FDG-PET in Cardiac Infections

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FDG-PET in Cardiac InfectionsPaola A. Erba, MD,*,† Martina Sollini, MD,† Elena Lazzeri, MD, PhD,* and Giuliano Mariani, MD*

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al Center of NAdvanced Tecr Medicine Unspedale SantaMs reprint requlear Medicineail: p.erba@m

Cardiac infections include a group of conditions involving the heart muscle, the pericardium,or the endocardial surface of the heart. Infections can extend to prostheticmaterial or the leadsin case of the implantation of devices. Despite their relative low incidence, these conditionsthat are associated with high morbidity and mortality involve a relevant burden of diagnosticworkup. Early diagnosis is crucial for adequate management of patient, as early treatmentimproves the prognosis; unfortunately, the clinical manifestations are often nonspecific.Accurate and timely diagnosis typically requires the correlation of imaging findings withlaboratory data. 18F-FDG-PET is a well-established imaging modality for the diagnosis andmanagement ofmalignancies, andevidence is also increasing regarding its value for assessinginfectious and inflammatory diseases. This article summarizes published evidence on theusefulness of 18F-FDG-PET for the diagnosis of cardiac infections, mainly focused onendocarditis and cardiovascular device infections. Nevertheless, the diagnostic potential of18F-FDG-PET in patients with pericarditis andmyocarditis is also briefly reviewed, consideringthemost likely future advances and newperspectives that the use of PET/magnetic resonancewould open in the diagnosis of such conditions.Semin Nucl Med 43:377-395 C 2013 Elsevier Inc. All rights reserved.

Cardiac infections include a group of conditions involvingthe heart muscle, the pericardium or the endocardial

surface of the heart. Infections can extend to prostheticmaterialor the leads in case of the implantation of devices. Despite theirrelative low incidence, these conditions that are associatedwithhigh morbidity and mortality involve a relevant burden ofdiagnostic workup; moreover, the number of patients present-ing with suspected cardiac infections is progressively risingbecause of the increased use of prosthetic valve and cardio-vascular electronic device implants. Early diagnosis is crucialfor adequate management of patient, as early treatmentimproves the prognosis; unfortunately, the clinical manifes-tations are often nonspecific.Accurate and timely diagnosis typically requires the corre-

lation of imaging findings with laboratory data. Echocardiog-raphy is always performed as a first-line test, primarily toevaluate the heart structures, wall thickness, wall motion,and cardiac function. CT and MRI are also being increas-ingly employed because of their possibility for tissuecharacterization.

ont matter & 2013 Elsevier Inc. All rights reserved.53/j.semnuclmed.2013.04.003

uclear Medicine, Department of Translational Researchhnologies in Medicine, University of Pisa, Pisa, Italy.it, Department of Oncology and Advanced Technology,ariaNuova-IRCCS, Reggio Emilia, Reggio Emilia, Italy.ests to Paola Anna Erba, MD, Regional Center of, University of Pisa, Via Roma 55, I-56125 Pisa, Italy.ed.unipi.it

18F-FDG-PET is a well-established imaging modality for thediagnosis and management of malignancies,1 and evidence isalso increasing regarding its value for assessing infectious andinflammatory diseases.2 This article summarizes publishedevidence on the usefulness of 18F-FDG-PET for the diagnosisof cardiac infections. As the majority of such reports deal withendocarditis and cardiovascular device infections, these 2 con-ditions constitute the main topic of this review. Nevertheless,the diagnostic potential of 18F-FDG-PET in patients withpericarditis and myocarditis is also briefly reviewed, consider-ing the most likely future advances and new perspectives thatthe use of PET/MR would open in the diagnosis of suchconditions.

Infective Endocarditis (IE)IE is an infection of the endocardial surface of the heart thatcan involve prosthetic material in case of valve replacement.3

The incidence of IE is approximately 2-4 cases per 100,000persons per year.4 Although this overall value has not changedin the past 50 years, it is however increasing in elderlysubjects. At present, 25%-50% of the cases occur in patientsolder than 60 years,5 an age-related pattern that impliesseveral diagnostic and therapeutic challenges. Since the 1960s,the clinical patterns of IE have changed significantly.6 Inparticular, the increasing diffusion in the population ofsubstance addiction (with intravenous self-administration),

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P.A. Erba et al.378

growing and wider applications of invasive vascular proce-dures and massive use of antibiotics have multiplied the casesof IE linked to intravenous drug abuse,7 prosthetic valveendocarditis,8 and nosocomial IE.9 The underlying valvularpathology has also changed from rheumatic disease (that waspredominant until about 30 years ago) to calcific aorticstenosis (now accounting for 50% of the cases in elderlypatients).10 However, mitral valve prolapse is currently themost common predisposing condition for native valve endo-carditis in young patients (about 30% of the cases).11 Lesscommonly, IE arises from arteriovenous fistulas used forhemodialysis,12 central venous and pulmonary artery cathe-ters, peritoneal-venous shunts for ascites, and ventriculoatrialshunts for hydrocephalus, or as a complication of liver, heart,and heart-lung transplants.13 IE may present as an acute,rapidly progressive infection, or else as a subacute or chronicdisease with low-grade fever and nonspecific symptoms thatmay thwart or confound initial assessment. Therefore, patientsmay be referred to a variety of specialists who may consider arange of alternative diagnoses.The diagnosis of IE is essentially clinical14 and should be

suspected in all patients presenting with fever of unknownorigin, particularly when fever (up to 90% of the cases) isassociated with laboratory signs of infection, anemia, andmicroscopic hematuria, and when septic embolic manifesta-tions are present (brain, lung, or spleen, in about 30% of thecases).15,16 The main cardiac signs include heart murmur (upto 85% of the cases) and progressive heart failure. Systemicsigns, typically represented by spleen enlargement, glomeru-lonephritis, and peripheral stigmata, occur when IE remainsundiagnosed for a long period. Vascular and immunologicphenomena, such as splinter hemorrhages and Roth spot, arecommon. However, atypical presentations may occur inelderly or immunocompromised patients.17

