Infection-associated Hemophagocytic Lymphohistiocytosis Research Articles

Serum high mobility group box protein 1 (HMGB1) levels reflect clinical features of childhood hemophagocytic lymphohistiocytosis.

PurposeHemophagocytic lymphohistiocytosis (HLH) is a potentially lethal hyperinflammatory disorder. For further understanding of the pathogenesis of HLH, we examined serum levels of high mobility group box protein 1 (HMGB1) in children with HLH.Patients and methodsSerum HMGB1 levels were measured in 28 patients with HLH and 6 normal controls using a quantitative enzyme-linked immunosorbent assay. The patients were 21 boys and 7 girls, aged from 10 days to 21 years, with a median age of 8.5 years. The underlying conditions of HLH were infection-associated HLH in 18 patients, malignancy-associated HLH in 7 patients, and genetic HLH in 3 patients. The relations between serum HMGB1 levels and clinical symptoms and laboratory parameters were analyzed.ResultsSerum HMGB1 levels were significantly higher in patients with HLH than in normal controls (median, 6.5 ng/mL, interquartile range, 4.25–13.1). The serial serum HMGB1 levels in one patient fell to reflect the disease activity. Serum HMGB1 levels were significantly higher in patients with disseminated intravascular coagulation (DIC) than in patients without DIC (p<0.001) and were also significantly higher in patients with central nervous system (CNS) complications than in patients without CNS complications (p<0.01). Serum HMGB1 levels were positively correlated with aspartate aminotransferase (rs =0.48, p<0.01, Spearman’s rank correlation coefficient) and negatively correlated with fibrinogen (rs = −0.475, p=0.011) and hemoglobin (rs = −0.465, p=0.013).ConclusionSerum HMGB1 levels reflect clinical features of childhood HLH. HMGB1 is a potential mediator involved in the pathogenesis and determining the clinical findings of HLH.

A case of hemophagocytic lymphohistiocytosis caused by an Epstein-Barr virus infection, presenting with unremitting fever and rash

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome caused by excessive activation of lymphocytes and macrophages, leading to cytokine storm. Infection-associated HLH is most common, and Epstein-Barr virus is the leading triggers. Quick diagnosis is essential for starting the treatment before irreversible damage. We report a case of 16-year-old boy who presented with unremitted fever, jaundice, and erythematous maculopapular rash all over the body. Investigations showed thrombocytopenia, hyperferritinemia, hypertriglycemia, and the bone marrow biopsy showed hemophagocytosis. Epstein-Barr virus antibody was positive. He responded to chemotherapy as per the HLH-2004 protocol and supportive treatment, and was discharged without complication on day 17. Key Words: Epstein-Barr Virus Infections; Exanthema; Ferritins; Fever; Lymphohistiocytosis, Hemophagocytic

Rapid Response to Low-Dose Rituximab Following Development of Severe Hemophagocytic Lymphohistiocytosis Due to Epstein-Barr Virus Infection

Viral infection-associated hemophagocytic lymphohistiocytosis is often observed in children. When Epstein-Barr virus is the pathogen, patients can develop serious coagulopathy and pancytopenia. Usually such patients respond to standard steroid therapy, but alternative therapy for steroid-refractory cases is limited. Here we present the clinical observation of a Japanese girl who was successfully treated with rituximab after she failed to respond to standard steroid therapy. Int J Clin Pediatr. 2019;8(1):8-11 doi: https://doi.org/10.14740/ijcp325

Hematopoietic Stem Cell Transplantation for the Treatment of Epstein-Barr Virus-Associated T- or NK-Cell Lymphoproliferative Diseases and Associated Disorders.

Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy), and step 3 (allogeneic hematopoietic stem cell transplantation; HSCT) for CAEBV and its related diseases. Allogeneic HSCT is the only cure for CAEBV with few exceptions. Primary-EBV infection-associated hemophagocytic lymphohistiocytosis (primary-EBV HLH) is also an EBV+ T/NK-cell lymphoproliferation. The nature of EBV+ T/NK cells in CAEBV and those in primary-EBV HLH differ. In primary-EBV HLH, most patients need step 1 only and some require step 2 for the successful induction of apoptosis in EBV-infected T cells; however, some exceptional patients require HSCT. We herein present our single institutional experience of CAEBV and primary-EBV HLH, together with that of post-transplant EBV+ T/NK-cell lymphoproliferative disease. We also discuss some practical points on HCST with a review of the literature.

