Adult Hemophagocytic Lymphohistiocytosis Research Articles

Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry

PurposeHemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome emerging from a deregulated immune response due to various triggers. In adults, systematic data are sparse, which is why recommendations on diagnosis and management have been adopted from pediatric guidelines. A nationwide clinical registry with associated consulting service as collaborative initiative of HLH-specialized pediatricians and hematologists was initiated to better characterize HLH in adults.MethodsPatients with proven or suspected HLH were registered by 44 institutions. Both HLH-2004 diagnostic criteria and the HScore (www.saintantoine.aphp.fr/score/) were used to confirm HLH diagnosis. Data referring to underlying disease, treatment, outcome, clinical presentation and laboratory findings were recorded.ResultsThe study included 137 patients and provides the first systematic data on adult HLH in Germany. Median age was 50 years with a wide range (17–87 years), 87 patients (63.5%) were male. Most common triggering diseases were infections in 61 patients (44.5%) and malignancies in 48 patients (35%). Virtually all patients had elevated ferritin concentrations, and 74% had peak concentrations greater than 10,000 µg/l. At time of analysis, 67 of 131 patients (51%) had died. Patients with malignancy-associated HLH had the shortest median survival (160 days), however no statistically significant difference between subgroups was observed (p = 0.077). Platelets under 20*109/l and low albumin concentrations (< 20 g/l) were associated with poor overall and 30-day survival.ConclusionClose multidisciplinary case consultation and cooperation is mandatory when treating adult HLH patients. Early contact with reference centers is recommended, especially in relapsing or refractory disease.

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis.

The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10-year period, with serum ferritin >5000ng/mL, were included. Among 1055 patients with serum ferritin >5000ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70398ng/mL (SD 122908), median 40019ng/mL (IQR 16051-68326). The prevalence of HLH only reached 50% as serum ferritin approached 90000ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16000ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH.

A Case of EBV-Associated Hemophagocytic Lymphohistiocytosis in Adult: Lessons from the Treatment Process

Hemophagocytic lymphohistiocytosis (HLH), which was first described in 1939 by paediatricians Scott and Robb-Smith, is a life-threatening disease. HLH is characterized as cytokine release syndrome which is caused by excessive but non-malignant activation of macrophages and/or histiocytes in bone marrow and other reticuloendothelial systems. EBV-HLH is the most common type of infection-associated HLH, has a high mortality rate without prompt and effective treatment. A previous study showed that the one-year mortality rate of EBV-HLH patients is 75%. Here we report a case of EBV-associated hemophagocytic syndrome in adult, and the lessons from the treatment process. Through this case, we think that for EBV-related HLH, EBV-DNA should also be monitored in addition to hemophagocytosis-related indicators during treatment. In addition, DEP regimen may not be suitable for patients who have received at least partial response, because impaired immunological functioning may lead to EBV and hemophagocytic re-activity.

Descriptive Study of Hemophagocytic Lymphohistiocytosis (HLH) Admissions in Adult Population: Data from Nationwide Inpatient Sample (NIS) Database

Background: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation, characterized by hyperactive macrophages and lymphocytes, resulting in multi-organ damage and high mortality. Epidemiologic data of HLH in the adult population is limited. The aim of our study is to characterize HLH admissions in the US adult population. Methods: We performed a retrospective study using the Nationwide Inpatient Database for the year 2016. 330 admissions with principal diagnosis of HLH in adults were identified, using ICD code specific for HLH. Using ICD 10 codes for malignancies and rheumatologic conditions, we subdivided HLH admissions into malignancy-associated HLH, autoimmune disease-related HLH and non-malignancy, non-autoimmune HLH. Statistical analyses were performed using STATA. One-way ANOVA was used to compare means of continuous variables and chi-square test was used to compare proportions of categorical variables. Results: Mean age of our study group was 50.1, with women making up 44% of the population. 15% of the patients had an underlying malignancy, most common type being mature T/NK cell lymphoma. Also, 15% of the patients had a rheumatologic diagnosis, SLE constituting half of this sub-group. 47% of the total population under study underwent either bone marrow, liver or splenic biopsy. Mortality rate was 21.2% and average length of stay was 17 days. 25.8% received systemic chemotherapy during the admission. Within the subgroups, we did not find a statistically significant difference in the age, gender, race, percentage undergoing biopsy or inpatient chemotherapy. There was also no statistically significant difference in mortality or length of stay between the three groups. Discussion: HLH is a life-threatening condition of immune hyper-activation and may be divided into primary HLH, which is an autosomal recessive condition, caused by mutations impairing the cytotoxic function of NK cells and cytotoxic T lymphocytes. Secondary HLH is the more frequent presentation in adults, and frequently identified triggers include hematologic malignancies, infections and autoimmune conditions. Autoimmune-associated HLH is usually termed as macrophage activation syndrome (MAS). Mortality in secondary HLH varies based on underlying condition, around 8% when associated with JIA, compared to more than 80% in malignancy associated HLH in some studies. Our study sample was underpowered to detect notable differences between the study groups. This can be attributed to the rarity of this condition. HLH is primarily a pediatric disease. Incidence of HLH in the pediatric age group has been estimated to be around 1 in 100,000 children. Incidence in the adult population is less clear. In our study, we were able to represent the epidemiologic aspects of adults with HLH in the real world. We need large observational studies to further characterize HLH in the adult population. Disclosures No relevant conflicts of interest to declare.

