HLH-2004 Diagnostic Criteria Research Articles

Hemophagocytic Lymphohistiocytosis: A Potentially Underrecognized Association With Systemic Inflammatory Response Syndrome, Severe Sepsis, and Septic Shock in Adults

Hemophagocytic lymphohistiocytosis (HLH) was originally described as a genetic disorder of immune regulation, presenting in neonates with protracted fever, hepatosplenomegaly, and cytopenia. A secondary form of HLH, triggered by serious infections, was subsequently described in adults. We report three adult patients who presented with systemic inflammatory response syndrome and features consistent with severe sepsis and septic shock, who subsequently received a diagnosis of secondary HLH. We reviewed the relationship between infection-triggered HLH and septic shock from the perspective of the adult intensivist. The hyperinflammatory pathophysiologic characteristics of HLH and septic shock are closely intertwined. Clinical and laboratory features of HLH and septic shock overlap in some patients, making the syndromes difficult to distinguish. In our experience and review, progressive pancytopenia was the feature most likely to suggest secondary HLH in the adult patient with presumed (or definite) septic shock. Use of other HLH-2004 diagnostic criteria is hindered by the poor operating characteristics of these tests in critically ill adults. Bone marrow aspiration is the most useful diagnostic test, but may yield an initial false-negative result. The HLH-2004 treatment protocol is not of proven benefit in critically ill adults, but observational data suggest that aggressive immunosuppressive therapy should not be delayed. Further study of HLH in the critical care setting might provide important insights into the pathogenesis and clinical treatment of sepsis.

Virus-Associated Hemophagocytic Syndrome Contributes to Fatal Outcome In Critical Ill Patients with 2009 Influenza A (H1N1) Infection.

AbstractAbstract 3795 Introduction:Virus-associated hemophagocytic syndrome (VAHS) is a severe complication of various viral infections often resulting in multiple organ failure syndrome and death. Based on previous experience with seasonal (H3N2) and avian (H5N1) infections the 2009 influenza A (H1N1) virus offers the potency of VAHS-development resulting in an aggressive and life-threatening disease. Most patients infected by the novel human influenza A (H1N1) experienced a mild clinical course; however some patients become critically ill with respiratory failure requiring intensive care and ventilator support. Multiple organ failure was one of the leading causes of death suggesting that patients with severe influenza A (H1N1) infection may develop a virus-associated hemophagocytic syndrome (VAHS). Methods:To evaluate frequency, clinical course and outcome of VAHS in critically ill patients a prospective observational study was performed at a single center intensive care unit in Hannover, Germany. Collected data include demographics, comorbid conditions, viral shedding, diagnosis of VAHS, illness progression, treatments and survival. VAHS was suspected when patients developed fever, cytopenia affecting at least two lineages, hepatitis or splenomegaly, hemophagocytosis in bone marrow samples and/or increased serum levels of sIL-2R and ferritin. Diagnosis of VAHS was made according to established HLH-diagnostic criteria. Primary outcome variables were the development of VAHS and VAHS-associated mortality. Results:Between October 5, 2009 and January 4, 2010 twenty five consecutive critically ill patients with RT-PCR confirmed 2009 influenza A (H1N1) infection and respiratory failure were identified. VAHS developed in nine out of 25 (36%) patients. Treatment of VAHS was started in 6 out of the 9 patients; three patients showed terminal disease and were no longer considered candidates for treatment with etoposide and dexamethasone. Despite VAHS-directed therapy, 5 out of the 6 patients died from uncontrolled progress leading to multiorgan failure. Overall, 8 out of the nine patients (89%) with confirmed VAHS died. In contrast, the mortality rate in the remaining 16 patients without VAHS was 25% (p=0.004). Patients were young (median, 45 [IQR, 35–56] years), however 18 (72%) presented one or more risk factors for a severe course of influenza illness. All 25 patients received mechanical ventilation for severe acute respiratory distress syndrome and refractory hypoxemia with duration of mechanical ventilation of median (IQR) 19 (13-26) days. Additionally 17 patients (68%) required extracorporeal membrane oxygenation for median (IQR) 10 (6-19) days. Oseltamivir and zanamivir were used as antiviral treatment in 24 patients (96%) for a median (IQR) of 7 (4-10) days and in 15 patients (60%) for a median (IQR) of 7 (5-12) days, respectively. The median (IQR) duration of viral shedding from disease-onset to the last positive H1N1 RT-PCR was 19 (14-26) days. In patients without VAHS the median (IQR) viral shedding time was 15 (12-22) days as opposed to 21 (14-26) days (p=0.13) in patients with VAHS. Conclusion:The present case series confirms previous post mortem analysis that severe influenza A (H1N1) infection is an important contributor to the development of VAHS in critically ill patients. Development of VAHS was associated with fatal outcome showing rapid clinical deterioration and multi organ failure syndrome and either contributes greatly to, or is itself causative of death in this patient population. Our findings are preliminary but potentially have important implications for future management of patients with influenza A (H1N1) disease as well as other severe virus infections which can induce secondary hemophagocytic syndromes. Disclosures:No relevant conflicts of interest to declare.

