Infective endocarditis (IE) is an infection of the endocardium, caused by bacteria, fungi or other infectious agents.1 It can be classified according to its course (acute or subacute/chronic), the valve involved (native or prosthetic), the number of valves affected, the way it was acquired (community, intravenous drug users or healthcare-associated) and the microorganism involved.2

Despite advances in diagnosis and therapeutic approach, neither the incidence nor the mortality of IE has reduced in the last 30 years, and mortality remains high.3 IE incidence is 3–7/100 000 person-years, and in-hospital mortality ranges from 15–30%.2,4 In most epidemiological studies, the male-to-female ratio is ≥2:1; female patients have a worse prognosis and undergo valve replacement surgery less frequently.5

In recent years, there have been considerable changes in the epidemiology of IE, especially in industrialized countries. In the past, IE mainly affected young adults with known valve disease (mostly affected by rheumatic fever6–8); nowadays, the typical IE patient is elderly (peak incidence between 70–80 years) with valve disease of a degenerative etiology, prosthetic valve(s) or intracardiac devices, including pacemaker or cardioverter defibrillator.5,9 Other predisposing factors for IE have emerged, including intravenous drug use, invasive surgical procedures, vascular instruments, diabetes, long-term care (hemodialysis centers and outpatient parenteral antibiotic therapy programs).9,10

The microbiological profile of IE has also changed significantly. Classically, the agent most often involved in IE was Streptococcus viridans, causing subacute IE.11,12 More recent studies show that Staphylococcus aureus has been the most frequently isolated microorganism, manifesting itself clinically as acute IE.13

This major change in epidemiology, together with the variability in the forms of presentation of the disease, has had direct consequences on the diagnosis, treatment and prevention of IE. To overcome these difficulties, the modified Duke criteria are used, which are based on clinical, echocardiographic and microbiological findings, providing a sensitivity and specificity of approximately 80% for the diagnosis of IE.14

Recent advances in imaging techniques, including computed tomography, magnetic resonance imaging, and single-photon positron emission tomography have improved the identification of endocardial involvement and extracardiac complications of IE, resulting in the reformulation of the above diagnostic criteria.2 However, echocardiography and blood cultures remain cornerstones in the diagnosis of IE. Transthoracic (TTE) or transesophageal (TEE) echocardiography enable the identification of the main findings/criteria for IE (vegetation, abscess, and de novo dehiscence of a prosthetic valve).15 They are also useful for assessing disease severity, establishing prognosis, and assessing the effectiveness of antibiotic therapy.16 Positive blood cultures are reported in about 69% of all cases of IE, and IEs with negative blood cultures are principally related to the prior administration of antibiotics, sometimes delaying diagnosis and initiation of treatment.2

Rapid initiation of antibiotic therapy is essential to prevent major complications: heart failure (HF), stroke, systemic embolization, and sepsis/septic shock.17 In addition to prolonged antibiotic therapy regimens, the treatment of IE relies — in about half of the patients — on surgical removal of the infected tissue.18,19 Prognostically, IE is influenced by four main factors: patient characteristics, presence or absence of complications, infectious agent and echocardiographic findings.20 To date, four Portuguese studies have been published in which an attempt was made to retrospectively identify which factors are predictors of in-hospital mortality from IE.21–24 The development of sepsis, septic shock and HF were the common predictors of unfavorable prognosis in three of the studies.22–24 In-hospital mortality ranged from 13.1–31.3%. Only one of the studies assessed follow-up at six months24 and none of them studied long-term follow-up.

There are significant geographical variations and guidelines are often based on expert opinion due to the low incidence of IE, the lack of randomized trials and the limited number of meta-analyses.25 For this reason, and as it is a disease with such high mortality, the aims of this study were to assess the evolution of the epidemiological profile of IE before and after 2007 (regarding risk/predisposing factors, previous risk procedures, infectious agents), to assess the temporal trend of this disease, to define the current prognosis of affected patients, both in the short and long-term, and to define the main prognostic factors (clinical, analytical, echocardiographic and treatment).

In this study, there was an annual oscillation in the number of patients hospitalized for IE, with a period with a higher number of cases between 2010/2011 and 2013. Males were the most affected individuals and valvular disease was the most common cardiac predisposing factor (33.5%).

In the first study period, IE occurred in younger individuals with active IV drug use, gastrointestinal disease, and concomitant HIV and HBV infection. In the second study period, IE occurred in older individuals with concomitant cardiovascular disease.

The most frequently isolated microorganism throughout the study period was Staphylococcus aureus. Enterococcus emerged significantly as the agent most responsible for IE in the second subperiod of the study.

Overall mortality associated with IE was 14.5% during hospitalization, 38% after one year, and 47% after five years. The referral rate for cardiac surgery was 34%, increasing in the second period of the study.

