Principal discussant: BERTRAND L. JABER
Department of Medicine, Tufts University School of Medicine; and Division of Nephrology, Department of Medicine,
Caritas St. Elizabeth’s Medical Center, Boston, Massachusetts
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A 62-year-old African American man with end-stage renal disease secondary to hypertension who had been treated with hemodialysis for almost 5 years had multiple
vascular access problems. After multiple thrombectomies of right and left arm arterio-venous grafts(AVGs), as well as an episode of life-threatening bleeding from the left arm AVG, he underwent insertion of a LifeSite® catheter in the left internal jugular vein 4 years ago. Four months later, he was hospitalized for an episode of chills and rigors, and was found to have methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, which was
treated with intravenous vancomycin and oral rifampin. A trans-esophageal echocardiogram revealed no valvular vegetation. Because he was a nasal carrier of MRSA,
he was given a 2-week course of mupirocin ointment to his nares for eradication of MRSA colonization.
Extensive discussions ensued with the patient about the future of his vascular access and the likelihood of eradicating the infection with medical therapy alone. Given his history of multiple thrombosedAVGs, and that the implanted catheter might have been his last option for satisfactory dialysis access, the decision was made not to remove the catheter and for him to receive an 8-week course of dual antibiotic therapy. The patient then did
well until 13 months later, when erosion of the skin over the arterial port of the LifeSite® catheter required surgical relocation of the port and skin closure.
Seventeen months later, he presented with fever and abdominal pain one day following a dialysis session. Blood cultures from a peripheral vein and from the dialysis catheter grew coagulase-negative staphylococcus species. An abdominal CT scan revealed pneumatosis and air tracking in the superior mesenteric and splenic veins consistent with ischemic bowel disease. Broadspectrum antibiotics were initiated and he was given intravenous fluids prior to undergoing an emergent exploratory surgery. Laparotomy revealed a gangrenous small bowel from the ligament of Treitz to the ileo-cecal valve. Intraoperative Doppler studies revealed no pulse in the arcade of the mesentery of the small intestine. Because of these findings and the overall poor prognosis, no intestinal resection was attempted, and the abdominal surgical wound was closed. As expected, the patient continued to deteriorate clinically and died due to this devastating complication and overwhelming staphylococcal sepsis. No autopsy was performed.
DR. BERTRAND L. JABER (Department of Medicine, Tufts University School of Medicine; and Vice Chairman for Clinical Affairs, Division of Nephrology, Department of Medicine, Caritas St. Elizabeth’s Medical Center, Boston, Massachusetts): Bacterial infections represent a common and important health problem for patients with end-stage renal disease (ESRD) who undergo maintenance hemodialysis (HD), and this patient illustrates the challenges inherent to this problem. Considerable gains have been made in deciphering the pathogenesis of bacterial infections in this high-risk population. These gains notwithstanding, the therapeutic goal of preventing bacterial infections in HD patients remains unfulfilled. This Forum reviews the magnitude of the problem in the HD patient population, our progress in understanding the pathogenesis of bacterial infections, the use of novel diagnostic tools, and prospects for preventing such occurrences, while outlining areas of uncertainty.
The clinical problem
Infection is an important cause of morbidity and mortality among patients with ESRD. According to the United States Renal Data System (USRDS) registry, infection is the second leading cause of death in patients withESRD(the first is cardiovascular disease), and septicemia accounts for more than 75% of these infectious deaths . Indeed, among ESRD patients undergoing dialysis, the total death rate is 176/1000 patient-years, and septicemia and pulmonary infections combined account for close to 26/1000 patient-years . Annual death rates due to pneumonia and sepsis are markedly higher in dialysis patients compared with the general population; in the 65- to 74-year-old category, the magnitude of difference is on the order of 10- and 100-fold, respectively (Fig. 1) [2, 3]. Whereas the presence of diabetes mellitus confers an additional risk for sepsis-related deaths, this comorbid condition appears to exert little influence on pneumonia-related deaths [2, 3].
Bacterial infections are a major cause of hospitalization. In a recent study on the epidemiology of septicemia in HD patients, hospital admission rates for septicemia during the first year of HD rose by 51% over the 8-year period from 1991 to 1999 . Hospitalization for septicemia also was associated with an increased risk of myocardial infarction, congestive heart failure, stroke, and peripheral vascular disease at 6 months and 5 years after the original hospitalization . These data suggest that septicemia has become more common in dialysis patients in the U.S. and is associated with an increased risk of cardiovascular events and death. Evidence is emerging that HD patients also have a higher incidence of infective endocarditis [5–7]. In one study, the proportion of patients with infective endocarditis who were undergoing HD increased from 7% to more than 20% over a 7-year period , and this observation was paralleled by a significant increase of Staphylococcus aureus-associated endocarditis from 10% to 68% . In the U.S., the incidence of infective endocarditis in the dialysis population has been estimated at 483 episodes/100,000 patient-years compared with only 7 episodes in the general population . In this study, HD therapy was a strong risk factor for infective endocarditis, which was associated with a 1.5-fold higher risk of death .
