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Infectious complications after cardiac transplantation in patients bridged with mechanical circulatory support devices versus medical therapy
Author’s Accepted Manuscript Infectious complications after cardiac transplantation in patients bridged with mechanical circulatory support devices versus medical therapyInfections post-transplant in MCS patients Brandon C Varr, Susan W Restaino, Maryjane Farr, Brian Scully, Paolo C Colombo, Yoshifumi Naka, Donna M Mancini
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To appear in: Journal of Heart and Lung Transplantation Received date: 5 January 2016 Revised date: 19 March 2016 Accepted date: 25 April 2016 Cite this article as: Brandon C Varr, Susan W Restaino, Maryjane Farr, Brian Scully, Paolo C Colombo, Yoshifumi Naka and Donna M Mancini, Infectious complications after cardiac transplantation in patients bridged with mechanical circulatory support devices versus medical therapyInfections post-transplant in MCS patients, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.04.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Infectious Complications After Cardiac Transplantation In Patients Bridged With Mechanical Circulatory Support Devices versus Medical Therapy
Brandon C Varr1, Susan W Restaino1, Maryjane Farr1, Brian Scully2, Paolo C Colombo1, Yoshifumi Naka3, Donna M Mancini1
1
Department of Medicine, Division of Cardiology, 2Division of Infectious Disease, 3Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
Short title: Infections post-transplant in MCS patients
Corresponding author: Brandon Varr Address: 622 W 168th St, PH 10-203, New York, NY 10032 Email: [email protected] Telephone: 212-342-1371 Fax: 212-305-4648 Abstract Background: Mechanical circulatory support (MCS) is increasingly used as a bridge to heart transplantation. It is not known whether patients who receive MCS as bridge to transplantation (BTT) suffer from more frequent and severe infectious complications in the first transplant year.
Methods: Using a retrospective cohort in a single large transplant center from 2009-2014, we compared rates of post-transplant infections among patients bridged to transplantation with medical therapy (n= 134) versus MCS (n= 178) over the first post-transplant year. Serious infections necessitated greater than 14 days of continuous intravenous antibiotic therapy.
Results: Pre-transplant device infections were common in the MCS group (32.6%). The proportion of patients with any infection (74.2% vs 60.5%, p=0.01, RR 1.23 [1.04-1.44]) or serious infections (45.5% vs 31.3%, p=0.01, RR 1.45 [1.08-1.96]) in the first post-transplant year was significantly higher in the MCS group versus the medical therapy group, respectively. MCS patients but not medical therapy patients had significantly higher one year all-cause mortality in the presence of postoperative infections (16.7% vs 4.3%, p=0.04). Device related infections occurred in 67 (37.6%) MCS patients up to 337 days posttransplant, including 26 (14.6%) patients without a known or active pre-operative device infection. In multivariable analysis, age, intensive care unit length of stay, presence of pre-transplant device infection, and use of an anti-thymocyte agent were associated with increased rates of infection.
Conclusion: More infectious complications are experienced by patients who receive MCS as BTT, with a significant occurrence of device related infections. MCS patients with post-transplant infections have increased mortality at one year compared to uninfected MCS patients.
Introduction
The utilization of mechanical circulatory support (MCS) continues to expand, with over 2,000 implantations per year reported in The Interagency Registry for Mechanically Assisted Circulatory Support since 2012 [1]. MCS is being increasingly utilized as a bridge to transplant (BTT) strategy due to longer waiting times for cardiac transplantation from a stagnating donor supply and an increasing heart failure prevalence [2, 3]. Device infection has been a known complication for patients on MCS primarily due to necessary externalization of the device or hematogenous seeding from bloodstream infections. The risk of device related infections becomes more problematic as wait list times for heart transplantation continue to lengthen.
In the HeartWare and HeartMate II BTT trials, the rates of device infection (driveline or pump pocket infection) were significant at 0.21 and 0.37 per patient year, respectively [4, 5]. Additionally, rates of device complication as a reason for a status 1A upgrade have increased, with more than 50% of patients in certain regions progressing through this route [6]. Even with improved management strategies, the HeartMate II destination therapy post-approval study reported a 19% device related infection rate at 2 years (0.22 events per patient year)[7]. Additionally, rates of allosensitization in transplant recipients have steadily increased in the past two decades, with higher rates of allosensitization in MCS patients [2, 8]. Treatment protocols for allosensitization (i.e. desensitization) may further predispose patients on MCS as BTT to infection. Infectious complications have been associated with increased mortality rates among both MCS and transplant recipients [9, 10]. The impact of pre-transplant device related infections on the posttransplant course and subsequent risk for infection is not well defined. Answers to these questions could provide significant clinical insight into post-transplant management. This study aims to determine the relative incidence and severity of post-operative infections in heart transplant recipients, comparing those bridged to transplantation with MCS versus medical therapy.
Methods We conducted a retrospective cohort study of consecutive patients who underwent heart transplantation at Columbia University Medical Center from 2009-2014, with at least one year of follow up from the date of transplant. A retrospective chart review was done to identify patient characteristics and obtain information related to post-operative infections and outcomes. The United Network for Organ Sharing database was also utilized to obtain supplementary information such as exact dates of transplant listing and listing status at time of transplant.
