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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.)

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.

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.)

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).)

Objective: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA., Method: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis., Results: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse., Conclusion: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Editora Ltda.)

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 investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2 weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

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).)

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Inc.)

To investigate the prognostic impact of serum beta-2 microglobulin (B2M) in adult lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). The clinical and laboratory characteristics of 326 adult patients in a multicenter cohort with lymphoma-associated HLH with available baseline serum B2M levels were retrospectively analyzed. A total of 326 cases were included in this study, and the median serum B2M level was 5.19 mg/L. The optimal cut-off of serum B2M was 8.73 mg/L, and the cases with serum B2M level >8.73 mg/L were older and had a more advanced stage, lower levels of platelets, albumin, and fibrinogen, and higher creatinine level. The serum B2M >8.73 mg/L, creatinine ≥133 μmol/L, fibrinogen ≤1.5 g/L, agranulocytosis (<0.5 × 10 9 /L), severe thrombocytopenia (<50 × 10 9 /L), and high Epstein-Barr virus DNA copy number were found to have independent prognostic values in all patients, and the serum B2M >8.73 mg/L was also an independent prognostic factor in patients with creatinine <133 μmol/L. Finally, a prognostic scoring system was established based on independent prognostic factors of all patients and categorized the patients into three groups with significant prognostic differences. This study confirmed that the serum B2M level can be an independent prognostic factor in lymphoma-associated HLH and established a prognostic scoring system to predict patients' survival., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aims: The role of beta2-microglobulin (β2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development., Methods: This retrospective observational cohort study conducted at a single-center involved 938 patients diagnosed with hemophagocytic lymphohistiocytosis, who were divided into AKI  group and non-AKI group. Patient data were collected and analyzed using univariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence.   RESULTS: Among the enrolled patients, 486 were male (51.9%), the median age was 37 years (interquartile range, 28.0, 52.0), 58.4% experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When β2-MG was used as a continuous variable, multifactorial analysis showed that β2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI., Conclusions: The incidence of morbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKI remains high. Monitoring levels of β2-MG may provide clinicians with timely indicators of changes in renal function,  facilitating adjustments to treatment strategies., (© 2024. The Author(s).)

Background: The goal was to study the difference of virological, immunologic, and inflammatory indicators between Epstein-Barr associated infectious mononucleosis (EBV-IM) and EBV associated hemophagocytic lymphohistiocytosis (EBV-HLH) and to explore the evaluation indicators for monitoring the therapeutic efficacy of EBV-HLH., Methods: Twenty children with EBV-IM (IM group) and 10 children with EBV-HLH (HLH group) were selected. Virology indicators were detected; the absolute count of lymphocyte, and lymphocyte subsets were detected; the levels of immunoglobulin and ferritin were assayed., Results: Compared to the IM group, the HLH group showed a decrease in EBV-specific VCA-IgM antibody levels (U = 29.0, p = 0.006) and an increase in EBV-specific NA-IgG antibody levels (U = 17.0, p = 0.001), while there was no significant difference in EB-DNA loads (t = 0.417, p = 0.680). The counts of lymphocytes, and various lymphocyte subsets in the HLH group were lower than those in the IM group. Inflammatory markers in the HLH group were significantly higher than those in IM group. Dynamic monitoring of virological, immunological, and inflammatory indicators in HLH patients during treatment showed that EBV DNA gradually decreased in patients with good prognosis. Inflammatory indicators significantly decreased and returned to normal, lymphocyte count significantly increased and returned to normal during treatment. However, patients with poor prognosis showed rebound increase in EBV DNA and inflammatory indicators in the later stage of treatment, while lymphocyte count further decreased with the recurrence of the disease., Conclusions: Exhausted and damaged immune function in host by persistent stimulation of EB viral antigen is one of the main pathogeneses of EB-HLH. Lymphocyte count and serum ferritin level are effective indicators to monitor the therapeutic efficacy during the treatment to HLH.

