Haemophagocytic Lymphohistiocytosis

Haemophagocytic lymphohistiocytosis is a rare and life-threatening condition where the immune system attacks the body’s own tissues instead of defending it against disease. Without prompt diagnosis and treatment, this severe inflammatory syndrome can lead to organ failure and death within months, but early intervention and proper care can save lives.

Table of contents

• What is haemophagocytic lymphohistiocytosis?
• Types of HLH
• What causes HLH?
• Signs and symptoms
• How common is HLH?
• Diagnosis
• Treatment approaches
• Outlook and prognosis

What is haemophagocytic lymphohistiocytosis?

Haemophagocytic lymphohistiocytosis, commonly known as HLH, is a severe condition where the immune system becomes dangerously overactive^[1]. To understand this condition, it helps to break down its name. Haemophagocytic refers to the eating of blood cells, lympho relates to lymphocytes (a type of white blood cell), and histiocytosis describes an abnormal increase in histiocytes, which are immune cells^[6].

Normally, your immune system defends your body against harmful invaders like bacteria and viruses. In HLH, the immune system malfunctions and produces too many white blood cells called histiocytes and T cells. Instead of fighting infections, these cells attack the body’s own tissues and organs, including the liver, spleen, bone marrow, and brain^[1][8].

The condition causes extreme inflammation throughout the body, often described as a cytokine storm, which occurs when overactive immune cells produce excessive amounts of signaling proteins called cytokines^[2][3]. This inflammatory response can damage multiple organs and lead to failure of vital body systems.

Types of HLH

HLH is classified into two main types based on its underlying cause^[1]:

Primary HLH, also called familial HLH, is an inherited form of the disease caused by genetic mutations. These genetic defects are present at birth, though symptoms typically appear during infancy or early childhood. In this form, genes that control the function of natural killer cells and cytotoxic T cells don’t work properly^[2][11]. Primary HLH is an autosomal recessive condition, meaning a child must inherit the defective gene from both parents to develop the disease^[7].

Several genetic mutations are associated with primary HLH, including defects in genes such as PRF1, UNC13D, STX11, STXBP2, RAB27, LYST, SH2D1A, and CD27^[1][7]. These genes provide instructions for cells to create proteins that help the immune system destroy foreign invaders. When these genes are mutated, the immune system cannot properly regulate itself.

Secondary HLH, also called acquired HLH, occurs when an underlying medical condition triggers the immune system to malfunction. This form can develop at any age, though it’s more common in adults^[1][6]. Common triggers include infections (especially Epstein-Barr virus), cancers (particularly blood cancers like leukemia and lymphoma), autoimmune diseases, or certain medications^[1][2][3].

The distinction between primary and secondary HLH is not always clear-cut. Many people who develop secondary HLH may have genetic factors that predispose them to the condition, even if they don’t have the classic inherited mutations^[6][10].

What causes HLH?

HLH develops when the immune system fails to properly control inflammation. In a healthy immune response, natural killer cells and cytotoxic T cells identify and destroy infected or abnormal cells, then shut down once the threat is eliminated. In HLH, this shut-down mechanism doesn’t work correctly^[2][4].

The overactive immune cells continue to multiply and release inflammatory signals. These cells and their chemical messengers then attack the body’s own blood cells and infiltrate organs. Macrophages, a type of immune cell, begin consuming red blood cells, white blood cells, and platelets in a process called hemophagocytosis, which gives the condition its name^[4][10].

In primary HLH, genetic defects prevent immune cells from functioning properly from birth. The most common genetic mutations affect perforin and other proteins involved in the immune system’s ability to kill infected cells and then turn itself off^[2][7].

In secondary HLH, various triggers can set off this abnormal immune activation. Infections are the most frequent trigger, with Epstein-Barr virus being particularly common. Other triggers include certain cancers, especially lymphomas and leukemias, autoimmune conditions like lupus or rheumatoid arthritis, and immunosuppressive therapies including organ transplants^[2][10].

Signs and symptoms

HLH symptoms can vary widely from person to person and often resemble other common illnesses, which makes diagnosis challenging^[4]. The most characteristic symptom is persistent high fever that doesn’t respond to antibiotics^[1][3].

Common symptoms include^[1][9]:

• Prolonged fever that won’t break with standard treatments
• Skin rash or discoloration
• Enlarged liver (hepatomegaly)
• Enlarged spleen (splenomegaly)
• Swollen lymph nodes
• Yellowing of the skin and eyes (jaundice)
• Weakness and fatigue
• Pale skin from anemia
• Easy bruising or bleeding
• Irritability, especially in infants
• Headaches
• Poor feeding in babies
• Failure to grow or gain weight

Laboratory findings in HLH patients often show low blood cell counts affecting red blood cells, white blood cells, and platelets (a condition called pancytopenia), extremely high levels of ferritin (a protein that stores iron), elevated triglycerides, and low fibrinogen levels^[2][7].

Neurological symptoms can develop and may include seizures, confusion, changes in mental status, difficulty with coordination, partial paralysis, or in severe cases, loss of consciousness or coma^[1][9]. These symptoms indicate that HLH is affecting the brain and require immediate medical attention.

Life-threatening complications include difficulty breathing, liver failure, and uncontrollable bleeding^[1][4]. If any severe symptoms develop, emergency medical care is essential.

How common is HLH?

Haemophagocytic lymphohistiocytosis is a rare condition. The exact frequency is difficult to determine because HLH is often misdiagnosed or goes undiagnosed^[1][7].

Primary HLH is estimated to occur in about 1 in 50,000 births worldwide each year, though some studies suggest the rate may be slightly higher^[3][4]. This form most commonly affects infants and young children, with about 70 percent of cases appearing in the first year of life^[1][7].

