Background Hemophagocytic Lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome driven by uncontrolled activation of cytotoxic T cells and natural killer cells, often culminating in a fatal cytokine storm. Diagnosis remains a clinical challenge due to the absence of a single pathognomonic symptom or laboratory finding.

Although historically associated with pediatric populations, adults now account for approximately 40% of HLH cases. Outcomes vary widely; a systematic review of 82 studies (1975–2015) reported mortality rates ranging from 20.4% to 88%, with the lowest mortality observed in patients with autoimmune disease and the highest in those with malignancy, particularly lymphoma.

This study aims to deepen understanding of HLH by analyzing the frequency of its various triggers and associated inpatient outcomes.

Methods We analyzed the NIS database for hospitalizations with a primary diagnosis of HLH (I10_DX1, ICD-10 code D76.1) and identified those with a secondary diagnosis of hematologic malignancy. Logistic and linear regression models were used to identify predictors of in-hospital mortality and length of stay (LOS), respectively. A p-value <0.001 was considered statistically significant, and 95% confidence intervals (CIs) were reported.

Results A total of 733 HLH hospitalizations were identified, of which 12.9% (n=94) had an associated hematologic malignancy. Among these, the most common malignancies were non-Hodgkin lymphoma (55.3%), followed by acute lymphoblastic leukemia (17.0%), Hodgkin lymphoma (12.7%), multiple myeloma (10.8%), and acute myelocytic leukemia (4.2%). Other identified secondary causes of HLH included Epstein-Barr virus (9%), cytomegalovirus (6.4%), juvenile idiopathic arthritis (9.8%), systemic lupus erythematosus (3.8%), adult-onset Still's disease (2.3%), HIV (1.4%), Kawasaki disease (2.4%), and tuberculosis (0.3%).

Overall, 51.7% of HLH hospitalizations had an identifiable secondary cause, and the in-hospital mortality rate was 17%. The presence of a hematologic malignancy was associated with higher mortality rate of 29.7% (adjusted odds ratio [aOR] 2.06; CI: 1.26–2.88) and a longer LOS by an average of 7.2 days compared to those without malignancy. Common complications included acute kidney injury (50%), acute respiratory distress syndrome (29.8%), sepsis (27.7%), and neutropenia (19.2%).

No significant associations with mortality or LOS were found for race, income, gender, primary payer, hospital size, or insurance status.

Discussion This study represents the largest analysis of HLH hospitalizations in the NIS to date. The higher aOR of mortality observed in patients with an associated hematologic malignancy underscore the need for vigilant clinical recognition and timely intervention in this high-risk group. Notably, approximately 48.3% of HLH cases lacked a documented secondary cause, which may reflect cases of familial HLH (F-HLH), for which no specific ICD-10 code exists, or secondary causes that were not identified or coded during hospitalization. This distinction is important, as treatment strategies differ while both forms require control of hyperinflammation, patients with F-HLH generally require allogeneic hematopoietic stem cell transplantation after achieving disease control. Emerging therapies targeting interferon-γ, JAK-STAT, and IL-6 pathways show promise and may expand treatment options in the future.

This content is only available as a PDF.
2025
Sign in via your Institution