Epidemiology of infective endocarditis in a large Belgian non-referral hospital K. Poesen1,2, H. Pottel3, J. Colaert1, C. De Niel4 1
Clinical Laboratory Department, AZ Groeninge Hospital, Kortrijk, Belgium, 2Department of Neurosciences, KU Leuven, Belgium, 3Interdisciplinary Research Center, Kulak, Kortrijk, Belgium, 4Cardiology Department, AZ Groeninge Hospital, Kortrijk, Belgium Objectives: Guidelines for diagnosis of infective endocarditis are largely based upon epidemiological studies in referral hospitals. Referral bias, however, might impair the validity of guidelines in non-referral hospitals. Recent studies in non-referral care centres on infective endocarditis are sparse. We conducted a retrospective epidemiological study on infective endocarditis in a large non-referral hospital in a Belgian city (Kortrijk). Methods: The medical record system was searched for all cases tagged with a putative diagnosis of infective endocarditis in the period 2003–2010. The cases that fulfilled the modified Duke criteria for probable or definite infective endocarditis were included. Results: Compared to referral centres, an older population with infective endocarditis, and fewer predisposing cardiac factors and catheter-related infective endocarditis is seen in our population. Our patients have fewer prosthetic valve endocarditis as well as fewer staphylococcal endocarditis. Our patients undergo less surgery, although mortality rate seems to be highly comparable with referral centres, with nosocomial infective endocarditis as an independent predictor of mortality. Conclusion: The present study suggests that characteristics of infective endocarditis as well as associative factors might differ among non-referral hospitals and referral hospitals.
Keywords: Infective endocarditis, Epidemiology, Referral bias, Community hospital
Introduction Infective endocarditis (IE) is an emerging disease with increasing incidence in the elderly and a 6-month mortality ranging from 14 to 33%.1,2 Risk factors as well as typical clinical signs and microbiological clues have been identified by several retrospective and prospective studies.3–16 Guidelines developed to enable clinicians to effectively diagnose IE17,18 are largely based upon epidemiological studies conducted in, or at least including (as referred to by Sy et al.)1 tertiary and university hospitals.3–8 As tertiary and university hospitals are often referral centres for complicated cases of IE or for heart valve surgery, it cannot be excluded that in their patients, the spectrum of IE differs significantly from the population in a non-referral community hospital.1,19 Findings from longitudinal population studies on IE are less prone to referral bias,1,13,15,16,19 but they also do not necessarily reflect the IE population in non-referral hospitals. Epidemiology of IE has changed over the past years.4,20 As recent studies in Correspondence to: K. Poesen, AZ Groeninge Hospital, Clinical Laboratory Department, Loofstraat 43, B-8500 Kortrijk, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551214Z.00000000046
non-referral care centres on the epidemiology of IE are sparse,21 we conducted a retrospective epidemiological study on IE in a large non-referral community hospital (AZ Groeninge) in a Belgian city Kortrijk.
Patients and Methods This single-centre study was conducted retrospectively in 2011 in a large non-referral community hospital (AZ Groeninge) in the Belgian city Kortrijk (agglomeration of about 125 000 citizens). The AZ Groeninge Hospital is the result of a fusion of four hospitals in Kortrijk. Our hospital uses a medical record system (the Minimal Clinical Data Set) in which information is collected by health-care clinicians in a single record for each patient. As the cardiology department of the former hospitals fused in 2003, medical records are easily retrievable from 2003 on. Using this system, all notifications of IE were identified until mid-2010. Cases that were diagnosed upon autopsy as well as new IE episodes that occurred during the study period in patients with a previous history of endocarditis were included as well.4 One of the investigators (KP) reviewed all cases and classified them according to the modified Duke criteria (for a
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summarizing table with the modified Duke criteria, see Table 1). The medical records of all classified cases were then reviewed to confirm the diagnosis of IE. Therefore, a standardized data form was used to collect the following information: sex, date of birth, history of heart disease, procedures and factors at risk for IE, comorbidities, clinical signs and symptoms, laboratory and microbiological examinations (number of positive blood cultures, result of valve culture and serological tests), echocardiographic data, medical and surgical treatment, and outcome data. Location of IE was determined according to echocardiographic and/or surgical findings. Origin of IE (nosocomial versus community) and the time interval during which was searched for procedures before IE were defined as previously described.20 Nearly all patients were followed up daily during the treatment of IE in the hospital by cardiology specialists, with additional consultation when indicated. Any uncertainties in data abstraction were discussed with an experienced cardiologist (CD) and microbiologist (JC), as well as with the physician responsible for the patient to confirm the diagnosis of IE. Only definite and possible IE cases as defined by the modified Duke criteria were used in the analysis.
Statistical analysis Normal distribution was evaluated using Kolmogorov–Smirnov. Depending on the outcome of normality testing, data are presented as mean [and standard deviation (SD)] or median [and interquartile range (IQR)], and continuous variables are compared with parametric (t-test/ANOVA) or non-parametric
(Mann–Whitney U/Kruskal–Wallis) statistics, respectively. Categorical variables were evaluated using Fisher’s exact or Chi-square test. The statistics were performed with Microsoft Excel 2010 [version 14.0.6112.5000 (32-bits)] with the use of the Analyseit (version 2.26 Excel10z) add-on. Logistic regression analysis of factors predicting fatal outcome was performed using Statpages [calculating the odds ratio (OR) with 95% confidence intervals (95% CI)]. The use of the appropriate statistical tests was verified by an expert statistician (HP).
Results Study population A total of 135 notifications were retrieved from the medical record system between 2003 and mid-2010. The number of hospitalizations during this period was 249 156, indicating that there were about five notifications per 10 000 hospitalizations. One hundred and twenty-seven episodes had a putative diagnosis of infective endocarditis (IE). Among these, 39 failed to fulfill the modified Duke criteria. A total of 83 patients suffered from 88 IE episodes during the study period. Characteristics of our population are summarized in Table 2. Sixty-six episodes (75.0%) were classified as definite IE. Four patients experienced more than one episode during the study period; the median interval between the episodes was 4 months (IQR: 3–49). In none but one of the patients the recurrent IE was caused by the same microorganism [episode 1: E. faecalis, episode 2: S. mitis and E. faecalis (double positive)].
Table 1 Summarizing table with the modified Duke criteria (according to Li et al.35) Major criteria Blood culture positive for IE Typical microorganisms consistent with IE from two separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci, in the absence of a primary focus; or Microorganisms consistent with IE from persistently positive blood cultures, defined as follows: At least two positive cultures of blood samples drawn . 12 h apart; or All of three or a majority of > four separate cultures of blood (with first and last sample drawn at least 1 hour apart) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer .1 : 800 Evidence of endocardial involvement Echocardiogram positive for IE [TEE recommended in patients with prosthetic valves, rated at least ‘possible IE’ by clinical criteria, or complicated IE (paravalvular abscess); TTE as first test in other patients)], defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or Abscess; or New partial dehiscence of prosthetic valve New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria Predisposition, predisposing heart condition or injection drug use Fever, temperature .38uC Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE Echocardiographic minor criteria eliminated
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Table 2 Demographic and clinical characteristics infective endocarditis episodes (n588) in 83 patients Characteristics
of
Infective endocarditis in a non-referral centre
Four episodes (4.5%) were hemodialyzed. Eighteen episodes (20.5%) suffered from diabetes mellitus.
No. (%)
Characteristics of IE Demographics Age, median (IQR), years Number of patients Male patients Of whom .1 episode Male episodes Female patients Of whom .1 episode Clinical Modified Duke classification Definite Possible Valves involved Aortic Mitral Aortic and mitral Right-sided or bilateral Unknown* Prosthetic IE
72 83 55 3 59 28 1
(59–81) (66.3) (67.0) (33.7)
66 (75.0) 22 (25.0) 32 37 10 5 4 7
(36.4) (42.0) (11.4) (5.7) (4.5) (8.0)
Note: *In one episode no echocardiography was performed.
