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Introduction
Infective endocarditis (IE) is a difficult and complex disease. Despite advances in its diagnosis and medical and surgical treatment, IE continues to be associated with high mortality and serious complications 1.
The epidemiological profile of IE has changed substantially over the last few years 2,3. Historically, it affected young patients with underlying predisposing valve disease, predominantly rheumatic, and Streptococcus viridans was the most frequent pathogen 4. Over the last few years, the age of patients with IE has increased and degenerative valve disease is the most common predisposing lesion in developed countries where rheumatic fever has ceased to be a public health problem. The number of patients with IE and no prior known history of valve disease has also increased considerably 5. The microbiology has also changed, with many recent studies reporting that Staphylococcus aureus is currently the main causative microorganism of IE6,7.
Numerous studies have evaluated the clinical, microbiological and echocardiographic characteristics of IE in the Western world. However, little is known regarding the epidemiology of IE in our setting, its echocardiographic characteristics, the main microbiological agents involved, the most common clinical manifestations and the complications in our patients. The local behavior of this entity must be observed in order to determine if there is a difference in the clinical profile which could serve as a basis for developing future management strategies.
This study analyzes the clinical, laboratory, microbiological and echocardiographic characteristics of IE in a group of patients at a tertiary care hospital in Medellín, Colombia over a period of three years.
Materials and methods
This was designed as a retrospective observational study. All patients over the age of 18 with a diagnosis of IE in their medical chart and seen by the echocardiography service at Hospital General de Medellin between March 2011 and June 2014 were included.
Data were collected from the medical charts regarding demographic characteristics, age, sex, underlying heart disease, presenting signs and symptoms, comorbidities, laboratory and microbiology results, echocardiographic findings, the need for surgery and complications.
All patients met the following requirements: 1. Over the age of 18 years, 2. Definitive or probable diagnosis of IE according to the modified Duke criteria, 3. Transthoracic and/or transesophageal two-dimensional echocardiography, and 4. Serial blood cultures.
Definition of terms
1. According to the modified Duke criteria:
Major criteria
Positive blood cultures: a typical microorganism consistent with IE from two separate blood cultures, or a microorganism consistent with IE from persistently positive blood cultures, or a single positive blood culture for Coxiella burnetti or IgG antibody titers > 1:800.
Echocardiographic evidence of endocardial involvement with the presence of vegetations, an abscess, a fistula, a pseudoaneurysm or a new dehiscence of a prosthetic valve; abnormal activity around a prosthetic valve on positron emission tomography (PET/CT) or single-photon emission computerized tomography (SPECT/CT) or paravalvular lesions on cardiac computerized tomography.
Minor criteria
Predisposing conditions such as underlying heart disease or the use of intravenous drugs, fever, vascular phenomena, immunological phenomena and positive blood cultures not classified as a major criterion.
Definitive IE: two major criteria, or one major and three minor criteria, or five minor criteria.
Possible IE: one major criterion and one minor criterion, or three minor criteria.
Safety and ethical considerations
According to Article 11 of Resolution 008430 of 1993 issued by the Ministry of Health of the Republic of Colombia, this project is classified as a no-risk study, since retrospective documentary techniques and methods are used; no intentional intervention of the individuals' physiological, psychological, biological or social variables was performed as the source of data was the medical chart, fulfilling, in turn, Resolution 8430 of 1993, issued by the Ministry of Health, which establishes the scientific, technical and administrative norms for healthcare research.
The data on each of the patients' variables were entered into a Microsoft Excel spreadsheet. The statistical analysis of the results was performed with SPSS version 21 software. Quantitative variables are presented with measures of central tendency (average) and dispersion (standard deviation). Categorical variables are presented as proportions. The bivariate analysis included the Chi square test for categorical variables and Student's t-test or Mann-Whitney U for quantitative variables. The confidence level for the hypothesis tests was 95%. The relationship between the size of vegetations and complications was analyzed using the Chi square test. Factors associated with inpatient mortality were analyzed through binary logistic regression, using a forward stepwise method. A p value less than 0.05 was considered statistically significant for all statistical analyses.
Results
Of the 48 cases included, 46 patients (95.8%) were classified as definitive endocarditis and two patients (4.2%) as probable endocarditis according to the modified Duke criteria.
