Cause Of Hemophagocytic Lymphohistiocytosis Research Articles

Treatment of hemophagocytic lymphohistiocytosis in adults.

Treatment of hemophagocytic lymphohistiocytosis (HLH) has been developed primarily in pediatric centers, where familial HLH (FHL) is the leading cause of HLH in newborns and toddlers. The Histiocyte Society Study Group for HLH developed the HLH-94 and HLH-2004 treatment protocols, and these are frequently also used by centers treating HLH in adults (aHLH). These protocols contain etoposide, dexamethasone, and cyclosporine A; these agents all have strong activity against proliferation of cytotoxic T/NK-cells and macrophages, as well as inhibitory activity against the cytokine storm that induces, and maintains HLH. In children with predominantly hereditary disease, the HLH-94 protocol can be regarded as a "one size fits all" algorithm. HLH in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the underlying trigger, disease severity and course, as well as genetic background. Additionally, treatment in adults usually needs to be modified in the face of the preceding disease history and comorbidities. Interdisciplinary patient care with rheumatologists, gastroenterologists, neurologists, pediatricians, the transplant team, and pathologists is a prerequisite to successful treatment. The preferred approach should reflect a disease- and risk-adapted treatment that includes rigorous supportive care with continuous reassessment of sequential therapeutic measures. It should be recognized that the algorithm of HLH treatment in adults is based more on expert opinion than on extensive scientific evidence.

Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by the activation of the mononuclear phagocytic system. The diagnosis of HLH in adults is challenging not only because the majority of the reported data are from pediatric patients, but also because HLH occurs in many disease entities. This study reports the clinical and laboratory findings and prognostic factors of adult HLH in a large cohort managed at a single medical center from 2003 to 2014. Seventy-three patients met the HLH-2004 diagnostic criteria. The median age was 51 years (range, 18-82 years); 41 (56.2%) were male. Patients manifested fever, cytopenias, and elevated ferritin in >85% of cases. Likely causes of HLH were as follows: 30 (41.1%) infections, 21 (28.8%) malignancies, 5 (6.8%) attributed to autoimmune disorders, 1 (1.4%) primary immunodeficiency, 2 (2.7%) post solid organ transplantation, and 13 (17.8%) idiopathic. The median overall survival was 7.67 months. Patients with malignancy-associated HLH had a markedly worse survival compared with patients with non-malignancy-associated HLH (median overall survival 1.13 vs. 46.53 months, respectively; P < 0.0001). In a multivariable analysis, malignancy (hazard ratio = 12.22; 95% CI: 2.53-59.02; P = 0.002) correlated with poor survival. Ferritin >50,000 µg/L correlated with 30-day mortality. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a registry for adults with HLH would improve our understanding of this syndrome, validate diagnostic criteria, and help develop effective treatment strategies.

Hemophagocytic Lymphohistiocytosis Complicating Dengue and Plasmodium vivax Coinfection.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder. Dysfunction of cytotoxic T and natural killer (NK) cells causes uncontrolled activity of lymphocytes and histiocytes which leads to HLH. Infections, malignancies, and autoimmune disorders are associated with development of HLH. Dengue and Plasmodium vivax are rare causes of HLH. We report the first ever case of a young man who developed fatal HLH that complicated Dengue Hemorrhagic Fever (DHF) and Plasmodium vivax infection.

