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Zoref-Lorenz A, Rocco J, Schwartz DM, Jordan M. Recognizing and Managing Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Practical Clinical Guide. Hematol Oncol Clin North Am 2025; 39:577-596. [PMID: 40222878 DOI: 10.1016/j.hoc.2025.02.007] [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: 04/15/2025]
Abstract
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory syndrome triggered by infections, malignancies, or rheumatologic conditions. Effective management requires identifying and treating the acute trigger while addressing underlying factors and calming the inflammatory response. Like sepsis, sHLH represents a cytokine storm resulting from diverse triggering events rather than a standalone diagnosis. This review synthesizes current literature and the authors' clinical experience to provide a comprehensive framework for diagnosing and managing sHLH, emphasizing the importance of tailored, trigger-specific interventions. Emerging diagnostic tools and therapeutic strategies and improved mechanistic understanding of sHLH hold promise for improving outcomes in this challenging condition.
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Affiliation(s)
- Adi Zoref-Lorenz
- Hematology Institute, Department of Medicine, Meir Medical Center, Tchernichovsky Street 59, Kfar Saba 4428164, Israel; Faculty of Medicine and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
| | - Joseph Rocco
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIH Clinical Center Building 10, Room 11B-17 10 Center Drive, Bethesda, MD 20892, USA. https://twitter.com/JMRocco5
| | - Daniella M Schwartz
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, 1551W Starzl Building, 200 Lothrop Street, Pittsburgh, PA 15213, USA. https://twitter.com/SchwartzLab9
| | - Michael Jordan
- Division of Immunobiology and Bone Marrow Transplant, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, ML 7038, Cincinnati, OH 45229-3039, USA. https://twitter.com/Mjordanlab
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Riahi S, Ammar S, Hassen H, Souilem E, Mbarki D, Dhaha Y, Ksiaa M, Bouatay A. Case Report: Macrophage activation syndrome due to multifocal tuberculosis in an immunocompromised patient. F1000Res 2025; 13:1439. [PMID: 40265046 PMCID: PMC12012428 DOI: 10.12688/f1000research.158982.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/04/2025] [Indexed: 04/24/2025] Open
Abstract
Macrophage Activation Syndrome (MAS) is a serious and life-threatening complication defined by excessive immune activation. While it's commonly associated with rheumatic diseases, infections can also trigger MAS, with tuberculosis being a rare but significant cause. This case report discusses a rare occurrence of Macrophage Activation Syndrome (MAS) caused by multifocal tuberculosis in an immunocompromised patient with Crohn's disease receiving immunosuppressive treatment. The patient is a 26-year-old woman with Crohn's disease who is being treated with azathioprine. She arrived at the hospital battling persistent abdominal pain, overwhelming fatigue, and fever. Upon examination, splenomegaly and ascites were noted. A chest X-ray revealed bilateral pleural effusion consistent with tuberculosis. A CT scan confirmed the presence of pleural, pericardial, and intraperitoneal fluid. Blood tests indicated pancytopenia, hyperferritinemia, and hypofibrinogenemia. The analysis of ascitic fluid suggested an exudate. The PCR test of the bone marrow aspirate was positive for tuberculosis without rifampicin resistance, and the smear showed hemophagocytosis images. The patient was diagnosed with Macrophage Activation Syndrome secondary to multifocal tuberculosis. This report delves into the complex relationship between MAS and tuberculosis, emphasizing the challenges in diagnosing MAS in such cases and the potential link to tuberculosis. The complex diagnostic landscape of multifocal tuberculosis, which can often mimic malignancies, underscores the importance of promptly detecting and starting anti-tuberculosis interventions for improved clinical outcomes and the prevention of associated complications.
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Affiliation(s)
- Salma Riahi
- University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia
- Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia
| | - Sana Ammar
- Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia
- University of Monastir Faculty of Pharmacy of Monastir, Monastir, Monastir, Tunisia
| | - Houssem Hassen
- University of Monastir Faculty of Medicine of Monastir, Monastir, Monastir, Tunisia
- Department of Gastroenterology, Sahloul Hospital, Sousse, Sousse, Tunisia
| | - Emna Souilem
- University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia
- Department of Gastroenterology, Sahloul Hospital, Sousse, Sousse, Tunisia
| | - Donia Mbarki
- Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia
- University of Monastir Faculty of Pharmacy of Monastir, Monastir, Monastir, Tunisia
| | - Yosra Dhaha
- University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia
- Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia
| | - Mehdi Ksiaa
- University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia
- Department of Gastroenterology, Sahloul Hospital, Sousse, Sousse, Tunisia
| | - Amina Bouatay
- Laboratory of Hematology, Sahloul Hospital, Sousse, Sousse, Tunisia
- University of Monastir Faculty of Pharmacy of Monastir, Monastir, Monastir, Tunisia
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Rakotonirina LN, Andrianiaina MO, Rakotonirainy OH, Ramanandafy H, Randriamifidy NH, Rapelanoro Rabenja F. Management Challenge of Coexistence of Macrophage Activation Syndrome, Systemic Lupus Erythematosus, and Hepatitis B: Case Report. Clin Case Rep 2025; 13:e70419. [PMID: 40226232 PMCID: PMC11985889 DOI: 10.1002/ccr3.70419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 03/02/2025] [Accepted: 04/02/2025] [Indexed: 04/15/2025] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal clinical and histological entity. Macrophage Activation Syndrome (MAS) is an HLH secondary to rheumatic and autoimmune diseases. Secondary MAS in systemic lupus erythematosus (SLE) is underdiagnosed. Its treatment is not yet standardized. The treatment of MAS in the context of SLE primarily involves corticosteroids and immunosuppressants, with the potential addition of Intravenous Immunoglobulins (IVIG) and biological treatments for refractory cases. Early detection and prompt intervention are crucial to reduce associated mortality. The presence of infection worsens the patient's prognosis. The coexistence of SLE and hepatitis B during MAS is rarely described in the literature, and its management remains debated. We report the case of a 42-year-old Malagasy woman presenting with SLE complicated by MAS at the time of diagnosis, associated with viral hepatitis B.
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Affiliation(s)
- L. N. Rakotonirina
- Department of RheumatologyJoseph Raseta Befelatanana University HospitalAntananarivoMadagascar
| | - M. O. Andrianiaina
- Department of Internal MedicineJoseph Raseta Befelatanana University HospitalAntananarivoMadagascar
| | - O. H. Rakotonirainy
- Department of RheumatologyJoseph Raseta Befelatanana University HospitalAntananarivoMadagascar
| | - H. Ramanandafy
- Department of Internal MedicineJoseph Raseta Befelatanana University HospitalAntananarivoMadagascar
| | - N. H. Randriamifidy
- Department of Hepato‐Gastro‐EnterologyJoseph Raseta Befelatanana University HospitalAntananarivoMadagascar
| | - F. Rapelanoro Rabenja
- Department of DermatologyJoseph Raseta Befelatanana University Hospital, Faculty of Medicine, University of AntananarivoAntananarivoMadagascar
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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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McEvoy C, Bjoraj P, Lee JS. Pulmonary Complications in Hematologic Malignancies. Clin Chest Med 2025; 46:115-127. [PMID: 39890283 DOI: 10.1016/j.ccm.2024.10.009] [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: 02/03/2025]
Abstract
Patients with hematologic malignancies are at risk for infectious and noninfectious pulmonary complications. An integrated diagnostic approach tailored to the patient's malignancy and treatment history and clinical presentation should be initiated with close interdisciplinary collaboration among specialists.
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Affiliation(s)
- Colleen McEvoy
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, 660 South Euclid Avenue, MSC 8052-43-14, St. Louis, MO 63110, USA.
| | - Pooja Bjoraj
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110, USA
| | - Janet S Lee
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110, USA
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Verran CD, Alexander MG, Shipman AR, Shipman KE. Interpretation of ferritin concentrations in the dermatology clinic. Clin Exp Dermatol 2025; 50:307-313. [PMID: 39152786 DOI: 10.1093/ced/llae342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 06/20/2024] [Accepted: 08/15/2024] [Indexed: 08/19/2024]
Abstract
Ferritin measurement is a common laboratory test in dermatology. Ferritin is a marker of iron storage in the human body but can also be -elevated in inflammatory states. Therefore, changes in ferritin are nonspecific, and correlation of specific clinical findings and risk factors with ferritin concentration and other biomarkers, e.g. iron studies or C-reactive protein tests, is recommended. This article discusses iron metabolism and the indications for ferritin measurement in dermatology and how to interpret the laboratory results.
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Affiliation(s)
- Callum D Verran
- University Hospital Southampton NHS Foundation Trust, Southampton, UK
- University Hospitals Sussex NHS Foundation Trust, Worthing, UK
| | | | | | - Kate E Shipman
- Brighton and Sussex Medical School, Brighton, UK
- University Hospitals Sussex NHS Foundation Trust, Worthing, UK
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Nguyen TH, Satwani P, Kumar D, Kapoor U, Malik S, Prince C, Montminy T, Smiley K, Martinez M, Goldner D, Marsh R, Remotti HE, Fazlollahi L, Rytting HB, Romero R, Chandrakasan S. Systemic T-cell activation and IFN-γ activity in indeterminate severe hepatitis are reminiscent of hemophagocytic lymphohistiocytosis: Implications for T-cell- and IFN-γ-directed therapies. J Allergy Clin Immunol 2025; 155:199-212. [PMID: 39278359 PMCID: PMC11890196 DOI: 10.1016/j.jaci.2024.08.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 08/06/2024] [Accepted: 08/14/2024] [Indexed: 09/18/2024]
Abstract
BACKGROUND Severe hepatitis cases in children are increasingly recognized, but the exact etiology remains unknown in a significant proportion of patients. Cases of indeterminate severe hepatitis (iSH) may progress to indeterminate pediatric acute liver failure (iPALF), so understanding its immunobiology is critical to preventing disease progression. Hemophagocytic lymphohistiocytosis (HLH) is a systemic hyperinflammatory disorder associated with T-cell and macrophage activation with liver injury. OBJECTIVES We hypothesized that a high proportion of patients with iSH demonstrate systemic T-cell activation similar to HLH before developing iPALF and that the degree of T-cell activation in iSH might correlate with outcomes. METHODS From 2019 to 2022, 14 patients with iSH and 7 patients with PALF of known, nonimmune etiology were prospectively enrolled. We compared immune signatures of iSH, HLH, known PALF, and healthy controls. RESULTS We found that patients with iSH have increased CD8+ T-cell activation and high IFN-γ activity similar to HLH. The amplitude of CD8+ T-cell activation was predictive of iSH progression to iPALF. We also found that in patients with iSH, ferritin had only modest elevation. However, the ratio of age-normalized plasma soluble IL-2 receptor to ferritin level can distinguish iSH from known PALF and HLH. As proof of concept, we report that in 3 patients with steroid-refractory iSH, emapalumab, an IFN-γ blocking antibody used in combination with steroids, improved liver function and may have prevented progression to PALF. CONCLUSIONS Flow-based T-cell activation markers could help in early identification and risk stratification for targeted intervention in patients with iSH.
