From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) is diagnosed through a combination of clinical findings, laboratory tests, and sometimes genetic testing, with a diagnosis established if Criterion 1 or 2 is fulfilled, including a molecular diagnosis consistent with HLH or diagnostic criteria for HLH fulfilled (5 of the 8 criteria). The diagnostic criteria for HLH include fever, splenomegaly, cytopenias affecting at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow/spleen/lymph nodes, low or absent NK cell activity, ferritin ≥500 ng/mL, and elevated soluble CD25 (IL-2 receptor) ≥2,400 U/mL 1. A bone marrow biopsy is typically performed to look for hemophagocytosis, though this finding may be absent early in the disease. For primary (genetic) HLH, molecular testing for known HLH-associated mutations is recommended, particularly in children. Secondary HLH requires identification of the underlying trigger, such as infection (particularly EBV), malignancy, or autoimmune disease. The HScore is another tool that can help calculate the probability of HLH. Early diagnosis is crucial as HLH can progress rapidly and become life-threatening if treatment is delayed.
Some key points to consider in the diagnosis of HLH include:
- Hyperferritinemia should always prompt inclusion of HLH in the differential diagnosis, with ferritin values characteristic of HLH in adults often >7000 to 10,000 mg/L 2
- The HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults, and may require modification for use in adult patients 3
- A scoring system, such as the HScore, can be used to predict the likelihood of presence of HLH, based on weighted features similar to the HLH-2004 criteria 4
- Differentiation between the effects of the underlying neoplasm and HLH can be difficult, and a repeat bone marrow aspirate may be indicated if cytopenias persist to determine whether they are related to treatment toxicity or active HLH 4
Overall, the diagnosis of HLH requires a combination of clinical and laboratory findings, and early recognition is crucial to prevent irreversible organ damage and subsequent death. The most recent and highest quality study recommends using the diagnostic criteria for HLH fulfilled (5 of the 8 criteria) to establish a diagnosis 1.
From the Research
Diagnosis of HLH
The diagnosis of Hemophagocytic Lymphohistiocytosis (HLH) is often challenging due to its diverse clinical manifestations and the presence of several diagnostic mimics 5. The current diagnostic guidelines for HLH were originally developed for pediatric cases and have not been validated for secondary HLH in adults 6.
Diagnostic Criteria
The HLH-2004 protocol is still widely used for the diagnosis of HLH, although its use in adults has not been formally validated 5. The diagnostic criteria for HLH include:
- High persistent fever
- Hepatosplenomegaly
- Blood cytopenia
- Elevated aminotransferase and ferritin levels
- Coagulopathy 7
Challenges in Diagnosis
The diagnosis of HLH can be difficult to confirm in critically ill patients, and the lack of specific diagnostic criteria can lead to delayed diagnosis and worsened outcomes 6. Some laboratory findings, such as hypoalbuminemia and elevated liver enzymes, are common in HLH patients but are not represented in the HLH-2004 guidelines 6.
Need for Improved Diagnostic Tools
There is a pressing need for more sensitive, context-specific diagnostic tools for HLH 7. The development of newer, more specific, and more rapidly obtainable diagnostic criteria is necessary to improve the understanding of HLH and to enable earlier therapy with more consistent monitoring of the response 6. Rapid testing strategies and genetic panels/testing algorithms may accelerate a genetic diagnosis and improve patient outcomes 8.