Natural-Killer Cell Cytotoxicity Is a Diagnostic and Prognostic Marker in Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis: Results from a Prospective Phase II Observational Study

Background: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. Diagnosing HLH can be confusing due to other similar febrile diseases that present with cytopenia. Although a decrease in natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH, the role in adult HLH has not been well-defined. Aim: To identify the diagnostic relevance and the significant cut-off values for NK cytotoxic function, we focused on patients that presented with fever with either cytopenia or evidence of hemophagocytosis. NK cytotoxicity was calculated at the time of diagnosis and we tried to identify significant differences between the causes of disease. Finally, the overall treatment response and survival outcomes were also evaluated based on the level of NK cytotoxicity in several subgroup analyses. Methods: We prospectively enrolled 123 adult patients that presented with fever accompanied by either cytopenia in at least two lineages or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. 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 K562-cell direct lysis using flow-cytometry. Results: HLH (n=60) was determined to be caused by Epstein-Barr virus (EBV, n=11), infection other than EBV (n=16), malignancies (n=19), and unknown (n=14). Febrile diseases other than HLH (n=63) were diagnosed as rheumatologic disease (n=22), malignancies (n=21), infection (n=12), non-malignant hematological diseases (n=6), and unknown (n=2). The results revealed that an HLH diagnosis was significantly correlated with lower NK-cytotoxicity, compared to other diseases (12.1% vs. 26.2%, p&lt;0.001), and a value less than 22% was a relevant cut-off for diagnosing HLH. Additionally, lower NK-cytotoxicity showed inferior 2-year overall survival in the non-malignancy subgroup (72.2% vs. 88.8%, p=0.038). Multivariate analysis showed that low NK-cytotoxicity, splenomegaly, and marrow hemophagocytosis were independent diagnostic parameters for HLH, and low NK-cytotoxicity and EBV-association were related with poor survival outcomes in non-malignant febrile diseases. Conclusion: We determined that decreased NK-cytotoxicity is a relevant marker that can be used for diagnosis of adult HLH compared with several similar febrile diseases and is also related to poor OS in non-malignant febrile diseases. Based on these results and other prospective studies, we hope that additional relevant diagnostic criteria for adult HLH can be identified in the near future. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL &amp; H: Research Funding. Lee:Alexion: Consultancy, Honoraria, Research Funding; Achillion: Research Funding.

