Added value of 18F-FDG-PET/CT and cardiac CTA in suspected transcatheter aortic valve endocarditis
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Transcatheter-implanted aortic valve infective endocarditis (TAVI-IE) is difficult to diagnose when relying on the Duke Criteria. Our aim was to assess the additional diagnostic value of 18F-fluorodeoxyglucose (18F-FDG) positron emission/computed tomography (PET/CT) and cardiac computed tomography angiography (CTA) in suspected TAVI-IE.
A multicenter retrospective analysis was performed in all patients who underwent 18F-FDG-PET/CT and/or CTA with suspected TAVI-IE. Patients were first classified with Duke Criteria and after adding 18F-FDG-PET/CT and CTA, they were classified with European Society of Cardiology (ESC) criteria. The final diagnosis was determined by our Endocarditis Team based on ESC guideline recommendations.
Thirty patients with suspected TAVI-IE were included. 18F-FDG-PET/CT was performed in all patients and Cardiac CTA in 14/30. Using the Modified Duke Criteria, patients were classified as 3% rejected (1/30), 73% possible (22/30), and 23% definite (7/30) TAVI-IE. Adding 18F-FDG-PET/CT and CTA supported the reclassification of 10 of the 22 possible cases as “definite TAVI-IE” (5/22) or “rejected TAVI-IE” (5/22). This changed the final diagnosis to 20% rejected (6/30), 40% possible (12/30), and 40% definite (12/30) TAVI-IE.
Addition of 18F-FDG-PET/CT and/or CTA changed the final diagnosis in 33% of patients and proved to be a valuable diagnostic tool in patients with suspected TAVI-IE.
KeywordsInfection valvular heart disease CT PET
European Association of Nuclear Medicine Research Ltd
European Society of Cardiology
Positron emission tomography
Prosthetic heart valve endocarditis
Standardized uptake value
Transcatheter aortic valve
Transcatheter aortic valve infectious endocarditis
Transcatheter aortic valve implantation (TAVI) is now an accepted and widely applied treatment for aortic valve stenosis in selected patient populations.1 As a major complication, prosthetic heart valve endocarditis (PVE) after a TAVI (TAVI-IE) has been reported to occur with an incidence of 1.6 events per 100 person-years.2 However, the timely diagnosis of this serious disease remains a challenge when using only the modified Duke Criteria because transthoracic or transesophageal echocardiography (TTE and TEE) may be impaired by artifacts (acoustic shadowing/reverberation) caused by the metallic stent around the valve.
The most recent European Society of Cardiology (ESC) guidelines for infectious endocarditis introduced 18F-fluorodeoxyglucose (18F-FDG) positron emission/computed tomography (PET/CT) and cardiac computed tomography angiography (CTA) as additional diagnostic tools for suspected PVE.3 For surgically implanted prosthetic valves, several reports have described the additional value of 18F-FDG-PET/CT (both visual and quantitative assessment) and CTA in diagnosing PVE as well as how to acquire and interpret the images.4, 5, 6, 7, 8 In suspected TAVI-IE, these additional imaging tools also may have diagnostic value resulting in a different treatment strategy; however, reports on TAVI-IE are still very scarce.9
The purpose of this study was to assess the additional diagnostic value of 18F-FDG-PET/CT and/or cardiac CTA in patients suspected of TAVI-IE when added to the modified Duke Criteria.
Materials and Methods
All patients with a history of TAVI who were referred to six different hospitals and underwent either 18F-FDG-PET/CT and/or cardiac CTA for suspicion of TAVI-IE were retrospectively included in this study. The institutional medical ethics committee approved the study and waived the need for informed consent.
All data were extracted from the electronic patient records in each hospital. Both the modified Duke Criteria (echocardiographic findings, blood cultures, and clinical features) and the 2015 ESC criteria (modified Duke Criteria with the addition of 18F-FDG-PET/CT and CTA) were used to score each patient and give them interim diagnoses.3 The final diagnosis (either rejected, possible, or definite TAVI-IE) was established by consensus via the multidisciplinary Endocarditis Team in each hospital, using the latest ESC criteria and all clinical records. This meeting was scheduled within 1 to 7 days after all clinical data (including PET/CT and the eventual CTA) were available. Participants of this multidisciplinary meeting included at least a cardiologist, cardiothoracic surgeon, an infectious disease specialist, and a cardiac radiologist/nuclear medicine physician.
