Treatment Of Hemophagocytic Lymphohistiocytosis Research Articles

Acute Epstein‐Barr virus associated haemophagocytosis in an Asian female: What is the diagnosis?

Acute <scp>Epstein‐Barr</scp> virus associated haemophagocytosis in an Asian female: What is the diagnosis?

&lt;i&gt;Ehrlichia chaffeensis&lt;/i&gt;&lt;i&gt;-&lt;/i&gt;associated Hemophagocytic Lymphohistiocytosis: A Case Series and Literature Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition characterized by abnormal, excessive immune activation resulting in severe cytopenias from an uncontrolled inflammatory response. It can be primary/ familial or secondary/sporadic. Infections, particularly viral infections are a common cause of secondary HLH. HLH due to Human monocytic ehrlichiosis (HME) is very rare, hence we are reporting our cases. Objective: To review cases of Ehrlichia-associated HLH at our institution and perform a literature review regarding this entity. Methods: We reviewed cases of Ehrlichia-associated HLH for the previous two years at our institution (Carilion Clinic). We then performed a review of the published literature on it, using Pubmed. Results: Over the past two years, five cases of Ehrlichia-associated HLH were diagnosed at our hospital. The average age of the patients was 67 years with predominantly males. All the patients were pancytopenic, and a majority had abnormal liver function tests. Diagnosis of ehrlichiosis was made by serum polymerase chain reaction (PCR) assay on blood. Patients had further testing done because of lack of clinical improvement. All patients had significantly elevated ferritin levels. Bone marrow biopsy samples of all patients showed findings of hemophagocytosis. All, but one, patients were treated with doxycycline and a combination of etoposide and dexamethasone. Three patients recovered while two died. On review of medical literature, we found a total of only 36 cases of Ehrlichia-associated HLH, including our five cases. There were 19 adults and 17 children. Both population groups showed varying degrees of pancytopenia. Splenomegaly was relatively uncommon, seen in less than one-third of the patients. Ferritin and triglyceride levels were routinely elevated. Bone marrow biopsy showing hemophagocytosis was the confirmatory test in all patients. A significant number of patients, both adults and children, required a combination of doxycycline and chemotherapy (etoposide and dexamethasone) to achieve clinical cure. Children had a better prognosis than adults, with one child and four adults succumbing to their illness. Conclusions: Ehrlichia-associated HLH is a rare but emerging disease entity. In endemic areas, a high degree of suspicion is required to diagnose ehrlichiosis and HLH resulting from it. Early diagnosis and prompt initiation of treatment for HLH is key to a favorable outcome.

Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder of immune regulation that can eventually result in end-organ damage and death. HLH is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm. The diagnosis of HLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics. The prognosis is generally poor, warranting rapid diagnosis and aggressive management. To provide a comprehensive review of the pathogenesis, clinical features, diagnosis, and management of HLH. Peer-reviewed literature. HLH is a condition where a complete understanding of the pathogenesis, early diagnosis, and proper management has an important role in determining patient outcome. Genetic mutations causing impairment in the function of cytotoxic T lymphocytes and natural killer cells have been identified as the root cause of familial HLH; however, the specific pathogenesis of acquired HLH is unclear. The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population. The HLH-2004 protocol still forms the basis of the diagnosis of HLH in adults, although its use in adults has not been formally validated yet. Treatment of HLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities.

The Role of Early Subspeciality Consultation in the Timing of Hemophagocytic Lymphohistiocytosis Diagnosis and Management.

