1974: Serial ferritin as a diagnostic surrogate marker in Hemophagocytic Lymphohistiocytosis (HLH), a retrospective single-center study

Background/Purpose: Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder characterized by cytokine dysregulation, resulting in multi-organ involvement and high mortality. (1-2) There is a time lag in the consideration of HLH diagnosis and initiation of treatment using HLH-2004 criteria. (1) There is a paucity of current literature to predict the ongoing cytokine storm in these patients, as it necessitates the analysis of soluble interleukin-2 receptor (sIL2r) and bone marrow biopsy, which has a delayed reporting time. Ferritin is a cost-effective and rapidly available biomarker. Our study in a tertiary center highlights the importance of periodic trending of ferritin levels in critically ill patients, which could be used as a surrogate for predicting patients who progress towards HLH and guiding the timely initiation of therapy.

Methods: After Institutional Review Board (IRB) approval, the electronic medical record (EMR) database was queried from 2016 to 2024 to identify patients ≥ 18 years, who were considered to have HLH during their hospital course. Patients were stratified into three groups based on the fulfillment of HLH-2004 criteria: those without HLH (≤ 3/8 criteria), probable HLH (4/8 criteria), and definitive HLH (≥ 5/8 criteria). A Retrospective EMR chart review was conducted. SAS software version 9.4 and R version 4.2.2 were used for the statistical analyses. Two-sample t-tests and Wilcoxon’s rank sum tests were used to compare continuous variables depending on whether the variable is normally distributed. Chi-square tests and Fisher’s exact tests were used for comparing categorical variables as appropriate. Receiver Operating Characteristic (ROC) curves were drawn, the Youden index was used to choose the best thresholds, and the DeLong method was used to calculate the confidence intervals on the area under the curve (AUC).

Results: We identified a total of 88 patients, with a mean age of 49 years, of whom 56 (63%) were males and 38 (43%) were Hispanics. (Table 1) This cohort was critically ill, 53 (60%) requiring intensive care unit, 22 (25%) new replacement kidney therapy and 37 (42%) mechanical ventilation.

Of these 88 patients, 59 were definitive HLH, 16 probable HLH and 13 without HLH. sIL2r is a highly specific marker with a high turnaround time, making its utility low in treatment initiation. Logistic regression analysis of sIL2r showed an odds ratio of 2.09 for in-hospital mortality (1.32-3.30 CI 95%; p-value 0.002). ROC analysis of ferritin levels (Figure 1) achieved a sensitivity of 89% at the time of considering the diagnosis, while a cut-off of 5000 ng/mL was associated with a high specificity of 91% in the first week of suspicion for HLH.

Conclusion: HLH-2004 criteria are not time-sensitive in managing these critically ill patients due to delays in reporting of sIL2r and bone marrow biopsy results. Our study emphasizes that periodically monitoring serial ferritin levels could serve as a valuable, cost-effective surrogate marker to sIL2r for the timely initiation of immunomodulator therapy and avoiding untoward patient outcomes.

References

(1) Hayden A, et al. Hemophagocytic syndromes (HPSs) including HLH in adults. Blood Rev (2016)

(2) Buyse S, et al. Intensive Care Med (2010)