Diagnosis Of Hemophagocytic Lymphohistiocytosis Research Articles

Hemophagocytic Lymphohistiocytosis in Early Infancy- Pitfall of Differentiation between Hereditary and Infectious Reasons

Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor.Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours.Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications. DisclosuresRusso:Novo Nordisk: Other: conference fee, travel and accomodation support ; Octapharma: Other: conference fee, travel and accomodation support. Lammle:Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support ; Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support .

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.

S100B Is a Useful Marker for the Diagnosis of Haemophagocytic Lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic inflammatory clinical syndrome that can be primary/familial or secondary to a variety of underlying conditions. The 2004 diagnostic criteria for HLH require 5 out of 8 of the following clinical and pathological variables to be present: fever, splenomegaly, cytopenia in at least 2 lineages, hypertriglyceridemia/hypofibrinogenemia, haemophagocytosis on pathology examination, low/absent NK cell activity, ferritin greater than 500µg/L or soluble IL-2 receptor (sCD25) greater than 2400 U/mL. At least 5 of these criteria must be met, as each one lacks specificity. With regard to the pathology detection of haemophagocytosis, the sensitivity and specificity reported in the literature were 83% and 60% respectively. Indeed, a degree of haemophagocytosis can be seen outside the context of HLH. Furthermore, some of the diagnostic features of HLH may not be useful when applied to single cases because they may be intrinsic to the underlying condition. Therefore, we wondered whether the histopathological diagnosis might be improved. We investigated whether testing for S100B expression in macrophages might render the detection of haemophagocytosis more specific and sensitive. S100B is a marker of macrophage activation, and can routinely be detected by immunohistochemistry. S100B has pro-inflammatory properties and has been shown to affect macrophage function. It is typically expressed in macrophages of Rosai-Dorfman disease apart of having also a tissue-specific expression pattern, marking melanocytes as well as Langerhans cells and other subsets of dendritic cells.A natural language search of the pathology database at our institution identified 32 patients with bone marrow samples reporting haemophagocytosis as evaluated on bone marrow smear preparations, between January 2002 and July 2015. Cases that did not have available paraffin-embedded bone marrow trephine biopsy and clinical data were excluded. The bone marrow samples of three patients without haemophagocytosis and without any clinical features of HLH were used as controls: a new diagnosis of acute leukemia, a follow-up of acute leukemia post-transplant and a known lymphoma patient with unexplained pancytopenia. Clinical parameters relevant to the diagnosis of HLH were evaluated. Cases were clinically categorized as diagnostic for HLH (≥5 criteria), clinically likely (<5 criteria, but clinical presentation consistent) or clinically non suspicious (<5 criteria and clinical presentation not consistent with HLH). Stains for S100B and CD68 were performed. The percentage of S100B positive cells of all bone marrow cells as well as the percentage of CD68 positive macrophages was calculated from 500-cell counts using a 40x objective lens.The median patient age was 57 years (range 18-80). Underlying clinical diagnoses are reported in Table 1. Expression of S100B ranged from 0-76.4%. Cases without morphological evidence of haemophagocytosis had less than 1% S100B-positive cells. Cases with presence of haemophagocytic cells showed various levels of S100B-positive cells. Of interest, >10% S100B-positive cells (of all cells) was 100% specific for cases meeting ≥4 HLH criteria, 91% specific for cases clinically likely HLH or confirmed HLH. The sensitivity was 60% for cases meeting ≥4 HLH criteria, 52% for cases being likely HLH or confirmed HLH. Percentage of CD68-positive cells or S100B/CD68 ratio did not add relevant information.The high specificity of S100B expression by immunohistochemistry indicates it may be an additional diagnostic feature of HLH. Of note, the test is available in routine immunohistochemistry laboratories. Since not all cases of HLH show increased numbers of S100B-expressing macrophages, the test does not obviate the need for the 2004 criteria. Serological immunoassays for S100B have been developed for use in the context of brain disease/injuries and malignant melanoma. Based on our data, we intend to further investigate the sensitivity and specificity of S100B as a serological marker of HLH. [Display omitted] DisclosuresKuruvilla:BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy, Honoraria; Leukemia and Lymphoma Society Canada: Research Funding; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Lundbeck: Honoraria.

