Histiocyte Society Research Articles

Hypoalbuminaemia is an independent predictor for hemophagocytic lymphohistiocytosis in childhoodEpstein–Barr virus‐associated infectious mononucleosis

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition in children with Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). This study aimed to identify commonly available clinical and laboratory predictors that might help clinicians decide to perform the bone marrow and immunological tests for HLH in paediatric EBV-associated IM. A retrospective case-control study of patients aged <18 yr diagnosed with EBV-associated IM and HLH from 1991 to 2010 in a tertiary medical centre was conducted. A diagnosis of HLH was defined as fulfilling the criteria of the guidelines of the HLH-2004 protocol of the Histiocyte Society and consisted of at least evidence of hemophagocytosis in a bone marrow biopsy. A total of 177 IM and 27 HLH patients were enrolled. The mean age was 5.3 yr with a female-to-male ratio of 1.06. The most common characteristics (>70% of patients) were fever, lymphadenopathy and hepatomegaly. In addition to the diagnostic criteria of HLH including fever, splenomegaly, cytopenia, hyperferritinaemia, hypertriglyceridemia and/or hypofibrinogenaemia, children with HLH had a significantly higher rate of prolonged fever >10 d, hepatomegaly, jaundice, general malaise, elevated aspartate aminotransferase, lactate dehydrogenase, C-reactive protein and hypoalbuminaemia compared to those with IM (all P < 0.01). Multiple logistic regression confirmed that hypoalbuminaemia (OR = 23.1, P = 0.01) was an independent predictor of paediatric HLH, with a high sensitivity (96%) and a good negative likelihood ratio (0.06) in patients with EBV-associated IM. Hypoalbuminaemia is a unique characteristic and potentially a valuable predictor for HLH in paediatric EBV-associated IM.

Haemophagocytic lymphohistiocytosis following culture-proven pneumococcal infective endocarditis of the tricuspid valve

We report a case of a 2-year-old boy presenting with persistent fever and splenomegaly who fulfilled the diagnostic criteria for haemophagocytic lymphohistiocytosis (HLH) according to the Histiocyte Society (2004). The persistence of a cardiac murmur despite multiple transfusions, and therapy which rendered him afebrile, led us to do an echocardiogram as part of surveillance for sepsis. This revealed tricuspid vegetation and a small ventricular septal defect. Blood culture and postoperative histology of the anterior leaflet of the tricuspid valve confirmed Streptococcus pneumoniae infection. The patient was successfully treated with intravenous antibiotic therapy for 6 weeks and dexamethasone for 8 weeks and remains well and in remission (from HLH) a year later with residual tricuspid regurgitation awaiting tricuspid valve replacement.

Measles and Secondary Hemophagocytic Lymphohistiocytosis

To the Editor: We found interesting the article by Lupo et al. about a case of fatal measles in an immunocompetent 29-year-old woman (Fatal measles without rash in immunocompetent adult, France; http://dx.doi.org/10.3201/eid1803.111300). Perhaps, however, the possible diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) should also have been considered in that setting. HLH is a potentially fatal hyperinflammatory syndrome characterized by histiocyte proliferation and hemophagocytosis. HLH may be inherited (i.e., primary, familial, generally occurring in infants) or may occur at any age secondary to infection, malignancy, or rheumatologic disease. Secondary HLH is determined according to clinical criteria from the HLH Study Group of the Histiocyte Society, which require >5 of the following for a diagnosis: fever; splenomegaly; cytopenia (affecting >2 cell lineages); hypertriglyceridemia or hypofibrinogenemia; hemophagocytosis in the bone marrow, spleen, or lymph nodes; low or absent natural killer cell cytotoxicity; hyperferritinemia; and elevated levels of soluble CD25. We conducted a PubMed search and found 5 articles that described 6 cases of HLH in patients with measles (1–5). Pneumonia was described in all of them (1–5), and central nervous system involvement was described in 3 (1,4). Four cases occurred in children, 3 of them immunocompetent (1,3–5). The 2 adults were an immunocompetent 18-year-old man who had acute respiratory distress (2) and a 19-year-old man with acute lymphocytic leukemia who had measles pneumonia and acute hemorrhagic leukoencephalitis (1). The only fatal case occurred in an immunocompromised 8-year-old boy with giant-cell pneumonia (3). The identification of hemophagocytosis in bone marrow aspirate represents only 1 of the 5–8 criteria needed for a diagnosis of HLH; conversely, a bone marrow aspirate lacking hemophagocytosis does not rule out the diagnosis of HLH. Still, we believe HLH should be considered for any patient with fever and pancytopenia, especially in the presence of respiratory distress or multiorgan dysfunction. An appropriate therapy could save the patient (Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature; http://dx.doi.org/10.1002/hon.960).

