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Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation. 2007;115:3173 80. 201. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive air- way pressure for central sleep apnea and heart failure. N Engl J Med. 2005;353:2025 33. 202. MacDonald M, Fang J, Pittman SD, et al. The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta-blockers. J Clin Sleep Med. 2008;4:38 42. 203. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure. N Engl J Med. 2015;373:1095 105. 204. McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovas- cular events in obstructive sleep apnea. N Engl J Med. 2016;375:919 31. 205. Holmqvist F, Guan N, Zhu Z, et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in pa- tients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J. 2015;169:647 54. Yancy et al Appendix 1.


Am Heart J. 2015;169:647 54. Yancy et al Appendix 1. Author Relationships With Industry and Other Entities (Relevant) 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (December 2015) Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Clyde W. Yancy, Chair Northwestern University Feinberg School of Medicine, Division of Cardiology Professor of Medicine and Chief; Diversity and Inclusion Vice Dean None None None None None None None Mariell Jessup, Vice Chair Fondation Leducq Chief Scientific Officer None None None None None None None Biykem Bozkurt Baylor College of Medicine, Department of Medicine Professor of Medicine; Cardiology Section, DeBakey VA Medical Center Chief; The Mary and Gordon Cain Chair & W.A. Tex and Deborah Moncrief, Jr. Chair; Winters Center for Heart Failure Research Director; Cardiovascular Research Institute Associate Director None None None Novartis None None 7.3.2.10, 9.5. Javed Butler Stony Brook University Division Chief of Cardiology Bayer Boehringer Ingelheim CardioCell Luitpold Medtronic Merck Novartis Relypsa Takeda Trevena Z Pharma Zensun Novartis None Amgen (DSMB) None None 7.3.2.10, 9.5. Donald E. Casey, Jr Thomas Jefferson College of Population Health Faculty; Alvarez & Marsal Founder None None None None None None None Monica M. Colvin University of Michigan Associate Professor of Medicine, Cardiology None None None None None None None Mark H. Drazner University of Texas Southwestern Medical Center Professor, Internal Medicine None None None None None None None Gerasimos S. Filippatos National and Kapodistrian University of Athens; Attikon University Hospital, Department of Cardiology, Heart Failure Unit Professor of Cardiology None None None Bayer Bayer (DSMB) Novartis Servier Pharmaceuticals Vifor None None 7.3.2.10, and 9.5.


Donald E. Casey, Jr Thomas Jefferson College of Population Health Faculty; Alvarez & Marsal Founder None None None None None None None Monica M. Colvin University of Michigan Associate Professor of Medicine, Cardiology None None None None None None None Mark H. Drazner University of Texas Southwestern Medical Center Professor, Internal Medicine None None None None None None None Gerasimos S. Filippatos National and Kapodistrian University of Athens; Attikon University Hospital, Department of Cardiology, Heart Failure Unit Professor of Cardiology None None None Bayer Bayer (DSMB) Novartis Servier Pharmaceuticals Vifor None None 7.3.2.10, and 9.5. Gregg C. Fonarow Ahmanson-UCLA Cardiomyopathy Center Director; UCLA Division of Cardiology Co-Chief Amgen Janssen Pharmaceuticals Novartis None None Novartis None None 7.3.2.10, 9.5. (Continued) 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES Michael M. Givertz Brigham and Women's Hospital Professor of Medicine Merck Novartis None None None None None 7.3.2.10, 9.5. Steven M. Hollenberg Cooper University Hospital Director, Coronary Care Unit, Professor of Medicine None None None None None None None JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute Director, Advanced Heart Failure and Transplant Section Professor of Medicine Abbott Janssen Pharmaceuticals Novartis Relypsa ResMed None None AstraZeneca Novartis None None 6.3, and 9.6.


Steven M. Hollenberg Cooper University Hospital Director, Coronary Care Unit, Professor of Medicine None None None None None None None JoAnn Lindenfeld Vanderbilt Heart and Vascular Institute Director, Advanced Heart Failure and Transplant Section Professor of Medicine Abbott Janssen Pharmaceuticals Novartis Relypsa ResMed None None AstraZeneca Novartis None None 6.3, and 9.6. Frederick A. Masoudi University of Colorado, Anschutz Medical Campus Professor of Medicine, Division of Cardiology None None None None None None None Patrick E. McBride University of Wisconsin School of Medicine and Public Health Professor of Medicine and Family Medicine; Associate Director, Preventive Cardiology None None None None None None None Pamela N. Peterson University of Colorado, Denver Health Medical Center Associate Professor of Medicine, Division of Cardiology None None None None None None None Lynne Warner Stevenson Brigham and Women s Hospital Cardiovascular Division Director, Cardiomyopathy and Heart Failure Program None None None Novartis PARENT trial (PI) NHLBI INTERMACS (Co PI) None None 7.3.2.10, 9.5. Cheryl Westlake Azusa Pacific University, School of Nursing, Doctoral Programs Professor None None None None None None None This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year.


A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; or b) the company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in the document, or makes a competing drug or device addressed in the document; or c) the person or a member of the person s household has a reasonable potential for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document. *Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may apply. Significant relationship. ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HFSA, Heart Failure Society of America; NHLBI, National Heart, Lung, and Blood Institute; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; PARENT, Pulmonary artery pressure reduction with entresto; UCLA, University of California, Los Angeles; and VA, Veterans Affairs. Appendix 1.


ACC indicates American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HFSA, Heart Failure Society of America; NHLBI, National Heart, Lung, and Blood Institute; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; PARENT, Pulmonary artery pressure reduction with entresto; UCLA, University of California, Los Angeles; and VA, Veterans Affairs. Appendix 1. Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Yancy et al Appendix 2.


