Infective endocarditis (IE) is a condition that mainly affects the heart valves with an incidence between 3 and 10 episodes per 100,000 people/year reaching a peak incidence of almost 14.5 episodes per 100,000 people/years in elderly patients (1,2).
Due to the increase in endovascular procedures, there has been an increase in nosocomial IE although community-acquired IE still prevails as far the general incidence of the disease. The increased life-expectancy and aging of the population, the growing incidence of age-related valve disease and the widespread use of implantable electrophysiological devices (CIED) constitute crucial factors in the current IE demographics. Patients with complex congenital heart diseases, intravenous drug abusers (IVDU) and patients with chronic renal failure under hemodialysis are becoming the new high risk subjects for IE (2). The increase in the incidence of bacteremia due to Staphylococcus species has increased the number of cases of acute IE with a faster and more destructive course (3). IVDU remain the most difficult to manage as burdened by worse long-term outcomes in comparison to age-matched population and most likely requiring surgery and prolonged hospitalization (4,5).
Clinical presentation of IE is variegated and includes systemic complication, infective embolization, as well as significant alteration of the physiological cardiac anatomy. Systemic complications with the development of multiorgan dysfunction and sepsis are unfortunately also frequent. It can cause serious complications and is associated with high mortality (1-3).
Early recognition and rapid medical treatment of patients with IE, as well as the identification of the correct timing of the surgical intervention, are strategic moments to optimize the outcome of these patients. It is very important that these patients are rapidly referred to specialized centers and evaluated by multidisciplinary teams of experts in order to be directed as quickly as possible towards the correct therapeutic path.
The establishment and formalization of multidisciplinary endocarditis management teams with approved protocols helped to achieve faster diagnosis and more standardized medical and surgical protocols, improving the survival of patients and decreasing their hospital stay (6,7).
However, despite attempts to standardize the practice in IE, the lack of powered randomized clinical evidence and the changing scenario of this daunting disease prompted over the course of the years new studies and updates of both the European and American Society’s guidelines for the management of IE (8).
When analyzing the current guidelines that regulate the treatment of this condition from both European Society of Cardiology (ESC) (9) and the American Heart Association (AHA)/American College of Cardiology (ACC) (3) it is possible to notice some aspects of non-univocal consensus regarding the diagnostics and treatment of the disease. A comparison focusing on the role of imaging in the evaluation and management of IE has been recently published (8).
In this review, we will compare the guidelines and discuss important aspects related to the clinical management and indications of for treatment.
We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/atm-20-5134).
The endocarditis team
A multidisciplinary approach is recommended and the “endocarditis team” integrates the specific knowledge and expertise of different specialists (cardiologists, anesthesiologists, cardiac surgeons, neurologists, neurosurgeons, infectious disease specialists, microbiologists) (9). Lately, the endocarditis team has acquired an increasing importance to optimize the diagnostic process, decision-making and treatment of the patient.
Implementation of an approach with an “endocarditis team” has shown significant clinical benefits, especially in high-risk patients and patients with heart failure (10,11). Also, the use of this multidisciplinary management framework has shown a significant reduction of 1-year mortality (from 18.2% to 8.2%) a better compliance to antimicrobial therapy and fewer cases of renal failure in addition to a reduction of deaths due to embolic events or multi-organ failure syndrome (6). Furthermore, a significant reduction in the overall in-hospital (28% vs. 13%, P=0.02) and 3-year mortality (34% vs. 16%, P≤0.001), as well as a lower mortality for surgery during the active phase (47% vs. 13%, P≤0.001) was reported (12).
Many professional figures constitute the endocarditis team: cardiologists with echocardiographic expertise, radiologists, microbiologists and infectious disease specialists to identify the adequate antibiotic therapy scheme, cardiac surgeons to define indications and timing for surgery, neurologists in case of neurological complications, surgeons and vascular interventionists to manage other systemic embolic complications (splenic abscesses and peripheral embolism).
Despite patients with isolated, non-high-risk IE could be managed in small, non-specialized centers, regular communication with a multidisciplinary team of endocarditis in the reference centers should be established. Onset of complications or the lack of improvement, should prompt a quick transfer of the patient to referral centers with an endocarditis team. It should also be considered that the role of the endocarditis team is not only limited to the management of patients with IE, but also involves education of medical students, health care workers and the contribute with clinical research to the improvement of the global care standard (13).
There are many factors that play a fundamental role in the development of the natural history of IE. Cardiac structural anomalies and pre-existing comorbidities, type of infected valve (native or prosthetic), position (aortic, mitral, or right-sided), the type of pathogenic microorganisms and its virulence and the systemic involvement other organs beyond the heart (14-16).
Staphylococci species (S. aureus being more aggressive and destructive) and streptococci are the most common, aggressive and destructive bacteria. The extent of the infection relates to microorganism virulence and duration of the infection (1). Early diagnosis of the disease and prevention of the development of local and systemic complications are essential in order to optimize the patient’s outcomes (17). Importantly, the timing and indication for invasive treatment also constitutes a fundamental part of the decision-making process.
It is sobering to note that one of the aspects of non-uniformity among the currently available guidelines for IE relies in the definition of criteria and timing for surgery.
Comparison of the ESC and AHA/ACC guidelines
Current guidelines were compared in terms of clinical evaluation (Table 1), surgical indications (Table 2 for heart failure, Table 3 for uncontrolled infection, Table 4 for prevention of embolism), management of neurologic complications (Table 5) and cardiac device-related IE (Table 6).
