HLH-2004 Protocol Research Articles

Case report: Aggressive natural killer cell leukemia and refractory hemophagocytic lymphohistiocytosis in an adolescent

Aggressive natural killer cell leukemia (ANKL) is a rare, aggressive hematologic malignancy which often presents as fulminant Epstein-Barr virus (EBV)- driven hemophagocytic lymphohistiocytosis (HLH). ANKL lacks a distinct immunologic and morphologic signature, making early diagnosis particularly challenging. Here we present a case of ANKL in a patient presenting with EBV-HLH. After poor treatment response to the HLH-2004 protocol (etoposide and dexamethasone), bone marrow biopsy demonstrated an atypical CD3-/CD56+ natural killer (NK) cell population with diminished CD7 expression consistent with EBV+ ANKL. Asparaginase-based chemotherapy was initiated but his disease progressed and he died from multiorgan failure. This case highlights the diagnostic challenges of ANKL given the lack of standardized diagnostic criteria, the importance of considering T/NK cell malignancies in the differential diagnosis of EBV-HLH, and adds to the literature on this rare disease.

Ruxolitinib, IV Immunoglobulin, and High-Dose Glucocorticoids for Critically Ill Adults With Secondary Hemophagocytic Lymphohistiocytosis: A Single-Center Observational Pilot Study.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a cytokine-driven inflammatory syndrome that is associated with substantial morbidity and mortality and frequently leads to ICU admission. Overall survival in adults with sHLH remains poor, especially in those requiring intensive care. Classical chemotherapeutic treatment exhibits myelosuppression and toxicity. Recently, inhibition of Janus kinase signaling by ruxolitinib has shown efficacy in pediatric HLH. We therefore aimed to determine the activity and safety of a ruxolitinib-based regimen, in critically ill adults with sHLH. Observational pilot study. Single-center tertiary academic ICU. Nine adults (≥ 18 yr) who fulfilled at least five of the eight HLH-2004 criteria. Triplet regimen combining: 1) ruxolitinib, 2) polyvalent human IV immunoglobulins (IVIG) at a dose of 1 g/kg bodyweight for 5 days, and 3) high-dose corticosteroids (CSs, dexamethasone 10 mg/m² body surface area, or methylprednisolone equivalent) with subsequent tapering according to the HLH-2004 protocol. Nine patients (median age: 42 yr [25th-75th percentile: 32-54]; male: n = 6 males, median H-score: 299 [255-304]) were treated with the triplet regimen. The median Sequential Organ Failure Assessment score at HLH diagnosis was 9 (median; 25th-75th percentile: 7-12), indicating multiple-organ dysfunction in all patients. Within 10 days a significant decrease of the inflammatory parameters soluble interleukin-2 receptor and ferritin as well as a stabilization of the blood count could be shown. All patients were alive at ICU discharge (100% ICU survival), 1 patient died after ICU discharge because of traumatic intracerebral hemorrhage that might be related to HLH or treatment, corresponding to an overall survival of 86% in a 6 months follow-up period. In this small case series, a triplet regimen of ruxolitinib in combination with IVIG and CS was highly effective and save for treating critically ill adults with sHLH.