Continued Committee Member Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Voting Recusals By Section* Yancy et al Appendix 2. Reviewer Relationships With Industry and Other Entities (Comprehensive) 2017 ACC/AHA/ HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure (October 2016) Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Kim K. Birtcher Official Reviewer ACC/AHA Task Force on Clinical Practice Guidelines University of Houston College of Pharmacy Clinical Professor Jones & Bartlett Learning None None None None None Akshay S. Desai Official Reviewer HFSA Brigham and Women s Hospital Director, Heart Failure Disease Management, Advanced Heart Disease Section, Cardiovascular Division; Associate Professor of Medicine, Harvard Medical School Medscape Cardiology* Merck Novartis* Relypsa* St. Jude Medical* None None None Novartis* Thoratec None Anita Deswal Official Reviewer AHA Michael E. DeBakey VA Medical Center Chief of Cardiology; Director, Heart Failure Program; Baylor College of Medicine Professor of Medicine None None None NIH* AHA AHA (GWTG Steering Committee) HFSA None Dipti Itchhaporia Official Reviewer ACC Board of Trustees Newport Coast Cardiology Robert and Georgia Roth Endowed Chair for Excellence in Cardiac Care; Director of Disease Management None None None None St. Jude Medical None Ileana L. Pi a Official Reviewer AHA Montefiore Medical Center Associate Chief for Academic Affairs, Cardiology; Professor of Medicine & Epidemiology and Population Health Albert Einstein College of Medicine Relypsa None None None None None Geetha Raghuveer Official Reviewer ACC Board of Governors University of Missouri- Kansas City School of Medicine Professor of Pediatrics; Children's Mercy Hospital Pediatric Cardiology None None None None None None James E. Udelson Official Reviewer HFSA Tufts Medical Center Chief, Division of Cardiology Lantheus Medical Imaging None None Gilead (DSMB) GlaxoSmithKline (DSMB) NHLBI Otsuka Abbott Laboratories AHA* Circulation/ Circulation: Heart Failure HFSA (Executive Council) Pfizer/ GlaxoSmithKline Sunshine Heart None Mary Norine Walsh Official Reviewer ACC Board of Trustees St Vincent Heart Center of Indiana Medical Director, Heart Failure and Cardiac Transplantation None None None None Corvia Medical Otsuka PCORI Thoratec None (Continued) 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES David A. Baran Organizational Reviewer ISHLT Newark Beth Israel Medical Center Director of Heart Failure and Transplant Research Maquet Otsuka* Novartis None XDx* NIH* None None Kenneth Casey Organizational Reviewer CHEST Wm.


S. Middleton Memorial Veterans Hospital Director, Sleep Medicine None None None None CHEST None M. Fuad Jan Organizational Reviewer CHEST Aurora Advanced Healthcare Cardiologist None None None None None None Kenneth W. Lin Organizational Reviewer AAFP Georgetown University School of Medicine Clinician Educator Track, Associate Professor None None None None None None Joaquin E. Cigarroa Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Oregon Health & Science University Clinical Professor of Medicine None None None None ACC/AHA AHA ASA Catheterization and Cardiovascular Intervention NIH Portland Metro Area AHA (President) SCAI Quality Interventional Council None Lee A. Fleisher Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines University of Pennsylvania Health System Robert Dunning Dripps Professor of Anesthesiology and Critical Care; Chair, Department of Anesthesiology & Critical Care Blue Cross/Blue Shield* NQF Yale University None None Johns Hopkins (DSMB) Association of University Anesthesiologists NIH None Samuel S. Gidding Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Nemours/Alfred I. duPont Hospital for Children Chief, Division of Pediatric Cardiology FH Foundation International FH Foundation None None FH Foundation NIH* None None James L. Januzzi Content Reviewer Massachusetts General Hospital Hutter Family Professor of Medicine in the Field of Cardiology Critical Diagnostics* Novartis* Phillips Roche Diagnostics* Sphingotec* None None Amgen (DSMB) Boeringer Ingelheim (DSMB)* Janssen Pharmaceuticals (DSMB) Prevencio* None None Jos A. Joglar Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines UT Southwestern Medical Center Professor of Internal Medicine; Clinical Cardiac Electrophysiology Program Director None None None None None None Edward K. Kasper Content Reviewer Johns Hopkins Cardiology E. Cowles Andrus Professor in Cardiology None None None None None None (Continued) Appendix 2.


Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness Yancy et al Wayne C. Levy Content Reviewer University of Washington Professor of Medicine Abbott Laboratories Biotronik GE Healthcare HeartWare PharminIN None None NIH Novartis* St. Jude Medical* Amgen* AHA HeartWare* Novartis* Resmed* Thoratec None Judith E. Mitchell Content Reviewer SUNY Downstate Medical Center Director/Heart Failure Center; SUNY Downstate College of Medicine Associate Professor of Medicine None None None None Association of Black Cardiologists None Sean P. Pinney Content Reviewer ACC Heart Failure and Transplant Council Mount Sinai School of Medicine Associate Professor of Medicine, Cardiology Acorda Therapeutics Thoratec XDx None None Thoratec NIH None None Randall C. Starling Content Reviewer ACC Heart Failure and Transplant Council Cleveland Clinic Department of Cardiovascular Medicine Vice Chairman, Department of Cardiovascular Medicine; Section Head,Heart Failure & Cardiac Transplant BioControl Medtronic Novartis None None Medtronic NIH* Novartis St. Jude Medical St. Jude Medical None W.H.


Wilson Tang Content Reviewer Cleveland Clinic Foundation Assistant Professor of Medicine None None None NIH* Alnylam Pharmaceuticals NIH NHLBI Roche Novartis Thoratec None Emily J. Tsai Content Reviewer Columbia University College of Physicians & Surgeons Assistant Professor of Medicine, Division of Cardiology None None None Bayer Bristol-Myers Squib NHLBI* None None Duminda N. Wijeysundera Content Reviewer ACC/AHA Task Force on Clinical Practice Guidelines Li Ka Shing Knowledge Institute of St. Michael s Hospital Scientist; University of Toronto Assistant Professor, Department of Anesthesia and Institute of Health Policy Management and Evaluation None None None CIHR (DSMB) CIHR* Heart and Stroke Foundation of Canada* Ministry of Health & Long- term Care of Ontario* PCORI DSMB) None None This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review, including those not deemed to be relevant to this document. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of 5% of the voting stock or share of the business entity, or ownership of $5000 of the fair market value of the business entity, or if funds received by the person from the business entity exceed 5% of the person s gross income for the previous year. A relationship is considered to be modest if it is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review. American College of Physicians did not provide a peer reviewer for this document. *Significant relationship. No financial benefit.


American College of Physicians did not provide a peer reviewer for this document. *Significant relationship. No financial benefit. AAFP indicates American Academy of Family Physicians; ACC, American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; ASA, American Stroke Association; CHEST, American College of Chest Physicians; CIHR, Canadian Institutes of Health Research; DSMB, data safety monitoring board; FH, familial hypercholesterolemia; GWTG, Get With The Guidelines; HFSA, Heart Failure Society of America; ISHLT, International Society for Heart and Lung Transplantation; NIH, National Institutes of Health; NHLBI, National Heart, Lung, and Blood Institute; NQF, National Quality Forum; PCORI, Patient-Centered Outcomes Research Institute; SCAI, Society for Cardiac Angiography and Interventions; SUNY, State University of New York; UT, University of Texas; and VA, Veterans Affairs. Appendix 2. Continued Reviewer Representation Employment Consultant Speakers Bureau Ownership/ Partnership/ Principal Personal Research Institutional, Organizational, or Other Financial Benefit Expert Witness 2017 ACC/AHA/HFSA Heart Failure Focused Update CLINICAL STATEMENTS AND GUIDELINES Appendix 3. Abbreviations ACE = angiotensin-converting enzyme ARB = angiotensin-receptor blocker ARNI = angiotensin receptor neprilysin inhibitor BNP = B-type natriuretic peptide BP = blood pressure COR = Class of Recommendation CPAP = continuous positive airway pressure EF = ejection fraction GDMT = guideline-directed management and therapy HFpEF = heart failure with preserved ejection fraction HFrEF = heart failure with reduced ejection fraction LOE = Level of Evidence LVEF = left ventricular ejection fraction NT-proBNP = N-terminal pro-B-type natriuretic peptide QoL = quality of life RCT = randomized controlled trial


