Diagnosis Of Hemophagocytic Syndrome Research Articles

New mutations and new phenotypes: a case of Major Histocompatibility Complex Class II Deficiency.

Major Histocompatibility Complex Class II Deficiency is a rare primary immunodeficiency disease with autosomal recessive inheritance. It is characterized by the absence of Major Histocompatibility Complex Class II molecules on the surface of immune cells. In this article, we will present a four-month-old baby girl who presented with recurrent fever and progressive exacerbation of respiratory symptoms since a month ago. Relevant examinations suggested pancytopenia, a decrease in CD4 and CD3 ratio, and CD4/CD8 inversion, hypogammaglobulinemia, and diagnosis of hemophagocytic syndrome during treatment which all led to the consideration of the presence of immunodeficiency diseases, and the diagnosis of Major Histocompatibility Complex Class II Deficiency was made by peripheral blood whole-exon sequencing (WES). This case is remarkable in that it reveals features of hemophagocytic syndrome in a Major Histocompatibility Complex Class II Deficiency infant, most probably caused by cytomegalovirus, which rarely reported before, and the Major Histocompatibility Complex Class II Deficiency caused by a novel mutation site in the RFXANK gene which never reported, and it also describes the diagnostic and therapeutic course in detail. In addition, we have summarized the information related to Major Histocompatibility Complex Class II Deficiency triggered by mutations in the RFXANK gene to assist clinicians in early recognition and diagnosis.

Renal involvement as a unique manifestation of hemophagocytic syndrome.

Renal-limited hemophagocytic syndrome (HPS) is a rare clinical setting characterized by abnormal activation of the immune system. Fever associated with pancytopenia, hepatosplenomegaly with liver dysfunction, and hypofibrinogenemia are usually observed in HPS. From a histological level, the presence of non-malignant macrophages infiltrating bone marrow and organs represents the hallmark of this condition. Non-malignant macrophages are associated with phagocytizing activities involving other blood cells. While primary HPS is usually associated with inherited dysregulation of the immune system, secondary HPS usually occurs in the context of infection or is linked to a neoplastic process. Clinical presentation varies and can potentially lead to life-threatening settings. While renal involvement has frequently been reported, however, detailed descriptions of the kidney manifestations of HPS are lacking. More critically, the diagnosis of HPS is rarely supported by renal biopsy specimens. We report four rare cases of biopsy-proven renal-limited HPS in patients presenting with acute kidney injury (AKI). The available evidence on this topic is critically discussed in light of the possible emergence of an autonomous entity characterized by an isolated kidney involvement.

Severe Visceral Leishmaniasis Associated With COVID-19 and Complicated by Hemophagocytic Syndrome.

To the Editors: Visceral leishmaniasis (VL) is a parasitic infectious disease that mainly affects children. if neglected the disease could become systemic.1 Coronavirus disease 2019 (COVID-19) is a viral disease that could complicate the management of several infectious diseases in different regions worldwide.2 Managing severe pediatric VL associated with COVID-19 and complicated by hemophagocytic syndrome (HPS) as well as finding an efficient therapeutic protocol to reduce mortality is a challenge. VL associated with HPS and COVID-19 have not been reported previously; therefore, a report of a case with a favorable outcome is extremely important. We present the case of a pediatric patient with VL complicated with HPS and associated with COVID-19. A 9-month-old infant, female, living in the northeastern region of Brazil was admitted caused by intermittent fever, vomiting after feedings, weight loss, and abdominal distention. Further investigations revealed pancytopenia with severe neutropenia and anemia, hypoalbuminemia, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high ferritin level, and urosepsis. Chest radiography showed diffuse perihilar infiltrates. A myelogram revealed numerous isolated forms of Leishmania sp. and hemophagocytosis figures. After severity score testing, the patient was diagnosed with severe VL complicated by HPS, and was treated with liposomal amphotericin B, corticoid, and human immunoglobulin. The patient developed acute respiratory failure, and reverse-transcriptase polymerase chain reaction (RT-PCR) for COVID-19 tested positive. The patient subsequently developed a renal injury, septic shock and coagulopathy, and required pediatric intensive care with invasive ventilation, peritoneal dialysis, vasoactive drugs and blood products. After 13 days of intensive care, clinical improvement was observed and the patient was transferred to the ward. The patient’s general clinical status improved; hence, the patient was discharged and followed up as an outpatient with favorable outcomes (Figure 1).FIGURE 1.: Diagram showing how the combination of Leishmania and SARS-CoV-2 led to HPS. HPS indicates hemophagocytic syndrome.HPS associated with VL is well known.1 The uniqueness of this case report is the pulmonary involvement of COVID-19, which increased its severity. Further, liposomal amphotericin B treatment was extended to 14 doses because of persistent clinical and laboratory signs of VL and symptoms of COVID-19; however, the Brazilian protocol prescribes 7 doses. VL is an immune-mediated disease that mainly affects children caused by their immature cell-mediated immunity. The amastigotes of the parasite multiply inside macrophages and subsequently spread through the blood to the lymph nodes, liver, spleen and bone marrow. This leads to uncontrolled activation of T lymphocytes, natural killer cells and macrophages, and could increase the levels of proinflammatory cytokines and lead to HPS.3 Generally, the clinical features of VL overlap with those of HPS. Regarding the COVID-19/HPS association, the immune syndrome induced by COVID-19 is not yet fully understood; however, the presence of an inflammatory response is certain.4 Another condition that is associated with COVID-19 is pediatric multisystemic inflammatory syndrome, which presents with inflammatory response with clinical and laboratory changes that can mimic HPS.5 Delayed diagnosis of HPS associated with VL, probably because of clinical similarities, may result in severe complications and death in up to 90% of untreated cases.6 The association of VL, HPS and COVID-19 have not been described in the literature; therefore, dissemination of this case report is fundamental, as it highlights the importance of therapeutic, clinical and epidemiological management.

