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.

HLH Parents Guide 3855 Histio_ (002)

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