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The immunopathogenesis of dengue severity remains an enigma. There is a growing body of evidence pointing towards a transient hyperinflammatory hypercytokinemic state responsible for the development of severe dengue including dengue hemorrhagic fever that coincides with the onset of thrombocytopenia, capillary leak, multiorgan dysfunction and hyperferritinemia. There are several reports of dengue associated hemophagocytic lymphohistiocytosis (HLH). However, the cytokine storm in dengue as well as in other infections may not conform to the classic HLH 2004 diagnostic criteria. Following the recent COVID-19 pandemic, there has been a paradigm shift in the understanding of infection-associated cytokine storms. There is a need to explore timely short-course immunotherapy for the management of selected patients with dengue spiraling into the critical phase.

Rationale: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne zoonotic disease characterized by a high fatality rate of 12% to 15%. Despite hematologic abnormalities being frequently reported in SFTS patients, detailed characterization of peripheral blood cells, especially in severe cases, is scarce. This case report aims to fill this gap by describing the unique morphological features of blood cells in a patient with a severe outcome., Patient Concerns: A male patient presented with severe symptoms of SFTS, including high fever and thrombocytopenia, and was subsequently infected with a highly virulent strain of the SFTS virus., Diagnoses: The patient was diagnosed with virus-associated hemophagocytic syndrome related to SFTS based on clinical presentation and laboratory findings., Interventions: The interventions included comprehensive supportive care and treatment aimed at managing the severe symptoms and complications associated with SFTS., Outcomes: Despite the interventions, the patient experienced significant morphological changes in white blood cells and ultimately succumbed to the illness., Lessons: The detailed description of abnormal cell morphology in this case provides valuable insights into the pathophysiology of SFTS. Recognizing these morphological abnormalities can aid in early detection and may have implications for assessing disease severity and guiding treatment strategies., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Haemophagocytic lymphohistiocytosis (HLH) that occurs concomitantly with leukaemia can be initially missed due to overlapping clinical features. In a series of three cases, Tanabe and colleagues illustrate the need for prompt recognition of HLH and institution of HLH-directed therapy to prevent hyperinflammation-mediated multi-organ damage and death. Commentary on: Tanabe et al. Paediatric acute lymphoblastic leukaemia-associated haemophagocytic lymphohistiocytosis develops during prednisolone prephase. Br J Haematol 2024; 205:2031-2035., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

The characteristic expansion of T CD38 high /HLA-DR + CD8 + lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38 high /HLA-DR + CD8 + frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38 high /HLA-DR + CD8 + frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0-49.0%) were compared with those who presented febrile conditions other-than-HLH (28 patients; median: 13.0%, IQR: 3.9-28.7%; p = 0.24). HLH and non-HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2-72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7-24.3%; p = 0.0035). CD38 high /HLA-DR + CD8 + percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen-specific expansion in Epstein-Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38 high /HLA-DR + CD8 + frequencies do not appear as an HLH-specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Adult-onset Still's disease (AOSD) and secondary hemophagocytic lymphohistiocytosis (sHLH) are both hyperferritinemic cytokine storm syndromes that can be difficult to distinguish from each other in hospitalized patients. The objective of this study was to compare the inflammatory markers ferritin, D-dimer, C-reactive protein (CRP), and soluble CD25 (sCD25) in patients with AOSD and sHLH. These four markers were chosen as they are widely available and represent different aspects of inflammatory diseases: macrophage activation (ferritin); endothelialopathy (D-dimer); interleukin-1/interleukin-6/tumour necrosis factor elevation (CRP) and T cell activation (sCD25)., Methods: This was a single-center retrospective study. Patients diagnosed by the Hematology service at Vancouver General Hospital for AOSD or sHLH from 2009 to 2023 were included., Results: There were 16 AOSD and 44 sHLH patients identified. Ferritin was lower in AOSD than HLH (median 11 360 μg/L vs. 29 020 μg/L, p = .01) while D-dimer was not significantly different (median 5310 mg/L FEU vs. 7000 mg/L FEU, p = .3). CRP was higher (median 168 mg/L vs. 71 mg/L, p <.01) and sCD25 was lower (median 2220 vs. 7280 U/mL, p = .004) in AOSD compared to HLH. The combined ROC curve using CRP >130 mg/L and sCD25< 3900 U/mL to distinguish AOSD from HLH had an area under the curve (AUC) of 0.94 (95% confidence interval 0.93-0.97) with sensitivity 91% and specificity 93%., Conclusions: These findings suggest that simple, widely available laboratory tests such as CRP and sCD25 can help clinicians distinguish AOSD from HLH in acutely ill adults with extreme hyperferritinemia. Larger studies examining a wider range of clinically available inflammatory biomarkers in a more diverse set of cytokine storm syndromes are warranted., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Pure erythroid leukemia (AML-M6) is a rare variant of acute myeloid leukemia (AML) with predominant erythroid lineage proliferation. The incidence of AIDS defining cancers including Kaposi sarcoma and non-Hodgkins lymphoma are on declining trends due to effective use of HAART (Highly Active Antiretroviral Therapy). Correspondingly, there have been increasing cases of leukemia in persons living with HIV. Our case is a 43 years old male living with HIV who was admitted with high grade fever and mucosal bleeds. On examination, he had periorbital swelling and ecchymosis with hepatosplenomegaly. The laboratory investigations revealed bicytopenia with high ferritin, low fibrinogen and hypertriglyceridemia. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) with H score of 222 was made. Bone marrow examination revealed hypercellular marrow with more than 80% cells of erythroid lineage with 47% proerythroblasts. Suggesting pure erythroid leukemia (AML-M6). This diagnosis with secondary HLH carries a very poor prognosis in persons living with HIV., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation that results in an uncontrolled hyperinflammatory state. HLH is classified into two main categories: primary (familial) HLH and secondary (acquired) HLH. Secondary HLH can result from various underlying, including infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS) associated with rheumatologic disorders, among others. Epstein-Barr virus (EBV) often causes IAHS, but central nervous system (CNS) involvement is rare among systemic lupus erythematosus (SLE) patients. We report a case of EBV encephalitis associated with HLH in a patient with childhood-onset SLE., Case Presentation: A 12-year-old girl had received a diagnosis of SLE 2 months before presentation. After a period of inactive disease on treatment, fever and seizures, with altered mental status and hallucinations, developed over several weeks. A complete blood cell count (CBC) revealed pancytopenia, accompanied by elevated levels of inflammatory markers: 86 mm/hr erythrocyte sedimentation rate, 8.9 mg/dl c-reactive protein, and 3,966 ng/mL of ferritin. The differential diagnosis included active neuropsychiatric SLE, CNS infection and neurological manifestations in secondary HLH, which could have represented either IAHS or MAS. Meropenem and acyclovir were initially administered for clinical acute encephalitis, followed by pulse methylprednisolone; however, the fever persisted, and another CBC revealed progressive cytopenia. A bone marrow study showed hypocellularity and active hemophagocytic activity, and intravenous immunoglobulin was additionally given due to the diagnosis of HLH. Cerebrospinal fluid (CSF) analysis showed 60/mm 3 white blood cells (N 55%, L 45%), 141 mg/dL glucose (0.7 blood-CSF glucose ratio), < 4 mg/dL protein; results of Gram stain and bacterial culture were negative. The viral encephalitis panel from the CSF confirmed EBV infection. Bone marrow immunohistochemistry examination revealed increasing levels of CD8 + T-cell and equivocal positive results for EBV-encoded RNA in situ hybridization; therefore, HLH potentially associated with EBV was diagnosed. After treatment with IVIg, cyclosporin A, and prednisolone, the patient's symptoms gradually improved and she was eventually able to return to school., Conclusions: Our case highlights the importance of a thorough differential diagnosis, including EBV encephalitis associated with HLH, in patients with childhood SLE, particularly in cases of clinical deterioration occurs after initial treatment., (© 2024. The Author(s).)

