Fungal infective endocarditis (IE) is a rare, serious, and potentially lethal disease, yet its clinical characteristics and short-term outcomes remain poorly understood. A detailed comparative analysis of fungal prosthetic valve endocarditis (PVE) and native valve endocarditis (NVE) has not been performed. This study was designed to explore the general characteristics, treatment patterns, and outcomes of patients with fungal IE in a Chinese hospital and compare these data between PVE and NVE. Four hundred ninety-three patients were admitted to Fuwai hospital from January 2002 to December 2010. Fungal IE accounted for 7% (32 cases) of cases. Of these patients, 19 (59%) patients had NVE, 12 (37%) PVE, and 1 (3%) cardiac device–related infective endocarditis (CDRIE). Candida albicans remained the predominant causative pathogen (47% of all IE). Patients with NVE, compared with PVE patients, were older (50 years vs 37 years, p = 0.034), had less frequent history of previous endocarditis (0 vs 25%, p = 0.049), and were more likely to have a history of diabetes (37% vs 0, p = 0.026) and be in an immunocompromised state (37% vs 0, p = 0.026). Nearly half of the patients died of refractory heart failure, followed by severe sepsis and stroke. In-hospital mortality rate was 38%, and the 3-month cumulative mortality rate was 47%. Recurrence of IE was more common in fungal PVE patients (42% vs 5%, p = 0.022) during the 90-day follow-up. In conclusion, fungal IE is associated with high mortality and recurrence rates. Surgery performed in selected cases may improve the outcomes, but the recurrence rate remains high.
Despite improvements in medical and surgical therapies, infective endocarditis (IE) is associated with a poor prognosis and a considerably high risk of mortality and morbidity. Fungal IE is a rare, extremely serious, and potentially lethal complication of fungemia that remains poorly understood among all forms of IE. The number of reported cases has increased steadily in Western countries, potentially because of increased use of intravascular devices, prosthetic heart valves, and more patients receiving broad-spectrum antibiotics or invasive interventions. Because of the rarity of this infection, few existing studies describe the characteristics of fungal IE. Fungal IE has not been widely reported in Eastern Asia. Therefore, this study was designed to explore clinical characteristics, treatment patterns, and short-term outcomes of patients with Fungal IE in a Chinese hospital and to compare the rates of fungal native valve endocarditis (NVE) with fungal prosthetic valve endocarditis (PVE).
Methods
This study was a retrospective cohort study and performed at Fuwai Hospital. All consecutive adult patients (aged ≥18 years) with a diagnosis of definite or possible IE admitted to our center from January 2002 through December 2010 were enrolled in the study. This study was approved by local ethics committees of Fuwai Hospital.
A case report form was used to collect the following data: demographic information, clinical signs and symptoms, duration of symptoms, antecedent disease, predisposing factors for IE, possible source of infection, previous episodes of IE, cardiac involvement, laboratory findings, echocardiographic and microbiological data, and treatment received during the course of hospitalization and treatment.
Early prosthetic valve endocarditis (PVE) was defined as occurring within 1 year of surgery and late PVE beyond 1 year. Cardiac device–related IE (CDRIE) is defined as an infection extending to the electrode leads, cardiac valve leaflets, or the endocardial surface. Patients with a relapse of IE were defined as isolation of the same pathogen within a 6-month period. Patients with a reinfection were defined as infection with a different pathogen or caused by the same microorganism beyond a 6-month period. Health care–associated IE was defined as either nosocomial infection or nonnosocomial health care–related infection. An IE episode was defined as nonnosocomial health care–associated when it occurred within 48 hours of admission in a patient fulfilling ≥1 of the following criteria: (1) received intravenous therapy, wound care, specialized nursing care, hemodialysis, or intravenous chemotherapy within 30 days before the onset of IE, (2) hospitalized in an acute care hospital for ≥2 days within 90 days before the onset of IE, or (3) resided in a nursing home or long-term care facility before admission. Nosocomial infection was defined as IE developing in a patient hospitalized for >48 hours before the onset of signs/symptoms consistent with IE. The infection was considered to be community-acquired when the symptoms and signs of IE occurred within 48 hours of admission in a patient not fulfilling the criteria for nonnosocomial health care–associated infection. Use of systemic corticosteroid or other immunosuppressive therapy for >30 days was defined as immunosuppression.
IE complications were defined as the development of any of the following conditions: uncontrolled infection (persistent fever and positive blood cultures >7 days, extension of perivalvular infection, and resistant organisms), heart failure (new condition or worsening of a known previous condition, diagnosed according to the Framingham criteria), intracardiac abscess (diagnosed using echocardiography or during surgery), neurological events, and peripheral embolism. The diagnosis of embolic events was based on clinical signs and data derived from noninvasive procedures (cerebral and thoracic-abdominal computed tomographic scans were performed in 70% of patients), acute renal failure (defined as a 50% increase in baseline creatinine concentration).
