Hemophagocytic lymphohistiocytosis (HLH)

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.

Signs and symptoms

The onset of hemophagocytic lymphohistiocytosis as well as the severity of the condition can vary quite a bit from one individual to the next. The particular symptoms that manifest themselves can also vary greatly, although the condition typically results in the involvement of multiple organs. In most cases, those who are infected will experience fevers, a rash, hepatomegaly (an abnormally enlarged liver), and splenomegaly (an abnormally enlarged spleen) (splenomegaly). A prolonged and persistent fever that, in many cases, does not respond to antibiotic treatment is possible. There are also cases in which the lymph nodes are abnormally large (lymphadenopathy). The lymphatic system is a circulatory network made up of vessels, ducts, and nodes that filter and distribute certain protein-rich (lymph) and blood cells to various parts of the body. Lymph nodes are a component of the lymphatic system. Lymph nodes are relatively small structures that can be found in clusters all over the body. They play a role in the process of filtering or draining harmful substances out of the body.

These preliminary signs and symptoms are referred to as being nonspecific. This means that these signs and symptoms are common to a wide variety of other disorders or conditions, which can make it challenging to obtain an accurate diagnosis.

Those who are afflicted may also suffer from low levels of circulating red blood cells (anaemia), as well as low levels of circulating platelets (thrombocytopenia). Platelets are responsible for clotting blood and stopping bleeding, while red blood cells are responsible for carrying oxygen throughout the body. Anemia can cause a person to feel fatigued, have an increased need for sleep, experience weakness, lightheadedness, dizziness, irritability, headaches, pale skin colour, difficulty breathing (dyspnea), and cardiac symptoms. Anemia can also cause a person’s heart rate to become irregular. People who have thrombocytopenia are more likely to experience excessive bruising after sustaining a minor injury and spontaneous bleeding from the mucous membranes, particularly those of the gums and nose.

A number of neurological symptoms, such as convulsions, alterations in mental status and irritability, paralysis (palsy) of particular cranial nerves, and difficulties coordinating voluntary movements, are possible in a subset of those who are affected by the condition (ataxia). People who are affected by this condition are at risk of developing posterior reversible encephalopathy syndrome, which is characterised by a sudden onset of headaches, changes in consciousness, seizures, and visual disturbances. In patients with familial hemophagocytic lymphohistiocytosis, neurological complications are almost always present.

Depending on which organ system is affected in a given individual, a person may also experience the following additional symptoms: These symptoms can include significant difficulties 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 (edoema), 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), alopecia, and alopecia (petechiae).

Causes

Primary and secondary (acquired) forms of hemophagocytic lymphohistiocytosis are the two primary classifications for this condition. The condition is the end result of the immune system’s abnormal and ineffective reaction to a stimulus, also known as a “trigger.” The underlying mechanisms that result in the development of signs and symptoms are quite complicated. There is an increase in both the production and activity of cells of the immune system known as histiocytes and T cells. These are the various types of white blood cells that are found in the human body. White blood cells are the primary cells that make up the immune system and aid the body in its fight against infection.

Histiocytes, which are also referred to as macrophages, are large phagocytic cells that normally play a role in the immune system’s response to injury and infection. Any cell that acts as a “scavenger” by ingesting foreign microorganisms or cellular debris and then destroying them is known as phagocytic. In addition to this, macrophages are responsible for the secretion of cytokines, which are proteins that can either stimulate or inhibit the activity of other immune system cells and promote inflammation in response to illness. An excessive production of cytokines will, in the long run, result in severe damage to the tissues. In a condition known as hemophagocytosis, macrophages can suffer from an error that causes them to consume and destroy healthy tissue, including healthy blood cells. Cytotoxic lymphocytes, which are made up of T cells and natural killer cells, are not operating at their full capacity. These cells eradicate any other cells that are unhealthy, under stress, or infected with a pathogen. HLH is characterised by the inability of cytotoxic lymphocytes to eliminate activated macrophages, which results in an abnormal accumulation of these cells in the organs and tissues of the body. This abnormal accumulation further activates this inefficient immune response. These abnormalities of the immune system are the root cause of the condition’s hallmark symptoms, which are excessive inflammation and tissue destruction.

Primary Hemophagocytic Lymphohistiocytosis

The primary form has been linked to abnormal variants in a number of genes. The instructions for making proteins, which are involved in a wide variety of processes throughout the body, are contained within genes. When a gene undergoes a mutation, the resulting protein product may be deficient, absent, overproduced, or otherwise altered in some way. This can have an effect on a great deal of the body’s organs and systems, depending on the functions that the protein in question performs.