The primary outcome of this study was the incidence of post-operative infections in the first year after transplant. Infections were defined as the need for antibiotic, antiviral, or antifungal medications, aside for those typically used at our institution for standard post-operative prophylaxis, for greater than 72 hours for suspected or culture proven infection. Moderate and serious infections were defined similarly but required greater than 7 or 14 days of consecutive intravenous antimicrobial therapy, respectively. Pre-transplant device infections were identified through documentation of a device infection (driveline, pocket/pump, cannula, or via hematogenous seeding) by the care teams as well as the need for device removal or long term suppressive intravenous or oral antibiotics. Both MCS device and pacemaker/implantable cardioverter-defibrillator infections were included as pre-transplant device infections. Post-operative device related infections included 1) mediastinitis 2) retrosternal abscess 3) infection or abscess of prior driveline or pump pocket or 4) continued need for post-operative treatment of an ongoing pre-operative device infection. Culture and clinical data, imaging studies and consultation notes from infectious disease specialists were used to assist with identification of infections. If the patient had a known pre-operative device infection, a device related infection was determined to be de novo post-transplant if there were no antibiotics given for greater than 30 days prior to the diagnosed infection, there was a new infection with a different organism from the prior known infection, or there was an infection at a new site (e.g. a patient with a history of mediastinitis with a readmission for abdominal wall abscess at the driveline site with >30 days off antibiotics). Post-operative vasodilatory state was defined as persistent dependence on vasoactive medications to maintain adequate perfusion pressure at post-operative day three. Statistical analysis was performed using Stata (StataCorp, College Station, Texas). Discrete variables were analyzed using Chi Squared or Fisher’s exact test based on cell counts. Continuous
variables were analyzed with the student’s t-test or Mann-Whitney U test for normally distributed and non-normally distributed data, respectively. Power analysis was performed using PS software [11] with Type I and II error rates of 0.05 and 0.8, respectively, and required at least 240 patients for an effect size estimate of 15% between groups. A multivariable model using logistic regression was created after identifying predictors of severe infection in univariate analysis using a p-value threshold of 0.20. Age, sex and body mass index (BMI) were included in the multivariable model independent of the results of the univariate analysis. The Kaplan-Meier method was used for survival analysis and the difference in survival curves between groups was evaluated with the log rank test. Poisson regression was used to compare between group differences in the absolute number of infections over the follow up period.
Results We identified 312 patients transplanted at our institution over the five year span, and 178 (57%) received MCS as BTT. Patient characteristics of those BTT with MCS versus medical therapy are detailed in Table 1. Of the 178 patients who received MCS, most patients received a HeartMate II (n=133, 74.7%), but other devices included Centrimag BiVAD (biventricular assist device, n=21, 11.8%), HeartMate XVE (n=10, 5.6%), Duraheart LVAD (left ventricular assist device, n=6, 3.4%), HeartWare HVAD (n=5, 2.8%), and one patient each (0.6%) with Centrimag LVAD, SynCardia Total Artificial Heart and Toyobo LVAD. Patients who received MCS as BTT were more likely to be blood type O (45.5% vs 22.4%, p<0.001), listed as status 1A (82.6% vs 60.4%, p<0.001) and have higher BMI (26.5 kg/m2 vs 25.1 kg/m2, p=0.01). The rates of both pre-transplant device infection (32.6% vs 4.5%, p<0.001) and all-cause infection 30 days prior to transplantation (39.9% vs 21.6%, p=0.001) were higher in the MCS group. All patients in the medical therapy group with pre-transplant device infection had pacemaker/defibrillator infections. After transplantation, patients who received MCS as BTT were more likely to receive antibiotics for any suspected or proven infection (74.2% vs 60.5%, p=0.01) and had increased rates of our
predefined criteria for serious infection (45.5% vs 31.3%, p=0.01, Table 2). The incidence rates of infections in the two groups showed a trend towards more infections in the MCS group but was not statistically significant (1.31 vs 1.15 infections per patient-year, p=0.25). The most common anatomical site of infection was the thorax with similar rates in the MCS and medical therapy groups (48.9% vs 47.4%, p=0.84, Figure 2). There were more skin and soft tissue associated infections in the MCS group (18.5% vs 6.5%, p=0.001). There were no differences seen in regards to causative microbial pathogens (bacteria vs virus/fungi) but there was a trend towards more patients with multi-drug resistant (MDR) organisms in the MCS group (20.2% vs 13.4%, P=0.11, Table 2). More infections occurred in the first month post-transplant in the MCS group (58.8% vs 39%, p<0.001). Infections in the first month were predominately bacterial (96.4% [20.3% MDR]) whereas infections after the first month had a greater proportion of non-bacterial organisms (75.8% bacterial [11.1% MDR], 15.8% viral, 7.4% fungal, 1% parasitic) and there were no significant differences between groups. Induction immunosuppression was less likely to be received by patients in the MCS group (61.2% vs 83.6%, p<0.001) due to concern over ongoing infection. There were trends toward higher usage of pre-transplant desensitization therapy (6.2% vs 2.2%, p=0.10) and higher rates of perioperative vasodilatory state (28.1% vs 19.4%, p=0.08) in the MCS group, but no difference in ICU length of stay between the two groups (8.7 vs 7.7 days, p=0.23). There were no significant differences in the rates of cellular (11.4% vs 12.3% for grade ≥ 2R, p=0.81) or humoral (8.4% vs 12.7%, p=0.22) rejection episodes experienced by the MCS and medical therapy groups, respectively. There was no statistically significant difference in all-cause (13.5% vs 7.5%, p=0.09) and infection related (5.6% vs 4.5%, p=0.64) mortality in the first post-transplant year. However, MCS patients but not medical therapy patients with postoperative infections had significantly higher mortality compared to patients without infections but analogous BTT strategy (Table 3). Specifically, patients in the MCS group with any degree of post-transplant infection had significantly higher rates of one year all-cause mortality
than MCS patients who did not experience an infection in the first postoperative year. Even though higher mortality was seen in the combined cohort of patients with post-transplant moderate or severe infection (compared to those without post-transplant infection in the first year), this difference was driven by differences in the MCS group as there were no significant differences in one year mortality by post-operative infection status in the medical therapy group. Post-transplant survival curves for patients in both groups by post-operative infection status are detailed in Figure 1. Patients in both groups had worse post-transplant survival if they experienced any infection in the first year after transplant. Univariate analysis identified several variables associated with serious infection to be included in the multivariable model including age , albumin , number of prior sternotomies , length of intensive care unit (ICU) stay , presence of pre-operative infection or device infection , cellular rejection episode grade ≥2R , any humoral rejection episode , and any use of an anti-thymocyte agent (Table 4). The results of the multivariable model are shown in Table 5. Age, ICU length of stay, receipt of an anti-thymocyte agent, and presence of pre-operative device infection were independent predictors of post-operative infection. ICU length of stay was the most consistent predictor of any degree of post-operative infection and pre-operative device infection was the strongest predictor of any or moderate infection. Overall, there were 67 (37.6%) patients with device related infections over the first posttransplant year, predominately occurring in the first month after transplant (Figure 3). Device related infections were due to mediastinal/sternal infection in 31 (46.3%) patients, driveline in 25 (37.3%) patients, and pocket in 11 (16.4%) patients. There were 26 total patients with device related infections in the first post-transplant year who did not have a known or active pre-transplant device infection, which comprised 14.6% of all patients in the MCS group. Of these 26 patients, de novo device related infections occurred in the first post-transplant month in 17 (65.4%), after 30 days in 9 (34.6%), and after 90 days in 4 (15.4%). In the first post-transplant month, new device related infections were attributable
to early mediastinitis or sternal wound infections (n=12) and subclinical device infections discovered at the time of explant (n=5). Although most device related infections occurred in the first month post-transplant, several patients exhibited device related infections several months after explant. Four patients (2.3%) developed new device related infections more than 90 days after transplant. Selected clinical and patient characteristics of those patients in the MCS group who developed late device related infections are detailed in Table 6. In the medical therapy group, 8 patients (6%) developed sternal wound infections or abscesses, including 2 patients (1.5%) whose infections occurred more than 90 days after transplantation. Sternal/device related infections were more common in the MCS group overall (14.6% vs 6%, p=0.03), as driveline related complications occurred exclusively in MCS patients.
