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Keywords:

  • Empyema;
  • lung transplant;
  • surgical site infection

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

We conducted a retrospective study of deep surgical site infections (SSIs) among consecutive patients who underwent lung transplantation (LTx) at a single center from 2006 through 2010. Thirty-one patients (5%) developed SSIs at median 25 days after LTx. Empyema was most common (42%), followed by surgical wound infections (29%), mediastinitis (16%), sternal osteomyelitis (6%), and pericarditis (6%). Pathogens included Gram-positive bacteria (41%), Gram-negative bacteria (41%), fungi (10%) and Mycobacterium abscessus, Mycoplasma hominis and Lactobacillus sp. (one each). Twenty-three percent of SSIs were due to pathogens colonizing recipients' native lungs at time of LTx, suggesting surgical seeding as a source. Patient-related independent risk factors for SSIs were diabetes and prior cardiothoracic surgery; procedure-related independent risk factors were LTx from a female donor, prolonged ischemic time and number of perioperative red blood cell transfusions. Mediastinitis and sternal infections were not observed among patients undergoing minimally invasive LTx. SSIs were associated with 35% mortality at 1 year post-LTx. Lengths of stay and mortality in-hospital and at 6 months and 1 year were significantly greater for patients with SSIs other than empyema. In conclusion, deep SSIs were uncommon, but important complications in LTx recipients because of their diverse microbiology and association with increased mortality.


Abbreviations
BAL

bronchoalveolar lavage

CF

cystic fibrosis

CI

confidence interval

COPD

chronic obstructive pulmonary disease

ECMO

extracorporeal membrane oxygenation

ESBL

extended spectrum beta-lactamase

ICU

intensive care unit

IPF

idiopathic pulmonary fibrosis

IRB

institutional review board

KPC

Klebsiella pneumoniae carbapenemase

LTx

lung transplantation

MRSA

methicillin-resistant Staphylococcus aureus

MSSA

methicillin-sensitive Staphylococcus aureus

NHSN

National Healthcare Safety Network

SSI

surgical site infection

UPMC

university of Pittsburgh Medical Center

VRE

vancomycin-resistant enterococcus

XDR

extensively drug resistant

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Lung transplantation (LTx) is a life-saving therapy for patients with end-stage lung diseases [1]. Advanced surgical techniques, organ preservation and better postoperative management have improved the likelihood of allograft and patient survival [2]. Infections are important causes of morbidity [3], and the most common cause of death within the first year after LTx [2]. To date, studies have reported on post-LTx infections caused by a wide range of bacteria, fungi and viruses, and serious diseases including pneumonia and bloodstream infections [4, 5]. To our knowledge, however, no study has investigated surgical site infections (SSIs) among LTx recipients. The lack of data is surprising, especially since the risk factors of SSIs and their associated poor outcomes are well-recognized in nontransplant cardiothoracic surgeries [6-9]. The objective of this study was to investigate the epidemiology, clinical manifestations, microbiology, risk factors and outcomes of SSIs following LTx.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

We conducted a retrospective study of consecutive LTx recipients at the University of Pittsburgh Medical Center (UPMC) from January 2006 to December 2010. The study was reviewed and approved by the Institutional Review Board (IRB) at the University of Pittsburgh (IRB #: PRO10080301). For patients requiring re-LTx, only the first transplant was included. Electronic medical records were reviewed independently by at least two investigators and pertinent clinical and microbiological data were extracted. During this period, the general practice within the lung transplant program at UPMC was to administer perioperative prophylaxis for 72 h with aztreonam and cefazolin. For patients with a beta-lactam allergy or known to be colonized with MRSA, vancomycin was substituted for cefazolin. Tailored antimicrobial therapy was instituted for 7 days against pathogens identified in routine donor's and recipient's sterility cultures (i.e. bronchial swab cultures from the donor or recipient at the time of LTx). If Pseudomonas aeruginosa or Staphylococcus aureus was isolated, patients received 14 days of appropriate antibiotics. In patients with bronchiectasis and chronic pulmonary infections or colonization due to multiple-drug resistant bacteria prior to transplant, antimicrobial agents were selected according to susceptibility data from pretransplant and sterility cultures; the duration of treatment was 14 days. Patients with cystic fibrosis (CF) were treated for 2–3 weeks with systemic antimicrobial therapy directed against pathogens recovered from pretransplant and sterility cultures. Patients with CF also received inhaled antibiotics until airways were fully healed, which was typically 2–3 months. CF patients colonized with Burkholderia cenocepacia were generally treated for 8–12 weeks with intravenous and inhaled antimicrobials; inhaled antibiotics were continued for 6 months or until airway cultures became negative. In addition, the chest cavities of CF patients were routinely irrigated with 0.5% betadine solution and an antibiotic solution based on pretransplant cultures. In certain cases, systemic antimicrobial therapy was continued beyond 2–3 weeks at the discretion of the treating physician.