Bi-Institutional Study of Etiology, Clinical Characteristics and Outcomes of Adult Patients with Hemophagocytic Lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a severe clinical syndrome characterized by the activation of mononuclear phagocytic system. Patients (pts) typically present with fever, cytopenias, splenomegaly, hyperferritinemia and hemophagocytosis. There are two categories of HLH: primary (familial) and secondary (acquired). Primary HLH (FHL) is caused by genetic defects in proteins involved in cytotoxic function in T and NK cells, and occurs most commonly in children; though hypomorphic mutations in the same genes may cause adult-onset FHL. In contrast, secondary HLH typically occurs in adults, and is due to underlying infectious, autoimmune, and malignant disorders. The limited knowledge about secondary adult HLH is derived from case reports or case series involving few pts. The current study is the first collaborative effort to describe the etiology, clinical characteristics and outcomes in a large cohort of adult HLH pts.Methods: All adult (≥18 years) pts with a diagnosis of HLH according to the HLH-04 criteria seen at Barnes Jewish Hospital, St. Louis, MO (from October 2003 through June 2014) and at Mayo Clinic, Rochester, MN (from January 1996 through May 2014) were identified. Five of the following eight criteria are considered diagnostic of HLH according to the HLH-04 criteria: 1) fever ≥38.50C; 2) splenomegaly; 3) cytopenia of two or three lines: ANC <1 × 109/L, hemoglobin <9 g/dL, platelet count <100 × 109/L; 4) serum triglycerides ≥265 mg/dL or serum fibrinogen ≤150 mg/dL; 5) serum ferritin ≥500 mcg/L; 6) soluble IL-2 receptor ≥2400 U/mL; 7) low/absent NK cell activity; and 8) biopsy-proven hemophagocytosis. Pts who were treated as HLH but did not fulfill the diagnostic criteria were excluded. The most likely etiology of HLH (malignancy, infection, autoimmune, and idiopathic) was assigned for each patient based on standard diagnostic criteria. Clinical characteristics were compared using Chi-square, student’s t-test and Mann-Whitney test, as appropriate. Overall survival (OS), defined as time from HLH diagnosis to death from any cause, was assessed using Kaplan-Meier survival analysis and log-rank tests. The Institutional Review Boards of both institutions approved this study.Results: One hundred and sixteen adult pts with HLH were identified. Their median age at diagnosis was 50 years (range, 18-82); 69 (58%) pts were male. The clinical and laboratory findings of pts according to HLH-04 criteria are summarized in Table 1. At diagnosis, the median serum ferritin was 18510 mcg/L (range, 561-684,000), median serum fibrinogen was 169 mg/dL (range, 50-766), and median serum triglycerides was 307 mg/dL (range, 68-1475). Ninety-one (78%) pts had transaminitis; 97/106 (92%) pts had hypoalbuminemia; 86/114 (75%) pts had elevated PT and/or aPTT; and 51 (44%) pts had renal insufficiency. The causes of HLH were as follows: 43 (37%) malignancies, 42 (36%) infections, 15 (13%) attributed to autoimmune disorders and primary immunodeficiencies, and 16 (14%) were idiopathic.After a median follow-up of 1.5 months, 70 (60.3%) pts have died. The median OS of the entire cohort was 2.8 months (range, 0.1-73.1 months), with a 5-year overall survival of 20%. Pts with malignancy-associated HLH had a markedly worse survival (median=1.2 months) compared to pts with non-malignancy-associated HLH (median=13.8 months, p < 0.0001, Figure 1). In a multivariable analysis, malignancy-associated HLH (hazard ratio [HR] = 4.4; 95% CI: 1.7-11.3; p = 0.002) and male gender (HR = 2.8, 95% CI: 1.2-6.5; p = 0.02) were independently associated with shorter survival.Conclusions: The triad of fever, cytopenias and elevated ferritin (present in >80% of pts in this series) should alert physicians to a possible diagnosis of adult HLH. Survival after a diagnosis of HLH is dismal, especially among those with malignancy-associated HLH. The development of a national registry for adults with HLH will be beneficial to further our understanding of this condition and develop effective treatment strategies.Table 1:Clinical and laboratory findings according to the HLH-04 criteriaCharacteristicNo. (%) of patientsFever112/116 (97)Splenomegaly75/116 (65)Bicytopenia or pancytopenia95/116 (82)Hypertriglyceridemia71/107 (66)Hypofibrinogenemia50/107 (47)Hemophagocytosis95/111 (86)Hyperferritinemia115/115 (100)Elevated soluble IL-233/40 (82)Absent or decreased NK cell function12/22 (54) [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Analysis of clinical and laboratory features of 217 pediatric hemophagocytic lymphohistiocytosis

To investigate the incidence, clinical symptoms, signs and laboratory features of childhood hemophagocytic lymphohistiocytosis (HLH) in China. A retrospective study was performed on 217 pediatric patients with HLH who were admitted to Children's Hospital of Chongqing Medical University from January 2006 to April 2013. All patients'medical records were reviewed and analyzed. The Male to female ratio was 1.11:1. The median onset age was 3 years and 5 months old (range of 6 months old to 16 years and 9 months old), and the age of onset peaked between 1-5 years old (61.3%). The most common causes of HLH was infection, especially Epstein-Barr virus-associated HLH (71.0%). Other causes included malignant hemophagocytic syndrome (MAHS), macrophage activation syndrome (MAS) and so on. The outstanding clinical manifestations including persistent fever (100.0%), hepatomegaly (92.6%), splenomegaly (88.4%), and more than half of cases with central nervous system involvement and pulmonary manifestations. Laboratory data indicated that the most prominent abnormality was elevated ferritin (98.0%), and the others were hemophagocytosis in bone marrow (90.7%) and coagulation abnormalities (76.5%). Abnormal lymphocytes classification is very common in HLH. HLH is a heterogeneous disease, with a variety of the etiology and clinical manifestations. HLH-2004 diagnostic protocol had theoretical basis and clinical operability. The hepatitis damages related indicators, lymphocytes classification, central nervous system involvement and pulmonary performance can be used as reference value for HLH diagnosis.

