Abstract
This study aims to clarify impacts of blood culture-negative on results of infectious endocarditis (IE) patients with nonsurgical and surgical intervention. This retrospective study was done to investigate patients with IE during study period at our hospital. There were 720 blood culture-negative endocarditis patients (35.7%). In-hospital mortality, aortic regurgitation ≥ 4 cm2, mitral regurgitation (MR) ≥ 4 cm2, vegetation size ≥ 10 mm, time between symptoms and admission ≥ 2 months, mechanical ventilation length, rate of surgical patients, and acute kidney injury postoperative in blood culture-negative group were significantly higher than those in blood culture-positive group. Time between symptoms and admission ≥ 2 months, vegetation size ≥ 10 mm, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2 vegetations on aortic valve, and vegetations of congenital heart disease were found to be related to blood culture-negative. Univariate and multivariate analysis indicated that blood culture-negative is statistically significantly related to in-hospital mortality, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2, vegetation size ≥ 10 mm, and mechanical ventilation length ≥ 72 hours, respectively. In our investigation, blood culture-negative status is associated with higher in-hospital mortality and more clinical complications including aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2, vegetation size ≥ 10 mm, and mechanical ventilation length ≥ 72 hours in IE.
Keywords: blood culture-negative, infectious endocarditis, nonsurgical, surgical intervention
1. Introduction
Infectious endocarditis (IE) is a kind of infection of cardiac valve and inner layer of cardiac cavity. It is still a dangerous disease. The mortality rate within 1 year is close to 30%, and the global incidence rate of IE is still rising. The mortality rate of IE is high globally, and its diagnosis is still a grave challenge. Up to 30% or even more cases of IE have been confirmed as blood culture-negative, indicating that the pathogen has not yet been identified. Blood culture-negative endocarditis remains a grave challenge in selecting the best antimicrobial regimen for this fatal infection and should be deal with targeted and effective regimens as much as possible.[1-6] Timely diagnosis, identification of pathogenic microorganisms, and targeted antimicrobial treatment can evidently affect the prognosis of diseases, thereby affecting the health status of patients.[7-9]
It has been demonstrated that blood culture-negative endocarditis is related to delayed diagnosis, worsening prognosis and course, as well as more intraoperative and postoperative complications. The microbial characteristics of IE vary by country and also by different centers in a single country, reflecting the local epidemiology of IE, the criteria of diagnosis adopted, the practice of starting antimicrobial drugs before blood collection, and the methods adopted for etiological diagnosis. The identification of pathogenic microorganisms is vital for choosing effective targeted antimicrobial treatment, which is a cornerstone of the treatment for IE.[10-12]
Data in literature of blood culture-negative on outcomes of IE patients are controversial. Investigations of the impacts of blood culture-negative on results of IE patients with nonsurgical and surgical intervention are rare.[9,10,13,14] The objective of this research was to analyze impacts of blood culture-negative on results of IE patients with nonsurgical and surgical intervention.
2. Materials and methods
The experiment protocol for involving humans was in accordance to Helsinki Statement and national guidelines and was approved by the Medical Ethics Committee of The People’s Hospital of Guangxi Zhuang Autonomous Region. We completed a retrospective study of medical records of all IE patients between years 2006 and 2022. Diagnosis was based on modified Duke Criteria. The Ethical Committee of our institution approved the research.
2.1. Definitions
The blood culture-positive endocarditis was defined as IE with the identification of pathogenic microorganisms from blood cultures and/or tissue cultures from the excised valve or vegetation, whereas blood culture-negative endocarditis was defined as IE with negative blood cultures and negative tissue cultures.[14]
Time between symptoms and admission referred to duration between onset of symptoms and the date admitted to hospital.
Based on the classification of Global Results for Improvement in Kidney Disease (KDIGO), acute kidney injury is diagnosed if serum creatinine increases by ≥0.3 mg/dL (26.5 μmol/L) within 48 hours, serum creatinine is 50% higher than baseline in the first 7 days, or urine output is<0.5 mL/kg/h within 6 hours.[15]
Multiple organ failure (MOF) is considered a continuous process of different levels of organ collapse, instead of complete or absent events. The lungs, cardiovascular system, kidneys, liver, coagulating system, and central nervous system are considered the “key organs” that characterize MOFs.[16]
2.2. Primary outcome and the secondary outcomes
2.2.1. Primary outcomes
The primary outcome was in-hospital mortality.
2.2.2. Secondary outcomes
The secondary outcomes include all-cause mortality in follow-up and the incidence of complications, such as aortic regurgitation, mitral regurgitation (MR), tricuspid regurgitation, mean intubation time, ICU retention time, hospitalized time after surgery, postoperative chest drainage, fresh-frozen plasma, packed red cells, acute renal injury.
2.3. Variables
Parameters were investigated (Data in Supplementary Materials, Supplemental Digital Content).
2.4. Blood culture
Usually, multiple blood samples are collected when patients have fever to improve the accuracy of testing. Blood samples have to be taken from different sites at an interval of 6 to 12 hours if the patient is symptomatically stable and within 2 hours if there is hemodynamically labile. The strategy of blood culture interpretation and resorting to other criteria will be very crucial if the patient doesn’t clinically improve.
