Author + information
- Received February 21, 2018
- Revision received March 16, 2018
- Accepted March 17, 2018
- Published online June 11, 2018.
- Isabel Zegri-Reiriz, MD, PhDa,
- Arístides de Alarcón, MD, PhDb,
- Patricia Muñoz, MD, PhDc,
- Manuel Martínez Sellés, MD, PhDd,
- Victor González-Ramallo, MD, PhDe,
- Jose M. Miro, MD, PhDf,
- Carles Falces, MD, PhDg,
- Claudia Gonzalez Rico, MDh,
- Xabier Kortajarena Urkola, MDi,
- José Antonio Lepe, MDb,
- Regino Rodriguez Alvarez, MDj,
- Jose Maria Reguera Iglesias, MDk,
- Enrique Navas, MDl,
- Fernando Dominguez, MD, PhDa,m,∗ (, )
- Pablo Garcia-Pavia, MD, PhDa,n,∗ (, )
- for the Spanish Collaboration on Endocarditis—Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España (GAMES)
- aDepartment of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Madrid, Spain
- bClinical Unit of Infectious Diseases, Microbiology and Preventive Medicine Infecious Diseases Research Group, Institute of Biomedicine of Seville, University of Seville/CSIC/University Hospitals Virgen del Rocío and Virgen Macarena, Seville, Spain
- cDepartment of Microbiology and Infectious Diseases, Hospital General Universitario Gregorio Marañón, Madrid, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERES, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
- dDepartment of Cardiology, Hospital General Universitario Gregorio Marañón, CIBERCV, Universidad Europea, Universidad Complutense, Madrid, Spain
- eDepartment of Internal Medicine, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- fDepartment of Infectious Diseases, Hospital Clínic- Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
- gDepartment of Cardiology, Hospital Clinic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain
- hDepartment of Infectious Diseases, Hospital Universitario Marqués de Valdecilla, Santander, Spain
- iDepartment of Infectious Diseases, Hospital Universitario de Donostia, San Sebastián, Spain
- jDepartment of Infectious Diseases, Hospital Universitario de Cruces, Bilbao, Spain
- kDepartment of Infectious Diseases, Hospital Regional Universitario de Málaga, Málaga, Spain
- lDepartment of Infectious Diseases, Hospital Universitario Ramón y Cajal, Madrid, Spain
- mFundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
- nUniversity Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain
- ↵∗Address for correspondence:
Dr. Pablo Garcia-Pavia OR Dr. Fernando Dominguez, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla, 2, Majadahonda, Madrid, 28222, Spain.
Background There is little information concerning infective endocarditis (IE) in patients with bicuspid aortic valve (BAV) or mitral valve prolapse (MVP). Currently, IE antibiotic prophylaxis (IEAP) is not recommended for these conditions.
Objectives This study sought to describe the clinical and microbiological features of IE in patients with BAV and MVP and compare them with those of IE patients with and without IEAP indication, to determine the potential benefit of IEAP in these conditions.
Methods This analysis involved 3,208 consecutive IE patients prospectively included in the GAMES (Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España) registry at 31 Spanish hospitals. Patients were classified as high-risk IE with IEAP indication (high-risk group; n = 1,226), low- and moderate-risk IE without IEAP indication (low/moderate-risk group; n = 1,839), and IE with BAV (n = 54) or MVP (n = 89).
Results BAV and MVP patients had a higher incidence of viridans group streptococci IE than did high-risk group and low/moderate-risk group patients (35.2% and 39.3% vs. 12.1% and 15.0%, respectively; all p < 0.01). A similar pattern was seen for IE from suspected odontologic origin (14.8% and 18.0% vs. 5.8% and 6.0%; all p < 0.01). BAV and MVP patients had more intracardiac complications than did low/moderate-risk group (50% and 47.2% vs. 30.6%, both p < 0.01) patients and were similar to high-risk group patients.