AHA Scientific Statement In 2002, the American Heart Association (AHA) published Unique Features of Infective Endocarditis in Childhood, 1 which reviewed epidemiology, pathogenesis, diagnosis, clinical and laboratory findings, treatment, and prevention of infective endocarditis (IE) with particular attention to children. Since that time, otherAHA reports have focused on new recommendations for treatment of IE in adults (in 20052 ) and on major changes regarding prevention of IE (in 20073 ). This document updates these issues and other concerns regarding IE, with specific atten- tion to the disease as it affects infants and children. In particular, theimpactofincreasedsurvivalforchildrenwithcongenitalheart disease (CHD) on the epidemiology of IE is updated, and newer tools useful for diagnosis and treatment in the pediatric popula- tion are reviewed. This review emphasizes changing manage- ment perspectives and discussion of new agents that have utility for treatment of resistant organisms. In addition, proper use of the diagnostic microbiology laboratory remains critical to the diagnosis and management of children with IE, and newer diag- nostic guidelines that have improved sensitivity and specificity for confirming the diagnosis of IE will be reviewed. Because of improved infrastructure available for home intravenous therapy, an update on outpatient management, an increasingly accepted approach for stable patients who are at low risk for complica- tions, will also be discussed. Finally, since the publication of the last AHA document on pediatric IE, recommendations for prevention of IE have been modified substantially, and the most current recommendations are incorporated from the perspective of pediatric cardiovascular concerns. Classification of Recommendations In pediatrics, there are not likely to be any randomized con- trolled trials for treatment of IE, which posed a challenge for the writing group in compiling recommendations. Therefore, many of the indications are based on consensus.


Classification of Recommendations In pediatrics, there are not likely to be any randomized con- trolled trials for treatment of IE, which posed a challenge for the writing group in compiling recommendations. Therefore, many of the indications are based on consensus. In cases of strong consensus that an intervention be considered as standard-of- care practice with scientific evidence, interventions were des- ignated as Class I indications. Where the wording of treatments indicates a recommendation, the standard classification is used. Strength of the recommendation is according to the ACC/AHA classification system for recommendations (Table 1). Epidemiology and Clinical Findings of IE in Children In a previous report, IE occurred less often in children than in adults and accounted for approximately 1 in 1280 (0.78 per 1000) pediatric admissions per year from 1972 to 1982 at a In a recent multicenter report,5 the annual incidence rate in the United States was between approximately 0.05 and 0.12 cases per 1000 pediatric admissions from 2003 to 2010, without a significant trend. Although the reported hos- pitalization rates for IE vary considerably among published series, both the overall frequency of endocarditis among chil- dren and a shift toward those with previous cardiac surgery appear to have increased in recent years in some reports.5 8 This may be related to improved survival among children who are at risk for endocarditis, such as those with CHD (with or without surgery) and hospitalized newborn infants. 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000298 TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.


Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000298 TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on May 4, 2015, and the American Heart Association Executive Committee on June 12, 2015. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Baltimore RS, Gewitz M, Baddour LM, Beerman LB, Jackson MA, Lockhart PB, Pahl E, Schutze GE, Shulman ST, Willoughby R Jr; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular and Stroke Nursing. Infective endocarditis in childhood: 2015 update: a scientific statement from the American Heart Association. Circulation. 2015;132:1487 1515. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page.


A link to the Copyright Permissions Request Form appears on the right side of the page. Infective Endocarditis in Childhood: 2015 Update A Scientific Statement From the American Heart Association Robert S. Baltimore, MD, Chair; Michael Gewitz, MD, FAHA, Vice Chair; Larry M. Baddour, MD, FAHA; Lee B. Beerman, MD; Mary Anne Jackson, MD; Peter B. Lockhart, DDS; Elfriede Pahl, MD, FAHA; Gordon E. Schutze, MD; Stanford T. Shulman, MD; Rodney Willoughby, Jr, MD; on behalf of the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young and the Council on Cardiovascular and Stroke Nursing Before the 1970s, 30% to 50% of US children with IE had underlying rheumatic heart disease.9 Because the prevalence of rheumatic heart disease has declined in developed coun- tries, including the United States, it has now become relatively unusual for patients with IE from the developed world to have underlying rheumatic heart disease. In the past 2 decades, CHD has become the predominant underlying condition for IE in children from the developed world >2 years of age. In fact, there has been an increase in cases of IE associated with CHD because most patients with CHD survive much longer than they did several decades ago. Early surgical correction of lesions that were major risk factors for IE in the past has also changed the substrate for this disease.


Early surgical correction of lesions that were major risk factors for IE in the past has also changed the substrate for this disease. Although congenital heart defects, such as aortic valve abnormalities, ventricular septal defect, and tetralogy of Fallot, are still common under- lying conditions, an increasing proportion of children with IE have had previous corrective or palliative surgery for complex cyanotic CHD, with or without implanted vascular grafts, patches, or prosthetic cardiac valves.10 14 Postoperative IE is a long-term risk after correction of complex CHD, especially in those with residual defects or in cases in which a surgical shunt is constructed or other prosthetic material is left in place. Increasingly, IE develops in the absence of CHD. This cir- cumstance is often associated with central indwelling venous catheters (central lines). The complexities of patient man- agement in neonatal and pediatric intensive care units have Table 1. Applying Classification of Recommendations and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1489 increased the risk of IE in children with structurally normal hearts.


Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1489 increased the risk of IE in children with structurally normal hearts. Currently, in approximately 8% to 10% of pediatric IE develops without structural heart disease or any other readily identifiable risk factors. In these situations, the infection usually involves the aortic or mitral valve second- ary to Staphylococcus aureus bacteremia.6,10 12 Recent initia- tives developed to reduce central line bloodstream infections will likely improve the prognosis for all critically ill children, including those with cardiac conditions, and may impact IE development further in the diverse group of vulnerable patients with central lines. Interestingly, children with congenital or acquired immunodeficiencies but without identifiable risk factors for IE do not appear to be at increased risk for endo- carditis compared with the general population. Furthermore, factors often associated with IE in adults, such as intravenous drug abuse and degenerative heart disease, are not common predisposing factors in children.7 11 IE in Children With Previous Cardiac Surgery or After Placement of Transcatheter Devices Corrective surgery with no residual defect eliminates the attrib- utable risk for endocarditis in children with ventricular and atrial septal defects or patent ductus arteriosus 6 months after surgery. However, surgery itself, including such elements as central vas- cular catheters, intravenous alimentation, and days the patient resides in the intensive care unit, may be important risk fac- tors for the development of IE. Approximately 50% of children with IE complicating CHD have had previous cardiac surgery, particularly palliative shunt procedures or complex intracardiac repairs. Morris et al12 reviewed cumulative incidences of endo- carditis for a number of congenital cardiac lesions in a follow- up series of Oregon residents. The highest annualized risk for IE was found in children who had had repair or palliation of cyanotic CHD.


