Next Article in Journal
Dyadic Interactions of Treatment-Resistant Schizophrenia Patients Having Followed Virtual Reality Therapy: A Content Analysis
Previous Article in Journal
Role of Vitrectomy in Nontractional Refractory Diabetic Macular Edema
Previous Article in Special Issue
Coxiella burnetii and Bartonella Endocarditis Diagnosed by Metagenomic Next-Generation Sequencing
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 12
Issue 6
10.3390/jcm12062298
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan

by
Shao-Ju Chien
1,2,3,
Yi-Ju Tseng
4,
Ying-Hua Huang
1,
Hsi-Yun Liu
1,
Yi-Hua Wu
1,
Ling-Sai Chang
1,2,
Yao-Hsu Yang
5,6,7 and
Ying-Jui Lin
1,2,8,*
1
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
2
College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
3
Department of Early Childhood Care and Education, Cheng Shiu University, Kaohsiung 83347, Taiwan
4
Department of Computer Science, National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
5
Health Information and Epidemiology Laboratory, Chiayi Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
6
Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
7
School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
8
Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2023, 12(6), 2298; https://doi.org/10.3390/jcm12062298
Submission received: 15 February 2023 / Revised: 11 March 2023 / Accepted: 14 March 2023 / Published: 15 March 2023
(This article belongs to the Special Issue Infections, Complications and Management of Endocarditis: Part II)
Review Reports Versions Notes

Abstract

:
Background: Infective endocarditis (IE) is an important cause of morbidity and mortality in pediatric patients with heart disease. Little literature has explored differences in the presentation of endocarditis in children with and without heart disease. This study aimed to compare the clinical outcomes and determine the risk of in-hospital death in the study population. Methods: Data were retrospectively collected from 2001 to 2019 from the Chang Gung Research Database (CGRD), which is the largest collection of multi-institutional electronic medical records in Taiwan. Children aged 0–20 years with IE were enrolled. We extracted and analyzed the demographic and clinical features, complications, microbiological information, and outcomes of each patient. Results: Of the 208 patients with IE, 114 had heart disease and 94 did not. Compared to those without heart disease, more streptococcal infections (19.3% vs. 2.1%, p < 0.001) and cardiac complications (29.8% vs. 6.4%, p < 0.001) were observed in patients with heart disease. Although patients with heart disease underwent valve surgery more frequently (43.9% vs. 8.5%, p < 0.001) and had longer hospital stays (28.5 vs. 12.5, p = 0.021), their mortality was lower than that of those without heart disease (3.5% vs. 10.6%, p = 0.041). Thrombocytopenia was independent risk factor for in-hospital mortality in pediatric patients with IE (OR = 6.56, 95% CI: 1.43–40.37). Conclusion: Among pediatric patients diagnosed with IE, microbiological and clinical features differed between those with and without heart disease. Platelet counts can be used as a risk factor for in-hospital mortality in pediatric patients with IE.

1. Introduction

Infective endocarditis (IE) occurs less often in children than in adults, accounting for approximately 1 in 1280 pediatric admissions per year [1,2]. However, the improved survival among children who are at risk of endocarditis, such as those with heart disease, has resulted in its increased incidence in recent decades [2]. With the change in IE epidemiology due to medical advances, the prevalence of rheumatic heart disease (RHD) has declined in developed countries, with an increase in association with congenital heart disease (CHD) in children. Ventricular septal defect (VSD), patent ductus arteriosus (PDA), aorta or aortic arch anomalies, and tetralogy of Fallot are common underlying conditions. An increasing proportion of corrective or palliative surgeries for CHD, with or without implanted patches, vascular grafts, or prosthetic cardiac valves, also contribute to IE incidence [3,4]. However, the clinical characteristics and outcomes of pediatric patients with IE and the differences in those with and without heart disease suffering from IE are limited. Therefore, this study aimed to describe and compare the clinical characteristics, outcomes, and major complications of IE between pediatric patients with and without heart disease. We also determined the risk factors of in-hospital death in the study population.

2. Materials and Methods

2.1. Study Design

In this retrospective cohort study, we collected data from 2001 to 2019 from the Chang Gung Research Database (CGRD), the largest multi-institutional database in Taiwan that includes de-identified electronic medical records from Chang Gung Memorial Hospitals (CGMHs) [5]. We collected data from seven branches of CGMHs that provide primary to tertiary medical care in Taiwan. Demographic patient data collected were the disease diagnoses, laboratory test results, management procedures, and prescribed medication from the inpatient departments. The diagnoses were identified using the International Classification of Diseases, Ninth and Tenth Revision codes (ICD-9 and ICD-10, respectively). Laboratory test results were recognized using the internally used codes in CGMHs and the procedures with the corresponding national health insurance (NHI) codes for valvular surgery. The study was approved by the Institutional Review Board (no. 201900978B0). The requirement for patient consent was waived because the identification numbers of all patients in the CGRD were encrypted to protect their privacy.