Preexisting valvular disease and non-cardiac risk factors Table 3 summarizes the distribution of preexisting valvular disease. Acquired valvular disease was the most frequent preexisting valvular disease in our population. A total of 13 episodes (14.8%) had experienced a medical or surgical procedure within 6 months before IE (dental procedures: 2, musculoskeletal or dermatological procedures: 10, broncho- or gastroscopy: 1). Two episodes (2.3%) were reported as intravascular catheter-related. One case was known as an intravenous drug user. With respect to non-cardiac risk factors, we concluded from the medical files that four episodes (4.5%) were immune-suppressed (immunosuppressive drugs), nine episodes (10.2%) suffered from cancer at time of diagnosis of IE (haematological: 4; gastrointestinal: 2, breast: 2, non-specified metastases: 1). Table 3 Distribution of preexisting episodes with infective endocarditis*
valve
disease
in
No. (%) Acquired (native) valve insufficiency Left heart Right heart Both sides Prosthetic valves Mechanical Biological Congenital heart disease Unspecified heart murmur Rheumatic heart disease Mitral valve prolapse History of IE Episodes without any (or unknown) preexisting valve diseases
19 17 0 2 16 4 12 5 1 2 1 8 50
(21.6) (19.3) (0.0) (2.3) (18.2) (4.6) (13.6) (5.7) (1.1) (2.3) (1.1) (9.1) (56.8)
Note: *One or more underlying heart diseases might be present for one and the same episode.4
For 20 cases, IE was solely detected by transthoracic echocardiography (TTE) [no transesophageal echocardiography (TOE) performed (n518) or TOE not suggestive for IE (n52)]. Twenty cases detected by TTE were confirmed by TOE. Forty-three cases were solely diagnosed by TOE [no evidence of TTE performed (n515) or TTE not suggestive for IE (n528)]. For three cases, no evidence for the presence of clear vegetation was reported upon echocardiography (all considered as culture positive endocarditis). For one case, evidence for the presence of vegetation was found upon autopsy. For one case, echocardiography was not performed on request of the family. Distribution of the IE location is summarized in Table 2. A major echocardiographic criterion was present in 84 episodes (95.5%), including 76 episodes with vegetation (86.3%), 4 with abscess (4.5%), 3 episodes with vegetation and abscess (3.4%), and 1 episode of prosthetic dehiscence. Fever (.38uC) was present in 73 episodes (83.0%). Immunological manifestations were observed in five cases (5.7%): glomerulonephritis was highly suspected in three cases based on functional and biochemical parameters (no kidney biopsies were taken and circulating immune complexes were determined in none of the cases); rheumatoid factor, 1 (rheumatoid arthritis was excluded and rheumatoid factor was negativized in 2008 after the episode of IE); and staphylococcal toxic shock syndrome, 1.
Causative microorganisms Sixty episodes (68.2%) met the modified Duke criteria for having a major criterion for positive blood cultures. Nineteen episodes (21.6%) met solely the modified Duke criteria for having a minor criterion of positive blood cultures. The distribution of causative organisms is displayed in Table 4. Oral streptococci (n520), Streptococcus gallolyticus (n513), and Staphylococcus aureus (n515) accounted for the three main causative organisms (Table 4). Blood cultures remained negative in nine episodes (10.2%): in the latter, infective serology was not performed (n57) or remained negative during hospitalization. For three cases, we could not find any evidence of previous antibiotic therapy. For six cases, however, a history of a recent previous antibiotic treatment was retrieved from the patient file. For 11 episodes who were referred to tertiary centres for cardiac surgery, culture (n59) or 16S ribosomal RNA gene amplification (n52) of the surgically removed heart valve was retrievable, confirming the findings of blood cultures for four
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Table 4 Distribution of causative microorganisms blood of cases with infective endocarditis Microorganism
in
No. (%)
Streptococcaceae Oral streptoccoci Viridans streptococci S. pneumoniae S. gallolyticus Pyogenic streptococci Granulicatella adjacens Gemella morbillorum Staphylococci Staphylococcus aureus Coagulase-negative Enterococci E. faecalis E. faecium Listeria monocytogenes HACEK Gram-negative rods* Propionibacterium species Candida glabrata Two microorganisms Negative blood cultures
20 (22.7) 17 3 13 (14.8) 4 (4.6) 1 (1.1) 1 (1.1) 15 (17.1) 4 (4.6) 9 (10.2) 8 1 1 (1.1) 1 (1.1) 4 (4.6) 2 (2.3) 1 (1.1) 3 (3.4) 9 (10.2)
Note: *Including one Pseudomonas aeruginosa, one Enterobacter aerogenes, one Escherichia coli, and one Klebsiella oxytoca.
cases [two with culture of the valve (one with major and one with minor criterion for positive blood cultures), two with 16S rRNA amplification (both with major criterion for positive blood cultures)]. Culture of the valve remained negative in six episodes, of which in five cases the diagnostic blood cultures were positive (three with major and two with minor criterion for positive blood cultures). For one episode, blood cultures yielded E. faecalis (major criterion), whereas culture of the valve yielded a coagulase negative staphylococcus, the latter most likely being a contaminant. Table 5 shows a comparison of patient characteristics across the three main groups of microorganisms. Oral streptococci and S. gallolyticus were predominant in the male IE population, whereas more women developed a S. aureus IE (ratio: 1.5 : 1) (Table 5). However, no other significant difference could be retrieved among the groups of the three main causative organisms.
In the group of cases with IE and a history of procedures at risk, no correlation was found between the procedure and the causative microorganism (P50.90). In 27 episodes (30.7%), the portal of entry was retrieved: dental, 7; gastro-intestinal, 8; cutaneous, 7; pneumonic, 2; bone-related, 2; and, presumably cerebral, 1 (S. pyogenes meningitis). Cutaneous portals of entry included four traumatic or chronic wounds, one intravenous drugs use and two port-acaths. In 4 out of 13 patients with S. gallolyticus IE colon polyps were reported to be present at time of diagnosis of IE.
Complications From time point of diagnosis till up to 6-months after discharge, at least one complication, likely related to IE, was reported in 50 cases (56.8%). Congestive heart failure or valve insufficiency were the most prominent complications (45 episodes or 51.1%). Six episodes were reported with an infection due to haematogenous dissemination during proper antibiotic treatment (joint, spine (n54), spleen); in five cases, a persistent IE was reported (defined as persistent IE after termination of proper antibiotic treatment after a complete course). There was no correlation between these infections and the valve involved, the causative organism, or mortality rate. Emboligenic phenomena or intracranial bleedings developed in 10 patients (11.4%). The distribution between central and peripheral emboli was 4/5.