Discussion This study demonstrates that patients receiving MCS as BTT have significantly higher rates of infection in the first post-transplant year, and MCS patients with postoperative infections were less likely to survive the first post-transplant year compared to uninfected MCS patients. A notable secondary finding of this study is that 26 patients (14.6%) in the MCS group had a device related infectious complication without evidence of prior or active infection at the time of transplant, and 34.6% of these infections occurred >30 days post-transplant (mean 117 ± 107 days). Prior registry based analysis have demonstrated pre-transplant infection to be a predictor of 1 and 5 year post-transplant mortality, though this study was not specifically powered for this endpoint [2]. Our study has demonstrated that patients who receive MCS as BTT and experience post-operative infections have worse survival compared to MCS patients without infections in the first year. Our analysis sheds light on the possible risk factors for the increased rates of infections seen in patients
receiving MCS as BTT. A central contributor to this finding is that almost a third of patients in the MCS group had a pre-operative device infection at the time of transplant, which is consistent with reports from other high volume centers regarding the rates of device infections while awaiting heart transplantation [9, 12-14]. Patients in the MCS group also had a significantly more sternotomies, which has been shown to be a risk factor for post-operative complications [15, 16]. Other contributory clinical factors were the predictors of either moderate or serious infection: age, pre-operative device infection, length of ICU stay and receipt of an anti-thymocyte globulin agent. An exploratory finding is the significant incidence of delayed device related infections in the MCS group, with infections occurring up to 337 days after transplant. The mechanism of late infection cannot entirely be attributed to inadequate treatment of known pre-transplant infections, though it may be a contributor to certain cases. One possible mechanism could be a manifestation of subclinical pretransplant infection in the setting of post-transplant immunosuppression. Other possible contributors may be colonization with MDR organisms due to increased antibiotic use and ICU exposure in MCS patients from the time of MCS implantation as well as rehospitalizations due to device related complications [17, 18]. In collaboration with infectious disease specialists, care must be taken to ensure appropriate antimicrobial coverage in these patients, drawing from prior literature addressing common pathogens and the patient’s own history [9, 12, 19]. To date at our institution, the longest interval to develop a sternal wound or device related infection came in a patient 13 months post-transplant who had a pre-operative device infection and had been off antibiotics for 11 months.
Limitations We acknowledge several important limitations of our study. The study was conducted at a single center in a UNOS region with long wait times for heart transplantation, limiting external validity in regions with significantly shorter waiting times [20]. The definition of device related infection was
intended to maximize their identification, but at the possible cost of specificity in differentiating from sternal wound complications unrelated to MCS. Whether the higher rate of sternal complications in the MCS group is attributable to device placement and subsequent infection or other risk factors such as an increased number of sternotomies prior to transplant cannot be determined from this study. Immunosuppression protocols may differ significantly between transplant centers, which may affect rates of post-operative infection. This study was not specifically powered to identify differences in incidence rates of infection, all-cause mortality, or rejection rates so pertinent results are considered exploratory. A larger registry-based or multicenter analysis to identify predictors of post-operative infection is warranted.
Conclusion Utilizing MCS as BTT is associated with an increased rate of infections in the first post-transplant year with a high prevalence of pre-transplant device related infections. MCS patients who experience post-transplant infections in the first year have increased mortality compared to uninfected MCS patients. Device related infectious complications after receiving MCS as BTT were not uncommon and could occur late after transplant, even in those not known to have prior active pre-transplant infections.
Acknowledgements The authors have no disclosures for this study.
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Figure 1. Survival after transplant by post-operative infection status.
Figure 2: Sites of infection in the first year after heart transplantation. GI, gastrointestinal; GU, genitourinary; SSTI, skin and soft tissue infections; Other – Neurologic and Ear, Nose, and Throat.
Figure 3. Timing of device related infections in the first post-transplant year in patients with and without pre-operative infection.