End points were death or discharge from the hospital. The follow-up period was 3 months. Follow-up data included surgical treatment and death occurring during initial hospitalization or follow-up. Surgical therapy was based on clinical judgment of the treating physician and of the surgical team, according to conventional guidelines predominantly in the presence of complications such as embolism events, large vegetation, heart failure, uncontrolled infection, severe regurgitation, or evidence of perivalvular extension. In-hospital mortality was defined as death occurring during hospitalization for IE. Three-month mortality was defined as death occurring during the hospitalization for IE or during the first 3 months following the start of IE treatment. Follow-up clinical data after hospital discharge were collected by outpatient visits or phone contacts. All events occurring after the first day of hospitalization were recorded including deaths from any cause and IE recurrences.
Quantitative variables were expressed as mean ± SD or median values and interquartile ranges and were compared between groups using a Student t test or Mann-Whitney test. Categorical variables were summarized using frequency percentages and analyzed by Fisher exact tests for binary variables. For all analyses, a p value <0.05 (2 -sided) was considered statistically significant. Statistical analyses were performed with SPSS software, version 13.0 (SPSS Inc., Chicago, Illinois).
Results
The enrollment profile is shown in Figure 1 . During the study period, 516 patients with suspected IE were treated at our hospital. Using the modified Duke criteria, 23 patients (5%) were classified as being excluded from the diagnosis of endocarditis. The final study population consisted of 32 (7%) patients with fungal endocarditis, of which 26 (81%) were diagnosed using blood culture and 6 (19%) by surgical findings and pathologic criteria. Nineteen cases of the 32 patients (59%) were classified as NVE, 12 (38%) were PVE, and 1 (3%) was cardiac CDRIE. Eight cases (25%) were classified as early PVE, which occurred at a median time of 83 days (interquartile range 33.5 to 120) following cardiac surgery.
There were 17 (53%) cases of community-acquired and 14 (44%) health care–associated IE. One patient was identified as intravenous drug abuse–associated IE. Ten (72%) of the 14 health care–associated IE were considered to be nosocomial. Among the 14 IE patients who met health care–associated infection criteria, the most likely sources of infection were cardiac surgery (8 cases), cardiac intervention (3 cases), and catheter-related fungemia (3 case).
The clinical features of all patients with fungal IE are summarized in Table 1 , and the characteristics of patients with PVE are compared with those of patients with NVE. The mean age of the patients was 45 years (interquartile range 32 to 57), and 69% were men. Patients with NVE were older (50 years vs 37 years, p = 0.034) than patients with PVE. Thirty-one (97%) patients with fungal IE had a cardiac factor that predisposed them to IE. Of these 31 patients, 19 (59%) had valvular disease, 11 (34%) had congenital heart disease, and 1 had hypertrophic cardiomyopathy. Twenty (63%) of the patients had anemia. The aortic valve was involved in 15 (47%), the mitral valve in 7 (22%), and both valves in 4 (13%) patients. Moderate to severe regurgitation was observed in 19 (59%) patients. The median diameter of vegetation was 12 mm, and large vegetation (>15 mm) was observed in 31% of the patients.
| All FE (n = 32) ∗ | PVE (n = 12) | NVE (n = 19) | p Value | |
|---|---|---|---|---|
| Clinical characteristics | ||||
| Mean age (yrs), median (IQR) | 45 (32–57) | 37 (25–53) | 50 (41–57) | 0.034 |
| Men | 22 (69%) | 9 (75%) | 13 (68%) | 1.00 |
| New precordial murmur | 25 (78%) | 8 (67%) | 16 (84%) | 0.384 |
| Fever ≥38°C at admission | 22 (69%) | 8 (67%) | 14 (74%) | 0.704 |
| Skin lesions † | 15 (47%) | 5 (42%) | 9 (47%) | 1.00 |
