From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) has two main etiological categories: primary (genetic) and secondary (acquired), with secondary HLH being more common in adults and often triggered by infections, malignancies, autoimmune diseases, or certain medications. The most recent and highest quality study on this topic is from 2019, published in the journal Blood 1. According to this study, primary HLH results from genetic mutations affecting cytotoxic function of natural killer cells and T lymphocytes, including mutations in PRF1, UNC13D, STX11, and STXBP2 genes. These genetic forms typically present in infancy or early childhood. Secondary HLH, on the other hand, develops as a consequence of strong immune activation, commonly triggered by infections (particularly Epstein-Barr virus, cytomegalovirus, and other herpesviruses), malignancies (especially lymphomas), autoimmune diseases (macrophage activation syndrome in rheumatic conditions), or certain medications.
Etiological Categories of HLH
- Primary (genetic) HLH: results from genetic mutations affecting cytotoxic function of natural killer cells and T lymphocytes
- Secondary (acquired) HLH: develops as a consequence of strong immune activation, commonly triggered by infections, malignancies, autoimmune diseases, or certain medications
Triggers of Secondary HLH
- Infections: particularly Epstein-Barr virus, cytomegalovirus, and other herpesviruses
- Malignancies: especially lymphomas
- Autoimmune diseases: macrophage activation syndrome in rheumatic conditions
- Certain medications
The pathophysiology of HLH involves dysregulated immune activation with excessive cytokine production, leading to uncontrolled inflammation, macrophage activation, and hemophagocytosis. This results in the clinical manifestations of persistent fever, hepatosplenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and hemophagocytosis in bone marrow or other tissues. Understanding the underlying etiology is crucial for appropriate treatment, which may include immunosuppressive therapy, treatment of triggering conditions, or hematopoietic stem cell transplantation in genetic cases, as recommended by the 2019 study in Blood 1. Additionally, the 2019 study in Blood also highlights the importance of considering lymphoma as a hidden trigger of HLH, and recommends the use of positron emission tomography–guided imaging, repetitive tissue sampling, and consultation with a lymphoma reference pathologist to detect lymphoma-associated HLH 1.
In terms of management, the 2019 study in Blood recommends that patients with HLH during chemotherapy should receive broad antimicrobial prophylaxis against Pneumocystis jirovecii and fungi, and that hospitalization in units with high efficiency particulate air–filtered air should be considered 1. The study also suggests antiviral prophylaxis due to the severe T-cell depletion associated with HLH-directed treatment.
Overall, the etiology of HLH is complex and multifactorial, and a thorough understanding of the underlying causes is essential for providing effective treatment and improving patient outcomes. The most effective approach to managing HLH is to identify and treat the underlying trigger, while also providing supportive care to manage the symptoms and complications of the disease.
From the Research
Etiology of Hemophagocytic Lymphohistiocytosis (HLH)
The etiology of HLH can be categorized into two main forms: primary and secondary.
- Primary HLH is associated with specific genetic mutations that cripple lymphocyte cytotoxicity, such as familial HLH, X-linked lymphoproliferative diseases, and mutations in Nod-like receptor caspase activation and recruitment domain containing protein 4 (NLRC4) 2.
- Secondary HLH occurs in response to strong immunologic triggers, including:
Pathogenesis of HLH
The pathogenesis of HLH involves the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines 3, 5. This leads to a cytokine storm, which can cause tissue damage and organ dysfunction. The sustained, aberrant activation of cytotoxic CD8+ T cells and resultant inflammatory cytokine release are core pathogenic mechanisms 5.
Clinical Features and Diagnosis
The clinical features of HLH include unexplained fever, hepatosplenomegaly, pancytopenia, and severe hyperferritinemia 6, 3, 4. Diagnosis can be made using a combination of clinical features, laboratory tests, and diagnostic tools, such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds 4.