High Mortality of HLH in ICU Regardless Etiology or Treatment

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.

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

“…Malignancy‐associated‐ and EBV‐positive HLH have historically demonstrated worse survival compared to those with autoimmune or non‐EBV infectious triggers, which may affect treatment outcomes 24–26 . However, as HLH mortality in the ICU is not influenced by underlying etiological triggers and ICU admissions were not drastically different across cohorts, this is less likely the case 27 . Finally, the criteria utilized for treatment response is not a validated tool in the assessment of HLH‐directed therapies so the general applicability of these findings may be limited.…”

B‑cell lymphoma‑associated hemophagocytic lymphohistiocytosis: A case report

“…Rarely, HLH precedes the diagnosis of the underlying malignancy ( 17 ). HLH carries a poor prognosis, but in the setting of a malignancy, the prognosis is worse regardless of the patient's age or intervention ( 6 ). A Swedish study reported all patients with malignancy-associated HLH died within of median time of 22 days (range 0–108) following diagnosis of HLH ( 18 ).…”

“…In HLH, there is a loss of this cytotoxic cell-mediated regulation, leading to excessive cytokine secretion, uncontrolled inflammation, multiple organ dysfunction, and failure ( 5 ). Mortality from HLH is very high approaching 60% among those treated in the intensive care unit, underscoring the importance of early diagnosis and aggressive intervention ( 6 ).…”

Did variants in inborn errors of immunity genes contribute to the extinction of Neanderthals?

“…This cytokine storm is thought to cause multi-organ failure in HLH ( 49 ). Patients with HLH usually have poor prognosis ( 50, 51 ), with the current treatments, mortality rates among HLH in adults are around 60% ( 52 ).…”