Hemophagocytic Lymphohistiocytosis

What is hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a condition that occurs when your immune system abnormally overreacts. Your immune system defends your body from things that make you sick, like bacteria and viruses. Cells, proteins, organs and tissues work together to keep you healthy. If you have HLH, an infection can trigger your immune system to produce too many cells. Instead of fighting the infection, these new cells attack your body and make you even more ill. HLH can be life threatening.

What are the types of hemophagocytic lymphohistiocytosis?

There are two types of hemophagocytic lymphohistiocytosis:

• Primary (familial): Primary HLH occurs if a genetic mutation caused the condition. You’re born with a genetic predisposition to primary HLH and symptoms usually arise during the first few years of life. Rarely do the symptoms develop later in adulthood.
• Secondary: Secondary HLH occurs when you have an underlying medical condition that affects the function of your immune system. Common conditions that can cause secondary HLH include cancers, infections (most commonly Epstein-Barr virus) or autoimmune conditions. Secondary HLH is more common than primary HLH.

Who does hemophagocytic lymphohistiocytosis affect?

Hemophagocytic lymphohistiocytosis can affect anyone at any age, but it most often affects children and infants.

How common is hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis is rare. The exact rate of occurrence is unknown since it’s often misdiagnosed or underdiagnosed. About 75% of people diagnosed with HLH have secondary HLH. Only 25% of people diagnosed with HLH have primary HLH, which equals about 1 in 50,000 people worldwide.

What are the symptoms of hemophagocytic lymphohistiocytosis?

Symptoms of hemophagocytic lymphohistiocytosis range in severity and vary from person to person. The most common symptoms could include:

• Fever that doesn’t respond to antibiotics.
• A rash.
• A large liver (hepatomegaly).
• A large spleen (splenomegaly).
• Enlarged lymph nodes.

Additional symptoms could include:

• Anemia.
• Thrombocytopenia.
• Weakness.
• Lightheadedness or dizziness.
• Irritability.
• Headaches.
• Pale skin.
• Jaundice.

Life-threatening signs of HLH include:

• Difficulty breathing (dyspnea).
• Seizures.
• Retinal hemorrhages.
• Loss of consciousness.
• Coma.

Visit the emergency room immediately if you have any of these life threatening symptoms. Visit your provider if you have common symptoms of HLH because an early diagnosis and treatment lead to the best outcomes for HLH.

What causes hemophagocytic lymphohistiocytosis?

An overactive or irregularly functioning immune system causes hemophagocytic lymphohistiocytosis. There are two forms of HLH with different causes. Both lead to an overproduction of your immune system’s cells, called histiocytes and T cells, which attack your body instead of attacking a foreign invader like a virus. These white blood cells don’t have the correct instructions in your DNA to perform their jobs as they should, which causes symptoms of HLH.

Causes of primary HLH

A genetic mutation causes primary HLH. Genetic mutations that cause primary HLH include:

• CD27.
• ILK.
• LYST.
• PRF1.
• RAB27.
• SH2D1A.
• STX11.
• STXBP2.
• UNC13D.

These genes provide instructions for your cells to create proteins. Proteins help your immune system destroy foreign invaders, like bacteria and viruses, to keep you healthy. When a mutation targets one of these genes, your cells don’t have the full instructions to produce these proteins. Any proteins that your cells produce aren’t complete or aren’t able to perform their function within your body.

These genetic mutations pass from both biological parents to the child during conception in an autosomal recessive pattern.

Causes of secondary HLH

Secondary HLH is an acquired condition. You’re not born with a genetic predisposition to HLH and it doesn’t run in your family history. Instead, you develop the condition after an abnormal immune system response. Research is ongoing to learn more about why this happens.

Sometimes, a medical condition can trigger secondary HLH. Such conditions include:

• Epstein-Barr virus.
• Bacterial, viral and fungal infections.
• A weakened immune system.
• An autoimmune condition.
• An autoinflammatory disease.
• Rheumatological diseases (juvenile idiopathic arthritis).
• Metabolic disorders.
• Cancer (non-Hodgkin lymphoma).

