Infective endocarditis represents a diagnostic and therapeutic challenge, particularly for those unfamiliar with the identification and management of this systemic disease that can express itself in a variety of ways. Certain terms that are still commonly used, especially in developing countries, can be misleading. In this paper, we aim to bring a new perspective to what is called “acute” IE by reviewing the origin of the term and offering a current clinical and echocardiographic approach and practical tools to identify the most severe cases that require timely decisions.

• Endocarditis

• Acute

• Subacute

• Severe sepsis

• Septic shock

• Echocardiography

• Acute regurgitation

• Mortality

Nacinovich F, Lombardi C, Vivas M, Oses PAF, Moltrasio LM, et al. (2024) Acute Infective Endocarditis: An Old Concept Revisited. J Cardiol Clin Res. 12(2): 1202.

Infective endocarditis (IE) is a serious and potentially fatal infection that represents a major public health problem: It is associated with high morbidity (heart failure, stroke, and other complications) and mortality (1723.59 disability-adjusted life years and 0.87 death cases per-100.000 population, respectively) [1].

Identification of the diseases is of critical importance and demand a high index of suspicion to exclude IE or avoid delays in diagnosis, especially in high-risk groups, such as those with congestive heart failure (CHD) or prosthetic valves. Recognition of IE continues to be a challenge, as its signs and symptoms can be subtle, laboratory results unspecified, and it can involve or mimic many other serious conditions [2,3]. On the other hand, conventional microbiological diagnostic methods may take a long time to become available and postpone making urgent therapeutic decisions.

With the increase in use of medical access devices, implantable cardiac devices, and the rise of intravenous drug use, the epidemiology of IE is changing in the last 20 years [4,5]. Diagnostic imaging has evolved, and the use of echocardiography became critical in making an early diagnosis. However, although diagnostic and treatment therapies have advanced over the decades, the mortality rate has changed very little. In a meta- analysis of worldwide outcomes including 22,382 patients, short- term 30-day all-cause mortality for IE was 20%, while long-term post discharge mortality rates approached 37% [6].

Diagnostic difficulties associated with identification of patients with IE are not the only ones, but there is debate over the best courses of treatment, routes of administration of antibiotics and when to advance to more aggressive therapies. There have been recent guideline changes and technical advances in identification and management of IE [7,8].

In the past, IE was classified as “acute” or “subacute” based on several clinical parameters: The clinical presentation and progression of the untreated disease (time to death) in the pre antibiotic era; the time of evolution from the first clinical sign and/or symptom to the time of first medical evaluation or index hospitalization and pathogenic virulence (Table 1) [9-18].

Table 1: Differences in Acute vs Subacute IE (adapted from cites: 9-16)

*Usually considered together

Sir William Osler, in his Gulstonian lectures, drew a distinction between “simple” and “malignant”   forms   of   endocarditis. The “simple” form correlates to what has become known as “subacute” bacterial endocarditis (SBE): Typically presents with subtle constitutional symptoms and is frequently not diagnosed until it has been present for weeks or months. On the other side, “malignant” form is characterized by a sudden onset and fulminant course (“acute” IE) [9]. Lately, this classification was reasonably questioned by Gross and Fried in 1937 [10]:

“... the division of the bacterial endocarditis into the acute and subacute form based on the duration of the illness is largely arbitrary, as much as on the one hand the clinical course may be prolonged for a number of months in frank cases of bacterial endocarditis which are known generally to run a very acute course (e.g. Staphylococcus aureus), and on the other hand death may supervene within a few weeks in such usually protracted conditions as Streptococcus viridans endocarditis.” Nevertheless, others defended its value in clinical practice, mainly to identify acute cases in view of their impact on mortality [11]:

“… we believe it important to continue, in our clinical approach to patients, the distinction between acute and subacute bacterial endocarditis. The prompt recognition of acute bacterial endocarditis, in particular, may lead to the saving of lives which may otherwise be lost.”

Starkebaum, Durack, and Beeson, during 1977, had defined the “incubation time” of IE (the time interval between the bacteremia and the probable sources of infection) and, on this basis, to presume the organism probably involved, particularly in SBE. Symptoms of IE were apparent within 2 weeks after any procedure in 85% of individuals infected by organisms’ other tan enterococci (average 6 weeks). Signs and/or symptoms more than 1 month were unfrequent [12].

