ijcs International Journal of Cardiovascular Sciences Int. J. Cardiovasc. Sci. 2359-4802 2359-5647 Sociedade Brasileira de Cardiologia gxxQJmQZ5jQ583B4wHzBBkt S2359-56472020000100087 10.36660/ijcs.20190207 REVIEW ARTICLE Molecular Imaging in the Diagnosis of Infectious Endocarditis - the Role of PET and SPECT 0000-0003-0810-6494 Albano Domenico 0000-0003-2980-5964 Bertagna Francesco 0000-0003-4275-2799 Giubbini Raffaele ASSTSpedali Civili di Brescia Brescia Lombardia Italy ASSTSpedali Civili di Brescia, Brescia, Lombardia - Italy Mailing Address: Domenico Albano ASST Spedali Civili di Brescia - Nuclear Medicine - Piazzale Spedali Civili, 1. Postal Code: 25125 Brescia, Lombardia - Italy E-mail: doalba87@libero.it

Author contributions

Conception and design of the research: Bertagna F, Giubbini R. Acquisition of data: Albano D. Analysis and interpretation of the data: Albano D, Bertagna F, Giubbini R. Statistical analysis: Albano D. Writing of the manuscript: Albano D. Critical revision of the manuscript for intellectual content: Albano D, Bertagna F, Giubbini R.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 17 02 2020 Jan-Feb 2020 33 1 87 93 06 11 2019 06 11 2019 09 12 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

18-fluorine-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and singlephoton emission computed tomography (SPECT) using radiolabeled white blood cells (WBC) are non-invasive techniques widely used in the diagnosis of infections, like endocarditis. The aim of our paper was to provide a systematic review of the published data on the use of 18F-FDG PET/CT and SPECT in infective endocarditis (IE). A comprehensive literature search of the PubMed/ MEDLINE, Scopus, Embase and Cochrane library databases was conducted to find relevant published articles about the diagnostic performance of SPECT using WBC and 18F-FDG PET/CT in the diagnosis of infectious endocarditis. Twenty papers were included, with a total of 1,154 patients (166 studies with WBC SPECT and 988 with 18F-FDG PET/CT). From the analyses of the studies, the following results were obtained: both SPECT and PET/CT had good diagnostic accuracy in the study of endocarditis. 18F-FDG PET/CT had good specificity (85.8%) and lower sensitivity (68%), with high heterogeneity among the studies; WBC SPECT/ CT had an overall sensitivity of 80% and specificity of 98%. Specific preparations for PET/CT can affect the diagnostic accuracy of the test. Both 18F-FDG PET/CT and WBC SPECT are useful for the diagnosis of IE, and WBC SPECT appears to be slightly more specific than 18F-FDG PET/CT. A specific diet could influence the diagnostic performance of PET/CT.

 Keywords Endocarditis,Infectious/ diagnostic imaging Positron Emission Tomography Computed/methods Positron Emission Tomography Computed Tomography/ methods Radiommunodetect/ methods Leukocytes Introduction

Infectious endocarditis (IE) is a serious, potentially life-threatening condition, and a challenge for clinicians due to difficulties in its diagnosis.1,2 The current diagnostic approach often revolves around the modified Duke criteria, which are composed of a composite of clinical criteria, blood cultures and echocardiographic findings,3 but cases of uncertain diagnosis are still significant.

Cardiac infections include a group of conditions involving the heart muscle, the pericardium or the endocardial surface of the heart. Infections can extend to the prosthetic material or the leads in case of device implantation. The heterogeneity of clinical presentations requires, besides the diagnostic criteria, a discussion by a multidisciplinary team.

IE is a representative example where the use of nuclear medicine has evolved as an important diagnostic tool.4,5

Single photon emission computed tomography (SPECT) using radiolabelled white blood cell (WBC) and fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) have been widely used in the diagnosis of infections and in IE, with controversial findings.

The aim of this review is to provide a systematic review of published data about the role of WBC SPECT and 18F-FDG PET/CT in the diagnostic work-up of patients with IE.

