Selection of literature
A total of 71 articles were identified through an electronic database search (Fig. 1). After removing one duplicate, the remaining 70 articles were screened based on title and/or abstract. Fifty-nine studies were excluded because they either had a different focus than the research question, presented no original data, or lacked a full text. Eleven studies were deemed eligible for full-text analysis. Cross-checking references for any additional publications yielded no extra results. One of the articles was excluded from further analysis because it contained insufficient data specific to our research question (only two patients in the study population had an LVAD) . In total, 10 studies (n = 382 scans in 318 patients) were included in the systematic review. Two of the studies that were included in the systematic review were excluded from the meta-analysis: one because of suspected data overlap with a later study published by the same author [23, 24], the other because of methodology/applicability concerns based on full-text analysis . The latter study included analyses of FDG-PET/CT accuracy, but microbiological diagnosis was based on driveline exit site swabs only, which cannot be used as a standalone reference test for any deeper infection of the driveline or central device components. Furthermore, this study included only patients with a relatively late stage of infection, leading to selection bias and applicability concerns. Therefore, for the meta-analysis, eight studies (n = 256 scans in 230 patients) were found eligible.
Systematic review: study characteristics
In the ten articles included in the systematic review, a total of 382 FDG-PET/CT scans were acquired for 318 patients. A suspicion of LVAD-related infection was the reason for performing the FDG-PET/CT in 232 scans, 6 of which were for evaluation of treatment, while all others were considered separate episodes. The remaining 150 scans were either part of work-up for heart transplantation or assessment of pathology unrelated to LVAD (e.g. malignancy). In 78 scans, only the driveline was evaluated [19, 20]. One publication had a prospective study design , while all others used retrospective patient data. Median age of participants ranged from 52 to 64 years. The study population was predominantly male, proportions ranging from 77.8 to 90.5%. The characteristics of the ten included studies are summarized in Table 1.
In all studies, FDG-PET scans were performed on a hybrid PET/CT system, combining an FDG-PET scan with a low-dose CT for anatomical reference and attenuation correction. In one study, the FDG-PET scan was combined with diagnostic CTA . Reporting of injected activity differed between studies: while some reported an injected activity per kilogram of body weight, others reported a mean total injected activity with lower and upper ranges. The injected activity was also highly variable for included studies, ranging from 215 to 474 MBq for the mean total activity and 2.3 to 5 MBq per kg body weight (EANM guidelines advice: 2.5–5.0 MBq/kg ). According to study protocols, all scans were performed approximately 60 min after injection of FDG. However, the actual time intervals in clinical practice were not reported.
Visual analysis of the scans was performed in all studies; in 5 studies, this was combined with semi-quantitative analyses, using SUVmax [19, 20, 24] and target-to-background ratios (TBR) [23, 24, 28], reference regions being lung parenchyma and deltoid muscle [23, 28], or thoracic aorta and liver . In one study, metabolic volume was also used: this was defined as the measured volume of a target lesion showing more FDG uptake than the mean FDG uptake in a delineated region of interest in the liver plus 2.5 standard deviations, with a minimum volume of 9 cm3 . The technical details of the included studies are summarized in Table 2.
Methodological quality of included studies
The QUADAS-2 risk of bias of all studies evaluated for meta-analysis eligibility is summarized in Fig. 2. Two studies had a high risk of bias for patient selection, one due to unexplained patient exclusions , the other because of a case series of patients with late-stage infections . All other studies described a suspicion of device-related infection as inclusion criterion, but this suspicion was not further elaborated or defined. Therefore, all other studies were considered to have an unknown risk for patient selection bias. Only one study had a low risk of bias for the index test, having assessors of the FDG-PET/CT blinded to findings of other clinical tests and final diagnosis for patients, while also performing the FDG-PET/CT scan according to EANM recommendations with a high-fat, low carbohydrate diet, a pre-scan fast of more than 6 h, and assessment of both attenuation-corrected and attenuation-uncorrected images . In other studies, observers were either not blinded to clinical context of patients or assessment of non-attenuation-corrected images was not described. Two studies performed the reference test fully in accordance with ISHLT recommendations [27, 29]. Two studies had high applicability concerns for both index test and reference test, because they focused on the LVAD driveline only [19, 20].
