Revisiting the effect of referral bias on the clinical spectrum of infective endocarditis in adults.

Referral bias occurs because of the clustering of patients at tertiary care centers. This may result in the distortion of observed clinical manifestations of rare diseases. This analysis evaluates the effect of referral bias on the epidemiology of infective endocarditis (IE) in the International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS). This is a prospective multicenter cohort study comparing transferred and non-transferred patients with IE. Factors independently associated with transfer status were evaluated using multivariable logistic regression. A total of 2,760 patients were included in the analysis, of which 1,164 (42.2%) were transferred from other medical centers. Transferred patients more often underwent surgery for IE (odds ratio [OR] = 2.5; 95% confidence interval [CI] 1.9-3.2). They were also more likely to have complications such as stroke (OR = 1.5; 95% CI 1.3-1.9), heart failure (OR = 1.4; 95% CI 1.1-1.6), and new valvular regurgitation (OR = 1.3; 95% CI 1.1-1.6). The in-hospital mortality rates were similar in both groups. Patients with IE who require surgery and suffer complications are referred to tertiary hospitals more frequently than patients with an uncomplicated course. Hospital transfer has no obvious effect on the in-hospital mortality. Referral bias should be taken into consideration when describing the clinical spectrum of IE.

Coagulase-negative staphylococcal prosthetic valve endocarditis--a contemporary update based on the International Collaboration on Endocarditis: prospective cohort study.

OBJECTIVE: To describe the contemporary features of coagulase-negative staphylococcal (CoNS) prosthetic valve endocarditis (PVE). DESIGN: Observational study of prospectively collected data from a multinational cohort of patients with infective endocarditis. Patients with CoNS PVE were compared to patients with Staphylococcus aureus and viridans streptococcal (VGS) PVE. SETTING: The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) is a contemporary cohort of patients with infective endocarditis from 61 centres in 28 countries. PATIENTS: Adult patients in the ICE-PCS with definite PVE and no history of injecting drug use from June 2000 to August 2005 were included. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Heart failure, intracardiac abscess, death. RESULTS: CoNS caused 16% (n = 86) of 537 cases of definite non-injecting drug use-associated PVE. Nearly one-half (n = 33/69, 48%) of patients with CoNS PVE presented between 60 days and 365 days of valve implantation. The rate of intracardiac abscess was significantly higher in patients with CoNS PVE (38%) than in patients with either S aureus (23%, p = 0.03) or VGS (20%, p = 0.05) PVE. The rate of abscess was particularly high in early (50%) and intermediate (52%) CoNS PVE. In-hospital mortality was 24% for CoNS PVE, 36% for S aureus PVE (p = 0.09) and 9.1% for VGS PVE (p = 0.08). Meticillin resistance was present in 68% of CoNS strains. CONCLUSIONS: Nearly one-half of CoNS PVE cases occur between 60 days and 365 days of prosthetic valve implantation. CoNS PVE is associated with a high rate of meticillin resistance and significant valvular complications.

Echocardiographic risk stratification for early surgery with endocarditis: a cost-effectiveness analysis.

BACKGROUND: Despite widespread acceptance of echocardiography for diagnosis of infective endocarditis, few investigators have evaluated its utility as a risk-stratification tool to aid therapeutic decision-making. METHODS: A decision tree and Markov analysis model were constructed using published and institutional data to estimate the cost-effectiveness of an echocardiographic risk-stratification strategy for infective endocarditis. The models compared surgery for high-risk patients based on clinical factors ("standard care") and surgery for high-risk patients based on echocardiographic findings ("echocardiography-guided"). RESULTS: The cost per patient for standard care and echocardiography-guided strategies was $47,766 and $53,669, respectively. The expected quality-adjusted life years (QALY) for standard care and echocardiography-guided strategies were 5.86 years and 6.10 years, respectively. Compared with standard care, the echocardiography-guided strategy cost an additional $23,867 per QALY saved. In one-way sensitivity analyses, the incremental cost of this strategy remained <$50,000/QALY across a broad range of scenarios. Baseline stroke risk had the greatest effect on cost-effectiveness. For populations with stroke risk less than 3.65%, the echocardiography-guided strategy was not cost-attractive (ICER >$50,000/QALY). At stroke risk between 3.65% and 14%, the ICER for the echocardiography-guided strategy was attractive (<$50,000 /QALY). The echocardiography-guided strategy became economically dominant at any baseline stroke risk greater than 18.3%. CONCLUSION: Echo-guided risk stratification for early surgery in patients with large vegetations is a cost-attractive treatment strategy for IE, as it improves outcome for an incremental cost <$50,000/QALY.

