Parisa Badiee

*Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran* 

### **1. Introduction**

268 Special Topics in Cardiac Surgery

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29.

99.

778.

2010;139:860-67.

Surg 2007;32:702-710.

Care 2009;25:485-96.

Infective endocarditis (IE) is a threatening disease associated with a high risk of morbidity and mortality. The most etiologic agents are the bacteria followed by fungi. Fungal Endocarditis (FE) is an uncommon occurrence and the most severe form of IE, however, its rate has increased in recent decades. The first report of FE after a mitral valve replacement was in 1964 (1) but there have been many cases reported in recent years indicating the importance of such infections (2-4). Fungal endocarditis accounts for 1.3% to 6% of all IE cases (5-8). Ranges between 1.7 to 3.8 per 100,000 person-years have been reported in different studies for mean annual incidence (5, 9). Increase in the number of cases of fungemia and FE has been seen during the last 2 decades (10, 11). Men are more at risk of infections than women (7, 12, 13), and younger persons (third to fourth decades of life) are in more risk factor. The incidence of FE varies based on the criteria and methods of diagnosis (5) and population under survey; in liver transplants (14) the incidence of FE after transplantation was 1.7%. The mortality rate was 72% (15) but is still high (about 50%) despite the treatments (7). In an international multicenter prospective cohort study that included 33 cases of *Candida* endocarditis treated between 2000 and 2005, the mortality rate was 30 % (16), and in post-surgical invasive aspergillosis (17) and *Aspergillus* endocarditis the rate was too high (100%) even with combined medical and surgical therapy (2).

Fungi are important causes of prosthetic valve endocarditis, responsible for 1%–10% of these infections (18). Also, there are reports that fungi are responsible for 9.6% of the early cases of prosthetic valve endocarditis (60 days after the insertion of prosthesis) and for 4.3% of late cases (>60 days after the insertion of prosthesis) (19, 20). The incidence of FE in culturedocumented cases has been reported to range from 12% to 20% (21) or to 37.5% (22).

Many fungal species cause FE, of which the most important are *Candida albicans* 60%-67% and filamentous *Aspergillus* spp. 20–30% (ratio rate 2/1) (7, 15, 23), In addition, non-*albicans*  species of *Candida*, *Torulopsis glabrata, Candida tropicalis*, and other filamentus fungi like *Aspergillus* spp., *Curvularia genuculata, Hormondendrum dermatitidis, Mucoracae*, *Scopulariopsis* spp., *Trichosporon spp. and Blastoschizomyces capitatus* have been reported in the literature (10, 15, 22, 24, 25). In some studies, the most common etiologic agent was different, as in Rubinstein E et al. *Candida parapsilosis* accounts for half of the culture-documented patients, whereas *C. albicans* and *Candida stellatoidea* account for 12%-15% only (21)*. Pneumocystis jiroveci* caused fungal infection in 9% to 11% of all heart transplant recipients in the past, with a mortality rate of 11% to 38% (26) but with use of prophylaxis, the rate of this infection has decreased.

Post-Cardiac Surgery Fungal Endocarditis 271

and evidence of emboli to viscera or skin







petechiae, Roth spots, Osler's nodes, Janeway lesions, splinter hemorrhages, aseptic meningitis, conjunctival hemorrhages,


positive blood cultures without an extra cardiac source

endocarditis likely, empiric antibiotic therapy warranted

phenomena, negative or intermittently positive blood cultures, plus three of the following: new regurgitant murmur, fever, vascular phenomena -

glomerulonephritis, or central nervous system, pulmonary, coronary or

predisposing heart disease - definite valvular or congenital heart disease, or a cardiac prosthesis (excluding permanent pacemakers) , vascular





phenomena and new regurgitant valvular heart murmurs

underlying valvular heart disease, and embolic episodes.

meet the above criteria due to lack of sensitivity.


embolus (staining or culture).

peripheral emboli.

phenomena

postmortem


**Pelletier and Petersdorf criteria**

Probable IE

Possible IE

Property

(35)

Definite

Probable

possible

Rejected

property

**von Reyn criteria** 

(34) Definite IE

The source of infection can be internal or external, the former usually with *Candida* spp*.* This organism is the normal flora of the patient's body and causes contamination during the surgery, and is recognized as the catheter-related blood stream infection (27). However, conidia of the external agents could contaminate the tissues during the surgery or post operative contamination by environmental isolates present in high counts (17).

Time of presenting of infection is different and maybe during the first 2 weeks in hospital period to months after heart surgery at home, and in some cases 12 years later (15). Diagnosis should be prompt because the time interval between the first symptom and hospital admission in some cases is long and may be one year (15). Early diagnosis could be helpful for the patients' survival. The onset of symptoms is usually about 2 weeks or less from the initiating bacteremia.

