Review A systematic review of biomarkers in the diagnosis of infective endocarditis Magnus G. Snipsøyr a,b,c , Maja Ludvigsen c , Eskild Petersen b , Henrik Wiggers a , Bent Honoré c, ⁎ a Department of Cardiology, Aarhus University Hospital, Skejby, Denmark b Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark c Department of Biomedicine, Aarhus University, Aarhus, Denmark abstract article info Article history: Received 13 May 2015 Received in revised form 11 September 2015 Accepted 19 September 2015 Available online 21 September 2015 Keywords: Infective endocarditis Biomarker Prognostic marker Diagnostic marker Timely diagnosis of bacterial infective endocarditis (IE) is crucial, as mortality remains high in this severe bacte- rial infection, currently without any distinct biological markers. Our goal was to evaluate potential diagnostic bio- markers by reviewing current literature. The MEDLINE, Embase and Scopus databases were searched for articles published from 1980 through June 2015 restricted to English, Norwegian, Danish and Swedish. Eighteen studies qualified, providing a review of the most promising candidates for future studies. Several studies are inconclusive, since they are characterized by using improper control groups. Patients with IE have bacteremia, and control groups should therefore be patients with bacteremia without IE. Based on current research, N-terminal-pro-B- type natriuretic peptide (NT-proBNP) alone or in combination with Cystatin C (Cys C), lipopolysaccharide-bind- ing protein (LBP), troponins, aquaporin-9 (AQP9), S100 calcium binding protein A11 (S100A11), E-selectin (CD62E) and VCAM-1 (CD54) and interleukin-6 (IL-6) are potential biomarkers for future studies. © 2015 Elsevier Ireland Ltd. All rights reserved. 1. Background Infective endocarditis (IE) is a life threatening bacterial infection [1, 2]. Cardiac valves can be destroyed which leads to heart failure [3] and vegetations can embolise to the brain and other organs. IE has a mortal- ity of almost 100% if left untreated. Early diagnosis and treatment with antibiotics and often surgery is therefore vital. With proper treatment, the mortality is still 15–40% during the primary submission, depending on factors like localization, microbiological agents and treatment delay which correlates with poor prognosis [4]. The diagnostic challenge is to determine if a febrile patient with either a positive blood culture or a suspected bacteremia has IE. At present the key diagnostic proce- dures are transthoracic and transesophageal echocardiography and in clinical practice there are no biomarkers, which can identify IE in patients with bacteremia. C-reactive protein (CRP) is an extremely valuable biomarker for inflammation, and is widely used in all pa- tients suspected for IE — but it lacks sensitivity and speci ficity to distinguish patients having IE from patients having bacteremia without endocarditis [5,6]. The average diagnostic delay of IE is re- ported to be approximately 30 days [4]. Any diagnostic biomarker, which could reduce the time from IE onset to diagnosis, and thereby start of correct treatment, would have the potential to reduce mortality. IE is initiated by bacterial adhesion to cardiac valves, and subse- quently bacteria invade and destroy the valve and form vegetations consisting of bacteria, fibrin clots, inflammatory proteins and leukocytes [1]. The aim of this study was to review the literature for proteins which have the potential to be used as biomarkers of heart valve infection, destruction and formation of vegetations, which could be selected for further analyses as markers of IE. 2. Literature search The MEDLINE, Embase and Scopus databases were used to identify publications relevant to the topic. The MEDLINE database was searched using PubMed with the search string (((“Endocarditis”[Mesh]) OR “Endocarditis”)) AND ((“Biological Markers”[Mesh]) OR (“Biological Markers” OR “biomarkers”)). Embase was searched with the following search string: ('endocarditis'/exp OR 'endocarditis') AND ('biological marker' OR 'biomarker') AND [1988–2015]/py. Scopus was searched using the search string (endocarditis) AND (“biological marker*” OR “biomarker”). We restricted our search to studies published in English, Norwegian, Danish and Swedish including all articles published from 1980 through June 2015. Articles not fulfilling these criteria were ex- cluded, resulting in a total of 256 articles with abstract after removal of duplicates. Screening based on study type, titles and abstracts exclud- ed 191 irrelevant articles, 40 case reports and 15 conference papers resulting in 10 remaining studies. Reference lists of retrieved papers were also searched for relevant studies, which resulted in eight addi- tional studies being included. Eighteen articles were included for review. International Journal of Cardiology 202 (2016) 564–570 ⁎ Corresponding author. E-mail address: bh@biomed.au.dk (B. Honoré). http://dx.doi.org/10.1016/j.ijcard.2015.09.028 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved. Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard