A 17-year-old female was admitted with features of heart failure and a febrile illness. Blood cultures were negative and ECG revealed normal.  Echocardiography revealed a ‘ kissing- type’ of vegetation on the bicuspid aortic valve with severe aortic regurgitation and a dilated left ventricle with moderate dysfunction. The management of aortic insufficiency occurring in infective endocarditis may differ and the presence of intractable pulmonary edema or shock is a clear indication for prompt valve replacement. The traditional diagnostic criteria are insufficient to diagnose infective endocarditis and the modified Duke criteria provide high sensitivity and specificity over 80% for the diagnosis of native valve endocarditis with positive blood cultures. 

Infective endocarditis is a microbial infection of a heart valve (native or prosthetic) or the mural endocardium, leading to tissue destruction and formation of vegetation. Its incidence varies from 1.7- 7.2 cases / one lakh persons-year and the female to male ratio was 1:2 [1]. There are substantial changes in the epidemiology profile over the last few decades [2] as median age group has increased from 30 – 40 to 47-69 years and rheumatic heart disease is no longer the main risk factor in Western countries. The most common predisposing lesion for aortic valve endocarditis is congenitally bicuspid aortic valve (BCAV). Inadequate production of fibrillin-1 during valvulogenesis may disrupt the formation of aortic cusps, resulting in a bicuspid aortic valve and a weakened aortic root [3], which may complicate infective endocarditis in 9.5 % of cases [4]. Isolated Aortic regurgitation was found in only one-twenteeth of a large series of patients in India, 2.7% of patients under 19 years in Brazil as a unique valvular dysfunction. The usual natural history is a long asymptomatic period in which mild-to-moderate regurgitation is well tolerated during the compensated phase and in adults, a rate of < 6>

A 17-year-old female was brought to the emergency room with a history of sudden onset of breathlessness. Her pulse rate was 87 bpm and blood pressure 110/60 mmHg. She had a history of rheumatic fever during childhood, an episode of febrile illness for 10 days and taken antibiotic treatment recently. Blood chemistry revealed normal and blood cultures were negative. ECG revealed normal as shown in Figure 1 and X-ray chest revealed dilated LV (left ventricle) as in Figure 2. Physical examination revealed grade 3/6 early diastolic murmur over left mid sternal border, basal crackles over lung fields and no peripheral signs of wide pulse pressure. Transthoracic echocardiography revealed vegetations on anterior and posterior leaflets of aortic valve as in Figure 3 and Figure 4, with a “kissing-type “as in Figures 5, 6 and 8. The aortic valve was bicuspid with an attached vegetation as in Figure 9 and it was severely regurgitant as in Figure 10 and Figure 11. The left ventricle is dilated as in Figure 12 with moderate LV dysfunction as in Figure 13. The thoracic aorta was prominent as in Figure 14 with a ‘holodiastolic flow reversal’ as in Figure 15. The patient was treated with digoxin (0.25 mg, half daily), diuretics (Injection. Furosemide 20 mg IV twice daily), ACE inhibitors (tablet. Enalapril 2.5 mg twice daily) along with 2 weeks course of intravenous (IV) cefotaxime (1g) and amickacin (500mg) twice daily and advised aortic valve replacement at the earliest with lifelong penicillin prophylaxis and continuation of antibiotics for 6 weeks since the vegetations remain stable after 2 weeks of treatment, but without any embolic episodes.

Figure 1: Showing the normal ECG in acute severe aortic regurgitation in a 17-year-old female

Figure 2: X-ray chest PA (postero-anterior) view showing the dilated left ventricle due to acute severe aortic regurgitation [6] in a 17-year old female.

Figure 3: Parasternal long axis view showing the vegetation on the anterior leaflet of aortic valve (arrows) in a 17-year old female.

Figure 4: Parasternal long axis view showing the vegetation on the posterior leaflet of aortic valve (arrow) in a 17-year old female. AV-aortic valve.

Figure 5: Parasternal long axis view showing the “ kissing-type” of vegetations (arrow) on the aortic valve in a 17-year old female.

Figure 6: Parasternal long axis view showing the “ kissing-type” of  vegetations (arrows) on the aortic valve in a 17-year old female- large view.

