Hemophagocytic Lymphohistocytosis Research Articles

L-DEP regimen salvage therapy for refractory primary hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection in 4 children

Objective: To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children. Methods: In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children's hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed. Results: Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT. Conclusion: L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.

Hemophagocytic lymphohistocytosis in trisomy 21: successful treatment with interferon inhibition

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation primarily driven by the cytokine interferon gamma. It can be either a genetic or acquired disorder associated with infection, malignancy, and rheumatologic disorders. Trisomy 21 can express a wide range of phenotypes which include immune dysregulation and shares inherent pathophysiology with a group of disorders termed interferonopathies. Knowledge of this overlap in seemingly unrelated conditions could provide a basis for future research, and most importantly, alternative therapeutic interventions in acute life threatening clinical scenarios. Herein, we describe two patients with trisomy 21 presenting with HLH that was refractory to conventional treatment. Both patients were successfully managed with novel interventions targeting the interferon pathway.Case presentationWe describe a 17-month-old male and 15-month-old female with trisomy 21 presenting with a myriad of signs and symptoms including fever, rash, cytopenias, and hyperferritinemia, both ultimately diagnosed with HLH. Each had relapsing, refractory HLH over time requiring several admissions to the hospital receiving conventional high dose corticosteroids and interleukin-1 inhibition therapy. Successful steroid-free remission was achieved after targeting interferon inhibition with emapalumab induction followed by long-term maintenance on baricitinib.ConclusionTo our knowledge, these are the first reported cases of relapsed, refractory HLH in patients with trisomy 21 successfully treated with emapalumab and transitioned to a steroid-sparing regimen with oral baricitinib for maintenance therapy. Trisomy 21 autoimmunity and HLH are both thought to be driven by interferon gamma. Targeting therapy toward interferon signaling in both HLH and autoimmunity in trisomy 21 may have potential therapeutic benefits. Further investigation is needed to determine if trisomy 21 may predispose to the development of HLH given this common pathway.

Risk factors of early death in pediatric hemophagocytic lymphohistocytosis: Retrospective cohort study.

Hemophagocytic lymphocytosis (HLH) is a rare life-threatening hyperinflammatory syndrome in which early mortality remains high in patients with HLH. We retrospectively collected the medical records of all pediatric patients diagnosed with HLH at the West China Second Hospital of Sichuan University between January 2014 and December 2020. Collect demographic, laboratory, clinical, genetic profiles, treatment information and perform statistical analysis from records. Risk factors for death 30 days after admission were evaluated using a multivariable logistic regression model. A total of 110 pediatric HLH patients were enrolled. The median age of patients was 44 months (IQR 23-100.5) and 62 (56.4%) in males. The 30-day mortality rate for admission to this cohort was 34 (30.9%). Multivariate logistic regression analysis showed that heart failure (OR = 13.389, 95% CI, 1.671-107.256, p = 0.015) and hypoproteinemia (OR = 4.841, 95% CI, 1.282-18.288, p = 0.020) were associated with increased early mortality in children with HLH. These identified risk factors may help clinicians stratify patients with HLH and develop targeted treatment strategies. More research is needed to explore the best treatment strategies for patients with HLH to reduce early mortality in patients with HLH.

Difficult Diagnosis: A Case of Hemophagocytic Lymphohistocytosis in an Infant

Hemophagocytic lymphohistocytosis is an extremely rare disease requiring early diagnosis and specific treatment.The objective: to demonstrate the clinical case of hemophagocytic lymphohistocytosis in an infant. The course of the disease in a 6-month-old child requiring treatment in the intensive care unit was retrospectively analyzed. The article presents the procedure of differential diagnosis of sepsis and hemophagocytic lymphohistocytosis in children, special attention is paid to the diagnostic criteria, and the clinical and laboratory differences of these diseases are described.Conclusion. The presence of leukopenia, neutropenia, thrombocytopenia, hypoalbuminemia and hypocoagulation in an infant with persistent fever is the basis for a thorough differential diagnosis in order to eliminate severe systemic diseases that manifest as childhood infections and sepsis.