Traitement du syndrome d’activation macrophagique sévère associé à une leishmaniose viscérale

The association of hemophagocytic syndrome (HS) and visceral leishmaniasis is a frequent disorder during infancy in endemic areas such as Tunisia. The range of severity of HS secondary to visceral leishmaniasis includes both pure biological forms that resolve with antimicrobial therapy and life-threatening emergencies that require specific treatment. We describe 2 cases of severe HS secondary to visceral leishmaniasis. The diagnosis of HS was based on the HLH-2004 diagnostic criteria. Therapy involved pentavalent antimonial (Glucantime) in both cases. The combination of corticosteroids with immunoglobulins, used in the 1st case, but introduced late, led to an unfavorable course and death. In the 2nd case, the specific treatment of HS was based on immunochemotherapy including etoposide and corticosteroids. Progression was favorable with a follow-up of 24 months. Etoposide containing therapeutic regimens can be proposed in severe forms of HS associated with visceral leishmaniasis.

High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis.

Abstract 1359▪▪This icon denotes an abstract that is clinically relevant.Poster Board I-381 BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare condition in which dysregulation of innate immune effectors including natural killer (NK) cells and macrophages leads to destruction of hematopoietic elements. HLH is most frequently reported in association with malignancies or viral infections, with heritable deficiencies in cytotoxicity pathways predisposing children (and rarely adults) to HLH. Criteria for diagnosing HLH include: histological evidence of hemophagocytosis, two or more cytopenias, hyperferritinemia, hypofibrinogenemia or hypertriglyceridemia, elevated soluble IL-2R, decreased in vitro NK cell function, fever, and splenomegaly. Patients meeting >=5 of these criteria are diagnosed with HLH.Source: We identified 19 consecutive adult patients (53% male; median age 43y, range 16-83) admitted to Stanford Hospital with clinical suspicion for HLH and histological evidence of hemophagocytosis between 1997 and 2009; 2 patients were excluded from analysis due to incomplete data. Of the remaining 17 patients, 11 (65%) met criteria for a diagnosis of HLH. ResultsAt presentation, all patients were anemic with a median Hgb concentration of 8.6 g/dL. Leukopenia was present in 8/11 (73%) with a median WBC count of 2 K/uL. Thrombocytopenia was present in 10/11 (91%) patients with a median Plt count of 30 K/uL. In 6 patients not meeting HLH criteria, median hematologic findings were Hgb 8.6 g/dL, WBC 2.6 K/uL, and Plts 126 K/uL. All patients demonstrated marked elevations of ferritin, median 3915 ng/dL (range 1039 – 29,700). Triglycerides were elevated in 7/10 (70%) for whom data were available, median 296 mg/dL (range 204 – 1,506). Fibrinogen was decreased in 3/13 (23%). Soluble IL-2 receptor level was above normal limits in all patients in whom it was measured (range 796 – 17,378 U/mL), but met the >2,400 U/mL criteria in only 3/6 (50%). In vitro NK function was diminished in 2/5 (40%) patients tested. Fever and splenomegaly were found in 94% and 59% of patients, respectively. Of 11 patients meeting HLH criteria, 5 had associated malignancies (DLBCL, NK cell leukemia, T cell lymphoma, AML, and Kaposi sarcoma) and 4 had concomitant viral infections (2 EBV, 1 EBV/B19, and 1 HIV-1/HHV-8). Three patients had isolated viral infections (all EBV), while 3 had idiopathic HLH. Amongst 6 patients not meeting HLH diagnostic criteria, 2 (33%) had an associated malignancy (SLL and NK cell lymphoma), 1 had an isolated EBV infection, and 3 had idiopathic disease. At a median follow-up of 16 months for surviving patients, the case fatality rate amongst those with established HLH diagnoses was 55%, with all deaths occurring within 2 months from diagnosis. Five patients were treated according the