Patients Diagnosed with Infective Endocarditis: a Retrospective Chart Review

Patients Diagnosed with Infective Endocarditis: A Retrospective Chart Review

Thesis

Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the

Graduate School of The Ohio State University

Chloe A. Wong, DMD

Graduate Program in Dentistry

The Ohio State University

2020

Thesis Committee

Ashok Kumar DDS, MS, Advisor

Paul Casamassimo, DDS, MS

Daniel Claman, DDS

John Kovalchin, MD

William Hunt, MD

Copyrighted by

Chloe A. Wong DMD

2020

Abstract

Purpose: To describe characteristics and associations of risk factors for patients admitted to

Nationwide Children’s Hospital (NCH) for infective endocarditis (IE), and to provide a descriptive overview of IE in a representative U.S. children’s hospital.

Methods: A retrospective chart review of electronic medical records from January 1, 2008 to

January 1, 2020 of patients who met the modified Duke criteria for definite or possible IE. Study variables include demographics, medical and cardiac history, predisposing conditions and risk factors, bacterial isolates, hospital course, treatment, complications, and dental history.

Results: Initial search query found 242 patients. 67 patients met inclusion criteria. 69% had an underlying cardiac condition. S. aureus and viridans streptococcus were most common. Age was significantly associated with presence of intracardiac hardware. The mean length of hospital stay was 25 days and the mortality rate was 9%. 32% patients had a dental consult during admission.

Conclusion: Increased survival of children with significant heart conditions increases the likelihood of them becoming pediatric dental patients. Occurrence of IE in healthy children and the questioning of IE association with dental procedures suggest further research is needed. It is recommended that pediatric dentists are aware of cardiac and non-cardiac factors that place patients at risk for IE, focus on prevention of oral disease, be up to date with guidelines for IE prophylaxis, and have a definitive plan before dental treatment.

Dedication

This document is dedicated to my family, who has supported me throughout my education and my research advisors, Dr. Ashok Kumar and Dr. Paul Casamassimo.

iii

Acknowledgments

I would like to thank my thesis committee for their support and guidance throughout my project, as well as Dr. Jin Peng for helping me with my data analysis.

Vita

June 2009 ...... Freehold Boro High School

May 2013 ...... B.A., Child Development, Community Health, Tufts University

May 2018 ...... D.M.D, Harvard School of Dental Medicine

2018 to present ...... Resident, Division of Pediatric Dentistry

The Ohio State University and Nationwide Children’s Hospital

Fields of Study

Major Field: Dentistry

Table of Contents

Abstract ...... ii Dedication ...... iii Acknowledgments ...... iv Vita ...... v List of Tables ...... vii List of Figures ...... viii Chapter 1. Introduction ...... 1 Chapter 2. Methods ...... 11 Study Design ...... 11 Study Variables ...... 11 Data Analysis ...... 12 Chapter 3. Results ...... 14 Demographics ...... 14 Predisposing Conditions and Risk Factors ...... 17 Diagnosis...... 19 Treatment ...... 20 Outcomes ...... 21 Dental History ...... 22 Chapter 4. Discussion ...... 24 Chapter 5. Conclusion ...... 31 Bibliography ...... 33

List of Tables

Table 1 Summary of Demographics ...... 15

Table 2 Distribution of CHD Lesions ...... 18

Table 3 Symptoms at Time of Admission ...... 19

Table 4 Causative Organisms of IE in Patients with and without Underlying CHD ...... 20

Table 5 Demographics and Cardiac Risk Factors in Prior Studies ...... 26

Table 6 Diagnostic Variables and Outcomes in Prior Studies ...... 27

Table 7 Dental Variables Assessed in Prior Studies ...... 29

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List of Figures

Figure 1 Pathogenesis of Infective Endocarditis ...... 2

Figure 2 Modified Duke Criteria ...... 4

Figure 3 Timeline of Variables ...... 13

Figure 4 Number of IE Cases by Year ...... 14

Figure 5 Gender Distribution ...... 16

Figure 6 Age Distribution ...... 16

Figure 7 Ethnicity Distribution ...... 17

Figure 8 Dental Needs of Patients with Dental Consults (N=21) ...... 23

Figure 9 Dental Treatment Rendered to Patients with Dental Consults (N=21) ...... 23

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Chapter 1. Introduction

Infective endocarditis (IE) is a microbial infection of the endocardial surface of the heart

(Baltimore et al., 2015). The challenges posed by IE are significant. It is heterogeneous in etiology, clinical manifestations, and course. Lack of research infrastructure and funding, with few randomized controlled trials, inhibit a guide to prevention and treatment. Longstanding controversies such as the timing of dental treatment or the role of antibiotic prophylaxis have not been resolved (Cahill et al., 2017).

