HLH involves over-production and activation of white blood cells called histiocytes and T cells, which normally combat infection. In contrast, often NK (natural killer) cell function is decreased. Decreased NK function is related to the consequence of genetic mutations which cause HLH. HLH is often referred to as either the “primary” form which is hereditary, or the “secondary” form associated with infections, viruses, autoimmune diseases, and malignancies (or cancers).

In the primary form, also known as Familial Haemophagocytic Lymphohistiocytosis (FHL or FHLH), defective genes are inherited from either both parents (autosomal recessive) or from the mother alone. In the latter case, the disease is called X-linked and only male children are affected. Since 1999, five genes have been identified which correspond with five subtypes of autosomal recessive HLH. The genes are PRF1 (perforin), MUNC13-4, STX11 (Syntaxin), STXBP2, and RAB27A. PRF1 encodes the protein (or toxin) normally involved in “killing” or eliminating abnormal immune cells. The proteins encoded by the other four genes facilitate the delivery of perforin to the cells which are to be killed. XIAP/BIRC4 mutations can also be considered as a cause of familial HLH.

While great progress has been made through research in recent years to define these genes, there remains a considerable proportion of FHL patients with as yet unknown underlying gene defects.

Onset of disease occurs under the age of 1 year in an estimated 70% of cases. FHL is suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. In the autosomal recessive form of the disease, each full sibling of a child with FHL has a 25% chance of developing the disease, a 50% chance of carrying one copy of the defective gene (which is very rarely associated with any risk of disease), and a 25% chance of not being affected and not carrying the gene defect. In the X-linked form of the disease 50% of male children will carry the defective gene and may develop disease. Fifty % of female children also carry the defective gene and may transmit it to their children but do not develop disease because they inherit a normal copy of the gene from their father.

So-called “secondary HLH” is often diagnosed in older patients who have no family history of this disease. It may be associated with viral infections as well as other underlying diseases, principally autoimmune disorders and cancers, as mentioned previously.

It is difficult to know whether a patient has primary or secondary HLH on the basis of symptoms, which may be very similar. Therefore, genetic testing is usually recommended in order to make the proper diagnosis, regardless of age.

As awareness and understanding of this disease have increased worldwide, the diagnosis and survival rates have improved significantly. However, HLH remains a rapidly progressive disease requiring effective immunosuppressive and anti-inflammatory therapy.

HLH also occurs in some closely related diseases. These include X-linked lymphoproliferative disease (XLP), which is due to mutations in the SH2D1A gene (XLP1) or XIAP / BIRC4 gene (XLP2), Griscelli syndrome type II, which is due to mutations in the Rab27a gene, and Chediak-Higashi syndrome, which is due to mutations in the LYST gene.

Why Do These Conditions Result in HLH?

The T cells and NK cells in patients with primary / familial HLH cannot kill virus-infected or other abnormal cells in the patient’s body like they normally would. T cells and NK cells normally do this by secreting signals into targeted abnormal cells.
The proteins made by the MUNC 13-4, STXBP2, STX11, Rab27a and LYST genes work like the machinery of a conveyor belt, and are responsible for the secretion of the signals out of T cells and NK cells. The PRF1 gene makes a protein called perforin. It works like a key, and allows the secreted death signals to enter inside a targeted abnormal cell, where the death signals can work.
SH2D1A is responsible for a more specialized mechanism, and also controls how the T cells themselves die. It is not yet entirely clear why XIAP / BIRC4 mutations cause HLH.

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.
Other symptoms may include:
• Rash
• Enlarged liver/liver failure
• Enlarged lymph nodes
• Anaemia
• Jaundice
• Hepatitis
• Respiratory issues (coughing, respiratory distress)
• Seizures
• Altered mental functions

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 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 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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