Figure 7: Apical view showing the vegetation on the aortic valve (arrow) in a 17-year old female.

Figure 8: Apical view showing the “ kissing-type” of vegetations (arrow) on the aortic valve in a 17-year old female.

Figure 9: Short axis  view showing the bicuspid aortic valve with vegetation (arrow) in a 17-year old female. AO-aorta, BCAV-bicuspid aortic valve, RVOT- right ventricular outflow tract, PV- pulmonary valve, LA- left atrium, VEG-vegetation.

Figure 10: CW (continuous wave ) Doppler showing the acute severe aortic regurgitation (arrow) in a 17-year old female.

Figure 11: Color M-mode (green line) showing the acute severe aortic regurgitation (arrow-AR jet)  in a 17-year old female.

Figure 12: Apical view showing the dilated left ventricle and a normal left atrium in a 17-year old female in acute severe aortic regurgitation.

Figure 13: M-mode LV study (green line) showing moderate LV dysfunction with an ejection fraction of 42% in a 17-year old female in acute severe aortic regurgitation.

Figure 14: Suprasternal view showing the prominent aortic arch in a 17-year old female in acute severe aortic regurgitation.

Figure 15: Suprasternal view showing the holodiastolic flow reversal (arrow) of severe aortic regurgitation [7] in a 17-year old female.

Review of literature

In 1885, William Osler presented the first comprehensive description of endocarditis. Thereafter, the description of clinical features of infective endocarditis  were largely based on data obtained several decades ago. At present, definite clinical evidence of vulnerable infection is based on retrieval of an organism via blood cultures. The ability of echocardiography to detect valvular vegetation was initially described by Dillon and coworkers [8] who identified characteristic thickened echoes, on the mitral and aortic leaflets in patients with tissue -documented valvular lesion.

Etiopathogenesis

The majority of cases of infective endocarditis are caused by gram-positive bacteria, the staphylococcus aureus is now more common than oral streptococci (streptococcus viridians) and it has become the most frequent microorganism causing infective endocarditis (31-54%). Methicillin-sensitive sytaphylococcus aureus (MSSA) is more frequently isolated in community-acquired infective endocarditis, affects mainly native valves, and it is associated with bacteremia of unknown origin, whereas Methicillin-resistant staphylococcus aureus (MRSA) is predominantly related to nosocomial infection, wound infection, IV catheters and surgical procedures. Viridans group is now less common (17-26%) and had partial resistance to antibiotics (‘penicillin tolerence’). The slow-growing HACEK group is an unusual cause of infective endocarditis (1.8-3%) and affects mainly the native valves. Patients with IV drug abusers and long-term central venous catheters are at high risk of fungal infective endocarditis (1-3%), suspected in presence of bulky vegetation, metastatic infection, persistent invasion or embolization to large blood vessels. Whenever blood culture negative infective endocarditis occurs, other organisms such as coxiella burnetti, Brucella, Bartonella, Chlamydia, Streptococcus pneumoniae (often affects the aortic valve [9]) and Legionellae species must be considered. When endothelium is damaged by high flow velocity jets, sterile thrombotic vegetation is formed, which facilitate bacterial adherence during transient bacteremia. Platelet and fibrin deposits at the damaged sites provide the nidus for the formation of vegetation, which causes tissue destruction, septic emboli and abscesses. Vegetation > 1 cm in diameter are associated with greatest risk of embolization [10] and 65 % of embolic events involve the central nervous system, mainly in the distribution of middle cerebral artery (90%). Patients with staphylococcus aureus infective endocarditis have a significant higher incidence of neurologic sequelae (53-71%). Infected embolic material may reach the adventitial layer of an artery through the vasa vasorum, resulting destruction of adventitia and muscularis [11], leading to aneurysm formation [12], usually within 46 hours of embolization [13]. Cerebral infected aneurysms develop in 1 to 12% of cases of infective endocarditis and located on the peripheral branches of middle cerebral artery (55%) [14], also in the secondary and tertiary branches in the region of Sylvian fissure [15] and it is multiple in 18-28% of cases, had saccular type morphology [16] and 10% of them will rupture. Infected intracranial aneurysms may leak slowly or enlarge before rupture and manifest as cranial nerve palsy, seizures, headache and nuchal rigidity due to meningeal irritation. In addition, vegetations often occur in conjunction with ulceration, perforation, and even total destruction of valve leaflets [17], producing abrupt valvular regurgitation, manifested clinically by severe hemodynamic changes [18],[19]. Gross elevation of LVEDP (LV end-diastolic pressure), pulmonary hypertension and depressed cardiac output are the characteristic findings. Valvular destruction causing acute regurgitation is the most characteristic lesion leading to heart failure in native valve infective endocarditis [20],[21]. When there is rapid disruption of the anatomic integrity of the aortic valve, the sudden imposition of a large regurgitant volume causes precipitous increase in LV diastolic pressure and a decrease in forward stroke volume, leading to acute pulmonary edema and, on occasion, circulatory collapse. In acute aoric regurgitation, murmurs may not be easily audible, the pulse pressure is usually reduced due to reduction in stroke volume and increased peripheral vascular resistance. The characteristic physical findings of chronic, severe aortic regurgitation (AR) depend on a widened pulse pressure are often absent. Compensated tachycardia helps to shorten diastolic time available to regurgitation to occur and so the cardiac output is often maintained. Early closure of mitral valve (ECMV) is a specific feature of acute onset, severe aortic regurgitation [22], first postulated by Austin Flint in 1886 [23] and observed echocardiographically by Pride in 1971 [24]. Normally, the mitral valve does not close until shortly after the onset of LV contraction, and leaflet closure occurs 40 ms after the onset of QRS complex in ECG. When the coaptation of both anterior and posterior mitral leaflets occur at or before the initial description of QRS (50 ms before the Q wavem but after the P wave, it is mild (grade 1) and upto 200 ms before the Q wave, it is very marked (grade II) [25]. The premature mitral valve closure is beneficial in the sense that the high LVDP (LV diastolic pressure) is not transmitted to the pulmonary venous system, thus preventing pulmonary edema and left heart failure. When LVDP exceeds the LA pressure, the protection offered by premature mitral valve closure is lost, the opening of mitral valve occurs in late diastole, leading to diastolic mitral regurgitation which is usually effective to lower the LVDP and thus left atrium serves as a reservoir for blood regurgitant from the aorta to left ventricle. 

