Abstract
In the diagnosis of infective endocarditis (IE), Modified Duke's criteria, coupled with clinical suspicion, serve as the guiding framework. For cases involving prosthetic valve endocarditis and infections affecting implantable devices, the use of metabolic imaging with 18 F–FDG PET/CT scans has gained prominence, as per the recommendations of the European Society of Cardiology guidelines. This imaging modality enhances sensitivity and specificity by identifying infective foci within the heart and extracardiac locations. Early utilization of these scans is crucial for confirming or ruling out IE, although caution is required to mitigate false positive responses, especially in the presence of ongoing inflammatory activity. A standardized ratio of ≥2.0 between FDG uptake around infected tissues and the blood pool has demonstrated a sensitivity of 100 % and specificity of 91 %. It is noteworthy that the sensitivity of FDG PET/CT varies, being lower for native valve and lead infections but considerably higher for prosthetic valve and pulse generator infections. This review provides a comprehensive overview of the advantages offered by FDG PET/CT in achieving a definitive diagnosis of IE.
Keywords: Infective endocarditis, Modified Duke's criteria, 18F- FDG PET/CT scan, Metabolic imaging
1. Introduction
The diagnosis of Infective Endocarditis (IE) is based on clinical suspicion, which may be categorized as low or high, in conjunction with modified Duke's Criteria (mDC). This diagnostic process can present challenges, especially in cases of partially treated infections, extracardiac vascular involvement, patients with prosthetic valves and implantable devices such as pacemakers. In rare cases healed vegetations or calcified tissues pose a suspicion of IE when they present with Pyrexia of Unknown Origin (PUO). Using mDC, the diagnosis of IE could be possible (Duke 1), definitive (Duke2) or rejected (Duke 0).1,2 Echocardiography has been the sheet anchor in the diagnosis of IE but it has been reported that the diagnosis can be delayed or missed in 30 % of cases using transthoracic echocardiography (TTE) or trans-esophageal echocardiography (TEE).2 The sensitivity and specificity of mDC was found to be around 80 % for native valve endocarditis (NVE), much less for prosthetic valve endocarditis (PVE) and implantable devices.1
Additional imaging like multi-detector computed tomography (MDCT) and metabolic imaging with 18 F-fluorodeoxyglucose Positive Emission Tomography/Computed Tomography (FDG PET/CT) has been used in challenging cases for augmenting the identification of additional foci and reclassifying possible cases of IE (Duke 1) as Duke 0 or Duke 2.3 European Society of Cardiology (ESC) guidelines 2015 recommended the integration of FDG PET/CT to mDC to increase sensitivity and specificity in making a definitive diagnosis of IE.4,5
2. Imaging
Three-dimensional TEE has proven to be a valuable tool in diagnosing IE, enabling the detection of even small-sized vegetations and paravalvular extension of infection in early stages.2 Habets et al6 in a meta-analysis of 20 studies involving 496 patients reported a pooled sensitivity for detecting vegetations were 29 % with TTE, and 82 % with TEE and when MDCT was added it increased to 89 %. As regards para-valvular complications the sensitivity with TTE alone was 36 %, TEE 86 % and when MDCT was coupled it increased to 100 %.6
FDG PET/CT has high sensitivity and specificity for the detection of PVE and can detect infections much before structural damage occur, even when blood cultures and echocardiograms are negative.5 This is more specific for PVE and pulse generator pocket infections but low for NVE and lead-related infections. In addition, in cases of PVE high uptake near the area of the valve was reported to be a marker of high embolic risk warranting early surgical intervention.7 Using mDC the clinical probability of IE can be low or high, adding FDG PET/CT in the diagnostic workup of 53 patients with a possible diagnosis of IE, Valentin et al7 reported that it helped in reclassifying Duke 1 cases as Duke 0 or Duke 2 with a sensitivity of 79 %, specificity of 100 %, positive predictive value (PPV) of 100 % and negative predictive value (NPV) of 89 % based on the final diagnosis confirmed by the Institutional multidisciplinary endocarditis team (Table 1). Similar observations were reported by others, that the addition of FDG PET/CT to standard workup has enhanced the detection of 15–32 % additional foci8, 9, 10, 11 and the number needed to test was only 7 for this additional detection.
Table 1.
