Incidence and epidemiology of infective endocarditis

The incidence of infective endocarditis (IE) is reported to vary from 1.5 to six cases per 100,000 persons per year in adults. The percentage of IE in congenital heart diseases (CHDs) has increased relative to the decrease in rheumatic fever . IE is supposed to occur much less frequently in children. However, more complex surgical CHD procedures with implanted material and prostheses and/or residual lesions are likely to result in ongoing IE occurrence. Moreover, more children can currently reach adulthood, even with complex CHD, so the cohort of patients with CHD is increasing. The relative incidence of IE is therefore likely to remain the same or even increase in paediatric and adult patients with CHD. An IE diagnosis and its sequelae are reported to account for 4–5% of in-hospital admissions of patients with CHD and a 2.3% frequency of adult-onset IE in adults with CHD. As a result, IE represents a lifelong risk in these patients. Various factors may impact on the level of risk, such as the type of underlying cardiac disease, the presence of prosthetic material and the microbial causal agent.

Prognosis of infective endocarditis (IE)

Despite improvement in early diagnosis, management, microbial diagnosis and therapeutics and even surgical techniques, the morbidity and mortality rates of IE remain significant ; the mortality rate varies from 10–15%. Therefore, IE represents a life-threatening, ongoing complication that may impair long-term outcomes in patients with CHD .

Data from the literature have shown IE to be less severe in children, which might be due to the higher proportion of right-sided IE in patients with CHD, particularly in those with a ventricular septal defect (VSD)-located infection .

In a recent review of IE in CHD, Knirsch et al. reported a 10% overall mortality rate, a 14% surgical mortality rate and a recurrence rate of inferior than 3% . Besides early mortality and morbidity, IE may also impact on the long-term functional status of patients with CHD, considering that many of them were asymptomatic before the IE occurred . In our own long-term experience with IE in adult and paediatric CHD patients, more than 50% of deaths in this cohort can be directly related to IE, while others are due to either IE sequelae management or CHD outcomes, regardless of the IE episode .

Pathogenesis

Three major components must interact to result in IE:

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  the underlying cardiac lesion and endocardial damage;

  
  
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  the circumstances leading to significant lesions of the mucosa, which are susceptible to bacteraemia;

  
  
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  the volume of the microbial inoculum and virulence of the bacterial agent.

The key factor for IE to develop is firstly endocardial damage. This lesion allows fibrinogen deposits, platelet aggregation and thrombi formation. Interactions with circulating pathogens may promote microbial adherence to thrombi, resulting in the development of an IE-specific lesion (so-called vegetation). A prosthetic surface is particularly exposed to fibrinogen binding and also promotes turbulence of blood flow and endothelial injuries, making prosthetic materials high-risk factors for IE.

Given the prognosis, morbidity and high cost of management of IE, prophylaxis has long been recommended in an attempt to minimize the incidence of IE. Guidelines have been published and revised over the years, to define the underlying CHD level of risk, the procedures and events that carry the highest risk and the protocols for antibiotic prevention of IE, thereby identifying ‘who’ should benefit from prophylaxis, ‘when’ to adequately apply prophylaxis and ‘how’ to administer prophylaxis. Nevertheless, IE still occurs and its incidence is not lessening significantly, which raises the question of whether non-compliance or lack of efficacy (or both) is implicated.

As yet, no randomized study has been conducted to elucidate whether or not IE prophylaxis should be applied, and if it should, then to whom and when it should be applied. Lockhart et al. conducted a prospective, comparative study designed to compare subjects who received amoxicillin before tooth extraction with subjects who had no antibiotics and were given a placebo before the dental procedure. The authors showed that bacteraemia was less frequent in the amoxicillin group (33%) than in the placebo group (84%) but this result does not demonstrate that IE would have occurred. Recommendations were based on experimental animal studies that previously demonstrated the efficacy of antibiotics in preventing IE when administered before bacteria inoculation , and also on medical practice and experience . Conversely, most published data have reported that IE can still occur despite prophylaxis being applied according to current recommendations.

Thus, recommendations for IE prophylaxis have eased dramatically over the years. Based on case-control studies, expert opinion and daily practice, the last revised American Heart Association (AHA) guidelines published in 2007 resulted in a drastic reduction and limitation of the cardiac diseases and procedures in which IE prophylaxis is indicated .

Rationale for revised recommendations for infective endocarditis (IE) prophylaxis

Several main points have led to the new expert consensus in the field of IE prophylaxis.

First, ‘IE is much more likely to result from frequent exposure to random bacteraemia associated with daily activities than from bacteraemia caused by a dental, gastrointestinal tract or genitourinary tract procedure’. IE occurs rarely and is unlikely to impair significantly the overall prognosis of patients. The ratio of the number of treated IE cases to the number of cases undergoing prophylaxis is far too low to support routine prevention of IE. ‘Prophylaxis may prevent an exceedingly small number of cases of IE, if any, in individuals who undergo a dental, gastrointestinal tract or genitourinary tract procedure’. However no mention exists about the costs due to IE management (hospitalization, antibiotics, techniques for anatomical and microbial diagnosis, iterative surgeries, long-term follow-up, management and complications) or about patients’ vital and functional prognosis. The low cost of prophylaxis has to be weighted against the high costs of IE diagnosis and treatment.