The differential features of acute and chronic AR are shown in Table 1.

(Table 1 showing the differential features of acute and chronic AR)

In left-sided endocarditis, vegetations usually develop on the edges of the valve leaflets, more prone for peripheral embolism and embolic events may occur before the clinical recognition of the disease as ‘silent 

embolism’, especially in spleen and kidney, and 30% of patients have renal or splenic infarcts at the time of diagnosis. Renal function may deteriorate as the result of worsening hemodynamics and emboli to kidney can lead to abscess formation,  presenting as flank pain, pyuria, or hematuria and cause ‘flea-bitten” appearance of cortex with focal segmental necrosis of the glomerular tuft [26].

Echocardiographic features

Echocardiography plays a key role in the diagnosis of infective endocarditis and the vegetation, the hallmark lesion of infective endocarditis is a majpr echocardiographuc criterion for its detection. Vegetation is a bulky, friable, frequently pedunculated mass composed of fibrin strands, platelets, blood cell debris, bacteria and presents as an oscillating mass attached to a valvular structure, with a motion independent to that of the valve. It may also presents as non-oscillating 

masses with atypical location. Transthoracic echocardiography detects  70% of vegetations > 6 mm and 25% of vegetation < 5>Figures 3 to 9. When endocarditis involves the aortic leaflets, the resultant acute, severe regurgitation as shown in Figures 10, 11 and 15, may often causes dilated left ventricle as in Figure 12  and a prominent aorta as in Figure 14. Secondary infection of mitral valve is a possible finding in primary aortic valve endocarditis. Large aortic valve vegetations (> 6 mm) prolapse into the left ventricular outflow tract and “kiss” the ventricular surface of the anterior mitral leaflet with the development of a vegetation [27],[28],[29]. The left ventricular outflow tract endocarditis may represent the initial site of infection with a possibility to spread by contiguity to both left-sided valves, the mitral and aortic [30], causes the “mitral-kissing vegetation” with a higher prevalence of embolic events [31].

