Diagnosis guide · Inherited immune disorders
Hemophagocytic lymphohistiocytosis (HLH)
If you or someone you love has just heard this diagnosis, start here. It covers several subtypes, and this guide shows how they differ, so you can find the one on your report.
Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening inflammation in which activated immune cells do not switch off. It has two broad forms. Primary (genetic) HLH, which includes familial HLH, the X-linked lymphoproliferative diseases and pigment disorders such as Chediak-Higashi syndrome and Griscelli syndrome type 2, is caused by inherited gene changes and is most common in children. Secondary (acquired) HLH is more common in adults and is usually triggered by an infection, a cancer or an autoimmune disease, so treatment also targets the trigger. Urgent treatment calms the inflammation first. A donor stem cell transplant can cure primary HLH, and it is also considered for some people whose HLH comes back. The pages below cover the inherited forms.
In short
- HLH is a severe, life-threatening inflammation. Activated immune cells do not switch off, and they can damage organs.
- Primary HLH is inherited and most common in children. Secondary HLH, mostly in adults, is usually triggered by an infection, a cancer or an autoimmune disease.
- Urgent treatment calms the inflammation first. A donor stem cell transplant can cure primary HLH.
5 subtypes
Find the subtype on your report
The exact diagnosis shapes the treatment options. Your care team can explain the name on your report.
Familial HLH (hemophagocytic lymphohistiocytosis)
Familial hemophagocytic lymphohistiocytosis (familial HLH) is an inherited immune disorder in which immune activation does not switch off properly. It can cause severe inflammation and organ damage; it is not a blood cancer.
Donor transplant optionX-linked lymphoproliferative disease type 1 (XLP1)
XLP1 is an SH2D1A-related immune-regulation disorder. It can cause life-threatening inflammatory illness such as HLH, abnormal antibody levels and lymphoma; Epstein–Barr virus is an important trigger, although disease is not limited to one infection.
Donor transplant optionXIAP deficiency (XLP2)
XIAP deficiency is an X-linked disorder of immune regulation, historically called XLP2. It can cause HLH, recurrent inflammation and inflammatory bowel disease, including illness that is not triggered by Epstein–Barr virus.
Donor transplant optionChediak-Higashi syndrome (CHS)
Chediak-Higashi syndrome (CHS) is a rare inherited disorder of the immune system, blood and pigment. It causes infections, easy bleeding, light coloring of the skin, hair and eyes, and a high risk of HLH, a life-threatening inflammation. Nerve problems develop later in life. It is not a blood cancer.
Donor transplant optionGriscelli syndrome type 2 (GS2)
Griscelli syndrome type 2 (GS2) is a rare inherited immune disorder caused by changes in the RAB27A gene. Many people have silvery-gray hair and light skin. Most develop HLH, a life-threatening inflammation that often affects the brain. It is not a blood cancer.
Donor transplant option
For some of these subtypes, a patient needs a donor who is not a relative. The registry that serves your country explains who can join.
See if you can joinWhat to know
Key facts
- How it is confirmed
- 5 of 8 HLH-2004 findings, or a family history or known HLH gene changeInternational HLH-2004 diagnostic guidelines, Histiocyte Society (Pediatric Blood & Cancer, 2007). Source: How it is confirmed
- Two broad forms
- Primary (inherited) and secondary (triggered)As described by Cincinnati Children's (last updated February 2026). Source: Two broad forms
- Common triggers in adults
- Infections and cancers; sometimes autoimmune diseaseAdults with HLH, international Histiocyte Society recommendations (Blood, 2019). Source: Common triggers in adults
- Transplant consultation
- At diagnosis, with an early donor searchU.S. NMDP/ASTCT transplant consultation timing guidelines, accessed 2026-09-26. Source: Transplant consultation
- Primary HLH
- A donor stem cell transplant is the only possible curePrimary HLH, international HLH-2004 study long-term results (Bergsten et al., Blood, 2017). Source: Primary HLH
How HLH is diagnosed
The early signs of HLH can look like common infections. Because HLH is rare, many doctors do not recognize it, and it is often misdiagnosed at first. Cincinnati Children’s, which runs an HLH center, says it can only be diagnosed with specific tests.
Doctors commonly use a checklist from HLH-2004, an international study guideline. HLH is diagnosed when a person has at least 5 of 8 findings. These are fever, a large spleen, low counts in at least two kinds of blood cells, and high blood fats (triglycerides) or low fibrinogen, a clotting protein. Another is immune cells seen eating blood cells (hemophagocytosis). The last three are low or absent natural killer (NK) cell activity, ferritin of 500 µg/L or more, and soluble CD25 of 2,400 U/mL or more. A family history of HLH or a known HLH gene change can also confirm it.
