Challenges and Insights in Aggregatibacter aphrophilus endocarditis: a review of literature

ABSTRACT Infective endocarditis is a serious disease associated with high mortality despite recent advances in diagnosis and treatment. Aggregatibacter aphrophilus is a fastidious Gram-negative member of the HACEK organisms (Haemophilus spp., Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae). A. aphrophilus is associated with dental infections but has also been implicated in cases of infective endocarditis. We highlight the importance of a high index of suspicion in symptomatic patients with an initial negative blood culture, particularly in high-risk groups such as patients with congenital valve disease and prosthetic valve. The knowledge of this rare entity may lead to early diagnosis and appropriate management. We review the main characteristics of Aggregatibacter aphrophilus endocarditis reported in the medical literature.

HACEK endocarditis is a rare disease with an excellent prognosis and simple management if the organism is properly identified.Due to the difficulty of Aggregatibacter aphrophilus isolation, this bacterium is rarely seen in blood cultures (2) .In this paper, we review the main characteristics of Aggregatibacter aphrophilus endocarditis reported in the medical literature.

Literature review
We reviewed PubMed® for cases of Aggregatibacter aphrophilus endocarditis.We used the MeSH database to search the terms "infective endocarditis" and "Aggregatibacter aphrophilus" in order to increase the sensibility and specificity of the search.The 20 cases with the most significant data are summarized in Table 1.The articles were reviewed to gather information about patient demographics, preexisting heart diseases, and treatment options.In total, 91 studies were identified, of which 20 met the inclusion criteria, describing a total of 20 patients (Table 1).The identified studies were performed between 2002 and 2021.

Underlying diseases and risk factors
A combination of the previous medical history of prosthetic valve, pacemaker placement, congenital heart disease, congenital valvular disease, prior rheumatic fever, poor dentition, chronic disease, drug abuse, and tongue piercings has been reported in the majority of the cases.Only six patients (30%) did not present risk factors.
According to previous reports, five patients (25%) had received a prosthetic valve.One patient had undergone aortic valve replacement (AVR) twice due to infective endocarditis (IE) and a subsequent failed bioprosthetic valve; a second patient had a bioprosthetic aortic valve replacement at the age of 17 for bicuspid aortic stenosis; a third patient had undergone AVR twice and a mitral valve replacement (MVR) at 51 years old, also, the patient presented rheumatic fever at 15 years old; he was being treated with beta-blocker (atenolol) and a vitamin K antagonist (acenocoumarol); the fourth patient had undergone AVR due to a bicuspid aortic stenosis, also the patient presented diabetes mellitus; and the fifth patient had rheumatic fever.
Only one case (5%) received a dual-chamber pacemaker placement for complete heart block.A 25% of the patients presented with congenital valvulopathy: true bicuspid aortic valve and ascending aortopathy were reported in one of the patients; while the second patient had a calcific aortic stenosis due to a congenital bicuspid aortic valve and a poor dentition.The third patient had a pierced tongue two months before onset of illness and a history of aortic valvuloplasty at eight years of age for correction of congenital aortic stenosis.Also, the patient had previous dental work with endocarditis prophylaxis.Among other reported conditions, one of the patients had a calcific aortic stenosis due to a congenital bicuspid aortic valve and a poor dentition.
Three cases (15%) had congenital heart disease.One patient had a perimembranous ventricular septal defect (PMVSD); a second patient had a Contegra D-valved conduit (CVC) placement due to a D-transposition of the great arteries with ventricular septal defect and pulmonary stenosis at two years old; a third patient underwent a surgical patch closure of patent foramen ovale at the age of 9 and dental care at five months before his admission.Only one case (5%) had a history of nicotine and alcohol abuse.

