Meta-Analysis: Methods for Diagnosing Intravascular DeviceRelated Bloodstream Infection

Context Several methods exist for diagnosing intravascular devicerelated bloodstream infection. Contribution This meta-analysis summarized data from 51 studies for 8 diagnostic methods. Paired quantitative cultures drawn concomitantly from a peripheral vein and the suspected catheter appeared most accurate, but several methods, including quantitative and semi-quantitative catheter segment cultures, acridine orange leukocyte cytospin tests, and quantitative blood cultures drawn through the catheter, had reasonable accuracy. Cautions Studies used different diagnostic reference standards. Some methods were evaluated in few studies. The Editors Safe and reliable vascular access is essential to modern medical practice. Nearly 200 million intravascular devices (IVDs) are sold in the United States every year (1). Noncuffed percutaneously inserted catheters placed in the femoral, internal jugular, or subclavian vein are the most common centrally placed devices for short-term use, with more than 7 million sold each year (2). Devices for intermediate- and long-term venous access include cuffed and tunneled surgically implanted catheters; totally implantable subcutaneous ports; and, most recently, peripherally inserted central venous catheters (3-7). The most common life-threatening complication of vascular access is bloodstream infection caused by colonization of the implanted IVD or contamination of the catheter hub or infusate administered through the device (2, 8). Central venous catheters of all types are the most frequent cause of nosocomial bloodstream infection (2, 9-12), and an estimated 250000 to 500000 episodes of IVD-related bloodstream infection occur in the United States annually (9-14). These episodes are associated with an attributable mortality rate of 12% to 25% (15, 16), prolongation of hospitalization by 10 to 40 days (15, 17), and marginal cost to the health care system of up to $35000 per episode (13-18). Accurate and early diagnosis is essential to guide management of IVD-related bloodstream infection. A variety of diagnostic tests that are based on current understanding of the pathogenesis of IVD-related bloodstream infection (12) have been developed (19-23). They can be broadly categorized as methods that necessitate removal of the IVD and those that do not require removal of the IVD (Table 1, Appendix). Table 1. Major Diagnostic Methods for Intravascular DeviceRelated Bloodstream Infection We performed a meta-analysis to determine the most accurate diagnostic methods for IVD-related bloodstream infection. Methods Search and Selection Processes We searched the MEDLINE database (1966 to 31 July 2004), Current Contents (1993 to 31 July 2004), PubMed (1966 to 31 July 2004), and the Cochrane Network by using the search terms intravascular device, vascular catheter, bloodstream infection, diagnosis, blood cultures, and infection, and combinations of these terms. Abstracts of meetings of the InterScience Conference on Antimicrobial Agents and Chemotherapy, the American Society of Microbiology, the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, and the Association for Professionals in Infection Control were also reviewed. References from recent published reviews (1-3, 7, 12, 13, 19-23, 38-43) and a previous meta-analysis (30) were also searched. Included studies had to evaluate a diagnostic method for IVD-related bloodstream infection compared with a reference standard and provide sufficient data to calculate the sensitivity and specificity of the test. We excluded case reports, review articles, and nonEnglish-language articles. Studies that assessed the utility of blood cultures drawn from venous or arterial catheters to test for true bacteremia as opposed to contamination were also excluded (44, 45), as were studies of IVD colonization rather than IVD-related bloodstream infection. Data Extraction We used a standard form to extract data on study quality, diagnostic methods studied, reference standard used, patient characteristics, duration of catheterization, antibiotic use, prevalence, sensitivity, and specificity. The Standards for Reporting of Diagnostic Accuracy statement and other published criteria were used to assess study quality (46-48). We evaluated studies for description of the sample; setting; type of IVD studied; method of participant recruitment (all patients with IVDs as opposed to only those with suspected IVD-related bloodstream infection); design (retrospective or prospective); reference standard; definition of cut-off values for positivity; whether evaluators of the test were blinded to the results; statistical methods used to compare diagnostic accuracy and precision; description of indeterminate results; subgroup analyses; and presence of biases that may affect study results, such as incorporation bias (in which the test being studied is part of the reference standard) and work-up bias (46). Data Synthesis