Objective: Epstein-Barr virus (EBV) is a common virus that infects a large portion of the world's population, with most people becoming infected during childhood or adolescence. The objective of this article is to analyze the clinical and laboratory examination results of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children, summarize its characteristics, identify critically ill children as soon as possible, and provide a basis for diagnosis and treatment., Method: The retrospective analysis in this study involved collecting data from 34 cases of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) admitted to Hebei Children's Hospital from January 2019 to December 2022. The inclusion criteria for the cases studied likely included confirmed diagnosis of EBV-HLH based on clinical symptoms, laboratory findings, and possibly viral testing results. Key parameters analyzed in the study may have included clinical manifestations, laboratory test results (e.g., levels of lactate dehydrogenase, sCD25, IL-10, calcium ions, glutathione aminotransferase, ferritin, alanine aminotransferase, D-dimer), survival rates, and other relevant indicators. Additionally, the cases were likely divided into high-risk groups (with multiple organ dysfunction or requiring ventilator-assisted ventilation) and non-risk groups for comparative analysis., Results: The results showed that 34 cases (100%) of EBV-HLH had elevated levels of lactate dehydrogenase, sCD25, IL-10, and decreased levels of calcium ions. 97.1% of the children had a fever and elevated levels of glutathione aminotransferase and ferritin, with an 8-week survival rate of 91.2%. The levels of alanine aminotransferase, alanine aminotransferase, lactate dehydrogenase, ferritin, D-dimer, and sCD25 in critically ill children were significantly higher than those in the non-critically ill group, with statistical significance (P < .05). The decreased levels of calcium ions in EBV-HLH patients suggest potential tissue damage and disruption of calcium homeostasis, contributing to the systemic manifestations of the disease. Compared with non-critical recombinant albumin, the decrease in critical recombinant albumin was statistically significant (P < .05)., Conclusion: Significant changes in laboratory results can contribute to the early diagnosis and targeted treatment of EBV-HLH, especially for critically ill children. We should pay timely attention to laboratory examinations, diagnosis and treatment, and avoid or reduce the occurrence of adverse consequences. Based on the results of the study on Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in children, specific strategies and criteria can be proposed to aid in the early identification of critically ill children with this condition in clinical practice: Clinical Screening, Risk Stratification, Early Intervention, Multidisciplinary Management and Educational Measures.

Background: There is no specificity in the clinical presentation of hemophagocytic lymphohistiocytosis (HLH)., Objective: To study some clinical, etiological, and prognostic features of HLH to improve the clinical understanding of the disease., Methods: Retrospective analysis of the clinical data of 125 patients with HLH admitted to our hospital from June 2015 to August 2021, including clinical characteristics, laboratory indicators, and survival period. Statistical analysis was performed from the overall group of study indicators, which included population, children, and adults., Results: In the whole population, sex, age, blood myoglobin, and NK cell ratio of M-HLH and non-M-HLH patients (P< 0.05), serum albumin, and direct bilirubin were independent correlates of M-HLH. In the pediatric group, age and the proportion of NK cells were significantly different between M-HLH and non-M-HLH patients (P< 0.05). Multivariate Logistic regression analysis showed that all factors were not significantly associated with M-HLH. The associated regression analysis showed that all factors were not significantly associated with M-HLH. ROC curve analysis showed that the best predictive value of NK cell percentage for M-HLH diagnosis in the overall population was 4.96% in the pediatric group and 4.96% in the adult group. The best predictive value for M-HLH diagnosis was 2.08%. The univariate analysis showed that platelet count, alanine aminotransferase, aspartate aminotransferase, serum albumin, direct bilirubin and indirect bilirubin affected prognosis; COX regression showed that none of these factors had a significant relationship. The overall median survival time was 20.7 months in the adult group, 44.3 months in non-M-HLH patients, and 7.73 months in M-HLH patients (p= 0.011); univariate analysis showed that platelet count and serum albumin level affected prognosis; COX regression results in serum albumin level was an independent risk factor for prognosis., Conclusion: The survival rate of non-M-HLH was significantly better than that of M-HLH; the proportion of NK cells had predictive value for the diagnosis of M-HLH; in the general population, non-M-HLH was more likely to have abnormal liver function than M-HLH: lower platelet count and serum albumin level were associated with poor prognosis, and the lower the platelet count and serum albumin level, the worse the prognosis: in addition, adults with lower serum albumin levels are also associated with poor prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation., (© 2022 by The American Society of Hematology.)

Object: Goal of this research was to investigate values of serum cytokines in childhood HLH with different triggers, with the expectation to find secretion spectrum of 5 main types of underlying diseases., Method: 118 newly diagnosed HLH were included, and serum concentrations of 6 cytokines were tested before treatment began. Absolute cytokine levels and ratios between them were then studied in the HLH groups collectively and separately RESULTS: In general, IFN-γ, IL-10 and IL-6 showed differences among 5 HLH groups. Specifically, relative levels of these three cytokines to each other were meaningful in distinguishing 4 types of HLH. Level of IL-6 was higher than those of IFN-γ or IL-10 in HLH driven by Systemic auto-inflammatory disorders (SAIDs) or Langerhans Cell Histiocytosis (LCH), while primary HLH and EBV-HLH shared elevated ratio of IL-10 to IL-6. Although more than one distinctive ratios were found in 3 HLH groups, combination of these parameters didn't offer optimal balance between sensitivity and specificity., Conclusion: As a group of easily gained laboratory findings, cytokine levels were reliable in the procedure of roughly classifying HLH cases with the help of patients' clinical phenotype. However, adequate data is still needed to explore the significance of these indicators in identifying one particular underlying disease accurately., (Copyright © 2021. Published by Elsevier Ltd.)