Specificity of cytokine abnormalities in HLH

Hemophagocytic lymphohistiocytosis (HLH) is both under-recognized and over-diagnosed currently. Despite the use of the revised criteria for diagnosis, established by the Histiocyte Society in 2004, it seems that patients with severe infections, as well as patients with severe underlying rheumatologic and oncologic conditions receiving modern therapies (in whom HLH, or macrophage activation syndrome, can indeed occur), can meet criteria without a convincing “fit” for the clinician (Pediatr Blood Cancer 2007;48:124-31). On the other hand, especially early in the course in previously healthy younger children, HLH sometimes seems to be the “best diagnosis” even though laboratory criteria are not met fully. Accuracy of diagnosis is critical because therapy for HLH is either extremely helpful in abrogating an abnormal inflammatory response if the diagnosis is correct, or extremely harmful in impeding an appropriate response if the diagnosis is incorrect, especially when infection is the sole or predominant pathology.In a particularly robust study, Xu et al evaluated 756 consecutive patients with fever hospitalized in the Hematology/Oncology Unit of the Children's Hospital of Zhejiang University School of Medicine between 2005 and 2010, categorized the etiologies of fever, and also studied three control groups of 202 patients with hematology/oncology conditions without fever, 100 healthy children, and 85 previously healthy children with confirmed bacterial sepsis. Multiplex Th1/Th2 cytokine kit assay was used to measure serum concentrations of defined interleukins (IL), tumor necrosis factors, and interferon.The 71 episodes of HLH showed a highly discriminating cytokine pattern of uniquely highly elevated IFN-γ level (94% sensitivity and 97% specificity for HLH using a cutoff point of 100 pg/mL) and IL-10 level, but only modestly elevated IL-6 level. Combined use of IFN-γ level >75 pg/mL plus IL-10 >60 pg/mL had sensitivity of 93% and specificity of 99% for HLH.The authors point out limitations of the study, as well as the heterogeneity of HLH itself, which probably encompasses multiple disorders, with a variety of etiologies and triggers, and a spectrum of severity. There is no question, however, that these results can help clinicians having to make weighty decisions and, with validation, can be considered by consensus groups for inclusion in diagnostic criteria for HLH.Article page 984▶ Hemophagocytic lymphohistiocytosis (HLH) is both under-recognized and over-diagnosed currently. Despite the use of the revised criteria for diagnosis, established by the Histiocyte Society in 2004, it seems that patients with severe infections, as well as patients with severe underlying rheumatologic and oncologic conditions receiving modern therapies (in whom HLH, or macrophage activation syndrome, can indeed occur), can meet criteria without a convincing “fit” for the clinician (Pediatr Blood Cancer 2007;48:124-31). On the other hand, especially early in the course in previously healthy younger children, HLH sometimes seems to be the “best diagnosis” even though laboratory criteria are not met fully. Accuracy of diagnosis is critical because therapy for HLH is either extremely helpful in abrogating an abnormal inflammatory response if the diagnosis is correct, or extremely harmful in impeding an appropriate response if the diagnosis is incorrect, especially when infection is the sole or predominant pathology. In a particularly robust study, Xu et al evaluated 756 consecutive patients with fever hospitalized in the Hematology/Oncology Unit of the Children's Hospital of Zhejiang University School of Medicine between 2005 and 2010, categorized the etiologies of fever, and also studied three control groups of 202 patients with hematology/oncology conditions without fever, 100 healthy children, and 85 previously healthy children with confirmed bacterial sepsis. Multiplex Th1/Th2 cytokine kit assay was used to measure serum concentrations of defined interleukins (IL), tumor necrosis factors, and interferon. The 71 episodes of HLH showed a highly discriminating cytokine pattern of uniquely highly elevated IFN-γ level (94% sensitivity and 97% specificity for HLH using a cutoff point of 100 pg/mL) and IL-10 level, but only modestly elevated IL-6 level. Combined use of IFN-γ level >75 pg/mL plus IL-10 >60 pg/mL had sensitivity of 93% and specificity of 99% for HLH. The authors point out limitations of the study, as well as the heterogeneity of HLH itself, which probably encompasses multiple disorders, with a variety of etiologies and triggers, and a spectrum of severity. There is no question, however, that these results can help clinicians having to make weighty decisions and, with validation, can be considered by consensus groups for inclusion in diagnostic criteria for HLH. Article page 984▶ Diagnostic Accuracy of a Specific Cytokine Pattern in Hemophagocytic Lymphohistiocytosis in ChildrenThe Journal of PediatricsVol. 160Issue 6PreviewThe study goal was to determine the diagnostic accuracy of a specific cytokine pattern including interferon-gamma (IFN-γ), interleukin (IL)-10, and IL-6 for hemophagocytic lymphohistiocytosis (HLH) in febrile children. Full-Text PDF