Treatment and outcome Eighty-four patients (95.5%) were reported to receive an IE specific antibiotic treatment. Two cases who did not receive antibiotic treatment were treated palliatively. For one case, no detailed antibiotic treatment was reported. One case was diagnosed post-mortem, before initiating of any specific antibiotic treatment. Fifty-nine cases of IE were caused by microorganisms that were susceptible to and treated with the antibiotic of primary choice according the ‘Sanford guide to antimicrobial therapy’. Twenty-five cases
Table 5 Comparison of main characteristics of infective endocarditis across the three main groups of causative microorganisms No. (%)
186
Characteristics
Oral streptococci (n520)
S. gallolyticus (n513)
S. aureus (n515)
Age, median, IQR, years Women Men History of IE Preexisting prosthetic valve Nosocomial Valve surgery Mortality
74 (58–81) 5 (25.0) 15 (75.0) 3 (15.0) 5 (25.0) 6 (30.0) 7 (35.0) 1 (5.0)
73 (57–81) 0 (0.0) 13 (100) 1 (7.7) 2 (15.4) 2 (15.4) 5 (38.5) 1 (7.7)
72 (62–82) 9 (60.0) 6 (40.0) 1 (6.7) 3 (20.0) 6 (40.0) 5 (33.3) 3 (20.0)
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P value
0.0020 0.68 0.80 0.36 0.96 0.33
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were treated according to an alternative antibiotic scheme due to (1) antibiotic side effects (penicillin allergy/drug fever) (n55); (2) progression of IE under antibiotic treatment of primary choice (n52); (3) (intermediate) resistance to antibiotic of primary choice (n57); (4) a concomitant pneumonia or a lower urinary tract infection (amoxicillinzclavulanic acid or piperacillin-tazobactam and amikacin, respectively), both having a culture negative endocarditis with vegetation confirmed with TOE (n52); (5) reasons other than mentioned above but retrospectively not ambiguously retrievable [susceptible strains but treated with the alternative antibiotic according to the ‘Sanford guide to antimicrobial therapy’ (n57) — culture negative IE and treated for IE according to an alternative scheme (n52)]. Referral to a tertiary hospital, of which the majority were university centres, was indicated for 33 episodes (37.5%) because of: cardiac valve surgery (n529) (for three referred cases, valve surgery was indicated but impeded by a worsening condition/ deceased before surgery); second opinion (MRI of the heart) (n51); procedures in pediatric patients (surgical implantation of peripherally inserted central catheter, surgical correction of a congenital heart defect; or complication by glomerulonephritis) (n53). The proportion of a history of congenital heart failure, emboligenic phenomena, and suspected glomerulonephritis was higher in the referred patient group than in the non-referred group [15.2% versus 0.0% (P50.012); 21.2% versus 3.6% (P50.025), and 9.1% versus 0.0% (P50.099), respectively]. The
Infective endocarditis in a non-referral centre
median interval between diagnosis of IE and referral for cardiac valve surgery (n529) was 10 days (IQR: 2–20). Of the episodes referred, three cases (9.1%) died, which did not significantly differ from nonreferred episodes. Twenty-six cases actually underwent valve surgery. Surgery rate did not differ among sex, origin of IE, heart valve involved or preexisting valvular disease (Table 6). Fifteen of all episodes died of IE (17.0% in-hospital mortality). Importantly, there was a significant difference in mortality rate between nosocomial IE and community-acquired IE (Table 6). No difference in mortality rate was detected in the other aforementioned subsets (Table 6). Nosocomial IE (OR: 5.68, 95% CI: 1.72–18.76) and heart failure/valve insufficiency as complication (OR: 4.85, 95% CI: 1.26–18.64) were found to be a significant independent predictor for mortality in the present study.
Discussion Epidemiology of IE has changed over the past 10– 20 years.4 Therefore, to assess epidemiological differences among different care centres, we compare our data with studies that collected data from a same period (2003–2012).1,19–29 Any comparison is further hampered by the significant difference in study population characteristics. For instance, epidemiological studies in large hospitals in metropoles such as Istanbul, Athens, Rome, and Paris are enriched with native valve IE in intravenous drug users.23,24,29,30 Nevertheless, comparison of studies is useful to detect trends. For instance, median age of patients
Table 6 Surgery and mortality as a function of different variables Valve surgery
Mortality
Variable
Total no. (%)
No. (%)
P value
No. (%)
P value
All Gender episodes Women Men Origin Nosocomial Community Location Only mitral valve Only aortic valve Aortic and mitral Right-sided or bilateral Unknown Preexisting valve disease Native valve disease Prosthetic valve History of IE Miscellaneous* No known heart disease Valve surgery Yes No
88 (100)
26 (29.5)
…
15 (17.0)
…
29 (33.0) 59 (67.0)
9 17
0.99
6 9
0.52
29 (33.0) 59 (67.0)
5 21
0.12
10 5
0.0023
37 (42.0) 32 (36.4) 10 (11.4) 5 (5.7) 4 (4.5)
10 10 4 2 0
0.68
5 6 3 0 1
0.58
14 (15.9) 6 (6.8) 3 (3.4) 15 (17.1) 50 (56.8)
3 1 2 5 15
0.59
6 0 0 1 8
0.085
26 (29.5) 62 (70.5)
… …
…
2 13
0.22
Note: *miscellaneous5congenital heart disease, .1 valve disease, rheumatic heart disease, mitral valve prolapse, unspecified heart murmur.
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with IE is increasing,1,19 as demonstrated in the present study compared to less recent studies.30,31 In contrast, recent prospective studies in referral centres as well as the Euro heart survey reported lower ages of onset ranging from 45 to 64 years.20,23,24,27 Risk to benefit ratio of valvular surgery might be considered more favorable for younger patients, possibly explaining the younger population in referral centres. As age is reported to be related to higher rates of abscess formation and lower rates of the presence of immune-mediated phenomena or embolic complications,1,28 revision of the current guidelines might be warranted to adjust the diagnostic criteria to the presentation of IE in an older population.1 Our study confirms indeed that immunological phenomena are less present than reported in previous studies on IE.3,30 Noteworthy, however, most studies do not report the percentages of e.g. immunological phenomena. Male-to-female ratio of about 2 : 1 is similar to other studies, with the exception of a recent population based study reporting a 1 : 1 ratio, explained by a higher prevalence of women in the older population with IE.19 We were not able to confirm this explanation, as in the present study, an older median age is observed as well, without, however, a disturbed male-to-female ratio. Whereas preexisting valvular disease is present in the vast majority of patients with IE,4,27 some recent studies report that the majority of patients (especially with native IE) have no preexisting valvular disease,4,27,32 as is the case in the present study. Major risks factors for IE shifted from rheumatic heart disease to native valvular disease.19,25,32 Compared to one of our nearest Belgian referral centres, cardiac risk factors such as native valve disease seem to be less frequent in our population.20 The percentage of nosocomial IE in the present study is similar to recent findings of referral and nonreferral centres20,30 and findings of population based studies.1 In 30% of the episodes, the presumable portal of entry is reported in patient’s medical records, which is comparable with a large multicentre prospective study in French university hospitals.3 Unfortunately, most recent studies do not report any presumable portal of entry. As the incidence of IE has not decreased over the past 30 years,4 identifying the portal of entry might yield valuable information with regard to actions that can be taken to prevent IE, especially for nosocomial IE as it is an independent risk factor for mortality (see below for further discussion). The distribution of the location of vegetation/ abscess in the present study is similar to the findings in other studies.1,19,20,25 Prosthetic valve IE is rather uncommon in our population, whereas prosthetic