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem disease wherein there is an exaggerated immune system activation following a trigger such as infection, malignancy, or autoimmune diseases. Here we report a case of a 3-year-old boy who presented to us with fever, was diagnosed with dengue fever, and treatment started for the same. Clinical response was poor to treatment and high-grade fever persisted. Subsequent evaluation showed Plasmodium falciparum malaria and treatment was initiated with antimalarial drugs. Further clinical deterioration with poor trend of laboratory values over the next few days prompted evaluation for HLH; workup was positive satisfying the HLH-2004 criteria and IV dexamethasone was started. The child gradually improved and was discharged with normal counts on follow-up over the next 3 months. This article emphasizes on the importance of high degree of suspicion, early workup, and initiation of treatment for HLH for a better outcome., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening clinical syndrome in children, and the knowledge of it is still limited. Two hundred twenty-seven children with HLH in our hospital were retrospectively analyzed from January 2001 to December 2018. The age of the patients on admission ranged from 1 day to 14 years old. The 3 most common clinical manifestations include fever (98.7%), hepatomegaly (95.6%), and splenomegaly (92.1%). The decrease of high-density lipoprotein cholesterol (99.1%) is very common in children with HLH. Albumin<25 g/L, activated partial thromboplastin time >65 s, and lactose dehydrogenase >1000 U/L were independent risk factors for poor early prognosis in children with HLH, and their odds ratio values were 2.515, 3.094, and 2.378, respectively, while age >28 months was identified as a protective factor (odds ratio=0.295). Of the 227 children, 67 (29.52%) died within 30 days of onset. The mortality rate in 2013 to 2018 was significantly lower than that in 2001 to 2012 (16.35% vs. 40.65%, P=0.000). The shortening of the time from onset to admission and the reduction of time from admission to definite diagnosis could be some of the reasons for the decrease of HLH mortality in 2013 to 2018 (P<0.05, respectively). Our study suggests that early identification of risk factors for HLH, timely diagnosis and treatment are important measures to improve the short-term prognosis of HLH in children., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes., Methods: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME)., Results: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy., Conclusion: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early., (© 2021 John Wiley & Sons Ltd.)

Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production., (© 2021. Springer Nature Limited.)

Background: Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the 'cytokine storm' such as adult-onset Still's disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group)., Patients and Methods: We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group., Results: Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and 'arthralgia or arthritis' are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83-1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data., Conclusions: IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH., Competing Interests: The 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 © 2021 Shiga, Nozaki, Tomita, Kishimoto, Hirooka, Kinoshita, Funauchi and Matsumura.)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation. Most studies on adult HLH have evaluated prognostic factors for overall survival; factors predicting early mortality have not been sufficiently investigated., Methods: This was a collaborative study between Henry Ford Hospital and Barnes-Jewish Hospital. We identified all adult HLH patients with at least 2 ferritin levels within 30 days from admission., Results: One-hundred twenty-four patients were identified. There were 77 males and 47 females; the median age at diagnosis was 48 years. Multivariate analysis showed that age (OR = 11.41; 95% CI:2.71-48.04; P = .001), hepatomegaly (OR = 15.68; 95% CI:3.24-75.96; P = .001), hyponatremia (OR = 5.94; 95% CI:1.76-20.1; P = .004), hypoalbuminemia (OR = 7.47; 95% CI:2.08-26.85; P = .002), and increasing ferritin levels (OR = 19.46; 95% CI:4.69-80.71; P < .001) were significant predictors of 30-day mortality. Patients with declining ferritin by more than 35% from the ferritin peak were more likely to survive the first 30 days of admission (OR = 4.33; 95% CI:1.04-18.1; P = .033). By risk stratifying our cohort, we identified changes in ferritin levels to be the most significant prognostic factor of 30-day mortality among other risk factors. Further investigating the prognostic utility of ferritin showed that increasing ferritin during the 1st week of admission (data available for 44 patients) was the only significant predictor of 30-day mortality., Conclusions: To the best of our knowledge, this is the first study reporting changes in ferritin to be a predictor for early death in adult HLH. Changes in ferritin might be a useful indicator of adult HLH disease activity and early prognosis., (© 2021 John Wiley & Sons Ltd.)