IE develops via different mechanisms in damaged endothelium. Endothelium can be damaged through multiple mechanisms, which include turbulent flow due to abnormal cardiac structures, direct damage produced by a foreign body, such as an implantable electronic device or prosthetic valve, directly against the endothelial structure or indirect damage when a device interferes with normal blood flow. The damaged endothelium elicits a host response that includes platelet and fibrin deposition which serves as a nidus for bacterial colonization in patients with bacteremia

(Baltimore et al., 2015). Bacteria that enter the bloodstream can be carried to the heart and cause

IE. IE can also be caused by direct infection of indwelling devices, such as prosthetic valves or leads, at time of placement, causing a surgical site infection. In the case of staphylococcal, streptococcal, and enterococcal species, bacterial adhesions then attach to either host cell

1 structures or extracellular molecules that bind to host cells or to extracellular matrix, respectively. These specialized proteins mediate attachment of the bacteria to extracellular host matrix proteins, a process which is facilitated by fibrin and platelet microthrombi (Cahill et al.,

2017). Bacterial adhesion gives rise to colonization, bacterial proliferation, thrombosis, monocyte recruitment, and inflammation, leading to formation of a mature vegetation (Cahill et al., 2017). Many pathogens can also produce biofilm that protects bacteria from host immune defense and impedes antimicrobial efficacy (Figure 1).

Figure 1 Pathogenesis of Infective Endocarditis Note. Reprinted from “Mechanisms of infective endocarditis: pathogen–host interaction and risk states,” by Werdan, K., Dietz, S., Löffler, B. et al. (2014). Nat Rev Cardiol 11, (2014).

The majority of organisms that cause IE in children are gram-positive cocci, including viridans group streptococci (VGS) (e.g. Streptococcus sanguis, Streptococcus mitis, and Streptococcus

2 mutans) Staphylococcus aureus, and Enterococci. Enterococcal endocarditis is relatively less common in children than in adults. Less frequently, other organisms such as the HACEK group of organisms (HACEK indicates Haemophilus species, Aggregatibacter actinomycetemcomitans,

Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) are implicated (Baltimore et al., 2015). After the first year of life, VGS are generally frequently isolated organisms in patients with IE caused by underlying congenital heart disease. S aureus was the second most common cause of IE in children, but is now the most common cause of IE in some series

(Baltimore et al., 2015). IE associated with indwelling vascular catheters, prosthetic material, and prosthetic valves frequently is caused by S. aureus or coagulase-negative staphylococci.

These organisms often are implanted at the time of surgery, and infection manifests within 60 days after cardiac surgery, but coagulase-negative staphylococci infection may present as late as a year or more after surgery. Among newborn infants, S. aureus, coagulase-negative staphylococci, and Candida species are the most common causes of IE (Baltimore et al., 2015).

The presentation of IE is generally non-specific, and may include prolonged low-grade fever, somatic symptoms such as weakness, arthralgias, myalgias, weight loss, rigors (severe chills), and diaphoresis. Occasionally, patients may become acutely ill with rapidly changing symptoms and high fevers. Streptococcus pneumoniae or S. aureus is more likely to be associated with acute, more severe presentations. The modified Duke criteria (Figure 2) can be helpful when diagnosing IE in children. These criteria integrate factors predisposing patients to the development of IE, the blood-culture isolate and persistence of bacteremia, and echocardiographic findings with other clinical and laboratory information.

Major •Positive blood culture for IE Criteria •Typical microorganism consistent with IE from ³2 blood cultures, as noted below •Viridans streptococci, Streptococcus bovis, or HACEK group •-or- •Community-acquired Staphylococcus aureus or enterococci, in the absence of a primary focus •Microorganisms consistent with IE from persistently positive blood cultures, defined as: •³2 positive cultures of blood samples drawn > 12 h apart •-or- •All of 3 or a majority of ³4 blood cultures, irrespective of the timing •1 positive blood culture for Coxiella burnetii or antiphase-I immunoglobulin G antibody titer > 1:800 •Evidence of endocardial involvement •Positive echocardiogram (TEE recommended in prosthetic valves, rated at least possible IE by clinical criteria, or complicated IE; TTE as the first test in other patients) for IE, defined as •Oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation •Abscess •-or- •New partial dehiscence of prosthetic valve •-or- •New valvular regurgitation (worsening or changing of preexisting murmur not sufficient)

Minor •Predisposition: predisposing heart condition or IV drug use •Fever: temperature ≥38.0°C Criteria •Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions •Immunologic phenomena: glomerulonephritis, Osler nodes, Roth’s spots, and rheumatoid factor •Microbiological evidence: positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE

•Pathologic Criteria Definite IE •Microorganisms: demonstrated by culture or histology in a vegetation, a vegetation that has embolized, or an intracardiac abscess •-or- •Pathological lesions: vegetation or intracardiac abscess present, confirmed by histology showing active endocarditis •Clinical Criteria •2 major criteria •-or- •1 major criterion and 3 minor criteria •-or- •5 minor criteria

•1 major criterion and 1 minor criterion Possible IE •-or- •3 minor criteria

Figure 2 Modified Duke Criteria Note. Adapted from “Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the

American Heart Association,” by Baddour, L., Wilson, W., Bayer, A., et al. (2015). Circulation

132, (2015).

In recent years, incidence of IE has increased. Hospital admissions for IE have increased from 11 per 100,000 people in 2000 to about 15 per 100,000 people in 2011, a 2.4% annual increase.

(Baltimore et al., 2015). Among pediatric cases, the estimated incidence of IE is 0.05 to 3.3 cases per 1,000 hospital admissions with an overall mortality rate of about 5% (Gupta et al., 2017).

