Haemophagocytic lymphohistiocytosis (HLH) is a severe condition where the immune system becomes dangerously overactive, attacking the body’s own cells instead of protecting it. This rare disorder, which can affect people of all ages but appears most often in infants and children, requires immediate medical attention to prevent life-threatening complications.
Understanding Haemophagocytic Lymphohistiocytosis
Haemophagocytic lymphohistiocytosis is a syndrome of pathologic immune activation that causes extreme inflammation throughout the body. When you break down the name, “haemophagocytic” refers to the eating of blood cells, while “lymphohistiocytosis” describes a buildup and overactivity of certain white blood cells and immune cells. In simple terms, HLH occurs when specific immune cells called histiocytes (cells that normally engulf and destroy harmful invaders) and lymphocytes (white blood cells that fight infection) become overactive and attack the body rather than just microorganisms.[3]
Your immune system normally defends your body from bacteria, viruses, and other threats through a coordinated effort of cells, proteins, organs, and tissues. In HLH, an infection or other trigger can cause the immune system to produce too many of these defense cells. Instead of fighting the infection effectively, these cells lose their ability to function properly and begin attacking your own tissues and organs. The immune cells release excessive amounts of chemical messengers called cytokines, creating what is often described as a “cytokine storm” that causes widespread inflammation and damage.[1][8]
The disease affects multiple organ systems simultaneously. White blood cells that are supposed to protect you instead damage critical organs including the liver, spleen, bone marrow, and brain. These abnormally functioning cells also attack and destroy blood cells, leading to severe reductions in red blood cells, white blood cells, and platelets. Without prompt diagnosis and aggressive treatment, this cascade of immune dysfunction can lead to multi-organ failure and death.[2]
Epidemiology: How Common Is HLH?
Haemophagocytic lymphohistiocytosis is rare, and the exact rate of occurrence remains uncertain because the condition is frequently misdiagnosed or goes unrecognized. The disease presents diagnostic challenges due to its rarity and the fact that its symptoms can resemble many other conditions. A population-based study from England in 2018 estimated the incidence of all forms of HLH at approximately 4.2 cases per 1 million people, though researchers believe the true incidence is likely higher than reported.[7]
Primary or familial HLH, which is caused by genetic mutations, occurs in about 1 in 50,000 children worldwide per year. This form accounts for only about 25% of diagnosed HLH cases. The numbers appear to be increasing slightly, possibly because doctors are becoming better at detecting the disorder rather than because more cases are actually occurring.[1][3]
The remaining 75% of diagnosed cases represent secondary or acquired HLH, which develops as a complication of other medical conditions. Secondary HLH is thought to be significantly underdiagnosed, particularly in adults, because its clinical signs and symptoms closely resemble sepsis and other severe inflammatory conditions. The true burden of disease may be much higher than current statistics suggest.[1][2]
Age and Demographic Patterns
HLH can affect anyone at any age, from newborns to elderly adults, but it shows distinct patterns based on the type of disease. Primary HLH typically manifests in early childhood, with approximately 70% of affected children developing symptoms during their first year of life. The median age of onset for familial HLH is between 3 and 6 months. Most children with primary HLH are asymptomatic at birth, and symptoms rarely develop later in adulthood, though this can occasionally occur.[7][11]
Secondary HLH more commonly presents in adults, though it can occur in children as well. Some studies suggest an average age at onset of 50 years for secondary HLH in adults. The disease affects both males and females, and while familial HLH is an autosomal recessive condition, family history is often negative despite its inherited nature.[6][11]
Causes of Haemophagocytic Lymphohistiocytosis
An overactive or irregularly functioning immune system lies at the heart of all forms of HLH. The disease is classified into two main types based on its underlying cause: primary (familial) HLH and secondary (acquired) HLH. Both forms lead to excessive production of immune system cells that attack the body instead of protecting it, but they arise from different mechanisms.[1]
Primary or Familial HLH