2.2. Definitions

Patients hospitalized with endocarditis diagnosis codes (ICD-9 codes 421.0, 421.1, 421.9, 424.9; ICD-10 codes I33, I38, I39) were retrieved [6] from the CGRD [6]. Echocardiographic reports with vegetation, abscess, aneurysm, pseudoaneurysm, perforation, fistula, and dehiscence were used to define infective endocarditis [7]. Predisposing heart conditions were defined as a history of having diagnosis codes of CHDs, cyanotic CHDs, pulmonary hypertension (Pul HTN), hypertrophic cardiomyopathy (HCM), Marfan syndrome, and RHD before admission. CHD lesions were further classified as VSD, atrial septal defect (ASD), endocardial cushion defect (ECD), PDA, and aorta/aortic arch lesions. Tetralogy of Fallot, univentricular heart, complete transposition complex, truncus arteriosus, and hypoplastic left heart syndrome with lesions most likely to be cyanotic at birth were grouped as cyanotic CHDs [6]. If one patient had multiple diagnoses, the diagnosis with the worst prognosis and highest complexity was established as the primary one [8]. For example, a patient with both ASD and TOF would be classified as having TOF. The involvement of different valves was also identified. In order to compare the clinical characteristics of pediatric patients with or without heart disease, the patients of above CHDs, cyanotic CHDs, or HCM were further grouped as heart disease (HD) for analysis. Complications that occurred during the admission period were retrieved and divided into three categories: (1) neurological (ischemic or hemorrhagic stroke), (2) respiratory (pulmonary embolism), and (3) cardiac (heart failure, myocardial infarction, or conduction disturbance) [9]. Appendix A provides a list of all ICD diagnoses or NHI procedure codes that were included in the study. To identify biomarkers to predict mortality, we analyzed the laboratory results of complete blood cell and differential counts that had been performed in 80% of the admitted patients. Leukocytosis and anemia were defined according to their normal ranges for the age group. A left shift indicated that more than 3% of immature neutrophils appeared in the blood. Thrombocytopenia was defined as a platelet count <150,000/mL.

2.3. Statistical Analysis

The characteristics of children with IE are described using absolute numbers, proportions, and median/interquartile ranges. Continuous variables are summarized as medians (interquartile ranges) and compared using the Kruskal–Wallis test. Categorical variables are presented as numbers (percentage) and were compared using Pearson’s χ2 test, or Fisher’s exact test if any expected cell count was <5 for the univariate analysis. Logistic regression with Firth’s correction, a solution to the problem of separation caused by rare events, was used to identify factors associated with mortality. We included age, sex, and variables with crude odds ratios (OR) that had a p-value of less than 0.2 in multiple variable analysis. From these analyses, we report the crude and adjusted ORs and their corresponding 95% confidence intervals (CI), estimated using the profile penalized likelihood method. Analyses were performed using R (version 4.1.3, the R Foundation for Statistical Computing, Vienna, Austria, www.r-project.org/, accessed on 13 August 2022). All statistical tests were two-sided, and p < 0.05 was considered statistically significant.

3. Results

3.1. Clinical Features and Major Outcomes

During the 19-year study period, 213,471 patients were diagnosed with IE in the emergency, outpatient, and inpatient departments. After excluding diagnoses made in the emergency and outpatient department or without image studies, 3455 cases of IE remained; 208 pediatric patients (aged 0–20 years old) were included in the final analysis.
Table 1 shows the demographic and clinical characteristics of the 208 pediatric patients with IE diagnostic codes. The median age was 13 years, and 57.8% of the patients were male (n = 118). Predisposing structural heart diseases (CHDs and cyanotic CHDs) were observed in 31.7% of patients (n = 66). Among the heart diseases, VSD was the most often encountered. The mitral valve was the most often involved. Several complications were observed, with cardiac complications being the most common (n = 40, 19.2%), including heart failure (n = 40, 19.2%), myocardial infarction (n = 1, 0.5%), and ventricular arrhythmias (n = 1, 0.5%). The second most common complication was pulmonary embolism (n = 15, 7.2%). Thirteen patients developed neurological complications, including ischemic and hemorrhagic stroke. Overall, 58 (27.9%) patients underwent valve surgery and 14 (6.7%) died.

3.2. Clinical Characteristics of the Subgroups

Approximately 27.9% of patients had positive blood cultures. Staphylococcus species (n = 33, 15.9%) was the most frequent contributing pathogen found in all the study participants, followed by Streptococcus species (n = 24, 11.5%). The clinical characteristics of the patients with and without HD are listed in Table 2. Streptococci were the most frequently identified pathogens in the HD group (n = 22; 19.3%). There were two Pseudomonas and Candida infections in the non-HD group. Staphylococci (n = 17, 18.1%) were the most common causative pathogens identified in the non-HD group, especially Staphylococcus aureus. Complications, especially cardiac problems, were more commonly found in the HD group than in the non-HD group (39.5% vs. 16%, p = 0.0002). No significant difference was observed in the frequency of neurological complications and pulmonary embolisms between the two groups. Although patients with HD underwent valve surgery more frequently (43.9% vs. 8.5%, p < 0.001) and had longer hospital stays (27.4 vs. 22.3 days, p = 0.021), non-HD patients had a significantly higher in-hospital mortality rate (10.6% vs. 3.5%, p = 0.0411).

3.3. Risk Factors for In-Hospital Mortality

Anemia and leukocytosis were common in IE; thrombocytopenia accounted for one-third (33.1%) of the patients. Fourteen patients (6.7%) died during hospitalization. The risk factors associated with in-hospital mortality were further analyzed in 166 patients with complete laboratory data (Table 3). There were more left-shifted immature neutrophils and thrombocytopenia in the mortality group than in the survival group (66.7% vs. 20.1%, p = 0.001 and 83.3% vs. 29.2%, p < 0.001, respectively). In thrombocytopenia episodes, the mean platelet count was 71.4 × 103 (SD 43.4 × 103), whereas, in those without thrombocytopenia, it was 269.2 × 103 (SD 99.5 × 103). Although streptococci infection, cardiac complications, valvular surgery, and longer hospital stay were more common in pediatric patients with HD than in those without HD suffering from IE, the only significant risk factor for in-hospital death was thrombocytopenia (adjusted OR: 6.56; 95% CI: 1.43–40.37; p = 0.015) in the multivariable analysis.

