Haemophagocytic Lymphohistiocytosis HLH
What is Haemophagocytic Lymphohistiocytosis (HLH)?

Haemophagocytic Lymphohistiocytosis is not a single disease, but is a word that covers a number of conditions that differ in cause, treatment and outcome. The name is a combination of medical terms derived from Greek words: haem – blood; phagocyte – cell that ingests and destroys; lymphohistiocytosis – excessive number of certain types of white blood cells.

HLH can be likened to a very severe form of inflammation which the body is unable to switch off. It results from an uncontrolled increase in the numbers of lymphocytes and histiocytes (white blood cells) due to an ineffective immune (defence) response. These cells can destroy other blood cells and can cause problems for many different parts of the body.

HLH is a very rare disease with an estimated 1.2 per million children affected by HLH each year. This may be an underestimation as the diagnosis may be missed in some patients.

HLH can be difficult to diagnose as it may initially resemble a normal response to an infection. It can therefore take a while for the medical team to realise that the immune system is not working properly. HLH is treated by haematologists/ immunologists/ oncologists with steroids +/- chemotherapy +/- bone marrow transplantation.

The outcome for children with HLH has improved dramatically over the last 20 years and now more than half of the patients are cured.

Are there different types?
There are two main types of HLH, primary (or familial) HLH which is inherited, and secondary (or acquired) HLH.

Primary HLH
Primary HLH is a genetic (inherited) disease and is most often referred to as familial HLH or FLH. In this genetic condition, defective genes are inherited from both the mother and the father (autosomal recessive inheritance). FLH is diagnosed if there is more than one affected child in the family and/or an FLH gene defect is identified. Several specific gene abnormalities (mutations) have been identified but not all patients with FLH have a recognised genetic mutation.

Approximately 1 child per 200 000 children will become unwell with FLH each year. Most children (70-80%) become unwell in the first year of life with infection-like symptoms, sometimes triggered by a viral infection. A small number (10%) develop symptoms within the first 4 weeks of life. In the same family, children with familial HLH usually develop symptoms around the same age.

Patients with FLH need treatment to get the FLH under control and will then need a bone marrow transplant to cure the disease.
If your child’s Consultant feels that the HLH is due to a genetic cause, you will be referred to a Clinical Geneticist. The Clinical Geneticist will discuss with you if additional blood tests are needed from your family, will arrange to analyse the blood samples and discuss the results and other implications with you.

Secondary Haemophagocytic Lymphohistiocytosis
In the absence of more than one affected child in the family and/or an identified FLH gene defect, HLH is thought to be an acquired disease (secondary HLH).
Secondary HLH can occur at any age. It is not clear how common this is but it is thought to be more common than familial HLH. Acquired HLH is usually triggered by an infection, often a viral infection. It can also occur in children with some cancers (notably specific types of lymphomas), in association with treatment for cancers with chemotherapy and in children undergoing bone marrow transplantation. HLH can also occur in association with rare inborn errors of metabolism (inherited problems with breakdown and production of sugars, proteins or fats in the body) and in association with genetic immune deficiencies such as Chediak-Higashi Syndrome 1 (CHS-1), Griscelli Syndrome 2 (GS-2) and X-linked lymphoproliferative syndrome (XLP).

Patients with secondary HLH need treatment to control the HLH and if possible, treatment for the underlying condition which caused the HLH.

Macrophage Activation Syndrome
Macrophage activation syndrome (MAS) is an extremely rare condition that occurs in both children and adults with autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosis (SLE). It has the same features of HLH, but some of the initial blood changes may be less severe, and problems with clotting and the function of the heart may be worse. Like the other forms of HLH, viruses have been shown to trigger MAS, but also some medications. The majority of children with MAS will recover completely, with treatment that is similar to that for HLH, but less intensive.

Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

Haemophagocytic Syndromes

Diagnosis and Treatment

It is sometimes difficult to establish the diagnosis of Haemophagocytic Lymphohistiocytosis (HLH), and the combination of the physical symptoms and certain laboratory tests is required. (Note: The understanding of the pathology underlying HLH/FHL disease is evolving, and recommended “diagnostic” criteria are likely to be revised in the future.)

