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Understanding HLH

Hemophagocytic Lymphohistiocytosis

What is HLH?

HLH stands for Hemophagocytic lymphohistiocytosis. It is a life-threatening condition that can be defined as either primary or secondary HLH. Primary, or “familial,” HLH is when the condition is inherited. The term secondary HLH is used when your doctor thinks the condition may have occurred for a variety of other non-inherited reasons.


Patients with primary HLH have cells of the immune system called T and NK cells that don’t work properly. These cells become overactive, causing too much inflammation. Ordinarily, these cells should destroy infected, damaged cells of the body. In HLH, the immune system begins to damage the patient’s own tissues and organs, including the liver, brain and bone marrow where blood is made.

Symptoms of HLH

HLH can be challenging to diagnose because the initial symptoms may mimic other problems such as common infections.  Signs and symptoms of HLH may include: 

  • Persistent fevers

  • Rash

  • Enlarged liver

  • Enlarged spleen

  • Enlarged lymph nodes

  • Anemia

  • Low platelets

  • Low white blood cells

  • Jaundice

  • Hepatitis

  • Liver failure

  • Respiratory issues

  • Seizures

Diagnosis and Treatment

It is sometimes difficult to establish the diagnosis of hemophagocytic lymphohistiocytosis (HLH), and the combination of the physical symptoms and certain laboratory tests is required.   A set of diagnostic criteria was recommended by the Histiocyte Society for use in the HLH-2004 research protocol, and this was revised in 2007.  This includes diagnosis of a specific gene defect and/or the presence of at least five of the following eight criteria:  

  • Low or absent NK (natural killer) cell function.

  • Prolonged fever.

  • Blood cell abnormalities (low white cells, low red cells, low platelets).

  • Enlarged spleen.

  • Increased triglycerides (fat) or decreased fibrinogen (protein necessary for clotting) in the blood.

  • Increased ferritin (protein that stores iron) in the blood.

  • Abnormal bone marrow test evidence of hemophagocytosis but not malignancy or other cause.

  • Abnormally high CD25 (also known as sIL2ra) in the blood indicating abnormally increased T-cell activation

Since it is difficult to tell the difference between secondary HLH and familial HLH, any case of HLH should be considered for genetic testing to confirm the diagnosis.  Since 1999, at least seven defective genes have been identified.

Treatment is very important for patients with HLH because the condition is life-threatening. The treatments that doctors use suppress the immune system. Patients are usually treated with steroids, chemotherapy (etoposide) and/or antibody therapies that target and destroy T cells (anti-thymocyte globulin / ATG as well as alemtuzumab). Patients may receive other medications that suppress the immune system. Additionally, your doctor may give medications that help prevent and/or treat any infections.

Many patients must also have their immune systems replaced by receiving a hematopoetic (blood or bone marrow) stem cell transplant in order to be cured of HLH. Your doctor can tell you if this is the case for you or your child.

All information was retrieved from Histiocytosis Association and Cincinnati Children's Hospital.

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