UNDER-RECOGNIZED DIAGNOSIS UNDERLYING A DESQUAMATING RASH WITH EOSINOPHILIA AND BANDEMIA.

Introduction Secondary Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition characterized by uncontrolled systemic inflammation and cytokine storm (1). Underlying confounders or diseases that mimic acute presentation (such as sepsis) can lead to delay in diagnosis (1) (3). High mortality is often due to missed or delayed diagnosis. (2). Case Description 45-year old woman with no significant past medical history admitted with a generalized pruritic, scaly, desquamating rash for 2 weeks associated with fevers, transaminitis, eosinophilia and bandemia. She was treated with antibiotics for presumed sepsis, but had negative cultures, however was persistently febrile and antibiotics were broadened to meropenem, levaquin, fluconazole and ivermectin. Two weeks in to admission, with continued fevers, she was found to have high inflammatory markers (ferritin 100,000, ESR>130, CRP >300) and an initial positive ANA 1:80 (negative on repeat). Patient continued to have eosinophilia, bandemia, lymphopenia but other autoimmune markers were negative with normal complements. BM biopsy showed hemophagocytosis on second week of admission consistent with diagnosis of HLH. Hospital course complicated by multi-organ failure, seizure and cardiopulmonary arrest. Patient started on chemotherapy with Etoposide and Dexamethasone, but unable to tolerate therapy due to unstable vital signs, hepato-renal failure and worsening pancytopenia. Patient did stabilize after initial treatment with supportive measures, however had a prolonged complicated hospital course including tracheostomy and PEG insertion as a sequelae of her cardiopulmonary arrest. Discussion Keeping HLH high on the differential, especially in patients not responding to antibiotics despite appropriate therapy, is important to avoid missed diagnoses and improved patient outcomes.

Establishment of a protein biochip to detect serum IgG antibodies against IL-2 and soluble CD25 in hemophagocytic lymphohistiocytosis

BackgroundInterleukin-2 (IL-2) and soluble CD25 (sCD25) are among the most important cytokines and diagnostic biomarkers in hemophagocytic lymphohistiocytosis (HLH). Detecting serum level of IL-2 and sCD25 is valuable for making clinical diagnosis and treatment decision in HLH. MethodsSince tests showing serum IgG antibody against IL-2 or sCD25 have never been carried out, a new protein biochip, which was modified with cysteine and activated sophorolipid (Cys-SL), was developed. ResultsLimits of detection on the biochip were 78 pg/ml for IL-2 and 39 pg/ml for sCD25, respectively. The data showed that on-chip seroimmunological responses to IL-2 and sCD25 proteins were 20.8% and 83.1% and the seroprevalence of IL-2 and sCD25 IgG antibodies were 45.5% and 57.2%, respectively. Data collection for the seroprevalence of serum antigen-antibody complex of sCD25 was 68.8%. The new biochip model shared similar sensitivity and specificity to chemiluminescent immunoassay (CLIA) in its measuring capacity of serum sCD25. ConclusionsWe addressed and confirmed the involvement of serum IgG antibodies against IL-2 and sCD25 as well as Ag-Ab complex of sCD25 in HLH patients. Therefore, this biochip platform would offer a new technological substitution for clinical serological diagnosis of HLH.

