Hemophagocytic Lymphohistiocytosis: Symptoms, Types, Causes and Treatment

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening condition marked by overwhelming inflammation and immune system dysfunction. Whether it arises from genetic predisposition or is triggered by infection, cancer, or autoimmune disease, HLH demands rapid recognition and aggressive management. In this comprehensive article, we explore the symptoms, types, causes, and modern treatments for HLH, weaving together the latest findings from clinical research.

Symptoms of Hemophagocytic Lymphohistiocytosis

HLH can be a medical chameleon, often masquerading as severe infections or other inflammatory diseases. Recognizing its key symptoms early is crucial for life-saving intervention, as HLH progresses rapidly and can lead to multi-organ failure if untreated. Here, we summarize and delve into the main clinical and laboratory features seen in HLH.

Symptom	Description	Frequency/Significance	Source(s)
Fever	Persistent, high, unremitting	Cardinal, almost universal	1 3 4 5
Hepatosplenomegaly	Enlarged liver and spleen	Common, early clinical sign	1 2 4 5 7
Cytopenia	Low counts of blood cells (anemia, etc.)	Key diagnostic marker	1 3 4 5 12
Hyperferritinemia	Excessively high blood ferritin	Highly suggestive, diagnostic	3 4 5 12
Hypertriglyceridemia	Elevated blood triglycerides	Biochemical marker	1 4 5
Hypofibrinogenemia	Low fibrinogen levels	Supports diagnosis	1 4 5
Neurological dysfunction	Seizures, irritability, coma	Possible, portends poor prognosis	5 12
Hemophagocytosis	Macrophages eating blood cells (marrow/tissue)	Hallmark (but not always present)	2 4 5

Table 1: Key Symptoms

The Core Clinical Picture

The typical case of HLH presents with prolonged high fever that does not respond to antibiotics. The liver and spleen often become enlarged (hepatosplenomegaly), sometimes accompanied by swollen lymph nodes. Blood tests reveal cytopenias—low levels of red and white blood cells, as well as platelets—due to immune-mediated destruction and suppression of the bone marrow 1 3 4 5.

Laboratory and Biochemical Markers

Biochemical hallmarks include:

• Hyperferritinemia: Ferritin levels (an iron-storage protein) are often extremely elevated, sometimes exceeding thousands of ng/mL, reflecting severe inflammation 4 5.
• Hypertriglyceridemia and hypofibrinogenemia: These disturbances indicate liver dysfunction and ongoing inflammation 1 4.
• Hemophagocytosis: Pathologists may observe macrophages engulfing blood cells in bone marrow or other tissues, but this finding is not always present or required for diagnosis 2 4 5.

Neurological and Other Organ Involvement

HLH can affect virtually any organ system. Neurological symptoms—such as irritability, seizures, stupor, or even coma—may develop, signaling central nervous system (CNS) involvement and a more severe prognosis 5 12. Liver dysfunction, jaundice, and coagulopathy (bleeding disorders) are also common as the disease progresses.

Types of Hemophagocytic Lymphohistiocytosis

HLH is not a single disease, but a syndrome with multiple underlying causes and forms. Distinguishing between the types is essential, as treatment and prognosis can differ dramatically.

Type	Defining Feature	Typical Age/Context	Source(s)
Familial (Primary) HLH	Genetic mutations impair cytotoxicity	Early childhood, sometimes adults	1 3 5 9 12
Secondary (Acquired) HLH	Triggered by infection, malignancy, or autoimmune disease	Any age, especially adults	1 3 5 6 7 12
Macrophage Activation Syndrome (MAS)	HLH in context of rheumatic (autoimmune) disease	Children/teens with rheumatologic disorders	1 3 4 12
Malignancy-Associated HLH	HLH as a complication of cancer	More common in adults	2 4 6 12
Infection-Associated HLH	HLH triggered by infections (esp. viruses)	All age groups	2 6 8 9

Table 2: Types of HLH

Familial (Primary) HLH

This form is due to inherited genetic mutations that disrupt the function of natural killer (NK) cells and cytotoxic T lymphocytes—cells critical for controlling infections and regulating inflammation. Mutations are often found in genes such as PRF1 and UNC13D 1 5 9. While most cases present in infancy or early childhood, late presentations in adolescents and adults are increasingly recognized 1 5 7 9.