Conclusions IE in patients with BAV and MVP have higher rates of viridans group streptococci IE and IE from suspected odontologic origin than in other IE patients, with a clinical profile similar to that of high-risk IE patients. Our findings suggest that BAV and MVP should be classified as high-risk IE conditions and the case for IEAP should be reconsidered.
Infective endocarditis (IE) is a rare disease with a high in-hospital mortality of 25% to 30% despite early diagnosis and advances in surgical and antibiotic treatments (1). Thus, it is important that efforts are directed toward preventive strategies that reduce the number of patients with IE. IE antibiotic prophylaxis (IEAP) is one of the strategies proposed to prevent IE.
IEAP was initially proposed in 1955 (2) and it has evolved over the past 50 years (3–9), founded on expert opinion and small case-control studies (10–14). Based on the risk of IE throughout life and the risk of complications from IE, predisposing cardiac conditions are classified as low, intermediate, and high risk, and IEAP was initially recommended for both intermediate- and high-risk conditions (8). However, owing to the lack of solid data the American Heart Association (AHA) in 2007 (9) and the European Society of Cardiology (ESC) in 2009 (15) restricted the recommendation for IEAP to only high-risk patients.
Bicuspid aortic valve (BAV) and mitral valve prolapse (MVP) are frequent cardiac abnormalities that show a higher incidence of IE than the general population (16–19). BAV and MVP are currently considered intermediate-risk cardiac conditions, and were among the conditions for which IEAP was restricted.
Several studies have shown a nationwide increase in the incidence of IE in individuals at high and moderate risk in the United Kingdom (20) and a rise in streptococcal IE in those at moderate risk in the United States (21), Canada (22), Germany (23), and the Netherlands (24) after the IEAP restriction. Accordingly, there remains controversy regarding the benefits of IEAP and which patients should receive it. Specifically, there is very little information on IE in intermediate-risk cardiac conditions such as BAV and MVP, and data about the potential usefulness of IEAP in individuals with these diseases are limited.
The aim of this study was 2-fold: 1) to describe the clinical and microbiological features of BAV and MVP patients with IE; and 2) to compare these features with those of patients with and without IEAP indication, to gain insight about the potential usefulness of IEAP to prevent IE in these situations.
From January 2008 to September 2016, 3,524 consecutive patients with confirmed or possible IE according to the modified Duke criteria were prospectively included in the Spanish Collaboration on Endocarditis–GAMES (Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España) registry, at 31 Spanish hospitals (25–30). Of the 31 hospitals participating in the GAMES registry, 24 are tertiary centers with cardiac surgery on site and 7 are community hospitals. Regional and local ethics committees approved the study and patients gave their informed consent. Multidisciplinary IE teams completed a standardized case report document with each IE episode, which included clinical, microbiological, and echocardiographic sections. Patients were classified according to underlying cardiac conditions and IEAP indication. IEAP indications were based on current AHA/ESC recommendations (9,15). Hence, patients with previous IE, prosthetic valves, unrepaired cyanotic congenital heart disease (CHD), repaired CHD with residual defects, and patients with CHD and <6 months since surgery were considered high-risk patients with an established indication of IEAP (high-risk group). IE was considered prosthetic when it occurred in biological or mechanical prostheses or in reconstructed native heart valves.
The remaining low- and moderate-risk patients without an established indication of IEAP constituted the low/moderate-risk group, after excluding those individuals with BAV and MVP (Figure 1). Patients with isolated device-related IE (n = 316) were excluded from the analysis.
Major IE adverse events considered were heart failure (HF), peripheral embolism, embolic stroke, persistent bacteremia (>7 days), and intracardiac complications. Indication for cardiac surgery was decided by treating IE teams based on ESC recommendations (15,31).
Microbiological data and the suspected portal of entry were recorded prospectively by the participating centers in the GAMES form. Regarding the determination of the causal microorganism, the centers recorded the isolated microorganism in blood cultures or in the surgically removed valve during admission. To consider a microorganism as causal at least 2 positive cultures were required. The flora of the oral microbiome comprised all microorganisms whose main reservoir is the oropharynx (32,33).