The patients' main characteristics are shown in Table 1; 29 patients (60.4%) were men, and 19 patients (39.6%) were women, with a 1.5:1 male to female ratio. The average age (±SD) was 53.8±19.2 years.
Table 1 Baseline characteristics of patients with infective endocarditis (IE).
| Variables | n=48 |
|---|---|
| Baseline characteristics at diagnosis | |
| Male sex, n (%) | 29 (60.4) |
| Age, X (DS) | 53.8 (19.2) |
| Comorbidities, n (%) | |
| Arterial hypertension | 24 (50) |
| Diabetes mellitus | 8 (16.7) |
| Chronic kidney disease | 9 (18.8) |
| Malignancy | 4 (8.3) |
| Prior IE | 1 (2.1) |
| Valve disease | 8 (16.6) |
| Aortic regurgitation | 2 (4.1) |
| Mitral regurgitation | 4 (8.3) |
| Mitral valve prolapse | 1 (2.1) |
| Double mitral lesion | 1 (2.1) |
| Congenital heart disease | 7 (14.6) |
| Bicuspid aorta | 1 (2.1) |
| VSD | 3 (6.2) |
| PDA | 1 (2.1) |
| Subaortic membrane | 1 (2.1) |
| AV canal | 1 (2.1) |
| Prosthetic valve | 3 (6.3) |
| Biological | 3 (6.3) |
| Mechanical | 0 (0) |
| Intracardiac device | 6 (12.5) |
| Inflammatory diseases | 7 (14.5) |
| Intravenous drug use | 0 (0) |
| HIV | 1 (2.1) |
| Use of steroids or other immunosuppressants | 6 (12.5) |
| IE: infective endocarditis, VSD: ventricular septal defect, PDA: patent ductus arteriosus, AV: atrioventricular, HIV: human immunodeficiency virus. | |
Native valve endocarditis occurred in 36 patients (75%), prosthetic valve endocarditis in three patients (6.3%) and endocarditis associated with an intracardiac device in nine patients (18.8%). With regard to how they acquired the infection, 20 patients (42%) had healthcare-related endocarditis and 28 patients (58%) had community-acquired endocarditis. Most patients had no underlying predisposing heart condition (62.5%).
Fever and fatigue were the patients' most common clinical manifestations (70.8 and 77.1%, respectively). A heart murmur was reported as a clinical finding in 47.9% of the patients (Table 2).
Table 2 Clinical manifestations of patients with infective endocarditis.
| Clinical manifestations | n (%) |
|---|---|
| Fever | 34 (70.8) |
| Fatigue | 37 (77.1) |
| Dyspnea | 25 (52.1) |
| Chills | 31 (64.6) |
| Seizures/neurological focalization | 5 (10.4) |
| Gastrointestinal symptoms | 15 (31) |
| Chest pain | 6 (12.5) |
| Headache | 8 (16.7) |
| Weight loss | 12 (25) |
| Muscle/joint symptoms | 21 (43.8) |
| Skin lesions | 15 (31.3) |
| Murmur | 23 (47.9) |
Thirty cases (62.5%) had positive blood cultures and 18 (37.5%) had negative blood cultures. Of the latter, one patient had a microbiological diagnosis with a valve tissue culture.
Table 3 summarizes the causative microorganisms of the infection during the study. Staphylococcus was the cause in 39.6% of cases and Streptococcus in 14.5%. S. aureus was isolated in 16 patients (33%) and was the most frequent microorganism, followed by Streptococcus sanguis in three patients (6.3%).
Table 3 Microorganism isolated.