Management

Endocarditis normally presents with fever, murmur, tachypnea, tachycardia, hyperfibrinogenemia, anemia and leukocytosis [32].[33]. Early and adequate diagnosis is important for the prognosis and treatment of patients with infective endocarditis.  New laboratory and molecular analysis techniques have been adapted for recognizing previously unidentified species as etiological agents of infective endocarditis. The management of infective endocarditis comprises antibiotic therapy, intensive medical care and surgery as three main pillars of treatment.

Medical therapy

Bacterial endocarditis must be treated with antibiotics. The objective is the selection of antibiotic based on the sensitivity shown by the antibiogram, but treatment generally begins with an empirical wide-spectrum antibiotic until the hemoculture results are ready [34]. Antibiotics commonly used are penicillin associated with gentamycin [35] and the treatment duration depends on the improvement and resolution of clinical signs, echocardiographic findings, white blood cells, and fibrinogen reduction within normal limits. Traditionaly, prolonged ( 4-6 weeks) treatment is mandatory to kill the dormant bacteria clustered in the infected foci [36]. The mean duration of antibiotic therapy was 5 weels and it is possible that similar results can be obtained after as little as two weeks of therapy [37],[38],[39], especially in uncomplicated NVE (native valve endocarditis) with normal renal function [40]. Almost all patients with acute aortic regurgitation (AR) exhibit tenuous hemodynamics and initial stabilization is required in the intensive care unit. Medical therapy is directed at reducing pulmonary venous congestion, reduction in systolic blood pressure to relieve the afterload and maximizing the cardiac output. Intravenous vasodilator and diuretic therapy can be effective and the principal aim of medical treatment is to optimize clinical status. The nitroprusside with an initial dose of 0.10 to 0.20 mg/kg/mt, gradually increased to attain the desired hemodynamic effects as a reduction in LV filling pressure to 15 mmHg or less and an increase in cardiac output that would ensure adequate tissue oxygen delivery, usually a cardiac index > 2.5 L/mt/m2 while maintaining a systemic blood pressure of ³ 90 mmHg. Patients with grade I premature mitral valve closure without clinical heart failure can be managed by medical therapy. Anticoagulation is not indicated for patients with endocarditis because of the risk of hemorrhagic neurological events [41]. It prevents neither the formation nor the embolization of vegetation as separation of small fragments from the infected vegetations. Three quarters of embolism occurs before the beginning of antibiotic treatment [42] and the embolic risk decreases over time, from 15

Since the patient had a bicuspid aortic valve as shown in Figure 9 and a history of rheumatic fever during childhood, rheumatic inflammation occurred on the aortic valve and harboured the infective vegetation through the vascular access during the treatment of febrile episodes.  Patients with infective endocarditis are at risk of developing acute aortic regurgitation and the ECG can appear normal as in Figure 1 and the chest X-ray usually shows pulmonary edema with normal heart size. A dilated left ventricular cavity with a normal left atrium as in Figure 12 indicates that the volume overload on the left ventricle resulted a compensatory mechanism to maintain an adequate forward stroke volume by accomodating a large regurgitant fraction without an increase in end-diastolic pressure. The heart rate appeared normal (87 bpm) as the result of this compensation. Even though the aortic regurgitation is acute as in Figure 10 which showed a steep deceleration slope with a narrow width of regurgitant jet due to endocarditic lesion of aortic valve (endocarditic regurgitation). It is compensated in this patient and showed a lesser degree of decompensation as moderate LV dysfunction with an ejection fraction of 42% as in Figure 13, necessitating elective aortic valve replacement along with removal of vegetations with a mechanical prosthetic valve. Anticoagulation with warfarin to maintain the INR (international normailised ratio) between 2 to 3 is indicated after the clearance of active stage of endocarditis with antibiotic therapy and surgery. 

 Complicated left-sided native valve infective endocarditis remain a serious disease with significant mortality and morbidity. Vascular-access-related infections are major source of bacteremia in this population [77]. Antimicrobial therapy can offer a curative treatment in only 50% of cases of infective endocarditis. Patients with large vegetations, intracardiac abscess (9-14 %) or persisting infection (9-11 %) almost always need surgery and most patients require valve replacement.