Objective: Infection with the novel coronavirus SARS-CoV-2 triggers severe illness with high mortality in a subgroup of patients. Such a critical course of COVID-19 is thought to be associated with the development of cytokine storm, a condition seen in macrophage activation syndrome (MAS) and secondary hemophagocytic lymphohistiocytosis (HLH). However, specific data demonstrating a clear association of cytokine storm with severe COVID-19 are still lacking. The aim of this study was to directly address whether immune activation in COVID-19 does indeed mimic the conditions found in these classic cytokine storm syndromes., Methods: Levels of 22 biomarkers were quantified in serum samples from patients with COVID-19 (n = 30 patients, n = 83 longitudinal samples in total), patients with secondary HLH/MAS (n = 50), and healthy controls (n = 9). Measurements were performed using bead array assays and single-marker enzyme-linked immunosorbent assay. Serum biomarker levels were assessed for correlations with disease outcome., Results: In patients with secondary HLH/MAS, we observed pronounced activation of the interleukin-18 (IL-18)-interferon-γ axis, increased serum levels of IL-1 receptor antagonist, intercellular adhesion molecule 1, and IL-8, and strongly reduced levels of soluble Fas ligand in the course of SARS-CoV-2 infection. These observations appeared to discriminate immune dysregulation in critical COVID-19 from the well-recognized characteristics of other cytokine storm syndromes., Conclusion: Serum biomarker profiles clearly separate COVID-19 from MAS or secondary HLH in terms of distinguishing the severe systemic hyperinflammation that occurs following SARS-CoV-2 infection. These findings could be useful in determining the efficacy of drugs targeting key molecules and pathways specifically associated with systemic cytokine storm conditions in the treatment of COVID-19., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy., (© 2021 Wiley Periodicals LLC.)

Background: To investigate whether red blood cell distribution width (RDW), platelet distribution width (PDW), and red blood cell distribution width to platelet ratio (RPR) can serve as biomarkers to distinguish hemophagocytic lymphohistiocytosis (HLH) from sepsis in children., Methods: This is a retrospective study, involving 71 HLH patients, 105 sepsis patients, and 88 normal controls from January 2018 to December 2019. RDW, PDW, and RPR values were obtained from peripheral blood samples before standard treatment. The clinical differential diagnostic values of RDW, PDW, and RPR were analyzed by receiver operating characteristic (ROC) curve. In addition, peripheral blood samples after treatment from HLH patients were also collected for the same analyses., Results: RDW, PDW, and RPR levels of the HLH patients were significantly higher than those of sepsis and normal controls (p < 0.001). In ROC curve analysis of the RDW, PDW, and RPR for diagnosis of HLH, the area under the curve (AUC) could reach to 0.7799 (95% CI = 0.7113-0.8486), 0.7835 (95% CI = 0.7093-0.8577), and 0.9268 (95% CI = 0.8886-0.9649), respectively. When using the criteria of RDW >13.75, PDW >13.30, and RPR >0.08, the sensitivity was 76.06%, 67.61%, and 84.51%, while the specificity was 68.57%, 85.71%, and 87.62%, respectively. After treatment of HLH patients, PDW and RPR were significantly reduced (p < 0.001)., Conclusions: This study shows that RDW, PDW, and RPR, which can be easily and cheaply detected, are novel indicators for differential diagnosis of HLH. PDW and RPR are useful indices for monitoring the effects of treatment on HLH., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Coagulation disorders are common in patients with hemophagocytic lymphohistiocytosis (HLH), associated with an increased risk of bleeding and death. We aim to investigate coagulation disorders and their outcome implications in critically ill patients with HLH., Methods: We prospectively evaluated 47 critically ill patients with HLH (median age of 54 years [42-67]) between April 2015 and December 2018. Coagulation assessments were performed at day 1. Abnormal standard coagulation was defined as prothrombin time (PT) <50% and/or fibrinogen <2g/L. HLH aetiology was mostly ascribed to haematological malignancies (74% of patients)., Results: Coagulation disorders and severe bleeding events were frequent, occurring in 30 (64%) and 11 (23%) patients respectively. At day 1, median fibrinogen level was 2∙65g/L [1.61-5.66]. Fibrinolytic activity was high as suggested by increased median levels of D-dimers, fibrin monomers, PAI-1 (plasminogen activator inhibitor) and tPA (tissue plasminogen activator). Forty-one (91%) patients had a decreased ADAMTS13 activity (A Disintegrin-like And Metalloproteinase with ThromboSpondin type 1 repeats, member 13). By multivariable analysis, the occurrence of a severe bleeding (OR 3.215 [1.194-8.653], p = 0∙021) and SOFA score (Sepsis-Related Organ Failure Assessment) at day 1 (OR 1.305 per point [1.146-1.485], p<0∙001) were independently associated with hospital mortality. No early biological marker was associated with severe bleeding., Conclusions: Hyperfibrinolysis may be the primary mechanism responsible for hypofibrinogenemia and may also participate in ADAMTS13 degradation. Targeting the plasmin system appears as a promising approach in severe HLH-related coagulation disorders., Competing Interests: The authors have declared that no competing interests exist.

