Understanding Hemophagocytic Lymphohistiocytosis (HLH): A Life-Threatening Inflammatory Condition

Table of Contents

• What is HLH and Why It Matters
• Types of HLH: Genetic vs. Acquired Forms
• How Common is HLH?
• Symptoms and Clinical Features
• Underlying Causes and Mechanisms
• How HLH is Diagnosed
• Treatment Approaches
• Key Patient Takeaways
• Source Information

What is HLH and Why It Matters

Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterized by overwhelming inflammation that often leads to multiple organ failure and death if not treated promptly and appropriately. This condition represents a dramatic failure of the immune system's regulatory mechanisms, where inflammation continues unchecked without normal shutdown processes.

From a biological perspective, HLH has taught researchers crucial lessons about immune system function and the dangerous consequences of insufficient immune regulation. Clinically, while HLH is often treatable, it remains significantly underdiagnosed worldwide, resulting in many unnecessary deaths that could potentially be prevented with earlier recognition and intervention.

The condition affects patients across multiple medical specialties including hematology, oncology, infectious diseases, pediatrics, rheumatology, intensive care, neurology, gastroenterology, genetics, and immunology. This broad impact means that awareness among healthcare providers across these fields is essential for timely diagnosis and treatment.

Types of HLH: Genetic vs. Acquired Forms

HLH is classified into two main categories with distinct characteristics and typical patient populations:

• Primary HLH (Genetic/Mendelian form): This inherited form typically affects children, mostly infants, and is caused by specific genetic defects that impair immune regulation. The most common form is familial HLH, which follows an autosomal recessive inheritance pattern.
• Secondary HLH (Acquired/Non-Mendelian form): This acquired form is much more common in adults and occurs without inherited genetic defects. The most common triggers include infections (52% of cases), cancers (28%), and autoimmune diseases (12%). When associated with autoimmune triggers, it's also referred to as macrophage activation syndrome (MAS-HLH).

The classification system for HLH includes numerous specific conditions and triggers as detailed in medical literature. Primary HLH may have an infectious trigger, while secondary HLH is almost always associated with a trigger, most commonly infections, cancers, or autoimmune conditions.

How Common is HLH?

The prevalence of HLH varies significantly across different countries and populations. The incidence of primary HLH among children in Sweden has been estimated at approximately 1 case per 50,000 live births. For comparison, the incidence of severe combined immunodeficiency is 1 case per 38,500 live births, making these two disorders among the most common inherited, rapidly fatal immunodeficiencies in humans.

Familial HLH occurs most frequently in areas where consanguinity (marriage between blood relatives) is common. The median age at onset for genetic forms is typically 3 to 6 months, highlighting why this condition primarily affects infants and young children.

The prevalence of secondary HLH is less well established. The overall incidence of all forms of HLH was estimated to be 4.2 cases per 1 million population in England in 2018. The annual incidence of cancer-associated HLH in Sweden from 2012 through 2018 was reported to be at least 6.2 cases per 1 million adults, with regional variations probably attributable to differences in awareness of the disorder.

Despite these statistics, secondary HLH remains largely underdiagnosed worldwide, meaning the actual numbers are likely higher than reported figures suggest.

Symptoms and Clinical Features

The presentation of HLH can vary but often includes a characteristic set of symptoms and laboratory findings that clinicians use for diagnosis.

Familial HLH Presentation

A typical presentation of familial HLH resembles a sepsis-like condition associated with blood cell deficiencies (cytopenias) and enlarged liver and spleen (hepatosplenomegaly) in a child, often an infant, with a febrile illness. Specific findings include:

• Thrombocytopenia (low platelets), anemia (low red blood cells), and to a lesser extent neutropenia (low neutrophils)
• Hepatosplenomegaly and elevated liver enzymes (aminotransferases) are almost always present
• Extremely high ferritin levels (a protein that stores iron)
• Hyperbilirubinemia (elevated bilirubin), predominantly conjugated, and elevated γ-glutamyl transferase and lactate dehydrogenase levels
• Disseminated intravascular coagulation, severe acute bleeding, and low fibrinogen levels

Approximately one third of patients have neurologic alterations at diagnosis that may be severe, including seizures, decreased consciousness, and signs of meningism. Ataxia and psychomotor retardation may develop. Neurologic symptoms may be the first manifestation of familial HLH, particularly in older children and adolescents.

