Introduction

Infective endocarditis (IE) is a heart valve infection which can also involve other cardiac structures at a site of endothelial damage. Rheumatic diseases, which can determine numerous types of valve damage, have decreased over the last few years, but surgical procedures, orthodontic approaches and cardiac surgeries, all of which can cause this condition, are rising with the progressive aging of the population. This means an increased risk for structural damage of the heart and rising infections.

Many organs may be adversely affected in patients with IE. Though technological advances have improved the diagnostic accuracy for IE, morbidity and mortality remain remarkably high. The outcome of these patients strongly depends on appropriate early approach (antibiotic therapy or cardiac surgery) and presence of extracardiac infection. Extracardiac infection can occur in several forms, such as spondylodiscitis, parenchymal septic infarction (spleen, liver and lung), septic lung or peripheral embolisms, septic arthritis or metastatic abscesses. The diagnosis of these findings is challenging and could include different diagnostic tools [chest CT, abdominal CT, rachis MRI, abdominal ultrasound (US)], resltung in high health care costs.

18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT is reported to be a sensitive imaging tool in the diagnosis of tumours [1–4], but it is well known that inflammatory and infectious diseases can be detected by the same technique. The tracer injected is the fluorinated glucose analogue. Increased uptake of FDG in tumoural cells has been described in detail [13]. FDG passes the cellular membrane mimicking glucose and is phosphorylated by glucose-6-hexokinase. The specific membrane transporter of glucose (GLUT) and also of FDG is increased in malignant tissue with increased metabolism [21]. In inflammatory cells, granulocytes and macrophages use glucose as an energy source during their metabolic burst [5, 14, 15]. The radioactive component bound to glucose, 18F-fluoride, has a physical half-life of 110 min. No side effects due to FDG injection have been reported. The patient dose that is administered is of the same magnitude as a CT scan [16].

Although PET/CT has proven effective in the diagnostic flow chart of inflammatory diseases and occult infections [6–12], we wanted to assess the added value of 18F-FDG PET/CT, that is a whole-body scan, in the detection of extracardiac infection in patients with suspected endocarditis and possibly define the prevalence of the different metastatic infections in these kind of patients.

Materials and methods

Patients

We enrolled 71 patients with clinical suspicion of IE (38 with prosthetic valve and 33 with native valve), established by modified Duke criteria (12 refused, 30 possible and 29 definite), physical exam, transthoracic and transoesophageal echocardiography where possible, blood cultures and serum markers of inflammation [C-reactive protein (CRP), procalcitonin, ferritin and haemoglobin].

The Duke criteria were calculated according to the well-known criteria of Duke University. As we knew, they included blood cultures and endocardial involvement, detected by echocardiogram, as major criteria. We analysed all patients (definite but also possible and refused), because we knew that negative blood cultures did not exclude cardiac endocarditis and because echocardiography is highly sensitive and highly specific, but strongly operator dependent. In addition, echocardiography, especially transoesophageal, is influenced by vegetation size, echogenicity and the presence of prosthetic materials [29].

Patients had a mean age of 55 years and were hospitalized in S. Orsola-Malpighi Hospital and followed for 6 months after the diagnosis. All patients underwent 18F-FDG PET/CT between June 2010 and December 2012 on a dedicated scanner with the standard procedure. The possible extracardiac infections were confirmed with other imagining tools (CT, MRI, abdominal US).

PET/CT

The PET/CT scan was performed near the time of the clinical suspicion of IE. All patients underwent PET/CT on a last-generation hybrid scanner (GE Healthcare, Italy). CT images were acquired at 120 kV and 80 mA, pitch 1.75, 0.8 s per tube rotation and slice thickness of 3.75 mm. PET images were corrected for attenuation on the basis of the CT data, and iterative reconstructions were performed. The PET scan was performed 45–60 min after the administration of 370 MBq of 18F-FDG, which is a standard dose. No side effects due to FDG injection have been reported. The dose absorbed by the patient is similar to that of a CT scan [17]. We analysed only corrected PET images, also for prosthetic valves, because the end point of this study was not to evaluate the correlation between valves positive on PET/CT and final diagnosis of IE, but the possibility of finding septic embolism.

Patient preparation: a real and open problem

The myocardium derives energy for a metabolic burst from free fatty acids (FFAs) at first, and then from glucose, lactate, pyruvate, ketone bodies or amino acids [18–20]. In fasting and resting conditions, heart metabolism should be based on FFA oxidation as a source of energy, inhibiting glycolysis and glucose oxidation with low levels of glucose and insulin. This condition results in an increase in lipolysis in peripheral tissue and in increased plasma FFA levels. This decreases GLUT activity and glucose transport into myocytes and causes a reduction in glucose metabolism. On the other side, after ingestion of carbohydrates or glucose load or during hyperglycaemic conditions, plasma concentrations of glucose and insulin rise, reducing FFA plasma concentrations and their availability to the myocardium [21]. Glucose then becomes the dominant substrate for myocardial energy production [22, 23], increasing cardiac glucose uptake.

As reported in the literature, in the present state of the art a validated method to prepare the patients for reducing physiological myocardial FDG uptake has not yet been determined. Some authors [24, 25] suggested a protocol where patients were asked to adhere to a very low-carbohydrate and a high-fat diet the day before imaging and then to fast overnight; 45 min before the injection of 18F-FDG a high-fat, low-carbohydrate beverage was administered to patients. The optimal duration of fasting to reduce myocardial FDG uptake has yet to be determined; the above protocol is also applied to hospitalized patients only. However, the myocardial FDG uptake in fasting healthy subjects changes by clinical condition.