Microbiological tests for germ characterization along withpositive echocardiographic findings are necessary to establisha diagnosis according to the modified Dukes criteria18,19

(Table 1). Overall sensitivity of the Duke criteria is 80%.20

However, in several instances blood culture or echocardiog-raphy or both are inconclusive, thus leading to a highproportion of unconfirmed cases of suspected IE. Indeed, upto 24% of the patients with pathologically proven endocarditiscan be misclassified as “possible” IE based on Duke criteriaalone.20 The main reasons for the relatively low diagnosticaccuracy of the Duke criteria are represented by either anegative blood culture or the failure to demonstrate avegetation on performing an echocardiography.Negative blood cultures occur in 2.5%-31% of IE patients,

more commonly because of prior antibiotic administra-tion.21,22 Subacute right-sided endocarditis and muralendocarditis,23 slow-growing and fastidious organisms, suchas Coxiella burnetii, Brucella spp., Abiotrophia spp., HACEK(Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans,Cardiobacterium hominis, Eikenella corrodens and Kingellakingae) group endocarditis, Listeria monocytogenes, and fungiaccount for other causes of culture-negative endocarditis. Anegative blood culture results in delayed diagnosis and there-fore negatively affects patients' outcome.22

Both transthoracic echocardiography (TTE) and transoeso-phageal echocardiography (TEE) may be used for detectingvegetations, with sensitivities ranging 40%-63% and 90%-100%, respectively. Three echocardiographic findings aremajor criteria in the diagnosis of IE: vegetation, abscess, andnew dehiscence of a prosthetic valve. A negative TEE has avery high negative predictive value for IE (86%-97%).24

However, identification of vegetations may be difficult in thepresence of preexisting severe anatomical changes, especiallyin the early phases when vegetations are very small. Further-more, several conditions may mimick vegetations, as it occursin degenerative valve disease, rheumatic disorders, valvularthrombus, chordal rupture, and with small intracardiactumors.3 Besides representing a crucial diagnostic aid for IE,echocardiography parameters are also useful for predicting thepotential embolic burden, even though CT and MRI aregenerally necessary for detecting septic embolism.25

Although attempts have been made at improving thediagnostic performance of the Duke criteria, by proposingseveral additional clinical and microbiological parameters,18

molecular imaging techniques (ie, radionuclide imaging) couldin principle be useful to integrate such traditional diagnosticcriteria and therefore fill such uncertainty gap with informationon the biochemical burden of the endocardial vegetations.However, during the last decades, the use of radionuclideimaging for IE has been rather limited in the daily clinicalroutine, because of the general perception of their relatively lowdiagnostic performance. The introduction of hybrid equipmentfor both conventional nuclear medicine (eg, single-photonemission computed tomography SPECT/CT) and PET (eg,PET/CT) has notably changed this scenario. In fact, thanks to atechnology that allows the 3-dimensional reconstruction ofsmall regions of interest and precise localization of the site(s) ofabnormal radiopharmaceutical accumulation, evidence isgrowing that SPECT andPETperformedwith suitable infectionimaging agents and coregisteredwithCT improve the diagnosisof IE. SPECT/CT imaging relies on the use of autologousradiolabeled leukocytes that accumulate in a time-dependentfashion in late images vs earlier images,26 whereas PET/CT isgenerally performed using a single acquisition time point(generally at 1 hour) after administration of 18F-FDG, whichis actively incorporated in vivo by activated leukocytes,27

monocyte-macrophages,28 and CD4þ T-lymphocytes29 accu-mulating at the sites of infection. Less common PET/CTapplications involve the use of autologous leukocytes labeledby in vitro incubation with 18F-FDG, a more cumbersomeprocedure that is still in the phase of clinical validation.30

Most of the published evidence concerning the use of 18F-FDG-PET/CT in patients with suspected IE is represented bycase reports or small series reports. The main findings ofsuch reports are summarized in Table 2. In particular, 18F-FDG-PET/CT has been used to confirm the presence of IEinvolving either native valves IE (9 patients) or prostheticvalves IE (18 patients). Suspicion of IE was based on clinicalsigns, laboratory tests, and positive blood culture or serology(n ¼ 24), whereas echocardiography was negative or incon-clusive in 17 of 24 cases (6 of 9 native valves and 11 of 18prosthetic valve). In the remaining 3 patients negative blood

Table 1 Modified Duke Criteria18,19

Major criteriaPositive blood culture with typical IE microorganism, defined as 1 of the following:Typical microorganism consistent with IE from 2 separate blood cultures, as noted below:� Viridans-group streptococci, or� Streptococcus bovis including nutritional variant strains, or� HACEK group, or� Staphylococcus aureus, or� Community-acquired enterococci, in the absence of a primary focus

Microorganisms consistent with IE from persistently positive blood cultures defined as:� Two positive cultures of blood samples drawn412 hours apart, or� All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 1 hour apart)� Coxiella burnetii detected by at least 1 positive blood culture or antiphase I IgG antibody titer41:800

Evidence of endocardial involvementEchocardiographic findings positive for IE (TEE recommended in patients with prosthetic valves, rated at least possible IE byclinical criteria or complicated IE [paravalvular abscess]; TTE as first test in other patients), defined as follows:� Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in theabsence of an alternative anatomic explanation, or

� Abscess, or� New partial dehiscence of prosthetic valve or new valvular regurgitation (worsening or changing of preexisting murmur notsufficient)

Minor criteriaPredisposition, predisposing heart condition, or intravenous drug useFever, temperature4381CVascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctivalhemorrhages, and Janeway lesions

Immunologic phenomena: glomerulonephritis, Osler nodes, Roth spots, and rheumatoid factorPositive blood culture (that does not meet a major criterion) or serologic evidence of infection with organism consistent with IE butnot satisfying major criterion

Positive echocardiogram (that does not meet a major criterion)a

aCriterion removed from the modified Duke criteria (2000).

