Diagnostic pitfalls in assessment of ferritin following CAR-T-cell therapy: Understanding the hook effect.

The hook effect is a well-described but clinically underappreciated immunoassay interference, where a falsely lowered result is caused by analyte excess. We describe a situation in which ferritin immunoassay results from a 27-year-old female with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome were more than 1000 times lower at a reference laboratory than those determined in-house after dilution. This case underscores the importance for clinical care providers to be aware of the impact of the hook effect on ferritin measurements, and to promptly communicate with the laboratory when there are discrepancies between clinical symptoms and test results.

A degranulation assay using Vγ9Vδ2 T cells for the rapid diagnosis of familial hemophagocytic syndromes.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune disorder characterized by uncontrolled lymphocyte and macrophage activation and a subsequent cytokine storm. The timely initiation of immunosuppressive treatment is crucial for survival. Methods: Here, we harnessed Vγ9Vδ2 T cell degranulation to develop a novel functional assay for the diagnosis of HLH. We compared the novel assay with the conventional natural killer (NK) cell stimulation method in terms of efficiency, specificity, and reliability. Our analysis involved 213 samples from 182 individuals, including 23 samples from 12 patients with degranulation deficiency (10 individuals with UNC13D deficiency, 1 with STXBP2 deficiency, and 1 with RAB27A deficiency). Results: While both tests exhibited 100% sensitivity, the Vγ9Vδ2 T cell degranulation assay showed a superior specificity of 86.2% (n=70) compared to the NK cell degranulation assay, which achieved 78.9% specificity (n=213). The Vγ9Vδ2 T cell degranulation assay offered simpler technical requirements and reduced labor intensity, leading to decreased susceptibility to errors with faster processing times. Discussion: This efficiency stemmed from the sole requirement of dissolving (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) powder, contrasting with the intricate maintenance of K562 cells necessary for the NK cell degranulation assay. With its diminished susceptibility to errors, we anticipate that the assay will require fewer repetitions of analysis, rendering it particularly well-suited for testing infants. Conclusion: The Vγ9Vδ2 T cell degranulation assay is a user-friendly, efficient diagnostic tool for HLH. It offers greater specificity, reliability, and practicality than established methods. We believe that our present findings will facilitate the prompt, accurate diagnosis of HLH and thus enable rapid treatment and better patient outcomes.

Hyperferritinemia screening to aid identification and differentiation of patients with hyperinflammatory disorders.

High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This single-center, real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Unmasking the Culprits: A Case of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis Presenting With Mouth Ulcers and Nosebleeds.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation. It usually occurs in children, mainly during the first year of life. Primary hemophagocytic lymphohistiocytosis is more common and usually occurs in immunocompromised patients. Secondary hemophagocytic lymphohistiocytosis, on the other hand, is less common, especially in immunocompetent patients. Here, we intend to present a case of a 55-year-old male patient who had no known immune deficiency, presented with epistaxis, and was found to have Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis.

Predicting relapsed/refractory disease in childhood hemophagocytic lymphohistiocytosis based on clinical features at diagnosis: A 13-year single-institute retrospective study in Thailand.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. Relapsed/refractory disease is the main cause of death. This study aims to determine the prognostic indicators for relapsed/refractory disease in childhood HLH (R/R HLH). Infants and children under 18 years of age who were diagnosed with HLH according to HLH-2004 criteria, MAS-HLH criteria for rheumatologic diseases, or H-score undergoing treatment in Chiang Mai University hospital between 2010 and 2022 were included. Demographic data, clinical characteristics, and laboratory parameters were retrospectively reviewed. Out of 86 childhood HLH cases, 30 patients (34.9%) experienced R/R HLH. All patients with primary HLH developed R/R HLH. The most common form of secondary HLH was infection-associated hemophagocytic syndrome (IAHS), comprising 43 cases. Of these, 37.2% had relapsed or refractory disease. Univariable analysis identified several potential risk factors for R/R HLH, including younger age, severe disease status, higher HLH-2004 criteria scores, higher H-scores, overt DIC, higher pSOFA scores, and increased levels of aspartate aminotransferase, total bilirubin, and direct bilirubin. Multivariable logistic regression analysis revealed that a pSOFA score of ≥ 8 and age < 3 years were independent risk factors for R/R HLH, with adjusted odds ratios of 6.35 (95% confidence interval [CI], 1.18-34.19; P = 0.032) and 3.62 (95% CI, 1.04-12.63; P = 0.044), respectively. Children with HLH who have a pSOFA score of ≥ 8, or are younger than 3 years, are at a higher risk of relapsed or refractory disease. Further evaluation of management strategies in this context is warranted.

Clinical Presentations, Diagnosis, and Genetic Features of Hemophagocytic Lymphohistiocytosis: A Single Institutional Experience With the Saudi Population.