Differential Diagnosis of Hemophagocytic Syndrome by 18F-FDG PET/CT: A Meta-Analysis.

Hemophagocytic syndrome (HPS) is a rare disease in clinical practice, and there are often cases of delayed diagnosis. At present, researchers have applied 18F-FDG PET/CT in the differential diagnosis of HPS, but no consensus has been formed. Therefore, this study aims to systematically evaluate the application value of 18F-FDG PET/CT in the diagnosis of HPS patients. PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Wangfang database (Wangfang), and Chinese Biomedical Network (CBM) were searched to collect the relevant studies of 18F-FDG PET/CT in the diagnosis of HPS. Data from the articles were screened and extracted for meta-analysis using Stata16.0 software. A total of 10 retrospective studies, including 300 patients, were included in this meta-analysis. The meta-analysis results showed that the pooled sensitivity was 0.82 (95% CI: 0.67–0.95), specificity was 0.72 (95% CI: 0.51–0.86), positive likelihood ratio was 2.89 (95% CI: 1.46–5.75), positive likelihood ratio was 0.25 (95% CI: 0.12–0.54), diagnostic odds ratio was 2.89 (95% CI: 1.46–5.75), and AUC was 0.84 (95% CI: 0.81–0.87). The SUVmax in the liver, spleen, lymph nodes, and bone marrow of HPS patients was greater than 2.5, and the SUVmax in the spleen, lymph nodes, and bone marrow of malignant HPS patients was higher than that of benign HPS patients. The difference was statistically significant (P < 0.05). According to the existing literature evidence, 18F-FDG PET/CT is an effective method for diagnosing HPS.

Diagnostic Performance of Hemophagocytic Lymphohistiocytosis Criteria and HScore in Critically Ill Patients With Severe Hemophagocytic Syndrome.

To assess whether critically ill hematologic patients without diagnosis of hemophagocytic lymphohistiocytosis may have features mimicking hemophagocytic lymphohistiocytosis according to both diagnostic scores. A retrospective case-control study. Hemophagocytic syndrome diagnosis was standardized and based on a consensual diagnosis by at least two experts of a university hospital which is a reference center for hemophagocytic syndrome. Cases (hemophagocytic syndrome+) consisted in a group of consecutive patients (n = 150) admitted in our ICU between 2007 and 2018. Control group (hemophagocytic syndrome-) consisted in patients included in a prospective multicenter cohort of hematologic patients in whom three independent experts ruled out the diagnosis of hemophagocytic syndrome (n = 1011). Overall, 1,161 patients were included. Hospital mortality was 45.8% in hemophagocytic syndrome- patients (n = 66) and 38.8% in control patients (n = 392; p = 0.126). Median HScore was 235 (205-262) in hemophagocytic syndrome+ and 42 (18-62) in hemophagocytic syndrome- patients (p < 0.001); number of hemophagocytic lymphohistiocytosis criteria was 4 (4-5) vs 1 (0-1), respectively (p < 0.001). Diagnostic performances of both scores were excellent with area under receiver operating characteristic curve of 0.99 (95% CI, 0.99-0.99) and 0.99 (95% CI, 0.99-0.99) for hemophagocytic lymphohistiocytosis and HScore, respectively. After propensity score matching (n = 144 × 2), the median HScore was 234 (205-262) in hemophagocytic syndrome+ patients versus 49 (18-71) in hemophagocytic syndrome- patients (p < 0.001). Median number of hemophagocytic lymphohistiocytosis criteria was 4 (4-5) in hemophagocytic syndrome+ and 1 (0-1) in hemophagocytic syndrome- patients (p < 0.001). Area under receiver operating characteristic curve was then of 0.98 (95% CI, 0.96-0.99) for hemophagocytic lymphohistiocytosis criteria and 0.99 (95% CI, 0.99-1) for HScore. In ICU patients, several conditions share some similarities with hemophagocytic syndrome, explaining the poor predictive value of isolated biological markers such as ferritin level. Despite these potential confounding factors, our study suggests HScore and hemophagocytic lymphohistiocytosis criteria to be highly discriminant identifying hemophagocytic syndrome in critically ill patients.