Secondary hemophagocytic lymphohistiocytosis in a patient with rheumatoid arthritis and vasculitis: a case report and review of the literature

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by excessive systemic inflammation, caused by uncontrolled activation of lymphocytes and macrophages, which secrete increased amounts of cytokines. HLH may be caused by gene mutations (primary HLH) or associated with malignancy, immunodeficiency, infection or autoimmune disease (secondary HLH). A 58-year-old woman with seropositive rheumatoid arthritis (RA) presented with fever, ulcers on the left foot and in the intergluteal cleft and increased inflammation markers. Clinical and laboratory evaluation, combined with findings from intra-arterial digital subtraction angiography of the lower limbs, pointed towards the diagnosis of vasculitis. Intravenous administration of low-dose cyclophosphamide resulted in recession of fever and decrease of inflammation markers. However, the patient later developed pancytopenia, hepatomegaly, hyperferritinemia, hypofibrinogenemia and hypertriglyceridemia, while bone marrow aspiration demonstrated hemophagocytosis. The diagnosis of HLH was established. An extensive workup excluded malignancies, systemic infections and immunodeficiencies. HLH in our patient was attributed to activation of RA and presentation of vasculitis. Treatment with corticosteroids and intravenous immunoglobulin led to resolution of fever, correction of pancytopenia and complete healing of the ulcers. Timely diagnosis and treatment of HLH is highly important for a favorable outcome for the patients. Treatment of secondary HLH associated with autoimmune diseases involves corticosteroids and/or other immunomodulatory agents, such as intravenous immunoglobulin.

Hemophagocytic Lymphohistiocytosis Masquerading as Alcoholic Hepatitis

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune activation. Timely diagnosis can be challenging and prompt treatment is the only hope for survival. A 35 year old male with history of alcohol dependence was sent to the gastroenterology clinic for evaluation of fatigue, bilateral lower extremity edema, and orange colored urine. Lab work showed abnormal liver function tests (AST 295, alkaline phosphatase (ALP) 505, ALT 230, bilirubin 3.4). Exam was significant for lower extremity edema and hepatosplenomegaly. Further testing revealed elevated ferritin (12799 ng/ml) and iron saturation (68%). Repeat LFTs one week later showed AST 356, ALP 569, ALT 155, bilirubin 9.5. The patient was admitted to the hospital for further evaluation. CT scan a month prior incidentally showed hepatosplenomegaly and diffuse lymphadenopathy. PET scan revealed hypermetabolic splenomegaly, mediastinal and retroperitoneal lymphadenopathy, and numerous bone marrow abnormalities. Bone marrow biopsy and endoscopic ultrasound (EUS) were then performed. EUS revealed many abnormal enlarged lymph nodes extending from the supraclavicular region to the liver. Biopsies taken were normal and bone marrow biopsy showed no cytogenetic evidence of an abnormal clone. The patient was started empirically on ganciclovir for possible CMV infection and dexamethasone for suspected HLH while cultures and biopsy results were pending. Viral cultures were positive for CMV IgG and IgM, and EBV IgG and nuclear antibody. A clinical diagnosis of HLH was made and he was started on etoposide, in addition to dexamethasone, but his clinical status deteriorated rapidly and he died of multiorgan failure seven days later. HLH is a rare aggressive disease that is more frequently observed in infants. Immune homeostasis disruption can be triggered by infection, the most common being Epstein-Barr virus. It presents as a febrile illness that mimics infections, fever of unknown origin, hepatitis, and encephalitis, making timely diagnosis especially difficult. Patients typically present with hepatomegaly, lymphadenopathy, cytopenias, and high ferritin levels. High ferritin in the absence of iron overload carries high sensitivity and specificity for this disease. It is important that gastroenterologists keep a high index of suspicion when a patient presents with liver failure, high ferritin, and cytopenia, as they can be the first to evaluate these patients when they present.2259 Figure 1. From: Hemophagocytic LymphohistiocytosisAn Update on Diagnosis and Pathogenesis Am J Clin Pathol. 2013;139(6):713-727. doi:10.1309/AJCP4ZDKJ4ICOUAT Am J Clin Pathol | © American Society for Clinical Pathology

Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis: Case report and systematic literature review.

