![]() ![]() According to HLH-2004 study criteria, HLH can be diagnosed in a patient with at least 5 of 8 diagnostic criteria and/or disease-causing mutations in HLH-related genes. Of note, these criteria were established in the pediatric setting along the HLH-1994 and HLH-2004 trial protocols including patients up to 18 years (Bergsten et al. ![]() HLH diagnosis is based on the HLH-2004 diagnostic criteria established by the Histiocyte Society (summarized in Table Table1) 1) (Henter et al. As a result, and despite a high index of suspicion, there is high likelihood for mis- or underdiagnosing HLH, especially in intensive care units (Lachmann et al. Specifically, HLH often is indistinguishable from sepsis or autoinflammatory diseases (e.g., adult-onset Still disease). The spectrum of possible underlying conditions and patient characteristics is reflected by distinct clinical presentations which also can mimic other diseases, making timely diagnosis challenging. However, a number of endogenous (i.e., genetic predisposition, preexisting inflammation) and exogenous factors (i.e., immunosuppression, triggering disease) play a role in HLH pathogenesis (Brisse et al. Clinically, a triad consisting of prolonged fever, hepatosplenomegaly and pancytopenia is common. Immunodeficiency syndromes, commonly associated with albinism, also predispose to HLH (Henkes et al. This includes PRF1, coding for perforin, or genes involved in the transport or exocytosis of perforin-containing lytic granules (Sepulveda and de Saint Basile 2017). ![]() In contrast, primary HLH typically manifests in childhood, often has a family history, and is linked to mutations in genes involved in lymphocyte cytotoxicity. The wide spectrum of HLH-initiating conditions in adults is reflected by the term “acquired” or “secondary” HLH. By convention, and with impact on differential treatment, HLH in patients with autoimmune/autoinflammatory diseases is also called macrophage activation syndrome (MAS-HLH) (Emile et al. 2014), as are patients with autoimmune/autoinflammatory disorders. Patients with long-term immunosuppression are at increased risk to develop HLH (Ramos-Casals et al. In adults, this often fatal aberrant immune response most frequently is triggered by infections and malignancies, or a combination of these. Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome driven by excessive activation and stimulation of cytotoxic T-lymphocytes, natural killer T-cells and macrophages with subsequent cytokine storm and organ damage (Janka and Lehmberg 2014). ![]()
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