Subsequently, some differences were established in terms of the pathophysiology of the disease and pathoanatomical findings (in association with the fast development of the disease from bacteremia) and the causal microorganism. Weinstein and Brush pointed out that “acute” cases corresponded to 50-60% of the episodes in previously normal valves. They attributed the delay in diagnosis to a number of reasons that, curiously, are still valid today: The presence of mild, early and nonspecific manifestations of the disease, reluctance to seek medical attention because the symptoms were mild, the failure of the physician to consider the diagnosis of IE until the disease had been manifesting for weeks or even months, and the administration of antibiotic treatment for an unspecific fever that leads to early defervescence by clearing the bacteria from the bloodstream [13,14].

Proposal for a current perspective: “Acute” as a clinical and echocardiographic approach

To date, many studies, guidelines, and relevant literature of IE, do not differentiate between acute and subacute disease; indeed, the overall principles of diagnosis and management are identical between acute and subacute disease. In addition, the literature evaluating incubation times and their eventual importance is scarce or almost unavailable. Although it is estimated that 20% to 33% of IE episodes present in an “acute” form, it depends on the published series [17]. In a recent prospective multicenter observational sub study of 502 patients with defined IE in a low and middle income country (LMIC) patients with a clinical evolution (arbitrarily selected as “acute”) of less than 1 month at the time of admission, were frequent (73%), had a significant higher incidence of positive blood culture (92.6% vs 85%; p=0.01), with a predominance of S. aureus (38% vs 17.7%; p=0.01) and higher in-hospital mortality (44% vs 26%; p=0.01); diabetic patients were more frequently affected (26% vs 17%; p=0.03) and health-care associated acquisition predominated in almost half of the cases (44% vs 26%; p=0.01) comparing with patients with >1 month of symptoms evolution. Finally, there was a not statistically significant tendency to occur in individuals with intracardiac devices (prosthetic valve, pacemakers/ICD).

Interestingly, as authors stated, the term “acute IE” has relative importance in the clinical decision making but for the opposite. Regardless of the evolution time of the symptoms until the medical diagnosis, S. aureus should always be considered in the empirical treatment of patients who require it; the absence of a presentation with CHF and/or severe sepsis/septic shock should not exclude this microorganism as a possible cause; moreover, it should be considered even in those with more than 1 month of symptoms´ evolution , with more subtle clinical presentations, especially if they are patients with diabetes and/ or with intracardiac devices [19,20].

In agreement with the point of view of several experts the terms “acute” and subacute” IE, ignores at least two relevant aspects. First, the frequent overlapping of manifestations of infection by different microorganisms. Second, the clinical course may be prolonged for weeks or even months with an unobvious and oligosymptomatic picture, but which (with the progression of the disease, e.g. rapidly valve damage leading to heart failure and circulatory collapse) may rapidly deteriorate into an acute picture (heart failure, sepsis, and septic shock). Also, metastatic infection can occur in any organ in the body and frequently they can be silent and have no clinical manifestations [21-25].

So, current practice prefers an approach that considers the structure in which IE is located (native tissue or intracardiac devices) and the suspected or confirmed microorganism, since it has implications both from the therapeutic viewpoint and on the course of the disease [7,26]. Even so, this strategy also contains some limitation itself. The ignorance of which is the microorganism involved to offer a correct empirical treatment in severe cases and the accurately assess for emergency or urgent surgical resolution, especially in patients in whom the presence of pre-existing valvular disease is unknown. This is not a minor problem since unfavorable evolution due to inadequate treatment can increase morbidity and mortality. Despite the wide availability of diagnostic and treatment guidelines, frequently the recommendations are not adequately followed in practice [27- 29].

In this complex and heterogeneous framework, the terms“acute” and “subacute” would seem to have an historical interest. ¿Does it make sense to use these concepts in the 21st century?

From a practical point of view, we currently could consider two ways of approaching a redefining the term “acute” IE, clinical and echocardiographic. The concepts described below are intended to contribute to a better interpretation of the disease to:

• Assess the need for early initiation of empirical antibiotic treatment.
• The most appropriate drugs and/or their combinations.
• The need for surgical consultation to define the strategy times (urgency/emergency).
• Eventually, the decision to refer the patient to a center with the necessary conditions for the management of this complex pathology.

