Frequently asked questions about Hemophagocytic Lymphohistiocytosis

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Introduction

1 - What is HLH?

Hemophagocytic lymphohistiocytosis (HLH), whether congenital or acquired, is a very rare and severe disease caused by an immune defect, leading to excessive inflammation. Infections (usually viral infections) may trigger the onset or reactivation of the disease. For symptoms and clinical signs of HLH refer to the part “Symptoms and laboratory tests”.

2 - What mechanisms cause HLH?

The research so far was mostly dedicated to the understanding of the processes leading to the genetic forms, while the mechanisms leading to the acquired form of this immunodeficiency are not yet known. In the genetic forms, the inability of the immune system to cope with a trigger (which is mostly infectious) leads to a sustained stimulation of the immune cells resulting in a highly inflammatory process.

3 - At what age does HLH usually occur?

The disease can affect people of all ages. The genetic forms manifest in about 80% of the cases during infancy or early childhood. However, they can also occur in older children and adults. Most patients are completely healthy until the onset of disease.

4 - Is there any association between HLH and other diseases?

Acquired HLH may also occur in association with other disorders, mainly rheumatic or malignant diseases. Patients receiving immunosuppressive treatment, also have an increased risk of developing HLH.

5 - What happens in HLH?

The disease is characterized by histiocytes and lymphocytes infiltrating all organs. The histiocytes are called „phagocytes“ because they can „eat“ other cells. The ingestion of blood cells is called hemophagocytosis. Lymphocytes are produced in the bone marrow and are the most important cells of our immune system. In HLH these two types of cells are highly activated and produce high amounts of inflammatory substances (cytokines) that cause the clinical symptoms.

6 - How serious is HLH?

Without treatment, the familial form of HLH is usually fatal and the acquired forms also have a high mortality.

7 - How can HLH be distinguished from normally progressing infections?

The initial symptoms of HLH can also be found in mild infections. However, in contrast to normal infection, the symptoms of HLH are much more pronounced and worsen over time, often despite antimicrobial treatment. Since in many cases HLH can be triggered by an infection, the identification of a pathogen does not help to distinguish, whether the patient suffers from a normal infection or an infection-triggered HLH. It is important to consider the severity of symptoms and their evolution over time. A set of clinical criteria have proven useful for the distinction (see “Symptoms and Laboratory tests).

Genetic Basics

1 - Can HLH be inherited? Do known genetic causes exist?

Some forms of HLH can be inherited (familial HLH, FHLH) in an autosomal recessive way. This means that the parents are carriers of the same defective gene, but healthy. Each of the parents can pass to their child either the normal gene or the defective gene. This happens by chance. For each child of the couple there is a risk of 25% of inheriting the defective gene of both parents and therefore the disease. In two forms (called “XLP1” and “XLP2”) the inheritance is x-linked. For a mother carrying one of these defective genes on the chromosome X, one of two boys has a risk to inherit the disease and girls have a 50% risk of being a healthy carrier of the disease.

The detection of genetic cases is very important to provide families with a good genetic counselling and the best therapy. A genetic disease must be suspected when there is another child in the family who is affected by the same disease.

2 - How many genes can play a role in FHL?

So far, eight genetic defects are known, all of which lead to functional defects of the cytotoxic cells which are important to kill infected cells. In four genetic defects, patients do not display abnormalities apart from HLH. In the other four genetic defects, the development of HLH is not obligatory, but it occurs very often, and patients may have other abnormalities such as pigmentary disorders. Often, these inherited immune defects are not discovered until HLH occurs. In approximately 10-20% of cases, the genetic defect has not yet been discovered.

3 - Is genetic counselling of the families and prenatal diagnosis possible?

Yes. In cases with identified genetic defects parents should be tested to confirm the child’s diagnosis. (The parents are usually carriers and there is a risk that the disease can affect further children.) Genetic counselling should be offered to all families. During further pregnancies a prenatal testing is possible, in order to analyse if the unborn child is affected by the specific genetic defect which has been identified in this family.

