One PET, Two PET – Endocarditis and Positron Emission Tomography

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PETs. We all love them. I have two of those, if the pictures in my “about me” page are any indication as well as the main pic of this post. This post will not cover our beloved (and sometimes only) friends. No, we will be talking about positron emission tomography, an imaging modality we usually associated with oncology. PET delivers high resolution images using biologically active compounds labeled with positron emitters (1). 18-FDG, a radiolabeled glycogen analogue, is accumulated in hypermetabolic cells and then a PET camera can identify hypermetabolic foci by detecting the positron emission of this radiolabeled tracer. The idea here is to take advantage of the fact infections tend to be hypermetabolic, and thus allow one to identify the source when all other modalities have failed. It would be helpful in cases of fever of unknown origin, however there is some literature to suggest it may also play a role in infective endocarditis. 

Results from PET/CT can be added as diagnostic modality to supplement the modified Duke criteria. A review of over 20 studies found that the sensitivity for PET/CT for diagnosis native valve endocarditis was 14%, with the addition of this modality resulting in an increase of 15-32% in diagnosis of other foci of infection (2). In prosthetic valve endocarditis, the sensitivity and specificity ranged from 73-100% and 71-100%, respectively. Moreover, adding PET/CT increased the diagnostic sensitivity of the modified Duke criteria from 52-70% to 91-97%. This was also seen in cardiac device-related infections, where the sensitivity was 80-89%% and specificity was 85-89%. Similarly, a prospective study of 92 patients found that the use of PET/CT in combination with the modified Duke criteria allowed the study group to reclassify 90% of cases from possible IE by the Duke Criteria to definitive diagnosis (3). This allowed the sensitivity to increase from 52 to 91%, with an increase in specificity of 95% to 90%. Indeed, the performance of PET/CTA in addition to diagnostic criteria outperformed all other modalities:

Importantly, however, PET/CT allowed for the identification of 15% of peripheral emboli. The sensitivity overall for cardiac devices was overall higher than when compared to prosthetic devices. 

Further, PET/CT provided an alternative diagnosis in 54% of negative IE cases. In a cohort of 73 patients with prosthetic valve endocarditis (4), the addition of PET/CT to the modified Duke criteria increased the sensitivity at admission from 70% to 97% (p=0.008). Of these, 23% presented with a positive PET/CT despite having an initial negative echocardiogram. 

A prospective study of 47 patients evaluated the role of PET/CT in cases of infective endocarditis. Here, the use of PET/CT led to an increase in the diagnosis of infectious complications in 57.4% when compared to 18% of cases (5). Relapses were also higher in the case group (9.6% vs 4.2%), though this did not reach statistical significance. Indeed, it may be even more diagnostic useful to use PET as opposed to clinical criteria. A retrospective cohort evaluated PET/CT in those patients who had possible/rejected IE according to the modified Duke criteria with high clinical suspicion (6). When compared to a final team consensus, PET/CT allowed to the highest accuracy in diagnostics, with PET/CT being superior to both mDC and clinical suspicion:

Moreover, PET/CT allowed for the identification of pathological extracardiac uptake in 17 cases that had a diagnosis of IE excluded with results of imaging contributing to patient management in 45% of cases. 

Increased Rates of Complications

When it comes to SAB, we tend to overtreat given the high risk of relapse and our inability to pick up metastatic complications on physical exam. Indeed, the concern is its ability to “stick” anywhere without making it obvious and thus, risk of relapse after cessation of antibiotics. One of the proposed utilities of PET/CT is to help pick up metastatic foci before becoming clinically apparent. This was evaluated in a prospective study of patients with gram positive bacteremia, where its role was compared to a historical control (7). 115 study patients were included along with 230 control patients, with a significantly higher number of metastatic infections being found in the study group:

Notably, in 50% of all patients who were eventually found to have metastatic infection, no signs or symptoms were present prior to advanced imaging. More importantly, however, was that 3 month and 6 month overall mortality was lower in the PET-CT group:

A retrospective cohort of patients with high-risk SAB was able to find a metastatic infection in 71% of patients who did not display any signs or symptoms of one (8). Nearly 75% of patients with positive PET results had adjustment to their treatment:

Multivariate analysis found that performance of PET/CT was associated with lower 3 month mortality:

A prospective cohort study evaluated 90-day all-cause mortality in 149 patients who were diagnosed with staphylococcus aureus bacteremia and underwent PET/CT compared to matched controls (9). 90-day mortality was significantly lower in the PET/CT cohort (14% vs 29%, p = 0.002), with multivariate analysis finding that PET/CT performance was associated with lower mortality:

This is largely due to the identification of high risk bacteremia, and the identification of an infectious focus. A systematic review of 5 studies, which included 880 patients, found that the use of PET-CT in SAB was associated with lower 3-month mortality (10):

Similarly, one of the quoted studies found lower incidence of relapse in the intervention cohort (1.4% vs 8.9%). I do not expect PET/CT to become in vogue given its cost and other tools we have for diagnosis. However, its use may be increasing in difficult cases of bacteremia of unclear source or fever of unknown origin. 