 Materials and Methods

The present meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) statement (see supplementary material for PRISMA Checklist).6

Search strategy

A comprehensive literature search of the PubMed/ MEDLINE, Scopus, Embase and Cochrane library databases was conducted to find relevant published articles about the diagnostic accuracy of WBC SPECT and 18F-FDG PET/CT in patients affected by IE. We used a search algorithm based on a combination of the terms: a) "SPECT" OR “Single-photon emission computed tomography" OR “WBC" OR “radiolabeled leukocytes" OR “PET" OR “positron emission tomography" AND b) “endocarditis" OR “heart infection". No beginning date limit was used; the search was updated until August 31, 2019. Only articles in the English language were selected; pre-clinical or not in vivo studies, review, letters, editorials and conference proceedings were excluded. To expand our search, references of the retrieved articles were also screened for additional studies. Studies considering cardiovascular implantable electronic device infections were excluded by this review. All literature studies collected were managed using EndNote Web 3.3.

 Study selection

All articles reporting patients with IE evaluated by WBC SPECT and 18F-FDG PET/CT in clinical setting were eligible for inclusion. Two researchers (DA and FB) independently reviewed the titles and abstracts of the retrieved articles. The same two researchers then independently reviewed the full-text version of the remaining articles to determine their eligibility for inclusion. Disagreements were resolved by a third opinion (RG). Moreover, in case of studies that included the same population, the report with the highest number of enrolled patients was considered for the analysis.

 Data abstraction

For each included study, the following data were extracted - authors' names, year of publication, type of study, number of patients, diagnostic test, diagnostic criteria, reference standard, diagnostic performance. The main findings of the articles included in the review are reported in the Results section.

 Results Literature search

The comprehensive computer literature search revealed 665 articles (Figure 1). On reviewing the titles and abstracts, 645 articles were excluded because the data reported data were not within the field of interest of this review. Twenty articles were selected and retrieved in full-text version7-25; no additional study was found when screening the references of these articles. In total, 20 articles were included in the systematic review, four about WBC SPECT7-10 and 16 about 18F-FDG PET/CT11-25

Flow-chart of the search strategy. Qualitative analysis

Characteristics of the studies are detailed in Tables 1 and 2. The IE group included 16 [18F] FDG PET/CT (overall 988 patients) and four SPECT/CT studies (overall 166 patients). Among the PET/CT studies, seven analyzed only prosthetic valve endocarditis (PVE),9,13,15,16,19-21 two only native valve endocarditis (NVE),11,23 and the remaining seven analyzed a mixed population or the type of endocarditis was not reported.12,14,17,18,22,24,25 Among SPECT studies, two included only PVE,8,9 and the remaining two papers included both NVE and PVE.7,10 In only one paper,9 both SPECT and PET/CT techniques were used to study IE.

Characteristics of the studies on single photon emission computed tomography using radiolabelled white blood cell and infectious endocarditis
Author Year Design study N pts Clinical setting Sensitivity Specificity Accuracy Diagnostic criteria Reference standard
Erba et al. 2012 Retrospective 51 16 NVE, 35 PVE 90% nr 90% Visual analysis Microbiological analysis or clinical follow-up
Hyafil et al. 2013 Retrospective 42 42 PVE nr 100% nr Visual analysis Pre-operative macroscopic analysis and bacteriological analysis + clinical follow-up
Rouzet et al. 2014 Retrospective 39 39 PVE 65% 100% 86% Visual and semiquantitative analysis Combination of modified Duke criteria and clinical follow-up
Caobelli et al. 2017 Retrospective 34 12 NVE, 22 PVE 86% 95% 91% Visual analysis Microbiological analysis + combination of modified Duke criteria and clinical follow-up

NVE: native valve endocarditis; PVE: prosthetic valve endocarditis; nr: not reported.

