Discussion
Infective endocarditis was first described by Osler, in 1857 as a pathology of patients with a pre-existent valvular disease7. Since then, significant progress in disease understanding has been achieved. The majority of large epidemiological studies come, however, from developed countries, with a gap in solid evidence from developing regions.
IE incidence varies from 2 to 6 cases per 100.000 inhabitants/year, a value quite steady over the last decades 1. This incidence, associated with prolonged hospital length of stay and elevated hospitalization costs, makes IE a real worldwide burden8.
The present study provides valuable insights into IE in the current era, bringing data from a tertiary hospital in South America, a complex demographic region with huge contrasts and a lack of comprehensive epidemiological reports.
In the present study, we demonstrated that the primary IE causative organisms were Staphylococcus aureus, followed by Enterococcus, Coagulase-negative staphylococci,  and Viridans streptococci. These findings are in accordance with the international literature, which demonstrates a significant increase in Staphylococcus aureus prevalence (21% - 30% in the last five decades)8, representing, currently, the most frequent microbiological agent in high-income health systems. Besides, our results are similar to the ones from other two Brazilian inquiries9, 10.
The transition in pathogen pattern, from viridans streptococcus to Staphylococcus aureus, has been associated with population-aging, decrease in rheumatic heart disease burden, and advanced device management, particularly in cardiac patients 11, 12. Precisely because of these factors, this transition was more pronounced in high-income countries; however, as reported in this study, also in less developed regions, Staphylococcus aureus has emerged as the primary IE pathogen.
A common issue in IE studies from developing countries is the high prevalence of negative blood cultures 2. In our study, blood cultures were negative in 23.3% of cases, a value beyond the 10% reported in recent scientific publications 12, 13, but similar to other developing countries inquiries (10-55%)9, and even lower than in Asiatic populations (30–65%) 14-16. Negative cultures are usually related to infections with highly fastidious bacterial or non-bacterial pathogens, inadequate microbiological technique, or prior administration of antibiotics before the diagnosis of IE 17.
Most of our patients were males (66%) e the majority of the cases were from native valves (73%), a similar pattern than that reported in other studies from developing countries 10, 18-21. IE has a well-recognized and consistent male predominance, with a reported male: female ratio of 1.2:1 to 2.7:1 22. The explanation for the male predominance could be related to the presence of congenital cardiac conditions, such as a bicuspid aortic valve that also has a male predominance 2.
Diverging from other developing countries reports, we observed a median age of 60 years, resembling western countries trends, in which patients age is typically 60 or 70 years old 23. According to Yew SH et al., increased longevity, decreased rheumatic heart disease incidence, staphylococci predominance, and increased use of invasive procedures and medically implanted devices represent the current IE scenario in developed countries 2. Taken these features into consideration, our epidemiological and microbiological profiles seem to be closer to those from developed countries instead of developing regions. This pattern is also disclosed when we analyze the most affected valve. While in developing countries, mitral valve involvement predominates, due to a higher prevalence of rheumatic disease 20, 24, 25, in our series, the aortic valve was the most affected (54.5%).
In terms of mortality, despite improvements in diagnostic accuracy, medical therapy, and surgical techniques, IE mortality rate remains relatively high. In our study, we observed an overall in-hospital mortality of 41.9%, meeting other Latin-American reports (46.4% and 31%) 9, 10, but much superior to that described in high-income healthy systems (15 to 22%) 26. This higher mortality rate may be justified by differences in patients’ profile, with a high prevalence of multiple comorbidities, and a delay in reaching medical assistance. In our study, for instance, the average time between symptoms onset and hospital admission was 7 days, resulting in a remarkable diagnosis and intervention delay. Besides, 25% of our patients were admitted on decompensated heart failure and 39% presenting an embolic event.
Another relevant factor is that our study reflects data from a tertiary referral center, which presents an inherent selection and referral bias. As describe by the International Collaboration on Endocarditis – Prospective Cohort Study (ICE-PCS), patients with IE who require surgery and suffer complications (e.g., stroke, heart failure, and new valvular regurgitation) are referred to tertiary hospitals more frequently than those with an uncomplicated course 27, contributing to increase the in-hospital mortality in referral centers.
In this same line, analyzing IE incidence and mortality in the Veneto Region (Italy) from 2000 to 2008, Fedeli U et al. observed an increase in 36-day mortality from 24.6 % (2000-2002) to 31.5 % (2006-2008), which was, at least partially, attributed to a growing number of the elderly patients (median age was 68 years) 28.
According to the present study, diabetes mellitus, previous structural heart disease, and mitral valve infection were the independent predictors of in-hospital mortality, while patients submitted to surgical treatment had 55% less chance of dying than those handled just with clinical treatment. This finding follows the new trends in IE treatment, which suggests that early valve surgery will result in better outcomes. Liang et al., for instance, conducted a meta-analysis revealing that, compared with non-early surgery, early surgery was associated with reduced in-hospital (OR 0.57) and long-term mortality incidence (OR 0.57) 26.
Last but not least, 49% of our patients received a cardiac surgical intervention, which fits the rate reported in the current IE European guideline (40–50%). This guideline also reinforces that despite early surgery is indicated to avoid progressive HF, irreversible structural damage and to prevent systemic embolism, it is associated with significantly higher risk. Therefore, surgical indication would be justified in patients with high-risk features that make the possibility of cure with antibiotic treatment unlikely, and who do not have comorbid conditions or complications that make the prospect of recovery remote29.
Unfortunately, the present cohort had not enough power to compare those patients that were submitted to an early intervention versus those that had more delayed surgery. However, our study adds evidence in the assumption that surgically treated patients have better outcomes than those clinically managed.
The major limitation of our study is its retrospective and single-center design, enrolling patients from a tertiary-care center, which could not represent the profile of entire South American health system. On the other hand, one of the major highlights of our study is that this is one of the largest cohorts of patients from Latin America and the largest in Brazil. It is also important to highlight that the description of temporal trends and associations does not provide evidence of causality. Despite a long-term enrollment period, this study focuses on short-term results. Properly designed trials with long-term follow-up are required to confirm the impact and trends in IE.