Hemophagocytic Lymphohistiocytosis (HLH): Symptoms, Causes, and Care
Updated: 3 days ago
Medically reviewed by Dr. Baraa Alnahhal, MD · Last reviewed: October 2026
Quick Answer
Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the immune system abnormally overreacts and attacks the body. It is either genetic or triggered by something like an infection. Warning signs include persistent fever, an enlarged liver or spleen and rashes. It is diagnosed when five of eight criteria are met, and urgent treatment with immunosuppressants is often required. [1] [4]
What the research says
Most children with HLH can be rescued with etoposide and dexamethasone, but outcomes remain serious. In the HLH-2004 study of 369 children (2004–2011), 62% were alive at a median follow-up of 5.2 years, with a five-year survival of 61%. After stem cell transplant, five-year survival was 66%. (Bergsten et al., Blood, 2017)
Emapalumab, an interferon-gamma blocking antibody, helped many children with primary HLH. In an open-label phase 2–3 study of 34 children, 63% of previously treated patients responded (compared with a prespecified 40% threshold, P = 0.02), 70% went on to transplantation, and 74% were alive at last observation. Severe infections developed in 10 patients during treatment. (Locatelli et al., N Engl J Med, 2020)
Diagnosis rests on a set of eight criteria. The HLH-2004 guidelines require five of eight: fever, enlarged spleen, low blood counts, high triglycerides or low fibrinogen, hemophagocytosis, low or absent NK-cell activity, high ferritin and high soluble CD25 (or a molecular diagnosis consistent with HLH). (Henter et al., Pediatr Blood Cancer, 2007)
What is hemophagocytic lymphohistiocytosis (HLH)?
Hemophagocytic lymphohistiocytosis (HLH) is a complex immune disorder characterized by an uncontrolled and ineffective inflammatory response. In a healthy body, the immune system identifies and destroys harmful bacteria and viruses. However, in individuals with HLH, the immune system's regulatory "off switch" fails. This leads to an overproduction of histiocytes and T cells, which then infiltrate and damage vital organs such as the liver, spleen, and bone marrow. [1]
Because HLH can be fatal if left untreated, medical professionals treat it as a clinical emergency. The condition most frequently affects infants and young children, but it can occur in individuals of any age. [1][5]
Feature | Primary (Familial) HLH | Secondary (Acquired) HLH |
Primary cause | Genetic mutations (inherited) | External triggers (infection, cancer) |
Common onset | Infancy or early childhood | Any age, often adulthood |
Prevalence | Rare (~25% of cases) | More common (~75% of cases) |
Hereditary | Yes (autosomal recessive) | No |
Identifying the types and triggers
HLH is broadly classified based on whether the condition is rooted in a person's genetics or acquired later in life due to environmental triggers.
Primary (familial) HLH
Primary HLH is caused by specific genetic mutations that are passed down from biological parents. These mutations affect the genes responsible for producing proteins that the immune system needs to function correctly. Without these instructions, the immune system cannot properly regulate its response to threats. Symptoms usually appear within the first few months or years of life. [1]
Secondary (acquired) HLH
Secondary HLH is more common and is triggered by an underlying medical condition that disrupts immune function. The most frequent trigger is the Epstein-Barr virus (EBV), but other infections, certain types of cancer (like non-Hodgkin lymphoma), and autoimmune diseases can also initiate the disorder. In these cases, the person was not born with a predisposition to HLH. [1]
Recognizing the symptoms and warning signs
The symptoms of HLH are often diverse and can mimic other common illnesses, which sometimes leads to delays in diagnosis. However, certain clusters of symptoms are highly characteristic of the condition.
Common clinical signs
Patients with HLH frequently present with a high, persistent fever that does not improve with standard antibiotics. Other common signs include:
Organ enlargement: An enlarged liver (hepatomegaly) or spleen (splenomegaly), often causing abdominal swelling.
Skin changes: Unexplained rashes, pale skin, or jaundice (yellowing of the skin and eyes).
Systemic weakness: Extreme fatigue, irritability, and dizziness.
Lymph node swelling: Noticeable swelling in the neck, armpits, or groin.
Emergency warning signs
In severe cases, HLH can affect the central nervous system or lead to organ failure. Seek immediate emergency care if you or a loved one experiences:
Neurological issues: Seizures, loss of consciousness, or falling into a coma.
Respiratory distress: Significant difficulty breathing.
Visual changes: Bleeding in the retina (retinal hemorrhages).
Diagnosis: The five-of-eight criteria
Because HLH is rare, doctors use a specific set of diagnostic criteria to confirm the condition. A diagnosis is typically made if a patient meets at least five of the following eight markers, or if a genetic test finds a mutation known to cause HLH: [4]
Fever: Persistent and high.
Splenomegaly: An enlarged spleen confirmed by imaging.
Cytopenia: Low counts in at least two blood cell lines (red cells, white cells, or platelets).
Hypertriglyceridemia or hypofibrinogenemia: Abnormal levels of blood fats or clotting proteins.
Hemophagocytosis: Evidence of immune cells eating blood cells in the bone marrow.
Low or absent NK-cell activity: Reduced function of natural killer cells, specialized immune cells that help keep immune responses in check.