The highest annualized risk for IE was found in children who had had repair or palliation of cyanotic CHD. The greatest risk among those patients was for those who had either undergone surgery for obstruction to pul- monary blood flow or had prosthetic aortic valve replacement. In a follow-up of the series of Oregon residents, the highest inci- dence of IE in postoperative patients has been in the cohort with aortic valve stenosis, and this has increased over time, with a Endocarditis may manifest as a late complication, with presentation years after congenital heart surgical repair, and may be associated with a fulminant course or antibiotic failure.14,15 The incidence of IE in the first postoperative month is low for most defects and increases with time after surgery. An exception to this trend is that when prosthetic valves or conduits are used in surgical repairs and hemodynamic prob- lems persist, the risk of IE is high even in the immediate post- operative period (first 2 weeks after surgery).12 Two recently published studies showed a 25% incidence of previous cardiac surgery in patients with congenital heart disease who required surgery during active IE.16,17 Russell et al18 reported 34 patients who met indications for surgical management of IE (of whom 37% had prior cardiac surgery) from a 21-year single-center review through 2011 at Children s Memorial Hospital, Chicago, IL. Five had opera- tive mortality, and all deaths occurred in infants, with a mean age of 2.5 months. The infective organisms were identified in 86% of cases, with the most common being S aureus (n=8) and viridans streptococci (n=6). The Ross operation was per- formed successfully in 5 children with severe aortic valve dis- ease. Ten of the 34 patients required reoperations at a later time.


Ten of the 34 patients required reoperations at a later time. The increasing prevalence of transcatheter placement of devices such as septal or vascular occluders and coils pro- vides another potential risk factor for IE, particularly in the early postdeployment period before endothelialization has Although a long-term study of transcatheter closure of atrial septal defects19 showed no cases of IE, several case reports of endocarditis related to transcatheter device treat- ment of atrial and ventricular septal defects and patent ductus arteriosus do suggest that residual defects after device place- ment may be a factor in the risk for IE.20 23 IE in Newborn Infants In a recent multicenter review, 7.3% of cases of pediatric IE (108 of 1480) were diagnosed in the first month of life.24 Improved and widely available imaging technology, particu- larly echocardiography, and increased clinical awareness have greatly facilitated the diagnosis of IE in this patient group. The incidence of neonatal IE has increased in the past 2 decades in large measure because of the increasing use of invasive tech- niques to manage neonates with multiple complex medical problems, even those with structurally normal hearts. Central venous catheters designed to be in place for prolonged peri- ods of time, such as peripherally inserted central catheters and tunneled central venous catheters, provide a portal of entry for surface bacterial despite the most meticulous management. As a result of the indwelling lines, infections frequently involve right-sided heart structures. It has been estimated that fewer than one-third of cases of neonatal endocarditis occur in the presence of congenital cardiac disease.24 26 A recent review showed that 31% of infants who died of IE were premature.24 The most common infecting organisms were S aureus, coagu- lase-negative staphylococcus strains, Gram-negative bacterial species, and Candida species.


It has been estimated that fewer than one-third of cases of neonatal endocarditis occur in the presence of congenital cardiac disease.24 26 A recent review showed that 31% of infants who died of IE were premature.24 The most common infecting organisms were S aureus, coagu- lase-negative staphylococcus strains, Gram-negative bacterial species, and Candida species. The clinical manifestations of IE in the neonate are vari- able and nonspecific and may be indistinguishable from sep- ticemia or from congestive heart failure associated with other In infants, septic emboli from IE are common, resulting in foci of infection outside the heart (eg, osteomy- elitis, meningitis, or pneumonia). Neonates with IE often have feeding difficulties, respiratory distress, tachycardia, and hypotension. As with older children, neonates also may have a new or changing heart murmur. Many neonates with IE also have neurological signs and symptoms (eg, seizures, hemipa- resis, or apnea). However, although arthritis and arthralgia are common findings in older children with IE, arthritis is rarely described in neonates. Osler nodes, Roth s spots, Janeway lesions, and splinter hemorrhages are also not mentioned in published cases of IE in neonates. Pathogenesis Early histopathologic studies in humans and decades-long investigations that have included an animal model of experi- mental endocarditis have confirmed 2 critical histopathologic findings: (1) Damaged or denuded endothelium is necessary for initial pathogen colonization of a cardiac nidus; and (2) Gram-positive cocci, the predominant pathogens in both native and prosthetic value infections, express multiple adhesins that serve as virulence factors through their ability to enhance host cell/substrate attachments that are important in both the initia- tion and propagation of endocardial infection. (Adhesins are discussed further in a separate section.)


Pathogenesis Early histopathologic studies in humans and decades-long investigations that have included an animal model of experi- mental endocarditis have confirmed 2 critical histopathologic findings: (1) Damaged or denuded endothelium is necessary for initial pathogen colonization of a cardiac nidus; and (2) Gram-positive cocci, the predominant pathogens in both native and prosthetic value infections, express multiple adhesins that serve as virulence factors through their ability to enhance host cell/substrate attachments that are important in both the initia- tion and propagation of endocardial infection. (Adhesins are discussed further in a separate section.) Denuded cardiac endothelium can occur when there is tur- bulence caused by abnormal cardiac structures, in particular stenotic or regurgitant valves, that results in high-velocity jets of blood. Once the endothelium is damaged, the host response includes platelet and fibrin deposition, leading to so-called nonbacterial thrombotic endocarditis (NBTE), at the wound site. NBTE serves as an excellent nidus for subsequent bac- terial or fungal colonization in a patient with bacteremia or fungemia. The prevailing notion is that activities of daily living, such as chewing food, toothbrushing, and flossing, account for most bloodstream seeding of an NBTE site. There are additional mechanisms involved in endocardi- tis pathogenesis. Right-sided endocarditis can occur when there are intravenous catheters, illicit intravenous drug use, or cardiovascular implantable electronic device leads that dwell in the right side of the heart. Damage to the endothe- lium occurs by 2 mechanisms. One involves direct damage produced by the foreign body rubbing directly against the endothelial surface. The other is via an indirect effect, such as when a foreign device interferes with normal tri- cuspid valve function and causes regurgitant jets of blood. Bacteremia may be caused by entry of organisms at the skin site of percutaneous catheters or leads, via the catheter lumen, or in contaminated infusate.