Leptotrichia endocarditis: report of two cases from the International Collaboration on Endocarditis (ICE) database and review of previous cases.

Leptotrichia species typically colonize the oral cavity and genitourinary tract. We report the first two cases of endocarditis secondary to L. goodfellowii sp. nov. Both cases were identified using 16S rRNA gene sequencing. Review of the English literature revealed only two other cases of Leptotrichia sp. endocarditis.

Prosthetic valve endocarditis due to coagulase-negative staphylococci: findings from the International Collaboration on Endocarditis Merged Database.

Infective endocarditis due to coagulase-negative staphylococci is increasingly recognized as a difficult-to-treat disease associated with poor outcome. The aim of this report is to describe the characteristics and outcome of patients with prosthetic valve endocarditis (PVE) due to coagulase-negative staphylococci versus those of patients with PVE due to Staphylococcus aureus and viridans streptococci. Patients were identified through the International Collaboration on Endocarditis Merged Database. A total of 54 cases of coagulase-negative staphylococci PVE, 58 cases of S. aureus PVE, and 63 cases of viridans-streptococci-related PVE were available for analysis. There was no difference between the three groups with respect to the type of valve involved or the rate of embolization. However, heart failure was encountered more frequently with coagulase-negative staphylococci (54%) than with either S. aureus (33%; p=0.03) or viridans streptococci (32%; p=0.02). In addition, valvular abscesses complicated 39% of infections due to coagulase-negative staphylococci compared with 22% of those due to S. aureus (p=0.06) and 6% of those due to viridans streptococci (p<0.001). Mortality was highest in patients with S. aureus and coagulase-negative staphylococcal endocarditis (47 and 36%, respectively; p=0.22) and was considerably lower in patients with viridans streptococcal endocarditis (p=0.002 compared to patients with coagulase-negative staphylococcal endocarditis). The results of this analysis demonstrate the aggressive nature of coagulase-negative staphylococcal PVE and the substantially greater morbidity and mortality associated with this infection compared to PVE caused by other pathogens.

Enterococcal prosthetic valve infective endocarditis: report of 45 episodes from the International Collaboration on Endocarditis-merged database.

Enterococcal prosthetic valve infective endocarditis (PVE) is an incompletely understood disease. In the present study, patients with enterococcal PVE were compared to patients with enterococcal native valve endocarditis (NVE) and other types of PVE to determine differences in basic clinical characteristics and outcomes using a large multicenter, international database of patients with definite endocarditis. Forty-five of 159 (29%) cases of definite enterococcal endocarditis were PVE. Patients with enterococcal PVE were demographically similar to patients with enterococcal NVE but had more intracardiac abscesses (20% vs. 6%; p=0.009), fewer valve vegetations (51% vs. 79%; p<0.001), and fewer cases of new valvular regurgitation (12% vs. 45%; p=0.01). Patients with either enterococcal PVE or NVE were elderly (median age, 73 vs. 69; p=0.06). Rates of in-hospital mortality, surgical intervention, heart failure, peripheral embolization, and stroke were similar in both groups. Patients with enterococcal PVE were also demographically similar to patients with other types of PVE, but mortality may be lower (14% vs. 26%; p=0.08). Notably, 93% of patients with enterococcal PVE came from European centers, as compared with only 79% of patients with enterococcal NVE (p=0.03). Thus, patients with enterococcal PVE have higher rates of myocardial abscess formation and lower rates of new regurgitation compared to patients with enterococcal NVE, but there are no differences between the groups with regard to surgical or mortality rates. In contrast, though patients with enterococcal PVE and patients with other types of PVE share similar characteristics, mortality is higher in the latter group. Importantly, the prevalence of enterococcal PVE was higher in the European centers in this study.

Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database.

PURPOSE: To describe clinical features and outcomes of enterococcal left-sided native valve endocarditis and to compare it to endocarditis caused by other pathogens. SUBJECTS AND METHODS: Patients in the International Collaboration on Endocarditis-Merged Database were included if they had left-sided native valve endocarditis. Demographic characteristics, clinical features, and outcomes were analyzed. Multivariable analysis evaluated enterococcus as a predictor of mortality. RESULTS: Of 1285 patients with left-sided native valve endocarditis, 107 had enterococcal endocarditis. Enterococcal endocarditis was most frequently seen in elderly men, frequently involved the aortic valve, tended to produce heart failure rather than embolic events, and had relatively low short-term mortality. Compared to patients with non-enterococcal endocarditis, patients with enterococcal endocarditis had similar rates of nosocomial acquisition, heart failure, embolization, surgery, and mortality. Compared to patients with streptococcal endocarditis, patients with enterococcal endocarditis were more likely to be nosocomially acquired (9 of 59 [15%] vs 2 of 400 [1%]; P <.0001) and have heart failure (49 of 107 [46%] vs 234 of 666 [35%]; P = 0.03). Compared to patients with S. aureus endocarditis, patients with enterococcal endocarditis were less likely to embolize (28 of 107 [26%] vs 155 of 314 [49%]; P <.0001) and less likely to die (12 of 107 [11%] vs 83 of 313 [27%]; P = 0.001). Multivariable analysis of all patients with left-sided native valve endocarditis showed that enterococcal endocarditis was associated with lower mortality (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.24 to 0.97). CONCLUSIONS: Enterococcal native valve endocarditis has a distinctive clinical picture with a good prognosis.

Emergence of endocarditis due to group D streptococci: findings derived from the merged database of the International Collaboration on Endocarditis.

The aim of the present study was to compare the epidemiological and clinical characteristics of Streptococcus bovis endocarditis with those of endocarditis caused by oral streptococci, using data obtained from a large international database of uniformly defined cases of infective endocarditis. S. bovis, a well-known cause of infective endocarditis, remains the common name used to designate group D nonenterococcal streptococci. In some countries, the frequency of S. bovis endocarditis has increased significantly in recent years. Data from the International Collaboration on Endocarditis merged database was used to identify the main characteristics of S. bovis endocarditis and compared them with those of infective endocarditis (IE) due to oral streptococci. The database contained 136 cases of S. bovis IE and 511 cases of IE due to oral streptococci. Patients with S. bovis IE were significantly older those with IE due to oral streptococci (63+/-16 vs. 55+/-18 years, P<0.00001). The proportion of streptococcal IE due to S. bovis increased from 10.9% before 1989 to 23.3% after 1989 (P=0.0007) and was 56.7% in France as compared with 9.4% in the rest of Europe and 6.0% in the USA (P<0.00001). Patients with S. bovis IE had more comorbidity and never used intravenous drugs. Complication rates, rates of valve replacement, and mortality rates were similar in the two groups. In conclusion, this study confirmed that S. bovis IE has unique characteristics when compared to endocarditis due to oral streptococci and that it emerged in the 1990s, mainly in France, a finding that is yet unexplained.

Prognostic factors in 61 cases of Staphylococcus aureus prosthetic valve infective endocarditis from the International Collaboration on Endocarditis merged database.