Background Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, potentially fatal condition caused by high immune activation. The present study aimed to identify the clinical manifestations, geographic distribution, and associated pathogenic genetic mutations of HLH in Saudi Arabia. Method A retrospective cross-sectional study was conducted at King Fahad Medical City (KFMC), with a total of 59 patients diagnosed with HLH in the period between 2006 and 2018. All genetic results and clinical and biochemical data were retrieved and statistically analyzed using IBM SPSS Statistics for Windows, Version 25 (Released 2017; IBM Corp., Armonk, New York, United States). Results The results revealed that 48 patients (81.4%) had 15 pathogenic mutations of primary HLH whereas 8 (13.6%) patients had no genetic mutation. The most common variant mutation identified was c.1430C>T of the STXBP2 gene (42.4% of total patients), followed by c.1122G>A of the PRF1 gene (10.2% of patients), which demonstrated a distinctive geographic and tribal association. Patients with RAB27A mutation tend to present at an older age than the others with a median age of presentation of 5.5 months vs 2 months for patients with PRF1 mutations. No significant differences in clinical features were observed among the various groups. Conclusion This study highlights the incidence of genetic mutations among the Saudi population with HLH. The STXBP2 is the most common mutation followed by PRF1 mutations, many mutation variants are associated with a distinctive tribal and geographic association.

Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

Comprehensive mapping of immune perturbations associated with secondary hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome characterized by immune disorders. It is imperative to elucidate the immunophenotypic panorama and the interactions among these cells in patients. Human peripheral blood mononuclear cells were collected from healthy donors and sHLH patients and tested using multicolor flow cytometry. We used FlowSOM to explore and visualize the immunophenotypic characteristics of sHLH. By demonstrating the phenotypes of immune cells, we discovered that sHLH patients had significantly higher levels of CD56+ monocytes, higher levels of myeloid-derived suppressor cells, low-density neutrophil-to-T cell ratio, and higher heterogeneous T cell activation than healthy donors. However, natural killer cell cytotoxicity and function were impaired. We then assessed the correlations among 30 immune cell types and evaluated metabolic analysis. Our findings demonstrated polymorphonuclear myeloid-derived suppressor cells, CD56+ monocytes, and neutrophil-to-T cell ratio were elevated abnormally in sHLH patients, which may indicate an association with immune overactivation and inflammatory response. We are expected to confirm that they are involved in the occurrence of the disease through further in-depth research.

Salvage treatment of ruxolitinib for refractory adenovirus-associated hemophagocytic syndrome post-haploidentical allogeneic stem cell transplantation: a case report.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare complication following hematopoietic stem cell transplantation (HSCT). Currently, there is a lack of consensus recommendations for the treatment of post-transplant HLH. This case report emphasizes the successful utilization of ruxolitinib as a salvage therapy for HLH post-HSCT. The aim is to provide valuable insights into the optimal management of this rare and complex complication. Case Description: We present a case study of an 11-year-old male patient diagnosed with severe aplastic anemia who received a haploidentical HSCT. On the 86th day post-transplantation, the patient developed recurrent fever, hepatomegaly, hypertriglyceridemia, severe pancytopenia, and elevated levels of inflammatory factors and ferritin. Hemophagocytosis was observed in the bone marrow, and subsequent DNA next-generation sequencing identified adenovirus type C infection, leading to a diagnosis of adenovirus-associated HLH. After unsuccessful treatment attempts with cidofovir, dexamethasone, immunoglobulin, plasmapheresis, and etoposide, ruxolitinib was administered. Remarkably, the patient's clinical symptoms rapidly improved, and his test results gradually normalized with ruxolitinib therapy. The adenovirus viral load became undetectable by the 180th day. With continuous remission, ruxolitinib was discontinued on the 137th day post-transplantation, and a 15-month follow-up examination showed no relapse. Conclusions: We present a case of adenovirus-related secondary HLH (sHLH) post-HSCT, which was effectively treated with ruxolitinib. Our case highlights the potential of ruxolitinib as a therapeutic option for patients with viral infections and sHLH. Nonetheless, the safety and efficacy of this innovative treatment should be evaluated in forthcoming large-scale clinical trials.

Managing adult-onset Still's disease in pregnancy: A case report.