The risk of death is related to the presence of underlying heart disease; mortality was 48% in patients with Tetralogy of Fallot and pulmonary atresia and 8% in patients who had prosthetic valves (Baltimore et al., 2015). Overall, rates for IE hospitalizations are lower in children compared to adults; however, there is a lack of research on IE trends in children (Sun et al.,

2017). Many studies about factors related to IE focus on adult populations and little information exists in children with congenital heart disease.

IE cases due to congenital heart defects (CHD) have increased because of an increase in known risk factors, advancements in cardiovascular surgery and survival for children with congenital heart disease, and advancements in microbiologic techniques for diagnosis. In the past two decades, CHD has become the predominant underlying condition for IE in children older than two years of age from the developed world. About 35 to 60% of children with IE have congenital heart disease (Cahill et al., 2017). The risk for IE varies among the types of congenital heart disease lesions. Cyanotic CHD lesions, left-sided lesions, and endocardial cushion defects were associated with increased risk of IE acquisition in childhood. The most common CHD group among children with IE were those with cyanotic CHD lesions, present in 34% of cases, followed by atrial septal defect (ASD) (16%) and ventricular septal defect (VSD) (15%) (Liew et al., 2004). Patients with IE and an underlying cyanotic heart disease appeared to be at higher risk 5 for in-hospital mortality than those IE patients with non-cyanotic heart disease (Cahill et al.,

2017). In recent years, the frequency of pediatric cases of IE has shifted towards those with previous cardiac surgery. This is attributed to improved survival among children who are at risk for developing IE (Baltimore et al., 2015). The relative risk of developing IE was substantially elevated during the six-month postoperative period of cardiac surgery and in children younger than three years of age (Gupta et al., 2017). Approximately 50% of children with IE complicating CHD had a previous cardiac surgery, particularly palliative shunt procedures or complex intra-cardiac repairs. Sun et al. (2017) found that invasive procedures, including central venous catheter, cardiac catheterization, open heart surgery, valve surgery, and shunt surgery within six months after the procedures were significantly associated with increased risk of infectious endocarditis in children with CHD (Cahill et al., 2017).

IE can also develop in the absence of CHD, and the concept of healthcare-associated IE in children has become more prevalent. Children with non-cardiac congenital malformations, genetic syndromes, malignancies, and prematurity, and who have been treated by either invasive procedures and/or intravenous medications, have emerged as high-risk groups for developing IE.

The risk for developing IE among these patients is attributed to the indwelling foreign devices, non-cardiac invasive procedures, and possible exposure to intravenous treatment and iatrogenic devices (Rushani et al., 2013).

An estimated 8 to 10% of pediatric cases of IE develop without structural heart disease or any other readily identifiable risk factors. In a pediatric cohort from Arkansas (1992 to 2002), one of

48 children who developed a community-acquired infection had a structurally normal heart and no predisposing factors. In a study published in 2008, five of the 26 pediatric IE cases occurred in healthy children. These reports of IE in otherwise healthy children suggest that the incidence of IE in children with structurally normal hearts and no identifiable predisposing factors may be increasing (Werdan et al., 2014). In these cases, IE usually involves the aortic or mitral valve secondary to S. aureus bacteremia (Gupta et al., 2017). Maron et al. found that IE in children with no known predisposing factors was associated with a community-acquired, left-sided infection caused by community pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, Kingella kingae, and Haemophilus species. Despite rapid eradication of the pathogen from the blood, the infections in these children were associated with a 100% severe complication rate and very high need for acute surgical intervention (Werdan et al., 2014).

The American Heart Association (AHA) recognizes that untreated caries can become a severe threat to children with congenital cardiac disease. Children with CHD are at high risk for developing dental caries and have poorer oral health than healthy children. Da Fonseca et al.

(2009) determined that children with CHD had a reduced oral health-related quality of life. Of those with cardiac lesions, 17% had decay compared to 13% of the control group. 48.8% of the healthy control group saw a dentist every 6 months, compared to 38.1% of those with cardiac lesions (da Fonseca et al., 2009). Children with CHD also have poorer oral hygiene. In a cross- sectional study, Nosrati et al, 2013 found that children with CHD have significantly higher levels of gingivitis, plaque, recession, and calculus than healthy controls.

Antibiotic prophylaxis for IE prior to dental procedures has been recommended for patients with

CHD since 1955. The most recent AHA recommendations for antibiotic prophylaxis prior to invasive dental procedures were released in 2007 and limited prophylaxis to high-risk patients.

These guidelines consider the protective efficacy and the cost-effectiveness of prophylaxis, the relative importance of daily bacteremia versus invasive procedures in causing IE, and the comparison between absolute and relative risk of IE between cardiac conditions. High-risk patients include those with a previous history of IE, cardiac valve replacement, prosthetic valve, and cyanotic congenital heart disease. Invasive dental treatments include procedures that may cause bleeding or introduce transient bacteremia such as dental cleaning, extraction, or surgery.

Antibiotic prophylaxis reduces bacteremia; however, it is not clear if the reduction in bacteremia translates into reduction in incidence of IE (Marom et al., 2013). The association between invasive dental treatments and IE, and the effectiveness of IE antibiotic prophylaxis prior to dental procedures has been controversial. The degree to which systemic antibiotics reduce the incidence, duration, nature, magnitude of bacteremia associated with dental procedures is controversial. Data determining absolute risk of IE after a dental procedure and that prophylactic antibiotic treatment can prevent endocarditis is limited. Chen et al. did not observe an association between invasive dental treatments and a significantly increased risk of IE, and antibiotic prophylaxis did not seem to provide substantial benefit to IE prevention (Werdan et al., 2014).