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Affiliation(s)
- Thinh H Nguyen
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Prakash Satwani
- Division of Pediatric Hematology-Oncology, Columbia University, New York, NY
| | - Deepak Kumar
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Urvi Kapoor
- Division of Pediatric Hematology-Oncology, Columbia University, New York, NY
| | - Sakshi Malik
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Chengyu Prince
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga
| | - Taylor Montminy
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Ga
| | - Kristi Smiley
- Division of Bone Marrow Transplantation and Immune Deficiency, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Mercedes Martinez
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, NewYork-Presbyterian Hospital, Columbia University, New York, NY
| | - Dana Goldner
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, NewYork-Presbyterian Hospital, Columbia University, New York, NY
| | - Rebecca Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Helen E Remotti
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Ladan Fazlollahi
- Department of Pathology and Cell Biology, Columbia University, New York, NY
| | - Heather B Rytting
- Department of Pediatrics, Division of Pediatric Pathology, Children's Healthcare of Atlanta, Atlanta, Ga
| | - Rene Romero
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Ga
| | - Shanmuganathan Chandrakasan
- Department of Pediatrics, Aflac Cancer and Blood Disorder Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Ga.
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Povedano Medina MA, Arnau Prieto Á, Parra Zurutuza A, Martínez Amunarriz C, Bustinduy Odriozola MJ, Camino Ortiz de Barrón X, Pérez Santaolalla E, Maíz Alonso O, Benavente Claveras I, Rodrigo de Tomas MT. Hemophagocytic Lymphohistiocytosis in a Kidney Transplant Recipient: Case Report. Transplant Proc 2025; 57:90-92. [PMID: 39753491 DOI: 10.1016/j.transproceed.2024.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 12/15/2024] [Indexed: 02/14/2025]
Abstract
Hemophagocytic lymphohistiocytosis is a potentially fatal multisystemic inflammatory syndrome that is better understood in the pediatric population. Consequently, the diagnostic criteria for adults still derives from studies conducted in the pediatric population. Several genetic mutations and secondary causes, including infections, autoimmunity, and malignancy, have been reported as significant actors in this condition, especially in adults. It is of the utmost importance to identify these triggers, as the treatment of this condition is largely dependent on addressing the underlying cause. Those who have undergone transplantation and whose immune response is already compromised are particularly susceptible to this condition. We present the case of a 74-year-old kidney transplant recipient who was admitted due to a persistent fever of unknown origin, pancytopenia, and splenomegaly. The patient was ultimately diagnosed with hemophagocytic lymphohistiocytosis in our hospital secondary to Epstein-Barr virus, aspergillosis, and leishmania infections. Targeted treatments for the aforementioned conditions led to the resolution of the syndrome and the recovery of the patient. Lymphohistiocytosis is a rare, albeit serious, condition that should be considered a differential diagnosis in the early stages of critical illness in transplant recipient patients. Doing so enables target treatments to be administered as soon as possible.
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Affiliation(s)
| | | | | | | | | | | | | | - Olga Maíz Alonso
- Rheumatology, Hospital Universitario Donostia, San Sebastián, España
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Ali MW, Rakshit S, Sarkar A, Mondal MK, Datta AK, Chatterjee U. A rare case of complicated typhoid fever presenting with secondary Hemophagocytic Lymphohistiocytosis. Oxf Med Case Reports 2024; 2024:omae151. [PMID: 39664923 PMCID: PMC11631300 DOI: 10.1093/omcr/omae151] [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: 03/21/2024] [Revised: 08/22/2024] [Accepted: 09/20/2024] [Indexed: 12/13/2024] Open
Abstract
Enteric fever is one of the important causes of tropical fever with a prevalence of 11-21 million cases worldwide annually. It encompasses both typhoid and paratyphoid fever. Salmonella enterica Typhi is the causative organism for typhoid fever, manifesting as an uncomplicated febrile illness to life-threatening sepsis with multiorgan dysfunction. It is complicated by neuropsychiatric manifestation (2%-40%), gastrointestinal bleeding (10%), and intestinal perforation (1%-3%). Hemophagocytic Lymphohistiocytosis (HLH) is a rare complication of typhoid fever. Herein we report the case of a 24-year-old male from North-Eastern India, presenting with spikes of fever, altered behavior, a generalized rash, haematochezia, and hemophagocytes on bone marrow examination due to hemophagocytic lymphohistiocytosis secondary to complicated typhoid fever.
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Affiliation(s)
- Mir Wasim Ali
- Department of Internal Medicine, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
| | - Soumadip Rakshit
- Department of Internal Medicine, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
| | - Atreyee Sarkar
- Department of Pathology, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
| | - Md Karimulla Mondal
- Department of Internal Medicine, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
| | - Anup Kumar Datta
- Department of Internal Medicine, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
| | - Uttara Chatterjee
- Department of Pathology, IPGMER & SSKM Hospital, 242 Harish Mukherjee Road, Kolkata 700020, India
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Khreisat A, Maria IMS, Grasso-Knight G, Mansour M. Hemophagocytic Lymphohistiocytosis in a Critically Ill Patient: A Case Report of a Potentially Fatal Entity. HCA HEALTHCARE JOURNAL OF MEDICINE 2024; 5:745-749. [PMID: 39790691 PMCID: PMC11708928 DOI: 10.36518/2689-0216.1741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a non-neoplastic proliferation and macrophage activation that induces cytokine-mediated bone marrow suppression and features of intense phagocytosis in the bone marrow and liver, leading to multi-organ dysfunction and ultimate failure. The diagnosis of HLH in an intensive care setting is challenging, and it is associated with high morbidity and mortality. HLH-94 is the standard protocol for treatment, consisting of dexamethasone and chemotherapy like etoposide. Case Presentation We present the case of a 73-year-old woman who had a prolonged hospitalization for vomiting, diarrhea, and dehydration. Her conditions were complicated by acute refractory pancytopenia on the 12th day of admission, leading to multi-organ failure, including anuric renal failure requiring renal replacement therapy and respiratory failure requiring intubation. After a thorough workup, she was diagnosed with HLH using HLH-2004 diagnostic criteria and confirmed by a bone marrow biopsy. She was started on supportive therapy and high-dose intravenous dexamethasone with an appropriate clinical response. Her pancytopenia improved, and she no longer required ventilator support for respiratory failure or dialysis for renal failure. Unfortunately, her hospital course was complicated by a sentinel event leading to her death. Conclusion This case emphasizes that early recognition and treatment initiation of HLH are crucial to prevent adverse outcomes and mortality. Treatment should be tailored based on the underlying HLH trigger, as chemotherapy-based treatment regimens may result in overtreatment and unnecessary toxicities. Further studies are needed to increase clinicians' awareness and management of secondary cases of HLH.
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Affiliation(s)
- Ali Khreisat
- Corewell Health William Beaumont University Hospital, Royal Oak, MI
| | | | | | - Meghan Mansour
- Oakland University William Beaumont School of Medicine, Rochester Hills, MI
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Pestana Santos C, Cruz D, Gonçalves de Sousa B, Judas T. From Diagnosis to Treatment: A Successful Case of Haemophagocytic Lymphohistiocytosis of Presumed Bacterial Aetiology in an Adult. Eur J Case Rep Intern Med 2024; 11:004812. [PMID: 39372158 PMCID: PMC11451842 DOI: 10.12890/2024_004812] [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: 09/01/2024] [Accepted: 09/09/2024] [Indexed: 10/08/2024] Open
Abstract
Haemophagocytic lymphohistiocytosis (HLH) affects patients across all age groups and can be classified as either primary HLH (P-HLH) or secondary HLH (S-HLH). The latter is associated with clinical conditions that disrupt normal immunological responses, such as infections, neoplasms or autoimmune diseases. Although HLH can occur sporadically in healthy individuals, it is more frequently observed in patients with haematological malignancies and autoimmune disorders. The diagnostic process for HLH is often challenging due to its non-specific signs and the absence of pathognomonic findings. The primary objective in treating S-HLH is to eliminate the underlying trigger and control immunological hyperactivation, making the identification and treatment of triggers critically important. Prompt diagnosis and treatment are essential, as the mortality rate remains high. In this context, we present the case of a young woman diagnosed with idiopathic S-HLH, likely triggered by a bacterial infection. The diagnosis was achieved due to a high index of clinical suspicion for S-HLH. The patient exhibited an excellent response to antimicrobial therapy, resulting in the complete resolution of haemophagocytosis. The authors deem it important to present this case to enhance awareness of S-HLH diagnosis, as well as the investigation and management of potential triggers. LEARNING POINTS Haemophagocytic lymphohistiocytosis is characterised as a rare inflammatory syndrome that occurs due to uncontrolled systemic immune activation.Timely diagnosis and treatment are essential, as mortality is still high.
