Hemophagocytic lymphohistiocytosis

Other Names

Familial erythrophagocytic lymphohistiocytosis; Familial histiocytic reticulosis; FHL; HLH; Familial HLH. Hemophagocytic lymphohistiocytosis (HLH) is a condition in which the body makes too many activated immune cells (macrophages and lymphocytes).

Introduction

People with HLH usually develop symptoms within the first months or years of life.

Types

There are five subtypes of inherited (or familial) HLH which are designated familial HLH, types 1-5.

• FHL1: HPLH1
• FHL2: PRF1 (Perforin)
• FHL3: UNC13D (Munc13-4)
• FHL4: STX11 (Syntaxin 11)
• FHL5: STXBP2 (Syntaxin binding protein 2)/UNC18-2

Cause

There are inherited and non-inherited (acquired) causes of hemophagocytic lymphohistiocytosis (HLH). Each subtype is caused by a change (mutation) in a different gene that helps regulate the immune system. Type 1 is due to a gene defect on chromosome 9.

Familial HLH, type 2 is caused by mutations in the PRF1 gene.

Familial HLH, type 3 is caused by mutations in the UNC13D gene.

Familial HLH, type 4 is caused by mutations in the STX11 gene.

Familial HLH, type 5 is caused by mutations in the STXBP2 gene.

All of the genes involved with HLH normally provide instructions for proteins that help destroy or turn off activated immune cells when they are no longer needed. Changes in these genes lead to an overproduction of immune cells which results in an excessive immune response and the many signs and symptoms of familial HLH. The acquired causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases.

When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition calledX-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.

Inheritance

Hemophagocytic lymphohistiocytosis (HLH) may be inherited or acquired (due to non-genetic factors).

Autosomal recessive inheritance, a 25% chance

Familial HLH is inherited in an autosomal recessive manner. This means that to be affected, a person must have a change (mutation) in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Acquired HLH is not inherited. The non-genetic causes of HLH include: infection, medications that suppress the immune system, autoimmune diseases, immunodeficiencies, certain types of cancer and/or metabolic diseases. When HLH results from an inappropriate immune response to Epstein-Barr virus or another viral illness, it may be due to a separate genetic condition called X-linked lymphoproliferative disease (XLP). XLP is caused by a mutation in the SH2D1A or XIAP gene and is inherited in an X-linked manner.

Symptoms

The features of this condition may include:

• Fever
• Enlarged liver and/or spleen
• Skin rash
• Lymph node enlargement
• Breathing problems
• Easy bruising and/or abnormal bleeding
• Kidney abnormalities
• Heart problems
• Increased risk for certain cancers (leukemia, lymphoma).

Many people with this condition also develop neurologic abnormalities. The neurological symptoms vary but may include irritability, fatigue, abnormal muscle tone, seizures, neck stiffness, mental status changes, ataxia, blindness, paralysis, and/or coma.

Diagnosis

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be established if 1 and/or 2 below is fullfilled:

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Light microscopic image of bone marrow showing stromal macrophages containing numerous red blood cells in their cytoplasm

1. A genetic test identifying a mutation in one of the genes involved with this condition

2. At least five out of the following 8 signs or symptoms:

• Fever
• Enlarged spleen
• Cytopenia (lower-than-normal number of blood cells)
• Elevated levels of triglycerides or low levels of fibrinogen in the blood
• Hemophagocytosis (the destruction of certain types of blood cells by histiocytes) on bone marrow, spleen or lymph node biopsy
• Decreased or absent NK cell activity
• High levels of ferritin in the blood
• Elevated blood levels of CD25 (a measure of prolonged immune cell activation).
• Clinical genetic testing is available for the four genes known to cause familial hemophagocytic lymphohistiocytosis, types 2-5.
• The bone marrow may show hemophagocytosis.

Treatment

The best treatment options for hemophagocytic lymphohistiocytosis (HLH) are determined by a number of factors, including the severity of symptoms, the age of onset, and the underlying cause of the condition.

In acquired HLH, it is often necessary to treat the underlying condition. For example, antiobiotics or antiviral medications can be used to treat or prevent infections that may have triggered the exaggerated immune response. Allogeneic hematopoietic cell transplantation is considered a cure for familial HLH. It is often recommended that people with confirmed or suspected familial HLH undergo this treatment as early in life as possible. Prior to hematopoietic cell transplanation, people with HLH are usually treated with chemotherapy and/or immunotherapy to destroy excess immune cells which can lead to life-threatening inflammation. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Emapalumab (Brand name: Gamifant)emapalumab (Gamifant) was approved for the treatment of adult and pediatric (newborn and older) patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent, or progressive disease or intolerance of conventional HLH therapy.

Prognosis

Even with treatment, only 21-26% are expected to survive 5 years. The course of the disease and life expectancy are not well studied in adults with familial HLH. The prognosis for people with acquired HLH varies.For example, the mortality rate reportedly is lower when HLH is associated with autoimmune diseases (8–22%), and greater when it is associated with tumors (especially T-cell lymphoma). Because affected people are being diagnosed earlier and treatment options are improving, the prognosis for people with HLH is likely to get better over time.

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