Sun et al. (2017) found that dental procedures are not significantly associated with IE in children with congenital heart disease regardless of antibiotic prophylaxis (Cahill et al., 2017). In another retrospective study from a national registry of 677 patients by Chirllo et al., only 4.7% of IE

8 cases were attributed to dental procedures. A retrospective analysis of 739 patients in Taiwan found no increased likelihood of exposure to dental procedures in a three-month period before IE hospitalization compared with a control group in which IE did not develop. Data from adult and pediatric studies suggest that most dental office visits result in some degree of risk for bacteremia. Blood cultures can remain positive for bacteria for an hour or more after a dental procedure. The incidence of positive blood cultures drops sharply after the procedure and the period of risk rarely exceeds 30 minutes. Given the variability in outcomes from bacteremia studies and the evidence that dental procedures are at most a rare cause of IE, direction has shifted away from an emphasis on antibiotic prophylaxis and toward a focus on oral hygiene and diseases (Gupta et al., 2017). Cases of IE from oral bacterial pathogens in children most likely result from exposure to relatively frequent, low-grade bacteremia from activities of daily living such as chewing, flossing, or tooth brushing, especially in patients with poor oral hygiene, which allows for bacteria to translocate across the oral mucosa.

The increased survival of children with significant heart conditions and the growing number of children with surgical corrections or devices make the likelihood of them becoming patients in pediatric dental practices more likely. In addition, the occurrence of IE in apparently healthy children and the questioning of the longstanding association of IE with dental procedures suggest further research is needed to better understand the complex interactions of predisposing factors related to IE and dental care. It is important to study IE among the pediatric population in order to understand the significance of the morbidity and mortality associated with the disease, the need for prolonged antibiotic treatment, and the potential complications from embolic and

9 immunological phenomena. The aims of the current study were to describe clinical and laboratory characteristics of IE in children admitted to Nationwide Children’s Hospital and determine associations among the risk factors for developing IE that may shed light on prediction of children at risk. This information would add to understanding of this complex systemic phenomenon and help insure safe dental care for children at risk. This study was conducted to address these gaps in our local knowledge, providing a descriptive overview of IE in a representative U.S. children’s hospital.

Chapter 2. Methods

Study Design

This retrospective study used patient data from Nationwide Children’s Hospital (NCH) electronic medical record database (Epic, Verona, WI). This study was reviewed approved by the

NCH Institutional Review Board, Columbus, OH (IRB ID: STUDY00000318).

Records of patients with IE diagnosed during a hospital admission between January 1, 2010 and

January 1, 2020 at NCH were considered for inclusion. This study included all patients who met the modified Duke criteria for definite or possible IE (Figure 2) during hospital admission. In accordance with previous literature, we defined IE as designated by the International

Classification of Diseases, Ninth Revision and Tenth Revision codes 421.0, 421.1, 421.9, 424.9,

I33, I38, and I39. We excluded those with non-infectious endocarditis, determined by chart review and diagnosis during hospital admission.

Study Variables

The date of hospital admission for IE served as the index date. The demographic details (age, gender, ethnicity), medical and cardiac history, predisposing conditions and risk factors for IE were reviewed. Information collected included presenting signs and symptoms, bacterial isolates,

11 hospital course, treatment, and morbidity and mortality. We also analyzed dental history including recommendation of prophylactic antibiotics related to dental procedures, dental treatment rendered prior to admission, dental consult completed during admission, dental needs determined during admission, and dental treatment rendered during admission (Figure 3).

Congenital heart defects were grouped as follows: lesions likely to be cyanotic at birth (tetralogy of Fallot, univentricular heart, complete transposition complex, truncus arteriosus, hypoplastic left heart syndrome), left-sided conditions (coarctation of the aorta, aortic stenosis/insufficiency, mitral stenosis/ insufficiency), right-sided conditions (Ebstein anomaly, anomalies of the pulmonary artery or pulmonary valve, congenital tricuspid valve disease), atrial septal defect

(ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA) (Rushani et al,

2013). Cardiac surgery included valve, shunt, or other cardiac surgical operations performed before the index date. Bacterial isolates for IE were categorized as oral or non-oral pathogens, as determined by the Human Oral Microbiome Database (Escapa et al., 2018).

Data Analysis

Descriptive statistics were used to analyze the study population. Pearson chi-squared test was used to determine percent differences in cardiac and non-cardiac risk factors by age groups, differences in number and type of complications between patients with and without CHD, differences in mortality between patients with and without CHD, and differences in need for surgical intervention between patients with and without CHD. Two sample T-test was used to

12 analyze the relationship between length of hospitalization and type of CHD, age and need for surgical intervention, mortality and cardiac history, and mortality and age.