In relation to the suspected portal of entry, this was established prospectively by the local teams during admission, based on patient history and physical examination. Teams determined the probable portal of entry at their discretion if factors such as poor oral hygiene, previous odontologic procedures, previous phlebitis, or concomitant line infection were present.
Clinical, echocardiographic, and microbiological features and adverse events of BAV and MVP patients were compared with those of patients from high-risk group and low/moderate-risk group.
Variables with normal distribution were expressed as mean ± SD, while non-normal distribution variables were described with median and interquartile range (IQR). Univariate analysis of data comparisons between 2 groups was performed using the unpaired Student’s t-test for continuous variables with normal distribution, or by the Mann-Whitney U test in the case of variables with non-normal distribution. Chi-square or Fisher exact tests were used for the categorical variables. A p value <0.05 was considered statistically significant. All hypothesis tests were bilateral. All statistical analysis was performed with SPSS Statistics version 16.0 (IBM Corporation, Armonk, New York).
A total of 3,208 patients with definite (n = 2,593, 80.8%) or possible (n = 615, 19.2%) IE were included in the study. Of these, 54 were patients with BAV (1.6%), 89 (2.7%) were patients with MVP, 1,226 (38.2%) were high-risk patients with IEAP indication (Group 1), and 1,839 (57.3%) were low/moderate-risk patients without IEAP indication (Group 2).
IE in patients with BAV
The BAV group comprised 54 patients; the majority were men (n = 43, 79.6%), with a median age of 43 years (IQR: 36 to 55 years) and low comorbidity. At the time of IE diagnosis, 35 (64.8%) patients had moderate or severe aortic valve dysfunction (Table 1). Concomitant involvement of the other valve was observed in 10 (18.5%) patients. The median time of hospitalization was 33 days (IQR: 18 to 50 days).
Most cases of IE (n = 49, 90.7%) had been acquired in the community. The most common organisms causing IE were microorganisms present in the oral cavity (42.6%), mainly viridans group streptococci (VGS) (35.2%), and the most frequently identified entry portal was the oral cavity (14.8%) (Table 2).
Intracardiac complications and HF were common (50.0% and 40.7%, respectively). Cardiac surgery was indicated in 75.9% and performed in 68.0% of patients. The in-hospital mortality was 5.6% (Table 3).
IE in patients with MVP
The MVP group comprised 89 patients; the majority were men (n = 60, 67.4%), with a median age of 63 years (IQR: 45 to 71 years). At the time of IE diagnosis, moderate or severe mitral regurgitation was present in 50 patients (56%) (Table 1). The median time of hospitalization was 32 days (IQR: 19 to 45 days).
Again, most cases of IE were due to bacteria of the oral microbiome (46.1%), mainly VGS (39.3%), and the oral cavity was the most frequent suspected entry portal (18.0%) (Table 2).
Intracardiac complications and HF were also very frequent and were present in 47.2% and 34.8% of patients, respectively. Cardiac surgery was indicated in 56 (62.9%) and performed in 35 (39.3%) patients. The majority of individuals who underwent surgery received a mechanical prosthesis (60.0%), and 59 (66.3%) patients had severe mitral regurgitation at discharge. The in-hospital mortality of individuals who underwent cardiac surgery was 3.0% and 10.0% in the entire MVP group (Table 3).
IE in BAV and MVP versus IE in patients with and without IEAP indication
BAV and MVP patients were younger and had fewer comorbidities than patients from Groups 1 and 2 (Table 1).
There was a higher incidence of VGS IE in BAV and MVP patients than in high-risk group (35.2% and 39.3% vs. 14.6%; both p < 0.01) and low/moderate-risk group (35.2% and 39.3% vs. 15.0%; both p < 0.01) patients. Furthermore, BAV and MVP patients showed higher rates of IE from suspected odontologic origin than did high-risk group (14.8% and 18.0% vs. 5.8%; both p < 0.01) and low/moderate-risk group (14.8% and 18.0% vs. 6.0%; both p < 0.01) patients (Central Illustration). While VGS were the most frequent causal microorganisms in the BAV and MVP groups, staphylococci were the most frequent organisms in high-risk and low/moderate-risk groups (Table 2). Furthermore, these findings were maintained when the BAV and MVP groups were compared with isolated native aortic valve IE and isolated mitral valve IE, respectively (Online Tables 1 and 2).