| Microbiology | |
|---|---|
| Staphylococcus | 19 (39.6) |
| Methicillin-sensitive Staphylococcus aureus | 13 |
| Methicillin-resistant Staphylococcus aureus | 3 |
| CNS | 3 |
| Enterococcus | 2 (4.1) |
| 1: E. faecalis | 2 |
| 2: E. faecium | 0 |
| Streptococcus | 7 (14.5) |
| Streptococcus viridans | 1 |
| Streptococcus bovis | 0 |
| Other species of Streptococci | 1 |
| Streptococcus gallolyticus | 1 |
| Streptococcus sanguis | 3 |
| Streptococcus milis | 1 |
| Gram negative organisms | 2 (4.1) |
| Brucella | 0 |
| Pseudomonas aeruginosa | 0 |
| HACEK group | 0 |
| Serratia marcescens | 1 |
| Klebsiella pneumoniae | 1 |
| Candida | 1 (2.1) |
| Candida albicans | 0 |
| Candida tropicalis | 1 |
| Candida parapsilosis | 0 |
| CNS: Coagulase-negative Staphylococcus, HACEK: Haemophilus parainfluenzas, Actinobacillus, Cardiobacterium, Eikenella corrodens and Kingella kingae. | |
The initial diagnosis was made by transesophageal echocardiography in 26 patients (54.2%) and by transthoracic echocardiography in 22 (45.8%). The mean time between the clinical suspicion and the first echocardiogram was 24 hours (15-48 hours). Forty-one patients required only one echocardiogram for diagnosis, seven patients required two echocardiograms for diagnosis. The main echocardiographic findings are summarized in Table 4. Vegetations were found in 45 of the 48 patients (93.7%), most were mobile (40/45, 88.8%), and the mitral valve was the most frequent location (17/45, 37.7%), followed by the aortic valve (16/45, 35.5%). The average size of the vegetations was 17.6±11.3 mm. The most frequent complication was embolism in 21 patients (43.7%), followed by heart failure in 41.7%. The most common sites of embolism were the lung and central nervous system (CNS) (nine and eight cases, respectively) (Table 5).
Table 4 Echocardiographic findings.
| Vegetations, n (%) | 45 (93.7) |
|---|---|
| Maximum size in mm (±SD) Number of vegetations | 17.6 (11.3) |
| 1 | 24 (53.3) |
| 2 | 11 (24.4) |
| 3 | 10 (22.2) |
| Mobile Location | 40 (88.8) |
| Aortic | 16 (35,5) |
| Mitral | 17 (37.7) |
| Tricuspid | 6 (13.3) |
| Intracavitary | 3 (6.6) |
| Device cables or catheters | 10 (22.2) |
| Common AV valve | 1 (2.2) |
| Pulmonary | 1 (2.2) |
| Aortic regurgitation | 21 (43.7) |
| Mitral regurgitation | 29 (60.4) |
| Tricuspid regurgitation | 22 (45.8) |
| Pulmonary regurgitation | 3 (6.3) |
| LVEF% | 60(46 - 65) |
| PASP mmHg | 45 (38-58) |
| LVEF: left ventricular ejection fraction, PASP: pulmonary artery systolic pressure, AV: atrioventricular | |
Table 5 Complications of patients with infective endocarditis.
| Complications | |
|---|---|
| Aortic root abscess, n (%) | 2 (4.2) |
| Pseudoaneurysm | 0 |
| Valve aneurysm | 0 |
| Perforation | 11 (22.9) |
| Fistula | 1 (2.1) |
| Paravalvular leak | 2 (4.2) |
| Prosthetic dehiscence | 2 (4.2) |
| Valve destruction | 0 |
| Rupture of chordae tendinae | 3 (6.3) |
| Pericardial effusion | 15 (31.3) |
| Heart failure | 20 (41.7) |
| Perivalvular extension | 4 (8.3) |
| Embolism | 21 (43.7) |
| Lung | 9 |
| CNS | 8 |
| Extremities | 6 |
| Spleen | 2 |
| Skin | 2 |
| Spondylodiscitis | 1 |
| Kidney | 1 |
| Septic shock | 13 (27.1) |
| AV block | 1 (2.1) |
| Kidney failure requiring renal replacement therapy | 14 (29.2) |
| CNS: central nervous system, AV: atrioventricular. | |
A statistically significant association was found between Staphylococcus infection and pulmonary embolism (p=0.01), but not CNS embolism (p= 0.390).
There was no statistically significant association between the location of the vegetation and embolism. Out of 17 patients with mitral valve endocarditis, eight had an embolism (47%); out of 16 patients with aortic valve endocarditis, eight had an embolism (50%); out of 10 patients with endocarditis related to device cables or catheters, four embolized (40%); and out of six patients with tricuspid valve endocarditis, two embolized (33%).
