Hemophagocytic Lymphohistiocytosis Syndrome Research Articles

Secondary Hemophagocytic Lymphohistiocytosis: Do We Really Need Chemotherapeutics for All Patients?

Because of the acute and life-threatening course of the hemophagocytic lymphohistiocytosis (HLH) syndrome, International Histiocyte Society guidelines recommend chemoimmune therapy for the treatment of both primary and secondary HLH (sHLH). To manage children with sHLH, instead of HLH-2004 protocol we considered less immunosuppressive/cytotoxic approach. We assessed 12 children who fulfilled the diagnostic criteria for sHLH between January 2009 and March 2015. Multivariate Cox regression analysis showed that ferritin levels (hazard ratio=1.02, P=0.006), pediatric logistic organ dysfunction scores (hazard ratio=1.01, P=0.001) were the predictors of the survival. The hospital survival was 83% for patients with sHLH who were treated with less immunosuppressive therapy. In conclusion initiation of HLH-specific therapy for the patients with hyperferritinemia-associated sHLH should be delayed while awaiting resolution of systemic inflammation with less immunosuppressive therapy.

Secondary hemophagocytic lymphohistiocytosis syndrome in adults: A case series and review of the literature

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening condition characterized by immune dysregulation and benign proliferation of phagocytic cells, macrophages, and histiocytes. Lymphocytes (CD8 T-cells and natural killer cells) also play a major role in HLH. The ensuing cytokine storm and blood cells phagocytosis can lead to fatal multiple organ failure. So any diseases that can lead to activation of these cytokines can lead to hemophagocytic syndrome. 5 adult patients presented to Dr. Soliman Fakeeh Hospital, Jeddah, Saudi Arabia during 2014–2016 and fulfill the diagnostic criteria of HLH according to HLH-2004 diagnostic and therapeutic guidelines for HLH , have been included in this case series. Two out of five had viral infection, one patient was diagnosed with tuberculosis, and one patient developed secondary HLH in due to malignancy. The fifth patient did not have an identiable etiology. All of our patients presented with different symptoms and were diagnosed based on the standard approved criteria. Only two Out of five patients survived and remained disease free for a follow-up period of 24 months. As a conclusion, HLH syndrome is a rare condition with a high mortality rate. Aggressive treatment approach and early Intensive Care Unit admission is strongly recommended in patients with the cardinal diagnostic features of this condition.

The Use of Ferritin to Identify Critically Ill Patients With Secondary Hemophagocytic Lymphohistiocytosis.

Thrombocytopenia is a common, multifactorial, finding in ICU. Hemophagocytosis is one of the main explanatory mechanisms, possibly integrated into hemophagocytic lymphohistiocytosis syndrome, of infectious origin in the majority of cases in ICU. The hemophagocytic lymphohistiocytosis is probably underdiagnosed in the ICU, although it is associated with dramatic outcomes. The main objectives of this work were to identify the frequency of secondary hemophagocytic lymphohistiocytosis, and the main prognostic factors for mortality. We conducted a retrospective observational study in all adult patients admitted with suspected or diagnosed hemophagocytic lymphohistiocytosis, between January 1, 2000, and August 22, 2012. A total of 106 patients (42%) had significant hemophagocytosis on bone marrow examination, performed for exploration of thrombocytopenia, bicytopenia, or pancytopenia. The median age was 56 (45-68) and the median Simplified Acute Physiology Score 2 was 55 (38-68). The main reason for ICU admission was hemodynamic instability (58%), predominantly related to sepsis (45% cases). The main precipitating factor found was a bacterial infection in 81 of 106 patients (76%), including 32 (30%) with Escherichia coli infection. Forty six of 106 patients (43%) died in the ICU. They were significantly older, had higher Simplified Acute Physiology Score 2, plasma lactate deshydrogenase bilirubin, and serum ferritin. The fibrinogen and the percentage of megakaryocytes were significantly lower in nonsurvivors when compared with survivors. In multivariate analysis, only serum ferritin significantly predicted death related to hemophagocytosis. A serum ferritin greater than 2,000 μg/L predicted death with a sensitivity of 71% and a specificity of 76%. A decreased percentage of megakaryocytes also predicted patient death in the ICU. Hemophagocytosis is common in thrombocytopenic patients with sepsis, frequently included in a postinfectious hemophagocytic lymphohistiocytosis setting. Our study reveals that ferritin could be a reliable prognostic marker in these patients, and hold particular interest in discussing a specific treatment for hemophagocytic lymphohistiocytosis.

