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LVAD Infections and Post-Transplant Outcomes: A Long Way to Go


Jorge Silva, MD
jsilvaenciso@ucsd.edu

Saima Aslam, MD, MS
Mayo Clinic
San Diego, CA, USA
saslam@ucsd.edu



The sixth INTERMACS annual report summarizes data from over 10,000 MCSDs implanted worldwide.(1) Up to a third of patients continue to develop infectious complications such as sepsis and driveline infection (DLI). Driveline infections continue to occur with increasing hazard associated with increasing duration of device placement. Risk factors for driveline infection include obesity, diabetes, trauma to the exit site, surgical factors such as extra- cutaneous placement of the velour portion of the driveline, and length of implantation of the device.

Some cases of DLI progress to deep DLI or bloodstream infection over time that can negatively impact survival. One study reported an increase in one- year mortality to 30% in those with DLIs; about 50% of these patients died of sepsis. (2) Predictors of death in those with bloodstream infections were the presence of postoperative right ventricular failure and infections due to non-gram positive cocci.(3) Others have identified bloodstream infection as a trigger for further events including cerebrovascular accidents, especially in those with persistent bloodstream infection. Potentially, early transplantation may be a successful approach to treat such patients and avoid further downstream complications.

The more recent HVAD system is considered to have a lower propensity for DLI thought to be due to decreased thickness of the driveline itself as well as lack of a peritoneal pocket for the device. ADVANCE bridge-to-transplant trial as well as data combined from the Continued Access Protocol demonstrated that DLIs occurred in 16.9% of patients at an incidence rate of 0.25 event per person year. Although there was no negative impact on survival in patients with DLIs, there was a trend for reduced survival in patients with sepsis events when compared to those patients without sepsis in this trial. (4) Data from the ongoing ENDURANCE trial was presented at the recent ISHLT meeting in Nice. This is a head to head randomized comparison of the HVAD system against a comparator arm (HMII) for the indication of destination therapy. Data from the presentation demonstrated a similar incidence of any infection (67.9% vs. 61.7%, p=NS) as well as DLI specifically (18.9% vs. 14.1%, p=NS) among the recipients of the HVAD system vs the comparator arm. Event per person year rate was similar in both arms as well (0.18 vs. 0.12, p=NS). It seems that the only way to eliminate DLIs is to eliminate the driveline. LVADs utilizing transcutaneous energy transfer are in development though still a long way from widespread clinical adoption.

The impact of device-related infections on post-transplant outcomes has been seen as a marker for potential graft dysfunction, rejection and impact on survival. This continues to be controversial as some studies have shown no difference in outcomes. A retrospective analysis of 149 patients reported that those with pre-transplant DLIs predicted post-transplant infection at former sites (driveline or pocket) and longer length of stay without affecting survival.(5) Of note, in this study, patients with device-related infections were transplanted less compared to those with no infections. Another retrospective analysis of 136 patients demonstrated that the presence of any infection during the period of LVAD support did not affect post-transplant survival when compared to patients transplanted without prior use of an LVAD. (6)

These results were challenged in a recent retrospective analysis of >15,000 status 1A patients from the United Network of Organ Sharing database. (7) The study compared patients with LVAD and associated complications with those without complications, and demonstrated similar survival. The subset of patients with device infection, however, had worse 1 year and 10 year post-transplant survival (79.3% vs. 83.9%, p=0.012 and 27.8% vs. 47.5%, p=0.017, respectively). Class I and II panel reactive antibodies (PRA) levels were higher in the complication group as well. Higher mortality in this subset may be due to a variety of factors, including more challenging surgery and physiology in systemically ill patients, presence of additional occult infections, and possibly greater rates of allosensitization.

Longer duration of LVAD support not only increases the risk for infections but also for development of antibodies. The interaction of antibodies and related post-transplant outcomes has shown that most patients with LVADs have elevated PRA likely due to blood products received post-operatively (unless leukocyte and platelet irradiated), inherent inflammation due to biomaterials from the LVAD, or possible "subclinical" or active infections. (8) Despite increasing rates of allosensitization, there have been several studies showing no difference in outcomes of rejection or mortality. (9,10) A more recent study presented at the ISHLT meeting in Nice this year, demonstrated that 10% of 78 LVAD-BTT patients developed antibodies after LVAD implantation, which incurred a higher risk for antibody mediated rejection after transplant. Cardiovascular and all-cause mortality was higher in this group although not statistically significant.

Investigators have noted that LVAD patients have compromised T cell function because of down-regulatory cytokines and increase in suppressive T cells. Moreover, after LVAD implantation, B cell hyper-reactivity is noted as well. (11) This imbalance may well lead to an increase antibody production and place the patient at increased risk of infectious complications. The interplay between device infection, allosensitization, and post-transplant outcomes is an area of active research interest.

As Socrates once said "Wonder is the beginning of wisdom" our understanding of the immunobiology and interaction with devices will grow…we just have to ride the white line. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Kirklin JK, Naftel DC, Pagani FD et al. Sixth INTERMACS annual report: a 10,000-patient database. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014 Jun;33(6):555-64.
  2. Koval CE, Thuita L, Moazami N, Blackstone E. Evolution and impact of drive-line infection in a large cohort of continuous-flow ventricular assist device recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014;33:1164-1172.
  3. Toda K, Yonemoto Y, Fujita T, Shimahara Y, Sato S, Nakatani T, Kobayashi J. Risk analysis of bloodstream infection during long-term left ventricular assist device support. The Annals of thoracic surgery. 2012;94:1387-1393.
  4. John R, Aaronson KD, Pae WE et al. Drive-line infections and sepsis in patients receiving the HVAD system as a left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014 Oct;33(10):1066-73.
  5. Schulman AR, Martens TP, Russo MJ, et al. Effect of left ventricular assist device infection on post-transplant outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2009;28:237-242
  6. Sinha P, Chen JM, Flannery M, Scully BE, Oz MC, Edwards NM. Infections during left ventricular assist device support do not affect posttransplant outcomes. Circulation. 2000 Nov 7;102(19 Suppl 3):III194-9.
  7. Healy AH, Baird BC, Drakos SG, Stehlik J, Selzman CH. Impact of ventricular assist device complications on posttransplant survival: An analysis of the united network of organ sharing database. The Annals of thoracic surgery. 2013;95:870-875.
  8. Drakos SG, Kfoury AG, Kotter JR, Reid BB, Clayson SE, Selzman CH, Stehlik J, Fisher PW, Merida M, 3rd, Eckels DD, Brunisholz K, Horne BD, Stoker S, Li DY, Renlund DG. Prior human leukocyte antigen-allosensitization and left ventricular assist device type affect degree of post-implantation human leukocyte antigen-allosensitization. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2009;28:838-842.
  9. Joyce DL, Southard RE, Torre-Amione G, Noon GP, Land GA, Loebe M. Impact of left ventricular assist device (lvad)-mediated humoral sensitization on post-transplant outcomes. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2005;24:2054-2059.
  10. Pagani FD, Dyke DB, Wright S, Cody R, Aaronson KD. Development of anti-major histocompatibility complex class i or ii antibodies following left ventricular assist device implantation: Effects on subsequent allograft rejection and survival. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2001;20:646-653.
  11. Itescu S, John R. Interactions between the recipient immune system and the left ventricular assist device surface: Immunological and clinical implications. The Annals of thoracic surgery. 2003;75:S58-65.




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