| Predisposing heart condition | 31 (97%) | 12 (100%) | 18 (95%) | 1.00 |
| Valvular heart disease | 19 (59%) | 7 (58%) | 11 (58%) | 1.00 |
| Congenital heart disease | 11 (34%) | 5 (42%) | 6 (32%) | 0.705 |
| Hypertrophic cardiomyopathy | 1 (3%) | 0 | 1 (5%) | 1.00 |
| History of endocarditis | 3 (9%) | 3 (25%) | 0 | 0.049 |
| Intravenous drug user | 1 (3%) | 0 | 1 (5%) | 1.00 |
| Diabetes mellitus | 7 (22%) | 0 | 7 (37%) | 0.026 |
| Hypertension | 3 (9%) | 1 (8%) | 2 (11%) | 1.00 |
| Immunocompromised state | 7 (21%) | 0 | 7 (37%) | 0.026 |
| Anemia (HB ≤100g/L) | 20 (63%) | 9 (75%) | 11 (58%) | 0.452 |
| Echocardiography | ||||
| LVEF (%) median (IQR) | 54.8 (49–61) | 59.3 (45–66) | 55.7 (43–62) | 0.293 |
| Valve involved | ||||
| Mitral | 7 (22%) | 1 (8%) | 6 (32%) | 0.201 |
| Aortic | 15 (47%) | 5 (42%) | 10 (53%) | 0.716 |
| Aortic and mitral | 4 (13%) | 1 (8%) | 3 (16%) | 1.00 |
| Vegetation | 25 (78%) | 8 (67%) | 16 (84%) | 0.384 |
| Vegetation diameter, median (IQR) | 12 (8–17.8) | 11 (8.3–21.8) | 12 (7–17) | 0.349 |
| <10 (mm) | 8 (25%) | 3 (25%) | 5 (26%) | 1.00 |
| 10–15 (mm) | 6 (19%) | 2 (17%) | 4 (21%) | 1.00 |
| >15 (mm) | 10 (31%) | 3 (25%) | 6 (32%) | 1.00 |
| Moderate to severe regurgitation | 19 (59%) | 2 (17%) | 17 (90%) | 0.000 |
| Perivalvular complications ‡ | 14 (44%) | 4 (33%) | 10 (53%) | 0.461 |
∗ Includes 1 patient with CDRIE.
† Skin lesions in IE include Osler nodes, Janeway lesions, splinter hemorrhages, and petechiae (embolic or vasculitic).
‡ Perivalvular complications include abscess formation, pseudoaneurysms, and perforation.
As shown in Table 1 , patients with PVE (compared with NVE) were more likely to have had previous endocarditis (25% vs 0, p = 0.049) and less likely to have a history of diabetes (0 vs 37%, p = 0.026) and be in an immunocompromised state (0 vs 37%, p = 0.026). Overall, there was little difference in signs and symptoms at presentation between the native valve fungal endocarditis prosthetic valve fungal endocarditis groups.
Hematologic and microbiological findings of patients with fungal IE are summarized in Table 2 . Candida (24 cases, 75%) remained the predominant causative pathogen in this group. C albicans accounted for 15 cases (47%), followed by C parapsilosis (6 cases, 19%); C tropicalis , C krusei , and C famata accounting for 1 case each (3% each). Filamentous fungi were identified in 6 patients (19%) and histoplasma capsulatum in 2 cases (6%). The microbiological profile of the patients with PVE showed no difference from patients with NVE ( Table 2 ). In fungal IE patients with native valves, albumin was lower compared with patients with prosthetic valves (29.2 vs 36.5, p = 0.01). Otherwise, no significant differences were observed between patients with native or prosthetic valves in terms of the high-sensitivity C-reactive protein, erythrocyte sedimentation rate, creatinine, and hemoglobin.
| All FE (n = 32) ∗ | PVE (n = 12) | NVE (n = 19) | p Value | |
|---|---|---|---|---|
| hsCRP increase at diagnosis (mg/L) | 11.2 ± 3.3 | 8.7 ± 3.8 | 11.8 ± 3.0 | 0.106 |
| ESR increase at diagnosis (mm/h), median (IQR) | 38 (25.5–71.5) | 32 (23–85) | 38 (28–68) | 0.703 |
| HGB at diagnosis, (g/L, mm ± SD) | 91.1 ± 18.8 | 93 ± 16.8 | 90.3 ± 20.8 | 0.704 |
| ALB at diagnosis, (g/L, mm ± SD) | 32 ± 6.3 | 36.54 ± 6.4 | 29.2 ± 4.5 | 0.001 |
| Cr at diagnosis (μmoI/L), median (IQR) | 91 (60–167) | 93 (48.2–162.7) | 91 (70.1–171.5) | 0.525 |
| Single infection | 22 (69%) | 8 (67%) | 13 (68%) | 1.00 |
| Multiple infection | 10 (31%) | 4 (33%) | 6 (32%) | 1.00 |
| Organisms | ||||
| C albicans | 15 (47%) | 4 (33%) | 10 (53%) | 0.461 |
| C parapsilosis | 6 (19%) | 3 (25%) | 3 (16%) | 0.653 |
| Other Candida † | 3 (9%) | 2 (17%) | 1 (5%) | 0.543 |
| Filamentous fungi | 6 (19%) | 5 (42%) | 1 (5%) | 0.022 |
| Histoplasma capsulatum | 2 (6%) | 1 (8%) | 1 (5%) | 1.00 |
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