7Overall diagnostic results compared to the final diagnosis according to the Endocarditis Team consensus.
| Sensitivity | Specificity | PPV | NPV | |
|---|---|---|---|---|
| Modified Duke Criteria (mDC) | 84 % (16/19) | 50 % (17/34) | 48 % (16/33) | 85 % (17/20) |
| Degreeof Clinical Suspicion | 95 % (18/19) | 53 % (18/34) | 53 % (18/34) | 95 % (18/19) |
| mDC + Clinical Suspicion | 95 % (18/19) | 32 % (11/34) | 44 % (18/41) | 92 % (11/12) |
| 18F-FDG PET/CT | 79 % (15/19) | 100 % (34/34) | 100 % (15/15) | 89 % (34/38) |
| 18F-FDG PET/CT (Prosthetic material) | 83 % (15/18) | 100 % (25/25) | 100 % (15/15) | 89 % (25/28) |
NPV – NEGATIVE PREDICTIVE VALUE.
PPV - POSITIVE PREDICTIVE VALUE.
3. Indications for FDG PET/CT study
In 2015, the European Society of Cardiology (ESC) recommended FDG PET/CT for those in whom the definitive diagnosis of IE remains unconfirmed despite clinical suspicion coupled with mDC. This test is devoid of nephrotoxicity and covers the area of interest ie the heart and also extra-cardiac structures and even it can pick up extra-cardiac sources of infective foci. By integrating this test with mDC, Valentin et al7 could confirm definitive diagnosis of IE in 36 % of their cases and excluded in the rest 64 %. They classified cases into 4 categories. Duke I with high or low clinical suspicion, Duke 0 with high or low clinical suspicion. In 41 cases of possible or rejected diagnosis of IE but with high clinical suspicion, the sensitivity, specificity, PPV, and NPV were 78 %, 100 %, 100 % and 85 % respectively.7 FDG PET/CT is particularly helpful in confirming or ruling out the diagnosis of IE in PVE, Cardiac device-related infective endocarditis (CDRIE) and vascular conduit infections. Table 2 shows the sensitivity and specificity of IE affecting different structures.
Table 2.
Diagnostic sensitivity and specificity of IE with FDG PET/CT.
| SENSITIVITY (%) | SPECIFICITY (%) | REFERENCE | |
|---|---|---|---|
| NVE | 36 | 99 | 5, 12 |
| PVE | 86 | 84 | 5, 13 |
| PULSE GENERATOR POCKET INFECTION | 93 | 98 | 14 |
| LEAD INFECTION | 65 | 88 | 14 |
| LV AD | 97 | 9 | 15 |
| CDRIE | 87 | 94 | 14 |
CDRIE - Cardiac device related infective endocarditis.
LVAD – Left ventrticular assist device
NVE – Native valve endocarditis, PVE – Prosthetic valve endocarditis.
4. Technical details
Preparation for FDG PET/CT should comply to the recommendations of the European Association of Nuclear Medicine (EANM). This includes adhering to a high-fat, low-carbohydrate diet for the 24 h preceding the test, fasting for a minimum of 12 h and ensuring blood sugar levels below 200 mg/dL at the time of the test. Using FDG PET/CT whole body and area-specific imaging has to be done and attenuation correction to be carried out and these images to be interpreted as per Mathien et al.16 Extracardiac findings can localize possible embolic events or extra-cardiac metabolically active foci which needs to be correlated with the clinical picture. It has been inferred that FDG PET/CT has the advantage of imaging the whole body for detecting metabolically active septic emboli as well as area-specific imaging of the heart.17
5. Illustrations
FDG PET/CT can detect metabolically active intra-cardiac foci due to native or prosthetic valve related infections. Fig. 1 demonstrates infective focus within the left ventricular apical clot in whom TTE and TEE were noncontributory and it was the first time we could confirm infective focus within the apical thrombus.18 Fig. 2a shows FDG PET/CT scans showing infective focus in the prosthetic aortic valve of a patient of IE who had prior Bentall's procedure. Fig. 2b shows follow-up scans done 3 months after antibiotic therapy, to assess the appropriateness of treatment and this case was reported by us earlier.18 FDG PET/CT being noninvasive, has got an advantage that it can be repeated during follow-up to assess the efficacy of therapy in selected cases.
Fig. 1.
a - Axial section of thorax showing CT image, b - Axial section of thorax showing PET image, c- Fusion image of PET/CT, arrows showing organized thrombus at the site of aneurysmorraphy patch with increased metabolic activity within the thrombus, d – Coronal section of CT image, e - Coronal section of PET image, f - Fusion image of PET/CT.
Fig. 2.