Bacteremia may be caused by entry of organisms at the skin site of percutaneous catheters or leads, via the catheter lumen, or in contaminated infusate. Microorganisms carried by the bloodstream enter the right side of the heart, poten- tially causing IE on preexisting NBTE. IE can also occur as a result of direct infection of an indwelling device. This occurs at the time of device placement into a cardiac locus (eg, valves, leads, other types of devices) and is an example of surgical site infection. These infections can occur despite the administration of antibiotic prophylaxis at the time of placement of cardiovascular devices such as heart valves, pacemaker leads, or left ventricular devices. Adhesins Virulence factors that are involved in bacterial adherence, so- called adhesins, have received the bulk of recent investigative attention. Advances in molecular biological techniques have been crucial in characterizing these cell surface structures, with attention specifically to staphylococcal, streptococcal, and enterococcal species, which account for the large majority of IE cases. These adhesins attach to either host cell structures or extracellular molecules that bind to host cells or to extracel- lular matrix. The availability of an experimental animal model of endocarditis has been a pivotal aspect of these pathogenesis investigations. It has served as the ultimate evaluation of in vitro molecular techniques to obtain mutant and recombinant isolates that are developed to examine the effects of a single purported virulence factor expressed by a wild-type strain. Considering the fact that Gram-positive cocci typically express multiple adhesins, the ability to demonstrate the role of a single adhesin in infection pathogenesis is remarkable. For example, this approach demonstrated pilus involvement in attachment to collagen by Streptococcus gallolyticus.


For example, this approach demonstrated pilus involvement in attachment to collagen by Streptococcus gallolyticus. This was the first time that a virulence factor was demonstrated in an animal model of Interestingly, strains that expressed pil1 did not adhere to either fibronectin or fibrinogen but did form biofilm in vitro. A nonpathological Lactococcus lactis strain that by recombinant techniques expressed Pil1 in vitro was examined with its parent strain that did not express Pil1 in a rat model of experimental endocarditis. The results suggested that Pil1 was important in vivo as a virulence factor; 82% of rats challenged with the Pil1+ strain developed experimental endocarditis, in contrast to the animals that received the Pil1 strain (36%, The big 3 pathogens (viridans group streptococci [VGS], S aureus, and Enterococcus species) that account for the large majority of endocarditis cases have been the primary focus of pathogenesis studies.31 Adhesins of S aureus, which have been referred to as MSCRAMMs (microbial surface com- ponents recognizing adhesive matrix molecules), are surface molecules involved in staphylococcal attachment to collagen, thrombospondin, laminin, fibrinogen, and fibronectin.32 These interactions with host proteins not only may be important in the initial adherence of bacteria to a site of endothelial damage but also may be operative in bacterial persistence and engulf- ment by the host cell (endothelial cells, platelets). Similarly, there have been several bacterial surface structures identified in strains of VGS and Enterococcus species that appear criti- cal in endocarditis pathogenesis. Study of pathogenic mechanisms in IE is pivotal as we consider potential advances in infection treatment and preven- tion in the future. This knowledge serves as a foundation for the development of novel clinical tools that include therapeu- tics and vaccines.


This knowledge serves as a foundation for the development of novel clinical tools that include therapeu- tics and vaccines. Indeed, identification of a virulence factor resulted in development of a vaccine that reduced the risk of endocarditis development in an animal model.33 Pathogenesis of IE on Prosthetic Material Because perivalvular infection that involves the sewing ring is commonplace among patients with prosthetic valve endocardi- tis, particularly mechanical valves, the pathogenic mechanisms reviewed previously in this section apply to prosthetic valve endocarditis. In addition, biofilm formation can be operative in infection of prosthetic valves, similar to infection of a broad array of indwelling cardiovascular and noncardiovascular devices.34 A mature biofilm represents a unique and complex environ- ment for organisms to attach to and thrive on a device surface. Both antimicrobial agents and immune cells have difficulty in penetrating biofilm, and because of metabolic changes of infecting organisms in biofilm, the ability of antimicrobial agents to kill biofilm-associated organisms is greatly reduced. Because of this, infection relapse at a prosthetic valve site is thought to be increased. Oral/Dental Considerations The oral mucosa and tooth surfaces of children who are beyond infancy are populated by a variety of pathogenic and Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1491 nonpathogenic bacteria, which are representative of hun- dreds of strains of aerobic and anaerobic species.,35,36 This oral flora, in both health and disease, is different from adults and less diverse, but it becomes more like that of adults as the child ages, including increases in the percentage of VGS ( -hemolytic streptococci), Prevotella, and Actinomyces spe- In health, the child s oral flora has a variety of VGS, Neisseria species, Haemophilus species, and Staphylococcus species.


Oral/Dental Considerations The oral mucosa and tooth surfaces of children who are beyond infancy are populated by a variety of pathogenic and Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1491 nonpathogenic bacteria, which are representative of hun- dreds of strains of aerobic and anaerobic species.,35,36 This oral flora, in both health and disease, is different from adults and less diverse, but it becomes more like that of adults as the child ages, including increases in the percentage of VGS ( -hemolytic streptococci), Prevotella, and Actinomyces spe- In health, the child s oral flora has a variety of VGS, Neisseria species, Haemophilus species, and Staphylococcus species. In older children, species responsible for periodontal diseases (eg, Capnocytophaga) can be found along with oth- ers known to cause IE (eg, Aggregatibacter actinomycetem- This is particularly relevant with regard to the formation of plaque on the teeth of children at risk for IE. Dental plaque biofilm formation begins soon after a tooth surface is cleaned, and in the absence of oral hygiene, this bio- film thickens and evolves to include a more pathogenic bacte- rial flora largely isolated from the immune system. In contrast to plaque in adults, plaque bacteria on the visible surfaces of the teeth (supragingival) in children are similar to those in the gingival crevice (subgingival space), where there are more Gram-negative and anaerobic species than other sites in the oral The host response to plaque is gingival inflammation and enlargement (gingivitis). Gingivitis can result in an increased depth to this shallow gingival crevice between the tooth surface and the gingival crevicular mucosa that is more difficult to clean with a toothbrush and floss. In the absence of disease, the cre- vicular mucosa serves as a barrier to bacterial invasion.