FDG-PET in cardiac infections 379

culture was associated with either a negative echocardiography(n ¼ 2) or with the echocardiographic finding of paravalvularleak (n¼ 1). Of interest, after a positive PET/CT scan, a repeatechocardiography detected vegetations in 3 patients. 18F-FDG-PET/CT confirmed the presence of IE in 8 of 9 patients withnative valve infection and in 16 of 18 patients with prostheticvalve. In 2 patients with complex prosthesis of the aortic valve,the aortic root and the ascending aorta (Bentall procedure), IEwas excluded by 18F-FDG-PET/CT that localized infection atthe aortic portion of the graft. Out of the 27 18F-FDG-PET/CTscans, 1 was false negative, in a patient with native valve IEsustained by Bartonella henselae that also exhibited a negativeechocardiography.Taken altogether, these data support the use of 18F-FDG-

PET/CT in association with echocardiography, to confirm orrule out IE in equivocal or difficult-to-explore situations orboth, such as those due to artifacts caused by mechanicalprosthesis or device's catheter. However, it should be notedthat all the cases that have been reported so far as beinginvestigated with 18F-FDG-PET/CT represent patients witha high pretest probability of IE. Therefore, the false-positive rateof 18F-FDG-PET/CT can be underestimated. In fact, somedrawbacks to the use of 18F-FDG for the diagnosis of IE shouldbe always considered when interpreting the scan to avoid

potential sources of false-positive findings in PET studies. First,variable focal of diffuse physiological 18F-FDG uptakeis often observed in the normal myocardium of fasting non-diabetic patients (6-12 hours to overnight) with normalglucose levels.31 Accumulation of 18F-FDG is most notablein the left ventricular myocardium, which has a greater musclemass than other cardiac chambers. Uptake in the wall of theright ventricle is typically equal to or less intense than that inthe left ventricular myocardium; uptake in the wall of the rightand left atria is usually not detected. Factors possibly influenc-ingmyocardial uptake of 18F-FDG include patients' age, fastingtime, blood glucose levels, and a low-carbohydrate diet. Inparticular, age and fasting time do not affect physiological 18F-FDG uptake in the myocardium, whereas blood glucose levelsmay have a nonlinear effect on myocardial uptake.32 Low-carbohydrate diet33 and very high-fat, low-carbohydrate,protein-permitted meal followed by fasting for 3-6 hours34

before 18F-FDG injection might be adopted to decreasemyocardial uptake. However, no specific protocol has yetbeen standardized or recommended or both to reduce thenonspecific myocardial uptake when assessing cardiac infec-tion with 18F-FDG-PET/CT. Another potential confoundingfactor for 18F-FDG-PET/CT is represented by increasedmetabolic activity along the posterior aspect of the heart,

Table 2 Published Evidence Concerning the Use of 18F-FDG-PET/CT in Patients With Suspected Infective Endocarditis

Native Valve

Patients ClinicalPresentation

Site of IE Microbiology 18F-FDG-PET/CTFindings

Echocardiography Refs

n ¼ 4 Prior ischemic strokewith left hemiparesis

Aortic (1) Staphylococcusepidermidis

Valve Perivalvular mass Yen et al107

Anemia, severetricuspidregurgitation, anddilated right ventricle

Tricuspid (1) Staphylococcus aureus Vegetation

Rheumatic heartdisease, mitralstenosis, mitral þ or− aortic regurgitation,and anemia

Mitral (2) Escherichia coli (1) ThrombusNegative culture (1)

40 y, F FUO (6 wk), severethrombocytopeniaerythematousswelling on right foot

Mitral Negative culture Base of left ventricle,cardiac fibrous ringnear aortic root

Negative Ho et al108

Spleen embolism47 y, F Fever4401C (1 wk),

productive cough,pain in left side ofchest, aortic stenosis,and systolic murmur

Aortic Haemophilusinfuenzae þStaphylococcus spp.

Valve No vegetation(stenosis); repeat TEEpost PET/CT:pseudoaneurysm

Vind and Hess109

64 y, M Persistent fever andsuspected IE

Aortic (bicuspid valve) Negative culture (finaldiagnosis: Bartonellahenselae)

Sigmoid diverticulosis(FN)

Negative, repeat TTE(1 mo) after positiveserology: vegetation

Sankatsing et al110

87 y, F Fever (39.61C) Mitral Pseudomonasaeruginosa

Valve Negative (calcification)Repeat after PET/CT:vegetation

Yeh et al111

Spleen embolism

59 y, F Persistent MRSAsepsis followingremoval of Hickmancatheter

Mitral Staphylococcus aureus Valve Vegetation Gheysens et al112

Lung embolismsSpleen embolismBone and muscleinfections

Prosthetic Valve

Unknown Chronic fever after totalknee replacement

Aortic biological Staphylococcus aureus Valve Unknown Belohlavek et al113

Left kneeUnknown Persistent bacteremia,

mitral valvereplacement

Mitral(unknown)

Positive culture(organism unknown)

Intracardiac uptake Valvular vegetationsand mitral annularabscess

Love et al114

P.A.Erbaetal.

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Table 2 (continued )

Native Valve




77 y, M FUO Unknown Enterococcus spp. Valve Unknown Klingensmith et al115

Lung embolism82 y, M Fever and

malaise (10 d)Aorticmechanical

Streptococcus viridans Right lateral atrial walland left atrialappendage orpulmonary outflowtract

No vegetation, mildaortic regurgitation,aortic leafletthickening

Moghadam-Kia et al116

Lumbar embolism71 y, M Ischemic occipital

stroke, FUOAortic biological Oxacillin resistant Valve Negative Huyge et al117

Staphylococcusepidermidis

Mediastinal lns

35 y, M Fever 381C-391C414 d; (tetralogy ofFallot, pulmonaryatresia repaired)

Pulmonarymechanical

Streptococcus viridans Artificial blood vesselsite of rightventricular outflowtract

Negative Kenzaka et al118

63 y, M Dyspnea, elevatedCRP, and WBC

Mitral biological Negative culture Valve Inconclusive Plank et al119

24 y, M Fever, cough, andvomiting (Konorepair)