Right sided panel-before antibiotic therapy (Jan 2018 Fig. 2a– d) arrows showing increased metabolic activity at the aortic annulus. a – Axial section of fusion PET/CT image. b- Coronal section of fusion PET/CT image. c- Coronal section of PET image. d – Sagittal section of PET image. Left sided panel −3 months post antibiotic therapy (April 2018 Fig. 2e–h) arrows showing regression in metabolic activity in comparison to Jan 2018. e - Axial section of fusion PET/CT image. f - Coronal section of fusion PET/CT image. g- Coronal section of PET image. h – Sagittal section of PET image.
FDG PET/CT is effective in detecting metabolically active extra-cardiac infective foci too, Fig. 3 shows infective focus within the abdominal aortic stent graft who presented with PUO in whom blood cultures were positive but echocardiograms and ultrasound abdomen could not localize the site of infection. Fig. 4 shows metabolically active infected right-sided pacemaker lead remnants in whom the right-sided pulse generator and proximal ends of leads were explanted earlier but left-sided leads and pulse generator were free from infection indicating the need for therapeutic explantation of right-sided lead remnants alone.
Fig. 3.
a – Axial section of fusion PET/CT showing circumferential increased metabolic activity of the saccular out pouching with soft tissue density surrounding the aortic stent graft along the abdominal aorta, b - Coronal section of fusion PET/CT showing hypermetabolic activity around tortuous graft extending into both common iliac arteries, c – Maximum intensity projection image showing features suggestive of infective etiology.
Fig. 4.
a –PA view of chest - Arrows showing lead remnants on right side and pulse generator with dual leads on left side, b – Coronal section of PET image, c- Coronal section of fusion PET/CT image – Arrows showing linear metabolic activity on right side of neck from the tips of lead remnants along the subclavian vein to superior vena cava and right atrium suggesting infective focus, d - Coronal section of CT image – Arrows showing status post removal of pulse generator and proximal lead tips on the right side.
6. Optimal timing of FDG PET/CT for IE
For patients with PVE, it is crucial to perform FDG PET/CT early in the diagnostic workup to prevent the potential confounding effects of prolonged antibiotic therapy, which may yield false negative results. During the first 3 months after surgery, the persistence of post-operative inflammatory response and use of surgical adhesives can cause false positive results16,19 but in the background of IE, the images should be carefully interpreted and there should be no reason to delay FDG PET/CT for diagnostic confirmation where ever it is indicated. A standardized uptake value (SUV) ratio of ≥2.0 between FDG uptake around the infected area and in the blood pool has a sensitivity of 100 % and specificity of 91 % as advocated by the Nuclear Medicine Research Limited Accredited System (NMRLAS). Diagnostic accuracy and yield were found high when done early, even before blood cultures and echocardiograms are suggestive. C-reactive protein (CRP) levels can guide in some cases and ideal timing can be when it is ≥ 40 mgs/L suggesting an increased inflammatory activity when FDG PET/CT can detect IE much before structural damage sets in.19,20 The risk of new embolic events can be predicted when increased CRP levels are associated with increased FDG uptake in the vicinity of the valve indicating the need for an early surgical intervention.19, 20, 21
7. Limitations and pitfalls in the diagnosis
Chronic indolent infections with slow-growing organisms and prior antibiotic therapy can lead to false negative images with FDG PET/CT. Proper patient preparation and correction of attenuation artefacts are needed before interpreting the scans. The cut-off value of SUV for early post-operative inflammatory response and true infection is quite narrow. Technical constraints, such as the spatial resolution of PET/CT and the blurring effect of valve motion can lead to reduced sensitivity in detecting vegetations in cases of NVE22 but gated CT study can reduce motion artefacts to some extent. Homografts may cause local immune response due to donor antigen activity and may result in increased FDG uptake without underlying infection23 and this should be considered while interpreting the images.
Major limitations of this test are non-availability in many centres and the additional cost burden to the patient, which can be minimized by judicious decision regarding its need in appropriately selected cases. Guidelines.
ESC guidelines recommend a minimum of 3 months interval between surgery and FDG PET/CT for diagnosing true positivity2 where as EANM recommended a minimum of 1 month24 and this has to be decided on a case-to-case basis. FDG PET/CT has been added as a major criterion in the ESC 2015 guidelines. The latest ESC guidelines 2023 stressed the importance of FDG PET/CT in suspected cases of PVE and CDRIE and if it is unavailable WBC- SPECT/CT should be considered. They recommended FDG PET/CT for ruling out peripheral foci in NVE and PVE which is equally important in the management.25
8. Future directions
Work is in progress on newer PET tracers, their safety and efficacy have to be evaluated before applying them in clinical practice. The introduction of bacteria-specific tracers and antibody-specific tracers developed against bacterial cell membranes is a way forward and work is underway.