 Characteristics of the studies on fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and infectious endocarditis
Author Year Design study N pts Clinical setting Sensitivity Specificity Accuracy Diagnostic criteria Reference standard
Van Riet et al. 2010 Prospective 25 25 NVE 12% 100% 18% Visual analysis Clinical follow-up
Ozcan et al. 2013 Retrospective 72 12 PVE, 52 NVE 18% nr 18% Visual analysis Clinical follow-up
Saby et al. 2013 Prospective 72 72 PVE 73% 80% 76% Visual analysis (AC and NAC) Modified Duke criteria and clinical follow-up
Kouijzer et al. 2013 Prospective 72 nr 39% 93% nr Visual analysis Modified Duke criteria
Rouzet et al. 2014 Retrospective 39 39 PVE 93% 71% 80% Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria and clinical follow-up
Ricciardi et al. 2014 Retrospective 27 27 PVE 55% 100% nr Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria and clinical/ microbiological follow-up
Pizzi et al. 2015 Prospective 92 92 PVE 87% 92% nr Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria and clinical follow-up
Jimenez-Ballvè et al. 2016 Prospective 41 39 PVE, 2 NVE 88% 79% 85% Visual (AC and NAC) Modified Duke criteria and clinical/ microbiological follow-up
Granados et al. 2016 Prospective 51 29 PVE, 21 NVE 82% 96% nr Visual (AC and NAC) analysis Clinical, imaging and microbiological follow-up
Fagman et al. 2016 Retrospective 30 30 PVE 75% 86% 83% Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria and clinical/ microbiological follow-up
Guenther et al. 2017 Retrospective 26 26 PVE 94% 29% 76% Visual and semiquantitative analysis Modified Duke criteria and clinical follow-up
Salomaki et al. 2017 Prospective 23 16 PVE, 7 NVE 100% 71% 91% Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria and clinical/ microbiological follow-up
Kouijzer et al. 2018 Retrospective 88 88 NVE 45% 100% 87.5% Visual (AC and NAC) analysis Modified Duke criteria and clinical/ microbiological follow-up
de Camargo et al. 2019 Prospective 303 188 PVE, 115 NVE 93% PVE70% NVE 90% PVE93% NVE 91% PVE69% NVE Visual (AC and NAC) and semiquantitative analysis Modified Duke criteria
El-Dalati et al. 2019 Retrospective 14 8 PVE, 6 NVE nr 100% nr Visual (AC and NAC) and semiquantitative analysis Histological diagnosis

The pooled sensitivity of 18F-FDG PET/CT was 68% (95% CI 55-87), with a high heterogeneity (I2 = 94%, p < 0.001), whereas pooled sensitivity of WBC SPECT was 80% (95% CI 67-94) with a lower heterogeneity (I2=75%, p = 0.017). The pooled specificity of 18F-FDG PET/ CT was 86.8% (95% CI 82-95) with a high heterogeneity (I2 = 86%, p < 0.001), whereas WBC SPECT showed a pooled specificity of 98% (95% CI 94-100) with no heterogeneity (I2 = 0%, p = 0.625). In a sub-analysis, pooled sensitivity of 18F-FDG PET/CT and WBC SPECT for NVE was 71% (95% CI 49-93) with a high heterogeneity (I2 = 95%, p < 0.001), while pooled sensitivity for PVE was 81% (95% CI 78-93) with a significant heterogeneity (I2 = 67%, p < 0.001). Pooled specificity of 18F-FDG PET/ CT and WBC SPECT for NVE was 96% (95% CI 93-100) with a low heterogeneity (I2 = 52%, p = 0.016), while pooled specificity for PVE was 92% (95% CI 86-96) with a significant heterogeneity (I2 = 79%, p < 0.001).

Of 17 manuscripts considering the diagnostic performance of 18F-FDG PET/CT, 11 showed specific preparation before PET/CT scan [9,13,15-18,21-25] and five did not.11,12,14,19,20 In six studies,9,13,21-24 participants underwent dietary preparation to promote myocardial suppression (high-fat, low-carbohydrate diet), without heparin injection; in two studied only heparin injection was suggested;16,18 in the remaining three works,15,17,25 both myocardial suppression and heparin injection were done. Despite this, there was strong heterogeneity in preparation for PET/CT, with different time of fasting or diet for myocardial suppression (Table 3). Pooled sensitivity of PET/CT was 47% (95% CI 18-81) in patients without specific protocol and 78% (95% CI 45-99) in patients who performed specific preparation (myocardial suppression diet and/or heparin injection).