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Affiliation(s)
| | - Daniela Cruz
- Internal Medicine Department, Hospital Garcia de Orta EPE, Almada, Portugal
| | | | - Tiago Judas
- Internal Medicine Department, Hospital Garcia de Orta EPE, Almada, Portugal
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Selvam S, Tuli A, Yuvasai KP, Saini S, Erla SR, Kaur J, Biswal M, Sharma N, Pannu AK. Predicting Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients with Scrub Typhus and Its Prognostic Significance. Indian J Crit Care Med 2024; 28:823-831. [PMID: 39360205 PMCID: PMC11443264 DOI: 10.5005/jp-journals-10071-24787] [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: 05/22/2024] [Accepted: 07/29/2024] [Indexed: 10/04/2024] Open
Abstract
Objective Secondary hemophagocytic lymphohistiocytosis (sHLH) is an increasingly recognized complication in patients with scrub typhus, potentially contributing to substantial mortality despite appropriate antibiotic treatment. This study aims to determine the prevalence and prognosis of sHLH and identify diagnostic factors in adult patients with scrub typhus in North India. Methods This prospective cohort study was conducted at PGIMER, Chandigarh, from August 2021 to November 2023. sHLH was defined as an HScore of 200 or above. The diagnostic performance of biomarkers such as ferritin, fibrinogen, triglycerides, and C-reactive protein was assessed through receiver operating characteristic curve analysis, evaluating area under the curve (AUC), sensitivity, and specificity. Results Out of 150 patients (mean age 39 years, 54% female), 28 (18.7%) were diagnosed with sHLH. Those presenting with high-grade fever, seizures, high pulse rate, hepatomegaly, splenomegaly, cytopenia, and significant hepatic dysfunction were more likely to have sHLH. Ferritin demonstrated the highest diagnostic utility (AUC 0.83), compared to fibrinogen (AUC 0.72), triglyceride (AUC 0.67), and C-reactive protein (AUC 0.69). The optimal cutoff for ferritin was 2000 ng/mL, with a sensitivity of 90% and a specificity of 66%. Higher ferritin thresholds (6000 ng/mL and 10000 ng/mL) increased specificity to 88% and 95%, respectively. Patients with sHLH often presented with multi-organ failure, necessitating mechanical ventilation and vasopressor support. In-hospital mortality was significantly higher in sHLH patients than in those without (21.4% vs 6.6%, p = 0.025). Conclusion Early detection of sHLH using the HScore and ferritin significantly influences the management of scrub typhus, underscoring the necessity for tailored therapeutic strategies to improve patient outcomes. How to cite this article Selvam S, Tuli A, Yuvasai KP, Saini S, Erla SR, Kaur J, et al. Predicting Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients with Scrub Typhus and Its Prognostic Significance. Indian J Crit Care Med 2024;28(9):823-831.
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Affiliation(s)
- Suresh Selvam
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Akshit Tuli
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Kumar P Yuvasai
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Shashikant Saini
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Sathvik R Erla
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Manisha Biswal
- Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Navneet Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashok K Pannu
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Ayyar S, Lantz R. A Case Report of Hemophagocytic Lymphohistiocytosis Masquerading as Sepsis. Cureus 2024; 16:e67393. [PMID: 39310631 PMCID: PMC11414419 DOI: 10.7759/cureus.67393] [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: 08/20/2024] [Indexed: 09/25/2024] Open
Abstract
Profound inflammation due to cytokine storm is often the underlying cause of death in patients with hemophagocytic lymphohistiocytosis (HLH). Sepsis, while a precipitant, is also the great masquerader that may hide early signs of HLH. Prompt recognition is important to prevent rapid clinical decline and death. A patient presented with two weeks of unremitting fever of 103°F, dysuria, bilateral flank pain, and confusion. Obstructive uropathy and pyelonephritis were treated with a Foley catheter and antibiotics. There were abnormal developments during his hospitalization including a deep vein thrombus despite prophylactic anticoagulation. Antibiotics and Foley management did not improve fevers or renal injury so he eventually required continuous renal replacement therapy and blood product transfusions. In rapid progression, the patient developed pancytopenia, neutropenia, hyperferritinemia, hypertriglyceridemia, and hypofibrinogenemia suspicious for HLH. A bone marrow biopsy was consistent with progressive T-cell lymphoma, the likely cause of secondary HLH. Antineoplastics, corticosteroids, and opportunistic prophylaxis were pursued. Unfortunately, the cytopenias worsened, and the patient developed shock with hypoxemia and hypotension, followed by cardiac arrest and demise.
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Affiliation(s)
- Saipriya Ayyar
- Internal Medicine, Wright State University Boonshoft School of Medicine, Beavercreek, USA
| | - Rebekah Lantz
- Hospital Medicine, Miami Valley Hospital, Dayton, USA
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14
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Wu Y, Yin W, Wen Y, Chen J, Tang H, Ding Y. An early predictive model for Kawasaki disease shock syndrome in children in central China. Front Cardiovasc Med 2024; 11:1405012. [PMID: 38859816 PMCID: PMC11163032 DOI: 10.3389/fcvm.2024.1405012] [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: 03/22/2024] [Accepted: 05/09/2024] [Indexed: 06/12/2024] Open
Abstract
Introduction This study aims to analyze the clinical features of Kawasaki disease (KD) shock syndrome (KDSS) and explore its early predictors. Methods A retrospective case-control study was used to analyze KD cases from February 2016 to October 2023 in our hospital. A total of 28 children with KDSS and 307 children who did not develop KDSS were included according to matching factors. Baseline information, clinical manifestations, and laboratory indicators were compared between the two groups. Indicators of differences were analyzed based on univariate analysis; binary logistic regression analysis was used to identify the risk factors for KDSS, and then receiver operating characteristic analysis was performed to establish a predictive score model for KDSS. Results Elevated neutrophil-to-lymphocyte ratio(NLR) and decreased fibrinogen (FIB) and Na were independent risk factors for KDSS; the scoring of the above risk factors according to the odds ratio value eventually led to the establishment of a new scoring system: NLR ≥ 7.99 (6 points), FIB ≤ 5.415 g/L (1 point), Na ≤ 133.05 mmol/L (3 points), and a total score of ≥3.5 points were high-risk factors for progression to KDSS; otherwise, they were considered to be low-risk factors. Conclusion Children with KD with NLR ≥ 7.99, FIB ≤ 5.415 g/L, and Na ≤ 133.05 mmol/L, and those with two or more of the above risk factors, are more likely to progress to KDSS, which helps in early clinical diagnosis and treatment.
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Affiliation(s)
| | | | | | | | - Hongxia Tang
- Department of Rheumatology and Immunology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
| | - Yan Ding
- Department of Rheumatology and Immunology, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China
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15
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Chen Y, Huang X, Chen H, Tong J, Huang L, Su J, Deng L. A Case Report of Pregnancy Complicated with Primary Hemophagocytic Lymphohistiocytosis. Int J Womens Health 2024; 16:843-851. [PMID: 38774152 PMCID: PMC11107908 DOI: 10.2147/ijwh.s460352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/10/2024] [Indexed: 05/24/2024] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by excessive activation of NK cells and cytotoxic T lymphocytes, subsequently leading to macrophage activation and increased cytokine production. Misdiagnosis due to nonspecific clinical presentations and inadequate understanding of the disease can significantly jeopardize the safety of both the mother and the infant. We report a case of pregnancy combined with HLH and conduct a literature review to provide insights into the diagnosis and treatment of pregnancy-related HLH. Case Presentation We discussed a case of a pregnant woman with persistent postpartum fever, serum ferritin, and elevated liver function, who failed to respond to repeated anti-infective therapy and was diagnosed with HLH after multidisciplinary diagnostic treatment. We gave dexamethasone treatment, and the patient's temperature and blood cells quickly returned to normal. Finally, exome sequencing revealed heterozygous variation in UNC13D gene, so we considered this case as pregnancy combined with primary HLH (pHLH). Conclusion We report the case of HLH diagnosed during pregnancy and show that early diagnosis and timely intervention can prevent rapid disease progression, reduce maternal mortality rates, and improve survival rates. Additionally, molecular genetic testing can confirm pathogenic gene mutations, providing essential genetic counseling for patients with pHLH who plan to conceive a healthy child.
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Affiliation(s)
- Yan Chen
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Xiaohuan Huang
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Hongfei Chen
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Junru Tong
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Lingling Huang
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Junyou Su
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
| | - Li Deng
- Department of Obstetrics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, People’s Republic of China
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Rodrigues CM, Carvalho AC, Ventura S, Domingues ÂP, Silva A, Ministro P. Persistent Fever after COVID-19 Vaccination in a Patient with Ulcerative Colitis: A Call for Attention. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2024; 31:129-135. [PMID: 38572438 PMCID: PMC10987068 DOI: 10.1159/000530834] [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: 11/04/2022] [Accepted: 02/06/2023] [Indexed: 04/05/2024]
Abstract
The development of vaccinations has been game-changing in the ongoing effort to combat the COVID-19 pandemic. Until now, adverse effects are being reported at low frequency, including thrombocytopenia and myocarditis. Careful monitoring for any suspicious symptoms and signs following vaccination is necessary. We report a case of hemophagocytic lymphohistiocytosis (HLH) after mRNA COVID-19 vaccine in a 23-year-old female with ulcerative colitis. Diagnosis was made according to HLH-2004 criteria and the patient was treated with dexamethasone with response. Our report aimed to draw attention to the potential relation between COVID-19 vaccines and HLH and the necessity of continued surveillance, especially in at-risk populations such as those with underlying immune dysregulation.
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Affiliation(s)
| | | | - Sofia Ventura
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | | | - Américo Silva
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
| | - Paula Ministro
- Department of Gastroenterology, Centro Hospitalar Tondela-Viseu, Viseu, Portugal
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Kim JH, Chung JY, Bong JB. Probable secondary hemophagocytic lymphohistiocytosis manifesting as central nervous system lesions after COVID-19 vaccination: a case report. Front Neurol 2024; 15:1363072. [PMID: 38529033 PMCID: PMC10962393 DOI: 10.3389/fneur.2024.1363072] [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: 12/29/2023] [Accepted: 02/26/2024] [Indexed: 03/27/2024] Open
Abstract
Background Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory disease commonly characterized by histiocyte infiltration in multiple organs, such as the liver, spleen, lymph nodes, bone marrow, and central nervous system. The clinical features of HLH include fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated blood ferritin levels. HLH is categorized as either primary or secondary. Coronavirus disease 2019 (COVID-19) vaccines may occasionally trigger secondary HLH, which is related to hyperinflammatory syndrome. Case presentation A 58-year-old woman, previously diagnosed with Graves' disease, presented with cognitive decline 2 weeks after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. Brain MRI revealed a hyperintense lesion on T2-weighted and fluid-attenuated inversion recovery images in the bilateral subcortical white matter and right periventricular area. Vaccination-associated acute disseminated encephalomyelitis was suspected and methylprednisolone and intravenous immunoglobulin (IVIg) were administered. From the 5th day of IVIg administration, the patient developed fever and pancytopenia. In the findings of bone marrow biopsy, hemophagocytosis was not observed; however, six of the eight diagnostic criteria for HLH-2004 were met, raising the possibility of HLH. Although there was no definitive method to confirm causality, considering the temporal sequence, suspicion arose regarding vaccine-induced HLH. Splenectomy was considered for therapeutic and diagnostic purposes; however, the patient died on the 28th day of hospitalization owing to multiple organ failure. Conclusion To date, 23 cases of COVID-19 vaccine-related HLH have been reported. Additionally, HLH in COVID-19 patients has been reported in various case reports. To the best of our knowledge, this is the first reported case of central nervous system involvement in HLH related to any type of COVID-19 vaccine. This case suggests that even when there are no systemic symptoms after COVID-19 vaccination, HLH should be considered as a differential diagnosis if brain lesions are suggestive of CNS demyelinating disease.