Primary HLH results from inherited genetic mutations that impair the interaction between natural killer cells, cytotoxic T-cells, and antigen-presenting cells. These genetic defects prevent the immune system from properly regulating itself. The genes that are commonly mutated in primary HLH include PRF1 (which makes perforin-1), UNC13D, STX11, STXBP2, CD27, LYST, RAB27, SH2D1A, and several others. At least 12 genetic mutations are currently associated with familial HLH.[1][7][11]
These genes provide instructions for cells to create proteins that help the immune system destroy foreign invaders. When these genes are mutated, the proteins don’t function correctly. The white blood cells don’t have the proper instructions in their DNA to perform their jobs as they should, which leads to the symptoms of HLH. Primary HLH is inherited in an autosomal recessive pattern, meaning a child must receive a defective gene from both parents to develop the condition. Each sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene without symptoms, and a 25% chance of not being affected and not carrying the gene defect.[1][7]
Primary HLH sometimes occurs in association with specific genetic syndromes that affect immune function, such as Chediak-Higashi syndrome, Griscelli syndrome type 2, and Hermansky-Pudlak syndrome type 2. These syndromes involve broader abnormalities in immune regulation and other body systems.[2]
Secondary or Acquired HLH
Secondary HLH develops when an underlying medical condition triggers an inappropriate immune response. This form occurs when the immune system is disturbed by various factors, though not necessarily because of an inherited condition affecting immune regulation. The most common triggers for secondary HLH include infections, malignancies (cancers), autoimmune diseases, certain medications, and transplants.[1][2]
Infections are the leading trigger of secondary HLH. The Epstein-Barr virus is the most commonly associated infection, but many other viruses, bacteria, fungi, and parasites can trigger the syndrome. In adults, secondary HLH frequently occurs as a complication of hematologic malignancies (blood cancers) such as lymphomas and leukemias. Autoimmune conditions, particularly rheumatologic diseases like systemic lupus erythematosus and juvenile idiopathic arthritis, can also trigger HLH. When HLH develops in the setting of rheumatologic disease, it is sometimes called macrophage activation syndrome.[1][2][10]
Risk Factors
Several factors increase the likelihood of developing haemophagocytic lymphohistiocytosis. Understanding these risk factors helps doctors identify patients who may be at higher risk and enables earlier recognition of the disease.
Family history represents a significant risk factor for primary HLH. If a sibling has been diagnosed with familial HLH or if there is a known history of the condition in the family, other children are at increased risk. Parents who are carriers of HLH-associated genetic mutations can pass the defective genes to their children. Consanguineous relationships (when parents are blood relatives) also increase the risk of inheriting autosomal recessive conditions like primary HLH.[1][11]
Infants and young children face elevated risk for primary HLH, with most cases presenting in the first few years of life. However, people of any age can develop secondary HLH, with adults being particularly susceptible to the acquired form. Older adults may be at increased risk due to higher rates of malignancies and infections that can trigger the syndrome.[6]
Individuals with certain underlying medical conditions are at higher risk for developing secondary HLH. Those with blood cancers, particularly lymphomas and leukemias, face increased risk. People with autoimmune or rheumatologic diseases such as systemic lupus erythematosus, juvenile idiopathic arthritis, and Still’s disease have a higher likelihood of developing HLH as a complication of their underlying condition. Patients with other primary immunodeficiencies or immune system disorders also carry elevated risk.[1][3]
Certain infections dramatically increase risk, particularly Epstein-Barr virus infection, which is the most common infectious trigger. Other viral infections, severe bacterial infections (sepsis), and certain fungal or parasitic infections can also trigger HLH. People who are immunosuppressed or receiving immunosuppressive medications may be more vulnerable to infections that can trigger HLH.[1][2]
Recent medical treatments can pose risk in susceptible individuals. Patients who have undergone organ transplants or bone marrow transplants face increased risk. Some medications and certain cancer therapies, including specific types of immunotherapy, have been associated with triggering HLH in vulnerable patients.[2][10]
Symptoms of HLH
Haemophagocytic lymphohistiocytosis presents as a severe illness with symptoms of extreme inflammation and multi-organ dysfunction. The symptoms can range in severity and vary considerably from person to person, making diagnosis challenging. Initial symptoms often mimic common infections or other medical conditions, which contributes to delayed recognition of the disease.[9]
