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The role of FDG-PET-CT in pediatric cardiac patients and patients with congenital heart defects
International Journal of Cardiology 220 (2016) 656–660
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The role of FDG-PET-CT in pediatric cardiac patients and patients with congenital heart defects Zora Meyer a,⁎, M. Fischer a,c, J. Koerfer b, K.T. Laser a, D. Kececioglu a, W. Burchert b, S. Ulrich c, R. Preuss b, N.A. Haas a,c a b c
Department for Congenital Heart Defects, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Germany Department for Radiology, Nuclear Medicine and Molecular Imaging, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Germany Department of Pediatric Cardiology and Intensive Care, Ludwig Maximilians University Munich, Campus Grosshadern, Munich, Germany
a r t i c l e
i n f o
Article history: Received 19 March 2016 Received in revised form 27 May 2016 Accepted 21 June 2016 Available online 23 June 2016 Keywords: PET-CT Pediatric cardiology Congenital heart defects Assist device Endocarditis
a b s t r a c t Aim: Medical imaging by using FDG-PET/CT (PET-CT) can detect, confirm or eliminate with high sensitivity areas of suspected infections in case of persistent fever of unknown origin in combination with other bacteriological examinations. The aim of this study was to assess the potential role of PET-CT in detecting or excluding infections or other inflammatory processes in patients with congenital heart defects (CHD). In addition we wanted to evaluate the practical impact of PET-CT on the subsequent clinical management. Methods: In this retrospective study we analyzed the data of all CHD patients who underwent PET-CT over a 5 year period in our institution. The results were then evaluated with regard to the potential impact on clinical decision making. Results: Between 2010 and 2015 PET-CT was performed in 30 patients. The mean age was 26 years (SD 15 years, range 1 to 66 years). The diagnoses covered a large field of CHD. 11 patients (4/11 with assist device) were assessed before heart transplantation; suspected malignancies or infections were excluded and transplant listing was possible. In another 5/6 patients suspected assist device infection could be confirmed with PET/CT. Endocarditis was suspected in 13 patients, 2 of whom underwent previous MRI without confirmation and ECHO was inconclusive. Endocarditis was finally excluded in 5/13 patients but confirmed in 8/13 patients by PET-CT. Conclusion: In this study we could show a high sensitivity of PET-CT for specific localization of infections and with high impact on subsequent therapy. Based on this results clinical management could be targeted and adapted. We could demonstrate that PET-CT has a high impact on the subsequent clinical therapy. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction The use of FDG-PET/CT (PET-CT) in pediatric care is a growing field of interest. Traditionally, PET-CT was increasingly used in the evaluation of children with various malignancies, based on a high glycolytic activity in malignant cells [1–3]. Similarly, many infectious and inflammatory processes can be imaged with PET-CT based on a high uptake of FGD in inflammatory cells [4]. This knowledge has prompted a growing interest to employ PET-CT in inflammatory and infectious disease [5,6]. The use of PET/CT in cardiologic patients has been described in adult patients, where a high sensitivity and specificity in the diagnostics of infectious endocarditis was reported. In addition an excellent negative
⁎ Corresponding author at: Department of Pediatric Cardiology and Intensive Care, Ludwig Maximilians University (LMU) Munich, Campus Grosshadern, Marchioninistrasse 15, D81377 Munich, Germany. E-mail addresses: [email protected] (Z. Meyer), [email protected] (N.A. Haas).
http://dx.doi.org/10.1016/j.ijcard.2016.06.109 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
predictive value offers an almost complete exclusion of infectious endocarditis [7]. Cardiac FDG uptake is however not specific for the diagnosis of endocarditis. FDG accumulation has been demonstrated with cardiac tumors, active cardiac sarcoidosis, and even in atheromatous plaques with active inflammation. Valve endocarditis remains also a severe complication of cardiac and valve surgery or catheterization intervention in patients with congenital heart disease (CHD). The diagnosis of valve associated endocarditis is challenging, especially when additional prosthetic material such a stent or artificial valves are involved. The gold standard for the diagnosis of endocarditis is trans-esophageal echocardiography (TEE). TEE can be however non-conclusive or even falsely negative especially in patients with artificial implants. In these circumstances PET-CT is a potentially promising diagnostic tool for several infectious conditions. The limited donor organ availability for heart transplantation has resulted in increasing numbers of patients with CHD and advanced heart failure resulting in the necessity to implant left or right ventricular assist devices as a bridge to transplant or destination therapy. Patient
Z. Meyer et al. / International Journal of Cardiology 220 (2016) 656–660
with assist device infection present signs of systemic illness and abnormal blood markers for infection. Local infection signs may also occur. However the clinical presentation is highly variable and patients may also present with only a mild or even absent local reaction posing a diagnostic challenge. Delay in diagnosis and treatment can result in progression to severe sepsis and therefore worsen clinical outcome. In these cases PET-CT may have a high diagnostic accuracy for confirm or exclude an assist device infection. We report the use of PET-CT in patients with CHD for the potential diagnosis of endocarditis, assist device infections and for screening for inflammation and malignancies before heart transplantation. 2. Methods In this retrospective study we analyzed the data of all CHD patients who underwent PET-CT in our institution between 2010 and 2015. The detailed patient data, the diagnosis, the clinical course and the indications for PET-CT were analyzed. Then the results of PET-CT were assessed and the impact on the subsequent medical management was evaluated.