The second and most important point is that procedures are less likely to cause IE than daily activities and poor patient hygiene. Que and Moreillon assessed the theoretical cumulative bacteraemia resulting from daily oral activities such as brushing teeth or chewing and concluded that 1-year everyday bacteraemia is six million times greater than that associated with 1-year bacteraemia due to a dental extraction. Thus, it is not clear whether daily-activity related bacteraemia could reach the cut-off inoculum volume to seed the cardiac tissue . Therefore, the experts stated that ‘Maintenance of optimal oral health and hygiene may reduce the incidence of bacteraemia from daily activities and is more important than prophylactic antibiotics for a dental procedure to reduce the risk of IE’.

Another point is that some patients who undergo dental procedures have an underlying cardiac disease that has not been recognized. We observed such cases in our experience of IE in CHD, where the underlying diseases were mostly minor valvular lesions, such as aortic bicuspidia or mitral valve prolapse (MVP). These patients with unrecognized CHD accounted for about 15% of our cases.

Lastly, the experts considered antibiotic side effects, including microbial-induced resistance and anaphylaxis. However, no report has been published about resistance due to one-dose amoxicillin and no case has been reported of death due to antibiotic-induced anaphylaxis, whereas mortality due to IE is still significant and widely reported.

Finally, the revised recommendations were also based on the lack of a controlled randomized study to prove the efficacy of IE prophylaxis. The number of patients necessary to conduct a controlled, randomized trial to assess the effectiveness of IE prophylaxis has been estimated to be superior to 6000 patients per group, which has discouraged centres from initiating such a study .

Underlying congenital heart disease (CHD)

In previous recommendations, CHDs were classified into high-risk, moderate-risk or mild-risk groups. Recent guidelines resulted in a drastic reduction in the target CHDs for IE prophylaxis and suppression of the CHD classification into at high, moderate or mild-risk for IE, assuming that only patients in the previously-named ‘high-risk’ group should receive IE prophylaxis. The other CHDs, previously in the moderate-risk or mild-risk groups, are no longer targets for IE prophylaxis .

In summary, cardiac conditions associated with the highest risk of adverse outcome from endocarditis, for which prophylaxis with dental procedures is reasonable, include :

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  prosthetic cardiac valve or prosthetic material used for cardiac valve repair;

  
  
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  previous IE;

  
  
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  unrepaired cyanotic CHD, including palliative shunts and conduits;

  
  
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  completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first 6 months after the procedure. In this case, prophylaxis is reasonable because endothelialization of prosthetic material occurs within 6 months after the procedure;

  
  
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  repaired CHD with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization);

  
  
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  cardiac transplantation recipients who develop cardiac valvulopathy.

Except for the conditions listed above, antibiotic prophylaxis is no longer recommended for any other form of CHD.

It is well recognized that surgical repair may nullify the lifetime risk of IE, provided that neither residual lesion nor prosthetic material is present. In fact, only a few CHDs can be completely cured; some kind of residual lesion often persists (residual shunt, valve anomaly, etc.) or prosthetic materials are implanted (valvular prosthesis, tubes, anastomosis, patches).

Considering that high-velocity and turbulent flow are more likely to generate endothelial lesions and promote IE, risk varies consecutively according to the underlying cardiac lesions, although the guidelines no longer attach any importance to this assessment.

Lastly, some IE episodes were reported in patients who underwent interventional procedures, which raised the question of whether these cases should receive prophylaxis.

Regarding cyanotic unrepaired or palliated CHD, there is a common consensus for IE prevention, as well for patients who have experienced a previous IE episode. These CHDs are considered at highest risk for IE.

IE prevention is no longer recommended in repaired CHD, in case of no residual lesion but prophylaxis should be applied within the first 6 months after repair, while endothelialization develops, particularly after patch closure of a VSD. However, any residual shunt or associated lesion, such as aortic insufficiency, will justify lifelong IE prophylaxis, given that endothelialization cannot occur. This assessment seems to be in discrepancy with the same native unrepaired lesion (i.e. VSD or aortic regurgitation).

A review by Knirsch et al. aimed to estimate the mean frequency of repaired and unrepaired CHD in an IE series . The author showed that IE is a lifetime risk for repaired, non-operated and palliated CHD. Aortic and mitral valves are the most frequent targets for IE, including unoperated and non-haemodynamically significant valvulopathies. If unrepaired, VSD is the most frequent CHD associated with IE. The cumulative incidence of IE over a 25-year follow-up after surgical repair (or interventional procedure) is as follows, according to the CHD:

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  1.3% for tetralogy of Fallot;

  
  
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  2.7%for VSD;

  
  
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  2.8% for primum-type atrial septal defect (ASD);

  
  
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  3.5% for coarctation of aorta;

  
  
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  13% for aortic valve stenosis;

  
  
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  0% for ostium secundum ASD, patent ductus arteriosus (PDA) and pulmonary valve stenosis.

A 30-year follow-up demonstrated a cumulative IE incidence of 4.0% for transposition of the great arteries, 5.3% for pulmonary atresia with intact ventricular septum and up to 6.4% for VSD . Risk is evidently increased by any prosthetic material and devices.