From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome that requires prompt diagnosis and aggressive treatment to prevent high mortality rates due to progressive multi-organ failure from uncontrolled inflammation and cytokine storm. HLH occurs in primary (genetic) and secondary (acquired) forms, with the latter typically triggered by infections, malignancies, or autoimmune diseases. The clinical features of HLH include:
- Persistent high fever
- Hepatosplenomegaly
- Cytopenias (particularly thrombocytopenia and anemia)
- Hyperferritinemia (often >10,000 ng/mL)
- Hypertriglyceridemia
- Hypofibrinogenemia
- Hemophagocytosis in bone marrow or other tissues
- Elevated soluble IL-2 receptor (sCD25)
- Decreased NK cell activity Patients may also present with neurological symptoms, coagulopathy, liver dysfunction, and skin rash. The management of HLH requires individualized therapy, including HLH-directed treatment, standard supportive care, and adjunctive critical care therapies, as recommended by the Histiocyte Society 1. Initial therapy typically includes dexamethasone (10 mg/m² daily) and etoposide (150 mg/m² twice weekly for 2 weeks, then weekly), following the HLH-94 or HLH-2004 protocols 1. Cyclosporine A (2-7 mg/kg/day) is often added once the patient's renal function stabilizes. For CNS involvement, intrathecal methotrexate and hydrocortisone may be necessary. Supportive care includes treating underlying triggers (antimicrobials for infections, chemotherapy for malignancies), transfusion support, and prophylaxis against opportunistic infections. In primary HLH, allogeneic hematopoietic stem cell transplantation is the definitive treatment. For refractory cases, salvage therapies include alemtuzumab, anakinra, or ruxolitinib 1. Early recognition and treatment are crucial as untreated HLH has a high mortality rate due to progressive multi-organ failure from uncontrolled inflammation and cytokine storm.
From the Research
Definition and Clinical Features of HLH
- Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory syndrome characterized by prolonged high fever, hepatosplenomegaly, and characteristic laboratory findings 2.
- HLH may be inherited (primary) or secondary to any severe infection, malignancy, or rheumatologic condition 2, 3.
- Key clinical features include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy 3, 4.
- Diagnostic features include anemia, thrombocytopenia, neutropenia, elevated ferritin, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis, low or absent natural killer cells, and elevated soluble interleukin 2 receptor assay 4.
Management of HLH
- Primary treatment goals are eliminating the underlying trigger and suppressing hyperinflammation with steroids, immunoglobulins, or immunomodulators 4.
- Specific treatment includes corticosteroids, etoposide, and antithymocyte globulin followed by hematopoietic stem cell transplantation in patients with refractory or relapsing disease 4, 5.
- Familial forms of HLH are currently treated with chemotherapy as a bridge to hematopoietic stem cell transplantation 3.
- HLH occurring in rheumatic disease (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A 3.
- Early escalation to the haematology team based on abnormally high ferritin levels and early critical care input is crucial for improving patient outcomes 6.