Prevalence and Outcome of Secondary Hemophagocytic Lymphohistiocytosis Among SIRS Patients: Results from a Prospective Cohort Study

Abstract

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening condition clinically presenting as SIRS (Systemic Inflammatory Response Syndrome). However, there is no comprehensive data concerning diagnostic algorithms, prevalence, outcome and biomarker performance in SIRS patients. We conducted a prospective observational cohort study on 451 consecutive patients fulfilling ≥2 SIRS criteria. The Hscore and the HLH-2004 criteria were used to determine the presence of sHLH, and the correlation of the screening-biomarkers ferritin, sCD25, and sCD163 with both scores was assessed. Out of 451 standard-care SIRS patients, five patients had high Hscores (≥169), suggesting incipient or HLH-like disease, and these patients were in urgent need for intensified therapy. However, none of these patients fulfilled five HLH-2004 criteria required for formal diagnosis. From the studied biomarkers, ferritin correlated strongest to both the HLH-2004 criteria and the Hscore (rs = 0.72, 0.41, respectively), and was the best predictor of 30-day survival (HR:1.012 per 100 μg/L, 95% CI: 1.004-1.021), when adjusted for patient's age, sex, bacteremia and malignant underlying-disease. Also, the HLH-2004 (HR per point increase: 1.435, 95% CI: 1.1012-2.086) and the Hscore (HR per point increase:1.011, 95% CI: 1.002-1.020) were independent predictors of 30-day-survival. The Hscore detected patients in hyperinflammatory states requiring urgent therapy escalation. Degrees of hyperinflammation, as assessed by ferritin and both HLH scores, are associated with worse outcomes.

Keywords: HLH; SIRS; hemophagocytic lymphohistiocytosis; hemophagocytosis; outcome; prevalence; survival.

Figure 1

Correlation between the HLH-2004 criteria and the Hscore; Boxplots of the corresponding score are displayed on the opposite side of the plot, r = Spearman rank correlation coefficient.

Figure 2

30-day and 1095-day survival with respect to ferritin.

Figure 3

Correlations between sCD25, sCD163 and Ferritin the studied HLH-scores; Boxplots of the corresponding score are displayed on the opposite side of the plot, r = Spearman rank correlation coefficient.