Standard immunosuppression consisted of preoperative methylprednisolone, intraoperative alemtuzumab induction, and postoperative tacrolimus, mycophenolate, and prednisone (5 mg/day). Antimicrobial prophylaxis included life-long trimethoprim/sulfamethoxazole (started within 4 weeks of transplant) and a minimum of 3 months of voriconazole and valganciclovir (started within 1 day of transplant). If donor and recipient serologies for cytomegalovirus were negative, valacyclovir was used instead of valganciclovir.

The surgical approach to LTx evolved over the study period. From 2006 to mid-2007, a clamshell incision was standard. Since mid-2007, a minimally invasive antero-axillary approach has become standard [10], except for cases that are anticipated to be unduly complicated, such as those with prior cardiac/thoracic surgery or combined lung transplantation and cardiac surgery (coronary artery bypass grafting, valve surgery, etc.). As standard procedure, skin edges were approximated prior to leaving the operating room.

SSIs were classified as empyema, mediastinitis, sternal osteomyelitis, pericarditis and surgical wound infections by standard criteria [11]. Surgical wound infections were divided into superficial and deep incision infections; superficial incision infections were excluded from our analysis. Deep incision site infections were defined by involvement of subcutaneous soft tissues (fascia or muscle layers). The diagnosis of SSI required a positive culture from a sterile site (e.g. pleural fluid, pericardium, tissue) and clinical evidence of infection (e.g. purulent discharge, abscess) within 90 days of LTx.

The primary outcome of our analysis was survival at 30 days following the onset of SSI. Secondary outcomes included the need for surgical intervention, lengths of hospitalization and intensive care unit (ICU) stay following LTx, and survival at 6 months, 1 year and during the initial hospital stay. Statistical analyses were performed using the PASW Statistics 18 software program (SPSS, Inc., Chicago, IL). Comparisons between two groups were performed by Wilcoxon rank sum test for continuous variables, and chi-squared or Fisher's exact tests for categorical variables. Variables significant by univariate analysis (p < 0.10) were entered into a multivariate logistic regression model to determine independent risk factors for SSIs by stepwise backward elimination procedures. Kaplan–Meier curves were used to calculate event-free survival; curves were compared by log-rank test. Significance was defined as p-value ≤ 0.05 (two-tailed).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

Five hundred eighty-six LTx patients were enrolled. The most common indication for lung transplant was chronic obstructive pulmonary disease (COPD, 34% (201/586)), followed by idiopathic pulmonary fibrosis (IPF, 28% (162/586)), cystic fibrosis (CF, 11% (67/586)) and scleroderma (5% (28/586)). Overall, 5% (31/586) of patients developed SSI at a median of 25 days (range: 2–90 days) posttransplant. Empyema (42%; 13/31) was the most common type of SSI, followed by surgical wound infections (29%; 9/31), mediastinitis (16%; 5/31), sternal osteomyelitis (6%; 2/31) and pericarditis (6%; 2/31).

Forty-one pathogens were recovered from 31 patients (Table 1). Seventy-seven percent (24/31) and 23% (7/31) of patients were infected with a single or multiple organisms, respectively. Gram-negative and Gram-positive bacteria were implicated equally in SSI (41%, 17/41 of isolates). Fifty-nine percent (10/17) of Gram-negative isolates were broadly resistant to multiple classes of antibiotics, including P. aeruginosa (n = 6), extensively drug resistant (XDR)-Acinetobacter baumannii (n = 2), Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (n = 1) and extended spectrum beta-lactamase (ESBL)-producing Escherichia coli (n = 1). S. aureus was the most common Gram-positive bacteria (59%, 10/17); methicillin-susceptible and-resistant S. aureus (MSSA and MRSA) accounted for 35% (6/17) and 24% (4/17) of Gram-positive isolates, respectively. The remaining Gram-positive bacteria were Enterococcus faecium (24%; 4/17), Enterococcus faecalis (12%; 2/17) and coagulase-negative Staphylococcus (6%; 1/17); 50% (2/4) of E. faecium were vancomycin-resistant (VRE). Ten percent (4/41) of causative organisms were fungi, including Scedosporium apiospermum (n = 2), Aspergillus fumigatus (n = 1) and Paecilomyces (n = 1). Single isolates of Lactobacillus, Mycoplasma hominis and Mycobacterium abscessus were also identified (Table 1).

