Saegeman V, Arribi A, Rello J, Andreoletti L, Cohen MC, Fernandez-Rodriguez A. Postmortem microbiology sampling following death in hospital: an ESGFOR task force consensus statement. J Clin Pathol 2019; 72:329-336. [PMID: 30661015 DOI: 10.1136/jclinpath-2018-205365] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 10/30/2018] [Accepted: 12/13/2018] [Indexed: 12/23/2022]
Abstract
Postmortem microbiology (PMM) is a valuable tool in the identification of the cause of death and of factors contributory to death where death has been caused by infection. The value of PMM is dependent on careful autopsy planning, appropriate sampling, minimisation of postmortem bacterial translocation and avoidance of sample contamination. Interpretation of PMM results requires careful consideration in light of the clinical history, macroscopic findings and the histological appearances of the tissues. This consensus statement aims to highlight the importance of PMM in the hospital setting and to give microbiological and pathological advice on sampling in deaths occurring in hospital.
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Affiliation(s)
- Julian L Burton
- Academic Unit of Medical Education, University of Sheffield Medical School, Sheffield, UK
| | | | - Ana Arribi
- Microbiology Department, Hospital Clínico Universitario San Carlos, Madrid, Spain
| | - Jordi Rello
- CIBERES and Vall d'Hebron Institute of Research, Barcelona, Spain
| | - Laurent Andreoletti
- Molecular and Clinical Virology Department, University of Reims Champagne-Ardenne, Reims, France
| | - Marta C Cohen
- Histopathology Department, Sheffield Children's NHS Foundation Trust, Sheffield, UK
| | - Amparo Fernandez-Rodriguez
- Microbiology Laboratory, Biology Department, Instituto Nacional de Toxicología y Ciencias Forenses, Las Rozas, Spain
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44
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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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45
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Lemiale V, Valade S, Calvet L, Mariotte E. Management of Hemophagocytic Lympho-Histiocytosis in Critically Ill Patients. J Intensive Care Med 2018; 35:118-127. [PMID: 30384814 DOI: 10.1177/0885066618810403] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Hemophagocytic syndrome remains a rare but life-threatening complication and is associated with intensive care unit (ICU) admission. The pathophysiology is based on a defect of cytotoxicity in T cells that results in a state of hyperinflammation in the presence of a trigger. As a consequence, patients may develop multiorgan failure. The diagnosis of hemophagocytic syndrome (HS) remains difficult and relies on persistant high-grade fevers in the absence of infection and on constellation of laboratory parameters. However, prompt diagnosis and treatment (supportive care and specific treatment) are associated with improved outcome. Interaction with other specialists (hematologist, internist) may improve the diagnosis and treatment strategy. This article describes diagnostic tools, organ failures associated with HS, main etiologies, and management.
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Affiliation(s)
| | | | - Laure Calvet
- Medical ICU, AP_HP Saint Louis hospital, Paris, France
| | - Eric Mariotte
- Medical ICU, AP_HP Saint Louis hospital, Paris, France
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46
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McCrory MC, Wang SS, Shetty AK, McLean TW, Lantz PE, Cannon ML. Sudden Cardiac Arrest Due to Hemophagocytic Lymphohistiocytosis in a Child. J Emerg Med 2018; 55:e119-e123. [DOI: 10.1016/j.jemermed.2018.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/29/2018] [Accepted: 08/03/2018] [Indexed: 12/22/2022]
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47
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Farias-Moeller R, LaFrance-Corey R, Bartolini L, Wells EM, Baker M, Doslea A, Suslovic W, Greenberg J, Carpenter JL, Howe CL. Fueling the FIRES: Hemophagocytic lymphohistiocytosis in febrile infection-related epilepsy syndrome. Epilepsia 2018; 59:1753-1763. [PMID: 30132834 DOI: 10.1111/epi.14524] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 01/03/2023]
Abstract
OBJECTIVES Although secondary hemophagocytic lymphohistiocytosis (HLH) has been reported in children with critical illness of various etiologies, it has not been reported in patients with febrile infection-related epilepsy syndrome (FIRES). We describe a series of patients with concurrent HLH and FIRES in an effort to establish common pathophysiologic abnormalities. METHODS Five patients with FIRES who were assessed for HLH were identified from a neurocritical care database. All were previously healthy and had extensive diagnostic testing. All had clinical deterioration with multiorgan dysfunction prompting HLH screening 20-29 days after hospitalization. Markers for inflammatory dysregulation were assessed in cerebrospinal fluid (CSF) and serum at various time points. Outcomes were assessed 6 months after presentation. RESULTS Three patients met clinical criteria for secondary HLH. Elevation of specific cytokines/chemokines was variable. CSF neopterin, high mobility group box 1 (HMGB1), and C-X-C motif chemokine ligand 8 (CXCL8) were significantly elevated in all. Interleukin-1β (IL-1β) and IL-18 were not elevated in any of the samples. Treatment and outcomes were variable. SIGNIFICANCE We describe 3 patients with HLH and FIRES. The co-occurrence of these 2 rare disorders suggests the possibility of a common immune dysregulation phenotype prolonging epileptogenesis. HLH screening in critically ill patients with FIRES may yield a broader understanding of shared inflammatory processes.