Hemophagocytic Lymphohistiocytosis (HLH) in 44 Adults: Results from the Retrospective Polish Registry

▪IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of extreme hyperinflammation. It does not self-limit and needs to be stopped by effective treatment. This reaction can be triggered by numerous factors, including infection, malignancy and autoimmune disease. HLH used to be diagnosed in children, but in last few years more and more adults with this syndrome are treated. This raising awareness enabled creating retrospective registry of adult HLH patients in Poland.MethodsA multicenter retrospective analysis of adult (≥18 years) patients was performed. Inclusion criteria were based on the HLH-2004 protocol.ResultsForty four adult (median age 34, range 18-80) patients from 13 clinical centers were reported. The gender ratio was balanced (M/F: 23/21). Patients fulfilled on the average 5.2 of HLH-2004 criteria. Due to the lack of possibility of sCD25 and NK activity testing in majority of centers only 6 criteria were actually evaluated. Also 6 patients with strong clinical suspicion (e.g. recurrent HLH) fulfilling 4 out of 6 available criteria were included. The most frequent triggering factor was malignancy (14/44) with lymphoma (T-cell 6/14, B-cell 4/14) being the most common. Infection-associated HLH was present in 13 patients, most of which was attributed to EBV (11/13; additionally CMV and B19 occurred). One patient suffered from both T-lymphoma and EBV infection. The most frequent autoimmune diseases identified were Still's disease (n=3) and systemic lupus erythematosus (n=2). In 11 patients clear triggering factor could not be identified. Three patients underwent liver transplantation.Baseline characteristics of all patients are shown in Table 1. Briefly, almost all patients presented with extreme hyperferritinemia, fever, splenomegaly. Other Important features are liver involvement and coagulopathy.Majority of patients were treated according to HLH-2004 protocol, except of patients with malignancy treated with disease-specific chemotherapy regimens (with emphasis on inclusion of etoposide if appropriate). None of the patients underwent stem cell transplantation (SCT) as HLH therapy; one patient had HLH triggered by EBV reactivation after alloSCT.Median survival was 66 days (Fig.1), 39% of patients survived with median observation of 21 months (3-98).ConclusionsHeterogeneity of HLH syndrome was confirmed in Polish population, with malignancy and EBV infection being the most frequent triggering factors.Awareness of HLH in adults is raising, but it should be fostered as HLH is still underdiagnosed. Further studies are needed to deepen our knowledge about HLH in adults.Analysis of additional, newly diagnosed cases is ongoing and will be presented at the meeting.Table 1Baseline patient characteristicsCharacteristic[unit](n)%MedianRangeFever(n=44)97.7Splenomegaly(n=44)90.9Hemophagocytosis(n=41)70.7Hyperferitinemia[µg/l](n=44)10014280846-126680Hemoglobin[g/dl](n=44)8.36.1-13.9Neutrophil count[G/l](n=41)1.10-173Platelet count[G/l](n=44)434-349Triglycerides[mg/dl](n=38)31674-1559Fibrinogen[mg/dl](n=43)16630-901PT[s](n=30)15.99-46.6APTT[s](n=39)3622-86.8CRP[mg/l](n=40)40.10.4-373LDH[U/l](n=39)970195-13160AST[U/l](n=39)15016-16280ALT[U/l](n=40)10018-12390Total Bilirubin[mg/dl](n=37)3.70.34-25.6PT indicates Prothrombin Time; APTT, Activated Partial Thromboplastin Time; CRP, C-Reactive Protein; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase [Display omitted] DisclosuresKnopinska-Posluszny:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Wiktor-Jedrzejczak:Amgen, Inc.: Research Funding; Onconova: Other: Advisory Board; Novartis: Research Funding; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board, Research Funding; Jansen: Other: Advisory Board; Celgene: Other: Advisory Board.

