A Minimal Parameter Set Facilitating Early Decision-making in the Diagnosis of Hemophagocytic Lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation syndrome characterized by uncontrolled immune cell activation. Timely diagnosis is important, since early treatment can improve survival rates. However, completing all assessments needed to reach ≥5 positive criteria out of the 8 HLH-2004 criteria can be time consuming and may delay timely initiation of treatment. Hence, we applied a data-driven approach to identify a minimal parameter set for early decision-making towards the initiation of HLH-specific treatment. We retrospectively evaluated 165 patients from five Dutch tertiary hospitals with suspected HLH. Sixteen pHLH (median age 0.5 years) and 70 sHLH patients (median age 8.7 years) were identified using the HLH-2004 criteria. Clustering analysis and multi-receiver operator characteristics were used to identify parameters distinctive of HLH. The presence of either increased ferritin, cytopenia in ≥2 lineages, or splenomegaly distinguished HLH from non-HLH cases with a negative predictive value of 100%. A minimal parameter set consisting of 2 major criteria (phagocytosis and splenomegaly) and 3 minor criteria (cytopenia, increased ferritin, and increased triglycerides/low fibrinogen) predicted HLH with 95% (88–99) sensitivity and 94% (86–98) specificity. This finding was replicated in an independent retrospective validation cohort of 109 US patients (n = 109). By dividing a subset of the HLH-2004 criteria into major and minor criteria, this strategy uses the evaluation of less than 5 criteria to quickly identify patients with HLH. When confirmed in a prospective setting, this approach could be of value for timely diagnosis and treatment of HLH.

Using a Minimal Parameter Set for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Non-European Children

“…To facilitate early diagnosis and treatment of HLH, simplified and rapid diagnostic criteria have been proposed [ 1 ]. A minimal parameter set was developed based on datasets from 5 medical centers in The Netherlands and validated by a dataset from Johns Hopkins Hospital.…”

“…Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease that requires rapid diagnosis and treatment. However, the HLH-2004 criteria include tissue biopsy and diagnostic assay for natural killer (NK) cell activity, both of which require time-consuming tests [ 1 ] that may be difficult to perform in a timely manner in clinical practice. In fact, a recent large case series study demonstrated that tissue biopsy was examined in 77 of 101 Egyptian children (76%) with HLH, while NK-cell activity was examined in 0 (0%) [ 2 ].…”

“…This diagnostic dilemma may be common around the world, particularly in facilities with limited clinical resources. To address this issue, a simplified and rapid prediction rule for the diagnosis of HLH has been proposed [ 1 ].…”

“…We recently encountered 2 cases of HLH, involving an Asian child and an African child. We used the clinical data from these cases to retrospectively evaluate the diagnostic utility of the HLH-2004 criteria [ 3 ] in comparison with a recently proposed rapid diagnostic rule of HLH, as a minimal parameter set [ 1 ], between 2 time points: on admission to our non-specialized center; and on transportation to a specialized tertiary center ( Table 1 ). Through this report of 2 cases, we evaluated the clinical utility of a minimal parameter set for early diagnosis of HLH in non-European populations.…”

Hemophagocytic Lymphohistiocytosis Secondary to Peripheral T Cell Lymphoma with Rapid Onset and Fatal Progression in a Young Patient: A Case Report and Review of the Literature

“…An interesting approach to the diagnosis of HLH was also presented by Smits et al [ 25 ]. The authors divided the HLH 04 criteria into 2 major (splenomegaly, presence of hemophagocytosis in tissue samples) and 3 minor (presence of >1 cytopenia, ferritin concentration >1000 µg/l, and a decrease in fibrinogen concentration with increased triglycerides).…”