Serum Ferritin is a Cost-effective Laboratory Marker for Hemophagocytic Lymphohistiocytosis in the Developing World

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease in children and presents many diagnostic difficulties. Without prompt intervention, the disease typically runs a rapidly fatal course. Diagnostic criteria were proposed by the Histiocyte Society in 1991 and have since been modified. Included in these criteria is a ferritin level >500 mcg/L. Although not diagnostic, a high ferritin level is highly suggestive of HLH. Serum ferritin assays are more accessible and cost-effective compared with other biochemical markers, particularly in resource-limited settings. Fifteen patients with HLH were treated at Red Cross War Memorial Children's Hospital between 1991 and 2010. Hyperferritinemia was a consistently reliable finding (93%) compared with either serum fibrinogen or triglycerides, which were elevated in only half of the patients. It is our contention that analysis of a complete blood count and serum ferritin (in addition to clinical criteria and tissue examination of marrow and/or cerebrospinal fluid) is probably the single most cost-effective and clinically helpful means to make the diagnosis of HLH when laboratory access is limited.

Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?

IntroductionHyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH.MethodsWe conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival.ResultsTwenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 μg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002).ConclusionsChildren with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.

Langerhans Cell Histiocytosis

The cutaneous presentation of Langerhans cell histiocytosis (LCH) is very rare and can be highly variable among individuals, which can often lead to a delay in diagnosis. To discuss a case report and literature review of important clinical indicators, histology, diagnosis, evaluation, and treatment guidelines. Case report and literature review. Skin biopsies positive for CD1a and/or langerin are diagnostic for LCH. A thorough review of systems, baseline laboratory tests, and imaging studies can determine the extent of LCH. Treatment of cutaneous disease is largely based on case report and small case studies, but baseline treatment should generally begin with oral or topical steroids. When patients have more severe disease that requires a systemic approach, the efficacy of therapy should be assessed 6 weeks into therapy, with subsequent treatment intensification in patients with limited response. Owing to the rarity of this condition, there are no specific guidelines for treatment of LCH, but guidelines put forth by the Histiocyte Society assist in categorization and basic treatment approaches for patients with systemic disease.