Prognostic Factors and Long-Term Outcome in 52 Turkish Children With Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis is a syndrome of pathologic immune activation that shares similar clinical and laboratory phenotypes with severe sepsis. Recent studies led to better recognition of hemophagocytic lymphohistiocytosis by clinicians, but no consensus exists on the criteria for high-risk patients. We retrospectively reviewed the medical records of patients diagnosed with hemophagocytic lymphohistiocytosis to analyze the risk factors associated with poor outcome. Pediatric intensive care and hematology units of three tertiary hospitals in Turkey. Fifty-two children with hemophagocytic lymphohistiocytosis. None. There were a total of 52 children meeting the diagnostic criteria of Histiocytic Society. Of them, 28 (54%) had a primary hemophagocytic lymphohistiocytosis. Mutation studies were performed in 18 of 28 patients (65%). Fourteen of them had PRF1, STX11, STXBP2, and UNC13D mutations, and four had Rab27a and LYST mutations. The remaining 24 patients (46%) were defined as having secondary hemophagocytic lymphohistiocytosis. Twenty-one of them had infection-associated hemophagocytic lymphohistiocytosis, and three had lysinuric protein intolerance. The mortality rate was significantly higher in primary hemophagocytic lymphohistiocytosis (64%) than in secondary hemophagocytic lymphohistiocytosis (16%) (p < 0.05). There were no significant differences for survival rate between hemophagocytic lymphohistiocytosis 94 (44%) and hemophagocytic lymphohistiocytosis 2004 (64%) protocols (p > 0.05). Age below 2 years, hyperferritinemia, thrombocytopenia, high disseminated intravascular coagulation score at diagnosis, and no clinical response at 2 weeks of treatment were independent prognostic factors for poor prognosis. Our data suggest that disseminated intravascular coagulation score greater than or equal to 5 can be used in the definition of high-risk patients. Early recognition of poor risk factors has important prognostic and therapeutic implications.

Hemophagocytic Lymphohistiocytosis Is Not Only a Childhood Disease: A Multi-Center Study of 613 Cases from Chinese HLH Workgroup

▪Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. It occurs as a primary or acquired disorder in a condition of chaotic and uncontrolled immune system stimulation. Recent studies showed that HLH occurs not only in children, but also in adult. Here we presented the data gathered from Chinese HLH Workgroup in order to make further understanding about the disease.Methods: We performed a multi-center study involving 613 cases of HLH patients. We analyzed the clinical features, laboratory tests, diagnosis, treatments and clinical outcomes of them. All the date came from 46 hospitals, between Jan 2006 to June 2014.Results: The median age was 29 years old (Range 1 month to 82 years old). Forty-nine cases of them were primary HLH, 489 cases were acquired HLH and the other 75 case had unknown underlying disease. Among the acquired HLH group, 211 cases were malignancy-associated HLH (M-HLH),207 cases were infection- associated HLH (I-HLH), 58 cases were macrophage activation syndrome (MAS), 9 cases were associated with pregnancy, 3 patients developed HLH after autologous hematopoietic stem cell transplantation, and one case was associated with hemolytic anemia. Over ninety percent (93.3%) of the patients had hepatic function damage. We found significant difference in some diagnostic criteria among M-HLH, I-HLH and MAS group. The mean leukocytes was (9.50±8.46)×109/L, and the mean thrombocytes was (100.69±87.61)×109/L , which were significantly higher in MAS group than the other. The brain natriuretic peptide (BNP) was higher in patients with M-HLH (5477.31±6048.08 pg/ml). The aspartate aminotransferase (AST) was and bilirubin were significantly higher in patients with I-HLH. The median survival time of 613 cases is 7 months. Until now, 258 cases of patients were still survived, 297 cases were died, and the other was lost. We observed 45 cases who underwent allogenic hematopoietic stem cell transplantation (allo-HCT), including 22 cases of primary HLH, 12 cases of M-HLH, 8 cases of EBV-HLH and 3cases with unknown underlying disease. In these allo-HCT patients, 26 cases were achieved complete remission (CR), 12 cases died from transplantation related mortality (TRM), and the other died from tumor relapse or refractory EBV infection. The dead exhibited much higher level in bilirubin, lactate dehydrogenase (LDH), creatinine, and urea nitrogen. On the contrary, they had lower leukocytes and thrombocytes counts, and hypoalbuminemia. Thrombocytopenia and hypoalbuminemia play an important role in poor prognosis.Conclusion: HLH is not only a childhood disease but also occurs in adult. It associated with many underlying conditions. Lymphoma and EBV infection were two major causes of acquired HLH. Hepatic function damage is one of the most typical HLH clinical manifestations, and it tends to be more serious for patients with I-HLH. In addition, the blood cells of the patients with MAS may not reduce in the early phase; and the patients with M-HLH are easy to catch cardiac dysfunction. Acquired HLH is still a high mortality disease, and allo-HCT is one of the effective means of treatment for acquired HLH. Thrombocytopenia and hypoalbuminemia play an important role in poor prognosis. DisclosuresNo relevant conflicts of interest to declare.