Hemophagocytic Syndrome Secondary to Cytomegalovirus Infection in a Patient with Human Immunodeficiency Virus

Hemophagocytic Syndrome (HPS) or Hemophagocytic Lymphohistiocytosis is characterized by a dysregulation of the immune system with activation of macrophages and T lymphocytes, the product of an uncontrollable and excessive inflammatory response to different stimuli. The case of a patient with a history of Human Immunodeficiency Virus (HIV) under current treatment is presented, a clinical picture of 10 days of evolution characterized by fever, anorexia and asthenia, on physical examination skin-mucosa paleness, dehydration, generalized lymphadenopathy, hepatosplenomegaly. Paraclinical tests are performed suggesting reactivation of infection by Cytomegalovirus (CMV), in addition, during its in-hospital evolution, marked pancytopenia is evidenced, with elevated ferritin values, a bone marrow biopsy is performed, observing proliferation of Histiocytes, the patient meets the diagnostic criteria for HPS proposed by the Histiocyte Society in 2004, treatment was instituted, however it presented a torpid evolution and reached death. It is concluded that the diagnosis of HPS is complex; it is usually overlapped by the underlying diseases, as is the case of this HIV patient with reactivation of CMV infection; both viruses by themselves are related to HPS; therefore, knowledge of the clinical and laboratory criteria of this entity is necessary to make an early diagnosis and establish timely treatment, thus reducing mortality.

Hemophagocytic syndrome in patients infected with the human immunodeficiency virus: A study of 15 consecutive patients.

ABSTRACTObjectivesHemophagocytic syndrome (HPS) is characterized by various clinical and biological data derived from cytokine hyperproduction and cell proliferation. The objectives of this study were to evaluate the epidemiological, etiological, clinical and evolutionary characteristics of patients diagnosed with hemophagocytic syndrome and HIV infection, as well as their comparison with data from the literature.Methods-A retrospective descriptive observational study was performed, including all adult patients with a diagnosis of HPS and HIV infection treated in the Infectious Diseases and Tropical Medicine Unit of the Hospital Universitario Insular, Las Palmas, Gran Canaria from June 1, 1998 to December 31, 2018.ResultsAn analysis of this series of case reports of 15 patients showed a higher percentage of males than females, with a mean age of 42 years. With respect to the diagnostic criteria for HPS, presence of fever, cytopenias and hyperferritinemia were a constant in all patients. Clinical neurological manifestations were frequent and clinical respiratory signs and symptoms absent. HPS was confirmed in some patients who were not severely immune-depressed and had undetectable viral loads. Furthermore, 40% of cases were not receiving ART. The most frequent triggering causes of HPS were viral, especially HHV-8. In addition, two new HPS triggers were identified: Blastocystis dermatitidis and Mycobacterium chelonae.ConclusionAdministration of treatment in HPS is arbitrary. This, together with the high mortality rate and the fact that it is underdiagnosed, indicates the importance of conducting future studies.