Pulmonary biological Haemophilusparainfluenzae

Pulmonic stent Negative Yedidya et al120

75 y, M Fungalsepsis Aortic biological Candida parapsilosis Valve Negative Wallner et al121

74 y, M TIA Aorticmechanical

Negative culture Valve Paravalvular leak Feuchtner et al122

64 y, M Fever42 mo Aorticmechanical

Unknown Valve, decreased afterantibiotic therapy

Negative Klaipetch et al123

30 y, F Asthenia, feverepisodes4391C(1 mo)

Aorticmechanical

Streptococcussanguinis

Valve No vegetations,thickened area atnoncoronary sinus ofValsalva

Pons et al124

84 y, F Right femurosteosynthesis,infection of total kneeprosthesis

Mitral biological þ PM Morganella morganii þEnterococcus fecalis

Valve þ lead Mitral regurgitation þprolapsing cusp

Gouriet et al125

24 y Fever and vomiting Pulmonar mechanicalþ pumonic stent

Staphylococcus aureus Pulmonic stent Echogenic mass withinthe pulmonic stent

Yedidya et al120

84 y, Ma FUO and weight loss Aortic biological Streptococcus bovis Valve Negative Dumarey et al44

FDG-PETincardiac

infections381


Native Valve




Septic Embolism Detection

n ¼ 25 IE definite according toDuke's criteria

Native unknown (15) Staphylococcus aureus(4)

12% IE 25 Positive,unspecified

Van Riet et al42

Prosthetic unknown(10)

Streptococcus spp.(10)

44% Septic embolismof metastaticinfectionEnterococcus faecalis

(9)Escherichia coli (1)Negative culture (1)

Prosthesis of Aortic Valve, Aortic Root, and Ascending Aorta (Bentall's Procedure)

n ¼ 2 Fever Aortic Staphylococcus spp. Aortic valve þ aorticroot

Inconclusive Yen et al107

Salmonella spp.61 y, F Fever and chills (1 d) Aortic Staphylococcus aureus Aortic arch Unknown Bleeker-Rovers et al82

47 y, F Fever4401C þ chills(6 d)

Aortic Staphylococcus aureus Valve þ base ofascending aorta oraortic wall or graft þaorta (atheroscleroticchanges, FP)

Negative Vind and Hess109

56 y, M Fever, chills, and nightsweats (3 wk)

Aortic Cardiobacteriumhominis

Aortic graft No vegetations,nonspecificthickening of aorticroot

El Hajjaji et al126

FUO, fever of unknown origin; lns, lymph nodes; CRP, c-reactive protein; FN, false negative; MRSA, methicillin-resistant Staphylococcus aureus; TIA, transient ischemic attack; PM, pacemaker; FP, falsepositive; WBC, white blood cell.

a18F-FDG-radiolabelled leukocytes.

P.A.Erbaetal.

382


where lipomatous hypertrophy of the interatrial septummay appear as a fat-containing mass with increased 18F-FDGuptake.35 Furthermore, a number of pathologic conditionscan mimick the pattern of focally increased 18F-FDGuptake that is typically observed in IE, such as activethrombi,31 soft atherosclerotic plaques,36 vasculitis,37 primarycardiac tumors,38 cardiac metastasis from a noncardiactumor,39 postsurgical inflammation,40 and foreign body reac-tions (such as BioGlue, a surgical adhesive used to repair theaortic root).41 Indeed, high specificity for IE using 18F-FDGcan be achieved only by adopting accurate patients selectionand inclusion criteria. On the contrary, the use of 18F-FDG-PET/CT in patients with lower pretest probability would relyon the high negative predictive value of this imaging proce-dure. Figure 1 shows examples of positive 18F-FDG-PET/CTscans in patients with IE. Figure 2 shows an example ofthe use of 18F-FDG-PET/CT to exclude the presence ofIE in a patient with doubtful echocardiographic findingand fever.An additional advantage of 18F-FDG-PET/CT imaging is its

ability to reveal the concomitant presence of extracardiacinfection sites as the consequence of septic embolism, there-fore of “metastatic” infections originated from IE. According toliterature reports, such occurrence was detected in a total of 11of 27 patients evaluated for suspected infection, the sites ofseptic embolism being mainly localized at the lungs, bones,and spleen. Similarly, in a prospective study carried out inpatients with definite IE according to the modified Dukecriteria prior to surgery, 18F-FDG-PET/CT was able to detectat least 1 focus of peripheral embolization or metastaticinfection or both in 11 of 24 patients (44%).42 Thesecomplications were detected even in patients without priorclinical suspicion and in patients without the typical echo-cardiographic findings considered as predictors of systemicembolism.43 This unique whole-body exploring ability ofPET/CT, shared only with conventional nuclear medicinescintigraphy, that is, to detect multiple sites of disease with asingle examination, can guide clinical management of patientsin view of the optimal time window for surgical intervention.A limitation to the use of 18F-FDG-PET/CT is represented bylocalization of septic emboli in the brain, due to the highphysiological uptake of this tracer in the brain cortex and tothe fact that at this site metastatic infections are generallysmaller than 5 mm,which is the spatial resolution threshold ofthe current PET/CT scanner. Figure 3 shows examples ofseptic embolism and metastatic infections in patients with IEdetected by 18F-FDG-PET/CT.Finally, an additional promising role of 18F-FDG-PET/CT is

to be seen in patients with established IE, in whom it can beemployed to monitor response to antimicrobial treatment. Infact, considering the difficulties in the choice of the propertype, dose, and duration of antimicrobial treatment, thepossibility to distinguish PET/CT imaging patients whorespond favorably to treatment from those who requireintensified administration or alternative treatment options isextremely attractive. Figure 4 shows an example of the useof 18F-FDG-PET/CT to monitor response to antimicrobialtreatment in a patient with IE.

