Abstract Rationale Bone-marrow examination is often impractical in unstable ICU patients with suspected Hemophagocytic Lymphohistiocytosis (HLH). There are many readily obtainable blood biomarkers including soluble IL-2 receptor (sCD25), IL-18, CXCL9, and interferon-γ (IFN-γ)/IL-10 ratios. Such markers may accelerate recognition and treatment, however their ICU-specific diagnostic performance is variably reported. Methods Following PRISMA-2020, we searched MEDLINE, Embase, Web of Science/Scopus, and CENTRAL (Jan 1, 2020-Nov 4, 2025) for adult HLH cohorts/series and diagnostic-accuracy studies reporting ≥1 target biomarker. Two reviewers screened/extracted and assessed bias (QUADAS-2/ROBINS-I). We synthesized prespecified outcomes: discriminative ability vs sepsis/other hyperinflammatory syndromes, pragmatic thresholds, and operational features (assay availability/turnaround). Because of assay heterogeneity, we prioritized effect sizes from higher-quality adult ICU cohorts and recent methodologically rigorous reviews and guideline statements. Results Across eligible adult studies, sCD25 was consistently elevated in HLH; values 2,400 U/mL showed high sensitivity in adults, and pairing sCD25 (∼3,900-5,000 U/mL) with ferritin 1,000 µg/L improved diagnostic specificity, particularly in malignancy-associated HLH. IL-18 was markedly increased in HLH/MAS and distinguished adult subtypes; reported AUCs ranged ∼0.72-0.85 in comparative analyses, with emerging roles for free IL-18 and IL-18BP biology. IFN-γ-axis readouts differentiated HLH from sepsis: CXCL9 (an IFN-γ-inducible chemokine) was significantly higher in HLH than in sepsis and fell with IFN-γ neutralization (emapalumab), supporting diagnostic and response-monitoring utility. Ratios that incorporate IFN-γ and IL-10 (and/or IL-6) improved discrimination in EBV-HLH vs sepsis in adult datasets. Practicality favored blood-based testing: sCD25 and IL-18 are widely available; CXCL9 testing with STAT (24 h) turnaround is offered by reference laboratories, enabling ICU-timely decisions. Contemporary consensus/guideline documents endorse these markers as adjuncts to HScore/HLH-2004 in adults when marrow is delayed or unsafe. Conclusion In critically ill adults with suspected HLH, non-marrow blood biomarkers add clinically actionable information. sCD25 (2,400 U/mL, with higher cutoffs plus ferritin for specificity), IL-18 (including free IL-18), CXCL9, and IFN-γ/IL-10-based ratios help distinguish HLH from sepsis and can be resulted within clinically meaningful timeframes. Integrating these assays with standard criteria may shorten time-to-immunomodulation and improve diagnostic certainty in the ICU. This abstract is funded by: none
Basta et al. (Fri,) studied this question.