Extracorporeal Membrane Oxygenation for Hemophagocytic Lymphohistiocytosis

Patient: Male, 21Final Diagnosis: Hemophagocytic LymphohistiocytosisSymptoms: Acute respiratory insufficiency • anemia • thrombocytopeniaMedication: —Clinical Procedure: Extracorporeal membrane oxygenationSpecialty: HematologyObjective:Rare diseaseBackground:Hemophagocytic lymphohistiocytosis (HLH) is a rare hematological disease characterized by an excessive inflammatory response to various triggers, resulting in rapid multi-organ failure. Its incidence may be underestimated due to its rarity, its variable clinical presentation, and its high mortality rate prior to diagnosis. Oftentimes, HLH is mistaken for refractory sepsis and improperly treated as such. Left untreated, the disease is universally fatal. With treatment, case series of adults with HLH report a 30-day mortality of up to 44% and an overall mortality of up to 75%.Case Report:We describe the use of extracorporeal membrane oxygenation (ECMO) in a previously healthy young man with HLH and acute respiratory distress syndrome (ARDS), a common sequela of HLH. ECMO was employed to provide temporary hemodynamic support, allowing for recovery of pulmonary function compromised during the initial cytokine storm. Additionally, and perhaps more importantly, implementation of ECMO provided the time necessary for the eventual diagnosis and treatment of HLH.Conclusions:Although limited case reports and case series suggest that the use of ECMO in pediatric patients with HLH is associated with high mortality, our experience suggests that ECMO should not be rejected as a supportive modality in adults with HLH who have potentially recoverable cardiopulmonary function. We believe that ECMO may be appropriately instituted in select patients with HLH, or in rapidly deteriorating patients with an unknown illness refractory to conventional therapy, to allow for end-organ recovery, to reach a diagnosis, and to administer appropriate therapy.

Hemophagocytic lymphohistiocytosis responding to withdrawal of gluten: a case report.

BackgroundThis is the first documented case of a patient with hemophagocytic lymphohistiocytosis in association with coeliac disease. There was complete clinical and biochemical remission of hemophagocytic lymphohistiocytosis following the introduction of a gluten-free diet.Case presentationA 7-year-old white girl presented with fevers and maculopapular rash with a recent history of tonsillitis. Blood tests revealed thrombocytopenia (64×109/L), anemia (80 g/L), hypofibrinogenemia (1 g/L), and hyperferritinemia (71,378 μg/L). A bone marrow revealed evidence of hemophagocytosis, but the results of tests for the genetic or familial-associated hemophagocytic lymphohistiocytosis syndromes were negative. The results of screening tests for known secondary causes were negative. She was diagnosed as having hemophagocytic lymphohistiocytosis and following treatment with the hemophagocytic lymphohistiocytosis-2004 protocol these symptoms, in addition to the biochemical and hematological markers, completely resolved.She presented again 10 months later with fever, rash, and biochemical abnormalities suggestive of hemophagocytic lymphohistiocytosis. Her tissue transglutaminase was markedly raised and the results of blood tests revealed a genetic susceptibly to coeliac disease in the form of HLA-DQ2 positivity. She commenced a gluten-free diet and there was complete symptomatic and biochemical response without any further chemotherapy. She had further episodic rashes, each associated with the accidental intake of gluten.ConclusionsThis is to the best of our knowledge the first documented case of hemophagocytic lymphohistiocytosis in association with coeliac disease. No other secondary cause found; she initially responded to chemoimmunotherapy specific for hemophagocytic lymphohistiocytosis but relapsed within a few months of cessation of treatment and then achieved complete remission on gluten withdrawal alone.

