From the Guidelines
Secondary hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening hyperinflammatory syndrome that occurs as a complication of infections, malignancies, autoimmune disorders, or certain medications, characterized by excessive activation of immune cells, particularly T lymphocytes and macrophages, leading to uncontrolled inflammation and organ damage.
Definition and Characteristics
Secondary HLH develops in individuals without known genetic predisposition, unlike primary HLH, which is caused by genetic mutations. The hallmark features of secondary HLH include persistent high fever, enlarged liver and spleen, abnormal blood counts (particularly low platelets and red blood cells), elevated ferritin levels, high triglycerides, low fibrinogen, and hemophagocytosis (immune cells engulfing other blood cells) in bone marrow, liver, or lymph nodes 1.
Triggers and Diagnosis
The most frequent triggers of secondary HLH are infections, particularly with viruses such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), as well as certain malignancies and autoimmune or autoinflammatory conditions 1. The diagnosis of secondary HLH can be challenging due to its similarity in presentation to sepsis or multiple organ dysfunction syndrome, and the application of pediatric diagnostic criteria, such as the HLH-2004 criteria, may not be validated for adults 1.
Treatment and Management
Treatment of secondary HLH focuses on suppressing the immune response with corticosteroids like dexamethasone, often combined with etoposide chemotherapy in severe cases, while simultaneously addressing the underlying trigger 1. The management of secondary HLH in adults requires a tailored approach, considering the heterogeneity of triggers and clinical outcomes, and the potential for overtreatment and unnecessary toxicity with pediatric-based protocols 1. In cases of EBV-triggered HLH, the addition of rituximab to HLH-directed therapy may be effective in clearing the reservoir of virus, and monitoring of ferritin, sCD25, cell counts, and EBV DNA can guide treatment response and the need for further interventions like stem cell transplantation 1.
Prognosis and Outcome
The prognosis for secondary HLH varies widely, with mortality rates ranging from 20% to 88%, primarily due to refractory HLH, secondary infections, and progression of the underlying triggering disease 1. Early recognition and prompt treatment are crucial for improving outcomes in secondary HLH, as delayed diagnosis and treatment can lead to rapid progression to multi-organ failure and death.
From the Research
Definition of Secondary HLH
- Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening inflammatory syndrome that can be triggered by autoimmune diseases, malignancy, or infection 2.
- It is characterized by uncontrolled activation of cytotoxic T lymphocytes, natural killer cells, and macrophages that can lead to a cytokine storm 3.
- sHLH is also known as hemophagocytic syndrome (HPS) and is most often characterized by fevers, hepatomegaly or splenomegaly, and bi- or trilineage cytopenias 4.
Clinical Features
- Key clinical features of sHLH include high persistent fever, hepatosplenomegaly, blood cytopenia, elevated aminotransferase and ferritin levels, and coagulopathy 5.
- Patients with sHLH may exhibit different laboratory parameters and clinical features, such as differences in platelet counts, soluble IL-2R concentration, and hepatomegaly 2.
- The diagnosis of sHLH is often challenging due to the diverse clinical manifestations and the presence of several diagnostic mimics 3.
Diagnosis and Treatment
- A high index of suspicion is necessary for early diagnosis, and a thorough diagnostic evaluation is necessary to prompt treatment of the underlying causes 4.
- The HLH-2004 protocol used in the diagnosis of HLH was originally developed for the pediatric population, but it still forms the basis of the diagnosis of HLH in adults 3.
- Treatment of sHLH is primarily based on the HLH-94 protocol, which involves suppressing the inflammatory response, but the treatment needs to be modified in adults depending on the underlying cause and comorbidities 3.
- In rheumatic disease, sHLH (macrophage activation syndrome) is treated with glucocorticoids, IL-1 blockade, or cyclosporine A 5.