JOURNAL OF PEDIATRIC CRITICAL CARE

Hemophagocytic lymphohistiocytosis(HLH) is a heterogeneous group of clinical syndromes, either familial or genetic in origin or secondary, characterised by uncontrolled non-malignant proliferation of Tlymphocytes, histiocytes and macrophages leading to a cytokine stomi and manifest as prolonged fever, organomegaly, cytopenia. hyperferritenemia and demonstrable hemophagocytosis in the bone marrow. Secondary infection associated HLH(IAHLH) can be triggered by many infections, mostly viral. Here we present a case of Pulmonary tuberculosis complicated by ARDS and HLH.

Diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics: Systematic review from the indian subcontinent

Hemophagocytic lymphohistiocytosis (HLH) is a catastrophic syndrome of unrestrained immune activation. Evaluation and management of HLH in the tropics is challenging. To examine the reported etiologies and management of HLH reported from the sub-continent. Systematic review of all published cases from the Indian sub-continent. We found only 156 published cases of HLH from the sub-continent. HLH was reported from the immediate perinatal period to 46 years of age. Infection-associated HLH (IAHS) constituted 46.8% of all cases of HLH (44% and 51% in children and adults respectively). In adults, tropical infections triggered 51% of these cases of IAHS. Steroids were used in 47% of children and 10% of adults. Etoposide and/or cyclosporine were used in 8% children and 8% of adults only. Intravenous immunoglobulin was used in another 30% of children and 4% of the adults. HLH-related mortality occurred in 31.8% and 28% of children and adults respectively. HLH is under-reported in the sub-continent and has high mortality. Cyclosporine and etoposide are seldom administered early despite diagnosis of HLH. Larger cohorts with IAHS triggered by tropical infections are urgently needed to understand its natural history and implications of this differing prescription pattern on mortality.

Severe hemophagocytic lymphohistiocytosis in adults-experience from an intensive care unit from North India

Background:Hemophagocytic lymphohistiocytosis (HLH) has been reported to complicate fulminant tropical infections but data on severe HLH with multi-organ dysfunction (MODS) are scant.Materials and Methods:Retrospective review of medical electronic records of our intensive care unit (ICU) over a 2-year period.Results:We describe 10 adult patients with HLH and MODS. Patients had short symptom duration prior to presentation and had rapid deterioration during their hospitalization course. Fever, organomegaly, neurologic abnormalities, hepatic abnormalities, and cutaneous signs were very common. No patient had diagnosed HLH at ICU admission (median 4 criteria [Inter Quartile Range 2-4.25]). All patients required mechanical ventilation and 80% required vasopressors. Infection-associated HLH (IAHS) was the most common etiology (80%). Seventy percent (7/10) of patients were treated with steroids and 20% received intravenous immunoglobulin. Etoposide and/or cyclosporine were administered in 20% (2/10). Nosocomial infections occurred in 40% and the ICU mortality was 70%.Conclusions:Severe HLH with MODS has a very high mortality. Data on adult cohorts with IAHS in the tropics with defined treatment protocols are urgently needed.