Independent predictors of in-hospital death or need for urgent surgery were septic shock and the occurrence of peri-annular complications. Independent predictors of long-term mortality were age, chronic kidney disease, and IE from multidrug-resistant microorganisms.

As this is not a population-based study, it was not possible to provide data regarding the incidence of IE over time. There was, however, an oscillation in the number of cases/year with a higher number of cases between 2010/2011 and 2013.

Data regarding on the incidence of IE have been controversial, and several studies have identified no change in the incidence of IE.4,32–35 However, some European population-based studies have shown an increase in the incidence of IE over time.36–38 This also occurred in a Spanish multicenter study, which included about 16 867 IE episodes over 12 years (2003-2014) and reported an increase in IE incidence of 2% yearly, from 2.72 in 2003 to 3.49 per 100 000 person-years in 2014, which was more evident in the older population.39

The increased incidence of IE in older populations was also reported by Hill et al.,40 who highlighted that half of all cases of IE in the United States of America and Europe occur in patients >60 years, and that the mean age of patients has increased steadily over the past 40 years. This increase seems to be represented in our study population as well, since the mean age of the population in the group that had endocarditis between 2008 and 2013 was higher than the group that had endocarditis between 1998-2007. The explanation for the increasing number of cases of IE in the older population may lie in the increased average life expectancy of the population and also in their greater contact with health services and with invasive techniques/procedures. In addition, more elderly populations also have a higher percentage of patients with valvular prostheses and intracardiac devices, such as pacemakers and cardioverter-defibrillators. This scenario was also represented in this study, where a higher percentage of patients with IE who had intracardiac devices/pacemakers or cardioverter-defibrillators was observed in the group that had endocarditis between 2008 and 2013. There was also a higher percentage of patients with prosthetic valves in this subgroup, although without statistical significance.

This study revealed a higher number of cases of IE in males (66.5%), with a male-to-female ratio of approximately 2:1, comparable to the results obtained by other studies.41–43

The microbiological profile showed that blood cultures in this study were positive in 76.3% of cases, a result consistent with other international studies.2,39 The most frequently isolated microorganism was Staphylococcus aureus (20.2%), as documented in most studies, and there was an increase in the number of Enterococcus-associated IE cases in the second study period. The increase in the number of Enterococcus-associated IE cases was also reported in the Spanish multicenter study39 and is likely related to the previously mentioned increase in the prevalence of invasive healthcare-related procedures in recent years, such as intravenous lines, catheterization, hemodialysis, etc.

Septic shock, a recognized unfavorable prognostic factor associated with high mortality in IE,44–46 occurred more frequently in the subgroup of patients in the second half of the study. The explanation for this occurrence may be, as previously mentioned, the older age of the population in this subgroup, despite a higher rate of surgical intervention.

In regression analysis, septic shock and peri-annular complications were the independent predictors of in-hospital mortality or need for urgent valvular surgery. These are known predictors and reported in the literature, particularly in Portuguese series from Level III centers.21,23

Independent predictors of long-term mortality were age, chronic kidney disease, and multidrug-resistant microorganism-associated IE. Both age and the presence of chronic kidney disease are known factors of adverse long-term prognosis. The explanation for the association between long-term death and the occurrence of multidrug-resistant microorganism-associated IE is more difficult to establish but may suggest there is greater “frailty” among patients, with more comorbidities associated with contact with healthcare systems and greater prior use of antibiotic therapy.

Even with the major advances in the last decades, IE mortality remains excessively high,47,48 in-hospital mortality lying between 15 and 30%.2 Two recently published multicentric studies, one a previously mentioned Spanish study, with more than 16 000 IE episodes,39 and the other a European, multinational study with data from 41 countries and including 867 patients,49 showed in-hospital mortality of 20.4% and 17.7%, respectively, slightly higher than the present study (14.5%). In Portugal, there are three large series of patients with IE from four level III centers, Centro Hospitalar e Universitário de São João and Centro Hospitalar do Porto,24 Hospital de Santa Marta,21 and Centro Hospitalar Vila Nova de Gaia Espinho.23 The perioperative mortality in these series was 23.8%, 16.3% and 13.1%, respectively. In comparison with the data from the Portuguese series, the in-hospital mortality found in this study overlapped or was slightly lower, which was greatest difference relative to that reported in the series of the two centers in Porto; they had higher mortality. This difference may be due to a referral bias, since patients transferred to referral hospitals are likely to be more severe and have more complications during the course of the disease requiring urgent surgery.