Table 1. Microbiology of surgical site infections
Gram-negative (n = 17)Gram-positive (n = 17)Fungi (n = 4)Others (n = 3)
  1. MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus.

Empyema
Acinetobacter baumanniiEnterococcus faecium Lactobacillus sp.
Pseudomonas aeruginosa (2)Enterococcus faecalis  
Stenotrophomonas maltophiliaMRSA (4) MSSA (3)  
Surgical wound infection
Escherichia coliCoagulase-negative StaphylococcusAspergillus fumigatusMycobacterium abscessus
Proteus mirabilisEnterococcus faecium (3)Paecilomyces species 
Pseudomonas aeruginosa (2)Enterococcus faecalisScedosporium 
Serratia marcescensMSSAapiospermum 
Mediastinitis
Acinetobacter baumanniiMSSA  
Enterobacter cloacae (2)   
Klebsiella pneumoniae (2)   
Pseudomonas aeruginosa   
Sternal osteomyelitis
Pseudomonas aeruginosa Scedosporium 
Serratia marcescens apiospermum 
PericarditisMSSA Mycoplasma hominis

In 23% (7/31) of patients, SSI was caused by an organism that was recovered from recipient sterility cultures at the time of LTx (Table 2). In 43% (3/7) of these patients, the pathogens were fungi.

Table 2. Surgical site infections (SSI) caused by pathogens present in recipient's lung at the time of transplant
SubjectUnderlying diseasePathogen1Susceptibility results Prophylactic antimicrobial (duration)Time from LTx to SSI (days)Type of SSI
  • BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; LTx, lung transplant.

  • 1

    All were recovered from recipient's sterility cultures.

  • 2

    Cefepime and vancomycin were used for prophylaxis in this patient instead of cefazolin and aztreonam because of an in-hospital aztreonam shortage.

1COPDProteus mirabilisSensitive to cefazolin, cefuroxime and aztreonam13Surgical wound infection
Cefuroxime (7 days)
5COPDStaphylococcus aureus (MSSA)Sensitive to cefazolin50Surgical wound infection
Cefazolin (10 days), then piperacillin–tazobactam (14 days) for Klebsiella pnemoniae bacteremia
6COPDStaphylococcus aureus (MSSA)Sensitive to cefazolin22Empyema
Cefepime and vancomycin for 5 days,2 then cefazolin for 14 days; empyema developed while on cefazolin
7PolymyositisAcinetobacter baumanniiResistant to cefazolin, aztreonam, meropenem; intermediate to tigecycline; susceptible to colistin22Mediastinitis
Cefazolin and aztreonam for 3 days, then tigecycline for 5 days, then colistin; mediastinitis developed while on colistin
2Cystic fibrosisScedosporium apiospermiumPatient with known S. apiospermium colonization that was treated with voriconazole pre-LTx; she had positive sputum culture 17 days before LTx; BAL culture 3 days before LTx was negative90Surgical wound infection
Voriconazole was continued post-LTx
3Cystic fibrosisScedosporium inflatumPatient with known S. inflatum colonization that was treated with voriconazole and terbinafine pre-LTx; positive sputum culture 56 days before LTx; no subsequent respiratory cultures until LTx15Sternal osteomyelitis
Voriconazole and terbinafine were continued post-LTx
4BronchiectasisAspergillus fumigatusPatient with known allergic bronchopulmonary aspergillosis, treated with voriconazole pre-LTx; positive sputum culture 17 days before LTx; no subsequent respiratory cultures until LTx72Surgical wound infection
Voriconazole was continued post-LTx

Risk factors for SSI

Significant patient-related risk factors for SSI by univariate analysis were previous thoracic surgery (nontransplant), diabetes mellitus and obesity (p = 0.0008, 0.005 and 0.048, respectively). Age, sex, underlying lung disease and lung allocation scores (LAS) were not associated with SSI (Table 3). By multivariate logistic regression, prior thoracic surgery and diabetes were identified as independent risk factors (p = 0.001 and 0.009, respectively; 4.15- and 3.03-fold increased odds of SSI).

