de Lange, Dylan W

Kemperman, Hans

Kesecioglu, Jozef

Roest, Mark

Schrijver, Irene T

Utrecht University Repository

RESEARCH LETTER Open AccessBeta-2-glycoprotein I as a biomarker forsepsis in critically ill patients in theintensive care unit: a prospective cohortstudyIrene T. Schrijver1* , Hans Kemperman2, Mark Roest3, Jozef Kesecioglu1 and Dylan W. de Lange1,4Keywords: B2GPI, Biomarkers, Sepsis, Critical care, ICU, SIRS, Apolipoprotein HTo the editor,It is difficult to diagnose sepsis in critically ill patientsadmitted to the intensive care unit (ICU). A biomarkercould help in sepsis identification and guide antibioticuse. A prognostic biomarker that identifies high-risk pa-tients for the development of sepsis or nosocomial infec-tions could help prevent those outcomes. However,current sepsis biomarkers often portray systemic inflam-mation and are unspecific to infection [1].The complement system is essential for defendingagainst infections, yet it can also contribute to severe sep-sis outcomes [2]. A potential complement regulator isbeta-2-glycoprotein I (B2GPI). B2GPI, also known as apo-lipoprotein H, exerts a complement control after bindingto specific surfaces such as apoptotic cells and bacteria.After the conformational change of B2GPI, monocytescan clear B2GPI, resulting in lower B2GPI plasma levels.Supporting this, previous studies found lower levels ofB2GPI after lipopolysaccharide (the main component ofthe outer membrane of bacteria) infusion in humans andmale mice [3, 4]. Therefore, we hypothesized that B2GPIlevels can differentiate between sepsis and non-infectiouscritically ill patients. To test this and to determine the dis-criminative and prospective value of B2GPI as a sepsisbiomarker, we conducted a prospective study.We included 313 critically ill adult patients (defined astwo or more systemic inflammatory response syndrome(SIRS) criteria upon admission) with an anticipated ICUstay of more than 24 h (Table 1) [5]. In 48 h following ICUadmission, blood was sampled twice to measure themaximum level of B2GPI using a semi-automated sand-wich ELISA on a Freedom EVO platform (Tecan)with goat anti-human beta-2-glycoprotein-1 and HRP-coupled goat-human beta-2-glycoprotein-1 antibodies(both Cedarlane). Supersignal West Pico Chemilumin-escent substrate (Thermo Scientific) was added, andthe luminescence signal was measured using aSpectramax-L microplate reader (MDS Analytical).The outcomes “no sepsis,” “sepsis,” and “septic shock”were defined according to the sepsis-3 criteria. Theoutcome “proven infection” was derived from Centersfor Disease Control (CDC) algorithms. Statisticalanalyses were performed using SPSS version 21.0 andR version 3.6.1.© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: i.t.schrijver@gmail.com1Department of Intensive Care Medicine, University Medical Centre,University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The NetherlandsFull list of author information is available at the end of the articleSchrijver et al. Critical Care          (2020) 24:341 https://doi.org/10.1186/s13054-020-03066-3We found that B2GPI levels were significantly lower inpatients with sepsis compared with patients without sep-sis. Patients with a septic shock had lower B2GPI levelscompared with patients with solely sepsis (Fig. 1a). Pa-tients with an infection had lower levels of B2GPI(Fig. 1b). Patients within the highest tertile of B2GPIlevels developed 44% fewer infections compared with thelowest tertile (P = 0.007, Fig. 1d) in the 10-day follow-up.There was no significant difference in B2GPI levels be-tween survivors and non-survivors (Fig. 1c) and betweengram-positive and gram-negative sepsis (162 [IQR 87–275] vs 131 [IQR 96–221]).We showed that B2GPI could differentiate betweenpatients with and without sepsis. Moreover, patientswith lower B2GPI levels in the first 48 h developedmore nosocomial infections. This suggests thatB2GPI may be a novel biomarker for both diagnos-ing sepsis and predicting nosocomial infections. Thisstudy took place in a general ICU; therefore, itseems feasible that our results could be generalizableto other ICUs.Most biomarkers spike in sepsis; therefore, the lowerB2GPI levels we found are relatively unique. Other bio-markers that decrease in sepsis are the inter-alpha in-hibitor protein, lysophosphatidylcholine, and uric acid[1, 6]. However, currently, they are not used in clinicalpractice.In summary, this is the first study that showed thevalue of the B2GPI biomarker in ICU patients with botha discriminative (for sepsis) and predictive (for nosoco-mial infections) role. Potentially, B2GPI can be helpfulin diagnosing sepsis and stratifying ICU patients for in-fection risk.AbbreviationsB2GPI: Beta-2-glycoprotein I; CDC: Centers for Disease Control; ICU: Intensivecare unit; SIRS: Systemic inflammatory response syndromeAcknowledgementsNot applicable.Authors’ contributionsMR, JK, and DWdL designed the study; HK and DWdL collected the data; ITSand DWdL analyzed and interpreted the data and performed the statisticalanalysis; ITS drafted the article; HK, MR, JK, and DWdL revised the articlecritically; and all authors gave final approval of the manuscript to bepublished.FundingThe authors received no financial support for the research, authorship, and/or publication of this article.Availability of data and materialsThe datasets used and/or analyzed during the current study are availablefrom the corresponding author on reasonable request.Table 1 Descriptive characteristics, medians (IQR) or N (%)Characteristic No sepsis Sepsis Septic shock P valueNumber of patients 180 75 47 n/aGender, male 113 (62%) 47 (38%) 33 (67%) 0.778Age (years) 60 (23) 61 (28) 65 (25) 0.656Diagnosis at admissionTrauma 8 (4%) 10 (13%) 5 (10%) 0.028*Infection (suspicion of) 40 (22%) 20 (26%) 19 (40%)Post surgery 35 (19%) 11 (15%) 6 (12%)Others 97 (54%) 35 (46%) 18 (38%)Severity of illness (at admission)Mechanical ventilation 104 (86%) 43 (78%) 26 (65%) < 0.001*APACHE IV score 70 (44) 74 (38) 93 (44) 0.003*SOFA score 6 (5) 5 (5) 11 (5) < 0.001*30-day mortality 39 (21%) 19 (25%) 17 (34%) 0.157ICU stay (days) 10 (10) 8 (10) 8 (9) 0.267Gram-negative infection 25 (14%) 25 (33%) 22 (45%) < 0.001*β2 Glycoprotein-1 (μg/mL) 198 (313) 165 (195) 129 (149) < 0.001*CRP (mg/L) 187 (166) 245 (200) 290 (168) < 0.001*Procalcitonin 1.0 (3.0) 2.9 (8.1) 4.5 (35.8) < 0.001*Leukocytes (× 109/L) 16 (9) 16 (10) 16 (10) 0.937Mechanical ventilation direct upon admission; IQR interquartile range, MPO myeloperoxidase, APACHE IV Acute Physiology and Chronic Health Evaluation IVseverity of illness model, CRP C-reactive protein, SOFA Sequential Organ Failure Assessment. Baseline characteristic comparisons were made using Mann-WhitneyU, chi-square, or Kruskal-Wallis tests for skewed variables and Student’s T test or chi-square test for normal distributed variables. *P < 0.05Schrijver et al. Critical Care          (2020) 24:341 Page 2 of 4Fig. 1 Beta-2-glycoprotein-1 (B2GPI) levels in different states of inflammation. a The correlation of the B2GPI level with no sepsis, sepsis, andseptic shock was assessed using the Kruskal-Wallis and the Mann-Whitney U tests. b The B2GPI level in non-infected and infected patientsassessed using the Mann-Whitney U test. c The B2GPI level in non-survivors and survivors assessed using the Mann-Whitney U test. dDevelopment of infection during ICU stay depended on beta-2-glycoprotein-1 (B2GPI, μg/mL). The cohort was divided into three equal tertilesbased on the B2GPI level. The relation between the development of infection and the different tertiles was calculated by applying the Kaplan-Meier method. Statistical differences between survival curves were analyzed using Cox proportional hazards regression analysis. Highest levels ofB2GPI differ significantly from the lowest levels of B2GPI (P = 0.007)Schrijver et al. Critical Care          (2020) 24:341 Page 3 of 4Ethics approval and consent to participateThe study methods were submitted to and approved by the institutionalreview board of the University Medical Centre Utrecht. It waived the needfor informed consent (University Medical Centre Utrecht Institutional ReviewBoard research protocol 108–188). The study was conducted in accordancewith the Declaration of Helsinki.Consent for publicationNot applicable.Competing interestsThe authors declare they have no conflict of interest.Author details1Department of Intensive Care Medicine, University Medical Centre,University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.2Department of Clinical Chemistry and Hematology, Central Laboratory(CDL), University Medical Centre, University of Utrecht, Heidelberglaan 100,3584 CX Utrecht, The Netherlands. 3Synapse B.V., Maastricht, The Netherlands.4Dutch Poisons Information Center (DPIC), University Medical Center,University of Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.Received: 13 May 2020 Accepted: 4 June 2020References1. Pierrakos C, Vincent JL. Sepsis biomarkers: a review. Crit Care. 2010;14(1):R15.https://doi.org/10.1186/cc8872.2. Markiewski MM, DeAngelis RA, Lambris JD. Complexity of complementactivation in sepsis. J Cell Mol Med. 2008;12(6A):2245–54.3. El-Assaad F, Qi M, Gordon AK, Qi J, Dong S, Passam F, et al. Beta 2-glycoprotein I protects mice against gram-negative septicaemia in asexually dimorphic manner. Sci Rep. 2017;7(1)8201.4. Agar C, de Groot PG, Morgelin M, Monk SD, van Os G, Levels JH, et al. β2-glycoprotein I: a novel component of innate immunity. Blood. 2011;117(25):6939–47.5. Hyseni A, Kemperman H, de Lange DW, de Groot PG, Linssen M, KeseciogluJ, et al. Increased mortality in systemic inflammatory response syndromepatients with high levels of coagulation factor VIIa. J Thromb Haemost.2013;11(12):2111–7.6. Mecatti GC, Messias MCF, de Oliveira Carvalho P. Lipidomic profile andcandidate biomarkers in septic patients. Lipids Health Dis 2020 13;19(1):68.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Schrijver et al. Critical Care          (2020) 24:341 Page 4 of 4

Beta-2-glycoprotein I as a biomarker for sepsis in critically ill patients in the intensive care unit: a prospective cohort study

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Beta-2-glycoprotein I as a biomarker for sepsis in critically ill patients in the intensive care unit: a prospective cohort study

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