Candida spp. are the most frequent fungal agent causing cardiac infection both in adults and children [137, 1981, 2361]. From a histopathologic perspective three types of cardiac candidiasis may occur and are discussed on this page: (A):endocarditis, myocarditis, and pericarditis.
Candidal endocarditis is a severe condition that has been traditionally associated with an exceptional high mortality and recurrence rates . Both native and prosthetic valves may be affected . Combining medical with surgical interventions, the hospital survival rates have been commonly below 50%. The highest long term survival rate is 67% [137, 1135, 1513, 1592, 2071].
Available data on the incidence of candidal endocarditis comes from studies on fungal endocarditis. High rates of candidal endocarditis have been reported in association with:
- Open heart surgery is one of the most frequent risk factors for fungal endocarditis, with a rate of 0.23% to 1% of all cardiac surgeries [1654, 1981]. Candida spp. explain more than half of these cases .
- Fungal prosthetic valve endocarditis has been reported to be 9.6% and 4.3%, respectively . Both early onset (within the first 60 days after insertion of the prosthesis) and late-onset endocarditis are described. The series by Muerhrcke et al. reported an incidence of 7% of fungal endocarditis among 184 patients with prosthetic valve endocarditis, and Candida was found to explain 75% of these cases . Gilbert et al. reviewed 34 cases of successfully treated fungal prosthetic valve endocarditis and found that Candida spp. were responsible for 88% of them . This higher proportion is possibly related with the better prognosis of Candida endocarditis when compared with other fungal valve endocarditis .
- Intravenous drug abusers have the highest rates of fungal endocarditis. Candida spp. account for between 50 and 60% of cases .
- Neonates may develop endocarditis as part of the picture of disseminated neonatal candidiasis. Mayayo et al. recently reviewed 17 cases of fungal endocarditis in premature infants that were published in the literature through 1995 . Candida spp. causes all of the infections.
Predisposing factors for candidal endocarditis include:
- Cardiac surgery [139, 1982].
- Prosthetic valves [1513, 1592, 1620, 1640].
- Intravenous drug abuse: Heroin addiction [1982, 2390].
- Neonates [1472, 2491].
- Iatrogenic immunosuppression (Chemotherapy) [371, 1982].
- Prolonged intravenous and/or antibiotic therapy [837, 1982].
- Previous valvular disease [371, 2390].
- Pre-existing bacterial endocarditis [837, 1513, 2390].
- Pacemaker implantation [1138, 2100].
- Intravenous catheters in place for long periods of time [2303, 2361].
Often, two or more of these predisposing factors are present. Nevertheless, cases without any known risk factor have been reported [1032, 1616].
Some unique epidemiologic patterns have been described for the acquisition of candidal endocarditis:
- Implantation of a contaminated heart valve allograft despite disinfection during allograft processing .
- Outbreaks related to valve replacement surgery possibly due to glove tears during the intervention .
Candida species and Candida Endocarditis
C. albicans is responsible for the majority of cases in non-addicts, including children [137, 837, 1472, 1593]. C. parapsilosis predominates in the group of patients with intravenous drug addiction [1981, 2390]. Unusual non-albicans species such as C. guillermondii, and C. krusei are frequently found among addicts .
The classic signs of bacterial endocarditis have all been described in cases of Candida endocarditis . They include in order of frequency:
- Changing murmur
- Peripheral embolism and their related signs
- Congestive heart failure
- Cutaneous lesions: petechiae, papules, pustules, ulcerative lesions and nodules
However, among all these, emboli to large vessels in the brain, kidneys, limbs and mesenteric organs, have been classically linked both to fungal endocarditis in general and candidal endocarditis in particular [1036, 1384, 1981, 2128, 2339]. Chorioretinitis is another important clinical manifestation that is commonly found, especially among drug abusers [247, 2100, 2303]. Onset of symptoms can be either insidious or abrupt . The most commonly involved valves are the aortic and mitral valves [1640, 2390]. Bad prognostic signs include persistent fungemia despite antifungal therapy, peripheral emboli, and/or congestive heart failure at the time of diagnosis .