Table 3. Patient demographics, clinical characteristics and risk factors for surgical site infections (SSI)
FactorSSI (n = 31)No SSI (n = 555)Univariate p-valueMultivariate p-valueOdds ratio95% CI
  1. BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; IPF, idiopathic pulmonary fibrosis.

Median age, years (range)58 (24–73)60 (16–81)0.32   
Female sex, n (%)14 (45)250 (45)1.00   
Indication for transplant, n (%)
COPD7 (23)194 (35)0.18   
IPF6 (19)156 (28)0.41   
Cystic fibrosis4 (13)63 (11)0.77   
Sclerodema1 (3)27 (5)1.00   
Other13 (42)115 (21)   
Prior thoracic surgery, n (%)11 (35)65 (12)0.00080.0014.151.79–9.62
Diabetes, n (%)12 (39)101 (18)0.0050.0093.031.32–6.98
Obesity (BMI > 30 kg/m2), n (%)11 (35)114 (21)0.0480.06  
Median lung allocation score (range)40.2 (30.9–94.2)38.7 (24.2–94.8)0.38   

Significant peritransplant risk factors by univariate analysis were a hospital admission for >3 days prior to LTx (p = 0.04), receipt of lungs from a female donor (p = 0.009), cardiopulmonary bypass (p = 0.02), number of red blood cell transfusions (p < 0.0001), prolonged mean ischemic time (p = 0.01), delayed chest closure (p = 0.003) and mechanical ventilation for >5 days posttransplant (p = 0.01; Table 4). Receipt of induction immunosuppression with alemtuzumab, type of transplant, donor age, gender mismatch, surgical approach, lung volume reduction and use of extracorporal mechanical oxygenation (ECMO) posttransplant were not significant risk factors. By multivariate logistic regression, LTx from a female donor, prolonged ischemic time and number of red blood cell transfusions were independent risk factors for SSI (p = 0.02, 0.04 and <0.0001, respectively). After controlling for pre-LTx risk factors (prior thoracic surgery and diabetes), these factors remained statistically significant. The final model demonstrated no evidence for a lack of fit (p = 0.62, Hosmer–Lemeshow chi-squared test) or muticollinearity.

Table 4. Peri-lung transplant clinical characteristics and risk factors for surgical site infections (SSI)
FactorsSSI (n = 31)No SSI (n = 555)Univariate p-valueMultivariate p-valueOdds ratio95% CI
  • CI, confidence interval; ECMO, extracorporeal membrane oxygenation; LTx, lung transplant.

  • 1

    Odds ratio per red blood cell unit given during LTx. Odds ratio for 10 units = 1.42 (95% CI: 1.18–1.71).

  • 2

    Odds ratio per minute beyond the overall mean ischemic time. Odds ratio for 10 min = 1.05 (95% CI: 1.01–1.09) and 50 min = 1.28 (1.05–1.57).

Admission prior to LTx8 (26)64 (12)0.040.33  
Alemtuzumab induction28 (90)516 (92)0.72   
Type of LTx
Double lung26 (84)397 (71)0.15   
Single lung4 (13)139 (25)0.19   
Heart–lung1 (3)19 (3)1.00   
Median donor age, years (range)40 (13–69)37 (9–73)0.44   
Female donor23 (74)279 (50)0.0090.022.401.21–6.50
Gender mismatch9 (29)176 (32)0.84   
Minimally invasive surgical approach18 (58)400 (72)0.12   
Cardiopulmonary bypass18 (58)199 (36)0.020.96  
Median number of red blood cell units (range)12 (1–96)4 (0–115)<0.0001<0.00011.041.02–1.061
Median ischemic time, minutes (range)361 (200–640)324 (104–676)0.010.041.0051.001–1.0092
Lung volume reduction7 (23)72 (13)0.17   
Delayed chest closure9 (29)52 (9)0.0030.21  
Posttransplant ECMO5 (16)39 (7)0.070.20  
>5 days of mechanical ventilation12 (39)104 (19)0.010.91  

