Infective endocarditis triangle.. Is it the time to revisit infective endocarditis susceptibility and indications for its antibiotic prophylaxis?

Notwithstanding diagnostic and therapeutic advances, infective endocarditis prognosis remains poor (in-hospital mortality of about 22%, rising to 40% at five-year follow-up). Morbidity rates are also high. Around 50% of patients require operative management in the acute phase of the disease, often with ongoing consequences to their quality of life.1 Infective endocarditis incidence has not been decreasing over the last decades, presumably at least in part because of the evolution and modification in risk factors, in particular the wider use of intracardiac prosthetic material compared with the past.2,3 Moreover, infective endocarditis incidence varies considerably according to regions, countries and even national borders. In the largest comprehensive review estimating the burden of infective endocarditis worldwide, different values were provided, even within the same country. This may be explained by the different periods of time when the studies were performed, as well as the different levels of awareness of the diagnostic tools.2 Preventive strategies historically were focused on preventing bacteraemia together with antibiotic prophylaxis. In 1955 the American Heart Association (AHA) first published guidelines recommending antibiotic prophylaxis for patients with rheumatic heart disease or congenital heart disease (CHD).4 These suggestions were accepted and reported for the first time also in the European Society of Cardiology (ESC) consensus in 1995.5 Conversely, in 2007 and 2009 the AHA and ESC Guidelines were substantially revised strongly to restrict prescription of antibiotic prophylaxis against infective endocarditis, on the basis of a few considerations: First, in the era of evidence-based medicine, antibiotic prophylaxis supporting literature was (and remains) based on non-randomized controlled trials for prevention of infective endocarditis in the context of dental extraction. Second, the efficacy of prophylaxis was questioned on the basis of an apparent failure rate of up to 50%. Third, the importance of widespread antibiotic use as a contributor to emerging antibiotic resistance was gaining recognition. Last, the significance of dental procedures as a cause of infective endocarditis was questioned owing to a few studies which did not identify dental procedures as a major risk factor for infective endocarditis.6,7 Actually, according with the ESC Guidelines released in 2015,8 infective endocarditis antibiotic prophylaxis is prescribed only in ‘high risk’ patients with pre-existing heart conditions (i.e. those with previous infective endocarditis, prosthetic valves or CHD) undergoing ‘high risk’ dental or invasive/surgical gastro-intestinal and genitourinary tracts procedures. However, the definition of ‘high risk’ may sometimes be difficult. Furthermore, none is capable of predicting the individual response of the immune system in these circumstances. Not only is this true, but in the United Kingdom the National Institute for Health and Care Excellence strongly recommended against routine administration of antibiotics to all patients potentially at risk of infective endocarditis.9 Recently some authors postulated that after the above stated restrictions in infective endocarditis antibiotic prophylaxis indications, its incidence may have even increased. Specifically, a significant increase in infective endocarditis incidence among high-risk individuals, a borderline significant increase in moderate-risk individuals, and no change for those at low/unknown risk was reported.10 Surprisingly, literature data regarding the failure of infective endocarditis antibiotic prophylaxis, that is, about patients at risk encountering infective endocarditis notwithstanding having taken an adequate and timely dose of antibiotics, reported a breakdown of about 50%.6,7 Based on these premises and similarly to Coumel’s triangle of arrhythmogenesis, we suggest a somewhat original approach (infective endocarditis triangle), considering three different key elements (Figure 1), namely: Infective endocarditis (IE) triangle. Anatomical substrate. A favourable substrate for developing infective endocarditis is constituted by ‘high risk’ patients, that is those with a previous history of infective endocarditis, prosthetic heart valve replacement, (operated or not) cyanotic CHD, acquired heart valve disease, and cardiac implanted electronic devices. In these patients, an up to 100-fold increased risk in the incidence of infective endocarditis compared with the rest of the population was reported in the Danish National Population Registry.11 Not only is this true, but reclassifying some ‘moderate risk’ patients into ‘high risk’ class (including subsets of patients with different types of bicuspid aortic valve/calcified aortic stenosis/mitral valve prolapse, native or residual ventricular septal defects, cardiac implanted electronic devices and chronic injection drugs users) is likely to play a pivotal role in infective endocarditis prevention. The majority of paediatric cardiologists worldwide have encountered children with bicuspid aortic valve affected by infective endocarditis, mainly due to Streptococcus viridans, having a clinical course similar to that in high-risk patients, with consequent increased need for surgery. Based on these data, these children should be considered as being at ‘high-risk’ and antibiotic prophylaxis revisited.12 Initiating factor/trigger. Whether the trigger factor for infective endocarditis is always a transient bacteraemia is largely accepted. Bacteraemia is very likely to be involved in infective endocarditis, although supportive evidence is poor, since it is based on limited research more similar to case series than randomized case–control studies. Sometimes bacteraemia may be of concern, for example when the source of infection is undetermined or in cases of potential bacteraemia in febrile children with recognizable viral syndromes (occult bacteraemia). As a general rule, bacteraemia is clinically benign and self-correcting in children who are not suffering from immune system deficiency as well as turbulent cardiac blood flow. In the trade-off between scientific evidence and uncertainty, too many questions are still awaiting a definitive answer (Is bacteraemia associated with or subsequent to a dental/surgical procedure? What invasive procedures are a risk factor for infective