HLH Patient Information Page : University College London Hospitals NHS Foundation Trust

This page aims to provide information about the syndrome haemophagocytic lymphohistiocytosis (HLH).

This information does not replace the advice and guidance of a clinician. Its aim is to provide a source of general information about HLH to patients at UCLH, their families and friends.

HLH stands for haemophagocytic lymphohistiocytosis. It is a rare syndrome that can make people very unwell.

The symptoms are caused by hyperinflammation following an overactive immune response to a trigger.

There are many possible triggers that include infection, an immune disorder, or cancer.

A typical immune response involves white blood cells being activated and then releasing chemical signals that lead to inflammation. However, in HLH this response goes into overdrive and damages the body’s tissues. This inflammatory response can worsen until the trigger is removed or treatment is given.

The term haemophagocytic lymphohistiocytosis refers to what we may see under a microscope if we take samples of bone marrow and other tissues in a patient with the condition:

Haemophagocytosis is when blood cells are ingested, or ‘eaten’, by activated immune cells.
Lymphohistiocytosis refers to a build-up of histiocytes (a type of white blood cell) in the tissues of the immune system, including the bone marrow, liver, spleen and lymph nodes.

HLH can be separated into two different classes: primary and secondary.

Primary (or familial) HLH is when the condition is inherited. This is more commonly seen in younger patients.

Secondary (or acquired) HLH can also sometimes be called macrophage activation syndrome (MAS). You may see this term being used interchangeably with HLH.

Secondary HLH is caused by a trigger. These triggers often involve challenges to the immune system. Some of the more common triggers include:

An infection, such as a virus or sepsis.
An immune disorder, such as an immunodeficiency or a rheumatological condition.
A cancer, such as lymphoma.
Some medicines or medical interventions.
Pregnancy.
Unknown; in some cases, we may not be able to identify a clear trigger.

Part of the reason HLH is hard to diagnose is because many investigations and tests are needed to distinguish between the different possible triggers.

Patients with HLH may present across a wide spectrum of severity and with varying symptoms, including:

Fever.
Rash.
Fatigue.
Weight loss.
Night sweats.
Enlarged liver, spleen, and lymph nodes.
Neurological signs such as irritability.
Symptoms of the initial triggering infection or condition.

HLH can be challenging to diagnose as it presents similarly to other serious conditions and infections.

Due to the complexity of the condition, many investigations are used to establish the diagnosis and to monitor response to treatment.

Blood tests:

Full blood count (FBC): this test looks at the number of red cells, white cells and platelets in the blood.
Blood tests looking at markers of inflammation: these markers include Ferritin, CRP and ESR.
Liver function tests (LFTs): blood markers of liver function.
Kidney function: this is monitored using both blood markers (called urea and creatinine) and looking at the urine for signs of protein or blood.
Genetic tests can be used to look for causes of primary HLH.

Tissue sampling tests (biopsies):

Sometimes multiple samples are needed to help identify the HLH trigger.
These may include lymph nodes or bone marrow biopsies.

If HLH has been triggered by an infection, this may need to be treated simultaneously. This may be with antibiotics or antiviral medication, depending on the trigger. We can also treat HLH without knowing the specific trigger.

As HLH is a condition that involves an overactive immune response, the mainstay of treatment is using medications that dampen down the body’s immune response. These are called immunosuppressants.

Two main immunosuppressive medications are used in the treatment of HLH:

Steroids (e.g. corticosteroids, prednisolone, methylprednisolone):

Steroids are a class of drug that mimic the actions of stress-hormones on the body.
Steroids are useful for reducing inflammation in the body and act broadly by reducing several different mechanisms of inflammation.
They can be given by infusion into the vein, by injection into the muscle or in oral tablet form.

Anakinra (or Kineret ®):

Anakinra is a biologic medicine - a medicine that comes from a biological source.
Anakinra blocks a specific pro-inflammation chemical in the body called IL-1.
This treats HLH as it helps to lessen the body’s inflammatory response.
Anakinra is given by daily injections under the skin, or as an infusion into the vein

HLH is a rare condition with lots of ongoing research and the way it is treated will depend on specific patient factors as well as the latest guidance.

UCLH is one of a handful of hospitals in the country which runs a HLH service. Patients may come to UCLH after being referred by their GP or from another hospital.

The HLH service is a multi-disciplinary team (MDT) consisting of nurses, clinical psychologists and doctors across of range of specialties. These include rheumatology, haematology, neurology, critical care, and infectious diseases.

All of the HLH MDT are here to support patients and their families through the difficult periods of being in hospital and intensive care as well as with the processes of discharge from hospital, outpatient follow-up and recovery.

For a full glossary of medical terms that you may hear when talking about HLH, please visit the Histio UK website.

Biopsy – the removal of a small piece of tissue from an organ or part of the body for microscopic examination.
Culture – when infection is suspected, samples of blood, urine, throat secretions etc. are taken and tested to try to identify the type of infection and the most appropriate treatment required.
Immunoglobulin – antibodies (type of protein) that are produced by certain white blood cells and play an essential role in the body’s immune system. It is sometimes necessary to give immunoglobulin (antibodies) collected from donors to patients to support their immune system (e.g. IVIG, ZIG).
Immuno-suppression – reduced function of the immune system leading to an increased risk of infection.
Lymphocytes – white blood cells responsible for the production of antibodies and for the direct destruction of invading organisms.
Macrophage – occur in the walls of blood vessels (adventitial cells) and in loose connective tissue (histiocytes, phagocytic reticular cells). Macrophages are usually immobile but become actively mobile when stimulated by inflammation; they also interact with lymphocytes to facilitate antibody production.
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. The term is typically used for the HLH-like syndrome that can occur in patients with systemic onset juvenile arthritis.
Platelets – the tiny cells in circulating blood which aid blood clotting.
Prognosis – an estimate of the outcome of a disease based on the patient’s current condition and accumulated medical knowledge about that disease and its best treatment.
Pyrexia – fever or abnormally high body temperature.
Sepsis – infection.
White blood cells – cells in the blood that are important in fighting infection (neutrophils, lymphocytes, etc.).

HLH is likely to require long term treatment and follow up. This may involve being on immunosuppressive medication. If this is the case, you should ask your doctor before getting live vaccines (e.g. MMR or yellow fever vaccines) and take some measures to avoid infection.

HLH can make people so unwell that they may require treatment in an intensive care unit (ICU/ITU). This can be traumatic for both the patient and their loved ones, and it is likely to require a long period of gradual recovery. The MDT at UCLH can offer advice regarding emotional support, physical rehabilitation and recovery in this period.

HLH is a rare condition. It can sometimes be difficult or frustrating for patients to discuss their experience of HLH with friends, family and non-specialist professionals who may not have heard of or fully understand the condition.

Please don’t hesitate to ask any questions to your doctor and any members of the MDT. The following resources are available for further reading. However, if you are feeling unwell it is always best to seek the advice of a clinician.