The specificity of hemophagocytic lymphohistiocytosis in adults

Hemophagocytic lymphohistiocytosis (HLH), also called hemophagocytic syndrome, is a clinical entity caused by an exaggerated inflammatory reaction. HLH can be triggered by various inherited or acquired factors. Uncontrolled activation of T lymphocytes and macrophages, together with an impaired cytotoxic function of NK cells, results in the massive cytokine release. Inherited HLH develops among children whilst HLH etiology in adults is usually acquired. The most common symptoms of HLH are unremitting fever, splenomegaly, and peripheral blood cytopenias. Laboratory tests disclose hyperferritinemia (often >10,000μg/L), increased level of sIL-2R (>2400U/L), hypertriglyceridemia, hypofibrinogenemia, coagulopathy, hyponatremia, and elevated liver transaminases and bilirubin. In 2004 The Histiocyte Society updated current diagnostic guidelines for HLH. In most cases, HLH is lethal if adequate therapy is not administered. The therapy of any HLH form is based on suppression of the hyperinflammation by destruction of activated CD8+ T-lymphocytes and macrophages, and treatment of any existing HLH triggers. Since HLH can be encountered by various medical specialists, basic knowledge of this entity and its diagnostic criteria should be familiar to all physicians. Treatment of HLH is difficult, long-lasting and often associated with a high morbidity. Early diagnosis and immediate introduction of adequate HLH therapy are crucial for the successful treatment of HLH

What hematologist needs to know about Gaucher disease

Hematological symptoms can be helpful for the diagnosis of inherited metabolic disorders, including Gaucher disease. Gaucher disease is a progressive, multisystem lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme, glucocerebrosidase, arising from autosomal recessive mutations in the GBA1 gene (1q21). Because of constant presence of hematological symptoms in Gaucher disease, hematologists have always been at the forefront of specialists, who performed initial diagnostics of Gaucher disease. Gaucher cells, the lipid-laden storage macrophages, are the pathologic hallmark of Gaucher disease. The clinical presentation of Gaucher disease is highly variable, giving a complex phenotype of multiorgan disease. Classically, three clinical types of Gaucher disease are distinguished according to the absence (type 1) or presence (types 2 and 3) of neurological symptoms and the dynamics of developing clinical signs. Thrombocytopenia, anemia, hepatosplenomegaly and bone manifestations are the most typical signs of type 1, the most prevalent form of Gaucher disease. This paper presents the most important, from the point of view of a hematologist, issues related to symptomatology, diagnosis, and treatment of Gaucher disease

Rare macrophage diseases in adults

Diseases of macrophages are rare entities characterized by the accumulation of macrophages, dendritic cells or monocyte-derived cells in various tissues and organs. This article focuses on macrophage disorders which can be present in adult patients. The review highlights pathogenesis, signs and symptoms, diagnostic criteria and principles of therapy in the most frequent macrophage diseases in adults: hemophagocytic lymphohistiocytosis, Rosai-Dorfman disease, Gaucher disease, Niemann-Pick disease, and Langerhans cell histiocytosis. Since macrophage disorders can be encountered by various medical specialists, basic knowledge of these entities and their diagnostic criteria should be familiar to all physicians, including hematologists

How to recognize and treat Gaucher disease: an outline of pathophysiology, clinical symptoms, diagnostic methods and therapy

Rare diseases are a diagnostic challenge for modern medicine. Gaucher disease is a rare autosomal recessive lipid storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase. In the absence of known affected family member, frequent symptoms of Gaucher disease, such as thrombocytopenia or splenomegaly, often lead to hematological diagnostic workup. This review highlights pathophysiology, signs and symptoms, diagnostic and therapeutic principles of Gaucher disease. Difficulties in diagnosis of Gaucher disease depends mainly on its rarity, but there is also the lack of awareness and limited knowledge about this disease. Basic knowledge of Gaucher disease should be familiar to all physicians, including hematologists

Zarys objawów klinicznych, leczenia oraz trudności w rozpoznawaniu choroby Gauchera

Gaucher disease, a rare autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, can be difficult to diagnose in the absence of a known affected family member. This is particularly true in non-Jewish patients with mild phenotypes due to the incomplete awareness of signs and symptoms of Gaucher disease among physicians (e.g., internists). Here, we present an outline of clinical manifestations of Gaucher disease with a particular focus on hematologic symptoms. A historical outline of Gaucher disease and currently available treatment options for this disorder are briefly summarized. Last but not least, we present issues related to possible diagnostic pitfalls in non-neuropathic patients with an undiagnosed Gaucher disease

Autoimmune-Associated Hemophagocytic Syndrome/Macrophage Activation Syndrome

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Rituximab-associated progressive multifocal leukoencephalopathy after a single cycle of R-CHOP for T-cell/histiocyte-rich large B-cell lymphoma