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3.2. Indications PET-CT was performed to screen for infections and malignancies before heart-transplantation (n = 11), for detecting endocarditis or foci of septic embolization (n = 13) and for detecting potential assist device infection (n = 6). 3.3. Detection of infections and malignancies before heart transplantation The patients (n = 11) assessed before heart transplantation showed no malignancies or infections and transplant listing was possible. 4/11 patients were on assist devices and therefore an assessment by MRI was not possible. 3.4. Detection of assist device infection In 5/6 patients assist device infection could be confirmed. The antibiotic therapy was continued in 5 patients and stopped in 1 (typical example see Fig. 1a and b). 3.5. Detection of endocarditis
3. Results 3.1. Patients Between 2010 and 2015 F 18 FDG PET-CT was performed in 30 patients; the detailed data are shown in Table 1. (See Tables 2 and 3.) The mean age was 26 years (SD 15 years, range 1 to 66 years), the height was 160 cm (SD 26 cm). and the weight was 60 kg (SD 24 kg) The diagnoses covered a large field of CHD: pulmonary atresia (PA) with ventricular septal defect (VSD) and major aortopulmonary collaterals (MAPCAS) (n = 1), transposition of the great arteries (TGA) after Mustard operation (n = 3) and assist device implantation (n = 2), congenital corrected (cc) TGA (n = 3) with assist device (n = 1), aortic coarctation (CoA) (n = 2), mechanical aortic valve (n = 1), Fallot group (n = 5) and conduit (n = 4), Ebstein's anomaly (n = 3) and Perimount™ prosthesis in tricuspid position (n = 1), Truncus and Contegra™ (n = 2), myocardial non-compaction (n = 1), Shone complex (n = 1), status post heart transplant (n = 1), atrioventricular septal defect (AVSD) and assist device (n = 1) and dilative cardiomyopathy (n = 6) with assist device (n = 6).
Endocarditis was suspected in 3/13 patients by TTE, 2 patients underwent MRI without confirmation of endocarditis. Endocarditis was confirmed in 8/13 patients by FDG-PET-CT. The patient with PA and MAPCASs had aortic valve endocarditis with embolization to the spleen and lung, 1 patient with CoA and a bicuspid aortic valve had aortic valve endocarditis with embolization in the spleen, 1 patient with ccTGA had a pulmonary valve endocarditis, 4 patients with tetralogy of Fallot (TOF) had conduit endocarditis and 2 patients with pulmonary valve conduits had septic embolization to the lung (example see Fig. 2) and 1 patient with TAC and a conduit in pulmonary position had recurrent endocarditis with embolizations in the lung. The antibiotic therapy was continued in 8/13 and stopped in 5/12. The patient with TAC (Truncus arteriosus communis) and conduit endocarditis had surgery during infection with conduit change. 4. Discussion FDG-PET-CT is an established diagnostic tool in the evaluation of children and adolescents with various malignancies [1,2]. Traditionally,
Table 1 Valve endocarditis cases diagnosed by FDG-PET-CT. CHD
Age Sex Prosthetic valve
PA, VSD, MAPCAs
29
m
CoA Aortic valve stenosis TOF
17
f
11
m
Contegra in PA-Position
TOF
55
f
TOF TAC
17 8
f f
TOF
22
f
Carbomedics-prosthetic valve in PA-position Contegra in PA-position Contegra in PA position, stent RPA, LPA Conduit in PA-position
ccTGA, VSD Ebstein's anomaly
14 66
m f
Ebstein's anomaly 16 Aortic valve stenosis 23
m m
TAC CoA
m m
15 26
Blood cultures
Multiples stent in MAPCAS Staphylococcus aureus
Sreptococcus mitis
Perimount prosthesis in tricuspid position Prosthetic valve in aortic position Contegra PA-position
Diagnosis
Initial TTE PET-CT
Therapy
Aortic valve IE Embolisation lungs, spleen Aortic valve IE
Positive
Embolisation lungs, spleen,
Antibiotic
Positive
Embolisation spleen
Staphylococcus aureus
IE Pa-position, embolisation lung Staphylococcus aureus IE of the prosthetic PA-valve Staphylococcus capitis Pa-valve IE Lactobazillus rhamnosus IE Pa position, embolisation lung Negative Conduit IE embolisation lung Negative Pa-valve IE Negative Excluded IE
Negative Negative
Antibiotic, homograft in aortic position Contegra IE embolisation Antibiotic in the lung Pa-valve endocarditis Antibiotic, homograft in PA-position Pa-valve IE Antibiotic Conduit IE with lung Antibiotic embolisation Conduit IE with lung Antibiotic embolisation Pa-valve IE Antibiotic Negative Antibiotic stop
Positive Negative Negative Negative Negative
Negative Negative
Excluded IE Excluded IE
Negative Negative
Negative Negative
Stop antibiotic Antibiotic stop
Negative Negative
Excluded IE Excluded IE
Negative Negative
Negative Negative
Antibiotic stop Antibiotic stop
Explanations: PA = pulmonary atresia, VSD = ventricular septum defect, ccTGA = congenital corrected transposition of the great arteries, MAPCAs = major aortopulmonary collaterals, CoA = aortic coarctation, TOF: tetralogy of Fallot, Pa = pulmonary artery, TAC = Truncus arteriosus communis, IE = infectious endocarditis.
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Table 2 Assist device infection diagnosed by PET-CT. CHD
Age
Sex
Assist device
Duration of implantation
Blood culture/lesion swab
PET-CT
Diagnosis
Therapy
Dilatative cardiomyopathy Dilatative cardiomyopathy Dilatative cardiomyopathy Dilatative cardiomyopathy TGA after Mustard
1.8
m
Berlin Heart, LVAD
8 months
Pseudomonas aeroginosas
Driveline infection
23
m
Heart ware LVAD
1 year 1 month
Negative
Outflow driveline infection Negative
Antibiotic, heart transplantation Antibiotic stop
20
m
Heart ware, LVAD
9 months
Staphyloccus aureus
18
m
Heart ware, LVAD
1 year 1 month
Staphylococcus aureus
39
w
Heart Ware, LVAD
2 years
Streptococcus mitis
AVSD
4.4
m
Berlin Heart, LVAD
3 months
Negative
Outflow driveline infection Driveline infection Outflow driveline infection Driveline infection
Excluded assist device infection Driveline infection
Antibiotic, HU listing
Driveline infection
Antibiotic, HU listing
Driveline Infection
Antibiotic, HU-listing, heart transplantation Antibiotic
Driveline infection
Explanations: AVSD = atrioventricular septal defect, TGA = transposition of the great arteries, LVAD = left ventricular assist device.