Hemophagocytic Lymphohistiocytosis (HLH) in a Post-COVID-19 Infection: A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper inflammatory process caused by extensive immune activation and characterized by multi organ dysfunction. During COVID-19 pandemic secondary hemophagocytic lymphohistiocytosis has been reported in acute phase of COVID-19 infection, but HLH in recovered post-COVID-19 patients is rare. We report a case of HLH following of COVID infection. Case Description: 72-year-old female with well-controlled rheumatoid arthritis and COVID infection 2 months prior presented with progressive shortness of breath. She was diagnosed with acute on chronic heart failure, acute kidney injury, worsening anemia and thrombocytopenia. She progressively got worse during hospitalization and on day 9 developed fever and multiorgan failure (pancytopenia, acute liver injury, respiratory failure requiring mechanical ventilation, renal failure requiring hemodialysis). Labs included hemoglobin of 7.9 g/dL, platelets 50 Th/uL, ANC 1.38 Th/uL, LDH 6000 IU/L, ferritin >10,000 ng/ml, fibrinogen 136 mg/dL, triglycerides 656 mg/dL. HLH was suspected and a bone marrow biopsy showed occasional macrophages with hemophagocytosis without evidence of lymphoproliferative disorder (Figure 1). Interleukin-2 receptor soluble was elevated at 57026.9 pg/mL. HLH diagnosis was established, and patient was started on HLH-94 protocol with etoposide and dexamethasone. She improved quickly with treatment and was extubated in a few days. After 4 weeks, there was continued clinical improvement with improving liver function, LDH was down to 373, ferritin 3586 but she remained cytopenic needing transfusion support. By week 6, she was off dialysis and repeat Interleukin-2 receptor soluble was 2500 pg/ml and ferritin was 2500 ng/ml. A positron emission tomography (PET) scan did not show any evidence of lymphoma. Patient was not considered to be suitable candidate for stem cell transplant and was monitored. Within 6-8 weeks, she was noted to have worsening LDH, ferritin, liver function and patient was started on ruxolitinib 5 mg twice a day and dexamethasone 2 mg daily. Patient continued to have worsening anemia, thrombocytopenia, LDH and ferritin. Patient was readmitted around week 6 of ruxolitinib treatment with progressive shortness of breath. Patient was re-treated with dexamethasone and etoposide. On day 10 of 2nd hospitalization, she developed acute respiratory failure needing mechanical ventilation and was diagnosed with abdominal viscus perforation. After discussion with family, she was transitioned to best supportive care given poor prognosis. Discussion: Few cases of HLH in post-covid-19 patients have been reported in the literature, but this entity may be likely under diagnosed given the delayed presentation, absence of definitive clinical, laboratory, or histopathological criteria. Immune dysregulation and macrophage activation due to subclinical inflammation following post-COVID-19 infection is postulated to underlie the pathogenesis of HLH in post-COVID-19 patients. The hyperinflammatory situation results in multi-organ failure and high mortality rates. The HLH2004 has been recommended as the diagnostic criteria of choice for HLH among post-COVID-19 patients. Immunosuppressive therapies with steroids, and etoposide are the conventional first-line agents based on the HLH94 protocol; however, refractory cases have been shown to respond to other immunosuppressive agents and biologics including ruxolitinib, alemtuzumab, and emapalumab. Figure 1: A. Hemophagocytosis (Macrophage ingesting lymphocyte) B. Hemophagocytosis, more specifically-erythrophagocytosis (macrophage ingesting red blood cell).

HLH-JAK the First Open-Label, Phase II Study Evaluating Anti-JAK1 Itacitinib, for Non Severe HLH in Adults

Background: HLH results in dysregulation of the immune system activation, characterized by excessive pro-inflammatory production, which are responsible for the main clinical and biological features of HLH syndrome. In sporadic/adult forms of HLH, treatment is challenging due to the negative effects of corticosteroids on potential infectious related HLH, and etoposide, which may mask hematological neoplasm (H)-associated hemophagocytic lymphohistiocytosis (H-HLH). Cytokines involved in HLH syndrome activate the JAK/STAT pathway in immune cells, particularly gamma- interferon through JAK1. Kinase inhibitors blocking JAK activity, particularly Ruxolitinib a JAK1/2 inhibitor, have shown some efficacy in murine genetic models of HLH. However, JAK2 inhibition may be responsible of cytopenia in contrast to JAK1, which may have an effect on Interferon-gamma signaling. HLH-JAK is the first open-label, phase II study evaluating the use of a selective and potent anti-JAK1 inhibitor, itacitinib, alone for non-severe adult HLH (including relapsing or refractory) Methods: Adult patients were included on criteria adapted from “HLH-2004 protocol'” and an “H Score” >169. Twenty-three French medical centers participated to the study. In the absence of organ failure, fibrinogen<0.5 g/L, platelets<20 G/l, the need for ICU transfer, or etoposide treatment, HLH patients were considered non-severe. The dose of itacitinib treatment administered was 300 mg per day. Seven clinical and biological parameters were used as a baseline (Hemoglobin, Platelets, Polynuclear neutrophil, Fibrinogen, Ferritin, Fever, Performans Status). Patients were classified as being in complete or partial if they normalized all 7 parameters or less, respectively. The primary endpoint of the study was the rate of response (RR), complete or partial (CR or PR), at day 15 of treatment. If patients had H-HLH requiring chemotherapy or severe HLH requiring etoposide, itacitinib treatment was stopped before day 15 and patients were considered in failure. In case of CR/PR at day 15, treatment could be followed until day 30 and increased to 400 mg (PR), which may result in delay of specific treatment of H-HLH. Patients were followed-up until D90. It was planned to include 63 patients with a Simon optimal 2-stage design. The number of responses to advance to stage 2 was 9 responses out of 24 included patients. These are the results from the first fifteen patients. Results : Fifteen patients were included between May 2022 and June 2023, 67% (10/15) were male and mean (±SD) age was 53 ± 22 y. At inclusion, 3 (20%) had relapsing and 12 (80%) de novo HLH. None but one of the patients has an associated disease known before inclusion. Associated diseases were distributed as Non Hodgkin Lymphoma (n=6), Autoinflammatory/immune disease (n=6) and unknown for 3 patients. At day 15, 10 out of 15 patients (67%) had a CR (n=6) or PR (n=4), reaching the level of efficacy (at least 9 responses) to advance to stage 2 of the protocol. Before D15, five patients stopped the treatment, with two in progression at D15 resulting in death during first months of treatment. Two patients died before D15 and one received chemotherapy for a B-cell non Hodgkin Lymphoma (NHL). Patients-related Adverse Effects (AEs) occurred in 24 of cases and fever was the most frequent AEs being detected. Conclusions : As first line treatment, itacitinib monotherapy provided encouraging clinical activity characterized by a high RR and durable response and no safety issues were notified. The second stage of HLH JAK is ongoing. Clinical trial information: NCT NCT05063110

Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Single Institution Case Series

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by the abnormal activation of macrophages and T cells. The primary form, resulting from lymphocyte-related mutations, is more common in children, while the secondary (acquired) form known as sHLH prevails in adults. sHLH is often triggered by infections or malignancies (Mal-HLH) but can also be induced by autoinflammatory disorders called macrophage activation syndrome (MAS; or MAS-HLH). We present a retrospective case series of adults treated for sHLH at a single institution from 2012 to 2023. Methods: Retrospective data was collected using the EDW database, and 36 patients were identified using ICD 9/10 codes 288.4 and D76.1 for HLH. Subsequently, a manual review of electronic medical records was conducted; criteria for inclusion were age >18 years at the time of diagnosis and meeting HLH-2004 criteria ( Panel-1). Results: Out of the 36 patients reviewed, 11 met the criteria and were included in the analysis. These cases occurred between 2015 and 2023. The median age at diagnosis was 52 (range 18 to 81). The female-to-male ratio in our study was 4:7. Most patients (73%) were white. Additionally, 45% of the patients were immunocompromised. 91% of the patients presented with fever, while only 45% had splenomegaly. Trilineage cytopenias were observed in all patients. In our study, 5/11 had hypofibrinogenemia, and 6/11 had hypertriglyceridemia. Hemophagocytosis was evident in 91% of the patients. Natural Killer (NK) cell activity was measured in 4 patients, and all exhibited low or no NK cell activity. In 10 out of 10 patients, soluble IL-2 receptors were elevated. None of the patients in the study had hepatomegaly, but all had transaminitis and hyperbilirubinemia, and 82% had elevated alkaline phosphatase levels. Elevated lactate levels were observed in 78% of patients, and 27% had a rash. Neurological features were observed in 6 out of 10 patients. Lactate dehydrogenase was elevated in all patients with a median value of 1551 U/L (range 354 - 3689) Presumed etiologies for sHLH included malignancy (4), infection (3), autoimmune disease (3), and unknown cause (1). Treatment was highly individualized based on the underlying trigger and was guided by the HLH-94 protocol ( Panel-2). All patients received high-dose steroids, 6/11 received etoposide, and 2 received intrathecal therapy for neurological involvement. Conclusion: At a median follow-up period of 16 days, five patients had died. The survival rates at 30 days and 1 year were 45% and 27%, respectively. The overall mortality rate was 55%. While mortality rates were 75% in the Mal-HLH arm and 67% in the infectious arm, all patients with MAS-HLH survived while performing the study indicating a better prognosis for patients with this type of HLH.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Predictive model for early death risk in pediatric hemophagocytic lymphohistiocytosis patients based on machine learning

BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening disease in children, with a high early mortality rate. This study aimed to construct machine learning model to predict the risk of early death using clinical indicators at the time of HLH diagnosis. MethodsThis observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data was collected from pediatric HLH patients diagnosed by the HLH-2004 protocol between January 2006 and December 2022. Six machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. ResultsThe study included 587 pediatric HLH patients, and the early mortality rate was 28.45 %. The logistic and XGBoost model with the best performance after feature screening were selected to predict early death of HLH patients. The logistic model had an AUC of 0.915 and an accuracy of 0.863, while the XGBoost model had an AUC of 0.889 and an accuracy of 0.829. The risk factors most associated with early death were the absence of immunochemotherapy, decreased TC levels, increased BUN and total bilirubin, and prolonged TT. We developed an online calculator tool for predicting the probability of early death in children with HLH. ConclusionsWe developed the first web-based early mortality prediction tool for pediatric HLH to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200061315).

Clinical characteristics and prognostic factors of 75 cases with acquired hemophagocytic syndrome

ABSTRACTObjectivesThe study's aim was to enhance awareness of acquired hemophagocytic syndrome (HPS) in adults by analyzing clinical features, and investigating the relationship between factors such as the Systemic Inflammation Index (SII) and the prognosis of HPS.MethodsClinical characteristics, survival data, and prognostic factors of 75 HPS patients admitted to our hospital between January 2012 and October 2022 were analyzed.ResultsIn the high SII group, red blood cells, white blood cells, platelets, neutrophils, fibrinogen, and CD4 + cell activity were higher, and survival time was longer compared to the low SII group. Conversely, total bilirubin and direct bilirubin were higher in the low SII group (P ≤ 0.05). After applying the log-Rank or Breslow tests, HPS patients in the high SII group and those following the HLH-2004 protocol experienced a notably longer survival time. (χ2 = 4.291, P < 0.05; χ2 = 5.210, P < 0.05). Patients with poor prognosis showed higher age of onset, elevated levels of total, direct, and indirect bilirubin, and a greater rate of EBV infection, but reduced levels of red blood cells, platelets, hemoglobin, albumin, globulin, and HLH-2004 protocol usage rate(P < 0.05). Multivariate analysis and ROC curve results indicate that special attention is needed for patients with platelets < 42.5 × 109/L, albumin < 27.7 g/L, fibrinogen < 1.085 g/L, those not following the HLH-2004 protocol, and those who are EBV (+).Discussion and ConclusionEarly diagnosis and following the HLH-2004 protocol are essential for patients with HPS clinical manifestations to improve prognosis. Additional research is necessary to examine the link between SII and HPS patients’ prognosis.

Anakinra versus etoposide-based therapy added to high-dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome usually treated with high-dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH-94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide-based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH-94 protocol, HDS alone, or supportive care. Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH-94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH-94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH-94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.

Modifying NHL-BFM-90 and HLH-2004 Protocols for a Child with SPLTCL and HLH; Prompt Initiation of Dexamethasone and Etoposide

Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL) which is similar to lobular panniculitis is a subtype of skin lymphoma that is characterized by pleomorphic T cells and benign macrophages. The simultaneous presence of hemophagocytic lymphohistiocytosis (HLH) is the most important and adverse prognostic factor in SPLTCL. SPLTCL is a rare disease with no well-established standard treatment. We report a child with SPLTCL and HLH, who were successfully treated with the modified NHL (non-Hodgkin lymphoma)-BFM(Berlin-Frankfurt-Münster)-90 and HLH-2004 protocols. Patient had persistent fever and subcutaneous masses. SPLTCL with HLH was diagnosed by immunohistochemistry, radiology and laboratory results. SPLTCL with HLH has shown high mortality when treated with a combination of intensive anticancer drugs. Thus, we first administered dexamethasone and etoposide. After this, when we used the modified protocol of NHL-BFM-90 and HLH-2004, patient showed complete resolution of the subcutaneous masses and features of HLH, except for persistent hyperferritinemia. We tried etanercept to reduce high serum ferritin with some effects. In children with diagnosis of SPLTCL with HLH, initiation of immediate and appropriate treatment affects prognosis. Thus, prompt initiation of the agents that can simultaneously control underlying disease as well as secondary HLH could have lead to successful results.