• Low or absent NK (natural killer) cell function.
• Prolonged fever.
• Blood cell abnormalities (low white cells, low red cells, low platelets).
• Enlarged spleen.
• Increased triglycerides (fat) or decreased fibrinogen (protein necessary for clotting) in the blood.
• Increased ferritin (protein that stores iron) in the blood.
• Abnormal bone marrow test with evidence of Haemophagocytosis (ingestion of red or white cells by histiocytes) but not malignancy or other cause.
• Abnormally high CD25 (also known as sIL2ra) in the blood indicating abnormally increased T-cell activation.

The test for low or absent natural killer cell (NK) function has been found useful in making a clinical diagnosis of HLH. This abnormality is found in many patients with FHL, as well as in many cases of secondary disease but rarely in the X-linked forms.

However, it is just one piece of information and should not be used to determine the diagnosis of HLH as primary or secondary. NK function cannot be determined before birth, and it may not be reliably studied until a child is at least 6 weeks of age. FHL is suspected if siblings have been diagnosed with HLH, if symptoms intensify during treatment for HLH, or if symptoms return after therapy has been stopped.

Since it is difficult to tell the difference between secondary HLH and FHL, any case of HLH should be considered for genetic testing to confirm the diagnosis. Since 1999, at least seven defective genes have been identified. Autosomal recessive: PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. X-linked: SH2D1A, BIRC4.

There are some FHL patients (approximately 30%) with no identified gene defect, so normal genetic test results do not necessarily rule out the diagnosis of FHL. Genetic testing is usually done on blood, although other kinds of tissue samples can be used. Once the genetic cause is known, the parents can quickly be tested to confirm that they are carriers for that specific genetic type of FHL. Other siblings can also be easily tested, even before birth, once the genetic cause of the disorder in the family is known. Even in the event of death, salvaged tissue can be tested to determine if siblings are at risk.

In 1994, as a result of an international cooperative effort, the first treatment protocol for patients with HLH/FHL was designed. This included a combination of chemotherapy, immunotherapy and steroids, as well as antibiotics and antiviral drugs, followed by a stem-cell transplant in patients with persistent or recurring HLH or those with FHL. The HLH-2004 protocol was based on the HLH-94 protocol with minor changes such as cyclosporin, an immunosuppressant drug, being started at the onset of therapy rather than week #8. This protocol has been widely accepted internationally and is used in numerous countries on all continents but should still be considered experimental.
Secondary HLH may resolve spontaneously or after treatment of the underlying disease, without the use of chemotherapy. Therefore treatment should be guided in part by the severity of the condition, as well as the cause of the disease.

FHL, however, when not treated, is usually rapidly fatal with an average historical survival of about 2 months. The treatment included in the HLH-2004 research protocol is intended to achieve stability of the disease symptoms so that a patient can then receive a stem-cell transplant, which is necessary for a cure.

In recent years, some transplant centers have adopted the use of reduced intensity conditioning (or “RIC”) to prepare for the stem cell transplant. This approach offers the possibility of better survival with stem cell transplant than the intensive chemotherapy protocols previously used.
As research continues, the outcome for patients with HLH/FHL has improved greatly in recent years. Approximately two-thirds of children with HLH who undergo transplantation can expect to be cured of their disease. However, there are a number of complications that can occur during the process of transplant, including severe inflammatory reactions, anemia, and graft-versus-host disease.

Long-term follow-up of survivors of transplants for HLH/FHL indicates that most children return to a normal or near-normal quality of life. The results of transplantation are generally better when the procedure is performed at a major pediatric transplant center where the doctors are familiar with this disease. Early and accurate diagnosis is essential. However, there is still a high rate of death, indicating that education of the medical community regarding prompt diagnosis and management of the diseases is required.
Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

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Haemophagocytic Syndromes (HLH)
These questions specifically relate to Haemophagocytic Syndromes (HLH).

