Hemophagocytic Lymphohistiocytosis Overview

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH is a distinct condition from clonal myeloid neoplastic "histiocytic disorders."
• It's characterized by dysfunctional T cells, activated macrophages, and pathologic inflammation (a syndrome of pathologic immune activation).
• Hemophagocytosis is the key clinical feature, where macrophages engulf erythrocytes or other hematopoietic cells in bone marrow, lymph nodes, spleen, or liver biopsies.

Types of HLH

• Primary (Familial) HLH: Occurs in neonates and infants (1 in 50,000 live births). It's an autosomal recessive disease, often resulting from genetic defects in genes like perforin (PRF1), Munc13-4 (UNC13D), and syntaxin 11 (STX11). Males and females are equally affected. Multiple gene defects have recently been identified.

• Secondary (Acquired) HLH: (Also known as macrophage activation syndrome) It's usually associated with conditions like Chediak-Higashi syndrome, Griscelli syndrome, X-linked lymphoproliferative syndrome, infections, autoimmune diseases, malignancies, immunosuppression, hematopoietic stem cell transplantation, organ transplantation, and HIV infection, and metabolic diseases.

Pathophysiology

• HLH is a hyperinflammatory uncontrolled immune response triggered by various stimuli.
• The pathogenesis of genetic HLH is understood more than acquired HLH.
• Both familial and acquired HLH are often triggered by infections (viral, bacterial fungal, and protozoan), especially in immunocompromised hosts.

Genetics of HLH

• Most genetic syndromes causing HLH share features of impaired cytotoxic NK and T-cell function.
• Mutations in genes like PRF1, UNC13D, STXBP2, STX11, and RAB27A lead to defects in the production, packaging, or secretion of perforin from NK cells and cytotoxic T cells. This impairs their ability to kill target cells leading to apoptosis of target cells.

Immunological Defects

• Inherited defects in genes regulating NK and cytotoxic T-cell function are described in HLH.
• HLH arises from pathologic activation of T cells and macrophages, resulting in the production of pro-inflammatory cytokines: IFNγ, TNF-α, IL-6, IL-10, IL-12, and soluble IL-2 receptor α (soluble CD25).
• This leads to hypercytokinemia, a condition with excessive cytokines in the blood, leading to multi-organ dysfunction and potential death.

Clinical Features

• HLH diagnosis is often challenging due to overlapping presenting signs and symptoms with other critical illnesses.
• Common features include prolonged high fever, hepatosplenomegaly, neurological symptoms (seizures, meningismus, altered mental status), rash, pulmonary dysfunction, lymphadenopathy and features related to hepatitis, and CNS symptoms (mimicking encephalitis).

Diagnostic Guidelines

• HLH diagnosis can be established through molecular methods or meeting clinical and laboratory criteria.
• Genetic testing is often used for screening or confirming suspected familial HLH (especially in siblings).
• Diagnostic criteria (8 criteria, at least 5 needed for diagnosis): fever, splenomegaly, cytopenias (affecting at least 2 of 3 cell lineages- hemoglobin, platelets, neutrophils), hypertriglyceridemia or hypofibrinogenemia, ferritin level, soluble CD25 levels, low or absent natural killer cell activity, and hemophagocytosis in bone marrow or spleen or lymph nodes with absence of malignancy.

Bone Marrow

• Bone marrow examination is necessary to evaluate for hemophagocytosis, identify underlying malignancy, and rule out benign or neoplastic mimics.
• Hemophagocytosis in a tissue or marrow biopsy is a characteristic finding, but isn't always conclusive.
• In 20% or more of patients, the marrow biopsy might not show hemophagocytosis..
• Bone marrow aspirates might show hypercellularity and increased histiocytes.
• Cellular damage in HLH stimulates inflammatory cytokines (TNF-α, IFN-γ) which suppress hematopoiesis, induce apoptosis in hematopoietic cells, and activate histiocytes.

Treatment and Prevention

• HLH treatment depends on the underlying cause and severity.
• Two main treatment goals are suppression of hyperinflammation and addressing the underlying disease when possible.
• Histiocyte Society protocol recommends a combination of chemotherapy and immunotherapy with potential bone marrow transplant for severe cases, those with gene defects, or who have relapsed or refractory HLH or CNS involvement.
• Possible regimens include cyclosporine A, etoposide, corticosteroid drugs.
• Potential hematopoietic cell transplantation (HCT) from sibling donors should be evaluated for inherited HLH genes and occult immune dysfunction.

Course and Prognosis

• Some patients respond well initially but relapse during treatment .
• The three-year survival rate of patients can vary depending on treatment methods.
• Children with Epstein-Barr virus (EBV)-associated HLH may have an underlying T-lymphoproliferative disorder.

Differential Diagnosis

• HLH should be considered in patients with fever of unknown origin, moderate infections, sepsis, multiorgan dysfunction, hepatitis, anemia and thrombocytopenia, and various autoimmune phenomena (ex: Kawasaki disease, lupus erythematosus, rheumatoid arthritis)
• HLH diagnosis is challenging because some overlapping clinical features may be seen in these conditions.