Epidemiological Profile of Patients with Infective Endocarditis at three Tertiary Centers in Brazil from 2003 to 2017

Background: Infective endocarditis (IE) is a disease with high morbimortality and an increasing incidence. With improved diagnosis and treatment, a number of epidemiological changes have been reported over time. Objectives: We sought to describe the epidemiological profile, mortality predictors, and analysis of a possible microbiological transition in patients admitted to three tertiary centers in Brazil. Methods : In this cross-sectional retrospective study, data from 211 patients with definite or probable IE were analyzed according to the modified Duke criteria between 2003 and 2017. The association between categorical variables was assessed using the chi-square or Fisher's exact test, and binary logistic models were built to investigate mortality. We considered p <0.05 statistically significant. Results: The median age of the sample was 48 (33-59) years old, 70.6% were men, and the most prevalent pathogen was Staphylococcus spp. (19%). Mortality was 22.3%, with increasing age being the leading risk factor for death (p = 0.028). Regarding the location of the disease, native valves were the most affected site, with the aortic valve being more affected in men than women (p = 0.017). The mean number of cases of Staphylococcus spp. (τ = 0.293, p = 0.148) and Streptococcus spp. (τ = -0.078, p = 0.727) has remained stable over the years. Conclusion: No trend towards reduced or increased mortality was evident between 2003 and 2017. Although Staphylococcus spp. were the most prevalent pathogen, the expected epidemiological transition could not be observed.

60893616.7.0000.5134). Informed consent was not required due to the retrospective nature of the study.

Statistical analysis
Categorical variables are presented as absolute and relative frequencies, and quantitative variables are presented as median (1 st -3 rd quartile). The normality of quantitative variables was assessed using the Shapiro-Wilk test, while the Wilcoxon-Mann-Whitney test was used to compare quantitative variables among groups. The association between categorical variables was assessed using the chi-square test and Fisher's exact test. Binary logistic models were constructed to verify the association with mortality, and the results are presented as odds ratios (OR) and 95% confidence intervals. The Mann-Kendall test was used to verify the temporal trend. The analysis was performed in R version 3.5.2, with p <0.05 considered significant.

Results
The sample consisted of 211 patients, whose profile has been described in a previous study: 8 110 from Belo Horizonte and 101 from Ipatinga. Their median age was 48.0 (33-59) years and 70.6% were men. Bacteria of the genus Staphylococcus were the most prevalent pathogens, observed in 19% of cases, with Staphylococcus aureus occurring in 10% and Coagulase-negative Staphylococci in 9%. Native valves were the site of IE in 70.6% of the cases, and the greatest prevalence was in the mitral valve (41.7%), (Table 1).

Mortality
Overall mortality was 22.3%. It was observed that increasing age is a risk factor for death (p = 0.028). However, when the sample was stratified into patients younger and older than 65 years of age, there was no statistical relevance (Table 2). Among patients younger than 65 years who died, the native aortic valve was the most affected site (33.3%) and Staphylococcus spp. was the most frequent pathogen, representing 30.6% of the cases. Regarding the 11 deaths in patients older than 65 years, most were due to Streptococcus spp., and the most prevalent location was the native mitral valve. Sex, blood culture findings, and lesion location had no statistical relevance on mortality. Mortality from IE remained stable between 2003 and 2017 (τ = 0.010). The highest and lowest death rates occurred in 2004 and 2012, respectively. and its incidence has increased over time. 1 However, most studies that observed this change were conducted in developed countries, and it is unclear whether developing countries are susceptible to this epidemiological transition to the same extent and magnitude, given the possible difference in access to medical resources. 3 Furthermore, it is extremely relevant to understand the risk factors associated with mortality as well as the profile of patients affected by IE. 5,6 Only 10 epidemiological studies on IE have been published in Brazil, and none of them addressed this possible change, especially since their samples were included over a limited time span. Considering the high regional variability and epidemiological transition in IE, the purpose of this study was to survey the characteristics of a population of patients with IE over 14 years to analyze the behavior of variables over time, determine predictors of mortality, and better understand the profile of affected individuals.