4. Discussion

The results of this study exhibited significant differences in the causative microbiological features, clinical characteristics, and outcomes between pediatric patients with and without HD suffering from IE. The proportion of Streptococci species and cardiac complication rates were significantly greater in the HD group than in the non-HD group. Although more valve surgeries and longer hospital stays were encountered in the HD group, the mortality rate was lower than that in the non-HD group. In this study, thrombocytopenia was independently associated with overall in-hospital mortality.
In our study, there were certain negative culture results. The different incidences of IE with negative blood culture in different countries resulted from the epidemiology of IE, the diagnostic criteria accepted, and the diagnostic technique [10,11]. Despite improvements in blood culture media and the introduction of automated growth detection systems, blood-culture-negative IE still represents 5–69.7% of all cases of endocarditis [12]. The main clinical scenario is early empiric antibiotic treatment started prior to blood sampling before the patient is diagnosed with or suspected of having IE in many critical clinical situations [10,13]. Due to the observational nature of the analysis, no detailed clinical information was captured regarding the exact timing of antimicrobial therapy with respect to IE diagnosis and culture methods.
Blood-culture-negative IE poses a significant challenge in clinical determination of the best specific and effective antibiotic choice for this life-threatening infection. Although blood and valve tissue cultures are the gold standard for IE pathogens’ detection, they are very time-consuming and unfeasible for fastidious or intracellular microorganisms [14]. Many modified criteria and diagnostic techniques, such as imaging, have been introduced in an effort to improve the diagnosis of pathologically proven native valve blood-culture-negative IE [15]. The value of echocardiography in the diagnosis of patients with culture-negative endocarditis is great since it improves sensitivity and specificity [16,17] and has proven to be a major criterion for endocarditis in 78–98.5% of definite IE cases [15,17]. Although there are no major microbiological criteria, blood-culture-negative endocarditis has been shown to be associated with younger age, shorter duration of symptoms at time of presentation [18], more a frequent need for surgical repair [19], a greater number of intra- and postoperative complications, and consequently, worse outcomes and disease courses [20]. Due to these important issues, we did not exclude patients with blood-culture-negative IE, and we used echocardiographic evidence as a major contributing factor in the diagnosis of IE cases.
Although IE is a rare condition, it remains a considerable concern in patients with underlying cardiac conditions, whether they are unrepaired, palliated, or corrected [2,21]. Even with modern medicine and improved survival of patients with CHD, it remains a major predisposing risk factor for IE in childhood and adolescence [22,23]. In a Canadian national study, the most common CHD with IE was cyanotic CHD lesions, followed by ASD and VSD [6]. The IE risk varies markedly with the complexity of lesions among patients with CHD; patients with more complex lesions or severe defects are at higher risk of IE. However, persistent turbulent flow after cardiac operation, even in simple CHD, can cause endocardial damage, allowing for adhesion of microorganisms following transient bacteremia [24]. In our study, we were unable to determine whether patients had completed surgical repair before IE or if there were residual cardiac lesions after surgery. Furthermore, the IE involved more left-sided mitral and aortic valves. In developed countries, there is an increasing temporal trend in mitral valve prolapse among patients suffering from IE with underlying HD [25,26]. The relatively high IE risk observed in children with left-sided lesions is in accordance with several research articles that have emphasized the IE risk in patients with left ventricular outflow obstruction lesions [6]. Isolated secundum ASD has negligible IE risk, but the IE risk in ASD is higher than that in the general population in the Quebec CHD database and CONCOR database of adults with CHD [6,27]. These patients may have had coexistent lesions that rendered them vulnerable to IE, such as valvular lesions (particularly regarding the mitral valve) or primum ASD that may have been misclassified and not contained in the ECD group [6]. The infrequency of IE prevented the investigation of individual CHD lesions, and the fewer IE events per specific CHD lesion prohibited any statistical analysis.
Patients with IE have a broad spectrum of complications. Cardiac complications were the principal cause of morbidity, and neurological or embolic complications were significantly fewer in our study than in the previous studies [3,28]. The highly variable clinical presentation of IE may reflect the variable causative microorganisms and underlying cardiac conditions. Patients with HD suffering from IE had significantly different clinical characteristics from those without HD patients. Our study showed that the most common causative pathogen of IE was Staphylococcus species (15.9%), followed by Streptococcus species (11.5%). However, among children with HD, the most frequent causative microorganism was Streptococcus, rather than Staphylococcus. These data concur with those of other studies, in which the frequency distribution of Staphylococcus aureus in IE in North America was significantly increased [29]. However, Staphylococcus distribution was less in patients with HD [30,31]. S. aureus in IE has a higher rate of complications, particularly neurological complications, and mortality when compared with other pathogens [3,32]. Although patients with underlying HD are known to have a worse prognosis [31], our decreased morbidity and mortality rate might be partially due to the lower percentage of S. aureus as the underlying pathogen. Among our pediatric patients, 27.9% underwent surgery. Management of progressive valvular damage and the consequential heart failure with medical therapy alone is often ineffective [1]. Cardiovascular surgery may be lifesaving in patients with IE if they have progressive cardiac failure, valvular obstruction, persistent bacteremia even under appropriate antibiotic therapy, or significant embolic events [33].
Our overall mortality rate was 6.7%, and thrombocytopenia was common in pediatric IE (33.1%) at a rate similar to that of 32.8% in an adult study [34]. Thrombocytopenia was the only laboratory parameter that was associated with mortality. A variety of nonspecific laboratory findings were noted in children by [1], such as anemia, leukocytosis, or immature forms of white blood cells, and their proportion was higher in our patients with mortality. However, none were independent predictors of mortality in the multivariable analysis. Thrombocytopenia was the only risk factor, superseding HD, involving valves, complications, or the need for surgery, which was associated with mortality. Patients with thrombocytopenia had a higher mortality rate than patients without thrombocytopenia. Although only a few retrospective studies have identified thrombocytopenia as a risk factor for death in adult patients with IE [35,36], it is a known risk factor for death in sepsis. Furthermore, patients with thrombocytopenia are more likely to develop stroke and persistent signs of infection and septic shock [37]. Thrombocytopenia has been included in several severity scores for sepsis and multiple organ dysfunction [38,39]. A prospective study in three tertiary care university hospitals was conducted by C. Ferrera Duran et al., who stated that thrombocytopenia at admission should be used to identify the patients with native valve IE at risk of complicated in-hospital complications and mortality. Thrombocytopenia could be included in IE guidelines as an early marker for risk stratification and predictor of a poor outcome [34]. Our study is the first pediatric series to identify thrombocytopenia as the laboratory parameter associated with mortality, though it echoes previous literature. Therefore, thrombocytopenia could be considered for integration into the triad of clinical, microbiological, and echocardiographic issues [40] that predict pediatric patient outcomes in IE. Platelets play the primary role in thrombosis, hemostasis, inflammation, and infection. They can directly interact with pathogens and immune cells via their surface receptors [41]. In endocarditis pathogenesis, platelets play an important role in the local host defense against endovascular infections [42]. In addition, they are sensitive monitors of the systemic host response to sepsis and other severe clinical symptoms [36]. In patients with sepsis, thrombocytopenia may be induced by impaired platelet production or increased immune and non-immune destruction/consumption of platelets [43]. A synergistic interaction between thrombocytopenia and Streptococcus aureus has also been observed to have an effect on mortality risk [34,44]. In addition, drug-induced thrombocytopenia might also represent a minority of cases among thrombocytopenic children. However, we could not definitively elucidate these in our patient cohort. Further bone marrow aspirates or autoantibody-specific assays may help investigate possible mechanisms of thrombocytopenia.