Progressive multifocal leukoencephalopathy (PML) is a disease of immunocompromised patients caused by reactivation of the John Cunningham polyomavirus (JCV). A monoclonal anti-CD20 antibody rituximab is widely used as an important part of therapy for B-cell non-Hodgkin lymphomas and various autoimmune diseases. It is not fully explained how rituximab reactivates JCV.In this report, we present the case of a 61-year-old man with T-cell/histiocyte-rich large B-cell lymphoma who was treated with R-CHOP and intrathecal methotrexate. Two weeks after the first R-CHOP course he developed dysarthria, diplopia, and disturbances in motor coordination. Based on CT/MRI results showing 3cm×2cm large hypodense white matter lesion in left cerebellar hemisphere, and detection of JCV in the cerebrospinal fluid (14300viral copies/mL), the patient was diagnosed with PML. Despite treatment attempt with cidofovir and IVIG, the patient's neurological status continued to worsen. He developed progressive motor neuron deficits but retained intact cognitive functions. The patient deceased nearly three months after onset of rituximab treatment.Rituximab is a milestone in treatment of many hematological and autoimmune diseases. Considering how widespread has the use of rituximab become, the overall risk of developing PML is relatively low. Nevertheless, since the end of 1990s several reports were published on PML development in association with usage of rituximab. The authors would like to emphasize that although the total risk of PML occurrence in patients treated with rituximab is low, it is important that physicians administrating rituximab therapy are aware of this serious complication

Diagnostic and clinical value of biomarkers and ferritinemia in Gaucher disease

Gaucher disease is a progressive, multisystem lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme, glucocerebrosidase (GBA), arising from autosomal recessive mutations in the GBA1 gene (1q21). There are several biomarkers used in Gaucher disease (i.e., chitotriosidase, CCL18/PARC, tartrate resistant acid phosphatase, angiotensin-converting enzyme), however, all of them have some disadvantages. It is believed that none of these biomarkers has a significant correlation with the clinical severity of Gaucher disease. A high proportion of patients with type 1 Gaucher disease present with hyperferritinemia, however, the pathophysiology of the high ferritin serum levels in Gaucher disease has not yet been elucidated and different mechanisms are possible. This review presents a current knowledge on biomarkers useful for diagnostic and monitoring of Gaucher disease with a focus on ferritinemia

Atypical cytomorphology of Gaucher cells is frequently seen in bone marrow smears from untreated patients with Gaucher disease type 1

Introduction. Gaucher cells (GCs), the lipid-laden storage macrophages, are the pathologic hallmark of Gaucher disease (GD). They are typically 20–100 μm in diameter with eccentrically placed nuclei and cytoplasm with characteristic crinkles and striations. A few previous observations have indicated that sometimes GD patients may display morphology of GCs which is different from this classical description. The aim of our study was to explore the morphological polymorphism of GCs in patients with untreated GD type 1 (GD1). Material and methods. May-Grünwald Giemsa stained bone marrow smears (BM-S) from 6 patients with sporadic GD1 were analysed; each patient sample consisted of two slides where all GCs and non-Gaucher cell macrophages were counted. We have defined for the study purposes and examined the following features of GCs which were considered as atypical: (1) foamy cytoplasm, (2) centrally placed nucleus, (3) cell diameter > 100 μm, (4) multinuclearity, (5) syncytial morphology, (6) unusually large cytoplasmic projections, and (7) apparent haemophagocytosis. Results. All analysed patients showed 22–40% GCs with atypical cytomorphology (median 29%). The median number of atypical features of GCs was 10 per patient (range 6–13). Multinuclearity was the most common atypical feature of GCs, followed by erythrophagocytosis and foamy cytoplasm. There was a strong positive correlation between erythrophagocytosis and foamy cytoplasm in GCs (Spearman’s rank correlation coefficient: 0.9). Although majority of atypical GCs had one atypical feature, there was a considerable amount of GCs presenting ≥ 2 atypical features. Conclusions. Untreated patients with GD1 often show a considerable proportion of GCs with atypical cytomorphology. The knowledge of possible atypical variant forms of GCs can contribute to a quicker and accurate diagnosis of GD, and minimize the risk for misdiagnosis. To the best of our knowledge, this is the first published report on atypical cytomorphology of GCs in untreated patients with GD1.

Elevated serum concentrations of β-2-microglobulin are often found at the time of diagnosis of hemophagocytic lymphohistiocytosis in adults with lymphoid and myeloid malignancies

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation. In patients over 60 years of age, HLH associated with hematological malignancies (hM-HLH) is the most prevalent. β-2-Microglobulin (B2M) plays an important role in antigen presentation and immunological regulation. Elevated B2M levels reflect T-cell activation. Objective: The aim of this study was to determine serum B2M concentrations in adults with hM-HLH and to interpret its significance in the context of overall survival (OS). Patients and methods: Serum B2M concentration was determined in 31 adults aged 22–84 years at the time of hM-HLH diagnosis. Lymphoid malignancy was diagnosed in 22 patients and myeloid malignancy in 9 patients. Results: The serum concentration of B2M was elevated in 100% of the examined patients. Mean and median serum B2M concentrations were 5.3 and 4.2mg/L, respectively (range 2–17mg/L). We have not found any significant differences in terms of the studied serum B2M concentrations between patients with T/NK-cell lymphomas, B-cell lymphomas, and myeloid malignancies. The outcome of HLH was poor in vast majority of patients with the median OS for the entire group of 46 days. Conclusions: Elevated serum B2M level is a frequent finding at the time of hM-HLH diagnosis in adults. It seems to be a useful indicator of HLH for its early detection and evaluation afterward, as well as for immediate therapeutic intervention. Further prospective studies answering the question whether serum B2M can be used as a prognostic factor in hM-HLH would be of interest