The possibility of efficient radiolabelling of autologousleukocytes with positron-emitting radionuclides can beexpected to change the whole scenario of PET imaging forpatients with suspected IE. In this regard, intense 18F-FDG-white blood cell uptake at the site of valve infection has beendescribed for the only patients with IE ever reported up tonow.44 Unfortunately, the physical half-life of 18F is too shortto encompass the whole kinetics of leukocyte migration intosites of infection, thus making the use of this proceduresuboptimal for this purpose.A new interesting radiopharmaceutical for PET imaging, a

prothrombin analog alkylated by the free thiol with amaleimide derivative of a diethylenetriaminepentaacetic acidchelator and then reacted with copper-64 (64Cu-DTPA-ProT)has been developed to tag prothrombin and therefore track itsdeposition to the fibrin-rich vegetations in Staphylococcusaureus' experimental IE.45 This interesting approach is certainlyworthy of further investigation.

Cardiovascular ImplantableElectronic Devices (CIED)InfectionsIn the past fewdecades, there has been a proliferation in the useof CIED, mostly related to an increasing population of theelderly, both in the developed and in the developing countries.Worldwide there are approximately 3.25 million functioningpacemakers and 180,000 functioning implantable cardioverterdefibrillators.46 Infection rates for these devices range from1%-7%.47-50 The majority of CIED infections are caused byeither Staphylococcus aureus or coagulase-negative staphylo-cocci; a variety of other bacteria and fungi are less commonlyidentified as causes of CIED infection.46,51,52 CIED-associatedinfections cause significant morbidity and high death rate,particularly regarding endovascular infection (20%).52 Theincremental cost for managing CIED infection has beenestimated to be about $28,676 to $53,349,53,54 nearly halfof this amount being due to intensive care procedures.55

Furthermore, device replacement procedures that are periodi-cally necessary for battery depletion or for upgrading areassociatedwith infection rates higher than those occurring afterinitial implantation.56,57

The interval between CIED implant or revision and theonset of infection varies widely, fromdays to years. The clinicalpresentation of CIED infection depends on several factors,including the site of infection (eg, generator's pocket vsintravascular leads or epicardial leads), the type of micro-organism, and the origin of the infection (eg, pocket erosion,localized infection of the generator's pocket, and bacteremiafrom a remote site). Early infections, that is, those occurringwithin a few months after implantation, manifest as acute orsubacute infections of the pulse-generator's pocket. Bacteremiamay occur even without clinical signs and symptoms. Feveris the most common finding and is the only sign in approx-imately 33%of patients. Although some cases ofCIED infectionpresent without obvious inflammatory changes of the skin, the

Figure 1 Examples of pattern of 18F-FDG uptake at PET/CT in patients with IE. (A) Biological aortic prosthesis with linearfocal uptake in the anteromedial portion. (B) Mechanical aortic prosthesis with predominant uptake at the posterior andmedial region of the aortic valve. (C) Mechanical aortic prosthesis with predominant uptake at the posterior region of thevalve. (D) Mechanical aortic prosthesis with perivalvular abscess. (E) Mechanical mitral valve IE with prevalent uptake atthe posterolateral region of the valve. Left column emission transaxial images, middle column CT transaxial images, rightcolumn transaxial superimposed PET/CT images.

P.A. Erba et al.384

diagnosis is most often (about 70% of cases) based on findingsat the generator's pocket site, including local pain, swelling,redness, drainage, and skin and soft-tissue ulceration. The firstsign of infection may be erosion through the skin at the site of

the generator's pocket, with external exposure of the generator,of 1 or more leads, or both the generator and leads, with orwithout local inflammatory changes. Late infections occur up toseveral years after implantation or reimplantation and have

Figure 2 18F-FDG-PET/CT excluding the presence of IE in a patient with fever and doubtful echocardiographic finding.Transaxial images (upper panel CT, left column emission transaxial images, middle column CT transaxial images, rightcolumn transaxial superimposed PET/CT images) show absence of significant uptake at the region of themitralmechanicalvalve. Transaxial images of the thorax at different levels (middle and lower panel, left column emission images, middlecolumn CT images using lung parenchima window, right column superimposed PET/CT images) show multiple sites of18F-FDG uptake at both lungs, resulting to be the cause of infection (pneumonia by Aspergillus).


much more subtle manifestations. Most often the transvenousor epicardial leads are involved; in the latter circumstance,complications such as pericarditis, mediastinitis, and right-sided endocarditis are often present.The diagnostic workup of CIED infections is problematic, as

patients can present with a variety of manifestations includingsubtle signs of systemic or local infection. Final diagnosis ofCIED infection is generally based on microbiological tests(blood cultures and culture of material from exposed sites ofthe device) and ultrasound evaluation of the cardiac region(either TTE or TEE) and of the venous pathway of the device.The above tests constitute the basis for defining the patients'likelihood to have CIED infection according to the Dukecriteria.58 However, in case of CIED infections, the Dukecriteria, originally developed for the diagnosis of IE, may beinadequate; even with the addition of clinical parameters59,60

the possibility remains high of missing the presence or under-estimating the extent of infection or both.61

Blood cultures are recommended in all suspected cases ofCIED infection, regardless of whether the patient is febrile or

has other signs or symptoms of systemic infection. However,blood cultures may be negative despite CIED infection,particularly in patients with pocket-site infection and in thosereceiving antibiotics shortly before blood samples are drawnfor culture. Moreover, positive blood cultures may be due toa source other than an infected CIED. The likelihood of CIEDinfection when blood cultures are positive varies accordingto the pathogen detected, the number and duration of positiveblood cultures, and the presence of other findings that suggestdevice-related infections.62-67

TEE is recommended for patients with bacteremia, espe-cially if the bloodstream infection is due to staphylococcalspecies or if the source is not identified, and for patients withsigns of systemic infection, regardless of the results of bloodculture.68 The main purpose of TEE is to identify complica-tions, such as valvular vegetations ormyocardial or perivalvularabscesses. In adults, TEE is more sensitive than TTE fordetecting signs of an intracardiac infection.69,70 Vegetations ona lead are consistent with, but not diagnostic of, lead-relatedendocarditis; bland (uninfected) clots on leads have been

Figure 3 Examples of septic embolisms detection using 18F-FDG-PET/CT. Upper panel: 18F-FDG-PET/CT uptake at thespleen (left column emission transaxial images, middle column CT transaxial images, right column transaxialsuperimposed PET/CT images) in the lower posterior portion in patients with aortic IE. Lower panel: 18F-FDG-PET/CTuptake at spine, involving the inferior portion of the vertebral body of L3 and the superior portion of the vertebral body ofL4 (left column emission transaxial images, middle column CT transaxial images, right column transaxial superimposedPET/CT images) in patients with aortic IE, identifying spondylodiscitis.