Patient outcomes

All patients were treated with antimicrobial therapy directed against pathogens isolated from relevant cultures, and 48% (15/31) underwent surgical interventions. Interventions included surgical debridement (n = 9) or video-assisted thoracic surgery (VATS; n = 6). Eighty percent (4/5), 69% (9/13) and 15% (2/13) of patients with mediastinitis, empyema, and other SSIs underwent surgical interventions, respectively. The length of stay for patients with SSI was significantly longer than patients without SSI (medians (ranges): 61 days (2–269) and 26 days (18–308), respectively; p < 0.001). Sixteen percent (5/31) of patients died within 30 days of SSI onset (Table 5). Twenty-three percent (7/31) of patients died in the hospital compared to 9% (50/555) of patients without SSI (p = 0.02). Overall, SSIs were associated with significantly increased risk of death at 6 months (p = 0.01) and 1 year post-LTx (p = 0.002; Figure 1). The increased risk of death was exclusively observed among patients with SSIs other than empyema (Figure 2).

Table 5. Outcomes of patients with surgical site infections (SSI)
Types of SSIDeath at:Surgical intervention,1 n (%)Median ICU length of stay (range)Median hospital length of stay (range)
30 days, n (%)Hospital discharge, n (%)1 year, n (%)
  • ICU, intensive care unit.

  • 1

    Includes surgical debridement and video-assisted thoracic surgery.

Empyema (n = 13)1 (8)1 (8)1 (15)9 (69)5 days (2–50)56 days (18–288)
Surgical wound infection (n = 9)2 (22)2 (22)4 (44)2 (22)36 days (3–82)61 days (18–144)
Mediastinitis (n = 5)1 (20)3 (60)3 (60)4 (80)52 days (6–190)100 days (23–308)
Sternal osteomyelitis (n = 2)1 (50)1 (50)2 (100)0 (0)44 days (25–63)59.5 days (56–63)
Pericarditis (n = 2)0 (0)0 (0)1 (50)0 (0)12.5 days (1–24)61.5 days (38–85)
Total (n = 31)5 (16)7 (23)11 (35)15 (48)22 days (1–190)61 days (18–308)
image

Figure 1. Differences in 1 year survival between lung transplant patients with and without surgical site infections (SSIs). By log-rank test, patients with SSIs were less likely to survive 1 year from the time of transplant (p = 0.002).

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image

Figure 2. Rates of survival among patients with empyema (gray line), nonempyema surgical site infections (SSI; dotted line), and no SSI (black line). By two-way log-rank tests, there was no difference in patient survival among those with empyema or no SSI (p = 0.79); however, patients with other SSIs were less likely to survive at 1 year posttransplant compared to both groups (p = 0.03 and <0.0001, respectively).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

To our knowledge, this is the first systematic study of SSIs following LTx. Although these infections were found to share a number of features in common with SSIs following other cardiothoracic surgeries, our most interesting findings highlight differences in the LTx population. LTx is a “clean-contaminated” surgery, as defined by the US Centers for Disease Control's National Healthcare Safety Network (NHSN), since it violates a nonsterile body site (the airways) [12]. Indeed, our SSI rate of 5% was higher than the ∼1% to 2% rate reported to NHSN or other national surveillance networks for nonsuperficial cardiothoracic SSIs [13, 14], but within the 4–10% range for clean-contaminated surgeries [12]. In this context, post-LTx SSIs were relatively uncommon, particularly given the profound induction immunosuppression patients received. Most importantly, however, the microbiology, clinical manifestations, outcomes and risk factors of SSIs among LTx recipients differed from previous studies of cardiothoracic surgical patients.

Gram-positive bacteria are the most common causes of SSIs following cardiothoracic surgery [14-19]. Although S. aureus and Enterococcus spp. were most frequently isolated from our patients, Gram-positive bacteria accounted for only 41% of cultured pathogens. Indeed, the microbiology of post-LTx SSIs was notable for P. aeruginosa and other Gram-negative bacteria (which were as common as Gram-positive bacteria), atypical pathogens like M. hominis and Lactobacillus, and nonbacterial organisms such as fungi and M. abscessus (which represented 12% of pathogens). It was particularly striking that 51% of pathogens were known, or likely to be broadly antimicrobial-resistant, including MRSA, VRE, P. aeruginosa, XDR-A. baumannii, KPC-producing K. pneumoniae, ESBL-producing E. coli, S. apiospermum, Paecilomyces sp., M. hominis, Lactobacillus and M. abscessus. Therefore, LTx recipients were highly susceptible to SSIs by both classic pathogens seen in nonimmunosuppressed patients and more-difficult-to-treat opportunistic and resistant pathogens. Somewhat surprisingly, Candida spp. were not identified as causes of SSI. This finding is in contrast with a previous study demonstrating that Candida spp. accounted for over half of pleural space infections early after lung transplant [20]. The lack of Candida infections may have resulted from our use of routine voriconazole prophylaxis, which was initiated immediately following LTx [21].