As nosocomial IE was more frequent in high-risk and low/moderate-risk groups than in BAV and MVP (Table 2), a subgroup analysis was performed including only those patients with community-acquired IE. Again, the BAV and MVP groups showed a higher proportion of VGS IE and suspected oral cavity entry portal than did high-risk and low/moderate-risk groups (Online Table 1). Again, the BAV and MVP groups showed a higher proportion of VGS IE when they were compared with isolated native aortic valve and isolated mitral valve community-acquired IE, respectively (Online Table 1).
As shown in Table 3, BAV and MVP patients had similar intracardiac complications to those in the high-risk group (50.0% and 47.2% vs. 44.8%; p < 0.53 and p < 0.74, respectively), which were more frequent than were those in patients from the low/moderate-risk group (50.0% and 47.2% vs. 30.6%; both p < 0.01) (Central Illustration). BAV patients had a significantly higher need for surgical treatment than did patients in the low/moderate-risk group (75.9% indicated and 68.0% performed vs. 62.2% indicated and 40.6% performed; p < 0.05 and p < 0.01, respectively). In comparison with the high-risk group, a significantly higher number of BAV patients underwent surgery (68.0% vs. 40.9%; p < 0.01). No differences were found regarding surgery indicated and performed in the MVP group versus the high-risk and low/moderate-risk groups.
In-hospital mortality of BAV and MVP groups (5.6% and 10.1%, respectively) was significantly lower than that of the high-risk and low/moderate-risk groups, which showed similar mortality rates (29.0% and 28.3%, respectively; both p < 0.01). To further investigate these differences in in-hospital mortality, we analyzed several factors known to be associated with an adverse prognosis in IE. Results of this analysis showed that patients from high-risk and low/moderate-risk groups were older, had higher comorbidity rates and higher surgical risk, and contracted nosocomial IE and staphylococcal IE more frequently than did patients with BAV and MVP (Table 4). When a propensity score analysis was performed between MVP and BAV individuals and high- and low/intermediate-risk subjects matched according to age, Charlson index, nosocomial IE, staphylococcal IE, and logEuroSCORE, in-hospital mortality rates between the BAV and MVP groups and the high-risk and low/moderate-risk groups were not statistically different (Online Tables 4 and 5).
This study presents the largest series yet described of IE in patients with BAV and MVP. It shows that patients with these cardiac conditions who contract IE are young and predominantly male individuals with few comorbidities. Despite this, the analysis of the clinical characteristics in BAV and MVP patients with IE revealed an aggressive clinical course with a similar proportion of IE complications to that of IE patients with high-risk cardiac conditions, and more intracardiac complications than in patients of the low-risk and intermediate-risk groups. Moreover, this study shows that the microbiological and epidemiological profile of IE in BAV and MVP patients differs substantially from that found in patients with other low-risk and intermediate-risk cardiac conditions, with a particularly high rate of VGS IE and also a more frequent rate of IE from suspected odontologic origin. Overall, our findings open the debate to consider IEAP before dental procedures not only in high-risk cardiac conditions, but also in patients with BAV and MVP.
BAV is the most common form of congenital heart disease (prevalence of 0.5% to 2.0%). Patients with BAV have an IE incidence of 236 cases per 100,000 individuals/year (16,17), which represents a ∼30-fold higher risk of IE than in the general population (5 to 7 cases per 100,000 individuals/year) (1). MVP is also a frequent cardiac condition (prevalence of 2.0% to 3.0%) and it is thought to be the most frequent predisposing cardiac condition for IE in developed countries. Accordingly, MVP patients have been reported to present an IE incidence of 87 per 100,000 habitants/year, which is higher in patients with flail leaflet or mitral regurgitation (18,19). Despite the previously mentioned facts, BAV and MVP are considered intermediate-risk cardiac conditions and IEAP is presently not recommended.
