Hemophagocytic Lymphohistiocytosis: Proposal for a New Terminology

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by severe systemic immune activation and hyperinflammation with the infiltration of organs, such as the bone marrow, spleen, lymph nodes, skin and central nervous system by activated lymphocytes and macrophages. The characteristic features of HLH including cytopenia, splenomegaly, lymphadenopathy, fever and hepatic failure occur [1, 2]. Hemophagocytic lymphohistiocytosis was first described in adults in 1939 as ‘histiocytic medullary reticulosis [3]’. Subsequently, Farquhar and Claireaux reported the first cases in children in 1952, introducing the term ‘familial hemophagocytic reticulosis’ which later evolved into familial HLH. In 1979, Risdall and colleagues identified an infection-triggered HLH and termed the condition ‘virus-associated hemophagocytic syndrome’ [3]. Cytotoxic T cells and (natural killer) NK cells eliminate target cells through various mechanisms, including the perforin-granzyme pathway, FasL-mediated pathway or release of proinflammatory cytokines, such as TNF-α and IFN-γ. Perforin and granzyme are stored in lytic granules, and upon T cell activation, are transported to the immunological synapse formed between the effector and target cell. The cellular cytoskeleton and vesicular transport facilitate this process, enabling their release into the intercellular space. Disruption of these pathways in cells, particularly impaired T cell activation, or inadequate regulatory control of T cell responses, may lead to HLH [2, 4-6]. The original definition of HLH was not based on genetic evidence, prompting its classification as primary (familial) or secondary (acquired) forms according to the clinical phenotype. In this setting, primary HLH, such as perforin deficiency, typically presents in early childhood without an identifiable trigger and is attributed to inherited genetic defects that compromise the cytotoxic function of CD8+ T lymphocytes and NK cells. In contrast, secondary HLH is considered an acquired condition that is more prevalent in adults, triggered by infections, malignancies, autoimmune, autoinflammatory and metabolic disorders (such as lysinuric protein intolerance) [2, 4, 6, 7]. This phenotype-based classification may inadvertently imply that genetic factors do not contribute to the pathogenesis of secondary HLH, thereby attributing disease onset solely to extrinsic factors [3, 5, 8]. However, accumulating evidence indicates that adult HLH cases generally have a genetic background, together with an apparent external trigger [2-8]. For instance, CD27 deficiency, a primary immunodeficiency or an inborn error of immunity (IEI), can lead to EBV-associated HLH. Loss of CD27-CD70 signalling, which enhances the T and NK cell cytotoxic activity, impairs the apoptosis of target cells [7]. Diverse types of IEI (e.g., vesicular transport defects, combined immunodeficiencies, chronic granulomatous disease) have been shown to contribute to HLH development [2, 5-7, 9, 10]. With the growing understanding of the pathogenesis and clinical heterogeneity of HLH, the traditional dichotomous classification may complicate both diagnosis and clinical management. We suggest not to divide HLH into primary and secondary HLH, and using the term ‘Immunodeficiency-based accelerated/systemic histiocytosis’ (Figure 1) for both entities. We believe that this terminology more accurately reflects current knowledge about the pathogenesis of HLH and the broad, heterogeneous spectrum of the disease. It may also support clinical decisions, including those related to hematopoietic stem cell transplantation. The terminology we propose covers the clinical entities, such as macrophage activation syndrome (MAS) and malignancy-associated HLH. Our aim is to avoid phenotypic labelling during the diagnostic process until the genetic background and the precise pathogenic mechanisms leading to HLH have been elucidated. In conclusion, HLH pathogenesis reveals that the disease emerges from an intricate, multifactorial process driven by immune system dysfunction. The traditional classification of HLH as primary or secondary is increasingly inadequate, and a new paradigm may be beneficial. Adopting the term ‘immunodeficiency-based accelerated/systemic histiocytosis’ may provide a more comprehensive and accurate description of the disease and aligns with current scientific knowledge. This integrated approach could provide a rational basis for clinical management and improve patient outcomes. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.