Biomarkers for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients

J Clin Immunol. 2021 Apr;41(3):658-665. doi: 10.1007/s10875-020-00950-z. Epub 2021 Jan 8.


Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163 and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-ɣ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18*HScore was identified as a highly potential score.

Keywords: Ferritin; HScore; hemophagocytic lymphohistiocytosis; hemophagocytic syndrome; interleukin-18.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Belgium
  • Biomarkers* / blood
  • Critical Illness*
  • Cytokines / blood
  • Disease Management
  • Disease Susceptibility
  • Early Diagnosis
  • Female
  • Humans
  • Inflammation Mediators
  • Lymphohistiocytosis, Hemophagocytic / blood
  • Lymphohistiocytosis, Hemophagocytic / diagnosis*
  • Lymphohistiocytosis, Hemophagocytic / etiology*
  • Male
  • Middle Aged
  • ROC Curve
  • Symptom Assessment


  • Biomarkers
  • Cytokines
  • Inflammation Mediators