AIMTo systematically review liver disease associated with hemophagocytic lymphohistiocytosis (HLH), propose reasonable contraindications for liver transplantation for liver failure in HLH, and report an illustrative case.METHODSSystematic review according to PRISMA guidelines of hepatic manifestations of HLH using computerized literature search via PubMed of articles published since 1980 with keywords (“hemophagocytic lymphohistiocytosis” or “HLH”) AND (“liver” or “hepatic”). Two authors independently performed literature search and incorporated articles into this review by consensus. Illustrative case report presented based on review of medical chart, and expert re-review of endoscopic photographs, radiologic images, and pathologic slides.RESULTSA 47-year-old Caucasian male, was hospitalized with high-grade pyrexia, rash, total bilirubin = 45 g/dL, moderately elevated hepatic transaminases, ferritin of 3300 ng/dL, leukopenia, and profound neutropenia (absolute neutrophil count < 100 cells/mm³). Viral serologies for hepatitis A, B, and C were negative. Abdominal computed tomography scan and magnetic resonance imaging revealed no hepatic or biliary abnormalities. Pathologic analysis of liver biopsy revealed relatively well-preserved hepatic parenchyma without lymphocytic infiltrates or macrophage invasion, except for sparse, focal hepatocyte necrosis. Bone marrow biopsy and aspirate revealed foamy macrophages engulfing mature and precursor erythrocytes, consistent with HLH. Interleukin-2 receptor (CD25) was highly elevated, confirming diagnosis of HLH according to Histiocytic Society criteria. Patient initially improved after high-dose prednisone therapy. Patient was judged not to be a liver transplant candidate despite model for end stage liver disease (MELD) score = 33 because liver failure was secondary to severe systemic disease from HLH, including septic shock, focal centrilobular hepatocyte necrosis from hypotension, bone marrow failure, and explosive immune activation from HLH. The patient eventually succumbed to overwhelming sepsis, progressive liver failure, and disseminated intravascular coagulopathy. Systematic review reveals liver injury is very common in HLH, and liver failure can sometimes occur. Data on liver transplantation for patients with HLH are very limited, and so far the results have shown a generally much worse prognosis than for other liver transplant indications. Liver transplantation should not be guided solely by MELD score, but should include liver biopsy results and determination whether liver failure is from intrinsic liver injury vs multisystem (extrahepatic) organ failure from HLH.CONCLUSIONThis case report illustrates that liver transplantation may not be warranted when liver failure associated with HLH is primarily from multisystem failure from HLH. Liver biopsy may be very helpful in determining the severity and pathophysiology of the liver disease.

Adult onset haemophagocytic lymphohistiocytosis prognosis is affected by underlying disease: analysis of a single-institution series of 174 patients.

Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterised by activation of the mononuclear phagocytic system, and often leads to progressive multiple organ failure. The diagnosis of HLH is made late by most physicians. To confirm the diagnosis of acquired HLH made in a single-institution series of adult patients with HLH-04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. A total of 174 patients with a median age of 51 years (range 17-90) were included. Male/female ratio was 111/63. In 92/174 (52.9%) patients, there were potential haematological diseases (4 acute leukaemia, 1 thrombotic thrombocytopenic purpura, 3 Hodgkin's lymphoma [HL], 17 B-cell non-Hodgkin's lymphoma [NHL], 67 T-cell NHL including 22 natural killer / T-cell NHL [NK/t-cell NHL). Six (3.4%) patients had autoimmune disease and 76 (43.7%) undiagnosed underlying disease. There were 44 (25.3%) patients with Epstein-Barr virus infection, 11 (6.3%) with cytomegalovirus, 1 (0.5%) syphilis, 9 (5.2%) hepatitis B virus and 3 (1.7%) human immunodeficiency virus. More than 95% of patients had hyperferritinaemia, high lactate dehydrogenase, fever and low albumin, whereas 89.1% of patients had bone marrow phagocytosis. By the HScore, 4/174 patients had a >50% and 16/174 patients had a >90% probability of not having HLH. All 174 patients fulfilled more than five of the HLH-04 diagnostic criteria, but 16 of them had a low probability of HLH by the HScore. In a multivariate analysis, lymphopenia and hypofibrinogenaemia were independent prognostic factors for death. In our study, viral infection was not an independent prognostic factor. NK/T-cell -NHL was associated with worse prognosis compared with B-cell NHL and T-cell NHL (p = 0.036) and similar to other aetiologies.

