NORD gratefully acknowledges Michael B. Jordan, MD, Division of Bone Marrow Transplantation and Immune Deficiency, HLH Center of Excellence, Cincinnati Children's Hospital, and Team Audrey, for assistance in the preparation of this report.
Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by an overactive, abnormal response of the immune system. The immune system is the body’s natural defense system against foreign or invading organisms or substances. The immune system is a complex network of cells, tissues, organs, and proteins that work together to keep the body healthy. In hemophagocytic lymphohistiocytosis, the immune system responds to a stimulus or ‘trigger’, often an infection, but the response is ineffective and abnormal. This ineffective, abnormal response, causes a variety of signs and symptoms, which, if not treated, can potentially become life-threatening. Some affected individuals may have a genetic predisposition to developing hemophagocytic lymphohistiocytosis. This is known as the primary or familial form. In other individuals, the disorder occurs sporadically usually when there is an underlying predisposing condition or disorder. This is known as the secondary form. The secondary forms are more common than the familial forms. Hemophagocytic lymphohistiocytosis most often affects infants from birth to 18 months, but can affect individuals of any age. Early diagnosis and prompt treatment is essential.
Hemophagocytic lymphohistiocytosis (HLH) is a condition with different underlying causes. There are several names used to describe this condition. Familial hemophagocytic lymphohistiocytosis (FHL) refers to genetic forms that are caused by an abnormal variant in a gene. As of April 2018, abnormalities in multiple genes have been identified as causes. Macrophage activation syndrome (MAS) is the term used for hemophagocytic lymphohistiocytosis that occurs in people with an autoimmune or autoinflammatory disease. This is a type of secondary HLH. The diseases most commonly associated with MAS are juvenile systemic arthritis, adult-onset Still’s disease, and systemic lupus erythematosus.
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).
Hemophagocytic lymphohistiocytosis is broadly broken down into primary and secondary (acquired) forms. The condition results from an ineffective, abnormal response of the immune system to a stimulus or ‘trigger’. The underlying mechanisms that cause signs and symptoms to develop are complex. There is overproduction and overactivity of immune system cells called histiocytes and T cells. These are types of white blood cells, which are the primary cell of the immune system and help the body to fight off infection.
Histiocytes (also called macrophages) are large phagocytic cells that normally play a role in responding to infection and injury. A phagocytic cell is any “scavenger” cell that engulfs and destroys invading microorganisms or cellular debris. Macrophages also secrete cytokines, which are proteins that stimulate or inhibit other immune system cells and promote inflammation in response to disease. Excessive cytokine production will eventually cause severe tissue damage. Macrophages may also mistakenly engulf and destroy healthy tissue including healthy blood cells, which is called hemophagocytosis. Cytotoxic lymphocytes, which include T cells and natural killer cells, do not function properly. These cells eliminate other cells that are damaged, stressed, or infected. In HLH, cytotoxic lymphocytes fail to eliminate activated macrophages allowing them to abnormally build up in the organs and tissues of the body, which further activates this ineffective immune response. These immune system abnormalities cause the excessive inflammation and tissue destruction that characterizes the condition.
Primary Hemophagocytic Lymphohistiocytosis
The primary form is associated with abnormal variants in certain genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
At least four different genes have been identified that result in a genetic predisposition to developing hemophagocytic lymphohistiocytosis. A genetic predisposition means a person has a gene or genes for a particular disorder, but the disorder will not develop unless other factors help to trigger the disorder. The four genes are PRF1 (familial hemophagocytic lymphocytosis type 2), UNC13D (familial hemophagocytic lymphocytosis type 3), STX11 (familial hemophagocytic lymphocytosis type 4, and STXBP2 (familial hemophagocytic lymphocytosis type 5). The gene for familial hemophagocytic lymphocytosis type 1 has yet to be identified.
These genes produce proteins that have an essential role in the immune system. They play a role in turning off or destroying activated immune cells when they are no longer needed. Because of variations (mutations) in these genes, the genes do not produce enough or produce ineffective versions of these proteins. As a result, activated immune cells that should normally be turned off or destroyed persist and continue to work, eventually damaging healthy cells and tissue.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Disorders inherited in a recessive pattern occur when an individual inherits the same variant gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Some individuals may have different variants affecting each copy of the one of the disease genes (compound heterozygotes), while other individuals may have digenic inheritance. Digenic inheritance means they have an abnormal variant in two different genes known to be associated with hemophagocytic lymphohistiocytosis.