Background: Hemophagocytic lymphohistiocytosis (HLH) is an inherited syndrome characterized by immune dysregulation. Central nervous system (CNS)-isolated disease is a rare presentation of familial HLH. We present a case of pediatric CNS-isolated HLH with a presentation complicated by unusual hemorrhagic intraparenchymal lesions., Case Presentation: A 15-year-old male presented with ataxia and MRI findings of multiple hemorrhagic lesions in his cerebral white matter, brainstem, and cerebellum, suggestive of vasculitis. After failing to improve with steroids and plasmapheresis, and progression to acute neurologic decompensation, new brainstem hemorrhages were noted. Further workup revealed 2 PRF1 mutations, confirming a diagnosis of familial CNS-HLH. He was later found to have a platelet granule defect, explaining his atypical neuroradiologic findings. The patient received treatment per the HLH-1994 protocol and underwent stem cell transplantation. Two years post-transplant, his perforin expression is nearly normal and his neurologic deficits have significantly improved., Conclusions: This case illustrates the variability in presentation of isolated CNS-HLH. Although rare, it is important to include this diagnosis on the differential in patients with CNS hemorrhagic lesions. If initial diagnostic studies remain inconclusive or response to early treatments is poor, CNS-HLH should be considered, as delay in diagnosis and treatment significantly affects morbidity and mortality., (© 2024. The Author(s).)

BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome that can occur either in genetically predisposed individuals (primary HLH) or in particular conditions in immunocompromised patients (secondary HLH). Secondary HLH is very rare among solid organ transplant recipients, especially in lung transplant recipients, for whom its prognosis is dismal. CASE REPORT We report an exceptional case of HLH occurring unusually late following lung transplantation. At 11 years after transplantation, the patient, aged 67 years, presented with pancytopenia, fever, hyperferritinemia, and hypertriglyceridemia, along with splenomegaly. Exhaustive serological and PCR tests ruled out active infection. Bone marrow aspirates showed signs of hemophagocytosis, and bone marrow biopsy was suggestive of post-transplant lymphoproliferative disorder (PTLD). Timely treatment with etoposide and corticosteroids led to a transient improvement in the patient's clinical condition, and rituximab was initiated as a treatment for PTLD. Unfortunately, pancytopenia persisted for weeks, and the patient died from refractory septic shock, despite appropriate intravenous antibiotics. Autopsy revealed lymphoid infiltration of the mediastinal lymph nodes, liver and bone marrow, with some lymphocytes expressing CD3. A final diagnosis of Ann-Arbor stage IV non-EBV-mediated monomorphic T-cell PTLD was established. CONCLUSIONS This case report highlights a very unusual and fatal presentation of HLH in a lung transplant recipient, secondary to a T-cell PTLD. Indeed, HLH is typically seen as infection-related and reported to occur in the initial months following transplantation. To date, no guidelines or consensus exist regarding the management of immunosuppression regimen in solid organ transplantation.

Background: Aggressive natural killer cell leukemia (ANKL) is rare and difficult to diagnose in early stages, with no standard treatment and a poor prognosis., Case Presentation: Two adolescents with ANKL presented with hemophagocytic lymphohistiocytosis (HLH), with Case-1 presenting as refractory HLH and Case-2 with lung involvement. The morphology of bone marrow showed an increase in unidentified cells, which mainly expressed CD56. Cytogenetic analysis showed complex karyotypes. Both patients received intensive combined chemotherapy based on pegaspargase and anthracyclines. Case-1 died of tumor lysis syndrome. Case-2 underwent hematopoietic stem cell transplantation and is currently alive and disease-free., Conclusions: HLH can serve as the initial manifestation of ANKL. Leukemia cells of ANKL have significant variations in the morphology and mainly express CD56. Intensive combination chemotherapy based on pegaspargase and anthracyclines may be considered for ANKL., Competing Interests: The authors declare that there is no conflict of interest.