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valve IE accounted for more than 15 or 30% of the episodes in large referral hospitals and populationbased studies.1,20,23,27,28 Normalized, 6 out of 894 (or 0.67%) of patients registered with prosthetic heart valve during the study period (period of 7.5 years) developed a prosthetic valve IE. In a large referral hospital,20 70 out of 2466 (or 2.84%) patients registered with a prosthetic heart valve developed a prosthetic valve IE (study period of 4.5 years) (personal communication). Recent studies reported that staphylococci surpassed streptococci as major cause of IE.1,19,20,22,25–28,33 In contrast, as in less recent studies,3,4 streptococci are the most prevalent species in our population. Main factors reported to be related with staphylococcal IE are health care-associated,28 such as chronic haemodialysis and intravascular devices.32,34 In referral centres, staphylococcal IE is associated with a higher mortality rate,3,20 unlike in non-referral centres as ours. Indeed, staphylococcal IE can be very fulminant, associated with a worse outcome.20,30 Therefore, referral centres might be artificially enriched with these fulminant episodes of staphylococcal IE. Intriguingly, the proportion of staphylococcal IE is reported to be significantly lower for men than it is for women,3 as confirmed by our study. Moreover, intravenous drug users have a significantly higher proportion of staphylococcal IE.3,26 Therefore differences in population characteristics might explain in part the discrepancy in major causative organisms of IE among care centres. The observation that nosocomial S. aureus infection is present in 45% of staphylococcal IE have led to the modification of the Duke criteria, where, besides community-acquired, nosocomial S. aureus bacteremia became one of the major criteria for IE as well.35 Our present study observes a similar percentage of nosocomial S. aureusrelated IE, which might confirm the justification of the modification of the Duke criteria. The same suggestion has recently been made by Hill et al. for nosocomial enterococcal bacteremia as it is observed to be an emerging cause of IE (nearly equally distributed between community and nosocomial origin of enterococcal IE, accounting for about 5% of all cases).20 Nevertheless, in our population, only two out of nine enterococcal IE is classified as nosocomial (about 2% of all cases of IE), and no putative episodes were rejected based on the fact that nosocomial enterococcal bacteremia was solely a minor criterion. Therefore, more evidence might be required to reclassify nosocomial enterococcal bacteremia as a major criterion in the modified Duke criteria. The decrease of viridans streptococcal IE has been attributed to the decrease of pre-existing rheumatoid heart disease.19 Our study proves that the latter is not
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entirely covering the cause of a putative decrease of viridans streptococcal IE, as in our population rheumatoid heart disease is rare, while viridans streptococcal IE remains the major causative organism of IE. The number of negative blood cultures (or unknown pathogen) is somewhat higher than reported in one population-based study (about 5%),19 but comparable with other recent referral centre or population-based studies (about 10% or higher).1,20,24 In a very recent multicentre study, the etiology remained unexplained in 33.6% of the episodes, likely due to previous antibiotic therapy.25 Remarkably, in 3.4% of the episodes, more than one microorganism was cultured from blood, a phenomenon seen as well in some referral centres.3 At least one complication was observed in about two out of three patients, which is rather high when compared to other non-referral centres or population based studies,1,19 but similar to referral centres.20 In the latter, the higher number was explained by referral of severely ill patients, whereas other confounding factors such as a relative older population might explain at least in part the observation in our study. Fewer patients hospitalized in our centre undergo valvular surgery than in the majority of the (non)referral centres (49–64%).20,27,30,33 Surgery rates in referral centres differ among e.g. sex, localization of the vegetation, and microorganism causing IE,3 unlike in the present study. In-hospital mortality rate in our study population is highly comparable with recent referral centre-based and population-based studies and with the Euro heart survey (about 15%),3,27,28 but lower than a recent referral centre study (21.7%)20,33 or a prospective multicentre study (27.5%).25 Nosocomial infection and heart failure/valve insufficiency are identified as independent predictors of mortality in our population, as reported before in populationbased studies1,28 and in one non-referral community hospital study30 but not in referral centres.20 No other predictors of mortality, such as age, gender, diabetes mellitus, staphylococcal IE, history of IE, or embolic events, are detected in our population, unlike in other studies.20,30 In conclusion, compared to referral centres, an older population with IE, characterized with fewer predisposing cardiac factors and catheter-related IE is seen in patients hospitalized in a large Belgian nonreferral community hospital. Our patients have fewer prosthetic valve IE as well as fewer staphylococcal IE. Our patients undergo less surgery, whereas severe complications as well as the mortality rate seem to be highly comparable with referral centres, with nosocomial IE as an independent predictor of mortality. The present study might suggest that characteristics
Infective endocarditis in a non-referral centre
of IE as well as associative factors in a community hospital differ from referral hospitals. Limitations of our study are for instance that the diagnosis of e.g. preexisting valvular disease or the presence of minor criteria such as Janeway lesions were made based upon the records in the medical files. It cannot be ruled out that the reported percentages in the present study are underestimated since non-apparent minor clinical signs of IE can be missed or were not described in the patient’s file. Moreover, the medical registry system did not allow us to retrospectively retrieve episodes with pacemaker IE. As the number of IE was rather limited in our retrospective study, follow-up via prospective studies in our community hospital, as well as via multicentre studies comparing features of IE in community and referral care centres, is required to further elucidate the effect of referral bias observed in the present study.
Acknowledgements The authors wish to thank P. Garre´ (AZ Groeninge, Kortrijk), Dr H. De Beenhouwer (OLV Hospital Aalst), Dr S. Steyaert (Maria Middelares Hospital Ghent), Professor Dr J. Verhaegen, Dr Meurisse and Professor Dr P. Herijgers (UZ Leuven, University of Leuven), and Prof. Dr D. Vogelaers (UZ Ghent, University of Ghent) for providing us with valuable information. The authors declare to have no conflicts of interest.
References 1 Sy RW, Kritharides L. Health care exposure and age in infective endocarditis: results of a contemporary populationbased profile of 1536 patients in Australia. Eur Heart J. 2010;31:1890–7. 2 Tleyjeh IM, Abdel-Latif A, Rahbi H, Scott CG, Bailey KR, Steckelberg JM, et al. A systematic review of population-based studies of infective endocarditis. Chest. 2007;132:1025–35. 3 Hoen B, Alla F, Selton-Suty C, Be´guinot I, Bouvet A, Brianc¸on S, et al. Changing profile of infective endocarditis: results of a 1-year survey in France. JAMA. 2002;288:75–81. 4 Tleyjeh IM, Steckelberg JM, Murad HS, Anavekar NS, Ghomrawi HM, Mirzoyev Z, et al. Temporal trends in infective endocarditis: a population-based study in Olmsted County, Minnesota. JAMA. 2005;293:3022–8. 5 Nissen H, Nielsen PF, Frederiksen M, Helleberg C, Nielsen JS. Native valve infective endocarditis in the general population: a 10-year survey of the clinical picture during the 1980s. Eur Heart J. 1992;13:872–7. 6 Delahaye F, Goulet V, Lacassin F, Ecochard R, Selton-Suty C, Hoen B, et al. Characteristics of infective endocarditis in France in 1991. A 1-year survey. Eur Heart J. 1995;16:394–401. 7 van der Meer JT, Thompson J, Valkenburg HA, Michel MF. Epidemiology of bacterial endocarditis in The Netherlands. I. Patient characteristics. Arch Intern Med. 1992;152:1863–8. 8 Dyson C, Barnes RA, Harrison GA. Infective endocarditis: an epidemiological review of 128 episodes. J Infect. 1999;38:87–93. 9 Moreillon P, Que YA. Infective endocarditis. Lancet. 2004;363:139–49. 10 Hogevik H, Olaison L, Andersson R, Lindberg J, Alestig K. Epidemiologic aspects of infective endocarditis in an urban population. A 5-year prospective study. Medicine (Baltimore). 1995;74:324–39. 11 Skehan JD, Murray M, Mills PG. Infective endocarditis: incidence and mortality in the North East Thames Region. Br Heart J. 1988;59:62–8.
