Treatment and Mortality of Hemophagocytic Lymphohistiocytosis in Adult Critically Ill Patients: A Systematic Review With Pooled Analysis

Abstract

Objectives: Hemophagocytic lymphohistiocytosis is a cytokine release syndrome caused by uncontrolled immune activation resulting in multiple organ failure and death. In this systematic review, we aimed to analyze triggers, various treatment modalities, and mortality in critically ill adult hemophagocytic lymphohistiocytosis patients. Data Sources: MEDLINE database (PubMed) at October 20, 2019. Study Selection: Studies and case series of patients greater than or equal to 18 years old, of whom at least one had to be diagnosed with hemophagocytic lymphohistiocytosis and admitted to an ICU. Data Extraction: Source data of studies and case series were summarized and analyzed on an individual basis. Multivariable logistic regression analysis was performed adjusting for age, sex, and trigger groups. Each single treatment agent was entered as a dichotomous variable to determine treatments associated with survival, regardless if given alone or in combination. Data Synthesis: In total, 661 patients from 65 studies and case series were included. Overall mortality was 57.8%. Infections were the most frequent trigger (49.9%), followed by malignancies (28.0%), autoimmune diseases (12.1%), unknown triggers (9.4%), and drugs (0.6%). Treatment with IV immunoglobulins was associated with improved survival (odds ratio, 0.548; 95% CI, 0.337–0.891; p = 0.015), while treatment with cyclosporine was associated with increased risk of death (odds ratio, 7.571; 95% CI, 3.702–15.483; p < 0.001). Considering different trigger groups separately, same results occurred only for infection-triggered hemophagocytic lymphohistiocytosis. No information was available on disease severity and other confounding factors. Conclusions: Mortality of hemophagocytic lymphohistiocytosis in the ICU is high. Most common triggers were infections. Results of survival analyses may be biased by treatment indication and disease severity. Future studies prospectively investigating treatment tailored to critically ill hemophagocytic lymphohistiocytosis patients are highly warranted.

Features of hemophagocytic lymphohistiocytosis in the intensive care unit (ICU) : a 260-patient retrospective analysis

“…We con rmed the association between acquired HLH and a poor prognosis, frequent multiorgan failure, and a propensity for a background of immunosuppression. The high ICU mortality rate varied from 50 to 60%, in accordance with both the adult and pediatric literature [25,26]. Mortality risk factors included age and the severity of organ failure assessed by the SOFA score [27][28][29].…”

“…We report on one of the largest cohorts of ICU-acquired adult HLH [25]. Our retrospective ndings need to be con rmed by further studies, as the number of HLH diagnoses could have been underestimated (potentially incomplete medical coding) or overestimated (low speci city of HLH-2004 and HScore criteria).…”

Die hämophagozytische Lymphohistiozytose bei kritisch kranken Patienten

“…An die Stellung der Diagnose HLH anhand der genannten Kriterien schließt sichdie Suche nacheinem möglichenauslösenden Trigger an. Gemäß einer systematischen Übersichtsarbeit, in die 661 kritisch kranke erwachsene HLH-Patienten eingeschlossen wurden, stellen Infektionen (50 %), Malignome (28 %) und Autoimmunerkrankungen (12 %) auf der Intensivstation die häufigsten auslösenden Faktoren dar [14].…”

“…So lag die Mortalität unter HLH-Patienten, die auf einer Intensivstation behandelt wurden, gemäß einer kürzlich publizierten systematischen Übersichtsarbeit bei knapp 60 %, unterschied sich jedoch zwischen verschiedenen Patientengruppen in Abhängigkeit vom auslösenden Trigger. Am ungünstigsten war die Prognose bei Patienten mit malignomassoziierter HLH [14]. » Der JAK2-Inhibitor Ruxolitinib stellt eine weitere Therapieoption dar Eine laufende Studie untersucht bei Patienten mit sekundärer HLH den Interferon-γ-Antikörper Emapalumab (NCT03985423).…”

“…Triggers zur Remission der HLH führen. Zudem scheint der Einsatz von Immunglobulinen bei Patienten mit infektiös getriggerter HLH zu einer Verbesserung der Prognose zu führen[14].…”