Type B Lactic Acidosis in Adults with Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that can present with variable clinical and laboratory manifestations, and some distinct features are seen in adults. Type B lactic acidosis, which occurs in the absence of tissue hypoxia, has been reported in a few adult patients with HLH. We report a case of HLH presenting with type B lactic acidosis, with a literature review of this association. A 48-year-old Saudi woman with a past medical history of hypertension, dyslipidemia, and morbid obesity, presented with a 1-month history of intermittent high-grade fever up to 39°C daily. The patient was admitted for further evaluation of fever and was in our hospital for 70 days. Initial laboratory investigations revealed normocytic hypochromic anemia (102 g/L [normal 120-160]), lactic acidosis (2.36 mmol/L [0.5-2.2]), mild transaminitis, and elevated levels of lactate dehydrogenase (1761 U/L [125-220]), erythrocyte sedimentation rate (95 mm/hr [0-20]), and ferritin (1090.5 μg/L [4.6-204.0]). Further investigations failed to reveal any autoimmune or rheumatologic disease and extensive septic workup was negative. Lymphocyte subset by flow cytometry showed a low percentage of absolute natural killer cells (5% [10-20%]). Abdominal CT revealed splenomegaly with a span of 16.5 cm. Positron emission tomography-CT scan showed diffuse prominence of splenic activity, with a standardized uptake value of 4.5, and bone marrow activity throughout the axial skeleton. Liver biopsy and bone marrow aspiration were unremarkable. A month after admission, her anemia worsened with the hemoglobin level gradually dropping to 63 g/L prompting multiple transfusions. Lactic acid levels remained persistently elevated throughout this period [Figure 1]. A trial of intravenous steroids and immunoglobulins failed to decrease the lactic acid level [Figure 1; A to B]. The hospital course was complicated by Acinetobacter baumannii pneumonia requiring antibiotics [Figure 1; C to E]. Two months after the initial presentation, she developed pancytopenia, and repeated bone marrow aspiration and biopsy showed hemophagocytosis. Repeated ferritin level was more than 40,000 μg/L with hypertriglyceridemia (2.92 mmol/L [&lt;1.7]), and hypofibrinogenemia (0.9 g/L [1.5-4.1]). HLH-94 protocol with etoposide (150 mg/m2twice weekly) and dexamethasone (10 mg/m2) was commenced; however, the patient continued to deteriorate prompting elective intubation. She then developed acute acalculous cholecystitis and brain CT revealed a large central pontine hypodensity. Nine days after initiation, the patient was switched from the HLH-94 protocol to alemtuzumab, however, the patient arrested and passed away. To our knowledge, this is the first report of HLH presenting with persistent lactic acidosis lasting several weeks. Although no cause was found, this patient likely had HLH that was not detected early. We searched the PubMed and EMBASE databases for English-language reports describing adult patients (&gt;18 years) with HLH and lactic acidosis. Patients with type A lactic acidosis, associated with tissue hypoxia, were excluded. Five case reports describing patients with variable underlying diagnosis causing HLH and type B lactic acidosis were identified (Table I). Lactic acidosis started before HLH was diagnosed in all patients except one, in whom lactic acidosis developed two days after diagnosis. All patients had neither sepsis nor hypotension at the time of lactic acidosis. The mechanism of type B lactic acidosis in HLH is poorly understood and is likely multifactorial. As HLH in adults is more likely to be secondary to malignancies, Warburg effect, a high rate of glycolysis exhibited by tumor cells, has been proposed as the cause in these cases. Alternatively, acute cytokine hyperactivation in inflammatory states can enhance lactate dehydrogenase activity leading to excess lactic acid production. Inflammation, infection, or tumor cells can also induce stress and accelerate aerobic glycolysis-which does not depend on hypoxia-resulting in excess lactate production. Finally, acute hepatic dysfunction, a common finding in adult-onset HLH, can impair lactate clearance and further elevate levels. This report suggests that type B lactic acidosis may be a manifestation of HLH. Analyses of large HLH registries can better clarify the diagnostic and prognostic value of type B lactic acidosis in adult-onset HLH. Disclosures No relevant conflicts of interest to declare.

Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

Hemophagocytic lymphohistiocytosis (HLH), an uncontrolled overactivation of the immune system, is well characterized in pediatric patients, yet, much less is known about this life-threatening condition in adult patients. As HLH is often complicated by organ failure, patients will require admission to the intensive care unit for organ support therapy. However, recognition of HLH patients in the intensive care unit (ICU) is challenged by the clinical overlap with sepsis. Here, we analyze HLH patients to better understand its clinical presentation, diagnosis, and treatment. For the purpose of this retrospective observational study, we searched for suspected and diagnosed adult HLH of all patients admitted to at least one adult surgical, anesthesiological or medical ICU between January 2006 and August 2018 at the university hospital Charité - Universitätsmedizin Berlin. All cases were reviewed by two HLH experts, who confirmed or declined the diagnosis. Of 6,340 ICU patients with ferritin measurement, 40 suffered from HLH (0.63%). Of these, in-hospital mortality was 60.0% over all cases, which was highest in malignancy-associated HLH (71.4%). Infections were identified as most common triggers (42.5%). A variety of 19 different treatment strategies were applied. Non-survivors showed higher ferritin at diagnosis compared with survivors (P = 0.021), which was also seen in multivariable analyses. A minimum ferritin of 4083 μg/L after diagnosis was most predictive for 30-day mortality (AUC 0.888, 95% CI 0.771-1.000; sensitivity 93.8%, specificity 78.9%). Mortality in adult HLH patients in the ICU is high, particularly in malignancy-associated HLH. Infections are the most frequent HLH triggers in critically ill patients. At present, there is no standardized treatment for HLH in adult patients available. Assessment of ferritin is valuable for diagnosis, prognosis, and treatment monitoring. The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol

IntroductionHaemophagocytic lymphohistiocytosis (HLH) in adults is characterised by toxic immune activation and a sepsis-like syndrome, leading to high numbers of undiagnosed cases and mortality rates of up to 68%. Early...