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Affiliation(s)
| | | | - Jeong Bin Bong
- Department of Neurology, Chosun University College of Medicine, Gwangju, Republic of Korea
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18
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Christensen BR, Kou CTJ, Lee LE. A Rare Case of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Associated With Hemophagocytic Lymphohistiocytosis in a Patient With Recurrent Sinusitis. Cureus 2024; 16:e56237. [PMID: 38618451 PMCID: PMC11016311 DOI: 10.7759/cureus.56237] [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: 03/14/2024] [Indexed: 04/16/2024] Open
Abstract
We present a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to nasal-type extranodal natural killer/T-cell lymphoma (ENKL). Nasal-type ENKL is a rare subtype of non-Hodgkin's lymphoma usually associated with Epstein-Barr virus (EBV). The patient was a 19-year-old woman who presented with facial numbness, diminished hearing, and dysgeusia. She was febrile with palatal necrosis, loss of gag reflex, and cranial nerve palsies. Labs revealed neutropenia. Broad-spectrum antimicrobials, including amphotericin, were started. Given concern for invasive fungal disease, she underwent surgical debridement, which revealed inflamed fibrous tissue and extensive necrosis. Pathology showed no fungal elements or malignancy. Lack of clinical improvement and worsening palatal necrosis prompted additional debridement. Histology identified an atypical CD3+/CD56+ cellular infiltrate. Bone marrow biopsy showed prominent hemophagocytosis, but no malignancy. She met the criteria for HLH and high-dose dexamethasone was started. Her fevers resolved. Additional labs and nasal tissue sampling with EBV-encoded RNA staining were recommended. Flow cytometry was negative, but histology revealed ENKL nasal-type, with positive EBV-encoded RNA in situ hybridization. Plasma EBV DNA level was 11,518 IU/mL. The M-SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) regimen was initiated; one cycle led to marked improvement. EBV level returned to zero. Subsequent radiation and chemotherapy, followed by autologous stem cell transplant consolidation, led to complete remission. We conclude that ENKL may mimic invasive sinusitis clinically. Fibrinoid necrosis in vessels and surrounding tissues often leads to diagnostic delay. It is important to have a high degree of clinical suspicion for malignancy in cases of HLH and sinusitis unresponsive to appropriate therapy. Obtaining proper tissue, communication with the pathologist, and prompt initiation of therapy are crucial.
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Affiliation(s)
- Bryce R Christensen
- Pulmonary and Critical Care Medicine, Mike O'Callaghan Military Medical Center, Nellis Air Force Base, USA
- Pulmonary and Critical Care Medicine, University of Nevada, Las Vegas, Las Vegas, USA
- Internal Medicine, Brooke Army Medical Center, Fort Sam Houston, USA
| | - Chung-Ting J Kou
- Hematology and Oncology, Brooke Army Medical Center, Fort Sam Houston, USA
| | - Lauren E Lee
- Hematology and Oncology, Brooke Army Medical Center, Fort Sam Houston, USA
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Jevtic D, da Silva MD, Haylock AB, Nordstrom CW, Oluic S, Pantic N, Nikolajevic M, Nikolajevic N, Kotseva M, Dumic I. Hemophagocytic Lymphohistiocytosis (HLH) in Patients with Tick-Borne Illness: A Scoping Review of 98 Cases. Infect Dis Rep 2024; 16:154-169. [PMID: 38525759 PMCID: PMC10961790 DOI: 10.3390/idr16020012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/15/2024] [Accepted: 02/18/2024] [Indexed: 03/26/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) secondary to tick-borne infections is a rare but potentially life-threatening syndrome. We performed a scoping review according to PRISMA guidelines to systematically analyze the existing literature on the topic. A total of 98 patients were included, with a mean age of 43.7 years, of which 64% were men. Most cases, 31%, were reported from the USA. Immunosuppression was present in 21.4%, with the most common cause being previous solid organ transplantation. Constitutional symptoms were the most common, observed in 83.7% of the patients, while fever was reported in 70.4% of cases. Sepsis was present in 27.6%. The most common laboratory abnormalities in this cohort were thrombocytopenia in 81.6% of patients, while anemia, leukopenia, and leukocytosis were observed in 75.5%, 55.1%, and 10.2%, respectively. Liver enzyme elevation was noted in 63.3% of cases. The H-score was analyzed in 64 patients, with the mean value being 209, and bone marrow analysis was performed in 61.2% of patients. Ehrlichia spp. was the main isolated agent associated with HLH in 45.9%, followed by Rickettsia spp. in 14.3% and Anaplasma phagocytophilum in 12.2%. Notably, no patient with Powassan virus infection or Lyme borreliosis developed HLH. The most common complications were acute kidney injury (AKI) in 35.7% of patients, shock with multiple organ dysfunction in 22.5%, encephalopathy/seizure in 20.4%, respiratory failure in 16.3%, and cardiac complications in 7.1% of patients. Treatment included antibiotic therapy alone in 43.9%, while 5.1% of patients were treated with immunosuppressants alone. Treatment with both antibiotics and immunosuppressants was used in 51% of patients. Appropriate empiric antibiotics were used in 62.2%. In 43.9% of cases of HLH due to tick-borne disease, patients received only antimicrobial therapy, and 88.4% of those recovered completely without the need for immunosuppressive therapy. The mortality rate in our review was 16.3%, and patients who received inappropriate or delayed empiric therapy had a worse outcome. Hence, we suggest empiric antibiotic treatment in patients who are suspected of having HLH due to tick-borne disease or in whom diagnostic uncertainty persists due to diagnostic delay in order to minimize mortality.
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Affiliation(s)
- Dorde Jevtic
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (D.J.); (A.B.H.)
- Department of Medicine, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA
| | | | - Alberto Busmail Haylock
- Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (D.J.); (A.B.H.)
- Department of Medicine, NYC Health + Hospitals/Elmhurst, New York, NY 11373, USA
| | - Charles W. Nordstrom
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54703, USA;
- Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USA
| | - Stevan Oluic
- Department of Internal Medicine, Mayo Clinic Health System, Mankato, MN 56001, USA;
| | - Nikola Pantic
- Clinic of Hematology, University Clinical Center of Serbia, 11000 Belgrade, Serbia;
| | - Milan Nikolajevic
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.N.); (N.N.)
| | - Nikola Nikolajevic
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia; (M.N.); (N.N.)
| | - Magdalena Kotseva
- Internal Medicine Residency, Franciscan Health, Olympia Fields, Chicago, IL 60461, USA;
| | - Igor Dumic
- Department of Hospital Medicine, Mayo Clinic Health System, Eau Claire, WI 54703, USA;
- Mayo Clinic College of Medicine and Science, Rochester, MN 55902, USA
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Masood M, Siddique A, Krishnamoorthi R, Kozarek RA. Liver Dysfunction in Adult Hemophagocytic Lymphohistiocytosis: A Narrative Review. Adv Ther 2024; 41:553-566. [PMID: 38145441 DOI: 10.1007/s12325-023-02768-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 12/08/2023] [Indexed: 12/26/2023]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition that has been increasingly recognized in adults and is characterized by a hyperinflammatory state due to immune dysregulation. Its nonspecific presentation, the lack of clinician familiarity given its rarity, and shared clinical features with sepsis and other syndromes can lead to a delay in diagnosis and a poor prognosis. Significant liver function abnormalities as the initial manifestation of HLH are uncommon and can range from mild elevation of aminotransferases to fulminant hepatic failure with high mortality rates. The authors encountered a case of adult HLH mimicking acute viral hepatitis in which a markedly elevated ferritin level led to a prompt diagnosis, early initiation of treatment, and a successful outcome. Clinicians, including gastroenterologists and hepatologists, are often called upon to evaluate patients with abnormal liver tests and may lack experience in the early diagnosis and management of liver dysfunction in the context of HLH. Thus, we expand our reporting to a narrative review of literature which explores the pathogenesis of HLH, challenges associated with its diagnosis, previous reports of liver disease associated with the syndrome, recommended treatments for the familial and adult variations including the role of liver transplantation, and the outcomes of these treatments.
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Affiliation(s)
- Muaaz Masood
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Asma Siddique
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Rajesh Krishnamoorthi
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA
| | - Richard A Kozarek
- Division of Gastroenterology and Hepatology, Center for Digestive Health, Virginia Mason Franciscan Health, Seattle, WA, USA.
- Center for Interventional Immunology, Benaroya Research Institute, Virginia Mason Franciscan Health, 1201 Ninth Ave, Seattle, WA, 98101, USA.
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Chen QT, Chen MH, Lin YK, Yeh RH, Lu CC, Hsiao PJ, Sung YF. Case report: Hemophagocytic lymphohistiocytosis complicated by multiple organ dysfunction syndrome following aseptic encephalitis. Front Immunol 2023; 14:1296575. [PMID: 38193074 PMCID: PMC10773876 DOI: 10.3389/fimmu.2023.1296575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening condition caused by excessive immune activation. Secondary HLH is usually triggered by infection, most often from viral infection or malignancy. Here, we present a case of secondary HLH, complicated by multiple organ dysfunction syndrome triggered by critical aseptic encephalitis. A 27-year-old man without any underlying disease presented to our hospital with fever, disturbance of consciousness, and generalized seizures. The patient was diagnosed with aseptic encephalitis with super-refractory status epilepticus. Although antiseizure medications and immunoglobulins were administered, the patient developed multiple organ dysfunction syndrome. HLH was later diagnosed based on hypertriglyceridemia, hyperferritinemia, splenomegaly, cytopenia, and phagocytosis of nucleated cells, as shown by a blood smear of bone marrow aspiration. Treatment with pulse steroid therapy and plasmapheresis was initiated rather than chemotherapy because of the patient's critical condition. However, the patient died of profound shock and multiple organ failure. Diagnosis of HLH is challenging in patients with severe infections because of similar clinical manifestations and laboratory findings. The early recognition of HLH provides patients with the opportunity to receive appropriate treatment, which can lead to increased survival and remission rates.