Reactive Hemophagocytic Syndrome after Hematopoietic Stem Cell Transplantation: A Multicenter Retrospective Study on Behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)

▪Reactive hemophagocytic syndrome (HS) is a rare but serious complication that may occur after both autologous and allogeneic hematopoietic stem cells transplantation (HSCT). Our knowledge of this post-HSCT complication mainly derives from single reports or small series and only about sixty cases have been reported in the literature so far. We present here the results of a multicenter retrospective study, performed on behalfof the SFGM-TC, including adult (>16 years) HSCT recipients transplanted in France, Switzerland or Stockholm (Sweden) and diagnosed with HS after transplantation. Patient data were extracted from medical files and the recently reported HScore [Fardet et al., Arthritis Rheumatol. 2014 66(9):2613-20] was applied for confirmation of HS diagnosis. Among the thirty-two patients reported, one patient was excluded because of insufficient data for HScore calculation and four patients for an HScore less than 169. We included in the final analysis 27 patients in which the HS diagnosis was confirmed (median HScore 218, median HS probability of 97%). The median age was 45 years (range 21-68) and 10 patients were female (37%). Three patients underwent autologous HSCT for non-Hodgkin lymphoma (NHL). Twenty-four patients received allogeneic HSCT for hematological malignancies (n=23) or severe aplastic anemia (n=1) from HLA-identical siblings (n=4), HLA-matched (n=10) or HLA-mismatched (n=6) unrelated donors, haploidentical donors (n=2) or cord blood (n=2). The median time from transplantation to HS diagnosis was 66 days (range 6-326). Fever was present in almost all patients (n=25, 93%) while we observed splenomegaly in 13 (48%), hepatomegaly in 11 (41%), and lymphadenopathy in 8 (30%) patients. All patients had cytopenia in at least one hematopoietic lineage and we found pancytopenia in 14 patients (52%). All patients displayed elevated ferritin levels with 22 patients (81%) having levels higher than 7500 µg/L. Eleven patients (41%) had triglyceride levels at >4 mmol/l, while only 7 patients (26%) had fibrinogen <2.5 g/L. Aminotransferases were elevated in half of the patients (n=14). Bone marrow hemophagocytosis was observed in 15 patients (56%). Twenty patients (74%) had pharmacological immune suppression at time of HS diagnosis. Twenty-two patients (81%) had an infection at HS diagnosis, mainly viral infections [17 patients with evidence of one or more viral infection or reactivation: Epstein-Barr virus (n=14), cytomegalovirus (n=10), adenovirus (n=2), human herpesvirus 6 (n=1), metapneumovirus (n=1) and human parainfluenza virus type 3 (n=1)], but also pyogenic bacterial infections (n=6), parasitic infections (n=3, toxoplasmosis) and fungal infections (n=3: two aspergillosis and one disseminated Rhizomucor infection). Eleven patients (41%) had evidence of active cancer at time of HS diagnosis, either as primary disease progression/relapse (n=5) or as post-transplant lymphoproliferative disease (PTLD; n=6). Graft-versus-Host-Disease (GvHD) was present in 11 patients (41%) at time of HS diagnosis (grade II-IV acute GvHD in 8 patients; chronic GvHD in 3 patients) and was considered a contributing triggering factor for HS in 4 of them. The median survival after HS diagnosis was 58 days (95%CI 21-86) and the 1-year overall survival (OS) was 22% (95%CI 8%-41%) [Figure 1]. Treatments most frequently employed, either alone or in combination, were glucocorticoids (GCs, n=16), intravenous immunoglobulins (IVIG, n=7) and Etoposide (VP-16, n=7). Etiological anti-infectious or anti-cancer agents were employed alone in 7 patients. We found no significant difference in OS of patients with malignancy-associated HS or infection-triggered HS compared with HS from other causes. Similarly, we detected no impact of the use of GCs, IVIG or VP-16 on patients survival. However these results should be interpreted with caution given the limited number of patients. Three patients underwent a second allogeneic HSCT that provided long-term rescue in one patient, while offered only a short-term benefit to the others. Our study, which is to the best of our knowledge the largest series of HS following HSCT reported so far, provides a description of HS as a rare but devastating complication of HSCT associated with an extremely high mortality. [Display omitted] DisclosuresPeffault De Latour:Alexion: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding.

Hemophagocytic Syndrome in Systemic Lupus Erythematosus : A Monocentric Review of 13 Cases