2.5. Two-dimensional Doppler echocardiography
Echocardiography was acquired by experienced cardiologists or technicians using standardized methods. LVEF was determined using the M-mode in the parasternal long-axis view or Simpson’s biplane method. Left ventricular end-diastolic diameter was collected using the American Society of Echocardiography guidelines. Left ventricular end-diastolic diameter was measured at end-diastole on parasternal views.
Two-dimensional transthoracic echocardiography is a first-line imaging of valve regurgitation, typically sufficient for diagnosis. Measure the reflux area using quantitative 2-dimensional echocardiography and proximal isokinetic surface area method. Collect color Doppler and continuous wave Doppler images of each blood flow condition using a Philips Sonos 7500 ultrasound system (Philips Medical Systems, Andover) equipped with an S3 multi frequency transducer. Due to the imaging window and transducer position being parallel to the blood flow, the ultrasound beam and reflux are well aligned.
2.6. Antibiotic treatment for infective endocarditis
The antibiotic treatment for infective endocarditis should follow the principles of early bactericidal agents, intravenous administration, and long course (4–6 weeks), and be adjusted according to drug sensitivity tests. The medication for autologous valve and artificial valve infections is different, and timely medical treatment and standardized medication are key. Core principles of antibiotic treatment include early use of fungicides, prioritize the use of antibiotics with strong bactericidal effects (such as penicillin, cephalosporin, vancomycin) to quickly control infections, intravenous administration as the main method, adequate drug concentration needing to be maintained through intravenous infusion, oral medication is only as an adjunct or for later maintenance, long course treatment, generally lasting 4 to 6 weeks, and adjustments based on drug sensitivity after identifying the pathogenic bacteria, selecting sensitive antibiotics specifically.
2.7. Follow-up
Echocardiogram, electrocardiogram, and X-ray chest film were investigated for all patients from discharge to date of death or the end date of the research once every 3 to 12 months. The patients were interviewed at the outpatient department or contacted by phone or WeChat at the last time follow-up.
2.8. Statistical analyses
We performed a normality test for all variates in the research by Kolmogorov–Smirnov test. We used the Wilcoxon rank-sum test for continuous variables. Continuous variables are presented as mean ± standard deviation if normally distributed and median (interquartile range) if not normally distributed. Continuous variables were analyzed using Wilcoxon rank-sum test if not normally distributed or Student t test if normally distributed. We investigated categorical data by Chi-square test or Fisher exact test. Logistic regression was used. We created Kaplan–Meier curves and compared the curves by log-rank test. All tests were 2-sided, with statistical significance defined by a P value of <.05. We completed the analyses by IBM SPSS version 24.0 software (IBM SPSS Inc., New York).
3. Results
3.1. Characteristics of the population with infectious endocarditis
2016 IE patients were enrolled into blood culture-negative group (n = 720) and blood culture-positive group (n = 1296). There were 720 blood culture-negative endocarditis patients (35.7%, 720/2016; Table 1).
Table 1.
Characteristics of the patients.
| Variable | Total (n = 2016) |
|---|---|
| Male, n | 1402 (74.3%) |
| Age, yr | 41.43 ± 17.12 (range, 18–82) |
| Body weight, kg | 55.94 ± 12.22 (range, 13–90) |
| Time between symptoms and admission, mo | 2.08 ± 1.93 (range, 0.1–12.3) |
| Vegetation size, mm | 9.72 ± 6.77 (range, 0–29) |
| Aortic regurgitation, cm2 | 5.05 ± 7.12 (range, 0–33) |
| Mitral regurgitation, cm2 | 6.60 ± 6.37 (range, 0–27) |
| Tricuspid regurgitation, cm2 | 4.10 ± 4.81 (range, 0–20) |
| Left ventricular end-diastolic dimension, mm | 58.06 ± 10.16(range, 29–84) |
| Left ventricular ejection fractions, % | 62.37 ± 8.91 (range, 25–83) |
| Symptomatic neurological complications, n (%) | 432 (21.43%) |
| Blood culture-negative, n (%) | 720 (35.7%) |
3.2. Comparison between blood culture-negative and -positive groups
Age (43.09 ± 14.64 versus 40.51 ± 18.30 years, P = .001), body weight (56.91 ± 9.07 versus 55.39 ± 13.63 kg, P = .008), time between symptoms and admission (2.48 ± 2.40 versus 1.86 ± 1.58 months, P<.001), vegetation size (10.97 ± 7.43 versus 9.03 ± 6.22 mm, P<.001), aortic regurgitation (5.83 ± 7.87 versus 4.61 ± 6.64 cm2, P<.001), aortic regurgitation ≥ 4 cm2 (48.6% versus 39.2%, P<.001), MR (6.99 ± 5.56 versus 6.39 ± 6.77 cm2, P = .045), MR ≥ 4 cm2 (68.5% versus 56.0%, P<.001), vegetation size ≥ 10 mm (53.3% versus 43.2%, P<.001), surgical patients (74.7% versus 21.3%, P<.001), time between symptoms and admission ≥ 2 months (51.1% versus 44.4%, P = .004), vegetations on aortic valve (46.7% versus 39.2%, P = .002), vegetations on aortic and mitral valves (15.6% versus 12.3%, P = .043), vegetations of congenital heart disease (6.7% versus 1.7%, P<.001), rate of surgical patients (74.7% versus 21.3%, P<.001), and in-hospital mortality (35.6% versus 17.3%, P<.001) in blood culture-negative group were significantly higher than those in blood culture-positive group (Table 2).
