Objective Ventricular septal defects (VSDs), if haemodynamically important, are closed whereas small shunts are left without intervention. The long-term prognosis in congenital VSD is good but patients are still at risk for long-term complications. The aim of this study was to clarify the incidence of infective endocarditis (IE) in adults with VSD.
Methods The Swedish registry for congenital heart disease (SWEDCON) was searched for adults with VSD. 779 patients were identified, 531 with small shunts and 248 who had the VSD previously closed. The National Patient Register was then searched for hospitalisations due to IE in adults during a 10-year period.
Results Sixteen (2%) patients were treated for IE, 6 men and 10 women, with a mean age of 46.3±12.2 years. The incidence of IE was 1.7–2.7/1000 years in patients without previous intervention, 20–30 times the risk in the general population. Thirteen had small shunts without previous intervention. There was no mortality in these 13 cases. Two patients had undergone repair of their VSD and also aortic valve replacement before the episode of endocarditis and a third patient with repaired VSD had a bicuspid aortic valve, all of these three patients needed reoperation because of their IE and one patient died. No patient with isolated and operated VSD was diagnosed with IE.
Conclusions A small unoperated VSD in adults carries a substantially increased risk of IE but is associated with a low risk of mortality.
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In the current era, patients with a ventricular septal defect (VSD) in general have a favourable long-term prognosis.1 In regions with a developed healthcare system, shunts of haemodynamic importance are diagnosed early in life and surgically closed before irreversible pulmonary hypertension occurs. Small shunts are usually left without intervention and the long-term prognosis is, in general, good.2 The current European guidelines suggest that patients with a VSD are followed in clinic at intervals ranging from 1 to 5 years depending on clinical factors such as type of VSD, associated lesions and symptoms.3 Besides problems emanating from associated lesions such as aortic valve disease, infective endocarditis (IE) may be a concern.4
Recent guidelines have restricted prophylaxis for endocarditis in patients with congenital heart disease to a few high-risk lesions that do not include VSD.5 One rationale for this is that prophylaxis has not proved effective.6 ,7 On the other hand, there is evidence that the incidence of IE has increased after application of the more restrictive guidelines in the UK.8 Among all patients with IE, 10–13% have an underlying congenital heart lesion.9 ,10 The incidence of IE in patients with VSD is difficult to assess due to inclusion bias and heterogenic populations. The reported incidence in adults varies between 1.45 and 8/1000 years.2 ,4 ,11 In children 0–18 years, however, an incidence of 0.24/1000 years has been reported.12 Such estimations must, however, be related to the risk in the general population. In Sweden, the contemporary incidence of endocarditis in the general population is reported to be 0.08 cases/1000 years.13
In the present study, all adult patients with VSDs in the national registry of congenital heart disease were identified. The National Patient Register was then searched for hospital admissions for IE in order to determine the incidence of IE in adults with VSDs and, if possible, identify subgroups of patients with higher or lower risk.
Patients and methods
The Swedish National Register on Congenital Heart Disease
This registry study is based on data in the Swedish National Register on Congenital Heart Disease (SWEDCON, http://www.ucr.uu.se/swedcon/). The registry has since 1998 covered all seven healthcare regions in Sweden, although registration started earlier in some centres. All seven Swedish university hospitals are participating and an increasing number of the county hospitals. Data are collected by each centre and contains information on diagnoses, interventions, demographics, functional class, symptoms, quality of life (EQ-5D), social variables, ECG, exercise tests, self-reported level of physical exercise, echocardiography, medications and pacemakers/implatable cardioverter defibrillators. Since the merging of the paediatric and adult congenital heart registry in 2008, patients are entered into the registry as children by paediatric cardiologists and subsequently reported to the adult part of the register at age 18. The register is updated at every clinic visit and the addition of retrospective data is supported and encouraged. All data collected until 17 February 2013 were considered. Data were obtained from the last available clinic visit/test.
The SWEDCON adult congenital heart disease section which at the time of data extraction contained information on 9864 patients was searched using the following inclusion criteria: adult age (≥18 of age), main diagnosis VSD and at least one clinical visit. Patients with associated complex congenital heart defects were excluded (eg, tetralogy of Fallot, coarctation of the aorta, transposition of the great arteries, Eisenmenger physiology and single ventricle), whereas those with simple associated lesions (ie, aortic valve disease, atrial septal defects and persistent ductus arteriosus) were included. After application of these criteria, 779 patients remained for analysis. The study was approved by the Regional Ethical Board in Umeå (Dnr 08-218 M and 2012-445-32 M).