Staphylococcus aureus prosthetic valve infective endocarditis (SA-PVIE) is associated with a high mortality rate, but prognostic factors have not been clearly elucidated. The International Collaboration on Endocarditis merged database (ICE-MD) contained 2212 cases of definite infective endocarditis (as defined using the Duke criteria), 61 of which were SA-PVIE. Overall mortality rate was 47.5%, stroke was associated with an increased risk of death, and early valve replacement was not associated with a significant survival benefit in the whole population; however, patients who developed cardiac complications and underwent early valve replacement had the lowest mortality rate (28.6%).

Risk factors for infective endocarditis in patients with enterococcal bacteremia: a case-control study.

BACKGROUND: Based on previous studies, enterococcal infective endocarditis (IE) is considered a unimicrobial, community-acquired disease of older Caucasian men. PATIENTS AND METHODS: We evaluated the relationship between enterococcal bacteremia and IE by comparing clinical and demographic characteristics of all cases of enterococcal IE within an 8-year period (n = 41) with controls randomly chosen from patients with enterococcal bacteremia without IE. RESULTS: By univariate and multivariable analyses, the presence of a prosthetic valve (PV) and infection with Enterococcus faecalis were significantly associated with IE, while age, gender, race, polymicrobial infection and community-acquired infection were not. Almost an equal number of women and men had enterococcal IE. Cases of enterococcal IE were commonly nosocomial (39%) and polymicrobial (17%). CONCLUSIONS: Enterococcal endocarditis can no longer be considered exclusively a unimicrobial, community-acquired disease of Caucasian men. Instead, our data suggest that the presence of a PV and infection by E. faecalis are associated with an increased risk for IE.

Stroke location, characterization, severity, and outcome in mitral vs aortic valve endocarditis.

OBJECTIVE: To characterize the incidence and clinical features of patients with infective endocarditis (IE) and stroke. METHODS: The authors reviewed the records of 707 patients diagnosed with definite or possible IE between January 1984 and November 1999. Stroke was confirmed by application of strict definitions and classified by type, pathophysiology, vascular territory, and severity. The authors determined mortality rates for the initial hospitalization and 12 months after admission. RESULTS: Strokes occurred in 68 (9.6%) of 707 patients with IE, 38 (17%) of 218 patients with mitral valve endocarditis (MVE), 14 (9%) of 149 patients with aortic valve endocarditis (AVE), and 16 (5%) of 340 patients with other forms of IE (OR for MVE vs AVE = 2.0, 95% CI 1.1 to 3.9). Among the patients with MVE or AVE and stroke, there were no significant relationships between site of vegetation and length of hospitalization, stroke severity, mortality during the initial hospitalization, or 12-month mortality. Fifty-two percent of patients with stroke and IE died within 1 year of admission. CONCLUSIONS: The overall incidence of stroke in patients with IE (9.6%) is lower than previous reports (21 to 39%). Patients with MVE had a greater risk of stroke than patients with AVE. Fifty-two percent of patients died within 1 year of admission for IE.

Cardiac conduction abnormalities in endocarditis defined by the Duke criteria.

BACKGROUND: Cardiac conduction abnormalities occur in endocarditis and have been associated with infection extension and increased mortality. There have been no prospective studies of electrocardiographic (ECG) conduction changes in endocarditis. We examined the incidence of ECG changes in a large prospective cohort with suspected endocarditis and correlated changes with echocardiographic evidence of invasive infection and mortality. METHODS: One hundred thirty-seven of 1396 (10%) suspected cases of endocarditis were classified as "definite" or "possible" by the Duke criteria and had an interpretable ECG. ECG conduction changes were classified as old (pre-existing hospitalization), new (evident on admission or developed during hospitalization), or indeterminate. New or indeterminate abnormalities were considered "ECG conduction changes." Echocardiogram results were reviewed to identify infected valves and invasive infection. RESULTS: ECG conduction changes were present in 36 of 137 (26%) patients. Patients with ECG conduction changes were more often male (69% vs 46%, P =.005) and had prosthetic valves (47% vs 23%, P <.001). There were no significant differences in microbiology results or treatment with cardiac surgery. In 76 (55%) patients, at least one infected valve was identified by echocardiography; 15 of 76 (20%) patients were determined to have evidence of invasive infection. Eight of 15 (53%) invasive infections exhibited ECG conduction changes compared with 16 of 61 (26%) isolated valve infections (P =.046). Eleven of 36 (31%) patients with ECG conduction changes died during hospitalization compared with 15 of 101 (15%) patients without changes (P =.039). CONCLUSIONS: ECG conduction changes commonly occur in endocarditis despite more sensitive diagnostic criteria and are associated with increased mortality and invasive infection.

