Hemophagocytic lymphohistiocytosis in critically ill patients: diagnostic reliability of HLH-2004 criteria and HScore

Abstract

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare though often fatal hyperinflammatory syndrome mimicking sepsis in the critically ill. Diagnosis relies on the HLH-2004 criteria and HScore, both of which have been developed in pediatric or adult non-critically ill patients, respectively. Therefore, we aimed to determine the sensitivity and specificity of HLH-2004 criteria and HScore in a cohort of adult critically ill patients. Methods In this further analysis of a retrospective observational study, patients ≥ 18 years admitted to at least one adult ICU at Charité – Universitätsmedizin Berlin between January 2006 and August 2018 with hyperferritinemia of ≥ 500 μg/L were included. Patients’ charts were reviewed for clinically diagnosed or suspected HLH. Receiver operating characteristics (ROC) analysis was performed to determine prediction accuracy. Results In total, 2623 patients with hyperferritinemia were included, of whom 40 patients had HLH. We found the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria (95.0% sensitivity and 93.6% specificity) and HScore cutoff of 168 (100% sensitivity and 94.1% specificity). By adjusting HLH-2004 criteria cutoffs of both hyperferritinemia to 3000 μg/L and fever to 38.2 °C, sensitivity and specificity increased to 97.5% and 96.1%, respectively. Both a higher number of fulfilled HLH-2004 criteria [OR 1.513 (95% CI 1.372–1.667); p < 0.001] and a higher HScore [OR 1.011 (95% CI 1.009–1.013); p < 0.001] were significantly associated with in-hospital mortality. Conclusions An HScore cutoff of 168 revealed a sensitivity of 100% and a specificity of 94.1%, thereby providing slightly superior diagnostic accuracy compared to HLH-2004 criteria. Both HLH-2004 criteria and HScore proved to be of good diagnostic accuracy and consequently might be used for HLH diagnosis in critically ill patients. Clinical trial registration The study was registered with www.ClinicalTrials.gov (NCT02854943) on August 1, 2016.

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“…However, there are several challenges in diagnosis of sHLH. In this study, HScore was used to confirm the diagnosis of sHLH [19] , which revealed a sensitivity of 100% and a specificity of 94.1% with a cutoff of 168 [20] . HLH-2004 diagnostic criteria were not used because they are developed for children but not validated for adults [6] .…”

Secondary Hemophagocytic Lymphohistiocytosis and Autoimmune Cytopenias: Case Description and Review of the Literature

“…In the described cases, features suggestive for HLH developed subacutely and were confounded by the presence of AIC and sepsis. A peculiar setting is that of ICU, where a recent study investigating 40 HLH patients out of 2623 displaying hyperferritinemia indicated that ferritin >3000 mcg/L and an HScore cutoff of 168 were the most sensitive and specific criteria [ 60 ].…”

Die hämophagozytische Lymphohistiozytose bei kritisch kranken Patienten

“…Sensitivität und Spezifität der HLH-Kriterien wurden hauptsächlich bei pädiatrischen Patienten untersucht. Es gibt jedoch auch Untersuchungen bei kritisch kranken erwachsenen Patienten, die eine Sensitivität zwischen 70 % und 95 % sowie eine Spezifität zwischen 90 % und 93,6 % zeigten [ 13 , 22 ].…”

“…Für den HScore werden die einzelnen Faktoren jedoch nicht nur qualitativ, sondern auch quantitativ berücksichtigt [ 4 , 5 ]. Wird im HScore ein Cut-off-Wert von 168 gesetzt, konnte für kritisch kranke erwachsene Patienten eine Sensitivität von 100 % und eine Spezifität von 94,1 % im Hinblick auf die Diagnose einer HLH gezeigt werden [ 13 ]. Auf der Intensivstation kommt zudem dem Ferritinwert als Screening- und Verlaufsparameter besondere Bedeutung zu [ 15 , 19 ].…”