Treatment of Hemophagocytic Lymphohistiocytosis with Cop Chemotherapy Protocol: A Retrospective Clinical Analysis of Fifteen Cases

Abstract 1121Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper-inflammatory syndrome with prolonged high fever, hepatosplenomegaly, pancytopenia, hepatic dysfunction, low fibrinogen level, hypertriglyceridemia and hemophagocytosis in the bone marrow, liver, spleen, or lymph nodes. Broadly, HLH can be classified into either primary or secondary HLH. The familial HLH (FHL) is an autosomal recessive disorder with a median survival of less than two months after diagnosis if untreated, and that typically has its onset during infancy or early childhood. Secondary HLH (sHLH) may occur in association with severe infections, malignancies or autoimmune diseases, although it may subside spontaneously, it may also be associated with pronounced mortality. The most present therapeutic regimes such as HLH-2004 protocol and allogene hemopoietic stem cell transplantation (allo-HSCT) have been designed for the primary, inherited disease FHL, in patients aged <18 years, as well as any severe form of HLH. Reports on the treatment of sHLH are rare, and no standard treatment protocol is as yet established. We implemented prednisone, vincristine, cyclophosphamide (COP) combined chemotherapy in treating adult hemophagocytic lymphohistiocytosis (HLH) and observed the therapeutic efficacy. Fifteen patients, among whom 7 were infection-associated HLH (IHLH), 4 had no apprent underlying causes, lymphoma-associated HLH (LHLH) and autoimmune disease-associated HLH took up of 2 respectively, were enrolled in our study. The initial therapy of COP protocol included cyclophosphamide (CTX) 0.3 g/m2 i.v. and vincristine (VCR) 1.4 mg/m2 i.v., once weekly for the first eight weeks, prednisone (PRED) 60 mg/m2/d p.o., for the first 2 weeks, and reduced by 50% of the previous dose every 2 weeks until the end of the 7th week, then progressively tapered it for 1 week. A continuation therapy of COP was CTX 0.3 g/m2 i.v., on day 1, day 8; VCR 1.4 mg/m2 i.v., on day 1, day 8; PRED 20 mg/m2 p.o. for 14 days and it was repeated every 4 weeks for a total of 4 to 6 cycles in responding. Patients were given COP protocol individually depending on their different etiologies and responses to therapy. With a mean follow-up of 72.5 weeks, the median overall survival (OS) was 43 weeks and the one-year probability of overall survival (OS) was 10/15(66.7%). The overall response rate was 80.0%, consisting of seven (46.7%) complete response (CR) and five (33.3%) partial response (PR). Different etiology induced HLH had different sensitivity and response rate to COP chemotherapy. Hematological and non-hematological toxicities were predominantly grade I or II and most patients could well tolerate without requiring a dose reduction of full-dose COP. In conclusion, as a mild and cost-effective chemotherapy, COP protocol showed a relatively favorable effect for adult patients with sHLH. In the following situations, like some with bacteria infection, some arose from an autoimmune disease, or else some who can not endure an intensive chemotherapy due to an old age or disease severity, the COP protocol may be the first choice. Disclosures:No relevant conflicts of interest to declare.

Hemophagocytic Lymphohistiocytosis (HLH) Associated withPlasmodium vivaxInfection: Case Report and Review of the Literature

Hemophagocytic lymphohistiocytosis (HLH) is an unusual syndrome characterized by fever, hepatosplenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and pathologic findings of hemophagocytosis in the bone marrow and other tissues. HLH may be familial or associated with different types of infections, autoimmune disorders, or malignancies. Infection-associated HLH has been reported in various viral, bacterial, fungal, and parasitic infections, and case reports of parasitic infections implicated in HLH include rare cases from Plasmodium vivax infection, which occasionally affects both military personnel and civilians in Korea. We describe an unusual case of HLH resulting from Plasmodium vivax infection and review the literature. This case suggests that clinical suspicion of HLH is important when P. vivax infection is accompanied by cytopenias. Administration of antimalarial drugs may prevent irreversible end organ damage resulting from P. vivax-associated HLH.