Approximately half of affected children have moderately increased lymphocyte count or protein content in the cerebrospinal fluid. MRI commonly shows diffuse, multifocal white-matter lesions and cerebellar involvement.

Secondary HLH Presentation

The signs and symptoms of all forms of HLH are generally quite similar, making it difficult to distinguish between primary and secondary forms based on presentation alone. Secondary HLH often manifests as a critical illness with sepsis-like manifestations that don't respond to standard sepsis-directed therapy.

In a review of 661 critically ill adults with HLH, the most common triggers were infections (50% of patients), cancers (28%), and autoimmune diseases (12%). The most common infectious triggers were Epstein-Barr virus (EBV) (25% of patients), bacteria (20%), and cytomegalovirus (7%).

Among cancer triggers, lymphomas accounted for 76% of malignant triggers, followed by leukemias (8%). Among autoimmune triggers, systemic lupus erythematosus and adult-onset Still's disease were most common (39% and 21% of cases respectively).

Neurologic symptoms occur less often in patients with secondary HLH than in those with familial HLH, affecting 10-25% of patients with secondary HLH in larger studies. Half of these patients have abnormal findings on MRI.

Underlying Causes and Mechanisms

The fundamental problem in HLH involves the immune system's inability to properly regulate and terminate inflammatory responses, leading to a dangerous cascade of hyperinflammation.

Genetic Defects in Primary HLH

Familial HLH is caused by biallelic variants (mutations in both copies) in four specific genes: PRF1, UNC13D, STX11, and STXBP2. These encode the proteins perforin, Munc13-4, syntaxin-11, and syntaxin-binding protein 2 (Munc18-2) respectively, causing familial HLH types 2 through 5.

The closely related Griscelli's syndrome type 2 (GS2) is caused by variants in RAB27A, encoding the small GTPase Rab27a. These proteins are all essential for normal functioning of natural killer (NK) cells and cytotoxic T cells, confirming that the underlying cause of familial HLH is defective lymphocyte cytotoxicity.

The frequency of gene variants that cause primary HLH varies among ethnic groups, but variants in PRF1, UNC13D, and STXBP2 are most common. Although most variants are associated with severe disease and early onset, some may cause a milder phenotype with later onset.

How the Immune System Fails in HLH

In normal immune response, cytotoxic cells (NK cells and cytotoxic T cells) kill target cells such as virus-infected and cancer-transformed cells by inducing programmed cell death through the perforin-granzyme pathway. In HLH, this process is deficient due to either insufficient production of perforin or reduced secretion of perforin-containing granules from cytotoxic cells.

This defective lymphocyte cytotoxicity leads to uncontrolled expansion of antigen-specific effector T cells, sustained by the inability of CD8+ T cells to deplete antigen-presenting cells and defective down-regulation of the immune response. Activated lymphocytes secrete high levels of interferon-γ, further activating macrophages, which in turn activate more T cells.

This creates a vicious circle of immune activation that can develop even without apparent infectious stimuli. The resulting excessive immune response leads to proinflammatory cell death that mediates cytokine release, causing escalating tissue destruction in several organs with high risk of multiorgan failure and death.

Mechanisms in Secondary HLH

The cause of secondary HLH is multifactorial, with various factors (genetic defects, background inflammation, underlying immunosuppression, and infectious triggers) combining to eventually reach a threshold where inflammation becomes uncontrolled and fulminant HLH develops.

People with secondary HLH may carry genetic variants that impair but don't completely eliminate the ability to terminate the immune response. Severe HLH in adults may correlate with HLH-related gene variants. In secondary HLH, the number of circulating NK cells and cytotoxic T cells is often reduced, and qualitative defects in lymphocyte cytotoxicity have also been reported.

