Hemophagocytic Lymphohistiocytosis: Symptoms, Diagnosis & Treatment

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a rare but serious disorder of the immune system. First identified in the 1950s, HLH occurs when certain immune cells, specifically histiocytes and lymphocytes, become overactive and begin attacking healthy tissues and organs. This leads to severe inflammation and damage to vital organs such as the liver, spleen, and bone marrow. While HLH can be life-threatening if left untreated, early diagnosis and intervention can significantly improve outcomes. This article provides a comprehensive overview of HLH, including its risk factors, symptoms, diagnostic tests, treatment options, and tips for managing symptoms at home. Understanding HLH empowers patients and their families to make informed decisions and work closely with healthcare providers.

What is Hemophagocytic Lymphohistiocytosis (HLH)?

Hemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder characterized by an overactive immune response. This article will explore its risk factors, symptoms, diagnostic tests, treatment options (including medications and procedures), and strategies for managing symptoms at home.

Description of Hemophagocytic Lymphohistiocytosis

HLH is a condition in which the immune system becomes dysregulated, leading to excessive inflammation. Normally, the immune system protects the body from infections and harmful invaders. However, in HLH, immune cells (histiocytes and lymphocytes) become overactive and attack the body’s own tissues, causing widespread inflammation and damage to critical organs such as the liver, spleen, and bone marrow.

HLH is classified into two types: primary (familial) HLH, which is inherited and often affects infants and young children, and secondary HLH, which can occur at any age and is typically triggered by infections, autoimmune diseases, or certain cancers. Without prompt treatment, HLH can rapidly progress to multi-organ failure and death. However, early diagnosis and appropriate treatment can lead to remission.

Although rare, HLH affects an estimated 1 in 50,000 to 1 in 100,000 people worldwide. It is more common in children, but adults can also develop HLH, particularly in the context of infections or other underlying health conditions. Early intervention is crucial, as untreated HLH can be fatal within weeks or months.

Risk Factors for Developing Hemophagocytic Lymphohistiocytosis

Lifestyle Risk Factors

While HLH is not typically associated with lifestyle choices, certain environmental factors can increase the risk of secondary HLH. Individuals exposed to infections, particularly viral infections like Epstein-Barr virus (EBV), are at higher risk. People with weakened immune systems, such as those undergoing chemotherapy or taking immunosuppressive medications, are also more vulnerable. Additionally, individuals who have undergone organ transplants or been exposed to certain toxins may face an increased risk.

Medical Risk Factors

Several medical conditions can elevate the risk of developing HLH. Viral infections like EBV, cytomegalovirus (CMV), and HIV are common triggers for secondary HLH. Autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, can also lead to HLH. Certain cancers, particularly blood cancers like lymphoma and leukemia, are associated with a higher risk of HLH. Patients with these conditions should be closely monitored for HLH symptoms, especially if new or worsening symptoms develop.

Genetic and Age-Related Risk Factors

Primary HLH is caused by genetic mutations that affect immune cell function. These mutations are inherited in an autosomal recessive pattern, meaning both parents must carry the defective gene for their child to develop the condition. Primary HLH usually presents in infancy or early childhood, though it can occasionally occur later in life. Genetic testing can identify individuals at risk, especially if there is a family history of HLH.

Age is another important factor. While primary HLH is more common in children, secondary HLH can occur at any age. Older adults may be at higher risk due to age-related changes in the immune system and the increased likelihood of underlying conditions, such as infections or cancer, that can trigger HLH.

Clinical Manifestations of Hemophagocytic Lymphohistiocytosis

Fever

Fever is one of the most common symptoms of HLH, occurring in about 95% of patients. The overactive immune response in HLH causes widespread inflammation, leading to a persistent, high-grade fever that often does not respond well to typical fever-reducing medications. Fever can be one of the earliest signs of HLH, making it a key symptom for early diagnosis.

Hepatomegaly

Hepatomegaly, or an enlarged liver, occurs in 60-70% of HLH patients. The liver enlarges due to immune cell accumulation and inflammation, causing discomfort or pain in the upper right abdomen. In severe cases, hepatomegaly can impair liver function, leading to complications like jaundice or elevated liver enzymes. Monitoring liver size and function is crucial, as liver involvement can indicate disease progression.

Splenomegaly

Splenomegaly, or an enlarged spleen, is seen in 80-90% of HLH cases. The spleen becomes overactive due to excessive immune activity, leading to its enlargement. This can cause discomfort or pain in the left upper abdomen and may contribute to cytopenias (low blood cell counts) as the spleen traps and destroys blood cells. Splenomegaly is often a sign of advanced disease and requires careful monitoring.