Table 2.
Comparison between blood culture-negative and -positive groups.
| Variable | Blood culture-negative group (n = 720) | Blood culture-positive group (n = 1296) | P value |
|---|---|---|---|
| Male, n | 544 (75.6%) | 928 (71.6%) | .056 |
| Age, yr | 43.09 ± 14.64 | 40.51 ± 18.30 | .001 |
| Body weight, kg | 56.91 ± 9.07 | 55.39 ± 13.63 | .008 |
| Time between symptoms and admission, mo | 2.48 ± 2.40 | 1.86 ± 1.58 | <.001 |
| Vegetation size, mm | 10.97 ± 7.43 | 9.03 ± 6.22 | <.001 |
| Aortic regurgitation, cm2 | 5.83 ± 7.87 | 4.61 ± 6.64 | <.001 |
| Mitral regurgitation, cm2 | 6.99 ± 5.56 | 6.39 ± 6.77 | .045 |
| Tricuspid regurgitation, cm2 | 4.37 ± 4.50 | 3.95 ± 4.97 | .058 |
| Aortic regurgitation ≥ 4 cm2, n (%) | 350 (48.6%) | 508 (39.2%) | <.001 |
| Mitral regurgitation ≥ 4 cm2, n (%) | 493 (68.5%) | 726 (56.0%) | <.001 |
| Vegetation size ≥ 10 mm, n (%) | 384 (53.3%) | 560 (43.2%) | <.001 |
| Symptomatic neurological complications, n (%) | 160 (22.2%) | 272 (21.0%) | .517 |
| Time between symptoms and admission ≥ 2 mo, n (%) | 368 (51.1%) | 576 (44.4%) | .004 |
| Left ventricular ejection fractions, % | 62.61 ± 10.05 | 62.23 ± 8.21 | .358 |
| Vegetations on aortic valve, n | 336 (46.7%) | 512 (39.2%) | .002 |
| Vegetations on mitral valve, n | 235 (32.6%) | 437 (33.7%) | .662 |
| Vegetations on aortic and mitral valves, n | 112 (15.6%) | 160 (12.3%) | .043 |
| Vegetations on tricuspid valve, n | 32 (4.4%) | 138 (10.6%) | <.001 |
| Vegetations of congenital heart disease, n | 48 (6.7%) | 22 (1.7%) | <.001 |
| Surgical patients, n | 538 (74.7%) | 276 (21.3%) | <.001 |
| In-hospital mortality, n | 256 (35.6%) | 224 (17.3%) | <.001 |
3.3. Factors associated with blood culture-negative endocarditis
By univariate analysis, time between symptoms and admission ≥ 2 months (OR: 1.307, 95% CI: 1.089–1.569, P = .004), vegetation size ≥ 10 mm (OR: 1.502, 95% CI: 1.251–1.804, P<.001), aortic regurgitation ≥ 4 cm2 (OR: 1.467, 95% CI: 1.221–1.763, P<.001), MR ≥ 4 cm2 (OR: 1.705, 95% CI: 1.408–2.065, P<.001), vegetations on aortic valve (OR: 1.340, 95% CI: 1.115–1.610, P = .002), and vegetations of congenital heart disease (OR: 4.136, 95% CI: 2.476–6.910, P<.001) were found to be related to blood culture-negative endocarditis (Table 3).
Table 3.
Factors associated with blood culture-negative status.
| Model | OR | 95% CI | P value |
|---|---|---|---|
| Univariate analysis | |||
| Time between symptoms and admission ≥ 2 mo | 1.307 | 1.089–1.569 | .004 |
| Vegetation size ≥ 10 mm | 1.502 | 1.251–1.804 | <.001 |
| Aortic regurgitation ≥ 4 cm2 | 1.467 | 1.221–1.763 | <.001 |
| Mitral regurgitation ≥ 4 cm2 | 1.705 | 1.408–2.065 | <.001 |
| Vegetations on aortic valve | 1.340 | 1.115–1.610 | .002 |
| Vegetations of congenital heart disease | 4.136 | 2.476–6.910 | <.001 |
| Multivariate analysis | |||
| Time between symptoms and admission ≥ 2 mo | 1.339 | 1.112–1.612 | .002 |
| Vegetation size ≥ 10 mm | 1.371 | 1.137–1.653 | .001 |
| Aortic regurgitation ≥ 4 cm2 | 1.333 | 1.103–1.612 | .003 |
| Mitral regurgitation ≥ 4 cm2 | 1.545 | 1.269–1.880 | <.001 |
| Vegetations on aortic valve | 1.347 | 1.109–1.636 | .003 |
| Vegetations of congenital heart disease | 4.478 | 2.655–7.555 | <.001 |
CI = confidence interval, OR = odds ratio.