5. Limitations

We measured IE from hospital administrative records, similar to several large-scale research studies designed to acquire absolute measures of IE frequency, underlying diseases, complications, and mortality [6,22]. However, the study design has potentially referral bias because all the participants were cared for by primary to tertiary medical hospitals of CGMHs. Furthermore, we conducted an analysis of a sub-cohort with complete laboratory data on mortality, for which there could have been a selection bias. Beyond that, some lack of data prevented the assessment of and adjustment for potential confounding factors across patient subpopulations. Additionally, an inherent limitation of such an administration-based study was that detailed clinical criteria to establish IE diagnosis were not available. The lack of proper validation studies for ICD codes for IE and misclassification of IE could result in overestimation or underestimation of the cumulative IE incidence. This would have led to bias toward the unfounded value in the predictor analysis. Furthermore, the retrospective design of the present study may have overlooked some clinical features, inconsistencies in patient care, and discrepancies in patients’ underlying background information. Within the CHD group, our data did not allow for a distinction between native anatomy without surgical repair and postoperative status. Moreover, the long-term survival and emergence of further complications after hospital discharge were not identified. Further refinement of more subtle clinical data and details about patient care and antimicrobial therapy are needed for more accurate and extensive determination of the risk of IE. Nevertheless, a unique feature and strength of the study was the use of the only large, long-term, multi-institutional inpatient database currently available in Taiwan. Furthermore, we were able to compare the manifestation of IE in the HD and non-HD pediatric patients and provide relevant information. In the future, further prospective studies or randomized trials could be conducted to generate further validation and evidence to support the management of IE.
In conclusion, although patients with HD had a higher proportion of IE and cardiac complications than those without HD, HD itself was not an independent risk factor for in-hospital mortality in our study. Thrombocytopenia during admission could be used for risk stratification in pediatric patients with IE to identify increased mortality. If antiplatelet agents are considered as adjunctive therapy for embolic complications of IE, clinicians should be cautious of coexistent thrombocytopenia as it might increase the risk of bleeding. In addition, patients with thrombocytopenia may warrant more intensive monitoring and dedicated adjustments to treatment, and, where relevant, surgery should be considered.

Author Contributions

Conceptualization, S.-J.C. and Y.-J.T.; methodology, S.-J.C. and Y.-J.T.; software, Y.-H.Y. and Y.-J.T.; validation, Y.-H.H., L.-S.C. and S.-J.C.; formal analysis, H.-Y.L. and Y.-H.W.; investigation, L.-S.C.; resources, Y.-H.H.; data curation, H.-Y.L. and Y.-H.W.; writing—original draft preparation, S.-J.C., Y.-J.L. and Y.-J.T.; writing—review and editing, S.-J.C., Y.-J.L. and Y.-J.T..; visualization, Y.-H.Y.; supervision, S.-J.C. and Y.-J.L.; project administration, S.-J.C., Y.-J.L.; funding acquisition, S.-J.C. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported in part by grants from Chang Gung Memorial Hospital (CFRPG8J0121). However, the institution had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Institutional Review Board Statement

The Institutional Review Board of Kaohsiung Chang Gung Memorial Hospital approved this study (number: 201900978B0).

Informed Consent Statement

Patient consent was waived due to because the identification numbers of all patients in the CGRD were encrypted to protect their privacy.

Data Availability Statement

The data is unavailable due to CGRD restrictions.

Acknowledgments

We would like to thank Wei-Ling Feng, Hsin-Yi Chien, Chih-Yun Lin, and the Biostatistics Center of Kaohsiung Chang Gung Memorial Hospital for contributing to the statistical analyses.

Conflicts of Interest

The authors declare that they have no conflicts of interest related to this article.