Preparations for fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography described in the studies included in the review
Author N pts Diet Heparin Specific preparation
Van Riet et al. 25 no no 4-hour fasting
Ozcan et al. 72 no no 6-hour fasting (4-hour for diabetic patients)
Saby et al. 72 yes no HFLW (only one meal) diet, 12-hour fasting
Kouijzer et al. 72 no no 6-hour fasting
Rouzet et al. 39 yes no HFLW (only one meal) diet, 12-hour fasting
Ricciardi et al. 27 yes yes HFLW diet, 6-hour fasting
Pizzi et al. 92 no yes 12-hour fasting, 50 IU/Kg heparin bolus 15 min before FDG
Jimenez-Ballvè et al. 41 yes yes 48-hours HFLC diet, 12-hour fasting, 50 IU/Kg heparin bolus 15 min before FDG
Granados et al. 51 no yes 12-hour fasting, 50 IU/Kg heparin bolus 15 min before FDG
Fagman et al. 30 no no 18-hour fasting
Kokalova et al. 13 no no 6-hour fasting
Guenther et al. 26 yes no HFLW diet, 12-hour fasting
Salomaki et al. 23 yes no 24-hour HFLW diet, 10-hour fasting
Kouijzer et al. 88 yes no 24-hour HFLW diet, 6-hour fasting
de Camargo et al. 303 yes no 24-hour HFLW diet, 8-hour fasting
El-Dalati et al. 14 yes yes 36-hour HFLC diet, 30 IU/kg of heparin administered in three boluses (10 IU/kg) at 10 min before FDG and 5 and 20 min after FDG

MS: myocardial suppression; HFLW: High-fat low-carbohydrate; NR: not reported.

Pooled sensitivity of PET/CT was 76% (95% CI 64-88) and 72% (95% CI 46-99) in patients with and without specific preparation, indicating a high heterogeneity. Also, a pooled specificity of 93% (95% CI 70-100) was observed in the first group and 91% (95% CI 85-94) in the second group.

 Discussion

An accurate diagnosis of IE is critical for clinical decision making and represents a challenge for clinicians; in the latest update of the European Society of Cardiology Guideline,26 nuclear medicine imaging was integrated in the diagnostic flow-chart of IE. Although blood cultures

and echocardiography continue to play a crucial role in the diagnosis and the subsequent clinical management of IE, they have limitations, with a significant number of doubtful reports. Also, ultrasound may have difficulties to study prosthetic valves and inconclusive results have been reported in up to 30% of cases.27

In this context, WBC SPECT and 18F-FDG PET/ CT studies have demonstrated a significant impact on the study of both PVE and NVE. In particular, in case of suspected PVE, abnormal 18F-FDG PET/CT and WBC SPECT/CT uptake should be considered as a pathological finding. In this systematic review we included 19 studies, with a total of 1,115 patients. Overall, 18F-FDG PET/CT had good specificity (86%) and low sensitivity (68%), with high heterogeneity among papers, while WBC SPECT had high specificity (98%) and good sensitivity (80%) but a small number of patients evaluated.

Our results are similar to those reported in previous reviews and meta-analysis.4,5

The 18F-FDG PET/CT has the advantage to be a whole-body study that allows the assessment of extracardiac sites of the disease, including clinically unsuspected distant foci, and more appropriate and timely intervention, including antibiotic therapy. In fact, whole-body 18F-FDG PET/CT leads to treatment modification in up to 35% of patients with IE.28 Several factors, such as antimicrobial therapy, small vegetation size and elevated blood glucose level may impact the accuracy of PET/CT and increase the number of false negative findings. The difficulty to detect small vegetations is directly related to the resolution power of the PET/CT device (about 4-5 mm), which is aggravated in case of high FDG uptake in the surrounding myocardium.

Physiological uptake of FDG is a common problem in the evaluation of heart infection; for this reason, preparation protocols before and/or after FDG injection were suggested, like dietary preparation for MS and heparin injection. However, different diets have been proposed in the literature, without consensus (Table 3). These MS protocols include patient preparation with the use of a low-carbohydrate and high-fat diet plus fasting for at least 6 hours, and use of heparin prior to imaging. Prolonged fasting and low-carbohydrate, high-fat diets lead to decreased insulin and blood glucose levels, and increased free fatty acid levels, reducing physiological FDG uptake. Heparin induces lipolysis and leads to an increase in free fatty acid levels.

Another possible limitation affecting FDG evaluation of IE is the time between valve surgical procedure and PET/CT scan; PET/CT studies performed shortly after cardiac procedures can also be affected by the presence of inflammation foci near to the prostheses.

Although 18F-FDG PET/CT is generally considered a method with higher accuracy than SPECT due to higher spatial resolution and detection efficiency, this was not observed in our results. In fact, in our analysis, both sensitivity and specificity of WBC SPECT were better than PET/CT. 18F-FDG PET/CT has several clear advantages over SPECT imaging such as the lack of blood handling, a shorter study time and high target-to-background ratio; however, a high specificity of 18F-FDG PET/CT requires specific protocols to increase diagnostic accuracy.29,30

Limitation of the studies

Several limitations affect the quality of our review on the role of SPECT and PET in IE such as the lack of multicenter studies, the low number of patients evaluated (also due to the rarity of this disease), and the heterogeneity of included papers. This heterogeneity arises from the diversity of patients' characteristics, methodological aspects, reference standards and global quality of the studies.

 Conclusion

Our findings support the utility of both WBC SPECT and 18F-FDGPET/CT as diagnostic tools in the study of IE, particularly in patients with prosthetic valve. Specific protocols including diet and/or heparin injection may improve the diagnostic performance of PET/CT.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