In the absence of disease, the cre- vicular mucosa serves as a barrier to bacterial invasion. As in adults, however, the child s gingival crevice is most likely the source of virtually all transient bacteremia that occur from the mouth, whether from office-based dental procedures or routine activities of daily living such as toothbrushing. Gingival inflam- mation, however, may lead to thinning and ulceration, allowing dense colonies of bacteria and bacterial byproducts ready access to the increased gingival capillary circulation. Bacteremia may then result from minimal gingival manipulation. Children have a much lower prevalence and severity of gingivitis and periodon- titis than adults, and data from bacteremia studies in adults may not be representative of children. Bacteremia From Dental Procedures Dental procedures are a frequent source of bacteremia, par- ticularly from VGS.40 48 Multiple clinical studies of chil- dren over the past 40 years focused on the impact of 1 of the following risks for development of bacteremia: class of prophylactic antibiotic drug49 ; nature and invasiveness of ; indices of oral hygiene and dis- ; timing of blood culture draws before, dur- ing, and after the dental procedure45,48,56 ; various methods of microbial analysis and identification44,57 ; and the impact of these variables on surrogate measures of risk for IE, such as the incidence, duration, nature, and magnitude of bactere- Clearly, these surrogate measures are also influenced by multiple host factors.


Bacteremia From Dental Procedures Dental procedures are a frequent source of bacteremia, par- ticularly from VGS.40 48 Multiple clinical studies of chil- dren over the past 40 years focused on the impact of 1 of the following risks for development of bacteremia: class of prophylactic antibiotic drug49 ; nature and invasiveness of ; indices of oral hygiene and dis- ; timing of blood culture draws before, dur- ing, and after the dental procedure45,48,56 ; various methods of microbial analysis and identification44,57 ; and the impact of these variables on surrogate measures of risk for IE, such as the incidence, duration, nature, and magnitude of bactere- Clearly, these surrogate measures are also influenced by multiple host factors. These variable risks are associated with a wide range (0% 97%) in the incidence of bacteremia in children after various dental procedures and other manipulations of the gingiva, for example, tooth extractions (0% 96%)41,44,45,48 50,53,57 60 ; teeth cleaning and electric toothbrushing (0% 78%)42,45,47,55,61 63 ; res- ; dental injections (16% 97%)52,64 ; and other manipulations (13% 44%).42,44,46,51 53 Of the more than 100 oral bacterial species recovered from blood cultures in children after dental procedures, the number and variety of species reflect the spectrum of oral flora in health and disease (Table 2). They also reflect the varied microbiological meth- odologies used in these studies (eg, culture-based rather than molecular), with the recognition that many bacterial species clearly enter the bloodstream but are not cultivable and there- fore not recorded.44,49,57 Of greatest importance is the subset of bacterial species reported in blood cultures after dental proce- dures that are known to cause IE.66 Finally, the varied method- ologies and results make it impossible to differentiate among procedures with regard to their risk for causing bacteremia.


They also reflect the varied microbiological meth- odologies used in these studies (eg, culture-based rather than molecular), with the recognition that many bacterial species clearly enter the bloodstream but are not cultivable and there- fore not recorded.44,49,57 Of greatest importance is the subset of bacterial species reported in blood cultures after dental proce- dures that are known to cause IE.66 Finally, the varied method- ologies and results make it impossible to differentiate among procedures with regard to their risk for causing bacteremia. The collective published data from adult and pediatric stud- ies suggest that the vast majority of dental office visits result in some degree of risk for bacteremia, and the emphasis has therefore changed from a focus on specific dental procedures to a focus on gingival manipulation of any kind.3 The role of duration of bacteremia as a risk factor for IE is uncertain. Older guidelines and some pediatric bacteremia studies reported positive blood cultures for only short peri- ods (10 15 minutes) after tooth extraction(s),56,67 but the vast majority of studies did not include blood draws beyond that time frame. A study of teenagers and adults demonstrated that blood cultures can remain positive for upwards of an hour after a dental procedure,48 and a pediatric study reported that blood cultures can remain positive for >45 minutes.46 The incidence of positive blood cultures drops sharply after the procedure such that the period of risk rarely exceeds 30 minutes. A few studies report the magnitude of bacteremia in chil- dren after dental procedures,43,44,47,49,56,57 often using cell lysis filtration or centrifugation rather than conventional broth- based methods. Cell lysis methods can be problematic, being time consuming, expensive, less sensitive for some oral bacte- rial species, and slower in detection, and having an increased risk of contamination.


Cell lysis methods can be problematic, being time consuming, expensive, less sensitive for some oral bacte- rial species, and slower in detection, and having an increased risk of contamination. Results from different studies reflect the difficulty of determining magnitude, but the collective results suggest that the magnitude from dental procedures is low. Data from a large study of adults that used broth-based meth- ods and molecular methodology for identification suggest that the magnitude of bacteremia resulting from toothbrushing and a dental extraction, opposite ends of the spectrum of gingival invasiveness, are both relatively low at <104 colony-forming units per milliliter of blood.68 The degree to which systemic antibiotic drugs reduce the incidence, duration, nature, or magnitude of bacteremia associated with dental procedures is controversial. Large, well-designed studies suggest that amoxicillin has a highly statistically significant impact on reducing the incidence and duration of bacteremia and changes the species identified after dental procedures in children.45 It is not clear whether this antibiotic elimination of bacteria takes place in the gingi- val crevice or the bloodstream or whether it reduces the risk for IE.


Large, well-designed studies suggest that amoxicillin has a highly statistically significant impact on reducing the incidence and duration of bacteremia and changes the species identified after dental procedures in children.45 It is not clear whether this antibiotic elimination of bacteria takes place in the gingi- val crevice or the bloodstream or whether it reduces the risk for IE. Given the variability in outcomes from bacteremia stud- ies and the mounting evidence that dental office procedures are at most a rare cause of IE, there has been a steady shift in the direction away from an emphasis on antibiotic prophy- laxis and toward a focus on oral hygiene and diseases as far more important risk factors for cases of IE that result from Impact of Oral Disease and Hygiene Versus Dental Procedures on Bacteremia AHA guidelines have long proposed that maintaining oral health may be important in the overall effort to prevent IE,67,69 and there is increasing support from studies that report a fre- quent occurrence of bacteremia with toothbrushing (39% It has also been suggested that chewing food may result in bacteremia, but there are no studies to confirm this in Some studies reported no impact from oral hygiene or disease on bacteremia after dental procedures.49,51,55 Other studies of bacteremia after den- tal procedures support an association between various indices of oral hygiene and gingival and dental disease (caries) with the incidence of bacteremia from dental office-based proce- dures and from routine daily activities. Virtually all dental office procedures have the potential to create a transient bacteremia. Because children are recom- mended to have dental cleaning procedures every 6 months, this suggests that office-based bacteremia may occur upwards of twice per year.