HLH-94/04 protocol combining dexamethasone, cyclosporine and etoposide. Two patients died within 2 months of initiating treatment, and 3 remain alive (survival to date ranges 4-31 months). The longest surviving patient underwent allogeneic HCT. A patient who presented with AML-associated HLH underwent induction chemotherapy then proceeded to allogeneic HCT and remains alive 9 months after diagnosis. Amongst 6 patients not meeting HLH criteria, the case fatality rate was 67% with a median survival of 2.3 months. None of these patients were treated with the HLH-94/04 protocol; however, 2 were treated with cyclosporine and remain alive 16 and 24 months after diagnosis. [Display omitted] ConclusionsOf the HLH diagnostic criteria, multiple cytopenias, hyperferritinemia, and hypertriglyceridemia were sensitive measures, whereas hypofibrinogenemia, markedly elevated sIL-2R, and decreased in vitro NK cell function were found in fewer than half of patients. At our institution, EBV-associated HLH predominates (7/17 cases, 41%). Most of the malignancy-associated HLH we have seen also occurred in the context of EBV infection. The case fatality rate amongst all patients with histologic evidence of hemophagocytosis, including those not meeting HLH criteria, is high. In most patients, treatment according to HLH-94/04 may be appropriate and likely improves survival. In our experience with the HLH-94/04 protocol, 60% of patients remain alive. Until sufficient evidence emerges that this treatment strategy leads to durable remissions in the majority of patients, allogeneic HCT should remain a consideration for most patients. DisclosuresNo relevant conflicts of interest to declare.

Early diagnostic value of low percentage of glycosylated ferritin in secondary hemophagocytic lymphohistiocytosis

Elevated levels of serum ferritin and a low percentage of glycosylated ferritin have been reported in adult-onset Still's disease (AOSD) as well as in hemophagocytic lymphohistiocytosis (HLH). The objective of the current study was to investigate total ferritin levels and the percentage of glycosylated ferritin in patients with secondary HLH. From October 2007 to October 2008, 29 patients with suspected HLH older than 14 years of age treated at Beijing Friendship Hospital were enrolled. Twenty-five healthy volunteers were recruited as controls. The suspected HLH patients were further divided into secondary HLH-confirmed (confirmed) (22 out of 29) and HLH-unconfirmed (unconfirmed) (7 out of 29) groups based on HLH-2004 diagnostic criteria. Total serum ferritin levels and the percentage of glycosylated ferritin were determined in subjects at the time of admission. Significantly higher levels of total serum ferritin were observed in confirmed (2,897.6 +/- 1,837.2 microg/L) compared with unconfirmed (653.1 +/- 249.1 microg/L) patients (P < 0.01) or controls (414.6 +/- 212.6 microg/L) (P < 0.01). A significantly lower percentage of glycosylated ferritin was observed in the confirmed (20.5 +/- 10.1%) compared with the unconfirmed (48.7 +/- 12.1%) group (P < 0.01) or the control group (53.6 +/- 13.3%) (P < 0.01). In addition, a low percentage of glycosylated ferritin was observed in HLH patients. Finally, regarding the diagnosis of HLH based on a low percentage of glycosylated ferritin, the sensitivity and specificity, as well as positive and negative predictive values were 0.86, 0.71, 0.91, and 0.63, respectively. For the diagnosis of HLH based on hyperferritinemia, the sensitivity, specificity, positive, and negative predictive values were 0.82, 0.43, 0.82, and 0.43, respectively. The results of this study suggest that a low percentage of glycosylated ferritin is associated with HLH. On comparison with hyperferritinemia, a low percentage of glycosylated ferritin appeared to be more specific, sensitive, and predictive of HLH. In conclusion, a low percentage of glycosylated ferritin may be a useful marker for the early diagnosis of secondary HLH.

