Modified soluble interleukin-2 receptor to ferritin ratio for diagnosis of lymphoma-associated hemophagocytic lymphohistiocytosis.

Abstract

e19115 Background: Lymphoma-associated hemophagocytic lymphohistiocytosis (L-HLH) has higher mortality than HLH due to other causes. Soluble IL-2 to ferritin ratio is thought to have diagnostic value in lymphoma-associated hemophagocytic lymphohistiocytosis with prior studies suggesting that high values are more suggestive of lymphoma as the underlying cause. However, its use is limited as it lacks generalizability. This is due to the heterogeneity of assays including differences in units and reference ranges. Methods: We used PUBMED, and Clinical Key for the literature search using keywords including HLH, and hemophagocytic lymphohistiocytosis for adult HLH cases that reported absolute sIL-2R and ferritin values with reference ranges with individual patient data. We introduced a modified soluble IL-2 to ferritin ratio, defined as multiples of sIL-2R above the upper limit of normal divided by multiples of ferritin above the upper limit of normal. We used receiver operating characteristic curve analysis to determine sensitivities and specificities. Results: Eighty-one studies with 97 patients met inclusion criteria, including 22 patients with L-HLH. The area under the ROC curve (AUC) for the modified ratio was 0.74 (95% CI, 0.62–0.87). An optimal cutoff value of 0.47 yielded a sensitivity of 59.09% and specificity of 81.33%. A higher cutoff (>1.68) demonstrated high specificity (90.67%) for L-HLH. The modified ratio performed better than sIL-2r or ferritin considered independently. Conclusions: The modified soluble IL-2 to ferritin ratio improves identification of L-HLH. Specificity is high at higher cutoff values. However, all included studies were case reports or case series, which limit clinical utility due to bias from case-based data. Prospective studies using standardized assays are needed to improve diagnostic accuracy. Distribution of ferritin and soluble IL-2 receptor values (expressed as multiples of the upper limit of normal) by etiology of hemophagocytic lymphohistiocytosis; values are shown as ranges. Pathology Ferritin / ULN (range) sIL-2R / ULN (range) Modified Ratio (range) Hodgkin lymphoma 21.7–127.1 2.3–24.5 0.02–0.38 T-cell lymphoma 1.7–1025.0 1.4–52.6 0.01–0.49 Diffuse large B-cell lymphoma 5.2–8.1 5.4–29.4 1.03–3.65 B-cell lymphoma (other) 4.3–11.6 8.1–10.3 0.89–1.90 Intravascular B-cell lymphoma 0.27–11.2 4.9–27.1 1.03–62.6 Chronic lymphocytic leukemia 83.2–492.4 1.3–5.7 0.00–0.03 Idiopathic HLH 7.6–320.0 1.0–29.4 0.01–2.99 Epstein–Barr virus 2.5–87.1 2.0–85.5 0.02–7.23 Cytomegalovirus 17.1–1004.0 4.1–4.3 0.00–0.24 Herpes simplex virus 11.7–886.7 5.1–17.9 0.01–0.44 Parvovirus B19 5.6–550.3 1.1–11.7 0.02–0.20 Tuberculosis 14.3–56.7 2.4–13.6 0.10–0.40 Histoplasmosis 106.7–134.2 6.3–25.6 0.06–0.19 Systemic lupus erythematosus 25.2–182.2 3.5–8.0 0.04–0.14 Still’s disease 32.9–234.3 2.2–25.7 0.05–0.11