Temporal trends of mortality, associated conditions, hospitalizations, and costsrelated to hemophagocytic lymphohistiocytosis in the US.

Abstract

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition that triggers an inflammatory cascade which leads to multi organ dysfunction and carries a high risk of mortality. Because of its severity, patients need to be hospitalized for an extended period to receive multidisciplinary care. Herein, we report the outcomes of hospitalized patients and evaluate the temporal trends and mortality risks associated with specific underlying conditions Methods: We analyzed data from the National Inpatient Sample (NIS) database between 2011 and 2022. We identified all adult patients who were admitted with the diagnosis of HLH using the appropriate International Classification of Diseases (ICD) codes. We described demographic characteristics, associated conditions and trends of in- hospital mortality and resource utilization. Multivariable regression models were utilized to estimate the in-hospital mortality rates adjusted for demographic variables and associated conditions. Finally, we estimated the trends of resource utilizations including cost of hospitalization and length of stay. Results: We identified 6,228 adult HLH admissions between 2011 and 2022. The majority of the patients were White (55.5%) and male (53.9%). The median age was 52.0 (IQR: 31) years. The population pyramid showed a bimodal distribution, with peaks among young adults aged 18 – 44 years (38.1%), and middle-aged adults 45 – 64 years (35.0%). The most common associated conditions were malignancies (1,888 admissions, 30.3%), infections (1,776 admissions, 28.5%), autoimmune conditions (1,002 admissions, 16.1%), organ transplant status (383 admissions, 6.2%), and congenital immunodeficiency syndromes (198 admissions, 3.2%). The absolute number of admissions for HLH showed an increasing trend from 166 in 2011 to 795 in 2022 (P < 0.001). The overall mean length of stay was 14.0 ± 16.6 days and showed minimal increase from 13.98 days in 2011 to 14.15 days in 2022 (p=0.999). There was an increase in the absolute number of mortality cases from 23 deaths in 2011 to 147 deaths in 2022, but this was not statistically significant (nptrends = 1.27, p = 0.203). At the same time there was a non-statistically significant increase in overall mortality rate over the same period from 15.5% in 2011 to 18.5% in 2022 (p=0.077), with a peak mortality rate of 22.1% in 2020. Infections had the worst in-hospital mortality rate of 25.6% (OR: 2.17, 95% CI: 1.87 – 2.52, p<0.001), followed by malignancies at 24.8% (OR: 1.82, 95% CI: 1.56 – 2.11, p<0.001), and post-organ transplant status with a rate of 24.5% (OR: 1.56, 95% CI: 1.19 – 2.03, p=0.001). The mortality rates for autoimmune conditions, 14.0% (OR: 1.04, 95% CI 0.83 – 1.29, p=0.744), and that for congenital immunodeficiency syndromes, 21.7% (OR: 1.16, 95% CI: 0.77 – 1.75, p=0.472) were not statistically significant. The temporal trends of mortality associated with each of the specific conditions showed significant variations. While the number of mortality cases associated with infections showed significant upward trends over the years (nptrends = 2.43, p=0.015), mortality associated with congenital immunodeficiency syndromes showed significant downward temporal trend (nptrend = -2.41, p=0.016). The trends of mortality associated with malignancies (nptrends = - 0.64, p=0.524), post-organ transplant status (nptrends = 0.15, p=0.880), and autoimmune conditions (nptrends = 1.0, p=0.316) did not show any significant trends. Majority of the mortality associated with infections was driven by covid-19 infection, which had the worst mortality rate of 35.6% (OR: 3.32, 95% CI: 2.67 – 4.12, p<0.001). The mean cost of hospitalization for HLH increased between 2011 and 2022. After adjusting for inflation, mean hospital charges per patient increased by 43.3%, from $188,178.06 in 2011 to $331,916.30 in 2022 (P < 0.001). The overall mean cost of hospitalization during the study period was $231,403 ± 433,478. Conclusions: The incidence HLH in the US has been increasing with a corresponding increase in healthcare resource utilizations, but outcomes remain poor especially when there is an associated infection. This underscores the growing need for the development of novel and/or improved treatment options for HLH.