Comparative Analysis of Primary and Reactivated EB Virus Infection Associated Hemophagocytic Lymphohistiocytosis

To compare the clinical characteristics of children with hemophagocytic lymphocytosis (HLH) associated with primary Epstein-Barr virus (EBV) infection and EBV reactivation, and explore the effects of different EBV infection status on the clinical indexes and prognosis of HLH. The clinical data of 51 children with EBV associated HLH treated in Henan Children's Hospital from June 2016 to June 2021 were collected. According to the detection results of plasma EBV antibody spectrum, they were divided into EBV primary infection-associated HLH group (18 cases) and EBV reactivation-associated HLH group (33 cases). The clinical features, laboratory indexes and prognosis of the two groups were analyzed and compared. There were no significant differences in age, gender, hepatomegaly, splenomegaly, lymphadenopathy, neutrophil count in peripheral blood, hemoglobin content, platelet count, plasma EBV-DNA load, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, albumin, fibrinogen, triglyceride, ferritin, hemophagocytosis in bone marrow, NK cell activity and sCD25 between the two groups(P>0.05). The central nervous system involvement and CD4/CD8 in EBV reactivation-associated HLH group were significantly higher than those in primary infection-associated HLH group, but the total bilirubin was significantly lower than that in primary infection-associated HLH group (P<0.05). After treatment according to HLH-2004 protocol, the remission rate, 5-year OS rate and 5-year EFS rate of patients in EBV reactivation-associated HLH group were significantly lower than those in EBV primary infection-associated HLH group (P<0.05). EBV reactivation-associated HLH is more likely to cause central nervous system involvement and the prognosis is worser than EBV primary infection-associated HLH, which requires intensive treatment.

Haemophagocytic lymphohistiocytosis: case series. Serum ferritin level as an indicator of treatment effectiveness

Introduction: Haemophagocytic lymphohistiocytosis (HLH) is a medical condition associated with over-activation of the immune system. HLH results from the inactivity of NK cells and uncontrolled activity of cytotoxic T lymphocytes and macrophages with the massive cytokine response.[1] Cytohistological examinations might show hemophagocytes in different tissues (e.g., bone marrow). Exceptionally high level of ferritin is often observed in the laboratory findings. Due to aggressive course of the disease mortality rate is extremely high. Material and methods: We presented three patients with acquired form of HLH treated successfully in Heaematooncology Department of Medical University of Lublin from September 2018 to April 2021. Results: In the first patient, HLH developed during pregnancy. Patient 2 was first hospitalized in the Intensive Care Unit (ICU) and 10 therapeutic plasma exchanges (TPE) were carried out. In both patients, stabilization -of ferritin levels and remission of the disease were achieved soon after the application of the treatment according to the HLH-2004 protocol. Case 3 presents a patient in whom HLH was induced by EBV and SARS CoV-2 infections. In the first stage of the treatment, the patient received drugs according to the HLH-2004 protocol, but the serum ferritin did not normalize. The reinfection with SARS CoV-2 virus occurred again in the course of the treatment. Due to the disease resistance and inability to continue the HLH-2004 protocol, it was decided to start ruxolitinib therapy, which resulted in stabilization of the serum ferritin and improvement of the general condition. The patient was qualified for allogeneic bone marrow transplantation. Conclusions: HLH is a difficult and interdisciplinary diagnostic and therapeutic problem. It is essential to popularize knowledge about fast and targeted diagnostics. Among laboratory finding, the ferritin concentration seemed to be particularly helpful as a predictor of treatment effectiveness. Proper diagnosis and treatment implemented as early as possible could save patients’ lives.