Some affected individuals have hemophagocytic lymphohistiocytosis as part of a broader genetic disorder. These disorders include Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative disorder, XMEN disease, interleukin-2-inductible T cell kinase deficiency, CD27 deficiency, Hermansky-Pudlak syndrome, lysinuric protein intolerance, and chronic granulomatous disease. In some individuals, hemophagocytic lymphohistiocytosis may be the only clinical problem that individuals with these disorders display. (For more information, choose the specific disorder name as your search term in the Rare Disease Database.)
Secondary Hemophagocytic Lymphohistiocytosis
Individuals with secondary (or acquired) hemophagocytic lymphohistiocytosis develop the disorder because of a heightened, abnormal immune system response that occurs for unknown reasons. There is no family history of the disorder and no known genetic factors can be identified. Conditions that can lead to secondary hemophagocytic lymphohistiocytosis include viral infections especially Epstein-Barr virus, other infections including bacterial, viral and fungal infections, a weakened or depressed immune system, autoimmune diseases, autoinflammatory diseases, rheumatological diseases such as juvenile idiopathic arthritis, metabolic disorders, and cancer such as non-Hodgkin lymphoma.
The exact manner that these predisposing conditions cause the signs and symptoms, and specifically how they cause an ineffective, abnormal immune response, in hemophagocytic lymphohistiocytosis are not fully understood.
Hemophagocytic lymphohistiocytosis most often affects infants or young children, but can affect individuals of any age. It affects boys and girls in equal numbers. In adults, it affects men slightly more often than women. The exact incidence and prevalence is unknown. Rare disorders often go misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. About 25% of the people with this disorder, have the familial form.
A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Guidelines have been published that detail the criteria necessary for a diagnosis of hemophagocytic lymphohistiocytosis. If five of the following eight symptoms are present, then a clinical diagnosis can be made. These eight symptoms are fever; an abnormally large spleen (splenomegaly); low red cell, white cell, or platelet levels (cytopenias); abnormally high levels of a type of fat called a triglyceride in the blood (hypertriglyceridemia) or low levels of a specific blood clotting protein (hypofibrinogenemia); destruction of blood cells by macrophages (hemophagocytosis) in the bone marrow; low or absent natural killer cell activity; abnormal high levels in the blood of a protein that binds to iron (ferritinemia); and elevated soluble interleukin-2 receptor (sCD25), a specialized protein that builds up in the blood when the immune system is stimulated.
Because the symptoms of hemophagocytic lymphohistiocytosis are nonspecific, affected individuals may often have been through a prolonged illness and be hospitalized before a diagnosis is made.
Clinical Testing and Workup
Physicians may order blood tests to take a complete blood cell count, which will measure the levels of red cells, white cells and platelets. Blood tests can also reveal abnormally high ferritin levels, or abnormal high levels of triglycerides. Physicians may also use blood tests to look for signs of infection in the blood and conduct tests to determine how well the blood clots (coagulation studies). Physicians may also order tests that can assess the health and function of the liver.
Sometimes, a bone marrow biopsy (the surgical removal and microscopic examination of a tissue sample) may be taken and studied for signs of hemophagocytosis, signs of infection or infectious organisms, and the accumulation of macrophages.
Molecular genetic testing can confirm a diagnosis of hemophagocytic lymphohistiocytosis in certain people. Molecular genetic testing can detect mutations in one of the four specific genes known to cause familial forms of this disorder, but is available only as a diagnostic service at specialized laboratories.
The 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 characterize 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).
Researchers are studying various drugs and drug combinations for the treatment of hemophagocytic lymphohistiocytosis. Several drugs including alemtuzumab, infliximab, anakinra, ruxolitinib, and other medications have shown promise as salvage therapy. Salvage therapy is drug or drug combination therapy that is used when the standard or preferred drug therapies have not been effective. An experimental drug called (emapalumab) is currently being tested specifically for the treatment of hemophagocytic lymphohistiocytosis. More research is necessary to determine the long-term safety and effectiveness of these drugs as potential therapies for hemophagocytic lymphohistiocytosis.
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