Hemophagocytic Lymphohistiocytosis

To investigate the clinical features of adult patients with hemophagocytic lymphohistiocytosis (HLH) and to explore possible risk factors for death, we retrospectively reviewed the medical records of 103 adult HLH patients hospitalized from 1997 to 2012. We analyzed the underlying diseases, clinical characteristics, 1aboratory findings, outcomes, and prognostic factors. The most common cause of HLH was hematologic malignancies (n = 49), followed by infectious diseases (n = 24) and autoimmune disorders (n = 14); 24 cases were of unknown etiology. Eight patients had a combination of underlying diseases. HLH was clinically characterized by high fever (96.1%), splenomegaly (79.6%), hepatomegaly (65.0%), lymphadenopathy (53.4%), proteinuria (31.1%), skin rash (25.2%), gastrointestinal hemorrhage (14.6%), disseminated intravascular coagulation (13.6%), increased creatinine (7.8%), and central nervous system involvement (12.6%) including altered mental status (9.7%) and cranial hemorrhage (2.9%). Laboratory abnormalities included cytopenia (99.0%), serum ferritin >500 ug/L (98.4%), liver dysfunction (98.1%), hypertriglyceridemia (88.5%), hemophagocytosis in bone marrow smear (87.4%), and hypofibrinogenemia (60.9%).In addition to the treatment they received for the underlying causes, patients received therapy for HLH consisting of corticosteroids, immunosuppressive drugs, and intravenous immunoglobulin. Twenty-six patients (25.2%) recovered after treatment, and 19 of them achieved long-term remission during follow-up. Seventy-seven patients (74.8%) died because of tumor, sepsis, multiple organ failure, or HLH-related organ hemorrhage and coagulopathy. The deceased patients were more likely to be older at disease onset, male, and to present with splenomegaly and thrombocytopenia, compared to the survivors. Treatment for the underlying diseases combined with corticosteroids, immunosuppressive agents, and immunoglobulin therapy may improve the prognosis of HLH. More attention should be paid to high-risk patients to prevent the development of serious complications associated with HLH.

Prognostic Factors and Outcomes of Adults With Hemophagocytic Lymphohistiocytosis

ObjectiveTo describe the prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis (HLH), a rare disorder caused by pathologic activation of the immune system. Patients and MethodsThe study population consisted of a consecutive cohort of adult (age ≥18 years) patients treated at Mayo Clinic in Rochester, Minnesota, from January 1, 1996, through December 31, 2011, in whom a diagnosis of HLH was suspected and subsequently confirmed by retrospective review using the HLH-04 diagnostic criteria. ResultsOf 250 adult patients suspected of having HLH, 62 met the HLH-04 diagnostic criteria and were included in the final analysis. The median age was 49 years (range, 18-87 years), and 42 (68%) were male. The underlying cause of HLH was malignant tumor in 32 patients (52%), infection in 21 patients (34%), autoimmune disorder in 5 patients (8%), and idiopathic disease in 4 patients (6%). After a median follow-up of 42 months, 41 patients (66%) had died. The median overall survival of the entire cohort was 2.1 months. The median overall survival of patients with tumor–associated HLH was 1.4 months compared with 22.8 months for patients with non-tumor–associated HLH (P=.01). The presence of a malignant tumor and hypoalbuminemia were significant predictors of inferior survival on multivariate analysis. ConclusionIn this large series of adults with secondary HLH treated at a single tertiary care center, patients with low serum albumin levels and tumor–associated HLH had a markedly worse survival. Hemophagocytic lymphohistiocytosis remains elusive and challenging to clinicians who must maintain a high index of suspicion. The recent discovery of several novel diagnostic and therapeutic modalities may improve outcomes of adult patients with HLH.