Sample description and design
This observational, retrospective, cross-sectional study included 211 patients admitted to 3 tertiary health centers in Ipatinga and Belo Horizonte in the state of Minas Gerais, Brazil, between 2003 and 2017. An initial survey of medical records containing International Classification of Diseases related to IE (ICD 10 I33.0) was conducted. These records were analyzed and information on epidemiological, microbiological, valvular, and outcome characteristics were collected in an Excel database.
The inclusion criterion was definite or probable IE according to the modified Duke criteria. 7 Patients whose medical records were incomplete, who were transferred during hospitalization, or who were still hospitalized at the time of analysis were excluded. After selection, data from the medical records were collected, including age, sex, blood culture, and prognosis. The microbiology was determined through blood culture results, and the location of the IE was determined through echocardiographic or perioperative findings. This study was approved by the ethics committee of the Faculty of Medical Sciences of Minas Gerais (CAAE

Differences between the sexes
Of the 211 patients, 149 were men and 62 were women. A total of 82.3% of the men and 81.9% of the women diagnosed with IE were younger than 65 years of age (no significant difference). Native valves were most affected, especially the mitral valve, regardless of the patient's sex, representing 40.3% of the infections in men and 45.2% in women, while the pulmonary valve was the least affected site. Of note, prosthetic valve endocarditis occurred in 22.8% and 27.4% of the men and women, respectively, at a ratio of approximately There was no association between the other findings (blood culture, age group, and other IE sites) and sex. Table 3 shows the relationship between microbiological findings, age, and affected valve. There was no association between a specific microorganism and age, with individuals younger or older than 65 being equally affected. Infection by atypical microorganisms was more common in patients with prosthetic valve endocarditis (p = 0.014). Individuals without mitral lesions were more prone to infection by Coagulase-negative Staphylococci (p = 0.026). Regarding the main pathogens found during the study period (Figure 1), all had a non-significant trend according to the Mann Kendall test: Staphylococcus spp. (τ = 0.293, p = 0.148), Streptococcus spp. (τ = -0.078, p = 0.727) and negative blood culture (τ = -0.332, p = 0.100), which indicates that the occurrence of these microorganisms was stable over the years.