We studied the 8 diagnostic methods that are most frequently used in clinical practice and for which performance data have been published: qualitative catheter segment culture, semi-quantitative catheter segment culture (roll-plate method), or quantitative catheter segment culture, each combined with demonstrated concordance with results of concomitant blood cultures; qualitative blood culture drawn through an IVD; quantitative blood culture drawn through an IVD; paired quantitative peripheral and IVD-drawn blood cultures; acridine orange leukocyte cytospin testing of IVD-drawn blood; and differential time to positivity of concomitant qualitative IVD-drawn and peripheral blood cultures (>2 hours). We did not include endoluminal brushing in the meta-analysis because few studies have assessed the test. Four of the 5 studies identified (37, 49-52) were performed by the same group of investigators, and 1 study did not define IVD-related bloodstream infection (51). We also excluded studies of cultures of catheter insertion sites or hubs because of methodologic differences among the studies and a wide range of cut-points for positivity. Statistical Analysis We calculated pooled sensitivities and specificities and 95% CIs for each category of diagnostic tests and an estimate of overall sensitivity and specificity by using a random-effects model and estimating equations similar to those proposed by Zhou and colleagues (53). Heterogeneity in the estimates of sensitivity and specificity was assessed by using the Pearson chi-square test or the Fisher exact test. To combine sensitivity and specificity, we used the approach of Moses and coworkers (54) and calculated D= logit (TPR)logit (FPR) and S= logit (TPR)+logit (FPR), where TPR is the true-positive rate or sensitivity and FPR is the false-positive rate (1specificity). D is interpreted as the log odds ratio, that is, the ratio of the odds that a person who has IVD-related bloodstream infection tests positive to the odds that a person who does not have the disease tests positive for it. We calculated the mean and median values of D by using the values computed within each study. Using the summary receiver-operating characteristic (ROC) curve method of Moses and coworkers (54), we also calculated Q*, which corresponds to the upper leftmost point on the summary ROC curve, where sensitivity equals specificity. The summary measure Q* has been advocated over area under the curve because it is meaningful in the ROC region of greatest interest (54, 55). The ROC curves were derived from linear regressions of D on S and account for random thresholds across studies, as discussed by Moses and coworkers (54). Because the tests for homogeneity were significant, the measure Q* may be better suited to comparing tests than are measures that do not adjust for these differences, since it accounts for random thresholds. The regression model was fit by using equally weighted least squares with the function *1m* in S-PLUS software, version 3.4 (MathSoft, Inc., Seattle, Washington), and a robust resistant method using median regression implemented in *11fit* in S-PLUS software (54). The 95% CIs were reported for mean D and for Q* based on the equally weighted least-squares method. Differences in mean D across all tests were evaluated by using analysis of variance of D computed within individual studies. We also assessed whether increasing degrees of quantitation for methods of catheter segment culture and blood culture would improve the accuracy of the tests. For mean D, separate linear regression analyses were performed for each set of tests, with a covariate for level of quantitation that was coded as an ordinal variable. The same analysis was also done for summary ROC curves (54). A difficulty with mean and median D and with Q* based on summary ROC curves is that these measures do not account for the prevalence of the disease in the group of interest (54). In selecting a test for clinical use, its practical utility will depend not only on its operating characteristics (sensitivity and specificity) but also the patients in which it is being used. The relevant quantities for decision making in this setting are positive predictive value and negative predictive value. We determined positive predictive value and negative predictive value over a wide range of prevalences for each of the tests, on the basis of prevalences from the studies in this meta-analysis. Pooled estimates of sensitivity and specificity were used in these calculations. Heterogeneity was assessed by using 2 subgroup analyses. One subgroup analysis was done to determine whether duration of IVD implantation affected the diagnostic accuracy of the various tests. Studies that did not report the type of IVD studied or that used a mix of short- and long-term catheterization were excluded from this analysis. For each diagnostic test category, pooled sensitivity, specificity, and mean D were calculated separately for short- and long-term catheter placemen