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Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients.
Sci Rep. 2020 10 26; 10(1):18277.SR

Abstract

Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

Authors+Show Affiliations

School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. georg.lorenz@mri.tum.de. School of Medicine, Klinikum rechts der Isar, Division of Rheumatology, Ismaninger Straβe 22, 81675, Munich, Germany. georg.lorenz@mri.tum.de.School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. philipp.moog@mri.tum.de. School of Medicine, Klinikum rechts der Isar, Division of Rheumatology, Ismaninger Straβe 22, 81675, Munich, Germany. philipp.moog@mri.tum.de.School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. School of Medicine, Klinikum rechts der Isar, Division of Rheumatology, Ismaninger Straβe 22, 81675, Munich, Germany.Clinic for Internal Medicine II, Schwarzwald-Baar Klinikum Villingen-Schwenningen, Klinikstr. 11, 78052, Villingen-Schwenningen, Germany.School of Medicine, Klinikum rechts der Isar, Department for Clinical Chemistry, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, II. Department for Internal Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, II. Department for Internal Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, II. Department for Internal Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. Comprehensive Cancer Center Munich at the Klinikum rechts der Isar, Technische Universität München, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, II. Department for Internal Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, II. Department for Internal Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.School of Medicine, Klinikum rechts der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. German Center for Infectious Research (DZIF), Technische Universität München, 81675, Munich, Germany.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33106497

Citation

Lorenz, Georg, et al. "Title: Cytokine Release Syndrome Is Not Usually Caused By Secondary Hemophagocytic Lymphohistiocytosis in a Cohort of 19 Critically Ill COVID-19 Patients." Scientific Reports, vol. 10, no. 1, 2020, p. 18277.
Lorenz G, Moog P, Bachmann Q, et al. Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients. Sci Rep. 2020;10(1):18277.
Lorenz, G., Moog, P., Bachmann, Q., La Rosée, P., Schneider, H., Schlegl, M., Spinner, C., Heemann, U., Schmid, R. M., Algül, H., Lahmer, T., Huber, W., & Schmaderer, C. (2020). Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients. Scientific Reports, 10(1), 18277. https://doi.org/10.1038/s41598-020-75260-w
Lorenz G, et al. Title: Cytokine Release Syndrome Is Not Usually Caused By Secondary Hemophagocytic Lymphohistiocytosis in a Cohort of 19 Critically Ill COVID-19 Patients. Sci Rep. 2020 10 26;10(1):18277. PubMed PMID: 33106497.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients. AU - Lorenz,Georg, AU - Moog,Philipp, AU - Bachmann,Quirin, AU - La Rosée,Paul, AU - Schneider,Heike, AU - Schlegl,Michaela, AU - Spinner,Christoph, AU - Heemann,Uwe, AU - Schmid,Roland M, AU - Algül,Hana, AU - Lahmer,Tobias, AU - Huber,Wolfgang, AU - Schmaderer,Christoph, Y1 - 2020/10/26/ PY - 2020/05/23/received PY - 2020/10/05/accepted PY - 2020/10/27/entrez PY - 2020/10/28/pubmed PY - 2020/11/5/medline SP - 18277 EP - 18277 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/33106497/Title:_Cytokine_release_syndrome_is_not_usually_caused_by_secondary_hemophagocytic_lymphohistiocytosis_in_a_cohort_of_19_critically_ill_COVID_19_patients_ DB - PRIME DP - Unbound Medicine ER -