Secondary (Acquired) HLH

Secondary HLH, sometimes called reactive HLH, occurs when a strong immune stimulus—such as a severe infection, cancer, or autoimmune disease—triggers the hyperinflammatory syndrome in individuals without a known genetic defect 1 3 5 6. Secondary HLH is more typical in adults but can occur at any age 3 7.

Special Subtypes

• Macrophage Activation Syndrome (MAS): This is HLH seen in the setting of autoimmune or autoinflammatory diseases, particularly systemic juvenile idiopathic arthritis and lupus 1 3 4.
• Malignancy-Associated HLH: Here, HLH is a complication of cancers (often lymphomas), especially in adults 2 4 6.
• Infection-Associated HLH: HLH can be triggered by various infections, most notably Epstein-Barr Virus (EBV), cytomegalovirus, and other herpesviruses 2 6 9.

Overlap and Diagnostic Challenges

These categories can overlap. For example, a patient with a genetic predisposition might only develop HLH after a viral infection, and some "sporadic" HLH cases in adults may harbor subtle genetic risks 9. Thus, a careful diagnostic workup is always necessary.

Causes of Hemophagocytic Lymphohistiocytosis

Understanding what causes HLH is key to grasping both its unpredictability and its severity. HLH arises from an interplay between genetic predisposition and powerful immune triggers—sometimes in combination.

Cause	Mechanism/Pathway	Notable Examples	Source(s)
Genetic Mutations	Impaired NK/T cell cytotoxic function	PRF1, UNC13D, STX11, others	1 5 7 9
Viral Infections	Immune overactivation, cytokine storm	EBV, CMV, Herpesviruses, COVID-19	2 3 4 6 9
Malignancy	Cancer-driven immune dysregulation	Lymphomas, leukemias	2 4 6 12
Autoimmune Disease	Uncontrolled immune activation	Systemic JIA, lupus	1 3 4 12
Immune Deficiency	Defective immune regulation	Primary immunodeficiencies	1 8 9
Drugs/Transplant	Iatrogenic immune suppression	Post-transplant, immunosuppressives	3 12

Table 3: Causes of HLH

Genetic Predisposition

Familial HLH is most commonly caused by biallelic mutations in genes responsible for the function of cytotoxic granules in NK and cytotoxic T cells. These granules contain proteins such as perforin, which are essential for killing infected or abnormal cells and shutting down the immune response once a threat is controlled 1 7 9. Defective cytotoxicity leads to ongoing activation of immune cells and a dangerous "cytokine storm."

Infections

HLH can be triggered by a wide range of infections, especially viruses in the herpes family (such as EBV and CMV) 2 3 4 6. In EBV-associated HLH, infected T cells release massive amounts of cytokines, fueling the hyperinflammatory state 2. Emerging evidence also implicates severe COVID-19 as a potential trigger for secondary HLH 3.

Malignancies and Autoimmune Diseases

• Malignancy-Associated HLH is most often seen with lymphomas and leukemias, whose abnormal cells can provoke uncontrolled immune activation 2 4 6.
• Autoimmune/Autoinflammatory HLH (MAS): Here, underlying rheumatic diseases cause immune dysregulation, with HLH developing as a severe complication 1 3 4 12.

Other Triggers

HLH can also complicate primary immunodeficiencies (distinct from classic FHL genes), sometimes with a different pathophysiology 8. In some cases, drugs, immune suppression after transplantation, or a combination of genetic and environmental factors may set off HLH 3 12.

The Two-Hit Model

Increasingly, the "two-hit" hypothesis is recognized: genetic susceptibility (even subtle or monoallelic mutations) combined with a potent immune trigger (such as infection) tips the balance toward HLH 9.