PET-CT use in oncology is based on the increased glycolytic uptake in malignant cells and overexpression of glucose transporters. The most common indications for FDG-PET-CT in pediatric oncology include lymphoma, sarcoma and neuroblastoma [8]. Tissue inflammation results also in an increased fluorine-18-fluorodeoxyglucose (FDG) accumulation based on a high uptake of FGD in inflammatory cells, making the PET-CT useful for detecting of chronic and acute infections [4,9–12]. As mentioned before, cardiac FDG uptake is not specific for the diagnosis of endocarditis. FDG accumulation has been demonstrated with other diseases or processes related to increased glucose metabolism such as cardiac tumors, active cardiac sarcoidosis, and even in atheromatous plaques with active inflammation. Guidelines for the use of PET-CT in inflammation and infection were published from the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging [13]. These guidelines state that the major indication for PET-CT are sarcoidosis, peripheral bone osteomyelitis, suspected spinal infection, evaluation of fever of unknown origin and primary evaluation of vasculitis. For endocarditis the guidelines described that it is unclear if PET-CT offers advantages over other imaging techniques. The guidelines haven't however described the role of PET-CT for patients with assist devices or patients with other artificial implants. Endocarditis is a high risk in patients with CHD and artificial or stented valves [14]. The diagnosis of endocarditis might be challenging due to the limited visualization of the stented valve or stent by echocardiography or trans-esophageal echocardiography. The added value of PET/CT consists in the possibility of examining the extracardiac portion of leads, the potential ability to differentiate between thrombus and vegetation especially when compared to TEE and the possibility of diagnosing septic emboli even when clinically silent. As many patients with congenital heart defects now have surgical implants such as stents, mechanical valves, conduits, and assist devices that are extremely difficult to assess by ECHO, MRI or even conventional CT based on the imaging artifacts, a more precise diagnostic tool is warranted in case of suspected infection.
Recently, PET with fluorine-18-fluorodeoxyglucose (FDG), combined with CT scan was shown to be useful in the identification and anatomic localization of inflammation and infection in patients with fever of unknown origin and may serve as an important tool in the diagnosis of endocarditis. We report the diagnosis of a pulmonary valve endocarditis in 1 patient (ccTGA), conduit endocarditis in 4 patients (TOF) (2 patients with clinically silent septic embolizations), conduit endocarditis with embolization in the lung in 1 patient with TAC and the diagnosis of aortic valve endocarditis with previously undiagnosed septic embolization in 2 patients (1 patient PA and MAPCASs, 1 patient CoA) by PET-CT. In all patients the endocarditis had not be definitely detected or confirmed by echocardiography before. In these cases PET-CT was an important tool in establishing a definitive diagnosis of endocarditis. There are few reports of the use of PET-CT for detecting endocarditis in patient with congenital heart defects. Yedidya et al. reported the cases of 2 young patients, the first patient had a Ross and Konno repair due to supravalvular aortic stenosis and subaortic stenosis and a percutaneous pulmonary valve implantation for homograft stenosis at the pulmonic position; In the second patient with correction of transposition of great arteries and insertion of pulmonic stent in whom a TEE-based diagnosis of endocarditis of the pulmonary valve was inconclusive and was confirmed by PET-CT only [15]. Bartoletti et al. described 6 patients with aortic prosthetic valves and high clinical suspicion of endocarditis. In all cases the TEE was firstly negative and only in 2 cases the TEE became positive later. In all cases PET-CT confirmed the diagnosis of valve endocarditis [16]. TEE as the diagnostic gold standard may be disappointing in aortic and pulmonary or aortic valve endocarditis, in this case PET-CT is a helpful tool for confirming the diagnosis. PET-CT is reported to have a high sensitivity (87%) and specificity (92%) for the diagnosis of infective endocarditis of prosthetic valves and intracardiac devices – mainly pacemakers – in adult cardiologic patients [17]. Theoretically, the early use of high-dose antimicrobial treatment could decrease the amount of active inflammation in endocarditis and therefore the FDG uptake, potentially leading to a false negative result.
Table 3 PET-CT before heart transplantation. CHD
Age
Sex
TOF TGA after Mustard TGA after Mustard ccTGA ccTGA Dilatative cardiomyopathy Dilatative cardiomyopathy Myocardial non-compaction Shone complex Heart transplantation Ebstein's anomaly
28 37 22 25 50 21 42 40 37 30 46
m f m m m m f f m w m
Assist-Device Heart ware, LVAD Heart ware, LVAD Heart ware, LVAD Heart ware, LVAD
PET-CT
Impact on the therapy
Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies
Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible
Explanations: TOF = tetralogy of Fallot, ccTGA = congenital corrected transposition of the great arteries, TGA = transposition of the great arteries, LVAD = left ventricular assist device.
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Fig. 1. a: Assist device in a 1 year old patient. 1 year old male infant with a history of dilatative cardiomyopahy and Berlin Heart (LVAD) implantation. The 3-D-reconstruction of the CT shows the localization of the left ventricular assist device (Berlin Heart ®) with the thicker left ventricular outlet cannula and the smaller aortic cannula. b: Assist device infection. In the same patient. Persisting fever occurred, inflammatory markers were elevated and Pseudomonas aeruginosa was identified in skin swabs at the entry site of the exit cannula. FDGPET-CT showed an outflow cannula infection.