This issue was addressed by two prospective cohort studies that analyzed differences comparing patients with IE who were or were not transferred to Level III centers.50,51 This situation may also explain a higher in-hospital mortality and longer length of stay at high-volume centers, as well as a higher rate of referral to surgery. However, when an adjustment is made for patient risk, it was found that among hospitals with cardiac surgery, the adjusted mortality was lower in centers with a higher volume of IE episodes per year. These results may suggest the creation of IE referral centers in an attempt to decrease the still high in-hospital mortality.

Unfortunately, IE-associated mortality does not end at the patient's discharge from the IE episode. If it is true that the European guidelines for prevention and treatment of IE recommend active surveillance of signs and symptoms of IE recurrence for 12 months after completion of treatment,2 the data on mortality risk among these patients in the short and long-term remain controversial. Some studies report that mortality is highest in the first year and then decreases, although it remains high compared to the general population.52,53 A Swedish study based on the entire population of the country with IE, showed that the increased risk of long-term mortality persists for more than 5 years after the IE episode.54 Additionally, a Dutch retrospective study showed that the 10-year survival rate of patients who received surgical treatment for IE was comparable to that of the general population.55 These data seem to equate the 10-year mortality of the population of patients who had IE to that of the general population, so it is also important to emphasize that this was the case in the population of patients who underwent surgical treatment. Thus, surgical intervention, when indicated, seems to be a key point not only for survival in the in-hospital period, but may also mean that survival could equal that of the general population in the long-term.

Assessing the mortality data from this study, we can conclude that IE survivors maintain an “excess” mortality at least until the 5th year after the IE episode, with a mortality of 38% and 47% at one and five years, respectively. From the 10th year after IE, there seems to be a stabilization in mortality, which in our study remained around 56%. There were no significant differences in mortality between the groups in the two study periods.

Regarding guidance for valve surgery, in this study 34% of patients underwent surgical treatment, which occurred more frequently in the second period of the study. This figure overlapped with that reported by the Spanish multicenter study (23–35%) and the Portuguese series from Level III Centers (36.9% and 38.8%).21,24,39

Regarding IE prophylaxis, both the latest recommendations of the European Society of Cardiology from 20152 and those of the British Society for Antimicrobial Chemotherapy (BSAC) from 200632 and the American Heart Association from 2007,56 recommend IE prophylaxis only for patients at higher risk of severe disease or death from endocarditis57 (mostly patients with congenital disease, especially cyanotic, previous endocarditis and patients with prosthetic valves) undergoing procedures considered high risk (some types of dental procedures). Additionally, the 2008 National Institute for Health and Clinical Excellence recommendations presented an even more radical restriction for IE prophylaxis, suggesting no prophylaxis prior to any type of procedure, even in high risk58 patients. The data on incidence of endocarditis in England show an increase in incidence after the aforementioned 200859 recommendations. In the present study few patients with an indication for prophylaxis according to the current recommendations were identified, given that few patients underwent previous dental procedures. However, several patients had undergone other invasive procedures (genital-urinary, broncho-pulmonary, etc.). Of these, only a few had prophylactic antibiotic therapy associated with the procedure itself and not necessarily with coverage for the main agents of IE. Thus, it was not possible to clarify the existence of a possible cause-effect relationship between prophylaxis and IE development, as well as the possible role of these invasive procedures not covered in current recommendations.

Although this is one of the few studies with long-term follow-up data and that attempts to present a temporal change in the epidemiology of IE, it has limitations. First, those inherent to the fact that it is an observational, single center and retrospective study (several data that may be relevant are missing or incomplete on the clinical files). Then, the fact that we included some patients who had IE over 16 years, which were certainly approached differently by those treating them. On the one hand, over that time, the European IE recommendations themselves changed, not only regarding prophylaxis but also regarding IE treatment. Then, there is the greater availability and evolution of imaging techniques, diagnostic laboratory techniques, and even surgical techniques and implanted prosthetic material. In addition, intensive/postoperative care itself has also undergone changes. Furthermore, some of the patients included had had an IE episode more than 20 years ago, at a time when records were scarce and in hardy copy. Information bias cannot, therefore, be ruled out.

Advances in diagnosis and treatment of IE have not led to a significant decrease in mortality in recent years. In fact, in the second time period, in-hospital mortality was double that of the previous period, almost achieving statistical significance. In an era in which IE prophylaxis is increasingly restricted and in which the population is increasingly aged, with multiple comorbidities and with more and more intracardiac devices, it is essential to invest in more effective strategies, focusing on the prevention of health system associated infections, reinforcing the general promotion of oral health and judicious use of antibiotic therapy, not forgetting the early identification of the disease and the rapid referral for valvular surgery, when necessary. The creation or reinforcement of high-volume level III referral centers and of an IE heart team may improve disease prognosis.

The authors have no conflicts of interest to declare.