Remarkably, 23% (7/31) of our patients developed SSIs that were likely to result from seeding by a pathogen that colonized the recipient's respiratory tract at the time of LTx, including three patients infected with fungi and one with XDR-A. baumannii. In contrast, pathogens colonizing donor lungs were not implicated in SSIs, reflecting the fact that colonized lungs by resistant organisms generally are not accepted for transplantation. Based on our data, clinicians should always consider pathogens within recipients' native lungs as possible causes of SSIs. Similar associations between pretransplant colonization (in particular by mycobacteria and fungi) and posttransplant respiratory tract infections are well-recognized [22]. Since mycobacteria and fungi can be refractory to antimicrobial agents, we recommend they be treated, and airway sterilization documented by several respiratory cultures prior to clearance for LTx.

The most common SSIs following nontransplant cardiothoracic surgery are deep sternal wound infections, a grouping that includes wound infections, sternal osteomyelitis and mediastinitis [19, 23, 24]. Deeper infections of the intra-thoracic space or organs are less common. As such, it is noteworthy that 48% of our patients developed intra-thoracic infections like empyema or pericarditis. In fact, empyema was the most common clinical manifestation of SSI (42%). Of note, patients with empyema were not more likely to die than LTx recipients without an SSI (Figure 2), indicating that these infections were well-managed by surgical drainage and antimicrobial therapy. The outcomes for empyema stood in stark contrast to other SSIs, for which in-hospital, 6 month and 1 year mortality were significantly increased. The 1-year mortality rate among patients with SSIs other than empyema was 56%, which far exceeds the rate of ∼20% reported for cardiothoracic surgical patients with mediastinitis and other deep sternal wound infections [19, 23, 24]. Furthermore, the mortality rate among our patients continued to increase after initial hospital discharge. Clearly, complicated SSIs following LTx can directly result in death, but they are also markers for complicated, critically ill recipients with severe comorbidities that are associated with substantial mortality. Not surprisingly then, SSIs were associated with significant prolongation of ICU and hospital stays.

The classic risk factors for SSIs after cardiothoracic surgeries are diabetes mellitus, prior cardiothoracic surgery, obesity and old age [6, 7, 9, 25, 26]. Diabetes and prior cardiothoracic surgery were independent risk factors for SSIs in our patients [27], but obesity and age were not. On one hand, diabetes is a well-recognized risk factor for infections due to its association with a wide range of immune defects [26]. At the same time, uncontrolled hyperglycemia is linked to impairment of leukocyte adherence, chemotaxis, phagocytosis and bactericidal activity [26, 28]. Intensive insulin therapy minimizes derangements of host defenses [29] and strict glycemic control reduces postsurgical infections [30, 31]. Our program employs stringent glucose control during the peritransplant period, demonstrating that these measures cannot eliminate the risk of SSIs. It is possible that LTx recipients with diabetes are at increased risk for microbial colonization of the skin or mucosal surfaces that may precede SSIs. Diabetic microvascular disease also results in impaired wound healing, local inflammatory responses and local delivery of antimicrobials [28]. Prior cardiothoracic surgeries such as coronary artery bypass grafting, lobectomy and pleurodesis are linked to worse outcomes of LTx [14, 27], and may increase the risk of infection due to the presence of adhesions or other anatomical derangements that complicate transplant procedures.

Obesity (defined as BMI > 30 kg/m2) was a significant risk for SSIs by univariate, but not multivariate analysis. It may be difficult to implicate obesity as an independent risk factor since it is linked to diabetes, longer operative times, need for larger incisions and greater dead space above the fascia, which are known or likely to impact susceptibility to infections in their own rights. Other mechanisms by which obesity may predispose patients to SSIs include impaired tissue oxygenation and wound healing due to the relatively low blood supply of adipose tissue, and physiologic alterations that affect distribution, protein-binding, metabolism and clearance of antimicrobial agents. Even without conclusive evidence that obesity is linked to SSIs among LTx recipients, structured weight loss programs are strongly advocated because obesity is associated with shorter posttransplant survival [32]. We previously reported that almost 80% of LTx recipients in our program who were 60 years of age or older developed a posttransplant infection [1]. Aging is associated with immunosenescence that leads to declining numbers of naïve T and B cells and innate immunity, all of which negatively impact the ability to respond to infectious challenges [33]. A possible explanation for the lack of association between age and SSIs is a selection bias toward transplanting relatively healthy, lowest risk older patients.