bacteraemia and require antibiotic prophylaxis? In the case of multiple procedures, can the same antibiotic be administered? How can dentists identify high-risk conditions for infective endocarditis? Do they verify their patients’ antibiotic prophylaxis intake? What are antibiotic prophylaxis requirements in cases of concomitant immune system impairment? What are the indications for second choice drug administration? Finally, are chlorhexidine mouthwashes before dental procedures combined with antibiotics useful or not?).13 Only a large, wide prospective, randomized controlled trial is likely to be able to answer these unresolved questions. Modulating factors. They are represented by the immune system and its fluctuations. As universally known, this system is a very complex network. It is usually subdivided into innate and adaptive immunities. The first acts through molecules (antibodies), the second by means of cells such as macrophages, T-lymphocytes and natural killer cells. Adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment.14 The immune system is not a stable barrier against pathogens, but in the same subject it responds differently at different times. No one is still capable of predicting the individual genetically determined biological response (inflammation). Regarding the host-susceptibility to infection, several genetic factors for susceptibility to infective endocarditis have been identified over the last years, including higher rates of infections in distinct ethnic populations (Maori and Pacific Island people versus European; Aboriginal Australian versus Australian; Black American versus White American), as well as rare genetic conditions associated with susceptibility to infective endocarditis.15 Genes responsible for variation in the response to infections and inflammation regulation of the immune system are the target of genome-wide association studies. In this respect, in a recent model of Staphylococcus aureus infective endocarditis, four single nucleotide genetic polymorphisms located on chromosome 3 were associated with predisposing host to this disease in 67 patients presenting definite native valve infective endocarditis (cases) and 72 matched patients with uncomplicated bacteraemia (controls) enrolled in the VIRSTA cohort study. A replication study was then performed using an independent Danish cohort of patients with S. aureus bacteraemia, with and without infective endocarditis.15 Again, a large number of clinical and pathological (in summary, environmental) variables (age, gender, diabetes, end-stage renal disease, immunosuppressive therapies, vaccinations, antibiotic resistance and so on) have a strong impact on immune system function, thus influencing its ups and downs, and consequent susceptibility to infective endocarditis.16 Another factor potentially influencing immune system reactions is the hypothalamic–pituitary–adrenal endocrine axis, which regulates the response to acute and chronic infections, acting through glucocorticoid hormones secretion, most of all cortisol. Glucocorticoid release is characterized by a circadian rhythm and is involved in various aspects of the immune system response to infections, suggesting a tight interplay of stress and circadian systems in the regulation of immunity.17 An association between increased cortisol levels, lymphocytopenia and in-hospital mortality in patients with infective endocarditis was described.18 Following the changes in the Guidelines on the indications for antibiotic prophylaxis against infective endocarditis, researchers and clinicians worldwide have been looking for signs of increased incidence of infective endocarditis that might indicate an adverse impact of these changes. Seven large studies have been carried out: one in France, four in the USA and two in the UK (the last the only ones conducted according to the ‘Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)’ Guideline). Only one of them reported an increase in the incidence of infective endocarditis following Guidelines modification.19 These still inconclusive findings are likely to be adversely affected by too many limitations in available data and methodology.20 Furthermore, it is unclear to what extent Guidelines are followed by clinicians, because of related medical legal implications (open problem). Second, inadequate and sparse data are available on how invasive medical procedures and bacteraemia interfere with antibiotic prophylaxis. Last, uncertainty persists also about the variability in each individual’s genetically determined (innate) and adaptive (acquired) immunity response to infections (see Figure 1, the right side of the infective endocarditis triangle). In our opinion, the latter is the explanation for the variable susceptibility to infective endocarditis in the same subject and in the same risk situation, but at different moments of his/her life. It may explain also the up to 50% failure of antibiotic prophylaxis. It appears somewhat astonishing how little attention has been paid so far to infective endocarditis medicine in relation to the (individual, genetically-determined, adaptive) immune system. In fact, the transition from uncomplicated bacteraemia to infective endocarditis, its most harmful medical issue, results from a complex interplay among predisposing anatomical conditions, the pathogen and the host susceptibility as influenced by the immune system. To sum up, we agree with the conclusion by Sun and O’Gara that ‘in the current era perhaps we understand less about [infective endocarditis] than we thought we did’.21 We do need to start to consider the genetic/innate and acquired/adaptive immune system response as playing a major role in susceptibility to infective endocarditis and maybe also response to antibiotic prophylaxis. We gratefully thank Doctor Elliot Shinebourne (United Kingdom) for having critically revised this paper. GC: contributed to conception, drafted and critically revised the manuscript, gave final approval to publication; AC: contributed to analysis, critically revised the manuscript, gave final approval to publication; PG: contributed to analysis, critically revised the manuscript, gave final approval to publication; GDS: contributed to interpretation, critically revised the manuscript, gave final approval to publication; PPB: contributed to conception and design, contributed to interpretation, drafted and critically revised the manuscript, gave final approval to publication. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.