In our patient series, we could however not detect any patients in whom we excluded endocarditis by PET-CT and who developed a relapse of signs of endocarditis or other infections despite adequate and complete follow-up. Endocarditis can present with disseminated embolization foci. In addition hidden septic embolization foci can be detected using a whole body imaging modality such as PET-CT. We report 4 cases (2 patients with conduit endocarditis, 2 patients with aortic valve endocarditis) with septic embolizations, that were not diagnosed before and were identified with PET-CT only. Orvin et al. evaluated the role of PET-CT in the early diagnosis of extra-cardiac complications in infective endocarditis and its implications for medical management [18]. 40 patients with confirmed endocarditis underwent a whole body FDG-PET-CT, in 42.5% of the patients FDG-PET-CT demonstrated extra-cardiac complications, 38.1% of them were asymptomatic. Gheysens et al. report a case of a 59 years old woman with mitral valve endocarditis with septic pulmonary embolisms and metastatic muscle abscesses and septic arthritis detected by PET-CT [19]. This clinical information has a significant
diagnostic and therapeutic impact in managing the endocarditis. In summary, PET-CT is described as an important tool for diagnosis of extra-cardiac complications in infective endocarditis [20]. Based on the limited donor organ availability for heart transplantation left or right heart assist device have been increasingly utilized in the management of advanced heart failure as a bridge to transplantation. Driveline or device infections are associated with a significant morbidity and mortality. In the REMATCH (Randomized Evaluation of Mechanical Assistance for the treatment of Congestive Heart Failure Trial), where LVAD was first evaluated as destination therapy, 48% of patients developed sepsis at 1 year and 58% of patients at 2 years after implantation [21]. In our study we could show that PET-CT is also useful for early definitive diagnosis of assist device infection. Metal-strut-related artifacts limit the ability to identify vegetations by TEE or MRI. In our report in 5/6 patients assist device infection was definitely diagnosed by PET-CT. In addition, 4/11 patients listed for transplant had assist devices implanted thereby not suitable for MRI screening. In our series PET-CT was the definitive tool to diagnose, confirm or exclude an assist device
Fig. 2. Conduit endocarditis with septic embolizations. 8 years old female infant with TAC and a conduit in pulmonalis position was hospitalized with recurrent endocarditis and positive blood cultures for Lactobacillus rhamnosus. ECHO showed no intracardiac foci. PET-CT revealed a pulmonary valve endocarditis and septic embolization in the lung. a. Enhancement in the area of the pulmonary valve. b. Septic embolization to the right lung.
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infection. Dell'Aquila et al. [22] report a sensitivity of 100% and a specificity of 80% of PET-CT in detecting infection of VAD in adults. Kim et al. [23] also reported a high sensitivity for detecting assist device infections by PET-CT. They report 4 cases of LVAD Infection in adults detected by PET-CT. Tili et al. [24] report a case of a 59 years old female with assist device (LVAD) as bridge to transplantation for a non-ischemic cardiomyopathy. In TEE and on CT scan no abnormalities on valves or device and septic complications were shown. PET-CT was finally performed and confirmed a driveline infection [24]. FDG does not accumulate only in sites of inflammation and infection and its high sensitivity for the detection of malignant cells has led to its successful and extensive use in oncology. The high sensitivity for detecting malignancies was confirmed in previews studies [25]. We report also the use of whole body FDG-PET-CT for malignity screening before heart transplantation. The patients assessed before heart transplantation showed no malignancies and transplant listing was possible. In 4 of them assist devices were implanted and therefore the routine MRI was not possible. In addition the existence of the mechanical implant did not interfere with the diagnostic accuracy of PET-CT. 5. Conclusion In this study we could show a high sensitivity of PET-CT for specific localization of infections with high impact on subsequent therapy in patients with CHD. We believe that even in the field of pediatric cardiology and patients with congenital heart defects PET/CT is a very reliable technique in detecting acute endocarditis, septic embolization foci and for ruling out or confirming assist-device related infections in this patient group. Conflict of interest There is no conflict of interest by any of the authors regarding this report. Grants No grants used, the funding is by hospital funding only. Authors' statement All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. References [1] H. Jadvar, L.P. Connolly, F.H. Fahey, B.L. Shulkin, PET and PET/CT in pediatric oncology, Semin. Nucl. Med. 37 (5) (Sep 2007) 316–331. [2] M.B. McCarville, PET-CT imaging in pediatric oncology, Cancer Imaging 9 (Jun 29 2009) 35–43. [3] J. Freebody, E.A. Wegner, M.A. Rossleigh, 2-Deoxy-2-(18F)fluoro-D-glucose positron emission tomography/computed tomography imaging in paediatric oncology, World J. Radiol. 6 (10) (Oct 28 2014) 741–755. [4] H. Zhuang, I. Codreanu, Growing applications of FDG PET-CT imaging in nononcologic conditions, Biomed. Res. 29 (3) (May 2015) 189–202. [5] A.W. Glaudemans, E.F. de Vries, F. Galli, R.A. Dierckx, R.H. Slart, A. Signore, The use of 18 F-FDG-PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases, Clin. Dev. Immunol. 2013 (2013) 623–636. [6] S. Servaes, Imaging infection and inflammation in children with 18F-FDG PET and 18 F-FDG PET/CT, J. Nucl. Med. Technol. 39 (3) (Sep 2011) 179–182 (J Heart Lung Transplant. 2012 Sep;31(9):958–66).