The National Patient Register
In Sweden, The National Board of Health and Welfare records all diagnoses at hospital discharges in the National Patient Register. All hospitals are by law required to report all discharges, including discharge diagnosis, to the National Board of Health and Welfare.
All patients with VSD identified in the SWEDCON were then matched with the National Patient Register, using the unique 10-digit personal identifier that all people permanently residing in Sweden are given. All matching hospital discharges for the treatment of IE were identified for the last 10 years but for patient age >18 years. All episodes of endocarditis were manually edited to avoid errors, such as transferrals between hospitals, for example, cases with first diagnosis in the local hospital with transferral to a regional cardiology department and finally intervention in an institution for cardiothoracic surgery was recorded as one episode of endocarditis. None of the patients reported by The National Board of Health and Welfare had a previous episode of endocarditis in the SWEDCON register.
Means and standard deviations were calculated for continuous variables. Student's t-test and χ2 tests were applied to compare patients with and without intervention. CIs were calculated for the mortality rates.14 Data were processed in Excel and SPSS V.22 (IBM, Armonk, New York, USA).
Seven hundred and seventy-nine patients were identified, 386 men and 393 women, with a mean age of 39.0±14.7. 531 had small shunts without previous intervention, whereas 248 had their VSD closed. Associated lesions were more common in patients with a closed VSD. The clinical data are shown in table 1. Patients with a previous intervention were more often on medication, had undergone interventions for other simple lesions and had more complications than those without a previous intervention (table 1).
Patients with endocarditis
Sixteen patients with IE were identified, 6 men and 10 women, with a mean age of 46.3±12.2 years at the time of IE. Thirteen episodes of IE were identified among the 531 patients with small shunts without previous intervention. None of the patients with small shunts needed intervention and none of them died. In addition, we found 3 cases of IE among the 248 patients who had had their VSD previously closed. Among those three, two had in addition aortic valve replacement >3 months, prior to the IE. The third patient with closed VSD had the infection localised to a bicuspid aortic valve. Eight of the patients with small shunts were known in the registry prior to the IE and five were included after or in relation to their infection. The three patients with previous aortic valve disease were known in the registry before the IE. All these three needed reintervention on the aortic valve and one of them died from complications (table 2). None of the patients with an isolated and previous closed VSD had IE.
Incidence of IE
For all patients, the incidence was 2.3/1000 years, for those with an isolated VSDs and previously known in the registry 1.7/1000 years and including all patients with isolated VSDs 2.7/1000 years (table 3). There was no obvious change in the incidence of IE over time.
This study on IE in adult patients with VSD is to our knowledge the largest so far presented and it demonstrates an incidence exceeding 2/1000 patient-years, at least a 20-fold to 30-fold increased risk compared with the general population. In terms of ratios, 2% of the cohort was diagnosed with endocarditis. Despite this high prevalence, no mortality was observed in patients with an isolated VSD and IE.
The risk of selection bias should be low as this study is based on a national registry in contrast to, for example, reports from single centres. It is, therefore, not surprising that our findings on the incidence harmonise with two earlier but smaller studies also regarded to have a limited selection bias.11 ,15 Neumayer et al reported an incidence of 8/1000 patient-years, around four times higher than in our study. However, emanating from a tertiary referral centre makes selection bias and overestimation of the risk very probable.4 In a single-centre study of 91 patients followed up to 40 years after closure VSD, the cumulative incidence of endocarditis was 4%. In one of these cases, the infection was pacemaker related.16
When compared with the general population, the influence of age must be considered, generally the risk of IE doubles from the age of 40 to 60.17 The mean age in our patient cohort was 39 and, considering the exclusion of those younger than 18 years of age, this is clearly lower than the mean age in the general population if children <18 years are excluded. The mean age at the time of IE in our series was 46 that should be compared with 66 years in IE in general in Sweden.13 Thus, if age-matched, the increased risk of IE in VSD might even be higher than the above-mentioned 20–30 times.