Age Male Sex Ethnicity
White Black Hispanic All others HF Etiology DCM - Ischemic DCM - Nonischemic HCM RCM CHD Retransplant Blood Type O A B AB BMI Diabetes Depression Creatinine (mg/dL) Albumin (g/dL)
Medical (n=134) 53.7 96 (71.6) 72 (53.7) 24 (17.9) 24 (17.9) 14 (10.5) 39 (29.1) 55 (41) 8 (6) 10 (7.5) 12 (9) 10 (7.5) 30 (22.4) 57 (42.5) 30 (22.4) 17 (12.7) 25.1 56 (41.8) 25 (18.7) 1.43 3.82
MCS (n=178) 53.4 142 (79.8) 90 (50.6) 46 (25.8) 29 (16.3) 13 (7.3) 67 (37.6) 99 (55.6) 5 (2.8) 2 (1.1) 0 5 (2.8) 81 (45.5) 64 (36) 28 (15.7) 5 (2.8) 26.5 62 (34.8) 32 (18) 1.36 3.95
p 0.70 0.10 0.35
<0.001
<0.001
0.01 0.21 0.88 0.79 0.04
Prior Sternotomy (#) 0.86 Total Time on Wait List (days) 366.9 Time on LVAD (days) 0 UNOS Status at transplant 1A 81 (60.4) 1B 47 (35.1) 2 6 (4.5) CI at listing 1.75 Pre-operative Infection and Immunotherapy Infection in prior 30 days 29 (21.6) Device infection 6 (4.5) Desensitization therapy 3 (2.2)
1.67 319.1 306.2
<0.001 0.01
147 (82.6) 31 (17.4) 0 1.72
<0.001
71 (39.9) 58 (32.6) 11 (6.2)
0.001 <0.001 0.10
0.44
Table 1: Patient characteristics. Discrete variables expressed as n (%). BMI, body mass index; CHD, congenital heart disease; CI, cardiac index; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HF, heart failure; ICU, intensive care unit; MCS, mechanical circulatory support; RCM, restrictive cardiomyopathy.
Postoperative Infection Moderate Infection Serious Infection 1 year all-cause mortality Infection related mortality Total Infections (n) Bacterial MDR organism Viral Fungal Parasitic MDR infections ICU length of stay (days) Postop vasodilatory state Induction immunosuppression Cellular rejection ≥ 2R Humoral Rejection Cytoxan Rituximab Anti-thymocyte globulin agent
Medical (n=134) 81 (60.5) 61 (45.5) 42 (31.3) 10 (7.5) 6 (4.5) 154 (1.15/pt-yr) 131 (85.1) 20 (13) 14 (9.1) 8 (5.2) 1 (0.6) 18 (13.4) 7.7 26 (19.4) 112 (83.6)
MCS (n=178) 132 (74.2) 133 (63.5) 81 (45.5) 24 (13.5) 10 (5.6) 233 (1.31/pt-yr) 203 (87.1) 41 (20.2) 12 (5.2) 17 (7.3) 1 (0.4) 36 (20.2) 8.7 50 (28.1) 109 (61.2)
p 0.01 0.002 0.01 0.09 0.65 0.25 0.55 0.09 0.10 0.40 1 0.11 0.23 0.08 <0.001
16 (12.3) 17 (12.7) 9 (6.7) 5 (3.7) 16 (11.9)
20 (11.4) 15 (8.4) 15 (8.4) 4 (2.3) 17 (9.6)
0.81 0.22 0.58 0.44 0.50
RR 1.23 (1.04-1.44) 1.40 (1.12-1.73) 1.45 (1.08-1.96)
Table 2: Post-transplant infections, postoperative course and immunotherapy. pt-yr, patient-year.
Postoperative 1 year mortality Both groups Medical MCS
*
No Infection
Any Postop Infection
p
6/99 (6.1) 4/53 (7.5) 2/46 (4.3)
28/213 (13.1) 6/81 (7.4) 22/132 (16.7)
0.06 1 0.04
*
Moderate Infection
p
25/174 (14.4) 5/61 (8.2) 20/113 (17.7)
0.04 1 0.04
*
Serious Infection
p
20/123 (16.3) 5/42 (11.9) 15/81 (18.5)
0.02 0.50 0.03
Table 3. Mortality analysis (all-causes at one year) by infection status. MCS, mechanical circulatory support. *compared to patients with no infection in the first post-operative year.
*
Age Male sex* BMI* Albumin Prior sternotomy (#) ICU LOS Pre-op infection Device infection Rejection ≥ 2R Humoral rejection Anti-thymocyte agent
Odds Ratio 1.01 0.87 1.03 0.61 1.41 1.13 2.93 3.05 2.05 1.61 2.28
95% CI 1.00-1.03 0.51-1.49 0.98-1.08 0.39-0.96 1.13-1.77 1.07-1.19 1.79-4.79 1.72-5.37 1.01-4.13 0.77-3.37 1.10-4.75
p 0.14 0.62 0.28 0.03 0.002 <0.001 <0.001 <0.001 0.04 0.20 0.02
Table 4: Univariate predictors of serious infection. ICU, intensive care unit; LOS, length of stay. * Prespecified variables included in the multivariable model.
Any Postoperative Infection Pre-op device infection ICU LOS Moderate infection Pre-op device infection Anti-thymocyte agent ICU LOS Age Serious Infection ICU LOS Age
Odds Ratio
95% CI
p
6.45 1.15
1.86-22.34 1.06-1.26
0.003 0.001
6.23 2.79 1.21 1.02
2.25-17.23 1.02-7.66 1.11-1.31 1.00-1.05
<0.001 0.046 <0.001 0.05
1.13 1.03
1.07-1.19 1.01-1.05
<0.001 0.03
Table 5: Predictors of infection using multivariable model. ICU, intensive care unit; LOS, length of stay.
Age Sex 62 M 57 M 60 M
Days after OHT 33 35
ICU LOS
Induction
5
Antithymocyte Agent No
Yes (driveline, S. epidermidis) No
4
Yes
Yes
15
Yes
No
Driveline related abscess (Enterobacter)
2
No
No
22
No
No
Abdominal abscess after off antibiotics for 55 days (Pseudomonas) Driveline related abscess (Serratia)
No
27 M
63
61 M 71 F 45 F 61 M
78
Yes (pocket, culture negative) Yes (mediastinitis, Pseudomonas) No
106
No
2
No
Yes
151
No
7
Yes
Yes
256
Yes (pocket, culture negative) Yes (driveline, Citrobacter)
3
No
No
5
No
No
56 F
43
Pre-op Infection
337
Details
Sternal abscess (Enterobacter/E. coli) Driveline related abscess (MRSA)
Sternal osteomyelitis/abscess (E. coli) Driveline tract infection/abscess (Klebsiella) Sternal osteomyelitis/abscess (Candida), off antibiotics for prior 247 days Abdominal wall abscess (Citrobacter), off antibiotics for prior 318 days
Table 6: Cases of device related infections >30 days post-transplant. ICU, intensive care unit; LOS, length of stay; MRSA, methicillin resistant staphylococcus aureus; OHT, orthotopic heart transplant.