Mass-Like Lesion on Brain Magnetic Resonance Imaging

This two-year-old previously healthy girl presented with seizures and severe septic shock. She had fever, upper respiratory tract symptoms, and progressive alteration of mental status. Examination revealed a comatose, intubated child with generalized edema, abdominal distension, hepatosplenomegaly, and diffuse petechial rash. Her evaluation was significant for pancytopenia, coagulopathy, hypertriglyceridemia, and elevated ferritin. Cerebrospinal fluid contained 24 white blood cells with many immature mononuclear cells and high protein of 277 mg/dL. Her initial computed tomography scan was normal, but magnetic resonance imaging (MRI) showed large mass-like lesions in both frontal-parietal regions (Fig) with compression of the posterior horn of the left lateral ventricle. Bone marrow biopsy was consistent with a diagnosis of hemophagocytic lymphohistiocytosis (HLH). She survived the initial treatment phase with an improvement in her neurocognitive status and continued to receive a combined chemo-immunotherapy regimen.

Progress in genetics of primary hemophagocytic lymphohistiocytosis

Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare and life-threatening hematological disorder.HLH is caused by the uncontrolled proliferation and activation of lymphocytes and macrophages, which secrete cytokines.The storm of cytokines can lead to systemic inflammatory response.HLH has been categorized as primary HLH and secondary HLH.Over the last decades, researches in the genetics show that gene mutations play an important role in the pathogenesis of primary HLH, including twelve gene mutations and four reported gene mutations.In addition, there are three unknown but high frequency gene mutations, which may present hemophagocytic syndrome-like clinical manifestations.The genetics of primary HLH has become the focus, and also is critical in the diagnosis and treatment of HLH. Key words: Primary hemophagocytic lymphohistiocytosis; Gene mutation; Pathogenesis; Immune regulation

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.

Disseminated BCG-osis with haemophagocytosis, tubercular bacteraemia, and unusual haematological findings with its haematology analyser-based expression

Infantile disseminated BCG-osis is an uncommon complication of BCG vaccination and the presence of haemophagocytic lymphohistiocytosis (HLH) further complicates the clinical course due to its fatal outcome. Here, we describe a rare case of disseminated BCG-osis with HLH in a 3-month-old male child and the unusual morphological findings in the peripheral blood with its haematology analyser-based expression. The child presented with fever, failure to thrive, hepatosplenomegaly, erythematous skin rashes, and left axillary lymphadenopathy with history of BCG vaccination at birth. He was the first born of second-degree consanguineous marriage with no significant family history of immunodeficiency disorders. Laboratory findings included anaemia, thrombocytopenia, hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia which supported a diagnosis of HLH. The peripheral blood showed evidence of phagocytosis by neutrophils, pseudo-Chediak-Higashi-like inclusions, blue-green inclusions, and intra-cytoplasmic vacuoles with shadowy appearance and cellular debris in the background. Acid-fast bacilli were demonstrated in the peripheral blood by Ziehl-Neelsen stain. His clinical condition gradually worsened with multi organ failure and fatality.

Hemophagocytic lymphohistiocytosis presenting with annular erythema multiforme-like eruptions in a patient with angioimmunoblastic T cell lymphoma: A case report.

