To our knowledge, this is the first study showing significant associations between causative bacteria and IE manifestations detected by ECHO. In this cohort of 492 patients from the SRIE, we found that patients with S. aureus were more likely to have tricuspid valve vegetation but less likely to have aortic valve vegetation. Furthermore, S. aureus-linked IE was more common among patients with a history of IV drug abuse but less so among patients with prosthetic valves. Associations were found between CoNS and the presence of a perivalvular abscess, with more than one manifestation on ECHO and with CIED-associated IE, but CoNS were less common among patients with a history of IV drug abuse. Although it should be noted that there were relatively few patients with CoNS (n = 24, 5%). Among patients with a native aortic valve, findings of aortic valve vegetations were associated to presence of E. faecalis, and closely associated to CoNS. However, this was not the case with prosthetic aortic valves. Further, significant associations were seen between viridans group streptococci and group B streptococcal infections and mitral valve vegetations and between HACEK- and CIED-associated IE.Associations between specific bacterial infections and IE manifestations detected by ECHO have been reported previously [10, 11]. Trifunovic et al. could not show any associations between specific IE manifestations and certain etiologies in their study of 246 patients with IE, even though their main findings were that S. aureus and gram-negative bacteria caused large vegetations, CoNS caused destructive leaflet lesions, CoNS and gram-negative bacteria caused perivalvular extension of the infective process, and that gram-negative bacteria were associated with multiple manifestations in the same patient . Those results were consistent with our findings that CoNS infections were associated with perivalvular abscesses (extension of the infective process). Furthermore, we found that S. aureus infections were associated with tricuspid valve IE, which is supported by Bonetti et al. in their study of 274 patients with IE .
In our analysis of the most common bacteria causing IE was S. aureus, present in 47% of all patients. These findings are in line with studies showing that S. aureus is the most common bacterium causing IE in industrialized countries [3, 12, 15, 16]. In this study, 51% of the patients with S. aureus etiology had IV drug abuse. However, when stratified for left-sided and right-sided IE, patients with S. aureus and left-sided IE were older and had significantly higher in-hospital mortality than those with S. aureus and right-sided IE. This stratified finding is more adherent to previous studies presenting that IE caused by S. aureus has high mortality rates compared to IE caused by other pathogens [3, 12, 15, 16]. In addition, we found that the presence of a perivalvular abscess, a serious IE manifestation of tissue destruction, was associated with in-hospital mortality. Similar results were reported by Lauridsen et al. who showed that perivalvular abscess and valve perforation independently predicted 1-year mortality in patients with left-sided native valve S. aureus-linked endocarditis .Furthermore, in our study, Streptococcus species were also common (27%), as was seen in studies presenting a high and increasing prevalence of streptococci in general, but more specifically viridans group streptococci and S. bovis [18, 19]. SurgeryIn our study, 28% of patients underwent surgical treatment, slightly less than the 31% of Swedish patients with IE who underwent surgical treatment in 2017 . This lower percentage in our cohort might be explained by the large proportion of patients with a history of IV drug abuse and right-sided IE, which were less frequently treated with cardiac surgery compared to the IE patients with no IV drug abuse. Patients with aortic valve vegetation, CIED-associated endocarditis, or a perivalvular abscess more often underwent surgical treatments. It has been argued whether S. aureus should be listed as an absolute indication for surgical treatment, as it often causes severe IE with the presence of emboli or abscesses, and/or severe valvular engagement, but the current recommendations promote individual evaluation of patients for decisions on using surgical treatments [6, 20, 21]. This individualized approach was adopted in decision-making at KUH.
Prosthetic valves and CIED-linked IE
It has been reported that prosthetic valve IE and CIED-linked IE are becoming more frequent . During the study period of this study, 2008-2017, there were no significant differences in the prevalence of CIED-associated IE and prosthetic valve IE, although it should be noted that there were only a few patients with CIED-linked IE and prosthetic valve IE. These cases can be challenging to diagnose, especially with TTE because of its relatively low resolution and shading from the prosthesis or chordae tendinae; thus, TEE is highly recommended [2, 18, 22]. The respective sensitivities for diagnosing native IE and prosthetic valve IE are approximately 96% and 70% with TTE and 96% and 92% for TEE, respectively . In our study, associations were found between prosthetic valve IE and S. aureus and E. faecalis, respectively. The associations between the incidences of prosthetic valve IE and E. faecalis infection found in our study differ from previous reports. S. aureus and CoNS infections have been described as common etiological factors for prosthetic valve IE .IV drug abuseKUH has a special ward for addicts with infections, with an uptake area covering Stockholm County Council (approximately 2.3 million inhabitants), which might contribute to the relatively high presence of IV drug abuse among endocarditis patients at KUH. Studies of patients with IE in the USA in 2012–2013 showed a lower incidence of IV drug abuse among IE patients (6.5–7.8% of the IE patients had IV drug abuse) than in our results (32% of the patients had a history of IV drug abuse), although recent US and European studies have noted that the presence of IV drug abuse is generally increasing among patients with IE [23, 24]. The high prevalence of IV drug abusers among the IE-patients have affected the association between S. aureus and tricuspid valve vegetation found in this study. When stratifying for IV drug abuse, we found that there were no association between S. aureus and tricuspid valve vegetation among patients with no IV drug abuse, but significant association was found among patients with IV drug abuse. S. aureus was the most common bacterial species among patients with IE and a history of IV drug abuse, which is consistent with previous studies [23-25].