In a longitudinal cohort study of incident ESRD patients, older age and diabetes were independent risk factors for septicemia in all patients .AmongHDpatients, low serum albumin level, temporary vascular access, and dialyzer reuse also were associated with increased risk , and septicemia carried a markedly increased risk of death. These data suggest that improving nutrition and avoiding temporary vascular access might decrease the incidence of septicemia, and that dialyzer reuse practices might contribute to this risk. In a recent study reporting on a staged program to stop dialyzer reprocessing, conversion to a single-use dialyzer practice was associated with improved survival . This trend lagged by at least 60 days following abandonment of the dialyzer reuse practice and was ascribed to a cumulative decline in exposure to trace industrial products or repeated inflammatory and infectious insults, which only become clinically manifest over time .
In the HEMO study, the incidence of infection-related deaths was not reduced by higher dose of dialysis or by high-flux dialyzers, and most infection-related hospitalizations were not attributed to vascular access . However, the frequency of infection-related hospitalizations attributed to vascular access was disproportionately higher among patients with central venous catheters compared with those who had grafts or fistulas .
In the past two decades, major gains have been realized in our understanding of the pathogenesis of bacterial infections inHDpatients. I will emphasize the interaction of three pivotal factors: host immunity, bacterial virulence, and the dialysis procedure per se (Fig. 2). The following section reviews the various components of this “access of evil,” with special emphasis on the pathogenesis of bacteremia and bacterial pneumonia.
Impaired host immunity. Uremia is associated with alterations in primary host defense mechanisms, which increase the risk of bacterial infections. Indeed, neutrophils exhibit impaired chemotaxis, oxidative metabolism, phagocytic activity, degranulation, and intracellular killing, as well as dysregulated programmed cell death or apoptosis [11–14].Anumber of factors have been incriminated in neutrophil dysfunction, including malnutrition, trace element deficiencies, iron overload, impaired glucose metabolism, hyperparathyroidism, dialysis per se, and uremic retention solutes [12, 15–18].
Abundant in vitro and clinical studies have linked iron overload to an increased risk of bacterial infections in HD patients [17, 19–21], including modest iron storage levels (ferritin level of 100–800 ng/mL and transferrin saturation of 10% to 50%) (Fig. 3) [22, 23]. Iron overload modulates this risk by affecting host defense mechanisms and bacterial virulence. Indeed, iron overload has been associated with reduced phagocytic function and oxidative burst, as well as impaired bacterial killing [17, 20, 21].
Iron dextran, at pharmacologically relevant concentrations, attenuates in vitro the function of polymorphonuclear cells harvested from HD patients with normal iron indices . Also, it is possible that the increased availability of iron can stimulate bacterial growth and increase virulence properties . Consequently, the increased use of parenteral iron might be an important contributory factor to the occurrence of bacterial infections.
In recent years, many uremic retention solutes that can adversely affect neutrophil function have been identified, including parathyroid hormone, p-cresol, polyamines, aminoguanidine products, and a series of granulocyte inhibitory proteins, angiogenin and complement factorD [12, 18]. In addition, neutrophil-membrane interactions, mainly with cuprophan membranes, result in transient leukopenia, increased expression of adhesion molecules, degranulation and release of proteolytic enzymes, and release of reactive oxygen species . These interactions might result in cellular “exhaustion” and decreased responsiveness to subsequent stimuli, such as bacteremia.
Other striking abnormalities occur in cell-mediated immunity and primarily involve T-lymphocytes. These include lymphocytopenia, impaired delayed skin reactivity, and decreased in vitro lymphocyte proliferation [26, 27]. Alterations in B-lymphocyte function affect humoral immunity and result in decreased immunoglobulin levels and a depressed antibody response to antigens. Dysregulated cytokine synthesis  and impaired macrophage Fc receptor function  further impair immune function in uremic patients. In one study, impaired macrophage Fc receptor function was associated with a higher risk of bacterial infection . Finally, impaired ex vivo cytokine production by mononuclear cells in response to IgG, an Fc-mediated response, was associated with an increased risk of hospitalization for bacterial infections in HD patients .