Patients with mobile vegetations tended to have more complications, although the relationship was not statistically significant, except for heart failure (p=0.04) (Table 6). Out of eight patients with CNS emboli, seven (87.5%) had mobile vegetations, and only one patient had non-mobile vegetations. Out of nine patients with pulmonary emboli, eight (88.8%) had mobile vegetations and only one had non-mobile vegetations. One hundred percent of patients with valve perforation as a complication had mobile vegetations.
Table 6 Vegetation mobility and complications.
| Vegetations and complications | |||
|---|---|---|---|
| Mobiles n (%) | Non-mobile n (%) | P value | |
| CNS embolism | 7 (87.5) | 1 (12.5) | 0.64 |
| Perforation | 11(100) | 0 (0) | 0.22 |
| Paravalvular leak | 1(100) | 0 (0) | 0.88 |
| Pericardial effusion | 14 (93.3) | 1 (6.7) | 0.45 |
| Heart failure | 20 (100) | 0 (0) | 0.04 |
| CNS: central nervous system | |||
Most patients had ≥10 mm diameter vegetations (35 patients); of these, 100% had an embolic complication. Of the patients with <10 mm vegetations (10 patients), only three had an embolus, although this relationship did not reach statistical significance.
A statistically significant relationship was found between the size of the vegetations (≥10 mm) and paravalvular leaks (p=0.03) and prosthetic dehiscence (p=0.03).
Among the patients' baseline characteristics, advanced age (over 55 years) was statistically significantly associated with the risk of peripheral embolism (p=0.04); other variables analyzed, such as diabetes mellitus, arterial hypertension or kidney failure were not significantly associated with emboli.
Heart failure was a complication in 20 patients, 19 with native valve endocarditis. Of these, 11 patients had aortic valve vegetations and eight patients had mitral valve vegetations.
There were two cases of aortic root abscess in patients with native valve endocarditis. In one, E. faecalis was isolated, and in the other, S. lugdunensis.
Perivalvular extension occurred in four patients with native valve endocarditis, with aortic valve (2), tricuspid valve (1) and intracavitary (1) vegetations. Staphylococcus was isolated in three patients and E. faecalis in one.
Eleven cases of valve perforation were found, seven involving the mitral valve and four the aortic valve. The most commonly involved germ in these cases was S. aureus (36.4%).
Using multivariate analysis, a significant association was found between mortality as an outcome and septic shock, kidney failure, Staphylococcus infection and the use of immunosuppressants. No association was found with the other variables analyzed (Table 7).
Table 7 Factors associated with inpatient mortality: multivariate analysis.
| Multivariate analysis | |||
|---|---|---|---|
| Variable | P value | Exp (B) | 95% CI |
| Septic shock | 0.005 | 14.91 | (2.30- 96.49) |
| Kidney failure with RRT | 0.033 | 6.57 | (1.16- 37.22) |
| Staphylococcus | 0.048 | 5.11 | (1.01- 25.79) |
| Immunosuppressants | 0.047 | 9.37 | (1.03- 85.24) |
| RRT: renal replacement therapy. | |||
Discussion
Although the incidence of IE in the general population was not analyzed, the results indicate that despite advances in health care, IE continues to pose a diagnostic and therapeutic challenge for physicians, especially now that the pattern of presentation differs substantially from that of a few years ago. Those at greatest risk of infection are no longer young patients with known rheumatic valve disease; now they are older people with no apparent valve disease 5,8. In this study, most patients did not have a predisposing underlying heart condition (62.5%), just as reported by Castillo et al. in an epidemiological study in Spain, where in the last seven years, 64% of the IE cases were patients with no predisposing heart disease 5.
The average age of onset was 53.8±19.2 years. The increase in the age of patients with IE coincides with other studies carried out within the last decade 9,10. This could be explained by greater survival of the population and by the increased number of IE cases related to hospitalization and health care. As in the vast majority of studies, we found a predominance in males, with a male: female ratio of 1.5:1 (5, 6, 11).
Our study confirmed many clinical characteristics of endocarditis which occur in other parts of the world. For example, most of the IE cases were in native valves (75%) and the mitral valve was most commonly affected, followed by the aortic valve 10,11.
Infective endocarditis with negative blood cultures may occur in up to 31% of IE cases, and often poses a considerable diagnostic and treatment challenge. It occurs most frequently due to prior antibiotic use, highlighting the need to suspend the antibiotics and repeat the blood cultures in this situation 12. In this study, we found a 37.5% prevalence of IE with negative blood cultures.