By multivariate analyses, time between symptoms and admission ≥ 2 months (OR: 1.339, 95% CI: 1.112–1.612, P = .002), vegetation size ≥ 10 mm (OR: 1.371, 95% CI: 1.137–1.653, P = .001), aortic regurgitation ≥ 4 cm2 (OR: 1.333, 95% CI: 1.103–1.612, P = .003), MR ≥ 4 cm2 (OR: 1.545, 95% CI: 1.269–1.880, P<.001), vegetations on aortic valve (OR: 1.347, 95% CI: 1.109–1.636, P = .003), and vegetations of congenital heart disease (OR: 4.478, 95% CI: 2.655–7.555, P<.001) were found to be related to blood culture-negative endocarditis (Table 3).
3.4. Analysis of the significance of blood culture-negative endocarditis
Univariate and multivariate analysis indicated that blood culture-negative is statistically associated with in-hospital mortality (P<.001), aortic regurgitation ≥ 4 cm2 (P<.001), MR ≥ 4 cm2 (P<.001), vegetation size ≥ 10 mm (P<.001), and mechanical ventilation length ≥ 72 hours (P<.001), respectively (Table 4).
Table 4.
Analysis of the significance of blood culture-negative endocarditis.
| Model | OR | 95% CI | P value | |
|---|---|---|---|---|
| Univariate analysis of risk factors of in-hospital mortality | ||||
| Blood culture-negative | 2.640 | 2.141–3.257 | <.001 | |
| Multivariable analysis of risk factors of in-hospital mortality | ||||
| Blood culture-negative | 2.592 | 2.100–3.200 | <.001 | |
| Univariate analysis of risk factors of aortic regurgitation ≥ 4 cm2 | ||||
| Blood culture-negative | 1.467 | 1.221–1.763 | <.001 | |
| Multivariable analysis of risk factors of aortic regurgitation ≥ 4 cm2 | ||||
| Blood culture-negative | 1.313 | 1.081–1.594 | <.001 | |
| Univariate analysis of risk factors of mitral regurgitation ≥ 4 cm2 | ||||
| Blood culture-negative | 1.705 | 1.408–2.065 | <.001 | |
| Multivariable analysis of risk factors of mitral regurgitation ≥ 4 cm2 | ||||
| Blood culture-negative | 1.595 | 1.312–1.939 | <.001 | |
| Univariate analysis of risk factors of vegetation size ≥ 10 mm | ||||
| Blood culture-negative | 1.502 | 1.251–1.804 | <.001 | |
| Multivariable analysis of risk factors of vegetation size ≥ 10 mm | ||||
| Blood culture-negative | 1.372 | 1.133–1.661 | <.001 | |
| Univariate analysis of risk factors of mechanical ventilation length ≥ 72 h | ||||
| Blood culture-negative | 1.417 | 1.055–1.902 | <.001 | |
| Multivariable analysis of risk factors of mechanical ventilation length ≥ 72 h | ||||
| Blood culture-negative | 2.594 | 1.841–3.654 | <.001 | |
CI = confidence interval, OR = odds ratio.
3.5. Impacts of blood culture-negative status on the clinical outcomes of infectious endocarditis patients with surgical intervention
Eight hundred ninety-six patients with IE who underwent cardiac operation during the research period were further divided into blood culture-negative (n = 272) and -positive (n = 624) subgroups. There were 48 in-hospital deaths (5.4%; Table 1, Fig. 1).
Figure 1.
Flow chart.
Vegetation size ≥ 10 mm (56.4% versus 35.3%, P<.001) and preoperative aortic regurgitation (6.30 ± 7.65 versus 5.17 ± 6.37 cm2, P = .022) in blood culture-negative subgroup were significantly higher than those in blood culture-positive subgroup (Table 5).
Table 5.
Comparison of operative and follow-up results between blood culture-negative and -positive subgroups (n = 896).
| Variable | Blood culture-negative subgroups (n = 272) | Blood culture-positive subgroups (n = 624) | P value |
|---|---|---|---|
| Preoperative | |||
| Male, n (%) | 176 (64.7%) | 416 (66.7%) | .569 |
| Age, yr | 38.41 ± 15.70 | 38.53 ± 10.37 | .909 |
| Weight s, kg | 55.86 ± 12.24 | 54.62 ± 10.92 | .150 |
| Time between symptoms and surgery, mo | 2.13 ± 1.73 | 2.32 ± 1.06 | .640 |
| Vegetation size ≥ 10 mm | 96 (35.3%) | 352 (56.4%) | <.001 |
| Preoperative LVEDD, mm | 60.92 ± 9.61 | 61.41 ± 8.52 | .469 |
| Preoperative LVEF, % | 62.03 ± 8.03 | 61.76 ± 7.00 | .643 |
| Preoperative aortic regurgitation, cm2 | 6.30 ± 7.65 | 5.17 ± 6.37 | .022 |
| Preoperative mitral regurgitation, cm2 | 7.01 ± 6.52 | 7.85 ± 5.42 | .065 |
| Preoperative tricuspid regurgitation, cm2 | 4.53 ± 5.00 | 4.98 ± 4.01 | .197 |
| Serum creatinine before surgery, μmol/L | 82.10 ± 38.73 | 79.06 ± 16.75 | .213 |
| Operative | |||
| Operative mortality, n | 27 (9.9%) | 21 (3.4%) | <.001 |
| Aortic cross-clamp time | 84.85 ± 35.55 | 83.56 ± 34.90 | .065 |
| Cardiopulmonary bypass time | 156.67 ± 50.11 | 149.41 ± 54.65 | .543 |
| Mechanical ventilation length, h | 52.47 ± 66.34 | 38.27 ± 41.55 | .001 |
| ICU retention time, d | 4.77 ± 3.24 | 4.71 ± 2.22 | .769 |
| Hospitalized time postoperative, d | 21.00 ± 9.53 | 18.05 ± 6.67 | <.001 |
| Serum creatinine 24 h after surgery, μmol/L | 90.31 ± 45.11 | 84.12 ± 38.46 | .049 |