Low total cholesterol predicts early death in children with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressive and potentially life-threatening disorder. Identifying risk factors and timely adjustment of the given treatment regimens is critical to reducing the early mortality in HLH patients. Hypocholesterolemia has been reported to be associated with poor prognosis in a variety of critical illnesses. However, serum cholesterol is rarely studied in HLH patients, and its prognostic value is unclear. We conducted a retrospective cohort study in National Clinical Research Center for Child Health and Disorders (Chongqing), identifying pediatric HLH patients (including genetically confirmed pHLH and not genetically confirmed pHLH) diagnosed with the HLH-2004 protocol and treated with immunochemotherapy between January 2008 and December 2020. The patients' blood lipid levels at initial diagnosis of HLH, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), were reviewed based on electronic medical records. Both Cox and logistic regression models were used to estimate the effects of blood lipid indicators on early death (within 30 days after diagnosis). A total of 353 patients were enrolled in the study, with a median age at diagnosis of 45 months. The observed 30-day mortality rate was 19.05% (64/336, 17 were lost to follow-up) and Kaplan-Meier-estimated 3-year survival rate was 61.67% (95% CI, 56.27%-67.59%). DNA-targeted sequencing of HLH-related genes was performed in 173 (49.0%, 173/353) patients (not all patients with suspected pHLH underwent genetic testing), and 29 patients were diagnosed with genetically confirmed pHLH. Lipid panel was performed in 349 patients: 91.98% (321/349) had TG ≥ 1.80 mmol/L, 62.75%(219/349) had TG ≥ 3.00 mmol/L, 92.84% (324/349) had HDL-C ≤ 1.04 mmol/L, 58.74% (205/349) had LDL-C ≤ 1.30 mmol/L and 24.64% (86/349) had TC ≤ 3.11 mmol/L. TC ≤ 3.11 mmol/L and BUN ≥ 7.14 mmol/L were the independent risk factors for 30-day mortality [HR(95%CI): 2.85(1.46, 5.57) and 2.90(1.48, 5.68), respectively]. The presence of one of these risk factors increased the 30-day mortality rate by 6-fold [HR = 6.24, 95%CI: (3.18, 12.22)] and the presence of two risk factors by nearly 10-fold [HR = 9.98, 95%CI: (4.23, 23.56)] compared with the patients with no risk factors. Severe derangement of lipoproteins is common in children with HLH, and decreased TC is an independent risk factor for early death. Hypocholesterolemia should be included as a biomarker during the diagnosis and management of HLH patients.

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT WITH COVID-19 AND HERPES SIMPLEX VIRUS (HSV): A CASE REPORT

SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT WITH COVID-19 AND HERPES SIMPLEX VIRUS (HSV): A CASE REPORT

SEVERE COVID-19 COMPLICATED WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

SEVERE COVID-19 COMPLICATED WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS: A CASE REPORT

Limited efficacy of tocilizumab in adult patients with secondary hemophagocytic lymphohistiocytosis: a retrospective cohort study

BackgroundInterleukin (IL)-6 is one of the key cytokines in the pathogenesis of secondary hemophagocytic lymphohistiocytosis (sHLH); however, the efficacy and safety of tocilizumab (TCZ), a monoclonal IL-6 receptor antibody, in patients with sHLH is uncertain.Methods/ResultsThis study included 64 adult patients who were diagnosed with sHLH based on the HLH-2004 criteria. Patients were classified into two groups based on treatment regimen at baseline: tocilizumab (TCZ group, n = 8) versus other treatments (control group), including HLH-2004 protocol (n = 35), chemotherapy (n = 7), glucocorticoid alone (n = 8), and with other immunosuppressants (n = 6). Primary outcome was overall 8-week survival. Baseline characteristics between the two groups were comparable. At day 56, one patient (12.5%) in the TCZ group and twenty-eight patients (51.9%) in the control group survived. Univariable and multivariable Cox proportional hazard analysis showed that TCZ significantly increased the risk of death (adjusted hazard ratio 5.55; 95% CI 2.13–14.49). The complete or partial response rate at day 14 was 44.6% in the control group, and nil in the TCZ group. In contrast, infectious complications occurred more frequently in the TCZ group than in the control group (14.3% vs. 50.0%).ConclusionOur results suggest that tocilizumab has limited efficacy in treating adult patients with sHLH and could increase the risk of infectious complications compared to the conventional treatments.

Fatal Case of EBV-negative Posttransplant Lymphoproliferative Disorder With Hemophagocytic Lymphohistiocytosis in an Adult Kidney Transplant Recipient.

Fatal Case of EBV-negative Posttransplant Lymphoproliferative Disorder With Hemophagocytic Lymphohistiocytosis in an Adult Kidney Transplant Recipient.

Characteristics and prognostic value of pleural effusion in secondary hemophagocytic lymphohistiocytosis.