Poor Clinical Outcome in Pediatric Immunotherapy Is Mediated By a Pre-Existing Overactive IL-18-IFNy Immune Phenotype

Background: CAR-T cells have revolutionized the treatment of relapsed B-cell acute lymphoblastic leukemia (ALL), however the field is plagued by 50% relapse, 10-15% non-response, 20% severe toxicity (cytokine release syndrome (CRS) and neurotoxicity) rates. Studies on CAR patient outcomes thus far have largely focused on the contribution of characteristics of the CAR product and post-CAR symptoms 1-8, largely overlooking the potential role of the patient's pre-CAR immunophenotype beyond T-cells in driving therapeutic response and toxicity.We hypothesized that a patient's inflammatory status prior to immunotherapy could be used clinically to inform interventional and therapeutic mechanistic strategies. Taking inspiration from the clinical presentation overlap between CRS and hemophagocytic lymphohistocytosis (HLH), we hypothesized a common pathophysiology. IL-18 signaling in HLH disorders is well known to play a causative role in anomalous T-cell function 9. Importantly, IL-18 is also linked to tumor regression and progression 10-13. This coupled with the poor overall 5-year survival of secondary HLH patients associated with malignancies 14,15 suggested to us that an overactive IFNγ (T-cell)-IL-18 (myeloid) axis may also drive post-CAR toxicity, as well as overall therapeutic efficacy.Methods: To test whether patient-specific immunity and an overactive IFNy-IL-18 axis could predict toxicity, response, and survival, we applied a machine learning classifier to cytokine and cell-type profiles of blood samples obtained to prior and at early time points following CD19 CAR T cell infusion of retrospective cohort based on response/non-response, across the continuum of toxicity severity (both CRS and neurotoxicity) and matched availability of samples from 30 of 43 patients on the PLAT phase1 trial (NCT02028455) 2,16.Results/Discussion: We found evidence for a pre-existing overactive HLH-like axis in some patients; this included both patients with no response to CAR-T therapy as well as patients who experienced high levels of toxicity and diminished long-term survival. Stratification based on this axis was significantly associated with survival rates - Group 2 patients with high levels of IFNy-IL-18 had a median survival of 16.8 months post-CAR, (versus >48 months post-CAR, Group 1). Importantly, we identified an immune sub-type (CD161+IFNy+ T cells which are hyper responsive to IL-18) that is increased in this poor survival Group 2 prior to therapy, which suggests that patients could be effectively stratified prior to CAR infusion.Given the poor clinical outcome associated with high levels of CD161+IFNy+ T cells, we hypothesized that high levels may be a marker for primed pro-inflammatory myeloid activation, independent of cancer. Thus, we reasoned that donor monocytes from healthy donors with high levels of CD161+IFNy+ T cells could be induced with continued interferon signaling/priming into a Group 2 low survival/neurotoxicity phenotype. Healthy donors with elevated CD161+IFNy+ T cells had increased pro-inflammatory potential including IL-18 signaling in response to IFNy prime. We drove healthy donors to an elevated CD161+ IFNy phenotype utilizing an IL-12 prime, suggesting that patents with high levels of CD161+ cells had a monocytic priming event (e.g., pathogenic exposure, genetic predisposition, vaccination, etc.) prior to therapy that drove the poor clinical outcomes. Based on this data, we propose that a child's cytokine pre-inflammatory status might be independent of cancer and drives immunotherapeutic response and therefore tumor response and toxicity.Conclusions: In summary, we have identified that an HLH-like signaling axis pre- and early time points post- CAR therapy stratify patient outcomes predicting the onset of poor clinical outcomes prior to their clinical onset such as neurotoxicity, non-response, and relapse. We have also identified biomarker signatures prior and at early time points post-CAR such as cytokines (IFNγ-IL-18 signaling) and immune cell subsets (CD161+ IFNγ+ cells) responsible for the HLH-like signaling axis that could serve as potential future interventional targets. Finally, this study highlights the need to study patient-specific immune characteristics prior to CAR therapy, as these may be predictive of CAR success and failure and may help to identify novel therapeutic approaches and targets improving clinical outcomes. [Display omitted] DisclosuresBurleigh: ShapeTx: Current holder of stock options in a privately-held company. Jensen: BMS: Patents & Royalties; Umoja Biopharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Research Funding. Masters: IFM therapeutics: Membership on an entity's Board of Directors or advisory committees. Vince: Avammune Therepeutics: Membership on an entity's Board of Directors or advisory committees; Exopharm: Membership on an entity's Board of Directors or advisory committees. Gardner: Novartis: Consultancy; BMS: Patents & Royalties.

