Written by Peter Liu
Spoon Feed
A validation study found HLH-2004 criteria (≥4 fulfilled) provided highest diagnostic accuracy, with the H-score (≥169) also demonstrating strong performance.
HLH criteria pass the test – relaxing the checklist gives accuracy a boost
Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening hyperinflammatory syndrome that inpatient clinicians must recognize early. Untreated, life expectancy is less than two months. Prompt diagnosis and intervention are critical, yet diagnosing HLH remains challenging, requiring familiarity with established criteria. The most commonly used tools are the HLH-2004, HLH-2024, and H-score, which incorporate findings such as fever, splenomegaly, cytopenias, hypertriglyceridemia, hyperferritinemia, hemophagocytosis, and elevated sIL2. HLH-2004 and HLH-2024 require 5 of 7-8 criteria; the H-score generates a probability-based score.
This recent validation study pooled data from 13 HLH studies (~3,000 patients) to test the criteria. The best-performing models were HLH-2004 and HLH-2024, if modified to require only 4 fulfilled criteria. HLH-2004 showed 86.5% sensitivity and 86.1% specificity; HLH-2024 had 83.8% and 87.8%, respectively. The H-score (cutoff 169) followed, with 82.4% sensitivity and 87.6% specificity. Ferritin alone as a screening test had high sensitivity (94%) but lacked specificity. Modified lab cutoffs did not improve performance.
One major caveat: diagnoses used as “ground truth” in the study were made by expert consensus, likely using the same criteria under validation, which introduces a recursive bias, like asking a professor to grade their own test. Still, the improved accuracy with a 4-criteria threshold merits consideration in clinical practice.
How does this change my practice?
This validation study demystified the HLH-2024 and H-score diagnostic criteria for HLH for me. I am now emboldened to apply these criteria when I am concerned about HLH and to feel justified in considering the diagnosis even when only 4 of the HLH-2024 criteria are fulfilled. Additionally, I feel emboldened to use a ferritin of 500 as a screening cutoff for most cases of HLH.
Source
Multicenter validation of secondary hemophagocytic lymphohistiocytosis diagnostic criteria. J Intern Med. 2025 Mar;297(3):312-327. doi: 10.1111/joim.20065. Epub 2025 Jan 27. PMID: 39868852