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12 Borer A, Riesenberg K, Uriel N, Gilad J, Porath A, Weber G, et al. Infective endocarditis in a tertiary-care hospital in southern Israel. Public Health Rev. 1998;26:317–30. 13 Benn M, Hagelskjaer LH, Tvede M. Infective endocarditis, 1984 through 1993: a clinical and microbiological survey. J Intern Med. 1997;242:15–22. 14 Allen KD, Vardhan MS. Epidemiology of infective endocarditis. J Infect. 2000;40:99–100. 15 Foghsgaard J, Pedersen SA, Launbjerg J. Incidence and diagnosis of infectious endocarditis in Frederiksborg county, 1990–2000. Ugeskr Laeger. 2004;166:2446–50. 16 Berlin JA, Abrutyn E, Strom BL, Kinman JL, Levison ME, Korzeniowski OM, et al. Incidence of infective endocarditis in the Delaware Valley, 1988–1990. Am J Cardiol. 1995;76:933–6. 17 Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J. 2009;30:2369–413. 18 Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baro´nEsquivias G, Baumgartner H, et al. Guidelines on the management of valvular heart disease (version 2012): the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg. 2012;42:S1–44. 19 Correa de Sa DD, Tleyjeh IM, Anavekar NS, Schultz JC, Thomas JM, Lahr BD, et al. Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2010;85:422–6. 20 Hill EE, Herijgers P, Herregods MC, Peetermans WE. Evolving trends in infective endocarditis. Clin Microbiol Infect. 2006;12:5–12. 21 Madsen RG, Ladefoged K, Kjaergaard JJ, Andersen PS, Clemmesen C. Endocarditis in Greenland with special reference to endocarditis caused by Streptococcus pneumoniae. Int J Circumpolar Health. 2009;68:347–53. 22 Selton-Suty C, Ce´lard M, Le Moing V, Doco-Lecompte T, Chirouze C, Iung B, et al. Preeminence of Staphylococcus aureus in infective endocarditis: a 1-year population-based survey. Clin Infect Dis. 2012;54:1230–9. 23 Leblebicioglu H, Yilmaz H, Tasova Y, Alp E, Saba R, Caylan R, et al. Characteristics and analysis of risk factors for
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mortality in infective endocarditis. Eur J Epidemiol. 2006;21:25–31. Giannitsioti E, Skiadas I, Antoniadou A, Tsiodras S, Kanavos K, Triantafyllidi H, et al. Nosocomial vs. community-acquired infective endocarditis in Greece: changing epidemiological profile and mortality risk. Clin Microbiol Infect. 2007;13: 763–9. Dzupova O, Machala L, Baloun R, Maly M, Benes J. Incidence, predisposing factors, and aetiology of infective endocarditis in the Czech Republic. Scand J Infect Dis. 2012;44:250–5. Jain V, Yang MH, Kovacicova-Lezcano G, Juhle LS, Bolger AF, Winston LG. Infective endocarditis in an urban medical center: association of individual drugs with valvular involvement. J Infect. 2008;57:132–8. Tornos P, Iung B, Permanyer-Miralda G, Baron G, Delahaye F, Gohlke-Ba¨rwolf Ch, et al. Infective endocarditis in Europe: lessons from the Euro heart survey. Heart. 2005;91:571–5. Leone S, Ravasio V, Durante-Mangoni E, Crapis M, Carosi G, Scotton PG, et al. Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian study on endocarditis. Infection. 2012;40:527–35. Cicalini S, Puro V, Angeletti C, Chinello P, Macrı` G, Petrosillo N. Profile of infective endocarditis in a referral hospital over the last 24 years. J Infect. 2006;52:140–6. Mouly S, Ruimy R, Launay O, Arnoult F, Brochet H, Trouillet JL, et al. The changing clinical aspects of infective endocarditis: descriptive review of 90 episodes in a French teaching hospital and risk factors for death. J Infect. 2002;45:246–56. Fefer P, Raveh D, Rudensky B, Schlesinger Y, Yinnon AM. Changing epidemiology of infective endocarditis: a retrospective survey of 108 cases, 1990–1999. Eur J Clin Microbiol Infect Dis. 2002;21:432–7. Tornos P, Gonzalez-Alujas T, Thuny F, Habib G. Infective endocarditis: the European viewpoint. Curr Probl Cardiol. 2011;36:175–222. Herregods MC, Hill E, Herijgers P, De Munter P, Vanderschueren S, Van Wijngaerden E, et al. Infective endocarditis. Acta Clin Belg. 2008;63:414–7. Thuny F, Grisoli D, Collart F, Habib G, Raoult D. Management of infective endocarditis: challenges and perspectives. Lancet. 2012;379:965–75. Li JS, Sexton DJ, Mick N, Nettles R, Fowler VG Jr, Ryan T, et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000;30:633–8.
Clinical Laboratory Department, AZ Groeninge Hospital, Kortrijk, Belgium, 2Department of Neurosciences, KU Leuven, Belgium, 3Interdisciplinary Research Center, Kulak, Kortrijk, Belgium, 4Cardiology Department, AZ Groeninge Hospital, Kortrijk, Belgium Objectives: Guidelines for diagnosis of infective endocarditis are largely based upon epidemiological studies in referral hospitals. Referral bias, however, might impair the validity of guidelines in non-referral hospitals. Recent studies in non-referral care centres on infective endocarditis are sparse. We conducted a retrospective epidemiological study on infective endocarditis in a large non-referral hospital in a Belgian city (Kortrijk). Methods: The medical record system was searched for all cases tagged with a putative diagnosis of infective endocarditis in the period 2003–2010. The cases that fulfilled the modified Duke criteria for probable or definite infective endocarditis were included. Results: Compared to referral centres, an older population with infective endocarditis, and fewer predisposing cardiac factors and catheter-related infective endocarditis is seen in our population. Our patients have fewer prosthetic valve endocarditis as well as fewer staphylococcal endocarditis. Our patients undergo less surgery, although mortality rate seems to be highly comparable with referral centres, with nosocomial infective endocarditis as an independent predictor of mortality. Conclusion: The present study suggests that characteristics of infective endocarditis as well as associative factors might differ among non-referral hospitals and referral hospitals.
Keywords: Infective endocarditis, Epidemiology, Referral bias, Community hospital
Introduction Infective endocarditis (IE) is an emerging disease with increasing incidence in the elderly and a 6-month mortality ranging from 14 to 33%.1,2 Risk factors as well as typical clinical signs and microbiological clues have been identified by several retrospective and prospective studies.3–16 Guidelines developed to enable clinicians to effectively diagnose IE17,18 are largely based upon epidemiological studies conducted in, or at least including (as referred to by Sy et al.)1 tertiary and university hospitals.3–8 As tertiary and university hospitals are often referral centres for complicated cases of IE or for heart valve surgery, it cannot be excluded that in their patients, the spectrum of IE differs significantly from the population in a non-referral community hospital.1,19 Findings from longitudinal population studies on IE are less prone to referral bias,1,13,15,16,19 but they also do not necessarily reflect the IE population in non-referral hospitals. Epidemiology of IE has changed over the past years.4,20 As recent studies in Correspondence to: K. Poesen, AZ Groeninge Hospital, Clinical Laboratory Department, Loofstraat 43, B-8500 Kortrijk, Belgium. Email: [email protected]
ß Acta Clinica Belgica 2014 DOI 10.1179/0001551214Z.00000000046
non-referral care centres on the epidemiology of IE are sparse,21 we conducted a retrospective epidemiological study on IE in a large non-referral community hospital (AZ Groeninge) in a Belgian city Kortrijk.
Patients and Methods This single-centre study was conducted retrospectively in 2011 in a large non-referral community hospital (AZ Groeninge) in the Belgian city Kortrijk (agglomeration of about 125 000 citizens). The AZ Groeninge Hospital is the result of a fusion of four hospitals in Kortrijk. Our hospital uses a medical record system (the Minimal Clinical Data Set) in which information is collected by health-care clinicians in a single record for each patient. As the cardiology department of the former hospitals fused in 2003, medical records are easily retrievable from 2003 on. Using this system, all notifications of IE were identified until mid-2010. Cases that were diagnosed upon autopsy as well as new IE episodes that occurred during the study period in patients with a previous history of endocarditis were included as well.4 One of the investigators (KP) reviewed all cases and classified them according to the modified Duke criteria (for a
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summarizing table with the modified Duke criteria, see Table 1). The medical records of all classified cases were then reviewed to confirm the diagnosis of IE. Therefore, a standardized data form was used to collect the following information: sex, date of birth, history of heart disease, procedures and factors at risk for IE, comorbidities, clinical signs and symptoms, laboratory and microbiological examinations (number of positive blood cultures, result of valve culture and serological tests), echocardiographic data, medical and surgical treatment, and outcome data. Location of IE was determined according to echocardiographic and/or surgical findings. Origin of IE (nosocomial versus community) and the time interval during which was searched for procedures before IE were defined as previously described.20 Nearly all patients were followed up daily during the treatment of IE in the hospital by cardiology specialists, with additional consultation when indicated. Any uncertainties in data abstraction were discussed with an experienced cardiologist (CD) and microbiologist (JC), as well as with the physician responsible for the patient to confirm the diagnosis of IE. Only definite and possible IE cases as defined by the modified Duke criteria were used in the analysis.