Clinical presentation and physical examination
The initial presentations of 20 patients with endocarditis due to Aggregatibacter aphrophilus were detailed.The mean duration of symptoms before diagnosis in 16 patients was 10 days (range, 5 -14 days).The clinical presentation was available for 19 patients.The most common symptoms were fever in 16 (80%), fatigue/general malaise in 5 (25%), weight loss in 5 (25%), and headache in 3 (15%) patients.On the physical examination, cardiac murmurs were found in 6 patients (30%).A total of seven patients (35%) showed embolic complications as initial presentation, neurological involvement being the most common.Four patients (25%) had an ischemic stroke; 1 patient presented a brain abscess; 1 splenic abscess and 1 ANCApositive glomerulonephritis were also described.Two patients (10%) were admitted with the initial diagnosis of heart failure.

Diagnosis
In 20 cases for which data were recorded, the mean positive blood culture was 0.59 (range: 1-8 taken) with a mean incubation time of 5 days (range: 3-7 days).In 8 patients, blood cultures yielded no organisms, but a definitive diagnosis of endocarditis was established by PCR/sequencing (Br-PCR) of the 16S ribosomal RNA gene in the resected valve or arterial embolus or by culture of the valve in surgery.In 1 case, Aggregatibacter aphrophilus was identified in the cerebrospinal fluid culture.
An echocardiogram was performed on 19 patients, of whom 6 underwent Trans thoracic echocardiogram (TTE) and 4 Trans-esophageal echocardiogram (TEE).In one patient, 2D-TEE, 2D-TTE and 3D-TTE were performed, of which only a positive result was obtained through 3D-TTE; 8 patients had both a TTE, and a TEE.In five patients, the vegetations were visible on the TEE, but not on the TTE.The size of the vegetations, determined by echocardiography, was described in only 8 cases.The mitral valve was involved in 8 of the 20 (40%) patients, the aortic valve in 1 (5%) patient, and both valves in 1 (5%) patient.One case of ventricular pacemaker lead infection was presented.In 9 patients (45%) the valve involved was not identified.

Treatment and susceptibility
The treatment of the 20 patients was detailed, all of whom received cephalosporins at some point during the course of therapy.The therapy was almost always administered intravenously.The most frequently administered therapy was cephalosporin monotherapy (10 patients, 47.6%) followed by dual cephalosporin and aminoglycoside therapy (3 patients, 15%).One patient received the combination of a cephalosporin plus a glycopeptide, while other regimens included tetracyclines, rifamycins, and penicillins.One patient received a cephalosporin, a fluoroquinolone, a glycopeptide, and 3 other antimicrobial agents.Cephalosporins were part of the antimicrobial therapy in 17 (89.5%)cases.The mean duration of treatment in 12 patients was 4.9 ± 6 weeks (range: 2 weeks to 8 weeks).The median duration of treatment for native valve endocarditis was 2.6 weeks and for prosthetic valve endocarditis 3.6 weeks; 50% of the patients (10) underwent valve replacement surgery.
Of the 4 cases of native valve endocarditis, the aortic valve was replaced in 1 and the mitral valve in 3 patients.Of the 6 cases of prosthetic valve endocarditis, 2 (33.33%) required aortic valve replacement.