Secondary HLH is more common than primary HLH, accounting for approximately 75 percent of all HLH cases^[1]. This form can affect people of any age, though it’s seen more frequently in adults. The true incidence of secondary HLH may be underestimated because its symptoms closely resemble other conditions like severe infections or sepsis^[7][10].

HLH can affect anyone regardless of gender or ethnic background, though certain genetic forms may be more common in specific populations^[1].

Diagnosis

Diagnosing HLH is challenging because the condition is rare and its symptoms overlap with many other diseases. Many healthcare providers are unfamiliar with HLH, which can lead to delays in diagnosis^[4][9].

The Histiocyte Society established diagnostic criteria for HLH that include five key features: fever, enlarged spleen, low blood cell counts affecting at least two cell types, high triglycerides or low fibrinogen, and evidence of hemophagocytosis (immune cells eating blood cells) in bone marrow, spleen, or lymph nodes^[9]. Additional supportive findings include elevated ferritin levels, reduced natural killer cell activity, high levels of soluble CD25 (also called soluble IL-2 receptor), and identification of a known genetic mutation^[4].

Several blood tests are essential for diagnosis. Complete blood counts typically show anemia, low platelets, and sometimes low white blood cells. Liver function tests often reveal abnormalities. Ferritin levels are usually extremely elevated, sometimes reaching thousands of times the normal range. Triglyceride and fibrinogen levels help confirm the diagnosis^[4][9].

Testing natural killer cell function or activity is particularly useful, as it’s decreased in up to 90 percent of HLH patients^[9]. This test helps distinguish HLH from other conditions.

A bone marrow biopsy is often performed to look for hemophagocytosis, where immune cells are observed consuming blood cells. However, this finding may not be present early in the disease^[4][9].

Genetic testing is crucial when primary HLH is suspected, particularly in children. Identifying specific genetic mutations helps confirm the diagnosis, guides treatment decisions, and provides information for family planning^[2][4].

Additional tests may include spinal fluid analysis if neurological symptoms are present, imaging studies like CT scans or MRI to assess organ involvement, and tests to identify potential triggers such as infections or underlying cancers^[4][9].

Early diagnosis is critical because HLH can progress rapidly. The median survival without treatment can be as low as two months^[6][9].

Treatment approaches

HLH requires urgent treatment to suppress the overactive immune system and prevent organ damage. Without treatment, the condition is usually fatal^[2][3].

The standard initial treatment protocol, called HLH-94 or HLH-2004, typically includes a combination of medications. The cornerstone is etoposide, a chemotherapy drug that suppresses the overactive immune cells, combined with dexamethasone, a powerful corticosteroid that reduces inflammation^[9][12]. This initial therapy usually lasts eight weeks.

Cyclosporine, an immunosuppressive medication, may be added to the initial regimen or used in continuation therapy. It helps prevent the immune system from continuing to attack the body^[9][19].

In 2018, a targeted therapy called emapalumab became the first drug specifically approved for primary HLH. Emapalumab blocks interferon-gamma, a key inflammatory protein involved in HLH. It’s used in patients who have not responded to conventional therapy or cannot tolerate it^[9][10][12].

For patients with primary HLH or those with severe disease that doesn’t respond adequately to medication, hematopoietic stem cell transplantation (also called bone marrow transplant) offers the only potential cure^[2][8][19]. This procedure replaces the patient’s defective immune system with healthy stem cells from a donor. The transplant is typically performed after the disease has been controlled with medications and a suitable donor has been found.

Secondary HLH may not require transplantation if the underlying trigger can be identified and treated successfully. For example, if an infection caused HLH, treating that infection along with immunosuppressive therapy may resolve the condition^[3][10].

Supportive care is essential and may include blood transfusions to replace depleted blood cells, antibiotics to prevent or treat infections, medications to support organ function, and nutritional support^[8][19].

Newer therapeutic approaches are being investigated in clinical trials, including other targeted therapies that block specific inflammatory pathways. These include drugs targeting interleukin-1, interleukin-6, and other cytokines involved in the inflammatory storm^[10][12].

Outlook and prognosis

The prognosis for HLH depends on several factors, including whether it’s primary or secondary, how quickly it’s diagnosed, how well it responds to treatment, and whether complications develop^[3][8].

Without treatment, primary HLH is almost always fatal, typically within a few months of symptom onset^[3]. Even with treatment, outcomes vary. Early diagnosis and prompt initiation of therapy significantly improve survival chances^[1][6].

For patients with primary HLH who receive appropriate chemotherapy followed by successful stem cell transplantation, long-term survival is possible. Many children who undergo transplantation can achieve a cure and live normal, healthy lives^[8][11].

The outlook for secondary HLH is generally better if the condition is detected promptly and treated aggressively, particularly if the underlying trigger can be identified and addressed^[3][10]. However, mortality rates remain significant, with 20 to 30 percent of patients dying within the first two months even with treatment^[6][9].

Factors associated with poorer outcomes include delayed diagnosis, presence of neurological involvement, older age at diagnosis in primary HLH, development of multi-organ failure, and disease that doesn’t respond to initial therapy^[2][10].

Long-term follow-up is important for survivors, as some may experience late complications related to their disease or treatment. Patients who received stem cell transplants require ongoing monitoring for potential transplant-related complications^[8].

There is no way to prevent HLH, as primary forms are genetic and secondary forms result from unpredictable triggers^[1]. However, for families with a known history of primary HLH, genetic counseling can provide information about the risk of having another affected child and discuss testing options.