Epidemiology, characteristics, and outcomes of adult haemophagocytic lymphohistiocytosis in the USA, 2006-19: a national, retrospective cohort study

Abstract

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by an excessive inflammatory response. Limited data exist on adult HLH.

Methods: In this national, retrospective cohort study, we analysed data from the US National Inpatient Sample database collected between October 1, 2006 and December 31, 2019. Using the International Classification of Diseases (ICD) codes, we identified all adult patients who were admitted non-electively with the diagnosis of HLH. We described demographic characteristics, triggers, and associated conditions. Trends of diagnosis, treatment, and in-hospital mortality were analysed using joinpoint models. In-hospital mortality rates were compared using multivariable logistic regression models that adjusted for demographic characteristics and associated conditions. Finally, we described resource utilization outcomes including cost of hospitalization and length of stay.

Findings: We identified 16,136 non-elective adult HLH admissions. The population pyramid showed a bimodal distribution, with peaks in young adults (16-30 years) and older adults (56-70 years). Joinpoint regression analysis revealed a significant increase in HLH incidence per 100,000 admissions over the study period (Average Annual Percent Change [APC] = 25.3%, p < 0.0001), and no significant change in rates of in-hospital mortality (slope = -0.01; p = 0.95) or administration of in-hospital HLH treatment (slope = 0.46, p = 0.20). The most common associated conditions were malignancy (4953 admissions [30.7%]), infections (3913 admissions [24.3%]), autoimmune conditions (3362 admissions [20.8%]), organ transplant status (639 admissions [4%]), and congenital immunodeficiency syndromes (399 admissions [2.5%]). In-hospital mortality was higher in older adults and males. Furthermore, Congenital immunodeficiency syndromes had the worst in-hospital mortality rate (mortality rate 31.1%, adjusted OR 2.36 [1.56-3.59]), followed by malignancies (mortality rate 28.4%, adjusted OR 1.80 [1.46-2.22]), infections (mortality rate 21.4%, adjusted OR 1.33 [1.10-1.62]), other/no trigger (mortality rate 13.6%, adjusted OR 0.73 [0.58-0.92]), autoimmune (mortality rate 13%, adjusted OR 0.72 [0.57-0.92]), and post-organ transplant status (mortality rate 14.1%, adjusted OR 0.64 [0.43-0.97]). The overall mean length of stay was 14.3 ± 13.9 days, and the mean cost of hospitalization was $54,900 ± 59,800.

Interpretation: We provide insight into the burden of adult HLH in the USA. The incidence has been increasing and the outcomes remain dismal. This signifies the growing need for the development of updated diagnosis and treatment protocols that are specific to adult HLH.

Funding: None.

Keywords: Cancer epidemiology; Haemophagocytic lymphohistiocytosis; National Inpatient Sample.

Fig. 1

Sampling process, exclusion criteria, and number of hospitalizations in each step. NIS, National Inpatient Sample.

Fig. 2

Population pyramid showing patient distribution across different age and sex groups.

Fig. 3

Geographic distribution of adult HLH cases by hospital region.

Fig. 4

List of triggers and associated diseases. 1. Chronic myeloid leukemia (CML) is counted in myeloid leukemias. 2. The list of bacterial pathogens is not inclusive; many pathogens (e.g, gram positive bacteria, E. coli, pseudomonas, opportunistic fungi) were not included either due to lack of specific coding, clinical irrelevance, or concern that they could be nosocomially acquired. 3. Include Coccidioides, Paracoccidioides, and Blastomyces. Created with BioRender.com.

Fig. 5

Trends and annual percentage changes. (a) Adult HLH rate per 100,000 admissions; (b) Rate of in-hospital mortality; (c) Rate of in-hospital HLH treatment; (d) Mean time to in-hospital treatment. APC, Annual Percent Change.

Fig. 6

In-hospital mortality rates and adjusted odds for different demographic groups and associated conditions. ∗Includes coccidioides, Paracoccidioides, and blastomycosis. ^†Includes polycythemia vera, essential thrombocythemia, and myelofibrosis. Chronic myeloid leukemia was counted in leukemias. OR, odds ratio; CI, confidence interval; EBV, Epstein–Barr virus; CMV, Cytomegalovirus; HIV, human immunodeficiency virus; TB, tuberculosis; NHL, non-Hodgkin lymphoma; HL, Hodgkin lymphoma; MPD, Myeloproliferative diseases; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis.