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Late Peaks of HMGB1 and Sepsis Outcome

Evidence For Synergy With Chronic Inflammatory Disorders

Karakike, Eleni*; Adami, Maria-Evangelia*; Lada, Malvina; Gkavogianni, Theologia*; Koutelidakis, Ioannis M.; Bauer, Michael§; Giamarellos-Bourboulis, Evangelos J.*,§; Tsangaris, Iraklis||

doi: 10.1097/SHK.0000000000001265
Clinical Science Aspects

ABSTRACT High mobility group box 1 (HMGB1) is released from macrophages as a late biomarker of sepsis. Conditions associated with pre-existing macrophage activation may modify HMGB1 expression. This study aimed to assess the impact of HMGB1 kinetics on 28-day mortality. In a sub-study of a previous randomized clinical trial among patients with systemic inflammatory response syndrome and gram-negative infections, patients were classified in early and late HMGB1 peak groups. Serial measurements of HMGB1, ferritin and interferon-gamma (IFNγ) were performed in all available sera. Two hundred ten patients were included; 118 (46.5%) had at least one inflammatory disease (diabetes, chronic obstructive pulmonary disease, chronic heart failure, or chronic renal disease). Mortality after 28 days was higher among patients with a late peak of HMGB1 (OR 2.640; P = 0.026). Co-existence of late peak and inflammatory disease synergistically impacted mortality (odds ratio of logistic regression analysis 3.17; P: 0.027). Late peak was concomitantly associated with higher values of ferritin (P = 0.035), and IFNγ (P = 0.002) among patients with hyperferritinemia. It is concluded that late HMGB1 peak was associated with worse prognosis, especially in patients with underlying chronic inflammatory conditions.

*4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece

2nd Department of Internal Medicine, Sismanogleion General Hospital, Athens, Greece

2nd Department of Surgery, Aristotle University of Thessaloniki, Medical School, Thessaloniki, Greece

§Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care, Jena University Hospital, Germany

||2nd Department of Critical Care Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece

Address reprint requests to Evangelos J. Giamarellos-Bourboulis, MD, PhD, Professor of Internal Medicine, 4th Department of Internal Medicine, ATTIKON University Hospital, 1 Rimini Street, 12462 Athens, Greece. E-mail:

Received 8 July, 2018

Revised 25 July, 2018

Accepted 11 September, 2018

EK, M-EA, EJG-B, and IT contributed equally to this work.

The study was funded by unrestricted educational grants provided by the Hellenic Institute for the Study of Sepsis, by the Horizon 2020 Marie Skłodowska-Curie Grant European Sepsis Academy (grant 676129) and by the German Federal Ministry for Education and Research via the Centre for Sepsis Control and Care integrated research and treatment center (grant 01EO1002).

EK is funded by the Horizon 2020 Marie Skłodowska-Curie Grant European Sepsis Academy (grant 676129 paid to the University of Athens).

EJG-B has received honoraria (paid to the University of Athens) from AbbVie USA, Abbott CH, Biotest Germany, Brahms GmbH, InflaRx GmbH, the Medicines Company; MSD Greece and XBiotech Inc. He has received independent educational grants from AbbVie, Abbott, Astellas Pharma, AxisShield, bioMérieux Inc, InflaRx GmbH, the Medicines Company and XBiotech Inc. He has received funding from the FrameWork 7 program HemoSpec and from the Horizon2020 Marie-Curie project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), outside the submitted work.

The other authors report no conflicts of interest.

© 2019 by the Shock Society