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The role of FDG-PET-CT in pediatric cardiac patients and patients with congenital heart defects Zora Meyer a,⁎, M. Fischer a,c, J. Koerfer b, K.T. Laser a, D. Kececioglu a, W. Burchert b, S. Ulrich c, R. Preuss b, N.A. Haas a,c a b c
Department for Congenital Heart Defects, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Germany Department for Radiology, Nuclear Medicine and Molecular Imaging, Heart and Diabetes Centre North Rhine Westphalia, Ruhr University Bochum, Germany Department of Pediatric Cardiology and Intensive Care, Ludwig Maximilians University Munich, Campus Grosshadern, Munich, Germany
a r t i c l e
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Article history: Received 19 March 2016 Received in revised form 27 May 2016 Accepted 21 June 2016 Available online 23 June 2016 Keywords: PET-CT Pediatric cardiology Congenital heart defects Assist device Endocarditis
a b s t r a c t Aim: Medical imaging by using FDG-PET/CT (PET-CT) can detect, confirm or eliminate with high sensitivity areas of suspected infections in case of persistent fever of unknown origin in combination with other bacteriological examinations. The aim of this study was to assess the potential role of PET-CT in detecting or excluding infections or other inflammatory processes in patients with congenital heart defects (CHD). In addition we wanted to evaluate the practical impact of PET-CT on the subsequent clinical management. Methods: In this retrospective study we analyzed the data of all CHD patients who underwent PET-CT over a 5 year period in our institution. The results were then evaluated with regard to the potential impact on clinical decision making. Results: Between 2010 and 2015 PET-CT was performed in 30 patients. The mean age was 26 years (SD 15 years, range 1 to 66 years). The diagnoses covered a large field of CHD. 11 patients (4/11 with assist device) were assessed before heart transplantation; suspected malignancies or infections were excluded and transplant listing was possible. In another 5/6 patients suspected assist device infection could be confirmed with PET/CT. Endocarditis was suspected in 13 patients, 2 of whom underwent previous MRI without confirmation and ECHO was inconclusive. Endocarditis was finally excluded in 5/13 patients but confirmed in 8/13 patients by PET-CT. Conclusion: In this study we could show a high sensitivity of PET-CT for specific localization of infections and with high impact on subsequent therapy. Based on this results clinical management could be targeted and adapted. We could demonstrate that PET-CT has a high impact on the subsequent clinical therapy. © 2016 Published by Elsevier Ireland Ltd.
1. Introduction The use of FDG-PET/CT (PET-CT) in pediatric care is a growing field of interest. Traditionally, PET-CT was increasingly used in the evaluation of children with various malignancies, based on a high glycolytic activity in malignant cells [1–3]. Similarly, many infectious and inflammatory processes can be imaged with PET-CT based on a high uptake of FGD in inflammatory cells [4]. This knowledge has prompted a growing interest to employ PET-CT in inflammatory and infectious disease [5,6]. The use of PET/CT in cardiologic patients has been described in adult patients, where a high sensitivity and specificity in the diagnostics of infectious endocarditis was reported. In addition an excellent negative
⁎ Corresponding author at: Department of Pediatric Cardiology and Intensive Care, Ludwig Maximilians University (LMU) Munich, Campus Grosshadern, Marchioninistrasse 15, D81377 Munich, Germany. E-mail addresses: [email protected] (Z. Meyer), [email protected] (N.A. Haas).
http://dx.doi.org/10.1016/j.ijcard.2016.06.109 0167-5273/© 2016 Published by Elsevier Ireland Ltd.
predictive value offers an almost complete exclusion of infectious endocarditis [7]. Cardiac FDG uptake is however not specific for the diagnosis of endocarditis. FDG accumulation has been demonstrated with cardiac tumors, active cardiac sarcoidosis, and even in atheromatous plaques with active inflammation. Valve endocarditis remains also a severe complication of cardiac and valve surgery or catheterization intervention in patients with congenital heart disease (CHD). The diagnosis of valve associated endocarditis is challenging, especially when additional prosthetic material such a stent or artificial valves are involved. The gold standard for the diagnosis of endocarditis is trans-esophageal echocardiography (TEE). TEE can be however non-conclusive or even falsely negative especially in patients with artificial implants. In these circumstances PET-CT is a potentially promising diagnostic tool for several infectious conditions. The limited donor organ availability for heart transplantation has resulted in increasing numbers of patients with CHD and advanced heart failure resulting in the necessity to implant left or right ventricular assist devices as a bridge to transplant or destination therapy. Patient
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with assist device infection present signs of systemic illness and abnormal blood markers for infection. Local infection signs may also occur. However the clinical presentation is highly variable and patients may also present with only a mild or even absent local reaction posing a diagnostic challenge. Delay in diagnosis and treatment can result in progression to severe sepsis and therefore worsen clinical outcome. In these cases PET-CT may have a high diagnostic accuracy for confirm or exclude an assist device infection. We report the use of PET-CT in patients with CHD for the potential diagnosis of endocarditis, assist device infections and for screening for inflammation and malignancies before heart transplantation. 2. Methods In this retrospective study we analyzed the data of all CHD patients who underwent PET-CT in our institution between 2010 and 2015. The detailed patient data, the diagnosis, the clinical course and the indications for PET-CT were analyzed. Then the results of PET-CT were assessed and the impact on the subsequent medical management was evaluated.
