Hemophagocytic lymphohistiocytosis: what is it, symptoms, treatment, prognosis

What is hemophagocytic lymphohistiocytosis?

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by an overactive, abnormal immune response. 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 HLH, the immune system responds to a stimulus or trigger, often an infection, but the response is ineffective and abnormal. This ineffective, abnormal reaction causes many signs and symptoms that, if left untreated, can potentially become life-threatening. Some patients may have a genetic predisposition to the development of hemophagocytic lymphohistiocytosis. It is called the primary or familial form. In others, the disease occurs sporadically, usually with a predisposing condition or disorder. It is called the secondary form. Secondary forms are more common than familial ones. Hemophagocytic lymphohistiocytosis most commonly affects infants from birth to 18 months of age, but can affect people of any age. Early diagnosis and prompt treatment are essential.

Hemophagocytic lymphohistiocytosis (HLH) is a condition that has different causes. There are several names used to describe this condition. Familial hemophagocytic lymphohistiocytosis (familial HLH) refers to genetic forms that are caused by an abnormal gene variant. As of April 2018, multiple gene abnormalities have been identified as causes. Macrophage Activation Syndrome (CAM) is a term used to describe hemophagocytic lymphohistiocytosis that occurs in people with autoimmune or autoinflammatory disease. It is a type of secondary HLH. The diseases most commonly associated with CAM are juvenile systemic arthritis, adult Still's disease and systemic lupus erythematosus.

Signs and 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 disease often causes damage to several organs. Usually, patients develop a fever, rash, liver enlargement (hepatomegaly) and increases spleen (splenomegaly). Fever can be prolonged and persistent, often without response to antibiotics. Sometimes the lymph nodes also enlarge (lymphadenopathy). Lymph nodes are part of the lymphatic system, blood vessels, ducts and nodes, which filter and distribute certain protein-rich (lymphatic) and blood cells throughout body. Lymph nodes are small structures located in clusters throughout the body that help filter or remove harmful substances from the body.

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

Patients may also have low levels of circulating red blood cells (anemia) and a low level of circulating platelets (thrombocytopenia). Red blood cells carry oxygen to the body, and platelets allow the body to form clots (blood clots) that stop bleeding. Patients with anemia may experience fatigue, increased need for sleep, weakness, dizziness, irritability, headaches, pale skin, shortness of breath (shortness of breath) and heart problems. Patients with thrombocytopenia are more susceptible to bruising after minimal trauma and to spontaneous bleeding from mucous membranes, especially from the gums and nose.

Some people may develop neurologic symptoms, including epilepsy, changes in mental status and irritability, paralysis of certain cranial nerves, and problems with coordination of voluntary movements (ataxia). Patients are at risk of developing posterior reversible encephalopathy syndrome, which causes rapid headaches, altered consciousness, seizures, and visual impairment. Neurological problems most often occur with familial hemophagocytic lymphohistiocytosis.

Additional symptoms may occur depending on the specific organ system of the person. These symptoms may include significant breathing problems (lung dysfunction), severe low blood pressure (hypotension), liver inflammation (hepatitis), kidney dysfunction, yellowing of the skin and proteins eye (jaundice), edema due to the accumulation of fluid, bloating due to fluid accumulation (abdominal ascites) and various skin problems, including widespread redness of the skin due to inflammation (erythroderma), rashes, blood stains (purpura), and tiny spots on the skin (petechiae).

Causes and risk factors

Hemophagocytic lymphohistiocytosis is divided 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 behind the development of signs and symptoms are complex. There is an overproduction and overactive immune system cells called histiocytes and T cells. These are types of white blood cells that are the primary cell of the immune system and help the body fight infection.

Histiocytes (also called macrophages) are large phagocytic cells that usually play a role in the response to infection and injury. A phagocytic cell is any scavenger cell that engulfs and destroys invading microorganisms or cellular debris. Macrophages also secrete cytokines, proteins that stimulate or suppress other cells of the immune system and promote inflammation in response to disease. Overproduction of cytokines will eventually lead to severe tissue damage. Macrophages can also mistakenly engulf and destroy healthy tissue, including healthy blood cells, 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 cannot kill activated macrophages, which allows them accumulate abnormally 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 characterize this condition.

- Primary hemophagocytic lymphohistiocytosis.

The primary form of HLH is associated with abnormal variants in certain genes. Genes provide instructions for making proteins that are critical to many bodily functions. When a gene mutation occurs, the protein product may be malfunctioning, ineffective, absent, or overproduced. Depending on the functions of a particular protein, it can affect many organ systems in the body.