The aim of this study was to investigate the relation between timing of subspeciality consult and hemophagocytic lymphohistiocytosis (HLH) consideration, immunosuppression initiation, and in-hospital mortality in patients with HLH. We conducted a medical records review study of patients 18 years or older with definite or probable HLH at Montefiore Medical Center between 2006 and 2019. Earlier subspeciality consultation (rheumatology, hematology, and infectious disease) was defined as consultation in less than or equal to 18 hours from time of admission. Demographic, clinical characteristics, and outcomes were compared between patients with early and later subspecialty consultation. A total of 28 patients were included. The median age was 40 years, and 61% of patients were male. Infection was identified as a cause of HLH in 13 patients (46%). Fifteen patients (54%) were classified as having an earlier subspeciality consultation with a median time (interquartile range) to HLH consideration of 1.0 day (0.3-4.2 days) compared with 7.9 days (3.1-9.9 days) for the later consultation group (p = 0.002). The median time (interquartile range) to immunosuppression initiation was 4.6 days (1.7-7.8 days) versus 10.9 days (5.1-13.4 days) (p = 0.01), respectively. Five patients (33%) had in-hospital deaths in the early consultation group compared with 7 patients (54%) in later consultation group (p = 0.27). Among the subset of patients who survived to discharge, the 90-day readmission rate was higher in the later consultation group (83% vs 30%, p = 0.12). In patients with HLH, earlier subspeciality consultation may play a role in earlier HLH consideration and treatment initiation.

The Clinical Impact of Impaired Natural-Killer Cell Cytotoxicity for Diagnosis and Prognostication in Adult Patients with Febrile Cytopenia Including Hemophagocytic Lymphohistiocytosis and Similar Diseases: The Results of Prospective Phase II Observational Study

Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory disease which is life-threatening if not detected earlier and treated appropriately. The diagnosis of HLH is sometimes confused due to other similar febrile diseases with cytopenia such as severe infection, flare-up of autoimmune disease, and malignant conditions. Decreased natural-killer cell (NK) cytotoxicity is an important diagnostic parameter for HLH, but we do not know the level and role in similar febrile diseases.Aim: We tried to identify the different levels in variable febrile diseases and find out the role for diagnosis and prognostication in adult patients with HLH compared to other similar diseases.Methods: We prospectively enrolled 41 patients from 2015 to 2017. Adult patients older than 18 years with fever>38℃ presenting cytopenia in at least two lineages (neutrophil<1,000/㎕, platelet<100,000/㎕, Hemoglobin<9.0/dL) were included. Patients with previous hematological diseases were excluded. Diagnosis of HLH was based on HLH2004 criteria. Infection was managed according to the protocol and HLH-suspected patients were initially treated with 10mg/BSA of dexamethasone, and etoposide was considered if clinical improvement was not observed within 7 days after dexamethasone. Patients other than HLH were treated with disease-specified therapy. NK cytotoxicity was calculated at diagnosis by antibody-dependent Raji-cell cytotoxicity (ADCC) assay and K562-cell direct lysis using flow cytometry. Concomitantly, CD107a expression and NK-induced interferon gamma were also calculated.Results: HLH was diagnosed in 29 patients caused by viral infection (n=8), malignancies (n=6), autoimmune diseases (n=6), bacterial infection (n=2), malaria (n=1), and unidentified origin (n=6). Febrile diseases other than HLH (n=12) were diagnosed with hematological disease (n=7), infectious mononucleosis (n=2), SLE (n=2), Kikuchi disease (n=1). The results of both K562 lysis and ADCC assay were highly correlated but the diagnostic power was greater in ADCC assay. In the entire group, ADCC lower than 40% was related with poor 1-year OS (70.2% vs. 100%, P=0.062). Median ADCC level was lower in HLH (20.5% vs. 37.7%, P=0.045) and in HLH with poor dexamethasone response (12.0% vs. 30.7%, P=0.009). ROC curve revealed that ADCC lower than 22.8% was useful for diagnosis of HLH and lower than 12.8% was related with poor treatment response. Unfortunately, CD107a expression and NK-induced interferon gamma was not useful for diagnosis and prognostication.Conclusion: Lower NK cytotoxicity was diagnostic for HLH compared to other febrile disease with cytopenia, and we identified ADCC lower than 40% was related with poor OS and lower than 12.8% was predictable for severe HLH presenting poor treatment outcome. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Adult Hemophagocytic Lymphohistiocytosis-a Quality Improvement Initiative