Appendix A. ICD Diagnosis or NHI Procedure Codes for Study

InclusionICD Diagnosis Codes or NHI Procedure Codes
Congenital heart disease (CHD)
Atrial septal defect (ASD)7455, Q211
Patent ductus arteriosus (PDA)7470, Q250
Ventricular septal defect (VSD)7454, Q210
Endocardial cushion defects (ECD)7456, 74560, 74561, 74569, Q212
Aortic arch anomaly7471, 74710, 74711, 7472, 74720, 74721, 74722, 74729, Q251.x, Q252.x, Q253.x, Q254.x
Cyanotic congenital heart disease (cyanotic CHD)
Teratology of Fallot/DORV/pulmonary atresia7452, 74511, 74601, Q201, Q213, Q220
Transposition of the great arteries or congenitally corrected transposition of the great arteries7451, 74510, 74512, 74519, Q203,
Common truncus/Aortopulmonary septal defect7450, Q200, Q214
Single ventricle physiology7453, 7461, 7467, Q202, Q204, Q226, Q234
Pulmonary HTN (Pul HTN)4160, 4168, 4169, I270, I272
Hypertrophic cardiomyopathy (HCM)4251, I421, I422, I424
Marfan syndrome75982, Q874
Rheumatic heart disease (RHD)390, 391, 3918, 3919, 3920, 3929, 3941, 3971, 398, 3989, 39890, 39891, 39899, I00, I01, I018, I019, I020, I029, I050, I051, I052, I058, I059, I080, I081, I082, I083, I09, I098, I0981, I0989, I099
Valve involved
Mitral valve7465, 7466, 394, 3940, 3942, 3949, 4240, I34, I340, I341, I342, I348, I349, Q232, Q233
Aortic valve7463, 7464, 74681, 7471, 74710, 74711, 7472, 74720, 74721, 74722, 74729, Q230, Q231, Q251, Q252, Q253, Q244, I35, I350, I351, I352, I358, I359
Aortic and mitral valves396, 3960, 3961, 3962, 3963, 3968, 3969, Q23, Q238, Q239
Pulmonic valve4243, 7460, 74600, 74601, 74602, 74609, 74683, I370, I371, I372, I378, I379, Q220, Q221, Q222, Q223, Q243
Tricuspid valve7461, 7462, 4242, 7462, I36, I360, I361, I362, I368, I369, Q224, Q225, Q228, Q229
Prosthetic valve99671, V433 (ICD-9); Z952, T820.x, T8222.x
Complications
Neurologic433.x, 434.x, or 436, I63, I65, I66, 431 or 432, I60, I61, I62,
Cardiac428.x, I50; 410.x, I21, I22, I23, I24; 427.1, 427.4, 427.41, or 427.42, I472, I490
Pulmonary embolism415, I26
Valve surgery68015B, 68016B, 68017B, 68018B, 68029B