Although there were significantly more men than women in our study (~2:1), we found no gender differences in IE etiology, which is consistent with earlier studies in which the ratio of men to women was typically higher than 2:1 [26, 27]. Previous work has evaluated the differences in etiology and manifestations, but with ambiguous results. For instance, Aksoy et al. showed that women were more likely to have vegetations on CIED and men were more commonly infected with CoNS , while Sambola et al. showed that mitral valve IE and aortic valve IE were more common among men, but the etiology did not differ between genders . In our study, men were more likely to have aortic valve IE, which is partly adherent to previous studies [27, 28]. The rates of in-hospital mortality and surgical treatment for IE in our study did not differ between men and women, which does not accord with previous reports indicating that women have higher mortality and receive surgical treatment to a lesser extent compared with men . In our cohort, the in-hospital mortality rate was low (7%), which contrasts with previously reported rates of 15–20% [29, 30], but is more in line with a Swedish study presenting a 30-days crude mortality rate of 10.4% . The low in-hospital mortality rate might be explained by the relatively low age of the patients (mean age 57.1 years) and high prevalence of right-sided, IV drug abuse-associated IE in our study.
Diagnosis of IE manifestations
TEE has been reported to have high sensitivity for the diagnosis of IE, ranging between 90% and 100%, as well as a high negative predictive value of 86–97% [22, 31]. Moreover, it has been shown that ECHO findings did not differ between patients who underwent ECHO early (<2 days) or late (³2 days) after starting antibiotic treatment for IE . We found IE manifestations most frequently on the mitral valve (n = 195, 40%), followed by the aortic valve (n = 190, 39%) and the tricuspid valve (n = 108, 22%). Our results resemble those of a study involving 68 autopsies of patients with IE, which reported that 35% of patients had mitral valve IE, 26% had aortic valve IE, and 5% had tricuspid valve IE . Our higher prevalence of tricuspid valve IE may be explained by the high prevalence of IV drug abuse among the patients in our cohort. Our results are also consistent with a multicenter study of 1055 patients in Europe and the USA, showing that the most common ECHO manifestations among patients with IE were on the mitral valve followed by the aortic valve .
The SRIE includes variables on IE manifestation, such as vegetation localization, but not the size or numbers of vegetations which should have been valuable to present together with the results. The SRIE does include information about known valvular disease prior to IE diagnosis, but no detailed information about the type or severity of degenerative structural heart diseases, such as aortic stenosis is available. Further, the SRIE did not include information about time for primary prosthetic valve implantation or classification into early or late onset prosthetic IE, which makes it impossible to present or distinguish the etiology between early or late onset prosthetic IE. This would be of great interest for the analysis of predisposition for specific bacteria or specific IE manifestations in this study. Comorbidities and underlying heart diseases such as degenerative structural heart disease and rheumatic heart disease (however relatively uncommon in this study and in Sweden in general), can contribute to important aspects of bacterial etiology, manifestations and mortality. Therefore, it should be taken into account that this study reflects the population of IE-patients from a large urban area, admitted to a University Hospital in Stockholm, Sweden and therefore may differ from other populations of IE-patients both nationally and globally. The SRIE does not include results from blood tests such as brain natriuretic peptide levels, which would have been interesting for the analysis especially in relation to in-hospital mortality. We were not able to assess how many days after initiating antibiotic treatment ECHO was conducted. Unfortunately, no follow-up information such as for example one-year mortality was included in the SRIE. In addition, it would be interesting to include in analysis, patients with IE with a more unusual etiology, such as infections with gram-negative bacteria and fungi; however, this was not possible in our study as there were very few cases with these infective agents. For this study, we did only include adult patients as no data from pediatric patients were available from the SRIE. To avoid selection bias, we included all patients admitted to the KUH from 2008 to 2017 that fulfilled the inclusion criteria.