A diagnosis of primary hemophagocytic lymphohistiocytosis (HLH) may feel scary or overwhelming, but there are resources and therapies that can help in the days ahead. The following information is for you and your family to learn about primary HLH, its signs and symptoms, and what you might expect after an HLH diagnosis.

This information does not replace the guidance of your medical team. Primary HLH can be different for everyone, so work with your doctors to make sure you or your child are getting the best care possible.

Understanding primary HLH

Primary HLH is known to be a rare genetic disease that generally affects infants and children, although it can affect adults as well. The disease occurs when a person’s immune system does not work properly.

  • When the immune system is working properly, it finds and attacks foreign invaders like a virus or other problem
  • In people with primary HLH, the immune system does not work properly and attacks a person’s own cells and organs
What does primary HLH stand for?

Here‘s how to pronounce primary HLH

What we know about the disease so far

Researchers are still working to fully understand HLH. Historically, HLH has been split into 2 main types: primary and secondary. Although the symptoms for both may be similar, it is thought that each has a different cause and may require different approaches to treatment.

  • Primary HLH could be inherited from a parent to a child, although not all genetic errors that may cause primary HLH are known
  • Secondary HLH could be triggered by another disease or infection

To understand more about your or your loved one’s condition, it’s important to know what happens in the body of someone with primary HLH and what some of the symptoms can be.

How primary HLH works

Primary HLH (also called familial HLH) can happen because of a genetic mutation, a family history consistent with primary HLH, or if a person meets certain medical criteria. Research is still being done to help provide further information. Generally, primary HLH can affect infants, but other people can be diagnosed with primary HLH later in life as well.

What happens in the body?
  • Every person has their own immune cells, which work inside the immune system. They travel throughout the body looking for problems, like harmful cells. When they find something suspicious, they bring it to the attention of T cells
  • The job of T cells is to search out and destroy the invaders, but they need help. T cells release inflammatory messenger proteins called cytokines that activate macrophages to help the T cells get rid of the problem
  • Macrophages are large cells that eat problem cells and white blood substances in the immune system

Learn more about how primary HLH affects the body

How does primary HLH cause a cytokine storm?

In a person’s immune system, T cells and macrophages work together to keep the body safe. In an immune system affected by primary HLH, the macrophages and T cells aren’t able to get rid of the problem. So, the body creates more macrophages and cytokines to destroy the invader, which causes inflammation.

  • In primary HLH, T cells do not shut off. Instead, they keep releasing more and more cytokines, especially one called interferon gamma (IFNγ)
  • This, in turn, activates more macrophages, and these macrophages release more inflammatory cytokines
  • The excess release of cytokines creates a cytokine storm, which overwhelms the body’s normal shut-off mechanism, causing inflammation to get out of control
  • As a result, long-lasting fever, organ damage, and other symptoms that happen with primary HLH can occur

Learn more about how primary HLH affects the body

Signs and symptoms of primary HLH

While everyone’s condition is different, there are some common signs and symptoms that you and your doctor can look for.

Signs and symptoms may include:
  • High fever that lasts a long time
  • Rash
  • Seizures and neck stiffness
  • Changes in mental state, such as confusion, memory loss, or disorientation
  • Enlarged spleen
  • Swollen lymph nodes
  • Anemia and a very pale appearance
  • Coughing and difficulty breathing
  • Muscle weakness and trouble walking
  • Visual disturbances, such as blurred vision
  • Jaundiced appearance (yellowing of the eyes and skin), hepatitis, liver failure, enlarged liver
  • Problems with clotting due to low levels of a protein called fibrinogen
  • Stomach ache, vomiting, or diarrhea
  • Failure to grow or to gain or maintain weight (in infants and young children)
  • Elevated levels of ferritin, a protein that stores iron (hyperferritinemia)
  • A reduction in the number of mature blood cells (cytopenia)
Signs and symptoms may include:
  • High fever that lasts a long time
  • Rash
  • Seizures and neck stiffness
  • Changes in mental state, such as confusion, memory loss, or disorientation
  • Muscle weakness and trouble walking
  • Visual disturbances, such as blurred vision
  • Jaundiced appearance (yellowing of the eyes and skin), hepatitis, liver failure, enlarged liver
  • Problems with clotting due to low levels of a protein called fibrinogen
  • Enlarged spleen
  • Swollen lymph nodes
  • Anemia and a very pale appearance
  • Coughing and difficulty breathing
  • Stomach ache, vomiting, or diarrhea
  • Failure to grow or to gain or maintain weight (in infants and young children)
  • Elevated levels of ferritin, a protein that stores iron (hyperferritinemia)
  • A reduction in the number of mature blood cells (cytopenia)

Signs and symptoms are not limited to only those listed above.

Symptoms of primary HLH can be serious and should be evaluated by a doctor. People are usually admitted to the hospital for further evaluation and treatment.

Diagnosis

Primary HLH can be difficult to diagnose. It can also be mistaken for other conditions such as viral infection, sepsis, or cancer. Many people may see multiple doctors before the disease is identified. To help diagnose primary HLH, doctors will work to rule out infections, malignancies, or other conditions that could be causing symptoms, and may order genetic testing to find out more.

  • If certain conditions or infections are found, a person may have secondary HLH
  • If your doctor decides that genetic testing is appropriate for you or your child, tests can include targeted individual gene sequencing, HLH gene panel testing, and clinical whole-exome sequencing (WES). These types of tests can help determine if you or your child have certain gene mutations that may contribute to a primary HLH diagnosis
  • It can be several weeks before the results of a genetic test come in. Meanwhile, managing inflammatory signs and symptoms like fever, rashes, stomach problems, spleen enlargement, and others, is very important
  • Your doctor may also start treatment before results of the genetic testing are in to help manage symptoms
Should other members of your family be tested for primary HLH?