| Serum creatinine 48 h after surgery, μmol/L | 109.64 ± 75.62 | 91.59 ± 48.97 | <.001 |
| Acute kidney injury postoperative, n | 208 (33.3%) | 64 (23.5%) | .003 |
| Postoperative LVEDD, mm | 48.08 ± 6.73 | 47.65 ± 7.71 | .401 |
| Postoperative LVEF, % | 58.94 ± 7.08 | 58.88 ± 6.32 | .905 |
| Fresh-frozen plasma | 612.82 ± 423.48 | 641.18 ± 555.21 | .404 |
| Packed red blood cells | 2.81 ± 3.40 | 2.50 ± 2.66 | .186 |
| Follow-up | Blood culture-negative subgroups (n = 276) | Blood culture-positive subgroups (n = 538) | P value |
|---|---|---|---|
| Length of follow-up, mo | 70.54 ± 54.35 | 66.85 ± 48.47 | .341 |
| All-cause mortality in follow-up, n | 52 (18.8%) | 81 (15.1%) | .167 |
LVEDD = left ventricular end diastolic diameter, LVEF = left ventricular ejection fractions.
Operative deaths (9.9% versus 3.4%, P<.001), mechanical ventilation length (52.47 ± 66.34 versus 38.27 ± 41.55 hours, P = .001), hospitalized time postoperative (21.00 ± 9.53 versus 18.05 ± 6.67 days, P<.001), serum creatinine 24 hours after surgery (90.31 ± 45.11 versus 84.12 ± 38.46 μmol/L, P = .049), serum creatinine 48 hours after surgery (109.64 ± 75.62 versus 91.59 ± 48.97 μmol/L, P<.001), and acute kidney injury postoperative (33.3% versus 23.5%, P = .003) in blood culture-negative subgroup were significantly higher than those in blood culture-positive subgroup (Table 5).
There is no statistically significant difference between blood culture-negative and -positive subgroups in terms of survival discharged from hospital (log-rank test, P = .077; Fig. 2).
Figure 2.
Kaplan–Meier curve. Blue line, group 1: group of blood culture-positive endocarditis; Green line, group 2: group of blood culture-negative endocarditis.
4. Discussion
It is vital to early diagnose and identify IE pathogens and complete targeted antimicrobial treatment to better the prognosis of the disease and the health status of patients. Blood culture negative may be due to low bacteremia during blood draw, previous antimicrobial therapy, picky intracellular pathogens, or because the type of culture medium is not suitable for certain rare bacteria. According to reports, IE may be polymicrobial in up to 5% of cases. Identification of patient risk factors and detection of atypical pathogenic microorganisms may help develop more precise and effective treatment strategies based on clinical conditions.[17-19]
In-hospital mortality, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2, vegetation size ≥ 10 mm, time between symptoms and admission ≥ 2 months, mechanical ventilation length, rate of surgical patients, and acute kidney injury postoperative in blood culture-negative group were significantly higher than those in blood culture-positive group. Time between symptoms and admission ≥ 2 months, vegetation size ≥ 10 mm, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2 vegetations on aortic valve, and vegetations of congenital heart disease were found to be related to blood culture-negative. Univariate and multivariate analysis indicated that blood culture-negative is statistically significantly related to in-hospital mortality, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2, vegetation size ≥ 10 mm, and mechanical ventilation length ≥ 72 hours, respectively. In our investigation, there were 720 blood culture-negative endocarditis patients (35.7%). In literature, the incidence rate of blood culture-negative endocarditis ranged from 2.5% to 70%.[20-22]
The pathogenic diagnosis of IE pathogens and fungi attaches to lesions formed before, forming vegetations getting along with platelets and fibrin, leading to leaflet perforation, leaflet prolapse caused by annulus destruction, or graft failure caused by vegetations, which can manifest as aortic and/or MR and cardiac failure. Vegetation may rupture with the influence of turbulence, pressure, and vegetation instability, forming embolism. These, in turn, may lead to sepsis, embolism, and ischemic areas in all kinds of organ systems.[23-26] The causes of acute heart failure, cardiogenic shock, and MOF in patients with IE upon admission include aortic and MR caused by valve injury or papillary muscle and tendon rupture, myocardial dysfunction caused by ischemia due to coronary artery vegetation embolism or occlusion, myocarditis, cardiac conduction disorders, ventricular pseudoaneurysms, and sepsis. Heart failure, cardiogenic shock, and MOF caused by IE are independent predictors of mortality.[27-30] Blood culture-negative was found to be significantly related to in-hospital mortality and clinical complications thus forming vicious circle. The vicious cycle must be broken by timely and effective targeted antimicrobial therapy.