Hemophagocytic Lymphohistiocytosis in Adults: Updates in Diagnosis and Treatment

Abstract 5037Hemophagocytic lymphohistiocytosis (HLH) is rare potentially life-threatening disorder that must be recognized and treated early to improve clinical response rates and outcomes. We describe a 36 year-old male with a longstanding history of ulcerative colitis who presented with a one-week history of lymphadenopathy, splenomegaly, fevers, and chills. Workup at an outside institution had been intensive - he had a long complicated hospital course that included hypoxemic respiratory failure requiring intubation and mechanical ventilation, acute kidney injury, hyperbilirubinemia, pancytopenia, coagulopathy, hypofibrinogenemia, CMV viremia, and Clostridium difficile colitis for which he was treated. At our facility, the patient presented with a white blood count of 0.19 109/L (N: 5%, L: 95%, M: 0%, E: 0%, B: 0%), hemoglobin 9.0 mg/L, platelets 54 x109/L, ferritin 538 ng/dL, and triglycerides of 280 mg/dL. A bone marrow biopsy revealed CMV positivity by immunohistochemistry and marked hemophagocytic histiocytosis. The patient was treated with the HLH-2004 chemo-immunotherapy protocol with dexamethasone, etoposide (VP-16), and cyclosporine A. He responded well and is now eight months status-post initial treatment.HLH in adults is a disorder that little is known about. Acquired forms of HLH can occur in otherwise healthy adults, whereas in children, HLH often presents in its inherited (familial) form. In adults it is often associated with infections (i.e. Epstein-Barr virus, herpes simplex, cytomegalovirus), rheumatologic diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, adult onset systemic Still's disease), malignancy (i.e. natural killer cell leukemia, peripheral T-cell lymphoma, EBV in T-cell lymphoma, B-cell lymphoma, and a variety of other lymphomas). HLH in adults is characterized by cytokine dysfunction and results in the systemic accumulation of activated T-lymphocytes and activated histiocytes (macrophages). Natural killer (NK)-cell and cytotoxic T cell activity in HLH patients is commonly depressed. The standard chemo-immunotherapy protocol as recommended by the Histiocyte Society (HLH-2004) includes therapy with dexamethasone, etoposide (VP-16), cyclosporine A upfront and, in selected patients, cortiocosteriods and intrathecal methotrexate. Thus, early recognition and treatment of this disorder is essential to decrease associated morbidity/mortality. Hemophagocytic lymphohistiocytosis in adults is a diagnosis that must be in the differential whenever a patient presents with fever, cytopenia, hepatosplenomegaly, hypertriglyceridemia and/or hypofibrinogenemia. Disclosures:Schiller:BMS: Research Funding; Celgene: Research Funding; Ambit: Research Funding; Novartis: Research Funding; Sunesis: Research Funding.

Use of the Anti-CD20 Antibody Rituximab In the Treatment of Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis

Abstract 2178 Introduction:Hemophagocytic lymphohistiocytosis (HLH) is a rare complication of Epstein Barr virus (EBV) infection that is characterized by the proliferation of EBV-infected B cells and the exuberant activation of T lymphocytes and macrophages. Current therapeutic approaches aim to curtail EBV-induced immune cell activation through the use of chemotherapy and/or immunosuppressive medications. The anti-CD20 antibody Rituximab targets EBV-infected B cells and reduces disease burden in individuals with EBV-associated post transplantation lymphoproliferative disorders. Its safety and efficacy in patients with EBV-HLH remain unknown. Methods:To gather information regarding experience with the use of Rituximab in the treatment of EBV-HLH, questionnaires were distributed to members of the Histiocyte Society who stated they had administered this medication to one or more patients. Retrospective clinical and laboratory data were gathered and analyzed for this report. Results:Here we describe 41 patients with EBV-HLH who received treatment with Rituximab. The cohort consists of 29 boys and 12 girls, ranging in age from 1 to 44 years (median 6.5 years). All patients met criteria for HLH according to HLH-2004 guidelines. A causal link to EBV was established in all patients based on positivity by monospot (n=9), EBV serology (n=27), EBV PCR (n=40) or a combination of these methods. Among the 37 patients for whom genetic data were available, 16 (43%) harbored germline mutations in HLH-associated genes, including PRF1 (n=2), SH2D1A (n=8), XIAP/BIRC4 (n=2), UNC13D (n=3) and STXBP2 (n=1). On average, patients received a total of 3 infusions of Rituximab (range 1 to 10) at a dose of 375 mg/M2. The first dose of Rituximab was administered within 1 month from the date of HLH diagnosis in most patients, and it was always given in conjunction with other medications, including chemotherapy (n=37), steroids (n=40), cyclosporine (n=33), immunoglobulin (n=33) and/or anti-viral medications (n=24). Rituximab administration was associated with reversible immediate side effects in 8 patients (fever, n=7; chills, n=2; allergic reaction, n=5; hypotension, n=2). Nine patients experienced later side effects, including transaminitis (n=1), neutropenia (n=4) and hypogammaglobulinemia (n=4); although in 1 patient the reduced immunoglobulin levels may have been secondary to this patient’s underlying SH2D1A mutation. In 22 of 23 (96%) patients for whom serial data are available, administration of Rituximab led to a significant reduction in EBV load, and in 18 of 24 (75%) patients, a reduction in ferritin levels was observed. For 21 of 39 (53%) patients, Rituximab ameliorated the clinical and laboratory features of HLH with a median time to improvement of 14 days (range 2–100 days). Conclusion:Rituximab is a well-tolerated medication with minimal side effects, even when administered to patients with HLH. Based on our data that Rituximab reduces viral load, diminishes inflammation and improves clinical status, we support its incorporation into future HLH therapeutic trials for patients whose disease is precipitated by EBV infection. Disclosures:No relevant conflicts of interest to declare.