BACKGROUND: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder characterized by fever, arthritis, skin rash, and systemic symptoms. The etiology of AOSD is unknown; however, it is thought to be related to immune dysregulation. Although a rare disease, AOSD can significantly impact reproductive health, particularly during pregnancy. This case study assesses the implications of pregnancy in a patient with AOSD, as well as the potential for heredity of the disease. Neonatal hemophagocytic lympho-histiocytosis (HLH) is a rare and life-threatening disorder characterized by hyperinflammation and uncontrolled activation of immune cells, leading to multiple organ dysfunction. This case report aimed to introduce neonatal HLH from a mother with AOSD. CASE SUMMARY: This case study presents a 29-year-old female with AOSD who became pregnant and gave birth to a premature infant who was diagnosed with neonatal HLH. AOSD can significantly impact pregnancy and childbirth, as it may become more severe during pregnancy, with an increased risk of fetal loss and preterm birth. The management of AOSD during pregnancy involves the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, as well as immunosuppressive agents in severe cases. However, the use of immunosuppressive agents during pregnancy may be associated with potential risks to the fetus. The hereditary implications of AOSD are unclear; however, available evidence suggests that genetic factors may play a role in the disease development. CONCLUSION: AOSD can have significant implications for pregnancy and childbirth, including an increased risk of fetal loss and preterm birth. Neonatal HLH, a complication of AOSD in pregnancy, requires prompt diagnosis and management. Women with AOSD who are considering pregnancy should discuss their options with their healthcare provider and develop a management plan that addresses the potential risks to both mother and fetus.

Overcoming Diagnostic Challenges: A Rare Presentation of Primary Hemophagocytic Lymphohistiocytosis (HLH) in a Young Female and the Importance of Timely Recognition.

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening hematological disorder characterized by the dysregulation of the immune system and a hyperinflammatory response. Prompt treatment is crucial to prevent fatality. Although primarily affecting infants, HLH can also occur in children and adults. It is classified as primary and secondary, with primary HLH being genetic and predominantly affecting children. Secondary HLH is triggered by infections, malignancy, metabolic disorders, and rheumatological conditions. Diagnosis is based on the HLH-2004 criteria, considering clinical and laboratory parameters. Early diagnosis and treatment improve prognosis. Treatment follows the HLH-94 and HLH-2004 protocol and consists of eight weeks of induction therapy with cyclosporine, corticosteroids, and etoposide. This case describes a 26-year-old female diagnosed with HLH and successfully treated according to the protocol. The patient exhibited improvement and was discharged, demonstrating the importance of early diagnosis and appropriate management in adult HLH cases.

Haploidentical Hematopoietic Stem Cell Transplantation for Paediatric Patients with X-linked Lymphoproliferative Syndrome.

The aim of this study was to investigate the prognostic factors of haploid hematopoietic stem cell transplantation in the treatment of X-linked lymphoproliferative syndrome. Seven children with X-linked lymphoproliferative syndrome diagnosed by XIAP gene analysis were enrolled. The conditioning regimens were tolerated in all seven patients, and the median time of neutrophil engraftment was 10 days (8-13 days), and that of platelet engraftment was 21 days (14-24 days). STR-PCR analysis on the peripheral blood cells showed complete donor origins. Four cases developed Grade I acute graft versus host disease (aGVHD), one developed Grade III aGVHD (intestinal tract), and two cases had limited chronic GVHD. Four cases had cytomegalovirus (CMV) reactivation, and two cases had Epstein-Barr virus (EBV) reactivation. One case was diagnosed as pneumocystosis, and thrombotic microangiopathy (TMA) occurred in three cases. During the follow-up period (median time of 42 months), one patient died of TMA and six patients survived. Statistical analysis showed that the status of disease remission and the positive result of virus in blood before transplantation were independent prognostic factors. Haplo-HSCT might be a curative option for children with refractory X-linked lymphoproliferative syndrome. Low-intensity conditioning regimens may reduce transplant-related mortality and improve overall survival.

Macrophage Activation Syndrome Presents as Initial Manifestation of Lupus in an Adult Female.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the immune system erroneously attacking healthy tissues and organs. SLE has a wide variety of clinical presentations. The signs and symptoms of SLE are very well-known, though rare presentations could occur that require early clinical attention. Macrophage activation syndrome (MAS) is a severe and life-threatening condition in which the immune system becomes overactive, leading to the excessive stimulation and proliferation of immune cells. MAS can occur as a primary immune disorder, which is not very common. It can also happen secondary to a wide variety of pathological conditions, which include infections, malignancies, autoimmune, and rheumatologic disorders. In rare cases, SLE can present with overlapping features of MAS, further complicating the clinical picture, and may require specialized management. Early recognition and intervention of this overlap are essential for improving outcomes, as delayed diagnosis and treatment can lead to significant morbidity and mortality. Here, we present a case of a young adult female who was diagnosed with SLE with the initial presentation of MAS in the form of fever, splenomegaly, cytopenia, and hemophagocytosis.

NLRC5 senses NAD+ depletion, forming a PANoptosome and driving PANoptosis and inflammation.