Clinical Significance of Cloned Expansion and CD5 Down‐Regulation in Epstein‐Barr Virus (EBV)–Infected CD8+T Lymphocytes in EBV‐Associated Hemophagocytic Lymphohistiocytosis

Epstein-Barr virus (EBV) is the pathogen that most commonly triggers infection-associated hemophagocytic lymphohistiocytosis (HLH) and ectopically infects CD8(+) T cells in EBV-associated HLH (EBV-HLH). We recently described an EBV-HLH patient who had a clonally expanded population of EBV-infected CD8(+) T cells with CD5 down-regulation. To determine whether this finding could serve as a useful marker for EBV-HLH, we investigated 5 additional patients. We found a significant increase in the subpopulation of CD8(+) T cells with CD5 down-regulation and bright human leukocyte antigen (HLA)-DR expression in all patients with EBV-HLH but not in patients with infectious mononucleosis or in control subjects. Such T cells were frequently found to be larger cells that stained positive for a specific T cell receptor VB. We also demonstrated that those cells were the major cellular target of EBV, and their numbers progressively declined in parallel with the serum ferritin levels. All together, our findings reveal the immunophenotypic characteristics of EBV-infected CD8(+) T cells and may provide a valuable tool for the diagnosis of EBV-HLH.

Cytotoxic T-Lymphocyte-Associated Antigen 4 Gene Polymorphisms in Japanese Children with Infection-Associated Hemophagocytic Lymphohistiocytosis

Objective: This study examined whether genetic polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a negative regulator of T cells, are associated with infection-associated hemophagocytic lymphohistiocytosis (IHLH) in Japanese children. Methods: We investigated the alleles of four polymorphisms in the CTLA-4 gene [–318CT, +49AG, CT60 and a dinucleotide repeat length polymorphism (AT)n] in 43 Japanese children with IHLH and 100 healthy Japanese controls. The hyper-polymorphic (AT)n alleles were divided into two types; the shortest allele (designated as AT₇) and the longer alleles (designated as AT_>₇). Results: A significant difference in the distribution of the (AT)n genotype was found between patients and controls (p = 0.028). Also, the frequency of the AT_>₇ allele was significantly higher in the patients with IHLH than in the controls (p = 0.007). No significant linkage disequilibrium was found between each polymorphism. With regard to laboratory data, patients homozygous for the CTLA-4 AT_>₇ allele showed significantly higher serum levels of lactate dehydrogenase and soluble interleukin-2 receptor than patients with the other alleles. Conclusion: These results suggest that CTLA-4 polymorphisms might play a role in the development of IHLH in Japanese children.

Hemophagocytic Syndrome in an Adolescent With Crohn Disease Receiving Azathioprine and Infliximab

Hemophagocytic Syndrome in an Adolescent With Crohn Disease Receiving Azathioprine and Infliximab

Clinical assessment of Mycoplasma pneumoniae‐associated hemophagocytic lymphohistiocytosis

Mycoplasma pneumoniae has been reported to be an etiologic pathogen of infection-associated hemophagocytic lymphohistiocytosis (HLH), but few case reports have been available to date. The clinical features of four childhood cases of M. pneumoniae-associated hemophagocytic lymphohistiocytosis (Mp-HLH) were retrospectively assessed to obtain data that might be useful for early diagnosis and effective management. The previous English-language literature pertaining to Mp-HLH was also reviewed. The patients were two boys and two girls, aged between 1 and 11 years of age. One patient was demonstrated to have concurrent infection with rubella. All the patients had typical radiographic features of M. pneumoniae pneumonia, and one patient also had encephalopathy as a complication. All the children underwent bone marrow examination because of antibiotic-refractory fever, mild hepatosplenomegaly, cytopenia, hyperferritinemia and elevated levels of urine beta2-microglobulin. Cytopenia and hepatosplenomegaly in the present patients were relatively mild as compared to those in cases of other infection-associated HLH such as Epstein-Barr virus infection-associated HLH. Treatment with corticosteroids resulted in prompt and complete resolution in two cases, and i.v. high-dose gammaglobulin therapy achieved a complete response in another child. Spontaneous resolution under treatment with antibiotics alone was observed in one case. Although Mp-HLH is a rare complication of M. pneumoniae infection, it should always be considered in patients with antibiotic-refractory M. pneumoniae infections with cytopenia. Mp-HLH might be effectively treated by corticosteroids or high-dose gammaglobulin. To clarify the diverse clinical manifestations of M. pneumoniae infections, immunological interactions between M. pneumoniae and the host immune system should be further investigated.

Nationwide Survey of Hemophagocytic Lymphohistiocytosis in Japan

Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.