Identifying Hemophagocytic Lymphohistiocytosis and Describing Outcomes Using Computable Phenotypes: Retrospective Cohort Study

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that requires rapid diagnosis and intervention. However, identifying these patients is difficult because the HLH-2004 diagnostic criteria are complex and not always captured systematically in electronic health records (EHRs). Furthermore, it is unclear how clinicians use these criteria to diagnose HLH and make treatment decisions. There is a critical need for validated computable phenotypes to accurately identify patients and study treatment-related outcomes in HLH. Objective The aim of this study is to compare different approaches to using the EHR to build computable phenotypes of patients with HLH and to evaluate characteristics and outcomes of patients meeting the HLH-2004 diagnostic criteria who received HLH-directed therapies compared to those who did not. Methods Three approaches to computable phenotype development in the EHR were taken by identifying patients (1) with an HLH-specific International Statistical Classification of Diseases, Tenth Revision ( ICD-10 ) code, (2) with an HLH-specific treatment plan, and (3) meeting the HLH-2004 clinical criteria for diagnosis of HLH. Among patients who met the HLH-2004 criteria, we evaluated the characteristics and outcomes of patients who received HLH-directed therapies compared to those who did not. HLH treatment was defined as either any chemotherapy or HLH-specific therapy (dexamethasone, methylprednisolone, anakinra, ruxolitinib, cyclosporine, etoposide, or emapalumab). Results We identified 388 patients with possible HLH across the three cohorts. An HLH ICD-10 diagnosis (n=220) and meeting 5 or more clinical criteria (n=245) were much more common than a HLH treatment plan (n=42). Among the patients meeting HLH-2004 clinical criteria, 193 (79%) received HLH-directed therapy. There was no difference in any specific HLH criteria between those who did and did not receive HLH-directed therapy. In-hospital mortality was very high among both groups and was 15% among those who received HLH-directed therapy and 13.5% among those who did not receive HLH-directed therapy. Among 1325 patients with an elevated ferritin and fever, only 252 (19%) met >5 clinical criteria. Conclusions Constructing HLH cohorts from EHR data is challenging, with diagnosis codes, treatment plans, and clinical criteria each capturing distinct but overlapping populations.