Current AHA and ESC recommendations for IE prevention restrict IEAP to patients with high-risk cardiac conditions based on the hypothesis that the potential risks associated with IEAP (antibiotic side effects and increase in resistant microorganisms) could exceed its benefits in those who are not high risk.
The benefits were questioned because of the lack of randomized-controlled data of IEAP efficacy to prevent IE, and because IE seems to be most frequently caused by bacteremia provoked by routine daily activities; therefore, even if IEAP is effective, it would prevent only a small number of IE cases (9).
Nevertheless, the reality is that previous studies on IE in intermediate-risk cardiac conditions like BAV and MVP are scarce and insufficient to evaluate IE characteristics and prognosis in these patients; however, a very recent study has shown that several intermediate-risk conditions present a similar risk of developing or dying from IE than some of those conditions currently considered high risk (34).
Furthermore, whereas several nationwide studies performed in North America and Europe have shown an epidemiological increase in IE and streptococcal IE following IEAP restrictions (20–24), other studies have not found this to be the case (35–37). Moreover, a recent nationwide population-based cohort study has shown a protective effect of IEAP in individuals with prosthetic heart valves, and the only available meta-analysis on IEAP in dental procedures has also suggested a protective effect, despite the limitation of the poor quality of the primary studies (38,39). In addition, if the increase in the population trends of IE is assumed to be due to IEAP restriction, IEAP would be cost effective (40).
It is unlikely that a prospective randomized placebo-controlled trial will ever be conducted to evaluate the efficacy of IEAP in dental procedures in intermediate- or even in high-risk cardiac conditions. This is due to the generally low incidence of IE, the wide variety of predisposing heart conditions, and the different types of dental procedures, which make it very difficult to carry out such types of studies. Because of this, registry-based investigations addressing clinical, microbiological, and echocardiographic characteristics of IE in patients with intermediate-risk cardiac conditions, and on which patients may benefit more from IEAP, are extremely necessary.
In the present study, we analyzed clinical and microbiological findings in the largest series of BAV and MVP with IE reported to date, and compared these with those of IE in patients with high-risk cardiac conditions where IEAP is advocated, and of IE patients with low and other intermediate risk cardiac conditions for whom IEAP is currently not recommended.
Until now, IE data in BAV were almost restricted to BAV series where a maximum of 4 to 13 individuals had this complication (16,17). In those series, around 70.0% of patients with BAV and IE underwent cardiac surgery, which is similar to the percentage of individuals operated on in our registry (68.0%). Of note, the number of BAV patients with IE requiring cardiac surgery (75.9% indicated and 68.0% performed) was much higher than in the low or intermediate group (indicated in 62.2% and performed in 40.6%; p < 0.05 and p < 0.01, respectively) and also in the high-risk group (indicated in 64.3% and performed in 40.9%; p < 0.11 and p < 0.01, respectively). The number of individuals operated on is also higher than what has been reported in both native and prosthetic IE series (surgical treatment around 50.0%) (41,42). The high surgery rate found in these patients illustrates the importance of preventing IE to avoid risks associated with cardiac surgery, but also long-term complications derived from prosthetic valves and anticoagulation therapy.
The clinical course of IE in MVP patients has never been described in detail in the literature due to the small number of cases reported. In the largest contemporary series of individuals with MVP, only 8 subjects developed IE, 2 of whom required emergent surgery (19). However, it is important to mention the high risk of IE reported in MVP patients with moderate or severe mitral regurgitation and those with flail leaflet: 289.5 cases per 100,000 person-years and 715.5 cases per 100,000 person-years, respectively (19).
In our series, we found that the need for cardiac surgery in the MVP group was similar to that found in the low/intermediate-risk and high-risk groups. However, a non-negligible percentage of MVP patients with IE (66.3%) had severe mitral regurgitation at discharge, which carries substantial risk of developing HF and requiring cardiac surgery during follow-up.