Blood culture results from the period in which patients were hospitalized were included and used for analysis. Blood cultures were deemed positive according to the modified criteria in the latest ESC guidelines for infective Endocarditis.3
Either TTE, TEE, or both were performed in all included patients, following the current guidelines. The examinations were reported by a certified cardiologist as part of clinical practice and the clinical reports were used for this study. TTE/TEE was considered positive if at least one echo demonstrated the presence of an anatomical and/or echocardiographic criteria for endocarditis according to the ESC guidelines.3.
Patients followed a 24-hour low carbohydrate diet (of which the last 12 hours were spent fasting) to induce free fatty acid metabolism and suppress glucose metabolism in the myocardium.10, 11, 12 One hour after an intravenous 18F-FDG injection [on average 215 megabecquerel (MBq)], a total body or skull-midthigh 18F-FDG-PET/CT scan was acquired using a Siemens Biograph mCT/mCT flow or Philips Gemini TF camera system. Additionally, a low dose CT was performed for attenuation correction.
CTA imaging was performed on a dual source CT scanner (Siemens, SOMATOM FORCE or Flash). Scans were performed either with retrospective ECG-gating or a dedicated CT acquisition protocol with ECG-gating tailored to the imaging of prosthetic heart valves to provide optimal image quality at minimal radiation exposure.13
Image Analysis and Interpretation
Visual analyses of 18F-FDG-PET/CT images had been performed by a nuclear medicine physician as part of clinical practice, while additional quantitative 18F-FDG-PET/CT analyses were performed by an experienced nuclear medicine physician (AS, RS).
The maximum standardized uptake value (SUVmax) was measured in an automated volume of interest (VOI) with a 40% isocontour around the valve on reconstructions that were provided through a standardized calibration and reconstruction method by the European Association of Nuclear Medicine Research Ltd (EARL) when available.7 The target to background ratio (SUVratio) was then calculated as the ratio of the SUVmax of the valve and the SUVmean of the blood pool in the descending aorta, not including the vessel wall. In all available cases, these measurements were also performed in non-EARL accredited reconstructions.
Additionally, extra cardiac 18F-FDG uptake was defined as either physiological, possible embolization, pathological lymph node, or extra cardiac infections/inflammation.
Cardiac CTA analysis
The CTA scans had been reported by a cardiac radiologist as part of clinical practice. We used the original clinical report to score for signs of infectious endocarditis (vegetations, mycotic aneurysms, abscesses, paravalvular leakage, and valve dehiscence).
For analysis of our main outcomes, descriptive statistics was used. Non-parametric statistical analyses (Mann-Whitney U test) were performed for the comparison of continuous variables in rejected and definite TAVI-IE. The interquartile ranges (IQR) and confidence intervals (CI) were denoted in square brackets. A significance level of P = 0.05 and 95% CIs were used. In case of missing data, patients were excluded from analyses of certain parameters. SPSS statistics v24.0 (IBM Corp) was used for all analyses.
Information on patient follow-up was derived from the electronic patient records in each hospital. Follow-up time was defined as the period between the admission date until the date of the last notation in the clinical records. Data about mortality were derived from the Central Bureau for Statistics (CBS) database (100% available).
Patient Characteristics and Classification
All patients with suspicion of TAVI endocarditis
Definite TAVI endocarditis
Possible TAVI Endocarditis
Rejected TAVI endocarditis (after initial suspicion)
n = 30
n = 12
n = 12
n = 6
Age, mean ± SD, years
77 ± 11
73 ± 9
79 ± 12
79 ± 11
Gender, male, n (%)
BMI median [IQR], kg/m2
Prior history of endocarditis, n (%)
Time since valve implantation, median [IQR], days
Valves implanted < 3 months prior to PET, n (%)
Type of valve, n (%)
Valve in valve TAVI, n (%)
Device, n (%)
1 lead pacemaker
2 lead pacemaker
Bloodcultures available, n (%)
Positive blood cultures, n (%)
Negative blood cultures
Days of IV antibiotic therapy prior to 18F-FDG-PET/CT, median[IQR]
CRPa,b, median[IQR], mg/L
Leukocytesa,b, median[IQR], ×109/L
Median follow-up period[IQR] (days)c
All-cause mortality, n (%)
Blood culture results were available for all patients and were positive at least once in 29/30 patients. Enterococcus faecalis was the most common type of microorganism in patients with a final diagnosis of “definite TAVI-IE” (4/12) and those with “rejected TAVI-IE” (3/6).