Human monocytic ehrlichiosis complicated by hemophagocytic lymphohistiocytosis and multi-organ dysfunction syndrome

Human monocytic ehrlichiosis can manifest as a disease causing multi-organ failure. Rarely, it can cause secondary hemophagocytic lymphohistiocytosis (HLH). Early diagnosis and initiation of treatment for both ehrlichiosis and HLH is lifesaving. Therefore, clinical suspicion of HLH must remain high in the setting of an ehrlichiosis infection.

Rare Presentation of Epstein Barr Virus

Two rare complication of infection with the Epstein-Barr virus is the development of hemophagocytic Lymphohistiocytosis and opsoclonus myoclonus syndrome. Here we are describing two cases which are describing these complications of Epstein-Barr virus infection. As they mimic several other condition but a strong suspicion is needed to diagnose these rare complications early as it will help us to reduce morbidity and mortality of these complications.J Nepal Paediatr Soc 2015;35(3):290-292

Prolonged Hemophagocytic lymphohistiocytosis syndrome as an initial presentation of salmonella infection

Prolonged Hemophagocytic lymphohistiocytosis syndrome as an initial presentation of salmonella infection

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.

Whole-Exome Sequencing Reveals Mutations in Genes Linked to Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome in Fatal Cases of H1N1 Influenza.

Severe H1N1 influenza can be lethal in otherwise healthy individuals and can have features of reactive hemophagocytic lymphohistiocytosis (HLH). HLH is associated with mutations in lymphocyte cytolytic pathway genes, which have not been previously explored in H1N1 influenza. Sixteen cases of fatal influenza A(H1N1) infection, 81% with histopathologic hemophagocytosis, were identified and analyzed for clinical and laboratory features of HLH, using modified HLH-2004 and macrophage activation syndrome (MAS) criteria. Fourteen specimens were subject to whole-exome sequencing. Sequence alignment and variant filtering detected HLH gene mutations and potential disease-causing variants. Cytolytic function of the PRF1 p.A91V mutation was tested in lentiviral-transduced NK-92 natural killer (NK) cells. Despite several lacking variables, cases of influenza A(H1N1) infection met 44% and 81% of modified HLH-2004 and MAS criteria, respectively. Five subjects (36%) carried one of 3 heterozygous LYST mutations, 2 of whom also possessed the p.A91V PRF1 mutation, which was shown to decrease NK cell cytolytic function. Several patients also carried rare variants in other genes previously observed in MAS. This cohort of fatal influenza A(H1N1) infections confirms the presence of hemophagocytosis and HLH pathology. Moreover, the high percentage of HLH gene mutations suggests they are risk factors for mortality among individuals with influenza A(H1N1) infection.

Etiologies and Short-Term Mortality in Patients with Ultraelevated Serum Ferritin.

Hyperferritinemia is common in states of iron overload, inflammation, and malignancy. There is evidence that higher ferritin levels may be associated with worse outcomes in several clinical conditions. Available data have been drawn primarily from cases of serum ferritin between 1000 and 5000 ng/mL and from relatively few cases of serum ferritin >5000 ng/mL. In addition, most studies have allowed for the assignment of only a single etiology per case of hyperferritinemia, when many cases may result from a combination of multiple etiologies. This study evaluates the distribution of etiologies and short-term mortality in patients with ultrahyperferritinemia (defined as a serum ferritin concentration >5000 ng/mL). We retrospectively identified 405 patients older than 18 years who had serum ferritin concentrations >5000 ng/mL measured within the Geisinger Health System between 2004 and 2014. For each patient, we evaluated demographics, serum ferritin concentration, contributing etiologies, and mortality at 30 days and 6 months following index serum ferritin measurement. Ultrahyperferritinemia was caused by a combination of multiple etiologies in 51% of cases, a single etiology in 44% of cases, and an undetermined etiology in 5% of cases. The majority of all cases were the result, at least in part, of chronic blood transfusions (48%), acute liver injury (44%), malignancy (33%), myelodysplastic syndrome (11%), or end-stage renal disease (ESRD;10%). Acute liver injury accounted for the majority of cases (73%) of ultrahyperferritinemia caused by a single etiology, whereas neither myelodysplastic syndrome nor ESRD was the sole etiology for a single case. Hemophagocytic lymphohistiocytosis and macrophage activation syndrome were associated with the highest mean serum ferritin levels by far, but acute liver injury remained the most common cause of single-etiology cases across all ferritin levels and accounted for 92% of cases >20,000 ng/mL. Mortality increased substantially between 30 days and 6 months for patients with ultrahyperferritinemia caused by malignancy (from 64% to 93%) but only modestly for patients with ultrahyperferritinemia caused by acute liver injury (from 33% to 39%). Many cases of ultrahyperferritinemia are caused by a combination of multiple distinct etiologies. Cases of ultrahyperferritinemia among patients with ESRD and myelodysplastic syndrome may be partially explained by their often concomitant chronic blood transfusions. Acute liver injury is by far the most common cause of ultrahyperferritinemia caused by a single etiology, even at the most astronomically elevated serum ferritin concentrations. Finally, patients with ultrahyperferritinemia caused by malignancy appear to have poor 30-day survival and abysmal 6-month survival.

