Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, 2Department of Biomedical Science, College of Medicine, The Catholic University of Korea, Seoul, Korea, 3Department of Laboratory Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Background: Hemophagocytic lymphohistiocytosis (HLH) is a disease showing severe systemic inflammatory cascade which is life-threatening if not detected and treated appropriately. The diagnosis of HLH is confused due to other similar febrile diseases with cytopenia such as severe sepsis, autoimmune disease, and malignancies. Although decreased or absent natural-killer cell (NK) cytotoxicity is known as an important diagnostic parameter for pediatric HLH, the role for adult HLH is not elucidated well and also the significant level is not reported compared to other similar febrile diseases.

Aim: We tried to identify the initial level of NK cytotoxicity in several febrile diseases and find out the role for diagnosis of HLH in adult patients in related with several cytokine levels.

Methods: We prospectively enrolled 55 patients from 2015 to 2017. Adult patients older than 18 years with fever>38℃ presenting cytopenia in at least two lineages (neutrophil<1,000/㎕, platelet<100,000/㎕, Hemoglobin<9.0/dL) were firstly included. Patients with previously diagnosed hematological diseases were excluded. Diagnosis of HLH was based on HLH2004 criteria. Infection was managed according to the protocol and HLH-suspected patients were initially treated with 10mg/BSA of dexamethasone, and etoposide was considered if clinical improvement was not observed within 7 days after dexamethasone or immediately when the disease progression was observed. Patients other than HLH were treated with disease-specified therapies. NK cytotoxicity was calculated at diagnosis, 4 and 8 weeks after diagnosis by antibody-dependent Raji-cell cytotoxicity (ADCC) assay and K562-cell direct lysis using flow cytometry. Concomitantly, IL-2, IL-2R, IL-6, Interferon-gamma, TNF-alpha, and CXCR10 were calculated CD107a expression and NK-induced interferon gamma were also calculated at the same time point from diagnosis.

Results: HLH was diagnosed in 37 patients caused by viral infection (n=11), malignancies (n=7), autoimmune diseases (n=5), bacterial infection (n=2), malaria (n=1), anaplasmosis (n=1) and unknown origin (n=10). Febrile diseases other than HLH (n=18) were diagnosed with hematological diseases (n=8), infectious mononucleosis (n=2), rheumatologic disease associated macrophage activation syndromes (n=6), and unknown origin (n=2). The results of both K562 lysis and ADCC assay was well correlated (correlation coefficient = 0.684, 95%CI 0.512-0.804, P<0.001) but ROC curve analysis revealed diagnostic power for HLH was greater in ADCC assay with the level of lower than 23.7% (AUC=0.781, P<0.001) which was also related with poor initial steroid response. Median ADCC level was significantly lower in HLH (21.6% vs. 33.5%, P=0.039) and in HLH with poor dexamethasone response (17.0% vs. 33.4%, P<0.001). Among the calculated cytokines, only IL-2R was significantly elevated in patients with HLH (2856 vs 1098 U/mL, P=0.006), especially in patients with poor steroid response.

Conclusion: We identified that decreased NK cytotoxicity and elevated IL-2R are relevant diagnostic markers for diagnosis of secondary HLH also in adult patients. We also identified ADCC lower than 23.7% was predictable for severe HLH presenting poor treatment outcome.


Kim:BMS: Research Funding; Ilyang: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.