Serious consequences of Epstein-Barr virus infection: Hemophagocytic lymphohistocytosis.

Human is the host of the Epstein-Barr virus (EBV) especially in childhood and adolescence. Most of them are asymptomatic infection and self-limiting. However, for those patients who suffer from immune dysfunction, EBV infection will be life-threatening. Epstein-Barr virus-associated hemophagocytic lymphohistocytosis (EBV-HLH) is one of the severe effects. The diagnosis and differential diagnosis of EBV-HLH and other EBV infectious diseases are mentioned in this paper. The molecular biology mechanism and complications of EBV-HLH are equally briefly presented. It also provides a practical method for the genetic diagnosis of such diseases and the differential diagnosis with other human immunodeficiency diseases for medical scientists in routine clinical practice.

A Rare Case of Cytomegalovirus Infection Induced Hemophagacytic Lymphohistocytosis Syndrome (HLH)

Introduction:Haemophagocytic Lymphohistiocytosis (HLH) is a rare immunopathological syndromes of excessive immune activation which results in multiorgan dysfunction and haemophagocytosis. Persistent stimulation of lymphocytes and histiocytes results in hypercytokinemia, leading to characteristic symptoms of HLH. Primary HLH is caused by the genetic mutation and secondary HLH occurs in autoinflammatory and autoimmune disease(macrophage activation syndrome), lymphoma, Iatrogenic immunosupression and healthy persons with infections. HLH is rare disease but has garnered increaed attension over past 10 years.Case description:This is 50 year old female patient with significant past medical history of autoimmune hepatitis controlled on Azathioprine for 2 years. She presented to the emergency room with worsening cough, fevers, chills and shortness of breath, and admitted to the Intensive Care Unit (ICU) due to acute respiratory failure and suspicious for septic shock. She was found to have new onset pancytopenia with White Blood Cell count of 0.7 x10 9, Hemoglobin of 6.9, and platelet 77,000. She did not improved with antibiotics and clinical deteriorating with worse hypoxia and suspicion for Acute Respiratory Distress Syndrome. She was Intubated and on pressor support. Mean while patient also developed Dissiminated Intravascular Coagulation which required multiple platelets, packed red blood cell and cryoprecipitate transfusions. Diagnostic bronchoscopy was done. Bronchial washing is positive for Cytomegalovirus (CMV). Serum CMV Polymerase chain reaction(PCR)test shows high viral load. Computed Tomogram (CT) of abdomen also showed splenomegaly. Patient was started on Valganlciclovir, CT guided bone marrow (BM) biopsy showed secondary hemophagocytosis, Consideration with immunosuppression along with systemic CMV infection, pancytopenia, fever, low fibrinogen (<70 mg/dl) and high ferritin (2292 ng/ml), the diagnosis of the hemophagocytic lymphohistocytosis was made. Steroid was added into treatment regimen. Lab works shows gradually decreasing CMV viral load, till undetectable before discharge. Patient clinically improved with the treatment. She was extubated and discharge with Valganciclovir 900mg 3 times daily for 3 months with weekly CMV PCR.Discussion:Disseminated CMV associated with HLH is uncommon in adults, this case is a type of secondary HLH. Early recognition and treatment is important. The clinical features raised the suspicion of HLH were fever, cytopenia, organomegaly, coagulopathy, elevated ferritin and hemophagocytic lymphohistocytic in the BM and not responded to initial antibiotics and Granulocyte colony stimulating factor. In this case patient met the 5 of 8 criteria and showed improvement of symptoms after treatment of the primary infection. DisclosuresNo relevant conflicts of interest to declare.