P.A. Erba et al.386

found on echocardiographic examination in 5%-10% ofpatients with CIED despite the absence of infection71,72 andthese mass lesions usually cannot be distinguished frominfected vegetations. A negative TEE result does not rule outthe possibility of lead infection.73 Fever or a positive bloodculture without identification of a primary source or both inpatients with a CIED represents device-associated IE, untilproven otherwise.The use of 18F-FDG-PET/CT in CIED infections has been

implemented to respond to specific clinical needs: (1) con-firming or excluding the presence of infection in patientswith equivocal echocardiographic findings or during febrileepisodes without evidence of a primary source; (2) definingthe extent of device involvement; (3) assisting in thedecision whether to treat medically or to remove the device;(4) evaluating the response to antimicrobial therapy; and(5) selecting the optimal time to reimplant. Although theearliest reports on the use of 18F-FDG-PET/CT for diagnos-ing CIED infection date back to 2006, original retrospectivestudies were published only in 2011 (Table 3). Overall, atotal of 159 patients have been evaluated so far, including 54controls. Based on these data, 18F-FDG-PET/CT appears toprovide useful information when added in the diagnosticworkup of CIED infection, mostly because of its ability to

confirm the presence of infection (70 of 78 total confirmedCIED-associated infections), to define the extent of deviceinvolvement, and to detect associated complications, suchas infectious endocarditis and septic embolism (occurring inmore than 20% of the patients).

18F-FDG-PET/CT enabled to discriminate patients withisolated pocket infections (Fig. 5) from patients with moresevere and extended infection, involving the pocket and leads(Figs. 6 and 7). This ability seems to be maintained also withearly device infection. In case of pocket infection 18F-FDG-PET/CT sensitivity ranges from 86.7%-100% and specificityfrom 85%-100%. However, in case of CIED infections theissue on 18F-FDG specificity becomes particularly relevantwhen the exam is requested for better classifying patients withundetermined echocardiographic findings, for example, blandclots adherent on leads at echocardiographywithout clear signsof infection. Therefore, in this circumstance and consideringthe high rate of false-positive findings (up to 8%) reported inasymptomatic patients with pacing systems,74 18F-FDG-PET/CT is of clinical value mostly because of its high negativepredictive value.High diagnostic accuracy of 18F-FDG-PET/CT was also

reported for ruling out involvement of the devices duringfebrile episodes and for defining the embolic burden in patients

Figure 4 Example of the use of 18F-FDG-PET/CT to monitor response to antimicrobial therapy. Upper panel: PET/CTimages in a patient with IE at the mechanical aortic prosthesis at baseline condition show intense 18F-FDG uptake at theposterior part of the aortic prosthesis. Concomitant uptake at the left ventricle wall is also evident, making difficult theimages reading.Mild pleural effusion is evident at theCT images. Lower panel: PET/CTperformed 4months after initiationof antimicrobial therapy shows normalization of the 18F-FDG uptake at the site of the mechanical valve. Increased pleuraleffusion is detected at the CT component of the scan, consistent with the worsening of the valve regurgitation as indicatedby echocardiography. Therefore, prosthetic valve substitution was performed at this stage based on the PET/CT finding ofsignificant reduction of infective burden. Left column emission transaxial images, middle column CT transaxial images,right column transaxial superimposed PET/CT images.


with ascertained infection. A negative scan (negative predictivevalue from 75%-100%) has consistently been associated witha favorable clinical outcome when antimicrobial therapy aloneis initiated.A strong correlation between sites of infection identified by

18F-FDG-PET/CT and outcome following various treatmentregimens was also demonstrated. Therefore, 18F-FDG-PET/CT has been suggested as a guide to clinicians for choosingthe most suitable treatment, that is, conservative treatment(antimicrobial agents alone, or removal of just the generator)vs full hardware extraction. This would be especially relevantconsidering the ongoing debate arising from the observationthat novel antimicrobial agents can penetrate the bacteria-produced biofilm,75 thus potentially decreasing the need ofhardware removal in CIED infection.76 However, the diag-nostic accuracy of 18F-FDG-PET/CT for cardiac device-related IE has been recently questioned, based on the verylow sensitivity (30.8%) and specificity (62.5%) reported byCautela et al.77 Prior antimicrobial therapy (that was ongoingin 9 of 13 patients with cardiac device-related IE) orvegetation size or both could account for the poor sensitivityof 18F-FDG-PET/CT in such report. Furthermore, 18F-FDGuptake in normal heart tissue may explain why low-intensitylesions went undiagnosed. Considering that the differentialdiagnosis between an infection limited at the skin or pocketand more severe infection that involves the device over thepocket remains the most important issue, which translatesinto a different management of patients (from medical tosurgical treatment)78; this issue requires further investigationbefore the technique can be introduced in the routinediagnostic workup of CIED infection.