Angioimmunoblastic T cell lymphoma (AITL)-associated hemophagocytic lymphohistiocytosis (HLH) rarely occurs with annular erythema multiforme-like rashes. The present case report describes a patient who was misdiagnosed with erythema multiforme at an early stage of the disease due to annular erythema multiforme-like eruptions. However, antihistamine treatment was ineffective. The patient progressed rapidly with high fever, hepatosplenomegaly and pharyngitis. The number of copies of Epstein-Barr virus DNA continuously increased. Accompanied by the swelling of lymph nodes, the blood cell count decreased. Further bone-marrow examination and biopsy of the lymph nodes were conducted. The patient was eventually diagnosed with AITL-associated HLH, and treated with etoposide together with cyclophosphamide, doxorubicin, vincristine and prednisolone. The patient was successfully treated with several courses of chemotherapy. In view of the fact that AITL-associated HLH with annular erythema multiforme-like rashes is relatively rare worldwide and is associated with a high mortality rate, the data on previous cases were reviewed with the hope of providing clinical bases for early diagnosis and treatment of AITL-associated HLH.

Case report of acquired hemophagocytic lymphohistiocytosis associated with progression of monoclonal gammopathy of unknown significance (MGUS)

Background: Acquired hemophagocytic lymphohistiocytosis (HLH) is an aggressive hyperinflammatory syndrome. Without prompt diagnosis and proper treatment, it can be life-threatening. HLH is commonly present in the setting of other autoimmune disorders, infection, organ transplantation, and malignancy. However, to our knowledge, HLH associated with monoclonal gammopathy of undetermined significance (MGUS) has not been reported.Case presentation: A 67-year-old woman with an extensive history of MGUS and renal transplant presented with progressive fatigue, weight loss, intermittent fevers, splenomegaly, and pancytopenia. Serum protein electrophoresis with immunofixation identified a new monoclonal protein IgG lambda and a rapidly increasing pre-existing free kappa light chain. A bone marrow biopsy revealed focal clusters of kappa restricted plasma cells which comprised less than 10\% of marrow cellularity. Skeletal survey was negative for osteolytic lesions. She was also free of any end-organ damage. Histological examination showed a prominent increase in histiocytes and macrophages, many of which show erythrophagocytosis and lymphophagocytosis. Together with her clinical presentation along with a hyperferritinemia, a diagnosis of HLH was confirmed utilizing the criteria of the Histiocyte Society. The patient underwent a splenectomy. Prompt treatment with etoposide and high dose dexamethasone eventually stabilized the patient and resulted in a full recovery, which coincided with the disappearance of the serum monoclonal IgG lambda.Conclusions: This report reveals a novel association of HLH with the progression of MGUS. Familiarity with this syndrome and its association with other conditions is indicated to ensure prompt diagnosis and appropriate patient treatment.

Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening syndrome that occurs secondary to severe systemic immune activation.1 Cytotoxic T-cell proliferation leads to increased cytokine production and activation of tissue resident macrophages. Ultimately, multi-system end organ damage caused by massive inflammation may lead to a fatal outcome without timely diagnosis and initiation of appropriate therapy.2 Hemophagocytic lymphohistiocytosis affects patients of all ages and occurs as an inherited disease, or secondarily in the setting of predisposing conditions that alter the normal immune response. The inherited form of the disease presents in early childhood and is associated with homozygous mutations in genes involved in CD8+ T-cell- and NK-cell-mediated immunity.3 These genetic forms of HLH are uniformly fatal without hematopoietic cell transplant or gene therapy. Secondary HLH may occur sporadically in healthy individuals, but is more often encountered in patients with hematologic malignancy, autoimmune disease, and iatrogenic immunosuppression. Virtually all cases are thought to require an infectious or noninfectious trigger to initiate the aberrant immune response, regardless of the underlying immune dysfunction.4–7 Hemophagocytic lymphohistiocytosis presents abruptly over a period of several days to weeks with a consistent pattern of fever, pancytopenia, and splenomegaly. Common laboratory abnormalities include hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated soluble IL-2 receptor, and abnormal liver func tion tests.1 The most widely used diagnostic criteria for HLH were developed for inclusion in the HLH-2004 trial which requires genetic evidence of a mutation associated with HLH or fulfillment of 5 of 8 clinical criteria including fever, splenomegaly, bicytopenia, hypertriglyceridemia or hypofibrinogenemia, evidence of hemophagocytosis in bone marrow or other tissues, low or absent NK-cell activity, elevated ferritin, and elevated soluble IL-2 receptor.3 Although not validated for adults, these HLH-2004 criteria are broadly applied in patients of all ages. Pathologists play a critical role in the diagnostic workup of patients suspected of having HLH. Bone marrow examination is performed to evaluate for hemophagocytosis, identify underlying malignancy, and exclude benign or neoplastic mimics. The presence of hemophagocytosis in the marrow fulfills one of the HLH-2004 diagnostic criteria; however, no accepted diagnostic threshold or reporting guidelines have been established. The lack of evidence-based guidelines leads to considerable uncertainty among pathologists as to what degree of hemophagocytosis is sufficient to satisfy this criterion. Adding to the challenge is that hemophagocytosis is not specific to the diagnosis of HLH in the absence of other clinical features of the disease. Rare erythrophagocytosis is commonly seen in bone marrow aspirates and increased hemophagocytosis may be encountered in the setting of sepsis, blood transfusions, hematopoietic transplantation, chemotherapy, and myelodysplastic syndrome.8–11 Given the lack of a defined threshold to fulfill the criterion for diagnosis of HLH, we designed this retrospective study to interrogate whether quantitative or qualitative morphological features of hemophagocytosis in bone marrow aspirates are predictive of the eventual diagnosis of HLH. We identified a cohort of patients presenting with clinical characteristics that were of concern for HLH and their aspirates were examined blindly. Hemophagocytes were enumerated per 1000 nucleated cells according to the lineage of their ingested hematopoietic contents [mature red blood cells (RBCs), nucleated RBCs (nRBCs), granulocytes, and lymphocytes] (Figure 1). In addition to quantitative features, we evaluated a binary morphological feature, the presence of multiple nucleated cells within a single hemophagocyte, as a possible predictive characteristic of HLH. Open in a separate window Figure 1. Examples of hemophagocytosis in patients with hemophagocytic lymphohistiocytosis (HLH). (A) Histiocytes in patients with HLH often display rounded contour with cytoplasmic projections. (B-D) Hemophagocytes with a single ingested mature red blood cell (RBC), nucleated RBC progenitor, and granulocyte, respectively. Hematopoietic progenitor cells (HPCs) often contain single nucleated hematopoietic cells in addition to multiple mature RBCs (E); however, the presence of multiple nucleated cells within the cytoplasm of a single HPC (F and G) is highly predictive of the diagnosis of HLH. (H) An example of a histiocyte with degenerating nuclear debris, indistinct cytoplasmic contour, and equivocal intracytoplasmic nucleated RBCs that we do not consider to be a definite hemophagocyte.

Case of an Obstetric Patient With Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition that is characterized by an overproduction of inflammatory cytokines by the immune system. Progressive illness, septic shock, and death can occur if the disease is not diagnosed and treatment initiated early. The authors describe the presentation, differential diagnosis, and evidence-based interprofessional management of HLH in a 1,200-bed Magnet®-designated institution.

Abstract P-282: SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS PATIENTS PRESENTING WITH MULTIPLE ORGAN DYSFUNCTION IN A VIETNAMESE PEDIATRIC INTENSIVE CARE UNIT