Hodgkin’s Lymphoma Revealed by Hemophagocytic Lymphohistiocytosis in a Child

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening disorder, responsible for extensive phagocytosis of hematopoietic cells and causing a multisystem organ failure. If lymphomas are common causes of HLH, the association with Hodgkin's lymphoma is rarely described in children. We report a case of a 9-year-old boy presenting with HLH as an initial manifestation of Hodgkin's lymphoma. He has been suffering from persistent high fever, asthenia, weight loss, and hepatosplenomegaly with no lymphadenopathy. The diagnosis of HLH secondary to infectious disease was initially worn. The patient received high-dose intravenous immunoglobulin with broad-spectrum antibiotics. However, his state got worse with the onset of dry cough and pleural effusion. Histopathologic examination of pleural fluid showed the presence of Reed-Sternberg cells. The outcome was favorable after treatment by corticosteroid and chemotherapy. Hodgkin's lymphoma revealed by HLH is a source of delayed diagnosis and should be borne in mind in children.

Hemophagocytic Syndrome in HIV-Infected Patients: A Prospective Clinicopathological Tertiary Care Centre Study from India

Background: Hemophagocytic lymphohistiocytosis (HLH) has been described in patients with human immunodeficiency virus (HIV) infection. However, limited data is available in the era of highly active antiretroviral therapy (HAART). Study design and methods: We conducted this prospective study over a two year period on 30 HIV infected patients. Our aim was to assess the frequency of hemophagocytosis in HIV-infected patients. We also tried to identify the underlying etiology and assess specificity of different parameters for HLH. Results: Hemophagocytosis was identified in 14(46%) patients. 10/14(71%) had pancytopenia while 4/14(29%) had bicytopenia. 6(43%) had elevated ferritin (>500 μg/l). Fever (5/14), splenomegaly (4/14) and raised triglyceride (2/14) were identified less frequently. Underlying etiology could be identified in 6/14(43%) cases - disseminated tuberculosis in 4/14(29%) and one case each of Japanese encephalitis and disseminated candidiasis. Median CD 4 count was 123/cu.mm. 12(40%) patients were on HAART. 4/30 (13%) patients fulfilled criteria for HLH. Bicytopenia was least specific (25%) for diagnosis of HLH. Morphological evidence of hemophagocytosis had low specificity for HLH (29%); however, moderate / severe hemophagocytosis had higher specificity (66%). Raised ferritin levels (>500 μg/l) had a specificity of 66% while ferritin levels (>800 μg/l) had 100% specificity. Increased triglyceride levels (>265 mg/dl) had 50% sensitivity and 100% specificity. Conclusion: Opportunistic infections represent the most common identifiable cause of HLH in HIV patients. Bicytopenia has got low specificity while moderate/severe hemophagocytosis, increased ferritin levels (>800 μg/l) and raised triglyceride levels have got high specificity for HLH in this setting. Larger prospective studies would be helpful in identifying modified diagnostic criteria in this setting.

Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: Beware of haemophagocytic lymphohistiocytosis

Neurologic symptoms can be the initial manifestation of haemophagocytic lymphohistiocytosis (HLH). In this case study, we present a 3-year old boy with a clinical picture of encephalitis, a cerebrospinal fluid (CSF) protein level up to 1165 mg/dl and diffuse cerebral MRI abnormalities. The diagnosis of HLH was established only 6 weeks after initial presentation. The boy recovered after HLH therapy with persisting mild cognitive defects. Genetic investigation demonstrated X-linked lymphoproliferative disease (XLP) as the underlying cause of HLH. The extremely elevated protein level in CSF in this case has not yet been reported in patients with HLH.

Unusual Cluster In Time and Space Of Dengue-Associated Hemophagocytic Lymphohistiocytosis In Puerto Rico

Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal hematologic syndrome characterized by hyperinflammation due to uncontrolled proliferation of activated lymphocytes, resulting in prolonged fever, pancytopenia, jaundice, and hepatosplenomegaly. While infection with Epstein Barr virus (EBV) is the most common recognized cause of infection-triggered HLH, there have been cases associated with other viral infections including dengue. Dengue is an acute febrile illness that is caused by any of four related but serologically distinct, mosquito-borne dengue viruses (DENV-1–4) that are endemic throughout the tropics and subtropics including Puerto Rico, a territory of the United States. Dengue can lead to a wide range of clinical outcomes, ranging from no symptoms or mild fever to potentially fatal severe dengue. In Puerto Rico, dengue most commonly affects adolescents 10–19 years old. Dengue-associated HLH (dengue-HLH) has been described in 26 case reports since 1966, but has not been previously recognized in Puerto Rico.During the start of a dengue epidemic in December 2012, the Centers for Disease Control and Prevention Dengue Branch were notified of several dengue-HLH cases at four hospitals in Puerto Rico. An investigation was conducted to: 1) determine the incidence of HLH in children since 2008; and 2) determine the infecting agent(s) associated with HLH cases. Medical records were queried to identify patients with findings compatible with HLH. To date, 681 records have been reviewed and 38 patients identified that met accepted criteria for HLH. The majority (25 patients) of the HLH cases had diagnostic evidence of DENV infection by anti-dengue IgM Enzyme Linked Immunosorbent Assay (36%) and/or DENV Polymerase Chain Reaction (68%): DENV types -1 and -4 were detected. Other causes of HLH identified were EBV and Cytomegalovirus co-infections (2), Herpes Simplex Virus (2), EBV (1), and systemic onset juvenile arthritis (2). There was one fatal dengue-HLH case (case-fatality rate [CFR]: 4.0%). Dengue-HLH cases ranged in age from 0.1–16 years, 48% were infants, and all resided in northern Puerto Rico. Among children aged 0–16 years, the average annual incidence of dengue-HLH cases in Puerto Rico from 2008 through 2011 was 0.1 cases per 100, 000 versus 2.2 cases per 100,000 in the last 12 months from June 1, 2012 to May 31, 2013, which demonstrates the dramatic increase in recent cases. The number of HLH cases may have been higher since in 14 additional cases with suspected HLH who only fullfilled 4 of the required 5/8 diagnostic criteria, laboratory investigations were incomplete.This is an unusual cluster of dengue-HLH cases in time and space afflicting mostly infants and cannot be explained by heredity. Currently there is no explanation for this outbreak of dengue-HLH. Some cases of dengue-HLH may have been overlooked in the past if severe dengue cases were not investigated for the presence of HLH criteria. We are presently conducting a case-control study to identify risk factors for developing dengue-HLH and determine why in contrast to previous experience infants were predominantly affected. Physicians in dengue endemic areas should be made aware that infection with dengue virus may lead to the hyperinflammatory syndrome HLH. Disclosures:No relevant conflicts of interest to declare.

Haemophagocytic Lymphohistiocytosis (HLH) Associated With a Heterozygous PRF1 Mutation Not Previously Described As Pathogenic

Case Presentation A 16 year old male presented with three weeks of fatigue, nausea, vomiting, anorexia, arthralgias, and pancytopaenia. He was febrile, with mouth ulcers, hepato splenomegaly, and palpable non tender supraclavicular and axillary lymphadenopathy. Neurological examination was normal. Remarkable abnormal tests: Hb 77 g/L, platelets 29 x109/L, WCC 0.7 x109/L (neutrophils 0.33), normal PT and APTT but hypofibrinogenaemia 0.8 g/L. Ferritin was elevated 56 061 ug/L (20– 150). Liver function tests showed a mixed pattern with elevated LDH (2137 U/L), mild hypertriglyceridaemia (4.6 mmol/L) and low haptoglobin (&lt; 0.06 g/L), EBV IgM was equivocal with reactive IgG. Bone marrow showed evidence of haemophagocytosis (Fig 1). All HLH-2004 criteria were fulfilled except elevated sCD25 (unavailable). NK cell chromium release assay revealed severely suppressed NK cell function. In addition, perforin gene (PRF1) sequencing for mutation screening showed a missense mutation Ala437Val (1310 C&gt;T) PRF1 heterozygous, a previously unclassified variant. There was no evidence of an underlying cause of HLH. Our patient received induction therapy with etoposide 150 mg/m2 and dexamethasone 10 mg/m2 with dosing and frequency as suggested by the HLH-94 protocol. Pancytopaenia recurred and an increase in ferritin concentration was interpreted as relapse of the condition. At that point, cyclosporine was added on in conjunction with maintenance etoposide and dexamethasone obtaining partial remission. He underwent allogeneic SCT successfully in another centre.Figure 1Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H &amp; E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow.Figure 1. Bone marrow aspirate of this patient showing evidence of haemophagocytosis (H &amp; E). A and B show large macrophages undergoing phagocytosis of different cellular elements of the bone marrow. Discussion Several genes have been implicated in the genesis of primary HLH; all of them have in common impaired cytotoxic function by NK and T cells. It has been reported that mutations of the PRF1 gene comprise approximately 20 to 30% of the cases of primary HLH. This variant has been reported as a polymorphism and was not conclusive for the diagnosis of perforin deficiency as the cause of HLH in this case. In addition, the mutation was heterozygous. Although HLH is usually a recessive disorder, there are reports of potential disease associations in the heterozygous state. There is significant overlap between primary and secondary HLH and the role of some heterozygous mutations remain to be investigated. Disclosures: No relevant conflicts of interest to declare.

