High Mortality of HLH in ICU Regardless Etiology or Treatment.

Amandine Bichon,Gilles Kaplanski,Laurent Papazian,Sami Hraiech,Vanessa Pauly,Julien Carvelli,Djamel Mokart,Jérôme Allardet-Servent,Jérémy Bourenne,Christophe Guervilly,Marc Gainnier

doi:10.3389/fmed.2021.735796

Abstract

Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population.Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH.Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% (n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16–1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21–1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28–1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11–24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09–1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04–1.41], p = 0.02).Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated.

Highlights

Adult hemophagocytic lymphohistiocytosis (HLH) can be defined as the most extreme form of the inflammatory process continuum
By defining the prognostic factors associated with ICU mortality, we focus on patients for whom their condition constitutes a diagnostic and therapeutic emergency
Severity was assessed using the Sepsis-related Organ Failure Assessment (SOFA) score, ranging from 0 to 24, with higher scores indicating a higher severity of organ failure [24], at ICU admission and again at HLH diagnosis

Summary

Introduction

Adult hemophagocytic lymphohistiocytosis (HLH) can be defined as the most extreme form of the inflammatory process continuum. Diagnostic criteria for HLH include clinical parameters (fever, adenopathy, splenomegaly, hepatomegaly) and biological variables (cytopenia, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia), these criteria are non-specific and may be inappropriate, as they are extrapolated from the pediatric population [4]. Pediatric primary HLH is mostly caused by genetic mutations in genes involved in lymphocyte cytotoxicity [5,6,7,8]. The analysis of adult HLH has highlighted the absence of a lymphocyte cytotoxicity defect [9]. Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population

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Conclusion