PII: DOI: Reference:
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S1053-2498(16)30120-6 http://dx.doi.org/10.1016/j.healun.2016.04.016 HEALUN6260
To appear in: Journal of Heart and Lung Transplantation Received date: 5 January 2016 Revised date: 19 March 2016 Accepted date: 25 April 2016 Cite this article as: Brandon C Varr, Susan W Restaino, Maryjane Farr, Brian Scully, Paolo C Colombo, Yoshifumi Naka and Donna M Mancini, Infectious complications after cardiac transplantation in patients bridged with mechanical circulatory support devices versus medical therapyInfections post-transplant in MCS patients, Journal of Heart and Lung Transplantation, http://dx.doi.org/10.1016/j.healun.2016.04.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Infectious Complications After Cardiac Transplantation In Patients Bridged With Mechanical Circulatory Support Devices versus Medical Therapy
Brandon C Varr1, Susan W Restaino1, Maryjane Farr1, Brian Scully2, Paolo C Colombo1, Yoshifumi Naka3, Donna M Mancini1
1
Department of Medicine, Division of Cardiology, 2Division of Infectious Disease, 3Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
Short title: Infections post-transplant in MCS patients
Corresponding author: Brandon Varr Address: 622 W 168th St, PH 10-203, New York, NY 10032 Email: [email protected] Telephone: 212-342-1371 Fax: 212-305-4648 Abstract Background: Mechanical circulatory support (MCS) is increasingly used as a bridge to heart transplantation. It is not known whether patients who receive MCS as bridge to transplantation (BTT) suffer from more frequent and severe infectious complications in the first transplant year.
Methods: Using a retrospective cohort in a single large transplant center from 2009-2014, we compared rates of post-transplant infections among patients bridged to transplantation with medical therapy (n= 134) versus MCS (n= 178) over the first post-transplant year. Serious infections necessitated greater than 14 days of continuous intravenous antibiotic therapy.
Results: Pre-transplant device infections were common in the MCS group (32.6%). The proportion of patients with any infection (74.2% vs 60.5%, p=0.01, RR 1.23 [1.04-1.44]) or serious infections (45.5% vs 31.3%, p=0.01, RR 1.45 [1.08-1.96]) in the first post-transplant year was significantly higher in the MCS group versus the medical therapy group, respectively. MCS patients but not medical therapy patients had significantly higher one year all-cause mortality in the presence of postoperative infections (16.7% vs 4.3%, p=0.04). Device related infections occurred in 67 (37.6%) MCS patients up to 337 days posttransplant, including 26 (14.6%) patients without a known or active pre-operative device infection. In multivariable analysis, age, intensive care unit length of stay, presence of pre-transplant device infection, and use of an anti-thymocyte agent were associated with increased rates of infection.
Conclusion: More infectious complications are experienced by patients who receive MCS as BTT, with a significant occurrence of device related infections. MCS patients with post-transplant infections have increased mortality at one year compared to uninfected MCS patients.
Introduction
The utilization of mechanical circulatory support (MCS) continues to expand, with over 2,000 implantations per year reported in The Interagency Registry for Mechanically Assisted Circulatory Support since 2012 [1]. MCS is being increasingly utilized as a bridge to transplant (BTT) strategy due to longer waiting times for cardiac transplantation from a stagnating donor supply and an increasing heart failure prevalence [2, 3]. Device infection has been a known complication for patients on MCS primarily due to necessary externalization of the device or hematogenous seeding from bloodstream infections. The risk of device related infections becomes more problematic as wait list times for heart transplantation continue to lengthen.
In the HeartWare and HeartMate II BTT trials, the rates of device infection (driveline or pump pocket infection) were significant at 0.21 and 0.37 per patient year, respectively [4, 5]. Additionally, rates of device complication as a reason for a status 1A upgrade have increased, with more than 50% of patients in certain regions progressing through this route [6]. Even with improved management strategies, the HeartMate II destination therapy post-approval study reported a 19% device related infection rate at 2 years (0.22 events per patient year)[7]. Additionally, rates of allosensitization in transplant recipients have steadily increased in the past two decades, with higher rates of allosensitization in MCS patients [2, 8]. Treatment protocols for allosensitization (i.e. desensitization) may further predispose patients on MCS as BTT to infection. Infectious complications have been associated with increased mortality rates among both MCS and transplant recipients [9, 10]. The impact of pre-transplant device related infections on the posttransplant course and subsequent risk for infection is not well defined. Answers to these questions could provide significant clinical insight into post-transplant management. This study aims to determine the relative incidence and severity of post-operative infections in heart transplant recipients, comparing those bridged to transplantation with MCS versus medical therapy.
Methods We conducted a retrospective cohort study of consecutive patients who underwent heart transplantation at Columbia University Medical Center from 2009-2014, with at least one year of follow up from the date of transplant. A retrospective chart review was done to identify patient characteristics and obtain information related to post-operative infections and outcomes. The United Network for Organ Sharing database was also utilized to obtain supplementary information such as exact dates of transplant listing and listing status at time of transplant.