Specific Diagnostic Strategies
Besides the non-specific hematologic and biochemical abnormalities classically related to infectious endocarditis (anemia, leucocytosis, elevated sedimentation rate, elevated LFTs and abnormal urinalysis) the following tools are important in diagnosing Candida endocarditis:
- Blood cultures.
The sensitivity of blood cultures to detect invasive candidiasis is generally low. However, the intravascular site of this infection changes that rule. Indeed, when compared with other fungal agents able to cause endocarditis, Candida is the most frequently cultured . Rates of 83 to 95% of positive blood cultures for Candida spp. have been reported in reviews of fungal endocarditis [1499, 1640]. In the review by Nguyen et al. of 18 prospectively identified cases of candidal prosthetic valve endocarditis, all patients had several positive blood cultures. The mean and median number of positive blood cultures for this group were 7 and 5 respectively .
The advent of two-dimensional echocardiography has improved dramatically the ability to detect valvular vegetations . Transesophageal echocardiography added an even more sensitive tool, particularly in cases of prosthetic endocarditis . A unique view of the mitral prosthesis can be obtained through the left atrium with this technique . This was proven by Melgar et al., who compared these two techniques in their series of 16 cases and found that transesophageal echocardiography was more sensitive (100%) than transthoracic echocardiography (60%) in detecting lesions due to fungal prosthetic valve endocarditis . Perhaps making echocardiography even more useful, fungal endocarditis is thought to usually cause relatively larger vegetations .
Candida endocarditis carries a high rate of mortality. Medical treatment alone usually fails. Surgical replacement of the infected valve as well as the administration of a prolonged antifungal regimen is strongly recommended . Non-surgical candidates have been treated with long-term suppressive oral therapy, but this approach should be used only in extreme cases as is considered non-curative .
Attempts to treat Candida endocarditis with antifungal agents alone were invariably unsuccessful . The best ever reported survival rate of this fatal infection (more than 50% at 5 years) has been achieved by combining an aggressive perioperative antifungal regimen with radical surgical debridement of all infected tissue and valve replacement, ideally using biologic tissue [1513, 1593]. A less aggressive approach with excision of just the fungal vegetation (so-called “valve-sparing debridement”) has been reported to be successful .
Very few authors have reported successful treatment with a non-surgical approach for this condition [137, 707, 973, 2491]. Indeed, the chronic nature of Candida makes eradication of this infection difficult and long-term antifungal therapy is usually necessary .
- Amphotericin B. Despite being the agent recommended by experts, amphotericin B has two disadvantages when treating this candidal endocarditis. First, its penetration into the vegetation has been shown to be poor . Second, its toxicity profile frequently limits therapy [1640, 2272]. Nevertheless, amphotericin B, alone or in combination with flucytosine, is still considered the gold standard for the initial phase of therapy . When compared with fluconazole in a Candida endocarditis rabbit model, amphotericin B has been found to be more efficient in reducing vegetation fungal density, especially at the beginning of therapy [425, 1373]. Daily doses should be the maximum tolerated dose in the range of 0.5 to 1 mg/kg/day, until a total dose of ~ 2 grams has been given. As discussed below, this regimen should be followed by an azole to complete no less than 6 weeks of therapy following the surgical intervention .
- Lipid preparations of Amphotericin B. There are no data on the lipid preparations of amphotericin B in the treatment of Candida endocarditis. A few case reports have been published describing successful use of these compounds, two with amphotericin B liposomal complex (ABLC) and two with liposomal amphotericin B (Ambisome) [153, 517, 1509].
- Flucytosine. Because of the previously mentioned difficulty on curing Candida endocarditis, the synergism between amphotericin B and flucytosine is attractive [983, 2362]. However there is no more than anecdotal data on the use of this agent. It must always be in combination with another antifungal agent and its role on the treatment of this condition has not been clearly defined.
- Azoles. The availability of oral antifungal agents has added a very important tool for the long term treatment of a condition with a very high relapsing rate . Experience with ketoconazole has been very limited and its pharmacology does not recommend it in this setting [1849, 2013, 2483]. Likewise, there are no useful data on the potential role of itraconazole. The characteristics of fluconazole make it attractive for the treatment of Candida endocarditis. However, as discussed above, a comparison of fluconazole with amphotericin B in a Candida endocarditis rabbit model, showed that amphotericin B was superior in reducing vegetation fungal density, especially at the beginning of therapy [425, 1373].