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a frequently fatal severe inflammatory syndrome. HLH evaluations are conducted by multiple inpatient services due to the protean manifestations of the disease in adults. We observed difficulty identifying HLH precipitating conditions, hemorrhage, and erroneous testing as impediments to optimal care. We embarked on a HLH quality improvement project to examine strategies of precipitant identification, quantify hemorrhagic complications, and decrease erroneous test ordering.Methods: The Johns Hopkins Institutional Review Board approved this single-institution retrospective review. Patients were identified from billing and laboratory databases at The Johns Hopkins Hospital. Patients were included if they were evaluated for HLH during an inpatient hospitalization by their treating clinicians between January 1, 2009 and July 30, 2016. Patients <18 years of age at the time of evaluation were excluded. Clinical, laboratory, and imaging findings were obtained by chart review (SAM). HLH was defined as patients meeting at least 5 of 8 HLH-2004 criteria (Henter et al 2007); Hscore during the first inpatient week was also computed (Fardet et al 2014).Interventions occurred in 2015 and consisted of: 1) a review of HLH diagnostic testing, 2) presentation of findings to hematology staff, 3) development of an evidence-based HLH consult template, and 4) consultation on suspected HLH cases. Ordering interleukin-2 levels (IL2) or quantitative natural killer cell (NK) flow cytometry, instead of soluble interleukin-2 receptor (sIL2R) or NK functional assays were defined as erroneous testing in HLH evaluations. Test costs were obtained from Quest Diagnostics. Test ordering between 2014-2016 were compared before and after the interventions.Practices identifying the HLH precipitant were determined by chart review. Major hemorrhage was defined as bleeding 1) into a critical site, 2) requiring modification of blood product support, 3) requiring procedural intervention, or 4) leading to death. Coagulation parameters were examined in the 24hrs before hemorrhage was clinically evident. Overall survival was defined as date of hospital admission until death. Descriptive statistics were computed with percentages and frequencies. Survival analysis was performed with STATA14. Quality metrics were evaluated with either Fisher's exact test or unpaired t-test; statistical analysis used two-tailed significance testing and P<0.05.Results: During the study period, 86 patients were evaluated for HLH, and 63 fulfilled HLH-2004 diagnostic criteria (Table 1). Most patients (64%) were initially admitted to a non-hematology/oncology service. Serologic testing and bone marrow biopsy were most likely to identify the HLH-precipitating illness in 27% and 17.5% of cases, respectively. Major hemorrhage occurred in 41.3% of patients and occurred at the time of at least two coagulation abnormalities. HLH median survival ranged from 45 days with malignancy to not reached with autoimmune diseases and non-EBV infections (Figures 1 & 2).The interventions significantly decreased the occurrence of erroneous testing from 74.3% to 23.5% of patients (P=0.0008), and decreased costs of erroneous testing from $338 to $34 per patient during the evaluation period (Table 2). The interventions also significantly reduced the time to fulfillment of HLH criteria (38 vs 5.7 days, P<.0001), and reduced the delay in obtaining sIL2R testing after initial erroneous ordering (10.3 vs 0 days, P=0.0005). There were no significant differences in time to steroid administration, time to definitive HLH treatment, or in patient number without treatment.Conclusions: Adults with HLH initially present to non-hematology/oncology inpatient services. Diagnostic uncertainty, hemorrhage, and erroneous testing impair patient care. We observed that serological testing and bone marrow biopsy were most likely to identify the HLH precipitant. Major hemorrhage was common and occurred when multiple coagulation abnormalities were evident. Our quality improvement project significantly decreased erroneous testing and improved time to diagnosis. With these data, we are developing an internal HLH decision support tool to facilitate identification of HLH precipitant illness, curtail erroneous testing, and minimize morbidity from major hemorrhage. [Display omitted] DisclosuresMerrill:True North Therapeutics: Consultancy. Streiff:Roche: Research Funding; Portola: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding. Lanzkron:HRSA: Research Funding; Bayer: Research Funding; Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; PCORI: Research Funding; Prolong: Research Funding. Brodsky:Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding.