The reports of TTE and/or TEE were available in all cases. TTE and/or TEE was positive in 6/12 patients with a final diagnosis of “definite TAVI-IE” and in 2/12 patients with “possible TAVI-IE” (1 with negative blood cultures and 1 with positive blood cultures but not meeting the major ESC criteria). In the “rejected TAVI-IE” group TTE and TEE were negative in all cases.
Time interval from implantation, infection parameters, days of iv antibiotic therapy, SUVmax , and SUVratio around the prosthetic valve prior to 18F-FDG-PET/CT in patients with a positive-reported and negative-reported 18F-FDG-PET/CT scan
Time since valve implantation, median [IQR], days
393 [105–1212], P = 0.29*
CRP, median [IQR], mg/L
62 [18–127], P = 0.15*
Leukocytes, median [IQR], ×109/L
9.6 [6.0–12.5], P = 0.63*
Days of IV antibiotic therapy prior to 18F-FDG-PET/CT, median [IQR]
9 [7–14], P = 0.48*
SUVmax, median [IQR]
3.6 [3.4–4.4], P = 0.01*
SUVratio, median [IQR]
1.9 [1.7–2.1], P = 0.04*
Extra cardiac 18F-FDG uptake was noticed in 19 patients, including 9 patients with a final diagnosis of definite TAVI-IE. Five patients were reclassified as rejected TAVI-IE after the 18F-FDG-PET/CT demonstrated abnormal 18F-FDG uptake elsewhere in the body, indicating an alternative infection that explained the clinical symptoms (without any signs of it being a septic embolic complication of endocarditis).
SUVmax and SUVratio on the 18F-FDG-PET/CT scans for patients with definite, possible, and rejected TAVI-IE
All EARL standardized scans
n = 8
n = 7
n = 5
SUVmax, median [IQR]
3.6 [3.3–3.9] P = 0.83*
SUVratio, median [IQR]
1.7 [1.3–2.3] P = 0.38*
Non-EARL standardized scans
n = 12
n = 11
n = 6
SUVmax, median [IQR]
4.2 [3.4–4.5] P = 0.85*
SUVratio, median [IQR]
1.9 [1.8–2.3] P = 0.40*
There was a significant difference between the SUVmax and SUVratio measured in the positive-reported 18F-FDG-PET/CT scans compared to the negative-reported 18F-FDG-PET/CT scans.
Cardiac CTA was performed in 14/30 patients (47%) including 9/12 patients with definite, 2/12 with possible, and 3/6 with rejected TAVI-IE. Positive signs of endocarditis such as vegetation (n =5), mycotic aneurysm (n = 1), and both vegetation and mycotic aneurysm (n = 1) were noticed in 7/9 (78%) patients with “definite TAVI-IE” (CTA not performed in 3/12 patients with definite endocarditis). The other 2/9 patients with definite TAVI-IE but negative CTA either had positive signs of TAVI-IE on the 18F-FDG-PET/CT (1/2) or TTE/TEE (1/2). Three out of 7 patients with a positive CTA had no signs of endocarditis on the TTE/TEE. The mycotic aneurysms detected in 2 cases on CTA were not visible on TTE/TEE
Impact of 18F-FDG-PET/CT and CTA
18F-FDG-PET/CT helped to reclassify 8 patients from the initial possible TAVI-IE group to either the definite TAVI-IE group (3/8) or the rejected TAVI-IE group (5/8). Additionally, CTA aided in the reclassification of an additional 2 patients that had a normal 18F-FDG-PET/CT by identifying vegetations or other structural abnormalities, while strengthening the reclassification by 18F-FDG-PET/CT in 4 patients by also depicting structural abnormalities when increased 18F-FDG uptake had already been identified. Details of reclassification and the number of imaging techniques used in each group are demonstrated in Figures 1 and 2.
In daily clinical practice, patients with a prosthetic valve who show signs of unexplained infection and develop positive blood cultures are highly suspected for endocarditis. Even if echocardiography does not show any signs of endocarditis, these patients may be pragmatically treated as such, however, this has major clinical implications. If 18F-FDG-PET/CT shows signs of infection elsewhere without any signs of endocarditis, this may lead to a change in diagnosis and reduction of the antibiotic treatment period. On the other hand, if the diagnosis is changed to definite endocarditis due to 18F-FDG-PET/CT findings, the antibiotic treatment may be prolonged or even adjusted to lifelong suppression therapy. All these changes might have effects on morbidity and mortality.
Although we did not encounter them in this study, false positive 18F-FDG-PET/CT results can occur in PVE and therefore cautious interpretation of 18F-FDG-PET/CT scans is advised, particularly taking into account the known confounders.7,12 Potentially, chronic inflammation and thus a false 18F-FDG uptake might also be caused by continuous movement and friction of the transcatheter-implanted valve. Moreover, the presence of calcifications on the native aortic valve, which are not removed during a TAVI procedure, may cause artifacts and thus false positive 18F-FDG-PET/CT results. Overcorrection of the 18F-FDG uptake signal inside the valve ring may occur during the attenuation correction (AC) due to (artifacts coming from) the metal stent around the TAVI prosthesis, necessitating side-by-side interpretation of AC and non-AC images. In a recent large study of patients suspected of PVE (including TAVI-IE), recent valve implantation was not found to be a significant predictor of a false positive 18F-FDG-PET/CT scan.6 In addition, the inflammation response caused by percutaneously implanted valves may even be less compared to the surgically implanted valves.
The standardization of calibration and reconstruction method between centers remains challenging and EARL reconstruction is not formally recommended for cardiac purposes. In our study we performed the quantitative analysis on both the EARL- as well as the non-EARL-reconstruction images and on both analyses we did not find a statistically significant difference between the rejected TAVI-IE and the definite TAVI-IE groups.
In a recent study, quantitative assessment of 18F-FDG-PET/CT after exclusion of significant confounders produced cutoff values with good diagnostic accuracy.6 Our results did not corroborate these findings in TAVI-IE (Table 3). Comparing our results to the earlier study, 18F-FDG-PET/CT seems more likely to underdiagnose TAVI-IE than PVE in general, although we must be cautious in generalizing our findings. Our study contained 5 patients with a false negative 18F-FDG-PET/CT scan, who had signs of a vegetation on either CTA (2/5), TTE/TEE (1/5), or both (1/5). This underlines the value of anatomic imaging with CTA and echocardiography (on top of metabolic imaging) in order to detect vegetations which may easily be missed by 18F-FDG-PET/CT due to the low inflammatory response associated with vegetations.
The value of 18F-FDG-PET/CT and cardiac CTA in the diagnosis of TAVI-IE was, besides case reports,13 only shown once before in a recently published case series of 16 patients.9 It showed significant potential of this multi-imaging approach and suggested the use of ESC criteria for the diagnosis of TAVI-IE. Our results confirm these findings. Moreover our study demonstrates the additional diagnostic value of 18F-FDG-PET/CT and CTA for patients suspected for TAVI-IE. It results in a change of the final diagnosis when the ESC criteria are applied instead of the modified Duke criteria alone and supports a more widened use of these relatively new techniques.
All the mentioned imaging techniques seem to have additional diagnostic value. Although the newer imaging techniques are expensive and associated with some radiation, they provide important extra information allowing a better diagnostic process, which is crucial for these seriously ill patients.
There are several limitations to our study. The most important is the way the final diagnosis was established. Since no patient had undergone surgery, we relied on the ESC criteria and the decision of the Endocarditis Team for the final diagnosis. Since 18F-FDG-PET/CT and CTA results were taken into account when making the decision for the final diagnosis, this can be seen as an incorporation bias and thus as a major limitation of this study. However, due to the retrospective design of the study, this could not readily have been prevented. This problem exists in most endocarditis studies as the pathological Duke criteria are often not available.3 Additionally, the retrospective nature of the study and relatively small number of patients limit the generalization of our findings to all patients with TAVI-IE.
In conclusion, the addition of 18F-FDG-PET/CT and CTA in the work-up of patients with suspected TAVI-IE provided valuable complementary information to echocardiography, resulting in reclassification of 33% of patients in our study.
New Knowledge Gained
18F-FDG-PET/CT and CTA help clinicians to assess patients with TAVI-IE and both of these imaging tools should be considered in the diagnostic work-up of patients with suspected TAVI-IE.
Ali R. Wahadat, Wilco Tanis, Laurens E. Swart, Asbjørn Scholtens, Gabriel P. Krestin, Nicolas M.D.A. van Mieghem, Carolina A.M. Schurink, Tycho I.G. van der Spoel, Floris S. van den Brink, Tessel Vossenberg, Riemer H.J.A. Slart, Andor W.J.M. Glaudemans, Jolien W. Roos-Hesselink, and Ricardo P.J. Budde have nothing to disclose.
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