Hemophagocytic Lymphohistiocytosis (HLH) in Children

Hemophagocytic Lymphohistiocytosis (HLH) in Children

Introduction

Hemophagocytic Lymphohistiocytosis (HLH) is a rare and potentially life-threatening syndrome characterized by dysregulated immune activation, leading to an excessive inflammatory response. It is a disorder of the mononuclear phagocyte system, which includes macrophages, histiocytes, and dendritic cells. HLH can occur in both genetic (primary) and acquired (secondary) forms, with children being particularly vulnerable to the genetic form.

Pathophysiology

HLH is a hyperinflammatory condition that results from defective cytotoxic function of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). This defect leads to uncontrolled activation and proliferation of lymphocytes and macrophages, resulting in the overproduction of inflammatory cytokines, such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6).

The dysregulated immune response in HLH leads to several clinical manifestations, including fever, hepatosplenomegaly, cytopenias, coagulopathy, and organ dysfunction. The hallmark feature of HLH is the presence of activated macrophages, which engulf and destroy other blood cells, a process known as hemophagocytosis.

Genetic (Primary) HLH

Genetic or primary HLH is caused by inherited genetic mutations that affect the cytotoxic function of NK cells and CTLs. These mutations can involve genes involved in the cytolytic pathway, such as PRF1 (perforin), UNC13D, STX11, and STXBP2. Other genetic defects associated with primary HLH include mutations in RAB27A, LYST, AP3B1, and SH2D1A (X-linked lymphoproliferative syndrome).

Primary HLH typically presents in infancy or early childhood, although some cases may manifest later in life. The clinical presentation can vary, but common features include persistent or recurrent fever, hepatosplenomegaly, cytopenias, coagulopathy, and neurological symptoms.

Acquired (Secondary) HLH

Acquired or secondary HLH can occur in the context of various underlying conditions, including infections (viral, bacterial, fungal, or parasitic), malignancies (especially lymphomas), autoimmune disorders, and metabolic disorders. In these cases, the dysregulated immune response is triggered by the underlying condition, leading to the clinical manifestations of HLH.

Common infectious triggers of secondary HLH in children include Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), and various herpesviruses. Malignancies, particularly lymphomas and leukemias, can also precipitate HLH due to the excessive activation of lymphocytes and macrophages.

Diagnosis

The diagnosis of HLH is based on a combination of clinical findings, laboratory tests, and diagnostic criteria. The most widely used diagnostic criteria are the HLH-2004 criteria, which include the following:

  1. Fever
  2. Splenomegaly
  3. Cytopenias (affecting at least two cell lines)
  4. Hypertriglyceridemia and/or hypofibrinogenemia
  5. Hemophagocytosis in bone marrow, spleen, lymph nodes, or liver
  6. Low or absent NK cell activity
  7. Ferritin ≥500 μg/L
  8. Soluble CD25 (IL-2 receptor) ≥2,400 U/mL

The presence of five out of these eight criteria is required for the diagnosis of HLH. Additional tests may include genetic testing for mutations associated with primary HLH, as well as evaluation for underlying conditions that may trigger secondary HLH.

Treatment

Primary HLH

The treatment of primary HLH typically involves initial immunochemotherapy to control the hyperinflammatory state, followed by hematopoietic stem cell transplantation (HSCT) as a curative therapy.

The initial treatment regimen often includes a combination of immunosuppressive and chemotherapeutic agents, such as dexamethasone, etoposide, and cyclosporine A. This is aimed at suppressing the dysregulated immune response and controlling the hyperinflammatory state.

Once the patient is stabilized, the definitive treatment is HSCT, which involves replacing the patient's abnormal immune system with healthy stem cells from a matched donor. HSCT offers the best chance for long-term cure and survival in patients with primary HLH.

Secondary HLH

The treatment of secondary HLH focuses on addressing the underlying condition that triggered the HLH episode, along with supportive care and immunosuppressive therapy.

If the underlying cause is an infection, appropriate antimicrobial therapy is initiated to control the infection. In cases of malignancy-associated HLH, treatment may involve chemotherapy or targeted therapies to address the malignancy.

Supportive care measures, such as blood product transfusions, fluid and electrolyte management, and nutritional support, are essential in managing the complications of HLH.

Immunosuppressive and immunomodulatory agents, similar to those used in primary HLH, may be employed to suppress the hyperinflammatory state. These include dexamethasone, etoposide, and other agents like anakinra (an IL-1 receptor antagonist) or emapalumab (an anti-interferon-gamma monoclonal antibody).

Prognosis

The prognosis of HLH largely depends on the underlying cause, the promptness of diagnosis, and the effectiveness of treatment.

In primary HLH, the prognosis is generally poor without definitive treatment with HSCT. However, with timely HSCT, survival rates have improved significantly, ranging from 60% to 80%.

In secondary HLH, the prognosis is highly variable and largely depends on the underlying condition and its response to treatment. Early recognition and prompt treatment of the underlying cause, along with supportive care and immunosuppressive therapy, can improve the chances of survival.

Factors associated with a poorer prognosis in HLH include delayed diagnosis, severe organ dysfunction, and the presence of underlying malignancies or refractory infections.

Further Reading

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