Introduction:

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by uncontrolled immune activation and overproduction of inflammatory cytokines. One of the most widely used diagnostic guidelines is the HLH-2004 criteria, which requires at least five of the following eight findings: fever, splenomegaly, cytopenia (affecting ≥2 of 3 peripheral blood lineages), hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis in the bone marrow, spleen, or lymph nodes, low or absent NK cell activity, ferritin >500 ng/mL, and a soluble interleukin-2 receptor (sIL-2R) >2400 U/mL (Henter et al., 2007).

Despite these guidelines, diagnosis can be challenging due to the nonspecific nature of presenting features and laboratory findings. Additionally, the HLH-2004 criteria were originally developed in pediatric populations with primary (genetic) HLH. This may limit its application in adult patients, who commonly present with secondary (acquired) HLH, due to infections, malignancies, or autoimmune diseases.

Among the HLH-2004 criteria, elevated sIL-2R has emerged as a promising marker due to its ease of measurement and utility in identifying immune dysregulation, as it reflects T cell activation. However, limited literature exists on its diagnostic performance in adult HLH cases. We aim to evaluate the clinical utility of sIL-2R testing in this population and to assess whether this marker can aid in earlier recognition and appropriate management of HLH in adults.

Methods:

Following IRB approval, a retrospective electronic health record review was conducted for all adult patients (age >18) who had a soluble interleukin-2 receptor lab ordered during hospital admission between January 2020-April 2025 at Baylor University Medical Center. Charts without hematology consultation were excluded. Diagnosis of HLH was made based on the HLH-2004 criteria and clinical judgement. Indeterminate cases were included with the negative patients for analysis.

To evaluate the diagnostic performance of sIL-2R, sensitivity and specificity were calculated using a cutoff value of >2400 U/mL and >4800 U/mL. Sensitivity and specificity were reported with 95% confidence intervals calculated using the Clopper-Pearson exact method.

Results:

A total of 75 patients were included: 27 with confirmed HLH, 33 without HLH, and 15 indeterminate cases (typically due to death before full diagnostic evaluation), which were analyzed with the non-HLH cohort. All confirmed HLH cases were secondary in origin, most commonly due to infection (EBV, CMV, COVID-19), malignancy (often diffuse large B-cell lymphoma), GVHD, or autoimmune conditions (SLE, dermatomyositis, Adult-onset Still's disease). Non-HLH diagnoses included septic shock, acute liver failure, and similar autoimmune or malignancy-associated syndromes.

The mean sIL-2R level in HLH-positive patients was 19,872 U/mL (median 5,273), compared to 13,246 U/mL (median 3,654) in the non-HLH group.

Using the HLH-2004 threshold of >2400 U/mL, sensitivity was 88.9% (95% CI: 0.71-0.98) and specificity 29.2% (95% CI: 0.17-0.44). The positive predictive value (PPV) was 41.4% (95% CI: 0.29-0.55), and the negative predictive value (NPV) was 82.4% (95% CI: 0.57-0.96). Raising the cutoff to >4800 U/mL reduced sensitivity to 59.3% (95% CI: 0.39-0.78) but improved specificity to 54.2% (95% CI: 0.39-0.69).

Conclusion:

Our study demonstrates that soluble IL-2 receptor (sIL-2R), when applied using the HLH-2004 criteria in adults, serves better as a tool to rule out HLH rather than confirm it. Although sIL-2R levels were elevated in confirmed HLH cases, they were similarly elevated in many non-HLH patients, limiting its specificity and correlation with underlying etiology. Notably, all confirmed cases of HLH in our study cohort were found to be secondary to an alternative, underlying etiology. These findings highlight the importance of a thorough evaluation for secondary causes to guide appropriate diagnosis and therapy. In addition, they underscore the need for adult-specific diagnostic criteria.

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2025
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