The primary outcome of this study was the incidence of post-operative infections in the first year after transplant. Infections were defined as the need for antibiotic, antiviral, or antifungal medications, aside for those typically used at our institution for standard post-operative prophylaxis, for greater than 72 hours for suspected or culture proven infection. Moderate and serious infections were defined similarly but required greater than 7 or 14 days of consecutive intravenous antimicrobial therapy, respectively. Pre-transplant device infections were identified through documentation of a device infection (driveline, pocket/pump, cannula, or via hematogenous seeding) by the care teams as well as the need for device removal or long term suppressive intravenous or oral antibiotics. Both MCS device and pacemaker/implantable cardioverter-defibrillator infections were included as pre-transplant device infections. Post-operative device related infections included 1) mediastinitis 2) retrosternal abscess 3) infection or abscess of prior driveline or pump pocket or 4) continued need for post-operative treatment of an ongoing pre-operative device infection. Culture and clinical data, imaging studies and consultation notes from infectious disease specialists were used to assist with identification of infections. If the patient had a known pre-operative device infection, a device related infection was determined to be de novo post-transplant if there were no antibiotics given for greater than 30 days prior to the diagnosed infection, there was a new infection with a different organism from the prior known infection, or there was an infection at a new site (e.g. a patient with a history of mediastinitis with a readmission for abdominal wall abscess at the driveline site with >30 days off antibiotics). Post-operative vasodilatory state was defined as persistent dependence on vasoactive medications to maintain adequate perfusion pressure at post-operative day three. Statistical analysis was performed using Stata (StataCorp, College Station, Texas). Discrete variables were analyzed using Chi Squared or Fisher’s exact test based on cell counts. Continuous
variables were analyzed with the student’s t-test or Mann-Whitney U test for normally distributed and non-normally distributed data, respectively. Power analysis was performed using PS software [11] with Type I and II error rates of 0.05 and 0.8, respectively, and required at least 240 patients for an effect size estimate of 15% between groups. A multivariable model using logistic regression was created after identifying predictors of severe infection in univariate analysis using a p-value threshold of 0.20. Age, sex and body mass index (BMI) were included in the multivariable model independent of the results of the univariate analysis. The Kaplan-Meier method was used for survival analysis and the difference in survival curves between groups was evaluated with the log rank test. Poisson regression was used to compare between group differences in the absolute number of infections over the follow up period.
Results We identified 312 patients transplanted at our institution over the five year span, and 178 (57%) received MCS as BTT. Patient characteristics of those BTT with MCS versus medical therapy are detailed in Table 1. Of the 178 patients who received MCS, most patients received a HeartMate II (n=133, 74.7%), but other devices included Centrimag BiVAD (biventricular assist device, n=21, 11.8%), HeartMate XVE (n=10, 5.6%), Duraheart LVAD (left ventricular assist device, n=6, 3.4%), HeartWare HVAD (n=5, 2.8%), and one patient each (0.6%) with Centrimag LVAD, SynCardia Total Artificial Heart and Toyobo LVAD. Patients who received MCS as BTT were more likely to be blood type O (45.5% vs 22.4%, p<0.001), listed as status 1A (82.6% vs 60.4%, p<0.001) and have higher BMI (26.5 kg/m2 vs 25.1 kg/m2, p=0.01). The rates of both pre-transplant device infection (32.6% vs 4.5%, p<0.001) and all-cause infection 30 days prior to transplantation (39.9% vs 21.6%, p=0.001) were higher in the MCS group. All patients in the medical therapy group with pre-transplant device infection had pacemaker/defibrillator infections. After transplantation, patients who received MCS as BTT were more likely to receive antibiotics for any suspected or proven infection (74.2% vs 60.5%, p=0.01) and had increased rates of our
predefined criteria for serious infection (45.5% vs 31.3%, p=0.01, Table 2). The incidence rates of infections in the two groups showed a trend towards more infections in the MCS group but was not statistically significant (1.31 vs 1.15 infections per patient-year, p=0.25). The most common anatomical site of infection was the thorax with similar rates in the MCS and medical therapy groups (48.9% vs 47.4%, p=0.84, Figure 2). There were more skin and soft tissue associated infections in the MCS group (18.5% vs 6.5%, p=0.001). There were no differences seen in regards to causative microbial pathogens (bacteria vs virus/fungi) but there was a trend towards more patients with multi-drug resistant (MDR) organisms in the MCS group (20.2% vs 13.4%, P=0.11, Table 2). More infections occurred in the first month post-transplant in the MCS group (58.8% vs 39%, p<0.001). Infections in the first month were predominately bacterial (96.4% [20.3% MDR]) whereas infections after the first month had a greater proportion of non-bacterial organisms (75.8% bacterial [11.1% MDR], 15.8% viral, 7.4% fungal, 1% parasitic) and there were no significant differences between groups. Induction immunosuppression was less likely to be received by patients in the MCS group (61.2% vs 83.6%, p<0.001) due to concern over ongoing infection. There were trends toward higher usage of pre-transplant desensitization therapy (6.2% vs 2.2%, p=0.10) and higher rates of perioperative vasodilatory state (28.1% vs 19.4%, p=0.08) in the MCS group, but no difference in ICU length of stay between the two groups (8.7 vs 7.7 days, p=0.23). There were no significant differences in the rates of cellular (11.4% vs 12.3% for grade ≥ 2R, p=0.81) or humoral (8.4% vs 12.7%, p=0.22) rejection episodes experienced by the MCS and medical therapy groups, respectively. There was no statistically significant difference in all-cause (13.5% vs 7.5%, p=0.09) and infection related (5.6% vs 4.5%, p=0.64) mortality in the first post-transplant year. However, MCS patients but not medical therapy patients with postoperative infections had significantly higher mortality compared to patients without infections but analogous BTT strategy (Table 3). Specifically, patients in the MCS group with any degree of post-transplant infection had significantly higher rates of one year all-cause mortality
than MCS patients who did not experience an infection in the first postoperative year. Even though higher mortality was seen in the combined cohort of patients with post-transplant moderate or severe infection (compared to those without post-transplant infection in the first year), this difference was driven by differences in the MCS group as there were no significant differences in one year mortality by post-operative infection status in the medical therapy group. Post-transplant survival curves for patients in both groups by post-operative infection status are detailed in Figure 1. Patients in both groups had worse post-transplant survival if they experienced any infection in the first year after transplant. Univariate analysis identified several variables associated with serious infection to be included in the multivariable model including age , albumin , number of prior sternotomies , length of intensive care unit (ICU) stay , presence of pre-operative infection or device infection , cellular rejection episode grade ≥2R , any humoral rejection episode , and any use of an anti-thymocyte agent (Table 4). The results of the multivariable model are shown in Table 5. Age, ICU length of stay, receipt of an anti-thymocyte agent, and presence of pre-operative device infection were independent predictors of post-operative infection. ICU length of stay was the most consistent predictor of any degree of post-operative infection and pre-operative device infection was the strongest predictor of any or moderate infection. Overall, there were 67 (37.6%) patients with device related infections over the first posttransplant year, predominately occurring in the first month after transplant (Figure 3). Device related infections were due to mediastinal/sternal infection in 31 (46.3%) patients, driveline in 25 (37.3%) patients, and pocket in 11 (16.4%) patients. There were 26 total patients with device related infections in the first post-transplant year who did not have a known or active pre-transplant device infection, which comprised 14.6% of all patients in the MCS group. Of these 26 patients, de novo device related infections occurred in the first post-transplant month in 17 (65.4%), after 30 days in 9 (34.6%), and after 90 days in 4 (15.4%). In the first post-transplant month, new device related infections were attributable
to early mediastinitis or sternal wound infections (n=12) and subclinical device infections discovered at the time of explant (n=5). Although most device related infections occurred in the first month post-transplant, several patients exhibited device related infections several months after explant. Four patients (2.3%) developed new device related infections more than 90 days after transplant. Selected clinical and patient characteristics of those patients in the MCS group who developed late device related infections are detailed in Table 6. In the medical therapy group, 8 patients (6%) developed sternal wound infections or abscesses, including 2 patients (1.5%) whose infections occurred more than 90 days after transplantation. Sternal/device related infections were more common in the MCS group overall (14.6% vs 6%, p=0.03), as driveline related complications occurred exclusively in MCS patients.