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Affiliation(s)
- Quan-Ting Chen
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Ming-Hua Chen
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Yu-Kai Lin
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ren-Hua Yeh
- Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chun-Chi Lu
- Division of Rheumatology/Immunology and Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Po-Jen Hsiao
- Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
| | - Yueh-Feng Sung
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Yao S, He L, Zhang R, Liu M, Hua Z, Zou H, Wang Z, Wang Y. Improved hemophagocytic lymphohistiocytosis index predicts prognosis of adult Epstein-Barr virus-associated HLH patients. Ann Med 2023; 55:89-100. [PMID: 36533966 PMCID: PMC9766494 DOI: 10.1080/07853890.2022.2149850] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of HLH with heterogeneous clinical presentations from self-limited to death, of which adults are worse than children. OBJECTIVE To establish predictors of mortality risk in adult EBV-HLH patients for timely and appropriate treatment. METHODS Patients with confirmed EBV-HLH admitted to Beijing Friendship Hospital from January 2015 to December 2019 were enrolled and statistical analysis of their laboratory test results was performed. RESULTS Among 246 adult patients with EBV-HLH, the deceased were older (p < 0.05), with fewer blood cells (p < 0.05), poorer renal function (p < 0.01), higher levels of procalcitonin (PCT) (p < 0.01), as well as soluble interleukin-2 receptor (sCD25) (p < 0.01). The overall median survival time of patients was 135 days, 87 days for patients without transplantation and 294 days with transplantation (p < 0.001). A combined index of sCD25, PCT, and estimated glomerular filtration rate (eGFR) was obtained to predict prognosis, named the Improved HLH index (IH index), and patients were divided into three groups meeting IH- (i.e. sCD25 ≤ 18,000 pg/mL, PCT ≤ 1.8 ng/mL, eGFR ≥ 90 mL/min/1.73m2), IH1+ (i.e. only sCD25 > 18,000 pg/mL or only eGFR < 90 mL/min/1.73m2), and IH2+ (i.e. the rest), respectively. In patients with the HScore ≥ 169 or meeting HLH-04, those meeting IH2+ had significantly worse prognoses than those who met IH1+ or IH- (p < 0.001). In the group meeting IH + or IH2+, patients who received allo-HSCT had better prognoses than those who did not (p < 0.05), but there was still a significant difference in prognosis among the three groups in transplanted patients (p < 0.001). CONCLUSION The IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.KEY MESSAGESA combined index of sCD25, PCT, and eGFR was obtained to predict prognosis, named the Improved Hemophagocytic Lymphohistiocytosis index (IH index).IH index can early identify adult patients with a poor prognosis of EBV-HLH, initiating timely and appropriate treatment.
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Affiliation(s)
- Shuyan Yao
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lingbo He
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Ruoxi Zhang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Menghan Liu
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhengjie Hua
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Heshan Zou
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhao Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yini Wang
- Department of Hematology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Department of General Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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23
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Sequeira C, Lopes SR, Neves A, Santos IC, Martins CR, Oliveira AP. Severe Acute Liver Injury due to Secondary Hemophagocytic Lymphohistiocytosis: A Case Report. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2023; 30:39-45. [PMID: 38020822 PMCID: PMC10661704 DOI: 10.1159/000529549] [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: 10/22/2022] [Accepted: 01/12/2023] [Indexed: 12/01/2023]
Abstract
Severe acute liver injury (ALI) is mostly triggered by viral infections and hepatotoxic drugs; however, it can also be seen in systemic diseases. Hemophagocytic lymphohistiocytosis (HLH) is a rare, immune-mediated syndrome that presents as a life-threatening inflammatory disorder affecting multiple organs. Secondary causes occur mainly in the set of malignancy, infection, and autoimmune disease, and are seldom triggered by vaccination. Although liver involvement is common, presentation as severe ALI is rare. We describe a case of a 65-year-old male with history of low-risk chronic lymphocytic leukemia and rheumatoid arthritis treated with prednisolone who presented with persistent fever and jaundice 1 week after COVID-19 vaccination. The diagnosis was challenging given the predominant liver impairment, characterized by hyperbilirubinemia, transaminases over 1,000 U/L, and prolonged INR, which prompted an extensive investigation and exclusion of autoimmune, toxic, and viral causes of hepatitis. Laboratory workup revealed bicytopenia, hyperferritinemia, which together with organ failure and evidence of hemophagocytosis in bone marrow suggested the diagnosis of HLH. After excluding infectious etiologies, flare of rheumatological disease, and the progression of hematological disease, HLH was diagnosed. He was successfully treated with etoposide and corticosteroids, with dramatic improvement of liver tests. After exclusion of other causes of secondary HLH, the recent vaccination for COVID-19 was the likely trigger. We report a case of double rarity of HLH, as it presented with severe liver dysfunction which was probably triggered by vaccination. In this case, the predominant liver involvement urged extensive investigation of liver disease, so a high index of suspicion was required to make an early diagnosis. Clinicians should consider HLH in patients with unexplained signs and symptoms of systemic inflammatory response and multiorgan involvement, including severe liver involvement as the first presentation.
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Affiliation(s)
- Cristiana Sequeira
- Gastrenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Sara Ramos Lopes
- Gastrenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Anabela Neves
- Oncology Department, Hematology Unit, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Inês Costa Santos
- Gastrenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | | | - Ana Paula Oliveira
- Gastrenterology Department, Centro Hospitalar de Setúbal, Setúbal, Portugal
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24
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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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25
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Wang L, Suo L, Kou F, Zhang Y, Li M, Wang H, Casalino G, Peto T, Chakravarthy U, Wang Y, Wu W, Dong N. Ocular Phenotypes in Patients With Hemophagocytic Lymphohistiocytosis: A Retrospective Analysis in a Single Center Over 7 Years. Am J Ophthalmol 2023; 253:119-131. [PMID: 37178948 DOI: 10.1016/j.ajo.2023.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 05/03/2023] [Accepted: 05/03/2023] [Indexed: 05/15/2023]
Abstract
PURPOSE To investigate the presence and type of ocular abnormalities in patients with hemophagocytic lymphohistiocytosis (HLH). DESIGN A retrospective cross-sectional study. METHODS Observational report of ocular findings and their associations with age, sex, underlying disease, and hematologic parameters. HLH was defined according to the 2004 criteria, and the patients were enrolled from March 2013 to December 2021. Analysis began in July 2022 and ended in January 2023. The main outcome measures were ocular abnormalities associated with HLH and their potential risk factors. RESULTS Of 1525 HLH patients, 341 had ocular examinations, and 133 (133 of 341, 39.00%) had ocular abnormalities. Mean age at presentation was 30.21 ± 14.42 years. The multivariate analysis indicated that old age, autoimmune disorders, decreasing red blood cell count, decreasing platelet count, and increasing fibrinogen level were independent risk factors of ocular involvement in HLH patients. The most common presenting ocular findings were posterior segment abnormalities (66 patients, 49.62%), including retinal and vitreous hemorrhage, serous retinal detachment, cytomegalovirus retinitis, and optic disc swelling. Other HLH-associated ocular abnormalities included ocular surface infection (conjunctivitis, 34 patients, 25.56%; keratitis, 16 patients, 12.03%), subconjunctival hemorrhage (11 patients, 8.27%), chemosis (5 patients, 3.76%), anterior uveitis (11 patients, 8.27%), glucocorticoid-induced glaucoma (5 patients, 3.76%), radiation cataract (1 patient, 0.75%), dacryoadenitis (2 patients, 1.50%), dacryocystitis (1 patients, 0.75%), orbital cellulitis (2 patients, 1.50%), orbital pseudotumor (2 patients, 1.50%), and strabismus (2 patients, 1.50%). CONCLUSIONS Eye involvement is not uncommon in HLH. Better awareness among both ophthalmologists and hematologists is necessary for prompt diagnosis and institution of appropriate management strategies with potential to save sight and life.
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Affiliation(s)
- Luping Wang
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China
| | - Lingge Suo
- Department of Ophthalmology, Peking University Third Hospital (L.S.), Beijing, China; Beijing Key Laboratory of Restoration of Damaged Ocular Nerve, Peking University Third Hospital (L.S.), Beijing, China
| | - Fangning Kou
- Department of Ophthalmology, Beijing Anzhen Hospital, Capital Medical University (F.K.), Beijing, China
| | - Youjing Zhang
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China
| | - Mingming Li
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China
| | - Hao Wang
- Department of Clinical Epidemiology and Evidence-Based Medicine, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University (H.W.), Beijing, China
| | - Giuseppe Casalino
- Eye Clinic, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, University of Milan (G.C.), Milan, Italy
| | - Tunde Peto
- Centre for Public Health, Queen's University of Belfast (T.P., U.C.), Belfast, United Kingdom
| | - Usha Chakravarthy
- Centre for Public Health, Queen's University of Belfast (T.P., U.C.), Belfast, United Kingdom
| | - Yanling Wang
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China
| | - Weizhen Wu
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China
| | - Ning Dong
- From the Department of Ophthalmology, Beijing Friendship Hospital, Capital Medical University (L.W., Y.Z., M.L., Y.W., W.W., N.D.), Beijing, China.
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26
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Zhang L, Dong C, Wu Q, Li Y, Feng L, Xing Y, Dong Y, Liu L, Li X, Huo R, Dong Y, Cheng E, Ge X, Xinrui T. Repeated pulmonary nodules as the primary symptom of familial hemophagocytic lymphohistiocytosis in adults: a case report and review. J Int Med Res 2023; 51:3000605231199019. [PMID: 37756585 PMCID: PMC10683577 DOI: 10.1177/03000605231199019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 08/11/2023] [Indexed: 09/29/2023] Open
Abstract
Pulmonary nodules are usually considered to be associated with malignant tumors and benign lesions, such as granuloma, pulmonary lymph nodes, fibrosis, and inflammatory lesions. Clinical cases of pulmonary nodules associated with hemophagocytic lymphohistiocytosis have rarely been reported. Therefore, when patients develop pulmonary nodules, the possibility of developing hemophagocytic lymphohistiocytosis is often not considered. We report the first case of familial hemophagocytic lymphohistiocytosis with recurrent pulmonary nodules as the first symptom. Our findings will hopefully provide new ideas for the diagnosis and treatment of pulmonary nodules in the future.
