Description

• Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by excessive activation of the immune system resulting in over production of inflammatory cytokines.
• It usually occurs in children; however, adults can be affected as well.
• Patients with HLH usually present with high fevers, cytopenia, hyperferritinemia, and hepatosplenomegaly.

Epidemiology

Incidence
Estimated annual incidence in Europe and United States together is 800,000 people and 1.2 per 1 million children.

Prevalence
Prevalence of all cases of HLH <18 years of age is 1.07/100,000. However, due to the under diagnosis of this condition, prevalence is considered to be significantly higher, especially for secondary HLH.

Etiology and Pathophysiology

• HLH can be primarily classified as primary and secondary. Primary HLH is usually seen in children and is genetic in origin. It results from mutations in genes involved in the cytotoxic granule activity pathways of the immune system. Secondary or acquired HLH usually results from infections, malignancy, or autoimmune diseases. Among the infectious etiologies, viral infections are more frequently associated with HLH, especially Epstein-Barr virus (EBV) and among malignancy-related etiologies, B- or T-cell lymphomas are most common.
• During the normal immune response, antigens of phagocytosed pathogens are presented by the antigen presenting cells (APCs) such as macrophages or dendritic cells to the natural killer (NK) cells and cytotoxic T lymphocytes (CTL), which recognize and destroy pathogen-infected cells by release of toxic granules. They also produce proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interferon-γ that activate and recruit macrophages to the tissues. NK cells and CTLs also play a role in removal of APCs by inducing apoptosis, thus providing negative feedback.
• In genetic HLH, defects in the cytolytic pathway causes failure to destroy the APCs, which causes deprivation of the negative feedback resulting in a storm of proinflammatory cytokines TNF-α and interferon-γ. This causes fever and infiltration of tissues with activated macrophages and lymphocytes causing end-organ damage.
• In secondary or acquired HLH, infections, malignancy, or autoimmune disease causes shifts in the immune system balance with proliferation of APCs more rapidly than could be disintegrated by CTLs producing the clinical picture of HLH.

Genetics

• Primary HLH occurs mainly due to mutations in seven genes which encode proteins required for the biogenesis, trafficking, docking, priming, or membrane fusion of the toxic granules in lymphocytes (1). Primary HLH is further classified into familial and genetic.
• Familial HLH results from mutation of five of the above-mentioned genes and has an autosomal recessive inheritance.
• Genetic HLH is seen with Chédiak-Higashi syndrome (CHS), Griscelli syndrome (GS), and X-linked lymphoproliferative (XLP) syndrome.

Risk Factors

• Children may have a genetic predisposition. There are no known modifiable risk factors in adults.
• Acquired HLH may occur secondary to infections, autoimmune conditions, or malignancy.

Commonly Associated Conditions

Metabolic disorders (lysosomal acid lipase deficiency), primary immune deficiencies in children; in adults, viral infections (most commonly EBV), malignancy (B- or T-cell lymphoma), autoimmune diseases (SLE, adult-onset Still disease)