Common Early Symptoms
Persistent high fever that doesn’t respond to antibiotics is one of the most common and characteristic symptoms of HLH. This fever is typically unremitting, meaning it continues without breaks and resists standard treatments for infection. Many patients develop a rash, which can appear as red blotches, purplish spots, or other skin changes. Some people experience yellowish discoloration of the skin and eyes, a condition called jaundice that indicates liver involvement.[1][4][9]
Physical examination often reveals an enlarged liver, a condition called hepatomegaly, and an enlarged spleen, known as splenomegaly. These organs swell because they are being damaged by the overactive immune cells and are attempting to filter excessive amounts of destroyed blood cells. Many patients also develop enlarged lymph nodes throughout the body, a condition called lymphadenopathy.[1][4]
Blood-Related Symptoms
The destruction of blood cells causes several serious symptoms. Anemia, a low red blood cell count, leads to weakness, fatigue, and pale skin. Patients may feel lightheaded or dizzy due to reduced oxygen delivery to tissues. Thrombocytopenia, a low platelet count, causes easy bruising and bleeding problems. Patients may notice purple and red blotches on their skin, unexplained bruises, or bleeding gums. Some people develop nosebleeds or notice blood when they brush their teeth. Low white blood cell counts increase susceptibility to infections.[1][4]
Neurological Symptoms
The brain can be significantly affected by HLH, leading to various neurological symptoms. Patients may experience severe headaches, confusion, or changes in mental status. Irritability is common, particularly in infants and young children who cannot communicate their symptoms clearly. Seizures can occur when the inflammation affects brain tissue. Some patients develop problems with coordination or movement, a condition called ataxia. More severe cases may progress to altered consciousness or even coma.[1][7][9]
Digestive and Other Symptoms
Gastrointestinal symptoms are common and can include abdominal pain, vomiting, and diarrhea. The liver dysfunction caused by HLH can lead to hepatitis and, in severe cases, liver failure. Infants may show feeding problems or failure to thrive, meaning they don’t gain weight or grow as expected. Some patients lose their appetite or experience unintended weight loss.[9]
Life-Threatening Symptoms
Certain symptoms indicate that HLH has progressed to a life-threatening stage and require immediate emergency medical attention. Difficulty breathing, called dyspnea, can indicate respiratory failure. Bleeding in the back of the eyes, known as retinal hemorrhages, represents severe disease. Loss of consciousness or coma signals critical brain involvement. Any of these severe symptoms demands immediate evaluation in an emergency room.[1]
Prevention
There is currently no way to prevent haemophagocytic lymphohistiocytosis. Both primary and secondary forms of the disease occur due to factors that cannot be modified through lifestyle changes or other preventive measures. Primary HLH results from genetic mutations present at birth, and these genetic factors cannot be prevented. Secondary HLH develops in response to triggers like infections, malignancies, or autoimmune conditions that themselves may not be preventable.[1]
However, for families with a known history of primary HLH, genetic counseling can provide valuable information. If a child has been diagnosed with familial HLH, genetic testing of family members can identify carriers of the disease-causing mutations. This information helps families understand the risk of future children developing the condition. Parents who are known carriers can be informed about their 25% risk of having another affected child with each pregnancy. Genetic counseling allows families to make informed decisions about family planning and to be vigilant for early signs of the disease in subsequent children.[7]
Early recognition and prompt treatment represent the best approach to preventing the severe complications and death associated with HLH. Families with a known history of HLH should ensure that healthcare providers are aware of this history so that symptoms can be recognized quickly if they develop. Newborn screening for HLH is not routinely performed, but genetic testing is available and can be pursued if there is a family history of the condition.[1]
For individuals at risk of secondary HLH, such as those with underlying autoimmune conditions or malignancies, close monitoring by healthcare providers is important. While the development of HLH cannot be prevented in these patients, awareness of the risk enables earlier recognition of symptoms should they occur. Prompt treatment of infections and careful management of underlying conditions may help reduce triggers that could lead to HLH, though this has not been definitively proven to prevent the syndrome.[2]