Dengue-Associated Hemophagocytic Lymphohistiocytosis With Severe Multiorgan Complications—A Case Report

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome characterized by pathologic immune hyperactivation, extreme inflammation, and multiorgan involvement with variable cytopenias. We report a case of a 53-year-old male with no known comorbidities, who presented with unrelenting dengue fever, pancytopenia, high ferritin levels, and multiple organ dysfunction with progressive clinical deterioration despite treatment. Based on the clinicolaboratory findings, he was diagnosed as dengue-associated HLH on day 6 of admission. As per HLH treatment protocol, he was started on immunosuppressants and showed significant improvement. In dengue patients with severe disease, prolonged hospital stay, persistent cytopenia, and multiorgan dysfunction out of proportion to the plasma leakage phase should prompt a high index of suspicion for the possibility of infection-triggered HLH. Although prompt diagnosis and early initiation of therapy is the key to prevent irreversible end organ damage and mortality, the hindrance lies in its rarity in adults, variable clinical presentation, and nonspecific laboratory findings.

MO697TUBERCULOUS PERITONITIS WITH HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS IN A PATIENT ON CONTINUOUS AMBULATORY PERITONEAL DIALYSIS: A CASE REPORT

Abstract Background and Aims Tuberculosis is a leading cause of morbidity and mortality worldwide. Tuberculous peritonitis in patients on Continuous Ambulatory Peritoneal Dialysis (CAPD), though uncommon, has been reported from different parts of the world. Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory disorder characterized by uncontrolled proliferation of lymphocytes &amp; histiocytes and is reported to have high mortality. Secondary forms of HLH have been described for various diseases. Here, we report a case of HLH secondary to Tuberculous peritonitis in a patient of End Stage Renal Disease (ESRD) on CAPD. Method A 49 years old male ESRD patient, on CAPD presented with peritonitis and was initially managed with antibiotics. He required catheter explantation in view of refractory peritonitis and was switched to haemodialysis. The patient continued to have low grade fever, yellowish discharge from infra-umbilical CAPD catheter explantation surgical wound along with lower abdominal pain &amp; tenderness. He was lost to follow up and presented again after 1 month with fever, weight loss, multiple cutaneous ecchymotic spots and copious amount of yellowish discharge from infra-umbilical surgical wound. On examination, he had fever, conjunctival pallor, hepatosplenomegaly and a 5 cm infra-umbilical midline poorly healed discharging surgical scar with surrounding skin erythema and induration. Blood investigations revealed Hb 5.1 gm/dl, TLC 1500/uL, Plts 32000/uL, Ferritin 1053 ng/ml, TG 350 mg/dl, LDH 650 U/l, Bil T/D 1.3/1.0 mg/dl, OT/PT 160/174 IU/l, ALP 219 U/l, GGT 238 U/l, TP/Alb 5.2/2.5 gm/dl, APTT C/T 27.9/63.0, INR 1.27. NCCT abdomen revealed hepatosplenomegaly, loculated collection in right subphrenic region extending into the abdominal and pelvic cavity, anterior abdominal wall defect infero-right lateral to the umbilicus and generalised increased density in mesenteric fat. Diagnostic sub-phrenic fluid Aspirate analysis revealed a yellow turbid fluid with TLC 22300, ADA 106 U/L and positive Real Time PCR for Mycobacterium tuberculosis complex. Aspirate pyogenic and fungal cultures were sterile. Bone marrow evaluation revealed marked degree of histiocytic hemophagocytosis. Patient fulfilled six out of eight criteria for diagnosis of HLH. He was started on Anti Tubercular Treatment along with dexamethasone. He gradually became afebrile with resolution of infra-umbilical wound discharge, improvement in clinical and laboratory parameters. Results We report a case of HLH secondary to Tuberculous peritonitis in a patient of ESRD. The patient was on CAPD and required catheter explantation in view of Refractory peritonitis. Despite explantation and adequate antibiotics, he continued to have fever, discharge from surgical wound, pain abdomen, weight loss and poor appetite. Further evaluation revealed evidence of Tuberculous Peritonitis. In addition, the patient fulfilled six out of eight criteria for diagnosis of HLH. The patient was managed with Anti Tubercular Treatment along with Dexamethasone and he showed a gradual improvement in overall clinical and laboratory parameters. Conclusion Secondary HLH may occur after Tuberculous peritonitis in patient of ESRD on CAPD. Refractory peritonitis with hyperferritenemia, cytopenias, hypertriglyceridemia should raise the suspicion for HLH. Timely identification and treatment of HLH may improve patient outcomes.