Hemophagocytic lymphohistocytosis in a COVID-19patient in the acute phase: case report.

The outbreak of coronavirus disease 2019 (COVID-19) has put health systems worldwide under great pressure on numerous levels. COVID-19 is a heterogeneous situation where some people experience mild symptoms for which no serious intervention is needed, while others may experience serious situations ranging from acute respiratory distress syndrome (ARDS) or even respiratory failure and end organ damage. Serious COVID-19 cases may be complicated with a cytokine storm caused by hemophagocytic lymphohistocytosis, which is a life-threatening situation. Efforts should be directed to reveal accompanying diseases that may trigger the cytokine storm. Early diagnosis leads to a better understanding of how to deal with this emergency status; however, even with early intervention, outcomes are still very poor.

Case report: Secondary HLH in COVID-19

We present case of a 53 year old lady who is a known case of rheumatoid arthritis and hypertension in Karnataka, South India, who presented with Severe Acute Respiratory Infection (SARI) like symptoms (fever, cough and breathlessness) due to COVID-19. During the course of treatment further investigations revealed evidence of Hemophagocytic Lymphohistocytosis (HLH). This case emphasizes the need for a thorough workup to identify the etiology of HLH as it may unmask a treatable entity in a COVID-19 patient.

Secondary Hemophagocytic Lymphohistocytosis in COVID-19

We present case of a 53-year-old lady who is a known case of rheumatoid arthritis and hypertension in Karnataka, South India, who presented with Severe Acute Respiratory Infection (SARI) like symptoms (fever, cough and breathlessness) due to COVID-19. During the course of treatment further investigations revealed evidence of Hemophagocytic Lymphohistocytosis (HLH). This case emphasizes the need for a thorough workup to identify the etiology of HLH as it may unmask a treatable entity in a COVID-19 patient.

Secondary Hemophagocytic Lymphohistiocytosis and Autoimmune Cytopenias: Case Description and Review of the Literature.

Hemophagocytic lymphohistocytosis (HLH) is a rare hyperinflammatory condition which may be primary or secondary to many diseases, including hematologic malignancies. Due to its life-threatening evolution, a timely diagnosis is paramount but challenging, since it relies on non-specific clinical and laboratory criteria. The latter are often altered in other diseases, including autoimmune cytopenias (AIC), which in turn can be secondary to infections, systemic autoimmune or lymphoproliferative disorders. In the present article, we describe two patients presenting at the emergency department with acute AICs subsequently diagnosed as HLH with underlying diffuse large B cell lymphoma. We discuss the diagnostic challenges in the differential diagnosis of acute cytopenias in the internal medicine setting, providing a literature review of secondary HLH and AIC.