Objective: To explore the clinical correlation and prognostic value of the Albumin-Bilirubin (ALBI) score in children with secondary hemophagocytic syndrome(sHLH)., Methods: A retrospective analysis was conducted on the data of children's sHLH cases clearly diagnosed in the Affiliated Hospital of Zunyi Medical University from January 2012 to March 2023. Survival analysis was conducted according to the ALBI classification. Spearman correlation analysis was conducted between the ALBI score and clinical indicators. The Receiver Operating Characteristic(ROC) curve was used to evaluate the ALBI score, select the best cutoff value, and evaluate the accuracy of prognostic prediction value. Kaplan-Meier method was used to draw the survival curve. Log-rank method was used to compare the differences of survival curve between groups. Cox regression was used for prognostic analysis and restricted cubic spline curves used to calculate the relationship between ALBI scores and the risk of death in children with sHLH., Results: A total of 128 children with sHLH were included in this study, with a median age of 38(13.25, 84) months. There were 70 males (54.69%) and 58 females (45.31%). The survival analysis results of ALBI grading showed that the survival rate of HLH patients with ALBI grade 3 was significantly lower than those with ALBI grades 1 and 2. Spearman correlation analysis results showed that ALBI score was positively correlated with splenomegaly, respiratory failure, disseminated intravascular coagulation(DIC), pulmonary hemorrhage, gastrointestinal hemorrhage, central nervous system involvement, ALT, AST, TG, LDH, PT, APTT, and SF (the correlation coefficients are: r =0.181, 0.362, 0.332, 0.221, 0.351, 0.347, 0.391, 0.563, 0.180, 0.448, 0.483, 0.37, 0.356), and was negatively correlated with HB, PLT, and FIB (the correlation coefficients are: r =-0.321, -0.316, -0.423), but was not significantly correlated with EBV infection, fungal infection, hepatomegaly, and ANC ( P ＞0.05). Using the ROC curve, the cutoff value of ALBI was -1.76. Single factor Cox regression analysis results showed that HB< 90 g/L, ALT≥80 U/L, AST≥200 U/L, LDH≥1 000 U/L, PT≥20 s, APTT≥40 s, FIB< 1.5 g/L, ALBI≥-1.76, combined pulmonary hemorrhage, DIC, central nervous system involvement, gastrointestinal bleeding, and not using blood purification may be the prognostic risk factors for children with sHLH ( P < 0.05). Multivariate Cox regression results showed that FIB< 1.5 g/L ( HR =2.119, 95% CI :1.028-4.368), ALBI≥-1.76 ( HR =2.452, 95% CI :1.233-4.875), and central nervous system involvement ( HR =4.674, 95% CI :2.486-8.789) were independent risk factors affecting prognosis, while blood purification ( HR =0.306, 95% CI :0.153-0.612) was an independent protective factor for prognosis. The application of restricted cubic splines shows that the risk of death increases with the increase of ALBI score. The area under the ROC curve (AUC) of the ALBI score for predicting the risk of 1-week, 2-week, 4-week, and overall mortality were 0.825, 0.807, 0.700, and 0.693, respectively, indicating good predictive performance for early mortality risk. According to subgroup analysis results of clinical manifestations, compared with the ALBI < -1.76 group, ALBI≥-1.76 was associated with age ≤2 years, EBV infection, HLH-1994/2004 treatment, concomitant respiratory failure, and ANC≤1.0×10 9 /L, HB< 90 g/L, PLT < 100×10 9 /L, TG≥3.0 mmol/L, LDH≥1 000 U/L, APTT≥40 s, and FIB< 1.5 g/L ( P < 0.05)., Conclusion: The ALBI score is related to the clinical characteristics and laboratory indicators of sHLH, and can be used as a beneficial indicator for assessing the prognostic risk of sHLH in children. It has good accuracy and clinical application value in predicting the prognosis of sHLH in children.

Objective: To investigate the clinical characteristics of patients with hemophagocytic lymphohistiocytosis (HLH) and quantify the diagnostic value of various indexes in patients with elevated soluble interleukin-2 receptor (sCD25), so as to construct a diagnostic prediction model of HLH., Methods: The clinical characteristics of 121 patients with elevated sCD25 (≥2 400 U/ml) in the Third Affiliated Hospital of Sun Yat-Sen University were analyzed retrospectively. The patients were divided into HLH group and non-HLH group according to the diagnostic criteria of HLH. The patients with HLH were divided into infection group, tumor group, macrophage activation syndrome (MAS) group and unknown etiology group according to their etiology. The basic data and treatment of the patients were collected for univariate and multivariate logistic analysis to establish a diagnostic prediction model of HLH., Results: Among the 121 enrolled patients with elevated sCD25, 68 were diagnosed as HLH. The proportion of patients using vasopressors, the incidence rate of disseminated intravascular coagulation (DIC), and the HScore in the HLH group were higher than those in the non-HLH group ( P < 0.05). Hepatomegaly, splenomegaly, and hemophagocytosis were more common in HLH patients( P < 0.05). Compared with the patients in non-HLH group, patients in HLH group had lower levels of neutrophils, platelets, fibrinogen, IgG, and IgM, while the levels of triglycerides, ferritin (FER), sCD25, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TBil), lactate dehydrogenase (LDH), and D-dimer were higher ( P < 0.05). In subgroup analysis, the level of sCD25 in tumor group was higher than that in infection group. The level of sCD25/ferritin in tumor group was higher than that in infection group and MAS group. Compared with HLH patients in the tumor group, the procalcitonin (PCT) level, proportion of patients using vasopressors, positive rate of hemophagocytosis, and incidence rate of DIC were all higher in the infection group, and the differences were statistically significant ( P < 0.05). The results of multivariate analysis showed that fever, splenomegaly, hemophagocytosis, cytopenias, IgM, M.sCD25 [multiple of sCD25 detection value relative to the diagnostic threshold (2400 U/ml)], fibrinogen, and triglycerides were independent predictive factors for HLH ( P < 0.05).The diagnostic prediction model H constructed based on temperature, splenomegaly, hemophagocytosis, cytopenias, IgM, M.sCD25, fibrinogen, triglycerides showed good predictive accuracy. The optimal cutoff value of H was 39.45, the sensitivity of the model was 94.12%, the specificity was 83.02%., Conclusion: sCD25, sCD25/FER, PCT, hemophagocytosis, hemodynamic instability and DIC could help to distinguish the underlying etiology of HLH. The prediction model H has high discrimination and calibration, which could be used as a relatively accurate clinical diagnostic tool for HLH.