Secondary hemophagocytic lymphohistiocytosis (HLH): Five years’ experience at the UTHealth McGovern Medical School at Houston, Texas.

e19578 Background: Secondary HLH in adults is associated to infections, malignancies, and autoimmune disorders. HLH in children has been the basis for the management and treatment of HLH in adults. Despite their clinical similarities there are fundamental differences. Children’s HLH is caused by gene mutations in granule-mediated cytotoxicity while secondary HLH does not have known apparent genetic causes. This may affect the clinical outcomes based in how we approach the diagnosis and management of secondary HLH in adults. Methods: We reviewed 49 cases of secondary HLH at our institution over a five-year period. Patients median age was 47 years, with 31 males, 18 females. Fifteen were Caucasian, 10 Asians, 8 African American and 15 Hispanics. One was not specified. Results: Fever, hyperferritenemia and cytopenia correlated with 100% elevation of sCD25R, the most important biomarker of HLH. Patients with these three criteria were urgently treated with dexamethasone-etoposide (HLH-94 protocol) or dexamethasone alone (autoimmune related) while completing identification of other criteria described in the pediatric population together with treatment of the secondary cause. Conclusions: Secondary HLH is not rare. Etoposide and dexamethasone (preferred dose:40 mg total/day initially) are the most important current therapeutic approaches. Secondary HLH must be treated urgently and independently of the secondary cause. Treatment should not be delayed awaiting results of sCD25R, NK-cell activity and presence of hemophagocytosis in the bone marrow (often absent). Further work needs to be done to elucidate the physiopathology of secondary HLH.[Table: see text]

Therapy-related acute myeloid leukemia with KMT2A-SNX9 gene fusion associated with a hyperdiploid karyotype after hemophagocytic lymphohistiocytosis

Therapy-related acute myeloid leukemia (t-AML) following treatment with topoisomerase-II inhibitors has been increasingly reported. These compounds (e.g. etoposide) promote DNA damage and are associated with KMT2A rearrangements. They are widely used as first-line treatment in hemophagocytic lymphohistiocytosis (HLH). Here we describe a newborn who developed t-AML after HLH treatment. We provide detailed clinical, cytogenetic, and molecular characteristics of this patient, including the identification of a novel gene fusion – KMT2A-SNX9 – in t-AML. Considering the dismal outcome of this case, we discuss the side-effects of etoposide administration during HLH treatment in infants.

Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.

Clinical Management of Relapsed/Refractory Hemophagocytic Lymphohistiocytosis in Adult Patients: A Review of Current Strategies and Emerging Therapies.