Statistical analysis Normal distribution was evaluated using Kolmogorov–Smirnov. Depending on the outcome of normality testing, data are presented as mean [and standard deviation (SD)] or median [and interquartile range (IQR)], and continuous variables are compared with parametric (t-test/ANOVA) or non-parametric
(Mann–Whitney U/Kruskal–Wallis) statistics, respectively. Categorical variables were evaluated using Fisher’s exact or Chi-square test. The statistics were performed with Microsoft Excel 2010 [version 14.0.6112.5000 (32-bits)] with the use of the Analyseit (version 2.26 Excel10z) add-on. Logistic regression analysis of factors predicting fatal outcome was performed using Statpages [calculating the odds ratio (OR) with 95% confidence intervals (95% CI)]. The use of the appropriate statistical tests was verified by an expert statistician (HP).
Results Study population A total of 135 notifications were retrieved from the medical record system between 2003 and mid-2010. The number of hospitalizations during this period was 249 156, indicating that there were about five notifications per 10 000 hospitalizations. One hundred and twenty-seven episodes had a putative diagnosis of infective endocarditis (IE). Among these, 39 failed to fulfill the modified Duke criteria. A total of 83 patients suffered from 88 IE episodes during the study period. Characteristics of our population are summarized in Table 2. Sixty-six episodes (75.0%) were classified as definite IE. Four patients experienced more than one episode during the study period; the median interval between the episodes was 4 months (IQR: 3–49). In none but one of the patients the recurrent IE was caused by the same microorganism [episode 1: E. faecalis, episode 2: S. mitis and E. faecalis (double positive)].
Table 1 Summarizing table with the modified Duke criteria (according to Li et al.35) Major criteria Blood culture positive for IE Typical microorganisms consistent with IE from two separate blood cultures: Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus; or community-acquired enterococci, in the absence of a primary focus; or Microorganisms consistent with IE from persistently positive blood cultures, defined as follows: At least two positive cultures of blood samples drawn . 12 h apart; or All of three or a majority of > four separate cultures of blood (with first and last sample drawn at least 1 hour apart) Single positive blood culture for Coxiella burnetii or antiphase I IgG antibody titer .1 : 800 Evidence of endocardial involvement Echocardiogram positive for IE [TEE recommended in patients with prosthetic valves, rated at least ‘possible IE’ by clinical criteria, or complicated IE (paravalvular abscess); TTE as first test in other patients)], defined as follows: Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or Abscess; or New partial dehiscence of prosthetic valve New valvular regurgitation (worsening or changing of pre-existing murmur not sufficient) Minor criteria Predisposition, predisposing heart condition or injection drug use Fever, temperature .38uC Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway’s lesions Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE Echocardiographic minor criteria eliminated
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Table 2 Demographic and clinical characteristics infective endocarditis episodes (n588) in 83 patients Characteristics
of
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Four episodes (4.5%) were hemodialyzed. Eighteen episodes (20.5%) suffered from diabetes mellitus.
No. (%)
Characteristics of IE Demographics Age, median (IQR), years Number of patients Male patients Of whom .1 episode Male episodes Female patients Of whom .1 episode Clinical Modified Duke classification Definite Possible Valves involved Aortic Mitral Aortic and mitral Right-sided or bilateral Unknown* Prosthetic IE
72 83 55 3 59 28 1
(59–81) (66.3) (67.0) (33.7)
66 (75.0) 22 (25.0) 32 37 10 5 4 7
(36.4) (42.0) (11.4) (5.7) (4.5) (8.0)
Note: *In one episode no echocardiography was performed.
Preexisting valvular disease and non-cardiac risk factors Table 3 summarizes the distribution of preexisting valvular disease. Acquired valvular disease was the most frequent preexisting valvular disease in our population. A total of 13 episodes (14.8%) had experienced a medical or surgical procedure within 6 months before IE (dental procedures: 2, musculoskeletal or dermatological procedures: 10, broncho- or gastroscopy: 1). Two episodes (2.3%) were reported as intravascular catheter-related. One case was known as an intravenous drug user. With respect to non-cardiac risk factors, we concluded from the medical files that four episodes (4.5%) were immune-suppressed (immunosuppressive drugs), nine episodes (10.2%) suffered from cancer at time of diagnosis of IE (haematological: 4; gastrointestinal: 2, breast: 2, non-specified metastases: 1). Table 3 Distribution of preexisting episodes with infective endocarditis*
valve
disease
in
No. (%) Acquired (native) valve insufficiency Left heart Right heart Both sides Prosthetic valves Mechanical Biological Congenital heart disease Unspecified heart murmur Rheumatic heart disease Mitral valve prolapse History of IE Episodes without any (or unknown) preexisting valve diseases
19 17 0 2 16 4 12 5 1 2 1 8 50
(21.6) (19.3) (0.0) (2.3) (18.2) (4.6) (13.6) (5.7) (1.1) (2.3) (1.1) (9.1) (56.8)
Note: *One or more underlying heart diseases might be present for one and the same episode.4
For 20 cases, IE was solely detected by transthoracic echocardiography (TTE) [no transesophageal echocardiography (TOE) performed (n518) or TOE not suggestive for IE (n52)]. Twenty cases detected by TTE were confirmed by TOE. Forty-three cases were solely diagnosed by TOE [no evidence of TTE performed (n515) or TTE not suggestive for IE (n528)]. For three cases, no evidence for the presence of clear vegetation was reported upon echocardiography (all considered as culture positive endocarditis). For one case, evidence for the presence of vegetation was found upon autopsy. For one case, echocardiography was not performed on request of the family. Distribution of the IE location is summarized in Table 2. A major echocardiographic criterion was present in 84 episodes (95.5%), including 76 episodes with vegetation (86.3%), 4 with abscess (4.5%), 3 episodes with vegetation and abscess (3.4%), and 1 episode of prosthetic dehiscence. Fever (.38uC) was present in 73 episodes (83.0%). Immunological manifestations were observed in five cases (5.7%): glomerulonephritis was highly suspected in three cases based on functional and biochemical parameters (no kidney biopsies were taken and circulating immune complexes were determined in none of the cases); rheumatoid factor, 1 (rheumatoid arthritis was excluded and rheumatoid factor was negativized in 2008 after the episode of IE); and staphylococcal toxic shock syndrome, 1.
Causative microorganisms Sixty episodes (68.2%) met the modified Duke criteria for having a major criterion for positive blood cultures. Nineteen episodes (21.6%) met solely the modified Duke criteria for having a minor criterion of positive blood cultures. The distribution of causative organisms is displayed in Table 4. Oral streptococci (n520), Streptococcus gallolyticus (n513), and Staphylococcus aureus (n515) accounted for the three main causative organisms (Table 4). Blood cultures remained negative in nine episodes (10.2%): in the latter, infective serology was not performed (n57) or remained negative during hospitalization. For three cases, we could not find any evidence of previous antibiotic therapy. For six cases, however, a history of a recent previous antibiotic treatment was retrieved from the patient file. For 11 episodes who were referred to tertiary centres for cardiac surgery, culture (n59) or 16S ribosomal RNA gene amplification (n52) of the surgically removed heart valve was retrievable, confirming the findings of blood cultures for four
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Table 4 Distribution of causative microorganisms blood of cases with infective endocarditis Microorganism
in
No. (%)
Streptococcaceae Oral streptoccoci Viridans streptococci S. pneumoniae S. gallolyticus Pyogenic streptococci Granulicatella adjacens Gemella morbillorum Staphylococci Staphylococcus aureus Coagulase-negative Enterococci E. faecalis E. faecium Listeria monocytogenes HACEK Gram-negative rods* Propionibacterium species Candida glabrata Two microorganisms Negative blood cultures
20 (22.7) 17 3 13 (14.8) 4 (4.6) 1 (1.1) 1 (1.1) 15 (17.1) 4 (4.6) 9 (10.2) 8 1 1 (1.1) 1 (1.1) 4 (4.6) 2 (2.3) 1 (1.1) 3 (3.4) 9 (10.2)
Note: *Including one Pseudomonas aeruginosa, one Enterobacter aerogenes, one Escherichia coli, and one Klebsiella oxytoca.