Novel mutations of STXBP2 and LYST associated with adult haemophagocytic lymphohistiocytosis with Epstein-Barr virus infection: a case report

BackgroundHaemophagocytic lymphohistiocytosis is a life-threatening disease resulting from primary or secondary hyper-inflammatory disorders. The typical symptoms include persistent fever, splenomegaly, cytopenia and significant elevation of serum ferritin.Case presentationWe report a 30-year-old Chinese female patient who was diagnosed with chronic active Epstein-Barr virus infection more than 9 months prior and has since been presenting with cutaneous lymphoproliferative disorders mimicking hydroa vacciniforme and subsequent haemophagocytic lymphohistiocytosis. Exome sequencing suggested novel digenic heterozygous STXBP2 (c.592A > C, p.Thr198Pro) and LYST (c.830A > T, p.His277Leu) mutations.ConclusionsThis is the first case report in which adult HLH was associated with novel digenic mutations of STXBP2 and LYST combined with Epstein-Barr virus infection. It could also be the first polygenic model report, given that the pathogenicity of other mutated genes still remains unclear. We additionally conducted an in-depth, two-generation pedigree analysis to further illustrate the mode of inheritance in this case.

Hemophagocytic Lymphohistiocytosis in Adults: Associated Diagnoses and Outcomes, a Ten-Year Experience at a Single Institution.

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive systemic inflammation which causes tissue damage due to abnormal immune system activation and has a high fatality rate even with treatment. HLH continues to be a difficult diagnosis to make because of lack of awareness and its overlap with other illnesses. This disorder is well defined in pediatric patients under the age of 18, but there is also a paucity of data in the adult population. The goals of this study were to describe associated disorders, clinical course and outcomes, and to determine if additional clinical criteria can be used to help with the diagnosis of HLH in adult patients.MethodsPatients’ electronic medical records from 2007 to 2017 (who were ≥ 18 years old at the time of the search) were screened by ICD 9 and ICD 10 codes which contain the diagnosis of HLH or hemophagocytic syndrome, infection-associated. We identified 41 adult cases of HLH that were treated at our medical center over the course of 10 years and assessed these patients using both the historical and newly proposed diagnostic criteria. We also identified underlying diagnoses related to the development of HLH and fatality rates.ResultsMedian age at diagnosis was 55 years old (18 - 87 years old) and 22 were male. Twenty-two had an infection, 16 with malignancy, seven had an autoimmune disorder and one with Sweet syndrome. Fifteen patients were treated with steroids alone, 18 with steroids and chemotherapy, three with steroids and antiviral agents, and two with chemotherapy alone. Sixteen (39%) died and 25 (60%) survived discharge. Seven patients died after discharge. Median survival of all patients was 1,095 days.ConclusionsOur data show that HLH is primarily associated with infections and malignancies. Newly proposed diagnostic criteria are not as specific, but can be helpful in making the diagnosis of HLH. We also showed that the fatality rate at our institution was lower than currently published rates of adult HLH.

Demographics, Treatment Outcomes and Resource Utilization Among Patients Hospitalized with Adult Onset Hemophagocytic Lymphohistiocytosis (HLH): A Nationwide Analysis