Secondary Hemophagocytosis in 3 Patients With Organic Acidemia Involving Propionate Metabolism

Hemophagocytic lymphohistiocytosis (HLH) may develop secondary to infections, malignancies, immune deficiency syndromes, and rheumatologic and metabolic disorders. Associations between HLH and inborn errors of metabolism, including lysinuric protein intolerance, multiple sulfatase deficiency, galactosemia, Gaucher disease, Pearson syndrome, and galactosialidosis, have previously been reported in the literature. In this report the authors present 3 children with disorders of propionate metabolism—1 with methylmalonic acidemia and 2 with propionic acidemia—who developed secondary HLH during their metabolic attacks. All patients fulfilled the 5 HLH criteria of the Histiocyte Society. Familial HLH was ruled out by molecular analysis. Plasma exchange was performed for 2 of them. Unfortunately 1 died of multiorgan failure despite intensive therapy. This is the first report of such an association.

Multisystem Langerhans Cell Histiocytosis in Children

Langerhans cell histiocytosis (LCH) is a rare (about 3-5 cases per million children aged 0-14 years), non-malignant disease characterized by proliferation and accumulation of clonal dendritic cells, extreme clinical heterogeneity, and an unpredictable course. Three large-scale, international, prospective therapeutic studies (LCH-I to III) for multisystem LCH (MS-LCH) have been conducted by the Histiocyte Society since 1991. The cumulative lessons from these studies are summarized in this review. Patients with MS-LCH represent a heterogeneous group with respect to disease severity and outcome, therefore treatment stratification and risk-tailored treatment are mandatory. The risk for mortality can be predicted based on involvement of 'risk organs' (e.g. hematopoietic system, liver, and/or spleen) at diagnosis and on response to initial therapy (assessed after 6-12 weeks of treatment). Thus, patients without involvement of risk organs (low-risk group) are not at risk for mortality but need systemic therapy in order to control the disease activity and avoid reactivations and permanent consequences. Patients with risk organ involvement (risk group) are at risk for mortality, and lack of therapy response defines a subgroup with a particularly dismal prognosis (high-risk group). Those patients in the risk group who respond to therapy and survive are at risk for reactivations and permanent consequences. The LCH-I study compared the efficacy of vinblastine and etoposide, and concluded that they are equivalent single-agent treatments for children with MS-LCH. However, the results of this trial were inferior with respect to response rate at week 6, disease reactivation rate, and sequelae, when compared with historical trials using more intensive regimens. The combination of prednisolone and vinblastine was established as a standard first-line treatment through the LCH-II and LCH-III studies. The regimen consists of one to two 6-week courses (continuous oral corticosteroids 40 mg/m2/day for 4 weeks, tapered over 2 weeks plus weekly vinblastine intravenous push) of initial therapy, followed by a continuation phase (three weekly pulses of oral prednisolone 40 mg/m2/day for 5 days plus a vinblastine injection). The addition of a third drug to the standard combination (etoposide in LCH-II and methotrexate in LCH-III) failed to significantly improve survival in the risk group. The remaining mortality in the risk group is about 20%, and up to 40% in the high-risk group. Concerning low-risk MS-LCH, comparison of results of the LCH-II study with historical data suggested that the remaining reactivation rate of about 50% (and possibly permanent consequences) could be reduced by prolongation of the total treatment duration. To study this hypothesis, in the low-risk group of the LCH-III study standard maintenance therapy was randomly given for a total treatment duration of 6 and 12 months. Unpublished preliminary data from this recently closed trial suggested that prolongation of the treatment duration may significantly improve reactivation-free survival. In summary, several studies have shown that systemic therapy is indicated for all patients with MS-LCH. A standard two-drug regimen consisting of an initial 'intensive' phase for 6-12 weeks, followed by a less intensive 'maintenance phase' for a total treatment duration of at least 12 months is recommended for patients treated outside of clinical trials. Non-responders, particularly those with progressive disease in risk organs, are eligible for experimental salvage approaches. Remaining questions will be addressed in the upcoming LCH-IV trial, which is in the process of intensive preparation.