At least four distinct genes have been found to result in a genetic predisposition to develop hemophagocytic lymphohistiocytosis. This genetic predisposition can be passed down from parents to children. A person has a genetic predisposition for a particular disorder if they carry one or more of the genes for that disorder. However, the disorder will not manifest itself in that person unless there are additional factors that help to trigger the disorder. The four genes are PRF1 (for familial hemophagocytic lymphocytosis type 2), UNC13D (for familial hemophagocytic lymphocytosis type 3), STX11 (for familial hemophagocytic lymphocytosis type 4) and STXBP2 (for familial hemophagocytic lymphocytosis type 2). (familial hemophagocytic lymphocytosis type 5). It has not yet been determined which gene is responsible for familial hemophagocytic lymphocytosis type 1.

These genes are responsible for the production of proteins that play critical roles in the immune system. They have a part to play in the deactivation or destruction of activated immune cells once their services are no longer required. These variations (mutations) in these genes cause the genes to either produce insufficient amounts of the protein or produce versions of the protein that are less effective. As a consequence of this, activated immune cells that ought to be turned off or destroyed in the normal course of events continue to exist and carry out their functions, eventually causing damage to healthy cells and tissue.

The combination of genes for a particular trait that are contained on the chromosomes that are inherited from both the mother and the father is what determines whether or not a person will have a genetic disease. When an individual inherits the same variant gene for the same trait from both of their parents, this can lead to the development of recessive disorders in that individual. If an individual receives one gene that is normal and one gene that is responsible for the disease, then the individual will be a carrier for the disease but will typically not show any symptoms of having the disease. With each pregnancy, there is a 25 percent chance that two carriers will pass on the defective gene to their offspring and, as a result, have a child who is affected by the condition. With each pregnancy, there is a fifty percent chance of having a child who shares the same carrier status as the parents. There is a one in four chance that a child will inherit normal genes from both of their parents and be normal in terms of their genetic makeup for that particular trait. Both males and females are exposed to the same level of danger.

Compound heterozygotes are individuals who have different variants affecting each copy of one of the disease genes, whereas digenic inheritance refers to individuals who inherit the disease from both of their parents. They have an abnormal variant in two different genes that are known to be associated with hemophagocytic lymphohistiocytosis, which is what is meant by the term “digenic inheritance.”

Individuals who are affected by this condition may be diagnosed with hemophagocytic lymphohistiocytosis as a symptom of a more extensive genetic disorder. These conditions include Hermansky-Pudlak syndrome, lysinuric protein intolerance, Griscelli syndrome type 2, Chediak-Higashi syndrome, X-linked lymphoproliferative disorder, XMEN disease, interleukin-2-inducible T cell kinase deficiency, CD27 deficiency, and interleukin-2-inducible T cell kinase deficiency. Other conditions include It’s possible that hemophagocytic lymphohistiocytosis is the only clinical issue that some people with these disorders are dealing with.

Secondary Hemophagocytic Lymphohistiocytosis

People who have secondary (or acquired) hemophagocytic lymphohistiocytosis develop the disorder as a result of an exaggerated and abnormal response from their immune system, which takes place for reasons that are not fully understood. There is no history of the condition in the patient’s family, and no identifiable genetic risk factors have been found. Conditions such as 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 cancers such as non-Hodgkin lymphoma can all lead to secondary hemophagocytic lymphohistiocytosis.

In hemophagocytic lymphohistiocytosis, the precise manner in which these predisposing conditions cause the signs and symptoms, and more specifically how they cause an ineffective and abnormal immune response, are not fully understood. This is one of the reasons why the disease is so difficult to treat.

Diagnosis 

The determination of a diagnosis requires the spotting of distinctive symptoms, the compilation of an exhaustive patient history, an exhaustive clinical evaluation, and the administration of numerous specialised tests. The diagnostic criteria for hemophagocytic lymphohistiocytosis have been laid out in exhaustive detail in a set of guidelines that have been published. When five of the following eight symptoms are present, a clinical diagnosis can be made. If all eight symptoms are present, a clinical diagnosis cannot 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 in the blood called a triglyceride (hypertriglyceridemia), or abnormally low levels of a specific blood clotting protein (hypofibrinogenemia); destruction of blood cells by macrophages (hemophagocytosis) in the

Due to the fact that the symptoms of hemophagocytic lymphohistiocytosis are not particularly specific, it is common for affected individuals to have suffered from an extended illness and to have been hospitalised prior to receiving a diagnosis.