Clinical data with fluconazole are limited to anecdotal reports. Several case reports have shown it to be useful as long-term therapy after variable courses of amphotericin B [153, 503, 837, 1037, 1976, 2303, 2483].
Fluconazole has also been employed for medical therapy alone in a few cases. Castiglia et al. summarized 9 cases of non-surgical candidates that were treated either with fluconazole alone (5 cases) or after a variable course of amphotericin B (4 cases/total dose range 725 mg – 2.1 grams) . A surprisingly high survival rate of 78% was reported for this group. Aspesberro et al. reported 4 similar cases in children that were treated medically with fluconazole . Even considering the limitation of such small retrospective analysis it is possible that fluconazole has a special role for the treatment of patients that cannot undergo valve replacement .
Candida pericarditis is a rare but serious condition that can lead to severe sepsis, cardiac tamponade and death if not diagnosed and treated promptly . Candidal pericarditis may occur in relation to obvious hematogenous seeding from invasive candidiasis . However, local contiguous dissemination is also well described [372, 668, 909, 2058].
For both cases related to hematogenous seeding as well as for those linked to contiguous infection, risk factors are the usual risk factors for invasive candidiasis. For the second group, however, thoracic or cardiac surgeries requiring pericardiotomy and pre-existing inflammatory pericardial diseases often also play a role.
Candida species and Candida Pericarditis
Candida albicans is the most frequent species, followed by C. tropicalis. Of the 26 cases reviewed by Rabinovici et al. only 18 had species identification. Of these 78% of them were caused by Candida albicans.
The majority of cases have a nonspecific clinical picture and the diagnosis is frequently established on post-mortem examination . The physician should be alert and suspect this condition in patients at risk presenting a combination of the following symptoms/signs: fever, increasing cardiac shadow, and pleural effusion. Ideally, a diagnosis should be established before the development of signs of cardiac tamponade.
To make the diagnosis of Candida pericarditis, one should :
- Recognize the patient populations at risk,
- Perform an echocardiogram when suspecting the picture,
- Perform a pericardiocentesis,
- Isolate Candida from the pericardial fluid or tissue, and
- Ideally, have a histopathologic confirmation of yeast forms in pericardial tissue.
Treating Candida pericarditis requires an aggressive approach that combines surgical and medical treatment . The mortality of 12 cases published before 1980 was 100% . Surgical treatment should include extensive pericardiectomy. Medical treatment has been successful only with prolonged courses of amphotericin B but the precise length of therapy is not defined [1915, 2058].
Hematogenous seeding of Candida into the myocardium was frequently found in the early autopsy reviews of patients dying with systemic invasive candidiasis [1082, 1245, 1376, 1602]. Classically, the histopathologic lesions are myocardial micro-abscesses showing yeast and pseudohyphal elements with minimal inflammatory response. The lack of inflammatory response is most notable in immunosuppressed patients . The frequency of heart involvement in the previously mentioned autopsy series ranged from 26 to 63%.
Antemortem diagnosis of this entity has been unusual. Franklin et al. characterized the electrocardiographic abnormalities associated with this condition . Among 31 patients dying with invasive candidiasis and having evidence of myocarditis without valvulitis, the following abnormalities were retrospectively present: new conduction disturbance (10 cases), supraventricular arrhythmias (5 cases), QRS changes mimicking myocardial infarction (3 cases), and pronounced T wave changes.
As with other forms of cardiac infection, candidal myocarditis can extend to involve critical structures. Hypotension or shock occurred in about half of these patients and was probably caused by Candida cardiac infection. One patient in this series died suddenly . Kirk et al. described a case of Candida myocarditis associated with complete atrioventricular block . Severe purulent Candida myocarditis was described as the cause of death in a young heroin drug addict . Contiguous myocardial involvement in association with candidal (A):endocarditis or (A):pericarditis can also occur [139, 909].