 References 1 Thuny F, Grisoli D, Cautela J, Riberi A, Raoult D, Habib G. Infective endocarditis: prevention, diagnosis, and management. Can J Cardiol. 2014;30(9):1046-57. Thuny F Grisoli D Cautela J Riberi A Raoult D Habib G Infective endocarditis: prevention, diagnosis, and management Can J Cardiol 2014 30 9 1046 1057 2 Thuny F, Grisoli D, Collart F, Habib G, Raoult D. Management of infective endocarditis: challenges and perspectives. Lancet. 2012;379(9819):965-75. Thuny F Grisoli D Collart F Habib G Raoult D Management of infective endocarditis: challenges and perspectives Lancet 2012 379 9819 965 975 3 Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30(4):633-8. Li JS Sexton DJ Mick N Nettles R Fowler VG Jr Ryan T Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis Clin Infect Dis 2000 30 4 633 638 4 Cantoni V, Sollini M, Green R, Berchiolli R, Lazzeri E, Mannarino T, et al. Comprehensive meta-analysis on [18F] FDG PET/CT and radiolabelled leukocyte SPECT-SPECT/CT imaging in infectious endocarditis and cardiovascular implantable electronic device infections. Clin Transl Imaging. 2018;6(1):3-18. Cantoni V Sollini M Green R Berchiolli R Lazzeri E Mannarino T Comprehensive meta-analysis on [18F] FDG PET/CT and radiolabelled leukocyte SPECT-SPECT/CT imaging in infectious endocarditis and cardiovascular implantable electronic device infections Clin Transl Imaging 2018 6 1 3 18 5 Juneau D, Golfam M, Hazra S, Erthal F, Zuckier LS, Bernick J, et al. Molecular imaging for the diagnosis of infective endocarditis: a systematic literature review and meta-analysis. Int J Cardiol. 2018 Feb 15;253:183-8. Juneau D Golfam M Hazra S Erthal F Zuckier LS Bernick J Molecular imaging for the diagnosis of infective endocarditis: a systematic literature review and meta-analysis Int J Cardiol 15 02 2018 253 183 188 6 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and metaanalyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-34. Liberati A Altman DG Tetzlaff J Mulrow C Gotzsche PC Ioannidis JP The PRISMA statement for reporting systematic reviews and metaanalyses of studies that evaluate health care interventions: explanation and elaboration J Clin Epidemiol 2009 62 10 e1 34 7 Erba PA, Conti U, Lazzeri E, Sollini M, Doria R, De Tommasi SM, et al. Added value of 99mTc-HMPAOlabeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis. J Nucl Med. 2012;53(8):1235-43. Erba PA Conti U Lazzeri E Sollini M Doria R De Tommasi SM Added value of 99mTc-HMPAOlabeled leukocyte SPECT/CT in the characterization and management of patients with infectious endocarditis J Nucl Med 2012 53 8 1235 1243 8 Hyafil F, Rouzet F, Lepage L, Benali K, Raffoul R, Duval X, et al. Role of radiolabelled leucocyte scintigraphy in patients with a suspicion of prosthetic valve endocarditis and inconclusive echocardiography. Eur Heart J Cardiovasc Imaging. 2013;14(6):586-94. Hyafil F Rouzet F Lepage L Benali K Raffoul R Duval X Role of radiolabelled leucocyte scintigraphy in patients with a suspicion of prosthetic valve endocarditis and inconclusive echocardiography Eur Heart J Cardiovasc Imaging 2013 14 6 586 594 9 Rouzet F, Chequer R, Benali K, Lepage L, Ghodbane W, Duval X, et al. Respective performance of 18F-FDG PET and radiolabelled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis. J Nucl Med. 2014;55(12):1980-5. Rouzet F Chequer R Benali K Lepage L Ghodbane W Duval X Respective performance of 18F-FDG PET and radiolabelled leukocyte scintigraphy for the diagnosis of prosthetic valve endocarditis J Nucl Med 2014 55 12 1980 1985 10 Caobelli F, Wollenweber T, Bavendiek U, Kühn C, Schütze C, Geworski L, et al. Simultaneous dual-isotope solid-state detector SPECT for improved tracking of white blood cells in suspected endocarditis. Eur Heart J. 2017;38(6):436-43. Caobelli F Wollenweber T Bavendiek U Kühn C Schütze C Geworski L Simultaneous dual-isotope solid-state detector SPECT for improved tracking of white blood cells in suspected endocarditis Eur Heart J 2017 38 6 436 443 11 Van Riet J, Hill EE, Gheysens O, Dymarkowski S, Herregods MC, Herijgers P, et al. (18) F-FDG PET/CT for early detection of embolism and metastatic infection in patients with infective endocarditis. Eur J Nucl Med Mol Imaging. 