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3.2. Indications PET-CT was performed to screen for infections and malignancies before heart-transplantation (n = 11), for detecting endocarditis or foci of septic embolization (n = 13) and for detecting potential assist device infection (n = 6). 3.3. Detection of infections and malignancies before heart transplantation The patients (n = 11) assessed before heart transplantation showed no malignancies or infections and transplant listing was possible. 4/11 patients were on assist devices and therefore an assessment by MRI was not possible. 3.4. Detection of assist device infection In 5/6 patients assist device infection could be confirmed. The antibiotic therapy was continued in 5 patients and stopped in 1 (typical example see Fig. 1a and b). 3.5. Detection of endocarditis
3. Results 3.1. Patients Between 2010 and 2015 F 18 FDG PET-CT was performed in 30 patients; the detailed data are shown in Table 1. (See Tables 2 and 3.) The mean age was 26 years (SD 15 years, range 1 to 66 years), the height was 160 cm (SD 26 cm). and the weight was 60 kg (SD 24 kg) The diagnoses covered a large field of CHD: pulmonary atresia (PA) with ventricular septal defect (VSD) and major aortopulmonary collaterals (MAPCAS) (n = 1), transposition of the great arteries (TGA) after Mustard operation (n = 3) and assist device implantation (n = 2), congenital corrected (cc) TGA (n = 3) with assist device (n = 1), aortic coarctation (CoA) (n = 2), mechanical aortic valve (n = 1), Fallot group (n = 5) and conduit (n = 4), Ebstein's anomaly (n = 3) and Perimount™ prosthesis in tricuspid position (n = 1), Truncus and Contegra™ (n = 2), myocardial non-compaction (n = 1), Shone complex (n = 1), status post heart transplant (n = 1), atrioventricular septal defect (AVSD) and assist device (n = 1) and dilative cardiomyopathy (n = 6) with assist device (n = 6).
Endocarditis was suspected in 3/13 patients by TTE, 2 patients underwent MRI without confirmation of endocarditis. Endocarditis was confirmed in 8/13 patients by FDG-PET-CT. The patient with PA and MAPCASs had aortic valve endocarditis with embolization to the spleen and lung, 1 patient with CoA and a bicuspid aortic valve had aortic valve endocarditis with embolization in the spleen, 1 patient with ccTGA had a pulmonary valve endocarditis, 4 patients with tetralogy of Fallot (TOF) had conduit endocarditis and 2 patients with pulmonary valve conduits had septic embolization to the lung (example see Fig. 2) and 1 patient with TAC and a conduit in pulmonary position had recurrent endocarditis with embolizations in the lung. The antibiotic therapy was continued in 8/13 and stopped in 5/12. The patient with TAC (Truncus arteriosus communis) and conduit endocarditis had surgery during infection with conduit change. 4. Discussion FDG-PET-CT is an established diagnostic tool in the evaluation of children and adolescents with various malignancies [1,2]. Traditionally,
Table 1 Valve endocarditis cases diagnosed by FDG-PET-CT. CHD
Age Sex Prosthetic valve
PA, VSD, MAPCAs
29
m
CoA Aortic valve stenosis TOF
17
f
11
m
Contegra in PA-Position
TOF
55
f
TOF TAC
17 8
f f
TOF
22
f
Carbomedics-prosthetic valve in PA-position Contegra in PA-position Contegra in PA position, stent RPA, LPA Conduit in PA-position
ccTGA, VSD Ebstein's anomaly
14 66
m f
Ebstein's anomaly 16 Aortic valve stenosis 23
m m
TAC CoA
m m
15 26
Blood cultures
Multiples stent in MAPCAS Staphylococcus aureus
Sreptococcus mitis
Perimount prosthesis in tricuspid position Prosthetic valve in aortic position Contegra PA-position
Diagnosis
Initial TTE PET-CT
Therapy
Aortic valve IE Embolisation lungs, spleen Aortic valve IE
Positive
Embolisation lungs, spleen,
Antibiotic
Positive
Embolisation spleen
Staphylococcus aureus
IE Pa-position, embolisation lung Staphylococcus aureus IE of the prosthetic PA-valve Staphylococcus capitis Pa-valve IE Lactobazillus rhamnosus IE Pa position, embolisation lung Negative Conduit IE embolisation lung Negative Pa-valve IE Negative Excluded IE
Negative Negative
Antibiotic, homograft in aortic position Contegra IE embolisation Antibiotic in the lung Pa-valve endocarditis Antibiotic, homograft in PA-position Pa-valve IE Antibiotic Conduit IE with lung Antibiotic embolisation Conduit IE with lung Antibiotic embolisation Pa-valve IE Antibiotic Negative Antibiotic stop
Positive Negative Negative Negative Negative
Negative Negative
Excluded IE Excluded IE
Negative Negative
Negative Negative
Stop antibiotic Antibiotic stop
Negative Negative
Excluded IE Excluded IE
Negative Negative
Negative Negative
Antibiotic stop Antibiotic stop
Explanations: PA = pulmonary atresia, VSD = ventricular septum defect, ccTGA = congenital corrected transposition of the great arteries, MAPCAs = major aortopulmonary collaterals, CoA = aortic coarctation, TOF: tetralogy of Fallot, Pa = pulmonary artery, TAC = Truncus arteriosus communis, IE = infectious endocarditis.
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Table 2 Assist device infection diagnosed by PET-CT. CHD
Age
Sex
Assist device
Duration of implantation
Blood culture/lesion swab
PET-CT
Diagnosis
Therapy
Dilatative cardiomyopathy Dilatative cardiomyopathy Dilatative cardiomyopathy Dilatative cardiomyopathy TGA after Mustard
1.8
m
Berlin Heart, LVAD
8 months
Pseudomonas aeroginosas
Driveline infection
23
m
Heart ware LVAD
1 year 1 month
Negative
Outflow driveline infection Negative
Antibiotic, heart transplantation Antibiotic stop
20
m
Heart ware, LVAD
9 months
Staphyloccus aureus
18
m
Heart ware, LVAD
1 year 1 month
Staphylococcus aureus
39
w
Heart Ware, LVAD
2 years
Streptococcus mitis
AVSD
4.4
m
Berlin Heart, LVAD
3 months
Negative
Outflow driveline infection Driveline infection Outflow driveline infection Driveline infection
Excluded assist device infection Driveline infection
Antibiotic, HU listing
Driveline infection
Antibiotic, HU listing
Driveline Infection
Antibiotic, HU-listing, heart transplantation Antibiotic
Driveline infection
Explanations: AVSD = atrioventricular septal defect, TGA = transposition of the great arteries, LVAD = left ventricular assist device.