The clinical features of patients with secondary hemophagocytic lymphohistiocytosis (sHLH) complicated with pleural effusion have rarely been evaluated. We retrospectively analyzed 203 patients newly diagnosed with sHLH from July 2015 to July 2019 according to the HLH-2004 protocol. Baseline characteristics, laboratory results, and imaging were reviewed. Pleural effusion was found in 58.6% of the studied sHLH population, and characteristic imaging findings were minimal volume and bilaterality. Patients with pleural effusion had lower PLT counts, HB levels and ALB levels as well as higher sCD25 levels than those without pleural effusion (all p values < 0.05). Multivariate analyses showed that lg(sCD25) and PLT ≤ 65 × 109/L were significant risk factors for developing pleural effusion in sHLH. Regarding prognostic value, survival analysis showed a lower survival probability for patients with pleural effusion than for those without pleural effusion (median OS, 90 vs. 164 days, p = 0.028). In multivariate analysis, pleural effusion was an independent prognostic factor for overall survival (OS) (HR 2.68; 95% CI 1.18–6.11, p = 0.019). Pleural effusion is frequently found in patients with sHLH and is associated with greater inflammation and worse outcomes.

Hemophagocytic lymphohistiocytosis: what's new in old diagnostic and clinical criteria?

Hemophagocytic lymphohistiocytosis (HLH) is a condition of overexpressed inflammatory response resulting in hypercytokinemia, macrophages infiltration and subsequent multiple organ failure. Without treatment, it leads to death. The main etiological factors include: viral, bacterial and parasitic infections, malignancies and autoinflammatory diseases. The main clinical manifestations are: high fever ≥38°C, lymphadenopathy, splenomegaly, hepatomegaly. Central nervous system involvement occurs in 30–70% of cases. Less common symptoms include: dyspnea, cough, arrhythmias, jaundice, peripheral edema, rashes, albinism and diarrhea. The picture of the disease seen in laboratory tests consists of: duopenia, hypofibrinogenemia ( &lt; 150 mg/dL) high D-dimers level, hyperferritinemia. Other abnormalities include hypertiglyceridemia, elevated liver enzymes, hyperbilirubinemia, hypoalbuminemia and hyponatremia. Diagnostics include: laboratory tests, histopathological examination, lumbar puncture, radiological imaging, functional test and genetic checking. It is important to rule out factors mimicking HLH. Some of the old, well known criteria are no more relevant nowadays. The aim of the therapy is immunosuppressive, immunomodulatory and anti-cytokine treatment, using HLH-2004 protocol. In secondary HLH, elimination of the causative agent is critical. In case of primary HLH, or relapse of secondary forms allogenic transplantation is the only curative treatment. The prognosis is uncertain.

Hemophagocytic lymphohistiocytosis in a child with human immunodeficiency virus infection – a case report

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition and furthermore human immunodeficiency virus (HIV)-associated HLH is rarely reported in the literature. The most frequent presentation of secondary HLH is in association with infections, malignancies or drugs. In HIV-positive patients, the viral infection itself or the antiretroviral therapy (ART) could trigger HLH. Case presentation: A 14-year-old boy was admitted for persistent diarrhea, severe weight loss and chest burns. Laboratory tests revealed important neutropenia, which led to HIV infection diagnosis. ART in combination was started associated with granulocyte-colony stimulating factor. Viral copies declined after six weeks of treatment, but the cluster of differentiation 4 (CD4) T-lymphocytes and neutrophil counts remained very low. Infections and malignancies were ruled out. The bone marrow aspirate revealed hemophagocytosis which in association with fever, bicytopenia, hypofibrinogenemia and hypertriglyceridemia established HLH diagnosis. Cortisone therapy and intravenous immunoglobulins were added. Due to lack of response, HLH-2004 protocol was initiated in collaboration with pediatric hematologist. In the first six months of treatment, CD4 T-lymphocytes and neutrophil count remained low and then they showed significant increase simultaneously. During treatment, the patient developed spontaneous severe back pain. Magnetic resonance imaging showed vertebral compression, osteomalacia and a thoracic vertebral fracture. Conclusions: Having ruled out the usual associated infections and malignancies, this is a case of HIV-associated with HLH. In this case, only the ART and immunomodulatory therapy were not enough and failed to work. Systemic immunosuppression also worked only after a prolonged course which led to an unfortunate complication: a vertebral fracture.