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To improve the understanding of aggressive NK-cell leukemia (ANKL) and summarize the progress of its diagnosis and treatment., Methods: We retrospectively analyzed a case of a patient who was initially diagnosed with T-cell lymphoma (non-specific type) and later transformed into ANKL through examinations such as bone marrow smear, flow cytometry, Q-mNGS, and pathology. We described the patient's diagnostic and treatment journey and conducted a literature review., Results: The patient presented with concomitant hemophagocytic syndrome upon admission. After treatment with the HLH-94 regimen, the patient developed tumor lysis syndrome, leading to a sudden onset of ventricular tachycardia and respiratory and cardiac arrest on the third day of admission. Despite aggressive resuscitation efforts, the patient did not survive., Conclusions: ANKL is rare in the world, and the disease is aggressive, so it is necessary to diagnose early and intervene timely. Bone marrow smear, flow cytometer and Q-mNGS are helpful to identify tumors quickly and determine the direction of diagnosis and treatment. This disease is often accompanied by hemophagocytic syndrome. When the pathogenesis is not clear, it is recommended to treat it with hormone and gamma globulin first, and after clarification, chemotherapy containing L-asparaginase may be added; pay attention to supportive treatment and vigilance against oncolysis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be performed as soon as possible, and the application of targeted drugs may further improve the curative effect. In a word, ANKL needs more data statistics and analysis to guide clinical diagnosis and treatment.

Background: The aim of this study was to analyze the clinical significance of cerebrospinal fluid (CSF) cytokines in hemophagocytic lymphohistiocytosis associated with central nervous system (CNS-HLH)., Methods: CSF cytokine levels, including interferon (IFN)-γ, soluble CD25 (sCD25), interleukin (IL)-6, IL-10, IL-18, and CXCL9 were measured at disease onset and during the treatment. Five newly diagnosed patients with demyelination disease were enrolled for comparison., Results: Sixty-five samples from 36 patients (13 in the CNS group and 23 in the non-CNS group) were detected. Levels of CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the non-CNS group ( P =0.038, <0.001, <0.001, 0.005, and <0.001), and levels of CSF sCD25, IL-10, IL-18, and CXCL9 in the CNS group were higher than those in the demyelination group ( P =0.001, 0.008, 0.004, and 0.003). There was no significant difference in IL-6 levels among the 3 groups ( P =0.339). CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 could assist in diagnosing CNS-HLH. The diagnostic efficiency of CSF sCD25, IL-10, and CXCL9 was better, with a cutoff value of 154.64, 1.655, and 19.54 pg/mL, respectively. The area under the curve was >0.9, with sensitivity and specificity >80%. Correlation analysis suggested that in the CNS group, IFN-γ levels in CSF and serum correlated positively ( R =0.459, P =0.007), while there was no correlation between CSF CXCL9 and serum IFN-γ ( P =0.915)., Conclusions: CSF IFN-γ, sCD25, IL-10, IL-18, and CXCL9 levels were significantly higher in HLH patients with CNS involvement than those without and could predict HLH patients with CNS involvement. CSF CXCL9 might be a more sensitive biomarker to CNS-HLH than IFN-γ, while CSF IL-6 does not seem to play a vital role., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This case report presents a 38-year-old male patient who, after a febrile infection, developed super-refractory status epilepticus and multiorgan failure, and died in 2 weeks despite the best possible intensive care. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH). This case shows that a rare immunological cause such as HLH may cause febrile infection-related epilepsy syndrome (FIRES), and complications of intensive care can mask the physiological and laboratory changes in HLH. PLAIN LANGUAGE SUMMARY: This case report presents a 38-year-old man who, after a febrile infection, developed intractable epileptic activity requiring intensive care treatment. During the intensive care, the patient showed signs of multiple organ damage and died in 2 weeks despite the best possible treatment. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH), which is a rare immune system regulation disorder leading to persistent inflammatory state and organ damages. This case shows that an immunological disorder like HLH may underlie treatment resistant fever-related epileptic seizures., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome with an abnormal activation of the immune system and is associated with a high mortality even with treatment. We present a case of a woman in her mid-50s who developed HLH triggered by miliary tuberculosis (TB) while receiving a tumour necrosis factor alpha inhibitor.The patient was admitted with a high fever and respiratory pain. Her condition deteriorated despite empirical treatment. Diagnosis of HLH was established based on clinical presentation, H-score and HLH-04 criteria. Concurrently, miliary TB was identified as the trigger. She was treated with anti-tuberculous therapy and HLH-directed treatment with dexamethasone, etoposide and anakinra. Initial improvement was observed, leading to the withholding of HLH-orientated treatment. However, several relapses occurred, necessitating prolonged HLH treatment.A literature review corroborated the importance of combined anti-tuberculous and immunosuppressive therapy for managing HLH. This case underscores the necessity of timely and comprehensive management of HLH-oriented treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hemophagocytic Lymphohistiocytosis (HLH) carries a high mortality rate. Current existing risk-evaluation methodologies fall short and improved predictive methods are needed. This study aimed to forecast 30-day mortality in adult HLH patients using 11 distinct machine learning (ML) algorithms., Methods: A retrospective analysis on 431 adult HLH patients from January 2015 to September 2021 was conducted. Feature selection was executed using the least absolute shrinkage and selection operator. We employed 11 ML algorithms to create prediction models. The area under the curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, F1 score, calibration curve and decision curve analysis were used to evaluate these models. We assessed feature importance using the SHapley Additive exPlanation (SHAP) approach., Results: Seven independent predictors emerged as the most valuable features. An AUC between 0.65 and 1.00 was noted among the eleven ML algorithms. The gradient boosting decision tree (GBDT) algorithms demonstrated the most optimal performance (1.00 in the training cohort and 0.80 in the validation cohort). By employing the SHAP method, we identified the variables that contributed to the model and their correlation with 30-day mortality. The AUC of the GBDT algorithms was the highest when using the top 4 (ferritin, UREA, age and thrombin time (TT)) features, reaching 0.99 in the training cohort and 0.83 in the validation cohort. Additionally, we developed a web-based calculator to estimate the risk of 30-day mortality., Conclusions: With GBDT algorithms applied to laboratory data, accurate prediction of 30-day mortality is achievable. Integrating these algorithms into clinical practice could potentially improve 30-day outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High ferritin is an important and sensitive biomarker for the various forms of 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 at UPMC Children's Hospital where serum ferritin > 1000 ng/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 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., (© 2024. The Author(s).)