▪Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease in which impaired natural killer and cytotoxic T-cell function results in excessive immune activation. It is predominantly seen in children; most of the available data comes from the pediatric population so it cannot be generalized to adult HLH. Treatment of HLH usually involves either treating the underlying cause in the secondary form (i.e. malignancy with chemotherapy, rheumatologic with immune suppression) or chemotherapy and stem cell transplantation for primary, familial etiology, multiple courses of intensive chemotherapy, with stem cell transplantation for relapse and familial disease. Recently, increasing adult HLH cases have been reported. The goal of this study is to describe the association between patient factors, geography, hospital resource utilization, and mortality among adult HLH patients.Methods: We performed a retrospective cohort analysis of the National Inpatient Sample 2012, 2013 and 2014 Databases (HCUP-NIS). Patients were included in the study if they had a principal diagnosis of HLH and were older than 18 years. We used descriptive statistics to characterize the cohort in terms of personal demographic factors (age, race, sex, insurance type, community-level income level), hospital characteristics (size, region, teaching status, and urban or rural location), and admission timing (weekend or weekday). We performed univariate and multivariate regression to analyze the association of the following factors with length of stay and mortality: age, sex, Charlson index, hospital region (Northeast NE, Midwest MW, South, West), income, insurance, hospital size, weekend versus weekday, hospital location (rural versus urban), teaching status. All analyses applied the HCUP-NIS weights.Results: The cohort comprised 760 patients, the majority of whom were male (57.9%), aged 21-30 years (26.3%), white (56.3%), and treated in large (78.9%) and/or teaching (92.1%) hospitals, third quartile for median household income (30.4%), covered by private insurance (43.4%), and treated in the southern US (32.2%). Per hospitalization, the average total hospital charges were $210,526 (95% CI $176,251 to $244,801) and the average length of stay (ALOS) was 18 days (95% CI 16 to 20). On multivariate analysis, ALOS was significantly longer with patients at teaching hospitals (AMD 5.10 95% CI 0.57 to 9.64, p=0.03) or with self-pay status (AMD 29.05 95% CI 21.62 to 36.48, p <0.01). Coverage with private insurance was associated with reduced ALOS (AMD -5.04 95% CI -10.19 to 0.11, p=0.05). Hospital charges was lower with age (AMD -4434 95% CI -7786 to -1082, p=<0.01); however Charlson index increased hospital charges (AMD 33876 95% CI 6043 to 61708, p=0.02). For mortality, age (OR 1.03, 95% CI 1.01-1.05, p=0.002), Charlson index (OR 1.29, 95% CI 1.05-1.57, p=0.013), and Medicaid coverage (OR 0.19, 95% CI 0.049 to 0.698, p=0.013) were statistically significant on univariate analysis, however only age (OR 1.02 95% CI 1.00 to 1.04, p=0.045) was statistically significant on multivariate analysis.Discussion: HLH in adults remains a rare disease which requires prolonged hospitalization and high resource utilization. Receiving care in teaching hospitals increases the length of stay most likely reason is that sicker and more complex patients often end up at teaching hospitals. Private insurance coverage reduced ALOS and self pay increased it. We hypothesize that the shorter ALOS with private insurance is due to increased scrutiny by the insurance provider, while the longer ALOS with self pay is related to difficulties ensuring outpatient follow up. In addition, we hypothesize that the decrease in hospital charges with increasing age may be because of early mortality among these patients. However, further studies are required to investigate the above noted associations. DisclosuresBussel:Rigel: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Protalex: Consultancy; Momenta: Consultancy; Novartis: Consultancy, Research Funding; Uptodate: Honoraria; Prophylix: Consultancy, Research Funding. Marks:UPMC: Employment; Heron: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Equity Ownership; Lilly: Membership on an entity's Board of Directors or advisory committees; Odonate: Membership on an entity's Board of Directors or advisory committees.

Natural-Killer Cell Cytotoxicity and Interleukin-2R As a Relevant Marker for Diagnosis of Secondary Hemophagocytic Lymphohistiocytosis in Adult Patients: The Results of Prospective Phase II Observational Study

Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, 2Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea, 3Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, KoreaBackground: Hemophagocytic lymphohistiocytosis (HLH) is a disease showing severe systemic inflammatory cascade which is life-threatening if not detected and treated appropriately. The diagnosis of HLH is confused due to other similar febrile diseases with cytopenia such as severe sepsis, autoimmune disease, and malignancies. Although decreased or absent natural-killer cell (NK) cytotoxicity is known as an important diagnostic parameter for pediatric HLH, the role for adult HLH is not elucidated well and also the significant level is not reported compared to other similar febrile diseases.Aim: We tried to identify the initial level of NK cytotoxicity in several febrile diseases and find out the role for diagnosis of HLH in adult patients in related with several cytokine levels.Methods: We prospectively enrolled 55 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 firstly included. Patients with previously diagnosed 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 or immediately when the disease progression was observed. Patients other than HLH were treated with disease-specified therapies. NK cytotoxicity was calculated at diagnosis, 4 and 8 weeks after diagnosis by antibody-dependent Raji-cell cytotoxicity (ADCC) assay and K562-cell direct lysis using flow cytometry. Concomitantly, IL-2, IL-2R, IL-6, Interferon-gamma, TNF-alpha, and CXCR10 were calculated CD107a expression and NK-induced interferon gamma were also calculated at the same time point from diagnosis.Results: HLH was diagnosed in 37 patients caused by viral infection (n=11), malignancies (n=7), autoimmune diseases (n=5), bacterial infection (n=2), malaria (n=1), anaplasmosis (n=1) and unknown origin (n=10). Febrile diseases other than HLH (n=18) were diagnosed with hematological diseases (n=8), infectious mononucleosis (n=2), rheumatologic disease associated macrophage activation syndromes (n=6), and unknown origin (n=2). The results of both K562 lysis and ADCC assay was well correlated (correlation coefficient = 0.684, 95%CI 0.512-0.804, P<0.001) but ROC curve analysis revealed diagnostic power for HLH was greater in ADCC assay with the level of lower than 23.7% (AUC=0.781, P<0.001) which was also related with poor initial steroid response. Median ADCC level was significantly lower in HLH (21.6% vs. 33.5%, P=0.039) and in HLH with poor dexamethasone response (17.0% vs. 33.4%, P<0.001). Among the calculated cytokines, only IL-2R was significantly elevated in patients with HLH (2856 vs 1098 U/mL, P=0.006), especially in patients with poor steroid response.Conclusion: We identified that decreased NK cytotoxicity and elevated IL-2R are relevant diagnostic markers for diagnosis of secondary HLH also in adult patients. We also identified ADCC lower than 23.7% was predictable for severe HLH presenting poor treatment outcome. DisclosuresKim:BMS: Research Funding; Ilyang: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Adult familial hemophagocytic lymphohistiocytosis: report of one case and review of literature