The patient´s clinical condition (severity at the arrival to medical consult) clearly determines the presence of a serious event with which appropriate decisions must be taken. Sepsis (Se) or septic shock (SeSh) at the time of the initial evaluation that motivates clinical suspicion of IE, induces to the rapid collection of blood cultures and the prompt initiation of empirical antibiotic treatment. In this scenario, the time of previous evolution is irrelevant because the diagnostic measures and empirical antibiotic treatment (and eventual surgical treatment) should be adapted to this first initial evaluation [30]. Almost half of IE patients develop complications, which are associated with mortality and ICU admission.

IE is the cause of 0.8 –3.0% of admissions to ICUs, with mortality exceeding 50% in some reported series of ICU patients. Because IE often occurs in patients with multiple co-morbid illnesses and those who have undergone recent invasive procedures, it is commonly diagnosed and treated in the intensive care unit (ICU) [31-35]. In a recent prospective cohort, of a total of 4864 IE patients evaluated, 11.5% presented with Se and 12.3% with SeSh. Patients with SeSh were younger and presented higher rates of diabetes, chronic renal and liver disease, transplantation, nosocomial acquisition, S. aureus, IE complications, and in-hospital mortality (62.5%, 37.7% for Se and 18.2% for non-sepsis nor SeSh, p< .001). S. aureus (OR 1.94; 95% CI, 1.34–2.81; p< .001), Gram negative (OR, 2.21; 95% CI,1.25–3.91;p = .006), nosocomial acquisition (OR, 1.44; 95% CI, 1.07–1.94; p= .015), persistent bacteremia (OR, 1.82; 95% CI,1.24–2.68; p = .002), acute renal failure (OR, 3.02; 95% CI, 2.28–4.01; p< .001), CNS emboli (OR, 1.48; 95% CI, 1.08–2.01; p =.013), and larger vegetation size (OR, 1.01; 95% CI, 1.00–1.02; p=020) were associated with a higher risk of developing SeSh. Also, Charlson score, heart failure, persistent bacteremia, acute renal failure, mechanical ventilation, worsening of liver disease, S aureus, and receiving aminoglycosides within the first 24 hours were associated with higher in-hospital mortality, whereas male sex, native valve IE, and cardiac surgery were associated with lower mortality [36].

Another study showed a 29.96% incidence of Se and SeSh out of a total of 294 patients admitted for IE and showed an increase on in-hospital mortality (OR 8.915, p <0.001 and OR 35.969, p<0.001, respectively) after adjusting for other risk factors of poor outcomes (neurological complications, congestive heart failure, and S. aureus IE). Surgical treatment had, also, a positive influence on in-hospital mortality (OR 5.157, p <0.001) as well as on 1-year survival (HR 3.092, p <0.001) [38]. In a LMIC as Argentina, according to EIRA 3 study, 27.1% of patients included in the registry, with “definite” IE, presented with Se/SeSh. In a sub study, the presence of embolisms at admission, positive blood cultures, CHF, and infection by S. aureus, were significantly related to the presence of Se and SeSh. This dramatic form of IE presentation involves a poor prognostic at the time of admission (particularly if the patient has a history of CHF, CKD, or previous IE) as mortality is almost tripled compared to patients without this clinical condition [19,38]. Interestingly, S. aureus presents with this severe form in a half of individuals, so initial empirical treatment should be broad-spectrum, targeting not only to this microorganism but also to others, that may be potentially involved. In addition, 20% of the patients with an evolution time >1 month, arrived at the medical consultation that led to the

diagnosis of IE, with a clinical picture of Se/SeSh. Of note, although not significant, almost a third of cases are health care-associated, demonstrating that they are potentially preventable events [38]. Regarding the infectious agent, as already mentioned, S. aureus and gram-negative bacilli are the main causal agents among IE patients presenting with SeSh. As expected, Se and SeSh were associated with higher in-hospital mortality [7,36-40].