Multidrug therapy has significantly reduced the global burden of Hansen's disease; however, complications from long-term treatment persist. A male resident of southern Kentucky, in his 30s and of Micronesian descent, presented with worsening abdominal pain associated with anorexia, fatigue, functional decline and occasional haemoptysis. He was compliant with multidrug therapy for leprosy. Laboratory investigations revealed pancytopenia. He was initially treated under a sepsis protocol and later switched to high-dose steroids due to a suspected immune reaction from missed corticosteroid doses. Despite aggressive treatment for refractory pancytopenia, the patient's condition deteriorated, and he passed away from cardiac arrest. Posthumous bone marrow biopsy revealed haemophagocytic lymphohistiocytosis secondary to disseminated histoplasmosis with bone marrow infiltration. This case highlights the importance of proactive fungal screening in immunocompromised leprosy patients, particularly in endemic regions, as early detection and timely intervention can prevent severe complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare, complicated and life threatening hyperinflammatory syndrome that maybe triggered by various infectious agents, malignancies and rheumatologic disorders. Early diagnosis and identification of the cause is essential to initiate appropriate treatment and improve the quality of life and survival of patients. The recently developed Onco-mNGS technology can be successfully used for simultaneous detection of infections and tumors., Methods: In the present study, 92 patients with clinically confirmed HLH were etiologically subtyped for infection, tumor and autoimmunity based on CNV and microbial data generated by Onco-mNGS technology, and a predictive model was developed and validated for the differential diagnosis of the underlying disease leading to secondary HLH. Furthermore, the treatment outcomes of patients with HLH triggered by EBV infection and non-EBV infection were evaluated, respectively., Results: The current study demonstrated that the novel Onco-mNGS can identify the infection and malignancy- related triggers among patients with secondary HLH. A random forest classification model based on CNV profile, infectious pathogen spectrum and blood microbial community was developed to better identify the different HLH subtypes and determine the underlying triggers. The prognosis for treatment of HLH patients is not only associated with CNV, but also with the presence of pathogens and non- pathogens in peripheral blood. Higher CNV burden along with frequent deletions on chromosome 19, higher pathogen burden and lower non-pathogenic microbes were prognosis factors that significantly related with unfavorable treatment outcomes., Discussion: Our study provided comprehensive knowledge in the triggers and prognostic predictors of patients with secondary HLH, which may help early diagnosis and appropriate targeted therapy, thus improving the survival and prognosis of the patients., Competing Interests: Author XC is employed by MatriDx Biotechnology Co., Ltd. Author RR is employed by EBV-Care Biotechnology Co., Ltd., Micro-Health Biotechnology Co., Ltd. and Foshan Branch, Institute of Biophysics, Chinese Academy of Sciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Cao, Wang, Kong, Hu, Shi, Dou, Song, Chen, Zhou, Liu, Ren and Wang.)

Hepatitis A virus (HAV) infection typically presents as a self-limiting illness but it can cause debilitating symptoms and rarely fulminant hepatitis (acute liver failure), which is often fatal. WHO estimates that in 2016, 7134 persons died from hepatitis A worldwide (accounting for 0.5% of the mortality due to viral hepatitis). Fulminant hepatic failure is observed in less than 1% of cases of acute viral hepatitis A. Haemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of excessive inflammation and tissue destruction owing to abnormal immune activation. Acquired HLH due to viral infections (also known as virus-associated haemophagocytic syndrome) is most commonly associated with Epstein-Barr virus and cytomegalovirus (CMV). HAV-associated HLH has been rarely reported. Haemolysis of mild to moderate degree is not unheard of in cases of hepatitis A, which is often immune-mediated. Here, we present the case of a man in his 30s, with G6PD deficiency unmasked by acute viral hepatitis A, which later on progressed to hyperacute liver failure, HLH and renal failure., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

To explore the clinical features, treatment, and prognosis of patients with lymphoma-associated hemophagocytic syndrome (LAHS) in a real-world clinical setting. We retrospectively examined LAHS patients diagnosed at our center between January 2016 and August 2023, focusing primarily on their clinical features, therapeutic approaches, overall response rate (ORR), and overall survival (OS). A combination of univariate and multivariate analyses was conducted to identify potential prognostic factors. A total of 86 patients diagnosed with LAHS were included to evaluate clinical characteristics and prognostic factors. Patients with T/NK cell lymphoma had a higher probability of developing hemophagocytic syndrome (HPS) during the clinical process than those with B cell lymphoma. The median survival time was 55 days for all patients, and 47 and 81 days for the T/NK cell LAHS and B cell LAHS cohorts, respectively (P = 0.025). Among the patients evaluated, the ORR was 42.2%. Patients starting with anti-lymphoma treatment had a better, albeit not significant, ORR than those beginning with anti-HPS treatment. In the univariate analysis, T/NK cell LAHS (P = 0.027), HPS onset at relapse (P = 0.036), higher baseline plasma EBV-DNA levels (> 4,000 copies/mL, P = 0.034), and treatments including cytokine adsorption and ruxolitinib (P < 0.001 and P = 0.017, respectively) were potentially associated with worse OS, while corticosteroid therapy benefited OS. In the multivariate analysis, T/NK cell LAHS (adjusted hazard ratio (aHR) = 2.007), cytokine adsorption therapy (aHR = 4.547), and corticosteroid therapy (aHR = 0.118) were independently associated with mortality. T/NK cell lymphoma was the main cause of LAHS and carried a worse prognosis. Whether anti-lymphoma or anti-HPS treatment should start first still requires prospective studies with larger sample sizes. The key point in controlling HPS is to block the cytokine storm promptly. Corticosteroid therapy is both effective and accessible and should be used early and in sufficient quantities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)-cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor-triggered NK-cell and T-cell receptor (TCR)-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell-based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