Discussion
Aggregatibacter aphrophilus is a member of the group of HACEK organisms.Typically, Aggregatibacter aphrophilus is part of the normal oropharyngeal flora and is frequently found in dental plaques and gingival scrapings (1) .Khiarat et al. described the first case of valvular Aggregatibacter aphrophilus infection in 1940 (23) .Aggregatibacter aphrophilus is an uncommon cause of EI (1-3%).The highest incidence of A. aphrophilus endocarditis is among middle-aged adults and preferentially infects males (2) .It is believed that the microorganism located in the oropharynx, enters the vascular chamber at the time of dental work or in the context of periodontal disease, normally in patients with poor dentition or recent dental work (1) .Therefore, the literature data suggest that the microorganism is generally considered to be low virulence and structurally damaged, or prosthetic cardiac valves seem to be the predisposing conditions most strongly associated with the incidence of Aggregatibacter aphrophilus endocarditis.Other groups at risk include those with pacemaker placement, congenital heart disease, prior rheumatic fever, poor dentition, chronic disease, drug abuse, and those with tongue piercings (1) .
Aggregatibacter aphrophilus endocarditis is remarkably insidious in its presentation (8) .The course of symptoms before the diagnosis has been reported to be prolonged, with a mean of 10 days, compared to endocarditis caused by traditional organisms (24,25) .Systemic symptoms, fever, weight loss, and anorexia were reported in most cases; however, embolic complications stood out as the initial clinical presentation.Embolic neurological involvement is the most common.The most reported conditions were cerebrovascular accidents and brain abscesses, patients can also have splenic infarction and other extracardiac emboli complications.The mitral valve is the most commonly infected valve, with a tendency to infect normal valves more often than other microorganisms do (7) .The presence of factor V on its structure is necessary for the infection of the native valve (26) .
The diagnosis is extraordinarily challenging (27) .Knowing that the identification of the pathogen is the key to the success of the treatment of the endocarditis with HACEK organisms the problem is that they are well known as culture negative.It is currently suggested that the PCR/sequencing study (Br-PCR) of the 16S ribosomal RNA gene overcomes the difficulty of finding this microorganism in a blood culture.The diagnosis of Aggregatibacter aphrophilus endocarditis with the modified Duke criteria has limitations (28) .The median number of cultures taken was 2.1 (range, 1-8 taken), of which 47% were positive for Aggregatibacter aphrophilus with a mean incubation time of 5 days (range, 3-7 days).In 8 patients, no organisms were isolated in the blood cultures, even though despite the fact that serial samples of more than 3 blood cultures were taken, separated by 24 hours each with an interval between samples of 60 minutes.Aggregatibacter aphrophilus needs to be considered as difficult organisms to culture and, therefore, they are classified within the group of "culture-negative endocarditis" (3) .
For the diagnosis of endocarditis, the identification of vegetation on the heart valve was made principally by a transesophageal echocardiogram.Most patients who had an TEE report a previous negative transthoracic echocardiogram.Normally the first exam is the TTE, but in cases where vegetation cannot be observed, the primary second-line examination is a TEE.In our review, we identified that the vegetation was identified in 13 (65%) of the 20 patients using transesophageal echocardiography; of which 8 presented a negative initial transthoracic echocardiography.
The American Heart Association (AHA) and European Society of Cardiology (ESC) recommend as a first-line treatment with intravenous third or fourth-generation cephalosporins and fluoroquinolones (27) .Of the 20 cases presented, 17 used ceftriaxone as central treatment, 8 of which used only monotherapy with a third-generation cephalosporin for a mean of 4 weeks (range 2-8 weeks).Eight patients used double therapy where fluoroquinolones were used in 60%.In 10 of the 20 patients, the condition resolved after 6 weeks of antibiotic therapy without the need for surgical intervention.The routine duration of treatment is fourweeks for non-valvular endocarditis (NVE) and six-weeks for prosthetic-valve endocarditis (PVE).Patients with endocarditis Arch Peru Cardiol Cir Cardiovasc.2023;4(3):102-108.doi:10.47487/apcyccv.v4i3.306.
due to Aggregatibacter aphrophilus achieve resolution of the condition through antibiotic therapy, valve replacement surgery is not frequent.Valve replacement surgery was necessary for 5 patients (25%), the aortic valve was replaced in 2 patients, and the mitral valve in 3 patients.No perioperative complications were reported.
Endocarditis secondary to HACEK organisms generally has an excellent prognosis with a significantly lower mortality rate at one year compared to IE due to EGV (13) .Most of the patients did not report complications, death, or recurrence of a new episode at follow-up for 1 year.
The review highlights the importance of a high index of suspicion in symptomatic patients with an initial negative blood culture as a Aggregatibacter aphrophilus endocarditis, particularly in high-risk groups such as patients with congenital valve disease and prosthetic valve.The knowledge of this rare entity may lead to early diagnosis and appropriate management.