Recognizing Hemophagocytic Lymphohistiocytosis (HLH) in an Urban Population: Clinical Characteristics, Treatment Patterns, and Outcomes

ABSTRACT Introduction Hemophagocytic lymphohistiocytosis (HLH) is a life‐threatening hyperinflammatory syndrome with high mortality in adults. Diagnosis remains challenging due to nonspecific clinical features and overlap with sepsis, malignancy, and other inflammatory conditions. Data on HLH in underserved populations are limited. Methods We performed a retrospective cohort study of adult patients at a single urban tertiary care center from 2019–2025. Patients were identified using ICD‐10 codes for HLH and/or ferritin > 6000 ng/mL. Hscores and HLH‐2004 criteria were calculated to identify high‐probability cases. Patients were stratified into those diagnosed with HLH during hospitalization (Cohort 1) and those meeting criteria retrospectively without clinical recognition (Cohort 2). Results Among 273 patients screened, 68 were identified as high‐probability of HLH, defined as an Hscore > 169 and/or fulfillment of at least five HLH‐2004 diagnostic criteria. Twenty‐five patients met inclusion criteria after secondary review. Seventeen patients were included in Cohort 1 and eight in Cohort 2. Cohort 1 patients were younger (median age 34 vs. 62 years) and predominantly Black or Hispanic, with high rates of uninsured status and social vulnerability. HIV (42.1%), infection (29.4%), and malignancy (17.6%) were the most common triggers. HLH‐directed therapy was administered in 82% of Cohort 1; mortality was 52.9%. In contrast, Cohort 2 patients demonstrated similar laboratory features but were not clinically recognized, with a high mortality rate of 87.57%. Hematology consultation occurred in 100% of Cohort 1 compared to 62.5% of Cohort 2. Conclusion HLH is associated with high mortality and may be underrecognized in complex hospitalized patients, particularly older individuals with competing diagnoses. Early use of diagnostic tools such as the Hscore and prompt hematology consultation may improve recognition and outcomes, especially in high‐risk populations including those with HIV, malignancy, or severe infection. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.