The published studies disagree on which causative microorganism is the most frequent; this variation may be related to the study population 10,11,14,15. The studies which include intravenous drug users report a higher prevalence of S. aureus as the causative agent; other studies predominantly include patients with prosthetic valve IE. According to reports from recent studies, the Staphylococcus species have surpassed Streptococcus species as the most frequent causative microorganism of native valve IE 12,13. In this study, which predominantly included native valve IE cases, with no intravenous drug use cases, the Staphylococcus species were the most frequent (39.6%), especially Staphylococcus aureus (33%), followed by Streptococcus species (14.5%), indicating that the globally reported shift from S. viridans as the main germ in the past to S. aureus currently, is also true in our study population and is probably related to the same reasons, such as a growing number of invasive procedures (vascular catheters, intracardiac devices, etc.).
The most common presenting symptoms were fatigue and fever; however, the prevalence of fever in our study was lower than that reported by other authors 12. A total of 29.2% of the patients did not report a fever, which suggests that the lack of fever should not exclude a diagnosis of IE in a patient with suggestive clinical characteristics.
The lack of a murmur in patients with IE has been described previously; however, the proportion of cases without a murmur (52.1%) was much greater in our study than what was reported in a retrospective study by Fefer P. et al. 16.
Echocardiography was the cornerstone of IE diagnosis in our study. Vegetations were found in most cases (93.7%). The size of the vegetations (17.6 ± 11.3 mm) was much greater in our study than what was reported in a Spanish registry by Roca B. et al. 17, in which the average length was 9 mm. Mitral regurgitation was the predominant heart condition in our study (60.4%), similar to what was reported by Winston and Bolger 18.
The prevalence of embolism was high in our study (43.7%), coinciding with what was published previously by Vilacost et al. 19. The most frequent sites of embolism were the lung (42.8%) and the central nervous system (38%). The prevalence of spleen embolism was much lower than that reported in the literature, and this may reflect an underdiagnosis due to fewer abdominal imaging studies being routinely performed on these patients 12.
Several observational studies have evaluated the relationship between the location of vegetations on the echocardiogram and the risk of complications 19-21, finding that vegetations on the mitral valve are a risk factor for embolism. In this study, we did not find a statistically significant relationship between the location of the vegetations and embolism, with a similar proportion of emboli in patients with mitral and aortic valve vegetations. Mobile vegetations were associated with a greater incidence of complications like embolism, although this association did not reach statistical significance in our study, perhaps due to the size of the sample.
As previously mentioned, the size of the vegetations in this study was much larger than what was reported in other studies; vegetations which were ≥ 10 mm had more frequent
The multivariate analysis showed an increased risk of death from endocarditis in the presence of septic shock, kidney failure, Staphylococcus infection and the use of immunosuppressants. Other studies on this aspect have reached similar conclusions as ours regarding the factors associated with greater mortality 22-25. However, there are also studies which have found a significant association of other factors with mortality, such as heart failure and advanced age 26. The discrepancies may be explained by the different study designs and the lack of uniformity in the analyzed variables.
Our study has several limitations, especially the sample size, its retrospective design and the low number of serological and molecular tests performed, which limits the detection of fastidious organisms such as Brucella, Bartonella, Coxiella and other rare causes of IE which cannot be ruled out with traditional microbiological studies.
This study provides an epidemiological profile of IE in Medellín, Colombia. Although this study included 48 patients over a period of three years in a tertiary care hospital, this frequency is comparable to or greater than that reported in other studies, such as that of Senior 27, in which 92 patients were included over a longer period (11 years) and from three reference centers, and that of Olaya Sánchez et al. 28 with 34 patients in four years. The sizes of these studies are explained by the low prevalence of infective endocarditis.
Conclusions
This study shows the epidemiological, clinical and echocardiographic characteristics of a population with IE in a tertiary care hospital in Medellín, Colombia. In our population, IE is currently a disease which predominantly affects older people without predisposing underlying heart disease. Most of the cases are native valve endocarditis, with greater involvement of the mitral valve. S. aureus was the most frequent causative microorganism. Echocardiography is the cornerstone of diagnosis. This study helps recognize the prognostic factors which identify patients at higher risk of inpatient mortality in our population.