The tests behind this include blood counts, liver tests and markers of immune activity, such as ferritin. Many people also have a bone marrow sample, a spinal tap to check whether HLH affects the brain, and scans. Genetic testing looks for primary (inherited) HLH. Genes include PRF1, UNC13D, STX11 and STXBP2. Changes in SH2D1A or XIAP point to the X-linked forms, XLP1 and XLP2. Changes in LYST or RAB27A point to Chediak-Higashi syndrome or Griscelli syndrome type 2.
In adults, HLH is commonly set off by an infection or a cancer, and sometimes by an autoimmune disease. So the care team also looks for a trigger. Some cancers, such as leukemia and lymphoma, can look like HLH, so doctors test for them too. The HLH-2004 checklist was built for children. Experts note it is commonly used in adults but has not been validated for them.
When transplant specialists are usually consulted
The U.S. transplant consultation guidelines from NMDP and ASTCT list diagnosis as the time to talk with a transplant center about HLH. They say an early donor search is essential for people newly diagnosed with HLH. A donor transplant is used for HLH that comes back or gets worse.
Read the guidanceLooking ahead
Outlook for HLH
HLH is life-threatening, but many more people survive it than in the past. Researchers wrote in 2017 that, three decades earlier, fewer than 5 in 100 people with HLH lived long term. Outlook today depends on the form of HLH, what set it off, the person’s age and how quickly treatment starts.
In the international HLH-2004 study, about 6 in 10 children were alive five years after starting treatment. About half of these children had a donor transplant. In England, about half of people of all ages were alive one year after diagnosis. Survival was higher in children and in adults under 55, and in HLH linked to an autoimmune or inflammatory disease. It was lower in people over 55 and when a blood cancer came with the HLH.
For primary HLH, a donor stem cell transplant is the only treatment that offers the chance to restore normal immune function for good. Cincinnati Children’s says patients who have a successful transplant often go on to lead full, productive lives. For secondary HLH, treatment aims at both the inflammation and its trigger. Finding and treating it promptly may improve the outlook.
About these numbers. Each one says which group of people it comes from, and the place and years where the source gives them. It describes what happened across that group, not what will happen to any one person. And a figure measured among people who had a transplant is not the same as the number of people who need one.
- 61%Alive 5 years after starting HLH treatment (estimated)
369 children under 18 treated on the international HLH-2004 study in 27 countries, enrolled 2004–2011; includes inherited and other forms of HLH; about half had a transplant
Read the source: Alive 5 years after starting HLH treatment (estimated) - 50%Alive 1 year after diagnosis, all ages
1,628 people of all ages diagnosed with HLH in England, 2003–2018 (national hospital, cancer registry and death records); crude survival, deaths from any cause counted
Read the source: Alive 1 year after diagnosis, all ages
These numbers describe large groups, some treated many years ago. They mix very different forms of HLH, and they cannot predict how any one person will do.
Common questions
What is HLH?
HLH stands for hemophagocytic lymphohistiocytosis. It is a severe, whole-body inflammation that can be fatal. Immune cells become overactive and do not switch off. Instead of only fighting germs, they attack the body, including blood cells, bone marrow, the liver, the spleen and even the brain. HLH is most common in babies and children, but it can happen at any age.
Is HLH a type of cancer?
No. HLH is a disorder of the immune system, not a cancer. But a cancer can set off HLH, especially in adults. Treatment often includes a chemotherapy medicine called etoposide, along with steroids. Here it is used to calm the overactive immune system, not because HLH is a cancer.
What causes HLH?
There are two broad forms. Primary HLH is inherited. It comes from changes in genes such as PRF1, UNC13D, STXBP2 and STX11. Changes in SH2D1A or XIAP cause the X-linked forms, XLP1 and XLP2. Changes in LYST or RAB27A cause Chediak-Higashi syndrome or Griscelli syndrome type 2, which also lighten the skin and hair. Secondary HLH happens when something strongly switches on the immune system, such as an infection, a cancer or a rheumatic (autoimmune) disease, without a known inherited cause. Epstein-Barr virus (EBV) is one of the main viral triggers.
What are the symptoms of HLH?
A high fever that does not go away is typical. Other signs include rash, an enlarged liver and spleen, yellow skin or eyes (jaundice), swollen lymph nodes and low blood counts. Some people have confusion, seizures or other brain problems. Early signs can look like common infections. This is one reason HLH is often diagnosed late.
What is the survival rate for HLH?
It depends on the form of HLH, the trigger and age. Many more people survive HLH than in the past. In England, one-year survival was about 1 in 4 for people over 55 and about 7 in 10 when HLH came with an autoimmune or inflammatory disease. The outlook section on this page gives the figures, with the groups they describe. No number can predict how one person will do.
Does HLH always need a bone marrow transplant?