IntroductionHaemophagocytic lymphohistiocytosis (HLH) is a severe disorder with high mortality. The aim of this review is to update clinical management of relapsed/refractory HLH in adults, with a focus on current and new therapies.MethodsWe searched relevant articles in Embase and PUBMED with the MESH term “hemophagocytic lymphohistiocytosis; refractory; relapsing; adult.”ResultsOne hundred eight papers were found; of these, 22 were retained for this review. The treatment of HLH in adult is based on the HLH-94 regimen. The response rate is lower than in pediatric patients, and 20–30% are refractory to this therapy. DEP regimen and allogenic hematopoietic stem cell transplantation (HSCT) are associated with complete response and partial response in 27% and 49.2%, respectively. However, many patients fail to achieve a stable condition before HSCT, and mortality is higher in them. New drugs have been developed, such as emapalumab, ruxolitinib, and alemtuzumab, and they may be used as bridges to the curative HSCT. They are relatively well tolerated and have few or mild side effects. With these agents, the rate of partial response ranges from 14.2% to 100%, while the rate of complete response is highly variable according to study and medication used. The number of patients who achieved HSCT ranged from 44.8% to 77%, with a survival rate of 55.9% to 100%. However, the populations in these studies are mainly composed of mixed-age patients (pediatric and adult patients), and studies including only adult patients are scarce.ConclusionRelapsed or refractory HLH in adult patients is associated with poor outcome, and consolidation with HSCT may be required in some cases. Mortality related to HSCT is mainly due to active HLH disease before HSCT and post HSCT complications. New drugs, such as empalumab, ruxolitinib, and alemtuzumab are interesting since these agents may be used as bridges to HSCT with increases in the numbers of patients proceeding to HSCT and survival rate.

Ruxolitinib treatment permits lower cumulative glucocorticoid dosing in children with secondary hemophagocytic lymphohistiocytosis

BackgroundThis study aimed to analyze the effects of ruxolitinib on children with secondary hemophagocytic lymphohistiocytosis (HLH).MethodsEleven pediatric patients diagnosed with HLH and treated with ruxolitinib (ruxolitinib group: group R) between November 2017 and August 2018 were retrospectively analyzed. Eleven age-matched pediatric patients with HLH undergoing conventional treatment (control group: group C) during the same period were also analyzed.ResultsIn group R, three patients who did not respond to methylprednisolone (MP) pulse and intravenous immunoglobulin (IVIG) therapies were treated with Ruxolitinib and their temperature decreased to normal levels. Four patients had normal temperature after conventional treatment (dexamethasone and etoposide, with or without cyclosporine A), but they had severe organ involvement, including obvious yellowing of the skin, increased liver enzyme levels and neuropsychiatric symptoms, and they were all ameliorated with ruxolitinib treatment. Four patients were relieved with ruxolitinib therapy alone. In group C, the body temperatures of eleven patients decreased to normal levels after conventional treatment. The body temperature of group R patients decreased to normal levels more rapidly than that of group C patients. The glucocorticoid dosage in group R was significantly lower than that in group C. Both groups were followed-up for 2–2.5 years. No obvious adverse drug reactions to ruxolitinib were observed during treatment and follow-up.ConclusionRuxolitinib might be an effective drug in controlling body temperature and reducing inflammation indicators. It might be a potential replacement for glucocorticoid therapy for HLH treatment in children, thereby reducing or avoiding glucocorticoid-related adverse reactions.