Cytopenias

Cytopenias, or low blood cell counts, occur in about 80% of HLH patients. This includes low levels of red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). The immune system’s overactivity leads to the destruction of these cells, either in the bone marrow or spleen. Cytopenias can cause fatigue, increased infection risk, and easy bruising or bleeding. Regular blood tests are essential for diagnosing and managing HLH.

Rash

A rash is present in 30-65% of HLH patients. It can range from small red spots to widespread skin irritation, caused by immune system overreaction and inflammation in the skin. The rash may be more common in HLH triggered by infections or autoimmune conditions. While not usually dangerous, it is a visible sign of underlying immune dysregulation.

Lymphadenopathy

Lymphadenopathy, or swollen lymph nodes, occurs in 40-60% of HLH patients. The lymph nodes, part of the immune system, become enlarged due to excessive immune activity. Swollen lymph nodes can be painful or tender and are often found in the neck, armpits, or groin. Lymphadenopathy can indicate both infection and immune overactivity, making it an important symptom to monitor.

Jaundice

Jaundice, or yellowing of the skin and eyes, occurs in 10-20% of HLH patients. It results from liver dysfunction caused by inflammation and immune cell infiltration. When the liver cannot process bilirubin (a byproduct of red blood cell breakdown), it builds up, leading to jaundice. This is often a sign of severe liver involvement and requires immediate medical attention.

Elevated Liver Enzymes

Elevated liver enzymes, such as ALT and AST, are found in about 85% of HLH patients. These enzymes are released into the bloodstream when liver cells are damaged. In HLH, liver inflammation and immune cell infiltration lead to elevated enzyme levels. Monitoring liver enzymes is crucial for assessing liver involvement and guiding treatment decisions.

Neurological Symptoms

Neurological symptoms occur in 30-50% of HLH patients and may include headaches, seizures, confusion, and even coma. These symptoms arise when the immune system’s overactivity affects the brain and central nervous system. In severe cases, HLH can cause brain inflammation (encephalitis), leading to significant neurological impairment. Early recognition and treatment of neurological symptoms are critical to prevent long-term damage.

Hemophagocytosis

Hemophagocytosis, the hallmark of HLH, is seen in 60-70% of cases. This process involves immune cells called macrophages engulfing and destroying other blood cells, including red blood cells, white blood cells, and platelets. Hemophagocytosis can occur in the bone marrow, spleen, liver, or lymph nodes. While it is a key feature of HLH, it may not always be present in early stages, so other diagnostic criteria should also be considered.

Diagnostic Evaluation of Hemophagocytic Lymphohistiocytosis

Diagnosing HLH can be challenging due to its symptom overlap with other conditions. A combination of clinical findings, lab tests, and sometimes genetic testing is used to confirm the diagnosis. Diagnosis is often based on meeting specific criteria, including clinical symptoms (like fever and splenomegaly) and lab abnormalities (such as elevated ferritin levels or cytopenias). In some cases, a bone marrow biopsy or specialized tests may be required to confirm hemophagocytosis. Early diagnosis is crucial, as HLH can progress rapidly and requires prompt treatment.

Bone Marrow Biopsy

A bone marrow biopsy involves taking a small sample of bone marrow, usually from the hip bone, using a needle. The sample is examined under a microscope for signs of hemophagocytosis, where immune cells engulf other blood cells. This test is important because hemophagocytosis is a key feature of HLH, though it may not always be present in early stages. The biopsy can also help rule out other conditions, such as leukemia or lymphoma, that may cause similar symptoms.

Results that Indicate HLH

If hemophagocytosis is observed in the bone marrow sample, it strongly suggests HLH. However, its absence does not rule out the disease, as it may not be present in all cases. Other findings, such as reduced blood cell production (cytopenias), can also support the diagnosis. If the biopsy is negative but clinical suspicion remains high, additional tests, such as genetic testing or cytokine assays, may be performed to confirm the diagnosis.

Blood Tests

Blood tests are critical for diagnosing HLH. These tests measure various blood components, including red and white blood cells, platelets, and markers of inflammation. Specific blood tests used in HLH diagnosis include ferritin levels, triglycerides, and soluble IL-2 receptor (sCD25) levels. Elevated ferritin and sCD25 levels are common in HLH and help differentiate it from other conditions. Blood tests also monitor the patient’s response to treatment and assess disease severity.

