Rising burden of hemophagocytic lymphohistiocytosis in the United States: A nationwide analysis of mortality, disparities, and underdiagnosis

Abstract

Abstract Title: Rising Burden of Hemophagocytic Lymphohistiocytosis in the United States: A Nationwide Analysis of Mortality, Disparities, and Underdiagnosis Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, often fatal hyperinflammatory syndrome characterized by excessive immune activation and multiorgan failure. Despite growing recognition, national patterns in HLH-related mortality and demographic disparities remain poorly defined. Methods: We conducted a retrospective analysis of HLH-related mortality in the United States from 1999 to 2020 using data from CDC WONDER. Crude and age-adjusted mortality rates (AAMR) per 100,000 population were calculated and stratified by year, age, sex, race, place of death, and urbanization. Results: A total of 2,724 HLH-related deaths were recorded from 1999 to 2020, with an overall AAMR of 0.0295 per 100,000. Males accounted for 59.0% of deaths, with a higher AAMR (0.0295) compared to females (0.0149). The age distribution revealed bimodal peaks in disease burden, among young children (ages <5, accounting for 18.2% of deaths) and older adults (ages 55–74, accounting for 32.4%). Racial analysis showed the majority of deaths occurred in White individuals (73.2%), followed by Hispanic (19.1%), Black or African Americans (17.4%), and Asian/Pacific Islander (8.3%) populations. The highest age-adjusted mortality rates were noted among Asian/Pacific Islanders (0.0514), Black or African Americans (0.0457), and Hispanic populations (0.0295), highlighting significant racial and ethnic disparities in HLH-associated mortality risk. Geographically, Utah reported the highest AAMR (0.0582), followed by Connecticut (0.0570) and Massachusetts (0.0433), while California recorded the largest number of deaths. Temporal analysis showed an increasing trend in mortality over two decades, with urban areas accounting for the majority of deaths, with 58.0% in large metropolitan areas. Most deaths occurred in inpatient medical facilities (90.2%). Conclusion: This study reveals a rising burden of HLH-related mortality in the United States. This analysis highlights significant disparities across various demographic categories, including race, sex, age, and geography. Although White individuals accounted for the majority of deaths, there are disproportionately high AAMRs among Asian, Black, and Hispanic populations, underscoring the need for targeted diagnostic awareness and access to timely care in vulnerable communities. The significantly higher impact on younger children and older adults demonstrates age-specific vulnerability, with males nearly twice as likely to be affected as females. The predominance of deaths occurring in urban areas and inpatient settings suggests a need for centralized disease recognition and resource utilization. Given the nearly 27-fold increase in mortality over the past two decades, these findings support the need for public health strategies aimed at improving early recognition, equitable access to treatment, and standardized reporting of HLH across healthcare settings, with increased awareness of HLH in historically underserved groups.