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Affiliation(s)
- Lulu Zhang
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Chuanchuan Dong
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Qiannan Wu
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yupeng Li
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Liting Feng
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanqing Xing
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | | | - Le Liu
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaohui Li
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Rujie Huo
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Yanting Dong
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Erjing Cheng
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoyan Ge
- The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Tian Xinrui
- The Second Hospital of Shanxi Medical University, Taiyuan, China
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27
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Yanagawa Y, Muramatsu KI, Abe M, Miyazaki Y. A Fatal Rhizopus Species Infection after Facial Injury in a Patient with Myelodysplastic Syndrome and Diabetes Mellitus. Intern Med 2023; 62:2279-2283. [PMID: 37532516 PMCID: PMC10465287 DOI: 10.2169/internalmedicine.0741-22] [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: 07/28/2022] [Accepted: 10/28/2022] [Indexed: 08/04/2023] Open
Abstract
A 73-year-old woman with myelodysplastic syndrome and diabetes mellitus, chronic renal failure and paroxysmal atrial fibrillation, received a diagnosis of facial cellulitis and was treated by antibiotics. However, her symptoms deteriorated. Facial magnetic resonance imaging (MRI) showed orbital cellulitis. She had weakness of visual acuity requiring changing the antibiotics. She also underwent steroid pulse treatment. Her symptoms temporarily improved, but she became comatose and died. Results of a molecular analysis of the residual cerebrospinal fluid indicated Rhizopus species infection. For immunocompromised hosts with refractory orbital cellulitis, mucormycosis should be considered as a differential diagnosis, and appropriate treatment should be promptly performed.
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Affiliation(s)
- Youichi Yanagawa
- Department of Acute Critical Care Medicine, Shizuoka Hospital, Juntendo University, Japan
| | - Ken-Ichi Muramatsu
- Department of Acute Critical Care Medicine, Shizuoka Hospital, Juntendo University, Japan
| | - Masahiro Abe
- Department of Fungal Infection, National Institute of Infectious Diseases, Japan
| | - Yoshitsugu Miyazaki
- Department of Fungal Infection, National Institute of Infectious Diseases, Japan
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28
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Shekhar S, Radhakrishnan R, Nagar VS. Secondary Hemophagocytic Lymphohistiocytosis Due to Typhoid Fever. Cureus 2023; 15:e42175. [PMID: 37602057 PMCID: PMC10439506 DOI: 10.7759/cureus.42175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper-inflammatory state that is caused by a highly activated but ineffective immune system. It can be primary or secondary to triggers like infections, malignancies, and autoimmune conditions. The authors present the case of a young male with a fever and abdominal pain due to typhoid. He continued to have a high-spiking fever and developed dyspnea, requiring oxygen therapy despite being treated with appropriate antibiotics. Laboratory evaluation revealed cytopenias and deranged liver function tests, and abdominal imaging revealed hepatosplenomegaly. These clinical and laboratory findings raised suspicion of HLH secondary to typhoid fever. Further investigations were suggestive of hyperferritinemia and hypofibrinogenemia, and bone marrow aspirates showed hemophagocytes. The patient was treated with immunosuppression (dexamethasone) and antibiotics and showed remarkable recovery. Hemophagocytic lymphohistiocytosis should be suspected in patients with tropical infections like enteric fever, tuberculosis, malaria, dengue, etc. that worsen despite appropriate treatment, as late diagnosis is associated with greater mortality.
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Affiliation(s)
| | - Rahul Radhakrishnan
- General Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy (JJ) Group of Hospitals, Mumbai, IND
| | - Vidya S Nagar
- General Medicine, Grant Medical College and Sir Jamshedjee Jeejeebhoy (JJ) Group of Hospitals, Mumbai, IND
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29
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Toledano M. Neurologic Manifestations of Rheumatologic Disease. Continuum (Minneap Minn) 2023; 29:734-762. [PMID: 37341329 DOI: 10.1212/con.0000000000001263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/22/2023]
Abstract
OBJECTIVE This article describes the neurologic manifestations of systemic rheumatologic disorders. LATEST DEVELOPMENTS Although most have historically been classified as autoimmune disorders, rheumatologic diseases are increasingly conceptualized as distributed along a spectrum with various contributions of autoimmune (adaptive immune dysregulation) and autoinflammatory (innate immune dysregulation) mechanisms. Our evolving understanding of systemic immune-mediated disorders has been accompanied by an expansion in our differential diagnoses and therapeutic options. ESSENTIAL POINTS Rheumatologic disease involves both autoimmune and autoinflammatory mechanisms. Neurologic symptoms can be the first manifestation of these disorders, and familiarity with the systemic manifestations of specific diseases is essential to establish the correct diagnosis. Conversely, knowledge of the neurologic syndromes that are most likely to be associated with specific systemic disorders can help narrow the differential and increase confidence when attributing a neuropsychiatric symptom to an underlying systemic disorder.
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30
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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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31
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Kaur P, Munikoty V, Chandramohan V. Carbamazepine-Triggered Hemophagocytic Lymphohistiocytosis: A Case Report and Review of Literature. Pediatr Neurol 2023; 144:69-71. [PMID: 37163798 DOI: 10.1016/j.pediatrneurol.2023.03.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 12/25/2022] [Accepted: 03/19/2023] [Indexed: 05/12/2023]
Affiliation(s)
- Prabhjot Kaur
- Department of Pediatric Neurology, Rainbow Children's Hospital, Bengaluru, India
| | - Vinay Munikoty
- Department of Pediatric Hemato-Oncology, Rainbow Children's Hospital, Bengaluru, India.
| | - Vaishnavi Chandramohan
- Department of Pediatrics & Pediatric Infectious diseases, Rainbow Children's Hospital, Bengaluru, India
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32
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Fadlallah MM, Salman SM, Fadlallah MM, Rahal H. Hemophagocytic Syndrome and COVID-19: A Comprehensive Review. Cureus 2023; 15:e36140. [PMID: 37065291 PMCID: PMC10101193 DOI: 10.7759/cureus.36140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2023] [Indexed: 03/17/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory hyperferritinemic syndrome, is triggered by various etiologies and diseases and can lead to multiorgan dysfunction and death. There are two types of HLH: primary and secondary. Primary HLH (pHLH) is caused by a genetic mutation resulting in dysfunction in cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, hyperactivated immune cells, and hypercytokinemia. In secondary HLH (sHLH), an underlying etiology is the cause of the disease. Infections, malignancy, and autoimmune diseases are well-known triggers for sHLH. Infectious triggers for sHLH are most frequently viruses, where different mechanisms, including dysregulated CTLs and NK cell activity and persistent immune system stimulation, have been reported. Similarly, in severe coronavirus disease 2019 (COVID-19) patients, a hyperinflammatory mechanism leading to hypercytokinemia and hyperferritinemia has been demonstrated. A similar dysfunction in CTLs and NK cells, persistent immune system stimulation with increased cytokines production, and severe end-organ damage have been reported. Therefore, a significant overlap is present between the clinical and laboratory features seen in COVID-19 and sHLH. However, SARS-CoV-2, similar to other viruses, can trigger sHLH. Hence, a diagnostic approach is needed in severe COVID-19 patients presenting with multiorgan failure, in whom sHLH should be considered.
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Affiliation(s)
- Mahdi M Fadlallah
- Department of Laboratory Medicine, Faculty of Medical Sciences, Lebanese University, Beirut, LBN
| | - Sarah M Salman
- Department of Laboratory Medicine, Al-Zahraa Hospital University Medical Center, Beirut, LBN
- Department of Laboratory Medicine, Faculty of Medical Sciences, Lebanese University, Beirut, LBN
| | | | - Hassan Rahal
- Department of Infectious Diseases, Bahman Hospital, Beirut, LBN
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33
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Jeyakanthan T, Ladel L, Khandpur B, Tan WY, Nasir SA. Coronavirus Does It Again: Post-COVID-19 Hemophagocytic Lymphohistiocytosis (HLH). Cureus 2023; 15:e35275. [PMID: 36968874 PMCID: PMC10036136 DOI: 10.7759/cureus.35275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/20/2023] [Indexed: 02/23/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hematological disorder that results from an uncontrolled activation of the immune system, which can then lead to multisystem organ failure. Given the nonspecific nature of this illness, it can go undetected for too long, thereby causing permanent damage to organ systems. In adults, HLH has been associated with a number of infectious etiologies, particularly viral infections. Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a global pandemic and has been associated with acute respiratory distress syndrome (ARDS). Among its other manifestations, COVID-19 has also been linked to HLH. In this report, we describe a case of a male patient who presented with multisystem organ failure and was found to have HLH. Since no clear etiology for his HLH could be elicited, it was determined to be a result of his recent COVID-19 infection.
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34
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Bazzi T, Benjamin M, Atal N, Mahmood R. Hemophagocytic Lymphohistiocytosis in a Patient With Human Immunodeficiency Virus. Cureus 2023; 15:e35139. [PMID: 36949985 PMCID: PMC10026869 DOI: 10.7759/cureus.35139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 02/20/2023] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive disorder that is often underdiagnosed due to its similarities in other forms of shock, most notably septic shock. In this case report, we discuss a patient who has a history of HIV presenting with altered mental status and cytopenias, ultimately going into shock and passing away. We initially thought we would be dealing with a case of septic shock, but a diagnostic workup during his hospital case lead to a diagnosis of hemophagocytic lymphohistiocytosis. This case illustrates how patients with HLH present very similar to septic shock and how to manage patients with this very aggressive disease.
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Affiliation(s)
- Talal Bazzi
- Internal Medicine, Ascension St John Hospital, Detroit, USA
| | - Mark Benjamin
- Internal Medicine, Ascension St John Hospital, Detroit, USA
| | - Nanaki Atal
- Internal Medicine, Ascension St John Hospital, Detroit, USA
| | - Rabia Mahmood
- Internal Medicine, Ascension St John Hospital, Detroit, USA
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35
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Ardern-Jones MR, Phan HTT, Borca F, Stammers M, Batchelor J, Reading IC, Fletcher SV, Smith T, Duncombe AS. A hyperinflammation clinical risk tool, HI5-NEWS2, stratifies hospitalised COVID-19 patients to associate risk of death and effect of early dexamethasone in an observational cohort. PLoS One 2023; 18:e0280079. [PMID: 36649371 PMCID: PMC9844906 DOI: 10.1371/journal.pone.0280079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 12/20/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19. METHODS Blood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status. FINDINGS Of 1265 patients, high risk of HI (high HI5-NEWS2) (n = 367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, p<0.001) compared to the low risk group (n = 455, 36.0%). An intermediate risk group (n = 443, 35.0%) also showed significantly higher mortality than the low risk group (17.6% vs 7.8%), aHR 2.2, p = 0.005). Early dexamethasone treatment conferred a 50.0% reduction in mortality in the high risk group (36.0% to 18.0%, aHR 0.56, p = 0.007). The intermediate risk group showed a trend to reduction in mortality (17.8% to 10.3%, aHR 0.82, p = 0.46) which was not observed in the low risk group (7.8% to 9.2%, aHR 1.4, p = 0.31). INTERPRETATION Higher HI5-NEWS2 scores measured at COVID-19 diagnosis, strongly associate with increased mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention in all cases.