目的 加深对成年人家族性噬血细胞综合征（FHL）的认识，重视噬血细胞综合征（HPS）相关基因检测。 方法 分析宁夏回族自治区人民医院1例高龄FHL患者的诊治过程，并进行相关文献复习。 结果 该患者经检查确诊为FHL 3型，治疗后病情逐渐缓解。 结论 FHS不受年龄限制，亦可见于成年人，其诊断和分型依赖于HPS相关基因检测，HPS应经验性和抢先治疗，高龄FHL应个体化治疗。

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS DISGUISED AS A PULMONARY EMBOLISM IN A YOUNG MALE

SESSION TITLE: Medical Student/Resident Pulmonary Manifestations of Systemic Disease 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome which results from excessive immune activation. Infection is a usual trigger in patients with genetic predisposition, but sporadic cases have also been reported. Mostly seen in infants and children, it commonly presents with fever, hepatitis, encephalitis, rash and lymphadenopathy. Pulmonary involvement is uncommon but can present as interstitial infiltrates and pulmonary edema. We present a case of a young male with pulmonary embolism, found to have HLH from EBV. CASE PRESENTATION: 22 y/o male presented to the hospital with fever and dyspnea for two days. He had a viral infection about a month ago which had resolved. Labs showed leukopenia and thrombocytopenia as well as hepatitis with elevated transaminases. A CTA thorax found Pulmonary emboli in the right upper and lower lobes. He was started on enoxaparin for the PE. After two days he had hemoptysis from pulmonary hemorrhage and his pancytopenia worsened. Enoxaparin was stopped and a bone marrow biopsy was done which showed patchy reticulin fibrosis and increased histiocytes and megakaryocytes suggestive of hemophagocytic syndrome. He fit >5 of 8 criteria for HLH with Fever, cytopenias, hypertriglyceridemia, hemophagocytosis, elevated ferritin and Interleukin 2 soluble receptor alpha (IL-2Rα) level at 22,789.Treatment with HLH-94 protocol was started with dexamethasone and etoposide & Rituximab was added as EBV titers were >1,000,000. He had an IVC filter placed as he could not be anticoagulated. He responded well initially to therapy with clinical improvement and reduction in IL-2Rα. His treatment was marred with multiple admissions and interruptions from febrile neutropenia, pancytopenia and DIC requiring transfusions with platelets, PRBC and FFP. Unfortunately he succumbed to his disease and died 3 months after he was diagnosed, from sepsis and pulmonary hemorrhage. DISCUSSION: HLH is a syndrome of unchecked immune activation which if left untreated, has a survival of only a few months, due to neurological complications, ARDS, sepsis and multi-organ failure. The greatest barrier to successful outcome for individuals with HLH is a delay in diagnosis. This patient was unfortunate to have severe HLH which lead to multiple complications, one of them being a pulmonary embolism. Anticoagulation was not a simple answer in his situation as the PE was caused by the coagulopathy from HLH thus resulting in pulmonary hemorrhage when he was anticoagulated. CONCLUSIONS: This case highlights the importance of recognizing the clinical features of HLH which can lack specificity, for a timely diagnosis and early administration of effective therapy. This case also urges us to find the cause of a VTE in a otherwise healthy patient with unprovoked VTE before instituting anticoagulation as it could result in disastrous consequences like pulmonary hemorrhage in this patient. Reference #1: Larroche C. Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment. Joint Bone Spine 2012; 79:356. DISCLOSURES: No relevant relationships by Maria Fariduddin, source=Web Response No relevant relationships by Muhammad Naqvi, source=Admin input No relevant relationships by Wajihuddin Syed, source=Admin input No relevant relationships by Kanica Yashi, source=Admin input

Hemophagocytic Lymphohistiocytosis: Potentially Underdiagnosed in Intensive Care Units.