A Review of Human Herpesvirus 8, the Kaposi's Sarcoma-Associated Herpesvirus, in the Pediatric Population

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma (KS)-associated herpesvirus, is the etiologic agent responsible for all types of KS. Although the majority of pediatric KS cases occur in sub-Saharan Africa, a rise in pediatric transplant KS has been reported in developed countries. In addition, HHV-8 is increasingly described as an infectious cause of hemophagocytic lymphohistiocytosis in children. Transmission of HHV-8 among children is poorly understood; however, the literature strongly suggests that horizontal transmission plays a critical role. Acute infection with HHV-8 and progression to KS in children may be different than in adults, and diagnosis may be overlooked. Currently, neither adult nor pediatric treatment guidelines exist. This review provides an overview of HHV-8 disease in children as it relates to epidemic KS, transplant KS, and other disease manifestations. The current state of the literature is reviewed and knowledge gaps are identified for future exploration.

Unremitting pyrexia, pancytopenia, hepatosplenomegaly, and extreme hyperferritinemia

Unremitting pyrexia, pancytopenia, hepatosplenomegaly, and extreme hyperferritinemia

HLH (Hemophagocytic Lymphohistiocytosis) At a Tertiary Care Hospital, B J Wadia Hospital for Children,In Mumbai, India

Abstract 4936We present a retrospective analysis of HLH diagnosed at B J Wadia Hospital for Children, a tertiary care exclusive pediatric institute in Mumbai. In all, 43 cases were diagnosed as HLH as per 2009 Guidelines (Filipovich et al). There were 15 (34.9%) males and 28 (63.1%) females. The mean age was 3 yrs 4 mths with a range of 15 days to 12 yrs. The commonest presenting symptom was fever in 85% of cases. RS, GI, Renal and CNS symptoms were seen in 48.8%, 65%, 11.6% and 24% of our cases. Skin pigmentation, Petachiae, Oedma and arthritis was present in 12(27.9%); 4(9.3%), 13(30.2%), and 4(9.3%) of cases respectively. 41(95.3%) babies had Hepatomegaly while 35(81.3%) had Splenomegaly. Lymphadenopathy was seen in 13(30.2%). 12 (27.9%) had pigmentation, 13(30.2%0 had oedema while 4 (9.3%) each had petachiae and arthritis.Mean Hb of 8.2 gm/dl and a range of 3.5 to 10 gm/dl. The Mean WBC count & ANC were 8030 (range 1300 – 29400) & 4614 (300-19400). 37(86%) had thrombocytopenia. Liver injury 27(62.7%), hyponatremia 28(65.1%) and renal failure in 6(13.95%) was seen at diagnosis. Coagulopathy was present in 38(88.4%) and serum ferritin was >500 in 36(83.7%) with a mean of 26135 ng/ml and range of 82 to 200,000 ng/ml. 24(55.8) cases had Hypertriglyceridemia with mean levels of 236. 13 patients had infections 6 UTI & 7 bacterial diarrhoea. Only 2 out of 16 children had CSF abnormality at diagnosis. BM was hypo cellular in 3 and hyper cellular in 40 and all showed hemophagocytosis. PS showed HLH in 4 cases. Cultures isolated K pneumoniae in 5, P aeruginosa in 2, S. Typhi in 1, Candida in 4, and H1N1 in 1. Kalazar was the cause of HLH in 1 and 2 patients had P vivax seen on PS. 1 child had SPTCL & HLH while another child has ALCl & HLH. The child with SPTCL had gross hemophagocytosis on skin biopsy as well as in the Bone Marrow.Perforin was done in 30(70%) and was low in 6/30 (20%) cases, while GRA (Granule Release Assay) was done in 15(35%) and was abnormal in 4/15(26.6%). GRA was established last year only. In 29(67.4%) cases IAHS was diagnosed. The IAHS were, HIV 1, Post Chicken pox 1, Dengue 2, Viral aseptic meningitis 1, P vivax 1, Leishmaniasis 1, MTB in 1, S. typhi in 1, gram −ve sepsis in 8, candidia in 3, viral infection 9. 2 cases had MAS (Macrophage Activation Syndrome) with JRA; serum ferritin was as high as 200,000 ng/ml at diagnosis. 1 child had Griscelli Syndrome with HLH. Perforin deficiency presented at a mean age of 5 mths & all had severe fulminant presentation with brief H/o of viral infection and hepatosplenomegaly. Hepatic injury was severe and rapidly progressive, CNS affection was present in 3/6 cases and all died. 2/4 children with GRA abnormalities presented early at 15 days & 1 mth of life, 1 had a gm −ve sepsis with response to HLH protocol but relapsed & Died, the other child presented with fever, hepatosplenomegaly, pancytopenia & neuroregression and BMA confirmed HLH. Of the other 2 babies with GRA abnormalities 1 was a case of Griscelli who presented at 4 yrs 6 mths of life while the other presented at 1 6 mths yr of life as what appeared like IAHS and sucumbed to his disease. 2/4 with GRA abnormalities are alive and well. 1 child had thrombocytopenia and Malena as the sole presentation of HLH and the Bone Marrow done 4 times showed gross hemophagocytosis. 2/4 children with elevated creatinine required peritoneal dialysis.All our cases received Dexa, CsA & Etoposide as in HLH 2004 protocol. We ensured that the 1st 2 doses of etoposide were given after which etoposide may be witheld depending on clinical situation. IT MTX was given when there was CSf abnormalities or gross CNS signs. The Mortality was 32.5% (14/43). 3 of them died during Follow up with relapse of HLH, 1 child with ALCL died of Lymphoma while child with SPTCL is alive but with systemic symptoms. 8/43 (18.6%) are lost to follow up. Majority of IAHS did well with treatment. 8 are presently on regular follow up. In IAHS reassesment of HLH status if normal at 8 weeks, treatment was discontinued. 21/43 children completed 8 weeks of treatment. Conclusions:HLH is not an uncommon diagnosis in tertiary care centre in India. IAHS was the commonest cause of HLH and prompt dignosis with treatment HLH 2004 protocol is necessary to control the hyperinflammation. Our Ferritin values were very high. Incidence of Perforin deficiency was 20% and 26.6% respectively. Mortality in perforin deficiency was 100%. Bacterial infection and fungal infections were also common among the IAHS. Disclosures:No relevant conflicts of interest to declare.