Discussion
IE is a serious infectious disease, and a multidisciplinary approach involving specialists is necessary to treat and monitor these patients. Although the incidence of IE has been increasing over the years, 9 few studies have been published on IE in developing countries, which makes a general analysis difficult. The overall mortality in our sample was 22.3%, which is consistent with several other observational studies, 10,11 including some conducted in developing countries. 12 The logistic regression model ( Table 2), showed that patient age was directly related to mortality [p = 0.028; OR 1.020, 95% CI 1.003; 1.039], which agrees with other studies, eg, Khan et al., 13 who obtained a similar result with a sample of 523,432 patients in the United States. Moreover, this study reported a trend over the years toward reduced mortality in IE patients, which the authors ascribed to improved medical services in the USA. However, such a trend was not observed in our analysis. No significant differences were found regarding microbiological profile and mortality, which contrasts   with the results of Joffre et al., 14 who found an association between Staphylococcus spp., Candida spp. and higher in-hospital mortality, as well as an association between IE due to Streptococcus spp. and a more favorable prognosis. It should also be pointed out that these authors found male sex to be a protective factor against death. Other authors have found a direct relationship between mortality and endocarditis location, with the aortic and mitral valves having the worst outcomes. 9,15,16 However, we did not observe this in the present study.
It is possible that comorbidities (e.g. hypertension, heart disease, etc.) and events (e.g. septic shock, need for surgical approach) affect prognosis more than the microbiological or valvular characteristics of the IE. Ren et al. 15 found significant associations between higher mortality and conditions such as hemorrhagic and ischemic stroke, constrictive heart failure, pneumonia, and renal failure. One limitation of our study is the lack of data on these variables.
In general, IE affected men the most (70.6%), at a ratio of 1.7:1. This difference has been found by other authors in Belgium, 17 Saudi Arabia, 18 and Brazil, 9,19 and Bakir et al., 20 ascribed it to the potential protective role of estrogen against endothelial injury. Other authors have reported a lower prevalence of IE in women, including a lesser likelihood of developing sepsis. 21,22 Nevertheless, none of these mechanisms are fully understood. It is curious that, although IE affects fewer women, it seems to be related to higher in-hospital mortality. 23,24 In fact, prognostic scales such as the EuroSCORE and the results of Martínez-Sellés et al., 25 indicate a worse outcome among women and a greater likelihood of death.
Furthermore, our analysis showed that native aortic valves are more affected in men than women (p = 0.017), which was also described by Sevilla et al., 26 and Elamragy et al., 27 who further described that the native mitral valve was more affected in women. Regarding the microbiological profile between the sexes, the most frequent microorganism was Staphylococcus spp. (22.6% men vs 17.4% women, p = 0.501), a result similar to other authors. 27 The equally high negative blood culture rate in men and women is also of note (32.9% and 35.5% respectively, p = 0.838), which may be explained by the indiscriminate use of antibiotics to treat any febrile disease before obtaining cultures, a common practice in Brazil. It should be pointed out that some studies have found a much higher percentage of negative blood cultures than ours, eg, in Egypt (69.5%) 27 and South Africa (55.3%), 28 while others have found lower percentages, eg, in France (9%) 29 and the United Kingdom (12.2%). 30 Thus, it could be cautiously inferred that Brazil is somewhere in the middle of a broad spectrum, which might be associated with improvements to the Brazilian public health system, as well as new and more effective hospital protocols.
The relationship between the affected valve and the blood culture results diverges greatly among studies. What became clear in our study was that a positive blood culture for coagulase-negative staphylococci is less related to mitral valve lesion (Table 3), which was also reported by Barrau et al.,31 These authors also found that Staphylococcus aureus affects the aortic valve the least. Another important result of our study was that patients with cardiac prostheses were more likely to be affected by bacteria in the "other" category, which may reflect inadequate laboratory techniques or less strict criteria for diagnosing IE. 32,33 Finally, we should point out that we found Staphylococcus spp. to be the most prevalent pathogen, which agrees with the literature. [1][2][3][4]34 However, we did not observe the reported epidemiological transition toward more cases due to Staphylococcus spp. and fewer cases due to Streptococcus spp. (Figure 1) over the years as consequence of medical progress. Most studies reporting this trend have been conducted in developed countries, 1 and little evidence for such a trend has been found in low/middle income countries, either due to the precariousness of medical systems or the scarcity of new studies.

Limitations
Our study is not without limitations. First, since we performed a retrospective analysis, associations between variables do not necessarily indicate a causal relationship. Second, the sample can be considered small, since we dealt with cases over 15 years at three different centers, as well as the fact that it included many probable IE cases (93 out of 211). However, few studies have been published on the epidemiological profile of Brazilian patients and, to the best of our knowledge, our study involves the largest such sample. It should also be pointed out that most of the probable IE cases involved a negative blood culture, which is related to the use of antibiotics. Third, no data on comorbidity, heart valve disorder, hemodynamic variables, heart failure, abscess formation, or heart valve surgery were collected. Thus, any discussion of mortality must be extremely limited. Finally, it was not possible to collect blood samples for blood culture in 34 patients, either because they received treatment prior to collection or because they began antibiotic therapy before being transferred to tertiary centers.

Conclusion
In conclusion, among the 211 IE cases included in this study, age had the greatest influence on mortality. However, a trend towards reduced or increased mortality was not evident during the study period. Although more infections occurred in native aortic valves in men than women, no specific bacteria stood out. Additionally, in patients whose IE was due to coagulase-negative staphylococci, the mitral valve was less likely to be affected, whereas patients with heart prostheses were more likely to be infected with bacteria in the "other" category. Even though Staphylococcus spp. were the most prevalent pathogen in the sample, we did not observe the epidemiological transition described in literature. Finally, further research is needed to better understand the risk factors associated with mortality in developing countries, especially comorbidities, symptoms present at admission, and the effects of surgical interventions.

Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.

Sources of Funding
There were no external funding sources for this study.

Study Association
This study is not associated with any thesis or dissertation work.