Aims & Objectives: Secondary hemophagocytic lymphohistiocytosis (HLH) has been associated with viral infections, malignancies, rheumatologic disorders and drug hypersensitivity reactions. Management of HLH remains challenging due to its highly rate of fatality and under diagnosis. In this study, we sought to characterize PICU patients meeting the criteria for HLH in Hanoi, Vietnam Methods Prospective study (June and December 2017) was conducted at a single PICU. Patients were screened for a diagnosis of HLH. The collected variables included clinical findings before and on admission, laboratory findings on admission, treatment modalities, and the presence and severity of multi-organ dysfunction (as assessed by the Pediatric Logistic Organ Dysfunction score (PELOD-2)). Results Sixteen consecutive patients (10 males and six females) with a mean (SD) age of 21 (20) months met the diagnostic criteria for HLH. The mean PIM-2 on admission was 7.1 (8.9). Clinical findings included fever for at least seven days (100%), cytopenia (100%), hyperferritinemia (100%), splenomegaly (94%), hypertriglyceridemia (93%), and hemophagocytosis in a lymphoid organ (40%). All cases were attributed to infections. CMV and EBV co-infections (n=10), EBV (n=4) and CMV infections (n=2). All patients presented with multi-organ dysfunction, with death occurring in nine patients (56.3%). Organ systems affected: hematologic (100%), respiratory (94%), hepatic (81%), cardiovascular (69%), renal (50%), neurologic (13%), and gastrointestinal (13%). PELOD-2 and corresponding predicted mortality rate were 13.9 (9.0) and 13.6% (21.4%). Conclusions All HLH cases presenting with multi-organ dysfunction were associated with viral infections, specifically EBV and CMV co-infections. PIM-2 and PELOD-2 scores reflected the mortality outcomes seen in this study.

A retrospective series of conditions and mortality associated with extreme hyperferritinaemia in adults.

Serum ferritin is commonly used in the diagnosis of iron deficiency anaemia. However, extreme hyperferritinaemia suggests a significant illness, including the differential diagnosis of haemophagocytic lymphohistiocytosis (HLH), which is rare and associated with a high mortality, particularly if untreated. This series aims to identify the causes and associated mortality of severe hyperferritinaemia in patients seen at a teaching hospital in London, UK. Demographic and medical data were collected for all patients over 18years of age with extreme hyperferritinaemia (defined as serum ferritin levels of ≥4000mcg/L). Conditions associated with hyperferritinaemia and in-hospital mortality were identified from medical records, laboratory data and discharge and death notification. One hundred and fifty-five cases of extreme hyperferritinaemia in adults were identified. Associated conditions included iron overload (35%), malignancy (24%), infectious disease (21%) and hepatocellular disease (12%). Autoimmune disease and HLH resulted in significantly higher median peak ferritin levels compared with all cases (10616mcg/L, P<.01 and 19138mcg/L, P<.05, respectively). Patients with confirmed HLH had the highest median peak ferritin. Uncommon infections were identified in this series, and included such as dengue, syphilis, HIV and murine typhus. HLH had been confirmed in seven patients (5%). In five patients (3%) no clear cause for raised ferritin was identified. Overall mortality in the whole cohort was 14% (n=22), but there was a very high mortality of 80% in the group where no cause was found for the hyperferritinaemia, and these patients were significantly more likely to die during the index admission (P<.01). Extreme hyperferritinaemia is associated with a broad differential diagnosis of significant medical conditions, including iron overload, infections, cancer and liver disease. Rare infectious causes were also identified, and this series reports a greater proportion of cases of HLH than has previously reported. Unexplained hyperferritinaemia was associated with significant mortality.

Clozapine-Induced Agranulocytosis Revealing a Hemophagocytic Lymphohistiocytosis: A Case Report

Context: The aim of this report is to illustrate a case of hemophagocytic lymphohistiocytosis (HLH) that was revealed in the context of treatment-resistant first-episode psychosis. The incidence of this life-threatening condition is increasing in adults. Prompt diagnosis and treatment are important for an optimal patient outcome. Case Report: The patient was a 20-year old female who had been admitted to the inpatient unit of a Psychiatric Hospital for disorganized behavior with psychotic features. Clozapine had been introduced as the clinical picture did not evolve despite several trials of antipsychotics. As severe agranulocytosis developed, the patient was transferred to a general hospital. A diagnosis of HLH was suggested. Patient responded well to treatment, and remission of psychotic symptoms was observed. Conclusion: This case demonstrates the occurrence of HLH in a complicated clinical scenario involving psychotic experiences and the use of clozapine. Further studies are necessary to understand the potential environmental and pathological factors related to HLH