Hemophagocytic lymphohistiocytosis, or HLH, is a severe condition in which the immune system becomes dangerously overactive and begins attacking the body’s own tissues and organs. It is rare, life-threatening, and often misdiagnosed because its symptoms, including high fever, enlarged spleen, and plummeting blood counts, overlap with many other illnesses. Without treatment, HLH can be fatal within weeks.
How HLH Works Inside the Body
In a healthy immune response, certain white blood cells activate to fight an infection or threat, then quiet down once the job is done. In HLH, that “off switch” is broken. Immune cells called macrophages, T cells, and natural killer (NK) cells become excessively activated and never stop firing. The result is a massive flood of inflammatory signaling molecules, sometimes described as a cytokine storm, that damages organs throughout the body.
The hallmark of HLH is hemophagocytosis: macrophages literally begin engulfing and destroying the body’s own blood cells, including red blood cells, white blood cells, and platelets. This is why blood counts drop so dramatically. The uncontrolled inflammation also attacks the liver, spleen, bone marrow, and sometimes the brain and lungs. Researchers describe the process as a “destructive inflammatory cascade” that, once started, feeds on itself and escalates rapidly.
Primary vs. Secondary HLH
HLH falls into two broad categories based on what triggers it.
Primary (familial) HLH is caused by inherited genetic mutations that impair the immune system’s ability to regulate itself. It affects roughly 1 in 50,000 people worldwide and typically appears in infancy or early childhood. The most commonly involved genes are PRF1 and UNC13D, which together account for 40 to 60 percent of familial cases. Other genes linked to primary HLH include STX11 and STXBP2. These mutations can also appear alongside genetic syndromes like Chediak-Higashi syndrome and Griscelli syndrome. Even in primary HLH, a trigger is usually needed to set the disease in motion. In children, the most common trigger is an infection from the herpes virus family, particularly Epstein-Barr virus (EBV).
Secondary (acquired) HLH develops in people without a known genetic predisposition. It is triggered by something that pushes the immune system into overdrive. In adults, the most common trigger is cancer, accounting for about 45 percent of adult cases. T-cell and NK-cell lymphomas, B-cell lymphomas, and diffuse large B-cell lymphoma are the malignancies most often involved. Infections like tuberculosis, fungal infections, and HIV-related infections are also frequent triggers. Some monoclonal antibody therapies and organ transplants can cause HLH as well.
Macrophage Activation Syndrome
You may also see the term macrophage activation syndrome (MAS), which is closely related to HLH but occurs specifically in the context of autoimmune diseases like systemic juvenile idiopathic arthritis and adult-onset Still’s disease. The symptoms and lab findings look nearly identical, but the treatment approach differs. MAS is managed primarily by controlling the underlying autoimmune condition, while HLH triggered by infection or cancer requires a combination of immunosuppressive and sometimes chemotherapy agents.
Symptoms and Warning Signs
HLH often starts with a persistent high fever (above 101.3°F or 38.5°C) that doesn’t respond to antibiotics. An enlarged spleen is present in most cases. As blood cells are destroyed, you may see signs of low blood counts: fatigue and pallor from anemia, easy bruising or unusual bleeding from low platelets, and frequent infections from low white blood cells.
As the disease progresses, liver dysfunction can cause jaundice and abnormal bleeding. Some patients develop neurological symptoms like confusion, seizures, or difficulty walking, which signal that inflammation has reached the brain. The rapid, multi-organ nature of HLH is what makes it so dangerous and why early recognition matters enormously.
How HLH Is Diagnosed
Diagnosing HLH requires meeting a specific set of criteria established by an international protocol called HLH-2004. A diagnosis can be made either through genetic testing that confirms a known HLH mutation, or by meeting at least 5 of 8 clinical and laboratory criteria:
- Fever above 101.3°F (38.5°C)
- Enlarged spleen
- Low blood counts in at least two of three cell lines: hemoglobin below 9 g/dL, platelets below 100,000, or neutrophils below 1,000
- High triglycerides or low fibrinogen (triglycerides above 265 mg/dL or fibrinogen at or below 150 mg/dL)
- Hemophagocytosis visible in a bone marrow, spleen, liver, or lymph node biopsy
- Low or absent NK cell activity
- Ferritin at or above 500 μg/L
- Elevated soluble IL-2 receptor (at or above 2,400 U/mL)
Ferritin is one of the most accessible and informative markers. While a level of 500 or above meets the diagnostic threshold, HLH patients often have ferritin levels in the thousands or even tens of thousands, far higher than what you would see with iron deficiency or most infections.
Bone marrow biopsy plays a key role. Pathologists look for macrophages that have swallowed other blood cells, a phenomenon visible under the microscope. Finding even one macrophage that has engulfed a white blood cell called a granulocyte, combined with evidence of ingested red blood cell precursors and lymphocytes, is extremely specific for HLH. In one study, patients with that pattern of findings had a 100 percent chance of having HLH confirmed. However, hemophagocytosis can be absent early in the disease, so a normal biopsy does not rule it out.
Treatment
HLH treatment focuses on two goals: suppressing the runaway immune response and treating whatever triggered it in the first place. The standard approach, based on the HLH-2004 protocol, uses a combination of a chemotherapy drug, a corticosteroid, and an immune-suppressing medication. For patients with brain involvement, medications may be delivered directly into the spinal fluid.
Treatment typically starts with an intensive induction phase lasting several weeks to bring the immune storm under control. For patients with primary HLH or those who relapse, a bone marrow transplant (also called a stem cell transplant) is often the only path to a long-term cure, since it replaces the faulty immune system entirely.
For patients whose disease doesn’t respond to standard treatment, a targeted therapy called emapalumab (brand name Gamifant) is FDA-approved for primary HLH that is refractory or recurrent. It works by neutralizing a specific inflammatory signaling molecule that drives much of the tissue damage in HLH. Clinical trials are also exploring combinations of targeted therapies for difficult-to-treat cases.
In secondary HLH, treating the underlying cause is just as important as controlling the immune response. If a viral infection triggered the episode, antiviral therapy is added. If cancer is the trigger, chemotherapy directed at the malignancy is essential.
Survival and Prognosis
HLH remains a high-mortality disease despite advances in treatment. Adult secondary HLH carries an overall mortality rate of about 57 percent in intensive care settings, regardless of treatment. When cancer is the underlying trigger, the outlook is particularly grim: overall survival at two years is estimated at just 20 to 30 percent. A Japanese study found that even when HLH was identified and treated in patients with known malignancies, mortality still reached 50 percent.
Outcomes are generally better for children with primary HLH who receive a successful bone marrow transplant, and for patients whose HLH is triggered by a treatable infection. The speed of diagnosis matters significantly. Because HLH can mimic sepsis, liver failure, or other critical illnesses, delays in recognition are common and directly affect survival. If you or someone you know has an unexplained persistent fever with rapidly declining blood counts and an enlarged spleen, bringing up HLH by name with the medical team can be the difference that prompts the right tests.