cases [two with culture of the valve (one with major and one with minor criterion for positive blood cultures), two with 16S rRNA amplification (both with major criterion for positive blood cultures)]. Culture of the valve remained negative in six episodes, of which in five cases the diagnostic blood cultures were positive (three with major and two with minor criterion for positive blood cultures). For one episode, blood cultures yielded E. faecalis (major criterion), whereas culture of the valve yielded a coagulase negative staphylococcus, the latter most likely being a contaminant. Table 5 shows a comparison of patient characteristics across the three main groups of microorganisms. Oral streptococci and S. gallolyticus were predominant in the male IE population, whereas more women developed a S. aureus IE (ratio: 1.5 : 1) (Table 5). However, no other significant difference could be retrieved among the groups of the three main causative organisms.
In the group of cases with IE and a history of procedures at risk, no correlation was found between the procedure and the causative microorganism (P50.90). In 27 episodes (30.7%), the portal of entry was retrieved: dental, 7; gastro-intestinal, 8; cutaneous, 7; pneumonic, 2; bone-related, 2; and, presumably cerebral, 1 (S. pyogenes meningitis). Cutaneous portals of entry included four traumatic or chronic wounds, one intravenous drugs use and two port-acaths. In 4 out of 13 patients with S. gallolyticus IE colon polyps were reported to be present at time of diagnosis of IE.
Complications From time point of diagnosis till up to 6-months after discharge, at least one complication, likely related to IE, was reported in 50 cases (56.8%). Congestive heart failure or valve insufficiency were the most prominent complications (45 episodes or 51.1%). Six episodes were reported with an infection due to haematogenous dissemination during proper antibiotic treatment (joint, spine (n54), spleen); in five cases, a persistent IE was reported (defined as persistent IE after termination of proper antibiotic treatment after a complete course). There was no correlation between these infections and the valve involved, the causative organism, or mortality rate. Emboligenic phenomena or intracranial bleedings developed in 10 patients (11.4%). The distribution between central and peripheral emboli was 4/5.
Treatment and outcome Eighty-four patients (95.5%) were reported to receive an IE specific antibiotic treatment. Two cases who did not receive antibiotic treatment were treated palliatively. For one case, no detailed antibiotic treatment was reported. One case was diagnosed post-mortem, before initiating of any specific antibiotic treatment. Fifty-nine cases of IE were caused by microorganisms that were susceptible to and treated with the antibiotic of primary choice according the ‘Sanford guide to antimicrobial therapy’. Twenty-five cases
Table 5 Comparison of main characteristics of infective endocarditis across the three main groups of causative microorganisms No. (%)
186
Characteristics
Oral streptococci (n520)
S. gallolyticus (n513)
S. aureus (n515)
Age, median, IQR, years Women Men History of IE Preexisting prosthetic valve Nosocomial Valve surgery Mortality
74 (58–81) 5 (25.0) 15 (75.0) 3 (15.0) 5 (25.0) 6 (30.0) 7 (35.0) 1 (5.0)
73 (57–81) 0 (0.0) 13 (100) 1 (7.7) 2 (15.4) 2 (15.4) 5 (38.5) 1 (7.7)
72 (62–82) 9 (60.0) 6 (40.0) 1 (6.7) 3 (20.0) 6 (40.0) 5 (33.3) 3 (20.0)
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0.0020 0.68 0.80 0.36 0.96 0.33
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were treated according to an alternative antibiotic scheme due to (1) antibiotic side effects (penicillin allergy/drug fever) (n55); (2) progression of IE under antibiotic treatment of primary choice (n52); (3) (intermediate) resistance to antibiotic of primary choice (n57); (4) a concomitant pneumonia or a lower urinary tract infection (amoxicillinzclavulanic acid or piperacillin-tazobactam and amikacin, respectively), both having a culture negative endocarditis with vegetation confirmed with TOE (n52); (5) reasons other than mentioned above but retrospectively not ambiguously retrievable [susceptible strains but treated with the alternative antibiotic according to the ‘Sanford guide to antimicrobial therapy’ (n57) — culture negative IE and treated for IE according to an alternative scheme (n52)]. Referral to a tertiary hospital, of which the majority were university centres, was indicated for 33 episodes (37.5%) because of: cardiac valve surgery (n529) (for three referred cases, valve surgery was indicated but impeded by a worsening condition/ deceased before surgery); second opinion (MRI of the heart) (n51); procedures in pediatric patients (surgical implantation of peripherally inserted central catheter, surgical correction of a congenital heart defect; or complication by glomerulonephritis) (n53). The proportion of a history of congenital heart failure, emboligenic phenomena, and suspected glomerulonephritis was higher in the referred patient group than in the non-referred group [15.2% versus 0.0% (P50.012); 21.2% versus 3.6% (P50.025), and 9.1% versus 0.0% (P50.099), respectively]. The
Infective endocarditis in a non-referral centre
median interval between diagnosis of IE and referral for cardiac valve surgery (n529) was 10 days (IQR: 2–20). Of the episodes referred, three cases (9.1%) died, which did not significantly differ from nonreferred episodes. Twenty-six cases actually underwent valve surgery. Surgery rate did not differ among sex, origin of IE, heart valve involved or preexisting valvular disease (Table 6). Fifteen of all episodes died of IE (17.0% in-hospital mortality). Importantly, there was a significant difference in mortality rate between nosocomial IE and community-acquired IE (Table 6). No difference in mortality rate was detected in the other aforementioned subsets (Table 6). Nosocomial IE (OR: 5.68, 95% CI: 1.72–18.76) and heart failure/valve insufficiency as complication (OR: 4.85, 95% CI: 1.26–18.64) were found to be a significant independent predictor for mortality in the present study.
Discussion Epidemiology of IE has changed over the past 10– 20 years.4 Therefore, to assess epidemiological differences among different care centres, we compare our data with studies that collected data from a same period (2003–2012).1,19–29 Any comparison is further hampered by the significant difference in study population characteristics. For instance, epidemiological studies in large hospitals in metropoles such as Istanbul, Athens, Rome, and Paris are enriched with native valve IE in intravenous drug users.23,24,29,30 Nevertheless, comparison of studies is useful to detect trends. For instance, median age of patients
Table 6 Surgery and mortality as a function of different variables Valve surgery
Mortality
Variable
Total no. (%)
No. (%)
P value
No. (%)
P value
All Gender episodes Women Men Origin Nosocomial Community Location Only mitral valve Only aortic valve Aortic and mitral Right-sided or bilateral Unknown Preexisting valve disease Native valve disease Prosthetic valve History of IE Miscellaneous* No known heart disease Valve surgery Yes No
88 (100)
26 (29.5)
…
15 (17.0)
…
29 (33.0) 59 (67.0)
9 17
0.99
6 9
0.52
29 (33.0) 59 (67.0)
5 21
0.12
10 5
0.0023
37 (42.0) 32 (36.4) 10 (11.4) 5 (5.7) 4 (4.5)
10 10 4 2 0
0.68
5 6 3 0 1
0.58
14 (15.9) 6 (6.8) 3 (3.4) 15 (17.1) 50 (56.8)
3 1 2 5 15
0.59
6 0 0 1 8
0.085
26 (29.5) 62 (70.5)
… …
…
2 13
0.22
Note: *miscellaneous5congenital heart disease, .1 valve disease, rheumatic heart disease, mitral valve prolapse, unspecified heart murmur.