Hemophagocytic syndrome (HS) can be either primary, with a genetic etiology, or secondary, associated with malignancies or infections. Among rheumatic or auto-immune disorders, HS occurs most frequently in systemic juvenile idiopathic arthritis. In recent years this syndrome has been increasingly reported in patients with systemic lupus erythematosus (SLE). We retrospectively studied SLE-associated HS in a monocentric lupus cohort patients.Methods :We reviewed the medical records of adult patients with SLE for a recent 6 years period (2010-2015) and identified patients who had developed HS. The diagnosis of SLE was made using ACR criteria (4 or more criteria) and HS has been diagnosed using Hunter criteria (5 or more). We conducted statistical analyses to identify the characteristics of those patients in comparison with SLE patients without HSResults :Among 110 consecutive lupus patients, 13 patients (12 women) was identified having HS. The mean age of patients was 37.69 +/- 11.4 years (21-68). HS revealed lupus in 3 patients; in the others the delay between diagnosis of SLE and HS was 12 months (1 months - 108). Fever, pericarditis and splenomegaly were found in 100%, 54% and 46% of patients at presentation of HS. Bone marrow aspiration indicated hemophagocytosis in all patients. Cutaneo-mucous and arthritis were present in 92% patients of patients at presentation of HS. Laboratory features were diverse, bicytopenia or pancytopenia, high C-reactive protein level (mean 93 mg/L) and hyperferritinemia (mean 11.082 ng/ml), hypertriglyceridemia (mean 4.2 g/L )were present in all patients. The mean hemoglobin level was 74 g/L (55-88 g/L), the mean neutrophils count was 6004 /µl (930-13.080), mean lymphocyte count 926/µl (350-1350) and the mean platelets 68.230/µl (10.000-98.000). All patients had anti-nuclear antibodies when the HS occurred. Anti-double-stranded DNA antibodies were present in 7 patients. Serum complement C3 was low in 10 patients.HS was associated with a lupus flare in 8 patients (3 renal flare, 3 central neurologic manifestations, one patient had proliferative nephropathy and polyradiculoneuritis and one patient pancreatitis). Infections was diagnosed in 11 patients (4 bacterial infections, 4 tuberculosis infection, 3 viral infections). Recognition of the cause of HS was particularly challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication; both conditions was considered present in 6 patients.The most commonly used therapy was corticosteroids, which were initially administered in all patients. All patients respond first to steroids. Immunosuppressant therapy was used together with corticosteroids in 7 patients (intravenous cyclophosphamide in 6, mycophenolate mofetil in 1). Intravenous immunoglobulin was given in 3 cases and Rituximab was used as the third line treatment in one patients (with polyradiculonevritis). Anti-tuberculosis treatment was used also as first line treatment in 4 patients with life threatening presentation. All patients had a good outcome without any mortality with a mean follow-up of 25 months.Compared with SLE patients without HS, those with HS was older and showed a higher serum C-reactive protein level (p = 0.039), a higher ferritinemia (p = 0.004), higher SLEDAI score (p = 0.003), a lower levels of plasma neutrophils (p < 0.001), lower level of hemoglobin (p = 0.013), as well as lower platelets count (p=0.03).Conclusion :HS was observed in 11.8 % Moroccan patients with SLE. The occurrence of HS was most frequently associated with the SLE disease activity and bacterial infection. Profound cytopenia, a high SLEDAI score, and notable changes in the level of acute-phase reactants are the characteristics of SLE patients with HS in our series. DisclosuresNo relevant conflicts of interest to declare.

One Hemophagocytic Syndrome Relating to Adult Epstein-Barr Virus Infection and a Literature Review

Background: Adult hemophagocytic syndrome is a critical condition that is often difficult to diagnose and results in a bad prognosis because of the lack of effective and unified treatment. Aim: To investigate the clinical, diagnosis and treatment of hemophagocytic syndrome. Case Presentation: A 22-year-old female patient received a splenectomy, and the spleen was sent to the King Med Center of Medical Inspection. The results confirmed the diagnosis of hemophagocytic syndrome related to EB (Epstein-Barr) virus infection. Conclusion: Early diagnosis and early intervention are important factors for affecting the progression of the disease and improving its prognosis.

An update on renal involvement in hemophagocytic syndrome (macrophage activation syndrome).

Context: Hemophagocytic syndrome (HPS) is mainly characterized by massive infiltration of bone marrow by activated macrophages and often presents with pancytopenia. Thrombotic microangiopathy (TMA) is also present with thrombocytopenia and renal involvement. Both conditions could coexist with each other and complicate the condition. Evidence Acquisition: Directory of Open Access Journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science with keywords relevant to; Hemophagocytic syndrome, macrophage activation syndrome, interferon-gamma and thrombotic microangiopathy, have been searched. Results: Viral infection, rheumatologic disease and malignancies are the main underlying causes for secondary HPS. calcineurin inhibitors and viral infections are also the main underlying causes of TMA in transplant recipients. In this review, we discussed a 39-year-old male who presented with pancytopenia and renal allograft dysfunction. With the diagnosis of HPS induced TMA his renal condition and pancytopenia improved after receiving intravenous immunoglobulin (IVIG) and plasmapheresis therapy. Conclusions: HPS is an increasingly recognized disorder in the realm of different medical specialties. Renal involvement complicates the clinical picture of the disease, and this condition even is more complex in renal transplant recipients. We should consider the possibility of HPS in any renal transplant recipient with pancytopenia and allograft dysfunction. The combination of HPS with TMA future increases the complexity of the situation.