Coupling multimodality imaging like PET/Magnetic resonance imaging (MRI) will play a major role in future as PET helps in localizing the infection/inflammation and MRI assists in tissue characterization.7 Adding FDG PET/CT scans in the workup of IE requires prospective randomized trials or multi-centred registries in larger cohorts of patients to enable updating the guidelines in future.
9. Conclusions
Integrating FDG PET/CT to mDC enhances diagnostic accuracy particularly in detecting extra-cardiac foci and the test is devoid of nephrotoxicity. It can help to predict the prognosis and risk of embolic events when indicated by elevated CRP levels with increased FDG uptake in the vicinity of the tissues. NMRLAS recommended SUV ratio of ≥2.0 has 100 % sensitivity and 91 % specificity for definitive diagnosis of PVE. Echocardiography has been the cornerstone in the diagnosis of IE and it can be enhanced by adding MDCT and FDG PET/CT scans. Metabolic imaging is an adjunct in the diagnostic armamentarium of IE.
Financial support and sponsorship
NIL.
Conflicts of interest
NIL.
Declaration of competing interest
The authors have none to declare.
References
- 1.Li J.S., Sexton D.J., Mick N., et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633–638. doi: 10.1086/313753. [DOI] [PubMed] [Google Scholar]
- 2.Habib G., Lancellotti P., Antunes M.J., et al. 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;36:3075–3128. doi: 10.1093/eurheartj/ehv319. 2015. [DOI] [PubMed] [Google Scholar]
- 3.Philip M., Tessonier L., Mancini J., et al. Comparison between ESC and Duke criteria for the diagnosis of prosthetic valve infective endocarditis. JACC Cardiovasc. Imaging. 2020;13:2605–2615. doi: 10.1016/j.jcmg.2020.04.011. [DOI] [PubMed] [Google Scholar]
- 4.Pizzi M.N., Roque A., Fernández-Hidalgo N., 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):1113–1126. doi: 10.1161/CIRCULATIONAHA.115.015316. [DOI] [PubMed] [Google Scholar]
- 5.Gomes A., Glaudemans A.W.J.M., Touw D.J., et al. Diagnostic value of imaging in infective endocarditis: a systematic review. Lancet Infect Dis. 2017;17:e1–e14. doi: 10.1016/S1473-3099(16)30141-4. [DOI] [PubMed] [Google Scholar]
- 6.Habets J., Tanis W., Reitsma J.B., et al. Are novel non-invasive imaging techniques needed in patients with suspected prosthetic heart valve endocarditis? A systematic review and meta-analysis. Eur Radiol. 2015;25(7):2125–2133. doi: 10.1007/s00330-015-3605-3507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Pretet Valentin, Blondet Cyrille, Ruch Yvon, et al. Advantages of 18F-FDG PET/CT imaging over modified Duke criteria and clinical presumption in patients with challenging suspicion of infective endocarditis. Diagnostics. 2021;11:720. doi: 10.3390/diagnostics11040720. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kestler M., Munoz P., Rodriguez-Creixems M., et al. Role of 1⁸F-FDG PET in patients with infectious endocarditis. J Nucl Med. 2014;55:1093–1098. doi: 10.2967/jnumed.113.134981. [DOI] [PubMed] [Google Scholar]
- 9.Glaudemans A.W., Signore A. FDG PET/CT in infections: the imaging method of choice? Eur J Nucl Med Mol Imag. 2010;37:1986–1991. doi: 10.1007/s00259-010-1587-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Asmar A., Ozcan C., Diederichsen A.C., Thomassen A., Gill S. Clinical impact of 1⁸F-FDG PET/CT in the extra cardiac work-up of patients with infective endocarditis. Eur Heart J Cardiovasc Imaging. 2014;15:1013–1019. doi: 10.1093/ehjci/jeu054. [DOI] [PubMed] [Google Scholar]
- 11.Orvin K., Goldberg E., Bernstine H., et al. The role of FDG PET/CT imaging in early detection of extra-cardiac complications of infective endocarditis. Clin Microbiol Infect. 2015;21:69–76. doi: 10.1016/j.cmi.2014.08.012. [DOI] [PubMed] [Google Scholar]