Bone Marrow and Peripheral Blood Findings in Patients Infected by SARS-CoV-2

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

Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells

AbstractChronic active Epstein-Barr virus (CAEBV) typically presents as persistent infectious mononucleosis-like disease and/or hemophagocytic lymphohistocytosis (HLH), reflecting ectopic Epstein-Barr virus (EBV) infection and lymphoproliferation of T and/or NK cells. Clinical behavior ranges from indolent, stable disease through to rapidly progressive, life-threatening disease. Although it is thought the chronicity and/or progression reflect an escape from immune control, very little is known about the phenotype and function of the infected cells vs coresident noninfected population, nor about the mechanisms that could underpin their evasion of host immune surveillance. To investigate these questions, we developed a multicolor flow cytometry technique combining phenotypic and functional marker staining with in situ hybridization for the EBV-encoded RNAs (EBERs) expressed in every infected cell. This allows the identification, phenotyping, and functional comparison of infected (EBERPOS) and noninfected (EBERNEG) lymphocyte subset(s) in patients' blood samples ex vivo. We have characterized CAEBV and HLH cases with monoclonal populations of discrete EBV-activated T-cell subsets, in some cases accompanied by EBV-activated NK-cell subsets, with longitudinal data on the infected cells' progression despite standard steroid-based therapy. Given that cytotoxic CD8+ T cells with relevant EBV antigen specificity were detectable in the blood of the best studied patient, we searched for means whereby host surveillance might be impaired. This revealed a unique feature in almost every patient with CAEBV studied: the presence of large numbers of myeloid-derived suppressor cells that exhibited robust inhibition of T-cell growth. We suggest that their influence is likely to explain the host's failure to contain EBV-positive T/NK-cell proliferation.

Macrophage Activation Syndrome in Adults: A Retrospective Case Series.

Macrophage activation syndrome (MAS) is a form of hemophagocytic lymphohistocytosis that occurs in patients with a variety of inflammatory rheumatologic conditions. Traditionally, it is noted in pediatric patients with systemic juvenile idiopathic arthritis and systemic lupus erythematous. It is a rapidly progressive and life-threatening syndrome of excess immune activation with an estimated mortality rate of 40% in children. It has become clear recently that MAS occurs in adult patients with underlying rheumatic inflammatory diseases. In this article, we describe 6 adult patients with likely underlying MAS. This case series will outline factors related to diagnosis, pathophysiology, and review present therapeutic strategies.

Doença de Kawasaki e COVID-19: uma revisão de literatura

Objetivo: Identificar a relação entre a Doença de Kawasaki e o novo Coronavírus (COVID-19). Revisão bibliográfica: Foram analisados 91 artigos, sendo 39 lidos integralmente e utilizados neste estudo. A análise viabilizou a percepção de que infecções pelo novo Coronavírus levam a uma resposta hiperinflamatória ou tempestade de citocinas, como interleucinas (IL) 1 e 6, ativação de macrófagos e presença de imunoglobulina (Ig) A, provocando patologias como linfohistiocitose hemofagocítica secundária, Síndrome de Disfunção Respiratória Aguda (SDRA) e alterações nas artérias coronarianas semelhantes à Doença de Kawasaki. O dano epitelial provocado pelo vírus em estágio inicial, assim como na DK, pode induzir à endotelite local secundária, o que pode explicar um fenótipo vasculítico autoinflamatório tardio com regulação positiva de interleucinas. Essa inflamação endotelial aumentada e lesão/disfunção após a infecção pelo novo Coronavírus, provavelmente, é devido à ação da enzima conversora de angiotensina (ECA). Considerações finais: Nos últimos 20 anos, os vírus da família dos Coronavírus foram propostos como participantes na patogênese da doença de Kawasaki (DK), uma vasculite sistêmica aguda. A associação documentada levanta a preocupação de saber se a infecção por COVID-19 aumenta o risco de DK.

Favorable Anakinra Responses in Severe Covid-19 Patients with Secondary Hemophagocytic Lymphohistiocytosis

SummaryDysregulation of inflammation is hypothesized to play a crucial role in the severe complications of COVID-19, with the IL-1/IL-6 pathway being central. Here, we report on the treatment of eight severe COVID-19 pneumonia patients—seven hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands—with the interleukin-1 receptor antagonist Anakinra. All patients scored positive for the hemophagocytosis score (HScore) and were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury, and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors, significantly improved respiratory function, and lower HScore. Although three patients died, the mortality was lower than historical series of patients with sHLH in sepsis. These data suggest that administration of Anakinra may be beneficial for treating severe COVID-19 patients with sHLH as determined by the HScore, and they support the need for larger clinical studies to validate this concept.