In addition to patient-related factors that were previously implicated in other cardiothoracic surgery populations, we identified LTx from a female donor, prolonged ischemic time and number of red blood cell transfusions as procedure-related risk factors for SSI. Increased risk of SSI with red blood cell transfusions has been observed in liver transplantation [34-36] and poststernotomy [37, 38]. The exact role of blood transfusions in the pathogenesis of SSI is not clear, but they have been linked to immune down-regulation stemming from the introduction of large amounts of foreign antigens [37]. Another possibility is that blood transfusion is a surrogate marker for complicated transplant procedures and/or greater underlying comorbidities that inherently predispose patients to SSI [38]. To our knowledge, this is the first study to identify a female allograft as a risk for posttransplant infection. In our cohort, female donors were significantly shorter than male donors (63 in. vs. 68 in., p < 0.0001), which suggests that smaller allografts from women may leave space in the chest cavity that is susceptible to infection. It is also possible that undefined immunologic mechanisms play a role in increasing the SSI risk. Female kidneys, for example, display more HLA antigens and are more antigenic than kidneys from men [39]. Long operations (as reflected by prolonged ischemic time) are likely to increase the risk of contamination of the surgical field.

Since mid-2007, our program has simplified the standard LTx surgical approach by pioneering a minimally invasive procedure [10], in which an antero-axillary incision accesses the chest cavity through the fourth or fifth intercostal space. This method minimizes scarring, spares the sternum, reduces severe wound complications and improves long-term survival [40]. Minimally invasive surgery did not reduce the overall risk of SSI compared to the more conventional clamshell or median sternotomy approaches, but it did eliminate mediastinitis and sternal osteomyelitis. Empyema and other types of SSI were observed among patients undergoing invasive and minimally invasive surgeries, as would be anticipated since both procedures expose the pleural space. It is important to point out that we did not observe a correlation between allograft volume reduction procedures and SSIs. Graft volume reduction is increasingly used to fit oversized lungs into chest cavities. Oversized lungs may lead to ventilatory dysfunction, perpetual atelectasis and hemodynamic instability, and volume reduction has been associated with improved short- and long-term outcomes in cases of size mismatches [41]. Our data demonstrate that this technique can be employed without fear of increasing the risk of SSIs.

There are several limitations to our study that must be acknowledged. Like all retrospective studies, our analysis was limited to available data. In this study, all variables were collected prospectively by transplant coordinators and analyzed in retrospective fashion. Next, antimicrobial prophylaxis strategies were universal throughout the study period, but intraoperative procedures (including antimicrobial irrigation) were not standardized and may have influenced the frequency of SSIs. Lastly, the study was conducted at a single transplant center. It is likely that factors such as immunosuppressive regimens and other management protocols, local infection control practices and surgical techniques had an impact on the rate and types of SSIs.

In conclusion, our study demonstrates that deep SSIs following LTx are relatively uncommon, but important complications due to their unique microbiology and association with increased mortality. Given the difficulties in treating SSIs due to resistant pathogens, deep-seated sites of infection and the highly immunosuppressed patient population, future research should focus on better identifying high-risk patients and developing effective preventive measures. Prevention will need to be employed in pre- and post-LTx clinical settings, and in the operating room since a significant minority of cases result from seeding of pathogens from recipients' native lungs.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

We would like to thank Lloyd Clarke and Michelle Navoney for their help in data collection. The project described was supported by the National Institutes of Health through Grant Numbers KL2 RR024154 and KL2TR000146 to R.K.S.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References

R.K.S. has received research funding from Astellas and Merck. M.H.N. has received research funding from Viracor-IBT Laboratories and grant support from Pfizer, Merck, CSL Behring, and Biotherapies for Life. C.J.C. has received grant support from Pfizer, Merck, and AstraZeneca. All other authors have no conflicts of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Disclosure
  9. References
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