Hemophagocytic lymphohistiocytosis in adults (aHLH) is a rare life-threatening hyperinflammatory syndrome caused by excessive activation of macrophages and CD8+ T-cells. Due to the clinical overlap with severe sepsis, aHLH often remains undiagnosed resulting in poor outcome. Here, we present a retrospective study of incidence, clinical findings, and the outcome of aHLH in intensive care units (ICUs). This retrospective analysis was performed at the university hospital Charité - Universitätsmedizin Berlin. We gathered data from 556 out of 46,532 patients admitted to our anesthesiological ICUs between 2006 and 2013, who had at least one plasma ferritin measurement during ICU treatment, and were at least 18 years old. Of these, 244 patients with ferritin at least 500 μg/L and available datasets of at least 4 HLH-2004 criteria were included. HLH-2004 diagnostic criteria and the recently published HScore were used. An aHLH expert team retrospectively reviewed the potential aHLH cases. Seventy-one of the included 244 patients died; 9 out of the 244 patients were retrospectively classified as aHLH of whom 4 patients had died (44.4%). Two of the 9 aHLH patients had been correctly diagnosed and had received specific aHLH treatment. Thus, 7 out of 9 patients (77.8%) remained undetected. ICU patients with at least 1 captured ferritin value and hyperferritinemia showed an aHLH rate of 3.7%, which rises up to 5.6% when only deceased patients are considered. Mortality in this selected cohort is 44.4%. Overall, 7 out of 9 patients (77.8%) suffering from aHLH remained undiagnosed. Awareness of this life-threatening syndrome, especially in ICUs, should be raised. The inclusion of ferritin into the admission lab panel for ICU is warranted.Clinical trial registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016. As this is a retrospective study, trial registration was after final data collection date.

A prospective quality improvement initiative in adult hemophagocytic lymphohistiocytosis to improve testing and a framework to facilitate trigger identification and mitigate hemorrhage from retrospective analysis.

Hemophagocytic lymphohistiocytosis (HLH) is a highly fatal, hyperinflammatory syndrome in adults triggered by an underlying illness in most cases. As such, suspicion of HLH dictates further investigation to identify the HLH trigger and determine treatment. HLH is clinically challenging due to diverse presentations and underlying triggers, provider unfamiliarity, and bleeding complications. Clinically, we observed diagnostic error from incorrect testing and cognitive biases (interleukin-2 confused with soluble interleukin-2 receptor and natural killer cell quantification confused with functional assays).This study reports our single institutional experience with adult HLH with the aim to reduce erroneous testing with a quality improvement (QI) project, and to facilitate trigger discovery and mitigate hemorrhage. Provider education on HLH testing was the prospective intervention, followed by mistaken test removal. HLH triggers and diagnostic utility were determined by retrospective chart review. Risk factors for hemorrhage were determined by multivariable analysis.Erroneous HLH testing was reduced from 74% to 24% of patients (P < .001) by the QI intervention. These changes were projected to save $11,700 yearly. The majority (64%) of patients evaluated for HLH were on non-hematology/oncology services, highlighting the need for vigilance in hematology consultation. Sixty-three patients met classic HLH-2004 criteria for HLH. Malignancy (38%), infection (27%), Epstein-Barr virus (EBV) (14%), or autoimmune disease (8%) triggered most HLH cases. HLH triggers were most commonly identified by serologic testing (27%) and bone marrow biopsy (19%). Biopsy of other affected organs based on PET-CT imaging after unsuccessful initial diagnostic measures was helpful, and focal fluorodeoxyglucose uptake was predictive of an underlying malignancy (likelihood ratio 8.3, P = .004). Major hemorrhage occurred in 41% of patients. On multivariable analysis the odds ratios (OR) for major hemorrhage were increased for patients with intensive care unit level care (OR 10.47, P = .005), and disseminated intravascular coagulation in the first week of admission (OR 10.53, P = .04).These data are incorporated into a framework to encourage early HLH recognition with the HScore, facilitate trigger identification, identify those at risk for hemorrhage, and minimize low-yield or erroneous testing.