At least four different genes have been identified that lead to a genetic predisposition to the development of HLH. A genetic predisposition means that a person has the gene or genes for a particular disorder, but the disorder will not develop unless other factors help trigger the disorder. There were four genes that have been identified - these 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 1).

These genes produce proteins that play an important role in the immune system. They play a role in shutting down or killing activated immune cells when they are no longer needed. Due to variations (mutations) in these genes, genes do not produce enough or produce ineffective versions of these proteins. As a result, activated immune cells, which normally must be disabled or destroyed, persist and continue to function, eventually damaging healthy cells and tissues.

Genetic diseases are defined by a combination of genes for a specific trait that are found on chromosomes received from the father and mother. Inherited disorders in a recessive pattern occur when a person inherits the same variant gene for the same trait from each parent. If a person receives one normal gene and one gene for the disease, they will be a carrier of the disease, but usually asymptomatic. The risk for two carrier parents of passing on the defective gene and therefore having a sick child is 25% with each pregnancy. The risk of having a child who will be a carrier, like the parents, is 50% with every pregnancy. The probability that a child will receive normal genes from both parents and be genetically normal for this trait is 25%. The risk is the same for men and women.

Some people may have different variants affecting each copy of one of the disease genes (complex heterozygotes), while other people may have digenic inheritance. Digenic inheritance means that they have an abnormal variant in two different genes that are known to be associated with hemophagocytic lymphohistiocytosis.

In some patients, hemophagocytic lymphohistiocytosis is part of a broader genetic disorder. These disorders include type 2 Griszelli syndrome, Chédiak-Higashi syndrome, X-linked lymphoproliferative syndrome, deficiency of interleukin-2-induced T-cell kinase, deficiency CD27, Germanic-Pudlak syndrome, lysinuric protein intolerance and chronic granulomatous disease. In some patients, hemophagocytic lymphohistiocytosis may be the only clinical problem.

- Secondary hemophagocytic lymphohistiocytosis.

In persons with secondary (or acquired) HLH, the disease develops due to an increased pathological response of the immune system, which occurs for unknown reasons. There is no family history of this disorder and no known genetic factors can be identified. Conditions that can lead to secondary hemophagocytic lymphohistiocytosis include viral infections, especially Epstein-Barr virusother infections, including bacterial, viral and fungal infections, a weakened or suppressed immune system, autoimmune diseases, autoinflammatory diseases, rheumatological diseases such as juvenile idiopathic arthritis, metabolic disorders. and cancer like non-Hodgkin lymphoma.

The exact way in which these predisposing conditions cause signs and symptoms, and in particular how they cause an ineffective, abnormal immune response in hemophagocytic lymphohistiocytosis, not completely studied.

Affected populations

Hemophagocytic lymphohistiocytosis most commonly affects infants or young children, but can affect people of any age. The disease affects boys and girls equally. Adult men are slightly more likely than women. The exact frequency and prevalence are unknown. Rare disorders are often misdiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. About 25% of people with this condition are familial.

Symptomatic disorders

Symptoms of the following diseases may be similar to those of hemophagocytic lymphohistiocytosis, and it is very important to distinguish these disorders from it.

There are many different conditions that can have signs and symptoms similar to those seen in hemophagocytic lymphohistiocytosis. These include

• Di Georgi syndrome (Di Georgie);
• Kawasaki disease;
• tuberculosis;
• leishmaniasis;
• multiple organ dysfunction syndrome;
• encephalitis;
• drug reaction with eosinophilia and systemic symptoms (DRESS syndrome);
• autoimmune lymphoproliferative syndrome;
• thrombotic thrombocytopenia purpura;
• hemolytic uremic syndrome.

Liver disease and some infections may also resemble hemophagocytic lymphohistiocytosis.

Diagnostics

The diagnosis is based on the identification of characteristic symptoms, a detailed history of the patient, a thorough clinical assessment, and various specialized tests. Guidelines have been published detailing the criteria required to diagnose HLH. If five of the following eight symptoms are present, a clinical diagnosis can be made.

