What are the other Names for this Condition? (Also known as/Synonyms)

• Acquired Hemophagocytic Lymphohistiocytosis
• Erythrophagocytic Lymphohistiocytosis
• Primary Hemophagocytic Lymphohistiocytosis

What is Hemophagocytic Lymphohistiocytosis? (Definition/Background Information)

• Hemophagocytic Lymphohistiocytosis (HLH) is a type of immune disorder, called cytokine storm syndrome (CSS). Cytokine storm syndromes exhibit excessive stimulation of the immune system, which results in a widespread inflammatory response that is often life-threatening
• Cytokines are small signaling proteins that various bodily cells use to coordinate an immune response. This includes immune cell activation and recruitment; it also includes inflammation
• Inflammation is associated with many of the familiar symptoms of injury and infection. These include redness, swelling, warmth, and pain. The purpose of an inflammation is to draw the body’s resources to the site of injury or infection
• When tissues are injured or infected, cells in the immune system that are located at that site, secrete cytokines and other chemicals that signal the body that there is a need to ‘fight-off’ an infection or repair tissue injury. The newly arriving immune cells then secrete additional cytokines, to activate even more of immune cells throughout the body. In such a manner, the immune response builds on itself. This process  is known as a positive feedback
• Proper regulation is necessary to prevent this process from going out of control. This is accomplished using other signals that limit the effect of the cytokines in a large number of complex ways
• Cytokine storm syndromes result, when the immune response system gets out of control. The inflammatory response that results from CSS is body-wide and debilitating. It is characterized by overabundant and hyperactive immune cells
• Hemophagocytic Lymphohistiocytosis is a CSS that is characterized by an excessive stimulation of inflammation and attack of the body’s own blood cells (termed as hemophagocytosis)

Who gets Hemophagocytic Lymphohistiocytosis? (Age and Sex Distribution)

Individuals at risk for Hemophagocytic Lymphohistiocytosis may include:

• Infants, less than 1 year old
• Both males and females are equally affected
• Europeans and African Americans, those who display a higher frequency of mutation of the genes, linked to HLH

What are the Risk Factors for Hemophagocytic Lymphohistiocytosis? (Predisposing Factors)

Following are factors that increase one’s susceptibility to Hemophagocytic Lymphohistiocytosis:

• Serious or body-wide infections: This includes infection by various viruses, which can range from viruses that cause mononucleosis, to the ones that cause the common cold
• Certain medications
• In rare cases, as a reaction to some immunizations
• Cancer: This syndrome is frequently associated with T cell lymphomas
• Rheumatological disorders - autoimmune diseases, such as lupus or rheumatoid arthritis
• Family history of HLH

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Hemophagocytic Lymphohistiocytosis? (Etiology)

• Hemophagocytic Lymphohistiocytosis can be either familial (primary) or acquired (secondary). In either case, the cause is not entirely known
• Primary Hemophagocytic Lymphohistiocytosis is inherited. It is associated with certain mutations in the functional regions of DNA (genes) that give instructions for regulation of the inflammatory response. Specifically, abnormalities in the following genes have been implicated in HLH:
  • STXBP2 (in 20% of north Europeans with HLH)
  • STX11 (in 1% of north Americans, 5% of central Europeans with HLH)
  • RAB27A
  • MUNC13-4 (in 1-2% of all north Europeans)
  • PRF1 (in 80% of African Americans, 20% of northern Europeans with HLH)
  • HPLH1
  • BIRC4
  • SH2D1A
• Secondary Hemophagocytic Lymphohistiocytosis is triggered by medical issues that arise after a strong activation of the immune system. This may follow a severe infection, an aggressive cancer, or exposure to a potent chemical

What are the Signs and Symptoms of Hemophagocytic Lymphohistiocytosis?

Signs and symptoms of Hemophagocytic Lymphohistiocytosis include:

• Prolonged fever
• Widespread rashes, bruising
• Skin discoloration, especially yellowing
• Altered mental status
• Difficulty breathing
• Pale appearance (pallor)
• Persistent bleeding
• Upper abdominal pain, especially in the left side
• Enlarged lymph nodes

How is Hemophagocytic Lymphohistiocytosis Diagnosed?

If it is suspected by the doctor based on the patient’s condition, Hemophagocytic Lymphohistiocytosis can be diagnosed by detection of  a genetic defect in an associated gene, or if any 5 of the following 8 criteria are present, in addition to the patient’s clinical symptoms:

• Prolonged fever
• Enlarged spleen (splenomegaly)
• Low blood cell levels (cytopenia), including:
  • Low white blood cell levels (leukopenia)
  • Low red blood cell levels (anemia)
  • Low platelet levels (thrombocytopenia)
• Increased levels of fat (triglycerides) or a clotting protein (fibrinogen) in blood
• Increased levels of an iron-storing protein (ferritin) in the blood
• Increased levels of an inflammation marker (sCD25) in the blood
• Decreased levels of a particular type of  white blood cells (NK, or natural killer cells)
• Evidence of attack on the body’s own blood cells (hemophagocytosis), through abnormal bone marrow, spleen, or lymph node findings, These are seen on tissue that is biopsied and looked at under the microscope

Following are diagnostic techniques that may aid in identification of Hemophagocytic Lymphohistiocytosis:

• Blood tests to detect:
  • Low blood cell levels
  • Elevated triglyceride levels
  • Elevated fibrinogen levels
  • Elevated ferritin levels
  • Elevated sCD25 levels
• Physical exam to detect:
  • Enlarged spleen (splenomegaly)
  • Enlarged lymph nodes (lymphadenopathy)
  • Fever
  • Rashes
• Bone marrow biopsy, to detect hemophagocytosis
• Genetic studies of the relevant genes to detect any abnormalities

Differential diagnoses of HLH may include:

• Genetic immune disorders that also exhibit hemophagocytosis
• Autoimmune lymphoproliferative syndrome

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Hemophagocytic Lymphohistiocytosis?

Following are complications that may arise from Hemophagocytic Lymphohistiocytosis:

• Systemic shock
• Serious infection
• Persistent bleeding, especially during surgery
• Brain damage, due to excessive and prolonged fever

How is Hemophagocytic Lymphohistiocytosis Treated?

Treatments for Hemophagocytic Lymphohistiocytosis include:

• The use of medications, such as:
  • Dexamethasone
  • Etoposide
  • Intrathecal methotrexate
  • Anti-viral medication
  • Alemtuzumab
• Bone marrow transplant

How can Hemophagocytic Lymphohistiocytosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Primary Hemophagocytic Lymphohistiocytosis genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

HLH cannot be prevented; however, a few methods that can help reduce incidence of the condition include:

• Limiting exposure to pathogens through proper sanitation
• Seeking medical attention early in the course of a progressively worsening illness

What is the Prognosis of Hemophagocytic Lymphohistiocytosis? (Outcomes/Resolutions)

• The mortality rate is very high with Hemophagocytic Lymphohistiocytosis
• There are many factors that influence the long-term outcome and chances of one’s survival
• Providing appropriate treatment is essential, because the average life expectancy without treatment is about 2 months
• Continuing therapy is necessary after a successful treatment, in order to ensure a better prognosis

Additional and Relevant Useful Information for Hemophagocytic Lymphohistiocytosis:

Familial Hemophagocytic Lymphohistiocytosis is a very rare disease, with an incidence rate of 1 in 1,000,000.