References

  1. Ferrieri, P.; Gewitz, M.H.; Gerber, M.A.; Newburger, J.W.; Dajani, A.S.; Shulman, S.T.; Wilson, W.; Bolger, A.F.; Bayer, A.; Levison, M.E.; et al. Unique features of infective endocarditis in childhood. Circulation 2002, 105, 2115–2126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Cahill, T.J.; Prendergast, B.D. Infective endocarditis. Lancet 2016, 387, 882–893. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Martin, J.M.; Neches, W.H.; Wald, E.R. Infective endocarditis: 35 years of experience at a children’s hospital. Clin. Infect. Dis. 1997, 24, 669–675. [Google Scholar] [CrossRef] [Green Version]
  4. Morris, C.D.; Reller, M.D.; Menashe, V.D. Thirty-year incidence of infective endocarditis after surgery for congenital heart defect. JAMA 1998, 279, 599–603. [Google Scholar] [CrossRef] [Green Version]
  5. Shao, S.C.; Chan, Y.Y.; Kao Yang, Y.H.; Lin, S.J.; Hung, M.J.; Chien, R.N.; Lai, C.; Lai, E.C. The Chang Gung Research Database—A multi-institutional electronic medical records database for real-world epidemiological studies in Taiwan. Pharmacoepidemiol. Drug Saf. 2019, 28, 593–600. [Google Scholar] [CrossRef]
  6. Rushani, D.; Kaufman, J.S.; Ionescu-Ittu, R.; Mackie, A.S.; Pilote, L.; Therrien, J.; Marelli, A.J. Infective endocarditis in children with congenital heart disease: Cumulative incidence and predictors. Circulation 2013, 128, 1412–1419. [Google Scholar] [CrossRef] [Green Version]
  7. Habib, G.; Badano, L.; Tribouilloy, C.; Vilacosta, I.; Zamorano, J.L.; Galderisi, M.; Voigt, J.-U.; Sicari, R.; Cosyns, B.; Fox, K.; et al. Recommendations for the practice of echocardiography in infective endocarditis. Eur. J. Echocardiogr. 2010, 11, 202–219. [Google Scholar] [CrossRef] [Green Version]
  8. Lytzen, R.; Vejlstrup, N.; Bjerre, J.; Petersen, O.B.; Leenskjold, S.; Dodd, J.K.; Jørgensen, F.S.; Søndergaard, L. Live-Born Major Congenital Heart Disease in Denmark: Incidence, Detection Rate, and Termination of Pregnancy Rate From 1996 to 2013. JAMA Cardiol. 2018, 3, 829–837. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Wang, C.Y.; Wang, Y.C.; Yang, Y.S.; Chang, C.Y.; Chen, K.Y.; Lai, J.J.; Lin, J.-C.; Chang, F.-Y. Microbiological features, clinical characteristics and outcomes of infective endocarditis in adults with and without hemodialysis: A 10-year retrospective study in Northern Taiwan. J. Microbiol. Immunol. Infect. 2020, 53, 336–343. [Google Scholar] [CrossRef]
  10. Brouqui, P.; Raoult, D. Endocarditis due to rare and fastidious bacteria. Clin. Microbiol. Rev. 2001, 14, 177–207. [Google Scholar] [CrossRef] [Green Version]
  11. Raoult, D.; Casalta, J.P.; Richet, H.; Khan, M.; Bernit, E.; Rovery, C.; Branger, S.; Gouriet, F.; Imbert, G.; Bothello, E.; et al. Contribution of systematic serological testing in diagnosis of infective endocarditis. J. Clin. Microbiol. 2005, 43, 5238–5242. [Google Scholar] [CrossRef] [Green Version]
  12. Lamas, C.C.; Fournier, P.E.; Zappa, M.; Brandao, T.J.; Januario-da-Silva, C.A.; Correia, M.G.; Barbosa, G.I.F.; Golebiovski, W.F.; Weksler, C.; Lepidi, H.; et al. Diagnosis of blood culture-negative endocarditis and clinical comparison between blood culture-negative and blood culture-positive cases. Infection 2016, 44, 459–466. [Google Scholar] [CrossRef] [PubMed]
  13. Tattevin, P.; Watt, G.; Revest, M.; Arvieux, C.; Fournier, P.E. Update on blood culture-negative endocarditis. Med. Mal. Infect. 2015, 45, 1–8. [Google Scholar] [CrossRef]
  14. Habib, G.; Lancellotti, P.; Antunes, M.J.; Bongiorni, M.G.; Casalta, J.P.; Del Zotti, F.; Dulgheru, R.; El Khoury, G.; Erba, P.A.; Iung, B.; et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective 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, 3075–3128. [Google Scholar]
  15. El-Ashry, A.H.; Saad, K.; Obiedallah, A.A.; Elhoufey, A.; Dailah, H.G.; Hussein, M.S.A. Molecular and Serological Diagnostic Approach to Define the Microbiological Origin of Blood Culture-Negative Infective Endocarditis. Pathogens 2022, 11, 1220. [Google Scholar] [CrossRef] [PubMed]
  16. Garg, N.; Kandpal, B.; Garg, N.; Tewari, S.; Kapoor, A.; Goel, P.; Sinha, N. Characteristics of infective endocarditis in a developing country-clinical profile and outcome in 192 Indian patients, 1992–2001. Int. J. Cardiol. 2005, 98, 253–260. [Google Scholar] [CrossRef] [PubMed]
  17. Topan, A.; Carstina, D.; Slavcovici, A.; Rancea, R.; Capalneanu, R.; Lupse, M. Assesment of the Duke criteria for the diagnosis of infective endocarditis after twenty-years. An analysis of 241 cases. Med. Pharm. Rep. 2015, 88, 321–326. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Tariq, M.; Alam, M.; Munir, G.; Khan, M.A.; Smego, R.A., Jr. Infective endocarditis: A five-year experience at a tertiary care hospital in Pakistan. Int. J. Infect. Dis. 2004, 8, 163–170. [Google Scholar] [CrossRef] [Green Version]
  19. Zamorano, J.; Sanz, J.; Moreno, R.; Almeria, C.; Rodrigo, J.L.; Samedi, M.; Herrera, D.; Aubele, A.; Mataix, L.; Serra, V.; et al. Comparison of outcome in patients with culture-negative versus culture-positive active infective endocarditis. Am. J. Cardiol. 2001, 87, 1423–1425. [Google Scholar] [CrossRef]
  20. Fournier, P.E.; Gouriet, F.; Casalta, J.P.; Lepidi, H.; Chaudet, H.; Thuny, F.; Collart, F.; Habib, G.; Raoult, D. Blood culture-negative endocarditis: Improving the diagnostic yield using new diagnostic tools. Medicine 2017, 96, e8392. [Google Scholar] [CrossRef]