•Medical History Pre-Exisiting Conditions •Cardiac History

•Prosthetic Valve Cardiac Pre-Disposing Factors •Intracardiac Device •Central Venous Catheter/ PICC Line (w/in 1 Year Index Date) •Cardiac Surgery •Cardiac Catheterization

•IV Medications Non-Cardiac Pre-Disposing •Immunosuppression Factors •IV Drug Use (w/in 1 Year Index Date) •Indwelling Hardware •Infection

•Antibiotic Prophylaxis Recommended Dental Pre-Disposing Factors •Dental Treatment Completed (Cleaning, Extraction, Nerve Treatment, (w/in 1 Year Index Date) Restoration)

Hospital Admission for IE (Index Date)

•Blood Culture IE Diagnostic Work-Up •Cardiac Vegetation

IE Treatment •Cardiac Surgery (During Admission) •Antibiotics •Dental Consult Dental Treatment •Dental Findings (Cavities, Abscess, Periodontal) (During Admission) •Dental Treatment (Cleaning, Sealant, Nerve Treatment, Extraction, Restoration) •Cardiac Complications •Central Nervous System Complications Complications •Pulmonary Complications (During Admission) •Renal Complications •Other Complications (Osteomyelitis, Ophthomological, Splenic, Sepsis) •Mortality

Complications •Mortality (Post-Discharge)

Figure 3 Timeline of Variables 13

Chapter 3. Results

Demographics

In this study, initial search query yielded 242 charts. Sixty-seven cases of infective endocarditis were diagnosed between January 1, 2008 and January 1, 2020 and met inclusion criteria. The range of IE cases per year was one to 14, with a maximum of 14 cases diagnosed in 2018 (Figure

4).

16 14 14 12 10 8 8 7 7 6 6 Count 6 5 5 4 4 2 2 1 1 1 0

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 Year

Figure 4 Number of IE Cases by Year

The general characteristics of the study population are summarized in Table 1. The majority

(63%) of patients identified as male (Figure 5). The patients ranged in age from 1.2 months to 47 years old (Figure 6). The median age of all patients was 16 years old. Pediatric patients (<18 years old) accounted for 57% of the study population. The median age of patients younger than

18 years old was 11 years. The median age of patients 18 years or older was 23 years.

Characteristics N Percent Age 0-1 2 3% 1-6 9 13% 6-12 9 13% 12-18 18 27% 18+ 29 43% Gender Female 25 37% Male 42 63% Ethnicity Asian 1 1% Bi-Racial 1 1% Black 10 15% Hispanic 2 3% Somali 3 4% White 50 75% Table 1 Summary of Demographics

37% Female

63% Male

Figure 5 Gender Distribution

Self-reported distribution of ethnicity was 75% White, 15% Black or African American, 4%

Somali, 3% Hispanic, 1% Asian, and 1% Bi-Racial (Figure 7).

35 29 30 25 20 18 Count 15 9 9 10 5 2 0 0--1 1--6 6--12 12--18 18+ Age (Years)

Figure 6 Age Distribution

60 50 50 40 30 Count 20 10 10 1 1 2 3 0 Asian Bi-Racial Black Hispanic Somali White Ethnicity

Figure 7 Ethnicity Distribution

Predisposing Conditions and Risk Factors

Two patients were diagnosed with IE as newborns, of whom one had a congenital heart defect.

Eight patients were diagnosed with 22q11.2 deletion syndrome (including DiGeorge syndrome); all eight patients had a congenital heart defect. Ten patients (15%) were previously healthy and did not have any medical or cardiac history. Of these patients, one had a recent facial cellulitis of odontogenic origin, one was recently diagnosed with meningitis, and one recently was tested positive for Streptococcal pharyngitis.

Forty-six (68.6%) the patients had underlying CHD. Of the patients with CHD, the most common defects were cyanotic lesions, present in 50% of patients (Table 2).

CHD Lesions N Percent Cyanotic 23 50% Left-Sided Lesions 18 39% Right-Sided Lesions 17 37% Ventricular Septal Defect 15 33% Atrial Septal Defect 5 11% Patent Ductus Arteriosus 2 4% Table 2 Distribution of CHD Lesions

82.6% of patients with CHD had prior cardiac surgery. 69.6% had a cardiac shunt, stent, or conduit, 65.2% had a prosthetic valve, 13% had an intracardiac device (defibrillator, pacemaker),

17.5% had a cardiac surgery within the previous 12 months, 13% had a cardiac catheterization in within the previous 12 months, 7% had a central catheter in place, and 10.9% had a previous IE diagnosis.

Twenty-one (31%) patients did not have a CHD at time of IE diagnosis. Of these patients, 38.1% were recently diagnosed with a separate infection (bacteremia, meningitis, rat bite fever, rhinovirus, enterovirus, strep throat), 14.3% had IV treatment via peripheral IV line within the previous 12 months, 14.3% had a feeding tube, 9.5% were had a primary immunodeficiency,

9.5% had a central venous catheter, 4.8% had a recent history of IV drug use, 4.8% were recently diagnosed with a fracture, and 4.8% had a ventriculoatrial shunt. The relationship between age and presence of cardiac hardware (prosthetic valve, shunt, stent, conduit, graft) was statistically significant (p=0.02); such that the older the patient, the higher likelihood for the patient to have cardiac hardware.

Diagnosis

Fever (93%) was the most common symptom at time of admission. Other significant symptoms included vomiting/ nausea/ diarrhea (48%), and cough/ respiratory distress (45%) (Table3).