The prognosis of patients with IE relies on timely and accurate diagnosis and treatment. It has been demonstrated that transesophageal tissue Doppler echocardiography expedites the detection of vegetations in IE. The implementation of transthoracic echocardiography with pulsed wave tissue Doppler imaging can improve the visualization and differentiation of intracardiac masses through different color coding of the pathological structure compared to surrounding tissue.[31-33]
Quick and accurate pathogen identification is important for diagnosing the etiology of IE, guiding antimicrobial selection and adjustment. Blood culture is now the standardized method for diagnosing IE, but sensitivity to IE of conventional blood culture is low mainly because of previous antimicrobial treatment and microbial sensitivity or inability to culture. It is reported that the incidence rate of blood culture-negative endocarditis ranges from 15% to 60%. The recent exposure to antimicrobial is the cause of most cases of blood culture-negative endocarditis. False negative rate high, long time of blood culture, delayed diagnosis and treatment have significant adverse effects on prognosis. Identifying infected organisms remains important for ensuring optimal antimicrobial treatment, and it is urgent to improve diagnostic accuracy and effectiveness through early intervention to reduce mortality rates in patients with IE.[34-36]
In our study, in-hospital deaths, mechanical ventilation length, and acute kidney injury postoperative in blood culture-negative group were evidently greater than those in blood culture-positive group, suggesting that diagnoses and/or evaluation for surgery in blood culture-negative endocarditis were more often completed later than in patients with blood culture-positive endocarditis, and after the incidence of complications of the heart or systems. It cannot be ruled out that the elevated incidence of cardiac failure and valve dysfunction is due to the unrecognized and lack of antimicrobial spectrum of pathogens in blood culture-negative endocarditis, possibly because of poor efficacy of antimicrobial therapy. Blood culture-negative endocarditis is a risk factor for in-hospital mortality related to advance and inappropriate antimicrobial treatment. Kong et al completed the greatest investigation with a large European registry, comparing the results of culture-positive and culture-negative endocarditis to get data of 1-year follow-up for 3113 cases. The 1-year mortality rate was evidently greater in the blood culture-negative endocarditis group and in the blood culture-negative endocarditis subgroup, surgery was significantly correlated with survival rate.[37-39]
Blood culture-negative endocarditis is a fatal disease with a high incidence rate and mortality. Rapid detection and identification of pathogenic pathogens are crucial for timely and targeted treatment. There are various reasons for blood culture-negative endocarditis, including: treatment with antimicrobial s before collecting blood cultures; Collection of suboptimal specimens; and/or infections caused by picky (such as Streptococcus mutans), intracellular (such as Burkholderia, Bartonella), or non-cultivable or difficult to cultivate organisms (such as Mycobacterium, Tropheryma whipplei, and fungi); and noninfectious causes. The diagnostic field has developed with the incidence of non-culture methods, such as serological testing, targeted and shotgun metagenomic sequencing, capable of identifying pathogens that have historically been difficult to find through traditional blood cultures. Because of validation and widespread use of these technologies outside of reference laboratories, their roles are becoming more and more evident.[40-42]
4.1. Perspectives
IE is a microbial infection on the cardia endocardium, often affecting the native or prosthetic valves. In the past few decades, the epidemiology and etiology of this disease have undergone significant changes. With the growth of the elderly people, the incidence rate of degenerative valvular disease and the use of prosthetic valves have elevated, being the most vital risk factor for susceptibility. The alteration epidemiology has resulted in a change in the potential microbiology in IE, with Staphylococcus replacing Streptococcus as the main pathogenic pathogen. Other rare microorganisms, such as Streptococcus agalactiae, Pseudomonas aeruginosa, Burkholderia baicalensis, and Brucella, have also appeared or reappeared. IE caused by these pathogens, especially Staphylococcus aureus, is usually related to serious results with high incidence rate and mortality. Molecular diagnostic techniques are considered breakthrough strategies for diagnosing IE and have been introduced into Duke University as the primary diagnostic criteria for early and timely guidance of clinical antimicrobial treatment.[34-39]
4.2. Limitations
The limitations of this research comprise its retrospective design, which may lead to bias of selection due to the retrospective nature of the research and the roles of our hospital as a tertiary referral center. Long term recruitment of patients may have adverse effects on the accuracy of the results. Prospective randomized controlled trials are needed, and plans to reduce the incidence rate and mortality of IE in-hospital are needed.
5. Conclusions
In our investigation, blood culture-negative status is associated with higher in-hospital mortality and more clinical complications including multiorgan failure at admission, aortic regurgitation ≥ 4 cm2, MR ≥ 4 cm2, vegetation size ≥ 10 mm, and mechanical ventilation length ≥ 72 hours in IE.
Author contributions
Conceptualization: Jing-bin Huang.
Data curation: Jing-bin Huang, Chang-chao Lu.
Formal analysis: Chang-chao Lu.
Investigation: Jing-bin Huang.
Resources: Chang-chao Lu, Zhao-ke Wen.
Software: Zhai Huang, Chang-chao Lu.
Supervision: Zhai Huang, Zhao-ke Wen.
Validation: Zhai Huang, Chang-chao Lu.
Writing – original draft: Jing-bin Huang.
Writing – review & editing: Zhao-ke Wen.