Additional susceptibility and risk factors that are specific for pulmonary infections in HD patients include obstructive and central sleep apnea, impaired inspiratory muscle strength, uremic pneumonitis/pleuritis, the hyperhydration syndrome (due to fluid gain during the interdialytic interval), pulmonary metastatic calcification (from an increased calcium × phosphate product), and intradialytic hypoxemia (due to complement activation and transient leukopenia) [2, 31].
Bacterial virulence and adherence properties. Bacteria can acquire virulence properties when specific conditions are met. In the normal host, under conditions of low density, bacteria are cleared by primary host-defense mechanisms. However, under conditions of high bacterial density, bacteria can produce extracellular polysaccharides referred to as “quorum sensors” [32, 33]. These molecules are secreted by the bacteria and freely diffuse within the bacterial community, where they interact with transcriptional activators such as LasR and RhlR.
This interaction increases expression of virulence genes, thereby facilitating bacterial survival by increased production of proteases, superoxide dismutase, and catalase, which enable the organisms to evade neutrophil killing and the bactericidal or bacteriostatic effects of antimicrobial agents. Bacteria also form a matrix of these extracellular polysaccharides, which is called biofilm or “slime.” This slime renders them less susceptible to antimicrobial agents, as the matrix constitutes a barrier between the antimicrobial agent and the bacterial cell wall. In the presence of foreign surfaces such as central venous catheters, biofilm formation is more likely to develop and can potentiate the pathogenicity of the skin bacterial flora (for example, coagulase-negative staphylococci).
The adherence properties of bacteria are also important determinants of catheter-related infection . For example, S. aureus adheres to host proteins that are commonly present on catheters, such as fibronectin, whereas coagulase-negative staphylococci directly adhere to polymer surfaces.
The hemodialysis procedure. During the normal course of HD, patients are exposed to several infectious risks. Potential sources of infection include the skin (through repeated disruption of the skin barrier and integrity due to the nature of the vascular access type), the dialysis water treatment system, and dialyzer reuse.
Central venous catheters used for HD include nontunneled, tunneled, and totally implantable devices, such as the one described in the case presentation. The risk of bacteremia by device type, site of insertion, and duration of use varies widely. In one study of non-tunneled catheters, the incidence of bacteremia was5%after three weeks of placement in the internal jugular vein, and 11% after one week in the femoral vein . Four pathogenic pathways have been incriminated in the development of catheter-related bloodstream infections, and include, in order of descending frequency: (1) colonization of the cutaneous catheter tract and tip with skin flora; (2) intraluminal colonization due to contamination of the catheter hub; (3) hematogenous seeding to the catheter from another focus of infection; and (4) very rarely, intraluminal contamination of the catheter with solvent/infusate. In addition to intrinsic bacterial virulence factors, another important determinant of catheter-related infection is the type of the device material . For example, catheters made of polyvinyl chloride or polyethylene are less resistant to the adherence of bacteria compared with catheters made of polytetrafluoroethylene (PTFE), silicone elastomer, or polyurethane . Finally, surface irregularities and thrombogenicity of the catheter material are also likely to influence microbial adherence and therefore increase the risk of catheter colonization and catheter-related infection.
Bacteremia also can result from contamination of dialysis fluids or equipment, inadequate dialyzer reprocessing procedures, or inadequate treatment of municipal water for use in dialysis [37, 38]. Contaminated medication vials also are a potential source of bacteremia .
Novel diagnostic approaches for catheter-related infections
The confirmation of peripheral bacteremia is paramount in the diagnosis of catheter-related infections. Unfortunately, for practical purposes often only one set of blood cultures is collected from the catheter lumen itself. Although blood culture testing is relatively inexpensive and easy to process, 24 to 48 hours often elapse before a preliminary report is provided to the clinician. In addition, if a catheter removed on suspicion of causing infection proves not to be infected, the patient is exposed unnecessarily to the risks associated with reinsertion. Consequently, rapid diagnostic approaches that help confirm a suspected catheter-related infection in HD patients and that implement the proper use of antibiotics are needed. Several novel but rather cumbersome diagnostic approaches include the use of an endoluminal brush, catheter hub culture, and electron microscopy [40, 41]. One rapid diagnostic technique, however, merits discussion. The acridine-orange leukocyte cytospin test (AOLC) is rapid (30 min), inexpensive, and requires only 100 lL of catheter blood and the use of ultraviolet microscopy . In a study of diagnostic approaches of catheter-related bloodstream infections in adult surgical patients, the AOLC provided a diagnostic sensitivity and specificity of 96% and 92%, respectively, compared with traditional quantitative peripheral blood cultures . Although this simple and rapid diagnostic method compares favorably with traditional blood culture techniques and might help stratify patients who require catheter removal and early antimicrobial therapy, further studies are needed on the sensitivity and specificity of this assay in the dialysis population.