Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol

Lachmann, Gunnar; Knaak, Cornelia; Haefen, Clarissa von; Paeschke, Nadine; Meisel, Christian; Nyvlt, Peter; Schuster, Friederike S; Piper, Sophie K.; Kruppa, Jochen; Vorderwülbecke, Gerald; Balzer, Felix; Rosée, Paul La; Schenk, Thomas; Unterwalder, Nadine; Kölsch, Uwe; Lachmann, Nils; Akyüz, Levent; Brunkhorst, Frank M.; Volk, Hans‐Dieter; Keh, Didier; Spies, Claudia

doi:10.1136/bmjopen-2019-032695

Cited by 6 publications

(5 citation statements)

References 23 publications

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“…Yet, these findings need further confirmation in prospective studies to validate safe HLH diagnosis in adults with only 4 fulfilled HLH-2004 criteria. Ongoing studies could contribute to improve safe HLH diagnosis in adult critically ill patients [10].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Neutrophils recruitment by activated endothelial cells and release of neutrophil extracellular traps (NETs), in turn, further amplify the coagulation process. The early recognition of such a massive inflammatory process resembling that of MAS-HLH remains a diagnostic challenge and research focused on the potential diagnostic application of specific biomarkers apart from ferritin [ 83 ]. Soluble (s) CD163 is the soluble counterpart of the CD163 receptor for the haemoglobin–haptoglobin complex located on M2 macrophage cell membrane and represents a marker of M2 macrophage activation and differentiation.…”

Section: Ferritin In Inflammation and Viral Diseasesmentioning

confidence: 99%

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

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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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“…Nevertheless, as reported by the 2019 guideline 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 confirmed or presumed case of sepsis, it is important to exclude the diagnose of HLH (60). It is important to underline that viremia, as it has been demonstrated for DNAemia due to Herpes simplex type 1, human herpesvirus 6, Epstein-Barr virus, cytomegalovirus, and adenovirus, was associated with hyperferritinemia and adverse outcome in paediatric severe sepsis (61).…”

Section: Septic Shockmentioning

confidence: 99%

COVID-19 as part of the hyperferritinemic syndromes: is there a role for iron depletion therapy?

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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 syndromes 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 COVID-19 pandemic.

show abstract

Diagnostic biomarkers for adult haemophagocytic lymphohistiocytosis in critically ill patients (HEMICU): a prospective observational study protocol

Cited by 6 publications

References 23 publications

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

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

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

COVID-19 as part of the hyperferritinemic syndromes: is there a role for iron depletion therapy?

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