  21. Mulder, B.J. Endocarditis in congenital heart disease: Who is at highest risk? Circulation 2013, 128, 1396–1397. [Google Scholar] [CrossRef] [Green Version]
  22. Day, M.D.; Gauvreau, K.; Shulman, S.; Newburger, J.W. Characteristics of children hospitalized with infective endocarditis. Circulation 2009, 119, 865–870. [Google Scholar] [CrossRef] [Green Version]
  23. Tutarel, O.; Alonso-Gonzalez, R.; Montanaro, C.; Schiff, R.; Uribarri, A.; Kempny, A.; Grübler, M.R.; Uebing, A.; Swan, L.; Diller, G.-P.; et al. Infective endocarditis in adults with congenital heart disease remains a lethal disease. Heart 2018, 104, 161–165. [Google Scholar] [CrossRef] [PubMed]
  24. Knirsch, W.; Haas, N.A.; Uhlemann, F.; Dietz, K.; Lange, P.E. Clinical course and complications of infective endocarditis in patients growing up with congenital heart disease. Int. J. Cardiol. 2005, 101, 285–291. [Google Scholar] [CrossRef]
  25. Tleyjeh, I.M.; Steckelberg, J.M.; Murad, H.S.; Anavekar, N.S.; Ghomrawi, H.M.; Mirzoyev, Z.; Moustafa, S.E.; Hoskin, T.L.; Mandrekar, J.N.; Wilson, W.R.; et al. Temporal trends in infective endocarditis: A population-based study in Olmsted County, Minnesota. JAMA 2005, 293, 3022–3028. [Google Scholar] [CrossRef] [Green Version]
  26. Mylonakis, E.; Calderwood, S.B. Infective endocarditis in adults. N. Engl. J. Med. 2001, 345, 1318–1330. [Google Scholar] [CrossRef]
  27. Verheugt, C.L.; Uiterwaal, C.S.; van der Velde, E.T.; Meijboom, F.J.; Pieper, P.G.; Veen, G.; Stappers, J.L.; Grobbee, D.E.; Mulder, B.J. Turning 18 with congenital heart disease: Prediction of infective endocarditis based on a large population. Eur. Heart J. 2011, 32, 1926–1934. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Coward, K.; Tucker, N.; Darville, T. Infective endocarditis in Arkansan children from 1990 through 2002. Pediatr. Infect. Dis. J. 2003, 22, 1048–1052. [Google Scholar] [CrossRef]
  29. Slipczuk, L.; Codolosa, J.N.; Davila, C.D.; Romero-Corral, A.; Yun, J.; Pressman, G.S.; Figueredo, V.M. Infective endocarditis epidemiology over five decades: A systematic review. PLoS ONE 2013, 8, e82665. [Google Scholar] [CrossRef]
  30. McKinsey, D.S.; Ratts, T.E.; Bisno, A.L. Underlying cardiac lesions in adults with infective endocarditis. The changing spectrum. Am. J. Med. 1987, 82, 681–688. [Google Scholar] [CrossRef] [PubMed]
  31. Castillo, J.C.; Anguita, M.P.; Torres, F.; Siles, J.R.; Mesa, D.; Valles, F. Risk factors associated with endocarditis without underlying heart disease. Rev. Esp. Cardiol. 2002, 55, 304–307. [Google Scholar] [CrossRef] [PubMed]
  32. Saiman, L.; Prince, A.; Gersony, W.M. Pediatric infective endocarditis in the modern era. J. Pediatr. 1993, 122, 847–853. [Google Scholar] [CrossRef]
  33. Tolan, R.W., Jr.; Kleiman, M.B.; Frank, M.; King, H.; Brown, J.W. Operative intervention in active endocarditis in children: Report of a series of cases and review. Clin. Infect. Dis. 1992, 14, 852–862. [Google Scholar] [CrossRef] [PubMed]
  34. Ferrera, C.; Vilacosta, I.; Fernandez, C.; Lopez, J.; Sarria, C.; Olmos, C.; Vivas, D.; Sáez, C.; Sánchez-Enrique, C.; Ortiz, C.; et al. Usefulness of thrombocytopenia at admission as a prognostic marker in native valve left-sided infective endocarditis. Am. J. Cardiol. 2015, 115, 950–955. [Google Scholar] [CrossRef]
  35. Sy, R.W.; Chawantanpipat, C.; Richmond, D.R.; Kritharides, L. Development and validation of a time-dependent risk model for predicting mortality in infective endocarditis. Eur. Heart J. 2011, 32, 2016–2026. [Google Scholar] [CrossRef] [Green Version]
  36. Sy, R.W.; Chawantanpipat, C.; Richmond, D.R.; Kritharides, L. Thrombocytopenia and mortality in infective endocarditis. J. Am. Coll. Cardiol. 2008, 51, 1824–1825. [Google Scholar] [CrossRef] [Green Version]
  37. Levy, M.M.; Fink, M.P.; Marshall, J.C.; Abraham, E.; Angus, D.; Cook, D.; Cohen, J.; Opal, S.M.; Vincent, J.-L.; Ramsay, G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003, 29, 530–538. [Google Scholar] [CrossRef] [PubMed]
  38. Ferreira, F.L.; Bota, D.P.; Bross, A.; Melot, C.; Vincent, J.L. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 2001, 286, 1754–1758. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Marshall, J.C.; Cook, D.J.; Christou, N.V.; Bernard, G.R.; Sprung, C.L.; Sibbald, W.J. Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit. Care Med. 1995, 23, 1638–1652. [Google Scholar] [CrossRef]
  40. San Roman, J.A.; Lopez, J.; Vilacosta, I.; Luaces, M.; Sarria, C.; Revilla, A.; Ronderos, R.; Stoermann, W.; Gómez, I.; Fernández-Avilés, F. Prognostic stratification of patients with left-sided endocarditis determined at admission. Am. J. Med. 2007, 120, e1–e7. [Google Scholar] [CrossRef]
  41. Deppermann, C.; Kubes, P. Start a fire, kill the bug: The role of platelets in inflammation and infection. Innate Immun. 2018, 24, 335–348. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Sullam, P.M.; Frank, U.; Yeaman, M.R.; Tauber, M.G.; Bayer, A.S.; Chambers, H.F. Effect of thrombocytopenia on the early course of streptococcal endocarditis. J. Infect. Dis. 1993, 168, 910–914. [Google Scholar] [CrossRef] [PubMed]
  43. Levi, M. Platelets in sepsis. Hematology 2005, 10 (Suppl. S1), 129–131. [Google Scholar] [CrossRef]
  44. Dall, L.; Miller, T.; Herndon, B.; Diez, I.; Dew, M. Platelet depletion and severity of streptococcal endocarditis. Can. J. Infect. Dis. 1998, 9, 359–366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Table
Table 1. General characteristics of 208 pediatric patients with infective endocarditis.
Table 1. General characteristics of 208 pediatric patients with infective endocarditis.