Management of the critically ill child with the sepsis/hemophagocytic lymphohistiocytosis/macrophage activation syndrome overlap syndrome.

Hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) is a frequently fatal disease, which can result in end-organ damage and death. This condition shares features with sepsis and systemic inflammatory response syndrome. Making a diagnosis of HLH can be challenging since most of the clinical and laboratory features of HLH are quite nonspecific. Timely diagnosis is critical to start therapy before damage by hypercytokinemia becomes irreversible. The treatment for patients with suspected acquired HLH/sepsis/systemic inflammatory response syndrome/multi organ dysfunction syndrome/ MAS overlap syndrome should be guided primarily by the severity of signs and symptoms, age of the patient, and underlying conditions. It is critical that the risks of treatment or non-treatment be weighed according to the clinical presentation of each patient. In this article, the authors discuss the diagnostic similarities between sepsis/HLH/MAS and management of the critically ill child with sepsis/HLH/MAS overlap syndrome.

Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion

AbstractFamilial hemophagocytic lymphohistiocytosis (F-HLH) and Griscelli syndrome type 2 (GS) are life-threatening immunodeficiencies characterized by impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell lytic activity. In the majority of cases, these disorders are caused by biallelic inactivating germline mutations in genes such as RAB27A (GS) and PRF1, UNC13D, STX11, and STXBP2 (F-HLH). Although monoallelic (ie, heterozygous) mutations have been identified in certain patients, the clinical significance and molecular mechanisms by which these mutations influence CTL and NK cell function remain poorly understood. Here, we characterize 2 novel monoallelic hemophagocytic lymphohistiocytosis (HLH)-associated mutations affecting codon 65 of STXPB2, the gene encoding Munc18-2, a member of the SEC/MUNC18 family. Unlike previously described Munc18-2 mutants, Munc18-2R65Q and Munc18-2R65W retain the ability to interact with and stabilize syntaxin 11. However, presence of Munc18-2R65Q/W in patient-derived lymphocytes and forced expression in control CTLs and NK cells diminishes degranulation and cytotoxic activity. Mechanistic studies reveal that mutations affecting R65 hinder membrane fusion in vitro by arresting the late steps of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-complex assembly. Collectively, these results reveal a direct role for SEC/MUNC18 proteins in promoting SNARE-complex assembly in vivo and suggest that STXBP2 R65 mutations operate in a novel dominant-negative fashion to impair lytic granule fusion and contribute to HLH.

Ebola Virus Disease has Features of Hemophagocytic Lymphohistiocytosis Syndrome.

The 2014 epidemic of Ebola virus disease (EVD) in several West African countries has mortality rates of up to 70%, as reported by WHO. The exponential increase in the number of infections and deaths, coupled with the absence of specific preventive and therapeutic strategies, represents one of the biggest global health challenges of this millenium. Insights in the pathophysiology and treatment of EVD are thus urgently needed. In this paper, we postulate that EVD has the characteristics of hemophagocytic lymphohistiocytosis (HLH) syndrome (syn., macrophage activation syndrome). The identification of HLH as part of severe EVD, however, brings the possibility for a pathophysiologically targeted approach of therapy; special promise is represented by cytokine-directed therapy in the form of recombinant interleukin-1 receptor antagonist (anakinra). Treatment with anakinra has the advantage to interrupt the deleterious IL-1-mediated hyperinflammatory loop in macrophage activation syndrome, and it has been shown to be associated with remarkable effectiveness and an excellent safety record.

Hemophagocytic lymphohistiocytosis syndrome in dengue hemorrhagic Fever: authors' reply.

To the Editor: This is in reply to the letter by B. Joob and V. Wiwanitkit on our study entitled “Hemophagocytic lymphohistiocytosis syndrome in dengue hemorrhagic fever” [1]. HLH is a life-threatening complication with variable clinical presentation [2] and is secondary to infections (viral, bacterial, fungal or protozoan) in tropical countries. In an Indian report by Ramachandran et al., dengue was reported as the leading cause for HLH [3]. Veerakul et al. also reported a similar experience [4]. Persistence of fever beyond 7–8 d in dengue is usually due to secondary sepsis or dengue associated HLH. In our study, all 23 children presented with fever of more than 8 d, malena in 86.95 %, organomegaly in all children, progressive cytopenias and abnormal chemistry, namely triglyceride, fibrinogen and ferritin. All children admitted to the intensive units had blood and urine cultures done as a routine and only those children who did not have bacterial growth in both were taken for the study. That excludes children with sepsis. In areas where dengue is endemic, the awareness of dengue-associated HLH as a cause of fatality, needs to be highlighted as its course is similar to severe dengue and sepsis induced multi organ dysfunction, but responds well to steroids and IV immunoglobulin.

Renal Involvement in a French Paediatric Cohort of Patients with Lysinuric Protein Intolerance.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive metabolic disorder, caused by defective transport of cationic amino acids at the basolateral membrane of epithelial cells, typically in intestines and kidneys. The SLC7A7 gene, mutated in LPI patients, encodes the light subunit (y+LAT1) of a member of the heterodimeric amino acid transporter family.The diagnosis of LPI is difficult due to unspecific clinical features: protein intolerance, failure to thrive and vomiting after weaning. Later on, patients may present delayed growth osteoporosis, hepatosplenomegaly, muscle hypotonia and life-threatening complications such as alveolar proteinosis, haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Renal involvement is also a serious complication with tubular and more rarely, glomerular lesions that may lead to end-stage kidney disease (ESKD). We report six cases of LPI followed in three different French paediatric centres who presented LPI-related nephropathy during childhood. Four of them developed chronic kidney disease during follow-up, including one with ESKD. Five developed chronic tubulopathies and one a chronic glomerulonephritis. A histological pattern of membranoproliferative glomerulonephritis was first associated with a polyclonal immunoglobulin deposition, treated by immunosuppressive therapy. He then required a second kidney biopsy after a relapse of the nephrotic syndrome; the immunoglobulin deposition was then monoclonal (IgG1 kappa). This is the first observation of an evolution from a polyclonal to a monotypic immune glomerulonephritis. Immune dysfunction potentially attributable to nitric oxide overproduction secondary to arginine intracellular trapping is a debated complication in LPI. Our results suggest all LPI patients should be monitored for renal disease regularly.

Hemophagocytic lymphohistiocytosis syndrome associated with Gaucher disease type 2.