Advances in the diagnosis of hemophagocytic lymphohistiocytosis

Hemophagocytic syndrome is a dangerous disease,with rapid progression and high mortality, which can be divided into primary and secondary hemophagocytic syndrome. This article reviews the research progress on the diagnosis of hemophagocytic syndrome in recent years. Key words: Hemophagocytic syndrome; Lymphoma, large cell, anaplastic

Hemophagocytic Lymphohistiocytosis Secondary to Diffuse B-Cell Lymphoma

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) arises in the setting of a highly stimulated but ineffective immune response. There is significant overlap between the presentations of HPS and lymphoma and there is still little knowledge and attention among caregivers for this life-threatening syndrome. The current case is a valuable reminder about the possibility of secondary HLH (malignancy-associated in this particular case) as a cause of prolonged unexplained fever. While diagnostic criteria for lymphoma-specific HPS have been previously suggested, their applicability is limited since the HLH 2004 criteria are used to diagnose all cases of HPS. This case shows the importance of accurate interpretation of laboratory and pathological data for the diagnosis of lymphoma-related HPS. HPS in the setting of B-cell lymphoma carries a poor prognosis. Early recognition and prompt treatment offers the best chance of survival, especially in the setting of multi-organ failure. J Hematol. 2015;4(1):151-154 doi: http://dx.doi.org/10.14740/jh192w

Highly Elevated IL-18 Is a Reliable Predictor of Progression to Hemophagocytic Syndrome in the Patients with Langerhans Cell Histiocytosis

▪Introduction:Langerhans cell histiocytosis (LCH) is a rare proliferative disorder of epidermal antigen-presenting cells such as dendritic cells (DCs). Historically, three distinct clinical syndromes have been described: eosinophilic granuloma (EG), Hand-Schuller-Christian disease and Letterer-Siwe disease (LSD). The disease has a broad spectrum of clinical behavior, from a mild self-limited form like EG-type LCH to an aggressive form associated with a high mortality rate like LSD-type LCH. Since one of the lethal complications of LCH is hemophagocytic syndrome (HPS), investigating a novel treatment approach for LCH associated HPS (LCH-HPS) is of paramount importance.We have reported the usefulness of cytokine profiles to differentiate HPS from various inflammatory diseases, in which macrophages/monocytes derived cytokines such as interleukin (IL)-18 and neopterin were highly elevated. Since clinical trials using neutralizing antibody to IL-18 in rheumatoid arthritis or plaque psoriasis are now underway, in this study, we examined cytokine profiles over time from six LCH cases and investigated the significance of IL-18 in the pathophysiology of HPS to establish a unique treatment strategy for LCH-HPS.Materials and Methods:The concentrations of serum IL-18 were measured in six patients with LCH, including three patients with EG-type LCH and three with LSD-type LCH. Diagnosis of LCH and HPS were based on clinical and histopathological findings. Serum IL-18 levels were measured by enzyme-linked immunosorbent assay (ELISA). Total RNA was extracted from tumor samples for analysis of IL-18 and LANGERIN mRNA expression. BRAF gene mutation was analyzed using DNA extracted from tumor cells as previously described.Results:Serum IL-18 level of LSD-type LCH was significantly higher than that of EG-type LCH (median 13,600 vs. 449, p<0.05) (Figure 1). In fact, two out of three LSD-type LCH cases developed LCH-HPS, whereas none of the cases with low level of IL-18 developed. When developed to HPS caused by various disorders, serum IL-18 concentrations became markedly increased as shown in Figure 1, suggesting that IL-18 plays a pivotal role in macrophage activation to develop HPS even in LCH. Serum concentration of IL-18 recovered to and maintained normal range after induction chemotherapy. We also observed a dominant increase of soluble tumor necrosis factor alpha-receptor type I (sTNF-RI) and type II (sTNF-RII) in LSD-LCH cases in addition to essential parameters for HPS: IL-18 and neopterin (Figure 2). This unique cytokine profile of LCH-HPS might be the cause of higher mortality rate (20%) compared to HPS caused by various disorders (5-10%).BRAF V600E mutation was detected in one of the three cases in each EG-type LCH and LSD-type LCH, suggesting that existence of BRAF V600E mutation does not correlate to the disease severity as previously reported.As recent studies demonstrated that LCH was originated from DCs, which were close to macrophages/monocytes systems, we hypothesized that LSD-type LCH tumor cells secret IL-18, and then directly initiate macrophage activation to develop HPS. To test this, we assessed IL-18 mRNA expression in tumor cells from LSD-type LCH by RT-PCR. LANGERIN mRNA expression was enhanced from all the LSD-type LCH tumor cells, however IL-18 mRNA did not seem to be derived from tumor cells, suggesting that LSD-type LCH cells themselves would trigger lethal HPS similar to lymphoma associated HPS.Conclusion:In conclusion, though LSD-type LCH tumor cells did not express IL-18 directly, the level of IL-18 was much higher in LSD-type LCH. Paying carful attention should be required to the patients with LSD-type LCH with highly elevated IL-18 to prevent the progression of lethal LCH-HPS. To hamper the macrophage activation, an application of IL-18 antibody may be clinically useful for the disease control of LCH-HPS. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