Ferritinemia: Exceptionally high levels of ferritin (a protein that stores iron).
Soluble CD25: High levels of a specific immune receptor in the blood.
Treatment pathways and modern care
The goal of HLH treatment is to dampen the overactive immune response and address the underlying trigger. Treatment plans are often intensive and require specialized care from hematologists and oncologists. [1]
Initial management
Doctors often begin by treating any active infections with antibiotics or antivirals. To stop the immune system's attack on the body, they may use immunosuppressants, corticosteroids, or cytokine inhibitors. [1] A specialized medication called emapalumab (Gamifant®) is FDA-approved for children and adults with primary HLH whose disease is refractory, recurrent or progressive, or who cannot tolerate conventional therapy. It blocks interferon-gamma, one of the inflammatory signals that drives HLH. [6]
Advanced procedures
If medications are not sufficient, more aggressive treatments may be necessary:
Chemotherapy: Used to destroy the overactive immune cells.
Blood transfusions: To support the body when blood cell counts are dangerously low.
Stem cell transplant: An allogeneic stem cell transplant can replace the faulty immune system with healthy donor cells, offering a potential permanent cure for primary HLH. [1]
Conclusion
Hemophagocytic lymphohistiocytosis is a serious and complex disorder, but advancements in genetic testing and targeted therapies have improved the outlook for many patients. Early recognition of symptoms and rapid intervention are the most critical factors in achieving a successful recovery. With a dedicated medical team and the right treatment plan, many people with HLH can recover, although the condition can return and some people need a stem cell transplant.
For more information on rare immune disorders and blood health, visit Rinnit.com.
Frequently Asked Questions
Is HLH a type of cancer?
No, HLH is an immune system disorder. However, it can be triggered by certain cancers, and its treatment often involves chemotherapy drugs.
Can adults get HLH?
Yes. While it is more common in infants and children, adults can develop secondary HLH, often triggered by an infection or autoimmune disease.
Is HLH contagious?
No. You cannot catch HLH from someone else. However, you can catch a virus (like EBV) that might trigger the condition in susceptible individuals.
How long does treatment take?
The duration of treatment varies widely depending on the cause and severity. Some patients may need treatment for several months or longer.
What is the survival rate for HLH?
The survival rate has improved significantly with modern treatments, but it remains a life-threatening condition that requires immediate medical attention. In the large HLH-2004 study of children, five-year survival was 61%.
Can primary HLH be prevented?
There is currently no way to prevent primary HLH as it is a genetic condition. Genetic counseling may be helpful for families with a history of the disorder.
What is a histiocyte?
A histiocyte is a type of white blood cell that is part of the immune system. In HLH, these cells become overactive and attack healthy tissues.
Why is ferritin so high in HLH?
Ferritin is an iron-storage protein that increases significantly during periods of intense inflammation, making it a key marker for HLH.
What happens during a stem cell transplant?
The patient's faulty immune system is wiped out with chemotherapy or radiation and then replaced with healthy stem cells from a donor.
Can HLH come back after treatment?
Yes, especially in secondary cases if the underlying trigger (like an autoimmune flare) recurs. Primary HLH requires a transplant for a permanent cure.
What is the Epstein-Barr virus?
EBV is a very common virus that causes mononucleosis ("mono"). In some people, it can trigger a dangerous immune overreaction leading to HLH.
Are there any long-term side effects of treatment?
Some treatments, like chemotherapy or transplants, can have long-term effects on growth, fertility, or organ function, which doctors will monitor.
How is the bone marrow biopsy performed?
A small sample of bone marrow is taken, usually from the hip bone, using a needle while the patient is under local anesthesia or sedation.
Is HLH the same as a "cytokine storm"?
HLH is a specific condition that causes a cytokine storm, a massive release of inflammatory chemicals that damage the body.
Can a child with HLH go to school?
During active treatment, children are often kept away from large groups to avoid infections. Once stable, many can return to their normal activities.
Related Reading
References
Cleveland Clinic. Hemophagocytic Lymphohistiocytosis. Cleveland Clinic. Last updated October 13, 2022. https://my.clevelandclinic.org/health/diseases/24292-hemophagocytic-lymphohistiocytosis
Bergsten E, et al. Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood. 2017;130(25):2728-2738. PMID 28935695. https://doi.org/10.1182/blood-2017-06-788349
Locatelli F, et al. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-1822. PMID 32374962. https://doi.org/10.1056/NEJMoa1911326
Henter JI, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-131. PMID 16937360. https://doi.org/10.1002/pbc.21039
National Organization for Rare Disorders (NORD). Hemophagocytic Lymphohistiocytosis. NORD Rare Disease Database. Last updated December 13, 2018. https://rarediseases.org/rare-diseases/hemophagocytic-lymphohistiocytosis/
Smith J. FDA approves first treatment for primary HLH. Hematology Times (MDedge). November 20, 2018. https://mdedge.com/content/fda-approves-first-treatment-primary-hlh
Medical disclaimer
This article is for general educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified healthcare provider with any questions you may have about a medical condition. Never disregard professional medical advice or delay seeking care because of something you have read here. If you think you may have a medical emergency, call your doctor or emergency services immediately.
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