**2. Epidemiology and risk factors for LVAD infections**

Several studies have looked at various aspects of LVAD candidates in terms of their risk of developing complications including infections. A significant reduction in infections has already been noted in a randomized trial comparing older pulsatile flow LVADs to current continuous flow (CF) LVADs [5]. The improvement in infection rates was felt to be due to the smaller size of the device and the driveline caliber [20]. An observational study of LVAD type (pulsatile versus CF) spanning 2000–2009 in a single institution concluded that differences in infectious complications in that cohort were more related to when the device had been implanted, with more recent implantations showing fewer infections [21]. Subsequent innovations (axial to centrifugal flow) have not resulted in a reduction in infectious complications [7, 8] with an actual increase in sepsis with the Heartware HVAD device compared to HeartMate II control [7]. Studies have looked at factors including age [22], gender [23], body habitus including both small patients [24] and obesity [25], trauma [26], duration of LVAD support [27] as well as presence of comorbid conditions such as diabetes [28–30], depression and chronic kidney disease (CKD) [31], alcoholism and immunosuppression [29], and malnutrition ([32, 33] and references therein). In a Japanese multicenter trial looking at 300 patients receiving HeartMate II between April 2013 and December 2016, patients older than 60 had similar overall survival and risk of driveline and pocket infections [22]. An older study found that age and the presence of diabetes were associated with increased risk of LVAD endocarditis [34] with a median age of 59 among patients with endocarditis compared with a median age of 53 in those without (p = 0.02). Women receiving LVADs were often sicker (Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) cohorts 1 or 2) and had significantly higher bleeding complications, arrhythmias and right heart failure, but not infectious complications [23]. Driveline infections were slightly more common in smaller (body surface area (BSA) < 1.5 m2 ) patients (13 vs. 12 patients, p = 0.003) but mediastinal infections occurred in 2 patient with BSA > 1.5 m2 with no cases among smaller patients [24]. Clerkin et al. examined data from a BTT cohort of 3856 patients between 2004 and 2014, and found that patients with a body mass index (BMI) >35 kg/m2 had a trend towards increased infection risk (hazard ratio 1.59, 95% confidence interval 0.99–1.94, p = 0.058) [25]. Diabetes mellitus as a risk factor for infection was studied among 341 individuals who underwent LVAD implantation at Mayo Clinic between 2007 and 2016 [28]. Thirty-eight percent of the LVAD recipients had diabetes, and those patients also had significantly more ischemic cardiomyopathy as a cause for LVAD implantation, more were receiving LVADS as destination therapy and these patients also had higher BMI than those without diabetes. Looking at a composite endpoint of stroke, pump thrombosis and infections, patients with diabetes were 2.1 times more likely to have a poor outcome. There was a 1.73 fold increased risk of all cause mortality among diabetic patients as well. Interestingly, pre-operative hemoglobin A1C (HgbA1c) levels were not related to adverse outcomes, and LVAD recipients experienced lower HgbA1cC levels and lower diabetes medication requirements post-implantation. A large prospective multicenter trial of 86 HeartMate II recipients identified depression and CKD as independent risk factors for infection [31], with adjusted hazard ratios of 2.8 (p = 0.007) and 1.7 (p = 0.023) respectively. A multicenter trial in France looked at 159 patients who received LVADs between 2007 and 2012 and found that 22.6% of the patients had at least one infectious complication [29]. LVAD infections in this cohort were associated with alcoholism in 33%, diabetes in 11% and other immunosuppression in 11%. Of note, a small case series of 4 HIV patients implanted with LVADs did not show an increased risk in infection and one of the patients was successfully transplanted [35]. The implantation of an LVAD itself seems to result in reduced cell mediated immunity with decreased interleukin-2 (IL-2) and tumor necrosis factor (TNF) production, and increased IL-10 by T-lymphocytes. Greater numbers of suppressive regulatory T-lymphocytes (Tregs)

followed by the implantation of the first artificial heart by Cooley in 1969, as a bridge to transplant. The famous Jarvik 7 artificial heart was implanted in 1984 by De Vries. It was not until 1994 that the FDA first approved the LVAD as a bridge to transplant, and only in 2010, was the HeartMate II LVAD, a continuous flow (CF) device, approved as destination therapy ([4, 5] and references therein). After January 2010, only continuous flow devices i.e. HeartMate II have been implanted. The HeartMate III, Heartware HVAD and the Jarvik 2000 LVADs are currently under study in clinical trials [6–8]. An increasing number of patients are receiving non-surgically deployed LVADs such as the Impella 5.0 (5 L/min flow) as they await a decision regarding cardiac transplantation versus destination therapy with a larger (10 L/min flow) standard device [9]. More and more patients who are not considered candidates for transplantation are receiving destination LVADs and have significant improvement in their NYHA functional class and quality of life despite the numerous potential complications that these patients often face [1, 10, 11]. As devices evolve, becoming ever smaller, more compact and potentially entirely contained within the patient, it is anticipated that many of the complications, particularly infectious complications, will diminish in frequency. However, with the current state-of-the-art, infectious complications including drive line infections, pocket infections, bacteremia and the most dreaded infectious complication, endocarditis and associated mycotic aneurysms, remain important causes of morbidity and mortality in LVAD recipients, both destination therapy (DT) and as a bridge-to-transplant (BTT). In this review, we will not consider complications of devices used in so-called "bridge to decision" therapy such as the Impella 5.0. The continuous axial flow HeartMate II is now the most common LVAD in use in the US; between 2006 and 2016 a total of 17,008 CF LVADS have been implanted with 81% 1 year survival [12]. LVADs including HeartMate II and other devices have been reviewed in [1, 3, 4, 13–17]. Newer centrifugal flow devices, HeartMate III and HeartWare HVAD that are smaller and reportedly less prone to thrombosis and device failure are in clinical trials in the US [7, 8,

18] but have been utilized successfully in other parts of the world [19].