Based only on physical examination findings may lead to misdiagnosis of acute regurgitation and its severity. Echocardiography plays a key role in the diagnosis of IE and must be performed as soon as IE is suspected. It allows to identify vegetation, abscess, new dehiscence of prosthetic valve and assesses the number, size, shape, location, echogenicity, and mobility of vegetations so it is also useful to prediction of embolic risk. Transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE) are widely accessible, but significant variation in the use of TOE still exists.

The presentation phenotype of IE in the ICU setting may hinder early diagnosis: fever without clear source or suggestion of an alternative diagnosis, neurological manifestations, such as confusion, delirium, or focal symptoms may initially mislead the clinician from the diagnosis of IE. Moreover, in cases with recent onset, echocardiographic findings may be initially absent or inconclusive. When the suspicion of IE is high, it is essential to repeat the study at a reasonable time lapse, as this increases the chances of an accurate diagnosis of the disease. EIRA III registry, which only included patients with definite IE, more than 30% of patients were diagnosed after a second echocardiogram, which highlights the importance of sequential studies when there is clinical suspicion [7,19-41].

Patients with acute severe aortic regurgitation (AAR) due to IE can progress rapidly from being hemodynamically stable to pulmonary edema and cardiogenic shock. The diagnosis of IE in ICUs follows the same modified criteria as in non-ICU patients; in this setting, TOE has a prominent role as a tool for diagnosis of IE and its complications. The severity of valve dysfunction (clinical and/or echocardiographic signs of acute valve insufficiency) is critical to define surgical treatment [7].

The key diagnostic criteria for severe acute IE are the identification of clinical and/or echocardiographic signs of acute and severe valvular regurgitation, as this represents a very complex clinical scenario and hemodynamic situation of extreme urgency.

Left ventricular (LV) volume overload in chronic aortic regurgitation occurs progressively; in this   setting   there   is an increase in LV distensibility over time, which enables an excess in end-diastolic volume, without significant increases in LV end-diastolic pressure (EDP). The increase in preload of this ventricular chamber through heterometric regulation of myocardial shortening increases LV ejection volume (despite the slight increase in afterload) which is compensated by the fall in peripheral resistances during the diastolic period of LV volume regurgitation [42-43].

In contrast, in acute aortic regurgitation secondary to valvular rupture or disruption, none of these compensatory mechanisms can develop become evident (there is no time for distensibility- mediated regurgitant volume compensation precluding heterometric regulation of myocardial shortening), so the LV is only slightly dilated or even has normal size, LV ejection fraction does not change, resulting in the consequent rapid and severe increase in in LVEDP, decrease in arterial pressure, leading to peripheral shock with increase in peripheral resistances, further increase in afterload and fall in cardiac output. This situation requires increased heart rate to maintain adequate peripheral perfusion. The clinical translation of this hemodynamic situation is the presence of acute pulmonary edema, arterial hypotension, sinus tachycardia, absence of elevated pulse pressure and short (and often even absent) regurgitant diastolic murmur (Table 2).

Table 2: Clinical and echocardiographic differences of Acute and Chronic Aortic insufficiency

LVEDP: Left ventricular end-diastolic pressure; LVOT: left ventricular outflow tract. The ratio between the width of the jet at the vena contracta and the width of the LVOT in the long-axis parasternal or apical three-chamber view.

Echocardiography is the ideal technique for evaluation of etiology and severity of valve dysfunction, LV hemodynamic status, and to assess prognosis to adequately choose the best timing of surgery. The presence of only mild or absent LV diastolic dilatation, an hyperdynamic status, coexistent with a color Doppler aortic regurgitation jet width >50% of the LV outflow tract, should be enough to suspect the presence of AAR. Other signs of severity of aortic insufficiency are often present such as, a very short deceleration time and/or decreased pressure half time at continuous doppler spectrum of regurgitant flow. Other signs of severity of aortic insufficiency are often present such as: AR spectrum on continuous Doppler with very short pressure half time with rapid decelerating slope. Other common findings in chronic AR, are often absent in AAR, such as holodiastolic reverse flow in the abdominal aorta and a large regurgitant jet throughout diastole in the LV cavity [41-44].