Histiocyte Society 26th Annual Meeting Abstracts, Boston, Massachusetts

Histiocyte Society 26th Annual Meeting Abstracts, Boston, Massachusetts

The Langerhans cell histiocytosis

The Langerhans cell histiocytosis

Hemophagocytic syndrome in classic dengue fever

A 24-year-old previously healthy girl presented with persistent fever, headache, and jaundice. Rapid-test anti-dengue virus IgM antibody was positive but anti-dengue IgG was nonreactive, which is suggestive of primary dengue infection. There was clinical deterioration during empiric antibiotic and symptomatic therapy. Bone marrow examination demonstrated the presence of hemophagocytosis. Diagnosis of dengue fever with virus-associated hemophagocytic syndrome was made according to the diagnostic criteria of the HLH 2004 protocol of the Histiocyte Society. The patient recovered with corticosteroid therapy. A review of literature revealed only a handful of case reports that showed the evidence that this syndrome is caused by dengue virus. Our patient is an interesting case of hemophagocytic syndrome associated with classic dengue fever and contributes an additional case to the existing literature on this topic. This case highlights the need for increased awareness even in infections not typically associated with hemophagocytic syndrome.

Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India

To describe the epidemiology, clinical features, laboratory findings, outcome and the difficulties in diagnosis and management of children with Hemo-phagocytic Lymphohistiocytosis (HLH) in a tertiary children's hospital in India. Retrospective analysis of case records of all the children with a diagnosis of HLH from December 2006 to December 2008. Tertiary care children's teaching hospital in Chennai, India. 43 children had a diagnosis of hemo-phagocytosis, of who only 33 (19 male, mean age 46 months, range 50 days-14 years) met the inclusion criteria based on the HLH 2004 protocol of the Histiocyte Society. The predominant presenting features included prolonged fever and hepatosplenomegaly. CNS symptoms were present in 36%. Anemia (Hb <9 gm/dL), and thrombocytopenia (platelets <1,00,000/mm3) were present in 97% and 72%, respectively. Among the biochemical markers, hyperferritinemia was present in 97%, and hypofibrinogenemia and high LDH in 92%. Bone marrow examination showed hemophagocytosis in 84%. Infectious agents were identified in 42% children, with viruses accounting for 2/3 of them (5 Dengue virus, 3 EBV, 1 CMV, 1 TB and 5 bacterial agents). The mean duration between the onset of symptoms and the diagnosis was 16 days. Corticosteroids were the most commonly used immunomodulatory agents (67%), followed by IVI g (64%). Cyclosporine was used in 33% and Etoposide in 15%. Improvement of laboratory parameters was noticed within 5-7 days of starting treatment. Overall survival rate was 76%. HLH should be considered in the differential diagnosis of children with prolonged fever, hepatosplenomegaly and cytopenia. Prompt recognition and appropriate therapy may result in good outcome, particularly in Infection associated HLH.

Lymphadenopathie und Diabetes insipidus – Assoziation?

We report the case of a 62 year old women with chronic idiopathic myelofibrosis who developed acute lymphadenopathy. At the same time diabetes insipidus, osteolytic bone lesions and exanthema of the skin were diagnosed. Suspected Langerhans cell histiocytosis could be proven by repeated biopsies of affected organs. Therapy was started in accordance with the recommendations of the Histiocyte Society.

Chronic Murine Typhoid Fever Is a Natural Model of Secondary Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory clinical syndrome associated with neoplastic disorders especially lymphoma, autoimmune conditions, and infectious agents including bacteria, viruses, protozoa and fungi. In both human and veterinary medicine, hemophagocytic histiocytic disorders are clinically important and frequently fatal. HLH in humans can be a primary (familial, autosomal recessive) or secondary (acquired) condition, with both types generally precipitated by an infectious agent. Previously, no mouse model for secondary HLH has been reported. Using Salmonella enterica serotype Typhimurium by oral gavage to mimic naturally-occurring infection in Sv129S6 mice, we characterized the clinical, hematologic and morphologic host responses to disease thereby describing an animal model with the clinico-pathologic features of secondary HLH as set forth by the Histiocyte Society: fever, splenomegaly, cytopenias (anemia, thrombocytopenia), hemophagocytosis in bone marrow and spleen, hyperferritinemia, and hypofibrinogenemia. Disease severity correlates with high splenic and hepatic bacterial load, and we show disease course can be monitored and tracked in live animals. Whereby secondary HLH is known to occur in human patients with typhoid fever and other infectious diseases, our characterization of a viable natural disease model of secondary HLH offers an important means to elucidate pathogenesis of poorly understood mechanisms of secondary HLH and investigation of novel therapies. We characterize previously unreported secondary HLH in a chronic mouse model of typhoid fever, and novel changes in hematology including decreased tissue ferric iron storage that differs from classically described anemia of chronic disease. Our studies demonstrate S. Typhimurium infection of mice is a natural infectious disease model of secondary HLH that may have utility for elucidating disease pathogenesis and developing novel therapies.