A Minimal Parameter Set Facilitating Early Decision-making in the Diagnosis of Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation syndrome characterized by uncontrolled immune cell activation. Timely diagnosis is important, since early treatment can improve survival rates. However, completing all assessments needed to reach ≥5 positive criteria out of the 8 HLH-2004 criteria can be time consuming and may delay timely initiation of treatment. Hence, we applied a data-driven approach to identify a minimal parameter set for early decision-making towards the initiation of HLH-specific treatment. We retrospectively evaluated 165 patients from five Dutch tertiary hospitals with suspected HLH. Sixteen pHLH (median age 0.5 years) and 70 sHLH patients (median age 8.7 years) were identified using the HLH-2004 criteria. Clustering analysis and multi-receiver operator characteristics were used to identify parameters distinctive of HLH. The presence of either increased ferritin, cytopenia in ≥2 lineages, or splenomegaly distinguished HLH from non-HLH cases with a negative predictive value of 100%. A minimal parameter set consisting of 2 major criteria (phagocytosis and splenomegaly) and 3 minor criteria (cytopenia, increased ferritin, and increased triglycerides/low fibrinogen) predicted HLH with 95% (88–99) sensitivity and 94% (86–98) specificity. This finding was replicated in an independent retrospective validation cohort of 109 US patients (n = 109). By dividing a subset of the HLH-2004 criteria into major and minor criteria, this strategy uses the evaluation of less than 5 criteria to quickly identify patients with HLH. When confirmed in a prospective setting, this approach could be of value for timely diagnosis and treatment of HLH.

Hemophagocytic lymphohistiocytosis in pregnancy evolving towards fulminant hepatitis.

Hemophagocytic lymphohistiocytosis is a rare disorder, especially in pregnancy, characterized by excessive immune activation leading to hemophagocytic activity. A 34-year-old woman presented at 31 weeks' gestation with fever, cytopenias, hyperferritinemia and fulminant hepatitis. Bone marrow biopsy was non-contributory, and no trigger was identified. Liver biopsy confirmed the diagnosis of hemophagocytic lymphohistiocytosis, and she received dexamethasone and etoposide, which was changed to anakinra to allow breastfeeding. Prompt diagnosis and treatment of hemophagocytic lymphohistiocytosis is crucial to the survival of pregnant women, but no consensus exists regarding the most appropriate therapy during pregnancy. Hemophagocytic lymphohistiocytosis is life-threatening and associated with significant morbidity and mortality. Important treatment considerations in pregnancy include maternal health, fetal prematurity and treatment toxicity. Anakinra has been successfully used in pregnancy and provides a promising alternative.

Emapalumab for adult and pediatric patients with hemophagocytic lymphohistiocytosis

ABSTRACT Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome. Standard treatment is based on immunosuppressive, cytotoxic drugs and hematopoietic stem cell transplantation (HSCT) in primary HLH. Interferon-gamma (IFN-γ) plays a key pathogenic role. Emapalumab, a monoclonal antibody directed against IFN-γ, is the first target therapy approved for primary HLH with refractory, recurrent or progressive disease or intolerance to conventional therapy. Areas covered We reviewed the pharmacological characteristics, safety, efficacy and clinical uses of emapalumab. We summarized the results of current standard treatment based on chemo-immunosuppressive protocols and outlined the alternative options available. Expert opinion Emapalumab is an effective treatment for HLH with a good safety profile. Its efficacy was demonstrated in a phase II/III study on primary HLH pediatric patients with refractory, relapsing HLH or intolerance to first-line treatment. The use of emapalumab allowed most patients to proceed to HSCT, with a high estimated probability of survival 12 months after transplantation. The outcomes in patients who underwent transplantation compare favorably with those reported previously with either myeloablative or reduced-intensity conditioning regimens. The potential role of emapalumab in the treatment of secondary HLH and as a prevention of graft failure after HSCT deserves to be further assessed.

Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and Signal Transducer and Activation of Transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines. Here, we review the basic biology of HLH, including the role of cytokines in disease pathogenesis, and discuss the use of ruxolitinib in the treatment of HLH.