References:

  1. Revest M, Patrat-Delon S, Devillers A, Tattevin P, Michelet C. Contribution of 18fluoro-deoxyglucose PET/CT for the diagnosis of infectious diseases. Med Mal Infect. 2014 Jun;44(6):251-60. doi: 10.1016/j.medmal.2014.04.007. Epub 2014 May 18. PMID: 24844599.
  2. Gomes A, Glaudemans AWJM, Touw DJ, van Melle JP, Willems TP, Maass AH, Natour E, Prakken NHJ, Borra RJH, van Geel PP, Slart RHJA, van Assen S, Sinha B. Diagnostic value of imaging in infective endocarditis: a systematic review. Lancet Infect Dis. 2017 Jan;17(1):e1-e14. doi: 10.1016/S1473-3099(16)30141-4. Epub 2016 Oct 18. PMID: 27746163.
  3. Pizzi MN, Roque A, Fernández-Hidalgo N, Cuéllar-Calabria H, Ferreira-González I, Gonzàlez-Alujas MT, Oristrell G, Gracia-Sánchez L, González JJ, Rodríguez-Palomares J, Galiñanes M, Maisterra-Santos O, Garcia-Dorado D, Castell-Conesa J, Almirante B, Aguadé-Bruix S, Tornos P. Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With 18F-Fluordeoxyglucose Positron Emission Tomography/Computed Tomography Angiography: Initial Results at an Infective Endocarditis Referral Center. Circulation. 2015 Sep 22;132(12):1113-26. doi: 10.1161/CIRCULATIONAHA.115.015316. Epub 2015 Aug 14. PMID: 26276890.
  4. Saby L, Laas O, Habib G, Cammilleri S, Mancini J, Tessonnier L, Casalta JP, Gouriet F, Riberi A, Avierinos JF, Collart F, Mundler O, Raoult D, Thuny F. Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis: increased valvular 18F-fluorodeoxyglucose uptake as a novel major criterion. J Am Coll Cardiol. 2013 Jun 11;61(23):2374-82. doi: 10.1016/j.jacc.2013.01.092. Epub 2013 Apr 10. PMID: 23583251.
  5. Kestler M, Muñoz P, Rodríguez-Créixems M, Rotger A, Jimenez-Requena F, Mari A, Orcajo J, Hernández L, Alonso JC, Bouza E; Group for the Management of Infectious Endocarditis (GAME). Role of (18)F-FDG PET in Patients with Infectious Endocarditis. J Nucl Med. 2014 Jul;55(7):1093-8. doi: 10.2967/jnumed.113.134981. Epub 2014 May 8. PMID: 24812248.
  6. Pretet V, Blondet C, Ruch Y, Martinez M, El Ghannudi S, Morel O, Hansmann Y, Schindler TH, Imperiale A. Advantages of 18F-FDG PET/CT Imaging over Modified Duke Criteria and Clinical Presumption in Patients with Challenging Suspicion of Infective Endocarditis. Diagnostics (Basel). 2021 Apr 18;11(4):720. doi: 10.3390/diagnostics11040720. PMID: 33919643; PMCID: PMC8073326.
  7. Vos FJ, Bleeker-Rovers CP, Sturm PD, Krabbe PF, van Dijk AP, Cuijpers ML, Adang EM, Wanten GJ, Kullberg BJ, Oyen WJ. 18F-FDG PET/CT for detection of metastatic infection in gram-positive bacteremia. J Nucl Med. 2010 Aug;51(8):1234-40. doi: 10.2967/jnumed.109.072371. Epub 2010 Jul 21. PMID: 20660384.
  8. Berrevoets MAH, Kouijzer IJE, Aarntzen EHJG, Janssen MJR, De Geus-Oei LF, Wertheim HFL, Kullberg BJ, Oever JT, Oyen WJG, Bleeker-Rovers CP. 18F-FDG PET/CT Optimizes Treatment in Staphylococcus Aureus Bacteremia and Is Associated with Reduced Mortality. J Nucl Med. 2017 Sep;58(9):1504-1510. doi: 10.2967/jnumed.117.191981. Epub 2017 Mar 23. PMID: 28336786.
  9. Ghanem-Zoubi N, Kagna O, Abu-Elhija J, Mustafa-Hellou M, Qasum M, Keidar Z, Paul M. Integration of FDG-PET/CT in the Diagnostic Workup for Staphylococcus aureus Bacteremia: A Prospective Interventional Matched-cohort Study. Clin Infect Dis. 2021 Dec 6;73(11):e3859-e3866. doi: 10.1093/cid/ciaa929. PMID: 32639560.
  10. Buis DTP, Sieswerda E, Kouijzer IJE, Huynh WY, Burchell GL, Berrevoets MAH, Prins JM, Sigaloff KCE. [18F]FDG-PET/CT in Staphylococcus aureus bacteremia: a systematic review. BMC Infect Dis. 2022 Mar 24;22(1):282. doi: 10.1186/s12879-022-07273-x. PMID: 35331165; PMCID: PMC8943998.

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