Hemophagocytic Lymphohistiocytosis (HLH): Overview and More

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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome in which the immune system responds inappropriately to a triggering event, causing damage to healthy cells and organs in the body. It can affect infants, children, and adults.

In the familial form of HLH, infants are born with genetic mutations that predispose their immune system to react inappropriately. This is very rare, occurring in 1 in 50,000 births.

In acquired HLH, the immune system reacts inappropriately in response to a triggering event, which may be from an infection, cancer, or autoimmune disease. HLH requires prompt treatment, as it is fatal if untreated.

Antibodies destroy a cell infected by a virus / immune defense kills the infected cell - stock photo

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Types of HLH

There are two types of HLH, familial and acquired:

  • Familial HLH: A mutation exists in a gene that affects how the immune system functions. In order for someone to be born with HLH, the affected person had to get a copy of the gene mutation from each parent.
  • Acquired HLH: This not a disease that people are born with. With acquired HLH, the immune system responds abnormally to a triggering event; though it may be from cancer, an infection, or autoimmune disease, sometimes the trigger is unknown. When HLH is secondary to an autoimmune disorder, it is called MAS, or macrophage activation syndrome.

Causes of HLH

In a normally functioning immune system, macrophages play an important role. These cells kill organisms that aren’t supposed to be in the body, such as bacteria or viruses. They also remove dead cells and stimulate other parts of the immune system to induce inflammation by the release of proteins called cytokines.

In both types of HLH, the immune system becomes overactive and starts to attack and destroy healthy cells in the body. This results in the destruction of cells in multiple organs in the body, including the bone marrow where blood cells are made.

When macrophages kill healthy blood cells, this is called hemophagocytosis. The immune system normally has a process of being able to turn off inflammatory responses. In HLH, this process is no longer functioning, and body organs and systems continue to be damaged. The excess release of cytokines also damages cells.

Familial HLH vs. Acquired HLH

The causes of familial HLH and acquired HLH are different:

  • Familial HLH: An affected person is born with a mutation in one of the genes responsible for developing a healthy immune system. In order for a person to be born with these abnormal genes,  they must receive a mutated copy from each of their parents.
  • Acquired HLH: There is no family history of the disorder. The immune system becomes overactive due to a triggering event. Many times the trigger is unknown but is commonly associated with Epstein Barr viral infection, other infections, autoimmune diseases, vaccinations, or cancers.

HLH Symptoms

For those with familial HLH, symptoms usually develop early in life, typically in the first months or years of childhood. Those with acquired HLH may develop symptoms at any time following a trigger exposure. These symptoms may include:

  • Fever
  • Enlarged spleen
  • Enlarged lymph nodes
  • Liver enlargement
  • Jaundice (yellow color) to the skin
  • Bleeding and easy bruising
  • Rash
  • Lung problems: cough, difficulty breathing
  • Neurological changes: headache, mental status changes, vision changes, weakness, seizures
  • Kidney failure
  • Digestive problems: nausea, vomiting, diarrhea
  • Abnormal blood tests: low red blood cells, white blood cells, and platelets
  • Elevated inflammatory markers in the blood

Diagnosis

A diagnosis of HLH can be made through an evaluation of symptoms and various blood tests.

If an infant or child has symptoms that make a healthcare provider suspicious of HLH, rapid blood testing for gene mutations can be done to confirm the diagnosis. 

A diagnosis of HLH can also be made if someone meets at least five of the following criteria:

  • Fever
  • Enlarged spleen
  • Low white blood cells, red blood cells, or platelets (at least two must be low)
  • High levels of triglycerides (fat in the blood) and/or low levels of fibrinogen (a blood-clotting protein)
  • Low activity of natural killer cells
  • High blood levels of ferritin (an inflammatory marker)
  • High levels of CD25 (also know as IL-2 levels) in the blood (a measure of active immune cells)

Bone Marrow Biopsy

An HLH diagnosis can be confirmed through a bone marrow biopsy, where evidence of bone marrow destruction by macrophages would be seen.

HLH Treatment

Treatment for HLH is individualized for each person, as treatment decisions are made based on symptoms they are experiencing.

It often begins with treating the triggering condition that started the overactive immune response, if known. Medications are also given to suppress the immune system and stop it from continuing to destroy healthy cells. These immune-suppressing medications include steroids and chemotherapy.

For those with familial HLH, an allogeneic stem cell transplant may be needed. During this procedure, high doses of chemotherapy are given to wipe out their immune system cells. They then receive a replacement of stem cells from a donor. This process comes with risks and side effects, and finding a donor can be difficult, as they must be matched to the recipient carefully to make sure the donated cells will work. 

In 2018, an antibody therapy, emapalumab, was approved for use in those with familial HLH. This infusion helps to decrease the immune response by stopping the over-signaling by the immune system. It can be used in those:

  • Who have recurrent HLH
  • Who fail standard therapy
  • Who are unable to tolerate standard therapy

Supportive treatments are also given as well, such as:

  • Blood or platelet transfusions
  • Intravenous fluid administration
  • Antibiotics

These therapies don’t treat the HLH but treat some of the symptoms HLH has caused. 

Prognosis

HLH can have a poor prognosis. For those born with primary HLH, the average survival after diagnosis is two to six months, with a five-year survival rate of 25%. The only potential cure is stem cell transplant.

For children who had a stem cell transplant, the five-year survival rate is about 66%.

Mortality rates of acquired HLH can vary and are typically worse when HLH is caused by cancer than by another trigger.

Clinical Trials

Clinical trials are ongoing for better treatments for HLH, with the hope that these can improve the prognosis of this disease.

Coping

HLH can be a difficult diagnosis to cope with, and living with a rare disease can be difficult for the affected person and their family. Especially when infants or young children are affected, the diagnosis and treatment of HLH are often stressful, scary, and overwhelming.

There are many support groups and resources available for those dealing with a diagnosis of HLH, and finding healthy ways to cope with the stress is important.

A Word From Verywell

A diagnosis of HLH can be scary and overwhelming. Although HLH is a life-threatening condition, there are treatments available that may help. If you are concerned that yourself or a friend or family member may have symptoms of HLH, reach out to a healthcare provider immediately. Earlier treatment may improve outcomes for this disease. 

If someone you know or love has been diagnosed with HLH, reach out to support groups, family, friends, or contacts at the provider’s office for help in coping with the stress of the diagnosis. 

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