Discussion This study demonstrates that patients receiving MCS as BTT have significantly higher rates of infection in the first post-transplant year, and MCS patients with postoperative infections were less likely to survive the first post-transplant year compared to uninfected MCS patients. A notable secondary finding of this study is that 26 patients (14.6%) in the MCS group had a device related infectious complication without evidence of prior or active infection at the time of transplant, and 34.6% of these infections occurred >30 days post-transplant (mean 117 ± 107 days). Prior registry based analysis have demonstrated pre-transplant infection to be a predictor of 1 and 5 year post-transplant mortality, though this study was not specifically powered for this endpoint [2]. Our study has demonstrated that patients who receive MCS as BTT and experience post-operative infections have worse survival compared to MCS patients without infections in the first year. Our analysis sheds light on the possible risk factors for the increased rates of infections seen in patients
receiving MCS as BTT. A central contributor to this finding is that almost a third of patients in the MCS group had a pre-operative device infection at the time of transplant, which is consistent with reports from other high volume centers regarding the rates of device infections while awaiting heart transplantation [9, 12-14]. Patients in the MCS group also had a significantly more sternotomies, which has been shown to be a risk factor for post-operative complications [15, 16]. Other contributory clinical factors were the predictors of either moderate or serious infection: age, pre-operative device infection, length of ICU stay and receipt of an anti-thymocyte globulin agent. An exploratory finding is the significant incidence of delayed device related infections in the MCS group, with infections occurring up to 337 days after transplant. The mechanism of late infection cannot entirely be attributed to inadequate treatment of known pre-transplant infections, though it may be a contributor to certain cases. One possible mechanism could be a manifestation of subclinical pretransplant infection in the setting of post-transplant immunosuppression. Other possible contributors may be colonization with MDR organisms due to increased antibiotic use and ICU exposure in MCS patients from the time of MCS implantation as well as rehospitalizations due to device related complications [17, 18]. In collaboration with infectious disease specialists, care must be taken to ensure appropriate antimicrobial coverage in these patients, drawing from prior literature addressing common pathogens and the patient’s own history [9, 12, 19]. To date at our institution, the longest interval to develop a sternal wound or device related infection came in a patient 13 months post-transplant who had a pre-operative device infection and had been off antibiotics for 11 months.
Limitations We acknowledge several important limitations of our study. The study was conducted at a single center in a UNOS region with long wait times for heart transplantation, limiting external validity in regions with significantly shorter waiting times [20]. The definition of device related infection was
intended to maximize their identification, but at the possible cost of specificity in differentiating from sternal wound complications unrelated to MCS. Whether the higher rate of sternal complications in the MCS group is attributable to device placement and subsequent infection or other risk factors such as an increased number of sternotomies prior to transplant cannot be determined from this study. Immunosuppression protocols may differ significantly between transplant centers, which may affect rates of post-operative infection. This study was not specifically powered to identify differences in incidence rates of infection, all-cause mortality, or rejection rates so pertinent results are considered exploratory. A larger registry-based or multicenter analysis to identify predictors of post-operative infection is warranted.
Conclusion Utilizing MCS as BTT is associated with an increased rate of infections in the first post-transplant year with a high prevalence of pre-transplant device related infections. MCS patients who experience post-transplant infections in the first year have increased mortality compared to uninfected MCS patients. Device related infectious complications after receiving MCS as BTT were not uncommon and could occur late after transplant, even in those not known to have prior active pre-transplant infections.
Acknowledgements The authors have no disclosures for this study.
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Figure 1. Survival after transplant by post-operative infection status.
Figure 2: Sites of infection in the first year after heart transplantation. GI, gastrointestinal; GU, genitourinary; SSTI, skin and soft tissue infections; Other – Neurologic and Ear, Nose, and Throat.
Figure 3. Timing of device related infections in the first post-transplant year in patients with and without pre-operative infection.
Age Male Sex Ethnicity
White Black Hispanic All others HF Etiology DCM - Ischemic DCM - Nonischemic HCM RCM CHD Retransplant Blood Type O A B AB BMI Diabetes Depression Creatinine (mg/dL) Albumin (g/dL)
Medical (n=134) 53.7 96 (71.6) 72 (53.7) 24 (17.9) 24 (17.9) 14 (10.5) 39 (29.1) 55 (41) 8 (6) 10 (7.5) 12 (9) 10 (7.5) 30 (22.4) 57 (42.5) 30 (22.4) 17 (12.7) 25.1 56 (41.8) 25 (18.7) 1.43 3.82
MCS (n=178) 53.4 142 (79.8) 90 (50.6) 46 (25.8) 29 (16.3) 13 (7.3) 67 (37.6) 99 (55.6) 5 (2.8) 2 (1.1) 0 5 (2.8) 81 (45.5) 64 (36) 28 (15.7) 5 (2.8) 26.5 62 (34.8) 32 (18) 1.36 3.95
p 0.70 0.10 0.35
<0.001
<0.001
0.01 0.21 0.88 0.79 0.04
Prior Sternotomy (#) 0.86 Total Time on Wait List (days) 366.9 Time on LVAD (days) 0 UNOS Status at transplant 1A 81 (60.4) 1B 47 (35.1) 2 6 (4.5) CI at listing 1.75 Pre-operative Infection and Immunotherapy Infection in prior 30 days 29 (21.6) Device infection 6 (4.5) Desensitization therapy 3 (2.2)
1.67 319.1 306.2
<0.001 0.01
147 (82.6) 31 (17.4) 0 1.72
<0.001
71 (39.9) 58 (32.6) 11 (6.2)
0.001 <0.001 0.10
0.44
Table 1: Patient characteristics. Discrete variables expressed as n (%). BMI, body mass index; CHD, congenital heart disease; CI, cardiac index; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HF, heart failure; ICU, intensive care unit; MCS, mechanical circulatory support; RCM, restrictive cardiomyopathy.