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Affiliation(s)
- Michael R Ardern-Jones
- Clinical Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom.,Division of Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom
| | - Hang T T Phan
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical Informatics Research Unit Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Florina Borca
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical Informatics Research Unit Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Matt Stammers
- Division of Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.,Clinical Informatics Research Unit Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - James Batchelor
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Clinical Informatics Research Unit Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Isabel C Reading
- Department of Primary Care, Population Sciences and Medical Education, University of Southampton, Southampton, United Kingdom
| | - Sophie V Fletcher
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.,Department of Respiratory Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Trevor Smith
- Division of Medicine, University Hospitals Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom
| | - Andrew S Duncombe
- Department of Haematology, University Hospitals Southampton NHS Foundation Trust, Southampton, United Kingdom
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36
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Chen Q, Zhang Q, Wang X. Connective tissue disease with macrophage activation syndrome: A case report. Medicine (Baltimore) 2022; 101:e32426. [PMID: 36595872 PMCID: PMC9794242 DOI: 10.1097/md.0000000000032426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Macrophage activation syndrome (MAS), or secondary hemophagocytic lymphocytosis (sHLH), is a rare systemic inflammatory response syndrome that is fatal. Adult patients lack clear criteria for diagnosis and treatment, primarily derived from guidelines and protocols for treating family hemophagocytic lymphocytosis and systemic juvenile idiopathic arthritis (sJIA)-related MAS in children or from retrospective case reports. As a subtype of sHLH, MAS has a clinical presentation like sHLH, but treatment varies. Herein, we report the case of a 40-year-old female with MAS caused by a connective tissue disease. PATIENT CONCERNS The patient presented to the Rheumatology and Immunology Clinic with recurrent fever and rash, and MAS was confirmed after a series of examinations. The patient had no significant effect after treatment with JAK inhibitors, but after the use of the IL-6 inhibitor tocilizumab, the fever and rash were significantly reduced, and laboratory indicators returned to normal levels. DIAGNOSIS Considering the patient's condition and laboratory test results, we judged that the patient had connective tissue disease with MAS. INTERVENTIONS We gave sequential treatment of tocilizumab. OUTCOMES ALL indicators are mostly back to normal when the patient was monitored at the outpatient clinic. LESSONS MAS/HLH lacks clear criteria for diagnosis or treatment in adult patients and is extremely difficult to distinguish from bacterial sepsis or other systemic inflammatory response syndromes. Consequently, early diagnosis and treatment are indispensable for enhancing patient survival.
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Affiliation(s)
- Qu Chen
- Department of Rheumatology, Binzhou Medical University Hospital, Binzhou, China
| | - Qiushuang Zhang
- Department of Rheumatology, Binzhou Medical University Hospital, Binzhou, China
| | - Xuebin Wang
- Department of Rheumatology, Binzhou Medical University Hospital, Binzhou, China
- *Correspondence: Xuebin Wang, Department of Rheumatology, Binzhou Medical University Hospital, Binzhou, Shandong Province, China (e-mail: )
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"A Dangerous Black Box:" Idiopathic Hemophagocytic Lymphohistiocytosis in Adult Patients-A Case Report and Review of the Literature. Case Rep Hematol 2022; 2022:5867129. [PMID: 36510501 PMCID: PMC9741541 DOI: 10.1155/2022/5867129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 12/05/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a rare potentially life-threatening condition characterized by aberrant inflammation that can be related to genetic or sporadic forms. In both forms, triggering factors may be involved. Early detection of the underlying cause is crucial for therapeutic decision, while early intervention might be associated with better outcomes. The largest descriptions in the literature on HLH refer to pediatric cases. Adolescents and adults may also be affected, but there is scarce evidence regarding their diagnosis and management. We describe here the case of a 68-year-old Swiss woman with HLH, in whom an extensive search for underlying causes was performed, but neither trigger nor pathogenic variant was found. An early intervention first with dexamethasone and later with cyclosporine was performed. The patient showed a favorable response and did not require further hospitalization; however, one year after diagnosis, it was not possible to suspend cyclosporine due to recurrence of laboratory inflammation signs by drug tapering. The occurrence of HLH idiopathic forms represents a challenge; failure to identify the underlying triggering cause generates uncertainty, endless diagnostic investigations, and consequently additional delays in the treatment. This manuscript addresses the difficulties on this issue.
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Schippers EE, Creemers SG, Paltansing S, van Zaanen HCT, Heijneman JAM. Fatal Hemophagocytic Lymphohistiocytosis in a Patient with Miliary Tuberculosis: a Case Report. SN COMPREHENSIVE CLINICAL MEDICINE 2022; 4:152. [PMID: 35856014 PMCID: PMC9281255 DOI: 10.1007/s42399-022-01232-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 06/30/2022] [Indexed: 11/24/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome induced by cytotoxic T-cells. Mostly, HLH is secondary to infections, malignancies, or autoimmune disorders. HLH triggered by miliary tuberculosis is rare and mortality rates are high. We report a case of a 58-year-old, Caucasian patient admitted to the ICU with respiratory failure. After extensive tests, the diagnosis of HLH was made. Despite aggressive treatment with antibiotics, etoposide, anakinra, and tocilizumab, our patient succumbed to the illness after 18 days in the ICU. Postmortem, a diagnosis of miliary tuberculosis was made, despite negative PCR and culture of mycobacteria during clinical course. Our case demonstrates the challenges of early diagnosis of HLH and the importance of considering miliary tuberculosis as a possible underlying trigger.
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Affiliation(s)
- Eva E. Schippers
- Department of Intensive Care, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Sara G. Creemers
- Department of Internal Medicine and Hematology, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Sunita Paltansing
- Department of Medical Microbiology and Infection Control, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Henk C. T. van Zaanen
- Department of Internal Medicine and Hematology, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
| | - Joyce A. M. Heijneman
- Department of Intensive Care, Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands
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39
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Tagawa M, Aoki M, Uemura A, Yanagawa M, Mineshige T, Watanabe K, Kobayashi Y. Hemophagocytic syndrome in a cat with immune‐mediated hemolytic anemia. Vet Clin Pathol 2022. [DOI: 10.1111/vcp.13176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/06/2022] [Accepted: 06/08/2022] [Indexed: 11/19/2022]
Affiliation(s)
- Michihito Tagawa
- Veterinary Medical Center Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
- Department of Veterinary Associated Science Okayama University of Science Imabari Japan
| | - Minori Aoki
- Veterinary Medical Center Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
| | - Akiko Uemura
- Department of Veterinary Medicine Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
| | - Masashi Yanagawa
- Department of Veterinary Medicine Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
| | - Takayuki Mineshige
- Research Center for Global Agromedicine Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
| | - Ken‐ichi Watanabe
- Research Center for Global Agromedicine Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
| | - Yoshiyasu Kobayashi
- Research Center for Global Agromedicine Obihiro University of Agriculture and Veterinary Medicine Obihiro Japan
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40
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Summerlin J, Wells DA, Anderson MK, Halford Z. A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis. Ann Pharmacother 2022:10600280221134719. [DOI: 10.1177/10600280221134719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Objective: To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). Data Sources: A literature search was conducted using the search terms “hemophagocytic lymphohistiocytosis,” “hemophagocytic syndrome,” “macrophage activation syndrome,” and “treatment” on Ovid and PubMed from January 1, 2017, through September 28, 2022. Study Selection and Data Extraction: Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH. Data Synthesis: Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH. Relevance to Patient Care and Clinical Practice: The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician’s armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab. Conclusions: Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.
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Affiliation(s)
- Jenna Summerlin
- Division of Pharmacy Practice, The University of Texas at Austin College of Pharmacy, Austin, TX, USA
| | - Drew A. Wells
- Internal Medicine, Department of Pharmacy, Methodist University Hospital, Memphis, TN, USA
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41
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Roccatello D, Sciascia S, Barreca A, Naretto C, Alpa M, Quattrocchio G, Radin M, Fenoglio R. Renal involvement as a unique manifestation of hemophagocytic syndrome. Front Med (Lausanne) 2022; 9:796121. [PMID: 36275824 PMCID: PMC9579315 DOI: 10.3389/fmed.2022.796121] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 08/25/2022] [Indexed: 11/21/2022] Open
Abstract
Renal-limited hemophagocytic syndrome (HPS) is a rare clinical setting characterized by abnormal activation of the immune system. Fever associated with pancytopenia, hepatosplenomegaly with liver dysfunction, and hypofibrinogenemia are usually observed in HPS. From a histological level, the presence of non-malignant macrophages infiltrating bone marrow and organs represents the hallmark of this condition. Non-malignant macrophages are associated with phagocytizing activities involving other blood cells. While primary HPS is usually associated with inherited dysregulation of the immune system, secondary HPS usually occurs in the context of infection or is linked to a neoplastic process. Clinical presentation varies and can potentially lead to life-threatening settings. While renal involvement has frequently been reported, however, detailed descriptions of the kidney manifestations of HPS are lacking. More critically, the diagnosis of HPS is rarely supported by renal biopsy specimens. We report four rare cases of biopsy-proven renal-limited HPS in patients presenting with acute kidney injury (AKI). The available evidence on this topic is critically discussed in light of the possible emergence of an autonomous entity characterized by an isolated kidney involvement.