Because primary HLH may be inherited from parents, it may be a good idea to have other members of your immediate family tested.

Talk to your doctor or genetic counselor about potential next steps for your family.

Specific criteria for diagnosis

Generally, if a person meets 5 out of the 8 medical criteria below, doctors may consider a diagnosis of primary HLH. These criteria include:

  • Long-lasting fever
  • Enlarged spleen
  • Lower numbers of mature blood cells (cytopenias)
  • An elevated level of triglycerides in the bloodstream
  • Hemophagocytosis in the spleen, bone marrow, or lymph nodes
  • Low or absent natural killer cell count
  • Elevated ferritin levels
  • Elevated soluble CD25 level

Your doctor is your number-one source of medical information. Talk with your doctor to learn more about diagnosing primary HLH.

Other medical tests

To help determine an appropriate diagnosis, your doctor may run additional tests, including:

  • Ferritin level testing
  • Bone marrow testing
  • Blood and liver function testing

Since primary HLH can be difficult to identify and diagnose, it's important to work closely with your healthcare team to learn all you can. If you think that your or your child's symptoms are getting worse, tell your doctor right away.

Treating primary HLH

Primary HLH is different for everyone, and some people may explore multiple treatment options with their doctor to achieve the goal of suppressing harmful inflammation associated with primary HLH, and to eventually help patients proceed to transplant.

Understanding treatment goals

Your individual experience can vary during treatment. However, this is generally how some journeys may unfold:

Remember that communication is key. Paying close attention to your or your child's disease progression and response to treatment is important so that you and your doctor can make informed decisions about your or your child's care.

Conventional treatment

In the past, doctors had limited options for helping patients with primary HLH. However, between 1994 and 2004, doctors identified 3 types of treatment that could potentially keep patients stable until it was time for transplant*:

A steroid called
dexamethasone

An immunosuppressant
called cyclosporine

A chemotherapy
called etoposide

While these treatments have helped many patients, they were not specifically designed to treat primary HLH and are not approved by the Food and Drug Administration (FDA) for the disease.

*The HLH-94 protocol included an 8 week induction therapy with dexamethasone, etoposide, and intrathecal methotrexate (in selected patients), followed by cyclosporine A given as maintenance therapy. The HLH-04 protocol includes dexamethasone, etoposide and cyclosporine A as induction therapy along with methotrexate and corticosteroids in selected patients.

Gamifant® (emapalumab-lzsg)

Gamifant could help:

  • People who need something other than conventional treatment due to unacceptable side effects or lack of results
  • Those who responded to conventional treatment at first, but their symptoms returned
  • People who experience rapidly progressive disease

Talk to your doctor to find out if Gamifant is right for you or your child, and learn more about Gamifant here.

Information about transplant

Hematopoietic stem cell transplantation (HSCT) is a procedure that infuses healthy blood stem cells into your or your child’s body to replace damaged or diseased bone marrow, and it is the only curative treatment for primary HLH. A transplant may be necessary if you or your child’s bone marrow stops working due to primary HLH.

Two of the most important things that can help make a transplant successful are:

Managing signs and symptoms

Finding a donor whose blood or bone marrow is a genetic match for you or your child

It may take some time to find a donor who is an appropriate genetic match. It’s important to work with your doctors to manage symptoms if you’re waiting for a donor.
Check out some other resources related to transplant.

It may take some time to find a donor who is an appropriate genetic match. It’s important to work with your doctors to manage symptoms if you’re waiting for a donor.
Check out some other resources related to transplant.

Your healthcare team

It can take a team of highly knowledgeable specialists across many different practices to help you or your child get the best possible care during treatment. Depending on your or your child's specific symptoms, you may work with specialists including:

Hematologist/Oncologists

These doctors specialize in conditions like primary HLH and will help direct your or your child’s treatment plan.

Genetic counselors

A genetic counselor can help you understand the results of a genetic test that confirms a diagnosis, and what to expect based on the results.

Social workers

Social workers can help you get the support you might need during this time. This could include emotional support, help finding financial resources, and more.

Nurses

Multiple nurses may be involved in your or your child’s care. Nurses will assist your doctor with general care, setting up and monitoring infusions, and appropriate care at home.

Transplant team

If you or your child requires a transplant, this team of specialists will guide you through the process. A transplant team may consist of coordinators, surgeons, and other doctors and specialists.

Other important specialists
  • Rheumatology
  • Infectious disease
  • Intensive care
  • Gastroenterology/hepatology
Hematologist/Oncologists

These doctors specialize in conditions like primary HLH and will help direct your or your child’s treatment plan.

Nurses

Multiple nurses may be involved in your or your child’s care. Nurses will assist your doctor with general care, setting up and monitoring infusions, and appropriate care at home.

Genetic counselors

A genetic counselor can help you understand the results of a genetic test that confirms a diagnosis, and what to expect based on the results.

Transplant team

If you or your child requires a transplant, this team of specialists will guide you through the process. A transplant team may consist of coordinators, surgeons, and other doctors and specialists.

Social workers

Social workers can help you get the support you might need during this time. This could include emotional support, help finding financial resources, and more.

Other important specialists
  • Rheumatology
  • Infectious disease
  • Intensive care
  • Gastroenterology/hepatology

Stay proactive: communication is key
Paying close attention to your or your child’s disease progression and response to therapy is important so that you and your doctor can make informed decisions about your or your child’s care.

If you or your child has been diagnosed with primary HLH, see how Gamifant could help

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