Hemophagocytic Lymphohistiocytosis (HLH): A guide

The immune system is what keeps us healthy. Influenza, infectious bacteria, the common cold—the immune system is the body’s defense against germs and pathogens. In the condition of hemophagocytic lymphohistiocytosis, the immune system does not function properly. A type of white blood cell known as histiocytes attack healthy cells and tissues causing life-threatening organ damage, susceptibility to infection, and problems with the central nervous system.

What is Hemophagocytic Lymphohistiocytosis?

White blood cells are made in the bone marrow. Their role is to protect the body against viruses and bacteria. Hemophagocytic lymphohistiocytosis, however, is a rare immunological condition in which the body produces activated immune cells—the types of white blood cells called lymphocytes and histiocytes specifically. These overactive cells begin to kill healthy tissues rather than pathogens and release inflammatory proteins like cytokines. The cells target the bone marrow, as well as the liver, spleen, the lymphatic system, nervous system, lungs, and skin.

Symptoms of Hemophagocytic Lymphohistiocytosis

• Fever
• Fatigue
• Splenomegaly (enlarged spleen)
• Hepatomegaly (enlarged liver)
• Liver failure
• Rash
• Swollen lymph nodes
• Coughing
• Difficulty Breathing
• Low blood cell counts (i.e. white blood cells, red blood cells, platelets)
• Anemia
• Easy bruising or bleeding
• Increased risk for malignancies (i.e. lymphoma or leukemia)
• Frequent infections
• Renal (kidney) dysfunction
• Heart problems

Hemophagocytic Lymphohistiocytosis and the Central Nervous System

Aside from the major organs, hemophagocytic lymphohistiocytosis also affects the central nervous system. Studies show approximately two-thirds of patients have neurological symptoms derived from inflammation of the central nervous system (Home et al., 2017). A prominent sign of neurological involvement is full-body weakness and uncontrolled muscle movements (ataxia).

Patients may later experience encephalopathy—an altered mental state characterized by brain dysfunction. These symptoms include mood swings and irritability, difficulty concentrating, and reduced consciousness. Adults with hemophagocytic lymphohistiocytosis are more prone to encephalopathy than children. The younger patient population is typically afflicted with seizures, which are the most common manifestation of neurological dysfunction, but all with HLH can experience any number of symptoms.

What Causes Hemophagocytic Lymphohistiocytosis?

The various forms of hemophagocytic lymphohistiocytosis are classified as either primary or secondary based on the underlying cause. Causes range from genetic mutations to conditions that alter the immune system. Despite a primary or secondary cause, the symptoms of HLH are identical.

Primary Hemophagocytic Lymphohistiocytosis

According to the Immune Deficiency Foundation, primary hemophagocytic lymphohistiocytosis occurs in about 1 to 50,000 births worldwide. Primary hemophagocytic lymphohistiocytosis is evident early in life. It is caused by one of five genetic mutations in the genes that provide instruction for proteins to turn off activate immune cells. Whether a patient has type 1-5 depends on the specific gene: chromosome 9 defects, PRF1, UNC13D, STX11, STXBP2.  

Secondary Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is not always due to genetics. The condition is secondary when there are no detectable genetic mutations. Because HLH is an inappropriate immune response, secondary cases result from other factors that influence the immune system. Viral illnesses are a significant cause of secondary hemophagocytic lymphohistiocytosis, but certain cancers and autoimmune diseases are frequent causes too.

Secondary hemophagocytic lymphohistiocytosis is caused by:  

• Epstein-Barr virus
• Cytomegalovirus
• Autoimmune disorders (i.e. Lupus, juvenile arthritis, Still disease)
• Immunodeficiencies
• Metabolic diseases
• Lymphoma
• Other cancers
• Medications that suppress the immune system
• Fungal infections

Diagnosing Hemophagocytic Lymphohistiocytosis

Physicians rely on a set of criteria to diagnose hemophagocytic lymphohistiocytosis. Patients must meet 5 of the 8 criteria to receive a diagnosis:  

1. Fever (peak temperature of > 38.5° C for at least 7 days)
2. Splenomegaly (spleen palpable > 3 cm below costal margin)
3. Cytopenia involving 2 or more cell lines (hemoglobin < 9 g/dl, absolute neutrophil < 100 mcL, platelets < 100,000 mcL)
4. Hypertriglyceridemia (fasting triglycerides > 177 mg/dL) or hypofibrinogenemia (fibrinogen < 150 mg/dL)  
5. Hemophagocytosis in biopsy samples of bone marrow, lymph nodes, or spleen
6. Low or absent natural killer cell activity
7. Serum ferritin greater than 500 ng/mL
8. Increased soluble interleukin-2 levels (above 2400)

Specialized testing helps assess the diagnostic criteria.

Bloodwork

Bloodwork is the first line of testing to diagnose hemophagocytic lymphohistiocytosis. By obtaining a blood sample, physicians measure the blood cell counts to determine if they are low, as well as triglyceride levels, fibrinogen levels, and serum ferritin. Bloodwork is also used to measure liver functions to determine if liver damage is present.

