Lachmann Gunnar, Heeren Patrick, Schuster Friederike S, Nyvlt Peter, Spies Claudia, Feinkohl Insa, Schenk Thomas, Ammouri Wafa, Debaugnies France, Galicier Lionel, Jia Yuan, Meena Nikhil, Nagant Carole, Neth Olaf, Nierkens Stefan, San Martin Juan, Sun Hao Wei Linda, Wang Yini, Wang Zhao, Yoon Jae-Ho, Brunkhorst Frank M, La Rosée Paul, Janka Gritta, Lachmann Cornelia
Department of Anesthesiology and Intensive Care Medicine (CCM, CVK), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany.
J Intern Med. 2025 Mar;297(3):312-327. doi: 10.1111/joim.20065. Epub 2025 Jan 27.
Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach.
We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search.
The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500 µg/L had 94.0% mean sensitivity over all cohorts.
In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.
五例符合噬血细胞性淋巴组织细胞增生症（HLH）-2004标准，HScore被广泛应用且得到国际专家共识推荐用于诊断继发性HLH。这两种诊断评分从未在继发性HLH患者的异质性队列中得到验证。我们旨在采用多中心方法系统地优化和验证继发性HLH的诊断标准。
第一步，我们在危重症患者队列中制定优化标准。接下来，我们使用通过系统文献检索确定的13个已发表队列的原始数据，将这些新标准与原始和修订后的HLH-2004标准以及HScore一起进行验证。
在所有13个验证队列中表现最佳的HLH诊断标准集是截断值降低的原始HLH-2004标准（截断值4，平均敏感性86.5%，平均特异性86.1%），其次是修订后的HLH-2004标准（去除自然杀伤细胞活性；截断值4，平均敏感性83.8%，平均特异性87.8%）和HScore（截断值169，平均敏感性82.4%，平均特异性87.6%）。我们新制定的HLH诊断标准表现较差。铁蛋白≥500μg/L在所有队列中的平均敏感性为94.0%。
在这项首次多中心验证研究中，四项符合HLH-2004标准且HScore为169适用于诊断继发性HLH，这将有助于快速诊断并改善患者预后。铁蛋白被证明是一种可靠的HLH筛查标志物。我们的结果应在临床建议和设计新研究时予以考虑。