The levels of red cells, white cells, and platelets can all be measured with a complete blood cell count, which can be measured with blood tests that your doctor orders for you. An abnormally high ferritin level, as well as an abnormally high triglyceride level, can both be discovered through blood testing. In addition, physicians may use blood tests to search for indications of infection in the blood and may also perform tests to evaluate the efficiency with which the blood coagulates (coagulation studies). Tests that evaluate the health and functionality of the liver are another type of examination that doctors might order.

Bone marrow biopsies, which involve the surgical removal of a tissue sample and its subsequent examination under the microscope, are sometimes performed in order to investigate the presence of hemophagocytosis, signs of infection or infectious organisms, and an accumulation of macrophages.

In certain individuals, a diagnosis of hemophagocytic lymphohistiocytosis can be verified through the use of molecular genetic testing. The molecular genetic testing that can detect mutations in one of the four particular genes known to cause familial forms of this disorder is only offered as a diagnostic service at specialised laboratories. However, this testing can detect mutations in one of the genes.

Treatment 

The specific symptoms that are manifest in each individual affected by hemophagocytic lymphohistiocytosis are what the treatment for this condition focuses on. It is possible that treatment will call for the concerted efforts of a group of specialists. Treatment may need to be planned in a methodical and all-encompassing manner by paediatricians, haematologists, oncologists, immunologists, geneticists (for familial forms), social workers, and possibly even other medical professionals. Additionally necessary is the provision of psychosocial support for the whole family. Genetic counselling might be helpful for affected individuals as well as for the families of those individuals.

It is possible for particular therapeutic procedures and interventions to vary, depending on a wide variety of elements, 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 aspects. Decisions regarding the use of specific 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. These decisions should be based on the particulars of the patient’s case, as well as a comprehensive discussion of the potential benefits and risks, including the possibility of side effects and long-term effects. Other relevant factors should also be considered.

People who are afflicted with the condition and whose general health is sufficient may be able to receive treatment for the underlying condition. This may include taking antibiotics to treat an underlying infection, or receiving the appropriate treatment for autoimmune disorders or cancer. If the underlying condition is treated, it is possible that the “trigger” that caused the abnormal immune system response will also be removed.

People who have been affected and whose health is deteriorating urgently need to be treated with medication that is specific for hemophagocytic lymphohistiocytosis. Treatment recommendations for this disorder were first published by the Histiocyte Society in the year 1994. (HLA-94). There were also studies that were published in 2004 (HLA-2004) that yielded slightly different results.

These treatment plans involve the use of chemotherapy as well as medications that dampen the activity of the immune system (immunosuppressive drugs). They specifically target and destroy the overactive immune system cells, which in turn helps to reduce the potentially lethal inflammation that is characteristic of hemophagocytic lymphohistiocytosis.

After an initial course of treatment that typically lasts between 6 and 8 weeks, patients are then transitioned gradually away from the drugs they were taking and onto other medications. If those who are afflicted with the condition have not shown a positive response to this treatment, an allogeneic stem cell transplant may be suggested. Individuals who have an abnormal variant in a known HLH gene, involvement of the central nervous system, or untreatable blood cancer (hematologic malignancy) are also candidates for this treatment, which is recommended for them.

An allogeneic stem cell transplant is a procedure in which stem cells from a patient who is afflicted with a disease are replaced with stem cells from a donor who is healthy and has the same genetic makeup as the patient. Stem cells are specialised cells that can be found in bone marrow and are responsible for the production of various cell types in the blood (e.g. red blood cells, white blood cells, platelets).

Patients with this condition are given extremely high doses of either chemotherapy or radiation in an effort to eradicate their stem cells. Next, stem cells from a donor will take their place in the patient’s body. The allogeneic stem cell transplant procedure is one that carries a high level of risk and has the potential to cause adverse effects.

Because they have low levels of circulating red blood cells or platelets, some of the affected individuals may require a blood transfusion. Antibiotics are one method that doctors might advise their patients to use to forestall the onset of an infection (prophylactic therapy).

The treatment of paediatric and adult patients with primary HLH who have refractory, recurrent, or progressive disease or who cannot tolerate conventional HLH therapy was approved for use of Gamifant (emapalumab) in 2018. Sobi will be in charge of marketing Gamifant.