Acute PericarditisPericarditis is an inflammatory process that can be caused bylocalized or systemic diseases, including infection, connec-tive tissue disorders, and uremia, or can occur after radiationtherapy. Although dyspnea and pleuritic chest pain thatchanges with patient’s position are the typical signs of thedisease, clinical manifestations can be more variable,depending on the extent of pericardial disease, the rate atwhich it develops, and its effect on cardiac function.79

Additional signs include pericardial friction rub at physicalexamination and nonspecific S-T segment and T-wavechanges on electrocardiogram.Discriminating pericarditis from myocardial disease or

pulmonary infarction can be difficult on the basis of physicalexamination alone; imaging may instead be helpful fordistinguishing these different conditions.Echocardiography, CT, andMRI are frequently employed to

identify and characterize the pericardium and pericardialspace, their typical findings including pericardial thickening,pericardial enhancement, and pericardial effusions.80 How-ever, echocardiographic assessment of pericardial thickeningcan be difficult, and the entire pericardium often cannot befully evaluated because of poor acoustic window. CT andMRIallow clearer characterization of the pericardium and pericar-dial space and can therefore help to distinguish betweenpericardial fluid effusion and thickening.81

18F-FDG-PET/CT is generally employed as a complement toother imaging modalities, as the different pattern of 18F-FDGaccumulation in the pericardium or in the pericardial fluidmight help in distinguishing infectious or inflammatory

Table 3 Cardiovascular Implantable Electronic Device


Site of IE Microbiology 18F-FDG-PET/CT Findings


40 y, F Fever, chills, tendernessat PM pocket aftertricuspid valvuloplastyreplacement, and PMbattery change (3 wkprevious)

PM and prosthetictricuspid valve

Staphylococcusaureus

PM pocket þ leads þ IE Initial TEE no vegetationsor valvular dysfunction;repeated TEE: valvularinsufficiency

Vos et al127

80 y, M Fever after PMreplacement forinfection (3 y previous)

PM Negative culture PM þ leads Negative Miura et al128

55 y, F Fever, axillary wire of PMremoved and replaced(3 mo previous)

AICD and PM Pseudomonasspp.

Oldwire track in left axillaþ lead þ tip of lead atcoronary sinus

Unknown Khamaisi et al129

8 y, F FUO, PM for congenitalatrioventricular blockprogressing tocomplete heart block(1 y previous)

PM or lead infection Staphylococcusaureus

PM pocket þleadsLung embolism

Initial TTEno vegetations.TEE after PET/CT:vegetations on PM leadþ tricuspid valveannulus

Abikhzer et al130

9 y, M Low-grade fever,induration in theepigastric region

Epicardial dual-chamberPM tunneled to the leftupper abdominalquadrant

Unknown Around PM, along thetunnelized wires, intra-abdominal leads

Abdominal US: negative Turpin et al131

n ¼ 50 (40controls)

PM implanted43 mopreviously

PM Staphylococcusaureus (2)

Sensitivity ¼ 100% TTE and TTE negative Ploux et al74

Staphylococcusepidermidis (4)

Specificity ¼ 93%PPV ¼ 66%NPV ¼ 100%

n ¼ 35 (14controls)

Suspected CIEDinfection (21) andasymptomatic (14)

PM and ICD Staphylococcusspp. (4)

Sensitivity ¼ 80% 31.25% TEE positive forvegetations

Bensimhon et al132

Streptococcusspp. (2)

Specificity ¼ 100%

Klebsiellapneumoniae (1)

PPV ¼ 100%

Corynebacteriumjeikeium (1)

NPV ¼ 84.6%

Pseudomonasaeruginosa (1)

Escherichia coli (1)59 y, M Swelling over PM box

(5 mo previous), rigorsand sweats (1 mo).Prior heart block afterCABG þ mitral valvesubstitution

PM and mechanicalmitral valve

Staphylococcusepidermidis,Candidaalbicans

PM pocket Negative Mehta et al133 P.A.Erbaetal.

388



Site of IE Microbiology 18F-FDG-PET/CT Findings


n ¼ 2 Severe sepsis or septicshock of unknownorigin

PM Unknown PM (unspecified) Positive Kluge et al134

75 y, M FUO (1 wk); PM (8 yprevious) with septicepisode (7 y previous)

PM Mycobacteriumperegrinum

Atrial lead Negative Amraoui et al135

60 y, M Bacteremia of unknownorigin

ICD Staphylococcusepidermidis

Intravascular lead Unknown van Oostrom et al136

PM dependent for 30 ywith 7 leads

n ¼ 42 Suspected CIEDinfections (35 of 42confirmed)

PM Staphylococcusspp. (18)

Qualitative analysis: 54.5% TEE positive Sarrazin et al137


Sensitivity ¼ 88.6%

Others n ¼ 5 Specificity ¼ 85.7%PPV ¼ 96.9%NPV ¼ 63.7%Semiquantitativeanalysisa: Sensitivity ¼88.7%

Specificity ¼ 100%PPV ¼ 100%

n ¼ 21 CIED infection PM Staphylococcusspp. (10)

For pocket infectionSensitivity ¼ 86.7%

77% positivity either TTEor TEE

Cautela et al77


Specificity ¼ 100%

Propionibacteriumacnes (3)

PPV ¼ 100%NPV ¼ 75%For cardiac device-related EI sensitivity ¼30.8%

Specificity ¼ 62.5%PPV ¼ 57%NPV ¼ 36%

60 y, M Infection at thepercutaneousretroauricular skull-mounted pedestal

Left ventricle assistancedevice (Jarvik, 2000)

Unknown Left cutaneousretroauricular pedestal,thoracic internal cable,Left lung, normalizedafter treatment

Unknown Costo et al138

FUO, fever of unknownorigin; lns, lymph nodes; PM, pacemaker; US, ultrasound; AICD, automatic implantable cardioverter defibrillator; PPV, positive predictive value; NPV, negative predictive value; ICD,implantable cardioverter-defibrillator; CABG, coronary artery bypass graft.

aUsing maximum count rate device or mean count rate between right and left lung parenchyma41.87.

FDG-PETincardiac

infections389

Figure 5 18F-FDG-PET/CT in patients with suspected infection of a pacemaker. Left column: chest x-ray with delineationof the generator site (yellow) and the leads course (red). Right column: PET/CT (from left to right: emission transaxialimages, CT transaxial images, and transaxial superimposed PET/CT images) showing intense 18F-FDG uptake at thepocket site.