Results that Indicate HLH

In HLH, ferritin levels are often extremely elevated, sometimes exceeding 10,000 ng/mL. Elevated triglycerides and low fibrinogen levels are also common. High sCD25 levels indicate excessive immune activation, a hallmark of HLH. Abnormal blood test results increase the likelihood of an HLH diagnosis. However, if results are normal but symptoms persist, further testing may be needed to rule out other causes or identify genetic mutations associated with HLH.

Liver Function Tests

Liver function tests (LFTs) measure enzyme and protein levels in the blood produced by the liver. These tests help assess whether the liver is affected by HLH. Elevated liver enzymes, such as ALT and AST, indicate liver inflammation or damage, which is common in HLH. LFTs are important because liver involvement can complicate the disease and may require specific treatments to protect liver function.

Results that Indicate HLH

In HLH, LFTs often show elevated ALT and AST levels, indicating liver inflammation. Bilirubin levels may also be elevated, leading to jaundice. Abnormal LFTs suggest liver involvement, helping confirm the diagnosis. If LFTs are normal but other HLH symptoms are present, additional tests, such as imaging studies or a liver biopsy, may be needed to assess liver involvement.

Imaging Studies

Imaging studies, such as ultrasound or CT scans, assess the size of the liver and spleen and look for signs of lymphadenopathy (swollen lymph nodes). These non-invasive tests provide valuable information about the extent of organ involvement in HLH. Imaging studies are often used alongside other tests to monitor disease progression and guide treatment decisions.

Results that Indicate HLH

In HLH, imaging studies often show an enlarged liver (hepatomegaly) and spleen (splenomegaly). Swollen lymph nodes may also be visible. These findings, combined with clinical symptoms and lab results, help confirm an HLH diagnosis. If imaging studies are normal but other HLH signs are present, further testing, such as a bone marrow biopsy or genetic testing, may be needed to confirm the diagnosis.

What if all Tests are Negative but Symptoms Persist?

If all tests are negative but HLH symptoms persist, it is important to continue working with your healthcare provider to explore other possible diagnoses. HLH can be difficult to diagnose, and additional testing or a second opinion may be necessary. Your healthcare provider may recommend repeating certain tests or trying new diagnostic approaches, such as genetic testing, to ensure no underlying condition is missed. Persistent symptoms should never be ignored, and ongoing communication with your healthcare team is essential for finding the right diagnosis and treatment plan.

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Treatment Options for Hemophagocytic Lymphohistiocytosis (HLH)

Medications for HLH Disease

Etoposide

Etoposide is a chemotherapy drug that inhibits the growth of rapidly dividing cells, including immune cells involved in Hemophagocytic Lymphohistiocytosis (HLH). By suppressing the overactive immune response characteristic of HLH, it helps control the disease.

As a first-line treatment, etoposide is often combined with dexamethasone and administered intravenously in a hospital setting. It is particularly effective in familial HLH or cases triggered by infections or malignancies.

Patients may begin to notice symptom improvement within a few weeks, though the full course of therapy can last several months. Etoposide helps regulate the immune system and prevents further organ damage.

Dexamethasone

Dexamethasone, a corticosteroid, reduces inflammation and suppresses the immune system, helping to control the excessive immune activity seen in HLH.

It is typically part of the initial treatment regimen, often used in combination with etoposide. Depending on the severity of the condition, dexamethasone can be administered orally or intravenously.

Patients may experience a reduction in fever and inflammation within days. Long-term use may be necessary to maintain control over the immune system.

Cyclosporine

Cyclosporine is an immunosuppressant that inhibits specific immune cells, particularly T-cells, which play a key role in the hyperactive immune response seen in HLH.

Often used alongside etoposide and dexamethasone, cyclosporine is typically administered orally or intravenously, especially in severe or refractory cases of HLH.

Patients may experience gradual symptom improvement over several weeks. Cyclosporine helps prevent further immune system attacks on the body’s tissues.

Anakinra

Anakinra is a biologic drug that blocks interleukin-1 (IL-1), a protein involved in inflammation. It is used to reduce immune system overactivity in HLH.

Anakinra is often considered when first-line treatments like etoposide and dexamethasone are ineffective or not well-tolerated. It is typically administered via subcutaneous injection.

Patients may experience reduced inflammation and fever within days to weeks. Anakinra helps stabilize the immune system and prevent complications.

Rituximab

Rituximab is a monoclonal antibody that targets B-cells, a type of immune cell involved in HLH. By reducing the number of B-cells, it helps control the immune response.

