Baseline characteristics and topography of LVAD infections

Baseline characteristics of the study population are shown in Table 1. The median interval between LVAD implantation and initial 18F-FDG-PET/CT was 700 (IQR: 3431589) days.

DLIs were detected in 92/118 (78%) patients by 18F-FDG-PET/CT. Irrespective of DLI, an exclusive infection of the internal LVAD-components was found in 10/118 (8%). It is noteworthy that with 65/118 (55%), only half of the entire cohort presented with clinically apparent DLI. As an important finding, DLI could be identified by PET/CT in 30/53 (57%) patients who had a clinically inapparent driveline entry sites. Besides increased metabolic activity at the driveline entry site or the subcutaneous driveline pathway, in 43/118 (36%) infection of the outflow graft and in 38/118 (32%) the pump pocket was found (Fig.2B). At the time of PET/CT, 75/118 (64%) patients had a positive microbiological smear at the driveline entry site. The pathogens most frequently detected were Staphylococcus aureus in 19/75 (25%), Staphylococcus epidermidis and Pseudomonas aeruginosa in 13/75 (17%) each, aerobic gram-positive bacilli in 8/75 (11%), enterobacteria in 7/75 (9%), Corynebacterium amycolatum, Escherichia coli and Serratia marcescens in 5/75 (5%) each. Bloodstream infections were detected in 13/118 (11%) patients, 3 of whom had VAD-related bloodstream infections. Compared to patients with negative blood culture results, those with positive results showed increased levels of CRP (p<0.001) and WBC (p=0.02). At the time of PET/CT, 83/118 (70%) patients were already covered by antibiotic therapy due to a LVAD-specific infection or an unknown infection focus with an indication for empiric antibiotic therapy. No patient was in the intensive care unit at the time of infection diagnosis. A comparison of PET/CT parameters between the patients with and without driveline infection in PET/CT is shown in Table 2. CRP levels correlated with metabolic tissue activity close to internal components such as the pump pocket (r=0.27, p=0.003) and the outflow graft (r=0.19, p=0.047), but less with the subcutaneous driveline (r=0.17, p=0.073) and not with the driveline entry site (r=-0.08, p=0.40). Also, CRP levels correlated with imaging-derived systemic inflammatory activity (spleen signal (r=0.22, p=0.022), bone marrow signal (r=0.22, p=0.021), and mediastinal lymph node signal (r=0.27, p<0.001)). Of note, only 21/89 (24%) patients with DLI on PET/CT showed CRP levels below the upper reference limit (5mg/L), but 82/88 (93%) patients had a normal WBC (<10,5109/L). Fever (>38C) was found in 1/82 (1%) of the patients at the time of the PET/CT-diagnosed infection. Pulmonary infiltrates as a competing focus of infection and cause of an increase in inflammation parameters were detected in 9/118 (8%) patients in PET/CT. This group showed a significantly higher CRP (10.4mg/L (4.626) vs. 32.1mg/L (18.3 99.2), p=0.004).

(A) Schematic illustration of the LVAD system, subdivided in 4 components: (1) driveline entry site, (2) subcutaneous driveline pathway, (3) pump pocket, (4) outflow graft; (B) Infection topography; (C) Infection of subcutaneous driveline pathway; (D) Infection of subcutaneous driveline pathway and thoracic components.

WBC count did not correlate with any imaging-derived inflammatory parameters.

Sternal co-infection was associated with pump pocket infection (p<0.001, OR=7.25, 95% CI 2.6120.11), outflow graft infection (p=0.005, OR=3.8, 95% CI 1.4410.01), number of infected LVAD components (p=0.002) and PET/CT signal of mediastinal lymph nodes (p=0.031).

Correlation analysis of PET signal with device components, activity of aortic vessel walls and lymphoid and hematopoietic organs is shown in Fig.3. Metabolic activity at the driveline entry site correlated with a) the aortic vessel signal (r=0.32, p<0.001) and b) both lymphoid organs, namely spleen signal (r=0.20, p=0.030), and bone marrow signal (r=0.20, p=0.030), highlighting systemic interactions. Metabolic activity of the aortic vessel walls itself correlated with spleen signal (r=0.46, p<0.001) and bone marrow signal (r=0.32, p<0.001).

Heatmap: Spearman correlation of the parameters of the first PET/CT, n=118, in four patients CRP and CBC were missing; blue: r=-1, red: r=1; CRP C-reactive protein, WBC white blood cell count, SUV standardized uptake value, thVSL thoracic vessels, SPL spleen, BM bone marrow, MLNs mediastinal lymph nodes, scDL subcutaneous driveline pathway, DLES driveline entry site, OG outflow graft, PP pump pocket.

Multivariable analysis including metabolic activity at the driveline entry site, aortic vessel wall activity, spleen signal and bone marrow signal revealed an independent association between aortic vessel wall activity and metabolic activity at the driveline entry site (=0.04, 95% CI 0.010.06, p=0.001) and spleen signal (=0.43, 95% CI 0.180.68, p<0.001).

A longitudinal sub-analysis of repeated PET/CTs was performed to investigate potential changes in metabolic activity in the vessel wall, revealing stability over time (ANOVA, p=0.27).

Within the observation period, 22/118 (19%) patients suffered a CVE, of which 15/22 (68%) had an ischemic stroke and 8/22 (36%) a haemorrhagic stroke. No patient suffered a transient ischemic attack (TIA) during the follow up period. One patient suffered both, an ischemic and haemorrhagic stroke. Seven patients had 2 or more CVE and 11/22 (50%) died within a median of 263days after the CVE (Table 3).