IE in general as well as in valvular heart disease has a male predominance, not because of the sex per se but rather to differences in the distribution of underlying cardiac lesions and differences in life style.17 However, in our study, the overall sex distribution is equal, as expected in VSD, but females dominate when it comes to IE, 9 out of 13 with an isolated VSD and IE were women. There is no obvious reason for that and it might be just by chance as the numbers are small.
The importance of associated lesions, particularly aortic valve disease, in this context, is emphasised by our findings. A prosthetic aortic valve increases the risk of IE and also carries a high risk of a complicated course and reoperation. The higher incidence of IE when there are associated lesions could support the opinion that the risk of IE in congenital heart disease is not the risk of the lesion with the highest risk but rather the sum of the risks of the individual lesions.
All 13 patients with IE and a VSD without previous intervention were conservatively managed and all of them survived the infection. Relatively young age and a low degree of comorbidity could be factors contributing to the favourable outcome. However, as the registry does not provide data on morbidity and complications, such a statement should be read with caution and it is clear that there is a need of deeper exploration of the subject.
In the new ESC guidelines on endocarditis, patients with VSD were not judged to belong to a high-risk group. Considering the outcome of IE, our findings support that view as the mortality rate appears to be low and that IE is not associated with the need for surgery. No episode of IE was observed in patients with previously closed VSD. The observed numbers are, however, small and it is difficult to conclude that closure of the VSD, based on the present data, is associated with a lower risk of IE.
During the period of investigation, 2003–2013, the more restrictive ESC recommendations on antibiotic prophylaxis were introduced in Sweden. Moreover, we do not know to what extent they have been applied and there is no information in the SWEDCON registry on such prophylaxis. However, having the low numbers in mind, there was no obvious change in incidence of IE over time in our study.
In a small study also including children, VSD was the most common underlying pathology in IE related to congenital heart disease.18 This reflects that VSD is a common congenital heart lesion and, also in children, the risk of IE is higher in cyanotic heart disease and in AV-septal defects.12
The conclusions are restricted to the patients within the SWEDCON registry and it cannot be ruled out that there are patients who are not followed up and therefore not found in the registry. Besides mortality and surgical interventions, the registry does not provide detailed information about complications and outcome, that is, there are no data in the register or in the information provided by the National Board of Health and Welfare with details on the localisation of the IE.
The detected number of cases is fairly small and it cannot be ruled out that some observations, for example distribution of IE between sexes, are affected by chance. Therefore, descriptive statistics within the group of 16 patients with IE must be interpreted with caution. The prevalence of IE, however, has a narrow 95% CI (2.3%, 95% CI 1.3 to 3.7%) and the incidence reported here is in line with previous reports.
In conclusion, we demonstrate that a small VSD carries a substantially increased risk of IE, that closure of the ventricular septal may reduce this risk and that IE in cases with a small VSD without previous intervention is associated with a low risk of mortality. Healthcare providers should be aware that this seemingly simple heart lesion is associated with a high risk of IE.
What is already known on this subject?
There are data on the incidence of infective endocarditis, but are based on fairly small cohorts and single-centre reports.
What might this study add?
Here, we add data from a national registry combined with information from a national database on hospital discharges. In adult patients with an isolated small ventricular septal defect, the incidence of infective endocarditis is approximately 2/1000 patient-years, that is, 20–30 times as high as in the general population. In contrast, when a ventricular septal defect is closed, the risk of infective endocarditis is very low.
How might this impact on clinical practice?
Clinicians should be aware of this high risk of endocarditis. In cases with borderline haemodynamic indication for closure of the ventricular septal defect, the low risk of endocarditis after closure may be an argument in favour of closure. The relative high risk of endocarditis warrants that the patients are seen periodically, although with long intervals, to be informed on, for example, dental hygiene and symptoms of infective endocarditis.
Contributors EB: Planning of study, data collection, establishing of database, analysis of data and drafting of manuscript. BJ: Planning of study, data collection, analysis of data and drafting of manuscript. MD, PS, CC and N-EN: Planning of study, data collection, critical revision and approving of manuscript. DR: Planning of study, analysis of data, critical revision and approving of manuscript. UT: Planning of study, data collection and drafting of manuscript.
Funding This study was supported by the Swedish Heart-Lung Foundation (Project grant 2014–2017), Umeå University and the county councils of Västerbotten and Västernorrland.
Competing interests None declared.
Ethics approval Regional Ethics Board, Umeå University.
Provenance and peer review Not commissioned; externally peer reviewed.