Introduction
The term ‘hemophagocytosis’ is used to describe a situation where certain cells, called macrophages, start to eat up red blood cells, white blood cells, platelets, and their young cells. This is a key finding in a condition known as hemophagocytic lymphohistiocytosis (HLH). HLH is a specific medical condition with symptoms like fever, low blood cell counts, a big spleen, and this ‘eating up’ of blood cells in the bone marrow, liver, or lymph nodes. This syndrome was first noticed in 1939 and was initially believed to be a rare disease caused by unusual cell growth. Later on, it was discovered that there is a family form of this disease, now called familial hemophagocytic lymphohistiocytosis.
What Are Hemophagocytic Syndromes?
Hemophagocytic syndrome (HPS) is a rare immune disorder that can be very dangerous. It causes a ‘cytokine storm,’ which means the immune system becomes overly active and causes a lot of inflammation in the body. This can lead to symptoms like high fever, a swollen liver and spleen, low blood cell counts, high levels of certain fats in the blood, and high levels of a protein called ferritin. In HPS, some immune cells also start to swallow up other cells in the bone marrow, liver, spleen, or lymph nodes. HPS can happen either because of a problem with a person's genes (primary hemophagocytic lymphohistiocytosis) or as a result of other things like cancers, infections, or certain autoimmune diseases (secondary hemophagocytic lymphohistiocytosis).
What Are the Clinical, Laboratory, and Histopathological Features of Hemophagocytic Syndrome?
When diagnosing hemophagocytic lymphohistiocytosis (HLH), doctors consider various clinical, lab, and tissue examination features. These criteria help them determine if a patient has HLH. Some common clinical signs include a high fever and an enlarged spleen, but patients may also show signs like a swollen liver, swollen lymph nodes, yellowing of the skin (jaundice), and rashes. The rash can look like red spots on the skin (maculopapular) or even raised lumps (nodular eruptions).
In cases where HLH affects the central nervous system, patients might experience problems like confusion (encephalopathy), neck stiffness (meningismus), and seizures. These signs can sometimes make it seem like the patient has a sudden viral infection, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), viral hepatitis, or acute HIV seroconversion. This can be complicated because these infections are linked to HLH.
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Laboratory Features - In terms of lab test results, a common finding is low blood cell counts (cytopenias), which can be severe. Blood tests may also suggest that the patient's red blood cells are breaking down (hemolysis), with high bilirubin levels and increased lactate dehydrogenase. Most patients with HLH have high levels of triglycerides in their blood and a significant increase in a protein called ferritin. Their blood's fibrinogen levels are usually low, and there might be a problem with blood clotting (disseminated intravascular coagulation).
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Histopathological Features - When examining tissues under a microscope, doctors might find a condition called hemophagocytosis. This means certain cells in the body, called macrophages, start to swallow up red blood cells, white blood cells, platelets, and their young cells. These cells appear ‘stuffed’ with other blood cells. Hemophagocytosis can be seen in the bone marrow, spleen, lymph nodes, and sometimes even in the central nervous system and skin. In the liver, doctors might notice an accumulation of lymphocytes in the hepatic portal tracts.
What Are the Steps Involved in the Assessment Of Hemophagocytic Syndromes?
The assessment of hemophagocytic syndromes (HPS) is a complex process that involves a combination of clinical evaluation, laboratory tests, and sometimes genetic studies. Diagnosing HPS can be challenging due to its diverse clinical presentations, but the following steps are generally involved in the assessment:
1. Clinical Evaluation
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Patient History: Begin by taking a detailed medical history, including the onset and duration of symptoms, any known triggers, family history of immune disorders, and any underlying medical conditions.
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Physical Examination: Conduct a thorough physical examination to identify signs and symptoms associated with HPS, such as fever, hepatosplenomegaly, skin rashes, and neurological abnormalities.
2. Diagnostic Criteria
Evaluate whether the patient meets the diagnostic criteria for HPS. For Hemophagocytic Lymphohistiocytosis (HLH), which is the most common form of HPS, diagnostic criteria are established by the Histiocyte Society. Meeting five out of eight criteria is considered indicative of HLH.
3. Laboratory Tests
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Blood Tests: Conduct a range of blood tests, including a complete blood count (CBC) to assess for cytopenias (reduced blood cell counts), liver function tests, coagulation profile, and assessment of ferritin levels. Extremely high levels of ferritin are a hallmark of HPS.