No. For primary HLH, a donor stem cell transplant is the only treatment that offers the chance to restore normal immune function for good. With medicines alone, primary HLH is expected to come back. European transplant guidance (EBMT, 2025) calls primary HLH a clear reason for a donor transplant, including from an unrelated or other alternative donor. For secondary HLH, treatment calms the inflammation and targets the trigger. A transplant is mainly used when HLH comes back or keeps getting worse. In the HLH-2004 study, about 4 in 10 children without a known inherited form were alive and off treatment for over a year without a transplant.
Are there newer medicines for HLH?
Yes, in some countries. In the U.S., emapalumab (Gamifant) was approved in 2018 for primary HLH in some situations. These are HLH that does not respond to standard treatment, comes back or gets worse, or when standard treatment cannot be tolerated. In June 2025, the FDA added HLH linked to Still’s disease, including systemic juvenile idiopathic arthritis, when steroids have not worked well enough.
For your next appointment
Hemophagocytic lymphohistiocytosis (HLH)
From the Jada Bascom Foundation disease library, jadabascomfoundation.org. Printed .
Questions to bring to your care team
- Is this primary (inherited) or secondary HLH, and which tests will tell us?
- What do you think set off this episode, and how are you treating that trigger?
- Should brothers and sisters be checked for the gene change, and for their tissue type (HLA), now?
- When will we meet the transplant team, and will a search for an unrelated donor start at the same time?
- What is the goal of each treatment you are suggesting?
- What happens if a fully matched donor is not found?
- Where can our family find support during treatment?
A one-page list to take to the next appointment, with room for notes.
Supporting someone with a diagnosisSupport for patients and families
These independent organizations offer information and support. JBF is not affiliated with them.
- Histiocytosis Association Global nonprofit for histiocytic disorders, including HLH, dedicated to the needs of patients and families and to research toward a cure.Worldwide
- HLH Heroes Foundation U.S. nonprofit started by HLH caregivers, offering hospital care packages, connections with other HLH families and financial help.United States
- Histio UK UK charity for histiocytic disorders, including HLH, that supports patients and families and raises awareness among the public and professionals.United Kingdom
Ways to help
Someone may be waiting for a match.
Some people with hemophagocytic lymphohistiocytosis (HLH) are treated with a transplant from a donor. When no relative matches, that donor is often a stranger who joined a registry.
Join the registry
JBF points you to the official registry that serves your country. It explains who can join and what donation involves.
Help someone you love find a donor
If someone you love needs a donor, our family guide explains practical ways to help. A registration drive can add many potential donors at once, for them and for others.
Support this work
Gifts to the Jada Bascom Foundation support donor-awareness education like this page, community outreach, drive planning and referrals to official registries.
Keep learning
Understanding transplant
Short explainers on what a transplant is and what it means for a family.
Sources and further reading
- Recommendations for the management of hemophagocytic lymphohistiocytosis in adults
Blood (American Society of Hematology) / Histiocyte Society working group, 2019-04-16 - Familial hemophagocytic lymphohistiocytosis
MedlinePlus Genetics, US National Library of Medicine, Accessed 2026-09-24 - Pediatric hemophagocytic lymphohistiocytosis
Blood (American Society of Hematology), 2020-04-16; accessed 2026-09-26 - HCT consultation timing guidelines: Hemophagocytic lymphohistiocytosis (HLH)
NMDP (with ASTCT), Accessed 2026-09-26 - HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis
Pediatric Blood & Cancer (Henter et al., Histiocyte Society), 2007-02 - Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study
Blood (American Society of Hematology) (Bergsten et al.), 2017-12-21 - 1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003–2018
Journal of Hematology & Oncology (West et al.), 2023-05-26 - Hemophagocytic lymphohistiocytosis (HLH)
Immune Deficiency Foundation, Accessed 2026-09-26 - Hemophagocytic Lymphohistiocytosis (HLH)
Cincinnati Children's Hospital Medical Center, Last updated February 2026; accessed 2026-09-26 - FDA approves emapalumab for hemophagocytic lymphohistiocytosis
U.S. Food and Drug Administration, 2018-11-20 - Supplement approval letter, BLA 761107/S-018, Gamifant (emapalumab-lzsg): HLH/macrophage activation syndrome in Still’s disease
U.S. Food and Drug Administration, 2025-06-27 - Indications for haematopoietic cell transplantation and CAR-T for haematological diseases, solid tumours and immune disorders: 2025 EBMT practice recommendations
EBMT / Bone Marrow Transplantation (open access, PMC12583170), 2025; accessed 2026-09-26 - Chediak-Higashi syndrome
MedlinePlus Genetics, US National Library of Medicine, Last updated 2014-01-01; accessed 2026-09-26 - Griscelli syndrome
MedlinePlus Genetics, US National Library of Medicine, Last updated 2013-09-01; accessed 2026-09-26
