Secondary Hemophagocytic Lymphohistiocytosis

Synonyms

sHLH, macrophage activation syndrome, acquired HLH,

Overview

Secondary Hemophagocytic Lymphohistiocytosis (sHLH) is a severe, life-threatening syndrome of hyperinflammation triggered by an underlying medical condition, such as a severe infection, malignancy, or autoimmune disease. It occurs when the immune system is overactivated, leading to a “cytokine storm” and excessive activation of macrophages and lymphocytes that damage tissues and organs. Treatment involves controlling the immune response with immunosuppressants, corticosteroids, or chemotherapy, while also treating the underlying trigger.  

Symptoms

Secondary HLH symptoms include persistent fever, enlarged spleen and liver, and swollen lymph nodes. Other common signs are rashes, jaundice, and digestive issues like vomiting and diarrhea. More serious symptoms can involve neurological problems such as headaches, seizures, or weakness, and blood-related issues like easy bruising, bleeding, and anemia. 

Common symptoms are:

Causes

Secondary hemophagocytic lymphohistiocytosis (HLH) is caused by underlying medical conditions, most commonly infections, malignancies, and autoimmune diseases. Infections like the Epstein-Barr virus (EBV), cytomegalovirus (CMV), and bacterial or fungal infections are major triggers. Cancers, particularly lymphomas and leukemias, are another significant cause, along with autoimmune and autoinflammatory diseases like lupus and rheumatoid arthritis. 

Prevention

There is no guaranteed way to prevent secondary HLH, but strategies focus on managing underlying conditions that trigger it, like infections or autoimmune diseases. For those at risk, early recognition of symptoms such as persistent high fever and fatigue, and prompt medical attention are crucial. Treating the underlying cause, like a viral infection or malignancy, is a key preventive measure for preventing a full-blown HLH episode. 

Diagnosis

Diagnosing secondary HLH involves a combination of clinical signs, laboratory tests, and potentially genetic and molecular analyses. Diagnosis is made using specific criteria, such as fulfilling at least five out of nine diagnostic criteria, which include symptoms like fever and splenomegaly, laboratory findings like high ferritin and triglycerides, and evidence of hemophagocytosis in a bone marrow biopsy. A molecular diagnosis, if available, is also a definitive criterion.  

Prognosis

The prognosis for secondary HLH (sHLH) varies significantly, with overall mortality rates as high as 50–75%. Key factors influencing survival include the underlying cause (malignancy, infections, autoimmune diseases), a patient’s age, and the promptness and aggressiveness of treatment. Specifically, sHLH from malignancies has a worse prognosis than that from non-malignant causes, and factors like older age, low platelet counts, and high LDH levels are associated with poor outcomes. 

Treatment

Treatment for secondary HLH involves addressing the underlying cause, such as an infection or cancer, and dampening the exaggerated immune response with immunosuppressants like high-dose glucocorticosteroids (e.g., dexamethasone) and cytotoxic chemotherapy (e.g., etoposide). Other therapies can include chemotherapy agents, such as rituximab for EBV-related HLH, or newer agents like anakinra or emapalumab. A hematopoietic stem cell transplant is a potential option for severe or refractory cases.