Septic shock is a major public health concern. However, the clinical and laboratory criteria for sepsis overlap with those for hemophagocytic lymphohistiocytosis (HLH), and their differentiation can be challenging. The aim of this study was to compare HLH criteria among patients diagnosed with neonatal sepsis and childhood sepsis and to study the outcomes in patients fulfilling the diagnostic criteria for HLH. A cross-sectional study included 50 neonates and children with severe sepsis and/or septic shock. Clinical and laboratory data and HLH diagnostic criteria were studied in relation to patients outcome. Of all patients, 18% fulfilled three of the eight HLH diagnostic criteria, 2% fulfilled four criteria, and 4% fulfilled five criteria. All patients who fulfilled three or more of the criteria died. Mortality was higher in the presence of more positive HLH criteria and in pediatric age groups. However, the distributions of the HLH criteria were comparable for pediatric and neonatal patients with severe sepsis/septic shock, and their mortality rates were not significantly different when based on the criteria.

Patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) have a poor prognosis. This study investigated the efficacy of rituximab-containing immuno-chemotherapy regimens for EBV-HLH. In this study, 15 patients were treated with rituximab-containing regimens. The treatment efficacy and adverse events were evaluated. In 10 patients, EBV DNA became negative after the first course of treatment. The lymphocyte types infected by EBV in the 10 patients were only infected with B cells and mainly infected with B cells. In the other 5 patients, the EBV DNA of peripheral blood mononuclear cells (PBMC) before and after treatment with the regimens had no statistical difference (P = 0.111). In addition, in these 5 patients, EBV mainly infected T and NK cells. Among the 5 patients without a significant decline in EBV DNA of PBMC, 2 patients received allogeneic hematopoietic stem cell transplantation and turned negative for EBV DNA. This study suggests that rituximab-containing regimens are effective therapy for EBV-HLH with only and mainly B lymphocytes infected by EBV, especially for eliminating EBV., (Copyright © 2021. Published by Elsevier B.V.)

HLH syndrome may mimic sepsis but requires entirely different treatment. The aim of the study was to assess the occurrence of HLH features in patients with sepsis and the influence these exert on the patients' prognosis. The prospective study included 108 patients with suspected sepsis who were routinely evaluated according to HLH criteria. They were divided into group I (SOFA = 2, n = 57) and group II (SOFA ≥ 3, n = 51). Four patients were excluded from analysis: 1 with real HLH, 2 with Still's disease and 1 with lymphoma. The median (IQR) concentration of ferritin was 613.4 (850.3) ng/mL, however 6 patients revealed a remarkedly high ferritin concentration > 3000 ng/mL, including 2 with ferritin > 10,000 ng/mL. In total, 21 patients met ≥ 4/8 HLH criteria and were found to have sepsis with HLH-like syndrome (SHLS). Out of these, 19 responded to antimicrobials, 2 died due to infection. The sepsis patients presented with the following HLH criteria: fever (95.2%), hyperferritinemia (57.3%), splenomegaly (43.4%), reduced NK cell activity (35.2%), high sCD25 activity (27.4%) and rarely: hypertriglyceridemia (14.4%), duopenia (5.8%), hypofibrinogenemia (1.9%). Although group II patients had higher odds for SHLS presentation (OR 3.26, p = 0.026) and for death (OR 14.3, p = 0.013), SHLS occurrence had no impact on the risk of death (OR 0.77, p = 0.75). Sepsis patients can present with SHLS exclusively due to severe infection. Duopenia, hypertriglyceridemia, hypofibrinogenemia and high level of sCD25 are unusual in sepsis and might indicate real HLH syndrome. Hyperferritinemia, even as high as in real HLH syndrome, can occur in sepsis patients.