Anatomical cardiac condition diseases (cardiac abnormality), intravenous drug abusers and open heart cardiac surgery are the top risk factors for the infections. There are many risk factors for progressive FE, including the use of multiple immunosuppressive drugs such as azathioprine, corticosteroids, cyclosporine A, and cyclophosphamide (12, 13, 15). Malignancy, exposure to multiple broad-spectrum antibiotics, prolonged use of intravenous catheters (28), use of high glucose concentrations intravenous catheters especially in premature neonates (29), rheumatic heart disease (22), previous bacterial endocarditis, prior surgery, prolonged intravenous hyper alimentation, pacemaker implantation, and reconstructive cardiovascular surgery are other risk factors (15,30-32). In some cases no predisposing factor has been identified (7, 33)

The mechanism of endocarditis includes high turbulent blood flow due to cardiac abnormality or other risk factors (e.g., particulate material in the repeated injections of drugs in IV drug abusers) which disrupt the surface of endocardia and endothelium. The response of the body is repairing the damaged tissue with platelet-fibrin meshwork which is sticky and proper site for infection. After temporary bacteremia, it sticks to this meshwork and proliferation of organism causes the infection that invades the cardiac valves.

Infective endocarditis is classified into definite, probable, and possible according to Pelletier and Petersdorf (34). Other classifications include definite, probable, possible and rejected by von Reyn (35) and definitive, possible and rejected by Duke criteria (36) (Table 1). Briefly, proven FE is defined as the isolation of fungi from the normally sterile sites, the blood or heart biopsy or vegetation, by culture and/or the evidence of fungal invasion of tissue by histopathological methods. Probable FE is defined as when the culture is negative for the infective agents, and clinical conditions of the respective patients are not recovered despite the administration of standard antibacterial therapy. Role of echocardiography, definition of rejected IE and major and minor clinical criteria were added to the previous definition in 1994 (37). According to Duke criteria, the diagnosis of definitive IE requires the presence of either two major criteria, one major and three minor criteria, or five minor criteria.

### **2. Clinical manifestations**

The clinical manifestations of acute or sub-acute IE are related to the underlying pathophysiology of embolization, bacteremia/ candidemia, immunologic response, and valvulitis (30). Common clinical features are changing heart murmur, fever, and major peripheral emboli (common in fungal endocarditis) (10, 33). Some cases presented with the systemic symptoms associated with bacteremia include fever, tachycardia, septic shock; and the general symptoms and signs of cardiac involvement including chest pain, arrhythmias,

The source of infection can be internal or external, the former usually with *Candida* spp*.* This organism is the normal flora of the patient's body and causes contamination during the surgery, and is recognized as the catheter-related blood stream infection (27). However, conidia of the external agents could contaminate the tissues during the surgery or post

Time of presenting of infection is different and maybe during the first 2 weeks in hospital period to months after heart surgery at home, and in some cases 12 years later (15). Diagnosis should be prompt because the time interval between the first symptom and hospital admission in some cases is long and may be one year (15). Early diagnosis could be helpful for the patients' survival. The onset of symptoms is usually about 2 weeks or less

Anatomical cardiac condition diseases (cardiac abnormality), intravenous drug abusers and open heart cardiac surgery are the top risk factors for the infections. There are many risk factors for progressive FE, including the use of multiple immunosuppressive drugs such as azathioprine, corticosteroids, cyclosporine A, and cyclophosphamide (12, 13, 15). Malignancy, exposure to multiple broad-spectrum antibiotics, prolonged use of intravenous catheters (28), use of high glucose concentrations intravenous catheters especially in premature neonates (29), rheumatic heart disease (22), previous bacterial endocarditis, prior surgery, prolonged intravenous hyper alimentation, pacemaker implantation, and reconstructive cardiovascular surgery are other risk factors (15,30-32). In some cases no

The mechanism of endocarditis includes high turbulent blood flow due to cardiac abnormality or other risk factors (e.g., particulate material in the repeated injections of drugs in IV drug abusers) which disrupt the surface of endocardia and endothelium. The response of the body is repairing the damaged tissue with platelet-fibrin meshwork which is sticky and proper site for infection. After temporary bacteremia, it sticks to this meshwork and

Infective endocarditis is classified into definite, probable, and possible according to Pelletier and Petersdorf (34). Other classifications include definite, probable, possible and rejected by von Reyn (35) and definitive, possible and rejected by Duke criteria (36) (Table 1). Briefly, proven FE is defined as the isolation of fungi from the normally sterile sites, the blood or heart biopsy or vegetation, by culture and/or the evidence of fungal invasion of tissue by histopathological methods. Probable FE is defined as when the culture is negative for the infective agents, and clinical conditions of the respective patients are not recovered despite the administration of standard antibacterial therapy. Role of echocardiography, definition of rejected IE and major and minor clinical criteria were added to the previous definition in 1994 (37). According to Duke criteria, the diagnosis of definitive IE requires the presence of

proliferation of organism causes the infection that invades the cardiac valves.

either two major criteria, one major and three minor criteria, or five minor criteria.