Postoperative Infection Moderate Infection Serious Infection 1 year all-cause mortality Infection related mortality Total Infections (n) Bacterial MDR organism Viral Fungal Parasitic MDR infections ICU length of stay (days) Postop vasodilatory state Induction immunosuppression Cellular rejection ≥ 2R Humoral Rejection Cytoxan Rituximab Anti-thymocyte globulin agent
Medical (n=134) 81 (60.5) 61 (45.5) 42 (31.3) 10 (7.5) 6 (4.5) 154 (1.15/pt-yr) 131 (85.1) 20 (13) 14 (9.1) 8 (5.2) 1 (0.6) 18 (13.4) 7.7 26 (19.4) 112 (83.6)
MCS (n=178) 132 (74.2) 133 (63.5) 81 (45.5) 24 (13.5) 10 (5.6) 233 (1.31/pt-yr) 203 (87.1) 41 (20.2) 12 (5.2) 17 (7.3) 1 (0.4) 36 (20.2) 8.7 50 (28.1) 109 (61.2)
p 0.01 0.002 0.01 0.09 0.65 0.25 0.55 0.09 0.10 0.40 1 0.11 0.23 0.08 <0.001
16 (12.3) 17 (12.7) 9 (6.7) 5 (3.7) 16 (11.9)
20 (11.4) 15 (8.4) 15 (8.4) 4 (2.3) 17 (9.6)
0.81 0.22 0.58 0.44 0.50
RR 1.23 (1.04-1.44) 1.40 (1.12-1.73) 1.45 (1.08-1.96)
Table 2: Post-transplant infections, postoperative course and immunotherapy. pt-yr, patient-year.
Postoperative 1 year mortality Both groups Medical MCS
*
No Infection
Any Postop Infection
p
6/99 (6.1) 4/53 (7.5) 2/46 (4.3)
28/213 (13.1) 6/81 (7.4) 22/132 (16.7)
0.06 1 0.04
*
Moderate Infection
p
25/174 (14.4) 5/61 (8.2) 20/113 (17.7)
0.04 1 0.04
*
Serious Infection
p
20/123 (16.3) 5/42 (11.9) 15/81 (18.5)
0.02 0.50 0.03
Table 3. Mortality analysis (all-causes at one year) by infection status. MCS, mechanical circulatory support. *compared to patients with no infection in the first post-operative year.
*
Age Male sex* BMI* Albumin Prior sternotomy (#) ICU LOS Pre-op infection Device infection Rejection ≥ 2R Humoral rejection Anti-thymocyte agent
Odds Ratio 1.01 0.87 1.03 0.61 1.41 1.13 2.93 3.05 2.05 1.61 2.28
95% CI 1.00-1.03 0.51-1.49 0.98-1.08 0.39-0.96 1.13-1.77 1.07-1.19 1.79-4.79 1.72-5.37 1.01-4.13 0.77-3.37 1.10-4.75
p 0.14 0.62 0.28 0.03 0.002 <0.001 <0.001 <0.001 0.04 0.20 0.02
Table 4: Univariate predictors of serious infection. ICU, intensive care unit; LOS, length of stay. * Prespecified variables included in the multivariable model.
Any Postoperative Infection Pre-op device infection ICU LOS Moderate infection Pre-op device infection Anti-thymocyte agent ICU LOS Age Serious Infection ICU LOS Age
Odds Ratio
95% CI
p
6.45 1.15
1.86-22.34 1.06-1.26
0.003 0.001
6.23 2.79 1.21 1.02
2.25-17.23 1.02-7.66 1.11-1.31 1.00-1.05
<0.001 0.046 <0.001 0.05
1.13 1.03
1.07-1.19 1.01-1.05
<0.001 0.03
Table 5: Predictors of infection using multivariable model. ICU, intensive care unit; LOS, length of stay.
Age Sex 62 M 57 M 60 M
Days after OHT 33 35
ICU LOS
Induction
5
Antithymocyte Agent No
Yes (driveline, S. epidermidis) No
4
Yes
Yes
15
Yes
No
Driveline related abscess (Enterobacter)
2
No
No
22
No
No
Abdominal abscess after off antibiotics for 55 days (Pseudomonas) Driveline related abscess (Serratia)
No
27 M
63
61 M 71 F 45 F 61 M
78
Yes (pocket, culture negative) Yes (mediastinitis, Pseudomonas) No
106
No
2
No
Yes
151
No
7
Yes
Yes
256
Yes (pocket, culture negative) Yes (driveline, Citrobacter)
3
No
No
5
No
No
56 F
43
Pre-op Infection
337
Details
Sternal abscess (Enterobacter/E. coli) Driveline related abscess (MRSA)
Sternal osteomyelitis/abscess (E. coli) Driveline tract infection/abscess (Klebsiella) Sternal osteomyelitis/abscess (Candida), off antibiotics for prior 247 days Abdominal wall abscess (Citrobacter), off antibiotics for prior 318 days
Table 6: Cases of device related infections >30 days post-transplant. ICU, intensive care unit; LOS, length of stay; MRSA, methicillin resistant staphylococcus aureus; OHT, orthotopic heart transplant.