A male in his 30s who was recently diagnosed with HIV arrived at the emergency department exhibiting an altered mental state and acute respiratory distress. Initial laboratory tests revealed a high anion gap metabolic acidosis, elevated liver enzyme levels and bicytopenia. A CT scan identified a miliary pattern. Bronchoscopy with bronchoalveolar lavage displayed epithelial and inflammatory cells. However, subsequent tests ruled out the presence of fungi, Pneumocystis organisms, malignancies, granulomas and viral inclusions. Broad-spectrum antibiotics with emphasis on Mycobacterium tuberculosis and antifungal treatments were administered. The regimen was adjusted after a positive urine test for the Histoplasma antigen.The patient later manifested signs and symptoms, including increased ferritin level, fever, splenomegaly, diminished natural killer cell function and heightened interleukin-2 receptor levels, confirming haemophagocytic lymphohistiocytosis. Given the patient's gravely decompensated state, the treatment incorporated dexamethasone, and the patient's vasopressor-resistant septic shock was addressed with methylene blue., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The identification of haemophagocytosis in bone marrow (BM) is recurrently identified in patients with severe COVID-19. These initial COVID-19 autopsy studies have afforded valuable insight into the pathophysiology of this disease; however, only a limited number of case series have focused on lymphoid or haematopoietic tissues., Methods: BM and lymph node (LN) specimens were obtained from adult autopsies performed between 1 April 2020 and 1 June 2020, for which the decedent had tested positive for SARS-CoV-2. Tissue sections (H&E, CD3, CD20, CD21, CD138, CD163, MUM1, kappa/lambda light chains in situ hybridisation) were examined by two haematopathologists, who recorded morphological features in a blinded fashion. Haemophagocytic lymphohistiocytosis (HLH) was assessed based on HLH 2004 criteria., Results: The BM demonstrated a haemophagocytic pattern in 9 out of 25 patients (36%). The HLH pattern was associated with longer hospitalisation, BM plasmacytosis, LN follicular hyperplasia and lower aspartate aminotransferase (AST), as well as ferritin at demise. LN examination showed increased plasmacytoid cells in 20 of 25 patients (80%). This pattern was associated with a low absolute monocyte count at diagnosis, lower white cell count and lower absolute neutrophil count at demise, and lower ferritin and AST at demise., Conclusions: Autopsy results demonstrate distinct morphological patterns in BM, with or without haemophagocytic macrophages, and in LN, with or without increased plasmacytoid cells. Since only a minority of patients met diagnostic criteria for HLH, the observed BM haemophagocytic macrophages may be more indicative of an overall inflammatory state., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the expression and diagnostic value of peripheral blood lymphocytes and functional activation status in non-Hodgkin lymphoma with hemophagocytic lymphohistiocytosis (NHL-HLH) . Methods: We retrospectively analyzed clinical data from 30 newly diagnosed NHL-HLH patients admitted to Jiangsu Province Hospital from September 2022 to September 2023. We assessed peripheral blood lymphocytes and activation status by flow cytometry. Forty newly diagnosed patients with NHL who received treatment at our hospital during the same period and had lymphocyte and functional activation indexes were selected as the control group. The differences in relative and absolute lymphocyte counts and functional activation indexes between the two groups were compared. The optimal cutoff values for continuous variables were calculated from the receiver operating characteristic curve and logistic regression analysis was used to evaluate the risk factors in NHL patients with HLH. Results: A total of 30 NHL-HLH patients were evaluated, including 12 T-cell lymphoma and 18 B-cell lymphoma patients. Forty individuals were in the control group, which included 19 T-cell lymphoma and 21 B-cell lymphoma patients. The absolute counts of CD3(+) T, CD4(+) T, CD8(+) T, and NK cells, along with the relative count of NK cells, were significantly lower in the HLH group compared with that in the control group (all P values<0.01) . The expression of CD38 and HLA-DR on CD8(+) T-cell activated subgroups was significantly higher in the NHL-HLH group compared with that in the control group (CD8(+)CD38(+)/CD8(+) T expression median: 57.4% vs 21.5%, P <0.001; CD8(+)CD38(+)/CD8(+) T expression median: 49.7% vs 33.5%, P =0.028, respectively) . In addition, CD28 expression on CD4(+) and CD8(+) T cells was significantly higher in NHL-HLH patients ( P <0.01) . ROC curve and multivariate logistic regression analyses revealed that absolute NK cell count ≤72.0 cells/μl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were risk factors for predicting the occurrence of NHL-HLH patients. The sensitivity and specificity of the regression model were 86.7% and 86.1%, respectively, with an area under the curve of 0.94 ( P <0.001) . Conclusions: In NHL patients with HLH, there was a significant reduction in the absolute number of peripheral blood lymphocyte subpopulations, whereas T-cell function was notably activated. Specifically, absolute counts of NK cells ≤72.0 cells/μl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were identified as risk factors for predicting the development of NHL-HLH patients. This will assist in early clinical diagnosis and treatment.