Haemophagocytic Syndromes

1. What causes HLH?
HLH can either be acquired (secondary HLH) or inherited (FHL). Both forms of the disease can be triggered by infections, although it is not known why this happens. Secondary HLH may be triggered by vaccinations, viral infections such as Epstein-Barr, CMV (cytomegalovirus) or other herpes viruses, or other underlying diseases such as autoimmunity or cancer. In FHL, defective genes are inherited from one or both parents. Some other rare inherited immunodeficiencies may also be associated with HLH. The underlying immune defect and/or triggering events result in an abnormal immune response with activation of certain types of white blood cells (lymphocytes and macrophages) and the release of inflammatory proteins which then cause disease.

2. Is there a cure for HLH?
HLH patients with an underlying genetic defect can only be cured when the defective immune system is replaced by a healthy one which is what happens with a hematopoietic stem cell transplant. Secondary HLH cases can usually be cured by treating the underlying disease and sometimes additional immunosuppressive/immunomodulatory therapy.

3. What are the different therapies/treatments commonly used to treat HLH?
Some cases of secondary HLH can resolve spontaneously or after treatment of the underlying disease. Other cases are treated with a combination of chemotherapy (VP-16, methotrexate), immunotherapy (ATG, cyclosporin), and steroids. Any triggering infection has to be treated with appropriate antimicrobial drugs. Patients with persistent or recurring HLH or those with FHL additionally require a hematopoietic stem-cell transplant for recovery.

4. Why is routine newborn screening not available?
Although HLH may occur more frequently than some of the diseases routinely tested for, genetic testing for this disease is very complicated and very expensive.

5. How do I know if my child has primary HLH (inherited/FHL) or secondary HLH?
The clinical symptoms and laboratory findings do not differ in genetic or acquired HLH. Specific immunologic testing can raise the suspicion of genetic disease. In families with more than one affected child or in cases with disease reactivations there is a high probability of genetic disease. However, the identification of a genetic defect is necessary to prove it. Genetic testing is therefore recommended, regardless of age. Depending on the ethnic background up to 30% of patients with FHL have no identified gene defect, so negative test results do not necessarily rule out FHL.

6. How can I find out if my child’s siblings have HLH?
In autosomal recessive forms of the disease, each sibling of a child with FHL has a 25% chance of being affected. In related genetic disorders, including X-linked lymphoproliferative disease, each male child has a 50% chance of being affected. If a genetic defect is known in your family, genetic testing (before or after onset of symptoms) is available to identify siblings who may also be affected.

7. How can I find out if future children are at risk for developing HLH?
If a genetic defect has been identified in your family, prenatal diagnosis is possible by performing either amniocentesis or chorionic villus sampling (CVS) to test if the fetus is affected.

8. What is MAS (macrophage activation syndrome)?
Macrophage activation syndrome is a severe, life-threatening illness caused by the excessive production of types of white blood cells called T cells and macrophages. MAS has strong similarities with familial Haemophagocytic Lymphohistiocytosis (FHL) and virus-associated Haemophagocytic Lymphohistiocytosis (HLH). The exact relationship between MAS and HLH is yet to be determined, although some researchers believe that MAS is a secondary HLH disorder. The term is typically used for the HLH-like syndrome that can occur in patients with systemic onset juvenile arthritis.

9. What is reduced-intensity conditioning (RIC)?
Reduced-intensity conditioning is a less toxic pre-transplant therapy with the goal of suppressing the patient’s immune system enough so that it will accept donor stem cells while reducing the side effects of high dose chemotherapy The RIC may be used in some HLH patients, as well as some LCH patients with severe, resistant disease.

The answers to the following questions may be found in the Support Information.

THE DISEASE
How is it diagnosed?
How is it treated?
What are the clinical trials?

COPING
How do I cope with the diagnosis?
How do I get the information I want?
How do I talk to my children about this?
How do we deal with the treatment?
What happens at the end of the treatment?
What resources are there for individuals or family support?
Where can I get financial support?
How do I find other patients?

Please be advised that all the information you read here is not a replacement for the advice you will get from your consultant and their team.

Help ensure that we can continue to bring you this vital informational material, make a donation today

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