The cardiac and thoracic movements, which could generate artefacts, are also challenging. They could be reduced with cardiac gating or beta blockade [26], but very frequent drawbacks (atrial standstill, atrial fibrillation, chronic obstructive pulmonary disease, adverse reaction to drugs) decrease the application of these methods.

In clinical practice, the physiological uptake of FDG in the myocardium could hide small infective vegetations, especially on native valves. Although in many of our patients we found “hot myocardium”, the lack of a correct preparation did not influence the search for septic embolisms, which was our end point.

Results

Of 71 patients with suspicion of IE, we found unexpected extracardiac findings in 17 patients (24 %): 6 cases of spondylodiscitis (1 not confirmed by other imagining tools), 7 lung embolisms, 1 splenic infarct, 2 cases of sternal osteomyelitis (Fig. 1) and 1 case of osteochondritis (Fig. 2) with an abscess. All these findings were confirmed by MRI, CT and abdominal US (Table 1).

Fig. 1
figure 1

Sternal osteomyelitis in a patient with suspected IE without valve involvement on PET/CT. a CT. b PET. c Fused image

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Fig. 2
figure 2

Osteochondritis with an abscess in a patient with suspected IE without valve involvement on PET/CT. a CT. b PET. c Fused image

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Table 1 Overview of patient characteristics, pathogens, clinical parameters, PET/CT findings and follow-up
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Other imaging procedures were positive for brain embolism or lower limb septic infarct in 3 of 71 patients, which were impossible to diagnose during PET/CT examination, because the brain and lower extremities were not included in the scan.

In most of these patients there was clinical suspicion of endocarditis on a native valve (11 of 17), probably due to the easier detachment of septic emboli from native valvular tissue compared to prosthetic valve, which may determine greater adhesion. Of 17 patients, 10 showed positive blood cultures for Staphylococcus (8 aureus, 1 hominis and 1 haemolyticus), 3 for Streptococcus (1 haemolyticus, 1 sanguis and 1 anginosus), 2 for Enterococcus (1 avium and 1 durans) and 1 for Micrococcus spp.

Of 17 patients, 11 had a clinical condition that could lead to the development of infectious processes or immunodepression (3 with type 2 diabetes mellitus, 3 with chronic renal failure on haemodialysis, 2 positive for hepatitis C virus,1 positive for human immunodeficiency virus, 1 positive for hepatitis B virus and 1 was severely malnourished). Of 17 patients, 13 had a CRP value over 1 (with a mean of 3.27) and 5 had a value of procalcitonin greater than 1 (with a mean of 3.18). Of 17 patients, 11 received a final clinical diagnosis of IE in the valve seat (Fig. 3) (with septic foci), but only 4 showed cardiac uptake and only 2 of the 4 have been validated at final follow-up (confirmation during cardiac surgery). Of 17 patients, 14 were on antibiotic therapy at the time of PET/CT, and this may partially explain the lack of uptake in the heart. After the discovery of infective findings, the antibiotic therapy was increased for all of the 14 patients and started for the others.

Fig. 3
figure 3

Patient with aortic prosthetic valve (a). These cross-axial images show the uptake in the cardiac valve (IE, true positive) and in the spine, consistent with spondylodiscitis (b) (confirmed by MRI). a CT. b PET. c Fused image. d Maximum intensity projection

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Discussion

The results obtained show that the role of 18F-FDG PET/CT in the diagnosis of IE is still controversial and not yet standardized [27]. This depends on poor visualization of small lesions, such as vegetations due to endocarditis, and on partial volume effect and suboptimal spatial resolution of PET (around several millimetres under ideal conditions [30]).

However, it has low impact in examining the presence of infected foci on native valves, compared to US examination, which has proven more accurate. On the contrary, PET/CT seems to be highly sensitive for infected prosthetic valves, where echocardiography often determines metal artefacts. However, significant confounding factors (inflammatory reaction to the prosthetic component in the absence of superinfection, fibrosis of the prosthesis, etc.) may decrease PET/CT specificity.

In the present state of the art the role of PET/CT in patients with clinical suspicion of endocarditis is not clear [27]. We outlined a particular subcategory of these patients (native heart valves, blood cultures positive for Staphylococcus aureus, elevated inflammatory markers in particular CRP and procalcitonin, conditions of immunodepression or conducive to the development of infectious processes) in which the finding of extracardiac septic foci appears highly probable (about one fourth of the total patients), in many cases without any clinical suspicion.

PET/CT in this particular category of patients is superior to any other method of imaging for the opportunity to examine the whole body in a single scan, with a highly reproducible method, whose only disadvantage, the high cost, is reduced by the possibility to undertake a targeted therapeutic strategy, reducing the cost of a long hospitalization, entailing a greater number of separate examinations.

These findings may have therapeutic implications such as changing the duration of antibiotic therapy, reconsidering the indications for cardiac surgery when detecting occult embolism and eradicating secondary foci to prevent seeding from the metastatic focus post-operatively [28].

Conclusion

In establishing the diagnostic accuracy compared to US examination, PET/CT could be assessed as an essential investigation in the diagnosis of metastatic septic foci in patients with clinical suspicion of IE and with the specific characteristics that this study outlined.