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Affiliation(s)
- Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy,*Correspondence: Dario Roccatello
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | | | - Carla Naretto
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Mirella Alpa
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Giacomo Quattrocchio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Massimo Radin
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
| | - Roberta Fenoglio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-net, ERN-Reconnect and RITA-ERN Member) With Nephrology and Dialysis Unit, Center of Immuno-Rheumatology and Rare Diseases (CMID), Coordinating Center of the Interregional Network for Rare Diseases of Piedmont and Aosta Valley (North-West Italy), Department of Clinical and Biological Sciences, San Giovanni Bosco Hub Hospital, University of Turin, Turin, Italy
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42
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Bris PN, Gauchez P, Devillier R, Galicier L, Collignon A, Piana G, Poizat F, Faucher M, Hospital MA, Vey N, Gonzalez F, Servan L, Chow-Chine L, Sannini A, Mokart D, Saillard C, Bisbal M. Hepatic haemophagocytosis in haematology patients with hepatic dysfunction: prognostic impact and contribution of liver biopsy combined with the haemophagocytic syndrome diagnostic score (HScore). Br J Haematol 2022; 199:106-116. [PMID: 35968907 DOI: 10.1111/bjh.18382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/05/2022] [Accepted: 07/12/2022] [Indexed: 01/07/2023]
Abstract
Hepatic dysfunction (HD) is common in patients with haematological malignancies. Hepatic haemophagocytosis (HH) was detected in >50% of liver biopsies taken when HD remained unresolved after standard examination. We aimed to explore the contribution of liver biopsy in patients with both haematological malignancies and HD, describe the population of patients with HH, assess the prognostic impact of HH, and investigate haemophagocytic syndrome diagnostic score (HScore) utility in patients with HH. Between 2016 and 2019, 116 consecutive liver biopsies (76 transjugular, 40 percutaneous) were taken in 110 patients with haematological malignancy and HD (hyperbilirubinaemia, elevated transaminases, and/or cholestasis) and without a clear diagnosis. Liver biopsies were safe and diagnostically efficient. Predominant diagnoses included: HH (56%), graft-versus-host disease (55%), associated infections (24%), sinusoidal obstruction syndrome (15%), and tumoral infiltration (8%). Of patients, 35% were critically ill and 74% were allogeneic haematopoietic stem cell transplantation recipients, while 1-year overall survival (OS) was 35% with HH versus 58% without HH (p = 0.026). The 1-year OS was 24% with a HScore of ≥169 versus 50% with a HScore of <169 (p = 0.019). Liver biopsies are feasible in and contribute significantly to haematology patients with HD. HH occurred frequently and was associated with a poor prognosis. Combined with liver biopsy, the HScore may be helpful in refining haemophagocytic syndrome diagnosis.
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Affiliation(s)
- Pierre-Nicolas Bris
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Philippe Gauchez
- Pathology Department, Centre Hospitalier Universitaire de la Réunion, Saint Pierre, France
| | | | | | - Aude Collignon
- Hematology Department, Institut Paoli Calmettes, Marseille, France
| | - Gilles Piana
- Imagery Department, Institut Paoli Calmettes, Marseille, France
| | - Flora Poizat
- Pathology Department, Institut Paoli Calmettes, Marseille, France
| | - Marion Faucher
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | | | - Norbert Vey
- Hematology Department, Institut Paoli Calmettes, Marseille, France.,Aix-Marseille University, Marseille, France
| | - Frederic Gonzalez
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Luca Servan
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Laurent Chow-Chine
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Antoine Sannini
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Djamel Mokart
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
| | - Colombe Saillard
- Hematology Department, Institut Paoli Calmettes, Marseille, France
| | - Magali Bisbal
- Anaesthesia and Critical Care Department, Intensive Care Unit, Institut Paoli Calmettes, Marseille, France
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43
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Caldirola MS, Raccio AG, Giovanni DD, Gaillard MI, Preciado MV. Pediatric inborn errors of immunity causing hemophagocytic lymphohistiocytosis: Case report and review of the literature. J Leukoc Biol 2022; 112:607-615. [PMID: 35899932 DOI: 10.1002/jlb.5mr0622-037r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/28/2022] [Indexed: 11/07/2022] Open
Abstract
Inborn errors of immunity are a group of genetic disorders caused by mutations that affect the development and/or function of several compartments of the immune system, predisposing patients to infections, autoimmunity, allergy and malignancies. In this regard, mutations that affect proteins involved in trafficking, priming, docking, or membrane fusion will impair the exocytosis of lytic granules of effector NK and cytotoxic T lymphocytes. This may predispose patients to hemophagocytic lymphohistiocytosis, a life-threatening immune disorder characterized by systemic lymphocyte and macrophage activation, and increased levels of cytokines, which lead to an uncontrolled hyperinflammation state and progressive multiorgan damage. In this review, we will describe a clinical case and recent advances in inborn errors of immunity predisposing to hemophagocytic lymphohistiocytosis. Summary sentence: Review of recent advances in inborn errors of immunity predisposing to hemophagocytic lymphohistiocytosis.
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Affiliation(s)
- María Soledad Caldirola
- Servicio Inmunología, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP- CONICET-GCBA)- Hospital de Niños "Dr. Ricardo Gutiérrez,", Buenos Aires, Argentina
| | - Andrea Gómez Raccio
- Servicio de Inmunología, Hospital de Niños "Dr. Ricardo Gutiérrez,", Buenos Aires, Argentina
| | - Daniela Di Giovanni
- Servicio de Inmunología, Hospital de Niños "Dr. Ricardo Gutiérrez,", Buenos Aires, Argentina
| | - María Isabel Gaillard
- Servicio Inmunología, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP- CONICET-GCBA)- Hospital de Niños "Dr. Ricardo Gutiérrez,", Buenos Aires, Argentina.,Sección Citometría - Laboratorio Stamboulian, Buenos Aires, Argentina
| | - María Victoria Preciado
- Laboratorio de Biología Molecular, División Patología, Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas (IMIPP), CONICET-GCBA, Hospital de Niños "Dr. Ricardo Gutiérrez,", Buenos Aires, Argentina
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44
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Steen EA, Hermiston ML, Nichols KE, Meyer LK. Digenic Inheritance: Evidence and Gaps in Hemophagocytic Lymphohistiocytosis. Front Immunol 2021; 12:777851. [PMID: 34868048 PMCID: PMC8635482 DOI: 10.3389/fimmu.2021.777851] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/19/2021] [Indexed: 12/26/2022] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disorder characterized by the inability to properly terminate an immune response. Familial HLH (FHLH) and related immune dysregulation syndromes are associated with mutations in the genes PRF1, UNC13D, STX11, STXBP2, LYST, AP3B1, and RAB27A, all of which are required for the assembly, exocytosis, and function of cytotoxic granules within CD8+ T cells and natural killer (NK) cells. Loss-of-function mutations in these genes render the cytotoxicity pathway ineffective, thereby failing to eradicate immune stimuli, such as infectious pathogens or malignant cells. The resulting persistent immune system stimulation drives hypercytokinemia, ultimately leading to severe tissue inflammation and end-organ damage. Traditionally, a diagnosis of FHLH requires the identification of biallelic loss-of-function mutations in one of these degranulation pathway genes. However, this narrow definition fails to encompass patients with other genetic mechanisms underlying degranulation pathway dysfunction. In particular, mounting clinical evidence supports a potential digenic mode of inheritance of FHLH in which single loss-of-function mutations in two different degranulation pathway genes cooperate to impair pathway activity. Here, we review the functions of the FHLH-associated genes within the degranulation pathway and summarize clinical evidence supporting a model in which cumulative defects along this mechanistic pathway may underlie HLH.
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Affiliation(s)
- Erica A Steen
- University of California, San Diego, San Diego, CA, United States
| | - Michelle L Hermiston
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
| | - Kim E Nichols
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Lauren K Meyer
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
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45
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Gómez CH, Vargas-Hernández DA, Largo J, Hernández S, Faccini-Martínez ÁA. Hemophagocytic lymphohistiocytosis and acute Chagas disease, Colombia. Travel Med Infect Dis 2021; 44:102213. [PMID: 34813938 DOI: 10.1016/j.tmaid.2021.102213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 11/29/2022]
Affiliation(s)
| | | | - Jorge Largo
- Departamento de Medicina Interna, Hospital Militar Central, Bogotá, Colombia
| | | | - Álvaro A Faccini-Martínez
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA; Asociación Colombiana de Infectología, Committee of Tropical Medicine, Zoonoses and Travel Medicine, Bogotá, Colombia.
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46
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Shen J, Wang JS, Xie JL, Nong L, Chen JN, Wang Z. Hemophagocytic lymphohistiocytosis secondary to composite lymphoma: Two case reports. World J Clin Cases 2021; 9:9159-9167. [PMID: 34786400 PMCID: PMC8567507 DOI: 10.12998/wjcc.v9.i30.9159] [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: 04/01/2021] [Revised: 05/19/2021] [Accepted: 07/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disease caused by inherited pathogenic mutations and acquired dysregulations of the immune system. Composite lymphoma is defined as two or more morphologically and immunophenotypically distinct lymphomas that occur in a single patient. Here, we report two cases of HLH secondary to composite lymphoma with mixed lineage features of T- and B-cell marker expression both in the bone marrow and lymph nodes in adult patients.
CASE SUMMARY Two patients were diagnosed with HLH based on the occurrence of fever, pancytopenia, lymphadenopathy, splenomegaly, hemophagocytosis and hyperferritinemia. Immunohistochemical staining of the axillary lymph node and bone marrow in case 1 showed typical features of combined B-cell and T-cell lymphoma. In addition, a lymph node gene study revealed rearrangement of the T-cell receptor chain and the immunoglobulin gene. Morphology and immunohistochemistry studies of a lymph node biopsy in case 2 showed typical features of T cell lymphoma, but immunophenotyping by flow cytometry analysis of bone marrow aspirate showed B cell lymphoma involvement. The patients were treated with high-dose methylprednisolone combined with etoposide to control aggressive HLH progression. The patients also received immunochemotherapy with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen immediately after diagnosis. Both patients presented with highly aggressive lymphoma, and died of severe infection or uncontrolled HLH.
CONCLUSION We present two rare cases with overwhelming hemophagocytosis along with composite T- and B-cell lymphoma, which posed a diagnostic dilemma. HLH caused by composite lymphoma was characterized by poor clinical outcomes.
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Affiliation(s)
- Jing Shen
- Department of Hematology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing 100050, China
| | - Jing-Shi Wang
- Department of Hematology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing 100050, China
| | - Jian-Lan Xie
- Department of Pathology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing 100050, China
| | - Lin Nong
- Department of Pathology, Peking University First Hospital, Beijing 100034, China
| | - Jia-Ning Chen
- Department of Clinical Laboratory, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing 100000, China
| | - Zhao Wang
- Department of Hematology, Capital Medical University Affiliated Beijing Friendship Hospital, Beijing 100050, China
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