Favorable Anakinra Responses in COVID-19 Patients with Severe Respiratory Failure

Dysregulation of inflammation is hypothesized to play a crucial role for inducing the severe complications of Covid-19, with IL-1/IL-6 pathway being central in these events. Eight patients with severe Covid-19 pneumonia treated with the interleukin-1 receptor antagonist anakinra are reported; seven patients hospitalized in intensive care units (ICUs) in Greece and one non-ICU patient in the Netherlands. Patients scored positive for the hemophagocytosis score and they were diagnosed with secondary hemophagocytic lymphohistocytosis (sHLH). At the end-of-treatment with anakinra, ICU patients had less demands on vasopressors; they also had lower C-reactive protein, procalcitonin, troponin I, D-dimers, and ferritin - the hallmark marker of sHLH. All patients improved their respiratory function. Only two patients died. These data argue that the administration of anakinra may be a viable treatment in severe Covid-19 with sHLH, supporting for larger clinical studies to validate this concept.

Early Recognition and Treatment of Hemophagocytic Lymphohistocytosis in A Child with the Early Symptom of DIC

Background: Hemophagocytic lymphohistocytosis (HLH) is a potentially fatal multiple organ inflammatory response syndrome that is characterized by proliferation of histiocytes and inflammatory factor storm. The disease progress varies fast and has a high death rate. Disseminated intravascular coagulation (DIC) is one of the leading causes of death in HLH. Here, we reported a child suffered from secondary HLH with the early symptom of DIC.

Macrophage Activation-Like Syndrome: A Distinct Entity Leading to Early Death in Sepsis.

Hemophagocytic lymphohistocytosis (HLH) is characterized by fulminant cytokine storm leading to multiple organ dysfunction and high mortality. HLH is classified into familial (fHLH) and into secondary (sHLH). fHLH is rare and it is due to mutations of genes encoding for perforin or excretory granules of natural killer (NK) cells of CD8-lymphocytes. sHLH is also known as macrophage activation syndrome (MAS). Macrophage activation syndrome (MAS) in adults is poorly studied. Main features are fever, hepatosplenomegaly, hepatobiliary dysfunction (HBD), coagulopathy, cytopenia of two to three cell lineages, increased triglycerides and hemophagocytosis in the bone marrow. sHLH/MAS complicates hematologic malignancies, autoimmune disorders and infections mainly of viral origin. Pathogenesis is poorly understood and it is associated with increased activation of macrophages and NK cells. An autocrine loop of interleukin (IL)-1β over-secretion leads to cytokine storm of IL-6, IL-18, ferritin, and interferon-gamma; soluble CD163 is highly increased from macrophages. The true incidence of sHLH/MAS among patients with sepsis has only been studied in the cohort of the Hellenic Sepsis Study Group. Patients meeting the Sepsis-3 criteria and who had positive HSscore or co-presence of HBD and disseminated intravascular coagulation (DIC) were classified as patients with macrophage activation-like syndrome (MALS). The frequency of MALS ranged between 3 and 4% and it was an independent entity associated with early mortality after 10 days. Ferritin was proposed as a diagnostic and surrogate biomarker. Concentrations >4,420 ng/ml were associated with diagnosis of MALS with 97.1% specificity and 98% negative predictive value. Increased ferritin was also associated with increased IL-6, IL-18, IFNγ, and sCD163 and by decreased IL-10/TNFα ratio. A drop of ferritin by 15% the first 48 h was a surrogate finding of favorable outcome. There are 10 on-going trials in adults with sHLH; two for the development of biomarkers and eight for management. Only one of them is focusing in sepsis. The acronym of the trial is PROVIDE (ClinicalTrials.gov NCT03332225) and it is a double-blind randomized clinical trial aiming to deliver to patients with septic shock treatment targeting their precise immune state. Patients diagnosed with MALS are receiving randomized treatment with placebo or the IL-1β blocker anakinra.