- 12.Kamani C.H., Allenbach G., Jreige M., et al. Diagnostic performance of 18F-FDG PET/CT in native valve endocarditis: systematic review and bivariate meta-analysis. Diagnostics. 2020;10(10):754. doi: 10.3390/diagnostics10100754. [This meta-analysis gives an overview of studies evaluating FDG-PET/CT accuracy for suspected native valve endocarditis] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Wang T.K.M., Sánchez-Nadales A., Igbinomwanhia E., Cremer P., Griffin B., Xu B. Diagnosis of infective endocarditis by subtype using 18Ffluorodeoxyglucose positron emission tomography/computed tomography: a contemporary meta-analysis. Circ Cardiovasc Imaging. 2020;13(6) doi: 10.1161/CIRCIMAGING.120.010600. [This meta-analysis gives an overview of studies evaluating FDG-PET/CT accuracy for suspected infective endocarditis of native valves, prosthetic valves, and implanted cardiac devices] [DOI] [PubMed] [Google Scholar]
- 14.Juneau D., Golfam M., Hazra S., et al. Positron emission tomography and single-photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2017;10 doi: 10.1161/CIRCIMAGING.116.005772. [DOI] [PubMed] [Google Scholar]
- 15.Ten Hove D., Treglia G., Slart R.H.J.A., et al. The value of 18F-FDG PET/CT for the diagnosis of device-related infections in patients with a left ventricular assist device: a systematic review and meta-analysis. Eur J Nucl Med Mol Imag. 2021;48(1):241–253. doi: 10.1007/s00259-020-04930-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Mathieu C., Mikaïl N., Benali K., et al. Characterization of 18F-fluorodeoxyglucose uptake pattern in noninfected prosthetic heart valves. Circ. Cardiovasc. Imaging. 2017;10 doi: 10.1161/CIRCIMAGING.116.005585. [PubMed] [DOI] [PubMed] [Google Scholar]
- 17.Zhou Wenhui, Moradi Farshad, Guido Davidzon, et al. A case-based primer on FDG PET/CT for imaging cardiovascular infections: protocol, interpretation, and pitfalls. Journal of Nuclear Medicine June. 2023;64(supplement 1):532. [Google Scholar]
- 18.Immaneni Sathyamurthy, Ramasubramanian V., Indirani M., Shelley S. Localization of focus by 18 F-fludeoxyglucose positron emission tomography computed tomography in the definitive diagnosis of infective endocarditis. Jour of Ind Coll of Card. 2020;10:187–189. [Google Scholar]
- 19.Swart Laurens E., Gomes Anna, Scholtens Asbjørn M., et al. Improving the diagnostic performance of 18F-fluorodeoxyglucose positron-emission tomography/computed tomography in prosthetic heart valve endocarditis. Circulation. 2018;138:1412–1427. doi: 10.1161/CIRCULATIONAHA.118.035032. [DOI] [PubMed] [Google Scholar]
- 20.San S., Ravis E., Tessonier L., et al. Prognostic value of 18F-Fluorodeoxyglucose positron emission tomography/computed tomography in infective endocarditis. J Am Coll Cardiol. 2019;74:1031–1040. doi: 10.1016/j.jacc.2019.06.050. [DOI] [PubMed] [Google Scholar]
- 21.Pelletier-Galarneau M., Abikhzer G., Harel F., Dilsizian V. Detection of native and prosthetic valve endocarditis: incremental attributes of functional FDG PET/CT over morphologic imaging. Curr Cardiol Rep. 2020;22:93–w. doi: 10.1007/s11886-020-01334-w. [DOI] [PubMed] [Google Scholar]
- 22.Erba P.A., Lancellotti P., Vilacosta I., et al. Recommendations on nuclear and multimodality imaging in IE and CIED infections. Eur J Nucl Med Mol Imag. 2018;45:1795–1815. doi: 10.1007/s00259-018-4025-0. [DOI] [PubMed] [Google Scholar]
- 23.Vogt P.R., Stallmach T., Niederhäuser U., et al. Explanted cryopreserved allografts: a morphological and immunohistochemical comparison between arterial allografts and allograft heart valves from infants and adults. Eur J Cardio Thorac Surg. 1999;15(5):639–645. doi: 10.1016/j.jtcvs.2015.10.069. [DOI] [PubMed] [Google Scholar]
- 24.de Camargo R.A., Sommer Bitencourt M., Meneghetti J.C., et al. The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the diagnosis of left-sided endocarditis: native vs prosthetic valves endocarditis. Clin Infect Dis. 2020;70:583–594. doi: 10.1093/cid/ciz267. [DOI] [PubMed] [Google Scholar]
- 25.Delgado V., Marsan N.A., de Waha S., et al. On behalf of the ESC scientific document group. 2023 ESC guidelines for management of endocarditis: key points. Journal of American coll cardiology. European Heart Journal. 2023:ehad193. doi: 10.1093/eurheartj/ehad193. [DOI] [Google Scholar]