Trends in Hemophagocytic Lymphohistiocytosis Incidence and Outcomes: A Nationwide Hospital-Based Analysis of 939 Hospitalizations
Authors: Rai Manoj , Bedi Prabhjot S , Kuruvila Arun , Arun Kumar Sumukh , Shatzel Joseph J. 
Published: December 2023

Background
Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder characterized by excessive activation and proliferation of histiocytes and lymphocytes in various organs resulting in excessive release of cytokines leading to dysfunction of natural killer and cytotoxic T-cell cells. Both infection and on occasion malignancies have been identified as a trigger in both sporadic HLH and genetically predisposed HLH. While more commonly reported in the pediatric population, HLH can also occur in adults. Consequently, the outcome data on adult HLH (aHLH) remains limited, highlighting a gap in understanding and presenting an opportunity for further research.
Methods:
We performed a retrospective analysis of the National Inpatient Sample (HCUP-NIS) 2011- 2018 Databases. We included hospitalizations with a principal diagnosis of HLH and an age greater than 18 years. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 288.4 was used to identify aHLH hospitalizations in the 2011 - 2014 database. ICD-10-CM diagnosis code D76.1 identified aHLH hospitalizations in the 2015 database. The primary outcome was in-hospital mortality. Secondary outcomes were total number of hospitalizations, mean hospitalization charges, percentage of HLH hospitalizations with associated diagnosis of Epstein-Barr Virus (EBV) or Lymphoma. The adjusted rates were estimated by identifying potential confounders using multivariate analysis (adjusted models). Statistical significance was set at p-value &lt; 0.01. Statistical tests were performed using STATA IC software. All analyses applied the HCUP-NIS weights.
Results:
Over an 8-year period from 2011 to 2018, we identified a total of 939 aHLH hospitalizations. The mean age was 28 years, with the most represented age group being 18-30 years (61.3%), followed by age 51-60 years (10.15%). The age group of 41-50 years accounted for the fewest hospitalizations, comprising 5.9% of the total. Males represented a larger proportion of the hospitalizations at 52.8 % compared to females at 47.12 %. The majority of patients are White (48.8%), followed by Hispanic (19.3%), Black (16.5%), Asian or Pacific Islander (8.5%), and Native American (1.16%). Other races accounted for 5.8% of the total. 59.6% were routine discharges but 7% were transferred to another acute care hospital. Our analysis revealed a steady increase in the number of aHLH hospitalizations over the span of 8 years (96 to 150). The mean length of stay was 19.4 days (17.6 - 21.09), with an significant downward trend in the length of stay from 2011 to 2018, with a parameter estimate of -0.08 (95% CI -0.09 to -0.07; p-value &lt;0.01). The mean hospitalization charges amounted to $ 275108, and we observed a statistically significant upward trend in these charges, marked by a coefficient of 1207 (95% CI 932 - 1483, p-value &lt;0.01). The mortality rate was 16%, we noted a downward trend in this rate, with an odds ratio (OR) of 0.93 (95% CI 0.92 to 0.93, p-value &lt;0.01). (See table). Additionally, 5.92% of aHLH hospitalizations were associated with the diagnosis of EBV, and 1.16% of aHLH hospitalizations were associated with lymphoma.
Discussion:
Our study, utilizing the NIS discharge dataset, uncovered a rising trend in the incidence of aHLH hospitalizations over an 8-year period. Concurrently, we observed a significant increase in the total hospital charges associated with aHLH hospitalizations. Intriguingly, despite these increases, we identified a downward trend in both the length of hospital stay and the mortality rate among aHLH cases during the study period. These findings may indicate that aHLH is being diagnosed earlier and managed more effectively, reflecting potential improvements in care and treatment strategies.