P.A. Erba et al.390

conditions from neoplastic perdicardial involvement. In fact,noninfectious and inflammatory processes involving thepericardium or pericardial space generally present mild tomoderate increase or no increase in 18F-FDG uptake, whereasneoplastic conditions generally present intense metabolicactivity often associatedwith a focal soft-tissuemass. Incidentalreports of cardiac infection or inflammation with increased18F-FDG activity have been described in patients evaluatedwith 18F-FDG-PET/CT for fever of unknown origin.82

In patients with meningococcal sepsis and acquired immuno-deficiency syndrome, intense pericardial uptake at 18F-FDG-PET allowed to recognize infectious pericarditis.83,84

Three cases of tuberculous pericarditis were diagnosed using18F-FDG-PET/CT that identified either tuberculouspericardial involvement alone85,86 or associated with diseasedissemination throughout the body.85 A recent study exploitedthe ability of 18F-FDG-PET/CT to distinguish acutetuberculous from idiopathic pericarditis.87 Patients with acutetuberculous pericarditis showed a diffuse or multifocalpattern of 18F-FDG uptake in the pericardium associated withmediastinal and supraclavicular lymph nodes with increaseduptake. Significantly higher mean pericardial thickness

Figure 6 18F-FDG-PET/CT in patients with suspected infection o(emission transaxial images, CT transaxial images images, anduptake at the pocket site (upper panel) and all along the intrav

(5.1 mm) and SUVmax at both pericardium and lymph nodeswas observed in tuberculous pericarditis (13.5 and 5.3,respectively) as compared with patients with acute idiopathicpericarditis (3.4 mm, 3.0, and 2.8) who presented withdiffuse or regional 18F-FDG uptake. On the contrary, con-strictive or effusive constrictive pericarditis, an uncommoncomplication of chemotherapy, can present with mildand diffuse pericardial 18F-FDG uptake.88 Similarly, the lackof significant 18F-FDG accumulation in the pericardialspace in a patient presenting with idiopathic pericarditisassociated with striking hypermetabolism of the thoracicand abdominal aortic wall (highly suggestive of largevessel vasculitis) is consistent with pericarditis as the initialmanifestation of giant cell arteritis.89 Figure 8 shows anexample of 18F-FDG-PET/CT in a patient with infectivepericarditis.

MyocarditisMyocarditis, or inflammation of the heart muscle, may presentas an acute, subacute, or chronic illness. A large proportion of

f a pacemaker. Transaxial PET/CT images at different levelstransaxial superimposed PET/CT) show intense 18F-FDGascular portion of the lead (lower panel).

Figure 7 18F-FDG-PET/CT in patients with suspected infection of a pacemaker. Left upper panel: chest x-ray withdelineation of the generator site (yellow) and the leads course (red). PET/CT images (from left to right: emission images, CTimages images, and superimposed PET/CT) in coronal views (right upper column) and transaxial views (lower panel) showintense 18F-FDG uptake at the intracardiac portion of the PM lead. PM, pacemaker.


afflicted individuals may be asymptomatic. Because of suchinsidious nature of the disease, its epidemiology has beendefined through postmortem studies. Prospective and retro-spective studies have identified myocardial inflammation in1%-9% of routine postmortem examinations.90-92 Myocarditisis a major cause of sudden, unexpected death (up to 20% ofcases) in adults younger than 40 years.93 The causes of

Figure 8 18F-FDG-PET/CT finding in patients with infection ofunknown origin demonstrating sites of increased 18F-FDG uptake atthe pericardium, finally diagnosed as cytomegalovirus related peri-carditis. Upper panel: coronal PET/CT images (left column emissionimages, middle column CT images and right column superimposedPET/CT). Lower panel: transaxial PET/CT images (left columnemission images, middle column CT images and right columnsuperimposed PET/CT).

myocarditis include a variety of infectious or systemic diseases,toxins, and drugs. Viruses, especially enteroviruses, are themost important causes of myocarditis in developed countries.The enterovirus genome has been identified in the myocar-dium of patients with myocarditis or with dilated cardiomy-opathy.94-96 Since the early 1980s, endomyocardial biopsy hasbeen employed to evaluate patients with suspected myocardi-tis. In 1986, the Dallas criteria for the histologic diagnosis ofmyocarditis were defined,97 based on the identification ofinfiltrating lymphocytes and of myocytolysis. Patients withlymphocytic infiltration but without myocytolysis were classi-fied as having borderline or ongoing myocarditis. However,less than 10% of the patients with suspected myocarditis hadpositive biopsies when assessed by the Dallas criteria,98 thusraising the issue of low sensitivity and high interobservervariability. A second clinicopathologic classification systemwas proposed in 1991,99 but has not been widely accepted.Although there have not been major advances in the

identification of the etiology of myocarditis in recent years,new molecular techniques such as polymerase chain reactionand genomic hybridization have allowed confirmation of theetiology in some cases, which would have otherwise remainedundiagnosed. On the one hand, the serum level of creatinekinase-MB has high specificity but limited sensitivity for thediagnosis of myocarditis; on the other hand, serum troponin Iis more often elevated than creatine kinase-MB in patients withmyocarditis.100,101 Echocardiography performed in the settingof acute myocarditis may demonstrate either normal heartfunction or global or regional left ventricular hypokinesis, withan overall low reported sensitivity.102 MRI allows discrim-ination of myocarditis frommyocardial infarction by depictingscattered areas of hyperenhancement with a nonvasculardistribution (in midmyocardial or subepicardial locations) incase of myocarditis. These areas of hyperenhancement corre-spond to inflammation and cell necrosis, and are most

P.A. Erba et al.392

commonly seen in inferior and inferolateral myocardialsegments.102,103

Diffuse increased metabolic activity in the left wall withmild heterogeneity suggesting the occurrence of myocarditishave been observed at 18F-FDG-PET/CT in a patient withchronic active Epstein-Barr virus infection presenting withfever, dyspnea on exertion, general malaise, hepatosplenome-galy; the patient subsequently developed heart failure andmyocarditis was confirmed by endomyocardial biopsy.104

This condition must be discriminated from congestiveheart failure, right ventricular strain, and hypertrophy dueto elevated pulmonary artery pressure, which can alsolead to increased 18F-FDG uptake in the right ventricularmyocardium.105,106

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FDG-PET in Cardiac Infections