Because children are recom- mended to have dental cleaning procedures every 6 months, this suggests that office-based bacteremia may occur upwards of twice per year. Data from bacteremia studies strongly sug- gest that the incidence of bacteremia annually from tooth- brushing and other daily activities far exceeds that of dental office procedures, perhaps by hundreds of times per year.43,68 It is unknown whether frequency of bacteremia is more impor- tant than magnitude with regard to risk for IE, but current data support the importance of a focus on maintenance of good oral hygiene, prevention of gingival and dental disease, and access to routine dental care for children at risk for IE. Cases of IE from oral bacterial pathogens in children most likely result from exposure to relatively frequent, low-grade bacteremia from these activities of daily living. Results of Clinical Studies of IE Prophylaxis for Dental Procedures There has not been a prospective, randomized, placebo- controlled study of the efficacy of antibiotic prophylaxis to prevent IE in people whose risk is from dental procedures. The few published retrospective, epidemiological studies that relate to this question have had varied outcomes with respect to benefit from antibiotic prophylaxis. When an invasive pro- cedure has occurred in close proximity to the onset of symp- toms of IE, it cannot be determined that it caused IE, because there may have been episodes of bacteremia from natural causes in the same time frame. Table 2.


When an invasive pro- cedure has occurred in close proximity to the onset of symp- toms of IE, it cannot be determined that it caused IE, because there may have been episodes of bacteremia from natural causes in the same time frame. Table 2. Bacteria Recovered From Blood After Dental Procedures* in Children ; A georgiae46 ; A gerensceriae46 ; A israelii45,47 ; ; A lingnae46 ; A meyeri56 ; A meyeri/odontolyticus45 ; A naeslundii46,56 ; ; A odontolyticus45,46,48 ; A viscosus45,46,56 ; A urinae57 ; A viridans46 ; B licheniformis57 ; B megaterium57 ; B pumilus57 ; B capillosus40 ; B distasonis48 ; B fragilis48 ; C hofmanii45,51 ; E aerofaciens45,48 ; E lentum45 ; E ventriosum40 ; F fusiforme45 ; F nucleatum45,48 ; F varium48 ; H parainfluenza40,42,44 46,48,50 ; L acidophilus48 ; L brevis47 ; L casei56 ; L paracasei56 ; L greyi47 ; M nonliquefaciens45 ; N catarrhalis45 ; N cinerea47,48 ; N flava46 ; ; N pharynges46 ; N polysaccharea53 ; N sicca/subflava48 ; P asaccharolyticus45 ; P micros45,48,56 ; P prevotii45 ; P acnes46 ; P corporis48 ; P melaninogenica45,50,61 ; P acnes43,54 ; P jensenii38 Rothia; R dentocariosa44,54 ; R mucilaginosus44 Staphylococcus; S aureus42,44,52,53,57 ; S auricularis48 ; S capitis46 48,56,57 ; S cohnii46 ; ; S haemolyticus46 48 ; S hominis46,47,53,56 ; ; S saccharolyticus48 ; S saprophyticus46 ; S schleiferi46,48 ; ; S warneri46,47,56 S anginosus group42,43,45,49,53,64 ; S anginosus48,56 ; S constellatus45,46 ; S bovis group; S bovis42,48,64 ; S gordonii46,52,57 S mutans group; S mutans42,44 46,48,51,53,54,56,57 ; S sobrinus47,56,64 S mitis group; S infantis44 ; S mitis42,44 48,51 53,56,57,64 ; S pneumoniae46,53 ; S oralis (S mitior, S sanguis II)40,44 47,49,52,57,64 S sanguinis group; S parasanguinis46,56 ; S sanguinis40,42,44 47,49,50,53,56,57,64 S salivarius group57 ; S salivarius45 48,52,53,56,57,64 ; S vestibularis47,52 ; V alcalescens61 ; V dispar56 ; V parvula40,44,48 *Dental procedures include dental extractions, restorations, dental hygiene (cleaning) procedures, toothbrushing, and other procedures.


Bacteria Recovered From Blood After Dental Procedures* in Children ; A georgiae46 ; A gerensceriae46 ; A israelii45,47 ; ; A lingnae46 ; A meyeri56 ; A meyeri/odontolyticus45 ; A naeslundii46,56 ; ; A odontolyticus45,46,48 ; A viscosus45,46,56 ; A urinae57 ; A viridans46 ; B licheniformis57 ; B megaterium57 ; B pumilus57 ; B capillosus40 ; B distasonis48 ; B fragilis48 ; C hofmanii45,51 ; E aerofaciens45,48 ; E lentum45 ; E ventriosum40 ; F fusiforme45 ; F nucleatum45,48 ; F varium48 ; H parainfluenza40,42,44 46,48,50 ; L acidophilus48 ; L brevis47 ; L casei56 ; L paracasei56 ; L greyi47 ; M nonliquefaciens45 ; N catarrhalis45 ; N cinerea47,48 ; N flava46 ; ; N pharynges46 ; N polysaccharea53 ; N sicca/subflava48 ; P asaccharolyticus45 ; P micros45,48,56 ; P prevotii45 ; P acnes46 ; P corporis48 ; P melaninogenica45,50,61 ; P acnes43,54 ; P jensenii38 Rothia; R dentocariosa44,54 ; R mucilaginosus44 Staphylococcus; S aureus42,44,52,53,57 ; S auricularis48 ; S capitis46 48,56,57 ; S cohnii46 ; ; S haemolyticus46 48 ; S hominis46,47,53,56 ; ; S saccharolyticus48 ; S saprophyticus46 ; S schleiferi46,48 ; ; S warneri46,47,56 S anginosus group42,43,45,49,53,64 ; S anginosus48,56 ; S constellatus45,46 ; S bovis group; S bovis42,48,64 ; S gordonii46,52,57 S mutans group; S mutans42,44 46,48,51,53,54,56,57 ; S sobrinus47,56,64 S mitis group; S infantis44 ; S mitis42,44 48,51 53,56,57,64 ; S pneumoniae46,53 ; S oralis (S mitior, S sanguis II)40,44 47,49,52,57,64 S sanguinis group; S parasanguinis46,56 ; S sanguinis40,42,44 47,49,50,53,56,57,64 S salivarius group57 ; S salivarius45 48,52,53,56,57,64 ; S vestibularis47,52 ; V alcalescens61 ; V dispar56 ; V parvula40,44,48 *Dental procedures include dental extractions, restorations, dental hygiene (cleaning) procedures, toothbrushing, and other procedures. (Continued) Table 2.


(Continued) Table 2. Continued Baltimore et al Infective Endocarditis in Childhood: 2015 Update 1493 In 2008, the National Institute for Health and Clinical Excellence (NICE) guidelines in the United Kingdom con- cluded that the use of antibiotic prophylaxis before any invasive procedures should cease, unless requested by the patient.71 A subanalysis of data from a large, nationwide study in England72 comparing the incidence and mortality from IE in 373 chil- dren <18 years old, both before and after the NICE guidelines, reported no change in the incidence of IE.73 Although small in size, this subanalysis is the strongest study currently available concerning the efficacy of antibiotic prophylaxis for children, and it lends support to the position that antibiotic prophylaxis is ineffective and that it would be reasonable to shift the dis- proportionately large focus on antibiotic prophylaxis for dental procedures to oral hygiene and prevention of oral disease. Recommendation 1. It is reasonable to shift the disproportionately large focus on antibiotic prophylaxis to an emphasis on oral hygiene and prevention of oral disease (Class IIa; Level of Evidence B). Diagnosis Clinical Findings in Children and Adolescents The presentation generally is indolent, with prolonged low- grade fever and a variety of somatic complaints, including fatigue, weakness, arthralgias, myalgias, weight loss, rigors, and diaphoresis. Although these are nonspecific findings, the presence of this cluster of symptoms requires careful evalu- ation for IE in certain settings, such as in the patient with underlying heart disease. In contrast, on occasion, the presen- tation may be fulminant, with rapidly changing symptoms and high, spiking fevers. These children are acutely ill, and some require urgent intervention. In these children, infection caused by Streptococcus pneumoniae or S aureus is likely.