PET-CT use in oncology is based on the increased glycolytic uptake in malignant cells and overexpression of glucose transporters. The most common indications for FDG-PET-CT in pediatric oncology include lymphoma, sarcoma and neuroblastoma [8]. Tissue inflammation results also in an increased fluorine-18-fluorodeoxyglucose (FDG) accumulation based on a high uptake of FGD in inflammatory cells, making the PET-CT useful for detecting of chronic and acute infections [4,9–12]. As mentioned before, cardiac FDG uptake is not specific for the diagnosis of endocarditis. FDG accumulation has been demonstrated with other diseases or processes related to increased glucose metabolism such as cardiac tumors, active cardiac sarcoidosis, and even in atheromatous plaques with active inflammation. Guidelines for the use of PET-CT in inflammation and infection were published from the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging [13]. These guidelines state that the major indication for PET-CT are sarcoidosis, peripheral bone osteomyelitis, suspected spinal infection, evaluation of fever of unknown origin and primary evaluation of vasculitis. For endocarditis the guidelines described that it is unclear if PET-CT offers advantages over other imaging techniques. The guidelines haven't however described the role of PET-CT for patients with assist devices or patients with other artificial implants. Endocarditis is a high risk in patients with CHD and artificial or stented valves [14]. The diagnosis of endocarditis might be challenging due to the limited visualization of the stented valve or stent by echocardiography or trans-esophageal echocardiography. The added value of PET/CT consists in the possibility of examining the extracardiac portion of leads, the potential ability to differentiate between thrombus and vegetation especially when compared to TEE and the possibility of diagnosing septic emboli even when clinically silent. As many patients with congenital heart defects now have surgical implants such as stents, mechanical valves, conduits, and assist devices that are extremely difficult to assess by ECHO, MRI or even conventional CT based on the imaging artifacts, a more precise diagnostic tool is warranted in case of suspected infection.
Recently, PET with fluorine-18-fluorodeoxyglucose (FDG), combined with CT scan was shown to be useful in the identification and anatomic localization of inflammation and infection in patients with fever of unknown origin and may serve as an important tool in the diagnosis of endocarditis. We report the diagnosis of a pulmonary valve endocarditis in 1 patient (ccTGA), conduit endocarditis in 4 patients (TOF) (2 patients with clinically silent septic embolizations), conduit endocarditis with embolization in the lung in 1 patient with TAC and the diagnosis of aortic valve endocarditis with previously undiagnosed septic embolization in 2 patients (1 patient PA and MAPCASs, 1 patient CoA) by PET-CT. In all patients the endocarditis had not be definitely detected or confirmed by echocardiography before. In these cases PET-CT was an important tool in establishing a definitive diagnosis of endocarditis. There are few reports of the use of PET-CT for detecting endocarditis in patient with congenital heart defects. Yedidya et al. reported the cases of 2 young patients, the first patient had a Ross and Konno repair due to supravalvular aortic stenosis and subaortic stenosis and a percutaneous pulmonary valve implantation for homograft stenosis at the pulmonic position; In the second patient with correction of transposition of great arteries and insertion of pulmonic stent in whom a TEE-based diagnosis of endocarditis of the pulmonary valve was inconclusive and was confirmed by PET-CT only [15]. Bartoletti et al. described 6 patients with aortic prosthetic valves and high clinical suspicion of endocarditis. In all cases the TEE was firstly negative and only in 2 cases the TEE became positive later. In all cases PET-CT confirmed the diagnosis of valve endocarditis [16]. TEE as the diagnostic gold standard may be disappointing in aortic and pulmonary or aortic valve endocarditis, in this case PET-CT is a helpful tool for confirming the diagnosis. PET-CT is reported to have a high sensitivity (87%) and specificity (92%) for the diagnosis of infective endocarditis of prosthetic valves and intracardiac devices – mainly pacemakers – in adult cardiologic patients [17]. Theoretically, the early use of high-dose antimicrobial treatment could decrease the amount of active inflammation in endocarditis and therefore the FDG uptake, potentially leading to a false negative result.
Table 3 PET-CT before heart transplantation. CHD
Age
Sex
TOF TGA after Mustard TGA after Mustard ccTGA ccTGA Dilatative cardiomyopathy Dilatative cardiomyopathy Myocardial non-compaction Shone complex Heart transplantation Ebstein's anomaly
28 37 22 25 50 21 42 40 37 30 46
m f m m m m f f m w m
Assist-Device Heart ware, LVAD Heart ware, LVAD Heart ware, LVAD Heart ware, LVAD
PET-CT
Impact on the therapy
Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies Excluded infections and malignancies
Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible Transplant listing possible
Explanations: TOF = tetralogy of Fallot, ccTGA = congenital corrected transposition of the great arteries, TGA = transposition of the great arteries, LVAD = left ventricular assist device.
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Fig. 1. a: Assist device in a 1 year old patient. 1 year old male infant with a history of dilatative cardiomyopahy and Berlin Heart (LVAD) implantation. The 3-D-reconstruction of the CT shows the localization of the left ventricular assist device (Berlin Heart ®) with the thicker left ventricular outlet cannula and the smaller aortic cannula. b: Assist device infection. In the same patient. Persisting fever occurred, inflammatory markers were elevated and Pseudomonas aeruginosa was identified in skin swabs at the entry site of the exit cannula. FDGPET-CT showed an outflow cannula infection.