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Affiliation(s)
- Raquel Farias-Moeller
- Department of Neurology, Division of Pediatric Neurology, Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin
| | - Reghann LaFrance-Corey
- Departments of Neurology and Immunology, Center for MS and Autoimmune Neurology, Translational Neuroimmunology Lab, Mayo Clinic, Rochester, Minnesota
| | - Luca Bartolini
- Clinical Epilepsy Section and Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke - National Institute of Health, Bethesda, Maryland
| | - Elizabeth M Wells
- Department of Neurology, Children's National Health System, Washington, District of Columbia
| | - Meredith Baker
- Department of Neurology, Children's National Health System, Washington, District of Columbia
| | - Alyssa Doslea
- Department of Neurology, Children's National Health System, Washington, District of Columbia
| | - William Suslovic
- Department of Neurology, Children's National Health System, Washington, District of Columbia
| | - Jay Greenberg
- Department of Hematology, Children's National Health System, Washington, District of Columbia
| | - Jessica L Carpenter
- Department of Neurology, Children's National Health System, Washington, District of Columbia
| | - Charles L Howe
- Departments of Neurology and Immunology, Center for MS and Autoimmune Neurology, Translational Neuroimmunology Lab, Mayo Clinic, Rochester, Minnesota
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48
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Stalder G, Ribi C, Duchosal MA. [Hemophagocytic Lymphohistiocytosis]. PRAXIS 2018; 107:902-911. [PMID: 30086687 DOI: 10.1024/1661-8157/a003045] [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: 06/08/2023]
Abstract
Hemophagocytic Lymphohistiocytosis Abstract. Hemophagocytic lymphohistiocytosis (HLH) is a group of rare diseases characterized by over-activation of the immune system. They form two groups: primary and secondary HLH. Primary HLH are linked to mutations impairing lymphocyte cytotoxicity. Secondary HLH are triggered by infections, autoimmune diseases or neoplasia, the remaining cases being labeled idiopathic. HLH manifest as febrile states, cytopenias and hepatosplenomegaly. In the absence of treatment, they quickly lead to multiple organ failure. The diagnosis is currently based on the presence of several clinical and biological markers. Treatment consists of suppression of the triggering factor, organ support and immunosuppression. Primary forms, affecting a pediatric population, have been the subject of intense research, and are nowadays treated with established therapeutic protocols. Several recent retrospective studies have improved our knowledge of secondary HLH, which affects mostly adults and whose incidence seems to be increasing. Thus, new diagnostic criteria are currently being studied for secondary HLH, and several treatment protocols have just been published or are being evaluated.
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Affiliation(s)
- Grégoire Stalder
- 1 Service et laboratoire central d'hématologie, Centre Hospitalier Universitaire Vaudois, Lausanne
| | - Camillo Ribi
- 2 Service d'immunologie et allergie, Centre Hospitalier Universitaire Vaudois, Lausanne
| | - Michel André Duchosal
- 1 Service et laboratoire central d'hématologie, Centre Hospitalier Universitaire Vaudois, Lausanne
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49
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Leinenkugel G, Buser L, Vallelian F, Herfs G. [CME: Acquired Hemophagocytic Lymphohistiocytosis]. PRAXIS 2018; 107:873-881. [PMID: 30086677 DOI: 10.1024/1661-8157/a003040] [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: 06/08/2023]
Abstract
CME: Acquired Hemophagocytic Lymphohistiocytosis Abstract. Acquired hemophagocytic lymphohistiocytosis comprises a heterogenous group of hyperinflammatory immunoreactions often resulting in uncontrolled immune responses, mainly throughout proliferation of cytotoxic T cells and hemophagocytosis by macrophages. Hemophagocytic lymphohistiocytosis is often underdiagnosed, contributing to its high morbidity and mortality. A systematic diagnostic approach and the use of established diagnostic criteria should lead to an early diagnosis, which is crucial for any therapeutic attempt to achieve a curative state of the disease.
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Affiliation(s)
- Georg Leinenkugel
- 1 Klinik und Poliklinik für Innere Medizin, Universitätsspital Zürich
| | - Lorenz Buser
- 2 Institut für Klinische Pathologie, Universitätsspital Zürich
| | | | - Gregor Herfs
- 2 Institut für Klinische Pathologie, Universitätsspital Zürich
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50
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Transfusion requirements and 30-day mortality predictors for adult hemophagocytic lymphohistiocytosis. Int J Hematol 2018; 108:485-490. [PMID: 30043331 DOI: 10.1007/s12185-018-2504-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 07/04/2018] [Accepted: 07/11/2018] [Indexed: 10/28/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an uncontrolled hyper-inflammatory response. We assessed the transfusion requirements and predictors of 30-day mortality for adult HLH patients. We identified all adult patients with a diagnosis of HLH at a large academic hospital from October 2003 through February 2017. We extracted patients' clinical and laboratory data, including transfusion requirements, from their medical records. One-hundred sixteen patients were identified. Their median age was 48 years (range 18-82); 72(62%) were male. Median duration of hospital stay was 19 days (range 1-89 days). At 30 days from admission, 81(70%) patients were alive. Death was attributed to sepsis in 21 patients, lymphoma in six, bleeding in four, GVHD in one, liver failure in one, metastatic solid tumor in one, and unknown in one. Transfusion requirements at 30 days from admission were as follows: RBC, 86% of patients, median 6 units (range 1-58); platelets, 74% of patients, median 6 units (1-67); plasma, 40% of patients, median 4 units (1-56). Renal failure (OR = 4.39; P = 0.008) and hypofibrinogenemia (OR = 4.07; P = 0.009) correlated with 30-day mortality. The transfusion requirements for adult HLH patients were high. Our study indicated that renal insufficiency and hypofibrinogenemia are predictors of early death in adult HLH.
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