Hemophagocytic Lymphohistiocytosis in Critically Ill Patients

Knaak, Cornelia; Schuster, Friederike S; Spies, Claudia; Vorderwülbecke, Gerald; Nyvlt, Peter; Schenk, Thomas; Balzer, Felix; Rosée, Paul La; Janka, Gritta; Brunkhorst, Frank M.; Keh, Didier; Lachmann, Gunnar

doi:10.1097/shk.0000000000001454

Cited by 30 publications

(42 citation statements)

References 31 publications

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“…Most of the current research about serum ferritin are focused on its diagnostic abilities in HLH but not on its prognostic abilities. Although, hyperferritinemia has been reported to predict a poor prognostic outcome in adult malignancy-associated HLH [23,24], these studies were inadequately powered, restricted to a single subgroup or a small population [25]. Moreover, the prognostic value of serum ferritin for other subgroups of adult HLH patients remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis

Zhou

Shen

et al. 2020

Orphanet J Rare Dis

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Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical syndrome with high mortality rate. The diagnosis of HLH draws on a constellation of clinical and laboratory abnormalities including extremely high serum ferritin levels. However, no biomarker has been firmly established as a clinically useful prognostic tool in HLH patients. We aimed to perform a retrospective analysis of two independent cohorts to explore the prognostic value of discharge serum ferritin for newly diagnosed adult HLH patients who recently started treatment. The prognostic value of serum ferritin levels at discharge (will be called as post-treatment ferritin level) was initially evaluated in a "test cohort" of 161 previously untreated consecutive adult HLH patients. It was then validated in a second cohort of 68 consecutive previously untreated patients (validation cohort). Results: Multivariate analysis revealed that significantly high post-treatment serum ferritin levels (>1050 μg/L) were associated with a higher risk of death and poor overall survival in the test cohort (hazard ratio (HR): 3.176, 95% confidence interval (CI) 1.468-6.869, P = 0.003), and the validation cohort (HR: 13.412, 95%CI 1.716-104.816, P = 0.013). At 6-month follow-up period in the test cohort, patients with a > 81% decrease in the serum ferritin level had a significantly higher probability of survival when compared with the patients with ≥14% increase in the serum ferritin level (94% vs. 31%, P < 0.001). Similar findings were observed on the analysis of the decrease in the serum ferritin level in the validation cohort. Conclusions: These results suggest that the serum ferritin level can be used as an independent prognostic marker in the adult HLH patients.

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Section: Discussionmentioning

confidence: 99%

Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis

Zhou

Shen

et al. 2020

Orphanet J Rare Dis

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“…As reported by the 2019 guidelines of HLH, forms of sepsis characterized by a marked inflammation, but less than a proper form of HLH, may not fulfil the diagnostic criteria of HLH and are described as ‘MAS-like’. For this reason, in critically ill patients with a confirmed or presumed case of sepsis, it is important to exclude the diagnosis of HLH [ 61 ]. It is important to underline that viremia, as it has been demonstrated for DNAemia due to HSV type 1, human herpesvirus 6, EBV, CMV and adenovirus, was associated with hyperferritinemia and adverse outcome in paediatric severe sepsis [ 62 ].…”

Section: Hyperferritinemic Syndromementioning

confidence: 99%

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

et al. 2020

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SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still’s disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

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“…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]. The worsening of organ failure prior to the HLH diagnosis led to a worse prognosis (Delta SOFA).…”

Section: Discussionmentioning

confidence: 57%

“…Although variable and non-speci c, bone-marrow hemophagocytosis is still a hallmark HLH criterion [34][35][36] and was associated with a higher ICU mortality rate in our study. Among biological factors, non regenerative profound anemia and hypo brinogenemia have been reported to be independent predictors of a poor outcome [27][28][29]37]. The severity of cytopenia and coagulopathy have been shown to correlate with both the prognosis and TNF-a and IFN-g-mediated cytokine storm ares [2,3].…”

Section: Discussionmentioning

confidence: 99%

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

Bichon¹,

Bourenne²,

Allardet-Servent³

et al. 2021

Preprint

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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-acquired HLH in the ICU. 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 260 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-acquired HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology. 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.

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Hemophagocytic Lymphohistiocytosis in Critically Ill Patients

Cited by 30 publications

References 31 publications

Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis

Development and validation of the prognostic value of ferritin in adult patients with Hemophagocytic Lymphohistiocytosis

COVID-19 as part of the hyperferritinemic syndromes: the role of iron depletion therapy

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

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