Pathophysiology: What Happens in the Body
Understanding the changes that occur in the body during HLH helps explain why the symptoms develop and why the condition is so dangerous. The disease fundamentally represents a breakdown in the normal regulation of immune system activation and deactivation. The pathophysiology involves complex interactions between immune cells, inflammatory signals, and the body’s organs.[2]
Normal Immune Function vs. HLH
In a healthy immune response, specialized white blood cells called natural killer cells and cytotoxic T-cells identify and destroy cells infected with viruses or other pathogens. These killer cells contain granules filled with toxic proteins, including one called perforin that creates holes in the target cell’s membrane. Once the infection is cleared, the immune response normally shuts down through a carefully controlled process. The activated immune cells receive signals to stop their activity and undergo programmed cell death.[2][10]
In HLH, genetic defects or other factors prevent this normal shutdown process. The cytotoxic cells cannot effectively kill their targets because the proteins they need don’t work properly. When these ineffective immune cells encounter infected or abnormal cells, they release their chemical messengers (cytokines) to call for help, but they cannot complete the job of destroying the target. Because the target cells persist, the immune cells continue trying to respond, leading to ongoing and excessive activation. More and more immune cells are recruited and activated, and they produce increasingly large amounts of inflammatory cytokines.[2][10]
The Cytokine Storm
The overproduction of cytokines creates what is described as a “cytokine storm.” Cytokines are protein messengers that coordinate immune responses, but when produced in excessive amounts, they cause severe inflammation throughout the body. Key cytokines involved in HLH include interferon-gamma, tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interleukin-18, among others. These inflammatory signals cause fever, activate more immune cells, and damage blood vessels and organs.[3][6][10]
The sustained inflammation is perpetuated by the uncontrolled activation of macrophages, a type of histiocyte. Normally, macrophages clean up debris and dead cells in the body. In HLH, these macrophages become “angry” and begin engulfing and destroying healthy cells, including red blood cells, white blood cells, and platelets. This process, called hemophagocytosis (the eating of blood cells), gives the disease its name. The destruction of blood cells leads to the low blood counts characteristic of HLH.[6]
Organ Damage
The combination of cytokine storm and abnormal cell activity causes widespread tissue damage. The liver becomes inflamed and enlarged, leading to hepatitis and potential liver failure. Liver function tests show elevated enzymes, and patients may develop jaundice. The spleen enlarges as it attempts to filter the excessive amounts of destroyed blood cells and becomes infiltrated with overactive immune cells. The bone marrow, where blood cells are produced, becomes damaged by invading immune cells, which impairs production of new blood cells and worsens the cytopenias.[2][7]
The brain can be severely affected, with inflammation causing seizures, confusion, and other neurological symptoms. The skin may develop rashes due to inflammation of blood vessels and deposition of immune complexes. The lymph nodes swell with accumulations of activated lymphocytes. The lungs can be affected, leading to breathing difficulties. This multi-organ involvement explains why HLH can lead to multi-organ failure and death if not treated promptly.[2]
Laboratory Abnormalities
The pathophysiologic changes in HLH produce characteristic laboratory findings. Blood tests show cytopenias affecting multiple cell lines. Ferritin, a protein that stores iron, becomes markedly elevated, often to extremely high levels of several thousand or even tens of thousands, because it is released from damaged cells and produced as part of the inflammatory response. Triglyceride levels in the blood increase due to effects on fat metabolism. Fibrinogen, a protein important for blood clotting, becomes depleted because it is consumed in the inflammatory process. These laboratory markers help doctors recognize and diagnose HLH.[2][7]
The function of natural killer cells, measured through specialized laboratory tests, is decreased in up to 90% of patients with HLH, making this one of the most useful diagnostic tests. Soluble interleukin-2 receptor, a marker of T-cell activation, is elevated and can be tracked as a marker of disease activity. These abnormalities reflect the underlying immune dysfunction that drives the disease process.[7][9]