HOW HIGH CAN FERRITIN LEVEL BE? A RARE CASE OF EHRLICHIOSIS-INDUCED HLH WITH REACTIVATION OF EBV

SESSION TITLE: Critical Care 3 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 PM - 02:15 PM INTRODUCTION: Hemophagocytic lymphohistocytosis (HLH) is often under recognized which leads to high mortality and morbidity. Prompt recognition and treatment can decrease mortality. We present a case of HLH triggered by infection with Ehrlichia with reactivation of EBV. CASE PRESENTATION: A 28-year-old man with no past medical history presented with fever, chills, generalized musculoskeletal pains, nausea, vomiting, loose stools and headache. He went to hiking at Roanoke river and Greenway a week prior to presentation. Physical exam revealed blood pressure 123/69 mmHg, pulse 96/min, temperature 103 F, respiratory rate 36/min. Pertinent physical examination findings include cervical lymphadenopathy, generalized muscle tenderness with bilateral shin petechiae. Laboratory data revealed leukopenia 0.9, platelets 17, transaminitis (AST-457, ALT- 96), CK- 8663, fibrinogen 162, and ferritin 61,437. He was admitted for neutropenic fever and was empirically started on vancomycin, cefepime and doxycycline for tick borne infection. Bone marrow biopsy was performed due to concern for HLH revealed histocytes with intracellular RBC and WBC’s. Further workup is negative for any autoimmune disease, malignancies, but positive for IgG EBV and Ehrlichia. PCR for EBV DNA was positive with viral load 2096 copies/ml (normal < 200 copies/ml). Received a dose of Etoposide and Decadron but he started to improve clinically. Doxycycline was continued and rest of the antibiotics and chemotherapy was discontinued. Patient was discharge in stable condition and completed total 14 days of doxycycline treatment. Patient remained asymptomatic one month after hospital discharge. DISCUSSION: HLH is a life-threatening disorder characterized by unregulated hyperimmune response to antigen which results in phagocytosis of white cells, RBCs and platelets by mononuclear macrophages. It was first described in 1952 by Farquhar and Claireaux. Secondary causes of HLH is seen in adults from autoimmune diseases, infections and malignancies. Viral infections are the most common triggers: EBV, CMV, HIV. Elevated ferritin >10,000 μg/L has been demonstrated to be 90% sensitive and 96% specific for HLH (3). If left untreated mortality is high with median survival less than 2 months. HLH-1994 treatment protocol recommended an 8-week induction with IV dexamethasone and etoposide, and HLH-2004 protocol added cyclosporine to help prevent relapse.Most patients respond to early initiation of doxycycline 100 mg twice daily in Ehrlichiosis induced HLH and can be continued 4-5 days after clinically resolution of symptoms. If refractory then can use chemotherapeutic agents like etoposide, cyclosporine, intrathecal methotrexate, methylprednisolone. CONCLUSIONS: HLH should be in differential diagnosis in patients who present from endemic regions of tick borne infections with fever, cytopenia’s and especially with high ferritin levels (> 500 μg/L). Reference #1: Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis: A Case Series. Zaher K et al. Blood 2014 124:4105 Reference #2: Ehrlichiosis-Induced Hemophagocytic Lymphohistiocytosis Presenting As Septic Shock - An Immune Response Gone Haywire And Its Lessons For The Icu Setting. N. G. Holtzman et al. Am J Respir Crit Care Med 189;2014: A6737 Reference #3: Hemophagocytic lymphohistiocytosis: review of etiologies and management. Melissa R George. J Blood Med. 2014; 5: 69–86. Published online 2014 Jun 12. https://doi.org/10.2147/JBM.S46255 DISCLOSURES: No relevant relationships by Venkateswara Kollipara, source=Web Response No relevant relationships by Umar Sofi, source=Web Response