Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening, cancer-like disorder in which the immune system becomes overactive, attacking the body's own cells and tissues. Symptoms include fever, enlarged liver and spleen, and low blood cell counts, necessitating urgent medical attention.1,2
What is HLH?
To understand what HLH is, let’s break down the full name of the disease, haemophagocytic lymphohistiocytosis:3,4,5
haemo
Haemo (or hemo) refers to blood – the term is often associated with red blood cells.
phagocytic
Phagocytic refers to the process of phagocytosis, in which cells engulf or ‘eat’ particles, such as pathogens, cellular debris, or blood cells.
lympho
Lympho refers to lymphocytes, a type of white blood cell involved in the immune response.
histiocytosis
Histiocytosis refers to a group of disorders involving an abnormal increase in histiocytes. Histiocytes are immune cells responsible for antigen presentation (how the body responds to attacks from pathogens).
Haemophagocytic refers to the ‘eating’ of red blood cells – and also of platelets and white blood cells.
Lymphohistiocytosis refers to a build-up and overactivity of certain types of white blood cells and immune cells.
Putting it all together, “haemophagocytic lymphohistiocytosis” refers to a condition characterised by an abnormal activation of immune cells, particularly histiocytes. In HLH, these histiocytes engulf and destroy red blood cells and other cells.6
HLH in simple terms
A macrophage is a cell whose job is to clean up the ‘mess’ in our bodies. (It’s a type of phagocyte – an eater of particles.)
Macrophages work with T cells. A T cell is a type of lymphocyte (white blood cell) that seeks out the mess caused by an infection in our bodies and alerts the macrophages to what it finds.
The T cells do this by releasing messenger proteins called cytokines. In a healthy individual, the macrophage then cleans up the mess made by the viral infection by engulfing it.
In an person with HLH, something goes wrong and the macrophages react inappropriately. They become ‘angry’, they cause damage, and they start to eat various other cells. They eat red blood cells and others, including the T cells that they should be working with.7
The result is a devastating inflammatory response. Inflammation is sustained by the uncontrolled activation of macrophages and high level of cytokines – called a cytokine storm.
This disorder is also known as haemophagocytic syndrome. It is most commonly known by the medical abbreviation HLH.
Critical need for early diagnosis of HLH
HLH is a life-threatening disease. The condition can worsen quickly, leading to multi-organ failure and life-threatening complications. The median survival rate can be a low as two months if HLH is not treated.8
Diagnosing haemophagocytic lymphohistiocytosis can be challenging because the initial symptoms mimic those of many other medical conditions. The similarities in symptoms often lead to misdiagnosis or delayed diagnosis.
Delays in diagnosis and treatment can have a significant impact on survival, with mortality rates reaching 20%–30% within the initial two months of diagnosis.9
Types of HLH and age of onset
HLH can be classified as primary or secondary10
- Primary HLH, also called familial HLH, is a genetic condition and usually affects babies and children in the first year of life.
- Secondary HLH, also called acquired HLH, is triggered by an external factor, such as an infection, cancer, medications, etc. It may develop later in childhood, although it can appear at any age, into adulthood. Some studies suggest an average age at onset of 50 years.11
The distinction between primary and secondary HLH is not always straightforward. Not all experts use the same definitions. In practice, some cases may exhibit features of both primary and secondary HLH. It is believed that most people who develop HLH will have some combination of genetic predisposing factors and an environmental trigger.12 Distinguishing primary from secondary HLH may help clinicians to make informed decisions about treatment and care.13,14
How common is HLH?
Primary HLH is a rare disease, reported in about 1 per 50,000 births worldwide.15 One study estimates the incidence of HLH at 1 in 800,000 persons per year, with 90% of these cases being secondary.16 As with other rare diseases, it’s not possible to put an exact figure on how many people are affected. However, healthcare providers and researchers have become increasingly aware of the condition in recent years, leading to improvements in diagnosis and management. Gender and race do not play a role in the incidence of HLH.17,18
What are the symptoms of HLH?
The first, and most common, symptom of HLH is raised temperature or fever. Other signs and symptoms are:19
- High fever
- Low blood cell counts (anaemia, low platelets, low white blood cells)
- Enlarged liver and spleen
- Elevated liver enzymes
- Swollen lymph nodes
- Skin rashes
- Neurological symptoms (irritability, seizures, or altered mental status)
- Respiratory symptoms (cough, shortness of breath)
- Gastrointestinal symptoms (nausea, vomiting, diarrhoea)
These symptoms can occur in both primary and secondary HLH. Their severity and order of appearance may vary among individuals and depending on the underlying causes.20
How is HLH diagnosed?
The symptoms of HLH can be confused with those of common illnesses. But it is essential to diagnose quickly if HLH is suspected. People may present with a combination of symptoms that can lead doctors to suspect HLH. Doctors may take blood samples, and bone marrow or lymph node tissue samples. If at least five out of the eight criteria below are met, HLH may be diagnosed.21
If primary HLH is suspected, genetic tests may be carried out to identify the faulty genes.
HLH criteria
A doctor is likely to diagnose HLH if five or more of these eight criteria are met:22,23,24
- Fever
- Enlarged spleen
- Low numbers of blood cells (cytopenias)
- A high level of triglycerides and/or low level of fibrinogen in the bloodstream
- High levels of ferritin, a protein that stores iron and increases with inflammatory states
- Evidence of blood cells damaging other blood cells in certain areas of the body
- Low levels, or absence, of immune cells called natural killer (NK) cells
- High levels of sCD25, a molecule that increases with inflammation
What causes HLH?
