Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Role of 18F-FDG PET/CT in the Diagnosis of Cardiovascular Implantable Electronic Device Infections: A Meta-Analysis Maryam Mahmood MbChB1, Ayse Tuba Kendi MD2, Saira Farid MD1, Saira Ajmal MD1, Geoffrey B. Johnson MD PhD2,3, Larry M. Baddour MD1,4, Panithaya Chareonthaitawee MD4, Paul A. Friedman MD4, M. Rizwan Sohail MD1,4 1Division of Infectious Disease, Department of Medicine, 2Division of Nuclear Medicine, Department of Radiology, 3Department of Immunology, 4Department of Cardiovascular Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN USA Institution Picture/Logo Optional Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology BACKGROUND Cardiovascular implantable electronic device (CIED) infections can present as generator pocket infection, lead infection, CIED infective endocarditis (IE) which can involve a lead and/or a cardiac valve, or a combination of these syndromes1 Nuclear imaging is increasingly being used to assist in the diagnosis of CIED infections, particularly in the absence of localizing signs at the generator pocket or definitive echocardiographic findings Fluorine 18 fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET)/computed tomography (CT) in particular has demonstrated potential as an adjunctive diagnostic test in these challenging scenarios, with high diagnostic accuracy reported in small studies Improving diagnostic certainty in CIED infections is important as current management guidelines recommend complete device removal for all patients with device infection due to the high risk of relapse with retained hardware1-3 Sohail MR et al. J Am Coll Cardiol, 2007. 49(18): p. 1851-9 Baddour LM et al. Circulation, 2010. 121(3): p. 458-77 Deharo JC et al. Heart, 2012. 98(9): p. 724-31. Copyright American Society of Nuclear Cardiology

METHODS Study type: Meta-analysis Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology METHODS Study type: Meta-analysis Search: PubMed, Embase, Cochrane library, CINAHL, Web of Knowledge and www.clinicaltrials.gov were searched from January 1990 to April 2017 for eligible studies Study endpoints: Accuracy of PET/CT in the diagnosis of CIED infection Study variables: Sensitivity and specificity of PET/CT for diagnosis of CIED infection Copyright American Society of Nuclear Cardiology

Summary of characteristics of studies Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Summary of characteristics of studies Study Setting Participants PET/CT protocol Sensitivity/ Specificity (95% CI) Ahmed 2015 [6] Prospective single center, England 46 4-6 hour fast, 60-90 minute FDG uptake time 1.00 (0.88-1.00) 0.94 (0.71-1.00) Bensimhon 2010 [7] Prospective single center, France 21 8 hour fast, 60 minute FDG uptake time, blinded interpretation, results masked from clinician 0.85 (0.55-0.98) 1.00 (0.72-1.00) Cautela 2013 [8] 8 hour fast, mean FDG uptake time 71 minutes (range 45-140) 0.70 (0.46-0.88) 1.00 (0.03-1.00) Corrigan 2014 [31] Retrospective single center, England 13  Not stated 0.70 (0.35-0.93) 0.67 (0.09-0.99) Granados 2016 [16] Retrospective single center, Spain 29 12 hour fast, MS diet, 60 minute FDG uptake time, heparin bolus 1.00 (0.75-1.00) 1.00 (0.79-1.00) Graziosi 2014 [9] Prospective single center, Italy 27 45-60 minute FDG uptake time 0.67 (0.35-0.90) 0.87 (0.59-0.98) Jimenez-Ballve 2016 [10] Prospective single center, Spain 41 12 hour fast, MS diet, 45-60 minute FDG uptake time, heparin bolus 0.91 (0.59-0.99) 0.00 (0.00-0.37) Klug 2015 [11] Prospective multicenter, France 79 Blinded interpretation 0.76 (0.63-0.86) 0.95 (0.76-0.99) Leccisotti 2014 [12] Prospective single center, Italy 15 hour fast, MS diet, blinded interpretation, final diagnosis based on microbiologic criteria 0.86 (0.65-0.97) 1.00 (0.48-1.00) Pizzi 2015 [13] 28 12 hour fast, 60 minute FDG uptake time, heparin bolus 0.87 (0.62-0.98) 1.00 (0.73-1.00)   Ploux 2011 [14] Retrospective single center, France 10 8 hour fast, 60 minute FDG uptake time 1.00 (0.54-1.00) 1.00 (0.39-1.00) Remo 2014 [32] Retrospective single center, USA 26 0.75 (0.51-0.91) Sarrazin 2012 [15] Prospective single center, Canada 42 8 hour fast, Mean FDG uptake time 65±17 minute 1.00 (0.89-1.00) 0.90 (0.58-0.99) Tlili 2015 [17] 40 6 hour fast, 60 minute FDG uptake time 0.83 (0.58-0.96) 0.96 (0.77-0.99) Insert a key table or a key figure If figure, insert legend Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology Overall, 14 studies involving 492 patients were included in the meta-analysis. The pooled sensitivity of PET/CT for diagnosis of CIED infection was 83% (95% CI, 78-86%) and the pooled specificity was 89% (95% CI, 84-94%). Pooled sensitivity = 0.85 (0.80 to 0.89) Chi-square = 40.90; df=13 (p=0.0001) Inconsistency (1=square) = 68.2% Pooled specificity = 0.90 (0.84 to 0.94) Chi-square = 45.79; df=13 (p=0.0000) Inconsistency (1=square) = 71.6% Copyright American Society of Nuclear Cardiology

Journal of Nuclear Cardiology | Official Journal of the American Society of Nuclear Cardiology CONCLUSIONS Use of PET/CT in the evaluation of CIED infection demonstrates a high sensitivity of 85% and high specificity of 90% PET/CT is a promising imaging modality as an adjunctive diagnostic tool in evaluating patients with suspected CIED infection Larger prospective studies are needed to validate the optimal preparatory and imaging protocols for evaluation of CIED infections Copyright American Society of Nuclear Cardiology