Symptoms and laboratory tests

1 - Why do the symptoms of HLH occur?

The symptoms of HLH are caused by high concentrations of inflammatory substances (cytokines) and the infiltration of all organs by lymphocytes and histiocytes.

2 - What are the most common symptoms of HLH?

The clinical presentation is highly variable. In most cases, there is persistent high fever of increasing severity without obvious cause. An extended belly caused by an enlarged liver and spleen called (hepato)splenomegalie is also a typical feature. Swollen lymph nodes, yellow (icteric) skin called jaundice and neurological symptoms (e.g. irritability and convulsions) may also occur. Skin swelling (edema) and bleeding are rare. Initially, many children are not in poor condition, but with persisting disease general performance is reduced.

3 - Which abnormal blood parameters can be observed?

Common changes include a reduction of all blood cells (pancytopenia) or a reduction of some blood cells, i.e. red blood cells (anemia), a special subset of white blood cells (neutropenia), or platelets (thrombocytopenia).

Additional laboratory findings may include elevated blood lipids (hypertriglyceridemia) and elevated ferritin (marker for inflammation). Coagulation abnormalities are also frequently detected. In addition the liver values (liver enzymes, bilirubin) may be increased and an inflammatory response in the cerebrospinal fluid may be present.

4 - Is there a specific marker for HLH?

No specific marker for the disease is known. Hemophagocytosis (ingestion of blood cells by histiocytes) can be present in the bone marrow or in other organs but it does not occur in all cases and it can also be observed in other diseases.

5 - Are there any specific immunologic assays?

Often an elevation of the Interleukin-2- receptor is seen which is produced by activated T-lymphocytes and is also called sCD25. A reduced activity of the natural killer cells (certain blood cells which kill other cells) also is a typical feature, in particular in genetic cases.

Diagnosis

1 - How is HLH diagnosed?

For diagnosis a clinical examination must be performed and the above mentioned laboratory values should be analysed. The latter two analyses will only be done in specialized laboratories and are not always available. The diagnostic approach includes blood testing, bone marrow and lumbar punctures (analysis of the cerebrospinal fluid). There is a diagnostic guideline of the Histiocyte Society indicating that a minimum of 5 out of 8 diagnostic criteria should be fulfilled.

More recent functional immunological studies (degranulation test, expression of certain proteins) which are performed in centralized reference laboratories, can usually indicate, if there is a genetic defect. This must then be verified by genetic analysis.

Therapy

1 - What is the therapeutic objective?

The therapy aims at suppressing the potentially life-threatening inflammatory reaction. Different approaches exist to achieve this. They include combinations of steroids, immunosupressants, cytostatics, and monoclonal antibodies against the activated T lymphocytes (immunomodulators). Unfortunately not all patients respond to therapy.

2 - Are there different therapeutic regimens for genetic or acquired HLH?

The initial treatment is the same in all severe cases. When acquired HLH is suspected, the treatment should be tapered off after the inflammatory reaction has been brought under control. Close monitoring thereafter is essential.

A relapse or poor response to treatment suggest that a genetic defect is likely. Genetic cases are indications for stem cell/bone marrow transplantation. Transplantations from family donors and from matched unrelated donors achieve the best results, but “haploidentical” transplantations from a parent are also possible.

Prognosis

1 - Can genetic (familial) HLH be cured?

The probability of survival after stem cell transplantation is about 50-70%. If the transplanted bone marrow is not rejected (rejection happens in about 10% of patients), the patients then have a fully functional immune system and can live a normal life.

2 - Are there international studies?

International therapeutic studies are coordinated by the Histiocyte Society since 1994.
Links:
[1] Histiocyte Society

3 - Why is further research important?

It is important to continue research on this disease to achieve a better understanding of its causes and to improve methods for diagnosis and treatment.

In particular, physicians must be better informed about this rare disease to ensure rapid diagnosis and treatment of all affected patients.

If you have any further questions please do not hesitate to contact the Histio Net team.