Treatment of Hemophagocytic Lymphohistiocytosis

Given the rapid, life-threatening nature of HLH, immediate and aggressive treatment is critical. Therapy is tailored to the type of HLH and the underlying cause, focusing on suppressing the hyperinflammatory response and, when possible, curing the underlying defect.

Treatment	Purpose	Main Indications	Source(s)
Immunosuppressive Therapy	Control inflammation	All HLH forms (initial)	1 5 10 12 13
Etoposide-based Chemotherapy	Eliminate activated immune cells	Severe or persistent HLH	5 10 12 13
Corticosteroids	Reduce cytokine production	All forms, especially acute	5 10 12 13
Cyclosporin A	Immunomodulation	With steroids/etoposide	10 12
Hematopoietic Stem Cell Transplantation (HSCT)	Cure genetic HLH	Familial/relapsed HLH	1 5 7 10 12
Biologics (e.g., emapalumab)	Targeted cytokine blockade	Refractory or primary HLH	11 14
Treat Underlying Cause	Infection, malignancy, autoimmune disease	Secondary HLH	2 6 13

Table 4: Treatment Modalities in HLH

Standard Immunochemotherapy

The cornerstone of HLH treatment is immunosuppressive therapy, often based on the HLH-94 protocol. This combines etoposide (a chemotherapy agent that destroys overactive immune cells), corticosteroids (to dampen inflammation), and cyclosporin A (an immunomodulator). Intrathecal methotrexate may be used if the central nervous system is involved 5 10 12 13.

• Early initiation is vital, as untreated HLH is almost always fatal.
• The HLH-94 protocol has improved survival rates significantly, especially in children 10.

Hematopoietic Stem Cell Transplantation (HSCT)

For patients with familial (genetic) HLH or persistent/recurrent disease, HSCT offers the only curative option. By replacing the defective immune system with healthy donor cells, it corrects the underlying immunologic defect 1 5 7 10 12. Survival rates now exceed 50% in children who receive timely transplantation 10 12.

Targeted Biological Therapies

Emapalumab, a monoclonal antibody targeting interferon-gamma (a key cytokine in HLH), has emerged as a promising therapy for primary or refractory HLH, improving response rates and allowing more patients to reach transplantation 11 14. Other agents targeting specific immune pathways are under investigation.

Treating the Underlying Trigger

• In secondary HLH, addressing the underlying cause is crucial:
  • Infection-associated HLH: Rapid treatment of the infection is essential 2 6.
  • Malignancy-associated HLH: Cancer-directed therapy is prioritized 2 6 13.
  • Autoimmune MAS: Disease-modifying immunosuppressants are used 1 3 4.

Supportive Care and Prognosis

• Supportive measures—such as transfusions, antibiotics, and intensive care—are often required.
• Prognosis varies: Early treatment response is the strongest predictor of survival; persistent disease, EBV-associated HLH, older age, and high ferritin are associated with poorer outcomes 13.
• Adults tend to have worse outcomes than children, though new therapies are improving the outlook 5 13.

Conclusion

Hemophagocytic lymphohistiocytosis is a complex, rapidly progressive syndrome that bridges immunology, genetics, infectious disease, and hematology. Early recognition and aggressive, targeted treatment are essential for improving patient outcomes.

Key takeaways:

• HLH is characterized by persistent fever, cytopenias, organomegaly, and severe inflammation.
• There are two major forms: familial (genetic) and secondary (acquired), with overlaps and subtypes such as MAS.
• Genetic mutations, infections (especially EBV), malignancies, and autoimmune diseases are leading causes.
• Treatment involves rapid immune suppression, chemotherapy, biological agents, and, in genetic cases, stem cell transplantation.
• Early diagnosis and prompt treatment are crucial for survival.

By understanding the warning signs and underlying mechanisms of HLH, clinicians can act quickly to save lives—and researchers can continue to develop new therapies for this devastating syndrome.