Transfusion requirements and 30-day mortality predictors for adult hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an uncontrolled hyper-inflammatory response. We assessed the transfusion requirements and predictors of 30-day mortality for adult HLH patients. We identified all adult patients with a diagnosis of HLH at a large academic hospital from October 2003 through February 2017. We extracted patients' clinical and laboratory data, including transfusion requirements, from their medical records. One-hundred sixteen patients were identified. Their median age was 48years (range 18-82); 72(62%) were male. Median duration of hospital stay was 19days (range 1-89days). At 30days from admission, 81(70%) patients were alive. Death was attributed to sepsis in 21 patients, lymphoma in six, bleeding in four, GVHD in one, liver failure in one, metastatic solid tumor in one, and unknown in one. Transfusion requirements at 30days from admission were as follows: RBC, 86% of patients, median 6 units (range 1-58); platelets, 74% of patients, median 6 units (1-67); plasma, 40% of patients, median 4 units (1-56). Renal failure (OR = 4.39; P = 0.008) and hypofibrinogenemia (OR = 4.07; P = 0.009) correlated with 30-day mortality. The transfusion requirements for adult HLH patients were high. Our study indicated that renal insufficiency and hypofibrinogenemia are predictors of early death in adult HLH.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults and adolescents—a life-threatening disease: analysis of 133 cases from a single center

ABSTRACTObjectives: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis is the most common type of infection-associated HLH. Previous studies were focused on pediatric EBV-HLH patients, therefore there lack of adult data.Method: We performed a retrospective analysis of 133 EBV-HLH patients (≥14 years old) in Beijing Friendship Hospital from March 2009 to April 2016 to evaluate the clinical manifestation and the effects and prognosis of existing regimens of EBV-HLH in adult and adolescents.Results: Of these patients, 91 male and 42 female cases had a median age of 26 (14–77) years. EBV-DNA load on admission was at a median of 6.6E + 05 IU/ml. The one-year mortality of these patients was 78%. 112 patients received the HLH-94/04 regimen as the initial treatment, 52 patients (46.43%) had response. Of the 6 patients who received the L-DEP regimen as the initial treatment, 5 patients (83.33%) had response. The rest 15 patients received initial treatment without etoposide, 5 cases achieved PR. 69 refractory or relapsed patients received DEP or L-DEP regimen, 55 (79.71%) cases had response. In addition, who received the L-DEP regimen, with the overall response rate significantly higher than the DEP regimen (88.37% VS 65.38%, P = 0.031). 36 out of 133 EBV-HLH patients eventually received allo-HSCT, with the overall survival rate of 52.78%. In summary, EBV-HLH is a highly lethal disease.Conclusion: DEP/L-DEP was a good salvage treatment. L-DEP might be a more effective first-line initial regimen than HLH-94/04 regimen for EBV-HLH. Finally, allo-HSCT is an effective radical treatment for EBV-HLH.

Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Analysis of 96 Patients in a Single Center.

Background:Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome. Central nervous system (CNS) involvement is a severe complication, which can lead to rapid disease development and higher morality. However, this has not been given enough attention in adult HLH. Therefore, we carried out this study to analyze the clinical features, laboratory findings, treatment outcomes, and other characteristics of adult HLH with CNS involvement.Methods:A retrospective analysis of 96 adult patients with HLH combined with CNS involvement between June 2003 and December 2016 was conducted. Clinical features, cerebrospinal fluid (CSF) features, image changes, and therapeutic outcomes were analyzed.Results:Among the 96 patients, 86 had various CNS symptoms and 33 (38.4%) had already presented symptoms before the HLH diagnosis was confirmed. A total of 59 patients received CSF examinations and showed abnormalities in 23 patients (39.0%). Seventy patients received imaging examinations and the results showed fifty patients with imaging changes (71.4%). Fifty-seven patients received multiple rounds of repeated intrathecal injection therapy and 35 patients improved (61.4%). As for the multiple analyses of effective factors on survival time, the results showed that the effects of combined Epstein–Barr virus (EBV) infection (P = 0.026, Exp(B) = 2.309, 95% confidence interval [CI] [1.108, 4.823) and intrathecal injection therapy (P = 0.013, Exp(B) = 0.422, 95% CI [0.214, 0.831]) on the survival time of the CNS-HLH patients were significant.Conclusions:Complication with EBV infection is a risk factor, and intrathecal injection is a protective factor. CNS involvement in HLH is not rare, which can result in a poor prognosis. Multiple rounds of repeated intrathecal injection therapy can improve the prognosis of CNS-HLH patients.

Secondary hemophagocytic lymphohistiocytosis in adults: a case series of 6 patients in a single institution in a brief period

Secondary hemophagocytic lymphohistiocytosis in adults: a case series of 6 patients in a single institution in a brief period