We performed a multicentre, non-randomised trial (NCT03533790) to investigate the efficacy of ruxolitinib combined with the doxorubicin-etoposide-methylprednisolone (Ru-DEP) regimen as a salvage therapy for refractory/relapsed haemophagocytic lymphohistiocytosis (HLH). All patients failing to achieve a complete or partial response 2 weeks after initial HLH-94/HLH-04 regimen or relapsed after remission were enrolled in the study between June 2018 and June 2019. The efficacy was evaluated 2 weeks after initiating Ru-DEP salvage therapy. Fifty-four eligible patients with refractory/relapsed (R/R) HLH were enrolled. One case could not be evaluated for efficacy. Excluding 12 patients who had previously received the DEP regimen, the overall response rate was 32 of 41 (78·0%) patients, with eight of 41 (19·5%) achieving complete response and 24 of 41 (58·5%) attaining a partial response. Of the R/R HLH patients who had previously received the DEP regimen, 7 of 12 (58·3%) achieved a partial response. Ferritin and soluble CD25 concentrations were significantly lower (P < 0·05), while the platelet count increased significantly (P = 0·034), and triglycerides decreased significantly (P = 0·002) compared with those before treatment. The Ru-DEP regimen may be a safe and effective salvage therapy, remaining effective in refractory/relapsed HLH following DEP treatment, especially in macrophage activation syndrome. In addition, the regimen can be considered for patients with contraindications to glucocorticoid, especially those with gastrointestinal bleeding., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Objectives: Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with diverse clinical, including hematologic, abnormalities. We describe peripheral blood and bone marrow findings in deceased and living patients with COVID-19., Methods: We examined bone marrows from 20 autopsies and 2 living patients with COVID-19 using H&E-stained slides and immunohistochemical stains. Clinical history and laboratory values were reviewed. HScore was calculated to estimate risk of hemophagocytic lymphohistocytosis (HLH)., Results: The deceased patients included 12 men and 8 women (aged 32 to >89 years; median, 63 years). Hematologic abnormalities included frequent neutrophilic leukocytosis, lymphopenia, anemia, and thrombocytopenia; one patient showed striking erythrocytosis. The bone marrows were all normocellular to hypercellular, most showing maturing trilineage hematopoiesis with myeloid left shift. In all 19 evaluable bone marrows, hemophagocytic histiocytes were identified. The HScore for secondary HLH ranged from 35 to 269 (median, 125; >169 in 5 patients). Coinfections were identified in 6 patients. In 2 living patients, bone marrow showed maturing trilineage hematopoiesis, including one showing few hemophagocytic histiocytes., Conclusions: Peripheral blood from deceased patients with COVID-19 frequently showed neutrophilic leukocytosis, lymphopenia, and, rarely, secondary polycythemia; hemophagocytosis was common in their bone marrow. Consistent with other studies, we provide histopathologic evidence of secondary HLH development in patients with COVID-19., (© American Society for Clinical Pathology, 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163 and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-ɣ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18 * HScore was identified as a highly potential score.

The HLH-2004 criteria were initially conceived as inclusion criteria for a clinical trial investigating therapy for (largely primary) pediatric hemophagocytic lymphohistiocytosis (HLH). These criteria have since been extrapolated to diagnose adult secondary HLH despite their questionable generalizability. It remains unclear whether these diagnostic criteria are truly applicable among adult secondary cases, and rigorous evidence for their use among such patients is lacking. This review critically examines the utility of the HLH-2004 criteria for the diagnosis of adult secondary HLH. It is framed as a reappraisal of each of the criteria's individual components, with an assessment of the relevance of, and/or evidence regarding, each. There are clear limitations to these criteria as they apply to adult secondary HLH, however they may help guide our understanding of the disease to some extent. Some new paradigms are emerging for the diagnosis of adult secondary HLH, however these too are limited by the difficulties inherent in formulating specific criteria for a very non-specific syndrome, which lacks any single gold-standard diagnostic test., (Copyright © 2020 The Author. Published by Elsevier GmbH.. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder of excessive immune activation. It is mostly seen in the paediatric population and is rarely observed in adults. HLH can be inherited or acquired and is commonly triggered by activation of the immune system by an underlying viral infection or in immune system deficiency such as malignancy or underlying rheumatological disease. HLH is a difficult entity to diagnose due to the rarity of this disorder, variable clinical presentation and non-specific clinical and laboratory findings. HLH carries a high mortality if left untreated, and therefore prompt diagnosis and initiation of immunosuppressive, immunomodulatory and cytostatic medications are critical to improve survival in affected patients. Here, we present a case of lamotrigine-associated HLH. To our knowledge, only eight other cases of lamotrigine-associated HLH have been reported in adult patients., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a potentially life-threatening syndrome. This is the first case of acquired HLH caused by dual infections with Candida albicans and reactivated EBV infections, which focuses on the importance of morphological awareness of peripheral blood and bone marrow because sometimes they are the only locations that HLH and fungal microorganisms can be diagnosed. A 29-year-old woman with a history of abdominal distension and 9 months of intermittent fevers ($38.8°C) was admitted to the hematology department with treatment for leukopenia and thrombocytopenia. Severe infection of bilateral pulmonary and marked hepatosplenomegaly were detected by computed tomography. EB virus-CA IgG, EB virus-NA IgG and EB virus-CA IgM were positive. Scattered yeast-like fungi were found on peripheral blood and bone marrow (BM) smears. BM smears indicated prominent hemophagocytosis. Cultures of bronchoalveolar lavage and BM confirmed the growth of C. albicans. A diagnosis of HLH caused by dual infections with Candida albicans and reactivated EBV infections was established based on the clinical features of the patient because 7 of the 8 diagnostic criteria were met. She was treated with etoposide, dexamethasone for HLH, as well as highly active antifungal and antiviral therapies for the underlying etiology of dual infections. The patient eventually recovered following the effective treatment. A timely and accurate diagnosis is crucial to the prognosis of the dangerous disease.