Fatal hemophagocytic syndrome in a patient with a previously well-controlled asymptomatic HIV infection after EBV reactivation

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) in a 70 year-old male patient with previously well-controlled HIV infection. We could confirm HLH in different organs post mortem. Since the diagnosis of HLH was delayed, the patient died despite initiation of chemotherapy. As cause for HLH, an EBV reactivation could be confirmed. In HIV infection, HLH may be the first HIV manifestation, often triggered by an opportunistic infection or immune reconstitution syndrome, but it is uncommon in the state of a well-controlled or aviremic HIV infection.

Reduced‐intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunodeficiency characterized by severe systemic hyper-inflammatory responses to infectious or other triggers of the immune system. In many patients, the underlying cause of HLH is a genetic defect leading to defective CD8(+) T cell and natural killer cell granule-mediated cytotoxicity. The treatment of HLH consists principally of immune suppression followed by allogeneic haematopoietic cell transplantation (HCT) to cure the underlying defect and prevent relapse of HLH. Initial treatment regimens consist of steroids coupled with either etoposide or antithymocyte globulin, ± ciclosporin. Complete responses are observed in only 50-75% of patients and even after a complete response, relapse and death still occur. The only definitive, long-term cure for patients with genetic forms of HLH is allogeneic HCT. Unfortunately, allogeneic HCT for patients with HLH is often complicated by critical illness, extensive organ involvement, active infections, or refractory HLH. For these reasons, patients are unusually prone to developing transplant-related toxicities and complications. In recent years, great strides have been made with regard to the care and transplantation of patients with HLH. Here we review the current state of the treatment of patients with HLH with allogeneic HCT, highlighting the important steps forward that have been made with reduced-intensity conditioning.