2010;37(6):1189-97. Van Riet J Hill EE Gheysens O Dymarkowski S Herregods MC Herijgers P Eur J Nucl Med Mol Imaging 2010 37 6 1189 1197 12 Ozcan C, Asmar A, Gill S, Thomassen A, Diederichsen AC. The value of FDG-PET/CT in the diagnostic work-up of extra cardiac infectious manifestations in infectious endocarditis. Int J Cardiovasc Imaging. 2013;29(7):1629-37. Ozcan C Asmar A Gill S Thomassen A Diederichsen AC The value of FDG-PET/CT in the diagnostic work-up of extra cardiac infectious manifestations in infectious endocarditis Int J Cardiovasc Imaging 2013 29 7 1629 1637 13 Saby L, Laas O, Habib G, Cammilleri S, Mancini J, Tessonnier L, et al. Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion. J Am Coll Cardiol. 2013;61(23):2374-82. Saby L Laas O Habib G Cammilleri S Mancini J Tessonnier L Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion J Am Coll Cardiol 2013 61 23 2374 2382 14 Kouijzer IJ, Vos FJ, Janssen MJ, van Dijk AP, Oyen WJ, Bleeker-Rovers CP. The value of 18FFDG PET/CT in diagnosing infectious endocarditis. Eur J Nucl Med Mol Imaging. 2013;40(7):1102-7. Kouijzer IJ Vos FJ Janssen MJ van Dijk AP Oyen WJ Bleeker-Rovers CP The value of 18FFDG PET/CT in diagnosing infectious endocarditis Eur J Nucl Med Mol Imaging 2013 40 7 1102 1107 15 Ricciardi A, Sordillo P, Ceccarelli L, Maffongelli G, Calisti G, Di Pietro B, et al. 18-Fluoro-2-deoxyglucose positron emission tomography-computed tomography: an additional tool in the diagnosis of prosthetic valve endocarditis. Int J Infect Dis. 2014 Nov;28:219-24. Ricciardi A Sordillo P Ceccarelli L Maffongelli G Calisti G Di Pietro B 18-Fluoro-2-deoxyglucose positron emission tomography-computed tomography: an additional tool in the diagnosis of prosthetic valve endocarditis Int J Infect Dis 11 2014 28 219 224 16 Pizzi MN, Roque A, Fernández-Hidalgo N, Cuéllar-Calabria H, Ferreira-González I, Gonzàlez-Alujas MT, et al. Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18F-fluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center. Circulation. 2015;132(12):1113-26. Pizzi MN Roque A Fernández-Hidalgo N Cuéllar-Calabria H Ferreira-González I Gonzàlez-Alujas MT Improving the diagnosis of infective endocarditis in prosthetic valves and intracardiac devices with 18F-fluordeoxyglucose positron emission tomography/computed tomography angiography: initial results at an infective endocarditis referral center Circulation 2015 132 12 1113 1126 17 Jiménez-Ballvé A, Pérez-Castejón MJ, Delgado-Bolton RC, Sánchez-Enrique C, Vilacosta I, Vivas D, et al. Assessment of the diagnostic accuracy of 18F-FDG PET/CT in prosthetic infective endocarditis and cardiac implantable electronic device infection: comparison of different interpretation criteria. Eur J Nucl Med Mol Imaging. 2016;43(13):2401-12. Jiménez-Ballvé A Pérez-Castejón MJ Delgado-Bolton RC Sánchez-Enrique C Vilacosta I Vivas D Assessment of the diagnostic accuracy of 18F-FDG PET/CT in prosthetic infective endocarditis and cardiac implantable electronic device infection: comparison of different interpretation criteria Eur J Nucl Med Mol Imaging 2016 43 13 2401 2412 18 Granados U, Fuster D, Pericas JM, Llopis JL, Ninot S, Quintana E, et al. Diagnostic accuracy of 18F-FDG PET/CT in infective endocarditis and implantable cardiac electronic device infection: a cross-sectional study. J Nucl Med. 2016;57(11):1726-32. Granados U Fuster D Pericas JM Llopis JL Ninot S Quintana E Diagnostic accuracy of 18F-FDG PET/CT in infective endocarditis and implantable cardiac electronic device infection: a cross-sectional study J Nucl Med 2016 57 11 1726 1732 19 Fagman E, van Essen M, Fredén Lindqvist J, Snygg-Martin U, Bech-Hanssen O, Svensson G. 18F-FDG PET/CT in the diagnosis of prosthetic valve endocarditis. Int J Cardiovasc Imaging. 