**2. Epidemiology and risk factors for LVAD infections**

LVAD infections will also be discussed.

172 Advanced Concepts in Endocarditis

This review will focus on several aspects of LVAD infections including the rare complication of endocarditis, and will identify gaps in knowledge regarding diagnosis of LVAD infections, treatment and prevention of these infections. Differences in rates of infection in bridge vs. destination therapy will be discussed but the focus of review will be on destination therapy as that is where we see the most infectious complications. The epidemiology and microbiology of LVAD infections will also be addressed including risk factors and the impact of device related complications on post-transplant infectious complications. *Mycobacterium chimaera*

Several studies have looked at various aspects of LVAD candidates in terms of their risk of developing complications including infections. A significant reduction in infections has already been noted in a randomized trial comparing older pulsatile flow LVADs to current continuous flow (CF) LVADs [5]. The improvement in infection rates was felt to be due to the smaller size of the device and the driveline caliber [20]. An observational study of LVAD type are found in these patients for an average of 6 months post-implantation ([36], also reviewed in [33]). LVAD induced immune deficits appear to resolve in CF devices as compared to older pulsatile devices ([33] and references therein).

**3.2. Driveline infections**

is not present [33, 40, 43, 49].

and he was maintained on lifelong *M. chimaera* therapy.

**3.3. Pocket infections**

**3.4. Mediastinitis**

Driveline infections are most common, and skin flora from patient's skin are the predominant pathogens detected (reviewed in [40]). Often, trauma of the driveline tunnel, due to rough manipulation of the driveline, and lack of skin fixation that reduces tension on the driveline, leads to infections. The microbiology includes *Staphylococcus aureus*, both methicillin susceptible (MSSA) and resistant (MRSA), coagulase negative *Staphylococci* (CNS) (*S. epidermidis*), *Corynebacterium* spp. [21, 26, 27, 33, 34, 45, 46], viridans streptococci [31], *Enterococcus faecalis* [31, 34], *E. faecium* including vancomycin resistant strains "VRE" [30], Gram negative enteric bacilli such as Enterobacteriaceae (*Enterobacter cloacae* and *E. aerogenese* [31] *Escherichia coli*, *Klebsiella* spp. [34], *Proteus mirabilis* [31], *Serratia marcescens* [21]), *Pseudomonas aeruginosa* [20, 26, 31] and *Stenotrophomonas maltophilia* [31]. There have been rare instances of fungal driveline infections with *Candida* spp. such as *C. albicans, glabrata* [20, 31, 34]. There have been recent series of reports of infections with *Mycobacterium chimaera*, related to open chest surgery and cooling units employed for cooling cardioplegia solution [47]. In rare cases, patients developed endocarditis in the setting of recent valvular surgery. To date, one case of a complicated LVAD driveline infection with abdominal wall abscess by *M. chimaera* has been reported [48]. Biofilm formation by many different organisms contributes to persistence of infections due to the poor efficacy of antibiotics against organisms within biofilms, even when drug resistance

Left Ventricular Assist Device Infections http://dx.doi.org/10.5772/intechopen.74621 175

Pocket infections can occur at the time of implantation, during trauma to the driveline and pocket from driveline manipulation or bleeding into the pocket from coagulopathies [20]. The microbiology of pocket infections is thus very similar to driveline infections, with skin flora such as Staphylococci and Corynebacteria predominating, as well as *Enterobacteriaceae*, Enterococci, *Pseudomonas* and *Candida* spp. [20, 26, 31, 40]. We are in the process of reporting on a patient with a HeartMate II LVAD for DT who cracked his driveline and had extensive hematoma formation in the pump pocket with subsequent persistent infection and bacteremia with *Enterobacter cloacae (*Skalweit, in preparation). Computed tomography images of this patient are shown in **Figure 1**, with hematoma, phlegmon and small air bubbles evident in the pump pocket (a) before debridement. **Figure 1b** is after debridement. **Figure 2a**–**c** shows the pump pocket wounds after debridement, with placement of a vacuum wound device and after closure of the defect. One case of a pocket infection with *M. chimaera* has been reported in a patient who developed a fluid collection contiguous with the pump pocket [48]. The patient underwent extensive debridement and omental flap coverage of the device. Operative specimens were routinely cultured and he was empirically treated with broad spectrum antibiotics but did not respond to therapy. Subsequent mycobacterial cultures revealed the pathogen

As a direct extension of pocket infections or as a result of sternal wound infections, LVAD associated mediastinitis is rarely observed [34, 43, 48]. *S. aureus* (MRSA), CNS, and vancomycin

#### **2.1. Impact on post-transplant infections**

Additional studies have looked at outcomes in transplant patients who developed LVAD infections either as BTT or DT (where the infection was treated in part by removal of the DT device, with subsequent receipt of an organ) [20, 30, 34, 37, 38]. In US studies, pretransplant LVAD infections appear to influence outcomes in cardiac transplant patients, with more infectious complications in those with prior LVAD infectious complications. Other risk factors in multivariate analysis included age, ICU length of stay and use of an anti-thymocyte agent [38]. A sub-study of the Swiss Transplant Cohort Study found that pre-transplant LVAD infections did not have an impact on post-transplant outcomes with slightly lower rates of infection and slightly higher survival rates among LVAD BTT patients [37]. Enterococcal infections including with VRE and Staphylococcal infections were most common among LVAD associated post transplant infections [30, 34]. The presence of infections with molds such as *Aspergillus* spp. are felt to be a strong relative contraindication for transplantation [6].