How HLH is Diagnosed

Diagnosis of HLH relies on specific clinical and laboratory criteria that help identify this condition amidst other inflammatory disorders.

The HLH-2004 diagnostic criteria were revised in 2024 by the Histiocyte Society. With the original HLH-2004 criteria, at least five of eight criteria must be fulfilled for diagnosis. The revised criteria remove natural killer cell activity as a criterion, requiring five of the remaining seven criteria to be met.

Key diagnostic features include:

• Fever ≥38.5°C: Caused by elevated pyrogens
• Splenomegaly ≥2 cm below costal margin: Due to infiltration by lymphocytes and histiocytes
• Cytopenia affecting ≥2 cell lines: Caused by multiple factors including cytokine suppression, ferritin effects, and hemophagocytosis
  • Hemoglobin <90 g/liter (in neonates <100 g/liter)
  • Platelets <100 × 10⁹/liter
  • Neutrophils <10⁹/liter
• Hypofibrinogenemia or hypertriglyceridemia: Fibrinogen ≤1.5 g/liter or triglycerides ≥3.0 mmol/liter
• Hyperferritinemia ≥500 μg/liter: Resulting from macrophage activation
• Hemophagocytosis: Seen in bone marrow or other tissues
• Elevated soluble CD25 ≥2400 U/ml: Indicating T-cell activation

Additional features that support the diagnosis include reduced or absent natural killer cell activity, hepatomegaly, elevated liver enzymes, elevated bilirubin, elevated lactate dehydrogenase (indicating cell death), elevated d-dimers (indicating hyperfibrinolysis), elevated cerebrospinal fluid cells or protein, and known underlying immunosuppression.

Treatment Approaches

Treatment of HLH requires addressing both the overwhelming inflammation and the underlying trigger when identified. The approach differs between primary and secondary forms.

For all patients with HLH syndrome, searching for and treating the underlying trigger is crucial. If the trigger is difficult to find in an adult, it is often a cancer that requires specific oncological treatment.

Familial HLH represents a success story in modern medicine. Initially a largely unknown and fatal disease, it is now understood on a molecular level and is curable through hematopoietic stem-cell transplantation (HSCT), which replaces the defective immune system with a healthy one.

Treatment protocols typically involve immunosuppressive therapies to control the dangerous inflammation, followed by definitive treatment addressing the underlying cause. For genetic forms, this means stem cell transplantation, while for secondary forms, treatment focuses on eliminating the trigger (infections, treating cancers, or managing autoimmune conditions).

Despite being life-threatening, HLH is treatable when recognized early. However, it remains underdiagnosed, and numerous lives could be saved through increased awareness of the disorder among both healthcare providers and patients.

Key Patient Takeaways

For patients and families dealing with or concerned about HLH, several crucial points deserve emphasis:

1. HLH is a medical emergency that requires prompt recognition and treatment to prevent organ failure and death
2. The condition exists in both genetic forms (primarily affecting infants) and acquired forms (more common in adults triggered by infections, cancers, or autoimmune diseases)
3. Diagnosis requires specific criteria including persistent fever, enlarged spleen, blood cell deficiencies, and characteristic blood test abnormalities
4. Genetic testing is important for children with HLH to identify inherited forms that may require stem cell transplantation
5. In adults with HLH, identifying and treating the underlying trigger (especially hidden cancers) is essential
6. Familial HLH, once fatal, is now curable through advances in medical treatment and stem cell transplantation
7. Increased awareness among both healthcare providers and the public is needed to reduce diagnostic delays and prevent unnecessary deaths

Patients with sepsis-like critical illness that doesn't respond to adequate empirical treatment should be evaluated for HLH, including checking ferritin levels, which are typically extremely elevated in this condition.

Source Information

Original Article Title: Hemophagocytic Lymphohistiocytosis
Authors: Jan-Inge Henter, M.D., Ph.D.
Publication: The New England Journal of Medicine, 2025;392:584-98
DOI: 10.1056/NEJMra2314005
Institutional Affiliation: Karolinska Institute, Stockholm, Sweden

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible while preserving all essential facts, data, and findings from the original scientific publication.