NLRs constitute a large, highly conserved family of cytosolic pattern recognition receptors that are central to health and disease, making them key therapeutic targets. NLRC5 is an enigmatic NLR with mutations associated with inflammatory and infectious diseases, but little is known about its function as an innate immune sensor and cell death regulator. Therefore, we screened for NLRC5's role in response to infections, PAMPs, DAMPs, and cytokines. We identified that NLRC5 acts as an innate immune sensor to drive inflammatory cell death, PANoptosis, in response to specific ligands, including PAMP/heme and heme/cytokine combinations. NLRC5 interacted with NLRP12 and PANoptosome components to form a cell death complex, suggesting an NLR network forms similar to those in plants. Mechanistically, TLR signaling and NAD+ levels regulated NLRC5 expression and ROS production to control cell death. Furthermore, NLRC5-deficient mice were protected in hemolytic and inflammatory models, suggesting that NLRC5 could be a potential therapeutic target.

Clinicopathological Characteristics and Outcome of Cytophagic Histiocytic Panniculitis: A Single-Center, Retrospective Study.

Background: Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, mimicking hemophagocytic lymphohistiocytosis (HLH) and subcutaneous panniculitis-like T-cell lymphoma (SPTCL). Purpose: To establish the clinicopathological features and response to treatment of CHP and evaluate the prognosis of patients and guide therapy based on the current state of knowledge. Material and Methods: Clinical, laboratory, histopathological, and outcome data of 12 patients with CHP were retrospectively collected between 2009 and 2022. Results: All the patients presented with plaques or nodules, mostly located in the lower extremities (11/12). Fewer cases involved systemic symptoms (9/12) and laboratory abnormalities (6/12), and none were positive for serum Epstein-Barr virus (EBV)-DNA. Histopathological examination revealed mixed septal and lobular inflammatory infiltration of histiocytes and lymphocytes. Large or atypical lymphocytes were rarely present (2/12). In some patients, varying proportions of plasma cells, neutrophils, and eosinophils were observed. The extent of histocytophagy was mild (9/12), moderate (2/12), and severe (1/12). HLH was not observed in any of our cases, none of which were fatal. Conclusion: The uniqueness of our study lies in the presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders (CTD) and streptococcal infections. Our study reveals that EBV-negative CHP tends to a better prognosis than previously research, filling the gap in the much-needed details of CHP in the Chinese population. Moreover, CHP may present as a reactive process in combined primary diseases; further studies are required to validate these findings.

Cytophagic histiocytic panniculitis (CHP) is a rare panniculitis associated with systemic features characterized by the infiltration of subcutaneous adipose tissue by benign-appearing T lymphocytes and phagocytic histiocytes, also may be present in hemophagocytic lymphohistiocytosis and subcutaneous panniculitis-like T-cell lymphoma. The presence of neutrophil-rich dermal and subcutaneous infiltrates, associated with connective tissue disorders and streptococcal infections. In addition, EBV-negative CHP has a better prognosis than previously thought and provides knowledge of its prognosis in the Chinese population. With changes in the disease pedigree supported by the development of medical technology, CHP may present as a reactive process of a combined primary disease.

Mechanisms and management of CAR T toxicity.

Chimeric antigen receptor (CAR) T cell therapies have dramatically improved treatment outcomes for patients with relapsed or refractory B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. Despite unprecedented efficacy, treatment with CAR T cell therapies can cause a multitude of adverse effects which require monitoring and management at specialized centers and contribute to morbidity and non-relapse mortality. Such toxicities include cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, neurotoxicity distinct from ICANS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, and immune effector cell-associated hematotoxicity that can lead to prolonged cytopenias and infectious complications. This review will discuss the current understanding of the underlying pathophysiologic mechanisms and provide guidelines for the grading and management of such toxicities.

Marked hyperferritinemia in critically ill cancer patients.

OBJECTIVES: To investigate characteristics and outcomes of critically ill cancer patients with marked hyperferritinemia. METHODS: A single-center retrospective analysis comprising cancer patients with a ferritin level >10.000 µg/L treated in the intensive care unit (ICU) between 2012 and 2022 was conducted. RESULTS: A total of 117 patients were included in the analysis. The median age was 59 years (range: 15-86 years). Females accounted for 48% of cases. 90% of patients had a hematologic malignancy. The median maximum ferritin level was 27.349 µg/L (range: 10.300-426.073 µg/L). The diagnostic criteria of septic shock were fulfilled in 51% of cases; 31% of patients had hemophagocytic lymphohistiocytosis (HLH) according to the HLH-2004 criteria. Mechanical ventilation, renal replacement therapy and the use of vasopressors were necessary in 59%, 35% and 70% of cases, respectively. The ICU, hospital, 90-day and 1-year survival rates were 33.3%, 23.1%, 23.7% and 11.7%. Patients with septic shock had a worse survival than those without septic shock (p = .001); the survival of patients who fulfilled the HLH-2004 criteria did not differ from those who did not (p = .88). CONCLUSION: Critically ill cancer patients with marked hyperferritinemia have poor outcomes. The present data may help to make informed decisions for this patient group.

Pathogenesis of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Case Report and Review of the Literature.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.