From the Guidelines
The diagnosis of Hemophagocytic Lymphohistiocytosis (HLH) can be established if either a molecular diagnosis consistent with HLH is made or at least five of the eight clinical and laboratory criteria are fulfilled, as outlined in the most recent guidelines 1. The eight clinical and laboratory criteria include:
- Fever
- Splenomegaly
- Cytopenias affecting at least two cell lines (hemoglobin < 90 g/L, platelets < 100 × 10^9/L, or neutrophils < 1.0 × 10^9/L)
- Hypertriglyceridemia and/or hypofibrinogenemia (fasting triglycerides ≥ 3.0 mmol/L or 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 (soluble IL-2 receptor) ≥ 2400 U/mL These criteria help identify the hyperinflammatory state characteristic of HLH, which results from dysregulated activation of macrophages and T cells leading to cytokine storm and multi-organ dysfunction. Early diagnosis is crucial as HLH can rapidly progress to multi-organ failure and death if not promptly treated with immunosuppressive therapy, typically including dexamethasone and etoposide according to HLH-94 or HLH-2004 protocols 1. It is also important to note that the diagnosis of HLH can be challenging, especially in adults, and may require a combination of clinical and laboratory findings, as well as a high index of suspicion 1. In addition, the use of soluble interleukin-2 (IL-2) receptor (sCD25) as a diagnostic test for adult HLH has been reported to have a good to excellent low-cost diagnostic test, with an area under the curve of 0.90 (95% confidence interval, 0.83-0.97) compared with an area under the curve of 0.78 (95% confidence interval, 0.67-0.88) for ferritin 1. Overall, a thorough understanding of the diagnostic criteria and a multidisciplinary approach are essential for the early diagnosis and effective management of HLH.
From the Research
Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH)
The diagnostic criteria for HLH include:
- Fever
- Splenomegaly
- Bicytopenia
- Hypertriglyceridemia and/or hypofibrinogenemia
- Hemophagocytosis
- Low/absent NK-cell-activity
- Hyperferritinemia
- High-soluble interleukin-2-receptor levels 2 At least five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH.
Validation of Diagnostic Criteria
The HLH-2004 criteria have been validated in a multicenter study, which found that four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH 3. Ferritin ≥500 µg/L had 94.0% mean sensitivity over all cohorts, making it a reliable HLH screening marker.
Challenges in Diagnosing HLH
Diagnosing HLH can be challenging due to its heterogeneous nature and non-specific symptoms, which can be similar to those of other conditions such as systemic inflammatory response syndrome, viral infections, or neoplastic diseases 4. The current HLH-2004 diagnostic guidelines were originally developed for pediatric cases and may not be applicable to adult secondary HLH cases 5.
Historical Context of HLH Diagnosis
Historically, the diagnosis of HLH was based on idiopathic fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, and the presence of hemophagocytosis 6. The understanding of HLH has evolved over time, with the recognition of its association with excessive activation of the immune system and the role of cytokines in its pathophysiology.