In these children, infection caused by Streptococcus pneumoniae or S aureus is likely. The clinical findings of IE in children relate to 4 underly- ing phenomena: bacteremia (or fungemia), valvulitis, immuno- logic responses, and emboli. Valvulitis may result in changing cardiac auscultatory findings or the development of congestive heart failure. Extracardiac manifestations of IE (eg, petechiae, hemorrhages, Roth s spots, Janeway lesions, Osler nodes, or splenomegaly) are considerably less common in children than in adults. Renal abnormalities (eg, glomerulonephritis, infarct) can result from an embolic or immune complex mediated pro- cess. Emboli to the abdominal viscera, the brain, or the heart are common (especially noted in the adult literature) and may produce symptoms associated with ischemia, hemorrhage, or both. In rare cases, central nervous system mycotic aneurysms can occur; their rupture can be catastrophic. The cardiac examination in the child with IE is highly variable and depends on the type of heart disease present and the particular site of infection. Valvular lesions that produce leaflet destruction result in regurgitant murmurs. In children with cyanotic CHD who have undergone systemic-pulmonary artery shunt procedures, however, the murmur may not change. Rather, declining systemic oxygen saturation may reflect graft infection with obstruction of flow. Patients with right-sided, catheter-related intravascular infection may have few or no specific cardiovascular signs or may present with asthma-like symptoms or signs related to septic pulmonary embolization As described above, an increase in the population of chil- dren requiring a long-term central venous catheter (CVC) and of those with complex congenital heart defects and correspondingly complex surgical interventions requiring prosthetic materials has changed the epidemiology and micro- biology of IE and impacted the diagnostic approach.


Patients with right-sided, catheter-related intravascular infection may have few or no specific cardiovascular signs or may present with asthma-like symptoms or signs related to septic pulmonary embolization As described above, an increase in the population of chil- dren requiring a long-term central venous catheter (CVC) and of those with complex congenital heart defects and correspondingly complex surgical interventions requiring prosthetic materials has changed the epidemiology and micro- biology of IE and impacted the diagnostic approach. Duke Criteria The modifications of the Duke criteria for diagnosis of IE74 76 have been demonstrated to be helpful in diagnosing IE in chil- dren, although the number of patients in these studies has been small, and there have been questions of specificity (Tables 3 The presence of a CVC may prolong a bacteremic state, thus requiring the removal of the CVC before criteria The incorporation into the modified Duke criteria of new molecular diagnostic methods on surgical specimens (eg, polymerase chain reaction [PCR]) has been proposed to help identify organisms in culture-negative IE.80 Although the revised Duke criteria have been validated for the diagno- sis of IE in children,9 the emergence of S aureus as the most common pathogenesis has important implications. The Duke criteria identify S aureus bacteremia as a major criterion, regardless of whether the infection was nosocomial or com- munity acquired or whether a primary source of infection was present or absent.75 suggests that the presence of a CVC may skew the diagnosis of IE, because the attempt to salvage the catheter rather than remove it serves to prolong the bacteremic state and raises the question of whether S aureus bacteremia should be regarded as a major microbiological cri- teria only if cultures remain positive after removal of the CVC.


The Duke criteria identify S aureus bacteremia as a major criterion, regardless of whether the infection was nosocomial or com- munity acquired or whether a primary source of infection was present or absent.75 suggests that the presence of a CVC may skew the diagnosis of IE, because the attempt to salvage the catheter rather than remove it serves to prolong the bacteremic state and raises the question of whether S aureus bacteremia should be regarded as a major microbiological cri- teria only if cultures remain positive after removal of the CVC. Laboratory Assessment Microbiology: Blood Cultures Blood cultures should be drawn for patients with fever of unexplained origin and a pathological heart murmur, a history of heart disease, or previous endocarditis. Because bactere- mia in patients with IE usually is continuous and low grade, it does not matter whether cultures are obtained at any particular phase of the fever cycle. For children, it is ordinarily not prac- tical to obtain the large volumes recommended for adults with suspected endocarditis. Lesser amounts (eg, 1 3 mL in infants and young children and 5 7 mL in older children) are optimal, depending on the blood culture detection system. Because IE is only rarely caused by anaerobic bacteria, emphasis is usu- ally given to inoculating blood into bottles for aerobic incuba- tion. It is reasonable to obtain 3 blood cultures by separate venipunctures on the first day, and if there is no growth by the second day of incubation, to obtain 2 or 3 more (Table 3). There is usually no value in obtaining >5 blood cultures over 2 days unless the patient has received antibiotic therapy within the past 2 weeks.


There is usually no value in obtaining >5 blood cultures over 2 days unless the patient has received antibiotic therapy within the past 2 weeks. In patients who are not acutely ill and whose blood cultures remain negative, withholding antibiotic drugs for 48 hours or longer while additional blood cultures are obtained may be considered, to determine the cause of IE. In patients with acute IE who are severely ill and unsta- ble, 3 separate venipunctures for blood cultures should be performed over a short period such as 1 to 2 hours (Table 3) and empirical antibiotic therapy initiated. Continuous- monitoring blood culture systems such as BACTEC (Becton, Dickinson and Co, Franklin Lakes, NJ) and newer molecular identification methods are more rapid and more sensitive than more conventional methods. If fastidious or unusual organisms are suspected, the director of the micro- biology laboratory should be consulted for help in diagno- sis. Culture of arterial blood is not useful because it does not increase yield. Recommendations 1. Blood cultures should be drawn for patients with fever of unexplained origin and a pathological heart murmur, a history of heart disease, or previous endocarditis (Class I; Level of Evidence B). 2. It is reasonable to obtain 3 blood cultures by sepa- rate venipunctures on the first day, and if there is no growth by the second day of incubation, to obtain 2 or 3 more (Table 3) (Class IIa; Level of Evidence B). 3. In patients who are not acutely ill and whose blood cultures remain negative, withholding antibiotic drugs for 48 hours while additional blood cultures are obtained may be considered to determine the cause of IE (Class IIb; Level of Evidence C). 4.