Abbreviations:
- cm
- centimeter
- ICU
- intensive care unit
- IE
- infectious endocarditis
- kg
- kilogram
- MR
- mitral regurgitation
This work was supported by the Natural Science Foundation of China (No. 81360014), the Natural Science Foundation of Guangxi (No. 2014GXNSFAA118234), the Guangxi key scientific and technological project (No. 2013BC26236), and the Projects in Guangxi Health Department (No. GZPT13-27).
The experiment protocol for involving humans was in accordance to Helsinki Statement and national guidelines and was approved by the Medical Ethics Committee of The People’s Hospital of Guangxi Zhuang Autonomous Region, and they gave the authors approval to waive the need for patient consent for publishing data in the study about the patients.
The authors have no conflicts of interest to disclose.
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Supplemental Digital Content is available in the online version of this article (http://dx.doi.org/10.1097/MD.0000000000048760).
How to cite this article: Huang J-b, Huang Z, Lu C-c, Wen Z-k. Impacts of blood culture-negative status on outcomes of infectious endocarditis patients with nonsurgical and surgical intervention. Medicine 2026;105:19(e48760).
J-bH and ZH contributed to this article equally.
Contributor Information
Zhai Huang, Email: lixiang20260201@163.com.
Chang-chao Lu, Email: lcc2020061@163.com.
Zhao-ke Wen, Email: wzk2020061@163.com.
References
- [1].Miao H, Zhang Y, Zhang Y, Zhang J. Update on the epidemiology, diagnosis, and management of infectious endocarditis: a review. Trends Cardiovasc Med. 2024;34:499–506. [DOI] [PubMed] [Google Scholar]
- [2].Mutagaywa RK, Vroon JC, Fundikira L, et al. Infectious endocarditis in developing countries: an update. Front Cardiovasc Med. 2022;9:1007118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Cahill TJ, Baddour LM, Habib G, et al. Challenges in Infectious endocarditis. J Am Coll Cardiol. 2017;69:325–44. [DOI] [PubMed] [Google Scholar]
- [4].Huang JB, Wen ZK, Lu CC, Yang J-R, Li J-J. Risk factors of prolonged intensive care unit stay following cardiac surgery for infectious endocarditis. Medicine (Baltim). 2023;102:e35128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [5].Pettersson GB, Hussain ST. Current AATS guidelines on surgical treatment of infectious endocarditis. Ann Cardiothorac Surg. 2019;8:630–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143:e72–e227. [DOI] [PubMed] [Google Scholar]
- [7].Huang JB, Liang SJ, Lu CC, Wen ZK. Vegetation length is associated with long-term survival in patients treated surgically for infective endocarditis. Rev Cardiovasc Med. 2024;25:354. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [8].Huang J-B, Lu C-C, Wen Z-K, et al. Modifiable risk factors of immediate and long-term outcomes in the operable and inoperable with left-sided infectious endocarditis. Heliyon. 2024;10:E32041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Lamas CC, Fournier PE, Zappa M, et al. Diagnosis of blood culture-negative endocarditis and clinical comparison between blood culture-negative and blood culture-positive cases. Infection. 2016;44:459–66. [DOI] [PubMed] [Google Scholar]
- [10].Meidrops K, Zuravlova A, Osipovs JD, et al. Comparison of outcome between blood culture positive and negative infectious endocarditis patients undergoing cardiac surgery. J Cardiothorac Surg. 2021;16:147. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Kouijzer JJP, Noordermeer DJ, van Leeuwen WJ, Verkaik NJ, Lattwein KR. Native valve, prosthetic valve, and cardiac device-related infectious endocarditis: A review and update on current innovative diagnostic and therapeutic strategies. Front Cell Dev Biol. 2022;10:995508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].El-Ashry AH, Saad K, Obiedallah AA, Elhoufey A, Dailah HG, Hussein MSA. Molecular and serological diagnostic approach to define the microbiological origin of blood culture-negative infectious endocarditis. Pathogens. 2022;11:1220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Li SL, Zhao X, Tao JZ, Yue Z-Z, Zhao X-Y. Application of metagenomic next-generation sequencing in patients with infectious endocarditis. Front Cell Infect Microbiol. 2023;13:1107170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Fournier PE, Gouriet F, Casalta JP, et al. Blood culture-negative endocarditis: Improving the diagnostic yield using new diagnostic tools. Medicine (Baltim). 2017;96:e8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Howitt SH, Grant SW, Caiado C, et al. The KDIGO acute kidney injury guidelines for cardiac surgery patients in critical care: a validation study. BMC Nephrol. 2018;19:149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Durham RM, Moran JJ, Mazuski JE, Shapiro MJ, Baue AE, Flint LM. Multiple organ failure in trauma patients. J Trauma. 2003;55:608–16. [DOI] [PubMed] [Google Scholar]
- [17].Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Microbiol Rev. 2001;14:177–207. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC Guidelines for the management of infectious endocarditis: the task force for the management of infectious endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36:3075–128. [DOI] [PubMed] [Google Scholar]