Impact on prognosis and patient management
The ability of FDG-PET/CT to predict outcome and help inform management of device infections was discussed in three of the articles included in the systematic review [24, 25, 27]. In one study, a positive FDG-PET/CT was associated with a 50% mortality during follow-up (median survival 87.5 days), which contrasted with the non-infected group, in which no patients died during follow-up (median follow-up duration of 165 days). Twelve out of the 14 (86%) patients who died had involvement of pump or pocket infection . In another study, FDG-PET/CT helped clinicians change their medical strategy for 12 out of 21 patients (57%), including four patients that were listed for high urgency heart transplantation based on FDG-PET/CT results. In all these cases, infection of the LVAD device or the deep driveline was confirmed at transplantation. . In the third study, an association was found between FDG uptake of thoracic lymph nodes and adverse outcome, although this was not found for increased FDG uptake along the driveline or around any central LVAD device component .
Meta-analysis: pooled diagnostic performance
In the eight articles included in the study-aggregate meta-analysis, a total of 256 FDG-PET/CT scans were acquired in 230 patients. A suspicion of device-related infection was the reason for performing FDG-PET/CT in 232 scans. In 78 scans, only the driveline was evaluated [19, 20].
For the assessment of overall device-related infections, pooled sensitivity and specificity of FDG-PET/CT were 0.95 (95% CI 0.89–0.97) and 0.91 (95% CI 0.54–0.99) respectively. NLR was 0.14 and positive likelihood ratio, PLR, was 3.54 with an overall DOR of 38.43. When only assessing the driveline, FDG-PET/CT pooled sensitivity, specificity, NLR, PLR, and DOR were respectively 0.97 (95% CI 0.88–0.99) and 0.99 (95% CI 0.13–1.0, 0.13, 3.93, and 92.46. When only assessing pump/pocket infections, FDG-PET/CT pooled sensitivity and specificity were 0.97 (95% CI 0.70–1.0) and 0.93 (95% CI 0.64–0.99) respectively. NLR was 0.12 and PLR was 5.56 with an overall DOR of 49.43.
The I2 test for heterogeneity was positive (> 50%) for PLR of FDG-PET/CT, for assessment of driveline only, pump/pocket only, and the combination of both. Results of the meta-analysis for LVAD-specific infections, in which findings for pump/pockets and driveline are combined, are summarized in Table 3 and Fig. 3. The split analyses of driveline and pump/pocket infections are shown as ROC curves in Fig. 4. The corresponding tables and forest plots can be found under supplemental data: Tables 4 and 5, Figs. 6 and 7. Plots for FDG-PET/CT diagnostic odds ratios are represented in supplemental data Figs. 8–10.
While 5 studies mentioned the use of semi-quantitative analysis [19, 20, 23, 24, 28], only 3 of these described its findings in comparison with visual analysis. Visual analysis outperformed semi-quantitative analysis in 2 studies [23, 28] while in one study , both semi-quantitative analyses using SUVmax and especially metabolic volume with a cutoff of > 9 cm3 outperformed visual analysis, with 2/3 false negatives and 2/5 false positives correctly classified using metabolic volume.
In one study, all patients underwent two scans: a baseline scan without suspicion of infection, and a second one for assessment of driveline infection . The baseline scan may have facilitated the interpretation of the second diagnostic scan, which might explain the absence of any false positives or false negatives in this study, although this warrants validation in further studies.
Analysis of false positive and false negative scans was performed in 4 studies [23, 27, 29, 30]. In one study, the cause of 2 false negatives could not be established . In another, it is implied that the reason for their single false negative result might have been the 30-day period of antibiotic treatment at the time of the scan . In the third study, out of 6 false positives, 4 patients had concurrent bacteraemia or other possible sources of infection, 1 patient had increased cardiac sarcoidosis activity, and 1 had a newly diagnosed chronic myeloid leukaemia. The exact effect of these comorbidities on FDG-PET/CT results in their study remained unclear. The most extensive analysis of false positives and false negatives was performed by Dell’ Aquila et al. . They described prolonged antibiotic use, infection limited to the pump housing as the causes for false negatives, and the presence of chronic fistulas as main causes for a false positives in 3 cases, whereas 7 other cases remained unexplained.
Analyses of scans performed shortly after LVAD implantation showed robustness of the scan in this setting: in one study, a true negative was reported 3 weeks after LVAD implantation  and in another, 5 true positives and 5 true negatives were reported within 3 months after LVAD implantation .