Background: Lymphoma is the most common secondary cause of hemophagocytic lymphohistiocytosis (HLH) in adults. Lymphoma-associated HLH (LA-HLH) in the elderly population is not rare, however, little has been reported regarding clinicopathological characteristics, prognostic factors, and outcomes of LA-HLH in the elderly population., Methods: We retrospectively analyzed a multicenter cohort of elderly patients with LA-HLH. Clinicopathological features and treatment information were collected. The impacts of baseline characteristics and treatments on survival outcomes were analyzed., Results: A total of 173 elderly patients with LA-HLH were included. Compared with young patients, elderly patients showed different clinical and laboratory features. Regarding lymphoma subtypes, B-cell lymphoma was more common in elderly patients (elderly 61.3% vs. young 32.3%, p < 0.001) while T/NK-cell lymphoma was more common in young patients (65.3% vs. 35.3%, p < 0.001). The median survival of elderly patients with LA-HLH was only 92 days. The prior use of HLH therapy or etoposide-containing HLH therapy was not associated with improved overall survival. T/NK-cell subtype, a lower platelet count (≤53 × 10 9 /L), a lower albumin level (≤32.1 g/L), a higher LDH level (>1407 U/L), and a higher creatinine level (>96.8 μmol/L) were independent predictors of decreased overall survival and 60-day survival. A prognostic index was established and demonstrated to be robust in predicting the overall survival and 60-day survival of elderly patients with LA-HLH., Conclusions: LA-HLH in elderly patients displayed heterogeneous clinicopathological features and survival outcomes. Treatments need to be optimized to improve the outcomes of elderly patients with LA-HLH., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Adult-onset Still disease (AOSD) is a rare inflammatory condition with a monophasic, intermittent, or chronic clinical course, and a subset may experience life-threatening complications such as hemophagocytic lymphohistiocytosis (HLH). This study aims to characterize concurrent AOSD and HLH and identify variables independently associated with in-hospital death., Methods: We performed a medical records review of AOSD with and without HLH from the 2016-2019 National Inpatient Sample database. We performed a multivariable logistic regression analysis for in-hospital death. Results were reported as adjusted odds ratios (OR adj )., Results: There were 5495 hospitalizations with AOSD, of which 340 (6.2%) had HLH. Thirty (9.0%) of the combined AOSD and HLH group died in the hospital compared with 75 (1.5%) of those without HLH. Multivariable analysis in AOSD inpatients showed that disseminated intravascular coagulation (OR adj 6.13), hepatic failure (OR adj 7.16), infection (OR adj 3.72), respiratory failure (OR adj 6.89), and thrombotic microangiopathy (OR adj 14.05) were associated with higher odds of death. However, HLH itself was not an independent predictor of mortality in AOSD population., Conclusions: HLH occurred in a small minority of inpatients with AOSD. HLH itself was not an independent risk factor for in-hospital death. Disseminated intravascular coagulation, hepatic failure, infection, respiratory failure, and thrombotic microangiopathy were associated with higher odds of in-hospital death in AOSD. Better awareness of these life-threatening complications may improve hospital outcomes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To understand the etiology, clinical characteristics and prognosis of secondary hemophagocytic syndrome (HLH), so as to improve the understanding of HLH and reduce the rates of misdiagnosis and missed diagnosis of HLH., Methods: A retrospective study was conducted to analyze the cause, clinical characteristics, laboratory findings, therapy and outcomes of 75 adult patients with secondary HLH admitted to our hospital from January 2015 to December 2021. Follow-up continued until the last discharge time., Results: Among 75 patients, infection-related HLH was the most common (45.33%), followed by lymphoma-related HLH (17.33%). Fever was the most common clinical manifestation (97.67%). Laboratory indicators such as NK cell activity (98.31% low or absent), sCD25 (93.22% increased), and serum ferritin (94.44% elevated) had higher sensitivity in diagnosis. By comparing the clinical manifestations and laboratory indicators of HLH patients with different causes, sex, lymph node enlargement and bone marrow morphology were more valuable for the diagnosis of primary disease (all P <0.05). By comparing the treatment and clinical outcomes of HLH patients with different causes, the highest clinical remission rate (83.3%) was achieved in patients with autoimmune disease-related HLH treated with hormone+cyclosporine ( P <0.05). The overall 12-month survival rate of all patients was 26.7%, in which the infection-related HLH was the lowest (14.7%) while autoimmune disease-related HLH was the highest (63.6%)., Conclusion: The causes and clinical characteristics of adult secondary HLH are varied, with poor prognosis and heterogeneity in disease severity. It is important to identify HLH cause early for diagnosis and needed to further understand HLH.

There has been no severity evaluation model for pediatric patients with hemophagocytic lymphohistiocytosis (HLH) that uses readily available parameters. This study aimed to develop a novel model for predicting the early mortality risk in pediatric patients with HLH using easily obtained parameters whatever etiologic subtype. Patients from one center were divided into training and validation sets for model derivation. The developed model was validated using an independent validation cohort from the second center. The prediction model with nomogram was developed based on logistic regression. The model performance underwent internal and external evaluation and validation using the area under the receiver operating characteristic curve (AUC), calibration curve with 1000 bootstrap resampling, and decision curve analysis (DCA). Model performance was compared with the most prevalent severity evaluation scores, including the PELOD-2, P-MODS, and pSOFA scores. The prediction model included nine variables: glutamic-pyruvic transaminase, albumin, globulin, myohemoglobin, creatine kinase, serum potassium, procalcitonin, serum ferritin, and interval between onset and diagnosis. The AUC of the model for predicting the 28-day mortality was 0.933 and 0.932 in the training and validation sets, respectively. The AUC values of the HScore, PELOD-2, P-MODS and pSOFA were 0.815, 0.745, 0.659 and 0.788, respectively. The DCA of the 28-day mortality prediction exhibited a greater net benefit than the HScore, PELOD-2, P-MODS and pSOFA. Subgroup analyses demonstrated good model performance across HLH subtypes. The novel mortality prediction model in this study can contribute to the rapid assessment of early mortality risk after diagnosis with readily available parameters., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the effect of pre-treatment plasma Epstein-Barr virus (EBV) DNA copy number on the clinical features and prognosis of patients with adult secondary hemophagocytic lymphohistiocytosis(sHLH)., Methods: The clinical characteristics, survival rate, and prognostic factors of 171 patients with adult sHLH treated at Jiangsu Province Hospital from June 2017 to January 2022 were retrospectively analyzed in this study. Patients were divided into three groups, including the EBV DNA-negative group(<5.0×10 2 copies/ml), lower EBV-DNA loads group(5.0×10 2 -8.51×10 4 copies/ml), and higher EBV-DNA loads group(＞8.51×10 4 copies/ml), according to pre-treatment plasma EBV-DNA copy number. Cox regression model was established for screening prognostic factors. Adult sHLH survival prediction model was constructed and realized through the nomogram based on EBV-DNA load after adjusted the factors affecting survival of etiology and treatment strategy.Concordance index (C-index) and calibration curves were calculated to verify model predictive and discriminatory capacity., Results: Among 171 adult sHLH patients, 84 patients were not infected with EBV (EBV DNA-negative group), and 87 with EBV (EBV DNA-positive group, 48 lower EBV-DNA loads group and 39 higher EBV-DNA loads group). Consistent elevations in the levels of liver enzymes (ALT and AST), LDH, TG, β 2 -microglobulin and ferritin across the increasing of EBV-DNA load (all P <0.05), while the levels of fibrinogen decrease ( P <0.001). The median follow-up time was 52 days (range 20-230 days), and 123 patients died. The overall survival (OS) rate of patients in EBV DNA-positive group was lower than that in EBV DNA-negative group (median OS: 40 days vs 118 days, P <0.001). Higher EBV-DNA loads had worse OS (median OS: 24 days vs 45 days vs 118 days, P <0.0001 for trend) compared to lower EBV-DNA loads and EBV DNA-negative group. Multivariate Cox analysis revealed that higher EBV-DNA loads ( P =0.005), fibrinogen≤1.5 g/L ( P ＝0.012), ferritin ( P ＝0.041), associated lymphoma ( P ＝0.002), and anti-tumor based strategy ( P ＝0.001) were independent prognostic factors for OS. The C-indexes of 30 day, 90 days, 365 days survival rate were all greater than 0.8 of the nomogram model and calibration curves provided credibility to their predictive capability. Subgroup analysis showed that patients with higher EBV-DNA loads had a significantly worse prognosis in adult sHLH who were women, ferritin＞5 000 μg/L, β 2 -microglobulin＞7.4 mmol/L and regardless of age, etiologies, HScore points., Conclusion: The EBV-DNA load is a strong and independent predictor for survival in patients with sHLH. The prognostic nomogram based on EBV-DNA loads was dependable and provides a visual tool for evaluating the survival of adult sHLH.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a severe, life-threatening hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway. Here we investigated the clinical presentation and outcome in a large cohort of 143 patients with pHLH diagnosed in the last 15 years and enrolled in the Italian registry. The median age at diagnosis was 12 months (interquartile range, 2-81), and 92 patients (64%) fulfilled the HLH-2004 criteria. Of 111 patients who received first-line combined therapy (HLH-94, HLH-2004, Euro-HIT protocols), 65 (59%) achieved complete response and 21 (19%) partial response. Thereafter, 33 patients (30%) reactivated, and 92 (64%) received hematopoietic stem cell transplantation, 78 of whom (85%) survived and were alive at a median follow-up from diagnosis of 67 months. Thirty-six patients (25%) died before hematopoietic stem cell transplantation and 14 (10%) after. Overall, 93 patients (65%) were alive after a median follow-up of 30 months. Unadjusted predictors of non-response were age <6 months and high ferritin and bilirubin levels, while predictors of pre-transplant and overall mortality were high ferritin and bilirubin levels. At multivariable analysis, high levels of ferritin predicted non-response, while high levels of bilirubin predicted pre-transplant and overall mortality. Despite recent advances in therapeutic management, pHLH remains a life-threatening condition with significant early mortality. Liver dysfunction is the main predictor of poor prognosis.

