how to detect hlh?

There are two types of HLH. “Primary,” or “familial,” HLH is caused by an inherited problem of the immune system. “Secondary” HLH can occur when the immune system is disturbed (e.g., infections), but not necessarily because of an inherited condition. Both types of HLH are life-threatening. HLH can lead to liver failure, breathing problems, inflammation in the brain, and the inability to fight infection.

HLH happens more often in infants and children. But it can occur at any age, including in the teenage years and adulthood.

HLH is considered a rare disease. Statistics say it occurs in about one in 50,000 children. Because of that, many healthcare providers are unfamiliar with its symptoms, and it often goes undiagnosed for too long.

HLH can be challenging to diagnose because the initial symptoms may mimic common infections. Symptoms of HLH that you may notice in your child include:

Other issues that your child’s doctor may find include:

Because HLH is so rare, many healthcare providers don’t recognize its symptoms. HLH can “look like” certain cancers in the early stages of the illness. For these reasons, the disease often is misdiagnosed or goes undiagnosed for too long.

HLH can only be diagnosed with proper blood tests in the appropriate clinical setting. Doctors might collect some fluid from the spinal canal to look for HLH in the brain. It is important to remember certain malignancies (including leukemia and lymphoma) can mimic HLH, therefore these conditions should be appropriately investigated during the work-up of a suspected patient with HLH.

Doctors must use the following tests to diagnose HLH and develop a personalized treatment plan.

“Primary” or “familial” HLH is caused by inherited problems in genes that control how the immune system kills virus-infected or other abnormal cells in a person’s body. These genes include PRF1, MUNC13-4, STXBP2 and STX11. Primary HLH also occurs in some closely related inherited diseases. These include:

“Secondary” HLH can occur when the immune system is disturbed (e.g., infections), but not necessarily because of an inherited condition.

The T and NK cells in patients with primary HLH can’t kill virus-infected or other abnormal cells like they normally would. T cells and NK cells usually do this by secreting death signals into targeted abnormal cells. When they can’t do this they get ‘overexcited’ and this leads to severe and unusual inflammation.

The proteins made by the MUNC13-4, STXBP2, STX11, Rab27a and LYST genes work like the machinery of a conveyor belt and are responsible for the secretion of the death signals produced by T and NK cells. The PRF1 gene makes a protein called perforin. It works like a key that allows the secreted death signals to enter inside a targeted abnormal cell, where the death signals can work.

SH2D1A is responsible for a more specialized killing mechanism and controls how the T cells themselves die. It is not yet entirely clear why XIAP mutations cause HLH.

Prompt treatment is very important for patients with HLH, as the condition is often fatal. The first treatments are typically used to stop the inflammation in the body. These treatments suppress the immune system which helps decrease the damage to a patient’s body.

Treatment may include:

The diagnosis of HLH is often challenging. HLH symptoms may mimic bad infections or even some kinds of cancers. Additionally, HLH can occur in patients with rheumatologic or autoimmune disorders.

Laboratory, radiologic and pathologic studies should be performed to evaluate for hidden infections or malignancies.

Laboratory evaluations can help with the diagnosis of HLH. These include:

Brain magnetic resonance imaging (MRI) may show evidence of HLH. Bone marrow aspirates and biopsies may show evidence of hemophagocytosis (macrophage engulfment of other cells), but this is not a required observation to make the diagnosis, nor does the absence of the sign rule out HLH.

In many cases, a genetic disorder underlies HLH.

Specialized blood tests can rapidly screen patients for many of the genetic forms of HLH. Flow cytometric testing is available to screen for perforin, XIAP and SAP protein deficiencies. A functional assay to measure the degranulation of NK cells is available (termed a “CD107a assay” in our laboratory). It detects patients with defects in the genes involved in degranulation (MUNC 13-4, STXBP2, STX11, Rab27a and Lyst).

If you suspect a patient has primary or secondary HLH, you can depend on Cincinnati Children’s laboratories for expert testing and clinical interpretation.

Leaders of the Diagnostic Immunology Laboratory and Molecular Genetics Laboratory supervise all aspects of the HLH diagnostic process. They offer expert advice regarding which tests to order for patients, the interpretation of results and how this data may impact treatment decisions.

> Learn more about our Diagnostic Immunology Laboratory

• Blood tests.
• Bone marrow aspirate and biopsy (taking samples from the patient's bone marrow, the organ that makes blood)
• Lumbar puncture.
• Imaging studies.
• Detailed genetic testing.