- [19].Zamorano J, Sanz J, Moreno R, et al. Comparison of outcome in patients with culture-negative versus culture-positive active infectious endocarditis. Am J Cardiol. 2001;87:1423–5. [DOI] [PubMed] [Google Scholar]
- [20].Murashita T, Sugiki H, Kamikubo Y, Yasuda K. Surgical results for active endocarditis with prosthetic valve replacement: impact of culture-negative endocarditis on early and late outcomes. Eur J Cardiothorac Surg. 2004;26:1104–11. [DOI] [PubMed] [Google Scholar]
- [21].Salsano A, Giacobbe DR, Del Puente F, et al. Culture-negative infective endocarditis (CNIE): impact on postoperative mortality. Open Med (Wars). 2020;15:571–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Naber CK, Erbel R. Infectious endocarditis with negative blood cultures. Int J Antimicrob Agents. 2007;30:S32–6. [DOI] [PubMed] [Google Scholar]
- [23].Díez-Villanueva P, Muñoz P, Marín M, et al. Infectious endocarditis: absence of microbiological diagnosis is an independent predictor of in hospital mortality. Int J Cardiol. 2016;220:162–5. [DOI] [PubMed] [Google Scholar]
- [24].Huang JB, Lu CC, Wen ZK, Yang J-R, Li J-J, Lu C-C. Impact of vegetation size on clinical complications during surgical intervention and long-term survival in infectious endocarditis. Am J Cardiol. 2023;201:335–40. [DOI] [PubMed] [Google Scholar]
- [25].Cabell CH, Pond KK, Peterson GE, et al. The risk of stroke and death in patients with aortic and mitral valve endocarditis. Am Heart J. 2001;142:75–80. [DOI] [PubMed] [Google Scholar]
- [26].Huang JB, Lu CC, Wen ZK, Yang JR, Li JJ. Surgical treatment of left-sided infective endocarditis with symptomatic neurological complications before surgery in China. Front Cardiovasc Med. 2023;10:1217148. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Hamirani YS, Dietl CA, Voyles W, Peralta M, Begay D, Raizada V. Acute aortic regurgitation. Circulation. 2012;126:1121–6. [DOI] [PubMed] [Google Scholar]
- [28].McHugh J, Saleh OA. Updates in culture-negative endocarditis. Pathogens. 2023;12:1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [29].Fournier PE, Thuny F, Richet H, et al. Comprehensive diagnostic strategy for blood culture-negative endocarditis: a prospective study of 819 new cases. Clin Infect Dis. 2010;51:131–40. [DOI] [PubMed] [Google Scholar]
- [30].Moter A, Musci M, Schmiedel D. Molecular methods for diagnosis of infectious endocarditis. Curr Infect Dis Rep. 2010;12:244–52. [DOI] [PubMed] [Google Scholar]
- [31].Bartel T, Müller S, Nesser HJ, Möhlenkamp S, Bruch C, Erbel R. Usefulness of motion patterns indentified by tissue Doppler echocardiography for diagnosing various cardiac masses, particularly valvular vegetations. Am J Cardiol. 1999;84:1428–33. [DOI] [PubMed] [Google Scholar]
- [32].Hiemetzberger R, Müller S, Bartel T. Incremental use of tissue Doppler imaging and three-dimensional echocardiography for optimal assessment of intracardiac masses. Echocardiogr. 2008;25:446–7. [DOI] [PubMed] [Google Scholar]
- [33].Sonaglioni A, Nicolosi GL, Muti-Schünemann GEU, Lombardo M, Muti P. Could pulsed wave tissue doppler imaging solve the diagnostic dilemma of right atrial masses and pseudomasses? A case series and literature review. J Clin Med. 2024;14:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Subedi S, Jennings Z, Chen SC. Laboratory approach to the diagnosis of culture-negative infectious endocarditis. Heart Lung Circ. 2017;26:763–71. [DOI] [PubMed] [Google Scholar]
- [35].Hill EE, Herijgers P, Herregods MC, Peetermans WE. Evolving trends in infectious endocarditis. Clin Microbiol Infect. 2006;12:5–12. [DOI] [PubMed] [Google Scholar]
- [36].Reisinger M, Kachel M, George I. Emerging and re-emerging pathogens in valvular infectious endocarditis: a review. Pathogens. 2024;13:543. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Kong WKF, Salsano A, Giacobbe DR, et al. The EURO-ENDO investigators. outcomes of culture-negative vs. culture-positive infectious endocarditis: the ESC-EORP EURO-ENDO registry. Eur Heart J. 2022;43:2770–80. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [38].Brouqui P, Raoult D. New insight into the diagnosis of fastidious bacterial endocarditis. FEMS Immunol Med Microbiol. 2006;47:1–13. [DOI] [PubMed] [Google Scholar]
- [39].Fournier PE, Lelievre H, Eykyn SJ, et al. Epidemiologic and clinical characteristics of Bartonella quintana and Bartonella henselae endocarditis: a study of 48 patients. Medicine (Baltim). 2001;80:245–51. [DOI] [PubMed] [Google Scholar]
- [40].Nappi F. Native infectious endocarditis: a state-of-the-art-review. Microorganisms. 2024;12:1481. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [41].Huang J-B, Lu C-C, Wen Z-K. Surgical treatment for infectious endocarditis in China. Medicine (Baltimore). 2025;104:pe41882. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [42].Huang J-B. Aortic root replacement is superior to isolated aortic valve replacement for aortic regurgitation secondary to Behcet’s disease. Front. Cardiovasc. Med. 2024;11:1437208. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.