Hemophagocytic Lymphohistiocytosis

HLH stands for hemophagocytic lymphohistiocytosis. It is a life-threatening condition that can be defined as either primary or secondary HLH. Primary, or “familial,” HLH is when the condition is inherited. The term secondary HLH is used when your doctor thinks the condition may have occurred for a variety of other non-inherited reasons.

Patients with primary HLH have cells of the immune system called T and NK cells that don’t work properly. These cells become overactive, causing too much inflammation. Ordinarily, these cells should destroy infected, damaged cells of the body. In HLH, the immune system begins to damage the patient’s own tissues and organs, including the liver, brain and bone marrow where blood is made.

Sometimes, doctors can see these angry immune cells “eating” other cells when they look at the bone marrow from a patient using a microscope. This process is called hemophagocytosis.

Signs & Symptoms

The onset and severity of hemophagocytic lymphohistiocytosis can vary greatly from one person to another. The specific symptoms that develop can also vary greatly, although the condition often causes multiorgan involvement. Generally, affected individuals develop fevers, a rash, an abnormally large liver (hepatomegaly), and an abnormally large spleen (splenomegaly). Fevers may be prolonged and persistent, often failing to respond to antibiotics. Sometimes, the lymph nodes are also abnormally large (lymphadenopathy). Lymph nodes are part of the lymphatic system, a circulatory network of vessels, ducts, and nodes that filter and distribute certain protein-rich (lymph) and blood cells throughout the body. Lymph nodes are small structures, found in groups throughout the body, that help to filter or drain out harmful substances from the body.

These initial sign and symptoms are described as nonspecific. This means that these signs and symptoms are common to many other different disorders or conditions, which can make getting a correct diagnosis difficult.

Affected individuals may also have low levels circulating red blood cells (anemia) and low levels of circulating platelets (thrombocytopenia). Red blood cells deliver oxygen to the body and platelets allow the body to form clots to stop bleeding. Individuals with anemia may experience tiredness, increased need for sleep, weakness, lightheadedness, dizziness, irritability, headaches, pale skin color, difficulty breathing (dyspnea), and cardiac symptoms. Individuals with thrombocytopenia are more susceptible to excessive bruising following minimal injury and to spontaneous bleeding from the mucous membranes, especially those of the gums and nose.

Some affected individuals may develop neurological symptoms including seizures, changes in mental status and irritability, paralysis (palsy) of certain cranial nerves, and problems coordinating voluntary movements (ataxia). Affected individuals are at risk of developing posterior reversible encephalopathy syndrome, which causes a rapid onset of headaches, altered consciousness, seizures, and disturbances in vision. Neurological problems are most common with familial hemophagocytic lymphohistiocytosis.

Additional symptoms can occur depending upon the specific organ system involved in an individual. These symptoms can include significant problems breathing (lung dysfunction), severe low blood pressure (hypotension), liver inflammation (hepatitis), kidney dysfunction, yellowing of the skin and whites of the eyes (jaundice), swelling due to fluid accumulation (edema), abdominal swelling due to fluid accumulation (ascites), and a variety of skin problems including widespread, reddening of the skin because of inflammation (erythroderma), rashes, blood spots (purpura), and tiny spots on the skin (petechiae).

Causes of Primary Hemophagocytic Lymphohistiocytosis

Primary HLH is caused by defects in several genes, including PRF1, UNC13D, STXBP2, STX11, RAB27A, LYST, AP3B1, SH2D1A, and XIAP/BIRC4.  When patients have mutations in SH2D1A, and XIAP/BIRC4, they are usually classified as having X-linked Lymphoproliferative Disease Type 1 or 2, respectively (XLP1 and XLP2).  When patients have mutations in RAB27A, they may be said to have Griscelli syndrome.  Patients who have mutations in LYST are said to have Chediak-Higashi syndrome.  There are other related disorder genes that can also cause HLH, such as NLRC4.  All of these genes normally produce proteins that regulate immune cells.  When these proteins are absent or don’t work right, the immune system cells activate and proliferate unchecked, and continue past the point of fighting actual infection.

In secondary HLH, the patient has often been disease-free for most of their life, but then HLH manifests when something like a severe illness triggers an immune response that cannot be shut off. One of the main viral triggers for the disease is Epstein-Barr virus.

HLH diagnosed

Your healthcare provider bases a diagnosis of HLH on your symptoms, physical exam findings, and several lab tests. A prolonged fever is a commonly occurring symptom. An enlarged liver or spleen (located in the upper left side of the abdomen) are key physical findings. Your healthcare provider conducts blood tests to look for:

• Low levels of white blood cells called natural killer cells (these cells are important for a healthy immune system)
• Low levels of white blood cells, red blood cells, and clotting cells called platelets
• High levels of triglycerides (fats in your blood)
• Low levels of fibrinogen (a protein important for clotting)
• High levels of ferritin (a protein that stores iron)
• High levels of a substance called CD25 which increases in your blood when your immune system is stimulated

Another important test, a bone marrow biopsy, calls for taking a sample of your bone marrow (the center of the bone, where blood cells are made) and examining it under a microscope. Other tests may include genetic testing and blood cultures, which are blood samples, to look for infection in your blood.

Treatment

Treatment is very important for patients with HLH because the condition is life-threatening. The treatments that doctors use suppress the immune system. Patients are usually treated with steroids, chemotherapy (etoposide) and/or antibody therapies that target and destroy T cells (anti-thymocyte globulin / ATG as well as alemtuzumab). Patients may receive other medications that suppress the immune system. Additionally, your doctor may give medications that help prevent and/or treat any infections.

Many patients must also have their immune systems replaced by receiving a hematopoetic (blood or bone marrow) stem cell transplant in order to be cured of HLH. Your doctor can tell you if this is the case for you or your child.

he treatment of hemophagocytic lymphohistiocytosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating blood disorders (hematologists), specialists in diagnosing and treating cancer (oncologists), specialists in diagnosing and treating immune system diseases (immunologists), geneticists (for familial forms), social workers, and other healthcare professionals may need to systematically and comprehensively plan treatment. Psychosocial support for the entire family is essential as well. Genetic counseling may be of benefit for affected individuals and their families.

Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause; the presence or absence of certain symptoms; the overall severity of the symptoms and the disorder; an individual’s age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.

Affected individuals whose overall health is strong enough may undergo treatment for the underlying condition such as medications to treat an underlying infection, or appropriate treatment for autoimmune disorders or cancer. Treating the underlying condition may remove the “trigger” that has led to the abnormal immune system response.

Affected individuals who health is deteriorating require treated specific for hemophagocytic lymphohistiocytosis immediately. In 1994, the Histiocyte Society published treatment recommendations for this disorder (HLA-94). There were also published studies from 2004 (HLA-2004) that were slightly different.

These treatment regimens include chemotherapy and drugs that suppress the activity of the immune system (immunosuppressive drugs). They target and destroy the hyperactive immune system cells and reduce the life-threatening inflammation that characterizes hemophagocytic lymphohistiocytosis.

After initial treatment, which lasts about 8 weeks, affected individuals are gradually weaned off the drugs onto different medications. If affected individuals have not responded well to this treatment, an allogeneic stem cell transplant may be recommended. This treatment is also recommended for individuals with an abnormal variant in a known HLH gene, central nervous system involvement, and blood cancer (hematologic malignancy) that cannot be treated.

An allogeneic stem cell transplant is a procedure in which stem cells from an affected individual is replaced with the stem cells from a matched, healthy donor. Stem cells are special cells found in bone marrow that manufacture different types of blood cells (e.g. red blood cells, white blood cells, platelets).

Affected individuals undergo high-doses of chemotherapy or radiation to wipe out their stem cells. The stem cells are then replaced with those from a donor. Allogeneic stem cell transplant is a high-risk procedure with the potential for side effects.

Some affected individuals may need blood transfusion because they have low levels of circulating red blood cells or platelets. Some physicians may recommend antibiotics to prevent the development of an infection (prophylactic therapy).

In 2018, Gamifant (emapalumab) was approved for the treatment of pediatric and adult patients with primary HLH who have refractory, recurrent or progressive disease or cannot tolerate conventional HLH therapy. Gamifant will be marketed by Sobi.