Bone Marrow Biopsy

The blood labs that are out of range indicates the need for a bone marrow biopsy. The bone marrow is located in the soft tissue of the large bones. It creates the majority of the blood cells. A bone marrow biopsy entails removing a portion of bone marrow from the bone by inserting a needle into the lower back. The sample is examined for abnormalities under a microscope. The patient is given a numbing medication to ensure they do not feel pain during the procedure.

For the diagnosis of hemophagocytic lymphohistiocytosis, the bone marrow biopsy may reflect hemophagocytosis, which is phagocytosis—the process in which a cell engulfs particles, specifically erythrocytes, leukocytes, platelets, and their precursors in the bone marrow by macrophages (white blood cells meant to digest cellular debris, viruses, and bacteria).

Imaging

Medical neuroimaging such as computed tomography (CT) and magnetic resonance imaging (MRI) aid in the diagnosis by allowing physicians to see structures in the body. Imaging frequently reveals abnormalities in patients with hemophagocytic lymphohistiocytosis (Bell & Weerakkody, 2016):

• Chest: pulmonary edema, infection, pleural effusions, nodules, lymphadenopathy
• Abdomen: enlarged liver or spleen (hepatosplenomegaly), gallbladder wall thickening, a buildup of fluid within the abdomen (ascites)
• Brain: Non-specific white matter abnormalities, enlargement of fluid spaces, loss of brain volume

Lumbar Puncture

To perform a lumbar puncture, a needle is inserted between the vertebrae to remove a sample of cerebrospinal fluid. For diagnosing hemophagocytic lymphohistiocytosis, a lumbar puncture is taken when the patient exhibits neurological symptoms. A lumbar puncture measures levels of cells and protein in the cerebral spinal fluid, evaluates for hemophagocytosis, and rules out infections like meningitis.   

Treatments for Hemophagocytic Lymphohistiocytosis

Urgent treatment is imperative in hemophagocytic lymphohistiocytosis, as the condition quickly becomes life-threatening without intervention. The exact therapies are chosen by the patient’s disease presentation. More severe cases require harsher treatment than milder cases.

Medications

A combination of therapies that suppress the immune system is part of the typical treatment regimen. This can entail chemotherapy, corticosteroids, immunosuppressives, and intravenous immunoglobins to protect against infection.

Chemotherapy

The goal of hemophagocytic lymphohistiocytosis treatment is to destroy the overactive immune cells to reduce life-threatening, systemic inflammation. Treating physicians often prescribe chemotherapy to kill the overactive cells.

Corticosteroids and Other Immunosuppressives

In addition to chemotherapy, high doses of steroids often have a favorable response. Corticosteroids reduce inflammation throughout the body, which is essential for patients with hemophagocytic lymphohistiocytosis suffering from the release of inflammatory proteins. Immunosuppressive drugs may also be considered. The immunosuppressive drugs are especially beneficial for secondary cases of hemophagocytic lymphohistiocytosis because they treat the underlying causative disease or bind to the viruses that invade the patient’s cells.

Intravenous Immunoglobulin (IVIG), Antibiotics, and Antivirals

Suppressing the immune system with high doses of immunosuppressives is not without repercussions. With the cytopenias typical of the condition in combination with chemotherapy reducing cell counts, the patient is prone to secondary infections. As infections occur, patients are given antibiotics and antiviral treatment. An infusion of immunoglobulins (IVIG), which are healthy antibodies to fight infections, successfully assist the weakened immune system.

Blood Transfusions

Supportive measures like blood transfusions are needed when cell counts are severely decreased. Blood from a donor is infused directly into the veins via an IV. The replacement blood boosts depleted blood cells (i.e. white cells, red cells, platelets, etc.) that were destroyed by the overactive immune system.

Stem Cell Transplant

If hemophagocytic lymphohistiocytosis proves treatment-refractory, a stem cell transplant cures the condition. HLH patients receive allogeneic hematopoietic cell transplantation. The transplant replaces the diseased immune system with healthy cells from a genetically similar donor. These cells can be obtained from the bone marrow, peripheral blood, or umbilical cord blood. Before transplantation, the patient undergoes a course of chemotherapy to kill off excess immune cells that cause inflammation.

References

Bell, D.J. & Weerakkody, Y. (2016). Hemophagocytic lymphohistiocytosis. Retrieved from https://radiopaedia.org/articles/haemophagocytic-lymphohistiocytosis?lang=us

Horne, A., Wickström, R., Jordan, M. B., Yeh, E. A., Naqvi, A., Henter, J. I., & Janka, G. (2017). How to Treat Involvement of the Central Nervous System in Hemophagocytic Lymphohistiocytosis?. Current treatment options in neurology, 19(1), 3. doi:10.1007/s11940-017-0439-4

Cheyanne Perry

Cheyanne is currently studying psychology at North Greenville University. As an avid patient advocate living with Ehlers Danlos Syndrome, she is interested in the biological processes that connect physical illness and mental health. In her spare time, she enjoys immersing herself in a good book, creating for her Etsy shop, or writing for her own blog.