Early Diagnosis and Treatment of the Patients with Acquired Hemophagocytic Lymphohistiocytosis

Acquired hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition characterized by uncontroling hyperinflammation on the basis of various infection, tumor and inherited immune deficiency. Awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time. In this study, we reviewed 57 suspected HLH patients from March 2006 to June 2008. 25 healthy subjects were enrolled in the study as control. NK cell activity in peripheral blood was tested by a released LDH assay. Meanwhile, solution interleukin-2 receptor (sCD25) was examined with ELISA double antibody sandwich assay. The level of glycosylated ferritin was also detected and the ratio of glycosylated ferritin to ferritin was determined. 41 out of 57 patients were definitely diagnosed according to HLH-2004 diagnostic criteria in this study and 16 patients were excluded. We found that the level of NK cell activity and the ratio of glycosylated ferritin in the all 41 final diagnozed HLH patients were significantly lower than those in the 16 excluded patients and 25 healthy control subjects (p<0.01). Meanwhile, the level of sCD25 in peripheral blood was much higher in all the 41 HLH patients than that in the excluded and healthy people (p<0.05). We compared the coincidence of each diagnostic index in the 41 HLH patients before and after final diagnosis. It was found that 100% patients had abnormal expression on NK cell activity, sCD25 and glycosylated ferritin in the early disease. The three diagnostic indexes were more sensitive and specific than other indexes, such as fever, hepatosplenomegaly, cytopenia, hyper-triglyceridemia, hypo-fibrinogenemia. 41 diagnosed patients received the regimen containing methylprednisolone and immunoglobulin, with or without fludarabine, 26 out of 41 were markedly improved after treatment, 10 out of 41 were exacerbated, and other 5 patients gave up treatment. It is concluded that detection of NK cell activity, sCD25 and glycosylated ferritin may play a very important role in the early diagnosis of HLH. Our data also suggest that fludarabine combined with methylprednisolone and immunoglobulin (FDIg) may provide a new viewpoint for HLH therapy.

Study on Treatment of Lymphoma-Associated Hemophagocytic Syndrome with Fludarabine Combined with Methylprednisolone and Globulin

Hemophagocytic syndrome (HPS) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Lymphoma-associated hemophagocytic syndrome (LAHS) clinically featured by histiocytic proliferation, fever, hepatosplenomegaly, cytopenia, deranged liver function and frequent coagulopathy. The immediate aim of therapy in LAHS is suppression of the severe hyperinflammation, which can be achieved with immunosuppressive/immunomodulatary agents and cytostatic drugs. In this study, we diagnosed 11 cases of LAHS according to HLH-2004 diagnostic criteria in Beijing Friendship Hospital during the period from June 2005 to Jan 2008, and collected informations about the patients with LAHS: primary diseases, manifestions, laboratory findings and survival. 2 cases large B cell lymphoma, 1 case mantle lymphoma, 4 cases extranodal NK/T cell lymphoma, 3 cases peripheral T cell lymphoma and 1 case angioimmunoblastic T-cell lymphoma were included in this research. The median age was 49 years, and the range was 33–74 years. 7 out of 11 were female and 4 were male. All the 11 patients received regimens containing fludarabine (25mg/m2/d, d1–5), methylprednisolone (2mg/kg/d, d1–14, 1mg/kg/d, d15–28) and immunoglobulin (0.5g/kg/d, d1–14) after finally diagnosed. 7 of the 11 patients were markedly improved after treatment and then received lymphoma chemotherapy. The median survival time had reached to 1.4 year. The other 4 aggravated. This outcome was much better than what A-Reum Han had reported (Ann Hematol 2007; 86: 493–498). It suggests that fludarabine will be a promising agent in the therapy of LAHS.