Causes, clinical symptoms, and outcomes of infectious diseases associated with hemophagocytic lymphohistiocytosis in Taiwanese adults

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon but a potentially life-threatening condition. Few systematic reviews have been published on the clinical manifestations, causes, and indicators for prognosis of HLH caused by infections. We retrospectively reviewed the medical records of patients diagnosed with HLH documented by bone marrow study at a teaching hospital between 2000 and 2007. HLH was defined according to the HLH-2004 diagnostic guidelines, which include fever; splenomegaly; cytopenia; hypertriglyceridemia; hypofibrinogenemia; and hemophagocytosis evident on pathological examination of bone marrow, spleen, or lymph node tissue; low or absent natural killer cell activity; hyperferritinemia; and high serum levels of soluble CD25. The demographic characteristics, clinical presentations, laboratory results, and final outcomes were recorded. The cause of HLH was diagnosed by microbiological, pathological, serological, and molecular biological methods. Among the studied patients, 66 had HLH because of noninfectious causes and 30 because of infections. Compared with patients with HLH related to noninfectious causes, those with HLH related to infections had lower mortality (70% vs. 47%, p=0.03). The most common causative pathogens causing HLH were virus (41%), mycobacteria (23%), bacteria (23%), and fungi (13%), in that order of frequency. Clinical presentations of HLH were variable and included fever (90%), tachypnea (83%), tachycardia (80%), hepatosplenomegaly (40%), lymphadenopathy (27%), and altered consciousness (23%). Laboratory findings revealed thrombocytopenia in 93%, hyperferritinemia in 90%, elevated serum lactate dehydrogenase levels in 80%, anemia in 67%, and leukopenia in 60% of the patients. Fourteen patients (47%) died. In multivariate analysis, age more than 50 years (p=0.05; odds ratio [OR], 3.46; 95% confidence interval [CI], 1.00-15.73), fever not subsiding within 3 days of diagnosing HLH (p=0.003; OR, 2.38; 95% CI, 1.21-11.25), and occurrence of disseminated intravascular coagulation as a complication (p=0.009; OR, 3.22; 95% CI, 1.68-10.01) were found to be statistically significant indicators of mortality in patients with HLH. The infectious diseases associated with HLH were diverse and resulted in a high mortality rate. Cases in which the patients were aged more than 50 years, developed DIC, and had persistent fever even after 3 days of being diagnosed with HLH showed poor prognosis.

Atypical varicella zoster infection associated with hemophagocytic lymphohistiocytosis

Two adolescents, on immunosuppressive therapy for graft-versus-host disease, developed hemophagocytic lymphohistiocytosis (HLH) after varicella zoster virus (VZV) reactivation. In the absence of dermatome restricted characteristic skin lesions, VZV reactivation was not immediately recognized and treatment with acyclovir was delayed. The first patient developed optical neuritis and died 2 months after the VZV episode due to massive intracranial hemorrhage. The second patient presented with severe abdominal pain and pancreatitis, followed by atypical skin eruptions, which prompted a faster diagnosis. Both patients recovered from their HLH, the first patient being successfully treated with immunosuppressive agents and the second with VZV treatment only. These two cases demonstrate the difficulties in recognizing VZV reactivation, and in order to start adequate and timely treatment, the need to consider VZV as a possible cause of HLH in severely immunocompromised patients.

A rapid flow cytometric screening test for X‐linked lymphoproliferative disease due to XIAP deficiency

Deficiency of X-linked inhibitor of apoptosis (XIAP), caused by BIRC4 gene mutations, is the second known cause of X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency that often presents with life-threatening hemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis of the known genetic causes of HLH, including XIAP deficiency, facilitates the initiation of life-saving treatment and preparation for allogeneic hematopoietic cell transplantation (HCT). Until now, a rapid screening test for XIAP deficiency has not been available. To develop a flow cytometric screening test for XIAP deficiency, we first used lymphoblastic cell lines generated from controls and patients with BIRC4 mutations to identify two commercially available antibodies specific for native intracellular XIAP. Next, we used these antibodies to study control whole blood leukocyte XIAP expression. We then studied XIAP expression in leukocytes from patients with XLP due to BIRC4 mutations, maternal carriers, and patients following HCT. XIAP was expressed by the majority of all whole blood nucleated cells in normal controls. In contrast, XIAP was absent or decreased in all lymphocyte subsets, monocytes and granulocytes from four unrelated patients with XLP due to BIRC4 mutations. Bimodal distribution of XIAP expression was evident in two maternal carriers, with significant skewing toward cells expressing normal XIAP. Bimodal distribution was also observed in a patient following HCT. Flow cytometric analysis of intracellular XIAP provides a rapid screening test for XLP due to XIAP deficiency. It also allows carrier detection and can be used to monitor donor versus recipient reconstitution following HCT.