Staphylococcus aureus bacteremia in patients with permanent pacemakers or implantable cardioverter-defibrillators.

BACKGROUND: Although cardiac device infections (CDIs) are a devastating complication of permanent pacemakers or implantable cardioverter-defibrillators, the incidence of CDI in patients with bacteremia is not well defined. The objective of this study was to determine the incidence of CDI among patients with permanent pacemakers or implantable cardioverter-defibrillators who develop Staphylococcus aureus bacteremia (SAB). METHODS AND RESULTS: A cohort of all adult patients with SAB and permanent pacemakers or implantable cardioverter-defibrillators over a 6-year period was evaluated prospectively. The overall incidence of confirmed CDI was 15 of 33 (45.4%). Confirmed CDI occurred in 9 of the 12 patients (75%) with early SAB (<1 year after device placement). Fifteen of 21 patients (71.5%) with late SAB (>/=1 year after device placement) had either confirmed (6 of 21, 28.5%) or possible (9 of 21, 43%) CDI. In 60% of the patients (9 of 15) with confirmed CDI, no local signs or symptoms suggesting generator pocket infection were noted. CONCLUSIONS: The incidence of CDI among patients with SAB and cardiac devices is high. Neither physical examination nor echocardiography can exclude the possibility of CDI. In patients with early SAB, the device is usually involved, and approximately 40% of these patients have obvious clinical signs of cardiac device involvement. Conversely, in patients with late SAB, the cardiac device is rarely the initial source of bacteremia, and there is a paucity of local signs of device involvement. The cardiac device is involved, however, in >/=28% of these patients.

The risk of stroke and death in patients with aortic and mitral valve endocarditis.

BACKGROUND: Previous studies have generated inconsistent results when attempting to define predictors of stroke and death in patients with endocarditis. We sought to examine the relationship between vegetation 2-dimensional size and stroke in those with infective endocarditis (IE) and to identify differences between aortic valve (AV) and mitral valve (MV) IE with regard to clinical characteristics, echocardiographic findings, stroke, and death. METHODS: We used the Duke Endocarditis Database to examine 145 episodes of definite IE involving the AV, n = 62, or MV, n = 83. A logistic regression model was developed to analyze important variables in predicting stroke, and a Cox proportional hazards model was used in predicting mortality. RESULTS: The mitral valve was infected in 57% of the cases. Vegetations were more commonly detected in patients with MV IE (92.8% vs 66.1%, P =.001) and these MV vegetations were significantly larger (P <.05). Thirty-four of 145 episodes (23.4%) were complicated by stroke. MV IE was associated with a greater stroke rate, 32.5% versus 11.3% (P =.003). Strokes tended to occur early in the course of illness, particularly in MV IE. In the multivariable model, the independent predictors of stroke were MV IE (P =.04) and vegetation length (P =.03). Independent predictors of 1-year mortality were age (P =.02) and vegetation area (P =.048). CONCLUSION: Stroke is more common in patients with MV IE. Vegetation 2-dimensional size and characteristics are important predictors of stroke and mortality. These findings may lead to predictive models that allow physicians to identify high-risk patients who need aggressive treatment strategies to prevent long-term morbidity and mortality.