We also found a relatively low in-hospital mortality rate both in BAV and MVP patients. Nevertheless, an in-hospital mortality of 5.0% to 10.0% should be still considered very high given the young age and the few comorbidities of patients included in these groups.
One of the most interesting findings of our work was the profound differences between groups regarding the IE microbiological profile and the rate of IE from suspected odontologic origin. While staphylococci were the predominant IE-causing agents in patients with IEAP indication and also in the nonindicated IEAP group, VGS were the most frequent in patients with BAV and MVP (35.2% and 39.3% of cases, respectively). Furthermore, the odontologic portal of entry was the most common origin of IE identified in BAV and MVP patients (14.8% and 18.0%, respectively), and it was significantly higher than that in the high-risk group (5.8%) and low/intermediate-risk group (6.0%). To determine whether IEAP is effective in preventing IE is beyond the scope of our study, but it is interesting to hypothesize that the microbiological spectrum found in patients with IEAP indication could have been influenced by IEAP, while the microbiological spectrum in IE patients with BAV and MVP reflects the absence of IEAP and an increased risk of IE compared with other low/intermediate-risk conditions.
Regarding IE adverse events, both BAV and MVP groups had more intracardiac complications than the low/intermediate-risk group (50.0% and 47.2% vs. 30.6%, respectively; both p < 0.01) and similar to the high-risk group (50.0% and 47.2% vs. 44.8%; p < 0.53 and p < 0.74). Of note, the incidence of intracardiac complications found in BAV and MVP patients are higher than that previously reported in native valve IE and is similar to that described in prosthetic valve IE (43).
In any case, the microbiological spectrum, the increased odontologic origin and the high rate of intracardiac complications and surgery (comparable to the high-risk group) (Central Illustration) poses the question of whether IEAP should be reconsidered for patients with BAV and MVP.
The information regarding IEAP before odontologic procedures was not included in the GAMES registry database. However, all the study participants were included after the publication of the 2007 IE guidelines that restricted IEAP to high-risk patients (11). The total number of BAV and MVP patients among the population under care at the 31 participating centers is unknown, so we cannot provide incidence or prevalence data. However, ours is the largest series yet described of IE in patients with BAV and MVP.
IE patients with BAV and MVP present a distinct clinical and microbiological profile that includes young age, male preponderance, and low comorbidity. They also present higher rates of VSG IE and increased IE from suspected dental origin than other IE patients. IE patients with BAV and MVP present a clinical course similar to that of high-risk patients, with more intracardiac complications than the low/intermediate-risk group and a higher need for surgery in the case of IE BAV patients. Based on these indirect data, we suggest that BAV and MVP should be considered high-risk IE cardiac conditions, and that IEAP indication should be reconsidered for this group of patients.
COMPETENCY IN MEDICAL KNOWLEDGE: Individuals with BAV and MVP have a higher risk of developing IE than the general population does. IE in BAV and MVP is characterized by an aggressive clinical course, comparable to that of high-risk patients in terms of adverse events, and with a higher surgical need in BAV patients.
TRANSLATIONAL OUTLOOK: Further studies are needed to assess IEAP efficacy and determine which patients may benefit from IEAP.
This work was supported in part by the Instituto de Salud Carlos III (grants RD012/0042/0066 and CB16/11/00432). Dr. Miro received a personal 80:20 research grant from the Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain during 2017 to 2019. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness and the ProCNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Grants from the Instituto de Salud Carlos III and the Spanish Ministry of Economy and Competitiveness are supported by the Plan Estatal de I+D+I 2013-2016—European Regional Development Fund “A way of making Europe.” The funders played no role in the design, collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Bernard Prendergast, BMedSChi, BM BS, DM, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- American Heart Association
- bicuspid aortic valve
- congenital heart disease
- European Society of Cardiology
- heart failure
- infective endocarditis
- infective endocarditis antibiotic prophylaxis
- interquartile range
- mitral valve prolapse
- viridans group streptococci
- Received February 21, 2018.
- Revision received March 16, 2018.
- Accepted March 17, 2018.
- 2018 American College of Cardiology Foundation
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