Symptom N Percent Fever 62 93% Rigor 28 42% Vomiting/ Nausea/ Diarrhea 32 48% New Murmur 6 9% Cough/ Respiratory Distress 30 45% Tachycardia 15 22% Fatigue/ Lethargy 24 36% Headache 18 27% Joint Pain 7 10% Myalgia 10 15% Altered Mental Status 7 10% Swelling 8 12% Table 3 Symptoms at Time of Admission

Blood cultures were positive in 58 (87%) patients. 31% of cases were associated with an organism commonly found in the oral cavity. Overall, S. aureus was the most common organism identified, making up 38.8% of total cases. Viridans streptococci made up 25.4% of the total cases (Table 4). Of the patients who were previously healthy (no cardiac or medical history), none were infected with viridians streptococci and 40% were infected with S. aureus.

Total Organism N CHD (N) No CHD (N) Percent Viridans streptococci 19.40% 13 11 2 Streptococcus mitis 4.48% 3 2 1 Streptococcus gordonii 1.49% 1 1 0 Haemophilus influenzae 1.49% 1 0 1 Aggregatibacter actinomycetemcomitans 1.49% 1 0 1 Cardiobacterium hominis 1.49% 1 1 0

HACEK Eikenella corrodens 1.49% 1 0 1 Kingella kingae 1.49% 1 0 1 Staphylococcus epidermidis 8.96% 6 5 1 Staphylococcus aureus 38.81% 26 17 9 Staphylococcus capitis 1.49% 1 1 0 Staphylococcus lugdunensis 1.49% 1 1 0 Streptococcus pneumoniae 4.48% 3 1 2 Streptococcus pseudopneumoniae 1.49% 1 0 1 Streptobacillus moniliformis 1.49% 1 0 1 Gemella morbillorum 2.9% 2 0 2 Corynebacterium pseudodiphtheriticum 1.49% 1 1 0 Escherichia coli 1.49% 1 0 1 Enterobacter cloacae 1.49% 1 1 0 Bartonella 2.99% 2 2 0 Table 4 Causative Organisms of IE in Patients with and without Underlying CHD

Vegetations were detected in 78% of all patients. 51% of vegetations were found on a native valve, 38.5% were found on a prosthetic valve, 7.7% on a conduit, 3.9% in the left atrium, 2% on a pacemaker, 1.9% in the right atrium, and 1.9% on an implantable cardioverter defibrillator.

Treatment

Sixty-one percent of patients were treated with surgical intervention during hospital admission.

All patients were treated with antibiotic therapy. The relationship between type of CHD and the need for surgical intervention was not statistically significant. Patient age at time of admission 20 was not significantly different between patients who required surgical intervention and patients who did not require surgical intervention (p= 0.38).

Outcomes

The mean length of hospitalization was 25 days; the median length of hospitalization was 14 days. Length of hospitalization was statistically different between patients with cyanotic lesions and patients without cyanotic lesions (p= 0.02); patients with cyanotic lesions on average had a shorter length of hospitalization (16 days vs. 30 days). Length of hospitalization was also statistically different between patients with right-sided lesions and patients without right-sided lesions (p= 0.002); patients with right-sided lesions on average had a shorter length of hospitalization (12 days vs. 29 days).

Cardiac complications were the most common (55%) and included heart failure or arrest, valvular insufficiency, embolic phenomena, myocardial abscess, and heart block. Central nervous system (CNS) complications (22.4%) included CNS emboli, infarct, seizures and hemiparesis. Pulmonary complications (23.9%) included emboli and abscesses. Renal complications (28.4%) including glomerulonephritis, osteomyelitis (6.0%), ophthalmologic complications (6.0%), splenic infarcts (3.0%), and sepsis were also experienced (4.5%). The total number of complications was not statistically different between patients with CHD and patients without CHD (p= 0.11). The relationship between age at admission and total number of complications was statistically significant (p= 0.04); the mean age of patients with no

21 complications was 20 years and the mean age of patients with three complications was 11 years.

The type of organism associated with IE was not associated with number of complications.

The mortality rate during admission was 9%, and 3% after discharge. Eight patients died due to complications related to IE; six of whom died during their hospital admission and two of whom were previously healthy. 75% of these were positive for S. aureus. The relationship between mortality and cardiac history was not statistically significant (p= 0.73). Mean age was not statistically significant between patients who died and patients who did not die (p= 0.55).

Dental History

54% (n=36) of patients were previously recommended to take antibiotic prophylaxis for dental procedures. Data regarding self-reported compliance was not readily available. Twenty-two percent (n=15) of patients self-reported having dental treatment within one-year prior to admission. 31% (n=21) of the patients did not have any recent dental information available in their chart.

Dental consults were completed on 32% (n=21) of patients age one and older during their admission. Of those with a completed dental consult, 47.6% (n=10) were diagnosed with caries,

23.8% (n=5) had a dental abscess, and 28.6% (n=6) had periodontal issues (Figure 8). 38% (n=8) of these patients had dental treatment completed during admission. Treatment included dental cleaning (15.8%), sealants (26.3%), nerve treatment (5.3%), extractions (21.1%), and restorations (21.1%) (Figure 9).