Resident utilization of information technology.

OBJECTIVE: To determine if a simple educational intervention can increase resident physician literature search activity. DESIGN: Randomized controlled trial. SETTING: University hospital-based internal medicine training program. PATIENTS/PARTICIPANTS: Forty-eight medical residents rotating on the general internal medicine service. INTERVENTIONS: One-hour didactic session, the use of well-built clinical question cards, and practical sessions in clinical question building. MEASUREMENTS AND MAIN RESULTS: Objective data from the library information system that included the number of log-ons to medline, searching volume, abstracts viewed, full-text articles viewed, and time spent searching. Median search activity as measured per person per week (control vs intervention): number of log-ons to medline (2.1 vs 4.4, P <.001); total number of search sets (24.0 vs 74.2, P <.001); abstracts viewed (5.8 vs 17.7, P=.001); articles viewed (1.0 vs 2.6, P=.005); and hours spent searching (0.8 vs 2.4, P <.001). CONCLUSIONS: A simple educational intervention can markedly increase resident searching activity.

MARCKS phosphorylation by individual protein kinase C isozymes in insect Sf9 cells.

Relatively little is known about the substrate specificity of individual protein kinase C (PKC) isozymes, particularly with respect to physiologically relevant substrates. One class of prominent cellular substrates for PKC is represented by the myristoylated alanine-rich C kinase substrate, or MARCKS, protein. In the present study, we have used a baculovirus expression system to coexpress human MARCKS with eight different isozymes of PKC, to determine which isozymes are capable of phosphorylating MARCKS in intact cells. In Sf9 cells, coexpression of MARCKS with individual PKC isozymes led to the following increases in MARCKS phosphorylation: alpha, 3.6-fold; beta iota, 4.6-fold; beta mu, 2.7-fold; gamma, 4.8-fold; delta, 3.0-fold; epsilon, 4.3-fold; and eta, 4.9-fold. In most cases, stimulation of cells with a phorbol ester led to a slight increase (20-30%) in MARCKS phosphorylation. PKC zeta did not phosphorylate MARCKS to any appreciable extent above control. In addition, in vitro kinetic analysis of PKC zeta showed that it has a 1000-fold lower affinity for a synthetic peptide comprising the MARCKS phosphorylation site domain compared to mixed conventional PKC isozymes from rat brain. These data indicate that MARCKS is a substrate in intact cells for at least seven isozymes of PKC: alpha; beta iota; beta mu; gamma; delta; epsilon; and eta. The isozyme PKC zeta does not appear to phosphorylate MARCKS in vivo or with significant affinity in vitro. Thus, PKC zeta, which is not activated by phorbol esters or diacylglycerol, also appears to behave differently with respect to this class of important cellular PKC substrates.

The 5' ends of LINE1 repeats in rabbit DNA define subfamilies and reveal a short sequence conserved between rabbits and humans.

The 5' ends of five full-length LINE1 (L1) repeats from the rabbit genome (L1Oc) were mapped and their nucleotide sequences determined. Computer-generated alignments showed that these five L1Oc repeats can be divided into subfamilies, each of which has a characteristic sequence upstream of the first open reading frame (ORF1). These five L1Ocs range in size from 6.5 to 7.3 kb, with 5' ends located 76 to 1125 bp upstream of ORF1. Two of these subfamilies appear to have diverged from a common ancestor at least 66 million years ago. Comparisons of the 5' ends of L1s from rabbit, human, mouse, and rat show no common sequence 5' to ORF1, except for a 22-bp sequence that is found near the beginning of all characterized full-length L1s from rabbit and human. A statistical analysis indicates that this 22-bp aligned block is highly significant. Part of this 22-bp sequence matches the microE1 binding site in immunoglobulin gene enhancers. This strong conservation suggests that the microE1 binding site may be part of a transcriptional regulatory element at the 5' ends of rabbit and human L1 repeats.