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with IE is increasing,1,19 as demonstrated in the present study compared to less recent studies.30,31 In contrast, recent prospective studies in referral centres as well as the Euro heart survey reported lower ages of onset ranging from 45 to 64 years.20,23,24,27 Risk to benefit ratio of valvular surgery might be considered more favorable for younger patients, possibly explaining the younger population in referral centres. As age is reported to be related to higher rates of abscess formation and lower rates of the presence of immune-mediated phenomena or embolic complications,1,28 revision of the current guidelines might be warranted to adjust the diagnostic criteria to the presentation of IE in an older population.1 Our study confirms indeed that immunological phenomena are less present than reported in previous studies on IE.3,30 Noteworthy, however, most studies do not report the percentages of e.g. immunological phenomena. Male-to-female ratio of about 2 : 1 is similar to other studies, with the exception of a recent population based study reporting a 1 : 1 ratio, explained by a higher prevalence of women in the older population with IE.19 We were not able to confirm this explanation, as in the present study, an older median age is observed as well, without, however, a disturbed male-to-female ratio. Whereas preexisting valvular disease is present in the vast majority of patients with IE,4,27 some recent studies report that the majority of patients (especially with native IE) have no preexisting valvular disease,4,27,32 as is the case in the present study. Major risks factors for IE shifted from rheumatic heart disease to native valvular disease.19,25,32 Compared to one of our nearest Belgian referral centres, cardiac risk factors such as native valve disease seem to be less frequent in our population.20 The percentage of nosocomial IE in the present study is similar to recent findings of referral and nonreferral centres20,30 and findings of population based studies.1 In 30% of the episodes, the presumable portal of entry is reported in patient’s medical records, which is comparable with a large multicentre prospective study in French university hospitals.3 Unfortunately, most recent studies do not report any presumable portal of entry. As the incidence of IE has not decreased over the past 30 years,4 identifying the portal of entry might yield valuable information with regard to actions that can be taken to prevent IE, especially for nosocomial IE as it is an independent risk factor for mortality (see below for further discussion). The distribution of the location of vegetation/ abscess in the present study is similar to the findings in other studies.1,19,20,25 Prosthetic valve IE is rather uncommon in our population, whereas prosthetic
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valve IE accounted for more than 15 or 30% of the episodes in large referral hospitals and populationbased studies.1,20,23,27,28 Normalized, 6 out of 894 (or 0.67%) of patients registered with prosthetic heart valve during the study period (period of 7.5 years) developed a prosthetic valve IE. In a large referral hospital,20 70 out of 2466 (or 2.84%) patients registered with a prosthetic heart valve developed a prosthetic valve IE (study period of 4.5 years) (personal communication). Recent studies reported that staphylococci surpassed streptococci as major cause of IE.1,19,20,22,25–28,33 In contrast, as in less recent studies,3,4 streptococci are the most prevalent species in our population. Main factors reported to be related with staphylococcal IE are health care-associated,28 such as chronic haemodialysis and intravascular devices.32,34 In referral centres, staphylococcal IE is associated with a higher mortality rate,3,20 unlike in non-referral centres as ours. Indeed, staphylococcal IE can be very fulminant, associated with a worse outcome.20,30 Therefore, referral centres might be artificially enriched with these fulminant episodes of staphylococcal IE. Intriguingly, the proportion of staphylococcal IE is reported to be significantly lower for men than it is for women,3 as confirmed by our study. Moreover, intravenous drug users have a significantly higher proportion of staphylococcal IE.3,26 Therefore differences in population characteristics might explain in part the discrepancy in major causative organisms of IE among care centres. The observation that nosocomial S. aureus infection is present in 45% of staphylococcal IE have led to the modification of the Duke criteria, where, besides community-acquired, nosocomial S. aureus bacteremia became one of the major criteria for IE as well.35 Our present study observes a similar percentage of nosocomial S. aureusrelated IE, which might confirm the justification of the modification of the Duke criteria. The same suggestion has recently been made by Hill et al. for nosocomial enterococcal bacteremia as it is observed to be an emerging cause of IE (nearly equally distributed between community and nosocomial origin of enterococcal IE, accounting for about 5% of all cases).20 Nevertheless, in our population, only two out of nine enterococcal IE is classified as nosocomial (about 2% of all cases of IE), and no putative episodes were rejected based on the fact that nosocomial enterococcal bacteremia was solely a minor criterion. Therefore, more evidence might be required to reclassify nosocomial enterococcal bacteremia as a major criterion in the modified Duke criteria. The decrease of viridans streptococcal IE has been attributed to the decrease of pre-existing rheumatoid heart disease.19 Our study proves that the latter is not
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entirely covering the cause of a putative decrease of viridans streptococcal IE, as in our population rheumatoid heart disease is rare, while viridans streptococcal IE remains the major causative organism of IE. The number of negative blood cultures (or unknown pathogen) is somewhat higher than reported in one population-based study (about 5%),19 but comparable with other recent referral centre or population-based studies (about 10% or higher).1,20,24 In a very recent multicentre study, the etiology remained unexplained in 33.6% of the episodes, likely due to previous antibiotic therapy.25 Remarkably, in 3.4% of the episodes, more than one microorganism was cultured from blood, a phenomenon seen as well in some referral centres.3 At least one complication was observed in about two out of three patients, which is rather high when compared to other non-referral centres or population based studies,1,19 but similar to referral centres.20 In the latter, the higher number was explained by referral of severely ill patients, whereas other confounding factors such as a relative older population might explain at least in part the observation in our study. Fewer patients hospitalized in our centre undergo valvular surgery than in the majority of the (non)referral centres (49–64%).20,27,30,33 Surgery rates in referral centres differ among e.g. sex, localization of the vegetation, and microorganism causing IE,3 unlike in the present study. In-hospital mortality rate in our study population is highly comparable with recent referral centre-based and population-based studies and with the Euro heart survey (about 15%),3,27,28 but lower than a recent referral centre study (21.7%)20,33 or a prospective multicentre study (27.5%).25 Nosocomial infection and heart failure/valve insufficiency are identified as independent predictors of mortality in our population, as reported before in populationbased studies1,28 and in one non-referral community hospital study30 but not in referral centres.20 No other predictors of mortality, such as age, gender, diabetes mellitus, staphylococcal IE, history of IE, or embolic events, are detected in our population, unlike in other studies.20,30 In conclusion, compared to referral centres, an older population with IE, characterized with fewer predisposing cardiac factors and catheter-related IE is seen in patients hospitalized in a large Belgian nonreferral community hospital. Our patients have fewer prosthetic valve IE as well as fewer staphylococcal IE. Our patients undergo less surgery, whereas severe complications as well as the mortality rate seem to be highly comparable with referral centres, with nosocomial IE as an independent predictor of mortality. The present study might suggest that characteristics
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of IE as well as associative factors in a community hospital differ from referral hospitals. Limitations of our study are for instance that the diagnosis of e.g. preexisting valvular disease or the presence of minor criteria such as Janeway lesions were made based upon the records in the medical files. It cannot be ruled out that the reported percentages in the present study are underestimated since non-apparent minor clinical signs of IE can be missed or were not described in the patient’s file. Moreover, the medical registry system did not allow us to retrospectively retrieve episodes with pacemaker IE. As the number of IE was rather limited in our retrospective study, follow-up via prospective studies in our community hospital, as well as via multicentre studies comparing features of IE in community and referral care centres, is required to further elucidate the effect of referral bias observed in the present study.
Acknowledgements The authors wish to thank P. Garre´ (AZ Groeninge, Kortrijk), Dr H. De Beenhouwer (OLV Hospital Aalst), Dr S. Steyaert (Maria Middelares Hospital Ghent), Professor Dr J. Verhaegen, Dr Meurisse and Professor Dr P. Herijgers (UZ Leuven, University of Leuven), and Prof. Dr D. Vogelaers (UZ Ghent, University of Ghent) for providing us with valuable information. The authors declare to have no conflicts of interest.
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