23.80% 28.60%

Periodontal Issues Caries Abscess

47.60% Figure 8 Dental Needs of Patients with Dental Consults (N=21)

15.80%

Cleaning 26.30% 61.90% Sealant Nerve treatment Extraction 5.26% Restoration No treatment 21.10% 21.10%

Figure 9 Dental Treatment Rendered to Patients with Dental Consults (N=21)

Chapter 4. Discussion

In this study, 67 patients were diagnosed with IE. The increase of IE cases in 2018 in this study warrants additional study. Day et al.(2009) had previously described a bi-modal age distribution of IE cases with peaks in infancy and later teens. In the study conducted by Gupta et al. (2016), the majority of IE cases were in children 11 years and older (56.2%). In our study, the median age of pediatric patients was 11 years. 27% of patients were between the ages of 12 and 18, and

43% of patients were older than 18. A summary of similar studies is presented in Table 5. Of note, our study population included had the widest age range and has a greater percent of patients with a history of cardiac surgery.

IE can also develop in the absence of CHD. In our study, 31% of patients did not have underlying cardiac conditions and 15% of patient did not have any previous cardiac or medical diagnosis. 8 patients had 22q.11 deletion syndrome. Gupta et al. (2016) previously reported 46% of children without underlying cardiac conditions and Day et al. (2009) reported 58%. This could possibly represent undiagnosed or missed cardiac conditions in children with IE during late childhood. Healthcare-associated IE in children has become more prevalent. Children who have been treated by either invasive procedures and/or intravenous medications are high-risk groups for developing IE. This is important for health-care providers to recognize and effectively screen

24 patients who may be high-risk for developing IE. More in-depth studies are needed to understand the non-cardiac risk factors

68.6% of patients had underlying CHD and 82.6% of patients with CHD had prior cardiac surgery. Previous pediatric studies have found that individuals with cyanotic CHD, left-sided lesions, and VSD have an increased risk for developing IE (Rushani et al., 2013, Sun et al.,

2017). In this study, cyanotic lesions (including tetralogy of Fallot) were most common, followed by left-sided lesions. Other studies have noted that cardiac surgery may increase risk of

IE (Table 5), presumably related to prolonging life and the period over which children can develop IE. Previous studies showed that the increased IE risk after cardiac surgery and catheter- related cardiac interventions is linked to implantation of prosthetic material or cardiovascular devices (Sun et al., 2017). Microorganisms introduced through medical procedures or routine daily activities may be more likely to attach to the site of repair during cardiac surgery and cardiac surgery itself may also introduce bacteremia (Rushani et al., 2013).

Hx of Date Total Age Median % Author Database CHD Cardiac Range (N) Range Age Male Surgery Martin Children’s Hospital 1958- 73 1 mo – 9 yrs 63% 85% 77% et al. of Pittsburgh 1992 18 yrs

Coward Arkansas 1990- 57 1 mo – 4 yrs 54% 81% 56% et al. Children’s Hospital 2002 28 yrs

Rushani Quebec, Canada 1988- 185 0-18 yrs 3.5 yrs 52% n/a n/a et al. 2010

Liew at KK Women’s and 1997- 27 0-17 yrs 8 yrs 50% 89% n/a al. Children’s 2004 Hospital, Singapore Sun et National Health 1997- 237 0-3 yrs 1.2 yrs 54% 100% 19% al. Research Institutes 2010 of Taiwan Day et Kids’ Inpatient 2000- 1588 0-21 yrs 12 yrs 50% 42% n/a al. Databases 2003

Gupta Nationwide 2000- 3840 0-19 yrs n/a 54% 81% n/a et al. Inpatient Sample 2010

Table 5 Demographics and Cardiac Risk Factors in Prior Studies

Day et al.(2009) found that Staphylococci or Streptococci were the predominant IE pathogens

identified in more than 90% of their culture-positive cases (Table 6). The majority of cases in the

study by Gupta et al. (2016) were caused by Staphylococcus species (43.1% hospitalizations)

followed by Streptococcus species (39.5%). Our study confirmed these results, with 38.8% of

total case causes by S. aureus and 25.4% of cases caused by Viridans streptococci. This is likely

a reflection of changing landscape for developing IE, with more children having a hospitalization

due non-cardiac risk factors. 61% of patients in this study had surgical intervention during

hospitalization, which is greater than other studies (Table 5). S. aureus is associated with acute

26 and more severe presentation of IE, and hence may require surgical intervention. Nationwide

Children’s Hospital is also a nationally recognized hospital with a dedicated heart center that may attract high-risk patients with more severe cases of IE.

The in-hospital mortality rate in our study was 9%. Six patients who died had CHD. 67% of these patients with CHD had an underlying cyanotic lesion. IE patients with cyanotic heart disease appears to have increased risk for inpatient mortality, as concluded by Sun et al. (2017).

Positive 2nd Most Most Common Surgical Author Vegetation Blood Common Deaths Organism Intervention Culture Organism Martin 25% 92% Viridans Staphylococcus 20% 18% et al. streptococci (38%) aureus (32%)

Coward 67% 91% Streptococci (30%) Staphylococcus 30% 12% et al. aureus (21%)

Rushani n/a n/a n/a n/a n/a n/a et al.

Liew et 56% 78% Viridans Staphylococcus n/a 7% al. streptococci (26%) aureus (19%)

Sun et n/a n/a n/a n/a n/a 5% al.