Objective: Neonatal sepsis and familial hemophagocytic lymphohistiocytosis (fHLH) have similar clinical and laboratory symptoms and the possibility of overlooking fHLH diagnosis is high in newborns with sepsis. History of consanguineous marriage and/or sibling death, hepatomegaly/splenomegaly, and hyperferritinemia (>500 ng/mL) are likely to support fHLH in newborns with sepsis. Therefore, in newborns with sepsis in whom at least 2 of these 3 criteria were detected, genetic variants was investigated for the definitive diagnosed of fHLH. According to the results of genetic examination, we investigated whether these criteria supporting fHLH could be used as a screening test in fHLH., Materials and Methods: fHLH-associated genetic variants were investigated in 22 patients diagnosed with neonatal sepsis who fulfilled at least 2 of the following criteria (1) history of consanguineous marriage and/or sibling death, (2) hepatomegaly/splenomegaly, and (3) hyperferritinemia (>500 ng/mL)., Results: Heterozygous variants were determined in 6 patients (27.2%): 3 STXBP2 , 1 STX11 , 1 UNC13D , and 1 PRF1 . Polymorphisms associated with the clinical symptoms and signs of HLH were determined in 5 patients (22.7%): 4 UNC13D , 1 PRF1 . Two patients were in the heterozygous variants and polymorphism associated with the clinical symptoms and signs of HLH groups. In 12 patients, benign polymorphisms were detected in STXBP2 and UNC13D genes. No change in fHLH associated genes were found in 1 patient., Conclusion: Some variants and/or polymorphisms identified in our patients have been previously reported in patients with HLH. Therefore, we recommend further investigation of fHLH in patients with neonatal sepsis who fulfill at least 2 of the above 3 criteria., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Epstein-Barr virus DNA (EBV-DNA) is closely related to the pathogenesis and prognosis of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The quantitative measurement of blood EBV-DNA is widely used in EBV-HLH, but there remains a lack of evidence to guide clinicians., Methods: A retrospective analysis was conducted on clinical manifestations, laboratory tests, 310 blood EBV-DNA loads, and prognosis of 51 pediatric patients diagnosed with EBV-HLH. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cutoff values of EBV-DNA for predicting mortality and evaluating the active status of EBV-HLH., Results: EBV-positive- lymphoma-HLH had higher initial plasma EBV-DNA load(1.10 × 10 6 copies/ml) compared to the EBV-HLH group (1.98 × 10 4 copies/ml) (P = 0.006), and experienced recurrently elevated plasma EBV-DNA levels during treatment. The optimal cut-off value of initial plasma EBV-DNA load in predicting mortality was 2.68 × 10 5 copies/ml, with a sensitivity of 88.57% and a specificity of 56.25%. For determining the active status of HLH, the optimal cutoff value of PBMC EBV-DNA load during treatment was 2.95 × 10 5 copies/ml, with a sensitivity of 69.14% and a specificity of 64.71%. The cut-off value of plasma EBV-DNA for determining active status was 1.32 × 10 3 copies/ml, with a sensitivity of 84.34%, and a specificity of 87.67%. Patients with higher PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses (P < 0.05)., Conclusion: Dynamic monitoring of EBV-DNA is a valuable tool for assessing disease status and predicting the prognosis of EBV-HLH, with plasma EBV-DNA being more effective than PBMC EBV-DNA. Patients with high levels of PBMC and plasma EBV-DNA at initial and those with repeated elevated plasma EBV-DNA during treatment had worse prognoses., (© 2024. The Author(s).)

Background: Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic., Case Presentation: This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection., Conclusion: This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV-2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future., (© 2024. The Author(s).)