PO-0170 Hemophagocytic Lymphohistiocytosis Associated With Visceral Leishmaniasis: A Case Report

Background and aims Hemophagocytic lymphohistiocytosis (HLH) is a rare, life threatening disorder characterizedby uncontrolled activation of T-helper 1 lymphocytes and macrophages and overproductionof inflammatory cytokines. Visceral leishmaniasis (VL), is a multisystem infection caused by the dissemination of Leishmania throughout the reticuloendothelial system. HLH associated VL is a rare and difficult to diagnose clinicopathological condition leading to delayed treatment. We report a rare case of HLH associated Visceral Leishmaniasis in a patient who presented with persistent high fever, hepatosplenomegaly and pancytopenia. Case A 11 month-old baby with persistent high fever for more than 3 weeks and hepatosplenomegaly was assessed. Laboratory testing revealed pancytopenia, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia. Bone marrow examination revealed hemophagocytosis. A diagnosis of hemophagocytic syndrome was made according to the HLH-2009 diagnostic criteria. Prior to establishing the diagnosis of Leishmaniasis by indirect fluorescent antibody testing, several potential infectious agents were excluded. Treatment with pentavalent antimonials provided relief of all signs and symptoms within ten days. Conclusion HLH should be included in the differential diagnosis of patients who present with persistent high fever, hepatosplenomegaly and pancytopenia. Besides, physicians should keep in mind Leishmaniasis among the potential etiologic factors of secondary HLH.

Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome.

Because it has no unique clinical, biologic, or histologic features, reactive hemophagocytic syndrome may be difficult to distinguish from other diseases such as severe sepsis or hematologic malignancies. This study was undertaken to develop and validate a diagnostic score for reactive hemophagocytic syndrome. A multicenter retrospective cohort of 312 patients who were judged by experts to have reactive hemophagocytic syndrome (n = 162), were judged by experts to not have reactive hemophagocytic syndrome (n = 104), or in whom the diagnosis of reactive hemophagocytic syndrome was undetermined (n = 46) was used to construct and validate the reactive hemophagocytic syndrome diagnostic score, called the HScore. Ten explanatory variables were evaluated for their association with the diagnosis of hemophagocytic syndrome, and logistic regression was used to calculate the weight of each criterion included in the score. Performance of the score was assessed using developmental and validation data sets. Nine variables (3 clinical [i.e., known underlying immunosuppression, high temperature, organomegaly], 5 biologic [i.e., triglyceride, ferritin, serum glutamic oxaloacetic transaminase, and fibrinogen levels, cytopenia], and 1 cytologic [i.e., hemophagocytosis features on bone marrow aspirate]) were retained in the HScore. The possible number of points assigned to each variable ranged from 0-18 for known underlying immunosuppression to 0-64 for triglyceride level. The median HScore was 230 (interquartile range [IQR] 203-257) for patients with a positive diagnosis of reactive hemophagocytic syndrome and 125 (IQR 91-150) for patients with a negative diagnosis. The probability of having hemophagocytic syndrome ranged from <1% with an HScore of ≤90 to >99% with an HScore of ≥250. The HScore can be used to estimate an individual's risk of having reactive hemophagocytic syndrome. This scoring system is freely available online (http://saintantoine.aphp.fr/score/).

Natural killer/T-cell lymphoma-associated hemophagocytic syndrome: A case report.