The clinical manifestations of acute or sub-acute IE are related to the underlying pathophysiology of embolization, bacteremia/ candidemia, immunologic response, and valvulitis (30). Common clinical features are changing heart murmur, fever, and major peripheral emboli (common in fungal endocarditis) (10, 33). Some cases presented with the systemic symptoms associated with bacteremia include fever, tachycardia, septic shock; and the general symptoms and signs of cardiac involvement including chest pain, arrhythmias,

operative contamination by environmental isolates present in high counts (17).

from the initiating bacteremia.

**2. Clinical manifestations** 

predisposing factor has been identified (7, 33)


Post-Cardiac Surgery Fungal Endocarditis 273

radiography. Gold standard tests for the detection of documented infections are the isolation of fungi from the blood, heart biopsy or vegetation by culture and the presence of tissue invasion by histopathology. Isolation of fungi from blood samples is difficult due to non-growth of fungal etiologic agents in blood culture. The rate of culture positive of *Candida* spp. in the blood is about 50% of the documented cases and positive blood culture for *Aspergillus* is rare (38-40). Fungi are cleared rapidly, due to large size, in the blood by the host's reticuloendothelial system; therefore, the blood culture results are negative in many suspicious patients. The use of lysis-centrifugation system (41), or Bactec blood culture (42), may help the isolation of fungal agents but none is recommend as a standard method. Heart tissue is the best sample for the isolation of fungal agents. As resistance to the antifungal agents has been reported in many studies (43-45), in case of positive culture, sensitivity test of the isolated fungi to antifungal agents can contribute to the best management of

Another definitive microbiologic diagnosis depends upon the evidence of fungal tissue invasion with histopathologic investigation. The samples (tissue valve or emboli) are stained with specific stains like Gomori methenamine silver or Periodic acid-Schiff. With histopathology examination, morphological differentiation between *Aspergillus* spp. and

Given the frequent negative blood cultures, and difficulty in obtaining the material from the surgical sites in the operating rooms, echocardiography, either transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE), are used as the diagnosis tools with the sensitivity of about 77% (15) for the evaluation of FE and the presence of vegetation, based on the major diagnostic Duke criterion. Echocardiography can also detect intra cardiac abscess, new or progressive valvular regurgitation, the size and location of vegetation. The size of vegetation may be small, medium, or large and anatomic site of the vegetation may be aortic valve, on tricuspid, mitral or endocardium, or on the

Transesophageal echocardiography should be considered as the standard diagnostic procedure for IE (46). This method is able to evaluate the prosthetic valves, intracardiac complications, inadequate TTE, fungemia or bacteremia, and has superior sensitivity (47), compared to TTE, but significantly more invasive and expensive than it. Transthoracic echocardiography is the first line procedure for the detection of FE especially in native valve and prosthetic valve vegetations, and local extension of infection. The sensitivity of TTE in infants and younger children is about 80 percent (48, 49), therefore, the negative result of it cannot definitively rule out FE and examination should be repeated in respective patients. If there is a high clinical suspicion for FE and the TTE is negative, we should turn to TEE. Once treatment is completed, repeated evaluation may be necessary to establish a new baseline of valvular and myocardial functions for the patient. Unfortunately, both TTE and TEE may yield false negative results if the vegetations are small, or large size of the vegetation suspected as a mural thrombus, vegetation is attached to the mural endocardium

Chest radiography and echocardiography are not useful in the diagnosis of IE; x-ray may present the septic pulmonary emboli (Minor Duke's Criteria) and echocardiography may

Over the last several decades, non-culture laboratory methods have been directed at the development for the diagnosis of systemic fungal infections such as FE. Serological diagnostic methods can serve as the non-invasive methods for detecting the circulating

infections.

other fungi is not completely available.

previous aortic valvular surgery.

and if embolization of the vegetation has occurred.

show evidence of some complications.


a Prosthetic heart valve or a valve lesion that leads to significant regurgitation or turbulence of blood flow; Vascular phenomenon like emboli to the brain or organs, hemorrhages in the mucous membranes around the eyes; Immunologic phenomenon include lesions such as Roth's spots or "Osler's nodes and glomerulonephritis.

Table 1. Definition of three criteria for the diagnosis of infective endocarditis

edema, dyspnea, murmur on examination, cardiac failure, and persistent sepsis would also present. Other symptoms include abdominal pain, malaise, weight loss, night sweats, arthritis, finger clubbing, cough, hemoptysis, sudden death, coagulopathy, jaundice, nausea, hypotension, and renal failure. *Candida spp*. is the most etiologic agent of FE; therefore, patients can present endophthalmitis, meningitis, osteomyelitis and other complications of candidemia. The more specific cutaneous or mucocutaneous lesions of IE include Osler's nodes, Roth spots (rare), and Janeway lesions are more specific signs but less common and not diagnostic . Petechiae and splinter hemorrhages (nonblanching, linear reddish-brown lesions found under the nail bed) are not specific but are common skin manifestations. They may be present on the extremities of skin, or on mucous membranes. Other organs may be involved due to embolic events such as splenic or renal infarcts, or immune reactions like arthritis and glomerulonephritis, or spread by the blood passing to other organs like soft tissues, vertebral osteomyelitis, and the brain causing meningitis and/or encephalitis.
