From the Guidelines
Hemophagocytic lymphohistiocytosis (HLH) is diagnosed through a combination of clinical findings, laboratory tests, and sometimes genetic testing, with the diagnosis established if Criterion 1 (a molecular diagnosis consistent with HLH) or 2 (fulfilling 5 of the 8 diagnostic criteria) is fulfilled. The diagnostic criteria for HLH include fever, splenomegaly, cytopenias affecting at least two cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in bone marrow or spleen or lymph nodes, low or no NK cell activity, ferritin ≥ 500 mg/L, and soluble CD25 (ie, soluble IL-2 receptor) ≥ 2400 U/mL 1.
Key Diagnostic Criteria
- Fever
- Splenomegaly
- Cytopenias (affecting ≥2 of 3 lineages in the peripheral blood)
- Hemoglobin < 90 g/L
- Platelets < 100 × 10^9/L
- Neutrophils < 1.0 × 10^9/L
- Hypertriglyceridemia and/or hypofibrinogenemia
- Fasting triglycerides ≥ 3.0 mmol/L
- Fibrinogen ≤ 1.5 g/L
- Hemophagocytosis in bone marrow or spleen or lymph nodes
- Low or no NK cell activity
- Ferritin ≥ 500 mg/L
- Soluble CD25 (ie, soluble IL-2 receptor) ≥ 2400 U/mL According to the study published in Blood in 2019 1, soluble interleukin-2 (IL-2) receptor has been reported as a good to excellent low-cost diagnostic test for adult HLH.
Additional Supportive Evidence
- Spinal fluid pleocytosis (mononuclear cells) and/or elevated spinal fluid protein
- Histological picture in the liver resembling chronic persistent hepatitis (biopsy)
- Cerebromeningeal symptoms, lymph node enlargement, jaundice, edema, skin rash, hepatic enzyme abnormalities, hypoproteinemia, hyponatremia, and elevated very low-density lipoprotein (VLDL↑)/low high-density lipoprotein (HDL↓) 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 2, 3, 4, 5, 6.
- Key clinical features that may indicate HLH include:
- High persistent fever
- Hepatosplenomegaly
- Blood cytopenia
- Elevated aminotransferase and ferritin levels
- Coagulopathy
- The HLH-2004 protocol is commonly used in the diagnosis of HLH, although its use in adults has not been formally validated yet 2.
- Diagnostic criteria for HLH include a combination of clinical and laboratory findings, such as:
- Fever
- Cytopenia
- Splenomegaly
- Hemophagocytosis
- Elevated ferritin and triglycerides
- Low fibrinogen
- Awareness of the clinical symptoms and diagnostic criteria of HLH is crucial to start life-saving therapy with immunosuppressive/immunomodulatory agents in time 5.
Diagnostic Challenges
- HLH is likely under-recognized, and mortality remains high, especially in adults, making prompt diagnosis and treatment essential 3.
- The diagnosis of HLH can be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings 6.
- There remains a pressing need for more sensitive, context-specific diagnostic tools to improve the diagnosis of HLH 3.