These eight symptoms include:

• fever;
• enlargement of the spleen (splenomegaly);
• low levels of red blood cells, white blood cells, or platelets (cytopenia);
• abnormally high levels of a fat called triglyceride in your blood (hypertriglyceridemia) or low levels of a certain blood clotting protein (hypofibrinogenemia);
• destruction of blood cells by macrophages (hemophagocytosis) in the bone marrow;
• low or absent activity of natural killer cells;
• Abnormally high blood levels of a protein that binds to iron (ferritinemia)
• elevated levels of the soluble interleukin-2 receptor (sCD25), a specialized protein that accumulates in the blood when the immune system is stimulated.

Because the symptoms of hemophagocytic lymphohistiocytosis are nonspecific, patients may often survive long-term illness and be hospitalized prior to diagnosis.

- Analyzes.

Doctors may order blood tests to determine the total blood cell count, which measure the levels of red blood cells, white blood cells, and platelets. Blood tests can also reveal abnormally high ferritin levels or high triglyceride levels. Doctors can also use blood tests to look for signs of an infection in the blood and do tests to determine how well the blood clots (coagulation studies). Doctors may also order tests that can assess the health and function of the liver.

Sometimes a bone marrow biopsy (surgical removal and microscopic examination of a tissue sample) and examine it for signs of hemophagocytosis, signs of infection or infectious organisms, or congestion macrophages.

Molecular genetic testing can confirm the diagnosis of hemophagocytic lymphohistiocytosis in some patients. Molecular genetic testing can detect mutations in one of four specific genes known to cause familial forms of this disorder, but is only available as a diagnostic service in specialized laboratories.

Standard treatments

Treatment of hemophagocytic lymphohistiocytosis is aimed at eliminating specific symptoms that manifest in each person. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in the diagnosis and treatment of blood diseases (hematologists), specialists in the diagnosis and treatment of cancer (oncologists), specialists in the diagnosis and treatment of diseases immune system (immunologists), geneticists (for familial forms), social workers and other health professionals may need systematic and integrated planning treatment. Psychosocial support is also important for the entire family. Genetic counseling can be beneficial for those affected and their families.

Specific therapeutic procedures and interventions can vary depending on many factors, such as the underlying cause; the presence or absence of certain symptoms; the overall severity of symptoms and disorder; age and general health of a person; and / or other elements. Decisions regarding the use of specific drug regimens and / or other treatments must be made doctors and other members of the medical team after careful consultation with the patient, based on the specifics of his case; a thorough discussion of the potential benefits and risks, including possible side and long-term effects; patient preferences; and other relevant factors.

Victims, whose general state of health is sufficiently strong, can undergo treatment for the underlying disease, for example, drugs to treat an underlying infection or appropriate treatment for autoimmune diseases, or cancer. Treating the underlying condition can remove the trigger that led to the abnormal response of the immune system.

Victims whose health conditions are deteriorating need immediate treatment specific to HLH. In 1994, the Histiocyte Society published guidelines for the treatment of this condition (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 immune system (immunosuppressants). They target and destroy overactive cells of the immune system, reducing the life-threatening inflammation that is characteristic of hemophagocytic lymphohistiocytosis.

After initial treatment, which lasts about 8 weeks, patients are gradually switched off from other medications. If victims have not responded well to this treatment, allogeneic stem cell transplantation may be recommended. This treatment is also recommended for people with mutations in known HLH genes, central nervous system and blood cancer (hematological malignant neoplasm) that does not respond treatment.

Allogeneic stem cell transplantation is a procedure in which stem cells from an affected person are replaced with stem cells from a suitable healthy donor. Stem cells are special cells in the bone marrow that produce different types of blood cells (for example, red blood cells, white blood cells, platelets).

Patients receive high doses of chemotherapy or radiation to destroy stem cells. The stem cells are then replaced with donor cells. Allogeneic stem cell transplantation is a high-risk procedure with potential side effects.

Some people may need a blood transfusion because they have low levels of circulating red blood cells or platelets. Some doctors may recommend antibiotics to prevent infection (prophylactic therapy).

In 2018, Hamifant (emapalumab) was approved for the treatment of pediatric and adult patients with primary HLH, in who have a refractory, recurrent or progressive disease or who cannot tolerate a traditional HLH therapy.

Forecast

The overall mortality rate is 50%. The adverse prognostic factors included HLH associated with malignant neoplasms, with half of the patients died after 1.4 months, compared with 22.8 months for patients with HLH not associated with tumor.

In some, secondary HLH can be self-limited, since patients can completely recover after receiving only supportive care (eg, intravenous only immunoglobulin). However, long-term remission without the use of cytotoxic and immunosuppressive therapy is unlikely in in most adults with HLH and in patients with central nervous system (head and / or spinal) brain).