To the Editor, We present the case of a 5.5-month-old female infant hospitalized because of fever, lethargy, pallor, poor feeding, convulsion, and developmental delay. She was the first child of the family and her parents were relatives. Physical examination revealed hepatosplenomegaly, opisthotonus, and pitting edema. Laboratory studies showed pancytopenia (WBC: 3500/mm3, Hb: 6 g/dL, Plt: 40.000/mm3), coagulopathy (PT: 19.4 s, aPTT: 41 s, fibrin degradation products: 1.8 mg/mL, D-dimer: 4 mg/L), AST of 132 U/L, ALT of 107 U/L, ALP of 313 U/L, triglycerides of 280 mg/ dL, and albumin of 2.7 g/dL. Analysis of the cerebrospinal fluid (CSF) revealed lymphocytic pleocytosis. Serum ferritin level was 1020 ng/mL and fibrinogen level was 150 mg/dL. Other test results, including renal function tests, electrolytes, serum and urine amino acid chromatography, TORCH study, and virology studies (HIV, HCV, HBV, HAV, EBV), were normal. Blood, urine, stool, CSF, and bone marrow cultures were all negative. Bone marrow examination revealed hemophagocytosis caused by macrophages (Figure 1). It also showed an increase in the number of histiocytic cells, which was not typical of Gaucher disease. However, dried blood spot testing showed a drastic reduction of 8.45 pmol/ spot (normal range: 200-2000 pmol/spot in 20 h) in the betaglucosidase enzyme activity and confirmed the diagnosis of Gaucher disease. Since 6 of the 8 criteria of hemophagocytic lymphohistiocytosis (HLH) syndrome were observed in the patient, she was subjected to treatment with the HLH 2004 Protocol [2], broad-spectrum antibiotics, and anticonvulsant drugs while supportive measures were also taken. Despite the aforementioned efforts, the patient’s clinical condition gradually worsened and she died 10 days after the beginning of the treatment. It was not possible to study the mutations associated with primary HLH or to measure the level of sIL2R and the activity of NK cells. Informed consent was obtained.

La actividad citotóxica de las células natural killer como herramienta diagnóstica en pacientes pediátricos críticos con sospecha de síndrome hemofagocítico

AimTo determine the role of natural killer (NK) cytotoxic activity in patients with suspected hemophagocytic lymphohistiocytosis syndrome (HLH). DesignA prospective study was conducted from September 2008 to February 2014. ScopeThe study was carried out in the Hematological Oncology Laboratory of Hospital Infantil Universitario Niño Jesús, Madrid (Spain). PatientsWe analyzed 30 peripheral blood samples from intensive care patients with suspected HLH. There were 18 males and 12 females, with a mean age of 4.7 years (range 0.2-22). NK cell cytotoxicity was compared with healthy controls according to age and sex. InterventionIn vitro NK cell cytotoxicity against the K562 cell line was determined by time-resolved fluorescence (Europium-TDA) under resting conditions, after interleukin 15 stimulation, and following block with Fas ligand antibody. Variable of interestNK cell cytotoxicity. ResultsA total of 20 patients showed a significant decrease of NK cell activity compared with controls (P=.001). Nine of these patients were diagnosed with primary HLH. A total of 10 patients were diagnosed with secondary HLH. Cytotoxic activity was normal in 10 subjects. None of them were diagnosed with HLH. Interleukin 15 stimulation increased NK cell cytotoxicity in secondary HLH, and blocking Fas ligand on NK cells decreased cytotoxic activity in primary HLH patients (P=.001). ConclusionsIn our experience, NK cell cytotoxic activity measured by time-resolved fluorescence is a simple and useful clinical diagnostic test for HLH. Interleukin 15 stimulation and Fas ligand blocking on NK cells could help differentiate between primary and secondary HLH.

Commentary

Commentary

Hemophagocytic lymphohistiocytosis syndrome in Dengue hemorrhagic fever.

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening florid activation of macrophages of the lymphoreticular system. It is reported to be associated with dengue in children in India and carries a high mortality. Patients present with high fever, worsening blood cell counts, splenomegaly, abnormal liver enzymes with features of liver failure, coagulopathy and neurological complications. The diagnosis is according to "Diagnostic Guidelines for HLH 2004", based on a triad of clinical, blood parameters and bone marrow cytology. In the present study, data of 212 children admitted with dengue were analyzed. Of 212 children, 31 children were classified as suspect HLH and advised bone marrow evaluation; of whom 23 children had marrow evidence of HLH. Worsening of blood cell counts were recorded in all children with a mean platelet count of 58,303.03 cells/cumm, low hematocrit in 95.65%, low mean hemoglobin level of 8.37g/dL, high erythrocyte sedimentation rate (ESR) and prolonged pro-thrombin time/international normalization ratio (PT/INR). Serum triglycerides, ferritin and transaminases were high. Of the 23 children, 19 patients received intravenous immunoglobulin (IVIG) and all of these children recovered. Dengue with multi-organ dysfunction is commonly concurrent to HLH in the marrow and hence, an early diagnosis based on clinical, laboratory and bone marrow evaluation is significant. A bone marrow evaluation confirms the diagnosis of HLH.