Day et n/a n/a Staphylococcus Viridans 34% 5% al. aureus (38%) streptococci (28%) Gupta n/a n/a Staphylococcus Viridans n/a 2.8% et al. aureus (37%) streptococci (26%) Table 6 Diagnostic Variables and Outcomes in Prior Studies

We intended for our study to include a more in-depth exploration of oral health risk factors but were limited by the nature of the data available. In previous studies, dental procedures were not significantly associated with IE in children with CHD regardless of antibiotic prophylaxis (Sun et al., 2017) (Table 7). In our study, 22% patients self-reported having dental treatment within one-year prior to admission . In comparison, 5% of patients in Sun et al. (2017) had dental procedures within six months preceding the onset of IE. The data in our studies relied on self- report and spanned a larger time frame, which may account for the increased percentage.

Previous studies have also concluded that dental procedures did not significantly contribute to the risk of IE. This was explained by the causative spectrum shifting from streptococci to S. aureus (Sun et al., 2017). In our study, S. aureus was the most common organism identified, making up 38.8% of total cases. Viridans streptococci made up 25.4% of the total cases. This trend is likely to reflect in changing risk factors for IE, with more children having a hospitalization with medical issues predisposing to IE.

Children also have a lower prevalence and severity of gingivitis and periodontitis than adults. In our study, 31% of all subjects did not have any recent oral health information available in chart and only 32% of patients age one and older had a dental consult during their admission and hence we have limited data about the oral health of our study population. There is a dearth of research assessing the relationship between risk of IE and dental health, procedures, and antibiotic prophylaxis. Children with CHD require special care in dentistry because of their susceptibility to infective endocarditis from dental and periodontal infections. Dental history, in the form of self-report, dental records, or dental consult (if available), should be a routine part of

28 the diagnostic work-up for patients with IE in order to assess the dental as a risk factor for developing IE. Since poor oral health could be a source of recurrent bacteremia, information about dental health should be a routine part of medical care for patients who are at high risk for developing IE.

Overall, there was a lack of comprehensive oral health history and information about antibiotic prophylaxis compliance in patient charts. Having oral health data and dental history in a patient's medical chart may helpful for future studies evaluating dental variables as risk factors for IE.

Although the relationship between oral health and IE is controversial and variable, the benefits of good oral health practices to reduce potential risk factors, outweighs the risks of potential consequences of infective endocarditis. Importantly, oral disease and the necessity for invasive dental procedures and antibiotic prophylaxis can be avoided with oral health education and prevention. Thus, medical and dental integration is recommended especially for children with complex medical conditions. This allows at-risk children to establish good oral health behaviors from a young age and address oral health needs with primary and even secondary care rather than tertiary interventions

Dental Procedure Presence of Caries Author Prior to Admission during Admission Martin et al. 11% 10% Sun et al. 5% n/a

Table 7 Dental Variables Assessed in Prior Studies

Our study has a few limitations. We used ICD-9-CM and ICD-10-CM codes for identification of patients with infective endocarditis. Diagnosis was determined by a comprehensive evaluation of all CHD-related data, including codes, surgical codes, and manual review of samples of the data. Misclassification and variations in coding practices could have added bias. Because of the low incidence of IE in children, a large number of patients per cohort is required to obtain statistical clinical significance when analyzing the risk factors for IE. We were unable to follow a large enough cohort to adequately assess clinical significance of risk factors. Another limitation is the lack of a control cohort. Risk factors examined in this study were limited by the nature of the data available in the chart. Overall, there was a lack of data regarding dental history, antibiotic compliance and we did not have access to medical and dental information that was not recorded in our EMR.

Chapter 5. Conclusion

Our study was a preliminary study that described clinical and laboratory characteristics of IE in children admitted to a representative U.S. children’s hospital. 68.6% of patients had underlying

CHD. 31% of patients did not have underlying cardiac conditions and 15% of patient did not have any previous cardiac or medical diagnosis. S. aureus was the most common causative organism in pediatric IE cases. It is important to research and understand the significance of the morbidity and mortality associated IE, the need for prolonged antibiotic treatment, and the potential complications. More in-depth research is needed on specific dental and non-dental risk factors for developing IE. This includes additional research of specific cardiac diagnosis and type of CHD lesion, types of prosthetic valves and cardiac hardware, type of cardiac procedure prior to development of IE, causative organism and antibiotic course, and how risk factors influence morbidity and mortality. We recommend improving the study by comparing patients who develop IE with controls who did not, and to evaluate the trends in incidence IE as they relate to guidelines for antibiotic prophylaxis and hospital-specific protocols.

Increased survival of children with significant heart conditions and surgical corrections increases the likelihood of them becoming pediatric dental patients. Occurrence of IE in healthy children

31 and the questioning of IE association with dental procedures suggest further research is needed to better understand the interactions of predisposing factors related to IE and dental care. More research is needed to evaluate the dental health and dental care utilization of patients with IE, and the focus on dental health by other medical specialties.

We recommend that pediatric dentists:

• Are aware of cardiac and non-cardiac factors that place patients at risk for IE

• Understand the histopathology of IE and high-risk cardiac conditions

• Stay current with AHA guidelines for IE prophylaxis and proper antibiotics dosing

• Have a definitive consult from a cardiologist before dental treatment

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