Characteristics of patients with ischemic stroke (n=15) compared with those without ischemic stroke (n=96) after excluding patients with haemorrhagic stroke (n=7) are shown in Table 4. The group with ischemic stroke after PET/CT demonstrated significantly higher metabolic activity at the driveline entry site (p=0.04), whereas the activity of other device components or CRP and WBC did not differ. In multivariable analysis adjusting for type of anticoagulant (VKA, heparin, others) and device exchange, higher metabolic activity at the driveline entry sitewas not significantly associated with ischemic stroke(OR=1.16, 95% CI 11.33, p=0.05). The type of anticoagulation (OR of heparin or others vs. VKA=3.22, 95% CI 1.317.88, p=0.01) proved to be an independent predictor for ischemic stroke. The type of anticoagulation in LVAD patients is often modified in the course of an inpatient stay and can therefore serve as an indicator for hospitalization with severe comorbidity, e.g., bleeding complications. Consequently, not only anticoagulation itself is a relevant competing cause of stroke, but also an indication of other contributing risk factors. The severity of infection as measured by fever (p=0.505), number of infected LVAD components on PET/CT (p=0.232) and laboratory parameters showed no association with the occurrence of CVEs. At the time of stroke, 14/22 (64%) patients were hospitalized due to following concomitant conditions: acute pump stop (n=1), driveline infection (n=6), gastrointestinal hemorrhage (n=1), heart transplant (n=2), device thrombosis (n=3) with indication for device exchange and domestic fall (n=1). In this context, VKA was paused in some patients, and anticoagulation was switched to heparin (n=6) or Argatroban (n=2). At the time of ischemic stroke, 8/15 (53%) patients were anticoagulated with vitamin K antagonists, four of whom were within, one was below and three were above the intended target International Normalized Ratio (INR) range. 7/15 (47%) patients were on heparin therapy under activated Partial Thromboplastin Time (aPTT) control, of which three were below and one was above the target aPTT range. At the time of haemorrhagic stroke, 6/7 (86%) patients were receiving anticoagulation with vitamin K antagonists, with one patient within and five patients above the intended target INR range. 1/7 (14%) patient was receiving heparin therapy and was within the target aPTT range. Ischemic stroke occurred more frequently in patients with Heparin/Argatroban compared to those who remained on VKA (p<0.001). In a log-rank test the incidence of ischemic stroke differed between patients with SUVmax of the driveline entry site above the median compared with those under the median (Fig.4; 2(1)=5.21, p=0.023). The hazard of ischemic stroke, adjusted for type of anticoagulation, hyperlipidemia and diabetes mellitus, was about 10 times higher in the group with an increased uptake of the driveline entry site (HR=10.21, 95% CI 1.6463.52, p=0.013). Receiver operating characteristics (ROC) analysis demonstrated the diagnostic ability of the activity of the driveline entry site to predict ischemic stroke after initial PET/CT (Fig. 1 in supplement; AUC=0.67, p=0.04).

Kaplan Meier analysis on ischemic stroke-free survival; differences in the incidence of ischemic stroke between patients with SUVmax of the driveline entry site above versus below the median. The analysis revealed a significantly differing hazard for ischemic stroke (2(1)=5.21, p=0.023; HR=10.21, 95% CI 1.6463.52, p=0.013).

A log-rank test was used to determine the incidence of CVE for the comparison of SUVmax of the subcutaneous driveline pathway above versus below the median. The incidence of stroke differed significantly between the two groups (Fig. 2 in supplement; 2(1)=6.76, p=0.009). The hazard of suffering a CVE was 3.5 times greater in the group with an increased uptake of the subcutaneous driveline pathway (HR=3.53, 95% CI 1.289.72, p=0.015).

During the observation period, 47/118 (40%) patients died within 1715 (1050) days after implantation. Causes of death were sepsis (50%), right heart failure (17%), hemorrhage (6%), pump thrombosis (6%) and brain herniation after intracerebral hemorrhage (4%) or middle cerebral artery infarction (2%). Cause of death was unknown for 9%.

Deceased patients showed more often hyperlipidemia (p=0.008), increased CRP values (p=0.001) and history of device exchange (p=0.016).

In addition, metabolic activity of the subcutaneous driveline pathway (p=0.005) and thoracic lymph node signal were significantly higher in deceased patients (p=0.017). Binary logistic regression analysis including metabolic activity of the subcutaneous driveline pathway, hyperlipidemia, mediastinal lymph node signal and device exchange revealed increased mortality in patients with hyperlipidemia (OR=1.90, 95% CI 1.292.79, p=0.001) and higher metabolic activity of the subcutaneous driveline pathway (OR=1.13, 95% CI 1.021.24, p=0.016). No association was found between mortality and severity of infection as measured by fever (p=0.232), number of infected LVAD components in PET/CT (p=0.268) and laboratory parameters.

A log-rank test revealed a significant difference in survival of patients with metabolic activity of the subcutaneous driveline pathway above the median compared with those below the median (Fig.5; 2(1)=9.18, p=0.002). Patients with increased subcutaneous driveline metabolic activity showed a 13% increase in the risk of mortality in Cox regression analysis after adjustment for age, diabetes mellitus and hyperlipidaemia (HR=1.13, 95% CI 1.051.21, p<0.001).

Kaplan Meier survival analysis: Mortality; differences in survival between patients with SUVmax of the subcutaneous driveline pathway above versus below the median. The analysis revealed a significantly differing distribution of survival (2(1)=9.18, p=0.002; HR=1.13, 95%CI 1.051.21, p<0.001).

We performed a ROC analysis for prediction of mortality (Fig. 2, 3 in supplement). The analysis showed that both, CRP in the morning of the first PET/CT (Fig.3; AUC=0.68, p=0.001) and metabolic activity of subcutaneous driveline (Fig. 4 in supplement; AUC=0.65, p=0.005), can help to predict mortality.

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