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe disease characterized by immune hyperactivation and cytokine storm. Given the high mortality rate of HLH, there is a need for more effective diagnostic tools and treatments. The present study developed a dendrimer‑based protein biochip for rapid, sensitive and simultaneous detection of serum interferon (IFN)‑γ and endogenous anti‑IFN‑γ antibody (Ab) in patients with HLH. A gold biochip was modified with 1, 4‑phenylene diisothiocyanate (PDITC), polyamidoamine (PAMAM) or PDITC‑activated PAMAM. The optimal immobilization concentration for Ab capture and the reaction concentration for detecting Ab on the PDITC‑activated PAMAM‑modified biochip were 6.25 and 3.12 µg/ml, respectively; the limit of detection of IFN‑γ protein was 50 pg/ml. The efficiency of the protein‑probed biochip in detecting IFN‑γ and anti‑IFN‑γ Ab in serum samples from 77 patients with HLH was evaluated; the positive rates for IFN‑γ and anti‑IFN‑γ IgG Ab were 63.6% (49/77) and 61.0% (47/77), respectively. The present results demonstrated that the PDITC‑activated PAMAM‑modified biochip might be a sensitive tool for the specific detection of IFN‑γ and anti‑IFN‑γ Ab in serum, and might have clinical applicability for the diagnosis of HLH.

Introduction: A hyperinflammatory environment has been a hallmark of COVID-19 infection and is thought to be a key mediator of morbidity. Elevated ferritin has been observed in many patients with COVID-19. Several retrospective studies have shown ferritin levels can be correlated and predictive of poor outcomes in COVID-19, though a rigorous analysis has been lacking., Methods: A retrospective analysis of 942 adult COVID-19 patients admitted in March 2020 at a large New York City health system with available ferritin levels., Results: The primary outcome, all-cause mortality, was observed in 265 (28.1%) patients. Patients who died had a significantly higher median admission and maximum ferritin levels than those who did not. However, death was poorly predicted by admission and maximum ferritin levels on receiver operator curve (ROC) analysis, with AUCs of 0.677 and 0.638, respectively. AUCs increased when the cohort was limited to progressively younger patients. Ferritin levels were minimally better at predicting our secondary outcomes. These included mechanical ventilation, observed in 280 (29.7%) patients with an ROC yielding an area under the curve (AUC) of 0.769, and new renal replacement therapy, observed in 80 (8.5%) of patients with an ROC yielding an AUC of 0.787. We also performed a subset analysis on 22 patients with ferritins >20 000 ng/mL. None of the patients met HLH-2004 diagnostic criteria. Fifteen (68.2%) of these patients had suspected or confirmed bacterial infections., Conclusions: Though many patients with COVID-19 present with hyperferritinemia, elevated ferritin levels are not accurate predictors of outcomes and do not appear to be indicative of hemophagocytic lymphohistiocytosis., (© 2020 John Wiley & Sons Ltd.)

Infection with SARS-CoV-2, the cause of coronavirus infectious disease-19 (COVID-19), has caused a pandemic. Few data are available about the risk of COVID-19 infection in persons with hematological cancer, but controversy whether these persons have the same clinical signs and outcomes. We describe a case of life-threatening COVID-19 infection complicated by severe anemia in patients affected also by chronic myelogenous leukemia. The screening for RBC antibodies and the direct antiglobulin test (DAT) turned positive. The identification of the antibodies, showed the presence of an alloantibody with anti-Lewis b specificity, which was reactive at room temperature, in the anti-human globulin phase (AGH) and with papain-treated red blood cells. At the same time hemophagocytic lymphohistiocytosis (HLH), on the basis of major laboratory findings including hyperferritnemia, increase of triglicerides levels and according to the HLH score was suspected. Patients received antiviral therapy, steroids and intravenous immunoglobulins. Hemolysis resolved and ferritin dramatically decreased after administration of Ig and a Afull recovery was achieved after viral infection resolution.This case highlights the novel and multifaceted hematological findings during sever COVID 19 infection. COVID 19-related pneumonia is mediated by hyper activation of effector T cells and excessive production of inflammatory cytokines, such as IL-6, IL-1, interferon-gamma, and TNF. This inflammatory process called "cytokine storm" is a life-threatening complication of COVID 19 infection. In this case severe immunohematological consequences are reported for the first time and recognition of this complications are probably underestimated., (Copyright © 2020. Published by Elsevier Ltd.)