Rituximab is typically reserved for HLH cases associated with autoimmune diseases or certain cancers and is administered intravenously in a hospital or clinic.

Patients may see symptom improvement within weeks. Rituximab helps reduce inflammation and prevent further immune system attacks.

Intravenous Immunoglobulin (IVIG)

IVIG is a blood product made from pooled antibodies from thousands of donors. It modulates the immune system and reduces inflammation in HLH.

IVIG is often used in combination with other treatments, particularly in HLH cases triggered by infections or autoimmune diseases. It is administered intravenously in a hospital setting.

Patients may experience symptom relief, such as reduced fever and inflammation, within days. IVIG helps stabilize the immune system and prevent complications.

Methotrexate

Methotrexate is an immunosuppressant that inhibits certain immune cells, helping to control the overactive immune response in HLH.

Typically used when other treatments are ineffective, methotrexate can be administered orally or by injection, depending on the patient’s condition.

Patients may see gradual symptom improvement over several weeks. Methotrexate helps prevent further immune system attacks on the body’s tissues.

Tocilizumab

Tocilizumab is a monoclonal antibody that blocks interleukin-6 (IL-6), a protein involved in inflammation. It helps reduce immune system overactivity in HLH.

Often used when first-line treatments like etoposide and dexamethasone are ineffective, tocilizumab is administered intravenously or subcutaneously.

Patients may experience reduced inflammation and fever within days to weeks. Tocilizumab helps stabilize the immune system and prevent complications.

Alemtuzumab

Alemtuzumab is a monoclonal antibody that targets and depletes certain immune cells, including T-cells and B-cells, to control the overactive immune response in HLH.

Typically reserved for severe or refractory HLH cases that haven’t responded to other treatments, alemtuzumab is administered intravenously in a hospital setting.

Patients may see symptom improvement within weeks. Alemtuzumab helps reduce inflammation and prevent further immune system attacks.

Procedures for Advanced HLH Treatment

In some cases of HLH, medications alone may not be sufficient. Advanced procedures may be necessary:

Stem Cell Transplant

A stem cell transplant, also known as a bone marrow transplant, replaces the patient’s diseased or damaged bone marrow with healthy stem cells from a donor. This procedure can restore the immune system and potentially cure HLH.

Stem cell transplants are typically reserved for patients with familial HLH or those unresponsive to other treatments. The procedure requires a compatible donor and is performed in a specialized hospital setting.

Patients may experience a complete cure after a successful stem cell transplant. However, recovery can take several months, and there is a risk of complications, such as graft-versus-host disease.

Improving Hemophagocytic Lymphohistiocytosis and Seeking Medical Help

While medical treatments are essential for managing HLH, there are steps you can take at home to support your health and improve your quality of life:

1. Rest: Fatigue is common in HLH, so getting plenty of rest helps your body recover.
2. Hydration: Staying well-hydrated supports your immune system and helps prevent complications like kidney damage.
3. Nutrition: A balanced diet rich in vitamins and minerals strengthens your immune system and promotes overall health.
4. Stress Management: Techniques like meditation or deep breathing can reduce inflammation and support your immune system.

It’s important to seek medical help if you experience HLH symptoms such as persistent fever, unexplained fatigue, or organ dysfunction. Telemedicine offers a convenient way to consult healthcare providers from home. Our primary care practice can help manage your symptoms, monitor your condition, and coordinate care with specialists if needed.

Living with Hemophagocytic Lymphohistiocytosis: Tips for Better Quality of Life

Living with HLH can be challenging, but there are steps you can take to improve your quality of life:

1. Follow Your Treatment Plan: Adhering to prescribed medications and treatments is crucial for managing HLH and preventing complications.
2. Stay Informed: Educate yourself about HLH and stay updated on the latest treatments and research to feel more in control of your condition.
3. Build a Support System: Surround yourself with supportive friends, family, and healthcare providers to help navigate the challenges of living with HLH.
4. Monitor Your Symptoms: Keep track of your symptoms and report any changes to your healthcare provider. Early intervention can prevent complications.

Conclusion

Hemophagocytic Lymphohistiocytosis (HLH) is a serious condition that requires prompt diagnosis and treatment. While life-threatening, early intervention with medications like etoposide, dexamethasone, and cyclosporine, along with advanced procedures such as stem cell transplants, can significantly improve outcomes.

If you or a loved one is experiencing HLH symptoms, seek medical attention immediately. Our telemedicine practice offers convenient access to healthcare providers who can help diagnose and manage your condition. Don’t wait—schedule a consultation today to take the first step toward better health.

James Kingsley

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