Natural killer (NK)/T-cell lymphoma-associated hemophagocytic syndrome (HPS) is a rare and fatal disease with no optimal treatment. The present study reports the clinical features, diagnosis and treatment process of three patients with relapsed NK/T-cell lymphoma-associated HPS. All of the patients were classified as Ann Arbor stage IV and presented with a poor performance status. Two patients were successfully treated with a pegaspargase-containing combination regimen and one patient succumbed due to serious complications. These cases indicate that for patients with a history of lymphoma, the diagnosis of HPS should be considered when patients present with progressive high fever, pancytopenia and liver dysfunction. Early identification and effective treatments, including pegaspargase-based regimens are essential for an enhanced prognosis.

Response Letter for Case Report Entitled “Pregnancy Induced Haemo-phagocytic Syndrome (HPS)”

To the Editor, Thanks for your interest in the case report entitled “Pregnancy Induced Haemo-phagocytic Syndrome (HPS).” The Histiocyte Society HLH study group revised the diagnostic guidelines of HLH [1]. The diagnosis of HLH is established either by a molecular diagnosis consistent with HLH (primary HLH) or by having five out of eight parameters. They are fever, splenomegaly, cytopenia affecting more than two cell lineages, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in the bone marrow, spleen, or lymph nodes without evidence of malignancy, low or absent natural killer cell cytotoxicity, hyperferritinemia, and elevated soluble CD25. The common causes of HPS like infections, autoimmune, or malignant diseases were not present in this patient. Even after the diagnosis of haemo-phagocytic syndrome was established, the pregnancy as the primary cause for HPS was not thought. According to criteria [1], she was suffering from HLH because patient had fever, splenomegaly, cytopenia more than two cell lineages, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis in bone marrow. The dramatic recovery after abortion led us to think it to be a pregnancy Induced. There was no need of any medications or interventions in this woman. Liver biopsy was done once platelets counts recovered subsequent to abortion. We also agree that for the diagnosis of HPS, only demonstration of haemo-phagocytosis is not necessary [1].

Comment on pregnancy-induced hemophagocytic syndrome.

To the Editor, I read with much interest the paper by Shukla et al. that appeared in a recent issue of the Journal (2013;63:203–205). The diagnosis of hemophagocytic syndrome can be considered established in the patient in light of the prolonged fever, pancytopenia, hyperferritinemia, hypertriglyceridemia, and splenomegaly. It needs mention that the microscopic visualization of hemophagocytosis is simply one of the possible diagnostic criteria and does not necessarily need to be present to establish the diagnosis of hemophagocytic lymphohistiocytosis [1]. The performance of liver biopsy in the pregnant woman with thrombocytopenia as described by the authors may have been unnecessary. Liver, spleen, and lymph node biopsies merely for demonstration of hemophagocytosis should be avoided [2]. Could the patient have had an undiagnosed infection by an obligate intracellular microbe e.g., Salmonella typhi or Brucella sp. that could have triggered the hemophagocytic syndrome? Details of antimicrobial therapy and the number of antibiotic days prior to the patient having the spontaneous abortion with resolution of the hemophagocytic syndrome are, thus, of interest.

Hematologic complication in rheumatoid polyarthritis

Objective: Hemophagocytic syndrome (HPS) is a severe complication of chronic rheumatic diseases particularly juvenile rheumatoid arthritis. But it is rarely described in Adult form of rheumatoid polyarthritis. We report a new case of HS complicating a seropositive rheumatoid polyarthritis. Case report: A 50- year old female with past history of a seropositive rheumatoid polyarthritis treated by corticosteroids and methotrexate, was admitted for deterioration of general status. She complained of fever and polyarthralgia. On physical examination, she had polyathritis and an hepato-splenomegaly. Routine blood analysis showed an increase of inflammatory indices with a pancytopenia, high levels of lactico-deshydrogenases and hepatic cytolysis. Intravascular disseminated coagulation was diagnosed. High levels of triglyceridemia and an hyperferritinaemia were noted. An hemophagocytic syndrome was suspected and cytological examination of bone marrow confirmed hemophagocytosis. Other aetiologies of HPS (immunodeficiency, infections, hemopathies, cancers and auto-immune diseases) were eliminated. We retained the diagnosis of HPS complicating a seropositive rheumatoid polyarthritis. The outcome was rapidly fatal with acute hepatocellular failure leading to death. Conclusion: Hemophagocytic syndrome is rarely reported with rheumatoid polyarthritis. In front of pancytopenia, it is important to be aware of this syndrome because its occurrence is associated with a poor prognosis and its optimal treatment has not been fully defined.