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Cytokine Levels: Measure levels of proinflammatory cytokines such as soluble interleukin-2 receptor (sIL-2R), interleukin-1, interferon-gamma, and tumor necrosis factor-alpha. Elevated cytokine levels are characteristic of HPS.
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Bone Marrow Aspiration: Perform a bone marrow aspiration and biopsy to assess for the presence of hemophagocytosis, which is the engulfing of blood cells by activated macrophages in the bone marrow.
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Natural Killer Cell Activity: Evaluate the function of natural killer (NK) cells, as reduced NK cell activity is often observed in patients with HPS.
4. Genetic Testing
Genetic testing is necessary to confirm primary HLH, which is usually caused by specific gene mutations, such as PRF1 (perforin 1), UNC13D (unc-13 homolog D), STX11 (syntaxin 11), or STXBP2 (syntaxin-binding protein 2). This step is especially relevant for individuals with a family history of HPS or those with recurring symptoms.
5. Imaging Studies
Imaging, such as CT (computed tomography) scans or MRI (magnetic resonance imaging), may be used to assess the extent of organ involvement and to identify complications related to HPS, including damage to the liver, spleen, or central nervous system.
6. Assess Underlying Triggers
In cases of secondary HPS, it is crucial to identify and treat the underlying cause. This might involve addressing infections, malignancies, or autoimmune diseases. Collaboration with a team of healthcare professionals, including hematologists, immunologists, geneticists, and specialists in the specific organ systems affected, is essential for a comprehensive evaluation and diagnosis.
7. Treatment Initiation
Once a diagnosis is established, treatment should begin promptly to control the excessive immune response and prevent further organ damage. The choice of treatment will depend on the type of HPS, its severity, and the patient's specific clinical circumstances.
What Are the Diagnostic Criteria Used in the Assessment Of Hemophagocytic Syndromes?
The diagnostic criteria used in the assessment of Hemophagocytic Syndromes (HPS), specifically Hemophagocytic Lymphohistiocytosis (HLH), are established by the Histiocyte Society and provide a standardized framework for clinicians to make a diagnosis. Meeting these criteria is a crucial step in confirming HPS. The criteria include a combination of clinical and laboratory parameters:
Fever: The patient must have a persistent fever, typically lasting for at least one week, and often unresponsive to conventional antipyretic medications.
Splenomegaly: Enlargement of the spleen, as confirmed by physical examination or imaging studies.
Cytopenias: This condition refers to low blood cell counts, including one or more of the following:
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Hemoglobin level less than 9.0 grams per deciliter (g/dL).
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Platelet counts less than 100,000 per microliter (µL).
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Neutrophils count less than 1,000 per microliter (µL).
Hypertriglyceridemia and Hypofibrinogenemia: Elevated levels of triglycerides (greater than 265 mg/dL) or low fibrinogen levels (less than 150 mg/dL) are characteristic of HPS. These abnormalities may be due to liver involvement and coagulopathies.
Hemophagocytosis: The presence of hemophagocytosis, where activated macrophages engulf blood cells, must be observed in the bone marrow, spleen, lymph nodes, or other tissues. This is often confirmed through bone marrow aspiration and biopsy.
Low or Absent Natural Killer (NK) Cell Activity: Patients with HLH typically have impaired NK cell function, which can be confirmed through laboratory testing.
Ferritin Levels: Extremely elevated levels of serum ferritin, typically greater than 500 ng/mL, are frequently seen in HPS.
Soluble Interleukin-2 Receptor (sIL-2R) Levels: Elevated levels of sIL-2R, often exceeding 2,400 U/mL, are indicative of HPS.
The presence of five out of these eight criteria is considered indicative of HLH. However, clinical judgment and the overall clinical picture should also guide diagnosis, as some patients may not meet all the criteria, but still exhibit signs of HPS. It is essential to differentiate between primary (genetic) and secondary (acquired) HLH, as the treatment approach and underlying causes can differ. Genetic testing may be necessary to confirm primary HLH, as it is often associated with specific gene mutations. Secondary HLH typically results from underlying conditions such as infections, malignancies, or autoimmune diseases, and treating the underlying cause is a key part of the diagnostic and management process.
Conclusion
Hemophagocytic syndromes are uncommon but very serious conditions where the immune system goes out of control. It is crucial to find out about them early and treat them quickly to help patients get better. Although the symptoms can vary, knowing how they happen in the body and using different ways to diagnose and treat them can really help. It is important for doctors like hematologists, immunologists, and geneticists to work together to give the best care to people with these syndromes.