Classically, the presence of the so-called “early mitral valve closure” (EMVC) was popularized as evidence of an extreme increase in LVEDP which (whether accompanied by diastolic mitral regurgitation or not) was considered an indication for urgent surgery. These signs, the former obtained with M-mode over the mitral valve and the latter observed with color Doppler, are highly specific of severe hemodynamic decompensation, although it is important to note that their absence does not preclude the need for urgent surgery. Moreover, waiting for the appearance of these signs in the setting of AAR could delay surgical indication endangering the patient. Another valuable parameter that can easily be obtained with TTE or TOE is the analysis of ventricular filling pressures with pulsed Doppler being a common finding severe LV diastolic dysfunction. The diagnosis of AAR, even under circumstances where aggressive medical treatment can stabilize the patient’s hemodynamics, demands urgent evaluation by an experienced cardiovascular surgery team owing the lability of this condition (Table 2).

Acute mitral regurgitation can be organic due structural disruption of the valve (leaflet perforation, chordal and/or papillary muscle rupture, paravalvular leakage in a prosthetic valve endocarditis) or functional (abnormalities of the left ventricle, acute ischemia - an akinetic wall segment and papillary muscle dysfunction can impair mitral valve closure; it may be incomplete due to changes in annular shape). In acute mitral regurgitation, regurgitant volume in a normal-sized, noncompliant left atrium results in a marked increase in left atrial pressure, the mechanism by which acute pulmonary edema develops. In comparison, left atrial size and compliance are increased in chronic mitral regurgitation, but left atrial pressures remain normal despite the regurgitant volumen; a preserved ventricular function might tolerate the marked increase in volume better. On the other hand, a patient with impaired LV function, heart would quickly decompensate upon the acute worsening of mitral regurgitation with a marked increases in LVEDP and left atrial pressure [44,45].

There are three possible hemodynamic scenarios for severe mitral insufficiency: acute, chronically compensated, and chronically decompensated. These depends primarily on the speed at which volume overload is established and the adaptive response of the left ventricle and left atrium to these conditions. If IE affects a previously diseased mitral valve that already had severe insufficiency, the regurgitation volume may increase. In this setting the clinical status may progress from chronically compensated to decompensated, depending on whether the left chambers still capability of adaptive response must manage this new volume overload. If IE affects a previously healthy valve or a valve in an early stage disease without significant insufficiency, a perforation or chordal rupture could rapidly lead to heart failure or shock, without necessarily involving a substantial regurgitant volume. In cases of severe mitral insufficiency without CHF, echocardiographic signs of elevated LVEDP or moderate to severe pulmonary hypertension can be taken into consideration when deciding early surgery (Table 3).

Table 3: Clinical and echocardiographic differences of Acute and Chronic Mitral insufficiency

LVEDP: Leftventricularend-diastolic pressure; EROA effectiveregurgitant orifice area

The global and regional differences in IE mortality are multifactorial and derive from a combination of disparities in health care, access to adequate diagnostic studies, differences in patient risk factors, valvular involvement, and microorganism epidemiology and its virulence [46,47]. Successful management depends on the close cooperation of medical and surgical disciplines. Endocarditis services and therapeutic protocols have been created at several tertiary care centers in the United States and Europe, as well as in many South American countries.

Beyond debate, IE has deservedly earned its place as the “great imitator” and there is still a real difficulty in suspecting its presence (and acting accordingly) which will surely have an impact on reducing the morbidity and mortality of this challenging disease. The approach based on the “evolution time” of the clinical picture (acute vs subacute) is no longer useful and only should be considered in association with the clinical and echocardiographic approach. This form of the disease assessment is closer to what can be done in daily practice to make key decisions that have a direct impact on morbidity and mortality. Facing the setting of a potentially life-threatening and underdiagnosed disease such as IE, although not mandatory in current sepsis management guidelines, perhaps an echocardiographic evaluation should be included in all patients admitted with Se and SeSh [30]. In cases that present in a dramatic way that demands quick and timely actions, where sometimes the presence of classic lesions is not evident in the echocardiogram, being able to differentiate acute valve dysfunction from those that are not, in addition to the presence of severe sepsis or septic shock (with tools that may be more easily accessible even for those not familiar with treating these patients) may have an effect in the immediate term, mitigating the devastating effects of IE.

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