Increased age-adjusted mortality rates from hemophagocytic lymphohistiocytosis (HLH), 2010-2023

Abstract Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome leading to multiorgan failure and death if not treated promptly. Although mortality in primary HLH has improved since the first HLH-94 diagnostic criteria were published (5-year survival of 50% in 1994, 59% in 2004, 3-year survival of 79% from 2016-2021), most cases in adults are secondary to infection, malignancy or autoimmunity (La Rosèe et. al., 2024). Although treatment options have expanded to include etoposide, anakinra, emapalumab, ruxolitinib and intravenous immunoglobulin therapy, and sometimes cyclosporins in patients with an autoimmune trigger, known as macrophage activation syndrome (MAS), secondary HLH itself remains underdiagnosed (Henter, 2025). Recent population-level analyses indicate a rising incidence and mortality rate of HLH among adults, and mortality remains high in hospitalized populations (Bichon et. al., 2021). Whether this reflects improved diagnostic recognition, improved survival times after autologous stem cell transplantation or a true rise in HLH-associated mortality remains unclear (Löfstedt et. al., 2024). We conducted a population-level analysis of age-adjusted mortality rates (AAMR) for adult HLH in the United states from 2010 to 2023 stratified by census region, sex and race. Methods: AAMRs from 2010 to 2023 in the United States were exported from the CDC WONDER database, specifically the “underlying cause of death” function, using the ICD codes D76.1 (Hemophagocytic Lymphohistiocytosis), the ICD codes D76.0, D76.2 AND D76.3 (Langerhans Cell Histiocytosis, Hemophagocytic Syndrome, Infection-Associated, and Other Histiocytosis Syndromes), and the ICD code D89.8 (Other Specified Disorders Involving the Immune Mechanism) which encompasses GvHD. Standard errors for death rates were calculated using the CDC WONDER functionality. AAMRs were reported as deaths per 1,000,000 population. Data was limited to patients 25 years or older at the time of death to enable stratification by 10-year cohort while limiting cases to HLH in adults. Results: There was a significant increase in the AAMR per 1,000,000 associated with HLH from 2010 (0.1106) to 2023 (1.3224) and a consistent increase between every year. When stratified by census region, these trends were again demonstrated in each region from 2013 to 2023. The AAMR per 1,000,000 increased in the Northeast from 2014 (0.5448) to 2023 (1.5969), in the Midwest from 2013 (0.5776) to 2023 (1.4584), in the South from 2013 (0.3003) to 2023 (1.1951), and in the West from 2013 (0.4295) to 2023 (1.3688). Males demonstrated a significant increase from 2018 (1.5718) to 2023 (2.4634) and females also demonstrated the same from 2018 (0.9433) to 2023 (1.4361). Whites demonstrated a significant increase from 2013 (0.3813) to 2023 (1.1534), Blacks demonstrated the same from 2015 (0.7381) to 2023 (2.0433), and Asians demonstrated an increase from 2020 (1.5591) to 2023 (1.9040) that was not statistically significant. The rest of the D76 cluster (Langerhans Cell Histiocytosis, Infection-Associated HLH and Other Histiocytosis Syndromes) including MAS did not demonstrate any consistent trend, with a significant overall increase from 1999 (0.1121) to 2010 (0.2020) and a minimal but significant increase from 2010 to 2023 (0.2077). GvHD did not show any consistent pattern from 2020 (0.195) to 2024 (0.195). Conclusions: There was a nearly linear increase in the AAMR per 1,000,000 from HLH between 2010 and 2023. We compared this to the rest of the D76 cluster, which demonstrated a significant increase in AAMR over the same time period. GvHD did not demonstrate any consistent pattern over the years that were available. We examined some stratifying factors like census region, sex and race and found a consistent pattern of increased AAMR across all dimensions. Although the AAMR remains highest in the Black population, the ratio of the White to Black AAMR in 2015 (0.6073), the first year in which this comparison could be made, has remained largely unchanged through 2023 (0.5645). Although there is a consistent pattern of higher AAMR in males, the ratio of female to male AAMR has increased from 2013 (0.4017) to 2023 (0.5434). In sum, there has been a significant and consistent increase in age-adjusted HLH deaths per 1,000,000 from 2010 to 2023, and this has occurred alongside a disproportionately larger increase in recorded deaths among women from 2013 to 2023.