Hemophagocytic lymphohistiocytosis (HLH) is a rare and severe immune disorder. It involves an uncontrolled activation of the body’s immune system, leading to widespread inflammation and potential organ damage. While more common in children, HLH in adults is increasingly understood, emphasizing the importance of timely diagnosis and management.
Understanding HLH in Adults
HLH in adults is a syndrome characterized by immune dysregulation, where the immune system overreacts and fails to properly shut down. This leads to an excessive production of inflammatory proteins, known as cytokines, which can harm healthy tissues and organs. The condition is not a single disease but a severe inflammatory state.
There are two main types of HLH: primary (familial) and secondary (acquired). Primary HLH is typically inherited, caused by genetic mutations, and is more common in children. In adults, HLH is predominantly secondary, arising from another underlying health issue. This distinction is important because management often involves treating the trigger.
A key feature of HLH is “hemophagocytosis,” where overactive immune cells, specifically macrophages, engulf and destroy other blood cells. This process contributes to the low blood cell counts seen in patients. These abnormal immune cells can also accumulate in organs like the spleen and liver, causing them to enlarge.
Causes and Triggers
HLH in adults is most often a secondary condition, triggered by various underlying factors. Infections are frequent culprits, with viruses being particularly significant. The Epstein-Barr virus (EBV) is a common viral trigger, but others include cytomegalovirus (CMV), herpes simplex virus (HSV), and even bacterial, fungal, or parasitic infections.
Malignancies, particularly lymphomas, are another major cause of HLH in adults. Lymphomas, especially T-cell lymphomas, are frequently associated, but leukemias and other solid tumors can also trigger the condition. HLH can even be the initial presentation of an undiagnosed cancer.
Autoimmune diseases, where the immune system mistakenly attacks the body’s own tissues, can also lead to HLH. When HLH occurs with rheumatologic conditions like systemic lupus erythematosus (SLE) or adult-onset Still’s disease, it is sometimes referred to as macrophage activation syndrome (MAS). Immunodeficiency states, whether inherited or acquired (such as after organ transplantation), can increase susceptibility. Rarely, some medications can also induce HLH.
Recognizing the Signs
Recognizing HLH can be challenging because its initial signs are often non-specific, mimicking other common illnesses. A persistent, high-grade fever unresponsive to standard treatments is a common and early indicator. This fever reflects widespread inflammatory activity.
Patients frequently experience cytopenias, which are low counts of various blood cell types, including anemia, leukopenia, and thrombocytopenia. These low cell counts contribute to symptoms such as fatigue, increased susceptibility to infections, and easy bruising or bleeding.
Enlargement of the spleen (splenomegaly) and/or liver (hepatomegaly) is another common physical sign due to the accumulation of activated immune cells. Some individuals may also develop neurological symptoms if the central nervous system is affected, including headaches, seizures, or changes in mental status. Other possible signs include skin rashes, swollen lymph nodes, jaundice, and lung or digestive issues.
Diagnosis and Treatment Approaches
Diagnosing HLH involves clinical findings, laboratory tests, and sometimes tissue biopsies. Physicians often use established diagnostic criteria, such as the HLH-2004 protocol, which require specific clinical and laboratory features. Key laboratory indicators include elevated ferritin (a protein that stores iron), high soluble CD25 (a marker of immune activation), and reduced or absent natural killer (NK) cell activity. Blood tests also check for low fibrinogen (a clotting protein) and high triglycerides (fats in the blood).
A bone marrow biopsy may be performed to look for evidence of hemophagocytosis, where immune cells engulf other blood cells. While hemophagocytosis supports the diagnosis, its absence does not rule out HLH, and it may be found in other tissues. Given the non-specific nature of symptoms, a high level of suspicion is often needed for timely diagnosis.
Treatment for HLH in adults aims to suppress the overactive immune system and address the underlying trigger. Immunosuppressive medications are a cornerstone of therapy, often including corticosteroids like dexamethasone and chemotherapy agents such as etoposide. Cyclosporine, another immunosuppressant, may also be used. For specific cases, targeted therapies like emapalumab, an antibody that blocks a key inflammatory protein, have been approved.
Treating the underlying cause is paramount for secondary HLH. This means addressing the infection, malignancy, or autoimmune disease that triggered the immune dysregulation. Supportive care is also crucial, involving management of complications, blood transfusions, and antibiotics for secondary infections. For refractory cases or those with a genetic predisposition, hematopoietic stem cell transplantation (HSCT) can be a potentially curative option.