Surgery for IE
IE treatment is based on a combination of medical therapy with antibiotics and surgery. The latter is necessary in some specific conditions identified by the guidelines. As shown in Tables 1-4, the ESC and ACC/AHA guidelines agree on multiple aspects. Antibiotic therapy, although necessary, is often ineffective in controlling extensive infections affecting large areas of myocardial or prosthetic tissue (large vegetations, abscesses, fistulas). In these cases, delaying surgery could adversely affect patient outcome by increasing the risk of developing local and systemic complications (18), destruction of valvular tissue and invasion of para-valvular structures (19). The micro-organism identified as responsible for the infection represents a possible surgical indication per se. The isolation of very aggressive and antibiotic-resistant micro-organisms as S. aureus (20) or some fungi are direct indications for surgery (1).
Presence of cerebral embolism is not a contraindication for early surgery, but in case of cerebral hemorrhage it is recommended to delay the surgery by four weeks. In these cases, consultation with neurologists or neurosurgeons is fundamental.
The goal of the endocarditis team should be to prevent the development of complications. In this context, decision-making on the timing for intervention is crucial to prevent embolic complications. Surgery should be performed at early stages in patients with large vegetations or intra-cardiac prosthetic material, where the risk of embolization or development of perivalvular abscesses is high (18,19). Delaying surgery in hemodynamically stable patients with adequate antimicrobial therapy but with established indication for surgery is not associated with further benefits or is even detrimental according to a number of observational studies (21-25).
The decision of the correct therapeutic strategy to be applied in patients with IE and neurological complications is a very challenging. The lines ESC and ACC/AHA provide substantially univocal indications although they present some differences (Table 5). There are many neurological complications that can be observed during IE: ischemic stroke, cerebral hemorrhage (ICH), cerebral microbleeds, intracranial infectious aneurysms, and remote dissemination of infectious foci.
In ischemic stroke, the guidelines seem to suggest early surgery. However, while on the one hand the removal of the embolic source would protect the patient from future embolic events, on the other hand there it has been reported an increase in the onset of further neurological complications in patients undergoing early surgery (26,27). An analysis of the available literature provides contradictive findings. While some studies suggest that delayed surgery in stroke patients would correspond to an improvement in the clinical outcomes (28,29), more recent report and meta-analysis of observational studies contest these hypotheses and showed that early surgery is non-inferior to delayed surgery for major stroke patients and would even improve outcomes in minor stroke patients (30,31).
In case of ICH, the guidelines suggest waiting at least 3–4 weeks before surgery. This indication is supported by studies showing rapid deterioration of neurological conditions in patients undergoing early surgery (31-34). On the other hand, recent studies have re-discussed this topic showing how the risk of disease progression in patients with ICH is very low, giving early surgery a greater safety profile (35,36). In support of this thesis, Salaun et al. in recent single center study have shown that patients who present with ICH show a higher mortality if treated conservatively when IE surgery is indicated (37). Other studies have shown not only non-inferiority of surgery performed within 2 weeks of the bleeding event, but also an improvement in the outcomes in terms of mortality (31,35,38). Parameters as the size of the hemorrhagic area and the presence of hemorrhagic infarction of brain tissue have become increasingly important in the stratification of patients presenting with ICH (39).
Surely, these controversies warrant the need for further studies deepening knowledge on this argument.
Gaps in knowledge
Despite several aspects of IE management are challenging and debated, the most important gaps in knowledge relate to the correct timing of surgery in patients with neurological complications, the role of early surgery to prevent embolism, and in patient with prosthetic valve endocarditis (PVE). These areas require further evidences to formulate a correct decisional algorithm.
The presence discrepancies between different guidelines is an indicator of the difficulty in the identification of the correct therapeutic strategy of patients with IE, especially in those burdened by neurological complications.
The difficulty in performing randomized trials in this field has conspired against the agreement on univocal indications on IE management and left the evidences on some particular aspects to the level of “expert opinion”. Despite a general adherence to the guidelines, the clinical practice is often multifaceted and inevitably influenced by surgeons’ experience or predilection.
The possibility of postponing surgery for 4 weeks after a cerebral hemorrhage protects patients from an increased risk of bleeding during cardiopulmonary by-pass. On the other hand, septic embolization of endocarditic vegetation is the most frequent cause of stroke with hemorrhagic degeneration. Delaying the surgery means exposing the patient to the risk of new embolic events with negative impact on clinical outcomes.
Currently, the literature does not provide sufficient information to provide an unambiguous answer to these questions. Elements of the clinical history, comorbidity, extent of the infection, presence of intra-cardiac prosthetic materials could guide decision-making in the context of the endocarditis team. However, only further investigations with specific aims could shed light on these challenging interrogatives.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Drs. Francesco Nappi, Christos Mihos, and Cristiano Spadaccio) for the series “Infective Endocarditis in the 21st Century” published in Annals of Translational Medicine. The article was sent for external peer review organized by the Guest Editors and the editorial office.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/atm-20-5134
Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5134). The series “Infective Endocarditis in the 21st Century” was commissioned by the editorial office without any funding or sponsorship. FN served as the unpaid Guest Editor of the series and serves as an unpaid editorial board member of Annals of Translational Medicine from Feb 2019 to Jan 2021. CS served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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