In our patient series, we could however not detect any patients in whom we excluded endocarditis by PET-CT and who developed a relapse of signs of endocarditis or other infections despite adequate and complete follow-up. Endocarditis can present with disseminated embolization foci. In addition hidden septic embolization foci can be detected using a whole body imaging modality such as PET-CT. We report 4 cases (2 patients with conduit endocarditis, 2 patients with aortic valve endocarditis) with septic embolizations, that were not diagnosed before and were identified with PET-CT only. Orvin et al. evaluated the role of PET-CT in the early diagnosis of extra-cardiac complications in infective endocarditis and its implications for medical management [18]. 40 patients with confirmed endocarditis underwent a whole body FDG-PET-CT, in 42.5% of the patients FDG-PET-CT demonstrated extra-cardiac complications, 38.1% of them were asymptomatic. Gheysens et al. report a case of a 59 years old woman with mitral valve endocarditis with septic pulmonary embolisms and metastatic muscle abscesses and septic arthritis detected by PET-CT [19]. This clinical information has a significant
diagnostic and therapeutic impact in managing the endocarditis. In summary, PET-CT is described as an important tool for diagnosis of extra-cardiac complications in infective endocarditis [20]. Based on the limited donor organ availability for heart transplantation left or right heart assist device have been increasingly utilized in the management of advanced heart failure as a bridge to transplantation. Driveline or device infections are associated with a significant morbidity and mortality. In the REMATCH (Randomized Evaluation of Mechanical Assistance for the treatment of Congestive Heart Failure Trial), where LVAD was first evaluated as destination therapy, 48% of patients developed sepsis at 1 year and 58% of patients at 2 years after implantation [21]. In our study we could show that PET-CT is also useful for early definitive diagnosis of assist device infection. Metal-strut-related artifacts limit the ability to identify vegetations by TEE or MRI. In our report in 5/6 patients assist device infection was definitely diagnosed by PET-CT. In addition, 4/11 patients listed for transplant had assist devices implanted thereby not suitable for MRI screening. In our series PET-CT was the definitive tool to diagnose, confirm or exclude an assist device
Fig. 2. Conduit endocarditis with septic embolizations. 8 years old female infant with TAC and a conduit in pulmonalis position was hospitalized with recurrent endocarditis and positive blood cultures for Lactobacillus rhamnosus. ECHO showed no intracardiac foci. PET-CT revealed a pulmonary valve endocarditis and septic embolization in the lung. a. Enhancement in the area of the pulmonary valve. b. Septic embolization to the right lung.
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infection. Dell'Aquila et al. [22] report a sensitivity of 100% and a specificity of 80% of PET-CT in detecting infection of VAD in adults. Kim et al. [23] also reported a high sensitivity for detecting assist device infections by PET-CT. They report 4 cases of LVAD Infection in adults detected by PET-CT. Tili et al. [24] report a case of a 59 years old female with assist device (LVAD) as bridge to transplantation for a non-ischemic cardiomyopathy. In TEE and on CT scan no abnormalities on valves or device and septic complications were shown. PET-CT was finally performed and confirmed a driveline infection [24]. FDG does not accumulate only in sites of inflammation and infection and its high sensitivity for the detection of malignant cells has led to its successful and extensive use in oncology. The high sensitivity for detecting malignancies was confirmed in previews studies [25]. We report also the use of whole body FDG-PET-CT for malignity screening before heart transplantation. The patients assessed before heart transplantation showed no malignancies and transplant listing was possible. In 4 of them assist devices were implanted and therefore the routine MRI was not possible. In addition the existence of the mechanical implant did not interfere with the diagnostic accuracy of PET-CT. 5. Conclusion In this study we could show a high sensitivity of PET-CT for specific localization of infections with high impact on subsequent therapy in patients with CHD. We believe that even in the field of pediatric cardiology and patients with congenital heart defects PET/CT is a very reliable technique in detecting acute endocarditis, septic embolization foci and for ruling out or confirming assist-device related infections in this patient group. Conflict of interest There is no conflict of interest by any of the authors regarding this report. Grants No grants used, the funding is by hospital funding only. Authors' statement All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. References [1] H. Jadvar, L.P. Connolly, F.H. Fahey, B.L. Shulkin, PET and PET/CT in pediatric oncology, Semin. Nucl. Med. 37 (5) (Sep 2007) 316–331. [2] M.B. McCarville, PET-CT imaging in pediatric oncology, Cancer Imaging 9 (Jun 29 2009) 35–43. [3] J. Freebody, E.A. Wegner, M.A. Rossleigh, 2-Deoxy-2-(18F)fluoro-D-glucose positron emission tomography/computed tomography imaging in paediatric oncology, World J. Radiol. 6 (10) (Oct 28 2014) 741–755. [4] H. Zhuang, I. Codreanu, Growing applications of FDG PET-CT imaging in nononcologic conditions, Biomed. Res. 29 (3) (May 2015) 189–202. [5] A.W. Glaudemans, E.F. de Vries, F. Galli, R.A. Dierckx, R.H. Slart, A. Signore, The use of 18 F-FDG-PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases, Clin. Dev. Immunol. 2013 (2013) 623–636. [6] S. Servaes, Imaging infection and inflammation in children with 18F-FDG PET and 18 F-FDG PET/CT, J. Nucl. Med. Technol. 39 (3) (Sep 2011) 179–182 (J Heart Lung Transplant. 2012 Sep;31(9):958–66).
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