The body's immune system fights off infections and anything else it sees as foreign invaders to the body. In HLH, the body makes too many immune cells. These immune cells see the body's internal organs as invaders.

The cells attack organs, including the:

HLH is a rare disease that affects about one in 50,000 births.

There are two main types of HLH:

With primary HLH, people can carry a gene for HLH without the disease. If both parents have a defective gene, there is a:

There is no difference in risk between males and females.

Secondary or acquired, HLH happens as a result of other conditions, including:

HLH symptoms often appear within the first few months or years of birth. Symptoms of HLH are much the same as those of other childhood illnesses, making it hard to diagnose.

Some symptoms are:

HLH causes the overactive immune system to attack the body, causing organ damage. Kids with this disease can have nervous system problems, spleen enlargement, and liver and lung damage.

If HLH is causing nervous system problems in your child, you may notice symptoms such as:

After talking to you about your child's medical history and symptoms, your doctor will use a blood test to help diagnose HLH.

If results are positive for HLH, your child might need further blood tests, including genetic testing. Genetic blood tests help doctors learn which genetic mutation is causing the disease or if there's no genetic cause.

The goal of treating HLH is to stop the immune system from attacking the body's organs. The doctor needs to identify and treat this disease quickly because of how fast it progresses.

Treatment may include medicines that suppress the immune system to control the damage it's doing to the body.

Treatments for HLH may include:

Some cases of HLH — mostly the type that's not genetic — go away after treatment and won't need further care.

If medicine doesn't resolve your child's genetic HLH, your doctor will offer other treatment options. A bone marrow or cord blood transplant may cure your child's disease.

Before a bone marrow transplant, your child receives chemo to destroy the immune system. Surgeons then transplant healthy bone marrow into your child.

If your child also has severe lung damage, surgeons might perform a lung transplant simultaneously. The lung tissue may potentially even be from the same donor. The Hillman Center for Pediatric Transplant has the only program in the world that offers tandem lung and bone marrow transplantation.

We also pioneered a reduced-intensity bone marrow transplant program. The program helps reduce the negative effects a bone marrow or stem cell transplant has on the body's organs.

Because transplants are high-risk treatments, your child may need to take medicine for their entire life.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that usually occurs in infants and young children. It may also occur in adults. Children usually inherit the disease. In adults, many different conditions, including infections and cancer, can cause HLH.

If you have HLH, your body's defense system, called your immune system, does not work normally. Certain white blood cells — histiocytes and lymphocytes — attack your other blood cells. These abnormal blood cells collect in your spleen and liver, causing these organs to enlarge.

HLH is a rare disease, and healthcare providers are still learning about its causes. There are 2 types of HLH: familial and acquired. Familial HLH accounts for about 25% of cases and families pass down the condition. If both parents are genetic carriers of HLH, a child has a 25% chance of having the disease, a 25% chance of not having the disease, and a 50% chance of being a carrier. A number of conditions cause acquired HLH. These include:

Fever and enlargement of the spleen are the most common symptoms of HLH. There are many other possible symptoms, including:

Young children and babies may have additional symptoms, like irritability and “failure to thrive." This means they don’t grow and develop normally.

Your healthcare provider bases a diagnosis of HLH on your symptoms, physical exam findings, and several lab tests. A prolonged fever is a commonly occurring symptom. An enlarged liver or spleen (located in the upper left side of the abdomen) are key physical findings. Your healthcare provider conducts blood tests to look for:

Another important test, a bone marrow biopsy, calls for taking a sample of your bone marrow (the center of the bone, where blood cells are made) and examining it under a microscope. Other tests may include genetic testing and blood cultures, which are blood samples, to look for infection in your blood.

Treatment of HLH depends on the cause, your age when the disease starts, and how severe the disease is. The acquired form of HLH may clear up when your healthcare provider identifies the cause and treats the disease. Familial-type HLH is usually fatal if not treated. Treatment for familial or persistent acquired HLH may include:

If drug treatments do not work, your healthcare providers may do a stem cell transplant. In this procedure, healthy bone marrow cells from a donor replace your diseased bone marrow cells. Stem cell transplant can cure HLH in most cases.

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

Additional symptoms could include:

Life-threatening signs of HLH include:

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.

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.

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

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.

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.