How is hemophagocytic lymphohistiocytosis diagnosed?

A healthcare provider will make a hemophagocytic lymphohistiocytosis diagnosis after performing a physical exam and ordering tests to learn more about your symptoms. A provider will test for the following diagnostic criteria including:

• A fever.
• A large spleen.
• Low red blood cell count, low white blood cell count or low platelet levels (cytopenia).
• High levels of triglyceride fat in your blood (hypertriglyceridemia) or a low level of a blood clotting protein (hypofibrinogenemia).
• Damaged or destroyed blood cells (hemophagocytosis) in your bone marrow.
• Low T cell activity in your blood.
• High levels of ferritin in your blood (ferritinemia).
• High level of soluble interleukin-2 receptor (sCD25) in your blood.

If you have at least five of these symptoms, your provider will suspect HLH.

Tests to diagnose hemophagocytic lymphohistiocytosis

Tests that lead to an HLH diagnosis could include:

• A genetic test.
• A complete blood count.
• Additional blood tests to determine ferritin, triglycerides, signs of infection and how well your blood clots.
• A liver function test.
• A bone marrow biopsy.

How is hemophagocytic lymphohistiocytosis treated?

Treatment for hemophagocytic lymphohistiocytosis could include:

• Taking medications to treat an infection (antibiotics or antivirals) or to reduce the activity of your immune system (immunosuppressants or cytokine inhibitors).
• Management or treatment for any underlying conditions such as chemotherapy for cancers.
• Blood transfusion.

A gamma-blocking antibody medication called emapalumab (Gamifant®) was approved for both infants and adults diagnosed with HLH to treat the condition.

If medications or condition management isn’t successful, providers may consider an allogeneic stem cell transplant. This procedure uses donor stem cells found in bone marrow to replace your stem cells. Usually, high doses of chemotherapy or radiation wipe out your unhealthy stem cells to make room for healthy donor stem cells. This procedure comes with a high risk and many possible side effects, which your provider will discuss with you so you can make a decision about your health.

How can I prevent hemophagocytic lymphohistiocytosis?

There isn’t a way to prevent hemophagocytic lymphohistiocytosis since you have no control over the causes. You can reduce your risk of developing an infection that could trigger secondary HLH by:

• Eating a well-balanced diet and exercising regularly.
• Avoiding contact with people who are ill with a virus.
• Wearing protective gear to prevent injuries.
• Properly cleaning and caring for any injuries to prevent infections.
• Managing any underlying conditions.

What is the prognosis for hemophagocytic lymphohistiocytosis?

With an early diagnosis and treatment, you may have a fair to good prognosis depending on the severity of your symptoms. If left untreated, HLH is life-threatening and could result in organ failure and ultimately death after only a couple of months.

Your healthcare provider will help you understand your diagnosis and what treatments are available for your symptoms. They’ll also explain the risks and side effects of your treatments to help you understand the procedures or medications.

Many people diagnosed with HLH choose supportive care for themselves and their families. This could include speaking with a mental health professional, genetic counselor or social worker to help them plan and cope with the potential risks and outcomes of this condition.

Is there a cure for hemophagocytic lymphohistiocytosis?

With proper treatment and care, HLH can go away, but it can return if something triggers the condition. Stem cell transplantation has successfully prevented HLH from recurring and causing life-threatening consequences in some people. Research is ongoing to learn more.

When should I see my healthcare provider?

Visit your healthcare provider if you have symptoms of HLH. Don’t wait to see a doctor because early diagnosis and treatment will lead to a better outcome. If you have trouble breathing, loss of consciousness or seizures, visit the emergency room immediately.

What questions should I ask my doctor?

• What tests do I need?
• What treatment do you recommend?
• What are the side effects of the treatment?
• What’s my life expectancy?

A note from Cleveland Clinic

It can be upsetting and painful to learn that you or a loved one has a rare, life-threatening condition. Many people find comfort in speaking with a mental health professional, genetic counselor or provider about how to cope with this news. They may also discuss how they can care for themselves and their families, and want to learn more about their treatment and prognosis. If you have any questions during this difficult time, reach out to people close to you or within your care team for support.