Establishment of a reference interval for natural killer cell activity through flow cytometry and its clinical application in the diagnosis of hemophagocytic lymphohistiocytosis

Recently, the Histiocyte Society revised the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) to include low or absent natural killer (NK) cell activity, according to local laboratory reference. The aim of this study was to establish reference interval for functional NK-cell activity in 63 healthy Korean individuals using a flow-cytometric assay. We used peripheral blood mononuclear cells (PBMCs) as effector cells and Fluorescein isothiocyanate-labeled K562 cells as target cells. NK-cell activity was calculated using the following equation: NK-cell activity (%) = (test lysis - spontaneous lysis) x 100/(maximum lysis - spontaneous lysis). NK-cell activity was analyzed in 13 known HLH patients and 16 suspected non-HLH patients using a flow-cytometric assay. The mean (+/-SD) cytotoxicity of PBMCs from healthy individuals was 20.9 +/- 5.3% and the reference interval was 11.8-31.9%. The mean NK-cell activity of HLH patients (8.3 +/- 8.9%) was significantly lower (P = 0.001) than that of non-HLH patients (20.1 +/- 7.8%). The sequential changes in NK-cell activity in the HLH group corresponded to clinical and laboratory findings following treatment. We successfully developed a functional NK-cell activity test for use in the clinical laboratory and obtained a reference interval of NK-cell activity from healthy donors. This assay, and associated reference interval, was used to analyze 30 clinically relevant specimens and the results were shown to be well correlated.

Kawasaki disease preceding haemophagocytic lymphohistiocytosis: Challenges for developing world practitioners

Kawasaki disease (KD) is a recognised precipitant of haemophagocytic lymphohistiocytosis (HLH). Although KD has been previously described in the developing world, there are no reported cases of KD preceding HLH. We report a case of a child with a persistent rash and unremitting fever consistent with the diagnosis of KD, who was found to have HLH, after intravenous gamma globulin failed to produce a clinical response. The diagnosis was made using the revised diagnostic criteria for HLH from the Histiocyte Society (1994). She fulfilled six of the eight clinical and laboratory criteria needed to make the diagnosis.

Langerhans Cell Histiocytosis in childhood

Histiocytoses are rare and heterogeneous group of disorders in childhood. The clinical presentation of Langerhans cell histiocytosis (LCH) is highly variable, from asymptomatic to clinically significant symptoms and consequences. As it can involve nearly every organ of the body, the clinical manifestations depend on the site of the lesions, on the organs and systems involved and whether their function is affected. The most common sites of involvement in LCH are bone, skin, lymph nodes, lung, bone marrow and hypothalamic-pituitary region. The classical presentation of LCH is a unifocal bone disease, previously known as eosinophilic granuloma. LCH can be divided according to disease extent: single- or multi-system disease. There is very high chance of spontaneous resolution and favourable outcome for single-system disease involving the skin or bone. In many cases, no therapy or only local therapy is enough. For patients with multi-system disease currently systemic therapy is the treatment of choice. The goal of treatment is to relieve clinical symptoms, to increase survival and prevent complications. Currently cooperative international trials of the Histiocyte Society are used for treatment of LCH based on a€Eœrisk group stratification' with therapeutic agents have generally paralleled those used for the treatment of malignancies. There is no standardized therapy for chronic relapsing, acute refractory and progressive disease, some alternative approaches have been tested. Childhood LCH is a well treatable disease and the survival rate is high. This article summarizes the classification, pathophysiology, diagnostic criteria, different clinical manifestations, treatment possibilities, prognosis and long-term sequelaes of LCH in children.