Circular RNAs (circRNAs) may be potential biomarkers or therapeutic targets of hemophagocytic syndrome (HPS) due to their high stability, covalently closed structure and implicated roles in gene regulation. The aim of the present study was to determine and characterize the circRNAs from natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (NK/T-LAHS). CircRNA in NK/T-LAHS and healthy control patient serum were assessed using next-generation sequencing (NGS). One hundred and forty-three differentially expressed circRNAs of which 114 were up-regulated and 29 were down-regulated in NK/T-LAHS patients were identified. Next, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to explore the roles of these circRNAs were utilized, and a microRNA (miRNA) target gene prediction software to predict the interaction of circRNAs and miRNAs was used. Moreover, five circRNAs were then selected as NK/T-LAHS candidate circRNAs which were related to tumors and contained NK/T-LAHS-related miRNA-binding sites. Using real-time PCR, the significant up-regulation of these five circRNAs in NK/T-LAHS patient serum were verified. Together these results show that circRNAs may serve as valuable diagnostic biomarkers of early NK/T-LAHS, with potential therapeutic targets in disease progression., (© 2020 The Author(s).)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias., Patient Concerns: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms., Diagnosis: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate., Interventions: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone., Outcomes: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient., Innovation: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT)., Conclusion: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.

Background: Soluble interleukin-2 receptor (sIL-2r) level is used as a diagnostic tool in hemophagocytic lymphohistiocytosis (HLH). However, evidence supporting its use among adults is inadequate., Objective and Methods: We conducted a retrospective study to assess the performance characteristics of sIL-2r for the diagnosis of adult HLH., Results: One hundred thirty-two adults with sIL-2r levels sent for evaluation of HLH over a ten-year period were included. Sixty-five (49%) met criteria for HLH. Mean sIL-2r was significantly higher among patients with HLH relative to all patients without HLH (12942U/ml vs. 6308 U/mL, P = .00311). However, when comparing mean sIL-2r in the HLH group to those in the non-HLH group with primary diagnoses of hematologic malignancy (8911 U/mL), sepsis (7127 U/mL), and rheumatologic disease (4624 U/mL), no significant differences were found (P = .241, P = .178, and P = .0607, respectively). There was only weak correlation between sIL-2r and diagnosis of HLH (r = .253). The standard cutoff sIL-2r > 2400 U/ml yielded a sensitivity of 89.2% and specificity of 38.8%. The area under the curve for the corresponding receiver-operator curve was 0.691, consistent with a poor discriminating ability for the diagnosis of HLH., Conclusions: sIL-2r is a limited test for the diagnosis of adult secondary HLH, and its role in this setting should be reevaluated., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Secondary hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal condition with various underlying disorders in adult patients and is diagnosed based on the HLH-2004 criteria, which were established based on experience in pediatric patients. However, few studies have prospectively evaluated the treatment outcomes and diagnostic performance of HLH criteria in adult patients with secondary HLH. Thus, we performed a single-center, prospective cohort study of adult patients with suspected HLH, and we analyzed treatment outcomes of patients enrolled between 2017 and 2019 as an interim analysis ( ClinicalTrials.gov Identifier: NCT03117010). Of the 73 patients with suspected HLH, 70 patients completed the evaluation for ≥ 7 of the HLH-2004 criteria, and 55 patients were diagnosed with HLH (55/73, 75%). Although serum ferritin and fever had a sensitivity of more than 90%, both had exceptionally low specificity, whereas soluble CD25 had a sensitivity of more than 90% and specificity of 80%. Forty patients with malignancy-associated HLH had B cell (n = 19) or T- or NK-cell (n = 21) lymphoid malignancy, whereas 15 patients had non-malignant disorders. Non-malignancy-associated HLH had greater than 90% 1-year overall survival (OS) after diagnosis of HLH, whereas that for malignancy-associated HLH was less than 40%. In conclusion, our study showed promising treatment outcomes for patients enrolled in our prospective cohort study, and prospectively demonstrated the diagnostic performance of the HLH-2004 criteria in adult patients with suspected HLH. Given that lymphoma was the most common cause of HLH in adults, thorough evaluation for lymphoma should be performed in adults with suspected HLH.