Causes of primary HLH
Primary, or familial, HLH is caused by mutations affecting several genes. The condition can be passed on from parent to child. Different forms of HLH can be transmitted in one of two ways:25
- Autosomal recessive inheritance – meaning that the condition is expressed only when an individual inherits two copies of the affected gene, one from each parent.
- X-linked inheritance – meaning that the condition is linked to a gene located on the X chromosome, r. It is typically more common in males because they have one X and one Y chromosome, while females have two X chromosomes.26
In rare cases, primary HLH may be caused by a spontaneous (de novo) mutation that happens by chance, and is not transmitted from parents.
The most common trigger in children with primary HLH is an infection, particularly herpesvirus family infections, and specifically Epstein–Barr virus.27
Causes of secondary HLH
In secondary HLH, the disease may manifest when a severe illness triggers an immune response that cannot be shut off. As with primary HLH, one of the main viral triggers for secondary HLH is Epstein–Barr virus (EBV).28
Apart from EBV, various viral, bacterial, fungal, and parasitic infections can trigger secondary HLH, such as cytomegalovirus (CMV), herpes simplex virus (HSV), influenza, and tuberculosis.29
Other triggers include:30,31
- Autoimmune diseases, including lupus, Still's disease, [LINK] and rheumatoid arthritis
- Malignancies – certain cancers, especially lymphomas and leukemias
- Immune deficiencies – in people with underlying immune system disorders
- Side effects of medication
- Complications following stem cell transplant
- Autoinflammatory diseases – such as systemic-onset juvenile idiopathic arthritis (SJIA)
What treatments are available for HLH?
The priority of treatment is to control the immune system’s excessive response, reducing the risk of tissue damage. This typically involves corticosteroids and chemotherapy, often through intravenous (IV) delivery in hospital. An immunosuppressant may also be used.32,33
Treatment will be tailored to the individual to minimise the risk of side effects. If an infectious trigger is suspected, the treatment may include antibiotics or other medication.34,35 In cases of primary HLH, this treatment usually leads to the condition going into remission, although there will always be a risk of relapse.36
The only possible long-term cure for HLH is haematopoietic stem cell transplant (HSCT) – bone marrow transplant.37,38 In HSCT, healthy stem cells are collected from a donor's bone marrow or blood. The aim is to replace dysfunctional blood and immune cells with healthy ones.
New medications are being developed as a second-line treatment for people who have refractory primary HLH, meaning that they:39
- Do not improve with other treatments.
- Have severe side effects with other treatments.
- Respond to other treatments at first, but then symptoms come back.
- Have symptoms that quickly get worse.
What is the prognosis for HLH?
HLH is a life-threatening condition. Primary HLH is usually fatal if not treated. Median survival in an untreated person with HLH may be as little as two months.40
Even with treatment, the prognosis is sometimes only a few years, unless a bone marrow transplant can be successfully performed.41 If secondary HLH is detected promptly and treated aggressively in parallel to underlying conditions, the prognosis may be better.42
It’s important for people with HLH to work closely with their healthcare team to tailor their care to their unique needs. HLH is a complex condition, and treatment and management plans may vary depending on the individual and the underlying triggers. Personalised care and open communication with healthcare providers are crucial in improving the quality of life for those living with HLH.
Outlook – leading as near normal a life as possible
Living with (HLH) can be challenging, and people with this condition often require ongoing medical care. Here are some ways people living with HLH can improve their lives:
Medical management
Consistent medical care and adherence to treatment plans are crucial. HLH typically requires treatment to suppress the excessive immune response. Regular follow-up appointments with healthcare providers are essential to monitor progress and adjust treatment as needed.
Education
Gaining a thorough understanding of the condition can empower people with HLH to actively participate in their care. It can be worthwhile to learn about HLH, its triggers, and treatment options.
Psychological support
Managing a chronic illness such as HLH can take a toll on mental health. People living with HLH and their caregivers may find it helpful to seek psychological support, such as counselling or support groups.43
Getting support
HLH treatment can be physically and emotionally taxing. Supportive care measures, such as pain management, nutritional support, and counselling, can help improve the quality of life for people with HLH. 44 Support of friends, family, and counsellors is important for anyone living with, or caring for child with, HLH. A number of organisations make resources and support available for people with HLH and their families.45
Immunology
The role of the immune system
Related links
Haemophagocytic lymphohistiocytosis (HLH), Great Ormond Street Hospital for Children
Information provided jointly by PID UK, Great Ormond Street Hospital (GOSH) and the Great North Children's Hospital
Immune Deficiency Foundation IDF
Works to inform and connect families facing conditions such as primary HLH.
Hemophagocytic Lymphohistiocytosis (HLH), Cincinnati Children's Hospital
Information on HLH including an explainer video for young children
Liam's Lighthouse Foundation LLF
Founded by the mother of a one-year-old boy who lost his life to HLH, to increase awareness of HLH and other similar conditions.
HLH Heroes Foundation
Launched in July 2021 by parents of children diagnosed with primary HLH, to support individuals and families impacted by HLH.
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Apr, 2024