Hemophagocytic lymphohistiocytosis in critically ill patients

Bei der hämophagozytischen Lymphohistiozytose (HLH) handelt es sich um ein Hyperinflammationssyndrom bedingt durch aberrant aktivierte Makrophagen und T‑Zellen. Beim Erwachsenen ist in erster Linie die erworbene Form anzutreffen. Häufige Auslöser sind Infektionen, Malignome und Autoimmunerkrankungen. Zuletzt wurden zudem zunehmend Fälle berichtet, in denen das Auftreten im Zusammenhang mit stattgehabten Immuntherapien zu sehen war. Auf der Intensivstation ist die HLH aufgrund des ähnlichen klinischen Erscheinungsbilds oft schwer von der Sepsis abzugrenzen. Zum Teil liegen beide zeitgleich vor. Die frühzeitige Diagnosestellung und Einleitung einer adäquaten immunsuppressiven Therapie ist für den weiteren Verlauf und die Prognose der HLH essenziell. Deshalb muss bei kritisch kranken Patienten mit persistierendem Fieber und entsprechenden Symptomen (z. B. Splenomegalie, neurologische Auffälligkeiten) oder Laborveränderungen (z. B. erhöhter Ferritinwert, Zytopenie von 2 oder 3 Zellreihen, erhöhte Transaminasen) das Vorliegen einer HLH in Betracht gezogen werden. Die Diagnose wird mithilfe der HLH-2004-Kriterien gestellt. Mit dem HScore kann die Wahrscheinlichkeit des Vorliegens einer HLH berechnet werden. Hochdosierte Kortikosteroide stellen den Grundpfeiler der HLH-Therapie dar. Je nach Auslöser werden Etoposid, Immunglobuline, Anakinra oder weitere Medikamente ergänzt. Der Verlauf hängt neben einem frühzeitigen Behandlungsbeginn vom Auslöser sowie dem Ansprechen auf die Therapie ab. Insgesamt ist die Prognose der HLH trotz maximaler intensivmedizinischer Behandlung ungünstig und sie ist mit einer hohen Letalität assoziiert.

Secondary Hemophagocytic Lymphohistiocytosis in a Young Hispanic Adult

Hemophagocytic lymphohistiocytosis (HLH) is a disease caused by a severe immune system reaction that involves an overwhelming inflammatory response with overproduction of cytokines and hemophagocytosis. HLH is classified as primary HLH or familial HLH (PHLH or FHLH) and secondary HLH. PHLH is due to mutations in several genes that regulate immune cells, while secondary HLH is triggered by a severe illness (viral infections or malignancies) that induce an excessive immune response that is difficult to control. We present a case of a young Hispanic adult female with a medical history of diabetes mellitus type 1 and hepatitis E that was diagnosed with HLH secondary to lymphoma caused by Epstein Barr virus infection. The patient was started on broad-spectrum antibiotics and steroid therapy; however, the patient succumbed to the disease. HLH is associated with high mortality, mainly because it is not a very common entity and patients usually present critically ill and deteriorate very fast. Immunosuppression and treatment of the underlying disorder is the target of the treatment of HLH, however, the prognosis remains poor.

The role of interferon-gamma and its signaling pathway in pediatric hematological disorders.

Interferon-gamma (IFN-γ) plays a key role in the pathophysiology of hemophagocytic lymphohistiocytosis (HLH), and available evidence also points to a role in other conditions, including aplastic anemia (AA) and graft failure following allogeneic hematopoietic stem cell transplantation. Recently, the therapeutic potential of IFN-γ inhibition has been documented; emapalumab, an anti-IFN-γ monoclonal antibody, has been approved in the United States for treatment of primary HLH that is refractory, recurrent or progressive, or in patients with intolerance to conventional therapy. Moreover, ruxolitinib, an inhibitor of JAK/STAT intracellular signaling, is currently being investigated for treating HLH. In AA, IFN-γ inhibits hematopoiesis by disrupting the interaction between thrombopoietin and its receptor, c-MPL. Eltrombopag, a small-molecule agonist of c-MPL, acts at a different binding site to IFN-γ and is thus able to circumvent its inhibitory effects. Ongoing trials will elucidate the role of IFN-γ neutralization in secondary HLH and future studies could explore this strategy in controlling hyperinflammation due to CAR T cells.