Background: Hemophagocytic Lymphohistiocytosis (HLH) is an immune hyperactivation disease characterized by widespread multiorgan damage and subsequent high mortality rates between 50% to 70%. Mortality has improved in recent years with the introduction of immunosuppressive therapeutic interventions, but the identification of risk factors of disease remains a challenge given the rarity of HLH. Development of novel treatment options, especially monoclonal antibody-based immunotherapies, has highlighted the need for a more comprehensive understanding of this condition. This retrospective cohort study aims to address this gap by leveraging real-world data within the tertiary university system to explore the most relevant risk factors for length of hospital stay and mortality in HLH, thus advancing our knowledge of this rare but life-threatening syndrome.

Methods: We utilized the Virtual Data Warehouse to identify all patients hospitalized at the SSM Health Saint Louis University Hospital diagnosed with HLH between 2018 and 2023. Inclusion criteria required patients to be ≥18 years of age and to have had at least one ambulatory visit within the two years preceding hospitalization. Demographic variables collected included age, sex, race, and Charlson Comorbidity Index (CCI), excluding malignancy and rheumatologic conditions. Hospitalization characteristics such as diagnostic procedures, treatments, and complications during the inpatient stay were also collected. The primary outcomes were inpatient mortality and length of hospital stay. Logistic regression using Firth's penalized likelihood method was used to evaluate predictors of mortality, and negative binomial regression was used to assess factors associated with hospital length of stay.

Results: A total of 105 patients were identified. The mean age was 57.2 years (SD 16.2), with similar proportions of female (45.7%) and male (54.3%) patients. The cohort was mainly White (72.4%) and noted to have a pre-existing history of autoimmune disease (17/105) and malignancy (34/105). Median length of inpatient stay was 4 days (IQR 2–9), with 43.8% of patients treated with steroids and 6.7% treated with immunosuppressive therapy while hospitalized. Upon discharge, about half the cohort (49.5%) was sent home, while 10.5% (11/105) experienced inpatient mortality. While CCI, gender, or age did not significantly affect inpatient mortality, elevated ferritin above 500 (OR 10.36, 95% CI: 2.71–57.03), low fibrinogen (OR 1.45, 95% CI: 0.15–7.54), and cytopenia (OR 6.17, 95% CI: 1.36–58.77) were predictive of inpatient mortality. When adjusted for confounders, elevated ferritin levels remained statistically significant for increased length of hospital stay (aRR 1.77, 95% CI: 1.27–2.48), and Black patients were more likely to have increased length of stay (aRR 1.48, 95% CI: 1.06–2.07).

Conclusion: This real-world cohort of HLH patients reveals that elevated ferritin levels (>500) are strongly predictive of both inpatient mortality and prolonged hospitalization, underscoring ferritin as a key early biomarker of disease severity. Additionally, cytopenias significantly predicted mortality risk. Importantly, our findings also expose racial disparities, with Black patients experiencing extended hospital stays even after adjusting for confounders. These results emphasize the need for early risk stratification and targeted interventions to improve HLH outcomes. Future studies should incorporate prospective data and chart-level review to validate these risk markers and address healthcare inequities in HLH care.

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2025
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