2016;32(4):679-86. Fagman E van Essen M Fredén Lindqvist J Snygg-Martin U Bech-Hanssen O Svensson G 18F-FDG PET/CT in the diagnosis of prosthetic valve endocarditis Int J Cardiovasc Imaging 2016 32 4 679 686 20 Kokalova A, Dell'Aquila AM, Avramovic N, Martens S, Wenning C, Sindermann JR. Supporting imaging modalities for improving diagnosis of prosthesis endocarditis: preliminary results of a single-center experience with 18F-FDG-PET/CT. Minerva Med. 2017;108(4):299-304. Kokalova A Dell'Aquila AM Avramovic N Martens S Wenning C Sindermann JR Supporting imaging modalities for improving diagnosis of prosthesis endocarditis: preliminary results of a single-center experience with 18F-FDG-PET/CT Minerva Med 2017 108 4 299 304 21 Guenther SPW, Cyran CC, Rominger A, Saam T, Kazmierzcak PM, Bagaev E, et al. The relevance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in diagnosing prosthetic graft infections post cardiac and proximal thoracic aortic surgery. Interact Cardiovasc Thorac Surg. 2015;21(4):450-8. Guenther SPW Cyran CC Rominger A Saam T Kazmierzcak PM Bagaev E The relevance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in diagnosing prosthetic graft infections post cardiac and proximal thoracic aortic surgery Interact Cardiovasc Thorac Surg 2015 21 4 450 458 22 Salomãki SP, Saraste A, Kemppainen J, Bax JJ, Knuuti J, Nuutila P, et al. 18F-FDG positron emission tomography/computed tomography in infective endocarditis. J Nucl Cardiol. 2017;24(1):195-206. Salomãki SP Saraste A Kemppainen J Bax JJ Knuuti J Nuutila P 18F-FDG positron emission tomography/computed tomography in infective endocarditis J Nucl Cardiol 2017 24 1 195 206 23 Kouijzer IJE, Berrevoets MAH, Aarntzen EHJG, de Vries J, van Dijk APJ, Oyen WJG, et al. 18F-fluorodeoxyglucose positron-emission tomography combined with computed tomography as a diagnostic tool in native valve endocarditis. Nucl Med Comm. 2018;39(8):747-52. Kouijzer IJE Berrevoets MAH Aarntzen EHJG de Vries J van Dijk APJ Oyen WJG 18F-fluorodeoxyglucose positron-emission tomography combined with computed tomography as a diagnostic tool in native valve endocarditis Nucl Med Comm 2018 39 8 747 752 24 de Camargo RA, Bitencourt MS, Meneghetti JC, Soares J, Gonçalves LFT, Buchpiguel CA, et al. The role of 18F-FDG-PET/CT in the diagnosis of left-sided endocarditis: native vs. prosthetic valves endocarditis. Clin Infect Dis. 2019 Apr 5;pii:ciz267. de Camargo RA Bitencourt MS Meneghetti JC Soares J Gonçalves LFT Buchpiguel CA The role of 18F-FDG-PET/CT in the diagnosis of left-sided endocarditis: native vs. prosthetic valves endocarditis Clin Infect Dis 05 04 2019 ciz267 25 El-Dalati S, Murthy VL, Owczarczyk AB, Fagan C, Riddell J 4th, Cinti S, et al. Correlating cardiac F-18 FDG PET/CT results with intra-operative findings in infectious endocarditis. J Nucl Cardiol. 2019 Sep 4. El-Dalati S Murthy VL Owczarczyk AB Fagan C Riddell J 4th Cinti S Correlating cardiac F-18 FDG PET/CT results with intra-operative findings in infectious endocarditis J Nucl Cardiol 04 09 2019 26 Habib G, Lancellotti P, Antunes MJ, Bongiorni MG, Casalta JP, Zotti F, et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Eur Heart J. 2015;36(44):3075-3128. Habib G Lancellotti P Antunes MJ Bongiorni MG Casalta JP Zotti F 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC) Eur Heart J 2015 36 44 3075 3128 27 Saby L, Laas O, Habib G, Cammilleri S, Mancini J, Tessonnier L, et al. Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion. J Am Coll Cardiol. 2013;61(23):2374-82. Saby L Laas O Habib G Cammilleri S Mancini J Tessonnier L Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion J Am Coll Cardiol 2013 61 23 2374 2382 28 Orvin K, Goldberg E, Bernstine H, Groshar D, Sagie A, Kornowski R, et al. The role of FDG-PET/CT imaging in early detection of extracardiac complications of infective endocarditis. Clin Microbiol Infect. 2015;21(1):69-76. Orvin K Goldberg E Bernstine H Groshar D Sagie A Kornowski R The role of FDG-PET/CT imaging in early detection of extracardiac complications of infective endocarditis Clin Microbiol Infect 2015 21 1 69 76 29 Bertagna F, Giubbini R, Treglia G. Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: suggestions to increase diagnostic accuracy. J Am Coll Cardiol. 2014;63(4):378-9. Bertagna F Giubbini R Treglia G Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: suggestions to increase diagnostic accuracy J Am Coll Cardiol 2014 63 4 378 379 30 Treglia G, Bertagna F. Factors influencing the sensitivity of 18F-FDG PET/CT in the detection of infective endocarditis. Eur J Nucl Med Mol Imaging. 2013;40(7):1112-3. Treglia G Bertagna F Factors influencing the sensitivity of 18F-FDG PET/CT in the detection of infective endocarditis Eur J Nucl Med Mol Imaging 2013 40 7 1112 1113