Discussion
This is the first systematic review that has included pooled trends of incidence of IE across multiple nationwide population-based studies in Europe. The current investigation has highlighted a 4% per year rise in incidence of IE which, when compounded, is an alarming doubling in incidence between 2000 and 2018. Based on findings of our extensive systematic review that involved multiple countries with nationwide databases, support the notion that the IE incidence escalation seen is valid and is likely due to multiple factors operative in the 21st century. Factors that need to be considered include (1) improvements in diagnosis; (2) changes in epidemiology and associated risk factors; (3) restrictions in AP use promulgated by updated versions of guidelines and (4) improvements in coding practice.
Diagnostic advances in IE have characterised the past two decades and, while not examined specifically in our review, these advances likely contributed to the increasing incidence of IE. Li et al19 modified the Duke criteria that included echocardiography as a pivotal tool in establishing an IE diagnosis in patients who do not undergo valve surgery or autopsy for diagnosis confirmation. Inpatient data available through the Nationwide Inpatient Sample for the first decade of this century in the USA supports the notion that echocardiography use has indeed increased among hospitalised patients20 21 and anecdotally the use of echocardiography is far more widespread in Europe too. Echocardiography, both transthoracic and transoesophageal has become a ‘mainstay’ of cardiovascular evaluation in suspect cases of IE and its complications. The increase in use of echocardiography, particularly the transoesophageal approach is expected to continue which is a potential factor in the increase in IE incidence due to enhanced diagnostic features.
Additional tools, in particular multislice CT, 18fluorodeoxyglucose positron emission tomography/CT, and single-photon emission CT, have also been helpful in securing an IE diagnosis when transoesophageal echocardiography has been insufficient or unavailable. Such methods were incorporated in the latest ESC guidelines.6 In addition, there have been significant laboratory advances in performing blood cultures, which are also key in the diagnosis of IE using the modified Duke criteria.22
Studies included in this review did not provide an analysis of factors that could have accounted for the increase in IE incidence and a temporal sequence of prevalence of epidemiological variables. It is, however, intuitive that contemporary aspects of healthcare that include invasive procedures and placement of indwelling cardiovascular devices have increased over the past two decades and likely impacted both IE incidence and its clinical features. Nevertheless, four investigations documented an increase in prosthetic valve placement.4 17 23 24
Although some studies have reported increasing IE incidence after guideline changes,23 this was not found universally. It would be premature to link a rise in IE incidence in Europe to restriction of AP use. Quan et al reported, for example, increasing trends of IE in England which neither correlated with the change in recommendations by NICE in 2008, nor to a rise in prevalence of VGS as a causative pathogen.25 Moreover, most of the included studies in this systematic review identified staphylococci and streptococci as the most common pathogens of IE over the past two decades (table 1). Hence, an increase in IE incidence cannot be explained simply by trends in pathogen prevalence, which has its own array of pitfalls. This includes the fact that not all patient records included secondary designated microbiology codes, which provides a partial profile of microbiology. Fedeli et al noted a shockingly low percentage (~21%) of secondary code designations of IE-related pathogens in Italy.26 Dayer et al reported that ~50% of cases in England were designated secondary codes for microbiology, which increased towards the end of the study period in 2013.2 Similarly, Quan et al reported that only 67% of the total cases were designated codes for microbiology.25 Perhaps the most important inherent limitation in all studies was the absence of a specific ICD-10 code for VGS. This has greatly hampered accuracy of reporting microbiological data as we strive to define the impact, if any, of changes in AP use in the prevention of IE.
The impact of ICD coding on IE incidence is often underappreciated and it is critical to emphasise because many of the investigations included in our review were dependent on ICD coding to identify IE admissions (table 2). Cresti et al, for example, found that 28% of IE cases extracted using ICD-9 codes were false positive and failed to pick up 14% of confirmed cases, which raised questions on the validity of current code designations.1 The potential impact of coding was also highlighted by Fawcett et al27 who reported a sensitivity of IE of 76% for specific codes in ICD-10 with more than half of cases coded by using ICD-10 as IE were not confirmed cases. The code I33 had a positive predictive value (PPV) of 82%–85%; in contrast, and the code I38 had a PPV of <6% and accounted for many of the false-positive cases and was used in seven investigations in the current systematic review. Although such coding practices may not have a major impact on estimating burden of disease for more prevalent diseases, for IE, an uncommon malady, consistent coding practices to accurately estimate temporal trends is essential. Because 12 of 23 studies that were included in our systematic review used ICD-10 coding and all included I33, the most specific code for IE, significant trend variation in IE incidence across investigations was not observed (figure 2).
The two Spanish investigations17 23 included in the systematic review reported incidence data for a similar time period. Ortega-Loubon et al included a larger sample size and a higher annual incidence but reported a similar trend to the Olmos study. However, Ortega-Loubon et al reported a higher prevalence (16%) of Gram-negative rods as compared with streptococcal species (2.5%), while Olmos et al identified streptococcal species as the most common causative pathogen of IE (20.4%). Two similar contemporary studies with the same methodology from the authors of the Ortega study reported that causative pathogens were ‘unspecified’ in ~86% of cases,28 29 while the 2019 study reported microbiological findings in 52.2% of cases. This suggests that microbiological data from the Ortega study may not be reliable and Olmos et al likely provided a more accurate representation of the pathogen distribution in Spain.
Williams et al recently published a systematic review detailing contemporary epidemiological changes in IE following major guideline changes.30 They included studies from North America and Europe and concluded that although there was no appreciable increase in IE incidence in North America following pertinent guideline changes, there was a potential rise in incidence in Europe. They included just five European studies in their review, whereas our current investigation includes 18 studies, where the incidence trends were examined statistically over 18 years. Furthermore, Williams et al specifically studied the impact of guideline changes for AP use on the incidence of IE, while we focused on trends, irrespective of AP guideline changes, to assess all factors responsible for increasing IE trends.
Despite the thoroughness of this review, there were some limitations to the current study. Data for patient demographics, microbiology, mortality and surgery were provided for most studies as a single percentage over the study period, and not as yearly trends. Hence, a risk factor meta-regression analysis could not be performed, which would have helped quantify the contribution of specific risk factors associated with the rising trends of IE. Furthermore, these studies are only observational and by design, unable to determine aetiological factors associated increasing incidence.