N (n (%))Age (Median (IQR))
Patient, n20813 (4, 18)
Sex, n (%)
Male118 (56.7)13 (3, 18)
Female90 (43.3)14 (6–19)
CHD40 (19.2)7 (2, 15)
ASD1 (0.5)5
PDA3 (1.4)17 (3, 19)
VSD28 (13.5)9 (3, 15)
ECD7 (3.4)1 (0, 8)
Ao arch9 (4.3)6 (1, 12)
Cyanotic CHD26 (12.5)4 (0, 15)
Pul HTN10 (4.8)14 (4, 15)
HCM3 (1.4)10 (3, 18)
Marfan1 (0.5)15
RHD6 (2.9)17 (12, 19)
Valve involved
Mitral48 (23.1)17 (14, 19)
Aortic16 (7.7)13 (8, 17)
Mitral and aortic3 (1.4)9 (8, 19)
Pulmonary19 (9.1)4 (0, 12)
Tricuspid8 (3.8)15 (9, 16)
Prosthetic valve4 (1.9)13 (10, 18)
Complications
Neurologic13 (6.3)17 (14, 19)
Cardiac40 (19.2)13 (3, 18)
Pulmonary embolism15 (7.2)15 (8, 20)
Valve surgery58 (27.9)14 (5, 19)
Mortality14 (6.7)9 (0, 19)
CHD, congenital heart disease; VSD, ventricular septal defect; ASD, atrial septal defect; ECD, endocardial cushion defect; PDA, patent ductus arteriosus; Ao arch, aorta/aortic arch lesions; Pul HTN, pulmonary hypertension; HCM, hypertrophic cardiomyopathy; RHD, rheumatic heart disease.
Table
Table 2. Comparison of the clinical characteristics of pediatric patients with and without heart disease suffering from infective endocarditis.
Table 2. Comparison of the clinical characteristics of pediatric patients with and without heart disease suffering from infective endocarditis.
CharacteristicsOverall (n = 208)Heart Disease 1 (n = 114)Non-Heart Disease (n = 94)p-Value
GENERAL
Age, y (median [IQR])13 (4, 18)13 (4, 18)11.5 (4, 18)0.7671
Male, n (%)118 (56.7)66 (57.9)52 (55.3)0.7091
MICROBIOLOGY58 (27.9)37 (32.5)21 (22.3)0.1054
Streptococci, n (%)24 (11.5)22 (19.3)2 (2.1)0.0001
Staphylococci, n (%)33 (15.9)16 (14.0)17 (18.1)0.4262
Staphylococcus aureus, n (%)27 (13.0)14 (12.3)13 (13.8)0.7408
Pseudomonas, n (%)2 (1.0)0 (0)2 (2.1)0.203
Candida, n (%)2 (1.0)0 (0)2 (2.1)0.203
COMPLICATIONS60 (28.9)45 (39.5)15 (16)0.0002
Neurologic 2, n (%)13 (6.3)10 (8.8)3 (3.2)0.098
Cardiac 3, n (%)40 (19.2)34 (29.8)6 (6.4)<0.0001
PE, n (%)15 (7.2)8 (7.0)7 (7.4)0.9052
VALVE SURGERY, n (%)58 (27.9)50 (43.9)8 (8.5)<0.0001
MORTALITY, n (%)14 (6.7)4 (3.5)10 (10.6)0.0411
Hospital stay (median (IQR))20 (6, 40.5)28.5 (8.25, 42.75)12.5 (5, 36.75)0.021
Heart disease 1 = congenital heart disease (CHD) + cyanotic congenital heart disease + hypertrophic cardiomyopathy (HCM). Neurologic 2 = ischemic + hemorrhagic stroke. Cardiac 3 = heart failure + myocardial infarction + ventricular arrhythmia.
Table
Table 3. Predictors for mortality in 166 patients with IE and complete laboratory data for blood cell counts.
Table 3. Predictors for mortality in 166 patients with IE and complete laboratory data for blood cell counts.
Risk FactorsOverall (n = 166)Recovered (n = 154)Died (n = 12)p-ValueUnivariable AnalysisMultivariable Analysis
OR (95% CI 6)aOR (95% CI)
Age (median [IQR])13.19 [4.78, 18.67]13.19 [4.95, 18.72]8.91 [0.26, 18.36]0.2010.96 (0.88–1.04)0.92 (0.83–1.01)
Male, n (%)76 (45.8)70 (45.5)6 (50.0)0.7731.2 (0.36–4.00)1.32 (0.36–4.9)
Heart disease 1, n (%)91 (54.8)87 (56.5)4 (33.3)0.1410.41 (0.11–1.29)0.5 (0.12–1.8)
Microbiology, n (%)57 (34.3)53 (34.4)4 (33.3)11 (0.28–3.19)- 7
Leukocytosis, n (%)114 (68.7)104 (67.5)10 (83.3)0.3442.03 (0.56–10.82)-
Left shift, n (%)39 (23.5)31 (20.1)8 (66.7)0.0017.41 (2.29–27.17)2.98 (0.78–12.67)
Anemia, n (%)131 (78.9)121 (78.6)10 (83.3)11.16 (0.32–6.22)-
Thrombocytopenia, n (%)55 (33.1)45 (29.2)10 (83.3)<0.00110.11 (2.79–53.99)6.56 (1.43–40.37)
Neurologic complications 2, n (%)12 (7.2)10 (6.5)2 (16.7)0.4643.28 (0.58–13.45)3.52 (0.49–19.71)
Cardiac complications 3, n (%)36 (21.7)34 (22.1)2 (16.7)0.9410.83 (0.15–3.05)-
Pulmonary embolism, n (%)12 (7.2)12 (7.8)0 (0.0)0.6710.46 (0–3.86)-
Lt-sided valve 451 (30.7)49 (31.8)2 (16.7)0.4410.51 (0.1–1.84)-
Rt-sided valve 520 (12.0)18 (11.7)2 (16.7)0.961.76 (0.32–6.72)-
Valve surgery, n (%)52 (31.3)50 (32.5)2 (16.7)0.4160.49 (0.09–1.78)-
Heart disease 1 = congenital heart disease (CHD) + cyanotic congenital heart disease + hypertrophic cardiomyopathy (HCM). Neurologic 2 = ischemic + hemorrhagic stroke. Cardiac 3 = heart failure + myocardial infarction + ventricular arrhythmia. Lt-sided valve 4 = mitral valve, aortic valve, and aortic and mitral valves. Rt-sided valve 5 = pulmonic valve, infundibular stenosis, tricuspid valve, and Ebstein anomaly. CI 6, confidence interval. - 7, variables were not included in the multivariable analysis.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chien, S.-J.; Tseng, Y.-J.; Huang, Y.-H.; Liu, H.-Y.; Wu, Y.-H.; Chang, L.-S.; Yang, Y.-H.; Lin, Y.-J. Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan. J. Clin. Med. 2023, 12, 2298. https://doi.org/10.3390/jcm12062298

AMA Style

Chien S-J, Tseng Y-J, Huang Y-H, Liu H-Y, Wu Y-H, Chang L-S, Yang Y-H, Lin Y-J. Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan. Journal of Clinical Medicine. 2023; 12(6):2298. https://doi.org/10.3390/jcm12062298

Chicago/Turabian Style

Chien, Shao-Ju, Yi-Ju Tseng, Ying-Hua Huang, Hsi-Yun Liu, Yi-Hua Wu, Ling-Sai Chang, Yao-Hsu Yang, and Ying-Jui Lin. 2023. "Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan" Journal of Clinical Medicine 12, no. 6: 2298. https://doi.org/10.3390/jcm12062298

APA Style

Chien, S.-J., Tseng, Y.-J., Huang, Y.-H., Liu, H.-Y., Wu, Y.-H., Chang, L.-S., Yang, Y.-H., & Lin, Y.-J. (2023). Evaluation of Infective Endocarditis in Children: A 19-Year Retrospective Study in Taiwan. Journal of Clinical Medicine, 12(6), 2298. https://doi.org/10.3390/jcm12062298

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop